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numbered
CONFIDENTIAL
CONFIDENTIAL GM2006/00652/00
GM2006/00652/00
TheGlaxoSmithKline
The GlaxoSmithKlinegroupgroup of companies
of companies NKT102553
NKT102553
Division: Worldwide Development

Retention Category: GRS019
Information Type: Clinical Study Report
Title: A Phase III, Multicenter, Randomized, Double-blind, Parallel

Group Study to Evaluate the Safety and Efficacy of 50mg Oral
Dosing with the Neurokinin-1 Receptor Antagonist GW679769
for the Prevention of Postoperative Nausea and Vomiting in
Female Subjects at High Risk for Emesis.
Phase: III
Compound Number: GW679769
Effective Date: 25 January 2008

Description: In this active-controlled, two-group study, female subjects at high risk for
developing postoperative nausea and vomiting scheduled to undergo surgeries associated
with high emetogenic risk, were randomized to receive a single dose of either oral
GW679769 (casopitant) placebo (i.e., Zofran™ [ondansetron hydrochloride] alone group)
or oral casopitant 50mg (casopitant group) in combination with Zofran 4mg IV
administered prior to induction of anesthesia. This study demonstrated the superiority of
casopitant, in combination with Zofran, over Zofran alone in the control of emesis, with a
10% absolute increase in the proportion of subjects achieving a complete response during
the first 24 hours following surgery (69% vs. 59%) (p<0.05). An increase of 15% (in
absolute terms) was seen for subjects reporting no vomiting over 0–24 hours in the
casopitant group (90%) compared with the Zofran alone group (75%) (p<0.05). No
significant difference was seen between the casopitant (52%) and Zofran alone (43%)
groups for complete protection 0–24 hours; therefore, hypothesis testing was stopped at
this point. No treatment difference was apparent for the nausea or total control endpoints
over 0-24 hours. On the categorical scale, severe nausea appeared to be reported by a
smaller proportion of subjects in the casopitant group (9%) than in the Zofran alone
group (16%). Oral casopitant administered in combination with Zofran was well
tolerated. Serious adverse events were reported in 11 subjects; none was considered
related to investigational product. No deaths were reported. There were no notable
differences in clinical laboratory values, vital signs or electrocardiogram findings among
treatment groups. Subject satisfaction and subject willingness to use the same regimens
for future surgical procedures were similar across treatment groups.
Subject: GW679769, Casopitant, NK-1 Receptor Antagonist, Postoperative Nausea and

Vomiting.
Authors: MDC BDS - Oncology US; USP

MDC Clinical Oncology; Niche Science & Technology Ltd;
Global Heath Outcomes-Oncology; USP MDC Clinical Oncology
11
CONFIDENTIAL
GM2006/00652/00
TheGlaxoSmithKline
The GlaxoSmithKlinegroupgroup of companies
of companies NKT102553
NKT102553
Indication Studied: Postoperative Nausea and Vomiting
Initiation Date: 20 March 2006
Completion Date: 31 August 2006
Date of Report: January 2008
Sponsor Signatory: MD
(and Medical Officer) Vice President, Global Clinical Development Oncology,
Medicine Development Center,
GlaxoSmithKline
This study was performed in compliance with Good Clinical Practices and
GlaxoSmithKline Standard Operating Procedures for all processes involved, including
the archiving of essential documents.
Copyright 2008 the GlaxoSmithKline group of companies. All rights reserved.

Unauthorized copying or use of this information is prohibited.
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TABLE OF CONTENTS
Page
LIST OF FIGURES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
LIST OF TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
ABBREVIATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
1. ETHICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
1.1. Independent Ethics Committee (IEC) or Institutional Review Board
(IRB) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
1.2. Ethical Conduct of the Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
1.3. Subject Information and Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
2. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE . . . . . . 12
3. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
4. STUDY OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
4.1. Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
4.1.1. Primary Objective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
4.1.2. Secondary Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
4.2. Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
4.2.1. Primary Endpoint . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
4.2.2. Secondary Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
5. INVESTIGATIONAL PLAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
5.1. Overall Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
5.1.1. Dosing of Antiemetics in NKT102553 . . . . . . . . . . . . . . . . . . . 19
5.1.2. Anesthetic and Analgesic Regimen . . . . . . . . . . . . . . . . . . . . . 19
5.1.3. Discussion of Study Design, Including the Choice of Control
Group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
5.2. Protocol Amendments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
5.3. Selection of Study Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
5.3.1. Inclusion/Exclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
5.3.2. Predetermined Criteria for Subject Withdrawal . . . . . . . . . . . . 24
5.4. Investigational Product and Study Medication . . . . . . . . . . . . . . . . . . 25
5.4.1. Description of Investigational Product and Study Medication . 25
5.4.2. Dosages and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . 26
5.4.3. Dose Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
5.4.4. Blinding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
5.4.5. Treatment Assignment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
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5.4.6. Assessment of Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

5.4.7. Treatment of Investigational Product Overdose . . . . . . . . . . . . 28
5.5. Prior and Concomitant Medications and Non-Drug Therapies . . . . . 28
5.5.1. Permitted Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
5.5.2. Prohibited Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
5.5.3. Necessary Caution with CYP3A4 Substrates . . . . . . . . . . . . . 29
5.5.4. Exclusions and Necessary Caution with CYP2C8 Substrates . 30
5.5.5. Necessary Caution with P-glycoprotein Substrates . . . . . . . . . 30
5.5.6. Non-drug Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
5.6. Study Assessments and Procedures . . . . . . . . . . . . . . . . . . . . . . . . . 31
5.6.1. Demographic and Baseline Assessments . . . . . . . . . . . . . . . . 31
5.6.2. Efficacy Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
5.6.3. Safety Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
5.6.4. Health Outcomes Assessments . . . . . . . . . . . . . . . . . . . . . . . . 38
5.6.5. Pharmacogenetic Assessments . . . . . . . . . . . . . . . . . . . . . . . . 38
5.7. Data Quality Assurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
5.8. Data Analysis Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
5.8.1. Timings of Planned Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . 40
5.8.2. Sample Size Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . 41
5.8.3. Analysis Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
5.8.4. Treatment Comparisons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
5.8.5. General Considerations for Data Analyses . . . . . . . . . . . . . . . 42
5.8.6. Data Handling Conventions . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
5.8.7. Study Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
5.8.8. Efficacy Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
5.8.9. Safety Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
5.8.10. Health Outcomes Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . 46
6. STUDY POPULATION RESULTS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
6.1. Disposition of Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
6.2. Protocol Deviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
6.3. Populations Analyzed. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
6.4. Demographics and Other Baseline Characteristics . . . . . . . . . . . . . . 48
6.4.1. Demographic Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . 48
6.4.2. Baseline Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
6.4.3. Current Medical Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
6.5. Concomitant Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
6.5.1. Peri-Operative Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
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6.5.2. Prior and Concomitant Medications . . . . . . . . . . . . . . . . . . . . . 52

6.5.3. Rescue Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
6.6. Treatment Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
7. EFFICACY RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
7.1. Primary Efficacy Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
7.1.1. Complete Response (0–24 hours) . . . . . . . . . . . . . . . . . . . . . . 55
7.2. Secondary Efficacy Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
7.2.1. Efficacy in the 0–24 Hour Period . . . . . . . . . . . . . . . . . . . . . . . 56
7.2.2. Efficacy in Other Time Periods. . . . . . . . . . . . . . . . . . . . . . . . . 58
7.3. Other Efficacy Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
7.3.1. Time to event endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
7.3.2. Rescue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
7.4. Efficacy Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
8. SAFETY RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
8.1. Extent of Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
8.2. Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
8.2.1. Adverse Events Irrespective of Causality. . . . . . . . . . . . . . . . . 65
8.2.2. Adverse Events by Relationship to Investigational Product . . . 66
8.2.3. Adverse Events by Intensity . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
8.3. Serious Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
8.3.1. Deaths . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
8.3.2. Non-Fatal Serious Adverse Events . . . . . . . . . . . . . . . . . . . . . 67
8.4. Adverse Events Leading to Premature Discontinuation of
Investigational Product and/or Study . . . . . . . . . . . . . . . . . . . . . . . . . 68
8.5. Pregnancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
8.6. Clinical Laboratory Evaluations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
8.6.1. Laboratory Values Over Time . . . . . . . . . . . . . . . . . . . . . . . . . 68
8.6.2. Individual Subject Changes in Liver Function Tests . . . . . . . . 69
8.6.3. Clinical Laboratory Values Outside the Reference Range . . . . 72
8.6.4. Laboratory Values of Potential Clinical Concern . . . . . . . . . . . 72
8.6.5. Shifts in National Cancer Institute Common Terminology
Criteria Grading from Baseline . . . . . . . . . . . . . . . . . . . . . . . . 72
8.7. Other Safety Evaluations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
8.8. Safety Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
9. HEALTH OUTCOMES RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
9.1. Subject Satisfaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
9.2. Subject Willingness to Use Same Regimen for Future Procedures . 76
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9.3. Medical Resource Utilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76

9.4. Health Outcomes Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
10. DISCUSSION AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
10.1. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
10.2. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
11. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
12. CASE NARRATIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
STUDY POPULATION DATA SOURCE TABLES . . . . . . . . . . . . . . . . . . . . . 97
EFFICACY DATA SOURCE FIGURES AND TABLES . . . . . . . . . . . . . . . . . . 176
SAFETY DATA SOURCE TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
OTHER ASSESSMENTS DATA SOURCE TABLES . . . . . . . . . . . . . . . . . . . 397
Attachment 1: Protocol Amendment 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399
Attachment 2 - Definitions American Society of Anesthesiologists (ASA)
Physical Status Classification System . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
Attachment 3: Reporting and Analysis Plan for NKT102553. . . . . . . . . . . . . . 480
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LIST OF FIGURES
Page
Figure 1 Kaplan-Meier curves for time from last suture/staple to first emetic
episode . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Figure 2 Kaplan-Meier curves for time from last suture/staple to first rescue
medication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Figure 3 Kaplan-Meier curves for time from last suture/staple to first
complete response failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
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LIST OF TABLES
Page
Table 1 Time and events table . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Table 2 Dosing of antiemetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Table 3 Flagging of laboratory values . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Table 4 Subject disposition (Intent-to-Treat population) . . . . . . . . . . . . . . . . . 47
Table 5 Summary of major protocol deviations (Intent-to-Treat population) . . 48
Table 6 Demographic characteristics (Intent-to-Treat population) . . . . . . . . . 49
Table 7 Summary of Race and Racial Combinations (Intent-to-Treat
population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Table 8 Summary of American Society of Anesthesiologists physical status
classification (Intent-to-Treat population) . . . . . . . . . . . . . . . . . . . . . . . . . 50
Table 9 Summary of total surgery time (Intent-to-Treat population) . . . . . . . . 50
Table 10 Summary of current medical conditions reported in 10% of
subjects or more in the study (Intent-to-Treat population) . . . . . . . . . . . . 51
Table 11 Summary of peri-operative medications reported in 10% of
subjects or more in either treatment group (Intent-to-Treat population) . . 52
Table 12 Summary of concomitant medications reported in 10% of subjects
or more in either treatment group (Intent-to-Treat population) . . . . . . . . . 53
Table 13 Summary of all subjects who received rescue medications
(Intent-to-Treat population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Table 14 Summary of treatment compliance (Intent-to-Treat population) . . . . 54
Table 15 Summary of proportion of subjects with complete response 0—24
hours (Modified Intent-to-Treat population) . . . . . . . . . . . . . . . . . . . . . . . . 55
Table 16 Summary of proportion of subjects with no vomiting 0–24 hours
(Modified Intent-to-Treat population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Table 17 Summary of proportion of subjects with complete protection 0—24
Table 18 Summary of proportion of subjects with nausea (categorical scale)
0–24 hours (Modified Intent-to-Treat population) . . . . . . . . . . . . . . . . . . . 58
Table 19 Summary of proportion of subjects with complete response
24—48 hours (Modified Intent-to-Treat population) . . . . . . . . . . . . . . . . . 59
Table 20 Summary of proportion of subjects with complete response 0—48
Table 21 Adverse events irrespective of causality reported in greater than
1% of subjects in either treatment group (Safety population) . . . . . . . . . . 66
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Table 22 Adverse events possibly related to investigational product

reported in at least 1% of subjects in either treatment group (Safety
population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Table 23 Summary of all subjects with serious adverse events irrespective
of causality (in alphabetical order) (Safety population) . . . . . . . . . . . . . . . 68
Table 24 Summary of laboratory values for selected parameters (Safety
population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Table 25 Laboratory values of interest in Subject ................. 70
Table 26 Other subjects with alanine aminotransferase values of interest . . . 71
Table 27 Proportion of subjects with laboratory values above the reference
range for selected parameters (Safety population) . . . . . . . . . . . . . . . . . . 72
Table 28 Vital signs values of interest in subjects with hypotension or
procedural hypotension reported as an adverse event . . . . . . . . . . . . . . . 74
Table 29 Summary of subject satisfaction 0–48 hours (Modified
Intent-to-Treat population). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
Table 30 Summary of subject willingness to use the same regimens for
future surgical procedures 0–48 hours (Modified Intent-to-Treat
population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
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Abbreviations
AE Adverse event
ALT Alanine aminotransferase
ASA American Society of Anesthesiologists
AST Aspartate aminotransferase
BUN Blood urea nitrogen
CI Confidence interval
CINV Chemotherapy-induced nausea and vomiting
CTCAE Common Terminology Criteria for Adverse Events
ECG Electrocardiogram
eCRF Electronic case report form(s)
5-HT3 Five (5)-hydroxytryptamine (serotonin), subtype 3
GCP Good Clinical Practice(s)
GCSP Global Clinical Safety and Pharmacovigilance
GSK GlaxoSmithKline
HCl Hydrochloride
IEC Independent Ethics Committee
IRB Institutional Review Board
ITT Intent-to-Treat
IV Intravenous
IVRS Interactive Voice Response System
MDC Medicines Development Center
MedDRA Medical Dictionary for Regulatory Activities
MITT Modified Intent-to-Treat
NCI National Cancer Institute
NK-1 Neurokinin subtype 1
PCA Patient controlled anesthesia
PDF Portable document format
PGP P-glycoprotein
PGx Pharmacogenetic(s)/pharmacogenomic(s)
PONV Postoperative nausea and vomiting
RAMOS Randomization and Medication Ordering System
RAP Reporting and analysis plan
SAE Serious adverse event
SD Standard deviation
SGOT Serum glutamate oxaloacetate transaminase
SGPT Serum glutamate pyruvate transaminase
ULN Upper limit of the normal range
VAS Visual Analog Scale
WBC White blood cell
10
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NKT102553
Trademark Information
Trademarks of the GlaxoSmithKline Trademarks not owned by the

group of companies GlaxoSmithKline group of companies
RANDALL Emend
ZOFRAN InForm
Lotus Notes Sametime Connect
SAS
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1. ETHICS
1.1. Independent Ethics Committee (IEC) or Institutional Review

Board (IRB)
The study protocol, the two amendments, the informed consent, and other information
that required pre-approval were reviewed and approved by a national, regional, or
independent ethics committee or institutional review board.
1.2. Ethical Conduct of the Study

This study was conducted in accordance with "good clinical practice" (GCP) and all
applicable regulatory requirements, and, the guiding principles of the 1996 Declaration of
Helsinki.
1.3. Subject Information and Consent

Written informed consent was obtained from each subject prior to the performance of any
study-specific procedures. Electronic case report forms (eCRFs) were provided for each
subject’s data to be recorded.
2. INVESTIGATORS AND STUDY ADMINISTRATIVE

STRUCTURE
A total of 43 centers in 11 countries recruited subjects for this multicenter study. All
centers were hospitals.
GlaxoSmithKline (GSK) was responsible for all aspects of study administration,

including supplying GW679769 (casopitant) investigational product and matched
placebo, and Zofran™ (ondansetron hydrochloride) study medication. As Zofran
Injection was an open label medication, it was not provided centrally by GSK. Each
Country Medical Department ensured that Zofran Injection was available to the centers.
Local laboratories were used for analysis of safety laboratory samples. The central
laboratory for pharmacogenetic samples was Quest Diagnostics Clinical Trials, Five
Moore Drive, Research Triangle Park, North Carolina 27709, US.
Study monitoring was performed by a Contract Research Organization, Parexel

International, 195 West Street, Waltham, MA 02451-1163, US. The vendor for eDiaries
was CRF Inc., 1690 Sumneytown Pike, Suite 140, Lansdale, PA 19446, US.
The following centers were audited by GSK for this trial: (US –
(US – (Hungary –
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3. INTRODUCTION
Postoperative nausea and vomiting (PONV) can occur following local, regional, or
general anesthesia. Anesthetics are thought to cause PONV primarily by acting on the
emetic center in the tractus solitarius region of the brainstem, via the chemoreceptor
trigger zone in the area postrema [Watcha, 1992]. Despite therapeutic advances, PONV
remains the most common complaint following general anesthesia [Gupta, 2003], and in
one study PONV was of greater concern than pain: the relative importance of PONV to
patients was 49% and postoperative pain, 27% [Eberhart, 2002]. In addition to anxiety
and discomfort, PONV may lead to post-surgical complications such as fluid and
electrolyte imbalance, surgical wound dehiscence, and aspiration of vomitus; thus, PONV
may delay discharge from the recovery area and lead to unscheduled hospital admissions
[Marcus, 1999].
The etiology of PONV is multi-factorial, and the frequency is influenced by type and
duration of surgery, intra- and peri-operative medications, post-operative pain,
ambulation and oral intake, and individual patient risk factors [Watcha, 1992; Gan,
2003]. Examples of common surgical procedures associated with increased risk of
emesis include gynecological procedures and breast augmentation for females, and
shoulder surgery for males. Anesthetics such as nitrous oxide have been reported to be
associated with higher rates of PONV [Sinclair, 1999], and intraoperative and post-
surgical administration of opioids often leads to emesis [Kovac, 2000]. Patient factors
that affect risk of PONV include gender, movement following surgery, pain control and
smoking status.
Overall, approximately 20–30% of surgical patients experience PONV [Watcha, 1992;

Kovac, 2000]. In the highest risk patients, PONV may occur in 70–80% of cases [Apfel,
1999; Gan, 2003]. The incidence in females undergoing minor gynecological surgery in
an ambulatory setting without prophylactic antiemetics was reported to be 60% [Carroll,
1995]. In patients undergoing laparoscopic cholecystectomy, an incidence of PONV of
up to 72% has been reported in patients who have not received prophylactic antiemetic
treatment [Naguib, 1996; Wang, 2002].
Several investigators have developed risk stratification schemas to help guide the
appropriate use of antiemetic therapy [Koivuranta, 1997; Apfel, 1999; Sinclair, 1999]. In
the Apfel simplified scoring scale, four factors predict the risk of PONV, namely; female
gender, a history of motion sickness or PONV, non-smoking status, and the use of
postoperative opioids. Each of these factors is an independent risk, and the chance of
experiencing PONV is proportional to the number of these risk factors present. The
Apfel Simplified Risk Scale has been validated in several studies [Apfel, 2002; Pierre,
2002] and was used to characterize subject risk in the present study.
Because multiple receptors are believed to be involved in the etiology of PONV [Watcha,
1992], several studies have evaluated the use of combinations of agents that target
different receptors. These have included 5-hydroxytryptamine (serotonin), subtype 3
(5-HT3) receptor antagonists, droperidol, and dexamethasone. There is a growing
consensus that prophylaxis against PONV, especially in high risk populations, may be
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better achieved by using a combination of antiemetic agents that act on different

neurotransmitter receptors that are involved in the emetic pathway [Ahmed, 2000; Habib,
2001; Gan, 2002; Gan, 2003; Habib, 2003; Apfel, 2004]. Current marketed antiemetics,
including 5HT3 receptor antagonists, do not fully protect all patients, and there is an
unmet medical need for more effective drugs to prevent PONV [Gan, 2007].
Human studies have demonstrated that neurokinin subtype 1 (NK-1) receptor antagonists
have antiemetic activity in the postoperative setting for both prevention and treatment.
Oral CP-122,721, an NK-1 receptor antagonist from Pfizer, was effective for the
prevention of postoperative vomiting in women undergoing abdominal hysterectomies,
but protection against nausea was not found [Gesztesi, 2000]. Diemunsch, et al.
[Diemunsch, 1999] reported that following PONV after major gynecological procedures,
the NK-1 receptor antagonist GR205171 (dosed IV) was effective in preventing further
episodes of emesis. In addition, aprepitant was approved in the United States and the
European Union in 2006, after the present study was underway, for the prevention of
PONV [Emend (aprepitant) Prescribing Information, 2006]. In a study of 805 patients
undergoing open abdominal surgery under general anesthesia, the proportion of subjects
with complete response (no vomiting and no use of rescue) over 0–24 hours was 45%
following oral aprepitant 40mg, 43% with aprepitant 125mg, and 42% with IV
ondansetron 4mg. The proportion of subjects with no vomiting over 0–24 hours was
90% following aprepitant 40mg, 95% with aprepitant 125mg, and 74% with ondansetron
[Gan, 2007].
GW679769 (casopitant) is another potent and selective NK-1 receptor antagonist, which
is in development for PONV and chemotherapy-induced nausea and vomiting (CINV).
The 50mg oral dose of casopitant used in this study was selected based on data from
previous Phase I and Phase II trials of the investigational product. In a repeat-dose
pharmacokinetic interaction study in healthy subjects, no relevant effect on ondansetron
kinetics was found after co-administration with single doses of casopitant 30 and 90 mg
[GM2004/00285/00]. In Phase II studies, nausea and vomiting occurred primarily within
the first 24 hours after surgery [GlaxoSmithKline Document Number
ZM2005/00131/00]; thus the 0–24 hour period was selected for the present study.
Nausea was assessed using an 11-point, linear, numerical rating scale referred to as a “0–
10 Likert scale”, and a categorical scale which classified nausea as none, mild, moderate
or severe.
4. STUDY OBJECTIVES
4.1. Objectives
4.1.1. Primary Objective
The primary objective of this study was to demonstrate the superiority of 50mg oral
GW679769 (casopitant), in combination with a single 4mg IV dose of Zofran
(ondansetron hydrochloride), over a single 4mg IV dose of Zofran alone in the control of
emesis during the first 24 hours following the placement of last suture/last staple (as
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measured by complete response, defined as no vomiting, no retching, and no rescue

medications) in surgical subjects who were predicted to have a high risk of emesis.
4.1.2. Secondary Objectives
The secondary objectives of this clinical trial were to:
• Assess the severity of nausea experienced by subjects in each cohort during the 2, 6,
24 and 48 hour periods.
• Assess the control of emesis in the 24–48 hour period following the placement of last
suture/last staple.
• Assess subject satisfaction with the prophylactic antiemetic regimens, and the
willingness of subjects to use the same regimens for future surgical procedures.
• Determine the safety and tolerability of the antiemetic regimens in surgical subjects
who had been predicted to have a high risk of emesis
4.2. Endpoints
4.2.1. Primary Endpoint
The primary endpoint of this study was the proportion of subjects who achieved a
complete response (defined as no vomiting or retching and no rescue therapy during the
first 24 hours following the placement of last suture/last staple).
4.2.2. Secondary Endpoints
The following secondary endpoints were analyzed:
1. The severity of nausea experienced by subjects in each cohort during the 2, 6, 24 and
48 hour periods, as assessed by an 11-point, linear, numerical rating scale referred to
as a “0–10 Likert scale”, and by a categorical scale (none, mild, moderate or severe),
as defined in the protocol (Attachment 1).
2. Time to first emetic event, defined as the time elapsed from placement of the last
suture/staple to the first emetic episode (regardless of antiemetic rescue use). If a
subject withdrew prematurely during the first 48 hours and did not have an emetic
event, then the time of withdrawal was considered to be their time to first emetic
episode, and the subject’s data were censored from that time point.
3. Time to first antiemetic rescue medication, defined as the time elapsed from
placement of the last suture/staple to the first use of antiemetic rescue medication. If
a subject withdrew prematurely during the first 48 hours and the subject did not take
rescue medication, then the time of withdrawal was considered to be their time to
first use of antiemetic rescue medication, and the subject’s data were censored at that
time point.
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4. Subject satisfaction with the prophylactic antiemetic regimens, and the willingness of
subjects to use the same treatment regimen for future surgical procedures, as
assessed by Subject Satisfaction Assessment in the Subject Diary.
5. Safety and tolerability of the antiemetic regimens, assessed by routine physical
examination, routine clinical laboratory tests, clinical observation (including time to
awakening from anesthesia, defined as ability to respond to a verbal command) and
adverse events (AE) reporting.
Additional efficacy endpoints were derived as follows:
• Complete protection: no vomiting/retching, no rescue therapy and maximum nausea

<3 on the Likert scale.
• Total control: no vomiting/retching, no rescue therapy and a maximum nausea <1 on
the Likert scale.
• Vomiting: vomit or retch, but included subjects who had received rescue therapy.
• Significant nausea: maximum nausea score greater than or equal to 3 on the Likert
scale for nausea from all nausea assessments.
• Nausea: maximum nausea score greater than or equal to 1 on the Likert scale for
nausea from all nausea assessments.
The proportion of subjects receiving rescue medication was also measured.
All endpoints (except safety, health outcomes and the time to event endpoints) were
assessed in the following time windows: 0–24, 24–48 and 0–48 hours following
placement of the last suture/staple. Health outcomes were assessed at 48 hours only, and
time to awakening within 24 hours. Nausea was also assessed in the following time
windows: 0–2 hours and 0–6 hours. Safety was also assessed at Day 6–10.
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5. INVESTIGATIONAL PLAN
5.1. Overall Study Design

This was a Phase III, multicenter, randomized, double-blind, active-controlled, two arm
parallel group study. A time and events table is presented in Table 1.
Two compounds were administered as part of this clinical trial. For the purposes of this
study, Zofran Injection was referred to as “study medication”, and casopitant was referred
to as the “investigational product”.
Due to potential drug interactions, participants in this study were not permitted to
consume grapefruit juice for 2 days prior to receiving the investigational product
casopitant.
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Table 1 Time and events table
Pre-surgical Day of Surgery Post-op. Post-op. Post-op.

Study Days: Baseline Study Day 1 Day 1 Day 2 Day 6-141
Screening Prior to Periop. Postop.
Study procedure Phase 2 dosing Phase Phase 3 24 h 48 h
Informed consent 4 X
Medical history X
Routine physical X
examination
ASA physical status X X
Vital signs X X X OR X5 X
Electrocardiogram X X OR X5
Hematology and X X OR X5 X
chemistry 6
Pregnancy test 7 X
Concomitant X X X X X X X
medications 8
Inclusion/exclusion crit. 9 X X
Randomization (IVRS)10 X X X
Administration of study X
medications 11
PGx sample 12 X
Follow-up (telephone) 13 X X
Follow-up visit X1
Nausea and emesis 14, 15 X X X16 X16 X16 X
Subject diary X17 X17 X X X17
Subject satisfaction X X18
Adverse events X X X X X
ASA=American Society of Anesthesiologists; IVRS=Interactive Voice Response System; PGx=pharmacogenetics;
RAMOS=Randomization and Medication Ordering System.
1. As soon as possible following the completion of the 48 hour assessment.
2. Screening could be done within 21 days prior to day of surgery or same day as surgery.
3. Began upon the placement of the last suture/last staple.
4. Written informed consent was provided by the subject prior to initiation of any study-specific procedures.
5. Prior to discharge from surgical facility or at end of 24 hour assessment phase on Postop. Day 1.
6. Conducted within 10 days prior to surgery.
7. If performed.
8. Medications taken within 7 days prior to scheduled day of surgery were recorded.
9. If Screening assessments were performed on a day other than the day of study medication and surgery, inclusion/exclusion
criteria were reviewed prior to administration of investigational product.
10. The IVRS (RAMOS) was contacted three times: twice during Screening Phase (to register subject and again to randomize
subject) and again when subject completed or was discontinued from the study.
11. Investigational product was administered as an oral tablet, approximately 60 minutes prior to the induction of anesthesia.
Zofran study medication was administered as an IV injection over 2 to 5 minutes, immediately prior to the induction of
anesthesia.
12. Recommended to be taken at first opportunity after a subject had been randomized and provided informed consent for PGx
research, but could be taken at any time while the subject was participating in the clinical study.
13. In the event that the subject was not discharged from the surgical center prior to the end of 24 hour assessment phase, the
same information was collected by study personnel at the appropriate assessment periods.
14. Nausea assessed using a discrete Likert scale, scored from 0 to 10; and a categorical scale (none, mild, moderate, severe).
15. These assessments were not completed as long as the subject remained incapable of adequately completing the assessments
required at a specified assessment period (e.g., 2 hours post-placement of last suture/last staple).
16. Nausea assessed at 2, 6, 24 and 48 hours following the placement of last suture/last staple.
17. Dispensed prior to receiving investigational product. Returned to subject when subject was capable of adequately completing
the required assessments. Returned to study personnel at Final Visit.
18. Overall satisfaction with study medications for preventing PONV and willingness to use same antiemetic drug treatment
regimen for subsequent surgical procedures were assessed on Postoperative Day 2, as soon as possible following the
completion of the 48 hour nausea assessment.
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5.1.1. Dosing of Antiemetics in NKT102553
Dosing of antiemetics is detailed in Table 2.
Table 2 Dosing of antiemetics
Cohort Medication Route of Timing of Administration Dose

Administration (Prior to Induction of Administered
Anesthesia)
A (Zofran GW679769 placebo oral ∼60 minutes prior 0mg
alone
group) Zofran (ondansetron IV (2–5 min) Immediately prior 4mg
HCl)
B GW679769 oral ∼60 minutes prior 50mg
(Casopitant
group) Zofran (ondansetron IV (2–5 min) Immediately prior 4mg
HCl)
5.1.2. Anesthetic and Analgesic Regimen
Participating investigators were required to adhere to a balanced general anesthetic

regimen as per their institutional guidelines and common practice. All surgeries were
anticipated to involve a minimum of 1 hour of general anesthesia. (Start time of general
anesthesia was the time of administration of the first anesthetic agent e.g., IV propofol
induction. The end time of general anesthesia was equal to the time of extubation or
equivalent). Propofol was permitted for induction of, but not maintenance of, anesthesia.
Total IV anesthesia was not allowed in this study.
Anticipated need for or requirement of opioids post-surgery was an eligibility

requirement for this study. Every effort was made to maintain adequate analgesia for
each subject. Administration of any medications through the use of an epidural catheter
was not permitted. The use of Patient Controlled Anesthesia (PCA) devices was
permitted. Local anesthetic infusion pumps were permitted as long as they were being
used in addition to the anticipated use of systemic opioids.
5.1.3. Discussion of Study Design, Including the Choice of Control

Group
The study was designed following analysis of the Phase II study NKT102260
[GlaxoSmithKline Document Number ZM2005/00131/00]. The results of that study
showed that most emetic events occurred in the first 24 hours postoperatively. Therefore,
this study was designed with the primary efficacy objective based on the first 24 hours.
Additional assessments at 48 hours were included to confirm that PONV did not appear
to be a significant problem during the 24 to 48 hour postoperative period. Additionally, it
was desirable to obtain health outcomes information which would not be practical to
assess at 24 hours because subjects would be sedated or anesthetized for a portion of that
time.
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Subjects who are at high risk for PONV would most likely benefit from treatment with a
combination of antiemetics that act on different neurotransmitter receptors that are
involved in the emetic pathway. Therefore, the surgical procedures required in this study
were those that are known to be of high risk for PONV. Because the population was at
high risk for PONV, it would have been inappropriate to have a control group in which
subjects received only placebo. With these considerations in mind, the treatment groups
chosen for this study were casopitant plus Zofran compared with Zofran alone.
5.2. Protocol Amendments

The original study protocol was dated 09 December 2005. Two protocol amendments
were issued.
Amendment 1, dated 23 January 2006, corrected internal inconsistencies. In the original

protocol, the specified times were ‘post emergence from anesthesia’. In Amendment 1,
this was changed to ‘following placement of last suture/staple’ as a more precise and
easily measurable time point to indicate the end of surgery.
Amendment 2, dated 17 April 2006, was issued in response to feedback from the Food
and Drug Administration and the Investigators’ Meeting. This amendment defined the
start and stop times for the 1 hour period of general anesthesia: “Start time of general
anesthesia was the time of administration of the first anesthetic agent e.g., IV propofol
induction. The end time of general anesthesia was equal to the time of extubation or
equivalent”. The amendment specified that local anesthetic infusion pumps were
permitted as long as they were being used in addition to the anticipated use of systemic
opioids. Inclusion criteria were altered to allow rare/infrequent smokers into the study.
The contraception requirement was increased from 3 days to 7 days after surgery.
Mirtazapine and olanzapine were added to the list of excluded medications.
Triglycerides and bicarbonate were deleted from the list of required tests. The original
protocol stated that the first dose of rescue antiemetic medication could be administered
when medically indicated, if three emetic episodes occurred within a 15-minute period, at
physician discretion, or at any time upon the subject's request. The amendment removed
the phrase ‘if three emetic episodes occurred within a 15-minute period’.
Inducers/inhibitors of cytochrome P450 3A4 (CYP3A4) were prohibited for an additional
period, 72 hours following the administration of casopitant. Investigators were no longer
required to discontinue from the study subjects who required placement of a nasogastric
or oral-gastric tube with suctioning.
5.3. Selection of Study Population

It was estimated that 462 subjects would be enrolled into this study. This was a
multinational, multicenter study, and it was anticipated that approximately 65 centers
would be required to complete enrollment.
Subjects were stratified to treatment assignments by planned intra-operative use of

nitrous oxide. Nitrous oxide has the potential to cause nausea.
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5.3.1. Inclusion/Exclusion Criteria
5.3.1.1. Inclusion criteria
A subject was eligible for inclusion in this study only if all of the following criteria
applied:
1. Was 18 years of age or older.

2. Had all four Apfel risk factors:
• Female gender.
• A history of PONV and/or motion sickness.
• A non-smoker: defined for this study as one who had not smoked or used (e.g.,
chewing) tobacco (including a nicotine patch or other nicotine-withdrawal
formulation) for at least the previous 6 months. Rare/infrequent (two or less
cigarettes a week) smoking was allowed, at the investigator’s discretion.
• Anticipated to receive opioids postoperatively.
3. Was scheduled to undergo one of the following surgical procedures: breast surgery,
orthopedic shoulder surgery, or thyroid surgery. The following laparoscopic or
laparotomic procedures were also permitted: cholecystectomy, hysterectomy, or
other gynecologic surgery.
4. Surgery was anticipated to involve general anesthesia of at least 1 hour duration.
(Start time of general anesthesia was the time of administration of the first anesthetic
agent e.g., IV propofol induction. The end time of general anesthesia was equal to
the time of extubation or equivalent).
5. Scheduled to receive general inhalation anesthesia with an anesthetic regimen as
described in the protocol (Attachment 1).
6. Met the American Society of Anesthesiologists (ASA) Physical Status Classification
of P1 or P2, preoperatively, on the day of surgery (see Attachment 2 for definitions).
7. Willing and expected to be able to complete daily components of the Subject Diary
preoperatively on the day of surgery and until the end of the 48 hour assessment
period, and return to the investigational site at the postoperative Day 6–14 final study
visit.
8. Understood the nature and purpose of this study and the study procedures and had
signed an informed consent form for this study to indicate this understanding.
9. Women of childbearing potential were required to commit to consistent and correct
use of an acceptable method of birth control, to be followed for a minimum of 7 days
postoperatively. GlaxoSmithKline acceptable contraceptive methods, when used
consistently and in accordance with both the product label and the instructions of a
physician, were as follows:
• Non-childbearing potential (i.e., physiologically incapable of becoming pregnant,
including any female who was postmenopausal. For purposes of this study,
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postmenopausal was defined as 1 year without menses). These subjects did not need
to follow the birth control practices outlined in this protocol.
• Child-bearing potential: had a negative serum pregnancy test result or a negative
urine dipstick pregnancy test at baseline (within 24 hours prior to investigational
product administration) and agreed to one of the following:
• male partner who was sterile prior to the female subject’s entry into the study
and was the sole sexual partner for that female subject;
• oral contraceptives (either combined or progestogen only) which had to be
combined with double-barrier method of contraception consisting of spermicide
with either condom or diaphragm;
• double-barrier method of contraception consisting of spermicide with either
condom or diaphragm;
• intrauterine device with a documented failure rate of less than 1% per year;
• complete abstinence from intercourse for 2 weeks prior to exposure to the
investigational product throughout the clinical trial, and for a period after the
trial to account for elimination of the drug (minimum of 7 days after exposure to
the investigational product).
5.3.1.2. Exclusion criteria
A subject was not eligible for inclusion in this study if any of the following criteria
applied:
1. Was pregnant or lactating.

2. Was scheduled to receive propofol for maintenance of anesthesia.
3. Had received an investigational drug in the previous 30 days or was scheduled to
receive any investigational drug in addition to GW679769 during the study period.
4. Had persistent or recurrent nausea and/or vomiting due to other etiologies, or had
experienced emesis or uncontrolled nausea at any time during the 24 hours prior to
scheduled receipt of the investigational product and study medication.
5. Was taking greater than 10mg of oxycodone, or an equivalent opioid dose, on a
regular, daily basis, for more than three consecutive days prior to entry into the
study.
6. Had a medical condition (e.g., vagotomy) or was receiving medication that could
confound the results of this study.
7. Was anticipated to require a nasogastric or oral-gastric tube with intermittent or
continuous suctioning postoperatively (if a nasogastric or oral-gastric tube was
inserted at the beginning of induction, ensure GW679769 had been given at least
60 minutes prior).
8. Had baseline alanine aminotransferase (ALT) or aspartate aminotransferase (AST)
>1.5x the upper limit of normal, unless related to the condition for which the subject
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was undergoing surgery, in which case the acceptable limit was 3x the upper limit of
normal.
9. Had baseline bilirubin >1.5x the upper limit of normal, unless related to the
condition for which the subject was undergoing surgery, in which case the acceptable
limit was 3x the upper limit of normal.
10. Had a known hypersensitivity to ondansetron, another serotonin, subtype 3 (5-HT3)
receptor antagonist, any component of GW679769, or any of the scheduled
anesthetic or analgesic agents.
11. Was scheduled to receive antiemetics not included in the study dosing scheme,
during the evaluation period, or had received medication with potential antiemetic
activity in the 24-hour period (or as specified below), prior to surgery. This
included, but was not limited to:
• 5-HT3 receptor antagonists (e.g., ondansetron, granisetron, dolasetron,
tropisetron, ramosetron). Palonosetron was not permitted for 7 days prior to the
study;
• benzamide/benzamide derivatives (e.g., metoclopramide, alizapride);
• phenothiazines (e.g., prochlorperazine, promethazine, fluphenazine,
perphenazine, thiethylperazine, chlorpromazine);
• butyrophenones (e.g., haloperidol, droperidol);
• corticosteroids (e.g., dexamethasone, methylprednisolone – with the exception
of topical steroids for skin and/or ocular disorders and inhaled steroids for
respiratory disorders);
• scopolamine;
• antihistamines (e.g., cyclizine, hydroxyzine, diphenhydramine); however,
diphenhydramine for pruritus was allowed;
• domperidone;
• cannabinoids;
• mirtazapine, olanzapine.
12. Had taken/received strong or moderate inhibitors of CYP3A4 and/or CYP3A5 within
the following time frames prior to administration of the investigational product:
• 2 days: clarithromycin, diltiazem, erythromycin, grapefruit juice, ketoconazole,
verapamil;
• 14 days: fluconazole, itraconazole.
These medications/products were also prohibited for 72 hours following the
administration of GW679769.
13. Had taken/received inducers of CYP3A4 and/or CYP3A5 within 14 days prior to the
administration of the investigational product, including: carbamazepine,
phenobarbital, phenytoin, rifabutin, rifampin, St. John’s Wort, troglitazone, efavirenz
and nevirapine.
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These medications were also prohibited for 72 hours following the administration of
GW679769.
14. Was taking the antidiabetic agent repaglinide or the diuretic torsemide. Investigators
were advised to exercise caution if including subjects taking the antidiabetic agents
rosiglitazone or pioglitazone, or antimalarial agents such as chloroquine and
amodiaquine, as the metabolite of GW679769 is a potential inhibitor of CYP2C8.
Note: Subjects taking digoxin, or other substrates of P-glycoprotein (PGP) were not
excluded from the study. However, if entered into the study, investigators were
cautioned to clinically monitor such subjects for signs of digoxin toxicity, as a
metabolite of GW679769 has been shown to inhibit PGP in vitro, which may result
in reduced PGP-mediated clearance of digoxin. The clinical relevance of this
interaction is not known at this time.
15. In France, a subject was neither affiliated with nor a beneficiary of a social security
category.
5.3.2. Predetermined Criteria for Subject Withdrawal
The subject was considered to have completed the study when she had completed the
postoperative Day 6–14 visit. However, for the purposes of evaluating all primary and
secondary study objectives, the subject was considered to have completed the study upon
completing all required assessments for 48 hours following placement of the last
suture/staple. A subject could not be considered evaluable if she failed to return the
Subject Diary that was provided upon discharge from the investigational site.
Any subject who had been registered into the study but did not receive any
investigational product was considered a screening failure. If a subject experienced
emesis or uncontrolled nausea at any time during the 24 hours prior to receiving the
investigational product, she was not eligible to receive the investigational product and
study medication, and was to be withdrawn from the study.
5.3.2.1. Subject withdrawal from the investigational product
A subject could withdraw from the study at any time at her own request, or she could be
withdrawn at any time at the discretion of the investigator for safety, behavioral, or
administrative reasons.
Subjects who received antiemetic rescue medication were to remain in the study and all
efficacy assessments were to be made through the end of the 48-hour follow-up
assessment phase. Safety assessments continued until the postoperative Day 6–14 visit
had been completed.
Subjects who did not return for the follow-up visit on postoperative Day 6–14 were to be
considered withdrawn from the study.
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5.3.2.2. Subject withdrawal from the study
Only one dose of Zofran Injection and casopitant/placebo was administered. Therefore, a
subject who withdrew consent prior to receiving the study medication and/or
investigational product also withdrew from the study.
5.4. Investigational Product and Study Medication
5.4.1. Description of Investigational Product and Study Medication
The contents of the label for investigational product and study medication (i.e.,
casopitant/placebo tablets and Zofran Injection) were in accordance with all applicable
regulatory requirements of the country where the investigational site was located.
Only subjects enrolled in the study were permitted to receive investigational product.
Only authorized site staff were permitted to supply or administer investigational product.
Investigational product and study medication were stored in a secure area with access
limited to the investigator and authorized site staff. Investigational product tablets
(casopitant/placebo) were stored as described on the product label. Zofran Injection was
stored between 2 and 30ºC (36– 86ºF), protected from freezing and avoiding excessive
heat, and protected from light.
Investigational Product
Casopitant was provided by GSK, and was supplied as 50mg (batch numbers
or matching placebo (batch number
tablets for oral administration. Casopitant was administered as GW679769B, the
mesylate salt of the free base GW679769X. Casopitant tablet supplies were blinded so
neither the research pharmacist, the investigator, nor the subject knew whether the dose
contained active or placebo investigational product.
Study medication
Each vial of Zofran Injection contained 4mg of ondansetron hydrochloride in 2mL of

solution (2mg/mL), and was supplied as a clear, colorless, non-pyrogenic, sterile solution
for IV injection that required no dilution prior to administration. Each 1mL of aqueous
solution in this single dose vial contained 2mg of ondansetron as the hydrochloride
dihydrate; 9.0mg of sodium chloride; 0.5mg of citric acid monohydrate, and 0.25mg of
sodium citrate dihydrate, as buffers in Water for Injection. The pH of the injection
solution was 3.3–4.0.
As Zofran Injection was an open label medication for this study, it was not provided
centrally by GSK. Each country medical department ensured that Zofran Injection was
available to centers in accordance with relevant regulatory guidelines.
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5.4.2. Dosages and Administration
All eligible subjects received a single oral dose of casopitant investigational product
(active 50mg or placebo) 60 minutes prior to the expected induction of anesthesia on
Day 1. Although the dose of oral investigational product was expected to be
administered at this time, it could be given up to 30 minutes prior to the anticipated
induction of anesthesia.
Investigational product was ingested orally as whole tablets and was not to be crushed or
altered in any way. It was recommended that the tablet be ingested with as little water as
practical (less than 30mL was recommended).
Study Medication
All subjects received a single IV administration of Zofran Injection immediately prior to

the induction of anesthesia. The ondansetron hydrochloride was administered by a slow
IV injection over 2 to 5 minutes (but not less than 2 minutes), per the Zofran for Injection
label [Zofran Product Information, 2005].
5.4.3. Dose Rationale
The dosing of Zofran Injection was based on regulatory approvals for Zofran Injection
for the prevention of PONV, recent consensus guidelines for the prevention of PONV,
and current clinical practice. For the prevention of PONV, the recommended IV dosage
of Zofran for adults is 4mg undiluted, administered IV over 2 to 5 minutes (but not less
than 2 minutes) immediately before the induction of anesthesia, in accordance with the
Zofran for Injection label [Zofran Product Information, 2005].
The oral dose of casopitant 50mg chosen for the present study was based on the
preliminary results of the Phase II study NKT102260, conducted in female subjects
undergoing surgical procedures associated with an increased emetogenic risk. Casopitant
was well tolerated at doses of 50-150mg. Complete response rate (no vomiting, rescue
therapy or withdrawal for the 24 hours after awakening from anaesthesia) did not
correlate with casopitant or GSK525060 exposure (AUC or concentration 24 hours post-
dose) over the dose range of 50-150mg. Time-to-event analysis showed that the
casopitant exposures produced by 50-150mg doses provided adequate protection against
emesis; however, subjects in the lowest quartile (25%) of casopitant exposure were at
higher risk for requiring rescue medications. These data suggest that casopitant
exposures below that produced by a 50mg single dose may not provide adequate
protection against the need for rescue medication.
The oral doses of casopitant in Study NKT102260 were based on NK-1 receptor
occupancy data generated in a Phase I positron emission tomography study in healthy
subjects [NKF10002]. An oral dose range of 50mg to 150mg was predicted to result in a
70% to >95% NK-1 receptor blockade in the striatal region of the brain at 24 hours
following a single dose of casopitant. Receptor occupancy in the striatal region is a
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surrogate for the nucleus tractus solitarius region of the brainstem, which was the
presumed site of action (from microinjection studies), as the brainstem cannot be imaged
quantitatively by positron emission tomography. Although the relationship between
NK-1 receptor blockade in the striatum and prevention of PONV has not been
established, studies with NK-1 receptor antagonists in the CINV setting suggest that a
24-hour trough level of ≥95% NK-1 receptor blockade in the striatum is a reasonable
surrogate for the prevention of nausea and vomiting via this centrally mediated
mechanism [Bergstrom, 2004]. Recently, the CINV data have been correlated with
clinical efficacy by the first NK-1 receptor antagonist, Emend, approved for marketing by
regulatory agencies in 2003 for the prevention of CINV [Emend (aprepitant) Product
Information, 2006].
5.4.4. Blinding
This was a double-blind, active-controlled, parallel group randomized study. The study
coordinator called the Randomization and Medication Ordering System (RAMOS) to
obtain a randomization code indicating treatment assignment. Casopitant supplies were
blinded so that the research pharmacist, the investigator, and the subject did not know
whether the numbered box contained active or placebo investigational product.
Only in the case of an emergency, when knowledge of the investigational product was
essential for the clinical management or welfare of the subject, was the investigator
permitted to unblind a subject’s treatment assignment.
If a serious adverse event (SAE) was reported to GSK, Global Clinical Safety and
Pharmacovigilance (GCSP) staff may have unblinded the treatment assignment for the
individual subject. If an expedited regulatory report to one or more regulatory agencies
was required, the report was to identify the subject’s treatment assignment. When
applicable, a copy of the regulatory report could be sent to investigators in accordance
with relevant regulations, GSK policy, or both.
5.4.5. Treatment Assignment
Subjects were assigned to study treatment in accordance with the randomization

schedule. GlaxoSmithKline used an interactive voice response system, RAMOS, for
registration of subjects. RAMOS is a telephone-based system which allows study centers
to register and randomize subjects, and also records stratification information. Detailed
RAMOS user instructions and worksheets were provided to the investigational site at
study start.
5.4.6. Assessment of Compliance
Investigational product and study medication were administered under the supervision of
study personnel on Day 1. The date and time of administration of the investigational
product and study medication were recorded.
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5.4.7. Treatment of Investigational Product Overdose
To date, there have been no cases of overdose with casopitant. Treatment of any
suspected or confirmed overdose with casopitant was therefore to be symptomatic, and
supportive care was recommended in cases where overdose was suspected. As per the
Clinical Investigator's Brochure for casopitant, GSK did not recommend specific
treatment for overdose or toxicity; however, the investigator was to use appropriate
clinical judgment in treating any overdose. For the purposes of this study, an overdose of
casopitant was defined as any dose greater than the highest daily dose included in the
protocol. While the potential for overdose is considered small, casopitant is an
investigational compound, and the potential for unexpected reactions is not known.
There is no specific antidote for an overdose of Zofran. In the event of a suspected

overdose of Zofran, subjects were to be managed with appropriate supportive therapy.
However, individual doses as large as 150mg (more than 37 times the amount
administered in this study) and total daily dosages (cumulative from three doses) as large
as 252mg have been administered IV without significant AEs [Zofran Product
Information, 2005].
5.5. Prior and Concomitant Medications and Non-Drug Therapies
5.5.1. Permitted Medications
All medications that would normally be prescribed for the care of the subject were
permitted, except as specified in Section 5.5.2 and Section 5.3.1. Each concomitant
medication taken during the study was recorded in the eCRF, and included the name of
the medication, the dose information, the date(s) of administration, and the indication for
the use of such medication.
Antiemetic rescue medication was permitted as described in Section 5.6.2. Subjects who
required rescue antiemetic medication(s) during the first 48 hours following the
emergence from anesthesia were considered treatment failures in the applicable period.
5.5.2. Prohibited Medications
The following medications were prohibited for use by subjects in this study:
1. Per the Exclusion Criteria:

• Greater than 10mg of oxycodone, or an equivalent opioid dose, on a regular, daily
basis, for more than three consecutive days prior to entry into the study.
• Any investigational drug in the previous 30 days, or during the study period.
2. Any “non-protocol” prophylactic antiemetic medications, within 24 hours prior to and
48 hours post the last suture/last staple assessment period. Antiemetic medications
given during this time were only to be given as rescue medications, in response to the
failure of the investigational product and the study medication to prevent the
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occurrence of PONV (that is, if the subject reported the occurrence of emesis or
intractable nausea).
The use of the following inhibitors/inducers of CYP3A4 and/or CYP3A5 was prohibited
during the evaluation phase of investigational product. In addition to the specified period
prior to administration of investigational product, the use of these medications was
prohibited for 72 hours following the final dose of investigational product. The lists are
not comprehensive.
The following strong or moderate inhibitors of CYP3A4 and/or CYP3A5 were prohibited
for the specified duration prior to administration of the investigational product:
• 2 days: clarithromycin, diltiazem, erythromycin, ketoconazole, grapefruit juice;

verapamil;
• 14 days: fluconazole, itraconazole.
The following inducers of CYP3A4 and/or CYP3A5 were prohibited for 14 days prior to
the administration of the investigational product: carbamazepine, phenobarbital,
phenytoin, rifabutin, rifampin, St. John's Wort, troglitazone, efavirenz and nevirapine.
Unless required by the protocol or used as antiemetic rescue medication as specified in

the protocol, medications with known or potential antiemetic activity were prohibited.
Other than the Zofran Injection required by the protocol, marketed antiemetics were only
to be used as rescue medication. Any NK-1 receptor antagonists other than those
supplied as the investigational product were specifically prohibited throughout the study.
5.5.3. Necessary Caution with CYP3A4 Substrates
As casopitant has been shown to be a mild to moderate inhibitor of metabolism via the
CYP3A4 pathway, caution was to be used when administering drugs that are known
substrates for CYP3A4. Unless specified in Exclusion Criteria 11, 12 or 13, such
medications were not specifically prohibited in this study.
Concomitant use of potential CYP3A4 substrates along with an inhibitor of CYP3A4

may result in higher than expected drug concentrations or exposures of the substrate,
which may lead to increased toxicity. As a result, there was a theoretical risk of
prolonged sedation from midazolam. This was based on data from study NKF101873
[GlaxoSmithKline Document Number VM2004/00042/00] with oral midazolam and
casopitant 75mg, where the area under the concentration-time curve extrapolated to
infinity and maximal observed concentration for midazolam were, on average, three-fold
and two-fold (respectively) greater than values seen for midazolam in the absence of
casopitant.
In addition, doses of agents such as midazolam are usually not adjusted when co-
administered with moderate CYP3A4 inhibitors such as verapamil and diltiazem; thus,
dose adjustments were not expected to be appropriate when used in combination with a
mild to moderate inhibitor such as casopitant. Finally, some other drugs may undergo
activation through the CYP3A4 pathway.
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Clinicians were advised to be diligent in monitoring for evidence of increased exposure,

and to utilize their usual judgment in adjusting doses of potential substrates on the basis
of observed clinical and/or laboratory effects. This was especially important for those
drugs that have a narrow therapeutic index.
5.5.4. Exclusions and Necessary Caution with CYP2C8 Substrates
Few therapeutic agents are metabolized by CYP2C8. As the metabolite of casopitant is a

potential inhibitor of CYP2C8, one might expect to see an increase in exposure and thus
an increase in clinical response or AEs with these drugs. Subjects who were taking the
antidiabetic agent repaglinide or the diuretic torsemide were excluded from this study.
Caution was to be exercised if subjects were taking the antidiabetic agents rosiglitazone
or pioglitazone, or antimalarial agents such as chloroquine and amodiaquine.
5.5.5. Necessary Caution with P-glycoprotein Substrates
The metabolite of casopitant may increase exposure to substrates of PGP (such as

digoxin) by decreasing PGP-mediated clearance. At this time there have been no serious
adverse events (SAEs) reported in clinical studies using casopitant which might suggest
over-exposure to digoxin. GlaxoSmithKline does not have enough information to
provide specific recommendations for digoxin dose adjustment at this time. Exclusion of
subjects was not required in studies where dosing of casopitant was of intermittent and
limited duration. If such subjects were enrolled into the study, they were to be monitored
clinically for signs of digoxin toxicity.
For the PGP class of drugs as a whole, clinicians were advised to be diligent in
monitoring for evidence of increased exposure, and to utilize their usual judgment in
adjusting doses of potential substrates on the basis of observed clinical and/or laboratory
effects. This was especially important for those drugs that have a narrow therapeutic
index.
Known or suspected PGP substrates include, but are not limited to:
• amprenavir, indinavir, nelfinavir, ritonavir, saquinavir;

• aldosterone, corticosterone, dexamethasone;
• digoxin;
• cyclosporin A, mitoxantrone;
• debrisoquine, erythromycin, lovastatin, terfenadine, quinidine;
• doxorubicin, paclitaxel, etoposide, mitoxantrone, fexofenadine, losartan, vinblastine,
tacrolimus, talinolol.
5.5.6. Non-drug Therapies
Any non-drug therapies (e.g., ginger preparations, acupressure bands) to treat emetic
episodes were discouraged. However, in the event that such non-drug therapies were
employed, the details of such use were to be documented in the subject's eCRF.
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5.6. Study Assessments and Procedures
5.6.1. Demographic and Baseline Assessments
Signed, written informed consent was obtained prior to screening assessments and before
any study-specific assessments were initiated. Unless specified to the contrary, the
screening period was within 21 days prior to administration of the investigational
product. All screening and baseline evaluations were completed prior to initiating
treatment with the investigational product.
The following assessments were obtained at Screening (Table 1):
1. Demographic data: date of birth, race, ethnicity, height, weight, and ASA Physical
Status Classification (Attachment 2).
2. Medical history and evaluation of inclusion/exclusion criteria, including previous
history of PONV, previous history of motion sickness and smoking history, current
medical conditions.
3. Prior and concomitant medications taken within 7 days prior to the scheduled surgery
were recorded.
4. Routine physical examination, which was performed by a qualified physician,
physician's assistant, or nurse practitioner, and included a thorough review of all body
systems.
5. Baseline 12-lead electrocardiogram (ECG).
6. Vital signs (including heart rate, blood pressure, and respiration rate).
7. Hematology and clinical chemistry laboratory assessments, including the following:
• Hematology: hemoglobin, hematocrit, white blood cell (WBC) count, WBC
differential, and platelet count.
• Chemistry: ALT, albumin, alkaline phosphatase, AST, blood urea nitrogen (BUN)
or serum urea, creatinine, electrolytes (sodium, potassium, chloride), glucose, total
bilirubin, and total protein.
These tests were assessed per local standards, but in no event longer than 10 days
prior to the scheduled surgery. If possible, the blood collection for glucose was to be
taken when the subject had fasted for at least 8 hours.
8. Urine or serum pregnancy testing for females of childbearing potential (per local
standards, but in no event longer than 24 hours prior to the first administration of
investigational product).
5.6.2. Efficacy Assessment
Each subject was given a Subject Diary that was used to record the occurrence of nausea,
emesis, and the use of rescue medications daily during the assessment period. Two
nausea assessment tools were also included in the Subject Diary: a “Likert scale”, and a
categorical scale. (Note: assessments of nausea were obtained using an 11-point, linear,
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numerical rating scale. However, the protocol referred to this scale as a “0–10 Likert
scale”. The Likert terminology has been continued throughout this report.).
During the assessment phase, subjects were instructed to complete their rating of nausea
over the preceding 2, 6, 24, and 48 hours (Table 1). A brief questionnaire about
satisfaction with the investigational product and the study medication in preventing
nausea and vomiting, and a question about the willingness of the subject to use the same
antiemetic drug treatment regimen for subsequent surgical procedures, was also included
in the Subject Diary.
Efficacy was assessed through the collection of data related to:
• Whether or not the subject experienced an occurrence of emesis (vomiting and/or

retching).
• The time that elapsed before the first occurrence of emesis.
• Whether or not the subject experienced nausea, and if so, the subject-reported degree
of nausea.
• The use of any additional antiemetic medications, irrespective of whether such
medications were given as rescue medications.
• The use of any opioid medication(s) to control post-surgical pain.
Until the subject was able to complete the assessments in the Subject Diary, study
personnel evaluated the subject for the occurrence of emesis, time to any occurrence of
emesis, and the use of any antiemetic rescue medications and/or opioid pain medications.
This information was entered into the Subject Diary or eCRF by study personnel. Note,
however, that as the nausea assessments could not be completed by study personnel and
had to be completed by the subject, these assessments were not to be completed as long
as the subject remained incapable of completing the assessments.
In addition, data from a contact in person (for inpatients) or from a follow-up telephone
call (for outpatients) on postoperative Days 1 and 2 were entered into the subject's source
documents and were reviewed with the subject upon their return for the final study visit
(postoperative Day 6–14). The study coordinator contacted the subject at the end of the
24-hour assessment phase to review the Subject Diary for accuracy and completeness.
The contact or telephone call was made as close to the end of the 24-hour post placement
of the last suture/staple as possible, but no later than 26 hours post last suture/last staple.
An additional assessment contact was made at the 48-hour post last suture/last staple time
point. During any contact with the subject in the assessment periods, data could be
collected that was not available at the time of the 24-hour assessment contact (e.g., if the
subject was unreachable at the 24–26 hour post last suture/staple period). Information
from the final study visit was entered into the study subject's eCRF.
5.6.2.1. Assessments of efficacy
The following definitions were used for the purposes of this study:
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Nausea: A subjectively unpleasant sensation associated with the awareness

of the urge to vomit; the desire to vomit without the presence of
expulsive muscular movements.
Emesis: Vomiting and/or retching.
Vomiting: The forceful expulsion of gastrointestinal contents through the

mouth or nose.
Retching: The labored, spasmodic, rhythmic contraction of the respiratory

and abdominal muscles in an attempt to vomit that is not
productive of gastrointestinal contents (also known as “dry
heaves”).
Emetic episode: A single vomit or retch or any number of continuous vomits or

retches. Emetic episodes were, by definition, separated by the
absence of vomiting or retching by at least 1 minute. Continuous
vomiting and/or retching were defined as two or more vomits
and/or retches that occurred within 1 minute of each other.
See Section 4.2.2 for additional definitions related to Efficacy Analysis.
5.6.2.2. Assessment of nausea
Nausea was assessed using an 11-point, linear, numerical rating scale referred to as a “0–
10 Likert scale” and a categorical scale, at 2, 6, 24 and 48 hours after placement of the
last suture/staple. The Likert scale used a range of 0 to 10, where 0=“No Nausea” and
10=“Nausea as bad as it can be”; study subjects were asked to quantify their nausea by
providing a simple general rating of their worst feeling of nausea. These data were
captured in the electronic diary system. The more traditional validated VAS [Boogaerts,
2000] was not available in this electronic diary system.
Numerical rating scales (verbal or graphic) have previously been used to measure the
severity of postoperative nausea [Lee, 2004; Jones, 2006; White, 2006]. Although the
use of the numerical rating scale has not been formally validated for postoperative
nausea, its use for postoperative nausea was considered reasonable because the
instrument has been validated for postoperative pain and it has been shown to correlate
strongly with VAS in measuring pain [DeLoach, 1998; Kaufman, 2002; Bijur, 2003]. A
score of <1 was chosen to define 'no nausea' and <3 to define 'no significant nausea'. In
addition to the "0–10 Likert scale" each subject was asked to complete a categorical scale
for which she was asked to rate the severity of her nausea, using the descriptions
provided below. This scale has not yet been validated and was used for exploratory
purposes.
• None: no nausea.
• Mild: queasiness/upset stomach that was manageable and minimally (if at all)
affected daily activities.
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• Moderate: increased queasiness, sometimes with the feeling of having to vomit (but
not vomiting), that had a significant negative effect on daily activities (for example,
being unable to work, eat and drink, prepare food, care for children or others).
• Severe: feeling sick and vomiting or feeling like you were going to vomit, and
unable to perform most daily activities.
5.6.2.3. Antiemetic rescue therapy
For the purposes of this study, antiemetic rescue medication was defined as medication
that was given specifically for the treatment of nausea and/or emesis during the study.
Study subjects who received antiemetic rescue medication(s) during the initial 24-hour
follow-up assessment phase were considered treatment failures. Antiemetics were
limited to rescue therapy; that is, only given in the event that the antiemetic prophylaxis
given at surgery had failed to prevent nausea or vomiting, and the subject required further
treatment. Any subject who took rescue medication was considered a treatment failure at
the time the rescue medication was taken, even in the absence of an emetic episode or
nausea.
Subjects who received antiemetic rescue medication were not withdrawn from the study
and all efficacy and safety assessments continued to be made through the end of the
48-hour assessment phase.
Use (“yes” or “no”) of antiemetic rescue medication was documented in the Subject
Diary. For any antiemetic rescue drug(s), the name of the antiemetic, the corresponding
dose(s), and the date(s) and time(s) of administration were recorded in the eCRF.
5.6.2.4. Subject diary
In order to collect safety and efficacy data, an electronic Subject Diary was used. The
Subject Diary was given to the subject prior to the administration of investigational
product on Day 1. The subject received instructions for completing the required
assessments in the Subject Diary. The subject also completed the baseline nausea Likert
and categorical assessments at this time.
Following last suture/last staple, the Subject Diary was returned to the subject when the
clinical staff considered the subject capable of adequately completing the required
assessments. Prior to discharge, the instructions for completing the Subject Diary were
reviewed with the subject. The Subject Diary was used to record efficacy and safety data
during the 48-hour assessment phase. The data recorded in the diary included
information about emesis, nausea, and medications.
During any contact with the subject during the assessment phase, data could be collected
that was not available at the time of a previous follow-up contact (e.g., if the subject was
unreachable at 24 hours post placement of last suture/staple) or subsequent assessment
phase. This information was also recorded in the eCRF.
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In the event that a subject was not considered capable of completing the assessments
required at a specified assessment period (e.g., 2 hours post placement of last
suture/staple), the necessary information (i.e., assessments of emesis, the use of rescue
medications for emesis, and other concomitant medications) was collected by study
personnel.
The Subject Diary was to be returned by the subject to the investigator and/or designee at
the investigational site during the study visit on postoperative Day 6–14. The Subject
Diary was reviewed with the subject to ensure that the information was complete,
consistent, and accurate.
5.6.3. Safety Assessments
5.6.3.1. Adverse events
Adverse events were recorded from the time of the first dose of investigational product
until the follow-up visit (Table 1). Open-ended, non-leading questions were used to
assess potential AEs. Adverse events were also assessed from information collected from
the Subject Diary and telephone follow-up contacts.
An AE was defined as any untoward medical occurrence in a clinical investigation

subject, temporally associated with the use of a medicinal product, whether or not
considered related to the medicinal product.
An AE could therefore be any unfavorable and unintended sign (including an abnormal

laboratory finding), symptom, or disease (new or exacerbated) temporally associated with
the use of a medicinal product. For marketed medicinal products, this also included
failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.
Adverse events could include pre- or post-treatment events that occurred as a result of
protocol-mandated procedures (i.e., invasive procedures, modification of subject’s
previous therapeutic regimen).
Abnormal laboratory findings (e.g., clinical chemistry, hematology, urinalysis) or other

abnormal assessments (e.g., ECGs, vital signs) that were judged by the investigator as
clinically significant were to be recorded as AEs or SAEs if they met the definition of an
AE (see above) or SAE (see Section 5.6.3.2). Clinically significant abnormal laboratory
findings or other abnormal assessments that were detected during the study or were
present at Baseline and significantly worsened following the start of the study were to be
reported as AEs or SAEs. However, clinically significant abnormal laboratory findings
or other abnormal assessments that were associated with the disease being studied, unless
judged by the investigator as more severe than expected for the subject’s condition, or
that were present or detected at the start of the study and did not worsen, were not to be
reported as AEs or SAEs.
During the 48-hour assessment phase, episodes of nausea or emesis that resulted in the
administration of rescue medication were considered treatment failures rather than AEs
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or SAEs, and were captured in the assessments of emesis and nausea in the Subject
Diary.
Nausea and emesis that occurred after the 48 hour assessment phase but prior to the
postoperative Day 6–14 visit were to be recorded as AEs or SAEs.
“Lack of efficacy” per se was not to be reported as an AE. The signs and symptoms or
clinical sequelae resulting from lack of efficacy were reported if they fulfilled the AE or
SAE definition.
The investigator assessed the intensity of each AE/SAE (mild, moderate, or severe), and
the relationship between investigational product and the occurrence of each AE/SAE.
5.6.3.2. Serious adverse events
All SAEs were recorded from the time of the first dose of investigational product until
the follow-up visit. Serious adverse events assessed as related to study participation (e.g.,
protocol-mandated procedures, invasive tests, or change in existing therapy) or related to
a GSK concomitant medication were recorded from the time a subject consented to
participate in the study until she had completed the study (up to the completion of the
postoperative Day 6–14 visit).
An SAE was defined as any untoward medical occurrence that, at any dose:
a. Resulted in death.
b. Was life-threatening.
c. Required hospitalization or prolongation of existing hospitalization.
d. Resulted in disability/incapacity.
e. Was a congenital anomaly/birth defect.
f. Medical or scientific judgment was to be exercised in deciding whether reporting
was appropriate in other situations, such as important medical events that may not be
immediately life-threatening or result in death or hospitalization but may jeopardize
the subject or may require medical or surgical intervention to prevent one of the
other outcomes listed in the above definition. These were also to be considered
serious.
5.6.3.3. Pregnancies
A screening serum beta-human chorionic gonadotropin or urine pregnancy test was

conducted for all subjects of childbearing potential per local standards, but in no event
longer than 24 hours prior to the first administration of investigational product (Table 1).
Unless a serum pregnancy test was required by the medical institution, a urine pregnancy
test was sufficient. Thereafter, the pregnancy test was only repeated if clinically
indicated or required per local regulation.
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The investigator was to collect pregnancy information on any subject who became
pregnant while participating in this study (during the treatment and follow-up period). In
the event that a pregnancy did occur, the subject was to be immediately withdrawn from
the study. The subject was to receive counseling regarding the nature of the
investigational product and the potential risk on fetal development. The subject was also
followed to determine the outcome of the pregnancy. Any premature termination of the
pregnancy was to be reported.
While pregnancy itself was not considered an AE or SAE, any pregnancy complication or
elective termination of a pregnancy for medical reasons was to be recorded as an AE or a
SAE. A spontaneous abortion was always considered to be an SAE.
5.6.3.4. Clinical laboratory evaluations
Blood samples for clinical laboratory evaluation were taken at Screening; prior to
discharge from the hospital/surgical facility or at the end of the 24-hour follow-up
assessment period on postoperative Day 1, whichever came first; and the final study visit
(Day 6–14 visit) (Table 1).
• Hematology: hemoglobin, hematocrit, WBC count, WBC differential, and platelet

count.
• Chemistry: albumin, alkaline phosphatase, ALT, AST, BUN or serum urea,
creatinine, chloride, potassium, sodium, glucose (fasting for >8 hours, if possible),
total bilirubin, and total protein.
Any subjects with abnormal liver function test results (ALT ≥3x the upper limit of
normal [ULN] and bilirubin ≥1.5x ULN) were to be monitored closely and a specialist or
hepatology consultation was to be considered. These subjects, as well as any additional
subjects with an ALT ≥3x ULN, were to be monitored twice weekly until liver function
tests (ALT, AST, alkaline phosphatase, bilirubin) stabilized or returned to baseline
values.
5.6.3.5. Other safety assessments
Vital signs (heart rate, systolic blood pressure, diastolic blood pressure, respiration rate)
were recorded at Screening; on the day of surgery prior to investigational product/study
medication administration; prior to discharge from the surgical facility or at the end of the
24-hour assessment phase on postoperative Day 1, whichever came first; and at the
postoperative Day 6–14 visit (Table 1).
A 12-lead ECG was performed at Screening, and prior to discharge from the surgical
facility or at the end of the 24-hour assessment phase on postoperative Day 1, whichever
came first (Table 1).
Time to awakening (from the placement of last suture/staple) was also assessed.
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5.6.4. Health Outcomes Assessments
5.6.4.1. Subject satisfaction questionnaires
Subjects were asked two questions relating to their overall satisfaction with the
antiemetic therapy. These assessments were completed in the Subject Diary on
postoperative Day 2, as soon as possible following the completion of the 48-hour
assessment phase. The Subject Diary was returned to the investigational site during the
post-op Day 6–14 final study visit.
The first question rated the overall satisfaction with the investigational product
(casopitant/placebo) and the study medication (Zofran Injection) in preventing PONV,
using a five-point rating scale, as follows:
1. = Very satisfied.
2. = Somewhat satisfied.
3. = Neither satisfied nor dissatisfied.
4. = Somewhat dissatisfied.
5. = Very dissatisfied.
In addition, subjects rated their willingness to use the same antiemetic drug treatment
regimen for subsequent surgical procedures, using a similar five-point rating scale:
1. = Definitely would be willing.

2. = Probably would be willing.
3. = Not certain.
4. = Probably would not be willing.
5. = Definitely would not be willing.
5.6.4.2. Medical resource utilization
A brief questionnaire of unscheduled nausea and vomiting-related medical resource

utilization during Days 1–5 was collected in the postoperative Day 6–14 final study visit.
The data collected included nausea and vomiting-related telephone calls, home visits,
nursing visits, physician office/clinic visits, urgent care/emergency room visits, and
inpatient days.
5.6.5. Pharmacogenetic Assessments
During the course of the study, subjects who signed a separate pharmacogenetics consent
provided a 7mL blood sample for deoxyribonucleic acid extraction and pharmacogenetic
analysis (preferably prior to administration of the investigational product) (Table 1). At
the time of the study, no specific pharmacogenetic analyses were planned. However, the
need to conduct pharmacogenetic analysis may be identified after a study (or set of
studies) of casopitant has been completed and the study data reviewed. For this reason,
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samples may be kept for up to 15 years after the last subject completes the study or GSK
may destroy the samples before then. Under certain circumstances, the samples may not
be studied. This might happen if there are not enough subjects, if the study is stopped for
other reasons, or if no substantial scientific questions remain unanswered regarding
safety, efficacy, drug metabolism or pharmacokinetics of casopitant.
5.7. Data Quality Assurance

This study used Phase Forward’s InForm® system. InForm is a web-based clinical trials
data management system that provides investigational sites a standardized and validated,
remote, electronic data capture system for the collection of clinical trial data. Activities
performed using InForm include data entry, modification, review and validation. Each
activity performed carries a unique user identification code and a date-time stamp.
InForm training for this multicenter study was provided to site staff at the Investigator
meeting by PharmaLink. Study-specific eCRF training for the monitors was provided via
teleconference, and Lotus Notes Sametime Connect™ web meeting software by GSK
Data Management. Additionally, an InForm interactive training database was available
to site staff and study monitors for independent follow-up training.
The application was fully validated using test data, prior to distributing the url for site
use.
Encrypted clinical trial data was transmitted from the site via the internet to a firewall-
protected network server, and then via an application server into the clinical database
(e.g., InForm puts data into a shared drive).
An electronic audit trail of all changes made to the eCRF was kept within the InForm
system. This audit trail identified the user making the change by userid (i.e., user
identification), and date and time of change.
Pre-defined data validation checks were run within the eCRF as the data were entered and
submitted by authorized site staff. The resulting data queries were then resolved.
Additional queries were generated within the eCRF by authorized GSK staff as a result of
data review (e.g., source document review, external data reconciliation).
In addition to InForm eCRF data, electronic laboratory data and ECG data were delivered
to GSK by external vendors. These data were reconciled with the eCRF data and
resulting discrepancies were queried within the eCRF.
Additional quality control was carried out by extracting SAS datasets, and comparing
printed copies against the eCRF for a percentage of the cases.
Adverse events and concomitant medications were coded by the autoencoder using a
company standard dictionary (GSK Drug) and the industry standard Medical Dictionary
for Regulatory Activities.
Serious adverse event data were documented according to standard GSK practice in the
GSK standard InForm eCRF. Upon submission of the SAE entry, a system-generated e-
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mail was sent to the GSK GCSP department to facilitate rapid reporting as outlined in the
study protocol.
The principal investigator electronically signed and dated each InForm casebook attesting
to his/her responsibility for the quality of all data included therein, and that the data
represented a complete and accurate record of each subject's participation in the study. At
the end of the study once all data queries were resolved, a CD-ROM containing eCRF
PDFs (the PDF contains all of the subject’s eCRF data, the data queries, and a copy of the
audit trail) was sent to each site along with a letter explaining how to view the data on the
PDF. Upon delivery of the CD-ROM, the study site notified GSK of receipt of the CD.
After data management procedures were completed, the database was released to GSK’s
Biostatistics and Programming. Following release, the database was frozen.
The original validated data (eCRFs, etc.) were archived according to company standard
procedures.
5.8. Data Analysis Methods

A detailed description of the data analysis methods was provided in the reporting and
analysis plan (RAP) (Attachment 3).
5.8.1. Timings of Planned Analyses
Clinical data management was performed in accordance with applicable GSK standards
and data cleaning procedures. Database freeze occurred after data management quality
control procedures had been completed.
5.8.1.1. Interim analyses and data monitoring
No interim analyses were planned or conducted for this study.
5.8.1.2. Changes in the conduct of the study or planned analyses
The Likert scale (0–10) referred to in the protocol was technically an 11-point numerical
rating scale. To keep the language consistent, it is referred to as a Likert scale in the
present report.
According to the RAP, laboratory values of clinical concern were prospectively defined
by GlaxoSmithKline and a listing identifying subjects whose results met those definitions
was to be identified. However, the clinical concern values were instead based on
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-
CTCAE) [NCI-CTCAE, 2003]. The change in analysis was made prior to unblinding the
study and was designed to provide a commonly known standard and to facilitate
comparison across different casopitant studies for nausea and vomiting. The
programmatically flagged parameters are detailed in Table 3.
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Table 3 Flagging of laboratory values
Metabolic/Laboratory Blood/Bone Marrow

Albumin, serum-low Hemoglobin
Alkaline phosphatase Leukocytes (total WBC)
ALT, SGPT Lymphopenia
AST, SGOT Neutrophils/granulocytes
Bilirubin Platelets
Creatinine
Glucose, serum-high
Potassium, serum-high
Sodium, serum-high
ALT=alanine aminotransferase; SGPT=serum glutamate pyruvate transaminase; AST=aspartate aminotransferase;
SGOT=serum glutamate oxaloacetate transaminase; WBC=white blood cells.
5.8.2. Sample Size Considerations
Based on Phase II data, assuming a 40% complete response rate for treatment arm A
(Zofran 4mg IV alone) at 24 hours, 231 subjects per arm were expected to be required to
show a 15% absolute difference in complete response rates between the two treatment
arms with 90% power and a two-sided level of significance of 5%.
See the study protocol (Attachment 1) for a detailed discussion of sample size sensitivity
calculations.
5.8.3. Analysis Populations
The intent-to-treat (ITT) population was defined as all subjects who were randomized to
one of two antiemetic treatment regimens. The ITT population was used to summarize
the study population and also to confirm the results of the primary analysis.
The primary population of interest was the modified intent-to-treat (MITT) population.
This population was the subset of the ITT population that received any investigational
product and had surgery. Subjects were excluded from this population only if there was
documented evidence that no investigational product (either casopitant or placebo) was
administered or there was no surgery. The MITT population was used to carry out the
efficacy analysis.
The Safety population was a subset of the ITT population that received investigational
product (either casopitant or placebo). Subjects were excluded from this population only
if there was documented evidence that no investigational product (either casopitant or
placebo) was administered. This population was used to create safety reports. The safety
reports were based on the actual treatment the subject received, not the treatment to
which they were randomized.
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5.8.4. Treatment Comparisons
All treatment comparisons were between oral casopitant 50mg given in combination with
Zofran versus Zofran alone.
5.8.4.1. Primary comparisons of interest
The primary comparison of interest was between casopitant 50mg given in combination
with Zofran 4mg IV and Zofran 4mg IV alone. Complete response rates between the two
treatment arms were tested using a two-sided test with a level of significance of 5%. The
primary comparison was carried out at the 24-hour endpoint. The MITT population was
used for this testing.
5.8.4.2. Other comparisons of interest
There were several comparisons of interest for the following secondary variables in the
testing hierarchy: no vomiting, complete protection, maximum nausea score, and total
control. Other secondary variables included in the comparisons of interest were
proportion of subjects with nausea/significant nausea, time to emesis, time to rescue, use
of rescue medication, time to awakening, subject satisfaction, and subject willingness.
Secondary comparisons were carried out in the 0–24, 24–48 and 0–48 hour assessment
windows.
5.8.5. General Considerations for Data Analyses
This study was conducted through Phase Forward's InForm system. Subject data were
collected by the investigator or designee using the eCRF defined by GSK. Subject data
necessary for analysis and reporting were entered/transmitted into a validated database or
data system. Clinical data management was performed in accordance with applicable
GSK standards and data cleaning procedures. Database freeze occurred after data
management quality control procedures had been completed.
5.8.5.1. Multicenter studies
This trial used a randomization that assigned subjects to treatment groups based on a
single, central allocation scheme across centers. Therefore, no adjustments were made
for center, and a treatment-by-center interaction was not examined.
5.8.5.2. Other strata and covariates
The randomization of this study was stratified by anticipated nitrous oxide use. The
primary analysis was thus adjusted for this stratification.
5.8.5.3. Examination of subgroups
No subgroup analyses were planned or conducted.
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5.8.5.4. Multiple comparison/multiplicity
This study had a single primary objective and as such was planned on one primary
endpoint. For the primary analysis, this endpoint was tested at 24 hours at the 5% level
of significance. There were several secondary hypotheses for this study. These were
tested hierarchically as given below. For brevity, only the hypotheses that are not similar
to the primary hypotheses are presented in detail.
Secondary hypothesis hierarchy:
1. No vomiting (similar to primary hypothesis).

2. Complete protection (similar to primary hypothesis).
3. Maximum nausea score:
Null hypothesis: There is no difference in the distribution of maximum nausea scores
between the two treatment arms in the first 24 hours following placement of last
suture/staple, and
Alternate hypothesis: The two treatments differ in the distribution of the maximum
nausea scores.
4. Total control (similar to primary hypothesis).

Secondary hypotheses were tested in the order shown above at the 5% level of
significance until a hypothesis failed to meet statistical significance at the 5% level of
significance. Once this point had been reached, all subsequent hypotheses were not
tested.
A detailed description of the data analysis methods was provided in the RAP
(Attachment 3).
5.8.6. Data Handling Conventions
5.8.6.1. Premature discontinuation and missing data
All premature discontinuations from the study were tabulated by reason for
discontinuation. Subjects who either received rescue medication or withdrew from the
study during an assessment period were considered to be treatment failures for that
period. However, subjects who received rescue medication were permitted to remain in
the study and continue to have safety and efficacy assessments performed. Withdrawal
reports were based on the ITT population.
Where data were missing, a conservative approach was taken and an event occurrence
was assumed. For response rates, this would translate to a failure. The time of event was
taken to be the last point of contact.
5.8.6.2. Derived and transformed data
Efficacy endpoints were derived as follows:
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• Complete response: no vomiting/retching and no rescue therapy.

