Protocol Rev 1

CONFIDENTIAL PROTOCOL
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference
Product Mirvaso
(brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with Moderate
to Severe Facial Erythema Associated with Rosacea

71304906 July 2, 2014 Novum Pharmaceutical Research Services, Inc Page 2 of 51

2.0 KEY STUDY PERSONNEL AND FACILITIES

Sponsor:

Watson Laboratories, Inc., USA
400 Interpace Parkway
Parsippany, NJ 07054

CRO:

Novum Pharmaceutical Research Services (Novum)
5900 Penn Avenue
Pittsburgh, PA 15206

Sponsors Representative:

Nageshwar R. Thudi, PhD
Director, Biopharmaceutics
Morris Corporate Center III
400 Interpace Parkway, Parsippany, NJ 07054
Tel: 862-261-7548
Fax: 862-261-9711
Email: nageshwar.thudi@actavis.com

CRO representative:

Gail Gongas
Vice President, Clinical Trials
Novum Pharmaceutical Research Services
5900 Penn Ave., Pittsburgh, PA 15206
Tel: 412-363-3300 x 522
Fax: 412-362-5783
Email: gdgongas@novumprs.com

Medical Monitor:

Darin B. Brimhall, DO, FACP,CPI
Medical Monitor
3760 Pecos McLeod
Las Vegas, NV 89121
Tel: 702-435-3739 x370
Fax: 412-291-3171
Email: dbrimhall@novumprs.com

Biostatistician:

Jianhua Liu, MSc
Senior Biostatistician
5900 Penn Ave.
Pittsburgh, PA 15206
Tel: 647-779-6883
Fax: 412-924-0522
Email: JLiu@novumprs.com

Product Mirvaso


PRINCIPAL INVESTIGATORS SIGNATURE

I _______________________________________, agree to conduct protocol 71304906 A Randomized,
Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design Study to Evaluate the Safety and
Therapeutic Equivalence of Brimonidine Topical Gel, 0.33% (Watson Laboratories, Inc., USA) to
Reference Product Mirvaso
(brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in

Patients with Moderate to Severe Facial Erythema Associated with Rosacea in accordance with FDA
regulations, ICH guidelines and Good Clinical Practice. I understand that no deviations from the protocol
may be made without the prior permission of the Sponsor (Watson Laboratories, Inc., USA) or Novum
Pharmaceutical Research Services, the company managing the study.

___________________________________ __________
Principal Investigator Date

Product Mirvaso


3.0 TABLE OF CONTENTS

1.0 TITLE PAGE ................................................................................................................................... 1
2.0 KEY STUDY PERSONNEL AND FACILITIES ............................................................................ 2
3.0 TABLE OF CONTENTS ................................................................................................................. 5
4.0 SYNOPSIS ....................................................................................................................................... 8
5.0 STUDY SCHEMATIC ................................................................................................................... 14
6.0 LIST OF ABBREVIATIONS AND TERMS ................................................................................. 15
7.0 INTRODUCTION ......................................................................................................................... 16
7.1 Disease Being Treated ................................................................................................................ 16
7.2 Availability and Efficacy of Already Approved Therapies ........................................................ 16
7.3 Scientific and Statistical Considerations ..................................................................................... 16
7.4 Justification for use of Placebo ................................................................................................... 18
7.5 Risks and Benefits ....................................................................................................................... 18
8.0 STUDY OBJECTIVES ................................................................................................................... 18
9.0 INVESTIGATIONAL PLAN ......................................................................................................... 19
9.1 Study Design and Plan Description ............................................................................................ 19
9.2 Selection of Study Design ........................................................................................................... 20
9.3 Selection of Study Population ..................................................................................................... 20
9.3.1 Inclusion Criteria................................................................................................................. 20
9.3.2 Exclusion Criteria ............................................................................................................... 21
9.3.3 Restrictions During The Study ............................................................................................ 23
9.3.4 Removal of Patients from the Study ................................................................................... 25
9.4 Treatments ................................................................................................................................... 25
9.4.1 Treatments Administration ................................................................................................. 25
9.4.2 Identity of Study Products ................................................................................................... 26
9.4.3 Method of Assigning Patients to Treatment Groups ........................................................... 27
9.4.4 Study Blind ......................................................................................................................... 27
9.4.5 Compliance ......................................................................................................................... 28
9.5 Study Conduct ............................................................................................................................. 28
9.5.1 Visit 1 (Day -14 to 1): Screening ........................................................................................ 28
9.5.2 Visit 2 (Day 1): Randomization .......................................................................................... 29
Product Mirvaso