• Complete protection: no vomiting/retching, no rescue therapy and maximum nausea
<3 on the Likert scale.
• Total control: no vomiting/retching, no rescue therapy and a maximum nausea <1 on
the Likert scale.
• Vomiting: vomit or retch, but included subjects who had received rescue therapy
(i.e., considered as no vomiting even if they received rescue but no retch/vomit).
• Significant nausea: maximum nausea score greater than or equal to 3 on the Likert
scale for nausea from all nausea assessments.
• Nausea: maximum nausea score greater than or equal to 1 on the Likert scale for
All endpoints were assessed in the following time windows: 0–24, 24–48 and 0–48 hours
following placement of the last suture/staple. Nausea was also assessed in the following
time windows: 0–2 and 0–6 hours.
Additionally, the following endpoints were analyzed:
• Time to first emetic event: the length of time from placement of the last
suture/staple until the time of the first emetic event. If a subject withdrew
prematurely during the first 48 hours and did not have an emetic event, then the time
of withdrawal was considered to be their first emetic episode, and the subject’s data
were censored at that time point.
• Time to rescue medication: the length of time from placement of the last
suture/staple until the time of the first use of rescue medication. If a subject
withdrew prematurely during the first 48 hours and had not taken rescue medication,
then the time of withdrawal was considered to be their time to first use of antiemetic
rescue medications, and the subject’s data were censored at that time point.
• Time to awakening: the time interval from the placement of last suture/staple until
the time the subject was able to understand and obey a command.
• Nausea severity on the categorical scale: none, mild, moderate or severe (from
Subject Diary).
5.8.6.3. Values of clinical concern
Number and proportion of subjects with clinically significant abnormalities of laboratory

values (chemistry and hematology) were tabulated. The values of clinical concern were
prospectively defined by GSK. In a change to the planned analyses (Section 5.8.1), the
clinical concern values were instead based on NCI-CTCAE criteria [NCI-CTCAE, 2003].
5.8.7. Study Population
Details of data displays for disposition of subjects, protocol deviations, and demographic
and baseline characteristics were provided in the RAP (Attachment 3).
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5.8.7.1. Treatment compliance
Since casopitant (or placebo) and Zofran were administered at site on Day 1 only,
compliance for each was considered to be 0% or 100%, depending on whether there was
an entry in the date and dose box of the relevant panel of the eCRF.
5.8.8. Efficacy Analyses
5.8.8.1. Primary efficacy measure
The primary analysis compared oral casopitant 50mg in combination with Zofran 4mg IV
with Zofran 4mg IV alone. Testing was conducted at a 5% level of significance. The
Cochran-Mantel-Haenszel test which adjusts for the stratification factors (anticipated
intra-operative nitrous oxide use) was used to make comparisons. The odds ratio was
presented along with the associated 95% confidence interval.
5.8.8.2. Secondary efficacy measures
Where the primary comparison was significant, the secondary endpoints were tested
using the pre-specified hierarchy at the 5% level of significance and 95% confidence
intervals were presented (no vomiting, complete protection, maximum nausea score, total
control).
Complete response in the 24–48 and 0–48 time periods was analyzed as described for the
primary efficacy analysis.
The other secondary efficacy analysis variables were grouped into four types:
1. Proportions of successes for each treatment arm were tabulated. The Cochran-
Mantel-Haenszel test which adjusts for the stratification factors was used to make
comparisons. A p value was reported and 95% confidence intervals were provided.
This analysis was carried out in the 0–24, 24–48 and 0–48 time periods, for the
following endpoints: complete protection, total control, vomiting, significant nausea,
nausea.
2. Time-to-event endpoints (time to first emetic event and time to first rescue
medication) were summarized using Kaplan-Meier estimates. Time-to-event data
were summarized using quartiles (25th percentile, median and 75th percentile) and the
associated 95% confidence intervals. Log-rank p values also were calculated. If no
event had occurred at the end of the 48-hour time period, then the observation was
censored for the purpose of this analysis.
3. Maximum nausea score was analyzed using a Wilcoxon Rank Sum test. Summary
statistics (mean, standard deviation, median etc.) and a p value were reported.
4. Categorical nausea score (none, mild, moderate and severe) was analyzed using a
non-zero correlation test. Proportions in each category were tabulated and a p value
was reported.
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5.8.9. Safety Analyses
Tabulation of extent of exposure, AEs, SAEs, deaths, withdrawals, clinical laboratory

evaluations, and pregnancies were detailed in the RAP (Attachment 3). Summary tables
were generated for vital signs and time to awakening data.
5.8.10. Health Outcomes Analyses
Frequencies and percentages of each subject satisfaction category on the 5-point scale
were presented for each treatment arm (postoperative Day 2).
Frequencies and percentages of each subject willingness category on the 5-point scale
were presented for each treatment arm (postoperative Day 2).
For medical resource utilization, unscheduled healthcare-related contacts made by

subjects were summarized using counts and percentages.
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6. STUDY POPULATION RESULTS

The study start date (first subject first visit) was 20 March 2006 and the study completion
date (last subject last visit) was 31 August 2006.
6.1. Disposition of Subjects

The study was conducted at 43 centers in 11 countries: Canada, France, Germany, Hong
Kong, Hungary, Ireland, Pakistan, Philippines, Thailand, United Kingdom and United
States. The country with the largest number of centers was the United States with
19 centers. The region in which the greatest number of subjects was recruited was North
America (282 subjects, including 242 in the United States), followed by Europe (115
subjects) and Asia (87 subjects) (Source Data Table 6.1).
Ninety-four percent of the subjects completed the study; i.e., completed the end of study
visit on Postoperative Day 6–14. There were no withdrawals due to lack of efficacy and
no withdrawals primarily due to AEs (Table 4).
Table 4 Subject disposition (Intent-to-Treat population)
Zofran Alone Casopitant Total

(+ Zofran)
Subject disposition N=242 N=242 N=484
n (%) n (%) n (%)
Completed 229 (95) 227 (94) 456 (94)
Prematurely withdrawn 13 (5) 15 (6) 28 (6)
Primary reason for withdrawal
Adverse event 0 0 0
Lost to follow-up 3 (1) 4 (2) 7 (1)
Protocol violation 2 (<1) 1 (<1) 3 (<1)
Subject decided to withdraw
from the study 1 (<1) 4 (2) 5 (1)
Other1 7 (3) 6 (2) 13 (3)
Source Data: Table 6.2
1. The other reasons for premature withdrawal included cancelled surgery (seven subjects: four randomized to
Zofran alone and three to casopitant); closed recruitment (two subjects, one in each group); and treatment failure
(one subject in the Zofran alone group).
6.2. Protocol Deviations

Thirty-five percent of subjects in the ITT population had major protocol deviations
recorded. The most frequently reported major protocol deviation was an anesthesia
duration of ≤45 minutes (Table 5).
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Table 5 Summary of major protocol deviations (Intent-to-Treat population)
Zofran Casopitant Total

Alone (+ Zofran)
Protocol deviations N=242 N=242 N=484
n (%) n (%) n (%)
Total number of major protocol deviations 1 89 (37) 81 (33) 170 (35)
Duration of anesthesia ≤45 minutes 47 (19) 47 (19) 94 (19)
Subject did not enter diary data 35 (14) 29 (12) 64 (13)
Received prohibited medication 13 (5) 14 (6) 27 (6)
No surgery record 7 (3) 9 (4) 16 (3)
No study medication taken 5 (2) 7 (3) 12 (2)
Inclusion criterion #7 2 1 (<1) 3 (1) 4 (<1)
Nasogastric tube and suction 2 (<1) 2 (<1) 4 (<1)
Received antiemetic medication 1 (<1) 2 (<1) 3 (<1)
Received medication - inhibitors of cytochrome P450 1 (<1) 1 (<1) 2 (<1)
1. Each subject could have more than one protocol violation reported.
2. Willing and expected to be able to complete daily components of the Subject Diary preoperatively on the day of
surgery and until the end of the 48-hour assessment period, and return to the investigational site at the post-op
Day 6–14 final study visit.
The treatment blind was not broken for any subject during the study.
6.3. Populations Analyzed
• The ITT population consisted of 484 subjects who were randomized to treatment.
• The MITT population (primary efficacy population) consisted of 468 subjects who
were randomized to treatment, received investigational product/study medication and
had surgery.
• The Safety population consisted of 472 subjects who received investigational
product/study medication.
Of the 16 subjects who were included in the ITT population but not in the MITT
population, 12 were randomized but not dosed and did not have surgery; and four were
randomized and dosed but did not have surgery.
6.4. Demographics and Other Baseline Characteristics
6.4.1. Demographic Characteristics
Treatment groups were balanced with regard to average age, ethnicity, height and weight.
All subjects were female (Table 6).
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Table 6 Demographic characteristics (Intent-to-Treat population)
Demographic Zofran Alone Casopitant Total

parameter (+ Zofran)
N=242 N=242 N=484
Age (years) n 237 235 472
Mean 44.8 44.4 44.6
Standard deviation 12.44 12.19 12.30
Median 44 44 44
Range 18–79 18–83 18–83
Ethnicity, n (%) n 242 242 484

Hispanic or Latino 19 (8) 22 (9) 41 (8)
Not Hispanic or Latino 223 (92) 220 (91) 443 (92)
Height, cm n 241 239 480

Mean 161.3 162.8 162.0
Median 161 162 162
Range 79–183 65–194 65–194
Weight, kg n 241 239 480

Mean 70.6 72.3 71.5
Median 67 69 68
Range 37–154 41–128 37–154
Treatment groups were also balanced with regard to racial characteristics (Table 7).
Table 7 Summary of Race and Racial Combinations (Intent-to-Treat

population)

(+ Zofran)
Race N=242 N=242 N=484
n (%) n (%) n (%)
Race N 236 (98) 233 (96) 469 (97)
African American/African heritage 20 (8) 19 (8) 39 (8)
American Indian or Alaskan Native & White 1 (<1) 1 (<1) 2 (<1)
Asian 50 (21) 46 (19) 96 (20)
Central/South Asian heritage 5 (2) 7 (3) 12 (2)
Japanese/East Asian/South East Asian
heritage 45 (19) 39 (16) 84 (17)
Native Hawaiian or other Pacific Islander 0 1 (<1) 1 (<1)
White – White/Caucasian/European
heritage 165 (68) 166 (69) 331 (68)
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6.4.2. Baseline Characteristics
The majority of subjects had an ASA physical status of P2 (mild systemic disease), with
less than 1% of subjects in the P3 (severe systemic disease) category (Table 8).
Table 8 Summary of American Society of Anesthesiologists physical status

classification (Intent-to-Treat population)

(+ Zofran)
Classification N=242 N=242 N=484
n (%) n (%) n (%)
P1 – A normal healthy patient 94 (39) 87 (36) 181 (37)
P2 – A patient with mild systemic disease 145 (60) 152 (63) 297 (61)
P3 – A patient with severe systemic disease 2 (<1) 1 (<1) 3 (<1)
The most frequently reported surgery types by verbatim term were hysterectomy
(119 subjects; 25%), cholecystectomy (77 subjects; 16%), breast operation (44 subjects;
9%), thyroid operation (34 subjects; 7%), and bilateral salpingo-oophorectomy
(12 subjects; 2%) (Source Data Table 6.9).
Average surgery time was similar in both treatment groups (Table 9).
Table 9 Summary of total surgery time (Intent-to-Treat population)
Zofran Alone Casopitant

(+ Zofran)
Total surgery time (minutes) N=242 N=242
n 235 232
Mean (standard deviation) 92.1 (56.96) 87.7 (50.39)
Median [range] 77.0 [10–414] 77.0 [14–270]
6.4.3. Current Medical Conditions
Current medical conditions were reported at screening in 95% of subjects in the study;
the most frequent were reproductive system and breast disorders, which were recorded in
275 subjects (57%). Nervous system disorders appeared to be reported more frequently
in the casopitant group than in the Zofran alone group (Table 10).
The most frequently reported current nervous system disorder was migraine and/or
headache, which was reported by 15 subjects (6%) in the Zofran alone group and
21 subjects (9%) in the casopitant group. Less frequently reported current medical
conditions included sleeplessness/insomnia and motion sickness/PONV (verbatim terms)
and dizziness and psychomotor seizures (group terms) (Source Data Table 6.16).
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Table 10 Summary of current medical conditions reported in 10% of subjects

or more in the study (Intent-to-Treat population)

(+ Zofran)
Current medical conditions N=242 N=242 N=484
n (%) n (%) n (%)
Any condition 231 (95) 229 (95) 460 (95)
Reproductive system and breast disorders 133 (55) 142 (59) 275 (57)
Immune system disorders 71 (29) 85 (35) 156 (32)
Cardiac disorders 66 (27) 59 (24) 125 (26)
Gastrointestinal disorders 49 (20) 58 (24) 107 (22)
Musculoskeletal and connective tissue
disorders 41 (17) 47 (19) 88 (18)
Hepatobiliary disorders 41 (17) 45 (19) 86 (18)
Nervous system disorders 36 (15) 50 (21) 86 (18)
Metabolism and nutrition disorders 37 (15) 43 (18) 80 (17)
Endocrine disorders 38 (16) 33 (14) 71 (15)
General disorders and administration site
conditions 30 (12) 34 (14) 64 (13)
Psychiatric disorders 31 (13) 29 (12) 60 (12)
Blood and lymphatic system disorders 25 (10) 32 (13) 57 (12)
Respiratory, thoracic and mediastinal
disorders 27 (11) 27 (11) 54 (11)
Neoplasms benign, malignant and
unspecified (incl. cysts and polyps) 30 (12) 23 (10) 53 (11)
Renal and urinary disorders 20 (8) 26 (11) 46 (10)
6.5. Concomitant Medications
6.5.1. Peri-Operative Medications
Peri-operative medications were those that were administered pre-operatively and intra-
operatively, including neuromuscular blocking and reversal agents. The most frequently
reported peri-operative medication was fentanyl, which was administered to 79% of
subjects in the Zofran alone group and 81% in the casopitant group (Table 11). It should
be noted that some sites may have inadvertently included some peri-operative
medications with the concomitant medications.
The use of ephedrine was more frequent in the casopitant group than in the Zofran alone
group (Table 11). Twenty-two subjects (9%) in the Zofran alone group received peri-
operative ephedrine (or one of its salt forms, ephedrine hydrochloride, or ephedrine
sulfate) compared with 42 (17%) in the casopitant group. Ephedrine is commonly
administered in the peri-operative setting as a vasopressor to counteract the hypotensive
effects of anesthesia. Ten subjects in the Zofran alone group had an AE of hypotension/
procedural hypotension, and nine received ephedrine, while all 17 subjects with AEs of
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hypotension/procedural hypotension in the casopitant group received ephedrine. None of

these was considered to be serious (Section 8.2.1).
Table 11 Summary of peri-operative medications reported in 10% of subjects

or more in either treatment group (Intent-to-Treat population)

(+ Zofran)
Peri-operative medication N=242 N=242
n (%) n (%)
Any peri-operative medication 235 (97) 233 (96)
Fentanyl 195 (81) 191 (79)
Propofol 189 (78) 188 (78)
Midazolam 133 (55) 128 (53)
Multiple ingredient 1 131 (54) 123 (51)
Nitrous oxide 111 (46) 108 (45)
Sevoflurane 108 (45) 99 (41)
Oxygen 102 (42) 93 (38)
Neostigmine 92 (38) 101 (42)
Glycopyrronium bromide 93 (38) 98 (40)
Lidocaine 70 (29) 84 (35)
Desflurane 68 (28) 69 (29)
Rocuronium bromide 69 (29) 65 (27)
Morphine 67 (28) 55 (23)
Rocuronium 53 (22) 57 (24)
Sodium chloride 53 (22) 57 (24)
Midazolam maleate 49 (20) 55 (23)
Cefazolin sodium 53 (22) 49 (20)
Atracurium besilate 48 (20) 44 (18)
Ketorolac trometamol 43 (18) 45 (19)
Atropine 37 (15) 45 (19)
Isoflurane 39 (16) 40 (17)
Suxamethonium 38 (16) 34 (14)
Neostigmine metilsulfate 33 (14) 38 (16)
Thiopental sodium 25 (10) 24 (10)
Ephedrine 17 (7) 29 (12)
Cefazolin 23 (10) 19 (8)
Ephedrine HCl 2 3 (1) 11 (5)
Ephedrine sulfate 2 0 1 (<1)
1. Medications that contained multiple active ingredients are included in this category and are also displayed as the
individual components.
2. These medications were included in the table to present a more complete picture of ephedrine use.
6.5.2. Prior and Concomitant Medications
Concomitant medications were those that were taken within 7 days prior to the day of
surgery and throughout the study, including antiemetic rescue medications but excluding
peri-operative medications. (However, it should be noted that some sites may have
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inadvertently included some peri-operative medications in the concomitant medications

panel of the eCRF.)
The most frequently reported concomitant medication was paracetamol, which was
received by 50% of subjects in the Zofran alone group and 54% in the casopitant group.
No significant imbalance was observed among treatment groups with regard to
concomitant medications (Table 12).
Table 12 Summary of concomitant medications reported in 10% of subjects

or more in either treatment group (Intent-to-Treat population)

(+ Zofran)
Concomitant medication N=242 N=242
n (%) n (%)
Any medication 230 (95) 236 (98)
Paracetamol 122 (50) 131 (54)
Morphine 69 (29) 60 (25)
Potassium chloride 69 (29) 53 (22)
Calcium chloride 60 (25) 40 (17)
Glucose 52 (21) 44 (18)
Ibuprofen 47 (19) 44 (18)
Hydrocodone bitartrate 39 (16) 46 (19)
Pethidine HCl 38 (16) 39 (16)
Fentanyl 33 (14) 40 (17)
Oxycodone HCl 37 (15) 35 (14)
Ketorolac trometamol 37 (15) 28 (12)
Dimeticone, activated 26 (11) 30 (12)
Vitamins NOS 35 (14) 20 (8)
Enoxaparin 21 (9) 31 (13)
Hydromorphone HCl 30 (12) 20 (8)
Docusate sodium 27 (11) 22 (9)
Oxygen 29 (12) 16 (7)
Hydrochlorothiazide 23 (10) 14 (6)
HCl = hydrochloride.
6.5.3. Rescue Medications
The most frequently reported rescue medication during the entire study was
promethazine/promethazine hydrochloride, which was administered to 10% of subjects in
the Zofran alone group and 12% in the casopitant group. No imbalance was observed
among treatment groups with regard to rescue medications (Table 13).
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Table 13 Summary of all subjects who received rescue medications (Intent-to-

Treat population)

(+ Zofran)
Rescue medication N=242 N=242
n (%) n (%)
Any rescue medication 1 74 (31) 61 (25)
Promethazine (HCl) 2 24 (10) 28 (12)
Ondansetron (HCl) 2 25 (10) 12 (5)
Metoclopramide (HCl) 2 11 (5) 13 (5)
Dimenhydrinate 11 (5) 12 (5)
Dexamethasone 8 (3) 5 (2)
Prochlorperazine 5 (2) 3 (1)
Dolasetron (mesilate) 2 6 (2) 0
Potassium chloride 4 (2) 1 (<1)
Granisetron (HCl) 2 2 (<1) 2 (<1)
Domperidone 1 (<1) 1 (<1)
Hyoscine 0 2 (<1)
Dimeticone, activated 1 (<1) 0
1. In Anatomical Therapeutic Chemical Level 1 ‘alimentary tract and metabolism’ category. Promethazine HCl was
inadvertently excluded from this category in the source document; however, it was included in the Respiratory
System category and has been included in the present table.
2. Includes comparable salt forms. Numbers were adjusted from the source document.
HCl=hydrochloride.
6.6. Treatment Compliance

Full treatment compliance was reported in greater than 95% of subjects in both groups
(Table 14).
Table 14 Summary of treatment compliance (Intent-to-Treat population)

Subjects with full treatment (+ Zofran)
compliance N=242 N=242
n (%) n (%)
Zofran 234 (97) 233 (96)
GW679769/placebo 237 (98) 235 (97)
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7. EFFICACY RESULTS
Complete response at 24 hours was tested as the primary endpoint and if significant the
following secondary endpoints were tested hierarchically as : no vomiting, complete
protection, maximum nausea score, and total control each at the 5% level of significance.
Analyses presented beyond the hierarchy were performed for descriptive purposes only.
When following this hierarchy, complete protection failed to reach statistical significance
and formal testing stopped at this point for the study.
7.1. Primary Efficacy Results
7.1.1. Complete Response (0–24 hours)
The primary efficacy endpoint was the proportion of subjects who achieved a complete
response (defined as no vomiting or retching and no rescue therapy during the first
24 hours following the placement of last suture/staple). The MITT population was the
primary efficacy population.
A significantly greater proportion of subjects in the casopitant group achieved the

primary endpoint of complete response over 0–24 hours compared with the Zofran alone
group, as indicated by a Cochran-Mantel-Haenszel test p value <0.05 in the MITT
population. The odds of achieving a complete response with the addition of casopitant
were 1.5 times the odds following Zofran alone (Table 15).
The proportion of subjects achieving a complete response in the Zofran alone group was
higher than had been anticipated in the sample size calculations (Section 5.8.2). Given
the emetogenic potential of nitrous oxide, the proportion of subjects with complete
response was expected to be lower in the ‘nitrous oxide anticipated’ stratum; however,
this was not the case. Thus, nitrous oxide did not appear to affect the complete response
endpoint (Table 15).

0-24 hours (Modified Intent-to-Treat population)

(+ Zofran)
Complete response 0–24 hours N=235 N=233
n/N (%) n/N (%)
Complete response 138/235 (59) 160/233 (69)
Cochran-Mantel-Haenszel test p value 0.0268
Odds ratio (95% confidence interval) 1.54 (1.05, 2.25)
Complete response by stratification

Nitrous oxide anticipated 75/123 (61) 95/125 (76)
No nitrous oxide anticipated 63/112 (56) 65/108 (60)
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In the supportive analysis of the ITT population, there was also a treatment difference
between the casopitant group (66%) and the Zofran alone group (57%) for complete
response over 0–24 hours (p=0.0391) (Source Data Table 7.2).
7.2. Secondary Efficacy Results

In the hierarchy of secondary endpoints, hypothesis testing for “no vomiting” reached
statistical significance at 24 hours. Results for the second level of the hierarchy,
complete protection, failed to reach statistical significance. As a result, the third and
fourth hypotheses, for maximum nausea score and total control, were not tested.
Analyses presented beyond the hierarchy were performed for descriptive purposes only.
7.2.1. Efficacy in the 0–24 Hour Period
7.2.1.1. No vomiting (0–24 hours)
Vomiting was defined as ‘subject vomited or retched’. If a subject took rescue

medications but did not vomit or retch, then they would be considered as not having
vomited.
There was a statistically significant treatment difference in favor of the casopitant group
for subjects with no vomiting over 0–24 hours (p<0.0001; odds ratio=0.34) in the MITT
population. The small odds ratio in the case of this endpoint indicates a reduction in the
likelihood of vomiting in the casopitant group. The proportion of subjects with no
vomiting in the ‘nitrous oxide anticipated’ stratum did not appear to be lower than the
overall proportion in either group (Table 16).
Table 16 Summary of proportion of subjects with no vomiting 0–24 hours

(Modified Intent-to-Treat population)

(+ Zofran)
No vomiting 0–24 hours N=235 N=233
n/N (%) n/N (%)
No vomiting 176/235 (75) 209/233 (90)
Cochran-Mantel-Haenszel test p value <0.0001
No vomiting by stratification
7.2.1.2. Complete protection (0–24 hours)
Complete protection was defined as no vomiting or retching, no rescue therapy and no

significant nausea (maximum nausea score <3 on the Likert scale).
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No statistically significant treatment difference was observed between the Zofran alone
group and the casopitant group for complete protection over 0–24 hours in the MITT
population (p>0.05) (Table 17). Therefore, as per the analyses pre-specified in the RAP,
hypothesis testing stopped here at the second level, and hypothesis testing was not carried
out for the third and fourth endpoints in the hierarchy (nausea and total control,
respectively).
The proportion of subjects with complete protection in the ‘nitrous oxide anticipated’
stratum did not appear to be lower than the overall proportion in either group (Table 17).
Table 17 Summary of proportion of subjects with complete protection


(+ Zofran)
Complete protection 0–24 hours N=235 N=233
n/N (%) n/N (%)
Complete protection 102/235 (43) 120/233 (52)
Complete protection by stratification

7.2.1.3. Nausea (0–24 hours)
As the previous hypothesis in the testing hierarchy (complete protection) failed to reach
statistical significance, formal hypothesis testing was not performed for the nausea
endpoints, and analysis results are presented for descriptive purposes only.
Maximum nausea score on the Likert scale (0–24 hours)
Mean (standard deviation) maximum Likert scale nausea score over 0–24 hours in the
MITT population was 3.2 (3.4) in the Zofran alone group and 2.6 (3.2) in the casopitant
group (Source Data Table 7.24).
Nausea (0–24 hours)
Nausea was defined as a maximum nausea score greater than or equal to 1 on the Likert
scale.
The proportion of subjects in the MITT population reporting nausea over 0–24 hours was
56% in the Zofran alone group and 49% in the casopitant group
(Source Data Table 7.21).
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Significant nausea (0–24 hours)
Significant nausea was defined as a maximum nausea score greater than or equal to 3 on
the Likert scale.
The proportion of subjects in the MITT population reporting significant nausea over
0-24 hours was 49% in the Zofran alone group and 42% in the casopitant group
Maximum nausea severity on the categorical scale (0–24 hours)
There appeared to be a smaller proportion of subjects in the casopitant group reporting

severe nausea as measured by the categorical scale over 0–24 hours in the MITT
population, compared with the Zofran alone group (Table 18).
Table 18 Summary of proportion of subjects with nausea (categorical scale)

0–24 hours (Modified Intent-to-Treat population)

(+ Zofran)
Nausea (categorical score) N=235 N=233
n/N (%) n/N (%)
Nausea category (0–24)
None 107/235 (46) 124/233 (53)
Mild 42/235 (18) 38/233 (16)
Moderate 48/235 (20) 51/233 (22)
Severe 38/235 (16) 20/233 (9)
Stratification (for the ‘none’ category)

7.2.1.4. Total control (0–24 hours)
Total control was defined as no vomiting or retching, no rescue therapy and no nausea
(maximum nausea score <1 on the Likert scale).
Total control over 0–24 hours was achieved by 40% of subjects in the Zofran alone group
and 46% in the casopitant group (MITT population) (Source Data Table 7.8).
7.2.2. Efficacy in Other Time Periods
Formal hypothesis testing was not performed for the other time periods, and analysis
results are presented for descriptive purposes only.
For the 24–48 hour endpoints, subject outcomes were calculated on the basis of events
occurring within this time period, without regard for the experience of subjects in prior
time periods.
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7.2.2.1. Complete response
Complete response over 24–48 hours in the MITT population is summarized in Table 19.


(+ Zofran)
n/N (%) n/N (%)

Complete response over 0–48 hours in the MITT population is summarized in Table 20.


(+ Zofran)
n/N (%) n/N (%)

7.2.2.2. No vomiting
No vomiting over 24–48 hours was reported by 95% of subjects in the Zofran alone
group and 98% in the casopitant group (MITT population) (Source Data Table 7.12).
No vomiting over 0–48 hours was reported by 73% of subjects in the Zofran alone group
and 88% in the casopitant group (MITT population) (Source Data Table 7.13).
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7.2.2.3. Complete protection
Complete protection over 24–48 hours was achieved by 60% of subjects in the Zofran
alone group and 65% in the casopitant group (MITT population) (Source Data Table 7.6).
Complete protection over 0–48 hours was achieved by 41% of subjects in the Zofran
alone group and 47% in the casopitant group (MITT population) (Source Data Table 7.7).
7.2.2.4. Nausea
Maximum nausea score on the Likert scale
Nausea
Nausea was reported by 23% of subjects in the Zofran alone group and 23% in the
casopitant group over 0–2 hours (Source Data Table 7.19), and by 40% in the Zofran
alone group and 36% in the casopitant group over 0–6 hours (Source Data Table 7.20)
(MITT population).
Nausea was reported by 15% of subjects in the Zofran alone group and 18% in the
(MITT population).
Significant nausea
Significant nausea was reported by 18% in the Zofran alone group and 21% in the
casopitant group over 0–2 hours (Source Data Table 7.14) and by 35% in the Zofran
(MITT population).
Significant nausea was reported by 13% in the Zofran alone group and 16% in the
(MITT population).
Maximum nausea severity on the categorical scale
Nausea as measured by the categorical scale is summarized over 24–48 hours in Source
Data Table 7.28 and over 0–48 hours in Source Data Table 7.29 (MITT population).
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7.2.2.5. Total control
Total control was achieved by 60% of subjects in the Zofran alone group and 64% in the
(MITT population).
7.3. Other Efficacy Results
7.3.1. Time to event endpoints
Time to first emetic episode
Time to first emetic episode was different between the Zofran alone group and the
casopitant group, with the first emetic episode occurring later in the casopitant group
(Source Data Table 7.30). The hazard ratio for emesis was 0.414, with a confidence
interval from 0.265 to 0.646. The hazard ratio is the risk of emesis at any given time,
relative to the risk of the subjects who received only Zofran (Source Data Table 7.38).
Kaplan-Meier curves for time to first emetic episode are presented in Figure 1.
episode
Chi-square p value=0.0001
Time to first rescue medication use
No difference was observed in the time to first rescue medication use

(Source Data Table 7.31). The hazard ratio for rescue was 0.841, with a confidence
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interval from 0.606 to 1.167. The hazard ratio is the risk of rescue at any given time,
relative to the risk of the subjects who received only Zofran (Source Data Table 7.39).
Kaplan-Meier curves for time to first rescue medication use are presented in Figure 2.
medication
Chi-square p value= 0.2998
Time to first complete response failure
In a post-hoc analysis, Kaplan-Meier curves were produced for time to first complete
response failure (Figure 3). The trend was as expected, and was consistent with the
overall clinical conclusion of benefit of casopitant plus Zofran over Zofran alone.
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Figure 3 Kaplan-Meier curves for time from last suture/staple to first

complete response failure
7.3.2. Rescue
Rescue medication use was reported by 31% of subjects in the Zofran alone group and
26% in the casopitant group over 0–24 hours (Source Data Table 7.34), by 6% in both
groups over 24–48 hours (Source Data Table 7.35), and by 33% in the Zofran alone
group and 29% in the casopitant group over 0–48 hours (MITT population)
7.4. Efficacy Conclusions
• The statistical and clinical superiority of single dose oral casopitant 50mg, in
combination with Zofran 4mg IV, over Zofran alone was demonstrated for the
following endpoints over 0–24 hours:
• Complete response (defined as no vomiting or retching and no rescue therapy).
A significant increase of 10% (in absolute terms) was observed (69% vs. 59%;
odds ratio 1.54; 95% confidence interval 1.05, 2.25).
• No vomiting. A significant increase of 15% (in absolute terms) was seen (90%
vs. 75%).
• No significant difference was seen between the casopitant group (52%) and the
Zofran alone group (43%) for complete protection (defined as complete response
with no significant nausea) over 0–24 hours; therefore, hypothesis testing was
stopped at this point.
• Mean (standard deviation) maximum Likert scale nausea score 0–24 hours was
3.2 (3.4) in the Zofran alone group and 2.6 (3.2) in the casopitant group.
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• Total control over 0–24 hours (defined as complete response with no nausea) was
achieved by 40% of subjects in the Zofran alone group and 46% in the casopitant
group.
• Nausea on the categorical scale: over 0–24 hours, severe nausea was reported by
16% of subjects in the Zofran alone group and 9% in the casopitant group.
• Complete response was achieved by 63% of subjects in the Zofran alone group and
70% in the casopitant group over 24–48 hours, and by 57% and 65%, respectively,
over 0-48 hours.
• Time to first emetic episode was greater in the casopitant group than in the Zofran
alone group.
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8. SAFETY RESULTS
8.1. Extent of Exposure

Of the 472 subjects in the Safety population, 237 subjects were randomized in the Zofran
alone group, and 235 subjects in the casopitant group. Three subjects in the Zofran alone
group and two in the casopitant group received investigational product, but were not
recorded as having received Zofran study medication
8.2. Adverse Events
8.2.1. Adverse Events Irrespective of Causality
One hundred and eighty-two subjects (39%) had at least one AE reported during the
study. The most frequently reported AE irrespective of causality was constipation, which
occurred in 25 subjects overall (5%). Adverse event profiles were similar in the two
treatment groups (Table 21). In particular, liver function test abnormalities were reported
as AEs in a similar proportion of subjects in each group. Fifteen subjects had increased
AST, ALT, transaminases or abnormal liver function test reported as an AE: seven in the
Zofran alone group and eight in the casopitant group. (All subjects with an AE of
increased ALT also had increased AST.)
However, constipation and hypotension were reported in a greater proportion of subjects

in the casopitant group than in the Zofran alone group. Twenty-seven subjects (6%) had
hypotension or procedural hypotension reported as an AE: 10 subjects in the Zofran alone
group and 17 in the casopitant group. Hypotension AEs included verbatim terms of
“hypotension” and “peri-operative hypotension”, while procedural hypotension AEs
related to the verbatim term “intra-operative hypotension”. Because peri-operative
events may have occurred before, during or after surgery, and the exact time of
hypotension was not recorded, it was thought more appropriate to look at the hypotension
and procedural hypotension events in combination, rather than considering them as
distinct events. None of these was classed as an SAE. Vital signs values of interest in
these subjects are presented in Section 8.7.
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Table 21 Adverse events irrespective of causality reported in greater than 1%

of subjects in either treatment group (Safety population)

(+ Zofran)
Adverse events N=237 N=235
n (%) n (%)
Any event 87 (37) 95 (40)
Constipation 8 (3) 17 (7)
Flatulence 12 (5) 11 (5)
Hypotension 8 (3) 15 (6)
Headache 11 (5) 8 (3)
Anemia 5 (2) 6 (3)
Cough 5 (2) 5 (2)
Insomnia 4 (2) 6 (3)
Nausea 4 (2) 6 (3)
Pruritus 5 (2) 4 (2)
Urinary retention 3 (1) 5 (2)
ALT increased 4 (2) 3 (1)
AST increased 4 (2) 3 (1)
Hypertension 5 (2) 2 (<1)
Diarrhea 4 (2) 2 (<1)
Transaminases increased 2 (<1) 4 (2)
Procedural hypotension 1 2 (<1) 2 (<1)
Liver function test abnormal 1 1 (<1) 1 (<1)
1. Included in the table to present a more complete picture of hypotension and liver function test abnormalities.
Note: during the 48-hour assessment phase, episodes of nausea or emesis that resulted in the administration of
rescue medication were considered treatment failures rather than AEs or SAEs and were captured in the assessments
of emesis and nausea in the Subject Diary, unless the severity was greater than expected.
ALT=alanine aminotransferase; AST=aspartate aminotransferase.
8.2.2. Adverse Events by Relationship to Investigational Product
Twenty-seven subjects (6%) had at least one AE that was considered possibly related to
the investigational product by the investigator, with similar profiles in both treatment
groups (Table 22).
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Table 22 Adverse events possibly related to investigational product reported

in at least 1% of subjects in either treatment group (Safety
population)

(+ Zofran)
Related adverse events N=237 N=235
n (%) n (%)
Any event possibly related to
investigational product 13 (5) 14 (6)
Alanine aminotransferase increased 4 (2) 2 (<1)
Aspartate aminotransferase increased 3 (1) 2 (<1)
Dizziness 1 (<1) 3 (1)
Headache 3 (1) 0
Adverse events possibly related to investigational product that were reported in less than
1% of subjects in each treatment group were as follows (Source Data Table 8.3):
• Zofran alone group: blood alkaline phosphatase increased, blood glucose increased,
diarrhea, liver function test abnormal, nausea.
• Casopitant group: blood alkaline phosphatase increased, liver function test
abnormal, nausea.
8.2.3. Adverse Events by Intensity
The majority of AEs were of mild or moderate intensity, and the treatment groups were
balanced with regard to AE profile by intensity. Twelve subjects in the study (3%)
experienced at least one AE of severe intensity, six subjects in each group. The most
frequently reported AEs of severe intensity were constipation, occurring in two subjects
(<1%) in the casopitant group; and musculoskeletal pain, occurring in one subject (<1%)
in each group (Source Data Table 8.6).
8.3. Serious Adverse Events
8.3.1. Deaths
There were no fatal SAEs reported in this study.
8.3.2. Non-Fatal Serious Adverse Events
Eleven subjects (2%) had at least one SAE reported in this study (Table 23). Narratives
are presented in Section 12. None of the SAEs was considered related to the
investigational product by the investigator.
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Table 23 Summary of all subjects with serious adverse events irrespective of

causality (in alphabetical order) (Safety population)

(+ Zofran)
Serious adverse events N=237 N=235
n (%) n (%)
Any serious adverse event 7 (3) 4 (2)
Chest pain 0 1 (<1)
Colon injury 1 (<1) 0
Constipation 0 1 (<1)
Deep vein thrombosis 1 (<1) 0
Dysfunctional uterine bleeding 1 (<1) 0
Dyspnea 0 1 (<1)
Ileus paralytic 1 (<1) 0
Musculoskeletal pain 0 1 (<1)
Ovarian adenoma 1 (<1) 0
Pain in jaw 0 1 (<1)
Pulmonary embolism 1 (<1) 1 (<1)
Spondylolisthesis 0 1 (<1)
Ureteric obstruction 1 (<1) 0
Urinary tract infection 1 (<1) 0
8.4. Adverse Events Leading to Premature Discontinuation of

Investigational Product and/or Study
There were no AEs leading to premature discontinuation.
8.5. Pregnancies
Data on pregnancy status were available for 273 of 472 subjects. One subject in the
Zofran alone group was reported to have become pregnant during the study, however,
there was an error in the eCRF, and the subject in question was not in fact pregnant. No
pregnancies were reported in the casopitant group (Source Data Table 8.14).
8.6. Clinical Laboratory Evaluations
8.6.1. Laboratory Values Over Time
No meaningful differences in mean or median hematology or clinical chemistry values

were observed between the two treatment groups (Source Data Table 8.8 and Table 8.11).
Elevations in liver function test parameters for individual subjects are detailed in Section
8.6.2. Mean and median values for the clinical chemistry parameters ALT, AST and total
bilirubin are summarized in Table 24. No meaningful differences were observed for
these parameters among the two treatment groups.
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Table 24 Summary of laboratory values for selected parameters (Safety

population)

Laboratory test (+ Zofran)
Visit N=237 N=235
Alanine aminotransferase (IU/L)
Pre-surgical Baseline n 235 229
Mean (SD) 21.3 (9.36) 22.1 (13.71)
Median [range] 19.0 [6.0–69.0] 18.0 [5.0–108.0]
Postoperative Day 1–2 n 220 222
Mean (SD) 26.7 (35.38) 25.1 (19.50)
Median [range] 19.0 [4.0–332.0] 18.0 [5.0–137.0]
Mean (SD) 26.3 (24.58) 30.1 (27.58)
Median [range] 19.0 [6.0–227.0] 20.5 [4.0–239.0]
Aspartate aminotransferase (IU/L)

Mean (SD) 21.9 (6.72) 21.4 (7.18)
Median [range] 21.0 [10.9–57.0] 21.0 [9.0–58.0]
Mean (SD) 29.8 (38.84) 26.3 (17.36)
Median [range] 21.0 [6.0–383.0] 21.0 [5.0–139.0]
Mean (SD) 24.4 (16.81) 25.2 (17.73)
Median [range] 20.6 [9.0–200.0] 20.0 [8.0–182.0]
Total bilirubin (µmol/L)

Mean (SD) 9.0 (4.59) 9.6 (5.30)
Median [range] 8.6 [0.0–31.1] 8.6 [0.0–38.5]
Mean (SD) 10.8 (5.92) 11.7 (6.52)
Median [range] 9.9 [0.0–33.6] 10.3 [0.0–55.2]
Mean (SD) 7.3 (3.65) 8.0 (4.23)
Median [range] 6.8 [0.0–20.5] 7.1 [0.0–27.2]
SD=standard deviation.
8.6.2. Individual Subject Changes in Liver Function Tests
Across both treatment groups, 11 subjects had ALT elevations (ALT values ≥3x ULN):
five subjects (2.1%) in the Zofran alone group, and six subjects (2.6%) in the casopitant
group. Nine subjects had AST elevations (AST values ≥3x ULN): seven subjects in the
Zofran alone group and two subjects in the casopitant group. Five subjects in the Zofran
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alone group and one subject in the casopitant group had both ALT and AST values
≥3x ULN (Source Data Table 8.18).
These out-of-
range chemistry values were not reported as an AE.
. Laboratory values of interest are presented

in Table 25.
Table 25 Laboratory values of interest in Subject

ULN=upper limit of the normal range.
Ten additional subjects had ALT values ≥3x ULN reported (Table 26). Five of these
subjects also had an AST value ≥3x ULN. None of the subjects had a concomitant total
bilirubin value ≥1.5x ULN.
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Table 26 Other subjects with alanine aminotransferase values of interest
Source Data: Table 8.18 and Data on File

1. ALT value ≥3x ULN.
2. Value associated with an adverse event.
3. Concomitant AST value ≥3x ULN.
Adverse events associated with elevated liver enzymes (see also Section 8.2.1) were
reported in two of these subjects, one in the casopitant group and one in the Zofran alone
group, as follows:
• Casopitant group:
• Zofran alone group:
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8.6.3. Clinical Laboratory Values Outside the Reference Range
For a number of chemistry laboratory parameters, the proportion of subjects with values
outside the reference range was increased at the postoperative Day 1/2 visit in both
treatment groups and had diminished at the postoperative Day 6–14 visit
(Source Data Table 8.9). For ALT, AST and total bilirubin in particular, the proportion
of subjects with elevated values was increased at the postoperative Day 1/2 visit, but no
notable differences were observed between the two treatment regimens (Table 27).
Table 27 Proportion of subjects with laboratory values above the reference

range for selected parameters (Safety population)

(+ Zofran)
Laboratory test N=237 N=235
Visit n/N (%) n/N (%)
Alanine aminotransferase
Pre-surgical Baseline 9/235 (4) 14/229 (6)
Postoperative Day 1/2 29/232 (13) 26/232 (11)
Postoperative Day 6–14 28/232 (12) 35/226 (15)
Aspartate aminotransferase
Postoperative Day 6–14 27/232 (12) 33/226 (15)
Total Bilirubin
Postoperative Day 6–14 1/232 (<1) 6/226 (3)
8.6.4. Laboratory Values of Potential Clinical Concern
Laboratory parameters for subjects with abnormalities of potential clinical concern

(CTCAE grades of 2, 3 and 4) are presented in Source Data Table 8.18. The number of
subjects reporting abnormalities was similar in both treatment groups. The abnormal
laboratory values reported in the greatest proportion of subjects were as follows:
• Decreased albumin: 63 subjects, 36 in the Zofran alone group and 27 in the

casopitant group.
• Decreased hemoglobin: 62 subjects, 29 in the Zofran alone group and 33 in the
casopitant group.
8.6.5. Shifts in National Cancer Institute Common Terminology Criteria

Grading from Baseline
Only one subject had a hematology toxicity shift to Grade 4 reported, a decreased
hemoglobin value following Zofran alone (baseline grade was zero). There were no
hematology toxicity shifts to Grade 4 reported in the casopitant group
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(Source Data Table 8.13). There were no clinical chemistry toxicity increases to Grade 4
reported in either group (Source Data Table 8.10). In addition to the tabulations for high
threshold values, a review of listings for low threshold values revealed three additional
clinical chemistry shifts to Grade 4:
• Two Grade 4 low glucose values, one in the Zofran alone group (from a baseline of
Grade 2), and one in the casopitant group (from a baseline of Grade 0);
• One Grade 4 low sodium value in the Zofran alone group (from a baseline of
Grade 0).
8.7. Other Safety Evaluations

No notable differences were observed between treatment groups with regard to median or
mean vital signs values (systolic blood pressure, diastolic blood pressure, respiration rate
and heart rate) at any of the time points tested. As might be expected in a surgical
population, modest decreases in mean systolic and diastolic blood pressures were
observed in both treatment groups at the postoperative Day 1 visit
Adverse events of hypotension or procedural hypotension were reported in 10 subjects in

the Zofran alone group and 17 subjects in the casopitant group (Section 8.2.1). Of these
27 subjects, seven (two in the Zofran alone group and five in the casopitant group) had
values of diastolic blood pressure less than 60mmHg recorded in the eCRF. None of
these subjects had a systolic blood pressure value less than 90mmHg recorded in the
eCRF (Table 28). None of these subjects had an SAE reported.
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Table 28 Vital signs values of interest in subjects with hypotension or

procedural hypotension reported as an adverse event

1. Recorded on day of AE onset.
2. Verbatim term for AE: ‘hypotension 85/51’.
3.
Pre/peri-op=pre/peri-operatively; Post-op=postoperatively; SBP=systolic blood pressure; DBP=diastolic blood
pressure.
Clinically significant abnormal ECG findings were reported in less than 1% of subjects.
At Screening, one subject in the casopitant group had a clinically significant abnormal
ECG finding. On Postoperative Day 1/2, two subjects in the casopitant group had a
clinically significant abnormal ECG finding, and none in the Zofran alone group
Median (range) time to awakening after surgery was 12.5 (0–130) minutes in the Zofran
alone group and 11.9 (0–1394) minutes in the casopitant group (Source Data Table 8.16).
The value of 1394 minutes was thought to have been recorded in the eCRF in error.
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8.8. Safety Conclusions
• Casopitant was well tolerated when administered as a single 50mg oral dose in
combination with Zofran 4mg IV in surgical subjects predicted to have a high risk of
emesis.
• No deaths were reported. Serious adverse events were reported in 11 subjects, with
similar numbers in both groups. None of the SAEs was considered related to the
investigational product by the investigator.
• Adverse event profiles were similar in the two treatment groups. However,
constipation and hypotension appeared to be reported in a greater proportion of
subjects in the casopitant group (constipation – 7%; hypotension – 6%) than in the
Zofran alone group (3% for both events).
• There were no notable differences in clinical laboratory values (hematology and
clinical chemistry) nor in vital signs and ECG among treatment groups.
• Median time to awakening was similar in the Zofran alone and casopitant groups.
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9. HEALTH OUTCOMES RESULTS
9.1. Subject Satisfaction

Subject satisfaction over 0–48 hours appeared to be similar in the two treatment groups
(Table 29).
Table 29 Summary of subject satisfaction 0–48 hours (Modified Intent-to-Treat

population)

(+ Zofran)
Subject satisfaction N=235 N=233
n (%) n (%)
Very satisfied 147 (63) 158 (68)
Somewhat satisfied 44 (19) 41 (18)
Neither satisfied nor dissatisfied 19 (8) 14 (6)
Somewhat dissatisfied 6 (3) 3 (1)
Very dissatisfied 8 (3) 7 (3)
9.2. Subject Willingness to Use Same Regimen for Future

Procedures
Subject willingness to use the same regimens for future surgical procedures appeared to
be similar in the two treatment groups (Table 30).
Table 30 Summary of subject willingness to use the same regimens for future
surgical procedures 0–48 hours (Modified Intent-to-Treat population)

(+ Zofran)
Subject willingness N=235 N=233
n (%) n (%)
Definitely would be willing 134 (57) 136 (58)
Probably would be willing 59 (25) 63 (27)
Not certain 14 (6) 13 (6)
Probably would not be willing 9 (4) 4 (2)
Definitely would not be willing 8 (3) 7 (3)
9.3. Medical Resource Utilization

There appeared to be a greater proportion of subjects with unscheduled healthcare-related
contacts in general in the Zofran alone group (5.0%) than in the casopitant group (2.1%).
However, it should be noted that in the casopitant group, there was an apparent error in
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recording, as more contacts due to AE (seven subjects, 2.9%) were reported than the total
number of contacts (five subjects, 2.1%) (Source Data Table 7.37).
9.4. Health Outcomes Conclusion
• Subject satisfaction and subject willingness to use the same regimens for future
surgical procedures were similar across treatment groups.
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10. DISCUSSION AND CONCLUSIONS
10.1. Discussion
Despite therapeutic advances, PONV remains the most common patient complaint
following surgery under general anesthesia [Gupta, 2003]. Postoperative nausea and
vomiting causes patient discomfort and anxiety and may lead to post-surgical
complications such as fluid and electrolyte imbalance, surgical wound dehiscence, and
aspiration of vomitus. Postoperative nausea and vomiting may delay discharge from the
recovery area and result in unscheduled hospital admissions. Casopitant, a potent and
selective NK-1 receptor antagonist, is in development for the prevention of PONV and
CINV. Zofran (ondansetron hydrochloride) and other 5-HT3 receptor antagonists are
currently considered a standard of care for prevention of PONV [Zofran Prescribing
Information, 2005; Gan, 2003].
The primary objective of this Phase III, multicenter, randomized, double-blind, active-
controlled, two arm parallel group study was to demonstrate the superiority of casopitant
50mg in combination with Zofran 4mg IV (both given as a single dose) over Zofran alone
in the control of emesis during the first 24 hours following surgery under general
anesthesia.
The study population consisted of subjects at high risk of PONV as determined by the
Apfel Simplified Risk Score [Apfel, 2002]. In these patients, PONV is anticipated to
occur in up to 80% of cases in the absence of effective antiemetic therapy. In addition,
eligible surgeries were restricted to those associated with high risk of PONV [Apfel,
2002]. Thus, the subjects included in this study represented patients with the highest risk
for PONV, and the greatest likelihood of benefiting from enhanced antiemetic therapy.
The selection of the 50mg oral dose of casopitant was based on the results of a GSK
Phase II PONV dose-rising study in 702 female subjects [GlaxoSmithKline Document
Number ZM2005/00131/00] which showed that oral casopitant at doses of 50, 100, and
150mg in combination with ondansetron hydrochloride resulted in a clinically and
statistically significant increase in the number of subjects who experienced a complete
response during the first 24 hours after emergence from general anesthesia. All active
doses appeared to be well tolerated. In this Phase II study, pharmacokinetic/
pharmacodynamic analyses showed that the proportion of subjects achieving complete
response did not differ with casopitant or GSK525060 (metabolite) exposure over the
dose range of 50–150mg.
Four hundred and sixty-eight subjects were included in the MITT population of this
study, defined as subjects who received investigational product/study medication and had
surgery. The primary endpoint of complete response, defined as no vomiting, no retching
and no rescue therapy during the first 24 hours following the placement of last suture/last
staple, was achieved in a significantly greater proportion of subjects in the casopitant
group (69%) compared with the Zofran alone group (59%) for the primary efficacy
(MITT) population (p<0.05). This difference was considered clinically significant. A
similar difference (9% absolute treatment difference) was seen in the supportive analysis
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of the ITT population, which was defined as all subjects who were randomized to
treatment. Thus, superiority was demonstrated for casopitant in combination with
Zofran, over Zofran alone for the control of emesis in the PONV setting. Although the
proportion of subjects achieving a complete response was higher than anticipated in the
sample size calculations (which had assumed a 40% complete response rate for the
Zofran alone group at 24 hours), a statistically significant difference was still
demonstrated.
A possible explanation for the higher than anticipated complete response rate in the
Zofran alone group is that many of the surgeries were of shorter duration than expected
and anesthesia times were less than the 1 hour duration required by the protocol.
Duration of surgery has been shown to correlate with PONV risk [Apfel, 2002]. In this
study, anesthesia duration ≤45 minutes was the most frequently reported major protocol
deviation, occurring in 19% of subjects in each group. In addition, there were differences
between the entry criteria for the Phase II studies and the present study. There was no
upper age limit in the present study, and subjects were not required to be pre- or peri-
menopausal (a possible risk factor) as in Phase II. Also, the definition of non-smoker
was relaxed: Phase II required that patients never smoked or had not smoked for 12
consecutive months while in Phase III the time frame was 6 months and subjects were
permitted 2 or less cigarettes per week. Anesthetic regimens were specified in Phase II
but were only required to be “balanced-general” according to institutional practices in the
present study. All of the above factors would tend to increase the proportion of subjects
achieving complete response [Watcha, 1992; Apfel, 2002].
If the primary analysis yielded a significant finding, secondary hypotheses were to be

tested hierarchically in the following order: no vomiting; complete protection (complete
response with no significant nausea); maximum nausea score; and total control (complete
response without any nausea). These were tested until a hypothesis failed to meet
significance. Once this point had been reached, all subsequent hypotheses were not
tested.
A clinically and statistically significant decrease of 15% (in absolute terms) was seen in
the proportion of subjects reporting vomiting in the casopitant group compared with
Zofran alone. Addition of casopitant to Zofran increased the proportion of subjects who
were free from vomiting in the 0–24 hour time period from 75% in the Zofran alone
group to 90% in the casopitant group.
Although a positive trend in favor of the casopitant group was observed, a significant
difference was not seen between the casopitant group (52%) and the Zofran alone group
(43%) for complete protection over 0–24 hours. Therefore, hypothesis testing stopped
here at the second level and was not carried out for the third and fourth endpoints in the
hierarchy (nausea and total control, respectively).
There was no apparent difference between treatment groups in the number and
percentage of subjects who experienced any nausea or significant nausea. No treatment
difference was observed for the proportion of subjects experiencing nausea as measured
on the 11-point, linear, numerical rating scale referred to as the “Likert scale” during the
2, 6, 24 and 48 hour periods. However, analysis of the severity of nausea measured on
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the categorical scale over 24 hours suggested that subjects in the Zofran alone group had
a greater frequency of severe nausea than those in the casopitant group (16% vs. 9%).
No treatment difference was apparent for total control over 0–24 hours; but again, a
positive trend in favor of the casopitant group was seen (46% vs. 40% of subjects).
Outcomes for the 24–48 hour endpoints were determined based on events occurring
within this time period independent of the subject’s experience in the 0–24 hour time
period. The proportion of subjects achieving complete response in the 24–48 hour time
period did not reach statistical significance (63% in the Zofran alone group and 70% in
the casopitant group). The proportion of subjects achieving complete response was not
statistically significant over the 0–48 hour period following completion of surgery, but
trended favorably (57% in the Zofran alone group and 65% in the casopitant group).
Therefore, the benefit of casopitant treatment appeared to persist over the 48 hours,
although was statistically significant only for the first 24-hour time period.
Conflicting evidence on the emetogenic effect of nitrous oxide exists in the literature.
Nitrous oxide is generally considered to be emetogenic, especially when administered in
combination with opioid analgesics [Sinclair, 1999]. However, other reports show that
nitrous oxide does not lead to increased emesis when given as an adjuvant to halogenated
anesthetics [Watcha, 1992]. In this study, subjects were required to receive “balanced
general anesthesia” which in almost all cases included a halogenated anesthetic, and
almost all subjects received opioids as well. Nitrous oxide use was expected to vary
among different surgical centers and across the geographic regions participating in the
study; therefore, a decision was made to stratify randomization based on nitrous oxide
administration in order to minimize any potential effect of nitrous oxide on outcome. As
randomization occurred prior to surgery, actual intra-operative nitrous oxide use could
not be used as the stratification factor, and anticipated nitrous oxide administration was
used instead. The results do not appear to indicate that nitrous oxide (based on
anticipated use) had an emetogenic effect in this setting, as both control (Zofran alone)
and experimental (casopitant) groups had higher complete response rates observed in the
nitrous oxide anticipated stratum. In the casopitant group, the complete response rate
was 16% higher in subjects anticipated to receive nitrous oxide than in those who were
not, but the significance of the difference was not tested statistically. Improvement in
complete response rate was observed with casopitant in both nitrous oxide (anticipated
and not anticipated) strata, however, the improvement appeared to be greater in the
nitrous oxide anticipated subjects.
Casopitant 50mg in combination with Zofran 4mg IV was well tolerated in this study.
Adverse event profiles were similar in the two treatment groups, but hypotension/
procedural hypotension was reported in a smaller proportion of subjects in the Zofran
alone group (4%) than in the casopitant group (7%). Constipation was the single most
frequently reported AE, occurring in 3% of subjects in the Zofran alone group and 7% in
the casopitant group.
There were no deaths in this study. Eleven subjects (2%) had non-fatal SAE(s) reported,
3% of subjects in the Zofran alone group and 2% in the casopitant group. None of these
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SAEs was considered related to investigational product/study medication by the

investigator. There were no AEs leading to premature discontinuation from study.
There were no notable differences in clinical laboratory hematology and biochemistry or

in vital signs and ECG among treatment groups. Across both treatment groups, several
subjects had ALT elevations (ALT values ≥3x ULN) (2.1% in the Zofran alone group
and 2.6% in the casopitant group). Two of these subjects, one in each group, had
elevated liver enzymes reported as an AE. Factors other than exposure to casopitant are
thought to be responsible for the observed ALT elevations as they were balanced in
frequency across the two treatment arms and they occurred within 1 day post-dosing,
which is atypical for drug-related liver injury (aside from acetaminophen). Other
confounding factors were present as well, such as concomitant medications, volatile
anesthetics and postoperative complications.
Subject satisfaction and subject willingness to use the same regimens for future surgical
procedures were similar across treatment groups.
The results of this pivotal Phase III study demonstrate the efficacy and tolerability of the
50mg oral casopitant dose, in combination with Zofran 4mg IV, in subjects at high risk of
PONV.
10.2. Conclusions
vs. 75%).
Zofran alone group (43%) for complete protection (defined as complete response
with no significant nausea) over 0–24 hours; therefore, hypothesis testing was
stopped at this point.
• No treatment difference was apparent for the nausea or total control (defined as
complete response with no nausea) endpoints over 0–24 hours.
emesis.
biochemistry) nor in vital signs and ECG among treatment groups.
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Naguib M, El Bakry AK, Khoshim MH, Channa AB, El Gammal M, El Gammal K, et

al. Prophylactic antiemetic therapy with ondansetron, tropisetron, granisetron and
metoclopramide in patients undergoing laparoscopic cholecystectomy: a randomized,
double-blind comparison with placebo. Can J Anaesth. 1996;43:226-231.
Pierre S, Benais H, Pouymayou J. Apfel’s simplified score may favourably predict the
risk of postoperative nausea and vomiting. Can J Anaesth. 2002;49:237-242.
Sinclair DR, Chung F, Mezei G. Can postoperative nausea and vomiting be predicted?
Anesthesiology. 1999;91(1):109-118.
Wang JJ, Ho ST, Uen YH, Lin MT, Chen KT, Huang JC, et al. Small dose
dexamethasone reduces nausea and vomiting after laparoscopic cholecystectomy: a
comparison of tropisetron with saline. Anesth Analg. 2002;95:229-232.
Watcha MF, White PF. Postoperative nausea and vomiting: its etiology, treatment, and
prevention. Anesthesiology. 1992:77;162-184.
White PF, Tang J, Hamza MA, Ogunnaike B, Lo M, Wender RH, et al. The use of oral
granisteron versus intravenous ondansetron for antiemetic prophylaxis in patients
undergoing laparoscopic surgery: the effect on emetic symptoms and quality of recovery.
Anesth Analg. 2006;102:1387-1393.
Zofran (ondansetron hydrochloride) Product Information. May, 2005.
85
82
This section contained patient narratives which are textual descriptions of medical history,
treatment and outcome for individual patients who experienced a clinically important adverse
event including serious adverse events during the trial. They have been excluded to protect
patient privacy. This data may be made available subject to an approved research proposal and
a determination of the ability to provide information from the specific narratives whilst protecting
the patient’s privacy. For further information please see the Patient Level Data section of
the GSK Clinical Study Register.
NKT102553
STUDY POPULATION DATA SOURCE TABLES
Page
Table 6.1 Summary of Recruitment (Intent-to-Treat Population) . . . . . . . . . . 98
Table 6.2 Summary of End of Study Record (Intent-to-Treat Population). . . . 101
Table 6.3 Summary of Inclusion/Exclusion Criteria Deviations
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Table 6.4 Summary of Demographic Characteristics (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Table 6.5 Summary of Race and Racial Combinations (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
Table 6.6 Summary of Race and Racial Combination Details
Table 6.7 Summary of ASA Physical Status Classification (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
Table 6.8 Summary of Current Medical Conditions (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Table 6.9 Summary of Surgery Type (Intent-to-Treat Population) . . . . . . . . . 109
Table 6.10 Summary of Surgery Time (Intent-to-Treat Population) . . . . . . . . 121
Table 6.11 Summary of Peri-operative Medications (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
Table 6.12 Summary of Concomitant Medications (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
Table 6.13 Summary of Anti-emetic Rescue Medications taken during
Entire Study (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . 155
Table 6.14 Summary of Treatment Compliance (Intent-to-Treat Population) . 158
Table 6.15 Summary of Major Protocol Deviations (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Table 6.16 Listing of Current Medical Conditions (Nervous System
Disorders Only) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . 161
Table 6.99 Listing of Selected Antiemetic Rescue Medication
97
Protocol: NKT102553 Page 1 of 3
Population: Intent-to-Treat
Table 6.1
Summary of Recruitment
4mg IV Zofran +
50mg Oral
4mg IV Zofran Casopitant
(N=242) (N=242)
-----------------------------------------------
Canada
0 2 (<1%)
1 (<1%) 1 (<1%)
4 (2%) 5 (2%)
12 (5%) 8 (3%)
2 (<1%) 5 (2%)
Total 19 (8%) 21 (9%)
CONFIDENTIAL
France
0 1 (<1%)
1 (<1%) 0
98
0 1 (<1%)
1 (<1%) 0
Total 2 (<1%) 2 (<1%)
Germany
8 (3%) 10 (4%)
0 2 (<1%)
Total 8 (3%) 12 (5%)
Hong Kong
2 (<1%) 5 (2%)
6 (2%) 8 (3%)
GM2006/00652/00
Total 8 (3%) 13 (5%)
Hungary
23 (10%) 27 (11%)
NKT102553
3 (1%) 2 (<1%)
1 (<1%) 3 (1%)
11 (5%) 11 (5%)
Total 38 (16%) 43 (18%)
Table 6.1
4mg IV Zofran +
50mg Oral
(N=242) (N=242)
-----------------------------------------------
Ireland
3 (1%) 3 (1%)
Total 3 (1%) 3 (1%)
Pakistan
3 (1%) 5 (2%)
Total 3 (1%) 5 (2%)
CONFIDENTIAL
Philippines
5 (2%) 2 (<1%)
99
10 (4%) 5 (2%)
Total 15 (6%) 7 (3%)
Thailand
20 (8%) 16 (7%)
Total 20 (8%) 16 (7%)
UK - CMD
1 (<1%) 1 (<1%)
1 (<1%) 1 (<1%)
Total 2 (<1%) 2 (<1%)
GM2006/00652/00
United States
12 (5%) 11 (5%)
1 (<1%) 1 (<1%)
6 (2%) 9 (4%)
NKT102553
7 (3%) 5 (2%)
0 1 (<1%)
8 (3%) 8 (3%)
1 (<1%) 3 (1%)
Table 6.1
4mg IV Zofran +
50mg Oral
(N=242) (N=242)
-----------------------------------------------
7 (3%) 7 (3%)
8 (3%) 8 (3%)
1 (<1%) 1 (<1%)
3 (1%) 8 (3%)
23 (10%) 11 (5%)
6 (2%) 5 (2%)
19 (8%) 24 (10%)
2 (<1%) 2 (<1%)
CONFIDENTIAL
3 (1%) 2 (<1%)
6 (2%) 5 (2%)
3 (1%) 1 (<1%)
100
8 (3%) 6 (2%)
Total 124 (51%) 118 (49%)
GM2006/00652/00
NKT102553
Table 6.2
Summary of End of Study Record
4mg IV
Zofran +
4mg IV 50mg Oral
(N=242) (N=242) (N=484)
--------------------------------------------------------
Completion Status
Completed 229 (95%) 227 (94%) 456 (94%)
Prematurely 13 (5%) 15 (6%) 28 (6%)
Withdrawn
Primary reason for
withdrawal
Adverse Event 0 0 0
CONFIDENTIAL
Lost to follow-up 3 (1%) 4 (2%) 7 (1%)
Protocol violation 2 (<1%) 1 (<1%) 3 (<1%)
Subject decided to 1 (<1%) 4 (2%) 5 (1%)
101
withdraw from the

study
Lack of efficacy 0 0 0
Sponsor terminated 0 0 0
study
Other 7 (3%) 6 (2%) 13 (3%)
GM2006/00652/00
NKT102553
Table 6.3
Summary of Inclusion/Exclusion Criteria Deviations
4mg IV
Zofran +
4mg IV 50mg PO
Criterion (N=242) (N=242) (N=484)
---------------------------------------------------------------
Any criteria 1 (<1%) 3 (1%) 4 (<1%)
deviations
Inclusion criteria
Willing and expected 1 (<1%) 3 (1%) 4 (<1%)
to be able to complete
daily components of
CONFIDENTIAL
the subject diary
preoperatively on the
day of surg and until
102
the end of the 48 hour

assmnt period, and
return to the
GM2006/00652/00
NKT102553
Table 6.4
Summary of Demographic Characteristics
4mg IV Zofran +
50mg Oral
4mg IV Zofran Casopitant Total
--------------------------------------------------------------------
Age (y) n 237 235 472
Mean 44.8 44.4 44.6
SD 12.44 12.19 12.30
Median 44.0 44.0 44.0
Min. 18 18 18
Max. 79 83 83
Sex n 242 242 484

Female 242 (100%) 242 (100%) 484 (100%)
CONFIDENTIAL
Male 0 0 0
Ethnicity n 242 242 484

103
Hispanic 19 (8%) 22 (9%) 41 (8%)

or Latino
Not 223 (92%) 220 (91%) 443 (92%)
Hispanic
or Latino
Height n 241 239 480

Mean 161.3 162.8 162.0
SD 8.74 9.98 9.40
Median 161.0 162.0 162.0
Min. 79 65 65
Max. 183 194 194
GM2006/00652/00
Weight n 241 239 480
Mean 70.6 72.3 71.5
SD 17.05 17.55 17.30
NKT102553
Median 67.0 69.0 68.0
Min. 37 41 37
Max. 154 128 154
Table 6.5
Summary of Race and Racial Combinations
4mg IV
Zofran +
4mg IV 50mg Oral
(N=242) (N=242) (N=484)
-------------------------------------------------------------------------
Race N 236 (98%) 233 (96%) 469 (97%)
African American/African 20 (8%) 19 (8%) 39 (8%)
Heritage
American Indian or 0 0 0
Alaskan Native
American Indian or 1 (<1%) 1 (<1%) 2 (<1%)
Alaskan Native & White
CONFIDENTIAL
Asian 50 (21%) 46 (19%) 96 (20%)
Central/South Asian Her 5 (2%) 7 (3%) 12 (2%)
itage
104
Japanese Heritage/East 45 (19%) 39 (16%) 84 (17%)

Asian Heritage/South
East Asian Heritage
Native Hawaiian or Other 0 1 (<1%) 1 (<1%)
Pacific Islander
White 165 (68%) 166 (69%) 331 (68%)
GM2006/00652/00
NKT102553
Table 6.6
Summary of Race and Racial Combination Details
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------------------
Race n 236 (98%) 233 (96%) 469 (97%)
African American/African 20 (8%) 19 (8%) 39 (8%)
Heritage
American Indian or Alaskan 0 0 0
Native
Native Hawaiian or Other 0 1 (<1%) 1 (<1%)
Pacific Islander
Asian - Central/South Asian 5 (2%) 7 (3%) 12 (2%)
CONFIDENTIAL
Heritage
Asian - East Asian Heritage 10 (4%) 13 (5%) 23 (5%)
Asian - Japanese Heritage 0 2 (<1%) 2 (<1%)
105
Asian - South East Asian 35 (14%) 24 (10%) 59 (12%)

Heritage
Asian - Mixed Race 0 0 0
White - Arabic/North African 1 (<1%) 0 1 (<1%)
Heritage
White - 164 (68%) 166 (69%) 330 (68%)
White/Caucasian/European
Heritage
White - Mixed Race 0 0 0
Mixed Race 1 (<1%) 1 (<1%) 2 (<1%)
GM2006/00652/00
NKT102553
Table 6.7
Summary of ASA Physical Status Classification
4mg IV Zofran +
50mg Oral
ASA Physical Status 4mg IV Zofran Casopitant Total
Classification (N=242) (N=242) (N=484)
--------------------------------------------------------------------------
P1 (I) - A normal healthy 94 (39%) 87 (36%) 181 (37%)
patient
P2 (II) - A patient with mild 145 (60%) 152 (63%) 297 (61%)
systemic disease
P3 (III) - A patient with 2 (<1%) 1 (<1%) 3 (<1%)

severe systemic disease
CONFIDENTIAL
106
GM2006/00652/00
NKT102553
Table 6.8
Summary of Current Medical Conditions
4mg IV Zofran
+
50mg Oral
-------------------------------------------------------------------------------
Any Condition 231 (95%) 229 (95%) 460 (95%)
Blood and lymphatic system 25 (10%) 32 (13%) 57 (12%)

disorders
Cardiac disorders 66 (27%) 59 (24%) 125 (26%)
CONFIDENTIAL
Congenital, familial and genetic 1 (<1%) 0 1 (<1%)
disorders
107
Ear and labyrinth disorders 4 (2%) 5 (2%) 9 (2%)
Endocrine disorders 38 (16%) 33 (14%) 71 (15%)
Eye disorders 8 (3%) 9 (4%) 17 (4%)
Gastrointestinal disorders 49 (20%) 58 (24%) 107 (22%)
General disorders and 30 (12%) 34 (14%) 64 (13%)

administration site conditions
GM2006/00652/00
Hepatobiliary disorders 41 (17%) 45 (19%) 86 (18%)
Immune system disorders 71 (29%) 85 (35%) 156 (32%)
NKT102553
Injury, poisoning and procedural 3 (1%) 0 3 (<1%)
complications
Metabolism and nutrition disorders 37 (15%) 43 (18%) 80 (17%)

Table 6.8
Summary of Current Medical Conditions
4mg IV Zofran
+
50mg Oral
-------------------------------------------------------------------------------
Musculoskeletal and connective 41 (17%) 47 (19%) 88 (18%)
tissue disorders
Neoplasms benign, malignant and 30 (12%) 23 (10%) 53 (11%)

unspecified (incl cysts and polyps)
Nervous system disorders 36 (15%) 50 (21%) 86 (18%)
CONFIDENTIAL
Psychiatric disorders 31 (13%) 29 (12%) 60 (12%)
108
Renal and urinary disorders 20 (8%) 26 (11%) 46 (10%)
Reproductive system and breast 133 (55%) 142 (59%) 275 (57%)
disorders
Respiratory, thoracic and 27 (11%) 27 (11%) 54 (11%)

mediastinal disorders
Skin and subcutaneous tissue 6 (2%) 5 (2%) 11 (2%)

disorders
Vascular disorders 8 (3%) 11 (5%) 19 (4%)
GM2006/00652/00
NKT102553
Table 6.9
Summary of Surgery Type
4mg IV Zofran
+ 50mg PO
Surgery Type (N=242) (N=242) (N=484)
-------------------------------------------------------------------------------------
Any Surgical Procedure 235 (97%) 233 (96%) 468 (97%)
Left salpingo-oophorectomy 0 1 (<1%) 1 (<1%)
Bilateral Salpingo oophorectomy 0 1 (<1%) 1 (<1%)
CONFIDENTIAL
Posterior Repair with Gynemesh 0 1 (<1%) 1 (<1%)
ABDOMINAL COLPOSACROPEXY WITH MARLEX 0 1 (<1%) 1 (<1%)

109
MESH, VAGINAL ANTERIOR AND POSTERIOR

REPAIR
ABLATION OF ENDOMETRIOSIS 0 1 (<1%) 1 (<1%)
ADVANCED OPERATIVE LAPAROSCOPY 2 (<1%) 1 (<1%) 3 (<1%)
ADVANCED OPERATIVE LAPAROSCOPY WITH LEFT 1 (<1%) 0 1 (<1%)

OVARIAN CYSTECTOMY
Abdominoplasty 1 (<1%) 0 1 (<1%)
GM2006/00652/00
Advanced Operative Laparoscopy
Right 0 1 (<1%) 1 (<1%)
Salpingo-Oopherectomy
NKT102553
Advanced Operative Laparoscopy 0 2 (<1%) 2 (<1%)
BILATERAL SALPINGO-OOPHERECTOMY 3 (1%) 2 (<1%) 5 (1%)
Bilateral Salpingo Oopherectomy 0 1 (<1%) 1 (<1%)

Table 6.9
4mg IV Zofran
+ 50mg PO
Surgery Type (N=242) (N=242) (N=484)
-------------------------------------------------------------------------------------
Bilateral Salpingo oophorectomy 0 1 (<1%) 1 (<1%)
Bilateral Salpingo-Oophorectomy 7 (3%) 5 (2%) 12 (2%)
Bilateral Salpingo-Oophorectomy with 0 1 (<1%) 1 (<1%)

node dissection with omentectomy
Bilateral Salpingo-oophorectomy 0 1 (<1%) 1 (<1%)
CONFIDENTIAL
Bilateral salpingo-oophorectomy 2 (<1%) 2 (<1%) 4 (<1%)
110
Bilateral salpino oophrectomy 0 1 (<1%) 1 (<1%)
Breast operation 18 (7%) 26 (11%) 44 (9%)
Cholecystectomy 37 (15%) 40 (17%) 77 (16%)
Combinded abdmonial vaginal fascia sling 0 1 (<1%) 1 (<1%)

with marlex mesh, cystoscopy and
suprapubic catheter
DIAGNOSTIC LAPAROSCOPY 1 (<1%) 1 (<1%) 2 (<1%)
GM2006/00652/00
DIAGNOSTIC LAPOROSCOPY 0 1 (<1%) 1 (<1%)
Debulking of ovarian tumor 0 1 (<1%) 1 (<1%)
NKT102553
Diagnostic Laparoscopy 1 (<1%) 1 (<1%) 2 (<1%)
Diagnostic laprascopy 1 (<1%) 0 1 (<1%)

Table 6.9
4mg IV Zofran
+ 50mg PO
Surgery Type (N=242) (N=242) (N=484)
-------------------------------------------------------------------------------------
Diagnostic laproscopy 1 (<1%) 0 1 (<1%)
Dilatation and Curretage, Laparoscopy 1 (<1%) 0 1 (<1%)

Tubal ligation and Endometrial ablation
EXPLORATORY LAPAROTOMY 0 1 (<1%) 1 (<1%)
Explorative laparotomy w/co2 laser 1 (<1%) 0 1 (<1%)
CONFIDENTIAL
ovarian wedge resect - bilat
Exploratory laparotomy, Bilateral 1 (<1%) 0 1 (<1%)

111
ovarian cystectomy
Gynecologic, hysteroscopy d&c, uterine 0 1 (<1%) 1 (<1%)

polyps
Hysterectomy 68 (28%) 51 (21%) 119 (25%)
LAP OVARIAN CYSTECTOMY 1 (<1%) 0 1 (<1%)
LAPAROSCOPIC BILATERAL TUBAL LIGATION 0 1 (<1%) 1 (<1%)
LAPAROSCOPIC MYOMECTOMY 1 (<1%) 1 (<1%) 2 (<1%)
GM2006/00652/00
LAPAROSCOPIC SUPRACERVICAL HYSTERECTOMY 3 (1%) 4 (2%) 7 (1%)
LAPAROSCOPIC TUBAL LIGATION 0 1 (<1%) 1 (<1%)
NKT102553
LAPAROSCOPY 1 (<1%) 0 1 (<1%)
LEFT OVARIAN BIOPSY 0 1 (<1%) 1 (<1%)

Table 6.9
4mg IV Zofran
+ 50mg PO
Surgery Type (N=242) (N=242) (N=484)
-------------------------------------------------------------------------------------
LSC cystectomy 0 1 (<1%) 1 (<1%)
Laparascopic Bilateral tubal Cautery 0 1 (<1%) 1 (<1%)
Laparoscopic Bilateral Salpingo 0 1 (<1%) 1 (<1%)

Oophorectomy
Laparoscopic bilateral ovarian 0 1 (<1%) 1 (<1%)
CONFIDENTIAL
cystectomies
Laparoscopic extensive adhesiolysis 0 1 (<1%) 1 (<1%)

112
Laparoscopic left ovarian cystectomy and 0 1 (<1%) 1 (<1%)

right ovarian drilling
Laparoscopy
Hysteroscopy
Dilation and 0 1 (<1%) 1 (<1%)
Curettage
Laparoscopy + sterilisation 0 1 (<1%) 1 (<1%)
GM2006/00652/00
Laparoscopy Hysteroscopy w/video-poss 1 (<1%) 0 1 (<1%)
laser lap Hysterosalpingogram
Laparoscopy and Lysis of Adhesions 1 (<1%) 0 1 (<1%)
NKT102553
Laparoscopy, cystectomy 1 (<1%) 0 1 (<1%)
Laparoscopy, lysis of omental adhesions, 0 1 (<1%) 1 (<1%)

right salpingectomy and aspiration of
left hydrosalpinx
Table 6.9
4mg IV Zofran
+ 50mg PO
Surgery Type (N=242) (N=242) (N=484)
-------------------------------------------------------------------------------------
Left Salpingo Oopharectomy 0 1 (<1%) 1 (<1%)
Left Salpingo-oopherectomy, right 1 (<1%) 0 1 (<1%)

Ovarian cystectomy.
Left Salpingo-oophorectomy due to 0 1 (<1%) 1 (<1%)

ovarian mass
CONFIDENTIAL
Left Salpingooophorectomy 1 (<1%) 0 1 (<1%)
Lysis of Adhesions/ Laparotomy 1 (<1%) 0 1 (<1%)

113
MONARC BLADDER SUSPENSION 1 (<1%) 0 1 (<1%)
MONARC SUBURETHRAL SLING 0 1 (<1%) 1 (<1%)
MYOMECTOMY 0 1 (<1%) 1 (<1%)
Myomectomy 1 (<1%) 2 (<1%) 3 (<1%)
OPERATIVE LAPAROSCOPY 1 (<1%) 0 1 (<1%)
Operative Laparoscopy and Left 0 1 (<1%) 1 (<1%)
GM2006/00652/00
Oopherectomy
Overian Cystectomy 1 (<1%) 0 1 (<1%)
NKT102553
RIGHT OVARIAN CYSTECTOMY 0 1 (<1%) 1 (<1%)
RIGHT SALPINGO OOPHORECTOMY 1 (<1%) 0 1 (<1%)

Table 6.9
4mg IV Zofran
+ 50mg PO
Surgery Type (N=242) (N=242) (N=484)
-------------------------------------------------------------------------------------
Right Salpingo Oophorectomy 0 1 (<1%) 1 (<1%)
Right salpingo-oophorectomy 0 1 (<1%) 1 (<1%)
SACRAL COLPOPEXY 1 (<1%) 0 1 (<1%)
Salpingo-oophorectomy 1 (<1%) 0 1 (<1%)
CONFIDENTIAL
Selective hysterosalpingogram, 1 (<1%) 0 1 (<1%)
hysteroscopy, laparoscopy, transcervical
endosalpingolysis, KTP laser
114
Selective hysterosalpingogram, 0 1 (<1%) 1 (<1%)

transcervical endosalpingolysis,
hysteroscopy, laparoscopy
Shoulder operation 2 (<1%) 5 (2%) 7 (1%)
TRANSVAGINAL PORCINE URETHRAL SUSPENSION 0 1 (<1%) 1 (<1%)
Tension Free Vaginal Tape , Bladder 1 (<1%) 0 1 (<1%)

Suspension
GM2006/00652/00
Tension Free Vaginal Tape with Obturator 1 (<1%) 0 1 (<1%)
Tension Free Vaginal with Obturator, 0 1 (<1%) 1 (<1%)

Prolift
NKT102553
Thyroid operation 20 (8%) 14 (6%) 34 (7%)
UMBILICAL HERNIA REPAIR 0 1 (<1%) 1 (<1%)

Table 6.9
4mg IV Zofran
+ 50mg PO
Surgery Type (N=242) (N=242) (N=484)
-------------------------------------------------------------------------------------
VAGINAL SEPTUM REMOVAL AND REPAIR 1 (<1%) 0 1 (<1%)
abdominal colposacropexy 0 1 (<1%) 1 (<1%)
abdominal myomectomy 1 (<1%) 0 1 (<1%)
adnexectomy 0 1 (<1%) 1 (<1%)
CONFIDENTIAL
bilateral salpingo-oopherectomy 1 (<1%) 1 (<1%) 2 (<1%)
bilateral salpingo-oophorectomy 2 (<1%) 1 (<1%) 3 (<1%)

115
bilateral salpingoophorectomy 2 (<1%) 0 2 (<1%)
bilateral tubal ligation 0 1 (<1%) 1 (<1%)
birch repair 1 (<1%) 0 1 (<1%)
colpopexy 0 1 (<1%) 1 (<1%)
cuff neosalpingostomy 0 1 (<1%) 1 (<1%)
diagnostic laparoscopy 1 (<1%) 1 (<1%) 2 (<1%)
GM2006/00652/00
explor laparotomy Excision pelvic mass 1 (<1%) 0 1 (<1%)
exploratory laparotomy 2 (<1%) 0 2 (<1%)
NKT102553
fixation of prolapsed vaginal truncus 1 (<1%) 0 1 (<1%)
per laparotomiam
Table 6.9
4mg IV Zofran
+ 50mg PO
Surgery Type (N=242) (N=242) (N=484)
-------------------------------------------------------------------------------------
hysteroscopy and laparoscopy 1 (<1%) 0 1 (<1%)
intrauterin adhesions 1 (<1%) 0 1 (<1%)
laparascopic Right Ovarian cystectomy 1 (<1%) 0 1 (<1%)

with cautery of endometrial cyst and
appedectomy.
CONFIDENTIAL
laparoscopic BSO 1 (<1%) 0 1 (<1%)
laparoscopic USO 1 (<1%) 0 1 (<1%)

116
laparoscopic cystectomy 0 2 (<1%) 2 (<1%)
laparoscopic hysteroscopy 0 1 (<1%) 1 (<1%)
laparoscopic left salpingoopherectomy 0 1 (<1%) 1 (<1%)
laparoscopic myomectomy 0 1 (<1%) 1 (<1%)
laparoscopic ovarian wedge resection 0 1 (<1%) 1 (<1%)

uterine suspension
GM2006/00652/00
laparoscopic right ovarian cystectomy 0 1 (<1%) 1 (<1%)
laparoscopy 0 1 (<1%) 1 (<1%)
NKT102553
laparoscopy + adhaesiolysis + pseudocyst 1 (<1%) 0 1 (<1%)
removal
Table 6.9
4mg IV Zofran
+ 50mg PO
Surgery Type (N=242) (N=242) (N=484)
-------------------------------------------------------------------------------------
laparoscopy + adhaesiolysis + 0 1 (<1%) 1 (<1%)
chromopertubatio
laparoscopy + chromohydrotubation + 1 (<1%) 0 1 (<1%)

adhaesiolysis + elektrofenestratio ov
ovaries
laparoscopy + chromohydrotubation + 1 (<1%) 0 1 (<1%)
CONFIDENTIAL
exploration of the pelvis
laparoscopy + electrofenestratio of 0 1 (<1%) 1 (<1%)

117
polycystic ovaries + chromopertubatio of

the tubes
laparoscopy + explorative laparotomy, 0 1 (<1%) 1 (<1%)

cystectomy, adhaesiolysis
laparoscopy AND laparotomy, 0 1 (<1%) 1 (<1%)

salpingo-oophorectomy l.s.
laparoscopy excision of right ovarian 0 1 (<1%) 1 (<1%)

dermoid mass
GM2006/00652/00
laparoscopy hysteroscopy 1 (<1%) 0 1 (<1%)
laparoscopy hysteroscopy KTP 0 1 (<1%) 1 (<1%)

W/video-poss LSR LAP W/KTP
NKT102553
hysterosalpingogram T.E.S. W/FLUORO
laparoscopy hysteroscoy 1 (<1%) 0 1 (<1%)

Table 6.9
4mg IV Zofran
+ 50mg PO
Surgery Type (N=242) (N=242) (N=484)
-------------------------------------------------------------------------------------
laparotomy 0 2 (<1%) 2 (<1%)
laparotomy and right 1 (<1%) 0 1 (<1%)

salpingooopherectomy
laparotomy left salpingo oophorectomy 1 (<1%) 0 1 (<1%)
laparotomy, division of adhesions, 1 (<1%) 0 1 (<1%)
CONFIDENTIAL
repair of right ovary
laparotomy,coseal, application of gore 1 (<1%) 0 1 (<1%)

118
tex, left salpingoplasty, laser lysis of

adhesions
laproscopic cystectomy 1 (<1%) 0 1 (<1%)
laraposcopic paratubal cystotomy 1 (<1%) 0 1 (<1%)
left ovarian excision 1 (<1%) 0 1 (<1%)
left salpingo-oophorectomy 0 1 (<1%) 1 (<1%)
lysis of adhesions 1 (<1%) 1 (<1%) 2 (<1%)
GM2006/00652/00
myoma extirpation 0 1 (<1%) 1 (<1%)
myomectomy 2 (<1%) 2 (<1%) 4 (<1%)
NKT102553
myomectomy with bilateral salopingectomy 1 (<1%) 0 1 (<1%)
Table 6.9
4mg IV Zofran
+ 50mg PO
Surgery Type (N=242) (N=242) (N=484)
-------------------------------------------------------------------------------------
open and drainage of cyst with cyst wall 1 (<1%) 0 1 (<1%)
biopsy
operative laparoscopy 2 (<1%) 0 2 (<1%)
operative laparoscopy and adnexectomy, 1 (<1%) 0 1 (<1%)

left
CONFIDENTIAL
operative laparoscopy and cystectomy 0 1 (<1%) 1 (<1%)
opertive laparoscopy 1 (<1%) 0 1 (<1%)

119
ovarian cystectomy 0 1 (<1%) 1 (<1%)
permanent sterilization 1 (<1%) 0 1 (<1%)
posterior colporrhaphy 1 (<1%) 0 1 (<1%)
pubovaginal sling - TVT 1 (<1%) 0 1 (<1%)
right oopherectomy 1 (<1%) 0 1 (<1%)
right ovarian cystectomy 0 1 (<1%) 1 (<1%)
GM2006/00652/00
right salpingetomy 0 1 (<1%) 1 (<1%)
right salpingo-oophorectomy 1 (<1%) 1 (<1%) 2 (<1%)
NKT102553
rt ovarian cystectomy 0 1 (<1%) 1 (<1%)
Table 6.9
4mg IV Zofran
+ 50mg PO
Surgery Type (N=242) (N=242) (N=484)
-------------------------------------------------------------------------------------
selective hysterosalpingogram, 0 1 (<1%) 1 (<1%)
transcervical endosalpingolysis,
hysteroscopy, laparoscopy
vaginal vault suspension 1 (<1%) 0 1 (<1%)
CONFIDENTIAL
120
GM2006/00652/00
NKT102553
Table 6.10
Summary of Surgery Time
4mg IV Zofran +
50mg Oral
(N=242) (N=242)
----------------------------------------------------
Total n 235 232
Surgery
Time
(minutes)
Mean 92.1 87.7
SD 56.96 50.39
Median 77.0 77.0
Min. 10 14
CONFIDENTIAL
Max. 414 270
121
GM2006/00652/00
NKT102553
Table 6.11
Summary of Peri-operative Medications
4mg IV Zofran
+ 50mg PO
Reason 4mg IV Zofran Casopitant
Ingredient (N=242) (N=242)
------------------------------------------------------------
Any Medication 235 (97%) 233 (96%)
Any Medication 235 (97%) 233 (96%)

FENTANYL 195 (81%) 191 (79%)
PROPOFOL 189 (78%) 188 (78%)
MIDAZOLAM 133 (55%) 128 (53%)
Multiple Ingredient 131 (54%) 123 (51%)
CONFIDENTIAL
NITROUS OXIDE 111 (46%) 108 (45%)
SEVOFLURANE 108 (45%) 99 (41%)
OXYGEN 102 (42%) 93 (38%)
122
NEOSTIGMINE 92 (38%) 101 (42%)

GLYCOPYRRONIUM BROMIDE 93 (38%) 98 (40%)
LIDOCAINE 70 (29%) 84 (35%)
DESFLURANE 68 (28%) 69 (29%)
ROCURONIUM BROMIDE 69 (29%) 65 (27%)
MORPHINE 67 (28%) 55 (23%)
ROCURONIUM 53 (22%) 57 (24%)
SODIUM CHLORIDE 53 (22%) 57 (24%)
MIDAZOLAM MALEATE 49 (20%) 55 (23%)
CEFAZOLIN SODIUM 53 (22%) 49 (20%)
ATRACURIUM BESILATE 48 (20%) 44 (18%)
KETOROLAC TROMETAMOL 43 (18%) 45 (19%)
GM2006/00652/00
ATROPINE 37 (15%) 45 (19%)
ISOFLURANE 39 (16%) 40 (17%)
SUXAMETHONIUM 38 (16%) 34 (14%)
NEOSTIGMINE METILSULFATE 33 (14%) 38 (16%)
NKT102553
THIOPENTAL SODIUM 25 (10%) 24 (10%)
EPHEDRINE 17 (7%) 29 (12%)
SUXAMETHONIUM CHLORIDE 21 (9%) 22 (9%)
CEFAZOLIN 23 (10%) 19 (8%)
Table 6.11
4mg IV Zofran
+ 50mg PO
------------------------------------------------------------
THIOPENTAL 18 (7%) 20 (8%)
PETHIDINE HYDROCHLORIDE 19 (8%) 18 (7%)
KETOROLAC 14 (6%) 17 (7%)
METRONIDAZOLE 12 (5%) 14 (6%)
AMINOPHYLLINE 15 (6%) 10 (4%)
ATRACURIUM 14 (6%) 11 (5%)
VECURONIUM 15 (6%) 10 (4%)
REMIFENTANIL 11 (5%) 12 (5%)
CONFIDENTIAL
BUPIVACAINE HYDROCHLORIDE 14 (6%) 8 (3%)
CEFOXITIN 10 (4%) 11 (5%)
CISATRACURIUM 9 (4%) 11 (5%)
123
LORAZEPAM 11 (5%) 9 (4%)

CISATRACURIUM BESILATE 12 (5%) 7 (3%)
ATROPINE SULFATE 7 (3%) 10 (4%)
DIPOTASSIUM CLORAZEPATE 7 (3%) 10 (4%)
METAMIZOLE SODIUM 7 (3%) 10 (4%)
PARACETAMOL 7 (3%) 10 (4%)
CLINDAMYCIN 7 (3%) 9 (4%)
SUFENTANIL 6 (2%) 10 (4%)
CEFUROXIME 6 (2%) 9 (4%)
DIAZEPAM 7 (3%) 7 (3%)
EPHEDRINE HYDROCHLORIDE 3 (1%) 11 (5%)
VECURONIUM BROMIDE 5 (2%) 9 (4%)
GM2006/00652/00
HEPARIN (NOS) 8 (3%) 5 (2%)
RANITIDINE 7 (3%) 4 (2%)
CEFOTETAN DISODIUM 6 (2%) 4 (2%)
HYDROMORPHONE HYDROCHLORIDE 5 (2%) 5 (2%)
NKT102553
IRRIGATING SOLUTIONS (NOS) 5 (2%) 5 (2%)
MORPHINE SULFATE 7 (3%) 3 (1%)
NALOXONE HYDROCHLORIDE 5 (2%) 5 (2%)
TRAMADOL 3 (1%) 7 (3%)
Table 6.11
4mg IV Zofran
+ 50mg PO
------------------------------------------------------------
FAMOTIDINE 6 (2%) 3 (1%)
LEVOFLOXACIN 5 (2%) 4 (2%)
NALBUPHINE 5 (2%) 4 (2%)
PHENYLEPHRINE 2 (<1%) 7 (3%)
RANITIDINE HYDROCHLORIDE 4 (2%) 5 (2%)
BACITRACIN 5 (2%) 3 (1%)
CEFOXITIN SODIUM 4 (2%) 4 (2%)
FUROSEMIDE 2 (<1%) 6 (2%)
CONFIDENTIAL
ALFENTANIL 4 (2%) 3 (1%)
ALPRAZOLAM 3 (1%) 4 (2%)
EPINEPHRINE 3 (1%) 3 (1%)
124
FENTANYL CITRATE 3 (1%) 3 (1%)

HETASTARCH 4 (2%) 2 (<1%)
INDIGO CARMINE 4 (2%) 2 (<1%)
LABETALOL 6 (2%) 0
ONDANSETRON 3 (1%) 3 (1%)
PHENYLEPHRINE HYDROCHLORIDE 1 (<1%) 5 (2%)
PIPECURONIUM BROMIDE 5 (2%) 1 (<1%)
URAPIDIL 3 (1%) 3 (1%)
BLOOD, WHOLE 4 (2%) 1 (<1%)
CEFOTETAN 5 (2%) 0
CIPROFLOXACIN 3 (1%) 2 (<1%)
DICLOFENAC SODIUM 1 (<1%) 4 (2%)
GM2006/00652/00
SALBUTAMOL 2 (<1%) 3 (1%)
SUFENTANIL CITRATE 2 (<1%) 3 (1%)
VASOPRESSIN 3 (1%) 2 (<1%)
CALCIUM CHLORIDE 2 (<1%) 2 (<1%)
NKT102553
ETOMIDATE 2 (<1%) 2 (<1%)
HYDROCORTISONE SODIUM 3 (1%) 1 (<1%)
SUCCINATE
KETOPROFEN 2 (<1%) 2 (<1%)
Table 6.11
4mg IV Zofran
+ 50mg PO
------------------------------------------------------------
NALBUPHINE HYDROCHLORIDE 1 (<1%) 3 (1%)
PLASMA PROTEIN FRACTION 2 (<1%) 2 (<1%)
(HUMAN)
POTASSIUM CHLORIDE 2 (<1%) 2 (<1%)
RED BLOOD CELLS, 3 (1%) 1 (<1%)
CONCENTRATED
ALBUMIN NORMAL HUMAN SERUM 1 (<1%) 2 (<1%)
ALGOPYRIN (NOS) 1 (<1%) 2 (<1%)
CONFIDENTIAL
CALCIUM GLUCONATE 2 (<1%) 1 (<1%)
CIPROFLOXACIN HYDROCHLORIDE 1 (<1%) 2 (<1%)
DICLOFENAC 3 (1%) 0
125
ENOXAPARIN 1 (<1%) 2 (<1%)

GENTAMICIN 2 (<1%) 1 (<1%)
METHYLTHIONINIUM CHLORIDE 2 (<1%) 1 (<1%)
METOCLOPRAMIDE HYDROCHLORIDE 0 3 (1%)
PANCURONIUM BROMIDE 2 (<1%) 1 (<1%)
POLYGELINE 2 (<1%) 1 (<1%)
BLOOD TRANSFUSION, AUXILIARY 0 2 (<1%)
PRODUCTS
BROTIZOLAM 0 2 (<1%)
BUPIVACAINE 1 (<1%) 1 (<1%)
DALTEPARIN SODIUM 2 (<1%) 0
DEXAMETHASONE 1 (<1%) 1 (<1%)
GM2006/00652/00
DOXYCYCLINE 1 (<1%) 1 (<1%)
EDROPHONIUM CHLORIDE 2 (<1%) 0
ESMOLOL 2 (<1%) 0
FLUMAZENIL 0 2 (<1%)
NKT102553
HYDRALAZINE 0 2 (<1%)
ISOSORBIDE MONONITRATE 1 (<1%) 1 (<1%)
KETAMINE 0 2 (<1%)
METOPROLOL 1 (<1%) 1 (<1%)
Table 6.11
4mg IV Zofran
+ 50mg PO
------------------------------------------------------------
MIVACURIUM 1 (<1%) 1 (<1%)
NEFOPAM HYDROCHLORIDE 2 (<1%) 0
NEOSTIGMINE BROMIDE 1 (<1%) 1 (<1%)
PARECOXIB SODIUM 2 (<1%) 0
PIRITRAMIDE 0 2 (<1%)
PROMETHAZINE HYDROCHLORIDE 1 (<1%) 1 (<1%)
REMIFENTANIL HYDROCHLORIDE 1 (<1%) 1 (<1%)
ROPIVACAINE HYDROCHLORIDE 1 (<1%) 1 (<1%)
CONFIDENTIAL
SODIUM AMIDOTRIZOATE 1 (<1%) 1 (<1%)
SODIUM CITRATE 1 (<1%) 1 (<1%)
ALFENTANIL HYDROCHLORIDE 1 (<1%) 0
126
AMPICILLIN 1 (<1%) 0
ANTIBIOTICS NOS 1 (<1%) 0
ATENOLOL 0 1 (<1%)
AZITHROMYCIN 1 (<1%) 0
BROMAZEPAM 0 1 (<1%)
CEFALEXIN 0 1 (<1%)
CEFTAZIDIME 0 1 (<1%)
CEFTRIAXONE SODIUM 1 (<1%) 0
CEFUROXIME SODIUM 0 1 (<1%)
CHLORPHENAMINE MALEATE 1 (<1%) 0
CLINDAMYCIN PHOSPHATE 0 1 (<1%)
DROPERIDOL 1 (<1%) 0
GM2006/00652/00
EPHEDRINE SULFATE 0 1 (<1%)
ESTROGENS CONJUGATED 0 1 (<1%)
FEXOFENADINE HYDROCHLORIDE 0 1 (<1%)
FLUTICASONE PROPIONATE 0 1 (<1%)
NKT102553
HEPARIN SODIUM 0 1 (<1%)
HYDROXYZINE 1 (<1%) 0
HYOSCINE 0 1 (<1%)
INSULIN NOS 1 (<1%) 0
Table 6.11
4mg IV Zofran
+ 50mg PO
------------------------------------------------------------
LEVOTHYROXINE SODIUM 1 (<1%) 0
LIDOCAINE HYDROCHLORIDE 1 (<1%) 0
MAGNESIUM 0 1 (<1%)
MAGNESIUM SULFATE 1 (<1%) 0
MEDROXYPROGESTERONE ACETATE 0 1 (<1%)
METHYLERGOMETRINE MALEATE 1 (<1%) 0
METHYLPREDNISOLONE SODIUM 1 (<1%) 0
SUCCINATE
CONFIDENTIAL
METOPROLOL TARTRATE 1 (<1%) 0
MIDAZOLAM HYDROCHLORIDE 0 1 (<1%)
MIVACURIUM CHLORIDE 1 (<1%) 0
127
MOXIFLOXACIN 0 1 (<1%)
NADROPARIN CALCIUM 0 1 (<1%)
NAPROXEN 0 1 (<1%)
OXIDISED CELLULOSE 0 1 (<1%)
PANTOPRAZOLE 0 1 (<1%)
PREDNISOLONE 1 (<1%) 0
PREDNISONE 0 1 (<1%)
PROMETHAZINE 0 1 (<1%)
ROPIVACAINE 1 (<1%) 0
SORBITOL 0 1 (<1%)
STERILE WATER 1 (<1%) 0
SULFANILAMIDE 0 1 (<1%)
GM2006/00652/00
UNASYN (NOS) 0 1 (<1%)
VANCOMYCIN 0 1 (<1%)
ZOLPIDEM TARTRATE 1 (<1%) 0
NKT102553
Table 6.12
Summary of Concomitant Medications
4mg IV
Zofran +
4mg IV 50mg PO
ATC Level 1 Zofran Casopitant
-------------------------------------------------------------
Any Medication 230 (95%) 236 (98%)
NERVOUS SYSTEM
Any Medication 219 (90%) 216 (89%)
PARACETAMOL 122 (50%) 131 (54%)
MORPHINE 69 (29%) 60 (25%)
IBUPROFEN 47 (19%) 44 (18%)
CONFIDENTIAL
PETHIDINE HYDROCHLORIDE 38 (16%) 39 (16%)
FENTANYL 33 (14%) 40 (17%)
OXYCODONE HYDROCHLORIDE 37 (15%) 35 (14%)
128

HYDROMORPHONE HYDROCHLORIDE 30 (12%) 20 (8%)
ALGOPYRIN (NOS) 11 (5%) 15 (6%)
ALPRAZOLAM 14 (6%) 10 (4%)
DEXTROPROPOXYPHENE NAPSILATE 9 (4%) 15 (6%)
NALBUPHINE HYDROCHLORIDE 8 (3%) 16 (7%)
PETHIDINE 14 (6%) 10 (4%)
TYLENOL #3 (NOS) 10 (4%) 13 (5%)
MIDAZOLAM 15 (6%) 7 (3%)
MORPHINE SULFATE 11 (5%) 10 (4%)
NALBUPHINE 13 (5%) 8 (3%)
GM2006/00652/00
ACETYLSALICYLIC ACID 7 (3%) 10 (4%)
METAMIZOLE SODIUM 5 (2%) 11 (5%)
PIRITRAMIDE 7 (3%) 9 (4%)
MEFENAMIC ACID 8 (3%) 5 (2%)
NKT102553
PROMETHAZINE 4 (2%) 7 (3%)
LORAZEPAM 4 (2%) 6 (2%)
ZOLPIDEM TARTRATE 6 (2%) 3 (1%)
*Some subjects have missing component data.

Table 6.12
4mg IV
Zofran +
4mg IV 50mg PO
-------------------------------------------------------------
HYDROCODONE 4 (2%) 4 (2%)
CITALOPRAM 1 (<1%) 6 (2%)
CODEINE PHOSPHATE 4 (2%) 3 (1%)
PAROXETINE HYDROCHLORIDE 4 (2%) 3 (1%)
SERTRALINE HYDROCHLORIDE 5 (2%) 2 (<1%)
TRAMADOL 2 (<1%) 5 (2%)
VENLAFAXINE HYDROCHLORIDE 3 (1%) 4 (2%)
CONFIDENTIAL
GABAPENTIN 3 (1%) 3 (1%)
PIRACETAM 3 (1%) 3 (1%)
BUPROPION HYDROCHLORIDE 3 (1%) 2 (<1%)
129
CODEINE 1 (<1%) 4 (2%)

PROPOFOL 4 (2%) 1 (<1%)
ZOPICLONE 3 (1%) 2 (<1%)
CLONAZEPAM 1 (<1%) 3 (1%)
DIAZEPAM 3 (1%) 1 (<1%)
FENTANYL CITRATE 3 (1%) 1 (<1%)
OXAZEPAM 2 (<1%) 2 (<1%)
TEMAZEPAM 2 (<1%) 2 (<1%)
TOPIRAMATE 2 (<1%) 2 (<1%)
ALLOBARBITAL 0 3 (1%)
AMINOPHENAZONE 0 3 (1%)
BETHANECHOL CHLORIDE 1 (<1%) 2 (<1%)
GM2006/00652/00
CAFFEINE 1 (<1%) 2 (<1%)
CLONIDINE 1 (<1%) 2 (<1%)
CYCLOBENZAPRINE HYDROCHLORIDE 1 (<1%) 2 (<1%)
DESFLURANE 2 (<1%) 1 (<1%)
NKT102553
FLUOXETINE HYDROCHLORIDE 3 (1%) 0
HYDROXYZINE 2 (<1%) 1 (<1%)
LIDOCAINE 2 (<1%) 1 (<1%)

Table 6.12
4mg IV
Zofran +
4mg IV 50mg PO
-------------------------------------------------------------
MAGNESIUM SALICYLATE 0 3 (1%)
NITROUS OXIDE 3 (1%) 0
REMIFENTANIL 2 (<1%) 1 (<1%)
SEVOFLURANE 2 (<1%) 1 (<1%)
TRAMADOL HYDROCHLORIDE 2 (<1%) 1 (<1%)
URETHANE 0 3 (1%)
ALMOTRIPTAN MALATE 1 (<1%) 1 (<1%)
CONFIDENTIAL
AMITRIPTYLINE 0 2 (<1%)
AMITRIPTYLINE HYDROCHLORIDE 2 (<1%) 0
BETAHISTINE HYDROCHLORIDE 1 (<1%) 1 (<1%)
130
CITALOPRAM HYDROBROMIDE 1 (<1%) 1 (<1%)

DEXTROPROPOXYPHENE HYDROCHLORIDE 1 (<1%) 1 (<1%)
DIFLUNISAL 1 (<1%) 1 (<1%)
DIHYDROCODEINE 2 (<1%) 0
DIPOTASSIUM CLORAZEPATE 1 (<1%) 1 (<1%)
DULOXETINE HYDROCHLORIDE 1 (<1%) 1 (<1%)
ESZOPICLONE 1 (<1%) 1 (<1%)
FLUOXETINE 0 2 (<1%)
LAMOTRIGINE 1 (<1%) 1 (<1%)
MIRTAZAPINE 1 (<1%) 1 (<1%)
MODAFINIL 1 (<1%) 1 (<1%)
MORPHINE HYDROCHLORIDE 2 (<1%) 0
GM2006/00652/00
NEOSTIGMINE 2 (<1%) 0
OXYCODONE 0 2 (<1%)
SUMATRIPTAN 0 2 (<1%)
TRAZODONE 1 (<1%) 1 (<1%)
NKT102553
VALERIAN ROOT 0 2 (<1%)
VINPOCETINE 1 (<1%) 1 (<1%)
AMFETAMINE ASPARTATE 1 (<1%) 0

Table 6.12
4mg IV
Zofran +
4mg IV 50mg PO
-------------------------------------------------------------
AMFETAMINE SULFATE 1 (<1%) 0
BROMOCRIPTINE MESILATE 0 1 (<1%)
BROTIZOLAM 0 1 (<1%)
BUPIVACAINE 1 (<1%) 0
BUPROPION 0 1 (<1%)
CAPSAICIN 1 (<1%) 0
CARBAMAZEPINE 1 (<1%) 0
CONFIDENTIAL
CARBIDOPA 1 (<1%) 0
CHLORDIAZEPOXIDE 0 1 (<1%)
CHLORDIAZEPOXIDE HYDROCHLORIDE 0 1 (<1%)
131
CHLORPROMAZINE HYDROCHLORIDE 1 (<1%) 0

CYCLOBENZAPRINE 0 1 (<1%)
DEXAMFETAMINE SULFATE 1 (<1%) 0
DEXTROPROPOXYPHENE 0 1 (<1%)
ENTACAPONE 1 (<1%) 0
EXCEDRIN (NOS) 1 (<1%) 0
FLUVOXAMINE MALEATE 0 1 (<1%)
HYDROMORPHONE 0 1 (<1%)
HYDROXYZINE HYDROCHLORIDE 1 (<1%) 0
IPRAZOCHROME 1 (<1%) 0
LEVODOPA 1 (<1%) 0
MEDAZEPAM 1 (<1%) 0
GM2006/00652/00
PAPAVER SOMNIFERUM 0 1 (<1%)
PAROXETINE 0 1 (<1%)
PASSIFLORA EXTRACT 1 (<1%) 0
PERPHENAZINE 1 (<1%) 0
NKT102553
PREGABALIN 0 1 (<1%)
PROXIBARBAL 1 (<1%) 0
PYRIDOSTIGMINE BROMIDE 0 1 (<1%)

Table 6.12
4mg IV
Zofran +
4mg IV 50mg PO
-------------------------------------------------------------
QUETIAPINE FUMARATE 1 (<1%) 0
RIZATRIPTAN BENZOATE 0 1 (<1%)
ROPIVACAINE 0 1 (<1%)
ROPIVACAINE HYDROCHLORIDE 1 (<1%) 0
SUFENTANIL 1 (<1%) 0
SUFENTANIL CITRATE 1 (<1%) 0
THIOPENTAL SODIUM 1 (<1%) 0
CONFIDENTIAL
TRAZODONE HYDROCHLORIDE 0 1 (<1%)
TYLENOL #1 (NOS) 0 1 (<1%)
VALERIANA OFFICINALIS 1 (<1%) 0
132
VALPROATE SODIUM 1 (<1%) 0

ZOLMITRIPTAN 0 1 (<1%)
ZOLPIDEM 1 (<1%) 0
ALIMENTARY TRACT AND METABOLISM

Any Medication 166 (69%) 162 (67%)
POTASSIUM CHLORIDE 69 (29%) 53 (22%)
DIMETICONE, ACTIVATED 26 (11%) 30 (12%)
VITAMINS NOS 35 (14%) 20 (8%)
DOCUSATE SODIUM 27 (11%) 22 (9%)
ASCORBIC ACID 15 (6%) 10 (4%)
GM2006/00652/00
FAMOTIDINE 15 (6%) 10 (4%)
MAGNESIUM HYDROXIDE 13 (5%) 10 (4%)
PYRIDOXINE HYDROCHLORIDE 12 (5%) 11 (5%)
ATROPINE 14 (6%) 4 (2%)
NKT102553
CALCIUM 11 (5%) 6 (2%)
DULCOLAX (NOS) 8 (3%) 9 (4%)

Table 6.12
4mg IV
Zofran +
4mg IV 50mg PO
-------------------------------------------------------------
GLIBENCLAMIDE 6 (2%) 6 (2%)
PANTOPRAZOLE 6 (2%) 6 (2%)
RANITIDINE 6 (2%) 5 (2%)
TOCOPHEROL 9 (4%) 2 (<1%)
BISACODYL 7 (3%) 3 (1%)
CONFIDENTIAL
GLYCEROL 4 (2%) 6 (2%)
CALCIUM CARBONATE 7 (3%) 2 (<1%)
CALCIUM PHOSPHATE 7 (3%) 2 (<1%)
133
ESOMEPRAZOLE MAGNESIUM 3 (1%) 6 (2%)

GLYCOPYRRONIUM BROMIDE 5 (2%) 4 (2%)
METFORMIN 6 (2%) 3 (1%)
RANITIDINE HYDROCHLORIDE 6 (2%) 3 (1%)
DOCUSATE 2 (<1%) 6 (2%)
OMEPRAZOLE 3 (1%) 5 (2%)
GLYCYRRHIZA (NOS) 3 (1%) 4 (2%)
METFORMIN HYDROCHLORIDE 3 (1%) 4 (2%)
LANSOPRAZOLE 4 (2%) 2 (<1%)
ONDANSETRON 4 (2%) 2 (<1%)
SENNA 2 (<1%) 4 (2%)
VITAMIN B SUBSTANCES NOS 3 (1%) 3 (1%)
GM2006/00652/00
DEXPANTHENOL 3 (1%) 2 (<1%)
DOMPERIDONE 3 (1%) 2 (<1%)
MACROGOL 1 (<1%) 4 (2%)
MAGNESIUM 3 (1%) 2 (<1%)
NKT102553
METOCLOPRAMIDE HYDROCHLORIDE 3 (1%) 2 (<1%)
SORBITOL 3 (1%) 2 (<1%)
MAGNESIUM CITRATE 2 (<1%) 2 (<1%)

Table 6.12
4mg IV
Zofran +
4mg IV 50mg PO
-------------------------------------------------------------
MINERALS NOS 2 (<1%) 2 (<1%)
SODIUM BICARBONATE 2 (<1%) 2 (<1%)
SODIUM PHOSPHATE DIBASIC 0 4 (2%)
VITAMIN D NOS 2 (<1%) 2 (<1%)
ERGOCALCIFEROL 1 (<1%) 2 (<1%)
INSULIN NOS 3 (1%) 0
POTASSIUM CITRATE 1 (<1%) 2 (<1%)
CONFIDENTIAL
RABEPRAZOLE SODIUM 0 3 (1%)
SIMETICONE 2 (<1%) 1 (<1%)
ALUMINIUM HYDROXIDE GEL, DRIED 1 (<1%) 1 (<1%)
134
CALCIUM CITRATE 1 (<1%) 1 (<1%)

CITRIC ACID HYDRATE 1 (<1%) 1 (<1%)
EPINEPHRINE 1 (<1%) 1 (<1%)
GLIMEPIRIDE 0 2 (<1%)
HYDROCORTISONE 0 2 (<1%)
HYOSCYAMINE SULFATE 1 (<1%) 1 (<1%)
INSULIN HUMAN 0 2 (<1%)
INSULIN LISPRO 0 2 (<1%)
LOPERAMIDE HYDROCHLORIDE 2 (<1%) 0
MECLOZINE 1 (<1%) 1 (<1%)
METOCLOPRAMIDE 1 (<1%) 1 (<1%)
MISOPROSTOL 0 2 (<1%)
GM2006/00652/00
PANTOPRAZOLE SODIUM 1 (<1%) 1 (<1%)
PHENTERMINE HYDROCHLORIDE 0 2 (<1%)
PIOGLITAZONE HYDROCHLORIDE 1 (<1%) 1 (<1%)
POTASSIUM BICARBONATE 1 (<1%) 1 (<1%)
NKT102553
POTASSIUM NOS 1 (<1%) 1 (<1%)
ROSIGLITAZONE MALEATE 0 2 (<1%)
SENNOSIDES 2 (<1%) 0

Table 6.12
4mg IV
Zofran +
4mg IV 50mg PO
-------------------------------------------------------------
TEGASEROD 1 (<1%) 1 (<1%)
URSODEOXYCHOLIC ACID 0 2 (<1%)
VITAMIN B NOS 0 2 (<1%)
ZINC 2 (<1%) 0
ALUMINIUM HYDROXIDE 0 1 (<1%)
APIS MELLIFERA EXTRACT 1 (<1%) 0
ATROPA BELLADONNA 0 1 (<1%)
CONFIDENTIAL
ATROPINE SULFATE 0 1 (<1%)
BIOTIN 1 (<1%) 0
BISMUTH SUBSALICYLATE 0 1 (<1%)
135
BUFORMIN HYDROCHLORIDE 0 1 (<1%)

CALCIUM GLUCONATE 1 (<1%) 0
CAROTENOIDS 1 (<1%) 0
CASANTHRANOL 1 (<1%) 0
CLIDINIUM BROMIDE 0 1 (<1%)
CLOTRIMAZOLE 1 (<1%) 0
DEXAMETHASONE 1 (<1%) 0
DEXAMFETAMINE SULFATE 1 (<1%) 0
DIHYDROTACHYSTEROL 0 1 (<1%)
DIMENHYDRINATE 0 1 (<1%)
DIPHENOXYLATE HYDROCHLORIDE 0 1 (<1%)
DOLASETRON MESILATE 1 (<1%) 0
GM2006/00652/00
DROTAVERINE HYDROCHLORIDE 0 1 (<1%)
ESOMEPRAZOLE 0 1 (<1%)
GLICLAZIDE 0 1 (<1%)
HYOSCINE BUTYLBROMIDE 0 1 (<1%)
NKT102553
INSULIN DETEMIR 1 (<1%) 0
INSULIN HUMAN INJECTION, ISOPHANE 0 1 (<1%)
ISOPHANE INSULIN 0 1 (<1%)

Table 6.12
4mg IV
Zofran +
4mg IV 50mg PO
-------------------------------------------------------------
KAOLIN 0 1 (<1%)
MAGNESIUM ACETATE 1 (<1%) 0
MESALAZINE 1 (<1%) 0
MICONAZOLE NITRATE 1 (<1%) 0
MULTIVIT (NOS) 1 (<1%) 0
NATEGLINIDE 0 1 (<1%)
NEOMYCIN SULFATE 0 1 (<1%)
CONFIDENTIAL
NIZATIDINE 0 1 (<1%)
PANCREATIN 1 (<1%) 0
PAPAVER SOMNIFERUM 0 1 (<1%)
136
PHENTERMINE 0 1 (<1%)
PHENTERMINE RESIN 1 (<1%) 0
PHOSPHORIC ACID, SODIUM SALT 0 1 (<1%)
PLANTAGO OVATA 1 (<1%) 0
POLYCARBOPHIL CALCIUM 0 1 (<1%)
POLYMYXIN B SULFATE 0 1 (<1%)
POTASSIUM ACETATE 1 (<1%) 0
RABEPRAZOLE 0 1 (<1%)
RETINOL 0 1 (<1%)
SELENIUM 1 (<1%) 0
SUCRALFATE 0 1 (<1%)
TETRACYCLINE 1 (<1%) 0
GM2006/00652/00
TRIAMCINOLONE ACETONIDE 0 1 (<1%)
TRIMETHOBENZAMIDE HYDROCHLORIDE 0 1 (<1%)
TROPISETRON HYDROCHLORIDE 0 1 (<1%)
ZINGIBER OFFICINALE 1 (<1%) 0
NKT102553
BLOOD AND BLOOD FORMING ORGANS
Any Medication 154 (64%) 147 (61%)

Table 6.12
4mg IV
Zofran +
4mg IV 50mg PO
-------------------------------------------------------------
POTASSIUM CHLORIDE 69 (29%) 53 (22%)
CALCIUM CHLORIDE 60 (25%) 40 (17%)
GLUCOSE 52 (21%) 44 (18%)
ENOXAPARIN 21 (9%) 31 (13%)
FERROUS FUMARATE 19 (8%) 18 (7%)
NADROPARIN CALCIUM 16 (7%) 16 (7%)
CONFIDENTIAL
FOLIC ACID 14 (6%) 15 (6%)
SODIUM LACTATE 16 (7%) 9 (4%)
HEPARIN (NOS) 13 (5%) 7 (3%)
137

DALTEPARIN SODIUM 6 (2%) 11 (5%)
FERROUS SULPHATE 3 (1%) 12 (5%)
ELECTROLYTES NOS 5 (2%) 6 (2%)
IRON 4 (2%) 7 (3%)
CYANOCOBALAMIN 3 (1%) 5 (2%)
SORBITOL 3 (1%) 2 (<1%)
LIVER EXTRACT 2 (<1%) 2 (<1%)
MAGNESIUM CITRATE 2 (<1%) 2 (<1%)
SODIUM BICARBONATE 2 (<1%) 2 (<1%)
RED BLOOD CELLS, CONCENTRATED 2 (<1%) 1 (<1%)
SODIUM CITRATE 2 (<1%) 1 (<1%)
GM2006/00652/00
GELATIN 0 2 (<1%)
HEPARIN SODIUM 1 (<1%) 1 (<1%)
NICOUMALONE 0 2 (<1%)
NKT102553
POTASSIUM NOS 1 (<1%) 1 (<1%)
CLOPIDOGREL BISULFATE 1 (<1%) 0
COLLAGEN 0 1 (<1%)

Table 6.12
4mg IV
Zofran +
4mg IV 50mg PO
-------------------------------------------------------------
ENOXAPARIN SODIUM 1 (<1%) 0
ETAMSYLATE 0 1 (<1%)
FERROUS GLUCONATE 1 (<1%) 0
FERROUS IRON 0 1 (<1%)
GLUCOSE INJECTION 0 1 (<1%)
HETASTARCH 1 (<1%) 0
CONFIDENTIAL
POTASSIUM ACETATE 1 (<1%) 0
TINZAPARIN SODIUM 0 1 (<1%)
WARFARIN SODIUM 1 (<1%) 0
138
RESPIRATORY SYSTEM
Any Medication 145 (60%) 131 (54%)
HYDROCODONE BITARTRATE 39 (16%) 46 (19%)
OXYGEN 29 (12%) 16 (7%)
BENADRYL (NOS) 6 (2%) 8 (3%)
SALBUTAMOL 6 (2%) 7 (3%)
FLUTICASONE PROPIONATE 7 (3%) 2 (<1%)
CETIRIZINE HYDROCHLORIDE 4 (2%) 4 (2%)
HYDROCODONE 4 (2%) 4 (2%)
GM2006/00652/00
LORATADINE 3 (1%) 5 (2%)
CODEINE PHOSPHATE 4 (2%) 3 (1%)
POTASSIUM IODIDE 4 (2%) 3 (1%)
CODEINE 1 (<1%) 4 (2%)
NKT102553
SALMETEROL XINAFOATE 4 (2%) 1 (<1%)
DIPHENHYDRAMINE HYDROCHLORIDE 3 (1%) 1 (<1%)
FEXOFENADINE HYDROCHLORIDE 3 (1%) 1 (<1%)

Table 6.12
4mg IV
Zofran +
4mg IV 50mg PO
-------------------------------------------------------------
GUAIFENESIN 2 (<1%) 2 (<1%)
MONTELUKAST SODIUM 3 (1%) 1 (<1%)
PSEUDOEPHEDRINE HYDROCHLORIDE 2 (<1%) 2 (<1%)
DESLORATADINE 2 (<1%) 1 (<1%)
EPHEDRINE 2 (<1%) 1 (<1%)
LIDOCAINE 2 (<1%) 1 (<1%)
AMBROXOL HYDROCHLORIDE 1 (<1%) 1 (<1%)
CONFIDENTIAL
AZELASTINE HYDROCHLORIDE 2 (<1%) 0
BENZALKONIUM CHLORIDE 2 (<1%) 0
CARBOCISTEINE 2 (<1%) 0
139
DIHYDROCODEINE 2 (<1%) 0
LEVOSALBUTAMOL HYDROCHLORIDE 1 (<1%) 1 (<1%)
MECLOZINE 1 (<1%) 1 (<1%)
MOMETASONE FUROATE 2 (<1%) 0
ACETYLCYSTEINE 1 (<1%) 0
BROMHEXINE 1 (<1%) 0
BROMHEXINE HYDROCHLORIDE 0 1 (<1%)
DEQUALINIUM CHLORIDE 0 1 (<1%)
DEXTROMETHORPHAN 0 1 (<1%)
GM2006/00652/00
DIMENHYDRINATE 0 1 (<1%)
DIPHENHYDRAMINE 1 (<1%) 0
FEXOFENADINE 0 1 (<1%)
LEVOCETIRIZINE 0 1 (<1%)
NKT102553
MECLOZINE HYDROCHLORIDE 0 1 (<1%)
MUPIROCIN 0 1 (<1%)

Table 6.12
4mg IV
Zofran +
4mg IV 50mg PO
-------------------------------------------------------------
OXYMETAZOLINE HYDROCHLORIDE 0 1 (<1%)
PSEUDOEPHEDRINE SULFATE 0 1 (<1%)
RETINOL 0 1 (<1%)
ROBITUSSIN (NOS) 1 (<1%) 0
SALBUTAMOL SULFATE 1 (<1%) 0
THEOPHYLLINE 0 1 (<1%)
TIOTROPIUM BROMIDE 0 1 (<1%)
CONFIDENTIAL
TYLENOL SINUS (NOS) 0 1 (<1%)
140
SENSORY ORGANS
Any Medication 132 (55%) 117 (48%)
DICLOFENAC SODIUM 10 (4%) 12 (5%)
HEPARIN (NOS) 13 (5%) 7 (3%)
KETOROLAC 11 (5%) 8 (3%)
ATROPINE 14 (6%) 4 (2%)
DICLOFENAC 6 (2%) 5 (2%)
CIPROFLOXACIN 6 (2%) 4 (2%)
CIPROFLOXACIN HYDROCHLORIDE 5 (2%) 4 (2%)
GM2006/00652/00
AMPICILLIN 5 (2%) 2 (<1%)
CLONIDINE 1 (<1%) 2 (<1%)
NKT102553
EPHEDRINE 2 (<1%) 1 (<1%)
ERYTHROMYCIN 2 (<1%) 1 (<1%)
LIDOCAINE 2 (<1%) 1 (<1%)

Table 6.12
4mg IV
Zofran +
4mg IV 50mg PO
-------------------------------------------------------------
DICLOFENAC RESINATE 0 2 (<1%)
GENTAMICIN 2 (<1%) 0
NEOSTIGMINE 2 (<1%) 0
CONFIDENTIAL
ACYCLOVIR 0 1 (<1%)
AMPICILLIN SODIUM 1 (<1%) 0
141
BIMATOPROST 0 1 (<1%)
CORTISONE ACETATE 1 (<1%) 0
DICLOFENAC DIETHYLAMINE 1 (<1%) 0
FAMCICLOVIR 0 1 (<1%)
HYPROMELLOSE 1 (<1%) 0
OFLOXACIN 1 (<1%) 0
OXYMETAZOLINE HYDROCHLORIDE 0 1 (<1%)
PINDOLOL 1 (<1%) 0
PREDNISOLONE ACETATE 0 1 (<1%)
GM2006/00652/00
PROPYLENE GLYCOL 0 1 (<1%)
RETINOL 0 1 (<1%)
TIMOLOL MALEATE 1 (<1%) 0
NKT102553
MUSCULO-SKELETAL SYSTEM

Table 6.12
4mg IV
Zofran +
4mg IV 50mg PO
-------------------------------------------------------------
Any Medication 122 (50%) 110 (45%)
IBUPROFEN 47 (19%) 44 (18%)
DICLOFENAC SODIUM 10 (4%) 12 (5%)
ETORICOXIB 14 (6%) 8 (3%)
KETOROLAC 11 (5%) 8 (3%)
MEFENAMIC ACID 8 (3%) 5 (2%)
CONFIDENTIAL
PARECOXIB SODIUM 8 (3%) 5 (2%)
CELECOXIB 8 (3%) 3 (1%)
DICLOFENAC 6 (2%) 5 (2%)
142
NAPROXEN 5 (2%) 5 (2%)

NAPROXEN SODIUM 6 (2%) 3 (1%)
ALENDRONATE SODIUM 5 (2%) 0
NIMESULIDE 2 (<1%) 3 (1%)
GLUCOSAMINE 4 (2%) 0
CYCLOBENZAPRINE HYDROCHLORIDE 1 (<1%) 2 (<1%)
MELOXICAM 0 3 (1%)
DICLOFENAC RESINATE 0 2 (<1%)
METAXALONE 1 (<1%) 1 (<1%)
MIVACURIUM 2 (<1%) 0
RISEDRONATE SODIUM 2 (<1%) 0
SUXAMETHONIUM 2 (<1%) 0
GM2006/00652/00
ALLOPURINOL 0 1 (<1%)
CAPSAICIN 1 (<1%) 0
CHONDROITIN SULFATE 1 (<1%) 0
CISATRACURIUM 1 (<1%) 0
NKT102553
CYCLOBENZAPRINE 0 1 (<1%)
DICLOFENAC DIETHYLAMINE 1 (<1%) 0
METHOCARBAMOL 0 1 (<1%)

Table 6.12
4mg IV
Zofran +
4mg IV 50mg PO
-------------------------------------------------------------
NIFLUMIC ACID 0 1 (<1%)
ROCURONIUM 1 (<1%) 0
ROCURONIUM BROMIDE 1 (<1%) 0
SODIUM IBANDRONATE 1 (<1%) 0
TIZANIDINE HYDROCHLORIDE 1 (<1%) 0
VECURONIUM 1 (<1%) 0
CONFIDENTIAL
GENITO URINARY SYSTEM AND SEX
HORMONES
Any Medication 94 (39%) 91 (38%)
143
IBUPROFEN 47 (19%) 44 (18%)

ESTRADIOL 11 (5%) 12 (5%)
MAGNESIUM HYDROXIDE 13 (5%) 10 (4%)
ETHINYLOESTRADIOL 9 (4%) 7 (3%)
ESTROGENS CONJUGATED 6 (2%) 5 (2%)
NAPROXEN 5 (2%) 5 (2%)
NAPROXEN SODIUM 6 (2%) 3 (1%)
CLINDAMYCIN 2 (<1%) 5 (2%)
MEDROXYPROGESTERONE ACETATE 2 (<1%) 4 (2%)
NORGESTIMATE 4 (2%) 1 (<1%)
SODIUM PHOSPHATE MONOBASIC 0 5 (2%)
GM2006/00652/00
DROSPIRENONE 1 (<1%) 3 (1%)
FURADONINE 3 (1%) 1 (<1%)
ESTROGENS ESTERIFIED 1 (<1%) 2 (<1%)
NORETHISTERONE 0 3 (1%)
NKT102553
NORETHISTERONE ACETATE 1 (<1%) 2 (<1%)
NORGESTREL 1 (<1%) 2 (<1%)
PROGESTERONE 1 (<1%) 2 (<1%)

Table 6.12
4mg IV
Zofran +
4mg IV 50mg PO
-------------------------------------------------------------
CLOMIFENE CITRATE 2 (<1%) 0
HORMONAL CONTRACEPTIVES FOR 0 2 (<1%)
SYSTEMIC USE
LEVONORGESTREL 2 (<1%) 0
MESTRANOL 0 2 (<1%)
METHYLTESTOSTERONE 0 2 (<1%)
MISOPROSTOL 0 2 (<1%)
CONFIDENTIAL
OXYBUTYNIN HYDROCHLORIDE 1 (<1%) 1 (<1%)
PHENAZOPYRIDINE HYDROCHLORIDE 2 (<1%) 0
TOLTERODINE TARTRATE 1 (<1%) 1 (<1%)
144
VACCINIUM MACROCARPON 1 (<1%) 1 (<1%)

BROMOCRIPTINE MESILATE 0 1 (<1%)
CHORIONIC GONADOTROPHIN 1 (<1%) 0
CIMICIFUGA RACEMOSA 1 (<1%) 0
COLLAGEN 0 1 (<1%)
FLAVOXATE HYDROCHLORIDE 0 1 (<1%)
HORMONE REPLACEMENT THERAPY (NOS) 1 (<1%) 0
MEDROGESTONE 1 (<1%) 0
MEDROXYPROGESTERONE 1 (<1%) 0
METHYLTHIONINIUM CHLORIDE 0 1 (<1%)
GM2006/00652/00
PHENYL SALICYLATE 0 1 (<1%)
RALOXIFENE HYDROCHLORIDE 1 (<1%) 0
TESTOSTERONE 1 (<1%) 0
NKT102553
ANTIINFECTIVES FOR SYSTEMIC USE

Table 6.12
4mg IV
Zofran +
4mg IV 50mg PO
-------------------------------------------------------------
CEFAZOLIN SODIUM 20 (8%) 14 (6%)
CEFALEXIN 18 (7%) 14 (6%)
CEFAZOLIN 10 (4%) 7 (3%)
CEFOXITIN 10 (4%) 6 (2%)
AMOXICILLIN TRIHYDRATE 6 (2%) 7 (3%)
CEFUROXIME SODIUM 6 (2%) 7 (3%)
CONFIDENTIAL
CLAVULANATE POTASSIUM 6 (2%) 6 (2%)
CIPROFLOXACIN 6 (2%) 4 (2%)
CIPROFLOXACIN HYDROCHLORIDE 5 (2%) 4 (2%)
145
AMPICILLIN 5 (2%) 2 (<1%)

CEFTRIAXONE 2 (<1%) 5 (2%)
DOXYCYCLINE 3 (1%) 4 (2%)
CEFUROXIME 1 (<1%) 4 (2%)
LEVOFLOXACIN 3 (1%) 2 (<1%)
SULFAMETHOXAZOLE 2 (<1%) 3 (1%)
TRIMETHOPRIM 2 (<1%) 3 (1%)
AMOXICILLIN 4 (2%) 0
FURADONINE 3 (1%) 1 (<1%)
SULBACTAM 4 (2%) 0
CEFOTETAN 3 (1%) 0
GM2006/00652/00
SULTAMICILLIN 2 (<1%) 1 (<1%)
CLOXACILLIN 0 2 (<1%)
ERTAPENEM SODIUM 2 (<1%) 0
NKT102553
UNASYN (NOS) 1 (<1%) 1 (<1%)
VALACICLOVIR HYDROCHLORIDE 2 (<1%) 0

Table 6.12
4mg IV
Zofran +
4mg IV 50mg PO
-------------------------------------------------------------
ACYCLOVIR 0 1 (<1%)
AMPICILLIN SODIUM 1 (<1%) 0
CEFADROXIL 1 (<1%) 0
CEFIXIME 1 (<1%) 0
CEFOTAXIME SODIUM 0 1 (<1%)
CEFOTETAN DISODIUM 1 (<1%) 0
CEFOXITIN SODIUM 0 1 (<1%)
CONFIDENTIAL
CEFTRIAXONE SODIUM 1 (<1%) 0
CLARITHROMYCIN 0 1 (<1%)
CLOXACILLIN SODIUM 0 1 (<1%)
146
FAMCICLOVIR 0 1 (<1%)
LAMIVUDINE 1 (<1%) 0
LOPINAVIR 1 (<1%) 0
METHENAMINE 0 1 (<1%)
MINOCYCLINE HYDROCHLORIDE 1 (<1%) 0
MUPIROCIN 0 1 (<1%)
OFLOXACIN 1 (<1%) 0
PHENOXYMETHYLPENICILLIN 0 1 (<1%)
RITONAVIR 1 (<1%) 0
GM2006/00652/00
SULBACTAM SODIUM 1 (<1%) 0
SULFADIAZINE SILVER 1 (<1%) 0
ZIDOVUDINE 1 (<1%) 0
NKT102553
VARIOUS

Table 6.12
4mg IV
Zofran +
4mg IV 50mg PO
-------------------------------------------------------------
GLUCOSE 52 (21%) 44 (18%)
OXYGEN 29 (12%) 16 (7%)
GLYCYRRHIZA (NOS) 3 (1%) 4 (2%)
ELECTTARIA CARDAMOMUM 5 (2%) 1 (<1%)
BLOOD TRANSFUSION, AUXILIARY 2 (<1%) 3 (1%)
PRODUCTS
CONFIDENTIAL
SORBITOL 3 (1%) 2 (<1%)
SOYBEAN 1 (<1%) 2 (<1%)
IRRIGATING SOLUTIONS (NOS) 1 (<1%) 1 (<1%)
147
MEGLUMINE AMIDOTRIZOATE 2 (<1%) 0

VACCINIUM MACROCARPON 1 (<1%) 1 (<1%)
ALLERGENS (NOS) 0 1 (<1%)
ALLIUM SATIVUM 1 (<1%) 0
APIS MELLIFERA EXTRACT 1 (<1%) 0
CHONDROITIN SULFATE 1 (<1%) 0
COLLAGEN 0 1 (<1%)
DIOSCOREA VILLOSA 0 1 (<1%)
HONEY 1 (<1%) 0
HYPROMELLOSE 1 (<1%) 0
LINUM USITATISSIMUM OIL 0 1 (<1%)
GM2006/00652/00
METHYLTHIONINIUM CHLORIDE 0 1 (<1%)
MONASCUS PURPUREUS 1 (<1%) 0
NALOXONE HYDROCHLORIDE 1 (<1%) 0
NALTREXONE 1 (<1%) 0
NKT102553
PHOSPHORIC ACID, SODIUM SALT 0 1 (<1%)
PLANTAGO OVATA 1 (<1%) 0
PROPYLENE GLYCOL 0 1 (<1%)

Table 6.12
4mg IV
Zofran +
4mg IV 50mg PO
-------------------------------------------------------------
SODIUM AMIDOTRIZOATE 1 (<1%) 0
STERILE WATER 1 (<1%) 0
VALERIANA OFFICINALIS EXTRACT 1 (<1%) 0
WATER 0 1 (<1%)
ZINGIBER OFFICINALE 1 (<1%) 0
CARDIOVASCULAR SYSTEM
CONFIDENTIAL
HYDROCHLOROTHIAZIDE 23 (10%) 14 (6%)
HEPARIN (NOS) 13 (5%) 7 (3%)
148
ATENOLOL 3 (1%) 9 (4%)

SIMVASTATIN 3 (1%) 9 (4%)
METOPROLOL SUCCINATE 5 (2%) 6 (2%)
LISINOPRIL 6 (2%) 4 (2%)
AMLODIPINE BESILATE 6 (2%) 3 (1%)
ENALAPRIL MALEATE 3 (1%) 6 (2%)
VALSARTAN 6 (2%) 3 (1%)
ATORVASTATIN CALCIUM 2 (<1%) 6 (2%)
ENALAPRIL 6 (2%) 2 (<1%)
METOPROLOL TARTRATE 3 (1%) 4 (2%)
FUROSEMIDE 3 (1%) 3 (1%)
METOPROLOL 4 (2%) 2 (<1%)
GM2006/00652/00
NIFEDIPINE 4 (2%) 2 (<1%)
RAMIPRIL 2 (<1%) 4 (2%)
TRIMETAZIDINE HYDROCHLORIDE 3 (1%) 3 (1%)
AMILORIDE HYDROCHLORIDE 4 (2%) 1 (<1%)
NKT102553
FENOFIBRATE 3 (1%) 2 (<1%)
GLYCERYL TRINITRATE 2 (<1%) 3 (1%)
PRAZOSIN HYDROCHLORIDE 4 (2%) 1 (<1%)

Table 6.12
4mg IV
Zofran +
4mg IV 50mg PO
-------------------------------------------------------------
AMLODIPINE 3 (1%) 1 (<1%)
BENAZEPRIL HYDROCHLORIDE 3 (1%) 1 (<1%)
BISOPROLOL FUMARATE 3 (1%) 1 (<1%)
DILTIAZEM HYDROCHLORIDE 2 (<1%) 2 (<1%)
TRIAMTERENE 3 (1%) 1 (<1%)
CAPTOPRIL 2 (<1%) 1 (<1%)
CLONIDINE 1 (<1%) 2 (<1%)
CONFIDENTIAL
IRBESARTAN 2 (<1%) 1 (<1%)
LIDOCAINE 2 (<1%) 1 (<1%)
OLMESARTAN 3 (1%) 0
149
PROPRANOLOL 2 (<1%) 1 (<1%)

VERAPAMIL HYDROCHLORIDE 2 (<1%) 1 (<1%)
BETAHISTINE HYDROCHLORIDE 1 (<1%) 1 (<1%)
BISOPROLOL 0 2 (<1%)
CLOPAMIDE 1 (<1%) 1 (<1%)
FELODIPINE 2 (<1%) 0
GUANFACINE 1 (<1%) 1 (<1%)
ISRADIPINE 0 2 (<1%)
LOSARTAN POTASSIUM 1 (<1%) 1 (<1%)
GM2006/00652/00
NITROMINT (NOS) 1 (<1%) 1 (<1%)
PENTOXIFYLLINE 1 (<1%) 1 (<1%)
PERINDOPRIL 1 (<1%) 1 (<1%)
PRAVASTATIN SODIUM 0 2 (<1%)
NKT102553
PROPRANOLOL HYDROCHLORIDE 2 (<1%) 0
SPIRONOLACTONE 1 (<1%) 1 (<1%)
TRIMETAZIDINE 2 (<1%) 0

Table 6.12
4mg IV
Zofran +
4mg IV 50mg PO
-------------------------------------------------------------
BENDROFLUMETHIAZIDE 1 (<1%) 0
BUMETANIDE 0 1 (<1%)
CAMPHOR 1 (<1%) 0
CARVEDILOL 1 (<1%) 0
CHLORTALIDONE 0 1 (<1%)
COLESEVELAM HYDROCHLORIDE 0 1 (<1%)
COLESTYRAMINE 1 (<1%) 0
CONFIDENTIAL
DILTIAZEM 0 1 (<1%)
DOXAZOSIN MESILATE 0 1 (<1%)
150
EPROSARTAN MESILATE 1 (<1%) 0

FOSINOPRIL SODIUM 0 1 (<1%)
GEMFIBROZIL 0 1 (<1%)
ISOSORBIDE MONONITRATE 0 1 (<1%)
LABETALOL 0 1 (<1%)
LERCANIDIPINE 0 1 (<1%)
LERCANIDIPINE HYDROCHLORIDE 0 1 (<1%)
LOVASTATIN 1 (<1%) 0
MANIDIPINE HYDROCHLORIDE 1 (<1%) 0
MOLSIDOMINE 0 1 (<1%)
MONASCUS PURPUREUS 1 (<1%) 0
MOXONIDINE 1 (<1%) 0
GM2006/00652/00
NADOLOL 1 (<1%) 0
NICERGOLINE 0 1 (<1%)
NICOTINIC ACID 1 (<1%) 0
NOREPINEPHRINE 1 (<1%) 0
NKT102553
OMEGA-3 MARINE TRIGLYCERIDES 1 (<1%) 0
PINDOLOL 1 (<1%) 0

Table 6.12
4mg IV
Zofran +
4mg IV 50mg PO
-------------------------------------------------------------
QUINAPRIL 0 1 (<1%)
QUINAPRIL HYDROCHLORIDE 1 (<1%) 0
ROSUVASTATIN CALCIUM 1 (<1%) 0
RUTOSIDE 0 1 (<1%)
TIMOLOL MALEATE 1 (<1%) 0
TROXERUTIN 0 1 (<1%)
VERAPAMIL 1 (<1%) 0
CONFIDENTIAL
DERMATOLOGICALS
151
BENADRYL (NOS) 6 (2%) 8 (3%)

TOCOPHEROL 9 (4%) 2 (<1%)
GLYCEROL 4 (2%) 6 (2%)
FLUTICASONE PROPIONATE 7 (3%) 2 (<1%)
ANTIMONY POTASSIUM TARTRATE 3 (1%) 4 (2%)
GLYCERYL TRINITRATE 2 (<1%) 3 (1%)
IODINE 3 (1%) 2 (<1%)
DIPHENHYDRAMINE HYDROCHLORIDE 3 (1%) 1 (<1%)
GM2006/00652/00
LIDOCAINE 2 (<1%) 1 (<1%)
BENZALKONIUM CHLORIDE 2 (<1%) 0
GELATIN 0 2 (<1%)
NKT102553
MOMETASONE FUROATE 2 (<1%) 0

Table 6.12
4mg IV
Zofran +
4mg IV 50mg PO
-------------------------------------------------------------
ACYCLOVIR 0 1 (<1%)
AZELAIC ACID 1 (<1%) 0
BACITRACIN ZINC 0 1 (<1%)
CALCIUM GLUCONATE 1 (<1%) 0
CAMPHOR 1 (<1%) 0
COLLAGEN 0 1 (<1%)
CONFIDENTIAL
DIPHENHYDRAMINE 1 (<1%) 0
152

MUPIROCIN 0 1 (<1%)
PHENYL SALICYLATE 0 1 (<1%)
RETINOL 0 1 (<1%)
SELENIUM 1 (<1%) 0
SULFADIAZINE SILVER 1 (<1%) 0
SULFUR 0 1 (<1%)
TERBINAFINE HYDROCHLORIDE 0 1 (<1%)
TITANIUM DIOXIDE 0 1 (<1%)
GM2006/00652/00
ANTINEOPLASTIC AND
IMMUNOMODULATING AGENTS
NKT102553
ESTRADIOL 11 (5%) 12 (5%)
ETHINYLOESTRADIOL 9 (4%) 7 (3%)

Table 6.12
4mg IV
Zofran +
4mg IV 50mg PO
-------------------------------------------------------------
ESTROGENS CONJUGATED 6 (2%) 5 (2%)
MEDROXYPROGESTERONE ACETATE 2 (<1%) 4 (2%)
TAMOXIFEN 3 (1%) 1 (<1%)
ESTROGENS ESTERIFIED 1 (<1%) 2 (<1%)
METHOTREXATE 1 (<1%) 2 (<1%)
URETHANE 0 3 (1%)
LEUPRORELIN ACETATE 1 (<1%) 1 (<1%)
CONFIDENTIAL
LETROZOLE 1 (<1%) 0
MEDROXYPROGESTERONE 1 (<1%) 0
METHOTREXATE SODIUM 1 (<1%) 0
153
RALOXIFENE HYDROCHLORIDE 1 (<1%) 0

TAMOXIFEN CITRATE 1 (<1%) 0
SYSTEMIC HORMONAL PREPARATIONS,

EXCL. SEX HORMONES
LEVOTHYROXINE SODIUM 21 (9%) 21 (9%)
IODINE 3 (1%) 2 (<1%)
LEVOTHYROXINE 3 (1%) 2 (<1%)
THIAMAZOLE 4 (2%) 1 (<1%)
LIOTHYRONINE 3 (1%) 1 (<1%)
GM2006/00652/00
CALCITONIN, SALMON 0 1 (<1%)
CORTISONE ACETATE 1 (<1%) 0
NKT102553
PROPYLTHIOURACIL 0 1 (<1%)

Table 6.12
4mg IV
Zofran +
4mg IV 50mg PO
-------------------------------------------------------------
ANTIPARASITIC PRODUCTS,
INSECTICIDES AND REPELLENT
CHLOROQUINE PHOSPHATE 1 (<1%) 0
SULFUR 0 1 (<1%)
CONFIDENTIAL
154
GM2006/00652/00
NKT102553
Table 6.13
Summary of Anti-emetic Rescue Medications taken during Entire Study
4mg IV
Zofran +
4mg IV 50mg PO
Zofran Casopitant
-------------------------------------------------------------
ALIMENTARY TRACT AND METABOLISM

ONDANSETRON 25 (10%) 12 (5%)
DIMENHYDRINATE 11 (5%) 12 (5%)
CONFIDENTIAL
METOCLOPRAMIDE HYDROCHLORIDE 10 (4%) 11 (5%)
DEXAMETHASONE 8 (3%) 5 (2%)
155
PROCHLORPERAZINE 5 (2%) 3 (1%)

DOLASETRON MESILATE 5 (2%) 0
POTASSIUM CHLORIDE 4 (2%) 1 (<1%)
GRANISETRON 2 (<1%) 1 (<1%)
DOMPERIDONE 1 (<1%) 1 (<1%)
HYOSCINE 0 2 (<1%)
DIMETICONE, ACTIVATED 1 (<1%) 0
DOLASETRON 1 (<1%) 0
GRANISETRON HYDROCHLORIDE 0 1 (<1%)
ONDANSETRON HYDROCHLORIDE 0 1 (<1%)
GM2006/00652/00
RESPIRATORY SYSTEM
NKT102553

Table 6.13
4mg IV
Zofran +
4mg IV 50mg PO
Zofran Casopitant
-------------------------------------------------------------
CYCLIZINE 1 (<1%) 0
FEXOFENADINE HYDROCHLORIDE 0 1 (<1%)
PSEUDOEPHEDRINE HYDROCHLORIDE 0 1 (<1%)
NERVOUS SYSTEM
CONFIDENTIAL
HALOPERIDOL 3 (1%) 1 (<1%)
HYOSCINE 0 2 (<1%)
156

CHLORPROMAZINE 1 (<1%) 0
DERMATOLOGICALS
SENSORY ORGANS
GM2006/00652/00
HYOSCINE 0 2 (<1%)
NKT102553

Table 6.13
4mg IV
Zofran +
4mg IV 50mg PO
Zofran Casopitant
-------------------------------------------------------------
SYSTEMIC HORMONAL PREPARATIONS,
EXCL. SEX HORMONES
BLOOD AND BLOOD FORMING ORGANS

CONFIDENTIAL
CALCIUM CHLORIDE 4 (2%) 1 (<1%)
POTASSIUM CHLORIDE 4 (2%) 1 (<1%)
157
GM2006/00652/00
NKT102553
Table 6.14
Summary of Treatment Compliance
4mg IV
Zofran +
4mg IV 50mg PO
Investigational Compliance Zofran Casopitant
Product Category (N=242) (N=242)
-------------------------------------------------------
Zofran 0% 8 (3%) 9 (4%)
100% 234 (97%) 233 (96%)
GW679769 0% 5 (2%) 7 (3%)

33% 0 0
67% 0 0
100% 237 (98%) 235 (97%)
CONFIDENTIAL
158
GM2006/00652/00
NKT102553
Table 6.15
Summary of Major Protocol Deviations
4mg IV Zofran
+ 50mg PO
Protocol Violation (N=242) (N=242) (N=484)
------------------------------------------------------------
Total Number of 89 (37%) 81 (33%) 170 (35%)
Major Protocol
Deviators
Duration of 47 (19%) 47 (19%) 94 (19%)

anesthesia <= 45
minutes
CONFIDENTIAL
Inclusion #7 1 (<1%) 3 (1%) 4 (<1%)
159
NG tube and 2 (<1%) 2 (<1%) 4 (<1%)

Suction
No study 5 (2%) 7 (3%) 12 (2%)

medication taken
No surgery record 7 (3%) 9 (4%) 16 (3%)
Received med 1 (<1%) 1 (<1%) 2 (<1%)

inhibitors of
CYP3A4/CYP3A5
GM2006/00652/00
Received 1 (<1%) 2 (<1%) 3 (<1%)
Anitemetic
Medication
NKT102553
Received 13 (5%) 14 (6%) 27 (6%)
Prohibited
Medication
Table 6.15
Summary of Major Protocol Deviations
4mg IV Zofran
+ 50mg PO
Protocol Violation (N=242) (N=242) (N=484)
------------------------------------------------------------
Subject did not 35 (14%) 29 (12%) 64 (13%)
enter diary data
CONFIDENTIAL
160
GM2006/00652/00
NKT102553
Table 6.16
Listing of Current Medical Conditions
(Nervous System Disorders Only)
Medical
condition MedDRA lower
Treatment Centre Subj. classification level term text Condition Status
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient
privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further
information please see the Patient Level Data section of the Sponsor Clinical Study Register.
CONFIDENTIAL
161
GM2006/00652/00
NKT102553
Table 6.99
Listing of Selected Antiemetic Rescue Medication
Treatment: 4mg IV Zofran

Drug Ongoing Was drug
Component Centre Medi- a rescue
Ingredient Subj. ID cation? med?
This section contained data from each individual patient, rather than in aggregate. They have been
excluded to protect patient privacy. Anonymized data from each patient may be made available subject to
an approved research proposal. For further information please see the Patient Level Data section of the
Sponsor Clinical Study Register.
CONFIDENTIAL
171
GM2006/00652/00
NKT102553
NKT102553
EFFICACY DATA SOURCE FIGURES AND TABLES
Page
episode . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
medication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
Figure 3 Kaplan-Meier curves for time from last suture/staple to first CR
failure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
Table 7.1 Summary of Complete Response (0 - 24 hours) (Modified
Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
Table 7.2 Summary of Complete Response (0 - 24 hours) (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
Table 7.5 Summary of Complete Protection (0 - 24 hours) (Modified
Table 7.8 Summary of Total Control (0 - 24 hours) (Modified Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
Table 7.9 Summary of Total Control (24 - 48 hours) (Modified
Table 7.10 Summary of Total Control (0 - 48 hours) (Modified
Table 7.11 Summary of Vomiting (0 - 24 hours) (Modified Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
Table 7.12 Summary of Vomiting (24-48 hours) (Modified Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
Table 7.13 Summary of Vomiting (0 - 48 hours) (Modified Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
Table 7.14 Summary of Significant Nausea (0 - 2 hours) (Modified
176
NKT102553

Table 7.17 Summary of Significant Nausea (24-48 hours) (Modified
Table 7.19 Summary of Nausea (0 - 2 hours) (Modified Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
Table 7.22 Summary of Nausea (24-48 hours) (Modified Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
Table 7.24 Summary of Maximum Nausea Score (0 - 24 hours) (Modified
Table 7.27 Summary of Nausea (Categorical Score) (0 - 24 hours)
(Modified Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
Table 7.30 Summary of Time-to-Emesis (Modified Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
Table 7.31 Summary of Time-to-Rescue (Modified Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
Table 7.32 Summary of Subject Satisfaction (0 to 48 hours) (Modified
Table 7.33 Summary of Subject Willingness (0 to 48 hours) (Modified
Table 7.34 Summary of Rescue (0 - 24 hours) (Modified Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
177
NKT102553
Table 7.35 Summary of Rescue (24-48 hours) (Modified Intent-to-Treat

Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
Table 7.36 Summary of Rescue (0 - 48 hours) (Modified Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
Table 7.37 Summary of Medical Resource Utilization (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
Table 7.38 Summary of Time-to-Emesis Hazard Ratios - Treatment Only
Model (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
Table 7.39 Summary of Time-to-Rescue Hazard Ratios - Treatment Only
Model (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
Table 7.54 Summary of Antiemetic Rescue Medication (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
178
NKT102553
179
NKT102553
180
NKT102553
181
Population: Modified Intent-to-Treat
Table 7.1
Summary of Complete Response (0 - 24 hours)
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
-----------------------------------------------------------
Complete Response
Yes 138/235 ( 59%) 160/233 ( 69%)
No 97/235 ( 41%) 73/233 ( 31%)
Stratification
N2O anticipated 75/123 ( 61%) 95/125 ( 76%)
No N2O anticipated 63/112 ( 56%) 65/108 ( 60%)
CMH p-value 0.0268
CONFIDENTIAL
Odds Ratio 1.5351
Confidence Interval (1.05, 2.25)
182
GM2006/00652/00
NKT102553
Table 7.2
4mg IV Zofran +
50mg Oral
(N=242) (N=242)
-----------------------------------------------------------
Complete Response
Yes 138/242 ( 57%) 160/242 ( 66%)
No 104/242 ( 43%) 82/242 ( 34%)
Stratification
N2O anticipated 75/128 ( 59%) 95/128 ( 74%)
CMH p-value 0.0391
CONFIDENTIAL
Odds Ratio 1.4723
183
GM2006/00652/00
NKT102553
Table 7.3
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
-----------------------------------------------------------
Complete Response
Yes 149/235 ( 63%) 163/233 ( 70%)
No 86/235 ( 37%) 70/233 ( 30%)
Stratification
N2O anticipated 83/123 ( 67%) 97/125 ( 78%)
CMH p-value 0.1400
CONFIDENTIAL
Odds Ratio 1.3393
184
GM2006/00652/00
NKT102553
Table 7.4
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
-----------------------------------------------------------
Complete Response
Yes 134/235 ( 57%) 152/233 ( 65%)
No 101/235 ( 43%) 81/233 ( 35%)
Stratification
N2O anticipated 73/123 ( 59%) 91/125 ( 73%)
CMH p-value 0.0720
CONFIDENTIAL
Odds Ratio 1.4093
185
GM2006/00652/00
NKT102553
Table 7.5
Summary of Complete Protection (0 - 24 hours)
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
-----------------------------------------------------------
Complete Protection
Yes 102/235 ( 43%) 120/233 ( 52%)
No 133/235 ( 57%) 113/233 ( 48%)
Stratification
N2O anticipated 64/123 ( 52%) 77/125 ( 62%)
CMH p-value 0.0838
CONFIDENTIAL
Odds Ratio 1.3882
186
GM2006/00652/00
NKT102553
Table 7.6
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
-----------------------------------------------------------
Complete Protection
Yes 142/235 ( 60%) 152/233 ( 65%)
No 93/235 ( 40%) 81/233 ( 35%)
Stratification
N2O anticipated 81/123 ( 66%) 92/125 ( 74%)
CMH p-value 0.2967
CONFIDENTIAL
Odds Ratio 1.2241
187
GM2006/00652/00
NKT102553
Table 7.7
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
-----------------------------------------------------------
Complete Protection
Yes 97/235 ( 41%) 110/233 ( 47%)
No 138/235 ( 59%) 123/233 ( 53%)
Stratification
N2O anticipated 62/123 ( 50%) 70/125 ( 56%)
CMH p-value 0.2081
CONFIDENTIAL
Odds Ratio 1.2707
188
GM2006/00652/00
NKT102553
Table 7.8
Summary of Total Control (0 - 24 hours)
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
-----------------------------------------------------------
Total Control
Yes 94/235 ( 40%) 107/233 ( 46%)
No 141/235 ( 60%) 126/233 ( 54%)
Stratification
N2O anticipated 60/123 ( 49%) 67/125 ( 54%)
CMH p-value 0.2072
CONFIDENTIAL
Odds Ratio 1.2714
189
GM2006/00652/00
NKT102553
Table 7.9
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
-----------------------------------------------------------
Total Control
Yes 140/235 ( 60%) 148/233 ( 64%)
No 95/235 ( 40%) 85/233 ( 36%)
Stratification
N2O anticipated 79/123 ( 64%) 90/125 ( 72%)
CMH p-value 0.3991
CONFIDENTIAL
Odds Ratio 1.1757
190
GM2006/00652/00
NKT102553
Table 7.10
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
-----------------------------------------------------------
Total Control
Yes 88/235 ( 37%) 99/233 ( 42%)
No 147/235 ( 63%) 134/233 ( 58%)
Stratification
N2O anticipated 57/123 ( 46%) 61/125 ( 49%)
CMH p-value 0.2804
CONFIDENTIAL
Odds Ratio 1.2299
191
GM2006/00652/00
NKT102553
Table 7.11
Summary of Vomiting (0 - 24 hours)
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
-----------------------------------------------------------
Vomitting
No 176/235 ( 75%) 209/233 ( 90%)
Yes 59/235 ( 25%) 24/233 ( 10%)
Stratification
N2O anticipated 91/123 ( 74%) 112/125 ( 90%)
CMH p-value 0.0000
CONFIDENTIAL
Odds Ratio 0.3422
192
GM2006/00652/00
NKT102553
Table 7.12
Summary of Vomiting (24-48 hours)
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
-----------------------------------------------------------
Vomitting
No 223/235 ( 95%) 228/233 ( 98%)
Yes 12/235 ( 5%) 5/233 ( 2%)
Stratification
N2O anticipated 119/123 ( 97%) 123/125 ( 98%)
CMH p-value 0.0905
CONFIDENTIAL
Odds Ratio 0.4111
193
GM2006/00652/00
NKT102553
Table 7.13
Summary of Vomiting (0 - 48 hours)
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
-----------------------------------------------------------
Vomitting
No 172/235 ( 73%) 205/233 ( 88%)
Yes 63/235 ( 27%) 28/233 ( 12%)
Stratification
N2O anticipated 90/123 ( 73%) 110/125 ( 88%)
CMH p-value 0.0001
CONFIDENTIAL
Odds Ratio 0.3729
194
GM2006/00652/00
NKT102553
Table 7.14
Summary of Significant Nausea (0 - 2 hours)
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
-----------------------------------------------------------
Significant
Nausea
No 192/235 ( 82%) 184/233 ( 79%)
Yes 43/235 ( 18%) 49/233 ( 21%)
Stratification
N2O anticipated 108/123 ( 88%) 106/125 ( 85%)
CONFIDENTIAL
CMH p-value 0.4254
Odds Ratio 1.2073
195
GM2006/00652/00
NKT102553
Table 7.15
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
-----------------------------------------------------------
Significant
Nausea
No 152/235 ( 65%) 158/233 ( 68%)
Yes 83/235 ( 35%) 75/233 ( 32%)
Stratification
N2O anticipated 95/123 ( 77%) 100/125 ( 80%)
CONFIDENTIAL
CMH p-value 0.5080
Odds Ratio 0.8736
196
GM2006/00652/00
NKT102553
Table 7.16
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
-----------------------------------------------------------
Significant
Nausea
No 120/235 ( 51%) 134/233 ( 58%)
Yes 115/235 ( 49%) 99/233 ( 42%)
Stratification
N2O anticipated 76/123 ( 62%) 87/125 ( 70%)
CONFIDENTIAL
CMH p-value 0.1709
Odds Ratio 0.7689
197
GM2006/00652/00
NKT102553
Table 7.17
Summary of Significant Nausea (24-48 hours)
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
-----------------------------------------------------------
Significant
Nausea
No 204/235 ( 87%) 196/233 ( 84%)
Yes 31/235 ( 13%) 37/233 ( 16%)
Stratification
N2O anticipated 109/123 ( 89%) 110/125 ( 88%)
CONFIDENTIAL
CMH p-value 0.3949
Odds Ratio 1.2515
198
GM2006/00652/00
NKT102553
Table 7.18
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
-----------------------------------------------------------
Significant
Nausea
No 115/235 ( 49%) 125/233 ( 54%)
Yes 120/235 ( 51%) 108/233 ( 46%)
Stratification
N2O anticipated 74/123 ( 60%) 81/125 ( 65%)
CONFIDENTIAL
CMH p-value 0.3279
Odds Ratio 0.8296
199
GM2006/00652/00
NKT102553
Table 7.19
Summary of Nausea (0 - 2 hours)
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
-----------------------------------------------------------
Nausea
No 181/235 ( 77%) 179/233 ( 77%)
Yes 54/235 ( 23%) 54/233 ( 23%)
Stratification
N2O anticipated 106/123 ( 86%) 103/125 ( 82%)
CMH p-value 0.9166
CONFIDENTIAL
Odds Ratio 1.0230
200
GM2006/00652/00
NKT102553
Table 7.20
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
-----------------------------------------------------------
Nausea
No 141/235 ( 60%) 149/233 ( 64%)
Yes 94/235 ( 40%) 84/233 ( 36%)
Stratification
N2O anticipated 90/123 ( 73%) 93/125 ( 74%)
CMH p-value 0.4048
CONFIDENTIAL
Odds Ratio 0.8482
201
GM2006/00652/00
NKT102553
Table 7.21
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
-----------------------------------------------------------
Nausea
No 104/235 ( 44%) 118/233 ( 51%)
Yes 131/235 ( 56%) 115/233 ( 49%)
Stratification
N2O anticipated 67/123 ( 54%) 74/125 ( 59%)
CMH p-value 0.1765
CONFIDENTIAL
Odds Ratio 0.7740
202
GM2006/00652/00
NKT102553
Table 7.22
Summary of Nausea (24-48 hours)
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
-----------------------------------------------------------
Nausea
No 200/235 ( 85%) 191/233 ( 82%)
Yes 35/235 ( 15%) 42/233 ( 18%)
Stratification
N2O anticipated 105/123 ( 85%) 107/125 ( 86%)
CMH p-value 0.3529
CONFIDENTIAL
Odds Ratio 1.2602
203
GM2006/00652/00
NKT102553
Table 7.23
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
-----------------------------------------------------------
Nausea
No 98/235 ( 42%) 110/233 ( 47%)
Yes 137/235 ( 58%) 123/233 ( 53%)
Stratification
N2O anticipated 64/123 ( 52%) 68/125 ( 54%)
CMH p-value 0.2444
CONFIDENTIAL
Odds Ratio 0.8018
204
GM2006/00652/00
NKT102553
Table 7.24
Summary of Maximum Nausea Score (0 – 24 hours)
4mg IV
Zofran +
4mg IV 50mg Oral
Zofran Casopitant
(N=235) (N=233)
---------------------------------------------------
Maximum N 235 233
Nausea
Mean 3.2 2.6
STD 3.4 3.2
CONFIDENTIAL
Median 2.0 0.0
Min 0.0 0.0

205
Max 10.0 10.0
PVAL 0.0857
GM2006/00652/00
NKT102553
Table 7.25
4mg IV
Zofran +
4mg IV 50mg Oral
Zofran Casopitant
(N=235) (N=233)
---------------------------------------------------
Maximum N 235 233
Nausea
Mean 0.8 0.9
STD 2.1 2.0
CONFIDENTIAL
Median 0.0 0.0
Min 0.0 0.0

206
Max 10.0 10.0
PVAL 0.4192
GM2006/00652/00
NKT102553
Table 7.26
4mg IV
Zofran +
4mg IV 50mg Oral
Zofran Casopitant
(N=235) (N=233)
---------------------------------------------------
Maximum N 235 233
Nausea
Mean 3.3 2.9
STD 3.4 3.2
CONFIDENTIAL
Median 3.0 2.0
Min 0.0 0.0

207
Max 10.0 10.0
PVAL 0.1492
GM2006/00652/00
NKT102553
Table 7.27
Summary of Nausea (Categorical Score) (0 – 24 hours)
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
-----------------------------------------------------------
Nausea Category (0-24)
None 107/235 ( 46%) 124/233 ( 53%)
Mild 42/235 ( 18%) 38/233 ( 16%)
Moderate 48/235 ( 20%) 51/233 ( 22%)
Severe 38/235 ( 16%) 20/233 ( 9%)
Stratification
Score=None
CONFIDENTIAL
N2O anticipated 67/123 ( 54%) 76/125 ( 61%)
208
p-value 0.0363
GM2006/00652/00
NKT102553
Table 7.28
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
-----------------------------------------------------------
None 201/235 ( 86%) 193/233 ( 83%)
Mild 14/235 ( 6%) 18/233 ( 8%)
Moderate 13/235 ( 6%) 19/233 ( 8%)
Severe 7/235 ( 3%) 3/233 ( 1%)
Stratification
Score=None
CONFIDENTIAL
N2O anticipated 106/123 ( 86%) 108/125 ( 86%)
209
p-value 0.7429
GM2006/00652/00
NKT102553
Table 7.29
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
-----------------------------------------------------------
None 101/235 ( 43%) 114/233 ( 49%)
Mild 42/235 ( 18%) 39/233 ( 17%)
Moderate 51/235 ( 22%) 57/233 ( 24%)
Severe 41/235 ( 17%) 23/233 ( 10%)
Stratification
Score=None
CONFIDENTIAL
N2O anticipated 64/123 ( 52%) 70/125 ( 56%)
210
p-value 0.0786
GM2006/00652/00
NKT102553
Table 7.30
Summary of Time-to-Emesis
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
------------------------------------------------
Subjects with 63/235(26.8%) 28/233(12.0%)
event
Censored 172/235(73.2%) 205/233(88.0%)

subjects
Log-Rank 0.0001
p-value
CONFIDENTIAL
1st Quartile 23.8 NE
(95% CI) (15.0,NE) (NE,NE)
211
Median hours NE NE
(95% CI) (NE,NE) (NE,NE)
3rd Quartile NE NE
GM2006/00652/00
NKT102553
Table 7.31
Summary of Time-to-Rescue
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
------------------------------------------------
Subjects with 77/235(32.8%) 67/233(28.8%)
event
Censored 158/235(67.2%) 166/233(71.2%)

subjects
Log-Rank 0.2978
p-value
CONFIDENTIAL
1st Quartile 9.1 20.4
(95% CI) ( 5.5, 22.0) (7.5,NE)
212
Median hours NE NE
3rd Quartile NE NE
GM2006/00652/00
NKT102553
Table 7.32
Summary of Subject Satisfaction (0 to 48 hours)
4mg IV
Zofran +
4mg IV 50mg PO
Subject Zofran Casopitant
Satisfaction (N=235) (N=233)
-----------------------------------------
Very satisfied 147 (63%) 158 (68%)
Somewhat 44 (19%) 41 (18%)

satisfied
CONFIDENTIAL
Neither 19 (8%) 14 (6%)
satisfied nor
dissatisfied
213
Somewhat 6 (3%) 3 (1%)

dissatisfied
Very 8 (3%) 7 (3%)

dissatisfied
GM2006/00652/00
NKT102553
Table 7.33
Summary of Subject Willingness (0 to 48 hours)
4mg IV
Zofran +
4mg IV 50mg PO
Subject Zofran Casopitant
Willingness (N=235) (N=233)
-----------------------------------------
Definitely 134 (57%) 136 (58%)
would be
willing
Probably would 59 (25%) 63 (27%)

be willing
CONFIDENTIAL
Not certain 14 (6%) 13 (6%)
214
Probably would 9 (4%) 4 (2%)

not be willing
Definitely 8 (3%) 7 (3%)

would not be
willing
GM2006/00652/00
NKT102553
Table 7.34
Summary of Rescue (0 - 24 hours)
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
-----------------------------------------------------------
Rescue
No 161/235 ( 69%) 172/233 ( 74%)
Yes 74/235 ( 31%) 61/233 ( 26%)
Stratification
N2O anticipated 89/123 ( 72%) 101/125 ( 81%)
CMH p-value 0.2154
CONFIDENTIAL
Odds Ratio 0.7751
215
GM2006/00652/00
NKT102553
Table 7.35
Summary of Rescue (24-48 hours)
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
-----------------------------------------------------------
Rescue
No 221/235 ( 94%) 220/233 ( 94%)
Yes 14/235 ( 6%) 13/233 ( 6%)
Stratification
N2O anticipated 113/123 ( 92%) 119/125 ( 95%)
CMH p-value 0.8541
CONFIDENTIAL
Odds Ratio 0.9255
216
GM2006/00652/00
NKT102553
Table 7.36
Summary of Rescue (0 - 48 hours)
4mg IV Zofran +
50mg Oral
(N=235) (N=233)
-----------------------------------------------------------
Rescue
No 158/235 ( 67%) 166/233 ( 71%)
Yes 77/235 ( 33%) 67/233 ( 29%)
Stratification
N2O anticipated 87/123 ( 71%) 98/125 ( 78%)
CMH p-value 0.3628
CONFIDENTIAL
Odds Ratio 0.8325
217
GM2006/00652/00
NKT102553
Table 7.37
Summary of Medical Resource Utilization
4mg IV Zofran +
50mg Oral
(N=242) (N=242)
-----------------------------------------------------------------------
Were there any rel. No 219 (90.5%) 222 (91.7%)
healthcare contacts?
Yes 12 ( 5.0%) 5 ( 2.1%)
Unknown 2 ( 0.8%) 1 ( 0.4%)
Missing 9 ( 3.7%) 14 ( 5.8%)
Was this contact due No 227 (93.8%) 220 (90.9%)

to an adverse event
CONFIDENTIAL
Yes 2 ( 0.8%) 7 ( 2.9%)
Missing 13 ( 5.4%) 15 ( 6.2%)
218
Number of primary N 232 228

care physician
visits
Mean 0 0
STD 0.31 0.09
Median 0 0
Min 0 0
Max 3 1
Number of nurse N 232 228

prac/p.a./nurse
visits
GM2006/00652/00
Mean 0 0
STD 0.99 0.00
Median 0 0
Min 0 0
NKT102553
Max 14 0
Number of non-study N 232 228

laboratory visits
Table 7.37
4mg IV Zofran +
50mg Oral
(N=242) (N=242)
-----------------------------------------------------------------------
Mean 0 0
STD 0.00 0.33
Median 0 0
Min 0 0
Max 0 4
Number of home N 232 228

healthcare visits
CONFIDENTIAL
Mean 0 0
STD 0.00 0.00
Median 0 0
219
Min 0 0
Max 0 0
Number of telephone N 232 228

calls
Mean 0 0
STD 0.15 0.52
Median 0 0
Min 0 0
Max 2 6
Number of medical N 232 228
GM2006/00652/00
specialist visits
Mean 0 0
STD 0.62 0.60
Median 0 0
NKT102553
Min 0 0
Max 6 6
Table 7.37
4mg IV Zofran +
50mg Oral
(N=242) (N=242)
-----------------------------------------------------------------------
Number of emergency N 232 228
room visits
Mean 0 0
STD 0.00 0.15
Median 0 0
Min 0 0
Max 0 1
CONFIDENTIAL
Number of N 232 228
hospitalisation days
Mean 0 0
220
STD 1.54 1.12

Median 0 0
Min 0 0
Max 12 7
GM2006/00652/00
NKT102553
Table 7.38
Summary of Time-to-Emesis Hazard Ratios - Treatment Only Model
4mg IV Zofran +
50mg Oral
Casopitant
(N=233)
-------------------------------
Hazard Ratio 0.414
(95% CI) (0.265,0.646)
Chi-Square 0.0001
p-value
CONFIDENTIAL
221
GM2006/00652/00
NKT102553
Note: Hazard ratio is calculated with the Zofran only arm in the denominator
Table 7.39
Summary of Time-to-Rescue Hazard Ratios - Treatment Only Model
4mg IV Zofran +
50mg Oral
Casopitant
(N=233)
-------------------------------
Hazard Ratio 0.841
(95% CI) (0.606,1.167)
Chi-Square 0.2998
p-value
CONFIDENTIAL
222
GM2006/00652/00
NKT102553
Note: Hazard ratio is calculated with the Zofran only arm in the denominator
Table 7.54
Summary of Antiemetic Rescue Medication
4mg IV
Zofran +
4mg IV 50mg PO
---------------------------------------------------
Any Medication 4 (2%) 1 (<1%)

Multiple Ingredient 4 (2%) 1 (<1%)
ALIMENTARY TRACT AND
CONFIDENTIAL
METABOLISM
223
ONDANSETRON 25 (10%) 12 (5%)

METOCLOPRAMIDE 10 (4%) 11 (5%)
HYDROCHLORIDE
DOLASETRON MESILATE 5 (2%) 0
SODIUM CHLORIDE 2 (<1%) 2 (<1%)
GRANISETRON 2 (<1%) 1 (<1%)
DOMPERIDONE 1 (<1%) 1 (<1%)
GM2006/00652/00
HYOSCINE 0 2 (<1%)
DIMETICONE, ACTIVATED 1 (<1%) 0
DOLASETRON 1 (<1%) 0
GRANISETRON 0 1 (<1%)
NKT102553
HYDROCHLORIDE
ONDANSETRON 0 1 (<1%)
HYDROCHLORIDE
Table 7.54
4mg IV
Zofran +
4mg IV 50mg PO
---------------------------------------------------
RESPIRATORY SYSTEM
CONFIDENTIAL
PROMETHAZINE 1 (<1%) 1 (<1%)
HYDROCHLORIDE
CYCLIZINE 1 (<1%) 0
224
PSEUDOEPHEDRINE 0 1 (<1%)
HYDROCHLORIDE+FEXOFENAD
INE HYDROCHLORIDE
NERVOUS SYSTEM
HALOPERIDOL 3 (1%) 1 (<1%)
HYOSCINE 0 2 (<1%)
HYDROCHLORIDE
GM2006/00652/00
CHLORPROMAZINE 1 (<1%) 0
DERMATOLOGICALS
NKT102553
HYDROCHLORIDE
Table 7.54
4mg IV
Zofran +
4mg IV 50mg PO
---------------------------------------------------
SENSORY ORGANS
HYOSCINE 0 2 (<1%)
CONFIDENTIAL
225
SYSTEMIC HORMONAL
PREPARATIONS, EXCL. SEX
HORMONES
BLOOD AND BLOOD FORMING

ORGANS
GM2006/00652/00
POTASSIUM 4 (2%) 1 (<1%)
CHLORIDE+SODIUM
CHLORIDE+CALCIUM
CHLORIDE+DL-LACTIC ACID
NKT102553
SODIUM SALT
NKT102553
SAFETY DATA SOURCE TABLES
Page
Table 8.1 Summary of Exposure Data (Safety Population). . . . . . . . . . . . . . . 227
Table 8.2 Summary of All Adverse Events (Safety Population) . . . . . . . . . . . 228
Table 8.3 Summary of Drug-Related Adverse Events (Safety Population) . . . 235
Table 8.4 Summary of Serious Adverse Events (Safety Population) . . . . . . . 236
Table 8.5 Summary of Adverse Events Leading to Permanent
Discontinuation of Study Drug or Withdrawal from Study (Safety
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
Table 8.6 Summary of Adverse Events By Maximum Intensity/Toxicity
(Safety Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
Table 8.7 Summary of Vital Signs (Safety Population) . . . . . . . . . . . . . . . . . . 250
Table 8.8 Summary of Chemistry Data (Safety Population) . . . . . . . . . . . . . . 253
Table 8.9 Summary of Chemistry Data Outside the Reference Range
Table 8.10 Summary of Chemistry Toxicity Grade Shifts from Baseline
Toxicity Grade (Safety Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
Table 8.11 Summary of Hematology Data (Safety Population). . . . . . . . . . . . 295
Table 8.12 Summary of Hematology Data Outside the Reference Range
Table 8.13 Summary of Hematology Toxicity Grade Shifts from Baseline
Toxicity Grade (Safety Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
Table 8.14 Summary of Pregnancy during Study (Safety Population) . . . . . . 328
Table 8.15 Summary of ECG Findings (Safety Population) . . . . . . . . . . . . . . 329
Table 8.16 Summary of Time to Awakening (Intent-to-Treat Population) . . . . 330
Table 8.17 Summary of Deaths (Safety Population) . . . . . . . . . . . . . . . . . . . . 331
Table 8.18 Listing of Laboratory Data for Subjects with Abnormalities of
Clinical Concern CTC Lab Toxicity Grades of 2, 3 and 4 (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332
Table 8.19 Listing of Vital Signs (Hypotension/Procedual Hypotension
Subjects Only) (Safety Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384
226
Population: Safety
Table 8.1
Summary of Exposure Data
4mg IV
Zofran +
4mg IV 50mg PO
Zofran Casopitant
Dose (N=237) (N=235)
--------------------------------------------------------
Zofran 234 (99%) 233 (>99%)
GW679769 237 (100%) 235 (100%)
CONFIDENTIAL
227
GM2006/00652/00
NKT102553
Population: Safety
Table 8.2
Summary of All Adverse Events
4mg IV Zofran +
50mg Oral
System Organ Class 4mg IV Zofran Casopitant
Preferred Term (N=237) (N=235)
--------------------------------------------------------------
ANY EVENT 87 (37%) 95 (40%)
Gastrointestinal disorders
ANY EVENT 26 (11%) 32 (14%)
Constipation 8 (3%) 17 (7%)
Flatulence 12 (5%) 11 (5%)
Nausea 4 (2%) 6 (3%)
Diarrhoea 4 (2%) 2 (<1%)
CONFIDENTIAL
Dyspepsia 3 (1%)
Abdominal pain upper 1 (<1%) 1 (<1%)
Vomiting 2 (<1%)
228
Hyperchlorhydria 1 (<1%)
Ileus paralytic 1 (<1%)
Intestinal spasm 1 (<1%)
Retching 1 (<1%)
Vascular disorders
ANY EVENT 13 (5%) 18 (8%)
Hypotension 8 (3%) 15 (6%)
Hypertension 5 (2%) 2 (<1%)
Deep vein thrombosis 1 (<1%)
Haematoma 1 (<1%)
Hypertensive crisis 1 (<1%)
GM2006/00652/00
Orthostatic hypotension 1 (<1%)
Nervous system disorders

ANY EVENT 14 (6%) 14 (6%)
NKT102553
Headache 11 (5%) 8 (3%)
Dizziness 3 (1%) 3 (1%)
Migraine 1 (<1%)
Paraesthesia 1 (<1%)
Population: Safety
Table 8.2
4mg IV Zofran +
50mg Oral
--------------------------------------------------------------
Somnolence 1 (<1%)
Syncope 1 (<1%)
Investigations
ANY EVENT 11 (5%) 15 (6%)
Alanine aminotransferase 4 (2%) 3 (1%)
increased
Aspartate aminotransferase 4 (2%) 3 (1%)
CONFIDENTIAL
increased
Transaminases increased 2 (<1%) 4 (2%)
Blood alkaline phosphatase 2 (<1%) 2 (<1%)
229
increased
Blood glucose increased 2 (<1%) 1 (<1%)
Body temperature increased 3 (1%)
Haemoglobin decreased 2 (<1%)
Liver function test abnormal 1 (<1%) 1 (<1%)
Neutrophil count increased 2 (<1%)
White blood cell count 2 (<1%)
increased
Blood potassium decreased 1 (<1%)
Blood pressure decreased 1 (<1%)
Blood triglycerides 1 (<1%)
increased
GM2006/00652/00
Lymphocyte count decreased 1 (<1%)
Oxygen saturation decreased 1 (<1%)
Urine output decreased 1 (<1%)
NKT102553
Respiratory, thoracic and
ANY EVENT 11 (5%) 14 (6%)
Cough 5 (2%) 5 (2%)
Population: Safety
Table 8.2
4mg IV Zofran +
50mg Oral
--------------------------------------------------------------
Hypoxia 2 (<1%) 2 (<1%)
Dyspnoea 2 (<1%)
Pulmonary embolism 1 (<1%) 1 (<1%)
Dysphonia 1 (<1%)
Hypoventilation 1 (<1%)
Nasal congestion 1 (<1%)
Pharyngolaryngeal pain 1 (<1%)
Pulmonary congestion 1 (<1%)
CONFIDENTIAL
Respiratory depression 1 (<1%)
Throat irritation 1 (<1%)
230
Injury, poisoning and

procedural complications
ANY EVENT 9 (4%) 9 (4%)
Procedural hypotension 2 (<1%) 2 (<1%)
Incision site complication 1 (<1%) 1 (<1%)
Post procedural complication 2 (<1%)
Procedural complication 1 (<1%) 1 (<1%)
Bladder injury 1 (<1%)
Colon injury 1 (<1%)
Excoriation 1 (<1%)
Operative haemorrhage 1 (<1%)
Post procedural nausea 1 (<1%)
GM2006/00652/00
Post procedural vomiting 1 (<1%)
Postoperative wound 1 (<1%)
complication
Procedural hypertension 1 (<1%)
NKT102553
Traumatic haematoma 1 (<1%)
Ureteric injury 1 (<1%)
Population: Safety
Table 8.2
4mg IV Zofran +
50mg Oral
--------------------------------------------------------------
Skin and subcutaneous tissue
disorders
ANY EVENT 10 (4%) 8 (3%)
Pruritus 5 (2%) 4 (2%)
Hyperhidrosis 1 (<1%) 1 (<1%)
Pruritus generalised 1 (<1%) 1 (<1%)
Rash 2 (<1%)
Dermatitis contact 1 (<1%)
CONFIDENTIAL
Erythema 1 (<1%)
Scar pain 1 (<1%)
231
General disorders and