9.5.3 Visit 3 (Day 7 1): Study Completion or Early Discontinuation ....................................... 30
9.6 Study Procedures ........................................................................................................................ 32
9.6.1 Informed Consent ................................................................................................................ 32
9.6.2 Demographics ..................................................................................................................... 32
9.6.3 Medical History................................................................................................................... 32
9.6.4 Vital Signs ........................................................................................................................... 32
9.6.5 Lesion Count ....................................................................................................................... 32
9.6.6 Concomitant Medication Use .............................................................................................. 32
9.6.7 Pregnancy Test .................................................................................................................... 32
9.6.8 Dispensing Study Drug ....................................................................................................... 33
9.6.9 Collecting Study Drug ........................................................................................................ 33
9.6.10 Dosing Instructions and Diary ............................................................................................ 33
9.6.11 Dosing Compliance ............................................................................................................. 34
9.6.12 Clinical Assessments............................................................................................................ 34
9.7 Adverse Events ........................................................................................................................... 34
9.7.1 Definitions ........................................................................................................................... 35
9.7.2 Severity of Adverse Events .................................................................................................. 35
9.7.3 Causality Assessment ........................................................................................................... 35
9.8 Serious Adverse Events ................................................................................................................. 36
9.8.1 Definition of a Serious Adverse Event ................................................................................. 36
9.8.2 Reporting Serious Adverse Events ..................................................................................... 36
10.0 STATISTICAL METHODS ........................................................................................................... 37
10.1 Statistical Plan ............................................................................................................................. 37
10.2 Determination of Sample Size .................................................................................................... 37
10.3 Study Populations ....................................................................................................................... 38
10.3.1 Per Protocol (PP) Population .............................................................................................. 38
10.3.2 Modified Intent-to-Treat (mITT) Population ...................................................................... 39
10.3.3 Safety Population ................................................................................................................ 39
10.4 Baseline Comparability ............................................................................................................... 39
10.5 Efficacy Endpoints ...................................................................................................................... 40
10.6 Bioequivalence ............................................................................................................................ 40
Product Mirvaso


10.7 Superiority to Placebo Analysis ................................................................................................. 40
10.8 Safety Analysis ........................................................................................................................... 40
11.0 REGULATORY OBLIGATIONS .................................................................................................. 41
11.1 Institutional Review Board ......................................................................................................... 41
11.2 Study Documentation .................................................................................................................. 41
11.2.1 Protocol ............................................................................................................................... 41
11.2.2 Informed Consent ................................................................................................................ 41
11.2.3 Protocol and Informed Consent Changes ............................................................................ 42
11.2.4 Source Documents and Case Report Forms ........................................................................ 42
11.2.5 Drug Accountability ............................................................................................................ 42
11.2.6 Drug Storage ....................................................................................................................... 42
11.2.7 Retention of Reserve Samples ............................................................................................ 42
11.2.8 Return of Clinical Supplies ................................................................................................. 43
11.2.9 Pregnancies ......................................................................................................................... 43
11.2.10 Withdrawals due to Adverse Events ................................................................................... 43
11.2.11 Reporting Safety Information to the IRB ........................................................................... 43
11.2.12 Record Retention................................................................................................................ 44
11.2.13 Study Monitoring and Auditing.......................................................................................... 44
11.2.14 End of the Trial ................................................................................................................... 44
11.2.15 Clinical Study Report ......................................................................................................... 44
11.2.16 Termination of the Study .................................................................................................... 45
12.0 REFERENCES ............................................................................................................................... 46
13.0 APPENDICES ................................................................................................................................ 48
13.1 Appendix A ..................................................................................................................................... 48
13.2 Appendix B ..................................................................................................................................... 49
13.3 Appendix C ..................................................................................................................................... 50
13.4 Appendix D ..................................................................................................................................... 51

Product Mirvaso


4.0 SYNOPSIS

Protocol
Number
71304906
Title
A Randomized, Double-Blind, Multiple-Site, Placebo-Controlled, Parallel-Design
Study to Evaluate the Safety and Therapeutic Equivalence of Brimonidine Topical
Gel, 0.33% (Watson Laboratories, Inc., USA) to Reference Product Mirvaso

(brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in Patients with
Moderate to Severe Facial Erythema Associated with Rosacea
Objectives
1. Evaluate therapeutic equivalence and safety of the test formulation Brimonidine
Topical Gel, 0.33%, 30 gram fill (Watson Laboratories, Inc., USA) and the RLD
Mirvaso
(brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in

the treatment of moderate to severe facial erythema associated with rosacea.
2. Demonstrate the superiority of the efficacy of the test and reference products over
a placebo (vehicle) gel in the treatment of moderate to severe facial erythema
associated with rosacea.
3. Compare the safety of test, reference and placebo treatments in patients with facial
erythema associated with rosacea.
Sponsor
Study Products
Test (A): Brimonidine Topical Gel, 0.33%, 30 gram fill (Watson Laboratories,
Inc., USA)
Reference (B): Mirvaso
(brimonidine) topical gel, 0.33% (Galderma

Laboratories, L.P., USA)
Placebo (C): Topical gel base only (Watson Laboratories, Inc., USA)
Route of
Administration
Topical application to the face
Treatment
Randomization
3:3:1 (Test: Reference: Placebo)
Patient
Population
Up to 462 patients 18 years of age and older, with confirmed clinical diagnosis of
rosacea will be enrolled to have 413 in the modified intent-to-treat (mITT) population
and 371 in the per-protocol (PP) population. Patients should have fewer than 3 facial
inflammatory lesions, and moderate to severe erythema according to both Clinicians
Erythema Assessment (CEA) and Patients Self-Assessment (PSA).
Product Mirvaso


Study Design Patients will complete 3 visits:
Visit 1 Screening (Day -14 to Day 1): Erythema severity will be assessed.
Visit 2 Randomization (Day 1): Eligible patients will receive randomized study
medication; first dose will be applied in the clinic; clinical assessment for
erythema will occur prior to dosing (pre-dose) and 6 hours ( 10 minutes) post-
dose.
Visit 3 End of Treatment (Day 7 1): The last dose will be applied in the clinic
on Day 7 ( 1); clinical assessment for erythema will occur prior to dosing (pre-
dose) and 6 hours ( 10 minutes) post-dose.
Patients will apply the study medication once-daily at home on non-clinic visit days
(Days 2-6). Erythema severity will be assessed on Day 1 (pre- and post-application)
and Day 7 (pre- and post-application), using CEA and PSA scores. Post-application
assessments will be relative to baseline (pre-dose) assessments on the application day.
Inclusion
Criteria
1. Male or non-pregnant, non-lactating female, 18 years of age or older.
2. Signed informed consent form, which meets all criteria of current FDA
regulations.
3. Females of child bearing potential must not be pregnant or lactating at
Screening and Randomization (as confirmed by a negative urine pregnancy
test with a sensitivity of less than 25 mlU/mL or equivalent units of human
chorionic gonadotropin). Women of childbearing potential must agree to the
use of a reliable method of contraception (e.g., total abstinence, IUD, a
double-barrier method [such as condom plus diaphragm with spermicide],
oral, transdermal, injected or implanted non- or hormonal contraceptive),
throughout the study. A sterile sexual partner is not considered an adequate
form of birth control.
All females will be considered to be of childbearing potential unless they:
Are post-menopausal, defined as women who have been amenorrheic
for at least 12 consecutive months, without other known or suspected
primary cause.
Have been sterilized surgically or who are otherwise proven sterile
(i.e., total hysterectomy, or bilateral oophorectomy) with surgery at
least 4 weeks prior to Screening. Tubal ligation will not be considered
a surgically sterile method.
Female patients of childbearing potential are defined as:
Women without prior hysterectomy, or who have had any evidence of
menses in the past 12 months.
Females who have been amenorrheic for 12 months, but the
Product Mirvaso