ANY EVENT 6 (3%) 10 (4%)
Pyrexia 2 (<1%) 3 (1%)
Application site vesicles 2 (<1%)
Chest pain 2 (<1%)
Chills 2 (<1%)
Application site erythema 1 (<1%)
Asthenia 1 (<1%)
Infusion site pain 1 (<1%)
Infusion site swelling 1 (<1%)
Pain 1 (<1%)
GM2006/00652/00
Peripheral coldness 1 (<1%)
Renal and urinary disorders

ANY EVENT 6 (3%) 8 (3%)
NKT102553
Urinary retention 3 (1%) 5 (2%)
Dysuria 1 (<1%) 2 (<1%)
Bladder spasm 2 (<1%)
Bladder disorder 1 (<1%)
Population: Safety
Table 8.2
4mg IV Zofran +
50mg Oral
--------------------------------------------------------------
Incontinence 1 (<1%)
Ureteric obstruction 1 (<1%)
Psychiatric disorders
ANY EVENT 4 (2%) 9 (4%)
Insomnia 4 (2%) 6 (3%)
Anxiety 3 (1%)
Restlessness 1 (<1%)
CONFIDENTIAL
Blood and lymphatic system
disorders
232
ANY EVENT 6 (3%) 6 (3%)

Anaemia 5 (2%) 6 (3%)
Lymphadenopathy 1 (<1%)
Infections and infestations

ANY EVENT 4 (2%) 7 (3%)
Urinary tract infection 3 (1%) 2 (<1%)
Postoperative wound 2 (<1%)
infection
Cellulitis 1 (<1%)
Cystitis 1 (<1%)
Gastroenteritis 1 (<1%)
GM2006/00652/00
Nasopharyngitis 1 (<1%)
Vulvovaginal mycotic 1 (<1%)
infection
NKT102553
Musculoskeletal and connective
tissue disorders
ANY EVENT 4 (2%) 7 (3%)
Musculoskeletal pain 2 (<1%) 1 (<1%)
Population: Safety
Table 8.2
4mg IV Zofran +
50mg Oral
--------------------------------------------------------------
Back pain 1 (<1%) 1 (<1%)
Musculoskeletal stiffness 2 (<1%)
Neck pain 2 (<1%)
Muscle spasms 1 (<1%)
Muscle tightness 1 (<1%)
Pain in extremity 1 (<1%)
Pain in jaw 1 (<1%)
Trismus 1 (<1%)
CONFIDENTIAL
Metabolism and nutrition
disorders
233
ANY EVENT 3 (1%) 3 (1%)

Hypokalaemia 2 (<1%) 1 (<1%)
Hypoglycaemia 2 (<1%)
Hyperglycaemia 1 (<1%)
Cardiac disorders
ANY EVENT 1 (<1%) 3 (1%)
Bradycardia 1 (<1%) 1 (<1%)
Cyanosis 1 (<1%)
Pericardial cyst 1 (<1%)
Reproductive system and breast
GM2006/00652/00
disorders
ANY EVENT 1 (<1%) 2 (<1%)
Breast haematoma 1 (<1%)
Dysfunctional uterine 1 (<1%)
NKT102553
bleeding
Vaginal haemorrhage 1 (<1%)
Ear and labyrinth disorders

Population: Safety
Table 8.2
4mg IV Zofran +
50mg Oral
--------------------------------------------------------------
ANY EVENT 2 (<1%)
Vertigo 2 (<1%)
Congenital, familial and

genetic disorders
ANY EVENT 1 (<1%)
Spondylolisthesis 1 (<1%)
CONFIDENTIAL
Eye disorders
ANY EVENT 1 (<1%)
Eye irritation 1 (<1%)
234
Hepatobiliary disorders
ANY EVENT 1 (<1%)
Gallbladder polyp 1 (<1%)
Immune system disorders

ANY EVENT 1 (<1%)
Sarcoidosis 1 (<1%)
Neoplasms benign, malignant

and unspecified (incl cysts
and polyps)
GM2006/00652/00
ANY EVENT 1 (<1%)
Ovarian adenoma 1 (<1%)
NKT102553
Population: Safety
Table 8.3
Summary of Drug-Related Adverse Events
4mg IV Zofran +
50mg Oral
--------------------------------------------------------------
ANY EVENT 13 (5%) 14 (6%)
ANY EVENT 6 (3%) 6 (3%)
Nausea 1 (<1%) 2 (<1%)
Diarrhoea 1 (<1%) 0
CONFIDENTIAL
Investigations
ANY EVENT 6 (3%) 6 (3%)
Alanine aminotransferase 4 (2%) 2 (<1%)
235
increased
Aspartate aminotransferase 3 (1%) 2 (<1%)
increased
Blood alkaline phosphatase 2 (<1%) 2 (<1%)
increased
Transaminases increased 1 (<1%) 3 (1%)
Liver function test abnormal 1 (<1%) 1 (<1%)
Blood glucose increased 1 (<1%) 0

ANY EVENT 3 (1%) 3 (1%)
Dizziness 1 (<1%) 3 (1%)
GM2006/00652/00
Headache 3 (1%) 0
NKT102553
Population: Safety
Table 8.4
Summary of Serious Adverse Events
4mg IV Zofran +
50mg Oral
--------------------------------------------------------------
ANY EVENT 7 (3%) 4 (2%)

Any event 1 (<1%) 2 (<1%)
Pulmonary embolism 1 (<1%) 1 (<1%)
Dyspnoea 0 1 (<1%)
CONFIDENTIAL
Any event 1 (<1%) 1 (<1%)
Constipation 0 1 (<1%)
236
Ileus paralytic 1 (<1%) 0

genetic disorders
Any event 0 1 (<1%)
Spondylolisthesis 0 1 (<1%)

Any event 0 1 (<1%)
Chest pain 0 1 (<1%)
GM2006/00652/00
Any event 1 (<1%) 0
Urinary tract infection 1 (<1%) 0
NKT102553
Any event 1 (<1%) 0
Colon injury 1 (<1%) 0
Population: Safety
Table 8.4
Summary of Serious Adverse Events
4mg IV Zofran +
50mg Oral
--------------------------------------------------------------

tissue disorders
Any event 0 1 (<1%)
Musculoskeletal pain 0 1 (<1%)
Pain in jaw 0 1 (<1%)
CONFIDENTIAL
and polyps)
Any event 1 (<1%) 0
237
Ovarian adenoma 1 (<1%) 0

Any event 1 (<1%) 0
Ureteric obstruction 1 (<1%) 0

disorders
Any event 1 (<1%) 0
Dysfunctional uterine 1 (<1%) 0
bleeding
GM2006/00652/00
Vascular disorders
Any event 1 (<1%) 0
Deep vein thrombosis 1 (<1%) 0
NKT102553
Population: Safety
Table 8.5
Summary of Adverse Events Leading to Permanent Discontinuation of Study Drug
or Withdrawal from Study
No data to report
CONFIDENTIAL
238
GM2006/00652/00
NKT102553
Population: Safety
Table 8.6
Summary of Adverse Events By Maximum Intensity/Toxicity
Treatment: 4mg IV Zofran (N=237)

System Organ Class
Preferred Term Mild Moderate Severe
---------------------------------------------------------------
ANY EVENT 50 (21%) 31 (13%) 6 (3%)
Any Event 14 (6%) 11 (5%) 1 (<1%)
Flatulence 9 (4%) 3 (1%) 0
Constipation 3 (1%) 5 (2%) 0
Diarrhoea 3 (1%) 1 (<1%) 0
Nausea 3 (1%) 1 (<1%) 0
Vomiting 1 (<1%) 1 (<1%) 0
CONFIDENTIAL
Abdominal pain upper 1 (<1%) 0 0
Hyperchlorhydria 1 (<1%) 0 0
Ileus paralytic 0 0 1 (<1%)
239
Retching 0 1 (<1%) 0
Vascular disorders
Any Event 4 (2%) 8 (3%) 1 (<1%)
Hypotension 2 (<1%) 6 (3%) 0
Hypertension 0 5 (2%) 0
Deep vein thrombosis 0 0 1 (<1%)
Hypertensive crisis 1 (<1%) 0 0
Orthostatic hypotension 1 (<1%) 0 0

Any Event 12 (5%) 2 (<1%) 0
GM2006/00652/00
Headache 9 (4%) 2 (<1%) 0
Dizziness 3 (1%) 0 0
Syncope 1 (<1%) 0 0
NKT102553
Investigations
Any Event 7 (3%) 4 (2%) 0
Alanine aminotransferase 2 (<1%) 2 (<1%) 0
increased
Population: Safety
Table 8.6

System Organ Class
---------------------------------------------------------------
Aspartate aminotransferase 2 (<1%) 2 (<1%) 0
increased
Blood alkaline phosphatase 1 (<1%) 1 (<1%) 0
increased
Blood glucose increased 2 (<1%) 0 0
Neutrophil count increased 2 (<1%) 0 0
Transaminases increased 1 (<1%) 1 (<1%) 0
White blood cell count 2 (<1%) 0 0
increased
CONFIDENTIAL
Blood potassium decreased 1 (<1%) 0 0
Liver function test abnormal 1 (<1%) 0 0
Lymphocyte count decreased 1 (<1%) 0 0
240
Oxygen saturation decreased 1 (<1%) 0 0

Urine output decreased 0 1 (<1%) 0

Any Event 7 (3%) 3 (1%) 1 (<1%)
Cough 5 (2%) 0 0
Hypoxia 0 2 (<1%) 0
Dysphonia 0 1 (<1%) 0
Pulmonary congestion 1 (<1%) 0 0
Pulmonary embolism 0 0 1 (<1%)
Respiratory depression 1 (<1%) 0 0
GM2006/00652/00
Any Event 4 (2%) 4 (2%) 1 (<1%)
NKT102553
Procedural hypotension 2 (<1%) 0 0
Bladder injury 0 1 (<1%) 0
Colon injury 0 0 1 (<1%)
Incision site complication 0 1 (<1%) 0
Population: Safety
Table 8.6

System Organ Class
---------------------------------------------------------------
Post procedural nausea 1 (<1%) 0 0
Post procedural vomiting 0 1 (<1%) 0
Procedural complication 1 (<1%) 0 0
Procedural hypertension 1 (<1%) 0 0
Ureteric injury 0 1 (<1%) 0

disorders
Any Event 8 (3%) 2 (<1%) 0
CONFIDENTIAL
Pruritus 3 (1%) 2 (<1%) 0
Rash 2 (<1%) 0 0
Hyperhidrosis 1 (<1%) 0 0
241
Pruritus generalised 1 (<1%) 0 0

Scar pain 1 (<1%) 0 0

Any Event 6 (3%) 0 0
Chills 2 (<1%) 0 0
Pyrexia 2 (<1%) 0 0
Infusion site pain 1 (<1%) 0 0
Infusion site swelling 1 (<1%) 0 0
GM2006/00652/00
Any Event 2 (<1%) 4 (2%) 0
Urinary retention 1 (<1%) 2 (<1%) 0
Bladder disorder 1 (<1%) 0 0
Dysuria 0 1 (<1%) 0
NKT102553
Incontinence 1 (<1%) 0 0
Ureteric obstruction 0 1 (<1%) 0
Population: Safety
Table 8.6

System Organ Class
---------------------------------------------------------------
Insomnia 4 (2%) 0 0

disorders
Any Event 3 (1%) 3 (1%) 0
Anaemia 2 (<1%) 3 (1%) 0
Lymphadenopathy 1 (<1%) 0 0
CONFIDENTIAL
Any Event 3 (1%) 1 (<1%) 0
Urinary tract infection 3 (1%) 0 0
242
Vulvovaginal mycotic 0 1 (<1%) 0

infection

tissue disorders
Any Event 1 (<1%) 2 (<1%) 1 (<1%)
Musculoskeletal pain 1 (<1%) 0 1 (<1%)
Back pain 0 1 (<1%) 0
Pain in extremity 0 1 (<1%) 0
Trismus 0 1 (<1%) 0
GM2006/00652/00
disorders
Hypokalaemia 2 (<1%) 0 0
Hyperglycaemia 1 (<1%) 0 0
NKT102553
Cardiac disorders
Any Event 1 (<1%) 0 0
Bradycardia 1 (<1%) 0 0
Population: Safety
Table 8.6

System Organ Class
---------------------------------------------------------------

disorders
Any Event 0 0 1 (<1%)
Dysfunctional uterine 0 0 1 (<1%)
bleeding
Immune system disorders

Any Event 1 (<1%) 0 0
CONFIDENTIAL
Sarcoidosis 1 (<1%) 0 0

243

and polyps)
Any Event 0 0 1 (<1%)
Ovarian adenoma 0 0 1 (<1%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.6
Treatment: 4mg IV Zofran + 50mg PO Casopitant (N=235)

System Organ Class
---------------------------------------------------------------
ANY EVENT 44 (19%) 45 (19%) 6 (3%)
Any Event 16 (7%) 14 (6%) 2 (<1%)
Constipation 6 (3%) 9 (4%) 2 (<1%)
Flatulence 8 (3%) 3 (1%) 0
Nausea 4 (2%) 2 (<1%) 0
Dyspepsia 3 (1%) 0 0
Diarrhoea 1 (<1%) 1 (<1%) 0
CONFIDENTIAL
Abdominal pain upper 1 (<1%) 0 0
Intestinal spasm 0 1 (<1%) 0
244
Vascular disorders
Any Event 13 (6%) 5 (2%) 0
Hypotension 11 (5%) 4 (2%) 0
Hypertension 1 (<1%) 1 (<1%) 0
Haematoma 1 (<1%) 0 0

Any Event 10 (4%) 3 (1%) 1 (<1%)
Headache 7 (3%) 1 (<1%) 0
Dizziness 3 (1%) 0 0
Migraine 0 0 1 (<1%)
Paraesthesia 0 1 (<1%) 0
GM2006/00652/00
Somnolence 0 1 (<1%) 0
Investigations
Any Event 11 (5%) 4 (2%) 0
NKT102553
Transaminases increased 3 (1%) 1 (<1%) 0
Alanine aminotransferase 2 (<1%) 1 (<1%) 0
increased
Population: Safety
Table 8.6

System Organ Class
---------------------------------------------------------------
Aspartate aminotransferase 2 (<1%) 1 (<1%) 0
increased
Body temperature increased 3 (1%) 0 0
Blood alkaline phosphatase 0 2 (<1%) 0
increased
Haemoglobin decreased 2 (<1%) 0 0
Blood glucose increased 1 (<1%) 0 0
Blood pressure decreased 0 1 (<1%) 0
Blood triglycerides 0 1 (<1%) 0
CONFIDENTIAL
increased
Liver function test abnormal 1 (<1%) 0 0
245

Any Event 8 (3%) 6 (3%) 0
Cough 5 (2%) 0 0
Dyspnoea 0 2 (<1%) 0
Hypoxia 0 2 (<1%) 0
Hypoventilation 0 1 (<1%) 0
Nasal congestion 1 (<1%) 0 0
Pharyngolaryngeal pain 1 (<1%) 0 0
Pulmonary embolism 0 1 (<1%) 0
Throat irritation 1 (<1%) 0 0
GM2006/00652/00
Any Event 4 (2%) 5 (2%) 0
Post procedural complication 0 2 (<1%) 0
NKT102553
Procedural hypotension 1 (<1%) 1 (<1%) 0
Excoriation 1 (<1%) 0 0
Incision site complication 1 (<1%) 0 0
Operative haemorrhage 0 1 (<1%) 0
Population: Safety
Table 8.6

System Organ Class
---------------------------------------------------------------
Postoperative wound 1 (<1%) 0 0
complication
Procedural complication 1 (<1%) 0 0
Traumatic haematoma 0 1 (<1%) 0

disorders
Any Event 3 (1%) 5 (2%) 0
Pruritus 2 (<1%) 2 (<1%) 0
CONFIDENTIAL
Dermatitis contact 0 1 (<1%) 0
Erythema 0 1 (<1%) 0
Hyperhidrosis 0 1 (<1%) 0
246
Pruritus generalised 1 (<1%) 0 0

Any Event 3 (1%) 5 (2%) 2 (<1%)
Pyrexia 2 (<1%) 1 (<1%) 0
Application site vesicles 0 2 (<1%) 0
Chest pain 0 1 (<1%) 1 (<1%)
Application site erythema 1 (<1%) 0 0
Asthenia 1 (<1%) 0 0
Pain 0 0 1 (<1%)
Peripheral coldness 0 1 (<1%) 0
GM2006/00652/00
Any Event 3 (1%) 5 (2%) 0
Urinary retention 3 (1%) 2 (<1%) 0
NKT102553
Bladder spasm 0 2 (<1%) 0
Dysuria 0 2 (<1%) 0
Population: Safety
Table 8.6

System Organ Class
---------------------------------------------------------------
Any Event 6 (3%) 3 (1%) 0
Insomnia 4 (2%) 2 (<1%) 0
Anxiety 2 (<1%) 1 (<1%) 0
Restlessness 1 (<1%) 0 0

disorders
Any Event 3 (1%) 3 (1%) 0
Anaemia 3 (1%) 3 (1%) 0
CONFIDENTIAL
Any Event 1 (<1%) 6 (3%) 0
247
Postoperative wound 1 (<1%) 1 (<1%) 0

infection
Urinary tract infection 0 2 (<1%) 0
Cellulitis 0 1 (<1%) 0
Cystitis 0 1 (<1%) 0
Gastroenteritis 0 1 (<1%) 0
Nasopharyngitis 0 1 (<1%) 0

tissue disorders
Any Event 5 (2%) 1 (<1%) 1 (<1%)
Musculoskeletal stiffness 2 (<1%) 0 0
GM2006/00652/00
Neck pain 2 (<1%) 0 0
Back pain 1 (<1%) 0 0
Muscle spasms 0 1 (<1%) 0
Muscle tightness 1 (<1%) 0 0
NKT102553
Musculoskeletal pain 0 0 1 (<1%)
Pain in jaw 0 0 1 (<1%)
Population: Safety
Table 8.6

System Organ Class
---------------------------------------------------------------
disorders
Any Event 2 (<1%) 1 (<1%) 0
Hypoglycaemia 1 (<1%) 1 (<1%) 0
Hypokalaemia 1 (<1%) 0 0
Cardiac disorders
Any Event 2 (<1%) 1 (<1%) 0
Bradycardia 1 (<1%) 0 0
CONFIDENTIAL
Cyanosis 0 1 (<1%) 0
Pericardial cyst 1 (<1%) 0 0
248

disorders
Any Event 1 (<1%) 0 1 (<1%)
Breast haematoma 0 0 1 (<1%)
Vaginal haemorrhage 1 (<1%) 0 0
Ear and labyrinth disorders

Any Event 2 (<1%) 0 0
Vertigo 2 (<1%) 0 0

genetic disorders
GM2006/00652/00
Any Event 0 0 1 (<1%)
Spondylolisthesis 0 0 1 (<1%)
Eye disorders
NKT102553
Any Event 0 1 (<1%) 0
Eye irritation 0 1 (<1%) 0
Population: Safety
Table 8.6

System Organ Class
---------------------------------------------------------------
Any Event 0 1 (<1%) 0
Gallbladder polyp 0 1 (<1%) 0
CONFIDENTIAL
249
GM2006/00652/00
NKT102553
Population: Safety
Table 8.7
Summary of Vital Signs
Treatment
Group N Visit n Mean SD Median Min. Max.
--------------------------------------------------------------------------------------------------
Systolic BP 4mg IV 237 SCREEN 235 122.7 16.09 120.0 90 190
(mmHg) Zofran
PRE/PERI OP DAY 1 179 125.3 15.71 123.0 95 172
POST OP DAY 1/2 235 119.7 16.67 120.0 82 170
POST OP DAY 6-14 223 120.5 14.55 120.0 90 155
4mg IV 235 SCREEN 232 124.9 15.87 121.5 92 192

Zofran +
50mg Oral
Casopitant
CONFIDENTIAL
PRE/PERI OP DAY 1 200 127.1 17.47 127.0 90 192
POST OP DAY 1/2 231 119.1 16.63 119.0 82 180
POST OP DAY 6-14 219 122.5 15.20 120.0 88 170
250
Diastolic BP 4mg IV 237 SCREEN 235 75.6 11.42 75.0 45 112

(mmHg) Zofran
PRE/PERI OP DAY 1 179 76.5 10.90 75.0 45 101
POST OP DAY 1/2 235 71.5 12.07 70.0 48 110
POST OP DAY 6-14 223 75.7 10.83 75.0 50 110
4mg IV 235 SCREEN 232 77.2 10.41 78.0 50 108

Zofran +
50mg Oral
Casopitant
GM2006/00652/00
PRE/PERI OP DAY 1 200 76.2 11.90 76.5 47 109
POST OP DAY 1/2 231 70.7 11.34 70.0 44 100
POST OP DAY 6-14 219 75.8 9.83 76.0 47 100
NKT102553
Respiration 4mg IV 237 SCREEN 230 16.6 3.08 18.0 8 24
rate Zofran
(breaths/min)
Population: Safety
Table 8.7
Treatment
--------------------------------------------------------------------------------------------------
Respiration 4mg IV 237 PRE/PERI OP DAY 1 177 16.6 3.13 18.0 8 22
rate Zofran
(breaths/min)
POST OP DAY 1/2 232 16.6 3.17 18.0 8 24
POST OP DAY 6-14 221 16.3 2.89 16.0 9 24
4mg IV 235 SCREEN 226 16.0 3.01 16.0 8 20

Zofran +
50mg Oral
Casopitant
CONFIDENTIAL
PRE/PERI OP DAY 1 198 16.2 3.24 18.0 8 24
POST OP DAY 1/2 229 16.4 2.98 16.0 10 26
POST OP DAY 6-14 220 16.1 2.80 16.0 10 22
251
Heart rate 4mg IV 237 SCREEN 235 77.1 10.24 79.0 50 112
(beats/min) Zofran
PRE/PERI OP DAY 1 179 76.8 10.88 76.0 50 111
POST OP DAY 1/2 235 76.3 11.58 77.0 50 110
POST OP DAY 6-14 223 76.8 10.95 76.0 52 147
4mg IV 235 SCREEN 232 76.7 11.03 76.5 53 120

Zofran +
50mg Oral
Casopitant
GM2006/00652/00
PRE/PERI OP DAY 1 200 76.3 12.20 76.0 42 117
POST OP DAY 1/2 232 76.7 11.97 78.0 42 106
POST OP DAY 6-14 220 75.7 9.52 75.0 50 100
NKT102553
Weight 4mg IV 237 SCREEN 237 70.6 17.16 67.0 37 154
Zofran
PRE/PERI OP DAY 1 0
Population: Safety
Table 8.7
Treatment
--------------------------------------------------------------------------------------------------
Weight 4mg IV 237 POST OP DAY 1/2 0
Zofran
POST OP DAY 6-14 0
4mg IV 235 SCREEN 234 71.9 17.33 68.5 41 128

Zofran +
50mg Oral
Casopitant
PRE/PERI OP DAY 1 0
POST OP DAY 1/2 0
CONFIDENTIAL
POST OP DAY 6-14 0
252
Height 4mg IV 237 SCREEN 237 161.3 8.77 161.0 79 183

Zofran
PRE/PERI OP DAY 1 0
POST OP DAY 1/2 0
POST OP DAY 6-14 0
4mg IV 235 SCREEN 234 162.7 10.05 162.0 65 194

Zofran +
50mg Oral
Casopitant
PRE/PERI OP DAY 1 0
POST OP DAY 1/2 0
GM2006/00652/00
POST OP DAY 6-14 0
NKT102553
Population: Safety
Table 8.8
Summary of Chemistry Data
Lab Test Treatment N Visit Flag n Mean SD Median Min. Max.

---------------------------------------------------------------------------------------------------
Albumin (G/L) 4mg IV Zofran 237 SCREEN R 234 41.8 3.50 42.0 33.0 50.0
POST OP DAY 1/2 N 217 34.7 5.05 35.0 15.0 49.0
POST OP DAY 6-14 N 227 40.3 4.08 40.8 21.0 49.0
4mg IV Zofran 235 SCREEN R 225 42.1 3.73 42.0 27.0 51.0
+ 50mg PO
Casopitant
POST OP DAY 1/2 N 218 34.9 4.75 35.0 21.0 47.0
POST OP DAY 6-14 N 218 40.2 4.38 41.0 28.0 50.0
CONFIDENTIAL
Alkaline 4mg IV Zofran 237 SCREEN R 232 89.0 54.85 73.0 26.0 376.0
Phosphatase
(IU/L)
253
POST OP DAY 1/2 N 219 82.2 57.04 61.0 16.0 377.0

POST OP DAY 6-14 N 227 94.1 58.36 72.0 23.0 366.0
+ 50mg PO
Casopitant
POST OP DAY 1/2 N 222 82.0 56.25 62.0 23.0 302.0
POST OP DAY 6-14 N 219 98.2 59.19 79.0 26.0 312.0
Alanine Amino 4mg IV Zofran 237 SCREEN R 235 21.3 9.36 19.0 6.0 69.0
Transferase
GM2006/00652/00
(IU/L)
POST OP DAY 1/2 N 220 26.7 35.38 19.0 4.0 332.0
POST OP DAY 6-14 N 228 26.3 24.58 19.0 6.0 227.0
NKT102553
+ 50mg PO
Casopitant
Flag: P=Pre-Therapy, R=Baseline, N=Post-Baseline

Population: Safety
Table 8.8

---------------------------------------------------------------------------------------------------
Alanine Amino 4mg IV Zofran 235 POST OP DAY 1/2 N 222 25.1 19.50 18.0 5.0 137.0
Transferase + 50mg PO
(IU/L) Casopitant
POST OP DAY 6-14 N 220 30.1 27.58 20.5 4.0 239.0
Aspartate 4mg IV Zofran 237 SCREEN R 233 21.9 6.72 21.0 10.9 57.0
Amino
Transferase
(IU/L)
POST OP DAY 1/2 N 219 29.8 38.84 21.0 6.0 383.0
CONFIDENTIAL
POST OP DAY 6-14 N 227 24.4 16.81 20.6 9.0 200.0
254
+ 50mg PO
Casopitant
POST OP DAY 1/2 N 221 26.3 17.36 21.0 5.0 139.0
POST OP DAY 6-14 N 220 25.2 17.73 20.0 8.0 182.0
Total 4mg IV Zofran 237 SCREEN R 231 9.0 4.59 8.6 0.0 31.1
Bilirubin
(UMOL/L)
POST OP DAY 1/2 N 219 10.8 5.92 9.9 0.0 33.6
POST OP DAY 6-14 N 227 7.3 3.65 6.8 0.0 20.5
GM2006/00652/00
+ 50mg PO
Casopitant
POST OP DAY 1/2 N 222 11.7 6.52 10.3 0.0 55.2
NKT102553
POST OP DAY 6-14 N 219 8.0 4.23 7.1 0.0 27.2

Population: Safety
Table 8.8

---------------------------------------------------------------------------------------------------
Blood Urea 4mg IV Zofran 237 SCREEN R 92 4.2 1.49 3.9 0.4 10.4
Nitrogen
(MMOL/L)
POST OP DAY 1/2 N 87 3.0 1.23 2.9 0.7 6.8
POST OP DAY 6-14 N 86 4.3 1.59 3.9 1.1 9.6

+ 50mg PO
Casopitant
POST OP DAY 1/2 N 62 3.2 1.18 3.0 1.1 7.5
POST OP DAY 6-14 N 57 4.7 1.49 4.6 2.1 8.9
CONFIDENTIAL
Chloride 4mg IV Zofran 237 SCREEN R 233 104.6 2.72 105.0 96.0 112.0
255
(MMOL/L)
POST OP DAY 1/2 N 221 104.9 3.30 105.0 94.0 114.0
POST OP DAY 6-14 N 226 103.8 2.88 104.0 90.0 111.0
+ 50mg PO
Casopitant
POST OP DAY 1/2 N 218 105.0 3.54 105.0 92.0 114.0
POST OP DAY 6-14 N 213 104.0 2.63 104.0 95.0 113.0
Creatinine 4mg IV Zofran 237 SCREEN R 234 67.3 12.20 67.0 44.2 132.6
GM2006/00652/00
(UMOL/L)
POST OP DAY 1/2 N 224 63.4 10.92 61.9 35.4 106.1
POST OP DAY 6-14 N 229 67.2 11.84 70.0 35.4 108.0
NKT102553
+ 50mg PO
Casopitant

Population: Safety
Table 8.8

---------------------------------------------------------------------------------------------------
Creatinine 4mg IV Zofran 235 POST OP DAY 1/2 N 225 63.9 13.70 61.9 35.4 141.4
(UMOL/L) + 50mg PO
Casopitant
POST OP DAY 6-14 N 219 67.0 13.86 65.4 38.0 132.6
Glucose 4mg IV Zofran 237 SCREEN R 233 5.3 1.64 5.0 2.9 21.4
(MMOL/L)
POST OP DAY 1/2 N 218 6.4 2.10 5.9 1.4 17.5
POST OP DAY 6-14 N 222 5.4 1.35 5.1 1.8 15.7
CONFIDENTIAL
+ 50mg PO
Casopitant
256
POST OP DAY 1/2 N 217 6.4 2.05 6.0 1.2 19.9

POST OP DAY 6-14 N 212 5.3 1.74 5.1 1.7 18.0
Bicarbonate 4mg IV Zofran 237 SCREEN R 17 24.9 1.93 25.0 21.0 28.0
(MMOL/L)
POST OP DAY 1/2 N 12 24.3 2.35 24.5 19.0 27.0
POST OP DAY 6-14 N 9 26.2 2.22 27.0 23.0 30.0

+ 50mg PO
Casopitant
GM2006/00652/00
POST OP DAY 1/2 N 14 25.0 2.45 25.5 21.0 29.0
POST OP DAY 6-14 N 11 26.3 1.49 27.0 23.0 28.0
NKT102553
Potassium 4mg IV Zofran 237 SCREEN R 236 4.1 0.39 4.1 3.0 5.6
(MMOL/L)
POST OP DAY 1/2 N 225 3.9 0.43 3.9 2.9 5.8

Population: Safety
Table 8.8

---------------------------------------------------------------------------------------------------
Potassium 4mg IV Zofran 237 POST OP DAY 6-14 N 227 4.2 0.45 4.2 3.0 7.0
(MMOL/L)
+ 50mg PO
Casopitant
POST OP DAY 1/2 N 222 3.9 0.40 3.9 2.9 5.2
POST OP DAY 6-14 N 214 4.2 0.41 4.2 2.9 5.8
Sodium 4mg IV Zofran 237 SCREEN R 236 140.3 2.33 140.0 133.0 148.0
CONFIDENTIAL
(MMOL/L)
POST OP DAY 1/2 N 226 138.9 2.83 139.0 128.0 149.0
POST OP DAY 6-14 N 229 140.0 3.49 140.0 102.0 147.0
257
+ 50mg PO
Casopitant
POST OP DAY 1/2 N 222 138.6 2.59 139.0 127.0 147.0
POST OP DAY 6-14 N 217 140.1 2.38 140.0 133.0 150.0
Triglycerides 4mg IV Zofran 237 SCREEN R 13 1.3 0.96 1.1 0.4 3.5
(MMOL/L)
POST OP DAY 1/2 N 9 1.3 0.79 1.2 0.1 2.7
POST OP DAY 6-14 N 7 1.6 0.98 1.4 0.5 3.4
GM2006/00652/00
+ 50mg PO
Casopitant
NKT102553
POST OP DAY 1/2 N 11 1.1 0.55 1.0 0.4 2.1
POST OP DAY 6-14 N 8 2.1 1.15 2.0 0.6 3.4

Population: Safety
Table 8.8

---------------------------------------------------------------------------------------------------
Total Protein 4mg IV Zofran 237 SCREEN R 228 73.2 5.57 73.0 55.0 88.0
(G/L)
POST OP DAY 1/2 N 216 62.3 7.31 62.6 41.0 85.0
POST OP DAY 6-14 N 224 71.8 6.36 72.0 46.0 86.7
+ 50mg PO
Casopitant
POST OP DAY 1/2 N 215 61.6 7.99 62.0 26.0 83.2
POST OP DAY 6-14 N 215 71.7 6.83 72.0 51.0 91.8
CONFIDENTIAL
Urea (MMOL/L) 4mg IV Zofran 237 SCREEN R 142 4.9 2.02 4.6 2.1 14.3
POST OP DAY 1/2 N 136 3.8 2.23 3.5 0.7 17.5
258
POST OP DAY 6-14 N 141 4.7 2.15 4.3 1.4 15.0
+ 50mg PO
Casopitant
POST OP DAY 1/2 N 163 3.8 2.27 3.4 0.4 15.7
POST OP DAY 6-14 N 162 4.9 2.38 4.3 1.4 17.5
GM2006/00652/00
NKT102553
Population: Safety
Table 8.9
Summary of Chemistry Data Outside the Reference Range
4mg IV
Zofran +
4mg IV 50mg Oral
Parameter/ Zofran Casopitant
Lab Test Visit Flag Category (N=237) (N=235)
------------------------------------------------------------------
Albumin SCREEN P n 3 9
(G/L)
> ref. 0 0
range high
< ref. 0 0
range low
U 3 (100%) 9 (100%)
CONFIDENTIAL
R n 234 225
> ref. 1 (<1%) 1 (<1%)
range high
259
< ref. 12 (5%) 10 (4%)

range low
U 0 0
POST OP DAY 1/2 N n 232 232

> ref. 1 (<1%) 1 (<1%)
range high
< ref. 101 (44%) 98 (42%)
range low
U 12 (5%) 9 (4%)
POST OP DAY N n 232 226
GM2006/00652/00
6-14
> ref. 0 1 (<1%)
range high
< ref. 19 (8%) 30 (13%)
NKT102553
range low
U 3 (1%) 4 (2%)
Flag: P=Pre-Therapy R=Baseline N=Post-Baseline

Population: Safety
Table 8.9
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Alkaline SCREEN P n 5 6
Phosphatas
e (IU/L)
> ref. 0 0
range high
< ref. 0 0
range low
CONFIDENTIAL
U 5 (100%) 6 (100%)
R n 232 228
> ref. 13 (6%) 5 (2%)
260
range high
< ref. 8 (3%) 9 (4%)
range low
U 0 0

> ref. 5 (2%) 4 (2%)
range high
< ref. 27 (12%) 23 (10%)
range low
U 10 (4%) 5 (2%)
GM2006/00652/00
6-14
> ref. 17 (7%) 11 (5%)
range high
NKT102553
< ref. 9 (4%) 8 (4%)
range low
U 2 (<1%) 2 (<1%)

Population: Safety
Table 8.9
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Alanine SCREEN P n 2 5
Amino
Transferas
e (IU/L)
> ref. 0 0
range high
< ref. 0 0
CONFIDENTIAL
range low
U 2 (100%) 5 (100%)
R n 235 229
261
> ref. 9 (4%) 14 (6%)

range high
< ref. 2 (<1%) 3 (1%)
range low
U 0 0

> ref. 29 (13%) 26 (11%)
range high
< ref. 3 (1%) 5 (2%)
range low
U 9 (4%) 5 (2%)
GM2006/00652/00
6-14
> ref. 28 (12%) 35 (15%)
NKT102553
range high
< ref. 3 (1%) 5 (2%)
range low

Population: Safety
Table 8.9
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Alanine POST OP DAY N U 2 (<1%) 2 (<1%)
Amino 6-14
Transferas
e (IU/L)
Aspartate SCREEN P n 4 6
Amino
CONFIDENTIAL
Transferas
e (IU/L)
> ref. 0 0
262
range high
< ref. 0 0
range low
U 4 (100%) 6 (100%)
R n 233 228
> ref. 10 (4%) 10 (4%)
range high
< ref. 1 (<1%) 6 (3%)
range low
U 0 0
GM2006/00652/00
> ref. 32 (14%) 35 (15%)
range high
< ref. 4 (2%) 2 (<1%)
range low
NKT102553
U 10 (4%) 6 (3%)

Population: Safety
Table 8.9
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Aspartate POST OP DAY N n 232 226
Amino 6-14
Transferas
e (IU/L)
> ref. 27 (12%) 33 (15%)
range high
< ref. 5 (2%) 1 (<1%)
CONFIDENTIAL
range low
U 3 (1%) 2 (<1%)
263
Total SCREEN P n 6 8
Bilirubin
(UMOL/L)
> ref. 0 0
range high
< ref. 0 0
range low
U 6 (100%) 8 (100%)
R n 231 226
> ref. 6 (3%) 7 (3%)
range high
< ref. 8 (3%) 10 (4%)
GM2006/00652/00
range low
U 0 0
NKT102553
> ref. 14 (6%) 16 (7%)
range high

Population: Safety
Table 8.9
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Total POST OP DAY 1/2 N < ref. 4 (2%) 2 (<1%)
Bilirubin range low
(UMOL/L)
U 10 (4%) 5 (2%)

6-14
CONFIDENTIAL
> ref. 1 (<1%) 6 (3%)
range high
< ref. 9 (4%) 12 (5%)
264
range low
U 3 (1%) 3 (1%)
Blood Urea SCREEN P n 1 1

Nitrogen
(MMOL/L)
> ref. 0 0
range high
< ref. 0 0
range low
U 1 (100%) 1 (100%)
R n 92 67
GM2006/00652/00
> ref. 3 (3%) 2 (3%)
range high
< ref. 6 (7%) 0
range low
NKT102553
U 0 0

Population: Safety
Table 8.9
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Blood Urea POST OP DAY 1/2 N > ref. 0 0
Nitrogen range high
(MMOL/L)
< ref. 22 (24%) 7 (11%)
range low
U 3 (3%) 2 (3%)
CONFIDENTIAL
6-14
> ref. 5 (6%) 4 (7%)
265
range high
< ref. 3 (3%) 1 (2%)
range low
U 1 (1%) 0
Chloride SCREEN P n 4 7
(MMOL/L)
> ref. 0 0
range high
< ref. 0 0
range low
U 1 (25%) 4 (57%)
GM2006/00652/00
R n 233 227
> ref. 22 (9%) 15 (7%)
range high
< ref. 3 (1%) 3 (1%)
NKT102553
range low
U 0 0

Population: Safety
Table 8.9
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Chloride POST OP DAY 1/2 N n 232 232
(MMOL/L)
> ref. 21 (9%) 27 (12%)
range high
< ref. 5 (2%) 5 (2%)
range low
U 5 (2%) 6 (3%)
CONFIDENTIAL
6-14
266
> ref. 16 (7%) 13 (6%)

range high
< ref. 7 (3%) 5 (2%)
range low
U 1 (<1%) 6 (3%)
Creatinine SCREEN P n 3 5
(UMOL/L)
> ref. 0 0
range high
< ref. 0 0
range low
GM2006/00652/00
U 3 (100%) 5 (100%)
R n 234 229
> ref. 3 (1%) 5 (2%)
range high
NKT102553
< ref. 11 (5%) 16 (7%)
range low
U 0 0

Population: Safety
Table 8.9
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Creatinine POST OP DAY 1/2 N n 232 232
(UMOL/L)
> ref. 2 (<1%) 3 (1%)
range high
< ref. 19 (8%) 28 (12%)
range low
U 5 (2%) 2 (<1%)
CONFIDENTIAL
6-14
267
> ref. 4 (2%) 7 (3%)

range high
< ref. 14 (6%) 19 (8%)
range low
U 1 (<1%) 3 (1%)
Glucose SCREEN P n 4 7
(MMOL/L)
> ref. 0 0
range high
< ref. 0 0
range low
GM2006/00652/00
U 4 (100%) 7 (100%)
R n 233 227
> ref. 28 (12%) 32 (14%)
range high
NKT102553
< ref. 12 (5%) 9 (4%)
range low
U 0 0

Population: Safety
Table 8.9
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Glucose POST OP DAY 1/2 N n 232 232
(MMOL/L)
> ref. 103 (44%) 100 (43%)
range high
< ref. 6 (3%) 5 (2%)
range low
U 11 (5%) 10 (4%)
CONFIDENTIAL
6-14
268
> ref. 37 (16%) 32 (14%)

range high
< ref. 7 (3%) 15 (7%)
range low
U 8 (3%) 10 (4%)
Bicarbonat SCREEN P n 220 216

e
> ref. 0 0
range high
< ref. 0 0
range low
GM2006/00652/00
U 155 (70%) 143 (66%)
R n 17 18
> ref. 0 2 (11%)
range high
NKT102553
< ref. 0 0
range low
U 0 0

Population: Safety
Table 8.9
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Bicarbonat POST OP DAY 1/2 N n 230 227
e
> ref. 0 1 (<1%)
range high
< ref. 2 (<1%) 0
range low
U 164 (71%) 154 (68%)
CONFIDENTIAL
6-14
269
> ref. 0 0
range high
< ref. 0 0
range low
U 158 (69%) 144 (65%)
Potassium SCREEN P n 1 3
(MMOL/L)
> ref. 0 0
range high
< ref. 0 0
range low
GM2006/00652/00
U 1 (100%) 3 (100%)
R n 236 231
> ref. 1 (<1%) 1 (<1%)
range high
NKT102553
< ref. 10 (4%) 11 (5%)
range low
U 0 0

Population: Safety
Table 8.9
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Potassium POST OP DAY 1/2 N n 232 232
(MMOL/L)
> ref. 1 (<1%) 1 (<1%)
range high
< ref. 39 (17%) 27 (12%)
range low
U 4 (2%) 5 (2%)
CONFIDENTIAL
6-14
270
> ref. 6 (3%) 2 (<1%)

range high
< ref. 8 (3%) 8 (4%)
range low
U 3 (1%) 8 (4%)
Sodium SCREEN P n 1 3
(MMOL/L)
> ref. 0 0
range high
< ref. 0 0
range low
GM2006/00652/00
U 1 (100%) 3 (100%)
R n 236 231
> ref. 3 (1%) 3 (1%)
range high
NKT102553
< ref. 2 (<1%) 2 (<1%)
range low
U 0 0

Population: Safety
Table 8.9
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Sodium POST OP DAY 1/2 N n 232 232
(MMOL/L)
> ref. 1 (<1%) 2 (<1%)
range high
< ref. 17 (7%) 14 (6%)
range low
U 3 (1%) 5 (2%)
CONFIDENTIAL
6-14
271
> ref. 4 (2%) 2 (<1%)

range high
< ref. 5 (2%) 3 (1%)
range low
U 1 (<1%) 5 (2%)
Triglyceri SCREEN P n 224 221

des
> ref. 0 0
range high
< ref. 0 0
range low
GM2006/00652/00
U 161 (72%) 156 (71%)
R n 13 13
> ref. 2 (15%) 4 (31%)
range high
NKT102553
< ref. 0 0
range low
U 0 0

Population: Safety
Table 8.9
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Triglyceri POST OP DAY 1/2 N n 230 227
des
> ref. 2 (<1%) 2 (<1%)
range high
< ref. 0 0
range low
U 164 (71%) 156 (69%)
CONFIDENTIAL
6-14
272
> ref. 2 (<1%) 4 (2%)

range high
< ref. 0 0
range low
U 161 (70%) 159 (71%)
Protein
(G/L)
> ref. 0 0
range high
< ref. 0 0
GM2006/00652/00
range low
U 6 (67%) 7 (70%)
R n 228 224
> ref. 14 (6%) 10 (4%)
NKT102553
range high
< ref. 8 (4%) 5 (2%)
range low

Population: Safety
Table 8.9
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Total SCREEN R U 0 0
Protein
(G/L)

> ref. 2 (<1%) 0
range high
CONFIDENTIAL
< ref. 107 (46%) 112 (48%)
range low
U 10 (4%) 9 (4%)
273

6-14
> ref. 4 (2%) 9 (4%)
range high
< ref. 12 (5%) 18 (8%)
range low
U 3 (1%) 4 (2%)
Urea SCREEN P n 2 5
> ref. 0 0
range high
GM2006/00652/00
< ref. 0 0
range low
U 1 (50%) 4 (80%)
R n 142 161
NKT102553
> ref. 10 (7%) 9 (6%)
range high

Population: Safety
Table 8.9
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Urea SCREEN R < ref. 4 (3%) 13 (8%)
range low
U 0 0

> ref. 4 (3%) 5 (3%)
range high
CONFIDENTIAL
< ref. 39 (27%) 41 (24%)
range low
U 2 (1%) 0
274

6-14
> ref. 11 (8%) 13 (8%)
range high
< ref. 8 (6%) 14 (8%)
range low
U 1 (<1%) 3 (2%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.10
Summary of Chemistry Toxicity Grade Shifts from Baseline Toxicity Grade
Parameter: Alanine Amino Transferase(IU/L)

----------------------Maximum Grade during Time Period----------------------
Planned Baseline Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Total
Time Grade
-------------------------------------------------------------------------------------------------------
Discharge/Post- Grade 0 188 (85%) 17 (8%) 2 (1%) 3 (1%) 0 210 (95%)
op Day 1
Grade 1 3 (1%) 6 (3%) 0 0 0 9 (4%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 0 1 (0%) 0 0 0 1 (0%)
CONFIDENTIAL
Total 191 (87%) 24 (11%) 2 (1%) 3 (1%) 0 220 (100%)
Post-Operation Grade 0 193 (85%) 22 (10%) 2 (1%) 1 (0%) 0 218 (96%)

275
- Study Day
5-10
Grade 1 7 (3%) 2 (1%) 0 0 0 9 (4%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 0 1 (0%) 0 0 0 1 (0%)
Total 200 (88%) 25 (11%) 2 (1%) 1 (0%) 0 228 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.10
Parameter: Alanine Amino Transferase(IU/L)

Treatment: 4mg IV Zofran + 50mg PO Casopitant
Time Grade
-------------------------------------------------------------------------------------------------------
Discharge/Post- Grade 0 187 (84%) 16 (7%) 1 (0%) 0 0 204 (92%)
op Day 1
Grade 1 4 (2%) 5 (2%) 2 (1%) 0 0 11 (5%)
Grade 2 0 2 (1%) 0 0 0 2 (1%)
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 5 (2%) 0 0 0 0 5 (2%)
CONFIDENTIAL
Total 196 (88%) 23 (10%) 3 (1%) 0 0 222 (100%)
Post-Operation Grade 0 176 (80%) 23 (10%) 3 (1%) 1 (0%) 0 203 (92%)

276
- Study Day
5-10
Grade 1 6 (3%) 5 (2%) 1 (0%) 0 0 12 (5%)
Grade 2 0 2 (1%) 0 0 0 2 (1%)
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 3 (1%) 0 0 0 0 3 (1%)
Total 185 (84%) 30 (14%) 4 (2%) 1 (0%) 0 220 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.10
Parameter: Albumin(G/L)
Time Grade
-------------------------------------------------------------------------------------------------------
op Day 1
Grade 1 1 (0%) 5 (2%) 4 (2%) 0 0 10 (5%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 0 1 (0%) 1 (0%) 0 0 2 (1%)
CONFIDENTIAL
Total 116 (53%) 67 (31%) 33 (15%) 1 (0%) 0 217 (100%)
Post-Operation Grade 0 204 (90%) 6 (3%) 3 (1%) 0 0 213 (94%)

277
- Study Day
5-10
Grade 1 2 (1%) 9 (4%) 1 (0%) 0 0 12 (5%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 2 (1%) 0 0 0 0 2 (1%)
Total 208 (92%) 15 (7%) 4 (2%) 0 0 227 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.10
Parameter: Albumin(G/L)
Time Grade
-------------------------------------------------------------------------------------------------------
op Day 1
Grade 1 0 7 (3%) 1 (0%) 0 0 8 (4%)
Grade 2 0 0 1 (0%) 0 0 1 (0%)
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 4 (2%) 2 (1%) 0 0 0 6 (3%)
CONFIDENTIAL
Total 119 (55%) 73 (33%) 26 (12%) 0 0 218 (100%)

278
- Study Day
5-10
Grade 1 2 (1%) 7 (3%) 0 0 0 9 (4%)
Grade 2 0 1 (0%) 0 0 0 1 (0%)
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 6 (3%) 0 0 0 0 6 (3%)
Total 188 (86%) 28 (13%) 2 (1%) 0 0 218 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.10
Parameter: Alkaline Phosphatase(IU/L)

Time Grade
-------------------------------------------------------------------------------------------------------
Discharge/Post- Grade 0 203 (93%) 1 (0%) 0 0 0 204 (93%)
op Day 1
Grade 1 8 (4%) 4 (2%) 0 0 0 12 (5%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 3 (1%) 0 0 0 0 3 (1%)
CONFIDENTIAL
Total 214 (98%) 5 (2%) 0 0 0 219 (100%)
Post-Operation Grade 0 203 (89%) 8 (4%) 0 0 0 211 (93%)

279
- Study Day
5-10
Grade 1 4 (2%) 8 (4%) 1 (0%) 0 0 13 (6%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 3 (1%) 0 0 0 0 3 (1%)
Total 210 (93%) 16 (7%) 1 (0%) 0 0 227 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.10
Parameter: Alkaline Phosphatase(IU/L)

Time Grade
-------------------------------------------------------------------------------------------------------
op Day 1
Grade 1 3 (1%) 2 (1%) 0 0 0 5 (2%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 6 (3%) 0 0 0 0 6 (3%)
CONFIDENTIAL
Total 218 (98%) 4 (2%) 0 0 0 222 (100%)

280
- Study Day
5-10
Grade 1 1 (0%) 4 (2%) 0 0 0 5 (2%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 4 (2%) 0 0 0 0 4 (2%)
Total 208 (95%) 11 (5%) 0 0 0 219 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.10
Parameter: Aspartate Amino Transferase(IU/L)

Time Grade
-------------------------------------------------------------------------------------------------------
op Day 1
Grade 1 5 (2%) 4 (2%) 0 0 0 9 (4%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 2 (1%) 0 0 0 0 2 (1%)
CONFIDENTIAL
Total 187 (85%) 26 (12%) 3 (1%) 3 (1%) 0 219 (100%)

281
- Study Day
5-10
Grade 1 6 (3%) 4 (2%) 0 0 0 10 (4%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 2 (1%) 0 0 0 0 2 (1%)
Total 200 (88%) 25 (11%) 2 (1%) 0 0 227 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.10
Parameter: Aspartate Amino Transferase(IU/L)

Time Grade
-------------------------------------------------------------------------------------------------------
op Day 1
Grade 1 5 (2%) 5 (2%) 0 0 0 10 (5%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 5 (2%) 0 0 0 0 5 (2%)
CONFIDENTIAL
Total 186 (84%) 33 (15%) 2 (1%) 0 0 221 (100%)

282
- Study Day
5-10
Grade 1 4 (2%) 5 (2%) 0 0 0 9 (4%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 3 (1%) 1 (0%) 0 0 0 4 (2%)
Total 187 (85%) 31 (14%) 2 (1%) 0 0 220 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.10
Parameter: Bicarbonate(MMOL/L)
Time Grade
-------------------------------------------------------------------------------------------------------
op Day 1
Grade 1 0 0 0 0 0 0
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 0 0 0 0 0 0
CONFIDENTIAL
Total 10 (83%) 2 (17%) 0 0 0 12 (100%)
Post-Operation Grade 0 9 (100%) 0 0 0 0 9 (100%)

283
- Study Day
5-10
Grade 1 0 0 0 0 0 0
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 0 0 0 0 0 0
Total 9 (100%) 0 0 0 0 9 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.10
Parameter: Bicarbonate(MMOL/L)
Time Grade
-------------------------------------------------------------------------------------------------------
Discharge/Post- Grade 0 14 (100%) 0 0 0 0 14 (100%)
op Day 1
Grade 1 0 0 0 0 0 0
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 0 0 0 0 0 0
CONFIDENTIAL
Total 14 (100%) 0 0 0 0 14 (100%)

284
- Study Day
5-10
Grade 1 0 0 0 0 0 0
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 0 0 0 0 0 0
Total 11 (100%) 0 0 0 0 11 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.10
Parameter: Creatinine(UMOL/L)
Time Grade
-------------------------------------------------------------------------------------------------------
op Day 1
Grade 1 1 (0%) 1 (0%) 0 0 0 2 (1%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 3 (1%) 0 0 0 0 3 (1%)
CONFIDENTIAL
Total 222 (99%) 2 (1%) 0 0 0 224 (100%)

285
- Study Day
5-10
Grade 1 1 (0%) 1 (0%) 0 0 0 2 (1%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 3 (1%) 0 0 0 0 3 (1%)
Total 225 (98%) 4 (2%) 0 0 0 229 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.10
Parameter: Creatinine(UMOL/L)
Time Grade
-------------------------------------------------------------------------------------------------------
op Day 1
Grade 1 3 (1%) 1 (0%) 0 0 0 4 (2%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 5 (2%) 0 0 0 0 5 (2%)
CONFIDENTIAL
Total 222 (99%) 3 (1%) 0 0 0 225 (100%)

286
- Study Day
5-10
Grade 1 3 (1%) 1 (0%) 0 0 0 4 (2%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 4 (2%) 0 0 0 0 4 (2%)
Total 212 (97%) 7 (3%) 0 0 0 219 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.10
Parameter: Glucose(MMOL/L)
Time Grade
-------------------------------------------------------------------------------------------------------
op Day 1
Grade 1 6 (3%) 11 (5%) 4 (2%) 0 0 21 (10%)
Grade 2 2 (1%) 1 (0%) 0 0 0 3 (1%)
Grade 3 1 (0%) 0 0 1 (0%) 0 2 (1%)
Grade 4 0 0 0 0 0 0
Missing 3 (1%) 5 (2%) 2 (1%) 0 0 10 (5%)
CONFIDENTIAL
Total 109 (51%) 84 (40%) 17 (8%) 2 (1%) 0 212 (100%)

287
- Study Day
5-10
Grade 1 12 (6%) 10 (5%) 0 1 (0%) 0 23 (11%)
Grade 2 3 (1%) 0 0 0 0 3 (1%)
Grade 3 1 (0%) 1 (0%) 0 0 0 2 (1%)
Grade 4 0 0 0 0 0 0
Missing 9 (4%) 1 (0%) 0 0 0 10 (5%)
Total 178 (83%) 33 (15%) 3 (1%) 1 (0%) 0 215 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.10
Parameter: Glucose(MMOL/L)
Time Grade
-------------------------------------------------------------------------------------------------------
op Day 1
Grade 1 6 (3%) 11 (5%) 7 (3%) 2 (1%) 0 26 (12%)
Grade 2 1 (0%) 0 2 (1%) 0 0 3 (1%)
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 3 (1%) 4 (2%) 0 0 0 7 (3%)
CONFIDENTIAL
Total 112 (53%) 82 (39%) 16 (8%) 2 (1%) 0 212 (100%)

288
- Study Day
5-10
Grade 1 15 (8%) 9 (5%) 2 (1%) 2 (1%) 0 28 (14%)
Grade 2 0 0 1 (1%) 0 0 1 (1%)
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 6 (3%) 1 (1%) 0 0 0 7 (4%)
Total 165 (84%) 26 (13%) 4 (2%) 2 (1%) 0 197 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.10
Parameter: Potassium(MMOL/L)
Time Grade
-------------------------------------------------------------------------------------------------------
Discharge/Post- Grade 0 176 (95%) 0 1 (1%) 0 0 177 (95%)
op Day 1
Grade 1 0 0 0 0 0 0
Grade 2 1 (1%) 0 0 0 0 1 (1%)
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 8 (4%) 0 0 0 0 8 (4%)
CONFIDENTIAL
Total 185 (99%) 0 1 (1%) 0 0 186 (100%)
Post-Operation Grade 0 204 (93%) 5 (2%) 0 1 (0%) 0 210 (96%)

289
- Study Day
5-10
Grade 1 0 0 0 0 0 0
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 9 (4%) 0 0 0 0 9 (4%)
Total 213 (97%) 5 (2%) 0 1 (0%) 0 219 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.10
Parameter: Potassium(MMOL/L)
Time Grade
-------------------------------------------------------------------------------------------------------
op Day 1
Grade 1 1 (1%) 0 0 0 0 1 (1%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 12 (6%) 0 0 0 0 12 (6%)
CONFIDENTIAL
Total 194 (99%) 1 (1%) 0 0 0 195 (100%)

290
- Study Day
5-10
Grade 1 1 (0%) 0 0 0 0 1 (0%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 11 (5%) 0 0 0 0 11 (5%)
Total 204 (99%) 1 (0%) 1 (0%) 0 0 206 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.10
Parameter: Sodium(MMOL/L)
Time Grade
-------------------------------------------------------------------------------------------------------
op Day 1
Grade 1 2 (1%) 1 (0%) 0 0 0 3 (1%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 2 (1%) 0 0 0 0 2 (1%)
CONFIDENTIAL
Total 208 (100%) 1 (0%) 0 0 0 209 (100%)

291
- Study Day
5-10
Grade 1 2 (1%) 1 (0%) 0 0 0 3 (1%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 3 (1%) 0 0 0 0 3 (1%)
Total 220 (98%) 4 (2%) 0 0 0 224 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.10
Parameter: Sodium(MMOL/L)
Time Grade
-------------------------------------------------------------------------------------------------------
op Day 1
Grade 1 2 (1%) 1 (0%) 0 0 0 3 (1%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 5 (2%) 0 0 0 0 5 (2%)
CONFIDENTIAL
Total 206 (99%) 2 (1%) 0 0 0 208 (100%)

292
- Study Day
5-10
Grade 1 2 (1%) 1 (0%) 0 0 0 3 (1%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 3 (1%) 0 0 0 0 3 (1%)
Total 212 (99%) 2 (1%) 0 0 0 214 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.10
Parameter: Total Bilirubin(UMOL/L)

Time Grade
-------------------------------------------------------------------------------------------------------
op Day 1
Grade 1 3 (1%) 1 (0%) 1 (0%) 0 0 5 (2%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 5 (2%) 0 0 0 0 5 (2%)
CONFIDENTIAL
Total 205 (94%) 11 (5%) 3 (1%) 0 0 219 (100%)

293
- Study Day
5-10
Grade 1 5 (2%) 1 (0%) 0 0 0 6 (3%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 5 (2%) 0 0 0 0 5 (2%)
Total 226 (100%) 1 (0%) 0 0 0 227 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.10
Parameter: Total Bilirubin(UMOL/L)

Time Grade
-------------------------------------------------------------------------------------------------------
op Day 1
Grade 1 0 1 (0%) 2 (1%) 0 0 3 (1%)
Grade 2 0 0 4 (2%) 0 0 4 (2%)
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 8 (4%) 0 0 0 0 8 (4%)
CONFIDENTIAL
Total 206 (93%) 10 (5%) 6 (3%) 0 0 222 (100%)

294
- Study Day
5-10
Grade 1 3 (1%) 0 0 0 0 3 (1%)
Grade 2 1 (0%) 2 (1%) 0 0 0 3 (1%)
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 6 (3%) 0 0 0 0 6 (3%)
Total 213 (97%) 6 (3%) 0 0 0 219 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.11
Summary of Hematology Data

-------------------------------------------------------------------------------------------------
Basophils 4mg IV 237 SCREEN R 114 0.0280 0.02849 0.0200 0.0000 0.1030
(GI/L) Zofran
POST OP DAY N 112 0.0129 0.01686 0.0100 0.0000 0.0900
1/2
POST OP DAY N 119 0.0315 0.04562 0.0200 0.0000 0.4000
6-14
4mg IV 235 SCREEN R 113 0.0360 0.03641 0.0300 0.0000 0.1700

Zofran +
50mg PO
Casopitant
CONFIDENTIAL
POST OP DAY N 113 0.0148 0.02190 0.0100 0.0000 0.1000
1/2
POST OP DAY N 110 0.0331 0.03349 0.0200 0.0000 0.1300
295
6-14
Basophils 4mg IV 237 SCREEN R 116 0.4397 0.35774 0.4000 0.0000 2.0000
(percentage) Zofran
(%)
POST OP DAY N 104 0.2356 0.26837 0.2000 0.0000 1.0000
1/2
POST OP DAY N 105 0.4790 0.40802 0.4000 0.0000 2.2000
6-14
4mg IV 235 SCREEN R 114 0.4640 0.35177 0.4000 0.0000 1.5000
GM2006/00652/00
Zofran +
50mg PO
Casopitant
POST OP DAY N 106 0.1991 0.24201 0.1000 0.0000 1.1000
NKT102553
1/2
POST OP DAY N 103 0.4505 0.35834 0.4000 0.0000 1.7000
6-14

Population: Safety
Table 8.11

-------------------------------------------------------------------------------------------------
Eosinophils 4mg IV 237 SCREEN R 117 0.1406 0.11446 0.1000 0.0000 0.7000
(GI/L) Zofran
POST OP DAY N 113 0.0771 0.13998 0.0300 0.0000 1.0000
1/2
POST OP DAY N 120 0.2160 0.21194 0.1950 0.0000 1.8000
6-14
4mg IV 235 SCREEN R 115 0.1647 0.16135 0.1000 0.0000 1.2600

Zofran +
50mg PO
Casopitant
CONFIDENTIAL
POST OP DAY N 114 0.0661 0.07544 0.0400 0.0000 0.3600
1/2
POST OP DAY N 112 0.2439 0.20554 0.2000 0.0000 1.1500
296
6-14
Eosinophils 4mg IV 237 SCREEN R 116 2.2733 1.59135 1.9500 0.0000 9.0000
(percentage) Zofran
(%)
POST OP DAY N 105 1.2695 1.56237 0.8000 0.0000 8.0000
1/2
POST OP DAY N 106 3.6179 2.63875 3.0000 0.4000 18.0000
6-14
4mg IV 235 SCREEN R 116 2.3888 1.87639 2.0000 0.0000 13.0000
GM2006/00652/00
Zofran +
50mg PO
Casopitant
POST OP DAY N 106 0.9453 0.95450 0.7500 0.0000 4.0000
NKT102553
1/2
POST OP DAY N 107 2.8645 1.96460 2.5000 0.0000 11.0000
6-14

Population: Safety
Table 8.11

-------------------------------------------------------------------------------------------------
Hemoglobin 4mg IV 237 SCREEN R 236 129.3347 13.44374 130.5000 68.0000 169.0000
(G/L) Zofran
POST OP DAY N 226 116.6867 14.09398 117.0000 59.1000 148.0000
1/2
POST OP DAY N 229 123.6987 13.07036 126.0000 80.0000 154.0000
6-14
4mg IV 235 SCREEN R 233 128.7210 13.49567 130.0000 64.0000 157.0000

Zofran +
50mg PO
Casopitant
CONFIDENTIAL
POST OP DAY N 229 115.9170 15.19802 117.0000 73.0000 157.0000
1/2
POST OP DAY N 221 124.0769 13.85176 127.0000 83.0000 151.0000
297
6-14
Hematocrit 4mg IV 237 SCREEN R 236 0.3873 0.03580 0.3900 0.2220 0.4920
(1) Zofran
POST OP DAY N 226 0.3512 0.03812 0.3520 0.2240 0.4510
1/2
POST OP DAY N 229 0.3716 0.03547 0.3740 0.2710 0.4590
6-14
4mg IV 235 SCREEN R 233 0.3854 0.03646 0.3920 0.2070 0.4500

Zofran +
GM2006/00652/00
50mg PO
Casopitant
POST OP DAY N 229 0.3491 0.04320 0.3520 0.2270 0.4680
1/2
NKT102553
POST OP DAY N 221 0.3726 0.03930 0.3770 0.2580 0.4570
6-14

Population: Safety
Table 8.11

-------------------------------------------------------------------------------------------------
Lymphocytes 4mg IV 237 SCREEN R 117 2.0359 0.64947 1.9000 0.9000 4.3100
(GI/L) Zofran
POST OP DAY N 113 1.5566 0.57852 1.5700 0.4000 3.7500
1/2
POST OP DAY N 120 1.9888 0.66139 1.9000 0.5300 4.4500
6-14
4mg IV 235 SCREEN R 115 2.0835 0.61877 2.0000 0.9300 4.0500

Zofran +
50mg PO
Casopitant
CONFIDENTIAL
POST OP DAY N 114 1.4553 0.60573 1.3950 0.3300 4.2000
1/2
POST OP DAY N 112 1.9154 0.59054 1.8550 0.6800 3.6900
298
6-14
Lymphocytes 4mg IV 237 SCREEN R 117 31.1829 9.07434 31.1000 7.8000 60.4000
(percentage) Zofran
(%)
POST OP DAY N 106 17.7236 7.75582 16.6500 2.0000 39.0000
1/2
POST OP DAY N 107 27.7346 7.66087 27.8000 13.1000 52.3000
6-14
4mg IV 235 SCREEN R 116 30.7233 8.32696 30.8000 10.0000 64.6000
GM2006/00652/00
Zofran +
50mg PO
Casopitant
POST OP DAY N 105 18.1162 10.88154 15.0000 2.0000 55.6000
NKT102553
1/2
POST OP DAY N 108 27.2769 8.38746 26.8000 6.0000 58.3000
6-14

Population: Safety
Table 8.11

-------------------------------------------------------------------------------------------------
Monocytes 4mg IV 237 SCREEN R 117 0.4633 0.15346 0.4500 0.1000 0.9100
(GI/L) Zofran
POST OP DAY N 113 0.5651 0.22507 0.5600 0.0000 1.2600
1/2
POST OP DAY N 120 0.5017 0.21267 0.4800 0.1600 1.7900
6-14
4mg IV 235 SCREEN R 115 0.4618 0.13628 0.4500 0.1900 1.0600

Zofran +
50mg PO
Casopitant
CONFIDENTIAL
POST OP DAY N 114 0.5912 0.24990 0.5550 0.1000 1.4000
1/2
POST OP DAY N 112 0.4834 0.18455 0.4600 0.1200 1.0000
299
6-14
Monocytes 4mg IV 237 SCREEN R 117 6.2547 2.01796 6.2000 2.0000 12.0000
(percentage) Zofran
(%)
POST OP DAY N 106 5.8708 2.62475 5.8000 1.0000 12.7000
1/2
POST OP DAY N 107 6.2542 2.00416 6.0000 2.0000 12.0000
6-14
4mg IV 235 SCREEN R 116 6.5250 2.30994 6.2500 2.5000 15.0000
GM2006/00652/00
Zofran +
50mg PO
Casopitant
POST OP DAY N 105 6.4029 2.52550 6.0000 1.6000 14.5000
NKT102553
1/2
POST OP DAY N 108 6.4130 2.26996 6.3500 0.0000 12.7000
6-14

Population: Safety
Table 8.11

-------------------------------------------------------------------------------------------------
Total 4mg IV 237 SCREEN R 117 4.0937 1.47769 3.9000 1.4000 8.9700
Neutrophils Zofran
(GI/L)
POST OP DAY N 113 7.4367 3.09878 7.1000 1.9000 22.4000
1/2
POST OP DAY N 120 4.6686 1.84731 4.3350 1.6000 11.9400
6-14
4mg IV 235 SCREEN R 115 4.4556 1.96588 4.0000 1.7000 16.9600

Zofran +
50mg PO
CONFIDENTIAL
Casopitant
POST OP DAY N 114 7.7267 3.08632 7.0300 2.6100 17.5800
1/2
300
POST OP DAY N 112 4.8030 1.89479 4.4100 1.9500 12.9000

6-14
Total 4mg IV 237 SCREEN R 117 59.7675 9.81009 59.0000 34.3000 83.3000
Neutrophils Zofran
(percentage)
(%)
POST OP DAY N 106 74.9528 8.97211 74.8500 55.0000 96.0000
1/2
POST OP DAY N 107 61.8804 9.01390 63.0000 32.0000 81.3000
6-14
GM2006/00652/00
4mg IV 235 SCREEN R 116 59.8457 9.00752 59.4500 27.5000 83.0000
Zofran +
50mg PO
NKT102553
Casopitant
POST OP DAY N 105 74.2905 12.19643 76.5000 31.0000 95.7000
1/2

Population: Safety
Table 8.11

-------------------------------------------------------------------------------------------------
Total 4mg IV 235 POST OP DAY N 108 62.8574 9.41688 62.0000 30.8000 91.0000
Neutrophils Zofran + 6-14
(percentage) 50mg PO
(%) Casopitant
Platelet 4mg IV 237 SCREEN R 236 288.3178 70.52651 281.5000 101.0000 581.0000
count (GI/L) Zofran
POST OP DAY N 226 247.3186 63.50395 240.0000 93.0000 508.0000
1/2
POST OP DAY N 229 335.6769 93.87814 322.0000 114.0000 744.0000
CONFIDENTIAL
6-14
4mg IV 235 SCREEN R 232 286.4526 67.08957 279.5000 114.0000 551.0000

301
Zofran +
50mg PO
Casopitant
POST OP DAY N 229 247.3886 69.67432 237.0000 128.0000 726.0000
1/2
POST OP DAY N 221 325.5475 98.47821 316.0000 91.0000 752.0000
6-14
White Blood 4mg IV 237 SCREEN R 236 6.8271 1.97371 6.4150 2.9000 13.6000
Cell Count Zofran
(GI/L)
GM2006/00652/00
POST OP DAY N 226 9.9288 3.48507 9.4500 3.2000 24.4000
1/2
POST OP DAY N 229 7.3873 2.14444 6.9400 2.3000 16.0900
6-14
NKT102553
Population: Safety
Table 8.11

-------------------------------------------------------------------------------------------------
White Blood 4mg IV 235 SCREEN R 233 7.0501 2.24913 6.6500 3.2400 21.2000
Cell Count Zofran +
(GI/L) 50mg PO
Casopitant
POST OP DAY N 229 9.9839 3.64559 9.3000 2.8000 22.0000
1/2
POST OP DAY N 221 7.5452 2.30568 7.2000 3.2000 17.9000
6-14
CONFIDENTIAL
302
GM2006/00652/00
NKT102553
Population: Safety
Table 8.12
Summary of Hematology Data Outside the Reference Range
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Basophils SCREEN P n 3 2
(GI/L)
> ref. 0 0
range high
< ref. 0 0
range low
U 0 0
CONFIDENTIAL
R n 114 113
> ref. 4 (4%) 3 (3%)
range high
303
< ref. 2 (2%) 0

range low
U 0 0

> ref. 3 (3%) 2 (2%)
range high
< ref. 3 (3%) 2 (2%)
range low
U 0 0
GM2006/00652/00
6-14
> ref. 6 (5%) 3 (3%)
range high
< ref. 2 (2%) 2 (2%)
NKT102553
range low
U 0 0

Population: Safety
Table 8.12
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Basophils SCREEN P n 4 5
(percentag
e) (%)
> ref. 0 0
range high
< ref. 0 0
range low
CONFIDENTIAL
U 2 (50%) 3 (60%)
R n 116 114
> ref. 1 (<1%) 1 (<1%)
304
range high
< ref. 0 0
range low
U 0 0

> ref. 0 0
range high
< ref. 0 0
range low
U 11 (9%) 9 (8%)
GM2006/00652/00
6-14
> ref. 4 (4%) 2 (2%)
range high
NKT102553
< ref. 1 (<1%) 1 (<1%)
range low
U 4 (4%) 5 (4%)

Population: Safety
Table 8.12
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Eosinophil SCREEN P > ref. 0 0
s (GI/L) range high
< ref. 0 0
range low
U 0 0
R n 117 115
> ref. 2 (2%) 1 (<1%)
CONFIDENTIAL
range high
< ref. 1 (<1%) 1 (<1%)
range low
305
U 0 0

> ref. 2 (2%) 0
range high
< ref. 3 (3%) 7 (6%)
range low
U 0 0

6-14
> ref. 4 (3%) 7 (6%)
GM2006/00652/00
range high
< ref. 0 0
range low
U 0 0
NKT102553
Population: Safety
Table 8.12
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Eosinophil SCREEN P n 4 3
s
(percentag
e) (%)
> ref. 0 0
range high
< ref. 0 0
CONFIDENTIAL
range low
U 2 (50%) 1 (33%)
R n 116 116
306
> ref. 3 (3%) 4 (3%)

range high
< ref. 2 (2%) 0
range low
U 0 0

> ref. 4 (3%) 0
range high
< ref. 3 (3%) 6 (5%)
range low
U 10 (8%) 9 (8%)
GM2006/00652/00
6-14
> ref. 14 (13%) 7 (6%)
NKT102553
range high
< ref. 0 1 (<1%)
range low

Population: Safety
Table 8.12
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Eosinophil POST OP DAY N U 3 (3%) 1 (<1%)
s 6-14
(percentag
e) (%)
Hemoglobin SCREEN P n 1 1
(G/L)
CONFIDENTIAL
> ref. 0 0
range high
< ref. 0 0
307
range low
U 1 (100%) 1 (100%)
R n 236 233
> ref. 2 (<1%) 1 (<1%)
range high
< ref. 41 (17%) 49 (21%)
range low
U 0 0

> ref. 0 0
range high
GM2006/00652/00
< ref. 123 (53%) 127 (55%)
range low
U 4 (2%) 1 (<1%)
NKT102553
6-14

Population: Safety
Table 8.12
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Hemoglobin POST OP DAY N > ref. 0 0
(G/L) 6-14 range high
< ref. 77 (33%) 76 (34%)
range low
U 0 1 (<1%)
Hematocrit SCREEN P n 1 1
CONFIDENTIAL
(1)
> ref. 0 0
range high
308
< ref. 0 0
range low
U 1 (100%) 1 (100%)
R n 236 233
> ref. 2 (<1%) 0
range high
< ref. 45 (19%) 48 (21%)
range low
U 0 0

> ref. 0 0
GM2006/00652/00
range high
< ref. 136 (59%) 134 (58%)
range low
U 4 (2%) 1 (<1%)
NKT102553
6-14

Population: Safety
Table 8.12
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Hematocrit POST OP DAY N > ref. 1 (<1%) 2 (<1%)
(1) 6-14 range high
< ref. 81 (35%) 77 (34%)
range low
U 0 1 (<1%)
Lymphocyte SCREEN P > ref. 0 0
CONFIDENTIAL
s (GI/L) range high
< ref. 0 0
range low
309
U 0 0
R n 117 115
> ref. 3 (3%) 2 (2%)
range high
< ref. 2 (2%) 0
range low
U 0 0

> ref. 1 (<1%) 1 (<1%)
range high
< ref. 14 (12%) 23 (20%)
GM2006/00652/00
range low
U 0 0
NKT102553
6-14
> ref. 6 (5%) 2 (2%)
range high

Population: Safety
Table 8.12
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Lymphocyte POST OP DAY N < ref. 6 (5%) 4 (4%)
s (GI/L) 6-14 range low
U 0 0
Lymphocyte SCREEN P n 3 3
s
(percentag
CONFIDENTIAL
e) (%)
> ref. 0 0
range high
310
< ref. 0 0
range low
U 1 (33%) 1 (33%)
R n 117 116
> ref. 9 (8%) 6 (5%)
range high
< ref. 13 (11%) 12 (10%)
range low
U 0 0

> ref. 0 4 (3%)
GM2006/00652/00
range high
< ref. 66 (55%) 70 (59%)
range low
U 9 (8%) 10 (8%)
NKT102553
6-14

Population: Safety
Table 8.12
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Lymphocyte POST OP DAY N > ref. 4 (4%) 2 (2%)
s 6-14 range high
(percentag
e) (%)
< ref. 18 (16%) 17 (15%)
range low
U 2 (2%) 0
CONFIDENTIAL
Monocytes SCREEN P > ref. 0 0
(GI/L) range high
311
< ref. 0 0
range low
U 0 0
R n 117 115
> ref. 2 (2%) 1 (<1%)
range high
< ref. 2 (2%) 1 (<1%)
range low
U 0 0

> ref. 10 (9%) 12 (11%)
GM2006/00652/00
range high
< ref. 2 (2%) 1 (<1%)
range low
U 0 0
NKT102553
6-14

Population: Safety
Table 8.12
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Monocytes POST OP DAY N > ref. 5 (4%) 5 (4%)
(GI/L) 6-14 range high
< ref. 2 (2%) 2 (2%)
range low
U 0 0
Monocytes SCREEN P n 3 3
CONFIDENTIAL
(percentag
e) (%)
> ref. 0 0
312
range high
< ref. 0 0
range low
U 1 (33%) 1 (33%)
R n 117 116
> ref. 8 (7%) 7 (6%)
range high
< ref. 5 (4%) 7 (6%)
range low
U 0 0
GM2006/00652/00
> ref. 13 (11%) 9 (8%)
range high
< ref. 6 (5%) 4 (3%)
range low
NKT102553
U 9 (8%) 10 (8%)

Population: Safety
Table 8.12
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Monocytes POST OP DAY N n 112 114
(percentag 6-14
e) (%)
> ref. 7 (6%) 9 (8%)
range high
< ref. 1 (<1%) 6 (5%)
range low
CONFIDENTIAL
U 2 (2%) 0
Total SCREEN P > ref. 0 0

313
Neutrophil range high

s (GI/L)
< ref. 0 0
range low
U 0 0
R n 117 115
> ref. 3 (3%) 8 (7%)
range high
< ref. 4 (3%) 2 (2%)
range low
U 0 0
GM2006/00652/00
> ref. 52 (46%) 53 (46%)
range high
< ref. 0 0
NKT102553
range low
U 0 0

Population: Safety
Table 8.12
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Total POST OP DAY N n 120 112
Neutrophil 6-14
s (GI/L)
> ref. 8 (7%) 7 (6%)
range high
< ref. 2 (2%) 2 (2%)
range low
CONFIDENTIAL
U 0 0
314
Neutrophil
s
(percentag
e) (%)
> ref. 0 0
range high
< ref. 0 0
range low
U 1 (33%) 1 (33%)
R n 117 116
> ref. 12 (10%) 10 (9%)
range high
GM2006/00652/00
< ref. 8 (7%) 5 (4%)
range low
U 0 0
NKT102553
> ref. 64 (54%) 66 (56%)
range high

Population: Safety
Table 8.12
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Total POST OP DAY 1/2 N < ref. 0 3 (3%)
Neutrophil range low
s
(percentag
e) (%)
U 9 (8%) 10 (8%)
CONFIDENTIAL
6-14
> ref. 13 (12%) 13 (11%)
315
range high
< ref. 5 (4%) 3 (3%)
range low
U 2 (2%) 0
Platelet SCREEN P n 1 2
count
(GI/L)
> ref. 0 0
range high
< ref. 0 0
range low
GM2006/00652/00
U 1 (100%) 2 (100%)
R n 236 232
> ref. 11 (5%) 16 (7%)
range high
NKT102553
< ref. 4 (2%) 2 (<1%)
range low
U 0 0

Population: Safety
Table 8.12
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
Platelet POST OP DAY 1/2 N n 232 232
count
(GI/L)
> ref. 3 (1%) 5 (2%)
range high
< ref. 6 (3%) 5 (2%)
range low
CONFIDENTIAL
U 4 (2%) 1 (<1%)

316
6-14
> ref. 38 (16%) 39 (17%)
range high
< ref. 1 (<1%) 3 (1%)
range low
U 0 1 (<1%)
White SCREEN P n 1 1
Blood Cell
Count
(GI/L)
> ref. 0 0
GM2006/00652/00
range high
< ref. 0 0
range low
U 1 (100%) 1 (100%)
NKT102553
R n 236 233
> ref. 12 (5%) 18 (8%)
range high

Population: Safety
Table 8.12
4mg IV
Zofran +
4mg IV 50mg Oral
------------------------------------------------------------------
White SCREEN R < ref. 14 (6%) 10 (4%)
Blood Cell range low
Count
(GI/L)
U 0 0
CONFIDENTIAL
> ref. 83 (36%) 86 (37%)
range high
< ref. 4 (2%) 5 (2%)
317
range low
U 4 (2%) 1 (<1%)

6-14
> ref. 18 (8%) 17 (8%)
range high
< ref. 5 (2%) 6 (3%)
range low
U 0 1 (<1%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.13
Summary of Hematology Toxicity Grade Shifts from Baseline Toxicity Grade
Parameter: Hemoglobin(G/L)
Time Grade
-------------------------------------------------------------------------------------------------------
Discharge/Post- Grade 0 100 (44%) 80 (35%) 9 (4%) 0 1 (0%) 190 (84%)
op Day 1
Grade 1 3 (1%) 17 (8%) 9 (4%) 1 (0%) 0 30 (13%)
Grade 2 0 0 2 (1%) 1 (0%) 0 3 (1%)
Grade 3 0 1 (0%) 1 (0%) 0 0 2 (1%)
Grade 4 0 0 0 0 0 0
Missing 0 0 1 (0%) 0 0 1 (0%)
CONFIDENTIAL
Total 103 (46%) 98 (43%) 22 (10%) 2 (1%) 1 (0%) 226 (100%)

318
- Study Day
5-10
Grade 1 7 (3%) 23 (10%) 3 (1%) 0 0 33 (14%)
Grade 2 0 2 (1%) 2 (1%) 0 0 4 (2%)
Grade 3 0 1 (0%) 1 (0%) 0 0 2 (1%)
Grade 4 0 0 0 0 0 0
Missing 0 1 (0%) 0 0 0 1 (0%)
Total 152 (66%) 68 (30%) 9 (4%) 0 0 229 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.13
Parameter: Hemoglobin(G/L)
Time Grade
-------------------------------------------------------------------------------------------------------
op Day 1
Grade 1 3 (1%) 23 (10%) 11 (5%) 3 (1%) 0 40 (17%)
Grade 2 0 1 (0%) 4 (2%) 1 (0%) 0 6 (3%)
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 1 (0%) 0 1 (0%)
Missing 1 (0%) 0 0 0 0 1 (0%)
CONFIDENTIAL
Total 102 (45%) 99 (43%) 21 (9%) 7 (3%) 0 229 (100%)

319
- Study Day
5-10
Grade 1 6 (3%) 27 (12%) 9 (4%) 0 0 42 (19%)
Grade 2 1 (0%) 3 (1%) 2 (1%) 0 0 6 (3%)
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 1 (0%) 0 0 0 0 1 (0%)
Total 145 (66%) 62 (28%) 14 (6%) 0 0 221 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.13
Parameter: Lymphocytes(GI/L)
Time Grade
-------------------------------------------------------------------------------------------------------
op Day 1
Grade 1 0 2 (2%) 0 0 0 2 (2%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 2 (2%) 0 0 0 0 2 (2%)
CONFIDENTIAL
Total 98 (87%) 8 (7%) 5 (4%) 2 (2%) 0 113 (100%)

320
- Study Day
5-10
Grade 1 2 (2%) 0 0 0 0 2 (2%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 4 (3%) 0 0 0 0 4 (3%)
Total 114 (95%) 4 (3%) 2 (2%) 0 0 120 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.13
Parameter: Lymphocytes(GI/L)
Time Grade
-------------------------------------------------------------------------------------------------------
op Day 1
Grade 1 0 0 0 0 0 0
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 3 (3%) 0 0 0 0 3 (3%)
CONFIDENTIAL
Total 91 (80%) 14 (12%) 7 (6%) 2 (2%) 0 114 (100%)

321
- Study Day
5-10
Grade 1 0 0 0 0 0 0
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 3 (3%) 0 0 0 0 3 (3%)
Total 108 (96%) 2 (2%) 2 (2%) 0 0 112 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.13
Parameter: Platelet count(GI/L)

Time Grade
-------------------------------------------------------------------------------------------------------
op Day 1
Grade 1 1 (0%) 3 (1%) 0 0 0 4 (2%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 1 (0%) 0 0 0 0 1 (0%)
CONFIDENTIAL
Total 220 (97%) 6 (3%) 0 0 0 226 (100%)

322
- Study Day
5-10
Grade 1 4 (2%) 0 0 0 0 4 (2%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 1 (0%) 0 0 0 0 1 (0%)
Total 228 (100%) 1 (0%) 0 0 0 229 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.13
Parameter: Platelet count(GI/L)

Time Grade
-------------------------------------------------------------------------------------------------------
op Day 1
Grade 1 1 (0%) 1 (0%) 0 0 0 2 (1%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 2 (1%) 0 0 0 0 2 (1%)
CONFIDENTIAL
Total 224 (98%) 5 (2%) 0 0 0 229 (100%)

323
- Study Day
5-10
Grade 1 2 (1%) 0 0 0 0 2 (1%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 2 (1%) 0 0 0 0 2 (1%)
Total 218 (99%) 3 (1%) 0 0 0 221 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.13
Parameter: Total Neutrophils(GI/L)

Time Grade
-------------------------------------------------------------------------------------------------------
op Day 1
Grade 1 3 (3%) 0 0 0 0 3 (3%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 2 (2%) 0 0 0 0 2 (2%)
CONFIDENTIAL
Total 113 (100%) 0 0 0 0 113 (100%)

324
- Study Day
5-10
Grade 1 3 (3%) 0 0 0 0 3 (3%)
Grade 2 0 1 (1%) 0 0 0 1 (1%)
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 4 (3%) 0 0 0 0 4 (3%)
Total 118 (98%) 2 (2%) 0 0 0 120 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.13
Parameter: Total Neutrophils(GI/L)

Time Grade
-------------------------------------------------------------------------------------------------------
op Day 1
Grade 1 2 (2%) 0 0 0 0 2 (2%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 3 (3%) 0 0 0 0 3 (3%)
CONFIDENTIAL
Total 114 (100%) 0 0 0 0 114 (100%)

325
- Study Day
5-10
Grade 1 1 (1%) 1 (1%) 0 0 0 2 (2%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 3 (3%) 0 0 0 0 3 (3%)
Total 110 (98%) 2 (2%) 0 0 0 112 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.13
Parameter: White Blood Cell Count(GI/L)

Time Grade
-------------------------------------------------------------------------------------------------------
op Day 1
Grade 1 10 (4%) 2 (1%) 0 0 0 12 (5%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 1 (0%) 0 0 0 0 1 (0%)
CONFIDENTIAL
Total 222 (98%) 4 (2%) 0 0 0 226 (100%)

326
- Study Day
5-10
Grade 1 9 (4%) 3 (1%) 0 0 0 12 (5%)
Grade 2 1 (0%) 0 0 0 0 1 (0%)
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 1 (0%) 0 0 0 0 1 (0%)
Total 224 (98%) 4 (2%) 1 (0%) 0 0 229 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.13
Parameter: White Blood Cell Count(GI/L)

Time Grade
-------------------------------------------------------------------------------------------------------
op Day 1
Grade 1 8 (3%) 1 (0%) 1 (0%) 0 0 10 (4%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 1 (0%) 0 0 0 0 1 (0%)
CONFIDENTIAL
Total 224 (98%) 4 (2%) 1 (0%) 0 0 229 (100%)

327
- Study Day
5-10
Grade 1 7 (3%) 3 (1%) 0 0 0 10 (5%)
Grade 2 0 0 0 0 0 0
Grade 3 0 0 0 0 0 0
Grade 4 0 0 0 0 0 0
Missing 1 (0%) 0 0 0 0 1 (0%)
Total 215 (97%) 6 (3%) 0 0 0 221 (100%)
GM2006/00652/00
NKT102553
Population: Safety
Table 8.14
Summary of Pregnancy during Study
4mg IV Zofran
+
50mg Oral
Subject became 4mg IV Zofran Casopitant Total
pregnant (N=237) (N=235) (N=472)
-----------------------------------------------------------
No 133 (56%) 139 (59%) 272 (58%)
Yes 1 (<1%) 0 1 (<1%)
CONFIDENTIAL
328
GM2006/00652/00
NKT102553
Following database freeze, GSK received confirmation that preganancy was an error in recording & did not occ
Population: Safety
Table 8.15
Summary of ECG Findings
4mg IV
Zofran +
4mg IV 50mg Oral
Zofran Casopitant
(N=237) (N=235)
------------------------------------------------------------------
SCREEN
n 234 (99%) 231 (98%)
Normal 173 (73%) 178 (76%)
Abnormal - not clinically significant 61 (26%) 52 (22%)
Abnormal - clinically significant 0 1 (<1%)
No result (not available) 0 0
CONFIDENTIAL
POST OP DAY 1/2
n 228 (96%) 226 (96%)
Normal 170 (72%) 169 (72%)
329
Abnormal - not clinically significant 58 (24%) 55 (23%)

Abnormal - clinically significant 0 2 (<1%)
No result (not available) 0 0
GM2006/00652/00
NKT102553
Table 8.16
Summary of Time to Awakening
4mg IV Zofran +
50mg Oral
(N=242) (N=242)
----------------------------------------------------
Time to n 233 231
Awakening
(mins)
Mean 20.6 27.8
STD 24.38 94.87
Median 12.5 11.9
Min. 0.0 0.0
Max. 130.0 1394.0
CONFIDENTIAL
330
GM2006/00652/00
NKT102553
Population: Safety
Table 8.17
Summary of Deaths
No data to report
CONFIDENTIAL
331
GM2006/00652/00
NKT102553
Table 8.18
Listing of Laboratory Data for Subjects with Abnormalities of Clinical Concern
CTC Lab Toxicity Grades of 2, 3 and 4

Cen./ Age/ Lab
Inv./ Sex/ Study Converted Data Flag Tox
Subj. Race Lab Test Unit Visit Date Day Value Normal Range NR Code
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy.
Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see
the Patient Level Data section of the Sponsor Clinical Study Register.
CONFIDENTIAL
332
GM2006/00652/00
NKT102553
Population: Safety
Table 8.19
Listing of Vital Signs
(Hypotension/Procedual Hypotension Subjects Only)
Inv./ Age(y)/ Systolic Diastolic

Cen./ Sex/ Actual Study BP BP
Treatment Subj. Race Visit date Day (mmHg) (mmHg)
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient
privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further
information please see the Patient Level Data section of the Sponsor Clinical Study Register.
CONFIDENTIAL
384
GM2006/00652/00
NKT102553
NKT102553
OTHER ASSESSMENTS DATA SOURCE TABLES
Page
Table 8.12 Summary of Common Adverse Events ( >= 5% Incidence in Any
Treatment Group) (Safety Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . 398
397
Population: Safety
Table 8.12
Summary of Common Adverse Events ( >= 5% Incidence in Any Treatment Group)
4mg IV Zofran +
50mg Oral
--------------------------------------------------------------
Any event 87 (37%) 95 (40%)

Flatulence 12 (5%) 11 (5%)
Hypotension 8 (3%) 15 (6%)
Headache 11 (5%) 8 (3%)
CONFIDENTIAL
398
GM2006/00652/00
NKT102553
NKT102553
UM2005/00121/03 CONFIDENTIAL
The GlaxoSmithKline group of companies NKT102553
Division: Worldwide Development

Information Type: Protocol Amendment
Title: A Phase III, Multicenter, Randomized, Double-blind, Parallel

Group Study to Evaluate the Safety and Efficacy of 50 mg Oral
Dosing with the Neurokinin-1 Receptor Antagonist GW679769
for the Prevention of Postoperative Nausea and Vomiting in
Female Subjects at High Risk for Emesis
Effective Date: 17-APR-2006

Protocol Amendment Number: 02
Description: This Phase III study investigates the superiority of 50 mg oral of

GW679769 (casopitant mesylate) combined with 4 mg IV Zofran over 4 mg IV Zofran
alone in preventing PONV in female surgical subjects.
Subject: NK-1; emesis; post operative nausea and vomiting; PONV; casopitant mesylate
Authors:
Oncology MDC, Upper Providence

Oncology MDC, Harlow
Oncology MDC, Harlow
Biomedical Data Sciences, Upper Providence
Revision Chronology:
UM2005/00121/00 2005 Dec 01 Original
UM2005/00121/01 2006 Jan 23 Amendment No. 1 (correction of

internal inconsistencies in document)
UM2005/00121/02 2006-Apr-17 Amendment No. 2 (response to

feedback from FDA, Investigators
Meeting)

Unauthorised copying or use of this information is prohibited.
399
NKT102553
NKT102553
400
NKT102553
NKT102553
SPONSOR INFORMATION PAGE

Clinical Study Identifier: NKT102553
GlaxoSmithKline
New Frontiers Science Park
Third Avenue
Harlow, Essex CM19 5AW, UK
Telephone:
GlaxoSmithKline
1250 South Collegeville Road
Collegeville, PA 19426, USA
Telephone Number:
Sponsor Contact Information:
Sponsor Serious Adverse Events (SAE) Contact Information:
Case Management Group – GCSP (Reports from North, Central and South America
will be sent to RTP; reports from all other countries outside the Americas will be sent to
Greenford).
Greenford: RTP:
Identifying Number: IND 70,175
401
NKT102553
NKT102553
INVESTIGATOR AGREEMENT PAGE

I confirm agreement to conduct the study in compliance with the protocol, as amended by
this protocol amendment.
Investigator Name: _____________________________
Investigator Signature Date
402
NKT102553
NKT102553
TABLE OF CONTENTS
Page
ABBREVIATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
PROTOCOL SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
1. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
1.1. Background and Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
1.1.1. Brief History of GW679769 Clinical Development Program:
Emesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
2. OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
2.1. Primary Objective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
2.2. Secondary Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
3. ENDPOINTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
3.1. Primary Endpoint . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
3.2. Secondary Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
4. STUDY DESIGN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
4.1. Dosing of Antiemetics in NKT102553 . . . . . . . . . . . . . . . . . . . . . . . . 22
4.2. Anesthetic and Analgesic Regimen . . . . . . . . . . . . . . . . . . . . . . . . . . 22
5. STUDY POPULATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
5.1. Number of Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
5.2. Eligibility Criteria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
5.2.1. Inclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
5.2.2. Exclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
5.2.3. Other Eligibility Criteria Considerations . . . . . . . . . . . . . . . . . . 26
6. STUDY ASSESSMENTS AND PROCEDURES . . . . . . . . . . . . . . . . . . . . . 26
6.1. Demographic and Baseline Assessments . . . . . . . . . . . . . . . . . . . . . 26
6.2. Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
6.2.1. Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
6.2.2. Liver Chemistry Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
6.3. Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
6.3.1. Assessments of Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
6.3.2. Assessment of Nausea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
6.3.3. Antiemetic Rescue Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
6.3.4. Subject Diary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
6.4. Health Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
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6.4.1. Subject Satisfaction Questionnaires . . . . . . . . . . . . . . . . . . . . 33

6.4.2. Medical Resource Utilization . . . . . . . . . . . . . . . . . . . . . . . . . . 33
6.5. Pharmacogenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
7. LIFESTYLE AND/OR DIETARY RESTRICTIONS . . . . . . . . . . . . . . . . . . . 34
8. INVESTIGATIONAL PRODUCT AND STUDY MEDICATION . . . . . . . . . . 34
8.1. Description of Investigational Product . . . . . . . . . . . . . . . . . . . . . . . . 34
8.2. Description of the Study Medication . . . . . . . . . . . . . . . . . . . . . . . . . 34
8.3. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
8.4. Dose Rationale. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
8.5. Blinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
8.6. Treatment Assignment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
8.6.1. Randomization and Medication Ordering System . . . . . . . . . . 36
8.7. Packaging and Labeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
8.8. Preparation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
8.9. Handling and Storage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
8.10. Product Accountability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
8.11. Assessment of Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
8.12. Treatment of Investigational Product Overdose . . . . . . . . . . . . . . . . 38
8.13. Occupational Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
9. CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES . . . . . . . 38
9.1. Permitted Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
9.2. Antiemetic Rescue Medication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
9.3. Prohibited Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
9.3.1. Inhibitors of CYP3A4 and CYP3A5 . . . . . . . . . . . . . . . . . . . . . 40
9.3.2. Inducers of CYP3A4 and CYP3A5 . . . . . . . . . . . . . . . . . . . . . . 41
9.3.3. Other Medications that May Confound Results . . . . . . . . . . . . 41
9.3.4. Necessary Caution with CYP3A4 Substrates . . . . . . . . . . . . . 42
9.3.5. Exclusions and Necessary Caution with CYP2C8 Substrates . 42
9.3.6. Necessary Caution with P-glycoprotein Substrates . . . . . . . . . 42
9.4. Non-Drug Therapies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
10. SUBJECT COMPLETION AND WITHDRAWAL . . . . . . . . . . . . . . . . . . . . 43
10.1. Subject Completion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
10.2. Subject Withdrawal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
10.2.1. Subject Withdrawal from Study . . . . . . . . . . . . . . . . . . . . . . . 44
10.3. Treatment After the End of the Study . . . . . . . . . . . . . . . . . . . . . . . 44
10.4. Screen and Baseline Failures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
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11. ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) . . 45

11.1. Definition of an AE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
11.2. Definition of a SAE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
11.2.1. Disease-Related Events and/or Disease-Related Outcomes
Not Qualifying as SAEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
11.3. Lack of Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
11.4. Clinical Laboratory Abnormalities and Other Abnormal
Assessments as AEs and SAEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
11.5. Time Period, and Frequency of Detecting AEs and SAEs . . . . . . . . 47
11.6. Prompt Reporting of SAEs to GSK . . . . . . . . . . . . . . . . . . . . . . . . . 47
11.6.1. Timeframes for Submitting SAE Reports to GSK . . . . . . . . . 47
11.7. AE and SAE Documentation and Follow-up Procedures . . . . . . . . . 48
12. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS . . . . . . . . . . 48
12.1. Hypotheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
12.2. Study Design Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
12.2.1. Sample Size Assumptions . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
12.2.2. Sample Size Sensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
12.2.3. Sample Size Re-estimation . . . . . . . . . . . . . . . . . . . . . . . . . . 49
12.3. Data Analysis Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
12.3.1. Analysis Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
12.3.2. Treatment Comparisons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
12.3.3. Interim Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
12.3.4. Key Elements of Analysis Plan . . . . . . . . . . . . . . . . . . . . . . . 50
13. STUDY CONDUCT CONSIDERATIONS . . . . . . . . . . . . . . . . . . . . . . . . . 52
13.1. Regulatory and Ethical Considerations, Including the Informed
Consent Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
13.2. Quality Control (Study Monitoring) . . . . . . . . . . . . . . . . . . . . . . . . . . 53
13.3. Quality Assurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
13.4. Study and Site Closure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
13.5. Records Retention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
13.6. Provision of Study Results and Information to Investigators . . . . . . 54
13.7. Data Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
13.8. Independent Data Monitoring Committee (IDMC) . . . . . . . . . . . . . . 55
14. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Appendix 1: Time and Events Table . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Appendix 2: Dosing of Antiemetics in NKT102553 . . . . . . . . . . . . . . . . . . 60
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Appendix 3: Glossary of Relevant Terms . . . . . . . . . . . . . . . . . . . . . . . . . 61

Appendix 4: American Society of Anesthesiologists (ASA) Physical
Status Classification System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Appendix 5: Laboratory Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
Appendix 6: Subject Satisfaction Assessment . . . . . . . . . . . . . . . . . . . . . 64
Appendix 7: PGx . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Appendix 8: Opioid Equivalents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Appendix 9: Medications with CyP3A4 and/or CYP3A5 Substrate
Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Appendix 10: Nausea Assessment Scales . . . . . . . . . . . . . . . . . . . . . . . . 73
Appendix 11: Lactose Excipient in GW679769 . . . . . . . . . . . . . . . . . . . . . 74
Appendix 12: Country Specific Requirements . . . . . . . . . . . . . . . . . . . . . 76
Appendix 13: Changes to Protocol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
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ABBREVIATIONS
AE Adverse Event
ALT Alanine aminotransferase
AST Aspartate aminotransferase
AUC Area under the plasma concentration-time curve
β-hCG Beta human chorionic gonadotropin
BUN Blood urea nitrogen
CIB Clinical Investigator's Brochure
Cmax Maximum observed drug concentration
DNA Deoxyribonucleic acid
ECG Electrocardiogram
eCRF Electronic case report form(s)
EDTA Ethylenediamine tetra-acetic acid
5-HT3 Five (5)-hydroxytryptamine (serotonin), subtype 3
GCP Good Clinical Practice(s)
GCSP Global Clinical Safety and Pharmacovigilance
h Hour(s)
HCl Hydrochloride
HMG-CoA Three (3)-hydroxy-three (3)-methylglutaryl-coenzyme A
hNK-1 Human neurokinin, subtype 1
ICF Informed Consent Form
IEC Independent Ethical/Ethics Committee
IND Investigational New Drug Application
IRB Institutional Review Board
ITT Intent-to-Treat
IUD Intrauterine device
IV Intravenous (route of administration)
IVRS Interactive Voice Response System
kg Kilogram(s)
MDC Medicine Development Centre
µg Microgram(s)
mg Milligram(s)
mL Milliliter(s)
MSDS Material Safety Data Sheet(s)
NK Neurokinin
NK-1 Neurokinin subtype 1
PCA Patient controlled anesthesia
PET Positron emission tomography
PGx Pharmacogenetic(s)/pharmacogenomic(s)
PO Per oral (route of administration)
PONV Post-operative nausea and vomiting
RAMOS Randomization and Medication Ordering System
SAE Serious adverse event(s)
SNP Single nucleotide polymorphism(s)
SRM Study reference manual
WBC White blood cell
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Trademarks
GSK Trademarks
ZOFRAN
10
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PROTOCOL SUMMARY
Rationale
general anesthesia. Despite therapeutic advances, it remains the most common patient
complaint following general anesthesia [Gupta, 2003], and in one study was of greater
concern to patients than postoperative pain [Eberhart, 2002]. In addition to anxiety and
discomfort, PONV may lead to post-surgical complications such as fluid and electrolyte
imbalance, surgical wound dehiscence, and aspiration of vomitus; thus, PONV may result
in delayed discharge from the recovery area or an unscheduled hospital admission
[Marcus, 1999].
The etiology of PONV is multi-factorial, and the frequency is influenced by type of

surgery, medications, and individual patient factors [Watcha, 1992; Gan, 2003]. Some
common surgical procedures associated with increased emesis include gynecological
procedures and breast augmentation for females, and shoulder surgery for males.
Anesthetics such as nitrous oxide are associated with higher rates of PONV [Sinclair,
1999], and intraoperative and post-surgical administration of opioids often leads to
emesis [Kovac, 2000]. Patient factors that affect risk of PONV include gender,
movement following surgery, pain control, and a patient’s smoking status.
Overall, approximately 20-30% of surgical patients experience PONV [Watcha, 1992;

Kovac, 2000]. In the highest risk patients, PONV may occur in up to 70-80% of cases
[Apfel, 1999; Gan, 2003]. The incidence in females undergoing minor gynecological
surgery in an ambulatory setting without prophylactic antiemetics was reported to be 60%
[Carroll, 1995]. In patients undergoing laparoscopic cholecystectomy, an incidence of
PONV of up to 72% has been reported in patients who have not received prophylactic
antiemetic treatment [Naguib, 1996; Wang, 2002].
Individuals at low risk for PONV may fare well without a prophylactic antiemetic, but
those at high risk may benefit from prophylaxis with more than one agent. Therefore, an
understanding of which patients are likely to benefit from therapy is important, and
several investigators have developed risk stratification schemas to help guide treatment
decisions. In the Apfel simplified scoring scale, four factors predict for risk of PONV:
female gender, a history of motion sickness or PONV, non-smoking status, and the use of
postoperative opioids [Apfel, 1999]. Each of these is an independent risk factor, and the
chance of experiencing PONV is proportional to a patient’s total number of risk factors.
For example, a single risk factor predicts a 21% risk of PONV within 24 hours following
the procedure, while three or four factors predict a 61% and 78% chance of PONV,
respectively [Apfel, 1999]. The Apfel Simplified Risk Scale has been validated by
several studies [Apfel, 2002; Pierre, 2002] and will be used to characterize patient risk in
this study.
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Objectives
Primary Objective
The primary objective of this study is to demonstrate the superiority of 50 mg oral
GW679769, in combination with a single 4 mg intravenous dose of ZOFRAN™
(ondansetron hydrochloride) over a single 4 mg intravenous dose of ZOFRAN
(ondansetron hydrochloride) alone in control of emesis during the first 24 hours
following surgery.
Secondary Objectives
The secondary objectives of this clinical trial are to:
24 and 48 hour periods following surgery.
• Assess the control of emesis in the 24-48 hour period following the placement of last
suture/last staple.
who are predicted to have a high risk of emesis.
Endpoints
Primary Endpoint
The primary endpoint of this study is the proportion of subjects who achieve a complete
response (defined as no vomiting or retching and no antiemetic rescue therapy during the
first 24 hours following the placement of last suture/last staple).
Secondary Endpoints
1. The severity of nausea experienced by subjects in each cohort during the 2, 6, and 24
and 48 hour periods, as assessed by a discrete Likert scale, and by a categorical scale
(i.e., none, mild, moderate, severe).
2. Time to first emetic event following placement of the last suture/staple
3. Time to first rescue medication
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adverse events reporting.
Study Design
This is a Phase III, multicenter, randomized, double-blind, active-controlled, two arm
parallel group study.
Two compounds will be administered as part of this clinical trial. For the purposes of
this study, ZOFRAN Injection will be referred to as “study medication”, and GW679769
will be referred to as the “investigational product”.
Study Population
The study will be conducted in female subjects age 18 and older, at high risk for
developing PONV, who are scheduled to undergo one of the following surgical
procedures: breast surgery, orthopaedic shoulder surgery, or thyroid surgery. The
following laparoscopic or laparotomic procedures are also permitted: cholecystectomy,
hysterectomy, or other gynaecologic surgery. All surgeries must be anticipated to
involve general anesthesia of at least one hour duration. All subjects will have the
following four Apfel significant risk factors that predict a high risk of PONV within 24
hours following the surgical procedure:
• female gender
• a history of PONV and/or motion sickness
• has not smoked or used (e.g., chewing) tobacco (including a nicotine patch or other
nicotine-withdrawal formulation) for at least the previous 6 months.
• anticipated to receive postoperative opioids
Subjects will be stratified to treatment assignments by anticipated use of intra-operative
nitrous oxide.
Number of Subjects
It is estimated that 462 subjects will be enrolled into this study. This will be a
multinational, multicenter study, and it is anticipated that approximately 65 centers will
be required to complete enrollment. Additional centers may be added to meet enrollment
requirements.
Study Assessments and Procedures

A signed, written informed consent form will be obtained prior to screening assessments,
and before any study-specific assessments are initiated. The screening phase will be
within 21 days prior to the administration of investigational product and study
medication.
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Study Day 1 will include the day of investigational product and study medication,
surgery, and placement of last suture/staple, and will incorporate pre-treatment, peri-
operative, intra-operative and postoperative assessments as well as postdischarge interim
assessments (if applicable).
The subject will return to the investigational site 6-14 days after surgery for a final
follow-up assessment. All efforts will be made for this visit to occur as soon as possible
during this assessment phase.
Study procedures are detailed in the following table:
Study Procedures
Study Procedure Timing

Informed Consent Screening
Medical History Screening
Routine Physical Screening
Examination
ASA Physical Status Screening; day of surgery pre-medication
Vital Signs Screening; day of surgery pre-medication; day of surgery in post-op
phase or post-op Day 1; post-op Days 6-14 visit
ECG Screening, day of surgery in post-op phase or post-op Day 1
Hematology and Chemistry Screening; day of surgery in post-op phase or post-op Day 1; post-
op Days 6-14 visit
Pregnancy Test (if Within 24 hours prior to the first administration of study
applicable) medication/investigational product
Concomitant Medications Screening; day of surgery pre-medication; peri op and post-op Days
6-14 Visit
Inclusion/Exclusion Criteria Screening; day of surgery pre-medication
Telephone to RAMOS Screening; day of surgery pre-medication; post-op Days 6-14 visit
Administration of Study Day of surgery peri op phase
Medications
Pharmacogenetic Sample Prior to study, if consent given
Collection
Subject Diary Day of surgery pre-medication and post-op Days 1 & 2; turned in
Day 6-14 visit
Adverse Event Day of surgery and post-op Days 1 & 2; post-op Days 6-14 visit
Assessment
The Subject Diary will include assessments of nausea, vomiting, and subject satisfaction
with the investigational regimen.
Study subjects who require antiemetic rescue medication(s) during the 24-hours
following the placement of last suture/last staple will be considered treatment failures.
For the purposes of this study, antiemetic rescue medication will be defined as
medication that is given specifically for the treatment of nausea and/or emesis during the
study. The choice of rescue antiemetic medication will be left to the discretion of the
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investigator. Details of the use of each antiemetic rescue medication will be documented
in the subject’s case report forms, including the name of the antiemetic, the
corresponding dose(s), and the date(s) and time(s) of administration.
Please note the importance of not giving study subjects additional medications with
antiemetic properties as prophylaxis against nausea and/or emesis. Antiemetics should
be limited to rescue therapy; that is, only given in the event that the antiemetic
prophylaxis given at surgery has failed and the subject is experiencing nausea and/or
vomiting and needs further antiemetic treatment. Any subject who takes additional
antiemetic medication as prophylaxis or rescue will be considered to be a treatment
failure at the time the rescue medication is taken, even in the absence of an emetic
episode or nausea.
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1. INTRODUCTION
1.1. Background and Rationale

general anesthesia. Despite therapeutic advances, it remains the most common patient
complaint following general anesthesia [Gupta, 2003], and in one study was of greater
concern to patients than postoperative pain [Eberhart, 2002]. In addition to anxiety and
discomfort, PONV may lead to post-surgical complications such as fluid and electrolyte
imbalance, surgical wound dehiscence, and aspiration of vomitus; thus, PONV may result
in delayed discharge from the recovery area or an unscheduled hospital admission
[Marcus, 1999].
The etiology of PONV is multi-factorial, and the frequency is influenced by type of

surgery, medications, and individual patient factors [Watcha, 1992; Gan, 2003]. Some
common surgical procedures associated with increased emesis include gynecological
procedures and breast augmentation for females, and shoulder surgery for males.
Anesthetics such as nitrous oxide are associated with higher rates of PONV [Sinclair,
1999], and intraoperative and post-surgical administration of opioids often leads to
emesis [Kovac, 2000]. Patient factors that affect risk of PONV include gender,
movement following surgery, pain control, and a patient’s smoking status.
Overall, approximately 20-30% of surgical patients experience PONV [Watcha, 1992;

Kovac, 2000]. In the highest risk patients, PONV may occur in up to 70-80% of cases
[Apfel, 1999; Gan, 2003]. The incidence in females undergoing minor gynecological
surgery in an ambulatory setting without prophylactic antiemetics was reported to be 60%
[Carroll, 1995]. In patients undergoing laparoscopic cholecystectomy, an incidence of
PONV of up to 72% has been reported in patients who have not received prophylactic
antiemetic treatment [Naguib, 1996; Wang, 2002].
Individuals at low risk for PONV may fare well without a prophylactic antiemetic, but
those at high risk may benefit from prophylaxis with more than one agent. Therefore, an
understanding of which patients are likely to benefit from therapy is important, and
several investigators have developed risk stratification schemas to help guide treatment
decisions. In the Apfel simplified scoring scale, four factors predict for risk of PONV:
female gender, a history of motion sickness or PONV, non-smoking status, and the use of
postoperative opioids [Apfel, 1999]. Each of these is an independent risk factor, and the
chance of experiencing PONV is proportional to a patient’s total number of risk factors.
For example, a single risk factor predicts a 21% risk of PONV within 24 hours following
the procedure, while three or four factors predict a 61% and 78% chance of PONV,
respectively [Apfel, 1999]. The Apfel Simplified Risk Scale has been validated by
several studies [Apfel, 2002; Pierre, 2002] and will be used to characterize patient risk in
this study.
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1.1.1. Brief History of GW679769 Clinical Development Program:

Emesis
1.1.1.1. Phase I Program
The following table summarizes the Phase I studies completed to date:
Table 1 Phase I Program
No. of Subjects
Study Purpose GW679769 Dose Enrolled (No.
(mg) receiving GW679769)
NKF10001 FTIH, SD 5, 15, 30, 60, 80, 22 (21)
100,120, 150
NKF10002 PET %RO, SD 2.5, 5, 20, 50, 120 12 (8)
NKF10004 Repeat dose and PK 30, 50, 60, 70, 90 64 (49)
SD&RD
NKF10006 Oral contraceptive, 60 11 (11)
RD
NKF10007 CYP450 interaction, 50, 100 48 (48)
SD
NKF10010 Food effect; relative 50, 100 tablet and 36 (36)
bioavailability, SD 50,100 oral solution
NKF101873 Repeat dose and 75, 100 and 120 30 (24)
PK,RD
NKV10001 Drug interaction with 30 and 90 59 (39)
dexamethasone and
ondansetron, RD
NKV100789 IV and drug 12, 30, 70, 90, 110 IV 48 (48)
interaction with IV over 15-20 minutes,
and oral 150mg oral tablet
dexamethasone
FTIH=First Time in Human
SD=single dose; RD=repeat dose (3, 7 and 28 days)
IV=intravenous
Total of 236 subjects exposed to oral GW679769 (113 SD; 123 RD)
Total of 48 subjects exposed to IV GW67976
GW679769 was first administered to humans in October 2002 and has been evaluated in
healthy volunteers in four single-dose studies and four repeat dose studies, with oral
doses ranging from 2.5 to 150 mg. A total of 282 subjects (236 dosed with GW679769)
have been enrolled in these studies.
GW679769 was well-tolerated in these Phase I studies with fatigue, somnolence and
headache being the most commonly reported adverse events (AEs). None of the AEs
were considered severe, and the majority were graded as mild, and resolved
spontaneously. Three serious adverse events (SAEs) have been reported following
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administration of GW679769: (1) peritonsillar cellulitis in study NKF10007 was

reported by the investigator as unrelated to GW679769 treatment; (2) perforated gastric
ulcer in study NKV10001 (conducted in support of the CINV indication) occurred in a
subject with an undisclosed history of peptic ulcer disease. This SAE was reported by the
investigator as unrelated to administration of GW679769, and was considered related to
administration of protocol-specified dexamethasone; (3) intermittent cough with
hemoptysis due to pulmonary tuberculosis occurred in a subject in study NKV10001.
The investigator reported this event as unlikely to be related to GW679769.
There were no trends in laboratory parameters of clinical concern, although two subjects
were withdrawn from Study NKF10004 (one on Day 1 and one on Day 16) due to
isolated moderate elevations in liver transaminases. In both cases, the increase in liver
transaminases was reversible. Clinical observations, including heart rate, blood pressure
and 12-lead ECGs did not reveal any changes believed to be of clinical significance.
After oral administration, the maximal plasma concentration was achieved at one hour
(range: 0.5-4 hours), and the half-life values typically ranged fronm 9 – 18 hours,
although a slight increase with dose and duration of dosing has been observed. The
elimination of GW679769 occurs mainly via the liver.
Overall, the clinical data to date indicate that, depending on the dose and dosing regimen,
GW679769 is a mild to moderate inhibitor of CYP3A4, such that the exposure of
CYP3A4 substrates can be elevated by 2 – 4 fold.
The food effect study (high fat breakfast) indicated that the Cmax was on average
decreased by 16% after a 50 mg dose, but no effect of food was observed for Cmax after
100 mg or for AUC both after 50 mg and 100 mg.
1.1.1.2. Phase II Program – PONV
Two multicenter, randomized double-blind, placebo-controlled dose-ranging Phase II

studies of GW679769 in PONV have completed enrollment and preliminary results are
available for one (NKT102260). The primary objectives of the two phase II PONV
studies were:
• NKT102260: determine the optimal single dose of oral GW679769 when

administered in combination with the standard of care prophylactic antiemetic
ZOFRAN Injection on the day of surgery for the prevention of emesis during the
first 24 hours following emergence from anesthesia.
• NKT102245: determine the optimal dose of oral GW679769 when administered for
three consecutive days in combination with the standard of care prophylactic
antiemetic ZOFRAN Injection on the day of surgery for the prevention of emesis
during the first 72 hours following emergence from anesthesia.
The primary endpoint for both studies was complete response (defined as no vomiting, no
retching, no rescue medications and no premature withdrawal from the study) assessed 24
hours (NKT102260) and 72 hours (NKT102245) post-emergence from anesthesia.
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In study NKT102260, GW679769 (oral doses of 50, 100 and 150 mg) in combination
with ZOFRAN Injection demonstrated significant improvement in the prevention of post-
operative emesis over ZOFRAN Injection alone at each dose tested at 24, 48 and 72
hours post emergence from anesthesia. No significant difference in efficacy was
observed among the three GW679769 doses tested, and all three doses appeared to be
safe and well tolerated (as displayed in Table 2, “Adverse Events Occurring in Greater
Than 5% of Subjects”). For example, the complete response rate for ZOFRAN Injection
at 0-23 hours was 40%, while that for the combination of 50 mg, 100 mg, and 150 mg of
GW679769 combined with ZOFRAN Injection yielded complete response rates of 59%,
62%, and 61%, respectively. A possible trend toward increased frequency of adverse
events of serum alanine amino transferase (ALT) elevation was observed with the 150
mg. dose. Serious adverse events were reported for 31 (5%) of subjects treated on the
study, and the rates of serious adverse events appeared similar across treatment groups.
Therefore, a dose equivalent to 50 mg oral GW679769 will be used in this phase III trial.
Table 2 Adverse Events Occurring in Greater Than 5% of Subjects
Placebo 50mg 100mg 150mg 150mg

(N = 130) (N = 135) (N = 134) (N = 131) alone
(N = 132)
Any Event 68 (52%) 62 (46%) 69 (51%) 68 (52%) 61 (46%)
Headache 16 (12%) 13 (10%) 10 (7%) 14 (11%) 11 (8%)
Dizziness 8 (6%) 9 (7%) 12 (9%) 8 (6%) 4 (3%)
Somnolence 0 1 (<1%) 2 (1%) 2 (2%) 2 (2%)
Constipations 13 (10%) 4 (3%) 0 6 (5%) 8 (6%)
Abdo. Distension 3 (2%) 4 (3%) 0 3 (2%) 6 (5%)
Flatulence 7 (5%) 0 5 (4%) 1 (<1%) 3 (2%)
ALT increased 1 (<1%) 2 (1%) 1 (<1%) 7 (5%) 1 (<1%)
Procedural 2 (2%) 3 (2%) 1 (<1%) 3 (2%) 6 (5%)
hypotension
2. OBJECTIVES
2.1. Primary Objective

The primary objective of this study is to demonstrate the superiority of 50 mg oral
GW679769, in combination with a single 4 mg intravenous dose of ZOFRAN
(ondansetron hydrochloride), over a single 4 mg intravenous dose of ZOFRAN
(ondansetron hydrochloride) alone in the control of emesis during the first 24 hours
following the placement of last suture/last staple (as measured by complete response,
defined as no vomiting, no retching, and no rescue medications,) in surgical subjects who
are predicted to have a high risk of emesis.
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2.2. Secondary Objectives

The secondary objectives of this clinical trial are to:
• Assess the control of emesis in the 24-48 hour period following the placement of last
suture/last staple.
who are predicted to have a high risk of emesis
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3. ENDPOINTS
3.1. Primary Endpoint

The primary endpoint of this study is the proportion of subjects who achieve a complete
response (defined as no vomiting or retching and no rescue therapy during the first 24
hours following the placement of last suture/last staple).
3.2. Secondary Endpoints

The secondary endpoints of this trial are:
1. The severity of nausea experienced by subjects in each cohort during the 2, 6, 24 and
48 hour periods, as assessed by a discrete Likert scale, and by a categorical scale, as
defined in the protocol (see Appendix 10, “Nausea Assessment Scales”).
2. Time to first emetic event, defined as the time elapsed from last suture/last staple to
the first emetic episode (regardless of antiemetic rescue use). If a subject withdraws
prematurely during the first 48 hours, then the time of withdrawal will be considered
to be their time to first emetic episode, and will be censored.
3. Time to first antiemetic rescue medication, defined as the time elapsed from last
suture/last staple to the first antiemetic rescue medication. If a subject withdraws
prematurely during the first 48 hours, then the time of withdrawal will be considered
to be their time to first use of antiemetic rescue medication, and will be censored.
adverse events reporting
4. STUDY DESIGN
This is a Phase III, multicenter, randomized, double-blind, active-controlled, two arm
this study, ZOFRAN Injection will be referred to as “study medication”, and GW679769
will be referred to as the “investigational product”.
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4.1. Dosing of Antiemetics in NKT102553

Administration (Prior to Induction of Anesthesia) Administered
A GW679769 oral ∼60 minutes prior Placebo
ZOFRAN IV (2-5 min) Immediately prior 4 mg

(ondansetron HCl)
B GW679769 oral ∼60 minutes prior 50 mg

(ondansetron HCl)
4.2. Anesthetic and Analgesic Regimen

Participating investigators will be required to adhere to a balanced general anesthetic
regimen as per their institutional guidelines and common practice. All surgeries must be
anticipated to involve a minimum of one hour of general anesthesia. (Start time of
genereal anesthesia will be the time of administration of the first anesthetic agent eg, IV
Propofol induction. The end time of general anesthesia will be equal to the time of
extubation or equivalent). Propofol will be permitted for induction of, but not
maintenance of, anesthesia. Total intravenous anesthesia (TIVA) is not allowed in this
study.
Anticipated use of opioids post-surgery is an eligibility requirement for this study. Every
effort should be made to maintain consistent subsequent analgesia for each subject.
Administration of any medications through the use of an epidural catheter will not be
permitted. The use of Patient Controlled Administration (PCA) devices is permitted.
Local anesthetic infusion pumps are permitted as long as they are being used in addition
to the anticipated use of systemic opioids.
5. STUDY POPULATION
The study will be conducted in female subjects age 18 and older, at high risk for
developing PONV, who are scheduled to undergo one of the following surgical
procedures: breast surgery, orthopaedic shoulder surgery, or thyroid surgery. The
following laparoscopic or laparotomic procedures are also permitted: cholecystectomy,
hysterectomy, or other gynaecologic surgery All surgeries must be anticipated to involve
general anesthesia of at least one hour in duration. All subjects will have the four Apfel
significant risk factors that predict a high risk of PONV within 24 hours following the
surgical procedure.
Subjects will be stratified to treatment assignments by planned intra-operative use of

nitrous oxide.
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5.1. Number of Subjects

It is estimated that 462 subjects will be enrolled into this study. This will be a
multinational, multicenter study, and it is anticipated that approximately 65 centers will
be required to complete enrolment. Additional centers may be added to meet enrolment
requirements.
5.2. Eligibility Criteria
5.2.1. Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria
apply:
1. is 18 years of age or older

2. has all four Apfel risk factors:
• female gender
• a history of PONV and/or motion sickness
• a non-smoker: defined for this study as one who has not smoked or used (e.g.,
chewing) tobacco (including a nicotine patch or other nicotine-withdrawal
formulation) for at least the previous 6 months. Rare/infrequent (2 or less
cigarettes a week) smoking is allowed, at the investigator’s discretion.
• anticipated to receive opioids postoperatively
3. is scheduled to undergo one of the following surgical procedures: breast surgery,
orthopaedic shoulder surgery, or thyroid surgery. The following laparoscopic or
laparotomic procedures are also permitted: cholecystectomy, hysterectomy, or other
gynaecologic surgery
4. surgery must be anticipated to involve general anesthesia of at least one hour
duration. (Start time of general anesthesia will be the time of administration of the
first anesthetic agent eg, IV Propofol induction. The end time of general anesthesia
will be equal to the time of extubation or equivalent).
5. scheduled to receive general inhalation anesthesia with an anesthetic regimen as
described in the protocol under Section 4.2., “Anesthetic and Analgesic Regimen”.
6. meets the American Society of Anesthesiologists (ASA) Physical Status
Classification of P1 or P2, preoperatively, on the day of surgery. (See Appendix 4,
“American Society of Anesthesiologists (ASA) Physical Status Classification
System” for definitions)
7. willing and expected to be able to complete daily components of the subject diary
preoperatively on the day of surgery and until the end of the 48 hour assessment
period, and return to the investigational site at the post-op Day 6-14 final study visit.
8. understands the nature and purpose of this study and the study procedures and has
signed an informed consent form for this study to indicate this understanding.
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9. women of childbearing potential must commit to consistent and correct use of an

acceptable method of birth control, to be followed for a minimum of seven days
postoperatively. GSK acceptable contraceptive methods, when used consistently and
in accordance with both the product label and the instructions of a physician, are as
follows:
a. non-childbearing potential (i.e., physiologically incapable of becoming pregnant,
including any female who is postmenopausal. For purposes of this study,
postmenopausal is defined as one year without menses). These subjects do not
need to follow the birth control practices outlined in this protocol.
b. child-bearing potential: has a negative serum pregnancy test result or a negative
urine dipstick pregnancy test at baseline (within 24 hours prior to investigational
product administration) and agrees to one of the following:
• male partner who is sterile prior to the female subject’s entry into the study
and is the sole sexual partner for that female subject
• oral contraceptives (either combined or progestogen only) which must be
combined with double-barrier method of contraception consisting of
spermicide with either condom or diaphragm
• double-barrier method of contraception consisting of spermicide with either
condom or diaphragm
• intra-uterine device (IUD) with a documented failure rate of less than 1% per
year
• complete abstinence from intercourse for two weeks prior to exposure to the
investigational product throughout the clinical trial, and for a period after the
trial to account for elimination of the drug (minimum of seven days after
exposure to the investigational product).
5.2.2. Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria
apply:
1. is pregnant or lactating
2. is scheduled to receive propofol for maintenance of anesthesia
3. has received an investigational drug in the previous 30 days or is scheduled to
receive any investigational drug in addition to GW679769 during the study period
4. has persistent or recurrent nausea and/or vomiting due to other etiologies, or has
experienced emesis or uncontrolled nausea at any time during the 24 hours prior to
scheduled receipt of the investigational product and study medication
5. is taking greater than 10 mg of oxycodone, or an equivalent opioid dose, on a regular,
daily basis, for more than three consecutive days prior to entryinto the study (see
Appendix 8, “Opioid Equivalents”, for further details).
6. has a medical condition (e.g., vagotomy) or is receiving medication that could
confound the results of this study
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7. is anticipated to require a nasogastric or oral-gastric tube with intermittent or

continuous suctioning post-operatively (please note that if an NG/OG tube is to be
inserted at the beginning of induction, be sure GW679769 has been given at least 60
minutes prior).
8. has baseline ALT/AST >1.5x the upper limit of normal, unless related to the
condition for which the subject is undergoing surgery, in which case the acceptable
limit is 3x the upper limit of normal
9. has baseline bilirubin >1.5x the upper limit of normal, unless related to the condition
for which the subject is undergoing surgery, in which case the acceptable limit is 3x
the upper limit of normal
10. as a known hypersensitivity to ondansetron, another 5-HT3 receptor antagonist, any
component of GW679769, or any of the scheduled anesthetic or analgesic agents
11. is scheduled to receive antiemetics not included in the study dosing scheme, during
the evaluation period, or has received medication with potential antiemetic activity in
the 24 hour period, (or as specified below), prior to surgery. This includes, but is not
limited to:
• 5-HT3 receptor antagonists (e.g., ondansetron, granisetron, dolasetron,
tropisetron, ramosetron). Palonosetron is not permitted for seven days prior to
the study.
• benzamide/benzamide derivatives (e.g., metoclopramide, alizapride)
• phenothiazines (e.g., prochlorperazine, promethazine, fluphenazine,
perphenazine, thiethylperazine, chlorpromazine)
• butyrophenones (e.g., haloperidol, droperidol)
• corticosteroids (e.g., dexamethasone, methylprednisolone – with the exception
of topical steroids for skin and/or ocular disorders and inhaled steroids for
respiratory disorders)
• scopolamine
• antihistamines (e.g., cyclizine, hydroxyzine, diphenhydramine); however,
diphenhydramine for pruritis is allowed
• domperidone
• cannabinoids
• mirtazapine, olanzapine
12. has taken/received strong or moderate inhibitors of CYP3A4 and/or CYP3A5 within
the following time frames prior to administration of the investigational product:
• 2 days: clarithromycin, diltiazem, erythromycin, grapefruit juice, ketoconazole,
verapamil
• 14 days: fluconazole, itraconazole
These medications are also prohibited for 72 hours following the administration of
GW679769.
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13. has taken/received inducers of CYP3A4 and/or CYP3A5 within 14 days prior to the
administration of the investigational product, including: carbamazepine,
phenobarbital, phenytoin, rifabutin, rifampin, St. John’s wort, and troglitazone
These medications are also prohibited for 72 hours following the administration of
GW679769.
14. is taking the anti-diabetic agent repaglinide or the diuretic torsemide. Investigators
are advised to exercise caution if including patients taking the anti-diabetic agents
rosiglitazone or pioglitazone, or antimalarial agents such as chloroquine and
amodiaquine, as the metabolite of GW679769 is a potential inhibitor of CYP2C8 (See
Section 9.3.5., “Exclusions and Necessary Caution with CYP2C8 Substrates”).
Note: Subjects taking digoxin, or other substrates of P-glycoprotein (PGP) are not
excluded from the study. However, if entered into the study, investigators are cautioned
to clinically monitor such subjects for signs of digoxin toxicity, as a metabolite of
GW679769 has been shown to inhibit PGP in vitro, which may result in reduced PGP-
mediated clearance of digoxin. The clinical relevance of this interaction is not known at
this time. (See Section 9.3.6., “Necessary Caution with P-glycoprotein Substrates”).
15. In France, a subject is neither affilitated with nor a beneficiary of a social security
category.
5.2.3. Other Eligibility Criteria Considerations
To assess any potential impact on subject eligibility with regard to safety, the investigator
must refer to the following documents for detailed information regarding warnings,
precautions, contraindications, adverse events, and other significant data pertaining to the
investigational products being used in this study: the Clinical Investigator's Brochure
(CIB) for GW679769, and the approved product label for ZOFRAN Injection. These
documents will be provided to the investigational site prior to study start.
6. STUDY ASSESSMENTS AND PROCEDURES
6.1. Demographic and Baseline Assessments

A signed, written informed consent form (ICF) will be obtained prior to screening
assessments and before any study-specific assessments are initiated. Unless specified to
the contrary, the screening period will be within 21 days prior to administration of the
investigational product. All screening and baseline evaluations must be completed prior
to initiating treatment with the investigational product.
The following assessments will be obtained at Screening:
1. Demographic data: date of birth, race, height, weight, and ASA Physical Status
Classification.
2. Medical history and evaluation of inclusion/exclusion criteria, including previous
history of PONV, previous history of motion sickness and smoking history.
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3. Prior and concomitant medications taken within seven days prior to the scheduled
surgery will be recorded.
4. Routine physical examination, which will be performed by a qualified physician,
physician's assistant, or nurse practitioner, and should include a thorough review of
all body systems.
5. Baseline 12-lead ECG
6. Vital signs (including heart rate, blood pressure, and respiration rate).
7. Hematology and clinical chemistry laboratory assessments, including the following:
• Hematology: hemoglobin, hematocrit, white blood cell (WBC) count, and WBC
differential, platelet count (see Appendix 5: “Laboratory Tests”).
• Chemistry: ALT, albumin, alkaline phosphatase, AST, blood urea nitrogen
(BUN) or serum urea, creatinine, electrolytes (sodium, potassium, chloride),
glucose, total bilirubin, and total protein (see Appendix 5: “Laboratory Tests”).
These tests will be assessed per local standards, but in no event longer than 10 days
prior to the scheduled surgery. If possible, the blood collection for glucose should be
taken when the subject has fasted for at least 8 hours.
8. Urine or serum pregnancy testing for females of childbearing potential (per local
standards, but in no event longer than 24 hours prior to the first administration of
GW679769 investigational product). See Section 6.2.1., “Pregnancy” for additional
information).
Once a subject has completed the baseline assessments, the Investigator, or his/her
designee, must register the subject into the study through GlaxoSmithKline's
Randomization and Medication Ordering System (RAMOS), an interactive voice
response system. See Section 8.6.1., “Randomization and Medication Ordering
System”).
6.2. Safety
Safety and tolerability of the investigational product and the study medication in this
population will be assessed from adverse event (AE) data collected from the time of
informed consent, through the final visit at post-op Days 6-14.
Hematology and clinical chemistry tests will be performed at Screening, prior to

discharge from the hospital/surgical facility or the end of the 24-hour follow-up
assessment period on Post-operative Day 1 (whichever comes first), and at the final study
visit (days 6-14 visit).
Vital signs will be assessed at baseline and prior to discharge from the hospital/surgical
facility or the end of the 24-hour assessment period, whichever comes first. The time to
awakening, as defined below, will be assessed following the reversal of anesthesia:
• Time to awakening is defined as the time interval from the end of the surgical
procedure (placement of last suture/last staple) until the time the subject can
understand and obey a command.
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6.2.1. Pregnancy
6.2.1.1. Pregnancy Testing
A screening serum β-hCG (beta-human chorionic gonadotrophin) or urine pregnancy test

is mandatory for all subjects of childbearing potential per local standards, but in no event
longer than 24 hours prior to the first administration of GW679769 investigational
product. Unless a serum pregnancy test is required by the medical institution, a urine
pregnancy test is sufficient. The results of this test must be negative. Thereafter, the
pregnancy test need only be repeated if clinically indicated or required per local
regulation.
In the event that a pregnancy does occur, the subject will be immediately withdrawn from
the study. The subject will receive counseling from the investigator, or his/her designee,
regarding the nature of the investigational product and the potential risk on fetal
development.
6.2.1.2. Time period for collecting pregnancy information
Details of all pregnancies in female subjects that occur during the treatment and the
follow-up period must be documented and reported to GlaxoSmithKline. In addition, any
pregnancies brought to the attention of the Investigator after this period, and where it is
known that investigational product was taken at the time of conception, must also be
reported.
Any pregnancies identified during the screening phase prior to investigational product
administration do not need to be collected, as the subject would no longer be eligible to
participate in the study and cannot receive any GW679769 investigational product.
6.2.1.3. Action to be taken if pregnancy occurs
The investigator will collect pregnancy information on any female subject, who becomes
pregnant while participating in this study. The investigator will record pregnancy
information on the appropriate form and submit it to GSK within 2 weeks of learning of a
subject's pregnancy. The subject will also be followed to determine the outcome of the
pregnancy. Information on the status of the mother and child will be forwarded to GSK.
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery
date. Any premature termination of the pregnancy will be reported.
While pregnancy itself is not considered to be an AE or SAE, any pregnancy

complication or elective termination of a pregnancy for medical reasons will be recorded
as an AE or SAE (see AE/SAE section of the protocol and the SRM for definitions and a
description of follow-up).
A spontaneous abortion is always considered to be an SAE and will be reported as such.

Furthermore, any SAE occurring as a result of a post-study pregnancy and is considered
reasonably related to the investigational product by the investigator, will be reported to
GSK as described in section entitled, "Post-study AEs and SAEs" of the SRM. While the
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investigator is not obligated to actively seek this information in former study participants,
he or she may learn of an SAE through spontaneous reporting.
6.2.2. Liver Chemistry Guidelines
Elevations in ALT greater than or equal to 3 times ULN were observed in 17 of 702
subjects in the Phase II clinical study NKT102260 in the PONV setting. Most of these
resolved within 6 days and are possibly consistent with the patient population under
study, and were noted in the placebo (control) group as well as active treatment groups.
Nevertheless, GSK is undertaking in-stream monitoring of hepatic transaminase and
bilirubin values in the Phase III program to ensure that any potential signal relating to
liver function is identified in a timely fashion.
Subjects with abnormal liver function test results (ALT ≥3x ULN and bilirubin ≥1.5x
ULN) should be monitored closely and a specialist or hepatology consultation should be
considered. Such events must be reported to GSK within 24 hours of learning of its
occurrence. These subjects, as well as any additional subjects with an ALT ≥3x ULN,
should be monitored twice weekly until liver function tests (ALT, AST, alkaline
phosphatase, bilirubin) stabilize or return to baseline values.
6.3. Efficacy
Each subject will be given a Subject Diary that will be used to record the occurrence of
nausea, emesis, and the use of rescue medications daily during the assessment period.
Two nausea assessment tools will also be included in the Subject Diary: a Likert scale
and a categorical scale (see Section 6.3.2., “Assessment of Nausea”). During the
assessment phase, subjects will be instructed to complete their rating of nausea over the
preceding 2, 6, 24, and 48 hours. A brief questionnaire about satisfaction with the
investigational product and the study medication in preventing nausea and vomiting, and
a question about the willingness of the subject to use the same antiemetic drug treatment
regimen for subsequent surgical procedures (see Section 6.4.1., “Subject Satisfaction
Questionnaires”), also will be included in the Subject Diary.
Efficacy will be assessed through the collection of data related to:
• whether or not the subject experienced an occurrence of emesis (vomiting and/or

retching).
• the time that elapsed before the first occurrence of emesis.
• whether or not the subject experienced nausea, and if so, the subject-reported degree
of nausea.
• the use of any additional antiemetic medications, irrespective of whether such
medications were given as rescue medications (see Section 5.2.2., “Exclusion
Criteria”).
• the use of any opioid medication(s) to control post-surgical pain.
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Until the subject is able to complete the assessments in the Subject Diary, study
personnel will evaluate the subject for the occurrence of emesis, time to any occurrence
of emesis, and the use of any antiemetic rescue medications and/or opioid pain
medications. This information will be entered into the Subject Diary or eCRF by study
personnel. Note, however, that as the nausea assessments cannot be completed by study
personnel and must be completed by the subject, these assessments will not be completed
as long as the subject remains incapable of completing the assessments.
In addition, data from the follow-up telephone calls on post-operative Days 1 and 2 will
be entered into the subject's source documents and will be reviewed with the subject upon
their return for the final study visit (post-op Days 6 – 14). The study coordinator will
telephone the subject at the end of the 24 Hour assessment phase, to review the Subject
Diary for accuracy and completeness. The telephone call should be made as close to the
end of the 24 hour post placement of last suture/staple as possible, but no later than 26
hours post emergence. An additional assessment contact will be made at the 48 hour post
last suture/staple time point. During any contact with the subject during the assessment
periods data may be collected that was not available at the time of the 24 hour assessment
contact (e.g., if the subject was unreachable at the 24-26 hour post last suture/last staple
period). Information from the final study visit will be entered into the study subject's
eCRF.
6.3.1. Assessments of Efficacy
The following definitions will be used for the purposes of this study:
Nausea: A subjectively unpleasant sensation associated with the awareness

expulsive muscular movements.
Emesis: Vomiting and/or retching.
Vomiting: The forceful expulsion of gastrointestinal contents through the

mouth or nose.
Retching: The labored, spasmodic, rhythmic contraction of the respiratory

and abdominal muscles in an attempt to vomit that is not
productive of gastrointestinal contents (also known as “dry
heaves”).
Emetic episode: A single vomit or retch or any number of continuous vomits or

retches. Emetic episodes will, by definition, be separated by the
absence of vomiting or retching by at least 1 minute. Continuous
vomiting and/or retching will be defined as two or more vomits
and/or retches that occur within one minute of each other.
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6.3.2. Assessment of Nausea
Each subject will complete two different nausea scales, a Likert scale and a categorical
scale, at 2, 6, 24 and 48 hours after placement of the last suture/staple. The Likert scale
will use a range of 0-10, where 0 = “No Nausea” and 10 = “Nausea as bad as it could be”.
In the categorical scale, each subject will be asked to rate the severity of her nausea,
using the descriptions provided below:
None: no nausea
Mild: queasiness/upset stomach that is manageable and minimally (if at all) affects daily
activities.
Moderate: increased queasiness, sometimes with the feeling of having to vomit (but not
vomiting), that has a significant negative effect on daily activities (for example, being
unable to work, eat and drink, prepare food, care for children or others).
Severe: Feeling sick and vomiting or feeling like you are going to vomit, and unable to
perform most daily activities. See Appendix 10, “Nausea Assessment Scales”, for further
details.
6.3.3. Antiemetic Rescue Therapy
Study subjects who receive antiemetic rescue medication(s) during the initial 24-hour
follow-up assessment phase will be considered treatment failures. As the objectives of
this study relate to evaluating the utility of GW679769 in the prevention of PONV, it is
important to assess the duration of antiemetic activity in all subjects. For this reason,
please note the importance of not giving study subjects additional medications with
antiemetic properties as prophylaxis against nausea and/or emesis, post-surgery.
Antiemetics should be limited to rescue therapy; that is, only given in the event that the
antiemetic prophylaxis given at surgery has failed to prevent nausea or vomiting, and
the subject requires further treatment. Any subject who takes rescue medication will
be considered to be a treatment failure at the time the rescue medication is taken, even
in the absence of an emetic episode or nausea.
Administration of rescue antiemetic medication will not result in the subject being
withdrawn from the study. Subjects who receive antiemetic rescue medication will
remain in the study and all efficacy assessment and safety assessments will continue to be
made through the end of the 48-hour assessment phase. Subjects who receive rescue
medication are considered treatment failures and are not considered to be withdrawn
solely upon receipt of rescue medication. Subjects who are withdrawn from the study for
other reasons will be categorized as withdrawn (see Section 10.2., “Subject
Withdrawal”).
For the purposes of this study, antiemetic rescue medication will be defined as
medication that is given specifically for the treatment of nausea and/or emesis during the
study. As a guide, the first dose of rescue antiemetic medication may be administered
when medically indicated, at physician discretion, or at any time upon the subject's
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request. The choice of rescue antiemetic medication will be left to the discretion of the
Investigator. Rescue medications will not be supplied by GlaxoSmithKline.
Use (“yes” or “no”)of antiemetic rescue medication will be documented in the Subject
Diary. For any antiemetic rescue drug(s), the name of the antiemetic, the corresponding
dose(s), and the date(s) and time(s) of administration will be recorded in the appropriate
page of the eCRF.
6.3.4. Subject Diary
In order to collect safety and efficacy data, an electronic Subject Diary will be utilized. It
is anticipated that most of the safety and efficacy information will be collected once the
subject has been discharged from the treating facility.
The Subject Diary will be given to the subject prior to the administration of the
GW679769 investigational product on Day 1. At this time, the subject will receive
instructions for completing the required assessments and become familiar with the
Subject Diary instrument. The subject also will complete the baseline nausea Likert and
categorical assessments at this time, which will help reinforce the instructions given for
its use.
Following emergence from anesthesia, the Subject Diary will be returned to the subject
when the clinical staff considers the subject capable of adequately completing the
required assessments. Prior to discharge, the instructions for completing the Subject
Diary will be reviewed with the subject. The Subject Diary will be used to record
efficacy and safety data during the 48-hour assessment phase. The data to be recorded in
the diary includes information about emesis, nausea, and medications.
During any contact with the subject during the assessment phase, data may be collected
that was not available at the time of a previous follow-up contact (e.g., if the subject was
unreachable at 24 hours post-placement of last suture/staple ) or subsequent assessment
phase. This information will also be recorded into the eCRF.
In the event that a subject is not considered capable of completing the assessments
required at a specified assessment period (e.g., 2 hours post-placement of last
suture/staple), the necessary information (i.e., assessments of emesis, the use of rescue
medications for emesis, and other concomitant medications) will be collected by study
personnel. Note, however, that as the nausea assessments can only be completed by the
subject. The nausea assessments will not be completed as long as the subject remains
incapable of completing the assessments.
The Subject Diary must be returned by the subject to the Investigator and/or designee at
the investigational site during the study visit on post-op Days 6 – 14. The Subject Diary
will be reviewed with the subject to ensure that the information is complete, consistent,
and accurate.
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6.4. Health Outcomes
6.4.1. Subject Satisfaction Questionnaires
Subjects will be asked two questions relating to their overall satisfaction with the
antiemetic therapy. These assessments are to be completed in the Subject Diary on
post-operative Day 2, as soon as possible following the completion of the 48-hour assessment
phase The Subject Diary will be returned to the investigational site during the post-op Days
6 – 14 final study visit. See Appendix 6, “Subject Satisfaction Assessment” for further
details.
The first question will rate the overall satisfaction with the investigational product
(GW679769) and the study medication ZOFRAN Injection in preventing PONV, using a
five-point rating scale, as follows:
1. = Very satisfied.
2. = Somewhat satisfied.
3. = Neither satisfied nor dissatisfied.
4. = Somewhat dissatisfied.
5. = Very dissatisfied.
In addition, subjects will rate their willingness to use the same antiemetic drug treatment
regimen for subsequent surgical procedures, using a similar five-point rating scale:
1. = Definitely would be willing.

2. = Probably would be willing.
3. = Not certain.
4. = Probably would not be willing.
5. = Definitely would not be willing.
6.4.2. Medical Resource Utilization
A brief questionnaire of unscheduled nausea and vomiting-related medical resource

utilization will be collected during the post-op Days 6-14 final study visit. The data
collected will include nausea and vomiting-related telephone calls, home visits, nursing
visits, physician office/clinic visits, urgent care/emergency room visits, and inpatient
days. The information will be used to evaluate the impact of PONV on the use of
medical resources.
6.5. Pharmacogenetics
A blood sample (approximately 10 mL) will be collected for pharmacogenetic (PGx)
analysis. This sample should be collected as soon as possible during the course of the
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study; it is preferred that the PGx sample be obtained prior to the first administration of
the GW679769 investigational product. The collection of a PGx sample will help
investigate a possible relationship between genetic variation and the ability of
GW679769 to prevent PONV. The background for PGx and the procedures to collect
this sample are found in Appendix 7: “PGx – Pharmacogenetic Research”.
Note that a separate informed consent form will be required for this sample, and only
those subjects who have signed the ICF for the PGx sample will have this sample drawn.
7. LIFESTYLE AND/OR DIETARY RESTRICTIONS

Due to potential drug interactions, participants in this study may not have grapefruit juice
for two days prior to receiving the investigational product GW679769.
8. INVESTIGATIONAL PRODUCT AND STUDY

MEDICATION
this study, GW679769 will be referred to as the “investigational product”, and ZOFRAN
Injection will be referred to as “study medication”.
8.1. Description of Investigational Product

GW679769 will be provided by GlaxoSmithKline, and will be supplied as 50 mg or
matching placebo tablets for oral administration. GW679769 will be administered as
GW679769B, the mesylate salt of the free base GW679769X. GW679769 tablet supplies
will be blinded so neither the research pharmacist, the investigator, nor the subject will
know whether the dose contains active or placebo investigational product.
Please see Appendix 11, “Lactose Excipient in GW679769” for information on lactose
intolerance/allergy.
8.2. Description of the Study Medication

Each vial of ZOFRAN Injection contains 4 mg of ondansetron hydrochloride in 2 mL of
solution (2 mg/mL), and is supplied as a clear, colorless, nonpyrogenic, sterile solution
for IV injection that requires no dilution prior to administration. Each 1 mL of aqueous
solution in this single dose vial contains 2 mg of ondansetron as the hydrochloride
dihydrate; 9.0 mg of sodium chloride, USP; 0.5 mg of citric acid monohydrate, USP, and
0.25 mg of sodium citrate dihydrate, USP, as buffers in Water for Injection, USP. The
pH of the injection solution is 3.3 – 4.0.
As ZOFRAN Injection is an open label medication for this study, it will not be provided
centrally by GlaxoSmithKline. Each country medical department will ensure that
ZOFRAN Injection is available to centers in accordance with relevant regulatory
guidelines.
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8.3. Dosage and Administration
All eligible subjects will receive a single oral dose of 50 mg GW679769 investigational
product (active or placebo) 60 minutes prior to the expected induction of anesthesia on
Day 1. Although the dose of oral GW679769 investigational product is expected to be
administered at this time, it may be given up to 30 minutes prior to the anticipated
induction of anesthesia.
GW679769 investigational product must be ingested orally as whole tablets and cannot
be crushed or altered in any way. It is recommended that the tablet be ingested with as
little water as practical (less than 30 mL is recommended).
Study Medication
All subjects will receive a single intravenous administration of Injection study medication
immediately prior to the induction of anesthesia. The ondansetron hydrochloride is to be
administered by a slow IV injection over two to five minutes (but not less than two
minutes), per the [ZOFRAN (ondansetron hydrochloride) Injection Package Insert, 2005].
8.4. Dose Rationale

The dosing of ZOFRAN Injection chosen for this study is based on the regulatory
approvals for ZOFRAN Injection for the prevention of PONV, recent consensus
guidelines for the prevention of PONV, and current clinical practice. For the prevention
of postoperative nausea and vomiting, the recommended intravenous dosage of ZOFRAN
for adults is 4 mg undiluted, administered intravenously over two to five minutes, (but
not less than two minutes) immediately before the induction of anesthesia, in accordance
with the [ZOFRAN (ondansetron hydrochloride) Injection Package Insert, 2005].
The oral dose of GW679769 is based on the preliminary results of study NKT102260.
Although a minimally effective dose was no found in the phase II study, the lowest dose
tested appeared to be safe and effective and was, therefore, selected for this study.
8.5. Blinding
This will be a double-blind, active-controlled, parallel group randomized study. The
study coordinator will call RAMOS to obtain a randomization code indicating treatment
assignment, as described in Section 8.6.1., “Randomization and Medication Ordering
System”, using the telephone number that will be supplied to the site.
GW679769 supplies will be blinded so that the research pharmacist, the Investigator, and
the subject will not know whether the numbered box contains active of placebo
investigational product.
Only in the case of an emergency, when knowledge of the investigational product is

essential for the clinical management or welfare of the subject, the investigator may
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unblind a subject’s treatment assignment. The investigator will, whenever possible,

discuss options with the Medical Monitor, on-call physician, or appropriate GSK study
personnel before unblinding. If the blind is broken for any reason and the investigator is
unable to contact GSK prior to unblinding, the investigator must notify GSK as soon as
possible following the unblinding incident without revealing the subject’s study
treatment assignment, unless the information is important to the safety of subjects
remaining in the study. In addition, the investigator will record the date and reason for
revealing the blinded treatment assignment for that subject in the appropriate data
collection tool (as defined in Section 13.7., “Data Management”).
If a serious adverse event (SAE; as defined in Section 11.2., "Definition of an SAE") is

reported to GSK, Global Clinical Safety and Pharmacovigilance (GCSP) staff may
unblind the treatment assignment for the individual subject. If an expedited regulatory
report to one or more regulatory agencies is required, the report will identify the subject’s
treatment assignment. When applicable, a copy of the regulatory report may be sent to
investigators in accordance with relevant regulations, GSK policy, or both.
8.6. Treatment Assignment

Subjects will be assigned to study treatment in accordance with the randomization
schedule.
8.6.1. Randomization and Medication Ordering System
GlaxoSmithKline will use an interactive voice response system, RAMOS, for registration
of subjects. RAMOS is a telephone-based system, and available 24 hours per day, 7 days
a week. This automated system can be accessed via an international toll-free call from
any touch-tone telephone.
RAMOS allows study centers to register and randomize subjects, and also records
stratification information. Each call to RAMOS is confirmed via facsimile, which is sent
to the Investigator upon completion of the call.
Detailed RAMOS user instructions and worksheets will be provided to the investigational
site at study start, including telephone contact numbers.
There may be circumstances in which an emergency unblinding will be required. If an

emergency unblinding of a subject’s treatment assignment is required, the Investigator, or
his/her designee, must also contact GlaxoSmithKline as per Section 8.5., “Blinding”.
8.7. Packaging and Labeling

The contents of the label for both study medications (i.e., GW679769 and ZOFRAN
Injection) will be in accordance with all applicable regulatory requirements of the country
where the investigational site is located.
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8.8. Preparation
For the 0 mg (placebo) and 50 mg oral GW679769 tablets, no specific preparation of

medication is required prior to administration.
Study Medication
The ondansetron hydrochloride is to be administered by a slow IV injection over two to

five minutes (but not less than two minutes), per the [ZOFRAN (ondansetron
hydrochloride) Injection Package Insert, 2005].
8.9. Handling and Storage

Investigational product must be dispensed or administered according to procedures
described herein. Only subjects enrolled in the study may receive investigational
product, in accordance with all applicable regulatory requirements. Only authorized site
staff may supply or administer investigational product. All investigational products must
be stored in a secure area with access limited to the investigator and authorized site staff
and under physical conditions that are consistent with investigational product-specific
requirements.
GW679769 investigational product tablets will be stored as described on the product

label. Oral GW679769 investigational product must be maintained as whole tablets and
cannot be crushed or altered in any way.
ZOFRAN Injection study medication is to be stored between 2º – 30ºC (36º – 86ºF),

protected from freezing and avoiding excessive heat. Protect ZOFRAN Injection study
medication from light.
8.10. Product Accountability

The investigator, institution, or the head of the medical institution (where applicable) is
responsible for investigational product accountability, reconciliation, and record
maintenance. In accordance with all applicable regulatory requirements, the investigator
or the head of the medical institution (where applicable), or designated site staff (e.g.,
storage manager, where applicable) must maintain investigational product accountability
records throughout the course of the study. The responsible person(s) will document the
amount of investigational product received from and returned to GSK (when applicable),
the amount supplied and/or administered to and returned by subjects, if applicable.
8.11. Assessment of Compliance

The investigational product (i.e., GW679769) and the study medication (i.e., ZOFRAN
Injection) will be administered under the supervision of study personnel on Day 1. The
date and time of administration of the investigational product and the study medication
will be recorded.
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8.12. Treatment of Investigational Product Overdose

To date, there have been no cases of overdose with GW679769. Treatment of any
suspected or confirmed overdose with GW679769 should therefore be symptomatic, and
supportive care is recommended in cases where overdose is suspected. As per the
Clinical Investigator's Brochure for GW679769, GlaxoSmithKline does not recommend
specific treatment for overdose or toxicity; however, the Investigator should use
appropriate clinical judgement in treating the overdose. For the purposes of this study, an
overdose of GW679769 is defined as any dose greater than the highest daily dose
included in the protocol. While the potential for overdose is considered small,
GW679769 is an investigational compound, and the potential for unexpected reactions is
not known.
There is no specific antidote for an overdose of ZOFRAN. In the event of a suspected

overdose of ZOFRAN, subjects should be managed with appropriate supportive therapy.
However, individual doses as large as 150 mg (more than 37 times the amount to be
administered in this study) and total daily dosages (cumulative from three doses) as large
as 252 mg have been administered intravenously without significant adverse events
[ZOFRAN (ondansetron hydrochloride) Injection Package Insert, 2005].
8.13. Occupational Safety

Neither the investigational product (oral GW679769) nor the study medication (IV
ZOFRAN Injection) is expected to pose significant occupational safety risk to site staff
under normal conditions of use and administration. Material Safety Data Sheets (MSDS)
describing occupational hazards and recommended handling precautions for both the
investigational product and the study medication will either be provided to the
Investigator, where this is required by local laws, or will be available upon request from
GlaxoSmithKline.
However, precautions are to be taken to avoid direct skin contact, eye contact, and
generating aerosols or mists. In the case of unintentional occupational exposure, treat as
if the substance contains the active pharmaceutical ingredient even though it is absent
from placebo formulations, and notify the monitor.
9. CONCOMITANT MEDICATIONS AND NON-DRUG

THERAPIES
9.1. Permitted Medications

All medications that would normally be prescribed for the care of the subject are
permitted, except as specified in Section 9.2., “Antiemetic Rescue Medication” and
Section 9.3., “Prohibited Medications”. Each concomitant medication taken during the
study will be recorded in the eCRF, and will include the name of the medication, the dose
information, the date(s) of administration, and the indication for the use of such
medication.
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Antiemetic rescue medication is permitted as described in Section 9.2., “Antiemetic

Rescue Medication”. Subjects who require rescue antiemetic medication(s) during the
first 48 hours following the emergence from anesthesia will be considered treatment
failures in the applicable period.
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9.2. Antiemetic Rescue Medication
Please note the importance of not giving study subjects additional medications with
antiemetic properties as prophylaxis against nausea and/or emesis. Antiemetics should
be limited to rescue therapy; that is, only given in the event that the antiemetic
prophylaxis given at surgery has failed and the subject is experiencing nausea and/or
vomiting, and requires further antiemetic treatment. Any subject who takes additional
antiemetic medication as prophylaxis or rescue will be considered to be a treatment
failure at the time the rescue medication is taken, even in the absence of an emetic
episode or nausea.
See Section 6.3.3., “Antiemetic Rescue Therapy” for further information.
9.3. Prohibited Medications

The following medications are prohibited for use by subjects in this study:
1. Per the Exclusion Criteria:

• Greater than 10 mg of oxycodone, or an equivalent opioid dose, on a regular,
daily basis, for more than three consecutive days prior to entry into the study
(see also., Appendix 8: “Opioids Equivalents” for further details).
• Any investigational drug in the previous 30 days, or during the study period.
2. Any “non-protocol” prophylactic antiemetic medications, within 24 hours prior to and
48 hours post the last suture/last staple assessment period. Antiemetic medications
given during this time should only be given as rescue medications, in response to the
failure of the investigational product and the study medication to prevent the
occurrence of PONV (that is, if the subject reports the occurrence of emesis or
intractable nausea).
9.3.1. Inhibitors of CYP3A4 and CYP3A5
The use of the following medications is prohibited during the evaluation phase of
GW679769 investigational product as described in this section. Subjects must have
discontinued use of the listed medications for at least the duration specified prior to the
administration of the GW679769 investigational product. These medications are
prohibited because inhibition of cytochrome P450 3A4, the isoenzyme primarily involved
in the metabolism of GW679769, may alter the pharmacokinetic/ pharmacodynamic of
GW679769, and confound the results of the study. Note that the following lists are not
comprehensive. (An additional resource for identifying drugs metabolised via the
CYP3A4 pathway can be found at http://medicine.iupui.edu/flockhart/table.htm).
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The following strong or moderate inhibitors of CYP3A4 and/or CYP3A5 are prohibited
for the specified duration prior to administration of the GW679769 investigational
product:
2 days: Clarithromycin, diltiazem, erythromycin, grapefruit juice,

ketoconazole, verapamil.
14 days: Fluconazole, itraconazole.
In addition, the use of these medications is prohibited for 72 hours following the final
dose of GW679769 investigational product.
9.3.2. Inducers of CYP3A4 and CYP3A5
The use of the following medications is prohibited during the evaluation phase of
GW679769 investigational product as described in this section. Subjects must have
discontinued use of the listed medications for at least the duration specified prior to the
administration of the GW679769 investigational product. These medications are
prohibited because induction of cytochrome P450 3A4, the isoenzyme primarily involved
in the metabolism of GW679769, may alter the pharmacokinetic/ pharmacodynamics of
GW679769, or GW679769 may alter the pharmacokinetic/ pharmacodynamics of the
other drug, and confound the results of the study. Note that the following lists are not
comprehensive.
The following inducers of CYP3A4 and/or CYP3A5 are prohibited for the specified
duration prior to the administration of the GW679769 investigational product:
14 days: carbamazepine, phenobarbital, phenytoin, rifabutin,

rifampin, St. John's wort, troglitazone, efavirenz and
nevirapine.
In addition, the use of these medications is prohibited for 72 hours following the final
dose of GW679769 investigational product.
9.3.3. Other Medications that May Confound Results
Unless required by the protocol or used as antiemetic rescue medication as specified in

the protocol, medications with known or potential antiemetic activity (see Section 5.2.2.,
“Exclusion Criteria”) may confound the efficacy results of the study and are therefore
prohibited.
Other than the ZOFRAN Injection required by the protocol, marketed antiemetics should
only be used as rescue medication. See Section 6.3.3.,“Antiemetic Rescue Therapy”.
Note: Any NK-1 receptor antagonists other than those supplied as the
investigational product are specifically prohibited throughout the study.
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9.3.4. Necessary Caution with CYP3A4 Substrates
As GW679769 has been shown to be a mild to moderate inhibitor of metabolism via the
CYP3A4 pathway, caution should be used when administering drugs that are known
substrates for CYP3A4. Unless specified in Exclusion Criteria 11, 12 or 13, such
medications are not specifically prohibited in this study. See Appendix 9: “Medications
with CYP3A4 and/or CYP3A5 Substrate Activity” for further details.
Concomitant use of potential CYP3A4 substrates along with an inhibitor of

CYP3A4 may result in higher than expected drug concentrations or exposures of the
substrate, which may lead to increased toxicity. As a result, it should be noted that
there is a theoretical risk of prolonged sedation from midazolam. This is based on
data from study NKV10001 with oral midazolam and GW679769 15 mg, where the
AUC(0-∞) and Cmax for midazolam were, on average, three-fold and two-fold
(respectively) greater than values seen for midazolam in the absence of GW679769..
In addition, doses of agents such as midazolam are usually not adjusted when co-
administered with moderate CYP3A4 inhibitors such as verapamil and diltiazem; thus,
dose adjustments are not expected to be appropriate when used in combination with a
mild to moderate inhibitor such as GW679769. Finally, it should also be noted that some
other drugs may undergo activation through the CYP3A4 pathway.
Clinicians are advised to be diligent in monitoring for evidence of increased exposure,

and to utilize their usual judgement in adjusting doses of potential substrates on the basis
of observed clinical and/or laboratory effects. This is especially important for those
drugs that have a narrow therapeutic index.
A list of known or suspected CYP3A4 substrates is included in Appendix 9,

“Medications with CYP3A4 and/or CYP3A5 Substrate Activity”.
9.3.5. Exclusions and Necessary Caution with CYP2C8 Substrates
Few therapeutic agents metabolized by CYP2C8. . As the metabolite of GW679769 is a

potential inhibitor of CYP2C8, one might expect to see an increase in the exposure and
thus an increase in clinical response or adverse events for these drugs. Subjects who are
taking the anti-diabetic agent repaglinide or the diuretic torsemide are to be
excluded from this study. Caution should be exercised if subjects are taking the anti-
diabetic agents rosiglitazone or pioglitazone, or antimalarial agents such as chloroquine
and amodiaquine.
9.3.6. Necessary Caution with P-glycoprotein Substrates
The metabolite of GW679769 may increase exposure to substrates of P-glycoprotein

(such as digoxin) by decreasing P-glycoprotein-mediated clearance. At this time there
have been no serious adverse events reported in clinical studies using GW679769 which
might suggest over-exposure to digoxin. GSK does not have enough information to
provide specific recommendations for digoxin dose adjustment at this time. Exclusion of
subjects is not required in studies where dosing of GW679769 is of intermittent and
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limited duration. If such subjects are enrolled into the study, they should be monitored
clinically for signs of digoxin toxicity.
For the P-glycoprotein class of drugs as a whole, clinicians are advised to be diligent in
monitoring for evidence of increased exposure, and to utilize their usual judgement in
adjusting doses of potential substrates on the basis of observed clinical and/or laboratory
effects. This is especially important for those drugs that have a narrow therapeutic index.
Known or suspected P-glycoprotein substrates include, but are not limited to:
• Amprenavir, indinavir, nelfinavir, ritonavir, saquinavir

• Aldosterone, corticosterone, dexamethasone
• Digoxin
• Cyclosporine A, mitoxantrone,
• Debrisoquine, erythromycin, lovastatin, terfenadine, quinidine
• doxorubicin, paclitaxel, etoposide, mitoxantrone, fexofenadine, losartan, vinblastine,
tacrolimus, talinolol
9.4. Non-Drug Therapies

Any non-drug therapies (e.g., ginger preparations, acupressure bands) to treat emetic
episodes are discouraged. However, in the event that such non-drug therapies are
employed, the details of such use will be appropriately documented in the subject's eCRF.
10. SUBJECT COMPLETION AND WITHDRAWAL
10.1. Subject Completion

The subject will have completed the study when she completes the post-op Days 6-14
visit. However, for the purposes of evaluating all primary and secondary study
objectives, the subject will have completed the study upon completing all required
assessments for 48 hours following the placement of last suture/staple. A subject cannot
be considered to be evaluable if she fails to return the Subject Diary that was provided
upon discharge from the investigational site.
Once the study subject is no longer participating in the study (whether by study
completion, withdrawal, or being lost to follow up), the GlaxoSmithKline RAMOS must
be called to inform GlaxoSmithKline that the subject has completed the study, as
indicated in Section 8.6.1., “Randomization and Medication Ordering System”.
10.2. Subject Withdrawal

A subject may withdraw from the study at any time at her own request, or she may be
withdrawn at any time at the discretion of the Investigator for safety, behavioral, or
administrative reasons. If the subject withdraws following administration of
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investigational product but prior to study completion, all follow-up procedures should be
performed, if possible.
If a subject is withdrawn from the study for any reason, the Investigator must make every
effort to perform the following evaluations: AEs, efficacy assessments, concurrent
medication, and use of antiemetic rescue medication. These data will be recorded, as
they comprise an essential evaluation that needs to be completed prior to discharging any
subject from the study. At the time of withdrawal (or completion), RAMOS must be
called (as per Section 8.6.1., “Randomization and Medication Ordering System”) to
inform GlaxoSmithKline that the subject has been withdrawn from (or completed) the
study. In addition, the reason for withdrawal will be recorded in the eCRF.
Subjects who receive antiemetic rescue medication will remain in the study and all
efficacy assessments will continue to be made through the end of the 48-hour follow-up
assessment phase. Safety assessments will continue until the post-op Days 6-14 visit is
completed. All information collected will be transcribed into the subject's eCRF. The
name, date, and time of antiemetic rescue medication will be recorded in the eCRF or
subject diary.
In the event that a subject is prematurely discontinued from the study at any time due to
an AE (as defined in Section 11.1, “Definition of an AE”) or an SAE (as defined in
Section 11.2, “Definition of a SAE”), the procedures stated in Section 11, “Adverse
Events (AE) and Serious Adverse Events (SAE)” must be followed.
Subjects who do not return for the follow-up visit on post-op Days 6-14 will be
considered to be withdrawn from the study.
10.2.1. Subject Withdrawal from Study
Only one dose of ZOFRAN Injection and/or GW679769 investigational product will be
administered. Therefore, a subject who withdraws consent prior to receiving the study
medication and/or investigational product also withdraws from the study.
10.3. Treatment After the End of the Study

There are no plans for subjects in NKT102553 to be offered study drug after completion
of the study. GW679769 does not currently have marketing authorization approval in
any market. Following completion of the study the subject’s physician will be
responsible for ensuring the subject receives appropriate care and treatment.
10.4. Screen and Baseline Failures

Any subject who has been registered into the study but does not receive any
investigational product will be considered to be a screening failure. If a subject
experiences emesis or uncontrolled nausea at any time during the 24 hours prior to
receiving the investigational product, she will not be eligible to receive the
investigational product and study medication, and must be withdrawn from the study. In
addition, for subjects screened prior to the day that the investigational product and study
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medication are administered, eligibility will be reviewed prior to administration of the

first dose of investigational product. If there are any other changes in eligibility
according to the inclusion/exclusion criteria in Section 5.2., “Eligibility Criteria”, the
subject must also be withdrawn from the study. Such subjects who are withdrawn prior
to receiving the first dose of investigational product and study medication should not
undergo any further study-related procedures. If the change in eligibility is due to an
adverse event that occurred after the subject has signed the informed consent, but prior to
administration of the first dose of the investigational product and study medication, it will
be recorded on the Current Medical Conditions form. If the event meets the definition of
“serious” as defined in Section 11.2., “Definition of a SAE”, it will be recorded on the
Serious Adverse Event form.
11. ADVERSE EVENTS (AE) AND SERIOUS ADVERSE

EVENTS (SAE)
The investigator is responsible for the detection and documentation of events meeting the
criteria and definition of an AE or SAE, as provided in this protocol. During the study,
when there is a safety evaluation, the investigator or site staff will be responsible for
detecting, documenting and reporting AEs and SAEs, as detailed in both this section of
the protocol and in the AE/SAE section of the SRM.
11.1. Definition of an AE
Any untoward medical occurrence in a patient or clinical investigation subject,
temporally associated with the use of a medicinal product, whether or not considered
related to the medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an

abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally
associated with the use of a medicinal product. For marketed medicinal products, this
also includes failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse.
11.2. Definition of a SAE

A serious adverse event is any untoward medical occurrence that, at any dose:
a. results in death
b. is life-threatening
NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in
which the subject was at risk of death at the time of the event. It does not refer to an
event, which hypothetically might have caused death, if it were more severe.
c. requires hospitalization or prolongation of existing hospitalization
NOTE: In general, hospitalization signifies that the subject has been detained
(usually involving at least an overnight stay) at the hospital or emergency ward for
observation and/or treatment that would not have been appropriate in the physician’s
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office or out-patient setting. Complications that occur during hospitalization are

AEs. If a complication prolongs hospitalization or fulfills any other serious criteria,
the event is serious. When in doubt as to whether “hospitalization” occurred or was
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen
from baseline is not considered an AE.
d. results in disability/incapacity, or
NOTE: The term disability means a substantial disruption of a person’s ability to
conduct normal life functions. This definition is not intended to include experiences
of relatively minor medical significance such as uncomplicated headache, nausea,
vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may
interfere or prevent everyday life functions but do not constitute a substantial
disruption.
e. is a congenital anomaly/birth defect
Medical or scientific judgement should be exercised in deciding whether reporting is
appropriate in other situations, such as important medical events that may not be
immediately life-threatening or result in death or hospitalization but may jeopardize the
subject or may require medical or surgical intervention to prevent one of the other
outcomes listed in the above definition. These should also be considered serious.
Examples of such events are invasive or malignant cancers, intensive treatment in an
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions
that do not result in hospitalization, or development of drug dependency or drug abuse.
11.2.1. Disease-Related Events and/or Disease-Related Outcomes Not

Qualifying as SAEs
During the 48-hour assessment phase, episodes of nausea or emesis that result in the
administration of rescue medication are to be considered treatment failures rather
than AEs or SAEs, and are to be captured in the assessments of emesis and nausea in
the subject diary.
Nausea and emesis that occur after the 48 hour assessment phase but prior to the
post-op Days 6-14 visit should be recorded as an AE or SAE (see Section 11.1 and
Section 11.2 for definitions).
11.3. Lack of Efficacy

“Lack of efficacy” per se will not be reported as an AE. The signs and symptoms or
clinical sequelae resulting from lack of efficacy will be reported if they fulfill the AE or
SAE definition (including clarifications).
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11.4. Clinical Laboratory Abnormalities and Other Abnormal

Assessments as AEs and SAEs
Abnormal laboratory findings (e.g., clinical chemistry, hematology, urinalysis) or other
abnormal assessments (e.g., EKGs, vital signs) that are judged by the investigator as
clinically significant will be recorded as AEs or SAEs if they meet the definition of an
AE or SAE. Clinically significant abnormal laboratory findings or other abnormal
assessments that are detected during the study or are present at baseline and significantly
worsen following the start of the study will be reported as AEs or SAEs. However,
clinically significant abnormal laboratory findings or other abnormal assessments that are
associated with the disease being studied, unless judged by the investigator as more
severe than expected for the subject’s condition, or that are present or detected at the start
of the study and do not worsen, will not be reported as AEs or SAEs.
The investigator will exercise his or her medical and scientific judgment in deciding
whether an abnormal laboratory finding or other abnormal assessment is clinically
significant.
11.5. Time Period, and Frequency of Detecting AEs and SAEs

If a change in the subject’s condition occurs after the subject signs the informed consent,
but before study medication is administered, the Medical History will be updated to
capture the relevant information. Once study medication is administered, any event
meeting the definition of an AE or SAE will be recorded in the eCRF, with the latter also
being transmitted to GSK as described in the study reference manual.
From the time a subject consents to participate in the study until he or she has completed
the study (including up to the completion of the post-op Days 6 – 14 visit), all SAEs
assessed as related to study participation (e.g., protocol-mandated procedures, invasive
tests, or change in existing therapy) or related to a GSK concomitant medication, will be
reported promptly to GSK.
11.6. Prompt Reporting of SAEs to GSK

SAEs will be reported promptly to GSK as described in the following table once the
investigator determines that the event meets the protocol definition of an SAE.
11.6.1. Timeframes for Submitting SAE Reports to GSK
Initial SAE Reports Follow-up Information on a Previously

Reported SAE
Type of SAE Time Frame Documents Time Frame Documents
All SAEs 24 hrs "SAE" data 24 hrs Updated "SAE"
collection tool data collection
tool
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11.7. AE and SAE Documentation and Follow-up Procedures

The investigator will review and adhere to the following procedures, which are outlined
in detail in the AE/SAE section of the SRM:
• Method of Detecting AEs and SAEs

• Recording of AEs and SAEs
• Evaluating of AEs and SAEs
• Completion and Transmission of SAE Reports to GSK
• Follow-up of AEs and SAEs
• Post-study AEs and SAEs
• Regulatory Reporting Requirements for SAEs
12. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
12.1. Hypotheses
The primary objective of this study is to demonstrate the superiority of oral GW679769
given in combination with 4mg IV ZOFRAN [B] over 4mg IV ZOFRAN [A] alone. The
null and alternative hypotheses are:
• Null Hypothesis: There is no difference in complete response rates at 24 hours in the

two treatment arms in the modified intent-to-treat (MITT) population; i.e.,
H0: pA = pB.
• Alternative Hypothesis: The complete response rates at 24 hours in the two
treatment arms differ, i.e.,
H1: pA ≠ pB,
where pA and pB represent the proportion of complete responders at 24 hours in
treatment arms A and B respectively.
12.2. Study Design Considerations
12.2.1. Sample Size Assumptions
Based on Phase II data, assuming a 40% complete response rate for the treatment arm A
(4mg IV ZOFRAN alone) at 24 hours, 231 subjects per arm would be required to show a
15% absolute difference in complete response rates between the two treatment arms with
90% power and a two sided level of significance of 5%.
12.2.2. Sample Size Sensitivity
The robustness of the above sample size calculation should be considered in order to
assess the impact on power, should the assumed underlying proportions vary. The
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following table shows the effect on power as these proportions vary with a fixed sample
size of 231 subjects per cohort.
Complete Response Rates

Treatment Assumed Rates Scenario I Scenario II Scenario III
Placebo 40% 40 42 45
50 mg oral 55% 52 53 55
GW679769
Power 90% 73% 65% 57%
12.2.3. Sample Size Re-estimation
No sample size re-estimation is required for this study.
12.3. Data Analysis Considerations

This study will be conducted through GlaxoSmithKline’s electronic data capture system.
Subject data will be collected by the investigator or designee using the eCRF defined by
GlaxoSmithKline. Subject data necessary for analysis and reporting will be
entered/transmitted into a validated database or data system. Clinical data management
will be performed in accordance with applicable GlaxoSmithKline standards and data
cleaning procedures. Database freeze will occur when data management quality control
procedures are completed. Original eCRFs will be retained by GlaxoSmithKline, while
the investigator will retain a copy.
12.3.1. Analysis Populations
The intent-to-treat (ITT) population is defined as all subjects who were randomized to
one of two antiemetic prophylactic regimens, A or B. The ITT population will be used to
summarize the study population.
The primary population of interest is the modified intent-to-treat (MITT) population.