amenorrhea is possibly due to other causes, including prior
chemotherapy, anti-estrogens, or ovarian suppression.
4. Have a clinical diagnosis of facial rosacea and fewer than 3 inflammatory
lesions on the face at Screening and at Randomization (before drug
application on Day 1).
5. Have moderate to severe facial erythema according to both CEA and PSA
(i.e., an erythema score of 3 or more for each of the CEA and PSA) at
Screening and at Randomization (before drug application on Day 1).
6. Free from any systemic or dermatologic disorder (other than rosacea) that, in
the opinion of the Investigator, will interfere with the study evaluations or
increase the risk of AEs.
7. Willing to minimize external factors that might trigger rosacea flare-ups (e.g.,
hot environments, prolonged sun exposure, strong winds and emotional stress)
within 24 hours of the Screening and Randomization visit.
8. Any skin type or race, providing the skin pigmentation will allow discernment
of erythema.
9. Willingness and capability to cooperate to the extent and degree required by
the protocol.
Exclusion
Criteria
1. Patients with particular forms of rosacea (rosacea conglobata, rosacea
fulminans, isolated rhinophyma, isolated pustulosis of the chin) or other
concomitant facial dermatoses similar to rosacea, such as peri-oral dermatitis,
demodicidosis, facial keratosis pilaris, seborrheic dermatitis, acute lupus
erythematosus, or actinic telangiectasia, that are present on the face (i.e., 5
areas: chin, nose, both cheeks, and forehead), that in the opinion of the
Investigator would interfere with study evaluations.
2. Have 3 or more facial inflammatory lesions of rosacea.
3. Have an erythema score of 2 (mild), 1 (almost clear), or 0 (clear) on the CEA
and/or the PSA at Screening and at Randomization (before drug application
on Day 1).
4. Patients with excessive facial hair (beards, sideburns, moustaches, etc.) that
would interfere with the diagnosis or assessment of rosacea.
5. Patients with moderate to severe telangiectasial masses in the 5 areas of the
entire face: forehead, chin, nose and each cheek, that would interfere with
study evaluations.
6. History of hypersensitivity or allergy to Mirvaso
including the active

ingredient brimonidine tartarate or other component within the formulation.
Product Mirvaso


7. Facial laser surgery for telangiectasia (or other conditions) within 6 weeks
prior to randomization.
8. Exposed to excessive ultraviolet (UV) radiation within 1 week before
Screening or Randomization visit and/or patient was unwilling to refrain from
excessive exposure to UV radiation during the course of the study.
9. History of blood dyscrasia.
10. Current diagnosis of Raynauds syndrome, thromboangiitis obliterans,
orthostatic hypotension, severe cardiovascular disease, cerebral or coronary
insufficiency, renal or hepatic impairment, scleroderma, Sjgrens syndrome,
or depression, or any other condition causing uncontrolled blood flow or
blood pressure.
11. Females who are pregnant, lactating or likely to become pregnant during the
study.
12. Significant history or current evidence of chronic infectious disease, system
disorder, organ disorder or other medical condition that in the Investigators
opinion would place the study patient at undue risk by participation.
13. Patients with severe, unstable or uncontrolled cardiovascular disease.
14. Patients who meet study restrictions at Screening and Randomization and/or
unwillingness to comply with all restricted treatments as detailed in section
9.3.3 of this protocol.
15. Receipt of any drug as part of a research study within 30 days before dosing.
16. Employees of the research center or Investigator.
17. Previous participation in this study.
18. Patients who are unable and/or unwilling to follow the study requirements,
and procedures.
Treatment
Administration
The patients will wash their face with Dove
facial soap and gently dry before each

study gel application. At Randomization (Visit 2), a designated site staff member will
administer the first dose of randomized study medication with a gloved hand (a thin
application of pea-sized amount to each of the 5 areas of the entire face: forehead,
chin, nose and each cheek), preferably in the morning or early afternoon.
Patients will be asked to dose at home for non-clinic visit days (Days 2-6), one
application daily, at approximately the same time each day (preferably in the morning
or early afternoon), as per provided dosing instructions. Patients will return to the
clinic on Day 7 ( 1) for application of the last treatment by a designated gloved site
staff member.
Clinical
Assessments
Erythema will be assessed based on a 5-point scoring scale in the clinic by an
Investigator (CEA) and a patient (PSA) at baseline (pre-dose) and at 6 hours ( 10
Product Mirvaso