This population is the subset of the ITT population that received any investigational
product and had surgery. Subjects will be excluded from this population only if there is
documented evidence that no GW679769 investigational product (either placebo or
active) was administered and/or that there was no surgery.
The safety population will be a subset of the ITT population that received any
investigational product (active or placebo). Subjects will be excluded from this
population only if there is documented evidence that no GW679769 investigational
product (either placebo or active) was administered.
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12.3.2. Treatment Comparisons
12.3.2.1. Primary Comparisons of Interest
The primary comparison of interest is between 50 mg oral GW679769 given in

combination with 4mg IV ZOFRAN and 4mg IV ZOFRAN alone. Complete response
rates between the two treatment arms will be tested using a two-sided test with a level of
significance of 5%. The primary comparison will be carried out at the 24 hour endpoint.
The MITT population will be used for this testing.
12.3.2.2. Other Comparisons of Interest
There are several comparisons of interest for the following secondary variables:
complete protection, total control, nausea, significant nausea, severity of nausea, time to
emesis, time to rescue, vomiting, use of rescue, subject satisfaction, and subject
willingness. Secondary comparisons will be carried out in the 0-24, 24-48 and 0-48
assessment windows.
12.3.3. Interim Analysis
No interim analysis is planned for this study.
12.3.4. Key Elements of Analysis Plan
12.3.4.1. Withdrawal
Withdrawals from the study will be tabulated by reason for discontinuation. Withdrawal
reports will be based on the ITT population.
12.3.4.2. Derived and Transformed Data
Efficacy variables will be derived as follows:
• Complete response: No vomiting/retching, and no rescue medication. Subjects who

received rescue in the 24 hours following placement of last suture/staple will be
considered as a complete response failure in the subsequent 24 hours.
• Significant nausea: Maximum nausea score greater than or equal to 3 on the Likert
scale.
• Nausea: Maximum nausea score greater than or equal to 1 on the Likert scale.
• Complete protection: Complete responders who had no significant nausea. Subjects
who received rescue in the 24 hours following placement of last suture/staple will be
considered as a complete protection failure in the subsequent 24 hours.
• Total control: Complete responders who had no nausea. Subjects who received
rescue in the 24 hours following placement of last suture/staple will be considered as
a total control failure in the subsequent 24 hours.
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• Vomiting: Vomit or retch. If a subject took rescue medication but there is no

evidence of vomiting or retching, she will be considered as not having vomited.
• Rescue: If antiemetic rescue medication is taken for any reason
12.3.4.3. Assessment Windows
All endpoints will be assessed in the following time windows: 0 – 24, 24 – 48, and 0 –
48 hours following placement of the last suture/staple. Nausea will also be assessed in
the following time windows: 0 – 2 and 0 – 6 hours.
12.3.4.4. Multiplicity
This study has one primary endpoint, which will be tested at 24 hours. If the primary
endpoint is significant, pre-specified secondary endpoints (specified in the statistical
analysis plan) will be tested hierarchically.
12.3.4.5. Multicenter
This trial will use a randomization that assigns subjects to treatment groups based on a
single, central allocation scheme across centers. Therefore, no adjustments will be made
for center, and a treatment-by-center interaction will not be examined.
12.3.4.6. Efficacy Analyses
12.3.4.6.1. Primary Efficacy Analysis
The Cochran-Mantel-Haenszel test will be used to compare treatment arms. Since this
study is stratified by the use of nitrous oxide, all analyses will be adjusted for this
stratification factor. Odds ratios, p-values and 95% confidence intervals for the odds
ratios will be calculated.
12.3.4.6.2. Secondary Efficacy Analysis
There are several secondary endpoints. Many of these (such as complete protection, total
control, etc.) will be analyzed in a manner similar to the primary endpoint. Details of the
analysis of other secondary efficacy variables will be spelled out in the Report Analysis
Plan (RAP).
12.3.4.7. Safety Analyses
Extent of Exposure
For each treatment arm, counts and percentages of subjects who were randomized and
treated will be displayed.
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Adverse Events
The incidence of adverse events up to and including the post-op Days 6-14 Visit will be
presented. The adverse events shall be categorized by the Preferred Term using the
Medical Dictionary for Regulatory Activities (MedDRA).
Clinical Laboratory Evaluations
Laboratory data will be summarized based on the statistical mean, standard error, median,
and minimum and maximum for each parameter.
Time to Awakening
Time to awakening will be summarized based on the statistical mean, standard error,
median, and minimum and maximum for each parameter.
12.3.4.8. Health Outcomes Analyses
The Subject Diary will contain two questions relating to the subject’s satisfaction with
the antiemetic therapy. The first will rate overall satisfaction with the study medication
and investigational product in preventing postoperative vomiting, using a 5 point rating
scale. In addition, subjects will rate their willingness to use the same antiemetic drug
treatment regimen for subsequent surgical procedures, using a similar 5 point rating scale.
Additional details can be found in Section 6.4.1., “Subject Satisfaction Questionnaires”,

and Appendix 6, “Subject Satisfaction Assessment”.
A descriptive data analysis of subject satisfaction and willingness to use questionnaires

will be performed. Frequencies and percentages of each satisfaction category will be
presented for each of the treatment arms. Subject satisfaction and willingness to use
scores will be compared among treatment arms.
13. STUDY CONDUCT CONSIDERATIONS
13.1. Regulatory and Ethical Considerations, Including the

Informed Consent Process
GSK will obtain favorable opinion/approval to conduct the study from the appropriate
regulatory agency in accordance with any applicable country-specific regulatory
requirements prior to a site initiating the study in that country.
The study will be conducted in accordance with all applicable regulatory requirements,
including a U.S. IND.
The study will also be conducted in accordance with "good clinical practice" (GCP), all
applicable subject privacy requirements, and, the guiding principles of the Declaration of
Helsinki. This includes, but is not limited to, the following:
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• IRB/IEC review and favorable opinion/approval to conduct the study and of any
subsequent relevant amended documents
• Subject informed consent
• Investigator reporting requirements
GSK will provide full details of the above either verbally, in writing or both.
Written informed consent will be obtained for each subject before she can participate in
the study.
13.2. Quality Control (Study Monitoring)

In accordance with applicable regulations, GCP, and GSK procedures, GSK-authorized
monitors will contact the site prior to the start of the study to review with the site staff the
protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and
GSK requirements. When reviewing data collection procedures, the discussion will also
include identification, agreement and documentation of data items for which the CRF
will serve as the source document.
GSK authorized monitors will monitor the study consistent with the demands of the study
and site activity to verify that the:
• Data are authentic, accurate, and complete.

• Safety and rights of subjects are being protected.
• Study is conducted in accordance with the currently approved protocol and any other
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to
allow the monitor direct access to all relevant documents
13.3. Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK may
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory
inspection of this study. Such audits/inspections can occur at any time during or after
completion of the study. If an audit or inspection occurs, the investigator and institution
agree to allow the auditor/inspector direct access to all relevant documents and to allocate
his/her time and the time of his/her staff to the auditor/inspector to discuss findings and
any relevant issues.
13.4. Study and Site Closure

Upon completion or premature discontinuation of the study, the monitor will conduct site
closure activities with the investigator or site staff, as appropriate, in accordance with
applicable regulations, GCP, and GSK procedures.
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In addition, GSK reserves the right to temporarily suspend or prematurely discontinue

this study at any time for reasons including, but not limited to, safety or ethical issues or
severe non-compliance. For multicenter studies, this can occur at one or more or at all
sites. If GSK determines such action is needed, GSK will discuss this with the
investigator or the head of the medical institution (where applicable), including the
reasons for taking such action, at that time. When feasible, GSK will provide advance
notification to the investigator or the head of the medical institution, where applicable, of
the impending action prior to it taking effect.
GSK will promptly inform all other investigators or the head of the medical institution
(where applicable), and/or institutions conducting the study if the study is suspended or
terminated for safety reasons. GSK will also promptly inform the regulatory authorities
of the suspension or termination of the study and the reason(s) for the action. If required
by applicable regulations, the investigator or the head of the medical institution (where
applicable) must inform the IEC/IRB promptly and provide the reason for the suspension
or termination.
13.5. Records Retention

Following closure of the study, the investigator or the head of the medical institution
(where applicable) must maintain all site study records, except for those required by local
regulations to be maintained by someone else, in a safe and secure location. The records
must be maintained to allow easy and timely retrieval, when needed (e.g., audit or
inspection), and, whenever feasible, to allow any subsequent review of data in
conjunction with assessment of the facility, supporting systems, and staff. Where
permitted by local laws/regulations or institutional policy, some or all of these records
can be maintained in a format other than hard copy (e.g., microfiche, scanned,
electronic); however, caution needs to be exercised before such action is taken. The
investigator must assure that all reproductions are legible and are a true and accurate copy
of the original, and meet accessibility and retrieval standards, including re-generating a
hard copy, if required. Furthermore, the investigator must ensure there is an acceptable
back-up of these reproductions and that an acceptable quality control process exists for
making these reproductions.
GSK will inform the investigator of the time period for retaining these records to comply
with all applicable regulatory requirements. The minimum retention time will meet the
strictest standard applicable to that site for the study, as dictated by any institutional
requirements or local laws or regulations, or GSK standards/procedures; otherwise, the
retention period will default to 15 years.
The investigator must notify GSK of any changes in the archival arrangements, including,
but not limited to, the following: archival at an off-site facility, transfer of ownership of
the records in the event the investigator leaves the site.
13.6. Provision of Study Results and Information to Investigators

When required by applicable regulations, the investigator signatory for the clinical study
report will be determined at the time the report is written. When the clinical study report
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is completed, GSK will provide the investigator with a full summary of the study results.
The investigator is encouraged to share the summary results with the subjects, as
appropriate. In addition, the investigator will be given reasonable access to review the
relevant statistical tables, figures, and reports and will be able to review the results for the
entire study at a GSK site or other mutually agreeable location.
GSK will provide the investigator with the randomization codes for their site after the
statistical analysis for the entire study has been completed.
13.7. Data Management

The data collection tool for this study will be GSK-defined case report forms (CRFs).
The electronic case report forms will be utilized at all sites. In all cases, subject initials
will not be collected nor transmitted to GSK. Subject data necessary for analysis and
reporting will be performed in accordance with applicable GSK standards and data
cleaning procedures. Original eCRFs will be retained by GSK, while the investigator
will retain a copy.
13.8. Independent Data Monitoring Committee (IDMC)

An IDMC will not be utilized during the conduct of this study. An IDMC is generally
assembled when there are significant safety or efficacy issues that warrant external
objective medical and/or statistical review in order to protect the ethical and safety
interests of subjects and to protect the scientific validity of the study.
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14. REFERENCES
American Society of Anesthesiologists. ASA Classification System.
http://www.asahq.org/clinical/physicalstatus.htm. Accessed 22 November 2005.
Apfel CC, Kranke P, Eberhart LHJ, Roos A, Roewer N. Comparison of predictive

models for postoperative nausea and vomiting. British Journal of Anaesthesiology.
2002;88:234-240.
Apfel CC, Laara E, Koivuranta M, Graim CA, Roewer N. A simplified risk score for
predicting postoperative nausea and vomiting. Anesthesiology. 1999;91:693-700.
Carroll NV, Miederhoff P, Cox FM, Hirsch JD. Postoperative nausea and vomiting after
discharge from outpatient surgery centers. Anesthesiology Analgesia. 1995;80:903-909.
Eberhart LHJ, Morin AM, Wulf H, Geldner G. Patient preferences for immediate
postoperative recovery. British Journal of Anaesthesia. 2002;89:760-761.
Gan TJ, Mayer T, Apfel CC, et al. Consensus guidelines for managing postoperative
nausea and vomiting. Anesthesia & Analgesia. 2003;97(1):62-71.
Gupta A, Wu CL, Elkassabany N, Krug CE, Parker SD, Fleisher LA. Does the routine
prophylactic use of antiemetics affect the incidence of postdischarge nausea and vomiting
following ambulatory surgery? Anesthesiology. 2003;99 (No.2):488-495.
Kovac A. Prevention and treatment of postoperative nausea and vomiting. Drugs.

2000;59(2):212-243.
Marcus J, Tyrone JW, Few JW, Fine NA, Mustoe TA. Optimization of conscious
sedation in plastic surgery. Plastic & Reconstructive Surgery. 1999;104(5):1338-1345.
Naguib M, Bakry AKEI, Khoshim MHB, et al. Prophylactic antiemetic therapy with
ondansetron, tropisetron, granisetron and metoclopramide in patients undergoing
laparoscopic cholecystectomy: a randomized, double-blind comparison with placebo.
Canadian Journal of Anaesthesiology. 1996;43:226-231.
Neuroland, Information for Healthcare Professionals. Opioid analgesic equivalents with

approximately equianalgesic potency. http://neuroland.com/pain/opioid_equi_dose.htm.
2005. Accessed 13 October 2005.
Pierre S, Benais H, Pouymayou J. Apfel’s simplified score may favourably predict the
risk of postoperative nausea and vomiting. Canadian Journal of Anesthesia.
2002;49:237-242.
Sinclair DR, Chung F, Mezei G. Can postoperative nausea and vomiting be predicted?
Anesthesiology. 1999;91(No. 1):109-127.
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Wang JJ, Shung-Tai H, Yih-Huei, et al. Small dose dexamethasone reduces nausea and
vomiting after laparoscopic cholecystectomy: a comparison of tropisetron with saline.
Anesthesia and Analgesia, 2002;95:229-232.
Watcha MF, Jones MB, Lagueruela RG, Schweiger C, White PF. Comparison of
ketorolac and morphine as adjuvants during pediatric surgery. Anesthesiology.
1992;76(3):368-372.
ZOFRAN (ondansetron hydrochloride) Product Information. May, 2005.
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Appendices
Appendix 1: Time and Events Table
Pre- Post-op.
surgical Day of Surgery Post-op. Post-op. Day 6-14
Study Days: Baseline Study Day 1 Day 1 Day 2 Visita
Screening Prior to Periop. Post-op.
Study Procedure Phaseb Study meds Phase Phasec 24 h 48 h
Informed Consentd X
Medical History X
Routine Physical X
Examination
ASA Physical Status X X
Vital Signs X X X OR Xe X
ECG X X OR Xe
Hematology and X X OR Xe X
Chemistryf
Pregnancy Testg X
Concomitant X X X X X X X
Medicationsh
Inclusion/Exclusion X X
Criteriai
Randomization (IVRS)j X X X
Administration of Study X
Medicationsk
Pharmacogenetic
Sample Collectionl X
Follow-up (Telephone)m
X X
Follow-up Visit Xa
Nausea and Emesis
Assessmentsn, o X X Xp Xp Xp X
Subject Diary Xq Xq X X Xq
Subject Satisfaction X Xr
Adverse Event X X X X X
Assessment
Key to the Time and Events Table
AE=Adverse Events
ASA=American Society of Anesthesiologists
PGx=Pharmacogenetics
RAMOS=Randomization and Medication Ordering System
IVRS = Interactive Voice Response System
a. All efforts should be made for this visit to occur as soon as possible following the completion of the 48 Hour
Assessment.
b. Screening may be done within 21 days prior to the day of surgery or the same day as surgery. If screening is
done on a day other than the day of surgery, the inclusion/exclusion criteria will be re-evaluated to confirm that the
subject continues to be eligible.
c. Begins upon the placement of the last suture/last staple.
d. Written informed consent must be provided by the subject prior to initiation of any study-specific procedures.
e. To be assessed prior to discharge from the surgical facility or at the end of the 24 Hour Assessment phase on
Post-operative Day 1, whichever comes first.
f. To be conducted within 10 days prior to surgery. See Appendix 5: “Laboratory Tests” for complete details.
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g. If performed. See Section 5.2.1.,“Inclusion Criteria” and Section 6.2.1.1., “Pregnancy Testing” for complete
details. When required, pregnancy testing must be conducted within 24 hours prior to the administration of
GW679769.
h. Medications taken within seven (7) days prior to scheduled day of surgery must be recorded.
i. If Screening assessments are performed on a day other than the day of study medication and surgery, the
Inclusion/Exclusion Criteria (including Concomitant Medications) will be reviewed prior to administration of
GW679769 investigational product to ensure that the subject continues to be eligible.
j. The IVRS (RAMOS) must be contacted three separate times: twice during the Screening Phase (to register the
subject and again to randomize the subject within 24 hours prior to the administration of GW679769
investigational product) and again when the subject is discontinued from the study. See Section 8.6.1.,
“Randomization and Medication Ordering System” for further details.
k. GW679769 investigational product will be administered as an oral tablet, administered approximately 60 minutes
prior to the induction of anesthesia. ZOFRAN (ondansetron hydrochloride) study medication will be administered
as an intravenous injection over two to five minutes, immediately prior to the induction of anesthesia.
l. See Appendix 7, “PGx – Pharmacogenetic Research” for more information.
m. In the event that the subject is not discharged from the surgical center prior to the end of the 24 Hour Assessment
phase, the same information will be collected by study personnel at the appropriate assessment periods.
n. Using a discrete Likert scale, scored from 0 to 10. See Section 6.3.2,. “Assessment of Nausea” and Appendix
10:, “Nausea Assessment Scale” for further details.
o. These assessments will not be completed as long as the subject remains incapable of adequately completing the
assessments required at a specified assessment period (e.g., 2 hours post-placement of last suture/last staple).
See Section 6.3.4., “Subject Diary” for further details.
p. To be assessed at 2, 6, 24 and 48 hours following the placement of last suture/last staple.
q. Dispensed prior to receiving GW679769 investigational product. Returned to the subject when the subject is
considered capable of adequately completing the required assessments. Returned to study personnel at Final
Visit.
r. The overall satisfaction with the study medications for preventing PONV and the willingness to use the same
antiemetic drug treatment regimen for subsequent surgical procedures will be assessed on Post-operative Day 2,
as soon as possible following the completion of the 48 Hour Nausea Assessment. The completed Subject
Satisfaction questionnaire will be returned to the investigational site during the Study Day 6-14 visit. See
Appendix 6, “Subject Satisfaction Assessment” for further details.
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Appendix 2: Dosing of Antiemetics in NKT102553

Administration (Prior to Induction of Anesthesia) Administered
A GW679769 oral ∼ 60 minutes prior Placebo

(ondansetron HCl)
B GW679769 oral ∼60 minutes prior 50 mg

(ondansetron HCl)
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Appendix 3: Glossary of Relevant Terms
Nausea: a subjectively unpleasant sensation associated with the awareness

expulsive muscular movements
Emesis: vomiting and/or retching
Vomiting: the forceful expulsion of gastrointestinal contents through the

mouth or nose
Retching: the labored, spasmodic, rhythmic contraction of the respiratory and

abdominal muscles in an attempt to vomit, that is not productive of
gastrointestinal contents (also known as “dry heaves”)
Emetic Episode: a single vomit or retch, or any number of continuous vomits or

retches. Emetic episodes will, by definition, be separated by the
absence of vomiting or retching by at least one (1) minute.
Continuous vomiting and/or retching will be defined as two (2) of
more vomits and/or retches that occur within one (1) minute of
each other
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Appendix 4: American Society of Anesthesiologists (ASA) Physical Status

Classification System
P1 A normal healthy patient
P2 A patient with mild systemic disease
P3 A patient with severe systemic disease
P4 A patient with severe systemic disease that is a constant threat to life
P5 A moribund patient who is not expected to survive without the operation
P6 A declared brain-dead patient whose organs are being removed for donor
purposes
Reference: American Society of Anesthesiologists. ASA Classification System.

http://www.asahq.org/clinical/physicalstatus.htm. Accessed 29 August 2005.
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Appendix 5: Laboratory Tests
The following laboratory tests will be assessed as described in Section 6.1.,

“Demographic and Baseline Assessments”:
Hematology:
Hemoglobin
Hematocrit
WBC count
WBC differential
Platelet count
Chemistry:
Albumin
Alkaline phosphatase
ALT
AST
BUN or serum urea
Creatinine
Electrolytes:
Chloride
Potassium
Sodium
Glucose (fasting for > 8 hours, if possible)
Total bilirubin
Total protein
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Appendix 6: Subject Satisfaction Assessment
Subjects will rate their overall satisfaction with the study medication in the management
of post-operative nausea and vomiting using a five (5) point rating scale , as follows:
How satisfied are you with the study medications in managing postoperative nausea and
vomiting?
• 1 = very satisfied
• 2 = somewhat satisfied
• 3 = neither satisfied nor dissatisfied
• 4 = somewhat dissatisfied
• 5 = very dissatisfied
In addition, subjects will rate their willingness to use the same antiemetic drug treatment
regimen for subsequent surgical procedures, using a similar five (5) point rating scale, as
follows:
• 1 = definitely would be willing
• 2 = probably would be willing
• 3 = not certain
• 4 = probably would not be willing
• 5 = definitely would not be willing
These assessments are to be completed in the Subject Diary on Post-operative Day 2, as

soon as possible following the completion of the 48 Hour Follow-up Assessment Phase.
The Subject Diary will be returned to the investigational site during the Day 6 - 14 final
study visit.
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Appendix 7: PGx
Pharmacogenetic Research
Pharmacogenetics – Background
Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary

factors in different populations. There is increasing evidence that an individual's genetic
composition (i.e., genotype) may impact the pharmacokinetics (absorption, distribution,
metabolism, elimination), pharmacodynamics (relationship between concentrations and
pharmacologic effects or the time course of pharmacologic effects) and/or clinical
outcome (in terms of efficacy and/or safety and tolerability). Some reported examples of
PGx analysis include:
Drug Disease Gene Outcome
Abacavir HIV HLA Caucasian males with HLA B57 variant were at
[Hetherington, (human increased risk for experiencing hypersensitivity to
2002 and Mallal, leukocyte abacavir
2002] antigen)
Tranilast Restenosis UGT1A1 Drug induced hyperbilirubinemia explained by high

prevention proportion of affected patients having 7/7 TA
following repeat genotype, consistent with clinically benign
coronary bypass Gilbert’s Syndrome
[Roses, 2002]
ABT-761 Asthma [Drazen, ALOX5 ALOX5 Sp1 promoter genotype (x,x) associated
1999] with reduced response to 5-lipoxygenase inhibitor
ABT-761
A key component to successful PGx research is the collection of samples during the
conduct of clinical studies.
Pharmacogenetic Research Objectives
If at any time it appears there is potential variability in response in this clinical study or in
a series of clinical studies with GW679769 that may be attributable to genetic variations
of subjects, the following objectives may be investigated:
• Relationship between genetic variants and safety and/or tolerability of GW679769

• Relationship between genetic variants and efficacy of GW679769
Study Population
Any subject who has given informed consent to participate in the clinical study, has met
all the entry criteria for the clinical study, and receives investigational product may take
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part in the PGx research. Any subject who has received an allogeneic bone marrow
transplant must be excluded from the PGx research.
Subject participation in the PGx research is voluntary and refusal to participate will not
indicate withdrawal from the clinical study. Refusal to participate will involve no penalty
or loss of benefits to which the subject would otherwise be entitled.
Study Assessments and Procedures
In addition to any blood samples take for the clinical study, a whole blood sample
(~10ml) will be collected for the PGx research using a tube containing EDTA. The PGx
sample is labeled (or “coded”) with a study specific number that can be traced or linked
back to the subject by the investigator or site staff. Coded samples do not carry personal
identifiers (such as name or social security number). The blood sample will be taken on a
single occasion unless a duplicate sample is required due to inability to utilize the original
sample. It is recommended that the blood sample be taken at the first opportunity after a
subject has been randomized and provided informed consent for PGx research, but may
be taken at any time while the subject is participating in the clinical study.
If deoxyribonucleic acid (DNA) is extracted from the blood sample, the DNA may be
subjected to sample quality control analysis. This analysis will involve the genotyping of
several genetic markers to confirm the integrity of individual samples. If inconsistencies
are noted in the analysis, then those samples may be destroyed.
Subject Withdrawal from Study
If a subject who has consented to participate in PGx research withdraws from the clinical
study for any reason other than lost to follow-up, the subject will be given the following
options concerning the PGx sample, if already collected:
1. PGx research continues per the subject’s consent; or,

2. Any remaining sample is destroyed
If a subject withdraws consent from the PGx research or requests sample destruction, the
investigator must complete the appropriate documentation to request sample destruction
within the timeframe specified by GSK and maintain the documentation in the site study
records. In either case, GSK will only keep study information collected/generated up to
that point.
Screen and Baseline Failures
If a blood sample for PGx research has been collected and it is determined that the
subject does not meet the entry criteria for participation in the clinical study, then the
investigator must complete the appropriate documentation to request sample destruction
within the timeframe specified by GSK and maintain the documentation in the site study
records.
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Pharmacogenetics Analyses
The need to conduct PGx analysis may be identified after a study (or set of studies) of
GW679769 has been completed and the study data reviewed. For this reason, samples
may be kept for up to 15 years after the last subject completes the study or GSK may
destroy the samples sooner. In special cases, the samples may not be studied. This might
happen if there are not enough subjects, if the study is stopped for other reasons, or if no
questions are raised about how people respond to GW679769.
Generally GSK will utilize two approaches to explore genetic variation in drug response.
1. Hypothesis driven approach: A specific hypothesis is generated about sections of

DNA (or individual single nucleotide polymorphisms (SNPs) or other genetic
markers) that may be associated with differential drug handling or response.
Specific sections of DNA may be selected from areas of the genome (e.g., candidate
genes) known to encode the drug target, drug metabolizing enzymes, areas
associated with mechanisms underlying adverse events, and those linked to study
disease and, thus, linked to drug response.
16. Genome-wide approach utilizing polymorphic markers (e.g., SNPs): By evaluating
large numbers of polymorphic markers (e.g., single nucleotide polymorphisms or
SNPs) throughout the genome, sets of markers may be identified that correspond to
differential drug response.
In addition, continuing research may identify other enzymes, transporters, proteins, or
receptors that may be involved in response to GW679769. The genes that may code for
these proteins may also be studied.
Hardy-Weinberg Equilibrium Testing
The genotypic frequencies of each polymorphism will be evaluated for conformity to

those expected under normal conditions by employing Hardy-Weinberg Equilibrium
testing.
Comparison of Demographic and Baseline Characteristics by Genotype
Differences in baseline clinical characteristics and potential contributing covariates may

be summarized and compared among genotype (or haplotype) subgroups.
Evaluation of Genotypic Effects
Analyses may be carried out to evaluate the degree of association between subject
genotype (or haplotype) and selected parameters (e.g., pharmacokinetics, efficacy and
safety). Where such genotypic tests are inappropriate (for example, where the number of
marker genotypes is too large and/or the frequency of individual genotypes too small),
allelic tests may be conducted. Allelic tests evaluate whether the frequency of each
marker allele is the same in responders and non-responders.
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Evaluation of Treatment by Genotype and Gene-Gene Interaction
In addition to evaluating the main effects of the genotypes (haplotypes or alleles) on the
selected parameters, the possibility of a treatment group by genotype (haplotype or allele)
interaction will also be explored. If appropriate, the joint effects of multiple markers
(gene-gene interactions) may also be evaluated.
Linkage Disequilibrium
For pairs of polymorphisms, the degree to which alleles from the two sites are correlated
(linkage disequilibrium) may also be evaluated. If the genotypes at two polymorphic
sites within a gene are shown to be statistically associated with a response to
investigational product, the degree of linkage disequilibrium will aid interpretation in that
it will indicate the extent to which the two sites are exerting independent effects.
Multiple Comparisons and Multiplicity
To the extent that multiple markers are evaluated (especially in the case of a genome scan
for association), an adjustment to observed p-values may be made to limit erroneous
conclusions due to multiple tests.
Power and Sample Size Considerations
The ability to detect differential drug response among genotypes at a polymorphic site
depends on the total number of subjects genotyped and the frequency distribution of the
different genotypes. Consequently, genotyping analyses are plausible for those
polymorphic sites where the number of subjects comprising the genotypic groups is
sufficiently large; however, these frequencies will not be known until sufficient samples
have been collected and genotyping is complete.
Estimates of sample sizes required to demonstrate genotype effects vary considerably,

depending on the assumptions made about allele frequency, genetic effect size, and
mechanism of inheritance [Cardon, 2000]. In the work by Palmer and Cookson [Palmer,
2001], which assumed a genotype relative risk of 1.5, it was estimated that more than 300
cases and 600 controls would be needed to conduct a genetic association analysis. In
contrast, McCarthy and Hilfiker [McCarthy, 2000] showed that with a genotype relative
risk of 2.16 and a relatively commonly occurring genotype, only 30 cases and 30 controls
would be needed to demonstrate an association.
Published PGx examples include abacavir hypersensitivity reaction [Hetherington, 2002

and Mallal, 2002] and tranilast induced hyperbilirubinemia [Roses, 2002] where genetic
markers have been found to significantly associate with hypersensitivity reaction
(abacavir) and hyperbilirubinemia (tranilast). These examples show that small sample
sizes typically encountered in Phase I and Phase II studies may be sufficient to identify
clinically relevant genetic associations.
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Informed Consent
Subjects who do not wish to participate in the PGx research may still participate in the
clinical study. PGx informed consent must be obtained prior to any blood being taken for
PGx research.
References
Cardon LR, Idury RM, Harris TJR, Witte JS, Elston RC. Testing drug response in the
presence of genetic information: sampling issues for clinical trials. Pharmacogenetics.
2000; 10:503-10.
Drazen JM, Yandava CN, Dube L, Szcerback N, Hippensteel R, Pillari A, Israel E,

Schork N, Silverman ES, Katz DA, Drajesk J. Pharmacogenetic association between
ALOX5 promoter genotype and the response to anti-asthma treatment. Nature Genet.
1999; 22:168-70.
Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E,

Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses
AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir.
Lancet. 2002; 359:1121-2.
Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte
C, Maxwell D, James I. Association between presence of HLA-B*5701, HLA-DR7, and
HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir.
Lancet. 2002; 359:727-32.
McCarthy JJ, Hilfiker R. The use of single-nucleotide polymorphism maps in

pharmacogenomics. Nat Biotechnol. 2000; 18:505-8.
Palmer LJ, Cookson WO. Using single nucleotide polymorphisms as a means to

understanding the pathophysiology of asthma. Respir Res. 2001; 2:102-12.
Roses AD. Genome-based pharmacogenetics and the pharmaceutical industry. Nat Rev
Drug Discov. 2002; 1:541-9.
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Appendix 8: Opioid Equivalents
OPIOID ANALGESIC EQUIVALENTS WITH

APPROXIMATELY EQUIANALGESIC POTENCY
Nonproprietary (Trade) Name IM or SC Dose Oral Dose
Morphine Sulfate 10 mg 40 – 60 mg
Hydromorphone HCl (Dilaudid) 1.3 – 2 mg 6.5 – 7.5 mg
Oxymorphone HCl (Numorphan) 1 – 1.1 mg 6.6 mg
Levorphanol tartrate (Levo-Dromoran) 2 – 2.3 mg 4 mg
Meperidine HCl (Demerol) 75 – 100 mg 300 – 400 mg
Methadone HCl (Dolophine) 10 mg 10 – 20 mg

Reference: Neuroland, Information for Healthcare Professionals. Opioid analgesic
equivalents with approximately equianalgesic potency.
http://neuroland.com/pain/opioid_equi_dose.htm
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Appendix 9: Medications with CyP3A4 and/or CYP3A5 Substrate Activity
Common medications with CYP3A4 and/or CYP3A5 substrate activity are shown below;
however, the list is not all-inclusive for such medications.
Clinicians are advised to be diligent in monitoring for evidence of increased exposure of

concomitant medications that are known substrates of CYP3A4, and to utilize their usual
judgement in adjusting dosages of potential substrates on the basis of observed clinical
and/or laboratory effects. This is especially important for those drugs that have a narrow
therapeutic index. Note that the use of CYP3A4 substrates is not prohibited during the
study, but particular caution is required. However, those agents that are inhibitors and/or
inducers of CYP3A4 are restricted in accordance with the footnotes indicated below:
Angiotensin II Inhibitor Agents

Losartan
Antiarrhythmic Agents
Amiodarone; disopyramide; lidocaine; quinidine; quinine
Anticonvulsant Agents
Carbamazepine2; ethosuximide; phenobarbital2; phenytoin2
Antiemetic Agents
Dronabinol; ondansetron
Antifungal Agents
Fluconazole2; itraconazole2; ketoconazole1; miconazole
Antihistamine Agents
Astemizole; fexofenadine; loratadine; terfenadine
Antiinfective Agents
Clindamycin; clarithromycin1; dapsone; erythromycin1
Antitubercular Agents
Rifampin
Benzodiazepines
Alprazolam; clonazepam; diazepam; midazolam; temazepam; triazolam
Calcium Channel Blockers

Amlodipine; diltiazem1; felodipine; isradipine; mibefradil; nicardipine; nifedipine;
nimodipine; nisoldipine; verapamil1
Chemotherapeutic Agents
Busulfan; cyclophosphamide; doxorubicin; etoposide; ifosfamide; paclitaxel; tamoxifen;
teniposide; vinblastine; vincristine; vinorelbine tartrate
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Corticosteroids
Dexamethasone; methylprednisolone; prednisolone; prednisone
Estrogens, Oral Contraceptives

Estradiol
HMG-CoA Reductase Inhibitors

Atorvastatin; lovastatin; pravastatin; simvastatin
Immunosuppressants
Cyclosporine; tacrolimus
Leukotriene Modifiers
Zileuton; montelukast
Miscellaneous
Cannabinoids; cisapride; cyclobenzaprine; dextromethorphan; donepezil; glyburide;
grapefruit juice1; nefazodone; pimozide; rifabutin2; rifampin2; St. John's Wort2; sildenafil;
testosterone; troglitazone2; venlafaxine,
Narcotic Analgesics
Alfentanil; cocaine; fentanyl
Protease Inhibitor
Amprenavir; efavirenz2; indinavir sulfate; nelfinavir mesylate; nevirapine2; ritonavir;
saquinavir mesylate
Proton Pump Inhibitors

Lansoprazole; omeprazole
Selective Serotonin Reuptake Inhibitors

Sertraline; citalopram
Tricyclic Antidepressants
Amitriptyline; clomipramine; imipramine
1
Prohibited for 2 days prior to administration of GW679769 investigational product, and
for 72 hours following the administration of GW679769 investigational product
2
Prohibited for 14 days prior to administration of GW679769 investigational product,
and for 72 hours following the administration of GW679769 investigational product
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Appendix 10: Nausea Assessment Scales
Likert Scale
The subject will be asked to rate the level of nausea they have experienced over the
previous (2 hours, 6 hours, 24 hours, and 48 hours), by selecting one of the numbers on
the scale below.
0 1 2 3 4 5 6 7 8 9 10
No nausea Nausea as bad as it could be
Categorical Nausea Scale
The subject will be asked to assess the severity of his/her nausea in the following manner;
Using the descriptions provided, please rate your nausea experience since the last time
you completed the diary:
• None; no nausea
• Mild
• Moderate
• Severe
None = no nausea
Mild = queasiness/upset stomach that is manageable and, if at all, minimally affects daily
activities
Moderate = increased queasiness, sometimes with the feeling of having to vomit/throw

up (but not vomiting), that has a significant effect on daily activities (for example, being
unable to work, eat and drink, prepare food, and care for children or others)
Severe = Feeling sick and vomiting or feeling like you have to vomit, and unable to
perform most daily activities.
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Appendix 11: Lactose Excipient in GW679769
Lactose Intolerance and the Use of Lactose as a Pharmaceutical Excipient

, Pharm.D
Senior Director Clinical Pharmacology and Discovery Medicine
5 May 2005
Several investigators have recently expressed concern that lactose is an excipient used in
the manufacture of GW679769 oral dosage forms. This concern is due to the fear that
patients in clinical trials who are lactose intolerant may have gastrointestinal (GI)
symptoms due to lactose that may be attributed to the test drug. Lactose is one of the
most frequently used diluents in tablets and capsules and Pharmaceutical Development
has had much experience with using it. Finding a substitute would be difficult and
resource intensive. The following is a brief summary of the problem of lactose
intolerance and the use of lactose in dosage forms.
• The primary cause of lactase deficiency is the genetically programmed loss of

intestinal lactase activity which occurs during the first or second decade of life
in approximately 70% of the worlds population.
• There is a dose-response relationship for the occurrence of symptoms after a
dose of lactose.
• Doses of 30-50 grams of lactose cause symptoms in 90-100% of lactose
intolerant patients while doses of 15-25 grams still cause symptoms in >50% of
patients but the severity is variable. At doses less than 12 grams, the percentage
of lactose-intolerant patients complaining of GI symptoms is no different than
that of those receiving a placebo (1).
• Patients who are lactose intolerant know that they are intolerant and know how
much milk than can tolerate.
• The average glass (8-10 fluid ounces) of cow’s milk contains approximately 15
to 25 grams of lactose. Table 1 presents the lactose content of various foods.
• 50 grams of lactose (amount of lactose in 1 L of milk) is the historical standard
test dose for lactose intolerance.
• The amount of lactose used as an excipient is small, eg the largest amount of
lactose proposed to be used in a tablet of GW 679769 is 114mg/150mg
tablet. The proposed dose of GW679769 is 150mg/day so a subject/patient
would be exposed to less than 200mg (0.2 grams) of lactose per day.
• A through literature search by the GSK Technical Information Department
failed to find any publication discussing an adverse reaction to lactose used as
an excipient in a dosage form.
• If an investigator is worried that lactose could increase their rate of adverse GI
symptoms they can exclude patients with known severe intolerance to lactose.
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Conclusion
Lactose should not be excluded as a possible excipient in solid dosage forms for clinical
trial material because (1.) the small amounts of lactose used in tablets and capsules is
much less than the amount documented to cause GI symptoms in lactose intolerant
patients and (2.) severely lactose intolerant patients could be excluded from clinical trials
where there is a concern that symptoms of lactose intolerance could be incorrectly
attributed to the test drug.
Table 1 Lactose Content of Various Foods [Savaiano , 1987]
Lactose
Food (grams/100 grams of food)
Cow's milk
Whole 4.7
Skim 5.0
Yogurt (lowfat) 4.0-4.6
Cream 3.0
Cottage cheese 1.4
Other cheeses trace
Ice cream (14% cream) 3.6
Milk chocolate 8.1
References
Jones DV, Latham MC, Kosikowski FV, et al. Symptom response to lactose-reduced
milk in lactose-intolerant adults. Am J Clin Nutr 1976; 29:633-39.
Savaiano DA, and Levitt MD. Milk intolerance and microbe-containing dairy foods. J
Dairy Sci 1987; 70:397-406.
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Appendix 12: Country Specific Requirements
No country-specific requirements exist.
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Appendix 13: Changes to Protocol
Amendment No. 1
Section 1.1.1.2. Phase II Program PONV
5th paragraph, 4th line: move “(as displayed in Table 2 . . . Than 5% of Subjects”)
from after the word “anesthesia” to after the words “well tolerated” (7th line)
Section 5 Study Population
1st paragraph, last sentence: deleted the word “following” from “All subjects will
have the following four Apfel . . . “.
Section 5.2.2. Exclusion Criteria
Corrected #15 to read “In France, a subject is neither affiliated with nor a
beneficiary of a social security category.”
Section 8.3. Dosage and Administration
1st paragraph, 1st line: change “. . . their first. . . ” to “. . .a single oral . . . ”
Added Section 10.3 Treatment After the End of the Study
“There are no plans for subjects in NKT102553 to be offered study drug after
completion of the study. GW679769 does not currently have marketing
authorization approval in any market. Following completion of the study the
subject’s physician will be responsible for ensuring the subject receives
appropriate care and treatment.”
Section 10.3 Screen and Baseline Failures
This section has re-numbered to Section 10.4
Section 12.1. Hypotheses
1st sentence: changed “IV” to “oral”
Section 12.2.2. Sample Size Sensitivity
Complete Response Rates table, Treatment column
Changed “30 mg iv” to “50 mg oral”
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Section 12.3.2.1. Primary Comparisons of Interest
1st sentence: changed “30 mg IV” to “50 mg oral”
Section 12.3.2.2. Other Comparisons of Interest
4th line: remove “and the impact of PONV on quality of life”; place “and”
between “subject satisfaction” and “subject willingness”, period after
“willingness”.
Section 12.3.4.2. Derived and Transformed Data
1st bullet: replace “post emergence from anesthesia” with “following placement
of last suture/staple”
4th bullet: :replace “post emergence from anesthesia” with “following placement
5th bullet: replace “post emergence from anesthesia” with “following placement
Appendix 1 Time and Events Table
Vital Signs: corrected to two separate cells for Screening and Prior to Study
Meds, and placed X in each cell
Key to Time and Events Table
k. changed reference to “intravenous infusion” and timing of administration to

“GW679769 investigational product will be administered as an oral tablet,
administered approximately 60 minutes prior to the induction of anesthesia.”
Appendix 10 Nausea Assessment Scales
Categorical Nausea Scale
Under definition for Moderate, 3rd line: change “. . . being able to work . . ” to
“being unable to work”.
Amendment No. 2
Section 4.2. Anesthetic and Analgesic Regimen
First paragraph: defined start and stop times for one hour period of general
anesthesia: “(Start time of general anesthesia will be the time of administration of
the first anesthetic agent ie, IV Propofol induction. The end time of general
anesthesia will be equal to the time of extubation or equivalent).”
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Second paragraph: addressed use of local anesthetic infusion pumps: “Local

anesthetic infusion pumps are permitted as long as they are being used in addition
to the anticipated use of systemic opioids.”
Section 5.2.1. Inclusion Criteria
Inclusion 2: added wording to allow rare/infrequent smokers into study:

“Rare/infrequent (2 or less cigarettes a week) smoking is allowed, at the
investigator’s discretion.”
Inclusion 4: defined start and stop times for one hour period of general
anesthesia: “(Start time of general anesthesia will be the time of administration of
the first anesthetic agent eg, IV Propofol induction. The end time of general
anesthesia will be equal to the time of extubation or equivalent).”
Inclusion 9: added statement that contraception required for seven days post
surgery; changed statement in 9b from “three days” to “seven days”; deleted
“equivalent to five half-lives”.
Section 5.2.2.Exclusion Criteria
Exclusion 4: added wording to be consistent with wording in Section 9.4.: “has

persistent or recurrent nausea and/or vomiting due to other etiologies, or has
experienced emesis or uncontrolled nausea at any time during the 24 hours prior
to scheduled receipt of the investigational product and study medication”
Exclusion 11: added mirtazapine and olanzapine to list of excluded medications
Exclusions 12 and 13: added “These medications are also prohibited for 72 hours
following the administration of GW679769.”
Section 6.1.Demographic and Baseline Assessments
Deleted triglyceride and bicarbonate from the list of required tests
Section 6.3.3.Antiemetic Rescue Therapy
Third paragraph: deleted statement “if three emetic episodes occur within a 15
minute period”
Section 10.2.Subject Withdrawal
Deleted instructions to discontinue from the study patients who require placement
of NG/OG tube with suctioning (was fourth paragraph).
Section 12.3.2.2. Other Comparisons of Interest
Deleted the sentence “If the primary comparison is statistically significant, then
no adjustments will be made for secondary analysis.”
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Section 12.1.Hypotheses
Corrected definitions of Arm A and Arm B: “The primary objective of this study
is to demonstrate the superiority of oral GW679769 given in combination with
4mg IV ZOFRAN [B] over 4mg IV ZOFRAN [A] alone”.
Section 12.3.1.Analysis Populations
Removed “had at least one post-surgical efficacy assessment” from the definition
of the MITT
Section 12.3.4.4. Multiplicity
Changed to read: “This study has one primary endpoint, which will be tested at
24 hours. If the primary endpoint is significant, pre-specified secondary
endpoints (specified in the statistical analysis plan) will be tested hierarchically
Appendix 5 Laboratory Tests
Deleted triglyceride and bicarbonate from the list of required tests
Appendix 9
Under “Miscellaneous”, added superscript 1 to grapefruit juice
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American Society of Anesthesiologists (ASA) Physical Status

Classification System
Category Status Description
P1 I A normal healthy patient
P2 II A patient with mild systemic disease
P3 III A patient with severe systemic disease
P4 IV A patient with severe systemic disease that is a constant threat to

life
P5 V A moribund patient who is not expected to survive without the

operation
P6 VI A declared brain-dead patient whose organs are being removed for

donor purposes
Reference: American Society of Anesthesiologists. ASA Physical Status Classification

System. http://www.asahq.org/clinical/physicalstatus.htm. Accessed 22 June 2004.
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CONFIDENTIAL ZM2006/00115/00
The GlaxoSmithKline group of companies NKT102553
Division: World Wide Development

Information Type: Reporting and Analysis Plan
Title: Reporting and Analysis Plan for NKT102553: A Phase III

Multicenter, Randomized, Double-blind, Parallel Group Study to
Evaluate the Safety and Efficacy of the 50 mg Oral Formulation
of the Neurokinin-1 Receptor Antagonist GW679769 for
Prevention of Postoperative Nausea and Vomiting in Female
Subjects at High Risk for Emesis
Effective Date: 15-SEP-2006
Description: Nausea and vomiting are among the most common and distressing adverse
effects of surgery and the incidence of these adverse effects may influence the quick
return of individuals to daily activities after surgery. Casopitant is a potent and selective
neurokinin, subtype I (NK-1) receptor antagonist with demonstrated activity in phase II
clinical trials in post-operative nausea and vomiting. This document describes the
statistical analyses plan for study NKT102553. The objective of this study is to
demonstrate the superiority of a single dose of oral casopitant when administered in
combination with ondansetron hydrochloride over ondansetron hydrochloride alone in the
prevention of post-operative nausea and vomiting (PONV) in female subjects with
known risk factors for PONV who are undergoing surgical procedures associated with an
increased emetogenic risk.
Identifier/Version Number: ZM2006/00115/00
Subject: PONV, Emesis, Nausea
Author’s Name, Title and Functional Area:
Approved by: (captured via email)

Unauthorised copying or use of this information is prohibited.
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TABLE OF CONTENTS
PAGE
ABBREVIATIONS ...........................................................................................................4
MODIFICATIONS............................................................................................................4
1. INTRODUCTION......................................................................................................5
2. STUDY OBJECTIVE(S) AND ENDPOINT(S) ...........................................................5

2.1. Study Objective(s) ........................................................................................5
2.2. Study Endpoint(s) .........................................................................................5
2.3. Statistical Hypotheses...................................................................................6
3. STUDY DESIGN ......................................................................................................7
4. PLANNED ANALYSES ............................................................................................7

4.1. Interim Analyses ...........................................................................................7
4.2. Final Analysis ...............................................................................................7
5. SAMPLE SIZE CONSIDERATIONS .........................................................................7
6. ANALYSIS POPULATIONS .....................................................................................7
7. TREATMENT COMPARISONS................................................................................8
7.1. Data Display Treatment and Other Sub-group Descriptors ...........................8
8. GENERAL CONSIDERATIONS FOR DATA ANALYSES.........................................8

8.1. Multicentre Studies .......................................................................................8
8.2. Other Strata and Covariates .........................................................................8
8.3. Examination of Subgroups............................................................................8
8.4. Multiple Comparisons and Multiplicity ...........................................................9
9. DATA HANDLING CONVENTIONS .........................................................................9

9.1. Premature Withdrawal and Missing Data ......................................................9
9.2. Derived and Transformed Data.....................................................................9
9.3. Values of Clinical Concern..........................................................................10
10. STUDY POPULATION ...........................................................................................10

10.1. Disposition of Subjects................................................................................10
10.2. Protocol Deviations.....................................................................................10
10.3. Demographic and Baseline Characteristics.................................................11
10.4. Treatment Compliance................................................................................12
11. EFFICACY ANALYSES..........................................................................................12

11.1. Primary Efficacy Analysis............................................................................12
11.2. Secondary Efficacy Analyses...................................................................... 12
12. SAFETY ANALYSES .............................................................................................13

12.1. Extent of Exposure .....................................................................................13
12.2. Adverse Events...........................................................................................13
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12.3. Deaths and Serious Adverse Events........................................................... 13

12.4. Device Incidents and Near Incidents...........................................................14
12.5. Adverse Events Leading to Discontinuation of Investigational
Product and/or Withdrawal from the Study and Other Significant
Adverse Events...........................................................................................14
12.6. Pregnancies (as applicable)........................................................................ 14
12.7. Clinical Laboratory Evaluations...................................................................14
12.8. Vital Signs...................................................................................................18
12.9. Time to awakening......................................................................................18
13. HEALTH OUTCOMES ANALYSES ........................................................................18

13.1. Subject Satisfaction ....................................................................................18
13.2. Subject Willingness.....................................................................................19
13.3. Medical Resource Utilization.......................................................................19
14. REFERENCES.......................................................................................................20
15. ATTACHMENTS ....................................................................................................21

15.1. Data Display Specifications ........................................................................ 22
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ABBREVIATIONS
AE Adverse Event
ANC Absolute Neutrophil Count
CPK/MS Clinical Pharmacokinetic/Modeling and Simulations
e-diary Electronic diary
ITT Intent-to-treat
IV Intravenous
MITT Modified intent-to-treat
PD Pharmacodynamics
PDNV Post-Discharge Nausea and Vomiting
PK Pharmacokinetic
PONV Post-Operative Nausea and Vomiting
RAP Report Analysis Plan
SAE Serious adverse event
SOC System Organ Classification
MODIFICATIONS
DATE MODIFICATION
3-Nov-2006 Deleted Table 6.8 (Summary of PONV Risk Factors) and
renumbered tables.
1-May-07 Added template information such as “Approved by:” etc.
Trademark Information
Trademarks of the GlaxoSmithKline Trademarks not owned by the

group of companies GlaxoSmithKline group of companies
ZOFRAN
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1. INTRODUCTION
The analysis described herein is intended to support the registration trial of 50mg oral
casopitant for Post-operative Nausea and Vomiting (PONV). The content of this RAP is
based on document number UM2005/00121/02 issued on 17 April 2006.
2. STUDY OBJECTIVE(S) AND ENDPOINT(S)
2.1. Study Objective(s)

This study has two treatment arms as shown below:
• A: 4mg IV Zofran
• B: 4mg IV Zofran + 50mg oral casopitant
The primary objective of this study is to demonstrate the superiority of treatment arm B
over treatment arm A in the control of emesis during the first 24 hours following
placement of the last suture/staple in surgical subjects who are predicted to have a high
risk of emesis.
2.2. Study Endpoint(s)

The primary endpoint of this study is complete response (CR), defined as no
vomiting/retching and no anti-emetic rescue medications during the first 24 hours
following placement of the last suture/staple.
Note: The Likert scale (0 – 10) referred to in the protocol is really an 11 point numerical
rating scale. To keep the language between the protocol and the RAP consistent, it will
continue to be referred to as a Likert scale in the RAP.
The secondary endpoints are:
1. Vomiting: regardless of use of anti-emetic rescue medication.
2. Nausea: defined as a score of greater than or equal to 1 on the 11-point Likert

scale.
3. Significant nausea: defined as a score of greater than or equal to 3 on the 11-point

Likert scale.
4. Maximum nausea score from the Likert scale.
5. Categorical nausea rating: None, mild, moderate and severe.
6. Complete Protection: Complete response and no significant nausea.
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7. Total Control: Complete response and no nausea.
8. Time to first emetic event.
9. Time to first rescue.
10. Subject satisfaction with study medication.
11. Subject willingness to use study medication.
2.3. Statistical Hypotheses

The primary hypothesis of this study is:
• Null hypothesis: There is no difference in the complete response rates between the
two treatment arms in the first 24 hours following placement of last suture/staple;
i. e.
H0: pA = pB
• Alternate hypothesis: The two treatments differ, i. e.
H1: pA ≠ pB,
where, pA and pB represent the proportion of complete responders in the treatment arms A
and B respectively. Testing will be conducted at the 5% level of significance.
There are several secondary hypotheses for this study. These will be tested hierarchically
as given below. For brevity, only the hypotheses that are not similar to the primary
hypotheses will be presented in detail.
Secondary hypothesis hierarchy:
1. No vomiting (similar to primary hypothesis).
2. Complete protection (similar to primary hypothesis).
3. Maximum nausea score:
o Null hypothesis: There is no difference in the distribution of maximum

nausea scores between the two treatment arms in the first 24 hours
following placement of last suture/staple, and
o Alternate hypothesis: The two treatments differ in the distribution of the

maximum nausea scores.
4. Total control (similar to primary hypothesis).
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Secondary hypotheses will be tested in the order shown above at the 5% level of
significance till a hypothesis fails to meet statistical significance at the 5% level of
significance. Once this point is reached, all subsequent hypotheses will not be tested.
3. STUDY DESIGN
This is a phase III, multicenter, randomized, double-blind, active-controlled, two arm
4. PLANNED ANALYSES
Prior to database freeze a formal review of the protocol violations will be conducted on
the blinded data. Once the protocol violations have been identified, the database will be
frozen. The treatment information will then be unblinded in RANDALL (GSK’s
randomization tool) and merged with the subject information.
4.1. Interim Analyses

No interim analyses are planned for this study.
4.2. Final Analysis

Prior to database freeze a formal review of the protocol violations will be conducted on
the blinded data. Once the protocol violations have been identified, the database will be
frozen. The treatment information will then be unblinded in RANDALL (GSK’s
randomization tool) and merged with the subject information. The formal statistical
analysis will then be conducted.
5. SAMPLE SIZE CONSIDERATIONS

See Section 11.2 of the protocol (UM2005/00121/00) for a detailed discussion.
6. ANALYSIS POPULATIONS
The intent-to-treat (ITT) population is defined as all subjects who are randomized to one
of two anti-emetic treatment regimens. The ITT population will be used to summarize the
study population and also to confirm the results of the primary analysis.
The primary population of interest is the modified intent-to-treat (MITT) population. This
population is the subset of the ITT population that received any investigational product
and had surgery. Subjects will be excluded from this population only if there is
documented evidence that no casopitant investigational product (either active or placebo)
was administered or there was no surgery. The MITT population will be used to carry out
the efficacy analysis.
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The safety population will be a subset of the ITT population that received casopitant
investigation product (either active or placebo). Subjects will be excluded from this
population only if there is documented evidence that no casopitant investigational
product (either active or placebo) was administered. This population will be used to
create safety reports. The safety reports are based on the actual treatment the subject
received not the treatment that they were randomized to.
7. TREATMENT COMPARISONS
All treatment comparisons will be between casopitant 50mg oral given in combination
with Zofran versus Zofran alone.
7.1. Data Display Treatment and Other Sub-group Descriptors

NA
8. GENERAL CONSIDERATIONS FOR DATA ANALYSES

This study will be conducted through GlaxoSmithKline's electronic data capture system.
Subject data will be collected by the investigator or designee using the web based Case
Report Form (Inform) defined by GSK. Subject data necessary for analysis and reporting
will be entered into a validated database or data system. Clinical data management will
be performed in accordance with applicable GSK standards and data cleaning procedures.
Database freeze will occur when data management quality control procedures are
completed.
Subjects will report episodes of vomiting, nausea etc. in an electronic diary (eDiary).
8.1. Multicentre Studies

This trial will use a randomization that assigns subjects to treatment groups based on a
single, central allocation scheme across centers. Therefore, no adjustments will be made
for center, and a treatment-by-center interaction will not be examined.
8.2. Other Strata and Covariates
The randomization of this study is stratified by anticipate nitrous oxide use. The primary
analysis will thus be adjusted for this stratification.
8.3. Examination of Subgroups

No subgroup analyses are planned.
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8.4. Multiple Comparisons and Multiplicity

This study has a single primary objective and as such is planned on one primary endpoint.
For the primary analysis, this endpoint will be tested at 24 hours at the 5% level of
significance. There are several secondary endpoints for this study. A subset of these will
be tested hierarchically at a 5% level of significance, provided the primary endpoint
meets statistical significance, as laid out in section 2.3.
9. DATA HANDLING CONVENTIONS
NA
9.1. Premature Withdrawal and Missing Data

All premature discontinuations from the study will be tabulated by reason for
discontinuation. Subjects who either receive rescue medication or withdraw from the
study during an assessment period will be considered to be treatment failures for that
period. However, subjects who receive rescue medication may remain in the study and
continue to have safety and efficacy assessments performed. Withdrawal reports will be
based on the ITT population.
If data are missing then a conservative approach will be taken and an event occurrence
will be assumed. For response rates, this would translate to a failure. The time of event
will be taken to be the last point of contact.
9.2. Derived and Transformed Data

Efficacy endpoints will be derived as follows:
• Complete response - no vomiting/retching and no rescue therapy.
• Complete protection - no vomiting/retching, no rescue therapy and maximum

nausea < 3 on the Likert scale.
• Total control - no vomiting/retching, no rescue therapy and a maximum nausea <

1 on the Likert scale.
• Vomiting - vomit or retch, but may include subjects who have received rescue
therapy.
• Significant nausea - maximum nausea score greater than or equal to 3 on the

Likert scale for nausea from all nausea assessments.
• Nausea - maximum nausea score greater than or equal to 1 on the Likert scale for
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All endpoints will be assessed in the following time windows: 0 – 24, 24 – 48 and 0 – 48
hours following placement of the last suture/staple. Nausea will also be assessed in the
following time windows: 0 – 2 and 0 – 6 hours.
Additionally, the following endpoints will be analyzed:
• Time to first emetic event – is the length of time from placement of the last
suture/staple until the time of the first emetic event. If a subject withdraws
prematurely during the first 48 hours, then the time of withdrawal will be
considered to be their first emetic episode, and will be censored.
• Time to rescue medication – is the length of time from placement of the last
suture/staple until the time of the first use of rescue medication. If a subject
withdraws prematurely during the first 48 hours, then the time of withdrawal will
be considered to be their time to first use of antiemetic rescue medications, and
will be censored.
• Time to awakening – the time interval from the placement of last suture/staple
until the time the subject can understand and obey a command.
9.3. Values of Clinical Concern

Number and proportion of subjects with clinically significant abnormalities of laboratory
values (chemistry and haematology) will be tabulated. The values of concern are GSK
defined (see section 12.7).
10. STUDY POPULATION
10.1. Disposition of Subjects

For each treatment group, the number and percentage of subjects who completed the
study as well as those subjects who were in the ITT, MITT, and safety populations will
be tabulated. The number and percentage of subjects in each treatment group, who
withdrew from the study early, along with the reasons for withdrawal, will be tabulated.
A supportive listing will be generated.
10.2. Protocol Deviations

Subjects in the study that violated inclusion/exclusion criteria will be classified as
protocol deviations. In addition to the inclusion/exclusion criteria protocol violators, the
following protocol deviations will be summarized:
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Definition Major Protocol

Violation
GW679769 No study medication given. Yes
Anesthetic No opioids post-operatively. Yes

regimen
Anesthesia < 45 mins. Duration. Yes
eDiary Did not return diary. Yes
Did not complete day 1 diary. Yes
Prohibited Received other prohibited medications within 48 hours Yes

Medication after last suture/staple.
Wrong Subject took wrong medication. Yes

medication
Surgery No surgery performed. Yes
NG tube NG tube place and suction applied. Yes
Anti-emetic Received anti-emetic medications other than rescue Yes

medication prior to or within 48 hours after last suture/staple.
A tabular summary and a supportive listing will be provided.
10.3. Demographic and Baseline Characteristics

Demographic characteristics of age, race, ethnicity, height, and weight will be
summarized.
Other baseline characteristics such as vital signs, ASA physical status, current medical
conditions and smoking history also will be summarized.
For continuous variables, the mean, standard deviation, median, minimum and maximum
will be presented. Categorical data will be summarized using counts and percentages.
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10.4. Treatment Compliance

Treatment compliance for ondansetron hydrochloride will be calculated as follows:
• Since ondansetron hydrochloride is administered at site on Day 1 only, the

compliance for ondansetron hydrochloride will be considered to be 0% or 100%,
depending on whether there was an entry in the date and dose box of the
ondansetron hydrochloride panel of the eCRF.
Treatment compliance for casopitant will be calculated as follows:
• Since casopitant is administered at site on Day 1 only the compliance for

casopitant will be considered to be 0% or 100% depending on whether there was
an entry in the date and dose box of the casopitant panel of the eCRF.
11. EFFICACY ANALYSES
11.1. Primary Efficacy Analysis

The primary analysis will compare:
• 50mg oral casopitant in combination with 4mg IV Zofran to 4mg IV Zofran alone.
Testing will be conducted at a 5% level of significance.
The Cochran-Mantel-Haenszel test which adjusts for the stratification factors (anticipated
intra-operative nitrous oxide use) will be used to make comparisons. A p-value will be
reported. A 95% confidence interval for the odds ratio will be provided.
11.2. Secondary Efficacy Analyses

See Section 9.2 for a detailed description of the secondary efficacy endpoints. If the
primary comparison is significant, then the secondary endpoints will be tested at the 5%
level of significance and 95% confidence intervals will be presented hierarchically as laid
out in Section 2.3.
Complete response in 24 – 48 and 0 – 48 will be analyzed as described in Section 11.1

above.
The other secondary efficacy analysis variables can be grouped into three types:
1. Proportion of successes for each treatment arm will be tabulated. The Cochran-
Mantel-Haenszel test which adjusts for the stratification factors will be used to make
comparisons. A p-value will be reported and 95% confidence intervals will be
provided. This analysis will be carried out in periods 0 – 24, 24 – 48 and 0 - 48, for
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the following endpoints: Complete protection, Total control, Vomiting, Significant

nausea, Nausea.
2. Time-to-event endpoint (time to first emetic event and time to first rescue
medication) will be summarized using Kaplan-Meier curves. Time-to-event data will
be summarized using quantiles (25th percentile, median and 75th percentile) and the
associated 95% confidence intervals. Log-rank p-values also will be calculated. If no
event has occurred at the end of the 48 hour time period, then the observation will be
censored for the purpose of this analysis.
3. The maximum nausea score will be analysed by using a Wilcoxon Rank Sum test.
Summary statistics (mean, standard deviation, median etc.) and a p-value will be
reported.
4. The categorical nausea score (none, mild, moderate and severe) will be analysed
using a non-zero correlation test. Proportions in each category will be tabulated and a
p-value will be reported.
12. SAFETY ANALYSES
12.1. Extent of Exposure

For each treatment arm, counts and percentages of subjects who were randomized and
treated will be displayed.
12.2. Adverse Events

All adverse events will be coded using the MedDRA dictionary. Adverse events data will
be presented using the system organ classification (SOC) and preferred term. Adverse
events will be summarised based on the number and percentage of subjects experiencing
a given adverse event. Adverse events will also be assessed by maximum intensity. All
adverse events reported from the administration of GW679769 IP to study conclusion
will be included in the tabulation.
All drug-related adverse events reported in the case report form will be tabulated in a
similar manner as above. The study investigator will assess each adverse event as related
to drug or not. The tabulation will be based on the number and percent of subjects
experiencing a drug-related adverse event.
12.3. Deaths and Serious Adverse Events

All deaths occurring any time from the time of informed consent to study conclusion will
be summarized based on the number and percentage of subjects. A supportive listing will
be generated to provide subject-specific details on subjects who died and the reason for
death.
All serious adverse events (SAEs) reported during the interval from informed consent to
study conclusion will be tabulated based on the number and percentage of subjects.
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12.4. Device Incidents and Near Incidents

Not applicable.
12.5. Adverse Events Leading to Discontinuation of

Investigational Product and/or Withdrawal from the Study
and Other Significant Adverse Events
Subjects who withdraw due to due adverse events will be summarised in a manner
consistent with Section 12.2. A supportive listing will be generated with subject level
details for those subjects who withdrew from the trial and the reason for discontinuation
from the study.
12.6. Pregnancies (as applicable)

A table and listing of female subjects who become pregnant will be provided.
12.7. Clinical Laboratory Evaluations

See also section 9.3.
Hematology Labs: Summary tables displaying the mean, standard deviation, median,
minimum and maximum will be presented for each clinical hematology labs by treatment
group and visit. Tables displaying the number and proportion of subjects with toxicity
grade shifts from baseline will also be presented.
Additionally, tables displaying proportion of subjects whose hematology labs fall outside
the normal ranges will also be provided. The local laboratory reference ranges will be
used:
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AUTOMATED CBC WITH DIFFERENTIAL -- SI UNITS
QUEST REFERENCE RANGES SHIFT FROM BASELINE (F2) CLINICAL CONCERN VALUES (F3)
ANALYTE UNITS (CONVERTED TO SI UNITS)*
*NOTE: Quest references ranges are only included in this table as a guide. F2 and F3 flags that are based on a proportion of the normal range are generated from the
lab that analyzed each individual patient, in which case the ranges may vary somewhat. (Some labs provide normal ranges and results in conventional units which are
converted by GSK to SI units.
HEMOGLOBIN G/L 120-156 (18-64yr) Shift in CTC Grade < 0.8 x LLN (low) or > 1.2 x ULN (high)
HEMATOCRIT 1 0.350-0.460 (18-64yr) Shift in CTC Grade < 0.8 x LLN (low) or > 1.2 x ULN (high)
CONFIDENTIAL
WHITE CELL COUNT GI/L 3.8-10.8 (18+yr) Shift in CTC Grade < 3.0 GI/L (low) or ≥ 15 GI/L (high)
NEUTROPHILS, TOTAL % 40.0-75.0 (18+yr) Shift in CTC Grade No value of concern

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NEUTROPHILS, BANDS % 0.0-8.0 (18+yr) Shift in CTC Grade No value of concern
LYMPHOCYTES % 16.0-46.0 (18+yr) NA No value of concern
MONOCYTES % 0.0-12.0 (18+yr) NA No value of concern
EOSINOPHILS % 0.0-7.0 (18+yr) Shift in CTC Grade > 14% (high)
BASOPHILS % 0.0-2.0 (0+yr) NA > 5% (high)
PLATELET COUNT GI/L 130-400 (1+yr) Shift in CTC Grade < 75 (low) or > 600 (high)
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• The following analytes will be summarized: Total WBC, WBC differential

(basophils, eosinophils, lymphocytes and neutrophils),hemoglobin, platelets, and
hematocrit.
Clinical Chemistry Labs: Summary tables displaying the mean, standard deviation,
median, minimum and maximum will be presented for each clinical chemistry labs by
treatment group and visit. Tables displaying the number and proportion of subjects with
toxicity grade shifts from baseline will also be presented.
Additionally, tables displaying proportion of subjects whose chemistry labs fall outside
the normal ranges will also be provided. The local laboratory reference ranges will be
used:
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CHEMISTRY PANEL -- SI UNITS

QUEST REF RANGES SHIFT FROM BASELINE (F2) CLINICAL CONCERN VALUES (F3)
ANALYTE UNITS (CONVERTED TO SI UNITS)*
*NOTE: Quest references ranges are only included in this table as a guide. F2 and F3 flags that are based on a proportion of the normal range are generated from the
lab that analyzed each individual patient, in which case the ranges may vary somewhat. (Some labs provide normal ranges and results in conventional units which are
converted by GSK to SI units.
ALT (SGPT) U/L 0-48 (13+yr) Shift in CTC Grade 2.5 x ULN (high)
ALBUMIN G/L 32-50 (3+yr) Shift in CTC Grade > 5 below LLN (low) or > 10 above ULN (high)
ALKALINE PHOS. U/L 30-165 (16-19yr) Shift in CTC Grade 2.5 x ULN (high)
20-125 (20+yr)
CONFIDENTIAL
AST (SGOT) U/L 0-42 (3-64yr) Shift in CTC Grade 2.5 x ULN (high)
UREA MMOL/L 2.1-7.1 (13-64yr) Shift in CTC Grade >20 (high)

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BUN MMOL/L 2.1-7.1 (13-64yr) Shift in CTC Grade >20 (high)
CREATININE UMOL/L 44-124 (13+yr) Shift in CTC Grade > 1.5 ULN (high)
SODIUM MMOL/L 135-146 (0+yr) Shift in CTC Grade < 130 (low) or ≥ 155 (high)
POTASSIUM MMOL/L 3.5-5.3 (13+yr) Shift in CTC Grade ≤ 3.0 (low) or > 6 (high)
CHLORIDE MMOL/L 95-108 (0+yr) NA NA
GLUCOSE MMOL/L 3.9-6.4 (13-49yr) Shift in CTC Grade < 2.2 (low) or ≥ 9 (high)
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3.9-6.9 (50+yr)
BILIRUBIN, TOTAL UMOL/L 0-22 (1+yr) Shift in CTC Grade > 1.5 x ULN (high)
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PROTEIN, TOTAL G/L 60-85 (13-64yr) NA > 15 below the LLN (low) or > 15 above the ULN (high)
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12.8. Vital Signs

A summary of vital signs displaying the mean, standard deviation, median, minimum and
maximum, at each planned time will be produced.
12.9. Time to awakening

Time to awakening will be summarized descriptively using the mean, standard deviation,
median, minimum and maximum. Subjects with a negative time to awakening will not be
included if it appears that the negative number was the result of an error in recording date
and/or time and that there is no evidence that suggests that the subject actually woke up
prior to the end of surgery. Also, subjects whose time to awakening is greater than 1 day
will be scrutinized and may not be included if an error in date and/or time is apparent and
there is no evidence that the subject actually had a delay in awakening.
13. HEALTH OUTCOMES ANALYSES
13.1. Subject Satisfaction

A Subject satisfaction questionnaire is included in the subjects' eDiary. Subjects will
complete this assessment on post-operative Day 2. Subjects are asked to rate overall
satisfaction with study medications in preventing post-operative nausea and vomiting,
using the following 5-point scale:
1 = Very satisfied
2 = Somewhat satisfied
3 = Neither satisfied nor dissatisfied
4 = Somewhat dissatisfied
5 = Very dissatisfied
A descriptive data analysis of the subject satisfaction questionnaire will be performed.

Frequencies and percentages of each satisfaction category will be presented for each
treatment arm.
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13.2. Subject Willingness

A Subject willingness questionnaire is included in the subjects' eDiary. Subjects will
complete this assessment on post-operative Day 2. Subjects are asked to rate overall
willingness to use study medications in preventing post-operative nausea and vomiting,
using the following 5-point scale:
1 = Definitely would be willing
2 = Probably would be willing
3 = Not certain
4 = Probably would not be willing
5 = Definitely would not be willing
A descriptive data analysis of the subject willingness questionnaire will be performed.

Frequencies and percentages of each willingness category will be presented for each
treatment arm.
13.3. Medical Resource Utilization

Health care related contacts made by subjects will be summarized using counts and
percentages. The following resource use:
• Number of emergency room visits
• Number of home healthcare visits
• Number of hospitalization days
• Number of medical specialist visits
• Number of nurse practitioner/p. a./nurse visits
• Number of primary care physician visits
• Number of telephone calls
will be summarized using summary statistics such as, mean, standard deviation,
minimum, maximum and the median.
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14. REFERENCES
20
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15. ATTACHMENTS
Table of Contents for Data Display Specifications available on request.
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15.1. Data Display Specifications

Available on request.
22
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CONFIDENTIAL
NKT102553
Synopsis
Identifier: GM2006/00652/00 Study Number: NKT102553
Title: A Phase III, Multicenter, Randomized, Double-blind, Parallel Group Study to

Evaluate the Safety and Efficacy of 50mg Oral Dosing with the Neurokinin-1 Receptor
Antagonist GW679769 for the Prevention of Postoperative Nausea and Vomiting in
Female Subjects at High Risk for Emesis.
Investigators: Multicenter study.
Study centers: 43 centers across 11 countries recruited subjects.
Publications: None at the time of report writing.
Study Period: 20 March 2006 – 31 August 2006 Phase of Development: III
Objectives: The primary objective was to demonstrate the superiority of 50mg oral
GW679769 (casopitant), in combination with a single 4mg IV dose of Zofran™
(ondansetron hydrochloride), over a single 4mg IV dose of Zofran alone in the control of
emesis during the first 24 hours following the placement of last suture/last staple (as
measured by complete response, defined as no vomiting, no retching, and no rescue
medications) in surgical subjects who were predicted to have a high risk of emesis.
The secondary objectives of this clinical trial were to:
• Assess the control of emesis in the 24–48 hour period following the placement of last
suture/last staple.
who were predicted to have a high risk of emesis.
Methodology: This was a randomized, double-blind, active-controlled, two arm parallel
group study. The screening phase took place within 21 days prior to GW679769
(casopitant) investigational product/Zofran study medication. Study Day 1 included
administration of investigational product and study medication, surgery, induction and
discontinuation of anesthesia, and incorporated pre-treatment, peri-operative, intra-
operative and postoperative assessments as well as post-discharge interim assessments (if
applicable). The subject returned to the investigational site 6–14 days after surgery for a
final follow-up. Subjects were stratified to treatment assignments by anticipated use of
intra-operative nitrous oxide. A Subject Diary included assessments of nausea, vomiting,
and subject satisfaction. Subjects who required antiemetic rescue medication(s) during
the 24 hours following placement of the last suture/staple were considered treatment
failures. Antiemetics were dosed per the following table.
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CONFIDENTIAL
NKT102553
Cohort Medication Route Timing (Prior to Induction of Anesthesia) Dose

A (Zofran alone GW679769 placebo oral ∼60 minutes prior 0mg
group) Zofran IV (2-5 min) Immediately prior 4mg
B (casopitant GW679769 oral ∼60 minutes prior 50mg
group) Zofran IV (2-5 min) Immediately prior 4mg
Number of subjects: Subject disposition is summarized in the table below.
Number of Subjects Zofran Alone Casopitant (+ Zofran) Total

Planned, N 231 231 462
MITT 1, N 235 233 468
Randomized (ITT), N 242 242 484
Completed, n (%) 229 (95) 227 (94) 456 (94)
Total Withdrawn (any reason), n (%) 13 (5) 15 (6) 28 (6)
Withdrawn due to Adverse Events n (%) 0 0 0
Withdrawn due to Lack of Efficacy n (%) 0 0 0
Lost to Follow-Up, n (%) 3 (1) 4 (2) 7 (1)
Protocol Violation, n (%) 2 (<1) 1 (<1) 3 (<1)
Subject decided to withdraw, n (%) 1 (<1) 4 (2) 5 (1)
Withdrawn for other reasons n (%) 7 (3) 6 (2) 13 (3)
MITT = Modified Intent-to-Treat Population; ITT= Intent-to-Treat Population.
1. Defined as subjects who received any investigational product and had surgery.
Diagnosis and main criteria for inclusion: Female subjects aged ≥18 years, at high risk
for developing postoperative nausea and vomiting (PONV), scheduled to undergo one of
the following procedures: breast surgery, orthopedic shoulder surgery, or thyroid
surgery. The following laparoscopic or laparotomic procedures were also permitted:
cholecystectomy, hysterectomy, or other gynecologic surgery. All surgeries were
anticipated to involve general anesthesia of at least 1 hour duration. All subjects had the
following Apfel significant risk factors: female gender; history of PONV and/or motion
sickness; had not smoked or used tobacco for at least the previous 6 months; anticipated
to receive postoperative opioids.
Treatment administration: GW679769 (casopitant) 50mg tablets for oral

administration (batch numbers or
matching placebo tablets (batch number Zofran Injection 2mg/mL solution
(ondansetron hydrochloride 4mg).
Criteria for evaluation: Efficacy information pertaining to emesis, assessments of

nausea, subject satisfaction/willingness was collected at least every 24 hours until the end
of the 48-hour assessment period, using a Subject Diary. Subjects were followed for
safety at least every 24 hours during the 48-hour assessment period following last
suture/staple, with additional follow-up 6 to 14 days postoperatively.
Statistical methods: The primary efficacy analysis compared the treatment groups for
complete response 0–24 hours in the MITT population (ITT was a supportive
population). Testing was conducted at the 5% level of significance using the Cochran-
Mantel-Haenszel test (stratified by anticipated intra-operative nitrous oxide use).
P values, odds ratios and 95% confidence intervals (CIs) were reported.
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NKT102553
Secondary hypotheses (0–24 hours) were tested hierarchically in the following order: no
vomiting; complete protection; maximum nausea score; and total control. Once a
hypothesis failed to meet significance, all subsequent hypotheses were not tested.
Beyond this point, p values may be provided for descriptive purposes only. Secondary
efficacy analyses: 1) The Cochran-Mantel-Haenszel test was used for complete response,
complete protection, total control, vomiting, significant nausea, and nausea. 2) Time to
emesis and time to rescue were summarized using Kaplan-Meier estimates. 3) Maximum
nausea score was analyzed using a Wilcoxon Rank Sum test. 4) Categorical nausea score
was analyzed using a non-zero correlation test.
Summary: Efficacy: The proportion of subjects achieving the primary endpoint of

complete response over 0–24 hours was significantly greater in the casopitant group than
in the Zofran alone group, as indicated by a Cochran-Mantel-Haenszel test p value <0.05
in the MITT population (see table below).
Zofran Alone Casopitant (+ Zofran)

MITT Population N=235 N=233
n/N (%) n/N (%)
Complete response 0–24 hours 138/235 (59) 160/233 (69)
A significant increase of 15% (in absolute terms) was seen in the proportion of subjects
with no vomiting in the casopitant group (90%) compared with Zofran alone (75%) over
0-24 hours. Similar proportions achieved complete protection over 0–24 hours in the
casopitant (52%) and Zofran alone (43%) groups (not significant). Therefore, hypothesis
testing stopped at this point, and was not carried out for nausea and total control.
Mean (standard deviation) maximum nausea score on a discrete Likert scale was 3.2 (3.4)
in the Zofran alone group and 2.6 (3.2) in the casopitant group over 0–24 hours. Total
control over 0–24 hours was achieved by 40% of subjects in the Zofran alone group and
46% in the casopitant group. Over 0–24 hours, severe nausea on the categorical scale
was reported by 16% in the Zofran alone group and 9% in the casopitant group.
Complete response was achieved by 63% in the Zofran alone group and 70% in the
casopitant group over 24–48 hours, and by 57% and 65%, respectively, over 0–48 hours.
Time to first emetic episode was greater in the casopitant group than in the Zofran alone
group.
Safety: One hundred and eighty-two of 472 subjects (39%) in the Safety population
experienced at least one AE. Overall AE frequency was similar in both treatment groups.
In particular, liver function test abnormalities were reported as AEs in a similar
proportion of subjects in each group. Fifteen subjects had increased AST, ALT,
transaminases or abnormal liver function test reported as an AE: seven in the Zofran
alone group and eight in the casopitant group. Constipation and hypotension were
reported in a greater proportion of subjects in the casopitant group than in the Zofran
alone group. Twenty-seven subjects (6%) had hypotension or procedural hypotension,
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NKT102553
10 subjects in the Zofran alone group and 17 in the casopitant group. The most
frequently reported AEs are summarized below.
Zofran Alone Casopitant (+ Zofran)

Most Frequent AEs On-Therapy N=237 N=235
n (%) n (%)
Subjects with any AE 87 (37) 95 (40)
Any AE possibly related to treatment 13 (5) 14 (6)
Most Frequent AEs
(>1% of subjects in either group)
Flatulence 12 (5) 11 (5)
Hypotension 8 (3) 15 (6)
Headache 11 (5) 8 (3)
Anemia 5 (2) 6 (3)
Cough 5 (2) 5 (2)
Insomnia 4 (2) 6 (3)
Nausea 4 (2) 6 (3)
Pruritus 5 (2) 4 (2)
Urinary retention 3 (1) 5 (2)
ALT increased 4 (2) 3 (1)
AST increased 4 (2) 3 (1)
Hypertension 5 (2) 2 (<1)
Diarrhea 4 (2) 2 (<1)
Procedural hypotension 1 2 (<1) 2 (<1)
Liver function test abnormal 1 1 (<1) 1 (<1)
1. These events were included to present a complete picture of hypotension and liver function test abnormalities.
ALT=alanine aminotransferase; AST=aspartate aminotransferase.
The treatment groups were balanced with regard to AE profile by intensity (mild,
moderate or severe). Twelve subjects in the study (3%) experienced at least one AE of
severe intensity, six subjects in each group. The most frequently reported AEs of severe
intensity were constipation, occurring in two subjects (<1%) in the casopitant group and
musculoskeletal pain, occurring in one subject (<1%) in each group.
Eleven subjects (2%) had at least one SAE reported; none was fatal or considered related
to investigational product by the investigator. There were no withdrawals due to AEs.
No meaningful differences in hematology or clinical chemistry values were observed

among the two groups. One subject in the Zofran alone group had an alanine
aminotransferase (ALT) value ≥3x ULN (118 IU/L; normal range: 0–34 IU/L) with a
concomitant total bilirubin value ≥1.5x ULN (33.6 µmol/L; normal range: 5–21 µmol/L)
on Postoperative Day 1/2 (Study Day 2). The subject also had an aspartate
aminotransferase (AST) value ≥3x ULN (108 IU/L; normal range 0-31 IU/L). Ten
additional subjects had ALT values ≥3x ULN without concomitant bilirubin elevations,
six in the casopitant group (one with an AE of increased transaminases) and four in the
Zofran alone group (one with an AE of increased transaminases).
No notable treatment differences were observed for vital signs values. Clinically
significant abnormal ECG findings were reported in less than 1% of subjects. At
Screening, one subject in the casopitant group had a clinically significant abnormal ECG
-4
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CONFIDENTIAL
NKT102553
finding. On Postoperative Day 1/2, two subjects in the casopitant group had a clinically
significant abnormal ECG finding, and none in the Zofran alone group. Median time to
awakening after surgery was similar in the two treatment groups.
Health outcomes: Subject satisfaction and subject willingness to use the same regimens
for future surgical procedures (both over 0–48 hours) appeared similar in the two groups.
In terms of medical resource utilization, there appeared to be a greater proportion of
subjects with healthcare related contacts in general in the Zofran alone group (5.0%) than
in the casopitant group (2.1%).
Conclusions:
vs. 75%).
Zofran alone group (43%) for complete protection over 0–24 hours; therefore,
hypothesis testing was stopped at this point.
• Mean (standard deviation) maximum Likert scale nausea score 0–24 hours was
3.2 (3.4) in the Zofran alone group and 2.6 (3.2) in the casopitant group.
• Total control over 0–24 hours was achieved by 40% of subjects in the Zofran alone
group and 46% in the casopitant group.
emesis.
biochemistry) nor in vital signs and ECG among treatment groups.
Date of Report: January 2008
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Annotated Trial Design Page 1 of 107
[Unspecified]
Annotated Design For Trial 'nkt102553_scm'
Protocol: NKT102553
Generated By InForm Architect®
CONFIDENTIAL
January 9, 2006 5:59AM
1
GM2006/00652/00
NKT102553
Time and Events Schedule For Trial 'nkt102553_scm'

Assessment CRF Screening/PreSurgical Pre and Peri-Op Post Operation Post Operation LOGS END Conflict
(SCREEN) Day 1 Study Day 1/2 Study Day 6-14 (LOGS) (END) (Conflict)
[S] (PRE/PERI-OP (POST OP DAY (POST OP DAY 6- [S] [S] [ U/R/D ]
DAY 1) 1/2) 14)
[S] [S] [S]
1 DATE OF VISIT/ASSESSMENT DOV 1 1 1 1 1 1
2 SUBJECT IDENTIFICATION SUB ID 2
3 ELIGIBILITY QUESTION ELIG 3
4 DEMOGRAPHY DEMOG 4
5 AMERICAN SOCIETY OF ANESTHESIOLOGISTS (ASA) ASA 5 2-DF

PHYSICAL STATUS (PS) CLASSIFICATION
6 MEDICAL CONDITIONS MEDHX 6
7 HISTORY OF TOBACCO USE TOBACCO 7

HISTORY
8 VITAL SIGNS VS 8
CONFIDENTIAL
9 12-LEAD ECG ECG 9
10 LOCAL LABORATORY - CLINICAL CHEMISTRY CHEM-SCR 10
11 LOCAL LABORATORY - HAEMATOLOGY HAEMA-SCR 11
12 VITAL SIGNS VS 3-DF 2 2

2
13 RANDOMISATION NUMBER RAND 4
14 INVESTIGATIONAL PRODUCT CONTAINER NUMBER PACK 5
15 INVESTIGATIONAL PRODUCT - GW679769 ORAL IP ORAL 6

DOSING
16 STUDY MEDICATION SM IV 7
17 SURGICAL PROCEDURES MEDSX 8
18 PERI-OPERATIVE MEDICATIONS PERI-OP 9-RF

MEDS
GM2006/00652/00
19 12-LEAD ECG ECG 3
20 LOCAL LABORATORY - CLINICAL CHEMISTRY CHEM 4 3
21 LOCAL LABORATORY - HAEMATOLOGY HAEM 5 4
NKT102553
22 Unscheduled Related Healthcare Utilisation HCU 5
23 PGx-PHARMACOGENETIC RESEARCH CONSENT GEN- 2

CONSENT
24 PGx-PHARMACOGENETIC RESEARCH WITHDRAWAL GEN-WD 3-DF
OF CONSENT
25 CONCOMITANT MEDICATIONS CONMEDS 4-RF
26 NON-SERIOUS ADVERSE EVENT AE 5-RF
27 SERIOUS ADVERSE EVENTS SAE 6-RF
28 STATUS OF TREATMENT BLIND BLIND 2
29 PREGNANCY INFORMATION PREG 3-DF
30 STUDY CONCLUSION CONC 4
Key: [S] = Scheduled Visit [O] = Optional Visit [D] = Dynamic Visit [U] = Unscheduled Visit [R] = Repeating Visit
C = Common Form DF = Dynamic Form RF = Repeating Form
CONFIDENTIAL
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NKT102553
FORM: INFORM SCREENING (SCREEN) TRIAL: nkt102553_scm
INFORM SCREENING
(MAPPINGS1:t_SCREEN.txtScrSINIT)
1.* Subject initials [hidden] A3
2. Date of birth / Req / Req (1900-1988) (MAPPINGS1:t_SCREEN.BIRTHDT)

Req
3. Was this subject a screen failure? (MAPPINGS1:t_SCREEN.rdcSCREENFAIL)

[N] No
[Y] (MAPPINGS1:t_SCREEN.SFREASCD1)
Yes, select primary reason
[1] Adverse Event
Record details on the Non-Serious Adverse Events or Serious Adverse Events forms as appropriate.
[2] Lost to follow-up
[3] Protocol violation
[4] Subject decided to withdraw from the study
[5] Prohibited medication use
[6] Did not fulfill eligibility criteria
[7] Exacerbation of medical condition under investigation.
[8] Non-compliance
[9] Genotype quota filled
CONFIDENTIAL
[10] Did not fulfill continuation criteria
[OT] Other, specify (MAPPINGS1:t_SCREEN.SFRSOTH)
A200
4
* Item is not required
Form Design Note:
IDSL Version 02.01A - 11 JUL 05 Trial designers must use this form as specified here. Allowed changes are mentioned in the particular item level notes.
GM2006/00652/00
Item Design Notes:
Item
Design Note
NKT102553
No.
1. This item is hidden to all users and will be autopopulated by the system as "---"
2. Will be automatically mapped to demography form
3. If screen failures are to be entered into InForm, the trial designer must ensure the correct study conclusion form is selected, that the screen failure reasons correspond, and the mapping rules
are configured. Update reasons according to protocol
CDD: MAPPINGS1 Table: t_SCREEN Key Type: PATIENTVISIT

Column Name Column Data Type Design Note
txtScrSINIT STRING(3) - A3
BIRTHDT DATE - DDMONYYYY
rdcSCREENFAIL STRING(1)
SFREASCD1 STRING(2)
SFRSOTH STRING(200) - A200
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5
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FORM: INFORM ENROLLMENT (ENROL) TRIAL: nkt102553_scm
SUBJECT NUMBER
1. Subject number (MAPPINGS1:t_ENROL.mtxtSubjectNumber)
A6
Form Design Note:
IDSL Version 01.01B - 13 JUN 05
Item Design Notes:
Item No. Design Note
1. Subject number will be entered on the ENROL form and will be mapped to the SUBID form, where it can be changed if needed.
CONFIDENTIAL
CDD: MAPPINGS1 Table: t_ENROL Key Type: PATIENTVISIT
mtxtSubjectNumber STRING(6) - A6
6
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NKT102553
FORM: DATE OF VISIT/ASSESSMENT (DOV) TRIAL: nkt102553_scm
DATE OF VISIT/ASSESSMENT
1. Date of visit/assessment / Req / Req (2006-2007) (MAPPINGS1:t_DOV.DOV)
Req
2.* 100% Random Sample SDV Performed on this Subject Visit [hidden] (MAPPINGS1:t_DOV.chkSDVYes)
[Y] Yes
Form Design Note:
IDSL Version 02.00A - 05 MAY 05
CDD: MAPPINGS1 Table: t_DOV Key Type: PATIENTVISIT

CONFIDENTIAL
DOV DATE - DDMONYYYY
chkSDVYes STRING(255)
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FORM: SUBJECT IDENTIFICATION (SUB ID) TRIAL: nkt102553_scm
SUBJECT IDENTIFICATION
If Subject number was entered incorrectly, please correct and submit; otherwise disregard
1. Subject number (MAPPINGS1:t_SUBID.mtxtSubjectNumber)
A6
Form Design Note:
Item Design Notes:
1. Subject number will be entered on the ENROL form and will be mapped to the SUBID form, where it can be changed if needed.
CONFIDENTIAL
CDD: MAPPINGS1 Table: t_SUBID Key Type: PATIENTVISIT
8
mtxtSubjectNumber STRING(6) - A6
GM2006/00652/00
NKT102553
FORM: ELIGIBILITY QUESTION (ELIG) TRIAL: nkt102553_scm
ELIGIBILITY QUESTION
1. Did the subject meet all the entry criteria? (MAPPINGS1:t_ELIG.IEELIG)
[Y] Yes
[N] No, please select all boxes corresponding to violations of any inclusion/exclusion criteria
Inclusion Criteria
(MAPPINGS1:t_ELIG.IECRTNUMI01)
[I01] Inclusion Criteria 1
CONFIDENTIAL
9
Exclusion Criteria
(MAPPINGS1:t_ELIG.IECRTNUME01)
[E01] Exclusion Criteria 1
GM2006/00652/00
NKT102553
Do not admit the subject into this study if any Inclusion / Exclusion criteria is checked unless an (MAPPINGS1:t_ELIG.txtEligExempt)
exception has been granted by the GSK Medical Monitor and subject is continuing in the study. Please
clarify the exemption(s) below
A200
Form Design Note:
IDSL Version 01.01A - 08 DEC 05
CONFIDENTIAL
CDD: MAPPINGS1 Table: t_ELIG Key Type: PATIENTVISIT
10

IEELIG STRING(1)
IECRTNUMI01 STRING(255)
GM2006/00652/00
NKT102553
IECRTNUME01 STRING(255)
txtEligExempt STRING(200) - A200
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11
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FORM: DEMOGRAPHY (DEMOG) TRIAL: nkt102553_scm
DEMOGRAPHY
1. Date of birth / Req / Req (1900-1988) (MAPPINGS1:t_DEMO.BIRTHDT)
Req
2. Sex (MAPPINGS1:t_DEMO.SEX)
[F] (MAPPINGS1:t_DEMO.CHDPOTCD)
Female : Record child-bearing potential
[2] Post-menopausal
[3] Sterile (of child-bearing age)
[4] Potentially able to bear children
3. Ethnicity (MAPPINGS1:t_DEMO.ETHNICCD)
[1] Hispanic or Latino
[2] Not Hispanic or Latino
4. Race Check all that apply
(MAPPINGS1:t_DEMO.RACECCD11)
[11] African American/African Heritage
[12] American Indian or Alaskan Native
CONFIDENTIAL
[13] Asian - Central/South Asian Heritage
[14] Asian - East Asian Heritage
12
[15] Asian - Japanese Heritage

[16] Asian - South East Asian Heritage
[17] Native Hawaiian or Other Pacific Islander
[18] White - Arabic/North African Heritage
[19] White - White/Caucasian/European Heritage
Form Design Note:
GM2006/00652/00
NKT102553
Item Design Notes:
1. Will be automatically mapped to demography form
2. This item is conditional; Use it if you need to collect childbearing potential information; Pre-menarcheal is optional. Remove the other Sex item
CDD: MAPPINGS1 Table: t_DEMO Key Type: PATIENTVISIT

BIRTHDT DATE - DDMONYYYY
SEX STRING(1)
CHDPOTCD STRING(1)
ETHNICCD STRING(1)
RACECCD11 STRING(255)
CONFIDENTIAL
13
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FORM: AMERICAN SOCIETY OF ANESTHESIOLOGISTS (ASA) PHYSICAL STATUS (PS) CLASSIFICATION (ASA) TRIAL: nkt102553_scm
1. Date of assessment / Req / Req (2006-2007) (MAPPINGS1:t_ASAPSC.ACTDTTM)

Req
2. Record subject's ASA PS: (MAPPINGS1:t_ASAPSC.ASACLACD)

[1] PI : A normal healthy patient
[2] P2 : A patient with mild systemic disease
[3] P3 : A patient with severe systemic disease
[4] P4 : A patient with severe systemic disease which is a constant threat to life
[5] P5 : A moribund patient who is not expected to survive without the operation
[6] P6 : A declared brain-dead patient whose organs are removed for donor purposes
Form Design Note:
IDSL Version 01.00 - Draft - dd mmm yy.
Item Design Notes:
CONFIDENTIAL
1. Date is required but time is optional.

14
CDD: MAPPINGS1 Table: t_ASAPSC Key Type: PATIENTVISIT

ACTDTTM DATE - DDMONYYYY
ASACLACD STRING(1)
GM2006/00652/00
NKT102553
FORM: MEDICAL CONDITIONS (MEDHX) TRIAL: nkt102553_scm
Cardiac Disorders
1. Myocardial infarction (MAPPINGS1:t_MEDHIST_A.MHSTATCD)
[1] Current
[2] Past
[4] Not Assessed
[5] No Medical Condition
2. Congestive Heart Failure (MAPPINGS1:t_MEDHIST_A.MHSTATC1)
[1] Current
[2] Past
[4] Not Assessed
3. Cardiomyopathy (MAPPINGS1:t_MEDHIST_A.MHSTATC2)
[1] Current
[2] Past
[4] Not Assessed
MedDRA lower level
CONFIDENTIAL
Sequence Number Specific Condition Modified Term MedDRA Synonym Failed coding Status
term code
4. [hidden] [hidden] [hidden] [hidden] [hidden]
Other Cardiac Disorders Entry Add Entry
15
(MAPPINGS1:t_MEDHIST_A.MHSEQ)
4.a* Sequence Number [hidden] xxxx
4.b Specific Condition (MAPPINGS1:t_MEDHIST_A.MHTERM)

A100
(MAPPINGS1:t_MEDHIST_A.MHMODIFY)
4.c* Modified Term [hidden] A100
MedDRA Synonym [hidden] (MAPPINGS1:t_MEDHIST_A.MHMEDSYN)
MedDRA lower level term code [hidden] (MAPPINGS1:t_MEDHIST_A.MHLLTCD)
GM2006/00652/00
Failed coding [hidden] (MAPPINGS1:t_MEDHIST_A.calMH_FAILED)
4.d Status (MAPPINGS1:t_MEDHIST_A.MHSTATCD1)

[1] Current
NKT102553
[2] Past
5. Peptic ulcer (MAPPINGS1:t_MEDHIST_A.MHSTATC3)
[1] Current
[2] Past
[4] Not Assessed
6. Gastroesophageal reflux (MAPPINGS1:t_MEDHIST_A.MHSTATC4)

[1] Current
[2] Past
[4] Not Assessed
7. Inflammatory bowel disease (MAPPINGS1:t_MEDHIST_A.MHSTATC5)
[1] Current
[2] Past
[4] Not Assessed
MedDRA lower level
term code
Other Gastrointestinal disorders Entry Add Entry
(MAPPINGS1:t_MEDHIST_A.MHSE1)
8.b Specific Condition (MAPPINGS1:t_MEDHIST_A.MHTER1)

A100
CONFIDENTIAL
(MAPPINGS1:t_MEDHIST_A.MHMODIF1)
16
MedDRA Synonym [hidden] (MAPPINGS1:t_MEDHIST_A.MHMEDSY1)
MedDRA lower level term code [hidden] (MAPPINGS1:t_MEDHIST_A.MHLLTC1)
Failed coding [hidden] (MAPPINGS1:t_MEDHIST_A.calMH_FAILE1)

[1] Current
[2] Past
9. Cholecystitis (MAPPINGS1:t_MEDHIST_A.MHSTATC6)
[1] Current
[2] Past
GM2006/00652/00
[4] Not Assessed
10. Choledocholithiasis (MAPPINGS1:t_MEDHIST_A.MHSTATC7)
NKT102553
[1] Current
[2] Past
[4] Not Assessed
11. Hepatitis (MAPPINGS1:t_MEDHIST_A.MHSTATC8)
[1] Current
[2] Past
[4] Not Assessed
MedDRA lower level

term code
Other Hepatobiliary disorders Entry Add Entry

A100

[1] Current
CONFIDENTIAL
[2] Past
Respiratory, thoracic and mediastinal disorders
13. Asthma (MAPPINGS1:t_MEDHIST_A.MHSTATC9)
17
[1] Current
[2] Past
[4] Not Assessed
14. Emphysema (MAPPINGS1:t_MEDHIST_A.MHSTAT10)
[1] Current
[2] Past
[4] Not Assessed
15. Chronic obstructive pulmonary disease (MAPPINGS1:t_MEDHIST_A.MHSTAT11)
[1] Current
[2] Past
GM2006/00652/00
[4] Not Assessed
MedDRA lower level
NKT102553
term code
Other Respiratory, thoracic and mediastinal disorders Entry Add Entry

A100

[1] Current
[2] Past
17. Urinary calculus (MAPPINGS1:t_MEDHIST_A.MHSTAT12)
[1] Current
[2] Past
[4] Not Assessed
18. Bladder infection (MAPPINGS1:t_MEDHIST_A.MHSTAT13)
CONFIDENTIAL
[1] Current
[2] Past
[4] Not Assessed
18
19. Proteinuria (MAPPINGS1:t_MEDHIST_A.MHSTAT14)

[1] Current
[2] Past
[4] Not Assessed
MedDRA lower level
term code
Other Renal and urinary disorders Entry Add Entry
GM2006/00652/00
A100
NKT102553


[1] Current
[2] Past
Reproductive system and breast disorders
21. Vulvovaginitis (MAPPINGS1:t_MEDHIST_A.MHSTAT15)
[1] Current
[2] Past
[4] Not Assessed
22. Pelvic inflammatory disease (MAPPINGS1:t_MEDHIST_A.MHSTAT16)
[1] Current
[2] Past
[4] Not Assessed
23. Papilloma viral infection (MAPPINGS1:t_MEDHIST_A.MHSTAT17)
[1] Current
[2] Past
[4] Not Assessed
CONFIDENTIAL
MedDRA lower level
term code
Other Reproductive system and breast disorders Entry
19
Add Entry

A100
GM2006/00652/00
NKT102553
[1] Current
[2] Past
Blood and Lymphatic System Disorders
25. Anaemia (MAPPINGS1:t_MEDHIST_A.MHSTAT18)
[1] Current
[2] Past
[4] Not Assessed
26. Thrombocytopenia (MAPPINGS1:t_MEDHIST_A.MHSTAT19)

[1] Current
[2] Past
[4] Not Assessed
27. Lymphadenopathy (MAPPINGS1:t_MEDHIST_A.MHSTAT20)
[1] Current
[2] Past
[4] Not Assessed
MedDRA lower level
term code
Other Blood and Lymphatic System Disorders Entry Add Entry

A100
CONFIDENTIAL
20

[1] Current
[2] Past
Immune System Disorders
29. Drug hypersensitivity (MAPPINGS1:t_MEDHIST_A.MHSTAT21)
[1] Current
[2] Past
GM2006/00652/00
[4] Not Assessed
30. Food allergy (MAPPINGS1:t_MEDHIST_A.MHSTAT22)
NKT102553
[1] Current
[2] Past
[4] Not Assessed
31. Seasonal allergy (MAPPINGS1:t_MEDHIST_A.MHSTAT23)
[1] Current
[2] Past
[4] Not Assessed
MedDRA lower level

term code
Other Immune System Disorders Entry Add Entry

A100

[1] Current
CONFIDENTIAL
[2] Past
Metabolism and Nutrition Disorders
33. Diabetes mellitus (MAPPINGS1:t_MEDHIST_A.MHSTAT24)
21
[1] Current
[2] Past
[4] Not Assessed
34. Hyperlipidemia (MAPPINGS1:t_MEDHIST_A.MHSTAT25)
[1] Current
[2] Past
[4] Not Assessed
35. Gout (MAPPINGS1:t_MEDHIST_A.MHSTAT26)
[1] Current
[2] Past
GM2006/00652/00
[4] Not Assessed
MedDRA lower level
NKT102553
term code
Other Metabolism and Nutrition Disorders Entry Add Entry

A100

[1] Current
[2] Past
Musculoskeletal and connective tissue disorders
37. Osteoporosis (MAPPINGS1:t_MEDHIST_A.MHSTAT27)
[1] Current
[2] Past
[4] Not Assessed
38. Rheumatoid arthritis (MAPPINGS1:t_MEDHIST_A.MHSTAT28)
CONFIDENTIAL
[1] Current
[2] Past
[4] Not Assessed
22
39. Systemic lupus erythematosus (MAPPINGS1:t_MEDHIST_A.MHSTAT29)

[1] Current
[2] Past
[4] Not Assessed
MedDRA lower level
term code
Other Musculoskeletal and connective tissue disorders Entry Add Entry
GM2006/00652/00
A100
NKT102553

40.d Status (MAPPINGS1:t_MEDHIST_A.MHSTATC10)

[1] Current
[2] Past
Neoplasms benign, malignant and unspecified (including cysts and polyps)
41. Biliary neoplasm (MAPPINGS1:t_MEDHIST_A.MHSTAT30)
[1] Current
[2] Past
[4] Not Assessed
42. Gastrointestinal neoplasm (MAPPINGS1:t_MEDHIST_A.MHSTAT31)
[1] Current
[2] Past
[4] Not Assessed
43. Hepatic neoplasm (MAPPINGS1:t_MEDHIST_A.MHSTAT32)
[1] Current
[2] Past
[4] Not Assessed
CONFIDENTIAL
MedDRA lower level
term code
Other Neoplasms benign, malignant and unspecified (including cysts and polyps) Entry
23
Add Entry
(MAPPINGS1:t_MEDHIST_A.MHS10)
44.b Specific Condition (MAPPINGS1:t_MEDHIST_A.MHTE10)

A100
(MAPPINGS1:t_MEDHIST_A.MHMODI10)
MedDRA Synonym [hidden] (MAPPINGS1:t_MEDHIST_A.MHMEDS10)
MedDRA lower level term code [hidden] (MAPPINGS1:t_MEDHIST_A.MHLLT10)
GM2006/00652/00
Failed coding [hidden] (MAPPINGS1:t_MEDHIST_A.calMH_FAIL10)
NKT102553
[1] Current
[2] Past
45. Dizziness (MAPPINGS1:t_MEDHIST_A.MHSTAT33)
[1] Current
[2] Past
[4] Not Assessed
46. Somnolence (MAPPINGS1:t_MEDHIST_A.MHSTAT34)

[1] Current
[2] Past
[4] Not Assessed
47. Psychomotor seizures (MAPPINGS1:t_MEDHIST_A.MHSTAT35)
[1] Current
[2] Past
[4] Not Assessed
MedDRA lower level
term code
Other Nervous system disorders Entry Add Entry

A100
CONFIDENTIAL
24

[1] Current
[2] Past
Vascular disorders
49. Wound haemorrhage (MAPPINGS1:t_MEDHIST_A.MHSTAT36)
[1] Current
[2] Past
GM2006/00652/00
[4] Not Assessed
50. Peripheral vascular disorder (MAPPINGS1:t_MEDHIST_A.MHSTAT37)
NKT102553
[1] Current
[2] Past
[4] Not Assessed
MedDRA lower level
term code
Other Vascular disorders Entry
Add Entry

A100

[1] Current
[2] Past
Infections and Infestations
52. Hepatitis A (MAPPINGS1:t_MEDHIST_A.MHSTAT38)
CONFIDENTIAL
[1] Current
[2] Past
[4] Not Assessed
25
53. Hepatitis B (MAPPINGS1:t_MEDHIST_A.MHSTAT39)

[1] Current
[2] Past
[4] Not Assessed
54. Hepatitis C (MAPPINGS1:t_MEDHIST_A.MHSTAT40)
[1] Current
[2] Past
[4] Not Assessed
MedDRA lower level
term code
GM2006/00652/00
Other Infections and Infestations Entry Add Entry
NKT102553

A100

[1] Current
[2] Past
Congenital, familial and genetic disorders
56. Congenital hepatobiliary anomaly (MAPPINGS1:t_MEDHIST_A.MHSTAT41)
[1] Current
[2] Past
[4] Not Assessed
57. Polycystic liver disease (MAPPINGS1:t_MEDHIST_A.MHSTAT42)
[1] Current
[2] Past
[4] Not Assessed
58. Long QT syndrome (MAPPINGS1:t_MEDHIST_A.MHSTAT43)
CONFIDENTIAL
[1] Current
[2] Past
[4] Not Assessed
26
MedDRA lower level

term code
Other Congenital, familial and genetic disorders Entry Add Entry

A100
GM2006/00652/00
NKT102553

[1] Current
[2] Past
Gernal disorders and administration site conditions
60. Adverse drug reaction (MAPPINGS1:t_MEDHIST_A.MHSTAT44)

[1] Current
[2] Past
[4] Not Assessed
61. Drug interaction (MAPPINGS1:t_MEDHIST_A.MHSTAT45)
[1] Current
[2] Past
[4] Not Assessed
MedDRA lower level
term code
Other General disorders and administration site conditions Entry Add Entry

A100
CONFIDENTIAL
27

[1] Current
[2] Past
Endocrine disorder
63. Adrenal insufficiency (MAPPINGS1:t_MEDHIST_A.MHSTAT46)
[1] Current
[2] Past
GM2006/00652/00
[4] Not Assessed
64. Hyperthyroidism (MAPPINGS1:t_MEDHIST_A.MHSTAT47)
NKT102553
[1] Current
[2] Past
[4] Not Assessed
65. Hypothyroidism (MAPPINGS1:t_MEDHIST_A.MHSTAT48)
[1] Current
[2] Past
[4] Not Assessed
MedDRA lower level

term code
Other Endocrine disorders Entry Add Entry

A100

[1] Current
CONFIDENTIAL
[2] Past
MEDICAL CONDITIONS
Check only one response for each MedDRA System Organ Class
28
67. Ear and labyrinth disorders (MAPPINGS1:t_MEDHIST_A.MHSTAT49)

[1] Current
[2] Past
[4] Not Assessed
68. Eye disorders (MAPPINGS1:t_MEDHIST_A.MHSTAT50)
[1] Current
[2] Past
[4] Not Assessed
69. Skin and subcutaneous tissue disorders (MAPPINGS1:t_MEDHIST_A.MHSTAT51)
GM2006/00652/00
[1] Current
[2] Past
[4] Not Assessed
NKT102553
70. Psychiatric disorders (MAPPINGS1:t_MEDHIST_A.MHSTAT52)
[1] Current
[2] Past
[4] Not Assessed
71. Injury, poisoning and procedural complications (MAPPINGS1:t_MEDHIST_A.MHSTAT53)
[1] Current
[2] Past
[4] Not Assessed

Form Design Note:
IDSL Version 03.01A - 15 Sep 05 This form is optional
Section Design Notes:
Title Design Note
Cardiac Disorders The following combinations are acceptable: 1. Current+No Medical Condition;2. Current+Past+No Medical Condition;3. Past+No Medical History.
Not Assessed is optional for all combinations. Combinations must be consistent for all terms specified
Gastrointestinal disorders The following combinations are acceptable: 1. Current+No Medical Condition;2. Current+Past+No Medical Condition;3. Past+No Medical History.
CONFIDENTIAL
Hepatobiliary disorders The following combinations are acceptable: 1. Current+No Medical Condition;2. Current+Past+No Medical Condition;3. Past+No Medical History.
Respiratory, thoracic and mediastinal disorders The following combinations are acceptable: 1. Current+No Medical Condition;2. Current+Past+No Medical Condition;3. Past+No Medical History.
29
Renal and urinary disorders The following combinations are acceptable: 1. Current+No Medical Condition;2. Current+Past+No Medical Condition;3. Past+No Medical History.
Reproductive system and breast disorders The following combinations are acceptable: 1. Current+No Medical Condition;2. Current+Past+No Medical Condition;3. Past+No Medical History.
Blood and Lymphatic System Disorders The following combinations are acceptable: 1. Current+No Medical Condition;2. Current+Past+No Medical Condition;3. Past+No Medical History.
Immune System Disorders The following combinations are acceptable: 1. Current+No Medical Condition;2. Current+Past+No Medical Condition;3. Past+No Medical History.
GM2006/00652/00
Metabolism and Nutrition Disorders The following combinations are acceptable: 1. Current+No Medical Condition;2. Current+Past+No Medical Condition;3. Past+No Medical History.
Musculoskeletal and connective tissue disorders The following combinations are acceptable: 1. Current+No Medical Condition;2. Current+Past+No Medical Condition;3. Past+No Medical History.
NKT102553
Neoplasms benign, malignant and unspecified The following combinations are acceptable: 1. Current+No Medical Condition;2. Current+Past+No Medical Condition;3. Past+No Medical History.
(including cysts and polyps) Not Assessed is optional for all combinations. Combinations must be consistent for all terms specified
Nervous system disorders The following combinations are acceptable: 1. Current+No Medical Condition;2. Current+Past+No Medical Condition;3. Past+No Medical History.
Vascular disorders The following combinations are acceptable: 1. Current+No Medical Condition;2. Current+Past+No Medical Condition;3. Past+No Medical History.
Infections and Infestations The following combinations are acceptable: 1. Current+No Medical Condition;2. Current+Past+No Medical Condition;3. Past+No Medical History.
Congenital, familial and genetic disorders The following combinations are acceptable: 1. Current+No Medical Condition;2. Current+Past+No Medical Condition;3. Past+No Medical History.
Gernal disorders and administration site The following combinations are acceptable: 1. Current+No Medical Condition;2. Current+Past+No Medical Condition;3. Past+No Medical History.
conditions Not Assessed is optional for all combinations. Combinations must be consistent for all terms specified
Endocrine disorder The following combinations are acceptable: 1. Current+No Medical Condition;2. Current+Past+No Medical Condition;3. Past+No Medical History.
MEDICAL CONDITIONS The following combinations are acceptable: 1. Current+No Medical Condition;2. Current+Past+No Medical Condition;3. Past+No Medical History.
Item Design Notes:
CONFIDENTIAL
4.b This item is optional
4.d This item is optional

30
GM2006/00652/00
NKT102553

CONFIDENTIAL

31
CDD: MAPPINGS1 Table: t_MEDHIST_A Key Type: PATIENTVISIT

GM2006/00652/00
MHSTATCD STRING(1)
MHSTATC1 STRING(1)
NKT102553
MHSTATC2 STRING(1)
MHSEQ NUMERIC - N4
MHTERM STRING(100) - A100
MHMODIFY STRING(100) - A100
MHMEDSYN STRING(255)
MHLLTCD STRING(255)
calMH_FAILED STRING(255)
MHSTATCD1 STRING(1)
MHSTATC3 STRING(1)
MHSTATC4 STRING(1)
MHSTATC5 STRING(1)
MHSE1 NUMERIC - N4
MHTER1 STRING(100) - A100
MHMODIF1 STRING(100) - A100
MHMEDSY1 STRING(255)
MHLLTC1 STRING(255)
calMH_FAILE1 STRING(255)
MHSTATCD2 STRING(1)
MHSTATC6 STRING(1)
MHSTATC7 STRING(1)
CONFIDENTIAL
MHSTATC8 STRING(1)
MHSE2 NUMERIC - N4
32

MHLLTC2 STRING(255)
MHSTATCD3 STRING(1)
MHSTATC9 STRING(1)
MHSTAT10 STRING(1)
GM2006/00652/00
MHSTAT11 STRING(1)
MHSE3 NUMERIC - N4
NKT102553
MHLLTC3 STRING(255)
MHSTATCD4 STRING(1)
MHSTAT12 STRING(1)
MHSTAT13 STRING(1)
MHSTAT14 STRING(1)
MHSE4 NUMERIC - N4
MHLLTC4 STRING(255)
MHSTATCD5 STRING(1)
MHSTAT15 STRING(1)
MHSTAT16 STRING(1)
MHSTAT17 STRING(1)
MHSE5 NUMERIC - N4
CONFIDENTIAL
33
MHLLTC5 STRING(255)
MHSTATCD6 STRING(1)
MHSTAT18 STRING(1)
MHSTAT19 STRING(1)
MHSTAT20 STRING(1)
MHSE6 NUMERIC - N4
GM2006/00652/00
NKT102553
MHLLTC6 STRING(255)
MHSTATCD7 STRING(1)
MHSTAT21 STRING(1)
MHSTAT22 STRING(1)
MHSTAT23 STRING(1)
MHSE7 NUMERIC - N4
MHLLTC7 STRING(255)
MHSTATCD8 STRING(1)
MHSTAT24 STRING(1)
MHSTAT25 STRING(1)
MHSTAT26 STRING(1)
MHSE8 NUMERIC - N4
CONFIDENTIAL
MHLLTC8 STRING(255)
34
MHSTATCD9 STRING(1)
MHSTAT27 STRING(1)
MHSTAT28 STRING(1)
MHSTAT29 STRING(1)
MHSE9 NUMERIC - N4
GM2006/00652/00
MHLLTC9 STRING(255)
NKT102553
MHSTATC10 STRING(1)
MHSTAT30 STRING(1)
MHSTAT31 STRING(1)
MHSTAT32 STRING(1)
MHS10 NUMERIC - N4
MHTE10 STRING(100) - A100

MHMODI10 STRING(100) - A100
MHMEDS10 STRING(255)
MHLLT10 STRING(255)
calMH_FAIL10 STRING(255)
MHSTATC11 STRING(1)
MHSTAT33 STRING(1)
MHSTAT34 STRING(1)
MHSTAT35 STRING(1)
MHS11 NUMERIC - N4
MHLLT11 STRING(255)
CONFIDENTIAL
MHSTATC12 STRING(1)
MHSTAT36 STRING(1)
35
MHSTAT37 STRING(1)
MHS12 NUMERIC - N4
MHLLT12 STRING(255)
GM2006/00652/00
MHSTATC13 STRING(1)
MHSTAT38 STRING(1)
MHSTAT39 STRING(1)
NKT102553
MHSTAT40 STRING(1)
MHS13 NUMERIC - N4
MHLLT13 STRING(255)
MHSTATC14 STRING(1)
MHSTAT41 STRING(1)
MHSTAT42 STRING(1)
MHSTAT43 STRING(1)
MHS14 NUMERIC - N4
MHLLT14 STRING(255)
MHSTATC15 STRING(1)
MHSTAT44 STRING(1)
CONFIDENTIAL
MHSTAT45 STRING(1)
MHS15 NUMERIC - N4
36

MHLLT15 STRING(255)
MHSTATC16 STRING(1)
MHSTAT46 STRING(1)
MHSTAT47 STRING(1)
GM2006/00652/00
MHSTAT48 STRING(1)
MHS16 NUMERIC - N4
NKT102553
MHLLT16 STRING(255)
MHSTATC17 STRING(1)
MHSTAT49 STRING(1)
MHSTAT50 STRING(1)
MHSTAT51 STRING(1)
MHSTAT52 STRING(1)
MHSTAT53 STRING(1)
CONFIDENTIAL
37
GM2006/00652/00
NKT102553
FORM: HISTORY OF TOBACCO USE (TOBACCO HISTORY) TRIAL: nkt102553_scm
HISTORY OF TOBACCO USE

1. What is the subject's history of tobacco use (includes all tobacco products)? (MAPPINGS1:t_SUBUSE_SMHS.SUSMHSCD)
[1] Never smoked
[3] Former smoker, when did the subject last smoke/use tobacco?
/ Req/Unk / Req/Unk (1900-2007) (MAPPINGS1:t_SUBUSE_SMHS.SUSMLSDT)
Req/Unk
Substance Use Type [hidden] (MAPPINGS1:t_SUBUSE_SMHS.SUTYPCD)
Form Design Note:
IDSL Version 01.00A - 01 DEC 04 This form is optional
CONFIDENTIAL
Title Design Note
sctSUTYPCD This section is required and should be the last section on this form.
38
Item Design Notes:
itmSUTYPCD This item will be calculated by InForm.
CDD: MAPPINGS1 Table: t_SUBUSE_SMHS Key Type: PATIENTVISIT

GM2006/00652/00
SUSMHSCD STRING(1)
SUSMLSDT DATE - DDMONYYYY
SUTYPCD STRING(255)
NKT102553
FORM: VITAL SIGNS (VS) TRIAL: nkt102553_scm
VITAL SIGNS
1. Actual date / Req / Req (2006-2007) (MAPPINGS1:t_VITALS.VSACTDTTM)
Req
2. Height xxx cm (MAPPINGS1:t_VITALS.HEIGHT)
3. Weight xxx.x kg (MAPPINGS1:t_VITALS.WEIGHT)
4. Blood pressure xxx / (MAPPINGS1:t_VITALS.SYSBP) xxx mmHg (MAPPINGS1:t_VITALS.DIABP)

(systolic/diastolic)
5. Heart rate xxx beats/min (MAPPINGS1:t_VITALS.HEART)
6. Respiration rate xxx breaths/min (MAPPINGS1:t_VITALS.RESP)
Calculated Subject position [hidden] (MAPPINGS1:t_VITALS.VSPOSCD1)
CONFIDENTIAL
Form Design Note:
IDSL Version 03.00A - 27 JUL 05. This form is optional. This form is to be used when one Vitals is taken at a visit.
39
Title Design Note
VITAL SIGNS All items are optional
sctVSPOS_CAL This section should be the last section on the form and is required when position of BP is consistent throughout the study.
Item Design Notes:
GM2006/00652/00
itmVSPOS_CAL This item should be used if only one position is stipulated for the trial. Remove the other Position item and adjust the calculation rule accordingly.
NKT102553
CDD: MAPPINGS1 Table: t_VITALS Key Type: PATIENTVISIT
VSACTDTTM DATE - DDMONYYYY
HEIGHT NUMERIC - N3
WEIGHT FLOAT - F5.1

SYSBP NUMERIC - N3
DIABP NUMERIC - N3
HEART NUMERIC - N3
RESP NUMERIC - N3
VSPOSCD1 STRING(255)
CONFIDENTIAL
40
GM2006/00652/00
NKT102553
FORM: 12-LEAD ECG (ECG) TRIAL: nkt102553_scm
12-LEAD ECG
1. Date of ECG / Req / Req (2006-2007) (MAPPINGS1:t_ECG_NOABN_1.EGDTTM)
Req
2. Result of the ECG (MAPPINGS1:t_ECG_NOABN_1.EGINTPCD2)

[1] Normal
[2] Abnormal - Not clinically significant
[3] Abnormal, clinically significant (complete the Medical history form)
Form Design Note:
IDSL Version 02.02B - 11 NOV 05. This form is optional and should be used when abnormalities are not collected, or when abnormalities are collected on a separate form. Trial designer to modify the
form and section title per protocol
Item Design Notes:
CONFIDENTIAL
1. Time is optional.
41
2. This item is conditional
CDD: MAPPINGS1 Table: t_ECG_NOABN_1 Key Type: PATIENTVISIT

EGDTTM DATE - DDMONYYYY
EGINTPCD2 STRING(1)
GM2006/00652/00
NKT102553
FORM: LOCAL LABORATORY - CLINICAL CHEMISTRY (CHEM-SCR) TRIAL: nkt102553_scm
If the lab result is clinically significant, record details on the Current Medical Conditions form (MEDHX).
LOCAL LABORATORY - CLINICAL CHEMISTRY
(MAPPINGS1:t_LAB_CHEM.LBIDCD)
1.* Laboratory ID [read-only] A20
2. Laboratory name (MAPPINGS1:t_LAB_CHEM.LBNAME1)

A80
3. Address (MAPPINGS1:t_LAB_CHEM.LBADRS1)
A80
4. Date sample taken / Req / Req (2006-2007) (MAPPINGS1:t_LAB_CHEM.LBDTTM)

Req
5. Has the subject fasted? (MAPPINGS1:t_LAB_CHEM.LBFAST)

[Y] Yes
[N] No
6. Albumin (MAPPINGS1:t_LAB_CHEM.rdcLBORRES)
CONFIDENTIAL
[-97] Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM.LBORRESN)
[-99] No result
7. Alkaline Phosphatase (MAPPINGS1:t_LAB_CHEM.rdcLBORRE1)
[-97] Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM.LBORRES1)
42
[-99] No result
8. ALT (MAPPINGS1:t_LAB_CHEM.rdcLBORRE2)
[-99] No result
9. AST (MAPPINGS1:t_LAB_CHEM.rdcLBORRE3)
[-99] No result
10. BUN or serum urea (MAPPINGS1:t_LAB_CHEM.rdcLBORRE4)
GM2006/00652/00
[-99] No result
11. Creatinine (MAPPINGS1:t_LAB_CHEM.rdcLBORRE5)
NKT102553
[-99] No result
12. Bicarbonate (MAPPINGS1:t_LAB_CHEM.rdcLBORRE6)
[-99] No result
13. Chloride (MAPPINGS1:t_LAB_CHEM.rdcLBORRE7)
[-99] No result
14. Potassium (MAPPINGS1:t_LAB_CHEM.rdcLBORRE8)
[-99] No result
15. Sodium (MAPPINGS1:t_LAB_CHEM.rdcLBORRE9)
[-99] No result
16. Glucose (MAPPINGS1:t_LAB_CHEM.rdcLBORR10)
[-97] Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM.LBORRE10)
[-99] No result
17. Total Bilirubin (MAPPINGS1:t_LAB_CHEM.rdcLBORR11)
[-99] No result
18. Total Protein (MAPPINGS1:t_LAB_CHEM.rdcLBORR12)
[-99] No result
CONFIDENTIAL
19. Triglycerides (MAPPINGS1:t_LAB_CHEM.rdcLBORR13)
[-99] No result
Item is not required
43
Form Design Note:
IDSL Version 01.01A - 01 Feb 2005 This form is optional. This form is to be used when a single lab is collected at a visit. This is only used for the Clinical Chemistry tests
Title Design Note
GM2006/00652/00
LOCAL LABORATORY - CLINICAL CHEMISTRY Use separate items for Name and address for the first occurrence of this form, and use the combined item for subsequent visits.
NKT102553
Item Design Notes:
1. This field will be entered by the Data Owner. Data Owner must be given enterable rights to this item
4. Time is optional
5. This item is optional
CDD: MAPPINGS1 Table: t_LAB_CHEM Key Type: PATIENTVISIT

LBIDCD STRING(20) - A20
LBNAME1 STRING(80) - A80
LBADRS1 STRING(80) - A80
LBDTTM DATE - DDMONYYYY
LBFAST STRING(1)
rdcLBORRES STRING(3)
LBORRESN FLOAT - F13.0
rdcLBORRE1 STRING(3)
LBORRES1 FLOAT - F13.0
CONFIDENTIAL
44

GM2006/00652/00
NKT102553
rdcLBORR10 STRING(3)
LBORRE10 FLOAT - F13.0

CONFIDENTIAL
45
GM2006/00652/00
NKT102553
FORM: LOCAL LABORATORY - HAEMATOLOGY (HAEMA-SCR) TRIAL: nkt102553_scm
If the lab result is clinically significant, record details on the Current Medical Conditions form (MEDHX).
LOCAL LABORATORY - HAEMATOLOGY
(MAPPINGS1:t_LAB_HAEMA.LBIDCD)
2. Laboratory name (MAPPINGS1:t_LAB_HAEMA.LBNAME1)

A80
3. Address (MAPPINGS1:t_LAB_HAEMA.LBADRS1)
A80
4. Date sample taken / Req / Req (2006-2007) (MAPPINGS1:t_LAB_HAEMA.LBDTTM)

Req
5. Has the subject fasted? (MAPPINGS1:t_LAB_HAEMA.LBFAST)

[Y] Yes
[N] No
6. Haemoglobin (MAPPINGS1:t_LAB_HAEMA.rdcLBORRES)
CONFIDENTIAL
[-97] Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA.LBORRESN)
[-99] No result
7. Haematocrit (MAPPINGS1:t_LAB_HAEMA.rdcLBORRE1)
[-97] Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA.LBORRES1)
46
[-99] No result
8. WBC (MAPPINGS1:t_LAB_HAEMA.rdcLBORRE2)
[-99] No result
9. Platelets (MAPPINGS1:t_LAB_HAEMA.rdcLBORRE3)
[-99] No result
10. Total Neutrophils (MAPPINGS1:t_LAB_HAEMA.rdcLBORRE4)
GM2006/00652/00
[-99] No result
11. Lymphocytes (MAPPINGS1:t_LAB_HAEMA.rdcLBORRE5)
NKT102553
[-99] No result
12. Monocytes (MAPPINGS1:t_LAB_HAEMA.rdcLBORRE6)
[-99] No result
13. Eosinophils (MAPPINGS1:t_LAB_HAEMA.rdcLBORRE7)
[-99] No result
14. Basophils (MAPPINGS1:t_LAB_HAEMA.rdcLBORRE8)
[-99] No result
Form Design Note:
IDSL Version 01.02A - 12 Aug 2005 This form is optional. This form is to be used when a single lab is collected at a visit. This is only used for the Haematology tests
Title Design Note
LOCAL LABORATORY - HAEMATOLOGY Use separate items for Name and address for the first occurance of this form, and use the combined item for subsequent visits.
CONFIDENTIAL
Item Design Notes:

47
4. Time is optional
CDD: MAPPINGS1 Table: t_LAB_HAEMA Key Type: PATIENTVISIT

GM2006/00652/00
LBNAME1 STRING(80) - A80
LBADRS1 STRING(80) - A80
NKT102553
LBFAST STRING(1)

CONFIDENTIAL
48
GM2006/00652/00
NKT102553
FORM: VITAL SIGNS (VS) TRIAL: nkt102553_scm
VITAL SIGNS
1. Actual date / Req / Req (2006-2007) (MAPPINGS1:t_VITALS_1.VSACTDTTM)
Req
2. Blood pressure xxx / (MAPPINGS1:t_VITALS_1.SYSBP) xxx mmHg (MAPPINGS1:t_VITALS_1.DIABP)

(systolic/diastolic)
3. Heart rate xxx beats/min (MAPPINGS1:t_VITALS_1.HEART)
4. Respiration rate xxx breaths/min (MAPPINGS1:t_VITALS_1.RESP)
Calculated Subject position [hidden] (MAPPINGS1:t_VITALS_1.VSPOSCD1)
Form Design Note:
IDSL Version 03.00A - 27 JUL 05. This form is optional. This form is to be used when one Vitals is taken at a visit.
CONFIDENTIAL
49
Title Design Note
VITAL SIGNS All items are optional
sctVSPOS_CAL This section should be the last section on the form and is required when position of BP is consistent throughout the study.
Item Design Notes:
itmVSPOS_CAL This item should be used if only one position is stipulated for the trial. Remove the other Position item and adjust the calculation rule accordingly.
GM2006/00652/00
CDD: MAPPINGS1 Table: t_VITALS_1 Key Type: PATIENTVISIT
NKT102553
VSACTDTTM DATE - DDMONYYYY
SYSBP NUMERIC - N3
DIABP NUMERIC - N3
HEART NUMERIC - N3
RESP NUMERIC - N3
VSPOSCD1 STRING(255)
CONFIDENTIAL
50
GM2006/00652/00
NKT102553
FORM: RANDOMISATION NUMBER (RAND) TRIAL: nkt102553_scm
RANDOMISATION NUMBER
1. Was the subject able to be randomised? (MAPPINGS1:t_RAND.rdcRandYN)
[N] No
[Y] Yes, provide:
Randomisation number (MAPPINGS1:t_RAND.RANDNUM)
xxxxxx
Date of randomisation
/ Req / Req (2006-2007) (MAPPINGS1:t_RAND.RANDDTTM)
Req
Form Design Note:
IDSL Version 03.00B - 27 JUL 05
CONFIDENTIAL
Item Design Notes:
1. Date and time of Randomisation are optional. Randomisation number should be changed to match RAMOS.
51
CDD: MAPPINGS1 Table: t_RAND Key Type: PATIENTVISIT

rdcRandYN STRING(1)
RANDNUM NUMERIC - N6
RANDDTTM DATE - DDMONYYYY
GM2006/00652/00
NKT102553
FORM: INVESTIGATIONAL PRODUCT CONTAINER NUMBER (PACK) TRIAL: nkt102553_scm
INVESTIGATIONAL PRODUCT CONTAINER NUMBER

Record the identifying number from the investigational product container dispensed at this visit
1. Investigational product container number (MAPPINGS1:t_EXPOSURE_CONTAINER.EXINVNUM)
A6
Form Design Note:
IDSL Version 01.00A - 01 DEC 04 This form is conditional on RAMOS being used in the trial. If additional container numbers are needed, copy the first item as needed, or change the repeating
property on this form to True
CDD: MAPPINGS1 Table: t_EXPOSURE_CONTAINER Key Type: PATIENTVISIT

EXINVNUM STRING(6) - A6
CONFIDENTIAL
52
GM2006/00652/00
NKT102553
FORM: INVESTIGATIONAL PRODUCT - GW679769 ORAL DOSING (IP ORAL) TRIAL: nkt102553_scm
INVESTIGATIONAL PRODUCT - GW679769 ORAL DOSING

1. Start Date and Time / Req / Req (2006-2007) (MAPPINGS1:t_EXPOSURE_IP_ORAL.EXSTDTTM)
Req
Hr:Min (00:00-23:59)
Req : Req
2.* Investigational Product [hidden] (MAPPINGS1:t_EXPOSURE_IP_ORAL.EXINVPCD)

[55] GW679769
Form Design Note:
IDSL Version 01.01B - 28 JUL 05 This form is required when IP is administered. If Planned Timepoint is not used, but repeats are needed, make this form repeating
Item Design Notes:
CONFIDENTIAL
1. Start date can be modified to collect partial dates. Time is optional

53
2. This item is optional and should be modified according to the trial design. Remove elements not required and add extra ones required.
CDD: MAPPINGS1 Table: t_EXPOSURE_IP_ORAL Key Type: PATIENTVISIT

EXSTDTTM DATE - DDMONYYYY HHMM
EXINVPCD STRING(2)
GM2006/00652/00
NKT102553
FORM: STUDY MEDICATION (SM IV) TRIAL: nkt102553_scm
STUDY MEDICATION (ZOFRAN)

1. Start Date and Time / Req / Req (2006-2007) (MAPPINGS1:t_EXPOSURE_SMIV.EXSTDTTM)
Req
Hr:Min (00:00-23:59)
Req : Req
2. Stop Date and Time / Req / Req (2006-2007) (MAPPINGS1:t_EXPOSURE_SMIV.EXENDTTM)

Req
Hr:Min (00:00-23:59)
Req : Req
3.* Investigational Product [hidden] (MAPPINGS1:t_EXPOSURE_SMIV.EXINVPCD1)

[205] Zofran
Form Design Note:
IDSL Version 01.01B - 28 JUL 05 This form is required when IP is administered. If Planned Timepoint is not used, but repeats are needed, make this form repeating
CONFIDENTIAL
Item Design Notes:
54
1. Start date can be modified to collect partial dates. Time is optional
2. Stop date can be modified to collect partial dates. Time is optional
3. This item is optional and should be modified according to the trial design. Remove elements not required and add extra ones required.
CDD: MAPPINGS1 Table: t_EXPOSURE_SMIV Key Type: PATIENTVISIT

GM2006/00652/00
EXSTDTTM DATE - DDMONYYYY HHMM
EXENDTTM DATE - DDMONYYYY HHMM
EXINVPCD1 STRING(3)
NKT102553
FORM: SURGICAL PROCEDURES (MEDSX) TRIAL: nkt102553_scm
SURGICAL PROCEDURES
1. Breast Operation (MAPPINGS1:t_SURGERY_1A.SPYN1)
[Y] Yes, provide:
Date and time of procedure
/ Req/Unk / Req/Unk (2006-2007) (MAPPINGS1:t_SURGERY_1A.SPDTTM)
Req/Unk
NReq : NReq
Stop date and time of procedure
/ Req/Unk / Req/Unk (2006-2007) (MAPPINGS1:t_SURGERY_1A.SPENDTTM)
Req/Unk
NReq : NReq
[N] No
[U] Unknown
2. Orthopedic Shoulder Surgery (MAPPINGS1:t_SURGERY_1A.SPYN2)
[Y] Yes, provide:
/ Req/Unk / Req/Unk (2006-2007) (MAPPINGS1:t_SURGERY_1A.SPDTT1)
Req/Unk
NReq : NReq
CONFIDENTIAL
/ Req/Unk / Req/Unk (2006-2007) (MAPPINGS1:t_SURGERY_1A.SPENDTT1)
Req/Unk
NReq : NReq
55
[N] No
[U] Unknown
3. Thyroid Operation (MAPPINGS1:t_SURGERY_1A.SPYN3)
[Y] Yes, provide:
Req/Unk
NReq : NReq
Req/Unk
NReq : NReq
[N] No
GM2006/00652/00
[U] Unknown
4. Cholecystectomy (MAPPINGS1:t_SURGERY_1A.SPYN4)
[Y] Yes, provide:
NKT102553
Req/Unk
NReq : NReq
Req/Unk
NReq : NReq
[N] No
[U] Unknown
5. Hysterectomy (MAPPINGS1:t_SURGERY_1A.SPYN5)
[Y] Yes, provide:
Req/Unk
NReq : NReq
Req/Unk
NReq : NReq
[N] No
[U] Unknown
MedDRA lower Date and Time of Stop Date and Time
Sequence Number Specific Procedure Modified Term MedDRA Synonym Failed coding
level term code Procedure of Procedure
OTHER GYNAECOLOGICAL SURGERY Entry Add Entry
Record only one per line for each specific procedure

(MAPPINGS1:t_SURGERY_1A.SPSEQ)
CONFIDENTIAL
6.b Specific Procedure (MAPPINGS1:t_SURGERY_1A.SPTERM)
A100
(MAPPINGS1:t_SURGERY_1A.SPMODIFY)
56
MedDRA Synonym [hidden] (MAPPINGS1:t_SURGERY_1A.SPMEDSYN)
MedDRA lower level term code [hidden] (MAPPINGS1:t_SURGERY_1A.SPLLTCD)
Failed coding [hidden] (MAPPINGS1:t_SURGERY_1A.calSP_FAILED)
6.d Date and Time of Procedure Date and time of procedure

Hr:Min (00:00-23:59) / Req/Unk / Req/Unk (2004-2005) (MAPPINGS1:t_SURGERY_1A.SPDTTM1)
Req/Unk
NReq : NReq
6.e Stop Date and Time of Procedure Stop Date and time of procedure
GM2006/00652/00
Hr:Min (00:00-23:59) / Req/Unk / Req/Unk (2005-2005) (MAPPINGS1:t_SURGERY_1A.SPENDTTM1)
Req/Unk
NReq : NReq
SURGERY DETAILS
NKT102553
7. Was this procedure laparoscopic? (MAPPINGS1:t_SURGERY_1A.SPLAPARO)
[Y] Yes
[N] No
8. Time of induction of anesthesia (MAPPINGS1:t_SURGERY_1A.SPINANTM)
NReq : NReq
9. Time anesthesia was discontinued (MAPPINGS1:t_SURGERY_1A.SPANDSTM)

NReq : NReq
10. Time subject was extubated : NReq (MAPPINGS1:t_SURGERY_1A.SPEXTBTM)

NReq
11. Was a naso-gastric or oral-gastric tube placed during surgery? (MAPPINGS1:t_SURGERY_1A.SPNASO)

[N] No
[Y] (MAPPINGS1:t_SURGERY_1A.SPSUCTAP)
Yes
If yes, Was suction applied post-operatively?
[Y] Yes
[N] No
Form Design Note:
IDSL Version 04.02A - 01 DEC 05 This form is optional. Use this form if specific procedure information is needed. Also, use if a yes/no response is required for each type of procedure. Unknown is an
optional choice. Stop date and time are optional.
CONFIDENTIAL
Title Design Note
OTHER GYNAECOLOGICAL SURGERY This section is optional

57
Item Design Notes:
1. Date and time of procedure and stop date and time of procedure are optional
GM2006/00652/00
6.d Date and time are optional.
NKT102553
6.e Date and time are optional.
CDD: MAPPINGS1 Table: t_SURGERY_1A Key Type: PATIENTVISIT

SPYN1 STRING(1)
SPDTTM DATE - DDMONYYYY HHMM

SPENDTTM DATE - DDMONYYYY HHMM
SPYN2 STRING(1)
SPDTT1 DATE - DDMONYYYY HHMM
SPENDTT1 DATE - DDMONYYYY HHMM
SPYN3 STRING(1)
SPYN4 STRING(1)
SPYN5 STRING(1)
CONFIDENTIAL
SPSEQ NUMERIC - N4
SPTERM STRING(100) - A100
SPMODIFY STRING(100) - A100
58
SPMEDSYN STRING(255)
SPLLTCD STRING(255)
calSP_FAILED STRING(255)
SPDTTM1 DATE - DDMONYYYY HHMM
SPENDTTM1 DATE - DDMONYYYY HHMM
SPLAPARO STRING(1)
SPINANTM DATE - HHMM
GM2006/00652/00
SPANDSTM DATE - HHMM
SPEXTBTM DATE - HHMM
SPNASO STRING(1)
NKT102553
SPSUCTAP STRING(1)
FORM: PERI-OPERATIVE MEDICATIONS (PERI-OP MEDS) TRIAL: nkt102553_scm New
Drug Name
# Unit Dose Units Frequency Route Reason for Medication Start Date and Time Ongoing?
(Trade Name preferred)
PERI-OPERATIVE MEDICATIONS
Sequence Number [hidden] (MAPPINGS1:t_CONMEDS_PO.CMSEQ)
1. Drug Name (MAPPINGS1:t_CONMEDS_PO.CMTERM)

A100

Modified reported term [hidden] (MAPPINGS1:t_CONMEDS_PO.CMMODIFY)
2.* A100
GSK Drug synonym [hidden] (MAPPINGS1:t_CONMEDS_PO.CMDRGSYN)
CONFIDENTIAL
GSK Drug Collection code [hidden] (MAPPINGS1:t_CONMEDS_PO.CMDRGCOL)
Failed coding [hidden] (MAPPINGS1:t_CONMEDS_PO.calCM_FAILED)
3. Unit Dose (MAPPINGS1:t_CONMEDS_PO.CMUDOS)

A10
59
4. Units (MAPPINGS1:t_CONMEDS_PO.CMUNIT)
Pulldown List 1
5. Frequency (MAPPINGS1:t_CONMEDS_PO.CMFREQ)
Pulldown List 2
6. Route (MAPPINGS1:t_CONMEDS_PO.CMROUTCD)
Pulldown List 3
7. Reason for Medication (MAPPINGS1:t_CONMEDS_PO.CMSTRSCD)

Pulldown List 4
8. Start Date and Time / Req/Unk / Req/Unk (2006-2007) (MAPPINGS1:t_CONMEDS_PO.CMSTDTTM)

Req/Unk
Hr:Min (00:00-23:59)
NReq : NReq
GM2006/00652/00
9. Ongoing? (MAPPINGS1:t_CONMEDS_PO.CMONGO)
Hr:Min (00:00-23:59) [Y] Yes
[N] No, specify End Date and Time
/ Req/Unk / Req/Unk (2006-2007) (MAPPINGS1:t_CONMEDS_PO.CMENDTTM)
NKT102553
Req/Unk
NReq : NReq
Medication Type [hidden] (MAPPINGS1:t_CONMEDS_PO.CMTYPCD)

Form Design Note:
IDSL Version 03.02A - 16 NOV 2005. This form can be used for disease specific conmeds or as a generic conmed form. If both are required in the trial, copy this form and adjust the form title and
section titles
Title Design Note
PERI-OPERATIVE MEDICATIONS The following items can be added and made hidden: CMCAT, CMSCAT.
sctCMTYPCD This section is required and should be the last section on this form.
Item Design Notes:
CONFIDENTIAL

60
8. Time is optional
9. Time is optional
itmCMTYPCD This item will be calculated by InForm
Pulldown List 1:
RefName Display Text Value Design Note
GM2006/00652/00
mestrUnitPer Percent %
mestrUnitCAP Capsule CAP
NKT102553
mestrUnitGM Gram G
mestrUnitGTT Drops GTT
mestrUnitL Litre L
mestrUnitLOZ Lozenge LOZ
mestrUnitMCG Microgram (MCG) MCG
mestrUnitUG Microgram (UG) UG
mestrUnitMCL Microlitre MCL

mestrUnitMEQ Milliequivalent MEQ
mestrUnitMG Milligram MG
mestrUnitML Millilitre ML
mestrUnitPUFF Puff PUFF
mestrUnitSP Spray SPR
mestrUnitTBSP Tablespoon TBLSP
mestrUnitTAB Tablet TAB
mestrUnitTSP Teaspoon TSP
mestrUnitUNIT Units U
mestrUnitUNK Unknown UNK
Pulldown List 2:
CONFIDENTIAL
mestrFreqQD Once daily QD
mestrFreqBID BID BID
61
mestrFreqTID TID TID

mestrFreqQID QID QID
mestrFreq5XD 5 times per day 5XD
mestrFreqHS HS HS
mestrFreqPRN PRN PRN
mestrFreqQH QH QH
mestrFreqQ2H Q2H Q2H
GM2006/00652/00
NKT102553
mestrFreqQOD Every other day QOD
mestrFreqQAM QAM QAM
mestrFreqQPM QPM QPM
mestrFreqQ3D Q3D Q3D
mestrFreqQWK Once a week QWK

mestrFreq2XWK 2 times per week 2XWK
mestrFreqQ2WK Every 2 weeks Q2WK
mestrFreqQM Once a month QM
mestrFreqQ3M Every 3 months Q3M
mestrFreqAC AC AC
mestrFreqCINF Continuous infusion CINF
mestrFreqONE Once only ONE
mestrFreqPC PC PC
mestrFreqUNK Unknown UNK
CONFIDENTIAL
Pulldown List 3:
62

mestrRouteIH Inhalation IH
mestrRouteIA Intra-arterial IA
mestrRouteIART Intra-articular IART
mestrRouteID Intradermal ID
mestrRouteIL Intralesional ILES
mestrRouteIM Intramuscular IM
mestrRouteIP Intraperitoneal IP
GM2006/00652/00
mestrRouteIT Intrathecal IT
mestrRouteIV Intravenous IV
NKT102553
mestrRouteNS Nasal NS
mestrRouteOTH Other OTH
mestrRoutePO Oral PO
mestrRoutePR Rectal PR
mestrRouteSC Subcutaneous SC
mestrRouteSL Sublingual SL
mestrRouteTP Topical TP
mestrRouteTD Transdermal TD
mestrRouteUNK Unknown UNK
mestrRouteVG Vaginal VG
Pulldown List 4:
estrCSMSTRSCD16 Pre-operative analgesia 16
estrCSMSTRSCD17 Intra-operative analgesia 17
estrCSMSTRSCD18 Induction of anaesthesia 18
estrCSMSTRSCD19 Maintenance of anaesthesia 19
estrCSMSTRSCD20 Pre-operative sedation 20
estrCSMSTRSCD21 Neuromuscular blocking agent 21
CONFIDENTIAL
estrCSMSTRSCD22 Neuromuscular blockade reversal 22
estrCSMSTRSCD23 Post-operative analgesia 23
estrCSMSTRSCDOT Other Other
63
CDD: MAPPINGS1 Table: t_CONMEDS_PO Key Type: PATIENTVISIT

CMSEQ STRING(255)
CMTERM STRING(100) - A100
CMMODIFY STRING(100) - A100
CMDRGSYN STRING(255)
CMDRGCOL STRING(255)
GM2006/00652/00
calCM_FAILED STRING(255)
CMUDOS STRING(10) - A10
NKT102553
CMUNIT STRING(255) - %, CAP, G, GTT, L, LOZ, MCG, UG, MCL, MEQ, MG, ML, PUFF, SPR, TBLSP, TAB, TSP, U, UNK
CMFREQ STRING(255) - QD, BID, TID, QID, 5XD, HS, PRN, QH, Q2H, Q4H, Q6H, Q8H, Q12H, QOD, QAM, QPM, Q3D, Q4D, QWK, 2XWK, 3XWK, 4XWK, 5XWK,
Q2WK, Q3WK, QM, Q3M, AC, CINF, ONE, PC, UNK
CMROUTCD STRING(255) - IH, IA, IART, ID, ILES, IM, IP, IT, IV, NS, OTH, PO, PR, SC, SL, TP, TD, UNK, VG
CMSTRSCD STRING(255) - 16, 17, 18, 19, 20, 21, 22, 23, Other
CMSTDTTM DATE - DDMONYYYY HHMM
CMONGO STRING(1)
CMENDTTM DATE - DDMONYYYY HHMM
CMTYPCD STRING(255)
CONFIDENTIAL
64
GM2006/00652/00
NKT102553
FORM: 12-LEAD ECG (ECG) TRIAL: nkt102553_scm
12-LEAD ECG
1. Date of ECG / Req / Req (2006-2007) (MAPPINGS1:t_ECG_NOABN.EGDTTM)
Req
2. Result of the ECG (MAPPINGS1:t_ECG_NOABN.EGINTPCD1)

[1] Normal
[2] Abnormal - Not clinically significant
[3] Abnormal, clinically significant (complete the AE/SAE form if clinically significant
abnormalities meet the protocol definition for an AE/SAE)
Form Design Note:
IDSL Version 02.02B - 11 NOV 05. This form is optional and should be used when abnormalities are not collected, or when abnormalities are collected on a separate form. Trial designer to modify the
form and section title per protocol
CONFIDENTIAL
Item Design Notes:
1. Time is optional.
65
CDD: MAPPINGS1 Table: t_ECG_NOABN Key Type: PATIENTVISIT

EGDTTM DATE - DDMONYYYY
EGINTPCD1 STRING(1)
GM2006/00652/00
NKT102553
FORM: LOCAL LABORATORY - CLINICAL CHEMISTRY (CHEM) TRIAL: nkt102553_scm
If the lab result meets the protocol definition of an adverse event, record the details on the Non-Serious Adverse Event or Serious Adverse Event form.
LOCAL LABORATORY - CLINICAL CHEMISTRY
(MAPPINGS1:t_LAB_CHEM1.LBIDCD)
2. Laboratory name and address (MAPPINGS1:t_LAB_CHEM1.rdcLBNAME)

[-98] Results from the same lab as in the previous visit
[-99] Please provide:
Laboratory name (MAPPINGS1:t_LAB_CHEM1.LBNAME)
A80
Address (MAPPINGS1:t_LAB_CHEM1.LBADRS)
A80
3. Date sample taken / Req / Req (2006-2007) (MAPPINGS1:t_LAB_CHEM1.LBDTTM)

Req
4. Has the subject fasted? (MAPPINGS1:t_LAB_CHEM1.LBFAST)
CONFIDENTIAL
[Y] Yes
[N] No
5. Albumin (MAPPINGS1:t_LAB_CHEM1.rdcLBORRES)
[-97] Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM1.LBORRESN)
66
[-99] No result
6. Alkaline Phosphatase (MAPPINGS1:t_LAB_CHEM1.rdcLBORRE1)
[-97] Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM1.LBORRES1)
[-99] No result
7. ALT (MAPPINGS1:t_LAB_CHEM1.rdcLBORRE2)
[-99] No result
8. AST (MAPPINGS1:t_LAB_CHEM1.rdcLBORRE3)
GM2006/00652/00
[-99] No result
9. BUN or serum urea (MAPPINGS1:t_LAB_CHEM1.rdcLBORRE4)
NKT102553
[-99] No result
10. Creatinine (MAPPINGS1:t_LAB_CHEM1.rdcLBORRE5)
[-99] No result
11. Bicarbonate (MAPPINGS1:t_LAB_CHEM1.rdcLBORRE6)
[-99] No result
12. Chloride (MAPPINGS1:t_LAB_CHEM1.rdcLBORRE7)
[-99] No result
13. Potassium (MAPPINGS1:t_LAB_CHEM1.rdcLBORRE8)
[-99] No result
14. Sodium (MAPPINGS1:t_LAB_CHEM1.rdcLBORRE9)
[-99] No result
15. Glucose (MAPPINGS1:t_LAB_CHEM1.rdcLBORR10)
[-97] Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM1.LBORRE10)
[-99] No result
16. Total Bilirubin (MAPPINGS1:t_LAB_CHEM1.rdcLBORR11)
[-99] No result
CONFIDENTIAL
17. Total Protein (MAPPINGS1:t_LAB_CHEM1.rdcLBORR12)
[-99] No result
67
18. Triglycerides (MAPPINGS1:t_LAB_CHEM1.rdcLBORR13)

[-99] No result
Form Design Note:
IDSL Version 01.01A - 01 Feb 2005 This form is optional. This form is to be used when a single lab is collected at a visit. This is only used for the Clinical Chemistry tests
GM2006/00652/00
Title Design Note
NKT102553
LOCAL LABORATORY - CLINICAL CHEMISTRY Use separate items for Name and address for the first occurrence of this form, and use the combined item for subsequent visits.
Item Design Notes:

3. Time is optional
CDD: MAPPINGS1 Table: t_LAB_CHEM1 Key Type: PATIENTVISIT

rdcLBNAME STRING(3)
LBNAME STRING(80) - A80
LBADRS STRING(80) - A80
LBFAST STRING(1)
CONFIDENTIAL
68
GM2006/00652/00
NKT102553

CONFIDENTIAL
69
GM2006/00652/00
NKT102553
FORM: LOCAL LABORATORY - HAEMATOLOGY (HAEM) TRIAL: nkt102553_scm
If the lab result meets the protocol definition of an adverse event, record the details on the Non-Serious Adverse Event or Serious Adverse Event form.
LOCAL LABORATORY - HAEMATOLOGY
(MAPPINGS1:t_LAB_HAEMA1.LBIDCD)
2. Laboratory name and address (MAPPINGS1:t_LAB_HAEMA1.rdcLBNAME)

[-98] Results from the same lab as in the previous visit
[-99] Please provide:
Laboratory name (MAPPINGS1:t_LAB_HAEMA1.LBNAME)
A80
Address (MAPPINGS1:t_LAB_HAEMA1.LBADRS)
A80
3. Date sample taken / Req / Req (2006-2007) (MAPPINGS1:t_LAB_HAEMA1.LBDTTM)

Req
4. Has the subject fasted? (MAPPINGS1:t_LAB_HAEMA1.LBFAST)
CONFIDENTIAL
[Y] Yes
[N] No
5. Haemoglobin (MAPPINGS1:t_LAB_HAEMA1.rdcLBORRES)
[-97] Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA1.LBORRESN)
70
[-99] No result
6. Haematocrit (MAPPINGS1:t_LAB_HAEMA1.rdcLBORRE1)
[-97] Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA1.LBORRES1)
[-99] No result
7. WBC (MAPPINGS1:t_LAB_HAEMA1.rdcLBORRE2)
[-99] No result
8. Platelets (MAPPINGS1:t_LAB_HAEMA1.rdcLBORRE3)
GM2006/00652/00
[-99] No result
9. Total Neutrophils (MAPPINGS1:t_LAB_HAEMA1.rdcLBORRE4)
NKT102553
[-99] No result
10. Lymphocytes (MAPPINGS1:t_LAB_HAEMA1.rdcLBORRE5)
[-99] No result
11. Monocytes (MAPPINGS1:t_LAB_HAEMA1.rdcLBORRE6)
[-99] No result
12. Eosinophils (MAPPINGS1:t_LAB_HAEMA1.rdcLBORRE7)
[-99] No result
13. Basophils (MAPPINGS1:t_LAB_HAEMA1.rdcLBORRE8)
[-99] No result
Form Design Note:
IDSL Version 01.02A - 12 Aug 2005 This form is optional. This form is to be used when a single lab is collected at a visit. This is only used for the Haematology tests
CONFIDENTIAL
Title Design Note
LOCAL LABORATORY - HAEMATOLOGY Use separate items for Name and address for the first occurance of this form, and use the combined item for subsequent visits.
71
Item Design Notes:
3. Time is optional
GM2006/00652/00
CDD: MAPPINGS1 Table: t_LAB_HAEMA1 Key Type: PATIENTVISIT
NKT102553
rdcLBNAME STRING(3)
LBNAME STRING(80) - A80
LBADRS STRING(80) - A80
LBFAST STRING(1)
CONFIDENTIAL
72
GM2006/00652/00
NKT102553
FORM: Unscheduled Related Healthcare Utilisation (HCU) TRIAL: nkt102553_scm
Unscheduled Nausea and Vomiting Related Healthcare Utilisation

1. Were there any nausea and vomiting related healthcare contacts up to the post-op Days 6-14 final (MAPPINGS1:t_UNSHCC.RELCONT)
study visit? [Y] Yes
[N] No
[U] Unknown
2. Number of primary physician care visits (MAPPINGS1:t_UNSHCC.PCPVSN)
xx
3. Number of nurse practicioner/physician's assist./nurse visits (MAPPINGS1:t_UNSHCC.PANURVSN)

xx
4. Number of non-study laboratory visits (MAPPINGS1:t_UNSHCC.NSTLBVSN)

xx
5. Number of home healthcare visits (MAPPINGS1:t_UNSHCC.HMHCVSN)

xx
6. Number of telephone calls (MAPPINGS1:t_UNSHCC.PHONEN)

xx
7. Number of medical specialist visits (MAPPINGS1:t_UNSHCC.MSPVSN)

xx
CONFIDENTIAL
8. Number of emergency room visits (MAPPINGS1:t_UNSHCC.ERVSN)
xx
9. Number of hospitalisation days (MAPPINGS1:t_UNSHCC.HOSPDYN)

xx
73
10. Was this contact due to an adverse event? (MAPPINGS1:t_UNSHCC.CONTAE)

[Y] Yes
[N] No
CDD: MAPPINGS1 Table: t_UNSHCC Key Type: PATIENTVISIT

RELCONT STRING(1)
PCPVSN NUMERIC - N2
PANURVSN NUMERIC - N2
GM2006/00652/00
NSTLBVSN NUMERIC - N2
HMHCVSN NUMERIC - N2
NKT102553
PHONEN NUMERIC - N2
MSPVSN NUMERIC - N2
ERVSN NUMERIC - N2
HOSPDYN NUMERIC - N2
CONTAE STRING(1)
NKT102553
Page 74 of 107
Annotated Trial Design 74
FORM: PGx-PHARMACOGENETIC RESEARCH CONSENT (GEN-CONSENT) TRIAL: nkt102553_scm
PGx-PHARMACOGENETIC RESEARCH CONSENT

1. Has informed consent been obtained for PGx-Pharmacogenetic research? (MAPPINGS1:t_GENPRO_CONSENT.GPCNS)
[Y] Yes, record:
Date informed consent obtained for PGx-Pharmacogenetic research
/ Req / Req (2006-2007) (MAPPINGS1:t_GENPRO_CONSENT.GPCNSDT)
Req
(MAPPINGS1:t_GENPRO_CONSENT.GPSMPCOL)
Has a blood sample been collected for PGx-pharmacogenetic (DNA) research?
[N] No
[Y] Yes, record date sample taken
/ Req / Req (2006-2007) (MAPPINGS1:t_GENPRO_CONSENT.GPSMPDT)
Req
[N] (MAPPINGS1:t_GENPRO_CONSENT.GPCNRSCD)
No, check reason
[1] Subject declined
[2] Subject not asked by Investigator
[Z] Other, specify (MAPPINGS1:t_GENPRO_CONSENT.GPCNSOTH)
A100
CONFIDENTIAL
Genetics Type [hidden] (MAPPINGS1:t_GENPRO_CONSENT.GPTYPCD)
Sample type [hidden] (MAPPINGS1:t_GENPRO_CONSENT.GPSMPTCD)

75
Form Design Note:
IDSL Version 02.00A - 21 APR 05 This form should only exist once in the study and is conditional upon inclusion of Pharmacogenetics in the protocol.
Title Design Note
sctGPTYPCD This section is required and should be the last section on this form.
GM2006/00652/00
Item Design Notes:
NKT102553
itmGPTYPCD This item will be calculated by InForm
itmGPSMPT This item will be calculated by InForm

CDD: MAPPINGS1 Table: t_GENPRO_CONSENT Key Type: PATIENTVISIT

GPCNS STRING(1)
GPCNSDT DATE - DDMONYYYY
GPSMPCOL STRING(1)
GPSMPDT DATE - DDMONYYYY
GPCNRSCD STRING(1)
GPCNSOTH STRING(100) - A100
GPTYPCD STRING(255)
GPSMPTCD STRING(255)
CONFIDENTIAL
76
GM2006/00652/00
NKT102553
FORM: PGx-PHARMACOGENETIC RESEARCH WITHDRAWAL OF CONSENT (GEN-WD) TRIAL: nkt102553_scm
PGx-PHARMACOGENETIC RESEARCH WITHDRAWAL OF CONSENT

1. Has subject withdrawn consent for PGx-Pharmacogenetic research? (MAPPINGS1:t_GENPRO_WD.GPCNSWD)
[Y] Yes
[N] No
2. Has a request been made for sample destruction? (MAPPINGS1:t_GENPRO_WD.GPDSREQ)
[N] No
[Y] (MAPPINGS1:t_GENPRO_WD.GPDSRSCD)
Yes, check reason
[1] Subject requested
[2] Screen failure
[Z] Other, specify (MAPPINGS1:t_GENPRO_WD.GPDSOTH)
A100
Genetics Type [hidden] (MAPPINGS1:t_GENPRO_WD.GPTYPCD)
Sample type [hidden] (MAPPINGS1:t_GENPRO_WD.GPSMPTCD)
CONFIDENTIAL
Form Design Note:
IDSL Version 01.00A - 01 DEC 04 This form will be dynamically created when question 1, Has a blood sample been collected is Yes. This form is conditional upon inclusion of Pharmacogenetics in the
77
protocol.
Title Design Note
sctGPTYPCD This section is required and should be the last section on this form.
GM2006/00652/00
Item Design Notes:
2. Screen failure is an optional choice
NKT102553
itmGPTYPCD This item will be calculated by InForm
itmGPSMPT This item will be calculated by InForm
CDD: MAPPINGS1 Table: t_GENPRO_WD Key Type: PATIENTVISIT


GPCNSWD STRING(1)
GPDSREQ STRING(1)
GPDSRSCD STRING(1)
GPDSOTH STRING(100) - A100
GPTYPCD STRING(255)
GPSMPTCD STRING(255)
CONFIDENTIAL
78
GM2006/00652/00
NKT102553
FORM: CONCOMITANT MEDICATIONS (CONMEDS) TRIAL: nkt102553_scm New
Drug Name
# Unit Dose Units Frequency Route Reason for Medication Start Date and Time Ongoing? Was drug administered as a rescue medication?
CONCOMITANT MEDICATIONS
Sequence Number [hidden] (MAPPINGS1:t_CONMEDS.CMSEQ)
1. Drug Name (MAPPINGS1:t_CONMEDS.CMTERM)

A100

Modified reported term [hidden] (MAPPINGS1:t_CONMEDS.CMMODIFY)
2.* A100
GSK Drug synonym [hidden] (MAPPINGS1:t_CONMEDS.CMDRGSYN)
CONFIDENTIAL
GSK Drug Collection code [hidden] (MAPPINGS1:t_CONMEDS.CMDRGCOL)
Failed coding [hidden] (MAPPINGS1:t_CONMEDS.calCM_FAILED)
3. Unit Dose (MAPPINGS1:t_CONMEDS.CMUDOS)

A10
79
4. Units (MAPPINGS1:t_CONMEDS.CMUNIT)
Pulldown List 1
5. Frequency (MAPPINGS1:t_CONMEDS.CMFREQ)
Pulldown List 2
6. Route (MAPPINGS1:t_CONMEDS.CMROUTCD)
Pulldown List 3
7. Reason for Medication (MAPPINGS1:t_CONMEDS.CMREAS)

A70
8. Start Date and Time / Req/Unk / Req/Unk (2006-2007) (MAPPINGS1:t_CONMEDS.CMSTDTTM)

Req/Unk
Hr:Min (00:00-23:59)
GM2006/00652/00
NReq : NReq
9. Ongoing? (MAPPINGS1:t_CONMEDS.CMONGO)
Hr:Min (00:00-23:59) [Y] Yes
NKT102553
[N] No, specify End Date and Time
/ Req/Unk / Req/Unk (2006-2007) (MAPPINGS1:t_CONMEDS.CMENDTTM)
Req/Unk
NReq : NReq
10. Was drug administered as a rescue medication? (MAPPINGS1:t_CONMEDS.CMDRGRES)

[Y] Yes
Answer 'Yes' only if the drug was administered as an antiemetic and/or anti-nausea rescue [N] No
medication.
Medication Type [hidden] (MAPPINGS1:t_CONMEDS.CMTYPCD)
Form Design Note:
IDSL Version 03.02A - 16 NOV 2005. This form can be used for disease specific conmeds or as a generic conmed form. If both are required in the trial, copy this form and adjust the form title and
section titles
Title Design Note
CONCOMITANT MEDICATIONS The following items can be added and made hidden: CMCAT, CMSCAT.
sctCMTYPCD This section is required and should be the last section on this form.
CONFIDENTIAL
Item Design Notes:

80
8. Time is optional
9. Time is optional
GM2006/00652/00
itmCMTYPCD This item will be calculated by InForm
NKT102553
Pulldown List 1:
mestrUnitPer Percent %
mestrUnitCAP Capsule CAP
mestrUnitGM Gram G
mestrUnitGTT Drops GTT
mestrUnitL Litre L
mestrUnitLOZ Lozenge LOZ
mestrUnitMCG Microgram (MCG) MCG
mestrUnitUG Microgram (UG) UG
mestrUnitMCL Microlitre MCL
mestrUnitMEQ Milliequivalent MEQ
mestrUnitMG Milligram MG
mestrUnitML Millilitre ML
mestrUnitPUFF Puff PUFF
mestrUnitSP Spray SPR
mestrUnitTBSP Tablespoon TBLSP
mestrUnitTAB Tablet TAB
CONFIDENTIAL
mestrUnitTSP Teaspoon TSP
mestrUnitUNIT Units U
mestrUnitUNK Unknown UNK
81
Pulldown List 2:
mestrFreqQD Once daily QD
mestrFreqBID BID BID
mestrFreqTID TID TID
mestrFreqQID QID QID
GM2006/00652/00
mestrFreq5XD 5 times per day 5XD
mestrFreqHS HS HS
NKT102553
mestrFreqPRN PRN PRN
mestrFreqQH QH QH

mestrFreqQOD Every other day QOD
mestrFreqQAM QAM QAM
mestrFreqQPM QPM QPM
mestrFreqQWK Once a week QWK
mestrFreqQM Once a month QM
CONFIDENTIAL
mestrFreqQ3M Every 3 months Q3M
mestrFreqAC AC AC
mestrFreqCINF Continuous infusion CINF
82
mestrFreqONE Once only ONE

mestrFreqPC PC PC
mestrFreqUNK Unknown UNK
Pulldown List 3:
mestrRouteIH Inhalation IH
GM2006/00652/00
mestrRouteIA Intra-arterial IA
mestrRouteIART Intra-articular IART
NKT102553
mestrRouteID Intradermal ID
mestrRouteIL Intralesional ILES
mestrRouteIM Intramuscular IM
mestrRouteIP Intraperitoneal IP
mestrRouteIT Intrathecal IT
mestrRouteIV Intravenous IV
mestrRouteNS Nasal NS
mestrRouteOTH Other OTH
mestrRoutePO Oral PO
mestrRoutePR Rectal PR
mestrRouteSC Subcutaneous SC
mestrRouteSL Sublingual SL
mestrRouteTP Topical TP
mestrRouteTD Transdermal TD
mestrRouteUNK Unknown UNK
mestrRouteVG Vaginal VG
CDD: MAPPINGS1 Table: t_CONMEDS Key Type: PATIENTVISIT

CONFIDENTIAL
CMSEQ STRING(255)
CMTERM STRING(100) - A100
CMMODIFY STRING(100) - A100
83
CMDRGSYN STRING(255)
CMDRGCOL STRING(255)
calCM_FAILED STRING(255)
CMUDOS STRING(10) - A10
CMUNIT STRING(255) - %, CAP, G, GTT, L, LOZ, MCG, UG, MCL, MEQ, MG, ML, PUFF, SPR, TBLSP, TAB, TSP, U, UNK
CMFREQ STRING(255) - QD, BID, TID, QID, 5XD, HS, PRN, QH, Q2H, Q4H, Q6H, Q8H, Q12H, QOD, QAM, QPM, Q3D, Q4D, QWK, 2XWK, 3XWK, 4XWK, 5XWK,
Q2WK, Q3WK, QM, Q3M, AC, CINF, ONE, PC, UNK
CMROUTCD STRING(255) - IH, IA, IART, ID, ILES, IM, IP, IT, IV, NS, OTH, PO, PR, SC, SL, TP, TD, UNK, VG
CMREAS STRING(70) - A70
GM2006/00652/00
CMSTDTTM DATE - DDMONYYYY HHMM
CMONGO STRING(1)
NKT102553
CMENDTTM DATE - DDMONYYYY HHMM
CMDRGRES STRING(1)
CMTYPCD STRING(255)
FORM: NON-SERIOUS ADVERSE EVENT (AE) TRIAL: nkt102553_scm New
# Event Start Date and Time Outcome Maximum Intensity Action Taken Subject Withdrawn? Relationship
NON-SERIOUS ADVERSE EVENT

Sequence Number [hidden] (MAPPINGS1:t_AE.AESEQ)
1.* A5
2. Event (MAPPINGS1:t_AE.AETERM)
A100
Diagnosis Only (if known) Otherwise Sign/Symptom
Modified term [hidden] (MAPPINGS1:t_AE.AEMODIFY)

3.* A100
MedDRA synonym [hidden] (MAPPINGS1:t_AE.AEMEDSYN)
MedDRA lower level term code [hidden] (MAPPINGS1:t_AE.AELLTCD)
CONFIDENTIAL
Failed coding [hidden] (MAPPINGS1:t_AE.calAE_FAILED)
4. Start Date and Time / Req / Req (2006-2007) (MAPPINGS1:t_AE.AESTDTTM)

Req
Hr:Min (00:00-23:59)
NReq : NReq
84
5. Outcome / End Date and Time (MAPPINGS1:t_AE.AEOUTCD)

Hr:Min (00:00-23:59) [1] Recovered/Resolved, provide End Date and Time
/ Req / Req (2006-2007) (MAPPINGS1:t_AE.AEENDTTM1)
Req
NReq : NReq
[2] Recovering/Resolving
[3] Not recovered/Not resolved
[4] Recovered/Resolved with sequelae, provide End Date and Time
/ Req / Req (2006-2007) (MAPPINGS1:t_AE.AEENDTTM2)
Req
NReq : NReq
GM2006/00652/00
6. Frequency [hidden] (MAPPINGS1:t_AE.AEFREQCD)
[1] Single Episode
[2] Intermittent
7. Maximum Intensity (MAPPINGS1:t_AE.AESEVCD)
NKT102553
[1] Mild
[2] Moderate
[3] Severe
[X] Not applicable
8.* Maximum Toxicity [hidden] (MAPPINGS1:t_AE.AETOXCD)

[1] Grade 1
[2] Grade 2
[3] Grade 3
[4] Grade 4
[5] Grade 5
[X] Not applicable
9.* Maximum Toxicity or Intensity [hidden] (MAPPINGS1:t_AE.AETXHVCD)

[1] Mild or Grade 1
[2] Moderate or Grade 2
[3] Severe or Grade 3
[4] Grade 4
[5] Grade 5
[X] Not applicable
10. Action Taken with Investigational Product(s) as a Result of the (MAPPINGS1:t_AE.AEACTRCD)
AE [1] Investigational product(s) withdrawn
[2] Dose reduced
[3] Dose increased
[4] Dose not changed
[5] Dose interrupted
[X] Not applicable
11. Did the subject withdraw from study as a result of this AE? (MAPPINGS1:t_AE.AEWD)
[Y] Yes
[N] No
CONFIDENTIAL
12. Is there a reasonable possibility that the AE may have been (MAPPINGS1:t_AE.AEREL)
caused by the investigational product? [Y] Yes
[N] No
(MAPPINGS1:t_AE.AEDURHR) (MAPPINGS1:t_AE.AEDURMIN)
13.* Duration of AE if < 24 hours [hidden] xx ( 0 =< n <= 23 ) xx ( 0 =< n <= 59 )
85
Hr(s) Min(s)
Time to Onset Since Last Dose [hidden] (MAPPINGS1:t_AE.AEONLDSH) (MAPPINGS1:t_AE.AEONLDSM)
14.* xx xx ( 0 =< n <= 59 )
Hr(s) Min(s)
Form Design Note:
IDSL Version 03.01A - 16 NOV 2005
GM2006/00652/00
Item Design Notes:
NKT102553
4. Start Time is optional
5. End Time is optional

7. Optional item:
This item may be hidden if either the "Maximum Toxicity" or "Maximum Toxicity or Intensity" item has been used.
Grade 5 is optional.
8. Optional item:
This item may be hidden if either the "Maximum Intensity" or "Maximum Toxicity or Intensity" item has been used
9. Optional item:
This item may be hidden if either the "Maximum Intensity" or "Maximum Toxicity" item has been used
13. If AE start and end time are used this item must be hidden.
CDD: MAPPINGS1 Table: t_AE Key Type: PATIENTVISIT

AESEQ STRING(5) - A5
CONFIDENTIAL
AETERM STRING(100) - A100
AEMODIFY STRING(100) - A100
AEMEDSYN STRING(255)
86
AELLTCD STRING(255)
calAE_FAILED STRING(255)
AESTDTTM DATE - DDMONYYYY HHMM
AEOUTCD STRING(1)
AEENDTTM1 DATE - DDMONYYYY HHMM
AEFREQCD STRING(1)
AESEVCD STRING(1)
GM2006/00652/00
AETOXCD STRING(1)
AETXHVCD STRING(1)
NKT102553
AEACTRCD STRING(1)
AEWD STRING(1)
AEREL STRING(1)
AEDURHR NUMERIC - N2
AEDURMIN NUMERIC - N2
AEONLDSH NUMERIC - N2
AEONLDSM NUMERIC - N2
CONFIDENTIAL
87
GM2006/00652/00
NKT102553
FORM: SERIOUS ADVERSE EVENTS (SAE) TRIAL: nkt102553_scm New
If Investigational
product(s) stopped,
Did SAE Relevant
RELEVANT did the reported
Follow- occur after SERIOUS RELEVANT Medical RELEVANT Relevant General
Initial MEDICAL event(s) recur after
# Up initiation of ADVERSE Serious? CONCOMITANT/TREATMENT History / DIAGNOSTIC diagnostic narrative
Report CONDITIONS/RISK further
Report study EVENT MEDICATIONS Risk RESULTS results comments
FACTORS investigational
medication? Factors
product(s) were
administered?
If you wish to record a new SAE please determine if the new SAE is clinically or temporally related to an SAE previously entered on this form. If
yes, please record details below. If no, please create a new SAE form for this subject. Do not record pre and post randomisation events on the
same form.
TYPE OF REPORT
1.* Initial Report [read-only] (MAPPINGS1:t_AE_SER.chkSAE)
CONFIDENTIAL
[1] Initial
2.* Follow-Up Report [read-only] (MAPPINGS1:t_AE_SER.chkFU)

[2] Follow-Up
RANDOMISATION
88
3. Did SAE occur after initiation of study medication? (MAPPINGS1:t_AE_SER.rdcSAERAND)

[N] No
[Y] Yes
MedDRA
Start Maximum Duration Was
SAE lower Was the
Modified MedDRA Failed Date Maximum Maximum Toxicity Action Subject of AE if Time to SAE
Sequence Event level Outcome Relationship event
term synonym coding and Intensity Toxicity or Taken Withdrawn? < 24 Onset study
Number term serious?
Time Intensity hours related?
code
4. [hidden] [hidden] [hidden] [hidden] [hidden] [hidden] [hidden] [hidden] [hidden] [hidden
SERIOUS ADVERSE EVENT Entry Add Entry
GM2006/00652/00
SAE Sequence Number [hidden] (MAPPINGS1:t_AE_SER.AESEQ)
4.a* A5
4.b Serious Adverse Event (MAPPINGS1:t_AE_SER.AETERM)

A100
NKT102553
Diagnosis Only (if known) Otherwise Sign/Symptom
Modified term [hidden] (MAPPINGS1:t_AE_SER.AEMODIFY)

4.c* A100
MedDRA synonym [hidden] (MAPPINGS1:t_AE_SER.AEMEDSYN)
MedDRA lower level term code [hidden] (MAPPINGS1:t_AE_SER.AELLTCD)

Failed coding [hidden] (MAPPINGS1:t_AE_SER.calAE_FAILED)
4.d Start Date and Time / Req / Req (2006-2007) (MAPPINGS1:t_AE_SER.AESTDTTM)

Req
Hr:Min (00:00-23:59)
NReq : NReq
4.e Outcome / End Date and Time (MAPPINGS1:t_AE_SER.AEOUTCD1)

Hr:Min (00:00-23:59) [1] Recovered/Resolved, provide End Date and Time
/ Req / Req (2006-2007) (MAPPINGS1:t_AE_SER.AEENDTTM1)
Req
NReq : NReq
[2] Recovering/Resolving
[3] Not recovered/Not resolved
[4] Recovered/Resolved with sequelae, provide End Date and Time
Req
NReq : NReq
[5] Fatal, record Date and Time of Death
Req
NReq : NReq
4.f Maximum Intensity (MAPPINGS1:t_AE_SER.AESEVCD)

[1] Mild
CONFIDENTIAL
[2] Moderate
[3] Severe
[X] Not applicable
4.g* Maximum Toxicity [hidden] (MAPPINGS1:t_AE_SER.AETOXCD)

89
[1] Grade 1
[2] Grade 2
[3] Grade 3
[4] Grade 4
[5] Grade 5
[X] Not applicable
4.h* Maximum Toxicity or Intensity [hidden] (MAPPINGS1:t_AE_SER.AETXHVCD)

[1] Mild or Grade 1
[2] Moderate or Grade 2
[3] Severe or Grade 3
[4] Grade 4
[5] Grade 5
GM2006/00652/00
[X] Not applicable
4.i Action Taken with Investigational Product(s) as a Result of (MAPPINGS1:t_AE_SER.AEACTRCD)
the AE [1] Investigational product(s) withdrawn
Dose reduced
NKT102553
[2]
[3] Dose increased
[4] Dose not changed
[5] Dose interrupted
[X] Not applicable
4.j Did the subject withdraw from study as a result of this AE? (MAPPINGS1:t_AE_SER.AEWD)
[Y] Yes
[N] No
4.k Is there a reasonable possibility that the AE may have been (MAPPINGS1:t_AE_SER.AEREL)
caused by the investigational product? [Y] Yes
[N] No
Duration of AE if < 24 hours [hidden] (MAPPINGS1:t_AE_SER.AEDURHR) (MAPPINGS1:t_AE_SER.AEDURMIN)
4.l* xx ( 0 =< n <= 23 ) xx ( 0 =< n <= 59 )
Hr(s) Min(s)
(MAPPINGS1:t_AE_SER.AEONLDSH) (MAPPINGS1:t_AE_SER.AEONLDSM)
4.m* Time to Onset Since Last Dose [hidden] xx xx ( 0 =< n <= 59 )
Hr(s) Min(s)
4.n Was SAE caused by activities related to study participation (MAPPINGS1:t_AE_SER.rdcAESREL)
(e.g. procedures)? [Y] Yes
[N] No
4.o* Was the event serious? [hidden] (MAPPINGS1:t_AE_SER.AESER)

[Y] Yes
[N] No
SERIOUSNESS
Specify the reason for considering this an SAE. Check all that apply.
5. Seriousness? (MAPPINGS1:t_AE_SER.AESERDTH)
[A] Results in death
CONFIDENTIAL
(MAPPINGS1:t_AE_SER.AESERLIF)
[B] Is life-threatening
(MAPPINGS1:t_AE_SER.AESERHOS)
[C] Requires hospitalisation or prolongation of existing hospitalisation
(MAPPINGS1:t_AE_SER.AESERDIS)
90
[D] Results in disability/incapacity

(MAPPINGS1:t_AE_SER.AESERCON)
[E] Congenital anomaly/birth defect
(MAPPINGS1:t_AE_SER.AESEROTH)
[F] Other, specify within general narrative comment
Drug Name
CM Sequence Primary
Dose Unit Frequency Route Start Date Ongoing? Drug Type
Number (Trade Name Indication
preferred)
6. [hidden]
RELEVANT CONCOMITANT/TREATMENT MEDICATIONS Entry Add Entry
GM2006/00652/00
Include details of any medication that may have contributed to the SAE or was used to treat the SAE.
(MAPPINGS1:t_AE_SER.txtSAECMSEQ)
6.a* CM Sequence Number [hidden] A4
NKT102553
6.b Drug Name (MAPPINGS1:t_AE_SER.txtCMTERM)
A100

Dose (MAPPINGS1:t_AE_SER.txtSAECMDOS)
6.c* xxxxxxxxx.
(MAPPINGS1:t_AE_SER.pdcCMUNIT)
6.d* Unit Pulldown List 1
(MAPPINGS1:t_AE_SER.pdcSAECMFRQ)
6.e* Frequency Pulldown List 2
(MAPPINGS1:t_AE_SER.pdcCMROUTCD)
6.f* Route Pulldown List 3
(1970-2007) (MAPPINGS1:t_AE_SER.dtmSAECMSTD)
6.g* Start Date Req/Unk / Req/Unk / Req/Unk
6.h* Ongoing? (MAPPINGS1:t_AE_SER.rdcSAECMONG)

[Y] Yes
[N] No, specify End Date
/ Req/Unk / Req/Unk (2006-2007) (MAPPINGS1:t_AE_SER.dtmSAECMEND)
Req/Unk
(MAPPINGS1:t_AE_SER.txtCMIND)
6.i* Primary Indication A50
6.j Drug Type (MAPPINGS1:t_AE_SER.pdcCMDRGTYP)

Pulldown List 4
MHx Sequence Number Specific Condition Name Date of onset Continuing?