minutes) post-dose on Days 1 and 7 ( 1). Refer to Appendix A.
Confinement Patients will enter the clinic on Days 1 and 7 and will remain confined for 6 hours
post dose. While in confinement the patients will remain in the ambulatory
sitting/standing position. No strenuous activities will be permitted during
confinement.
Efficacy
Endpoints
Primary Endpoint:
Proportion of patients with a clinical response of treatment success on Day 7 ( 1).
Treatment success is defined as at least a 2-grade improvement on both CEA and PSA
scores from baseline (pre-dose) on Day 7 ( 1) to 6 hours post-application on Day 7
( 1).
Secondary Endpoint:
Proportion of patients with a clinical response of treatment success on Day 1.
Treatment success is defined as at least a 2-grade improvement on both CEA and PSA
scores from baseline (pre-dose) on Day 1 to 6 hours post-application on Day 1.
Safety
Parameters
The frequency, severity and relationship to the study drug for adverse events will be
monitored. Localized AEs (identified in the treatment areas) and systemic AEs will be
tabulated per patient.
Evaluation of
Therapeutic
Equivalence
and Superiority
Therapeutic equivalence of the test product to the reference product will be evaluated
in the PP population. If the 90% confidence interval (calculated using Yates
continuity correction) for the absolute difference between the proportion of patients
considered a treatment success (at least a 2-grade improvement on CEA and PSA over
6 hours) in the test and reference groups is contained within the range [-20%, +20%]
then bioequivalence of the test product to the reference product will be considered to
have been demonstrated.
Superiority of the test and reference gels against the placebo will be tested at the 5%
significance level (p < 0.05; using two-sided, continuity-corrected Z-test) in the mITT
population using last observation carried forward.
Determination
of Sample Size
The primary statistical analysis of interest is the proportion of patients in the PP
population with a clinical response of treatment success (at least a 2-grade
improvement on CEA and PSA over 6 hours) at study Day 7 ( 1) (end of 7-day
treatment period).
The treatment success rate for the reference treatment group at the end of the 7-day
treatment period is assumed to be 45% in the PP population. Assuming that the
treatment success rate for the test treatment group will be an absolute difference of 5%
higher than the reference success rate in this study, a sample size of 159 patients per
active group will provide at least 82% power to demonstrate bioequivalence (i.e., the
90% confidence interval (Yates continuity-corrected) of the absolute difference
between the test and reference composite success rate rates is within a defined
equivalence range [-20%, +20%]).
The rates of treatment success for the placebo and active treatment groups at the end
Product Mirvaso


of the 7-day treatment period are assumed to be 10% and at least 40%, respectively, in
the mITT population. Therefore, one-third of the number of patients will be enrolled
in the placebo group as in each of the two active treatment groups to maintain an
adequate sample size in the placebo treatment group. Assuming the conversion rate
from mITT to PP will be about 90%, 177 patients in each of active groups and 59
patients in the placebo group of the mITT population will provide at least 98% power
to demonstrate superiority of active over placebo. Under the above assumptions, the
overall study power to demonstrate bioequivalence and superiority is estimated to be
at least 80% (0.82 x 0.98), assuming 100% correlation between the two superiority
tests. To allow for about 10% of patients who may drop out from the study or are
otherwise non-evaluable, up to 462 patients may be enrolled (198 in each active group
and 66 in the placebo group).

Product Mirvaso


5.0 STUDY SCHEMATIC

*Clinical assessments (both CEA and PSA): conducted at Screening and before application (pre-application) and at 6 hours post-application on
Days 1 and 7 ( 1). Assessments conducted 6 hours post-application will allow for a 10 minute window at each interval. Patients will be
administered first and last doses of blinded and randomized medication in the clinic on Day 1 and Day 7 ( 1), respectively. On these two study
days, patients will remain in the clinic during the time interval between their pre- and post-dose erythema evaluations.
** Scheduled AE assessment: conducted before release from confinement. AEs will be assessed throughout the study.

PROCEDURE

Visit 1
Screening
Days -14 to 1

Visit 2
Randomization
Day 1

Visit 3
End of
Treatment
Day 7 1
Informed Consent X
Demographics X
Medical History X X
Inclusion/Exclusion X X
Vital Signs X X X
Pregnancy Test X X X
Lesion Count X X X
Dispense Medication X
Collect Medication X
Dispense Dosing Diary X
Collect Dosing Diary X
Dose Application in Clinic X X
Clinicians Erythema
Assessment
X* X* X*
Concomitant Medication X X X
Patients Self Assessment X* X* X*
Adverse Events X** X**
Discharge and End of Study
Procedures
X
Product Mirvaso


6.0 LIST OF ABBREVIATIONS AND TERMS
ADR Adverse Drug Reaction
AE Adverse Event
C Celsius
CEA Clinicians Erythema Assessment
CRF Case Report Form
CRO Clinical Research Organization
eCTD electronic Common Technical Document
F Fahrenheit
FDA
Galderma
Food and Drug Administration
Galderma Laboratories, L.P., USA
ICF Informed Consent Form
ICH International Conference on Harmonization
IND Investigational New Drug
IRB Institutional Review Board
IUD Intrauterine Device
LOCF
mg
Last Observation Carried Forward
Milligram
mITT Modified Intent-to-Treat
NDA New Drug Application
OGD Office of Generic Drugs
OHRP Office of Human Rights Protection
OTC Over-the-Counter
PP Per Protocol
PSA Patients Self Assessment
RLD Reference Listed Drug
SAE Serious Adverse Event
SDTM Study Data Tabulation Model
USA
Watson
United States of America
90%CI
Ninety Percent Confidence Interval

Product Mirvaso


7.0 INTRODUCTION
7.1 Disease Being Treated
Rosacea is a chronic, inflammatory and vascular disorder affecting the face in adults aged
30 to 60 years. Rosacea affects an estimated 16 million Americans.
1
The condition is
characterized by flushing and persistent erythema in the central facial area. Other
cutaneous signs such as telangiectasia, papules, and pustules are typically present on the
central portion of the face.
2, 6
The clinical appearance of rosacea can range from very
mild (mild erythema on the cheeks) to severe (large numbers of inflamed lesions and
nodular cysts overlying erythema and telangiectasia on the face, neck, and upper trunk).
Triggers for the condition may include spicy foods, alcohol, emotional stress, sun
exposure, and hot baths.
3
The physical manifestation of rosacea on the face can result in
embarrassment
4
, anxiety and frustration and can have a negative impact on the patients
social life.
5
Patients selected for this study will be considered to have persistent moderate
to severe facial erythema of rosacea, with fewer than 3 facial inflammatory lesions.
7.2 Availability and Efficacy of Already Approved Therapies
There are a number of medications including topical metronidazole (Noritate
), azelaic
acid (Finacea
), doxycycline, and oral antibiotics that are approved by the FDA for
treatment of lesions (papules and pustules) in rosacea. However, their effectiveness in
significantly reducing erythema has not been successfully demonstrated.
7
In the absence
of effective treatment, patients are frequently advised to avoid environmental and
lifestyle triggers that can exacerbate erythema.
8-10
Mirvaso
(brimonidine) topical gel

0.33% (Galderma Laboratories) received FDA approval in August 2013. The active
ingredient, brimonidine tartrate (BT) is a highly selective alpha-2 adrenergic receptor
agonist, with potent vasoconstrictive activity. Clinical studies in support of the NDA for
Mirvaso
have shown that it can effectively and rapidly reduce erythema in rosacea, with
effects lasting for up to 12 hours after application.
11

7.3 Scientific and Statistical Considerations
Facial erythema of rosacea is thought to result from dysregulation in the cutaneuous
vasomotor responses, which leads to abnormal, involuntary, and persistent dilation of
facial blood vessels
12-14
. Alpha-2 receptor agonists have been reported to induce
cutaneous vasoconstriction, and hence are considered strong candidates for treatment of
erythema in rosacea.
Clinical studies of Mirvaso

evaluated treatment effects in adult patients with moderate to
severe erythema associated with rosacea. These studies revealed that Mirvaso
treatment
exhibited a significantly higher rate of treatment success (2-grade improvement on both
the Clinicians Erythema Assessment (CEA) and Patients Self-Assessment (PSA) over
baseline at various times over 12 hours post-application on Days 1, 15 and Day 29 of
treatment) compared to placebo (vehicle gel).
11, 15-17
In clinical studies supporting the
NDA for the reference drug, Mirvaso
, maximal treatment success was observed about 6

Product Mirvaso


hours following drug application, and the post-treatment success rates of Mirvaso
were
similar from first to last dose over the 4-week treatment period whereas those of the
vehicle gel increased with duration of treatment.
11, 16, 17
Composite (treatment) success
rates of 23%-30% and 3%-10% were observed for Mirvaso
and vehicle gel,

respectively, at the 6-hour post-application evaluation time on Days 1, 15 and 29 of
treatment (see Figures 1-2 below).
11

The Office of Generic Drugs (OGD) recommends a clinical endpoint bioequivalence
study in the treatment of moderate to severe rosacea.
18-19