7. [hidden]
RELEVANT MEDICAL CONDITIONS/RISK FACTORS Entry Add Entry
Specify past or current medical disorders, allergies, surgeries, family or social history that may help explain the SAE
CONFIDENTIAL
(MAPPINGS1:t_AE_SER.txtMHXSEQ)
7.a* MHx Sequence Number [hidden] A4
7.b Specific Condition Name (MAPPINGS1:t_AE_SER.txtSAEMHTRM)

A100
91
(1970-2007) (MAPPINGS1:t_AE_SER.dtmMHSTDTM)
7.c* Date of onset Req/Unk / Req/Unk / Req
7.d* Continuing? (MAPPINGS1:t_AE_SER.rdcMHCONT)

[Y] Yes
[N] No, specify date of last occurrence
/ Req/Unk / Req (1970-2007) (MAPPINGS1:t_AE_SER.dtmMHLSTOC)
Req/Unk
[U] Unknown
8.* Relevant Medical History / Risk Factors not noted above A1000
GM2006/00652/00
Lab Sequence Number Test Name Test Date Test Result Test Units Normal Low Range Normal High Range
NKT102553
9. [hidden]
RELEVANT DIAGNOSTIC RESULTS Entry Add Entry
Provide details of any tests or procedures carried out to diagnose the SAE.
(MAPPINGS1:t_AE_SER.txtSAELBSEQ)
9.a* Lab Sequence Number [hidden] A4
9.b Test Name (MAPPINGS1:t_AE_SER.pdcLBTST)

Pulldown List 5
9.c Test Date / Req/Unk / Req (2006-2007) (MAPPINGS1:t_AE_SER.dtmLABDTM)

Req/Unk
9.d Test Result (MAPPINGS1:t_AE_SER.txtLABRES)

A50
(MAPPINGS1:t_AE_SER.txtLABUNIT)
9.e* Test Units A35
(MAPPINGS1:t_AE_SER.txtLABNLR)
9.f* Normal Low Range xxxxxxx.
(MAPPINGS1:t_AE_SER.txtLABNHR)
9.g* Normal High Range xxxxxxx.
10.* Relevant diagnostic results not noted above A1000
A1000
CONFIDENTIAL
INVESTIGATIONAL PRODUCTS
11.* If Investigational product(s) stopped, did the reported event(s) recur after further investigational (MAPPINGS1:t_AE_SER.rdcSAEIP)
product(s) were administered? [N] No
[Y] Yes
92
[U] Unknown at this time

GENERAL NARRATIVE COMMENTS
Provide a brief narrative description of SAE, possible other causes of the event (e.g. lack of efficacy, withdrawal of investigational product, the disease under study or other
medical conditions) and details of the treatment.
12. General narrative comments A1000
A1000
GM2006/00652/00
NKT102553
NON CLINICAL
13.* Send incomplete SAE data to GSK Safety [hidden] (MAPPINGS1:t_AE_SER.chkSAESENDI)
[3] Incomplete SAE
(2004-2010) (MAPPINGS1:t_AE_SER.dtmSAEDTM)
14.* Receipt by GSK date [hidden] Req / Req / Req
Req : Req
15.* Was the event serious? [hidden] (MAPPINGS1:t_AE_SER.AESE1)

[Y] Yes
[N] No
(MAPPINGS1:t_AE_SER.AESE2)
16.* SAE Sequence Number [hidden] A5
(MAPPINGS1:t_AE_SER.txtSAEVERSION)
17.* Version Number [hidden] A4
(MAPPINGS1:t_AE_SER.txtSAEID)
18.* Case ID [hidden] A20
(MAPPINGS1:t_AE_SER.txtSAERNDNO)
19.* Randomisation Number [hidden] A255
(MAPPINGS1:t_AE_SER.txtOCEANSCD)
20.* OCEANS Code [hidden] A12
Email Flag [hidden] (MAPPINGS1:t_AE_SER.calSAEEmailFlag)
Form Design Note:
Version 04.01A - 16 NOV 2005
CONFIDENTIAL
Item Design Notes:
93
4.d Start Time is optional
4.e End Time is optional
4.f Optional item:

This item may be hidden if either the "Maximum Toxicity" or "Maximum Toxicity or Intensity" item has been used.
4.g Optional item:

This item may be hidden if either the "Maximum Intensity" or "Maximum Toxicity or Intensity" item has been used
GM2006/00652/00
4.h Optional item:
This item may be hidden if either the "Maximum Intensity" or "Maximum Toxicity" item has been used
NKT102553
4.l If AE start and end time are used this item must be hidden.
4.m This item is optional
5. Optional Criterion
G is an optional criterion and may be removed
2006
Pulldown List 1:
estrSaeUnitACTU Actuation ACTU
estrSaeUnitAMP Ampoule AMP
estrSaeUnitAPP Application AP
estrSaeUnitBOT Bottle BT
estrSaeUnitCAP Capsule CAP
estrSaeUnitCC Cubic centimeter CC
estrSaeUnitGTT Drops 031
estrSaeUnitGM Gram 002
estrSaeUnitIU International units 025
estrSaeUnitIUKG International units per kilogram 028
CONFIDENTIAL
estrSaeUnitIUML International units per millilitre IUML
estrSaeUnitL Litre 011
estrSaeUnitLPM Litre per minute LM
94
estrSaeUnitLOZ Lozenge LOZ

estrSaeUnitMU Megaunits (million units) MEGU
estrSaeUnitMCG Microgram (MCG) 004
estrSaeUnitUG Microgram (UG) 004
estrSaeUnitMCGKG Microgram/kilogram 008
estrSaeUnitMCGKGMIN Microgram/kilogram per minute MCG/KG/MIN
estrSaeUnitMCGMIN Micrograms per minute MCG/MIN
estrSaeUnitMCL Microlitre 013
GM2006/00652/00
estrSaeUnitMEQ Milliequivalent 029
estrSaeUnitMEQ24HR Milliequivalent per 24 hours MEQ24
NKT102553
estrSaeUnitMG Milligram 003
estrSaeUnitMGPER Milligrams percent MGPER
estrSaeUnitMGHR Milligram per hour MGH
estrSaeUnitMGKG Milligram/kilogram 007
estrSaeUnitMGKGHR Milligram/kilogram per hour MGKH
estrSaeUnitMGKGMIN Milligram/kilogram per minute MGKM
estrSaeUnitMGM2 Milligram/metre squared 009

estrSaeUnitMGML Milligram/millilitre MGML
estrSaeUnitML Millilitre 012
estrSaeUnitMLHR Millilitre per hour MLH
estrSaeUnitMLMIN Millilitre per minute MLM
estrSaeUnitMMOL Millimole 023
estrSaeUnitMIU Million international units 027
estrSaeUnitMAC Minimum alveolar concentration MAC
estrSaeUnitNEB Nebule NEB
estrSaeUnitPATCH Patch PAT
estrSaeUnitPer Percent 030
estrSaeUnitPUFF Puff PUFF
estrSaeUnitSACH Sachet SAC
estrSaeUnitSP Spray SPR
CONFIDENTIAL
estrSaeUnitSUPP Suppository SUP
estrSaeUnitTBSP Tablespoon TBS
estrSaeUnitTAB Tablet TAB
95
estrSaeUnitTSP Teaspoon TSP

estrSaeUnitUNIT Units UNT
estrSaeUnitUNK Unknown U
estrSaeUnitVIAL Vial VIA
Pulldown List 2:
GM2006/00652/00
estrSaeFreq2XWK 2 times per week 2W
NKT102553
estrSaeFreq5XD 5 times per day 5D
estrSaeFreqAC AC AC
estrSaeFreqBID BID 2D
estrSaeFreqCINF Continuous infusion CO
estrSaeFreqQ2WK Every 2 weeks FO

estrSaeFreqQ3WK Every 3 weeks Q3WK
estrSaeFreqQ3M Every 3 months Q3M
estrSaeFreqQOD Every other day AD
estrSaeFreqHS At Bedtime 1N
estrSaeFreqQM Once a month MO
estrSaeFreqQWK Once a week WE
estrSaeFreqQD Once daily 1D
estrSaeFreqONE Once only 1S
estrSaeFreqPC PC PC
estrSaeFreqPRN PRN PRN
estrSaeFreqQ2H Q2H 12D
estrSaeFreqQ3D Q3D Q3D
estrSaeFreqQ4D Q4D Q4D
CONFIDENTIAL
96
estrSaeFreqQAM QAM 1M
estrSaeFreqQH QH 24D
estrSaeFreqQID QID 4D
estrSaeFreqQPM QPM 1N
estrSaeFreqTID TID 3D
estrSaeFreqUNK Unknown U
GM2006/00652/00
Pulldown List 3:
NKT102553
estrSaeRouteOU Both eyes 047
estrSaeRouteEP Epidural 008
estrSaeRouteGTT Gastrostomy tube GT
estrSaeRouteIH Inhalation 055
estrSaeRouteINJ Injection INJ
estrSaeRouteIA Intra-arterial 013

estrSaeRouteIB Intra-bursa IBU
estrSaeRouteIL Intralesional 026
estrSaeRouteIM Intramuscular 030
estrSaeRouteIN Intranasal 045
estrSaeRouteIO Intraocular 031
estrSaeRouteIOS Intraosteal IOS
estrSaeRouteIP Intraperitoneal 033
estrSaeRouteIT Intrathecal 037
estrSaeRouteIU Intrauterine 015
estrSaeRouteIV Intravenous 042
estrSaeRouteNS Nasal 045
estrSaeRoutePO Oral 048
estrSaeRoutePR Rectal 054
CONFIDENTIAL
estrSaeRouteSC Subcutaneous 058
estrSaeRouteSL Sublingual 060
estrSaeRouteTP Topical 061
97
estrSaeRouteTD Transdermal 062

estrSaeRouteUNK Unknown 065
estrSaeRouteVG Vaginal 067
Pulldown List 4:
estrDRUGTYPE01 Concomitant 2
GM2006/00652/00
estrDRUGTYPE02 Treatment T
estrDRUGTYPE03 Cause of SAE 1
NKT102553
Pulldown List 5:
estrSAELBTST01 Activated partial thromboplastin time Activated partial thromboplastin time
estrSAELBTST02 Albumin Albumin
estrSAELBTST03 Alkaline phosphatase Alkaline phosphatase

estrSAELBTST04 Amylase Amylase
estrSAELBTST05 Basophils Basophils
estrSAELBTST06 Bicarbonate Bicarbonate
estrSAELBTST07 Bilirubin Bilirubin
estrSAELBTST08 Bilirubin direct Bilirubin direct
estrSAELBTST09 Bilirubin total Bilirubin total
estrSAELBTST10 Blood myoglobin Blood myoglobin
estrSAELBTST11 Blood pH Blood pH
estrSAELBTST12 Blood pressure Blood pressure
estrSAELBTST13 Blood urea nitrogen Blood urea nitrogen
estrSAELBTST14 Body temperature Body temperature
estrSAELBTST15 Calcium Calcium
estrSAELBTST16 CD4 lymphocytes CD4 lymphocytes
CONFIDENTIAL
estrSAELBTST17 CD8 lymphocytes CD8 lymphocytes
estrSAELBTST18 Chloride Chloride
estrSAELBTST19 Cholesterol total Cholesterol total
98
estrSAELBTST20 C-reactive protein C-reactive protein

estrSAELBTST21 Creatine Creatine
estrSAELBTST22 Creatine phosphokinase Creatine phosphokinase
estrSAELBTST23 Creatine phosphokinase MB Creatine phosphokinase MB
estrSAELBTST24 Creatinine Creatinine
estrSAELBTST25 Creatinine clearance Creatinine clearance
estrSAELBTST26 Diastolic blood pressure Diastolic blood pressure
GM2006/00652/00
estrSAELBTST27 Eosinophils Eosinophils
estrSAELBTST28 Erythrocyte sedimentation rate Erythrocyte sedimentation rate
estrSAELBTST29 Fasting blood glucose Fasting blood glucose
NKT102553
estrSAELBTST30 FEV 1 FEV 1
estrSAELBTST31 Gamma-glutamyltransferase Gamma-glutamyltransferase
estrSAELBTST32 Glutamic-oxaloacetic transferase Glutamic-oxaloacetic transferase
estrSAELBTST33 Glutamic-pyruvate transaminase Glutamic-pyruvate transaminase
estrSAELBTST34 HbA1c HbA1c
estrSAELBTST35 HBV-DNA decreased HBV-DNA decreased

estrSAELBTST36 HBV-DNA increased HBV-DNA increased
estrSAELBTST37 Heart rate Heart rate
estrSAELBTST38 Hematocrit Hematocrit
estrSAELBTST39 Hemoglobin Hemoglobin
estrSAELBTST40 High density lipoprotein High density lipoprotein
estrSAELBTST41 HIV viral load HIV viral load
estrSAELBTST42 INR INR
estrSAELBTST43 Lactic dehydrogenase Lactic dehydrogenase
estrSAELBTST44 Lipase Lipase
estrSAELBTST45 Low density lipoprotein Low density lipoprotein
estrSAELBTST46 Lymphocytes Lymphocytes
estrSAELBTST47 Magnesium Magnesium
estrSAELBTST48 Mean cell hemoglobin concentration Mean cell hemoglobin concentration
CONFIDENTIAL
estrSAELBTST49 Mean corpuscular hemoglobin Mean corpuscular hemoglobin
estrSAELBTST50 Mean corpuscular volume Mean corpuscular volume
estrSAELBTST51 Monocytes Monocytes
99
estrSAELBTST52 Neutrophils Neutrophils

estrSAELBTST53 Oxygen saturation Oxygen saturation
estrSAELBTST54 pCO2 pCO2
estrSAELBTST55 pH pH
estrSAELBTST56 Phosphate Phosphate
estrSAELBTST57 Platelet count Platelet count
estrSAELBTST58 pO2 pO2
GM2006/00652/00
estrSAELBTST59 Potassium Potassium
estrSAELBTST60 Protein total Protein total
estrSAELBTST61 Prothrombin time Prothrombin time
NKT102553
estrSAELBTST62 Red blood cell count Red blood cell count
estrSAELBTST63 Respiratory rate Respiratory rate
estrSAELBTST64 Reticulocyte count Reticulocyte count
estrSAELBTST65 Serum glucose Serum glucose
estrSAELBTST66 Serum uric acid Serum uric acid
estrSAELBTST67 Sodium Sodium

estrSAELBTST68 Systolic blood pressure Systolic blood pressure
estrSAELBTST69 Thrombin time Thrombin time
estrSAELBTST70 Total lung capacity Total lung capacity
estrSAELBTST71 Triglycerides Triglycerides
estrSAELBTST72 Troponin Troponin
estrSAELBTST73 Troponin I Troponin I
estrSAELBTST74 Troponin T Troponin T
estrSAELBTST75 Urine myoglobin Urine myoglobin
estrSAELBTST76 Urine pH Urine pH
estrSAELBTST77 Vital capacity Vital capacity
estrSAELBTST78 White blood cell count White blood cell count
CONFIDENTIAL
CDD: MAPPINGS1 Table: t_AE_SER Key Type: PATIENTVISIT
chkSAE STRING(255)
100
chkFU STRING(255)
rdcSAERAND STRING(1)
AESEQ STRING(5) - A5
AETERM STRING(100) - A100
AEMODIFY STRING(100) - A100
AEMEDSYN STRING(255)
AELLTCD STRING(255)
calAE_FAILED STRING(255)
GM2006/00652/00
AESTDTTM DATE - DDMONYYYY HHMM
AEOUTCD1 STRING(1)
NKT102553
AESEVCD STRING(1)
AETOXCD STRING(1)
AETXHVCD STRING(1)
AEACTRCD STRING(1)
AEWD STRING(1)
AEREL STRING(1)
AEDURHR NUMERIC - N2
AEDURMIN NUMERIC - N2
AEONLDSH NUMERIC - N2
AEONLDSM NUMERIC - N2
rdcAESREL STRING(1)
AESER STRING(1)
AESERDTH STRING(255)
AESERLIF STRING(255)
AESERHOS STRING(255)
AESERDIS STRING(255)
AESERCON STRING(255)
CONFIDENTIAL
AESEROTH STRING(255)
txtSAECMSEQ STRING(4) - A4
101
txtCMTERM STRING(100) - A100

txtSAECMDOS FLOAT - F10.0
pdcCMUNIT STRING(255) - ACTU, AMP, AP, BT, CAP, CC, 031, 002, 025, 028, IUML, 011, LM, LOZ, MEGU, 004, 004, 008, MCG/KG/MIN , MCG/MIN , 013, 029, MEQ24,
003, MGPER, MGH, 007, MGKH, MGKM, 009, MGML, 012, MLH, MLM, 023, 027, MAC, NEB, PAT, 030, PUFF, SAC, SPR, SUP, TBS, TAB, TSP, UNT, U, VIA
pdcSAECMFRQ STRING(255) - 2W, 3W, 4W, 5D, 5W, AC, 2D, CO, FO, Q3WK, Q3M, AD, 1N, MO, WE, 1D, 1S, PC, PRN, 12D, Q3D , Q4D, 6D, 4D, 3D, 2D, 1M, 24D, 4D, 1N,
3D, U
pdcCMROUTCD STRING(255) - 047, 008, GT, 055, INJ, 013, IBU, 026, 030, 045, 031, IOS, 033, 037, 015, 042, 045, 048, 054, 058, 060, 061, 062, 065, 067
dtmSAECMSTD DATE - DDMONYYYY
rdcSAECMONG STRING(1)
GM2006/00652/00
dtmSAECMEND DATE - DDMONYYYY
txtCMIND STRING(50) - A50
pdcCMDRGTYP STRING(255) - 2, T, 1
NKT102553
txtMHXSEQ STRING(4) - A4
txtSAEMHTRM STRING(100) - A100
dtmMHSTDTM DATE - DDMONYYYY
rdcMHCONT STRING(1)
dtmMHLSTOC DATE - DDMONYYYY
txtSAELBSEQ STRING(4) - A4
pdcLBTST STRING(255) - Activated partial thromboplastin time, Albumin, Alkaline phosphatase, Amylase, Basophils, Bicarbonate, Bilirubin, Bilirubin direct, Bilirubin total,
Blood myoglobin, Blood pH, Blood pressure, Blood urea nitrogen, Body temperature, Calcium, CD4 lymphocytes, CD8 lymphocytes, Chloride, Cholesterol total, C-
reactive protein, Creatine, Creatine phosphokinase, Creatine phosphokinase MB, Creatinine, Creatinine clearance, Diastolic blood pressure, Eosinophils, Erythrocyte
sedimentation rate, Fasting blood glucose, FEV 1, Gamma-glutamyltransferase, Glutamic-oxaloacetic transferase, Glutamic-pyruvate transaminase, HbA1c, HBV-DNA
decreased, HBV-DNA increased, Heart rate, Hematocrit, Hemoglobin, High density lipoprotein, HIV viral load, INR, Lactic dehydrogenase, Lipase, Low density
lipoprotein, Lymphocytes, Magnesium, Mean cell hemoglobin concentration, Mean corpuscular hemoglobin, Mean corpuscular volume, Monocytes, Neutrophils,
Oxygen saturation, pCO2, pH, Phosphate, Platelet count, pO2, Potassium, Protein total, Prothrombin time, Red blood cell count, Respiratory rate, Reticulocyte count,
Serum glucose, Serum uric acid, Sodium, Systolic blood pressure, Thrombin time, Total lung capacity, Triglycerides, Troponin, Troponin I, Troponin T, Urine
myoglobin, Urine pH, Vital capacity, White blood cell count
dtmLABDTM DATE - DDMONYYYY
txtLABRES STRING(50) - A50
txtLABUNIT STRING(35) - A35
txtLABNLR FLOAT - F8.0
txtLABNHR FLOAT - F8.0
rdcSAEIP STRING(1)
chkSAESENDI STRING(255)
CONFIDENTIAL
dtmSAEDTM DATE - DDMONYYYY HHMM
AESE1 STRING(1)
AESE2 STRING(5) - A5
102
txtSAEVERSION STRING(4) - A4
txtSAEID STRING(20) - A20
txtSAERNDNO STRING(255) - A255
txtOCEANSCD STRING(12) - A12
calSAEEmailFlag STRING(255)
GM2006/00652/00
NKT102553
FORM: STATUS OF TREATMENT BLIND (BLIND) TRIAL: nkt102553_scm
STATUS OF TREATMENT BLIND

1. Was the treatment blind broken during the study?If yes, complete Non-Serious Adverse (MAPPINGS1:t_BLIND.BLBRK)
Events, Serious Adverse Event and/or Investigational Product forms as appropriate [N] No
[Y] Yes, complete the following :
Date blind broken
/ Req / Req (2006-2007) (MAPPINGS1:t_BLIND.BLDTTM)
Req
(MAPPINGS1:t_BLIND.BLREASCD)
Reason blind broken
[1] Medical emergency requiring identification of investigational product for further treatment
[Z] Other, specify (MAPPINGS1:t_BLIND.BLRSOTH)
A200
CONFIDENTIAL
Form Design Note:
IDSL Version 02.00A - 21 APR 05

103
Item Design Notes:
1. Time blind broken is optional
CDD: MAPPINGS1 Table: t_BLIND Key Type: PATIENTVISIT

GM2006/00652/00
BLBRK STRING(1)
BLDTTM DATE - DDMONYYYY
BLREASCD STRING(1)
NKT102553
BLRSOTH STRING(200) - A200
FORM: PREGNANCY INFORMATION (PREG) TRIAL: nkt102553_scm
PREGNANCY INFORMATION
1. Did the subject become pregnant during the study? (MAPPINGS1:t_STATUS_PREG_F.PGYN)
If Yes, complete the paper Pregnancy Notification form [N] No
[Y] Yes
Form Design Note:
IDSL Version 01.00A - 01 DEC 04 This is an optional form but is conditional upon females in the trial; This form will be dynamically generated to appear at the End visit if Female is selected on the
Demographics form
CDD: MAPPINGS1 Table: t_STATUS_PREG_F Key Type: PATIENTVISIT

PGYN STRING(1)
CONFIDENTIAL
104
GM2006/00652/00
NKT102553
FORM: STUDY CONCLUSION (CONC) TRIAL: nkt102553_scm
STUDY CONCLUSION
1. Date of subject completion or date and time of subject withdrawal / Req / Req (2006-2007) (MAPPINGS1:t_DISPOSIT_CONCLUSION.DSDTTM)
Req
Hr:Min (00:00-23:59)
NReq : NReq
2. Was the subject withdrawn from the study? (MAPPINGS1:t_DISPOSIT_CONCLUSION.DSWD)

[N] No
[Y] (MAPPINGS1:t_DISPOSIT_CONCLUSION.DSREASCD1)
Yes, select primary reason for withdrawal
[1] Adverse Event
Record details on the Non-Serious Adverse Events or Serious Adverse Events forms as appropriate.
[2] Lost to follow-up
[3] Protocol violation
[4] Subject decided to withdraw from the study
[6] Sponsor terminated study
[Z] Other, specify (MAPPINGS1:t_DISPOSIT_CONCLUSION.DSRSOTH)
A200
CONFIDENTIAL
LOG STATUS
105
3. Did the subject experience any non-serious adverse events during the study? (MAPPINGS1:t_DISPOSIT_CONCLUSION.rdcConcAEAny)
[N] No
[Y] Yes
4. Did the subject experience any serious adverse events during the study? (MAPPINGS1:t_DISPOSIT_CONCLUSION.rdcConcSAEAny)
[N] No
[Y] Yes
5. Were any concomitant medications taken by the subject prior to screening and/or during the (MAPPINGS1:t_DISPOSIT_CONCLUSION.rdcConcCMAny)
study? [N] No
[Y] Yes
6.* Case book ready for signature [hidden] (MAPPINGS1:t_DISPOSIT_CONCLUSION.chkReadyForSig)

[Y] Yes
CRA should check the box when data cleaning is complete
GM2006/00652/00
7.* Q1 [hidden] (MAPPINGS1:t_DISPOSIT_CONCLUSION.AXCOMPLETERADIO)
[Y] Yes
[N] No
NKT102553
8.* Q2 [hidden] (MAPPINGS1:t_DISPOSIT_CONCLUSION.REASONRADIO)
[?] PF_SC_LOST
[?] PF_SC_DEATH
[?] PF_SC_SPONSORDECISION
[?] PF_SC_PHYSICIANDECISION
[?] PF_SC_PATIENTDECISION
[?] PF_SC_AE
[?] PF_SC_ALE
[?] PF_SC_CRITERIA
[?] PF_SC_OTHER
Form Design Note:
IDSL Version 03.00A - 14 SEP 05
Item Design Notes:
1. Time is optional
2. Choices after Subject decided to withdraw from the study are optional choices. Other is required
3. This item is not part of the SI datasets
CONFIDENTIAL

106
6. This item is used for Phase I trials only. Remove for Phase II-IV
CDD: MAPPINGS1 Table: t_DISPOSIT_CONCLUSION Key Type: PATIENTVISIT

DSDTTM DATE - DDMONYYYY HHMM
DSWD STRING(1)
DSREASCD1 STRING(1)
DSRSOTH STRING(200) - A200
GM2006/00652/00
rdcConcAEAny STRING(1)
rdcConcSAEAny STRING(1)
NKT102553
rdcConcCMAny STRING(1)
chkReadyForSig STRING(255)
AXCOMPLETERADIO STRING(1)
REASONRADIO STRING(42)
CRB Electronic Signature Affidavit

By my dated signature below, I, [First Name] [Last Name], verify that all case report form pages accurately display the results of the examinations, tests, evaluations and treatments performed on this
patient.
Pursuant to Section 11.100 of Title 21 of the Code of Federal Regulations, this is to certify that I intend that this electronic signature is to be the legally binding equivalent of my handwritten signature.
To this I do attest by supplying my password and clicking the button marked Submit below.
CRF Electronic Signature Affidavit

By my dated signature below, I, [First Name] [Last Name], verify that this case report form accurately displays the results of the examinations, tests, evaluations and treatments noted within.
Pursuant to Section 11.100 of Title 21 of the Code of Federal Regulations, this is to certify that I intend that this electronic signature is to be the legally binding equivalent of my handwritten signature.
To this I do attest by supplying my password and clicking the button marked Submit below.
CONFIDENTIAL
107
GM2006/00652/00
NKT102553
CONFIDENTIAL
NKT102553
LIST OF INVESTIGATORS AND IECS/IRBS FOR NKT102553 GM2006/00652/00
Investigator Investigator/Site No. Hospital / Institution and Address IEC/IRB Committee / Name of
Committee/ Chair
CANADA
/
CANADA
CONFIDENTIAL
Chairperson:
Dr.
/
1
CANADA
Chairperson:
GM2006/00652/00
CANADA
NKT102553
Chairperson:
(Lawyer)
1
CONFIDENTIAL
NKT102553
CANADA
Chairperson:
Dr.
/
CANADA
Chairperson:
CONFIDENTIAL
FRANCE
/
2
France France
Chairperson:
Prof.
/
GM2006/00652/00
(No Patients Enrolled)
France
NKT102553
France
Chairperson:
Prof.
2
CONFIDENTIAL
NKT102553
France
France
Chairperson:
Prof.
/
(No Patients enrolled)
France France
CONFIDENTIAL
Chairperson:
/
3
France
France
Chairperson:
GM2006/00652/00
France France
NKT102553
Chaiperson:
Prof.
3
CONFIDENTIAL
NKT102553
France
France
Chaiperson:
Prof.
/
France
CONFIDENTIAL
France Chaiperson:
Prof.
4
France France
Chaiperson:
Prof.
GM2006/00652/00
NKT102553
4
CONFIDENTIAL
NKT102553

France
France
Chaiperson:
Prof.
GERMANY
/
CONFIDENTIAL
Germany Germany
Chairperson:
5
Prof. Dr. Med.

/
Germany Germany
Chairperson:
Prof. Dr. Med.
GM2006/00652/00
NKT102553
5
CONFIDENTIAL
NKT102553
Germany Germany
Chairperson:
Prof. Dr. Med.
HONG KONG
MD /
(Site Did Not Enrol

Patients)
CONFIDENTIAL
Chairperson:
Hong Kong Prof
MD /
6
Hong Kong Chairperson:

Prof
MD /
Hong Kong
GM2006/00652/00
Hong Kong
NKT102553
Chairperson:
Dr
6
CONFIDENTIAL
NKT102553
Hong Kong
Hong Kong
Chairperson:
Prof.
HUNGARY
/
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IRELAND
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Ireland Ireland
GM2006/00652/00
Ireland
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Dr
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Ireland Ireland
Ireland
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Dr
PAKISTAN
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Dr
Pakistan
PHILIPPINES
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Philippines
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THAILAND
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UNITED KINGDOM
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United Kingdom
(Committee Co-ordinator)
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UNITED STATES
MD /
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MD PhD /
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MD /
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J.D.
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This section contained Principal Investigator’s Curriculum Vitae and has been excluded to
protect Principal Investigator privacy.
NKT102553
Informed Consent Form and Information Sheet for Pharmacogenetic Research
GlaxoSmithKline Protocol Title: A Phase III Multicenter, Randomized, Double-blind,

Parallel Group Study to Evaluate the Safety and Efficacy of 50 mg Oral Dosing with the
Neurokinin-1 Receptor Antagonist GW679769 for the Prevention of Postoperative Nausea and
Vomiting in Female Subjects at High Risk for Emesis
GlaxoSmithKline Protocol Number: NKT102553
Study Doctor: _________________________________________________________
Site Address: _________________________________________________________
_________________________________________________________
_________________________________________________________
Site Phone Number: _________________________________________________________
Subject Number: _________________________________________________________
This form is in addition to the consent form you signed for the clinical study for GW679769.
Purpose and Description of the Research

The purpose of this consent form is to explain what pharmacogenetic research is and to ask you
to give a blood sample that may be used in this research. The sponsor of the research is the
GlaxoSmithKline group of companies [referred to as GSK in this consent]. The study doctor and
institution are paid by GSK to conduct this research. This study may have about 462 subjects at
about 65 sites.
What is pharmacogenetic research?

Genes, which we inherit from our parents, may control the way we react to or handle a medicine.
Pharmacogenetics is the study of differences in how our bodies respond to or handle medicines.
This pharmacogenetic research is looking at genetic differences to better understand why people
react differently when they get the same medicine. If it appears that there is a difference in the
way people respond to or handle GW679769. GSK may study these differences using your genes
or genetic material taken from your blood sample.
What are the benefits of participating in this research study?

There will be no direct benefit to you by taking part in this pharmacogenetic research. You may
help scientists understand why people react to or handle GW679769 differently. This may help
identify who is more likely to respond to GW679769 and who may experience side effects.
What exactly will participation in the research involve?

If you choose to take part in this research, a qualified medical worker will take about 10 ml (or 2
teaspoons) of your blood. In the unlikely case that there is a problem processing your sample,
then we may ask you to give a second sample.
Is participation in this study voluntary?

Participation in this pharmacogenetic research is voluntary. You may decline to take part now or
you may decide to take part and then change your mind. GSK may store your sample for up to
15 years after the last subject completes the study or GSK may destroy your sample at an earlier
F-GRD-003 v05
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time. If you decide not to participate or to withdraw your consent after starting the study, you do
not have to give a reason and there will be no change to your medical treatment or to your
participation in the GW679769 study. If you withdraw from this research, your sample will be
destroyed and GSK will only keep and study information collected/generated up to that point.
In special cases, your sample may not be used. This might happen if there are not enough
subjects, if the study is stopped for other reasons, or if no questions are raised about how people
respond to or handle GW679769.
What are the risks involved with blood sampling?

The physical risks of giving a blood sample are the same as those for any blood sample taken
from a vein. You may feel faint, experience mild pain, bruising, irritation or redness at the site of
puncture. In rare cases an infection could develop.
Compensation for Study-Related Injury

If you are physically injured by the properly performed blood draw and you have followed the
directions of the study staff, the sponsor will cover the reasonable medical expenses necessary to
treat the injury. No other compensation is offered by GSK, but you do not waive any legal rights
by signing this consent form.
What other options are there?

You have the choice not to take part in this research.
How are privacy, data protection and confidentiality protected?

As part of the study, medical information about you will be collected and analyzed along with
your sample. This medical information can include [describe the types of information to be
collected; give examples].
To protect your privacy, your sample and medical information will be labeled (or “coded”) with a
study subject number, not your name. Only your study doctor and his or her staff will keep the
link between your subject number and your name.
Your study doctor has been told to keep your pharmacogenetic information including your
consent in a separate, secure file, which is not part of your medical records. GSK will control
access to its files that hold your coded information and results. Your name will not appear in any
publications or reports about this research.
GSK or those working with GSK (for example, other researchers) will only work with your
sample for the use stated in this consent. Samples will be stored securely. GSK will require
anyone who works with your sample to agree to hold the research information and any individual
results in confidence.
If your sample is studied, your individual results will only be shared with you through the study
doctor if you request in writing to see the results and it is a requirement of a governmental
agency or other legal authority that GSK make these results available. GSK will not release
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individual results to anyone else (e.g., family members, primary care physicians, insurers, or
employers) under any circumstance, unless required by law. Your results are not for clinical
diagnosis or treatment. The information generated is for scientific purposes.
GSK has taken appropriate measures to ensure the confidentiality of the research-related
information. However, if you pass on your individual results (if obtained by you), there is a
possibility that this could have an effect on your insurance or employment. This risk is similar as
if you were to disclose any type of personal medical information to a third party.
Medical information, samples and research results from you and other research participants may
be studied by GSK to make medicines or tests to determine the body’s response to or handling of
medicine. Your information and any results will be put in a computer and stored in electronic
databases. International regulations for information on computers and relevant laws on
processing personal information will be strictly adhered to. Your information, sample, and
results could be sent to other researchers working with GSK and to other GSK sites.
By agreeing to take part in this research, you will allow your medical information, sample, and
pharmacogenetic results to be reviewed as part of collecting and analyzing study results. The
people who may check this research include GSK, people working with GSK on this research,
ethics committees, institutional review boards, and regulatory authorities such as the FDA.
These persons are required to maintain the confidentiality of the information.
Disclosure of Protected Health Information

Authorization to use or disclose your medical information as described above is not time-limited
(that is, will not expire). If you decide not to sign this consent, you will not be included in the
study. You may withdraw this authorization at any time in writing. If you sign this consent and
decide later to withdraw the authorization, you will be withdrawn from the study at that time.
Information collected up to the time you withdraw your authorization will continue to be used as
study data. Once information is disclosed under this authorization to someone who is not a
health care provider, the information is no longer protected by the US privacy rules (called the
HIPAA privacy regulations) and could be disclosed to others by the recipient.
Will there be compensation for participation in the research?

You will be paid $XX for your time and travel related expenses.
Commercial Issues
GSK and/or others intend to claim sole ownership of any research results consistent with this
consent. The results of this research may have commercial or intellectual property value. By
signing this consent, you agree that GSK can apply for patents and you understand that you will
not receive any financial benefit that might come from the research.
Who can you call for more information about this research study?
You may contact __________ at telephone number __________ at any time if you have
questions about this study, an injury related to the blood draw for this research, or wish to
withdraw from this research. If you have questions about your rights as a research subject, you
F-GRD-003 v05
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NKT102553
may contact __________ of the Institutional Review Board/Ethics Committee at telephone

number________.
CONSENT
A copy of this Consent Form (signed and dated) must be given to the subject or legal
representative.
My signature below indicates that:

1. I have read this form and the research has been explained to me.
2. I have been able to discuss the research and ask questions. I am satisfied with the answers.
3. I have been given the time to consider whether or not to take part in this research.
4. I have freely decided to take part in the research study described in this form.
Subject’s Name (Please Print): __________________________________
Subject’s Signature: _______________________________________ Date: ____________

(or that of Legal Representative) (Day/Month/Year)
Name and Signature of Individual Obtaining the Subject’s Consent:
Name (Please Print): _________________________________
Signature: ________________________________________________ Date: ____________

(Day/Month/Year)
F-GRD-003 v05
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NKT102553 CONFIDENTIAL ICF Version No: 04

Date: 14 Dec. 05
Model Written Informed Consent Form

Study Title A Phase III Multicenter, Randomized, Double-blind, Parallel Group
Study to Evaluate the Safety and Efficacy of 50 mg Oral Dosing with the
Neurokinin-1 Receptor Antagonist GW679769 for Prevention of
Postoperative Nausea and Vomiting in Female Subjects at High Risk for
Emesis
A study to see if a relatively new substance, called GW679769, when used in

combination with ZOFRAN™, is safe and effective in preventing nausea and vomiting
after surgery.
ICR Version 04, 14 December 2005 (10 pages total)
Company Name: GlaxoSmithKline
Subject Identification: __________________
Written Information Sheet
What does giving consent mean?
You have been asked to be part of a research study. This form describes the study to help
you decide if you want to participate. This form will tell you about what you will be
asked to do during the study, and the potential risks and benefits of the study as we
currently understand them. If you have any questions about or do not understand
something in this form, you should ask the doctor or healthcare professional reviewing
this consent with you. Do not sign this form unless you are satisfied with the answers to
your questions, and have decided that you want to participate in this study.
If you sign this consent form, you are saying that you agree to be entered into this
research study. Your decision about participating in this study is voluntary, and you may
decide that you do not want to participate. If you do sign the consent form, you can still
decide that you want to withdraw from the study at any time. There is no penalty or loss
of benefits to you if you do not wish to participate in this study, or wish to withdraw at a
later time.
When reading this form, please note that the word “we” refers to GlaxoSmithKline, the
pharmaceutical company which makes the two study drugs, and which is running and
sponsoring this study; “you” and “your” refers to the person in the study (yourself).
Why is this study being carried out, and are there any alternative treatments?
Some people experience nausea and vomiting after they have surgery. Although this can
happen to anyone, there are certain things which put a person at higher risk for nausea
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and vomiting after surgery. Some of these things include being a female, having a
history of motion sickness or previous nausea and vomiting after surgery, being a non-
smoker, and receiving certain pain medications after surgery. Also, certain types of
surgeries are known to have a higher risk for nausea and vomiting after the surgery than
other types of surgery.
Zofran (also called ondansetron hydrochloride) is a drug that has been used by doctors to
prevent nausea and vomiting in certain situations for more than ten years. It is approved
by drug regulatory authorities for preventing post-operative (after surgery) nausea and
vomiting. It has been used to prevent nausea and vomiting after surgery in more than 60
million surgeries, but it (like all other medications) is not 100% effective. Despite the
success of marketed medications to prevent nausea and vomiting, 35% to 50% of high
risk patients will still experience nausea and vomiting after surgery.
At GlaxoSmithKline, we are investigating a new potential drug called GW679769 (also

called casopitant mesylate). We would like to find out if adding GW679769 to the drug
Zofran, is safe and has a better effect on preventing nausea and vomiting after surgery
than when Zofran is given alone.
Using the combination of GW679769 and Zofran to try to prevent nausea and vomiting
after surgery is investigational. The word “investigational” means that this use of
GW679769 with Zofran is still being tested. Using these two drugs together is not
approved by drug regulatory authorities for preventing post-operative nausea and
vomiting.
This study has been approved by the ethics committee of the participating health care
institution, and by the relevant government authorities.
There are other treatments to help prevent post-operative nausea and vomiting. If you do
not choose to participate in this study, you can still be given medicine to help prevent
nausea and vomiting after surgery. Your health care provider can discuss various options
with you.
What does the study involve?
If you think you might be interested in participating in this study, a health care
professional will talk with you about the details of the study. If you decide to give your
consent to participate in this study, you will be asked to sign this informed consent form.
Once you have signed this form, you will be “screened” (asked questions and a sample of
blood will be taken for some lab tests) to see if you meet certain conditions that are
required for you to participate in this study (for example, for this study you have to be
able and willing to fill out a study diary for a couple of days, you cannot be pregnant or
nursing, etc). If you meet these conditions, you will be enrolled in the study. Your
participation in the study lasts from the time of your screening visit until a final study
visit 6-14 days after your surgery.
You will be placed by chance (like flipping a coin), into one of two study groups:
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• Group A: people in this group receive 4 mg of Zofran and placebo GW679769

(a substance that looks like GW679769, but has no active ingredient) just before
surgery.
• Group B: people in this group receive 4 mg of Zofran and 50 mg of GW679769
just before surgery.
In this study, Zofran is given intravenously, which means by a needle inserted into your
vein. GW679769, or its placebo, is given in the form of a pill, which you take by mouth
with a drink of water.
As you can see, some people in the study (those in Group A) will receive Zofran alone,
and some people (those in Group B) will receive Zofran and GW679769. This study
design helps the researchers to know which works better to stop nausea and vomiting
after surgery. A 4 mg intravenous dose is the standard approved dose of Zofran to
prevent nausea and vomiting after surgery.
You have an equal chance of being in either one of the study groups. A computer will
pick which study group you are in.
This is a double-blind study. Double-blind means that neither you nor the study doctor
will be able to choose which study group you are in, and that you will not know and the
study doctor will not know which study group you are in. (The study doctor can find out
which group you are in, though, if there is an emergency or if he or she feels it is
necessary to know).
As part of this study, you should not take any medication that may prevent or cause
nausea or vomiting for 24 hours before your scheduled surgery. Your health care
professional will discuss any medications that are not allowed, and for how long you
would not be able to take them.
After you have signed the informed consent form, the study doctor or study staff will do
some routine procedures before your surgery to make sure you are in good health. These
include:
• Asking you questions about your health and the medicines you take.
• Giving you a physical examination, including taking a blood sample.
• Measuring your height, weight, and blood pressure. You will also be given an
electrocardiogram (ECG). This is a standard test which measures the electrical
activity of your heart.
• Doing a pregnancy test if you are possibly able to become pregnant (if you are
still having your monthly period). You will be told if the results of the test are
positive. The results of the test must be negative in order for you to be in the
study.
The study doctor may also request additional routine testing that is appropriate in
preparation for your surgery.
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On the day of your surgery, the study doctor will give you one of the study drug
combinations described above (depending on which group you were assigned by
computer). When you wake up from the anesthesia in the recovery room, you will be
checked for any episodes of vomiting, and you will be asked if you are having any
feelings of nausea. A small amount of your blood will be taken again for lab testing
sometime before you go home after surgery.
Before your surgery, the staff will give you an electronic diary to answer some questions
about nausea and vomiting. This is a small, hand-held computer, slightly larger than a
deck of cards. You will be instructed (and reminded just before you are ready to go
home) on how to record information in the diary over the 48 hours (2 days) after
completion of your surgery. The questions in the diary will be about any nausea and
vomiting you might experience, how you feel about the treatment you received to help
prevent nausea and vomiting, and any changes in how you have been feeling since the
surgery. A health care professional will call you at the end of the first day, and again at
the end of the second day, to remind you to fill in your diary, and to assist you with any
questions you might have at that time.
You will be asked to remember not to take any medication that prevents or may
possibly cause nausea or vomiting for the 48 hours following your surgery. This is
very important because, if you take these kinds of medications, it will not be possible for
us to figure out if the study medications you were given to prevent nausea and vomiting
worked. However if, following your surgery, you find that the study medicines are not
working (that is, that you feel very nauseous, or you vomit), the study doctor can give
you a prescription for medication to help you feel better.
Six to fourteen days after your surgery, you will be asked to return to your health care
professional and return the electronic diary. At this visit, you will be asked some
questions about how you’ve been feeling, and another blood sample will be taken for
regular blood tests.
How many other patients are there in the study?
We are planning to enroll 462 people into this study. This is a global study, so patients
will be from North America, Europe, and other international locations.
Do I have to stay in the study?
No, you do not have to stay in the study; you are free to withdraw at any time, without
giving a reason, and without any effect on the subsequent medical care that you receive.
If you want to stop being in the study, tell the study doctor or study staff, and return all
study materials, including your diary. If you stop being in the study early, the study
doctor or study staff may ask you some questions about being in the study. They may
also ask you to have some more tests done to help your withdrawal from the study
happen safely. You do not have to give a reason for stopping, but it would be useful to us
if you were to tell us your reasons for wanting to stop.
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Any information/study data that has been collected prior to your withdrawal from the
study will be used by GlaxoSmithKline in the study analysis.
Any new information that becomes available which might affect your willingness to stay
in the study will be made available to all study participants in a timely manner.
What are the foreseeable risks for taking part in the study?
Zofran has been used for many years to help prevent nausea and vomiting. Because so
many patients have taken it, the potential side effects are well known. The most common
(adverse) bad effects of Zofran include:
• headache
• dizziness
• muscle pain
• constipation
• tiredness
GW679769 is an experimental drug which is still under study. This means we are still
trying to get a complete picture of the potential side effects of GW679769. These are the
potential adverse events that we know about at this time:
Liver Enzymes
In studies we have already done with GW679769, some patients had increases in their
liver enzymes. Liver enzymes are chemicals the liver puts out into the bloodstream.
When liver cells are injured or sick, the amount of liver enzymes in the blood increases.
These increases were found in some of the blood tests that were done in previous studies
of GW679769 in people. In all of the cases that we know about, the level of the liver
enzymes returned to normal. We do not know yet whether these increases are related to
taking GW679769, or to something else. We are going to be looking carefully at the liver
enzyme blood test results throughout this study, to try to answer this question.
Birth Control
If a woman is pregnant or nursing a child when she takes Zofran or GW679769, there
may be risks to the unborn baby or nursing child. Nobody knows what these risks are at
this time. Some drugs can cause babies to be born prematurely (earlier than they should
be) or to have birth defects.
Women who join the study are required to have a pregnancy test, but a pregnancy test
does not stop you from becoming pregnant. For this reason, women in the study who are
capable of becoming pregnant must use strict birth control, which the study doctor will
discuss with you at screening.
Recent data has shown some signs of a drug interaction between GW679769 and oral
birth control pills. This interaction could decrease the effectiveness of your birth control
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pills, which means your risk of becoming pregnant could be increased. Because of this, if
you are a woman of childbearing potential (someone who could become pregnant) you
will need to use an additional method of birth control while you are in this study.
Some acceptable methods of birth control are:
• You use hormonal contraceptives (birth control pill, patch, or ring) combined
with a double barrier method of birth control (which means two methods; for
example, a condom and spermicide). You will need to continue using the
additional double-barrier method for seven days after your surgery.
• You use a double-barrier method alone (for example, a condom and spermicide)
• You have only one male sexual partner, and he is sterile
• You are with a same-sex partner and you do not participate in bisexual activities
where there is any risk of pregnancy
• You abstain from sexual intercourse
A pregnancy test will be required prior to your entering the study; this test must be
negative, meaning that you are not pregnant.
Digoxin and Other Medications
You should be sure to let your doctor know about all medications you are taking at the
time you join the study. This includes all prescription drugs, all over-the-counter drugs
(drugs that you buy at the drugstore or grocery store), and all herbal or non-traditional
treatments that you take. Your doctor can make sure that none of the drugs you take is
known to act in a bad way with GW679769.
If you take a drug called digoxin, you should talk with your doctor before participating in
this study. Digoxin is a drug which is taken for certain heart conditions; it is also called
Lanoxicaps, Lanoxin, and Novo-Digoxin. In studies we have done so far, we have not
seen any side effects in people taking digoxin with GW679769, but there were some
interactions seen in test tubes in the laboratory. Because of this, your doctor will want to
monitor your digoxin level, if you take digoxin and join this study.
Allergic Reactions
Although we have not seen any allergic reactions to GW679769 or the combination of
GW679769 and ZOFRAN, sometimes people have an unexpected allergic reaction to
drugs. It is possible that you could have a very bad allergic reaction, which could even
be fatal. However, these kinds of very bad allergic reactions are very rare. Some things
that could happen during an allergic reaction are:
• a rash
• having a hard time breathing
• wheezing when you breathe
• sudden drop in blood pressure
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• swelling around the mouth, throat, or eyes

• fast pulse (heartbeat)
• sweating
Please tell the study doctor or study staff right away if you have any of these side effects.
Please tell them if you have any other problems with your health or the way you feel
during the study.
You cannot be in this study if you are pregnant or nursing a baby. If you decide to be in
the study:
• you must not be pregnant

• you must not plan to become pregnant during the study
• you must not be nursing a baby
Zofran and GW679769 have been given together to people in other studies, at the dose
levels to be given in this study. However, the combination of Zofran and GW679769
used in this study may have other risks that we do not know about at this time.
Are there any benefits for taking part in the study?
Being in this study might or might not help you, since no one knows for certain whether
you will develop nausea and vomiting after your surgery. However, the study doctor has
identified you as having a high chance of experiencing nausea and vomiting after surgery.
The study drugs might help to prevent such nausea and vomiting, but there is no
guarantee that being in this study will help you.
Information from this study might help to determine if adding GW679769 to ZOFRAN is
safe and more effective than ZOFRAN alone in preventing nausea and vomiting after
surgery, which could benefit future patients.
What payments will be made for the study?
You will not receive payment for taking part in this study.
However, GSK has made provisions with the study doctor to reimburse you for the cost
of travelling to and from study visits and for other costs if appropriate (such as expense
for a meal) up to a maximum of < xxxxxx >.
Who should you contact to answer any questions on the study?
You can ask questions about the study at any time. If you feel sick, you can call the
study doctor at <phone number> during the day. You can also call <after hours phone
number> at any time.
This study was reviewed by < xxxxxxxx> Institutional Review Board (IRB). An IRB is a
group of people who review the risks and benefits of a study. If you want to ask
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questions about what it means to be in a research study or about your rights as a research
participant, you can call < xxxxxxxx> IRB.
Secondary authors: Insert IRB contact information here
In the event if you are injured in the study what compensation will be available?
If you are injured by the investigational medicines being studied, or by any clinical
procedure that would not have been given outside of this study, GlaxoSmithKline will
pay for reasonable and necessary medical expenses to treat the injury that are not covered
by your medical insurance. GlaxoSmithKline is not offering to compensate you for any
other expenses, but you keep all of your legal rights if you sign this consent form.
Who will have access to medical and personal information about you that is
collected in this study?
If you decide to participate in the study, the study doctor and staff will collect medical
and personal information about you as part of doing the study. People who work for or
with GlaxoSmithKline (GSK), and others like the independent ethics committee or the
institutional review board (IEC/IRB) for the study or the regulatory authorities
responsible for approving medicines, will have access to this information at the site in
order to check that the study is done properly. GSK staff who see this information at the
site will keep it confidential.
The study site will also transfer to GSK some of the information it collects, in a coded
form. The information transferred will not include your name, initials, address, or other
direct identifiers. It will be assigned a code number that only the site can connect back to
your name.
Your permission to the study doctor and staff to use this information or share it with GSK
and others as described below for the study doesn’t automatically end at a particular time.
You should know that once identifiable medical information about you is given to
someone that is not a health care provider, it is not protected by the US federal privacy
rules called the HIPAA Privacy Regulations.
While you are in the study, the study site will not share certain new medical information
about you that is created as part of the study (such as whether or not you are getting a
particular study drug, or the results of certain tests) unless the study doctor decides it is
medically important to do so. This is done to stop the study results from being distorted.
Once the study is over, you will be given access to medical information about you that
you are entitled to see. At any time, you may ask your study doctor to let you see your
personal information, e.g., name and address, and to correct it if necessary.
What will GlaxoSmithKline (GSK) do with the information it gets?
GSK may use the information that the study doctor gives it (i.e. the coded information):
• By storing and analyzing it electronically to find out what this study is telling us.
8 of 10
12
NKT102553

Date: 14 Dec. 05
• By sharing it with regulatory authorities that approve new medicines, or with groups
that check that research is done properly
• By publishing the results of the study (this will not include any information that
directly identifies you)
• By sharing it as part of research with other companies or universities for the purpose
of further understanding or developing this drug and with other GSK offices in this
country and in other countries. If the information is sent to another country, GSK
will apply the same level of protection to your information, to the extent permitted
by local law.
• By using it to plan new studies or other types of research or other medical purposes
related to the development of the drug.
What will happen to tissue samples from this study?
Blood samples collected from you for tests for this study will be discarded once the tests
have been done.
How is GlaxoSmithKline involved?
GlaxoSmithKline is the pharmaceutical company which makes both Zofran and

GW679769. GlaxoSmithKline is paying the doctor and the health care facility to conduct
this study.
Consent Form
I have read all of the written information about this study, and the study procedures have
been explained to me by the site staff. I have been given an opportunity to ask questions
about the study, and received answers which I understood. I have had enough time to
think about whether or not I want to participate in this study, and have decided I am
willing to participate in this study.
Subject’s Signature Date:

DD/ MM/ YY
Printed name of Subject
*Signature of Legally
Acceptable
Representative Date:
DD/ MM/ YY
*Printed name of Legally
Acceptable
Representative
*Signature of Witness Date:

DD/ MM/ YY
*Printed name of
9 of 10
13
NKT102553

Date: 14 Dec. 05
Witness
Signature of Person
conducting Consent Date:
DD/ MM/ YY
Printed name of Person
conducting Consent
10 of 10
14
Listing 9.2
Listing of Demographic Characteristics
Assessment Date of
Treatment Centre Subj. Date Birth Age (y) Sex Ethnicity Height Weight
-------------------------------------------------------------------------------------------------------
4mg IV Zofran 63 F Not Hispanic or 153 69
Latino
37 F Not Hispanic or 173 73

Latino

Latino
CONFIDENTIAL
Latino

Latino
1

Latino

Latino

Latino
36 F Hispanic or 158 72
GM2006/00652/00
Latino
Latino
NKT102553
Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
Latino

Latino

Latino
CONFIDENTIAL
Latino

Latino
2

Latino

Latino
F Not Hispanic or 168 73

Latino
GM2006/00652/00
Latino

Latino
NKT102553
Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
4mg IV Zofran 34 F Hispanic or 156 80
Latino
F Hispanic or 152 61
Latino

Latino
CONFIDENTIAL
Latino

Latino
3

Latino

Latino

Latino
GM2006/00652/00
Latino

Latino
NKT102553
Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
4mg IV Zofran F Hispanic or
Latino
Latino
Latino
CONFIDENTIAL
Latino

Latino
4
Latino

Latino

Latino
GM2006/00652/00
Latino

Latino
NKT102553
Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
Latino

Latino

Latino
CONFIDENTIAL
Latino

Latino
5

Latino

Latino
Latino
GM2006/00652/00
Latino

Latino
NKT102553
Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
Latino
Latino

Latino
CONFIDENTIAL
Latino

Latino
6

Latino

Latino

Latino
GM2006/00652/00
Latino

Latino
NKT102553
Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
Latino
Latino
Latino
CONFIDENTIAL
Latino
Latino
7

Latino

Latino

Latino
GM2006/00652/00
Latino

Latino
NKT102553
Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
Latino

Latino

Latino
CONFIDENTIAL
Latino

Latino
8

Latino

Latino

Latino
GM2006/00652/00
Latino

Latino
NKT102553
Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
Latino

Latino

Latino
CONFIDENTIAL
Latino

Latino
9

Latino

Latino

Latino
GM2006/00652/00
Latino

Latino
NKT102553
Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
Latino

Latino

Latino
CONFIDENTIAL
Latino

Latino
10

Latino

Latino

Latino
GM2006/00652/00
Latino

Latino
NKT102553
Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
Latino

Latino

Latino
CONFIDENTIAL
Latino

Latino
11

Latino

Latino

Latino
GM2006/00652/00
Latino

Latino
NKT102553
Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
Latino

Latino

Latino
CONFIDENTIAL
Latino

Latino
12

Latino

Latino

Latino
GM2006/00652/00
Latino

Latino
NKT102553
Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
Latino

Latino

Latino
CONFIDENTIAL
Latino

Latino
13

Latino

Latino

Latino
GM2006/00652/00
Latino

Latino
NKT102553
Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
Latino

Latino

Latino
CONFIDENTIAL
Latino

Latino
14

Latino

Latino

Latino
GM2006/00652/00
Latino

Latino
NKT102553
Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
Latino

Latino

Latino
CONFIDENTIAL
Latino

Latino
15

Latino

Latino

Latino
GM2006/00652/00
Latino

Latino
NKT102553
Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
Latino

Latino

Latino
CONFIDENTIAL
Latino

Latino
16

Latino

Latino

Latino
GM2006/00652/00
Latino

Latino
NKT102553
Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
Latino

Latino

Latino
CONFIDENTIAL
Latino

Latino
17

Latino

Latino

Latino
GM2006/00652/00
Latino

Latino
NKT102553
Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
Latino

Latino

Latino
CONFIDENTIAL
Latino

Latino
18

Latino

Latino

Latino
GM2006/00652/00
Latino

Latino
NKT102553
Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
Latino

Latino

Latino
CONFIDENTIAL
Latino

Latino
19

Latino

Latino

Latino
GM2006/00652/00
Latino

Latino
NKT102553
Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
Latino

Latino

Latino
CONFIDENTIAL
Latino

Latino
20

Latino

Latino

Latino
GM2006/00652/00
Latino

Latino
NKT102553
Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
Latino

Latino

Latino
CONFIDENTIAL
Latino

Latino
21

Latino

Latino

Latino
GM2006/00652/00
Latino

Latino
NKT102553
Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
Latino

Latino

Latino
CONFIDENTIAL
Latino

Latino
22

Latino

Latino

Latino
GM2006/00652/00
Latino

Latino
NKT102553
Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
4mg IV Zofran + 30 F Not Hispanic or 165 77
50mg PO Latino
Casopitant
Latino

Latino
CONFIDENTIAL
Latino

23
Latino

Latino

Latino

Latino
GM2006/00652/00
Latino
NKT102553
Latino

Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
50mg PO Latino
Casopitant

Latino

Latino
CONFIDENTIAL
Latino

24
Latino
Latino

Latino

Latino
GM2006/00652/00
Latino
NKT102553
Latino
Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
4mg IV Zofran + 50 F Hispanic or 158 75
50mg PO Latino
Casopitant
F Hispanic or
Latino
Latino
CONFIDENTIAL
Latino
25
Latino
Latino
Latino
Latino
GM2006/00652/00
Latino
NKT102553
Latino
Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
4mg IV Zofran + 40 F Hispanic or 160 70
50mg PO Latino
Casopitant

Latino

Latino
CONFIDENTIAL
Latino

26
Latino

Latino

Latino

Latino
GM2006/00652/00
Latino
NKT102553
Latino

Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
50mg PO Latino
Casopitant

Latino

Latino
CONFIDENTIAL
Latino

27
Latino

Latino

Latino
Latino
GM2006/00652/00
Latino
NKT102553
Latino

Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
50mg PO Latino
Casopitant

Latino
Latino
CONFIDENTIAL
Latino

28
Latino

Latino

Latino
Latino
GM2006/00652/00
Latino
NKT102553
Latino

Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
50mg PO Latino
Casopitant

Latino

Latino
CONFIDENTIAL
Latino

29
Latino

Latino

Latino
65 F Not Hispanic or
Latino
GM2006/00652/00
Latino
NKT102553
Latino

Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
50mg PO Latino
Casopitant

Latino

Latino
CONFIDENTIAL
Latino

30
Latino

Latino

Latino

Latino
GM2006/00652/00
Latino
NKT102553
Latino

Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
50mg PO Latino
Casopitant

Latino

Latino
CONFIDENTIAL
Latino

31
Latino

Latino

Latino

Latino
GM2006/00652/00
Latino
NKT102553
Latino

Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
50mg PO Latino
Casopitant

Latino

Latino
CONFIDENTIAL
Latino

32
Latino

Latino

Latino

Latino
GM2006/00652/00
Latino
NKT102553
Latino

Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
50mg PO Latino
Casopitant

Latino

Latino
CONFIDENTIAL
Latino

33
Latino

Latino

Latino

Latino
GM2006/00652/00
Latino
NKT102553
Latino

Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
50mg PO Latino
Casopitant

Latino

Latino
CONFIDENTIAL
Latino

34
Latino

Latino

Latino

Latino
GM2006/00652/00
Latino
NKT102553
Latino

Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
50mg PO Latino
Casopitant

Latino

Latino
CONFIDENTIAL
Latino

35
Latino

Latino

Latino

Latino
GM2006/00652/00
Latino
NKT102553
Latino

Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
50mg PO Latino
Casopitant

Latino

Latino
CONFIDENTIAL
Latino

36
Latino

Latino

Latino

Latino
GM2006/00652/00
Latino
NKT102553
Latino

Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
50mg PO Latino
Casopitant

Latino

Latino
CONFIDENTIAL
Latino

37
Latino
Latino

Latino

Latino
GM2006/00652/00
Latino
NKT102553
Latino

Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
50mg PO Latino
Casopitant

Latino

Latino
CONFIDENTIAL
Latino

38
Latino

Latino

Latino

Latino
GM2006/00652/00
Latino
NKT102553
Latino

Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
50mg PO Latino
Casopitant

Latino

Latino
CONFIDENTIAL
Latino

39
Latino

Latino

Latino

Latino
GM2006/00652/00
Latino
NKT102553
Latino

Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
50mg PO Latino
Casopitant

Latino

Latino
CONFIDENTIAL
Latino

40
Latino

Latino

Latino

Latino
GM2006/00652/00
Latino
NKT102553
Latino

Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
50mg PO Latino
Casopitant

Latino

Latino
CONFIDENTIAL
Latino

41
Latino

Latino

Latino

Latino
GM2006/00652/00
Latino
NKT102553
Latino

Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
50mg PO Latino
Casopitant

Latino

Latino
CONFIDENTIAL
Latino

42
Latino

Latino

Latino
F Not Hispanic or
Latino
GM2006/00652/00
Latino
NKT102553
Latino

Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
50mg PO Latino
Casopitant

Latino

Latino
CONFIDENTIAL
Latino

43
Latino

Latino

Latino

Latino
GM2006/00652/00
Latino
NKT102553
Latino

Latino
Listing 9.2
Assessment Date of
-------------------------------------------------------------------------------------------------------
50mg PO Latino
Casopitant

Latino

Latino
CONFIDENTIAL
Latino

44
Latino

Latino

Latino

Latino
GM2006/00652/00
Latino
NKT102553
Latino

Latino
NKT102553
1
NKT102553
2
NKT102553
3
NKT102553
4
NKT102553
5
NKT102553
ICH Listings
Page
Listing - ICH 9.1 Listing of End of Study Record (Intent-to-Treat Population) . 2
Listing - ICH 9.5 Listing of All Adverse Events (Safety Population) . . . . . . . . 5
Listing - ICH 9.6 Listing of Fatal Adverse Events (Safety Population) . . . . . . 96
Listing - ICH 9.7 Listing of Non-Fatal Serious Adverse Events (Safety
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
Listing - ICH 9.8 Listing of Subjects with Inclusion/Exclusion Criteria
Deviations (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Listing - ICH 9.9 Listing of Exposure Data (Safety Population) . . . . . . . . . . . . 103
Listing - ICH 9.11 Listing of Subjects for Whom the Treatment Blind was
Broken During the Study (Safety Population) . . . . . . . . . . . . . . . . . . . . . . 182
Listing - ICH 9.14 Listing of Race (Intent-to-Treat Population) . . . . . . . . . . . . 183
Listing - ICH 9.15 Listing of Subject Protocol Deviations (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
Listing - ICH 9.16 Listing of All Adverse Events that led to withdrawal
1
This section contained data from each individual patient, rather than in aggregate. They have
been excluded to protect patient privacy. Anonymized data from each patient may be made
available subject to an approved research proposal. For further information please see the
Patient Level Data section of the GSK Clinical Study Register.
NKT102553
Other Listings
Page
Listing - Other 9.4 Listing of Subject Numbers for Individual Adverse Events
Listing - Other 9.10 Listing of Study Drug Discontinuation Record
Listing - Other 9.13 Listing of Deaths (Intent-to-Treat Population) . . . . . . . . . 23
1
This section contained data from each individual patient, rather than in aggregate. They have
been excluded to protect patient privacy. Anonymized data from each patient may be made
available subject to an approved research proposal. For further information please see the
Patient Level Data section of the GSK Clinical Study Register.
CONFIDENTIAL
Table 1: Protocol Level Administration
Study Title: A Phase III Multicenter, Randomized, Double-blind, Parallel Group Study to Evaluate the Safety and Efficacy of 50
mg Oral Dosing with the Neurokinin-1 Receptor Antagonist GW679769 for Prevention of Postoperative Nausea and Vomiting in
Study Number: NKT102553 Female Subjects at High Risk for Emesis.
Statistics Group
Medical Writing: Site of Medical Writing: GCP
Protocol Data Management Manufacture & Clinical Report Site of EU Location of Study Regulatory
Study Sponsor Authorship Group Randomisation Assembly Authorship release Master File inspection
Names of authors Company and Names of authors Name of
Address and their Address Address Address Address Address and their Address Address Address Agency
GlaxoSmithKline Statitician RAMOS GSK Operations GlaxoSmit GlaxoSmithKline None Done
New Frontiers GlaxoSmithKline, GlaxoSmithKline, Biomedical Data Priory Street GlaxoSmithKline, hKline New Frontiers
Science Park, 1250 South GlaxoSmithKline, Biomedical and Data Services, Ware, MDC, Clinical Clinical Science Park, Third
CONFIDENTIAL
Third Avenue, Collegeville Road, Biomedical and Data Services, Biostatistical Biostatistical and Hertfordshire Oncology, trial Avenue, Harlow,
Harlow, Essex, Collegeville, PA, Services, and Programming, Programming, SG12 ODJ Upper Providence Supplies Essex, CM19 5AW
CM19 5AW 19426 Biostatistical and Greenford, UK GlaxoSmithKline, GlaxoSmithKline, GlaxoSmit
Programming 2301 GSK 1250 South hKline
Upper Providence Rennaissance Via Alessandro Collegeville Road, Research
GlaxoSmithKline, GlaxoSmithKline, Biomedical and Data Blvd, King of Fleming, 2 Collegeville, PA, &
1
1250 South 1250 South Services, Biostatistical Prussia, PA 19406 Verona 19426 Developm
Collegeville Road, Collegeville Road, and Programming, Italy ent Ltd
Collegeville, PA, Collegeville, PA, Greenford, UK 37135 New
19426 19426 GlaxoSmithKline, Frontiers
Global Heath Science
Programmer Outcomes- Park
GlaxoSmithKline, Oncology, (South)
1250 South GlaxoSmithKline, Upper Providence Third
Collegeville Road, Biomedical and Data GlaxoSmithKline, Avenue
Collegeville, PA, Services, 1250 South Harlow
19426 Biostatistical and Collegeville Road, Essex
Programming Collegeville, PA, CM19
Upper Providence 19426 5AW
GM2006/00652/00
GlaxoSmithKline, GlaxoSmithKline, UK
1250 South 1250 South
Collegeville Road, Collegeville Road, USP MDC Clinical
Collegeville, PA, Collegeville, PA, Oncology,
NKT102553
19426 19426 1250 South
Collegeville Road,
1
CONFIDENTIAL
mg Oral Dosing with the Neurokinin-1 Receptor Antagonist GW679769 for Prevention of Postoperative Nausea and Vomiting in
Study Number: NKT102553 Female Subjects at High Risk for Emesis.
Statistics Group
Medical Writing: Site of Medical Writing: GCP
Protocol Data Management Manufacture & Clinical Report Site of EU Location of Study Regulatory
Study Sponsor Authorship Group Randomisation Assembly Authorship release Master File inspection
Collegeville, PA,
GlaxoSmithKline, 19426"
Harlow UK
Niche Science &

GlaxoSmithKline Technology Ltd,
New Frontiers Greenford
Science Park, Third
CONFIDENTIAL
Avenue, Harlow,
Essex, CM19 5AW GlaxoSmithKline,
Biomedical and
Data Services,
Biostatistical and
2
Programming
GlaxoSmithKline, 5
Moore Drive, PO
Box 13398,
Research Triangle
Park, NC 27709.
GM2006/00652/00
NKT102553
2
CONFIDENTIAL
Table 2 Country Level Administration
mg Oral Dosing with the Neurokinin-1 Receptor Antagonist GW679769 for Prevention of Postoperative Nausea and Vomiting
Study Number: NKT102553 in Female Subjects at High Risk for Emesis.
Participating Responsible for Sites of distribution

Countries Monitoring which sites Laboratory Assessments in Europe Audits
Were Audits Centre Number of
done? Site(s) Conducted by:
Laboratory name and Name and address
CONFIDENTIAL
Country Name Address of resource Centre Numbers address Address yes/no Centre numbers of audit group
Canada GlaxoSmithKline Quest Diagnostics Inc. Pharm Tech Upper No
7333 Mississauga 7600 Tyrone Avenue Providence
Road Van Nuys, CA 91405-1449 GlaxoSmithKline
North Mississauga, Pharmaceuticals
Ontario L5N 6L4 St. Paul’s Hospital Clinical Trial Supplies
3
CANADA Laboratory Shipping UP9105

1081 Burrard Street 1250 S Collegeville
Vancouver, British Columbia Road
Canada V6Z 1Y6 Doc 9B
Collegeville
Lab CHUQ Hopital St. PA 19426
Francois D’Assise
10 rue de l’Espinay
Quebec, Quebec
Canada G1L-3L5
Centre Hosp du Centre de la

Mauricie
GM2006/00652/00
50, 119e Street
Shawinigan, Sud
Canada G9P 5K1
NKT102553
Centre de Sante de Portneuf
700, St-Cyrille Street
3
CONFIDENTIAL

St. Raymond, Quebec
Canada G3L 1W1
Reseau de Sante du
Temiscouata
CONFIDENTIAL
58 rue de I’Eglise
Notre-Dame du Lac
Canada GO1 1X0
Dynacare Kasper Medical

Lab
4
RAH Site
10240 Kingsway Avenue
Edmonton, Alberta
Canada T5H 3V9
Dynacare Kasper Medical

Lab
#200, 10150-102 St.
Edmonton, Alberta
Canada T5J 5E2
Regina Qu’Appelle Health

Region
GM2006/00652/00
1440-14th Avenue
Regina, Saskatchewan
Canada S4P 0W5
NKT102553
Queen Elizabeth Hospital
Box 660
4
CONFIDENTIAL

Charlottetown, Prince
Edward Island
Canada CIA 8T5
France GSK, 100 Route De Quest Diagnostics Clinical GlaxoSmithKline No
CONFIDENTIAL
Versailles, Marly Le Trials Clinical trial Supplies
Roi, France Unit B1, Parkway West GlaxoSmithKline
Crawford, Lane, Heston, Research &
Middlesex, TWA 9QA, UK Development Ltd
New Frontiers
Hopital De Riom, 73 Science Park (South)
5
Boulevard Clementel, 63204 Third Avenue

Riom Cedex France Harlow
Essex CM19 5AW
Hotel Dieu,1 Palce de UK
L'hopital, 69288 Lyon Cedex
2 France
Lab Bioch Hema PR Daniel

Chu Saint Andre 1 Rue Jean
Burguet 33075 Bordeaux
Cedex France
Lab Hematologie-Lab
GM2006/00652/00
Biochimie, Hopital TENON, 4
rue de le Chine, 75020 Paris
France
NKT102553
Germany GSK Quest Diagnostics Clinical GlaxoSmithKline No
Theresienhohe 11 Trials Clinical trial Supplies
5
CONFIDENTIAL

80339 Munich Unit B1, Parkway West GlaxoSmithKline
Crawford, Lane, Heston, Research &
Middlesex, TWA 9QA, UK Development Ltd
New Frontiers
Zentrallab Science Park (South)
CONFIDENTIAL
Universitatsklinikum RWTH Third Avenue
Aachen Pauwelsstr 30 52074 Harlow
Aachen Germany Essex CM19 5AW
UK
Zentrallabor,Universitat der
RWTH Aachen
6
Pauwelsstr.30, 52074
Aachen, Germany
Zentrallabor,Universitat
Giessen,Standort
Marburg,Baldingerstr,1,35033
Marburg Germany
Hong Kong 23/F Tower 6 the Quest Diagnostics Clinical GlaxoSmithKline No
Gateway Trials Clinical trial Supplies
9 Canton Road Unit B1, Parkway West GlaxoSmithKline
Tsimshatsui Kowloon Crawford, Lane, Heston, Research &
Hong Kong Middlesex, TWA 9QA, UK Development Ltd
New Frontiers
GM2006/00652/00
Div of Haem and Blood Science Park (South)
Bank,Blk K,Queen Mary Third Avenue
Hospital,Pokfulam,Hong Harlow
Kong Essex CM19 5AW
NKT102553
UK
The Prince of Wales Hospital,
6
CONFIDENTIAL

Shatin, New Territories, Hong
Kong
Hungary GSK Kft Quest Diagnostics Clinical GlaxoSmithKline Yes WW Regulatory
MOM Park Trials Clinical trial Supplies Compliance
Gesztenyes torony Unit B1, Parkway West GlaxoSmithKline GlaxoSmithKline
CONFIDENTIAL
Csorsz u 43 Crawford, Lane, Heston, Research & Via Alessandro
1124 Middlesex, TWA 9QA, UK Development Ltd Fleming 4
New Frontiers Verona
Dr Bugyi lstvan Korhaz Science Park (South) ITALY
Kozponti Laboratorium, 6600 Third Avenue
Szentes,Sima F u. 58 Harlow
7
Hungary Essex CM19 5AW

UK
Miskoic MJVO Semmelweis
Kozponti Lab,3529
Miskoic,Csabai Kapu 9-11,
Hungary
Multilab Diagnostica LTD, H-

8000 Szekesfehervar,
Seregelyesi u. 3 Hungary
Petz Aladar County

Hospital,Central Lab,Vasvari
GM2006/00652/00
P. str. 2-4,H-9024
Gyor,Hungary
Varosi Onkorm Rl
NKT102553
Mezokovesd 3400
Mezokovesd Matyas Kiraly
7
CONFIDENTIAL

74 Hungary
Ireland GSK Quest Diagnostics Clinical GlaxoSmithKline No
Stonemason’s Way Trials Clinical trial Supplies
Rathfarnham Unit B1, Parkway West GlaxoSmithKline
Dublin 16 Crawford, Lane, Heston, Research &
CONFIDENTIAL
Ireland Middlesex, TWA 9QA, UK Development Ltd
New Frontiers
Portiuncula Hospital Lab, Science Park (South)
Portiuncula Hosp, Third Avenue
Ballinasloe, Co Galway Harlow
Ireland Essex CM19 5AW
8
UK
Pakistan GlaxoSmithKline Quest Diagnostics Clinical GlaxoSmithKline No

Pakistan Ltd Trials Clinical trial Supplies
35 Dockyard Road Unit B1, Parkway West GlaxoSmithKline
West Wharf Crawford, Lane, Heston, Research &
Karachi 74000 Middlesex, TWA 9QA, UK Development Ltd
Pakistan New Frontiers
Liaquat National Science Park (South)
Hospital,Stadium Third Avenue
Road,Karachi,Pakistan Harlow
74800 Essex CM19 5AW
GM2006/00652/00
UK
Philippines 2266 Chino Roces Quest Diagnostics Clinical GlaxoSmithKline No

Ave, Trials Clinical trial Supplies
Makati City 1231, Unit B1, Parkway West GlaxoSmithKline
NKT102553
Metro Manila, Crawford, Lane, Heston, Research &
Philippines Middlesex, TWA 9QA, UK Development Ltd
8
CONFIDENTIAL

New Frontiers
Hi-Precision Diagnostics, 674 Science Park (South)
N.S. Amoranto Sr. Avenue, Third Avenue
Quezon City, Philippines Harlow
Essex CM19 5AW
CONFIDENTIAL
UK
Thailand GSK Thailand Ltd Quest Diagnostics Clinical GlaxoSmithKline No

12th Floor, Wave Trials Clinical trial Supplies
Place, 55 Unit B1, Parkway West GlaxoSmithKline
Wireless Road, Crawford, Lane, Heston, Research &
9
Lumpini, Middlesex, TWA 9QA, UK Development Ltd

Patumwan, Bangkok New Frontiers
10330 Department Of Clinical Science Park (South)
Thailand Pathology Siriraj Hospital, Third Avenue
Bangkok, Thailand Harlow
Essex CM19 5AW
UK
UK Quest Diagnostics Clinical GlaxoSmithKline No

GSK Trials Clinical trial Supplies
Stockley Park West Unit B1, Parkway West GlaxoSmithKline
Uxbridge Crawford, Lane, Heston, Research &
GM2006/00652/00
Middlesex Middlesex, TWA 9QA, UK Development Ltd
UB11 1BT New Frontiers
Royal Liverpool Uni Hosp, 4th Science Park (South)
Fl Duncan Build, Prescot St, Third Avenue
Liverpool, L7 8XP UK Harlow
NKT102553
Essex CM19 5AW
St. John's Hospital, Howden UK
9
CONFIDENTIAL

Road, Livingston EH54 6PP
UK
United States PAREXEL Quest Diagnostics Inc. Pharm Tech Upper No
International 7600 Tyrone Avenue Providence
2520 Meridian Van Nuys, CA 91405-1449 GlaxoSmithKline
CONFIDENTIAL
Parkway Pharmaceuticals
Durham, NC 27713 UPMC (Presbyterian) Clinical Trial Supplies
Shadyside Hospital Shipping UP9105
PAREXEL 5230 Centre Avenue 1250 S Collegeville
International Pittsburgh, PA 15232 Road
10
200 West Street Doc 9B

Waltham, MA 02451 Altoona Hospital Campus Collegeville
Lab PA 19426
620 Howard Avenue
Altoona, PA 16601
Baptist Health Systems Lab

1225 North State Street
Jackson, MS 39202
Baptist Medical Center East

400 Taylor Road
Montgomery, AL 36117
GM2006/00652/00
Memorial Hermann Hopsital
6410 Fannin
Houston, TX 77030
NKT102553
Arcadia Methodist Hospital
300 West Huntington Drive
10
CONFIDENTIAL

Arcadia, CA 91007
Hahneman Hospital Lab

5th Floor, North Tower
Broad and Vine Streets
CONFIDENTIAL
Philadelphia, PA 19102
Helen Keller Hospital

Laboratory
1300 South Montgomery
11
Avenue
Sheffield, AL 35660
LabCorp Phoenix
3930 East Watkins, Suite 300
Phoenix, AZ 85034
St. Luke’s-Roosevelt Hospital

Center
1111 Amsterdam Avenue
New York, NY 10025
Quest Diagnostics
4225 East Fowler Avenue
GM2006/00652/00
Tampa, FL 3361-2026
Laboratory Corporation of
America
NKT102553
7207 North Gessner
Houston, TX 77040
11
CONFIDENTIAL

New York University Medical

Center
The Tish Hospital Clinical
Laboratory
CONFIDENTIAL
550 First Avenue
New York, NY 10016
Bridger Pathology Labs

2005 Normandie Drive
12
St. Peter’s University

Hospital Lab
254 Easton Avenue
New Brunswick, NJ 08901
Jackson Memorial Clinical

Laboratory
1611 NW 12th Avenue
Holtz Center, Suite 2070
Miami, FL 33136
Spectrum Health Blodgett
GM2006/00652/00
Campus Lab
1840 Wealthy Street SE
Grand Rapids, MI 49506
NKT102553
Baptist Medical Center South
2105 East South Boulevard
12
CONFIDENTIAL

Community Clinical Research

Center
1622 North Madison, 5th
CONFIDENTIAL
Floor
Anderson, IN 46011
Palms West Hospital Clinical

Laboratory
13
13001 Southern Boulevard

State Road 80
Loxahatchee, FL 33470
Quest Diagnostics Clinical

Laboratory, Inc.
1300 East Newport Center
Drive
Deerfield Beach, FL 33442
New York University Medical

Center
160 E 35th Street LL
New York, NY 10016
GM2006/00652/00
SW Washington Medical
Centre
400 NE Mother Joseph Place
NKT102553
Vancouver, WA 98662
13
CONFIDENTIAL

Lab Corp – SW Fort Worth
6210 Johan Ryan Drive,
#108
Fort Worth, TX 76132
CONFIDENTIAL
SED Medical Laboratories
5601 Office Boulevard NE
Albuquerque, NM 87109
Quest Diagnostics
14
1611 NW 12th Avenue

Room 734
Miami, FL 33136-1005
Magee Women’s Hospital

300 Halket Street
Pittsburgh, PA 15213-3108
Creighton University Medical

Center
601 North 30th Street
Omaha, NE 68131
LAC & USC Medical Center
GM2006/00652/00
Laboratory
1200 North State Street
Los Angeles, CA 90033
NKT102553
14
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In February 2013, GlaxoSmithKline (GSK) announced a commitment to further clinical

The following guiding principles have been applied to the disclosure:

Division: Worldwide Development

Title: A Phase III, Multicenter, Randomized, Double-blind, Parallel

Compound Number: GW679769

Effective Date: 25 January 2008

Subject: GW679769, Casopitant, NK-1 Receptor Antagonist, Postoperative Nausea and

Authors: MDC BDS - Oncology US; USP

Indication Studied: Postoperative Nausea and Vomiting

Initiation Date: 20 March 2006

Completion Date: 31 August 2006

Date of Report: January 2008

Copyright 2008 the GlaxoSmithKline group of companies. All rights reserved.

5.4.6. Assessment of Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

6.5.2. Prior and Concomitant Medications . . . . . . . . . . . . . . . . . . . . . 52

9.3. Medical Resource Utilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76

Table 22 Adverse events possibly related to investigational product

Trademarks of the GlaxoSmithKline Trademarks not owned by the

1.1. Independent Ethics Committee (IEC) or Institutional Review

1.2. Ethical Conduct of the Study

1.3. Subject Information and Consent

2. INVESTIGATORS AND STUDY ADMINISTRATIVE

GlaxoSmithKline (GSK) was responsible for all aspects of study administration,

Study monitoring was performed by a Contract Research Organization, Parexel

Overall, approximately 20–30% of surgical patients experience PONV [Watcha, 1992;

better achieved by using a combination of antiemetic agents that act on different

4.1.1. Primary Objective

measured by complete response, defined as no vomiting, no retching, and no rescue

4.1.2. Secondary Objectives

The secondary objectives of this clinical trial were to:

4.2.1. Primary Endpoint

4.2.2. Secondary Endpoints

The following secondary endpoints were analyzed:

• Complete protection: no vomiting/retching, no rescue therapy and maximum nausea

5.1. Overall Study Design

Table 1 Time and events table

Pre-surgical Day of Surgery Post-op. Post-op. Post-op.

5.1.1. Dosing of Antiemetics in NKT102553

Dosing of antiemetics is detailed in Table 2.

Table 2 Dosing of antiemetics

Cohort Medication Route of Timing of Administration Dose

5.1.2. Anesthetic and Analgesic Regimen

Participating investigators were required to adhere to a balanced general anesthetic

Anticipated need for or requirement of opioids post-surgery was an eligibility

5.1.3. Discussion of Study Design, Including the Choice of Control

5.2. Protocol Amendments

Amendment 1, dated 23 January 2006, corrected internal inconsistencies. In the original

5.3. Selection of Study Population

Subjects were stratified to treatment assignments by planned intra-operative use of

5.3.1. Inclusion/Exclusion Criteria

5.3.1.1. Inclusion criteria

1. Was 18 years of age or older.

5.3.1.2. Exclusion criteria

1. Was pregnant or lactating.

5.3.2. Predetermined Criteria for Subject Withdrawal

5.3.2.1. Subject withdrawal from the investigational product

5.3.2.2. Subject withdrawal from the study

5.4. Investigational Product and Study Medication

5.4.1. Description of Investigational Product and Study Medication

Each vial of Zofran Injection contained 4mg of ondansetron hydrochloride in 2mL of

5.4.2. Dosages and Administration

All subjects received a single IV administration of Zofran Injection immediately prior to

5.4.3. Dose Rationale