NDA studies conducted for Mirvaso
indicated that a similar treatment response was

observed on Days 1, 15 or 29, based on 12 hour erythema assessments. Based on this
information and discussions with Sponsor, a Day 1 and Day 7 treatment assessment was
sought for this study.
Product Mirvaso


The pivotal efficacy studies that supported the Mirvaso
NDA showed similar rates of

treatment success on Days 1, 15 and 29, with maximal success rates observed at about 6
hours post-application of the gel.
11, 16, 17
Based on data from these studies, additional
evidence from a single-dose pilot study (71304909) conducted by Watson Laboratories
Inc., USA for a generic formulation of Brimonidine Topical Gel, 0.33%, and discussions
with the Sponsor, a clinical endpoint study evaluating responder rate at the start and end
of a 7-day treatment period, with clinical assessments conducted at pre-dose and at 6
hours post-application on each study day, was considered the optimal approach to
minimize drug exposure to patients and to increase chance of demonstrating superiority
of active treatments over placebo.
11, 16, 17, 24

7.4 Justification for use of Placebo
To confirm the sensitivity of a clinical endpoint study to differentiate between two
possibly bio-inequivalent products (i.e., to prevent a false positive result of
bioequivalence) OGD/FDA recommends that a placebo group be included in such
studies. In addition to the test product demonstrating therapeutic equivalence to the
reference product, both the test and reference products should demonstrate statistical
superiority to the placebo group.
18-19

7.5 Risks and Benefits
The risks and benefits to patients enrolled in clinical research studies that include a
placebo treatment group must be carefully considered based on three main criteria,
namely: the disease being treated, the availability, efficacy and safety of already
approved therapies and the scientific and statistical requirements of the desired outcome
of the research study. The Office of Human Rights Protection (OHRP), a Division of the
USA Federal Governments Department of Health and Human Services, has issued a
detailed guidebook to Institutional Review Boards (IRBs) that includes discussion on the
use of placebos in clinical studies.
20

Qualifying patients entering the active treatment period have a 14% chance they may be
treated with placebo. Although the potential for any drug-related side effects of
significance occurring during the study are low, the risk is higher in the two active
treatment groups than in the placebo group.
All patients enrolled in this study will receive the benefit of free specialized medical care
beyond standard medical treatment that would be expected through most health insurance
plans. In addition, the patient will receive a stipend for participation to cover costs and
expenses associated with trips to the medical facility.
8.0 STUDY OBJECTIVES
The objectives of this study are to 1) evaluate the therapeutic equivalence and safety of the test
product Brimonidine Topical Gel, 0.33%, 30 gram fill (Watson Laboratories, Inc., USA) and the
marketed reference product, Mirvaso

(brimonidine) topical gel, 0.33% (Galderma Laboratories
Product Mirvaso


L.P., USA) in treatment of facial erythema associated with rosacea, 2) demonstrate the superiority
of the test and reference (active) treatments over placebo (vehicle) gel in the treatment of
moderate to severe facial erythema associated with rosacea, and 3) compare the safety of test,
reference and placebo treatments in patients with facial erythema associated with rosacea
9.0 INVESTIGATIONAL PLAN
9.1 Study Design and Plan Description
This double-blind, randomized, placebo-controlled, parallel-design, multiple-site study
has been designed to evaluate the therapeutic equivalence and safety of a generic product
brimonidine topical gel, 0.33%, 30 gram fill (Watson Laboratories, Inc., USA) and the
FDA Reference Listed Drug, Mirvaso

Laboratories L.P., USA), in the relief of moderate to severe facial erythema associated
with rosacea. Additionally, both the test and the RLD products will be tested for
superiority against a placebo.
At least 462 adult patients with moderate to severe facial erythema associated with
rosacea will be randomized. To qualify for inclusion in the study, patients must be at least
18 years of age, with a, diagnosis of facial rosacea. Please refer to section 9.3 for a
comprehensive list of inclusion/exclusion criteria for the study. Before any study-specific
procedures are performed, all patients will read and sign the IRB-approved informed
consent form.
Plan Description
Screening, Visit 1 (Days -14 to 1)
Patients will be screened for all inclusion/exclusion criteria prior to study
enrollment.
Randomization, Visit 2 (Day 1)
Randomization: Patients will be assigned randomization numbers in a 3:3:1
scheme for Test: Reference: Placebo.
Baseline: Before dosing, patients will be assessed for facial erythema severity
based on a 5-point scoring system (Refer to section 9.6.12 Clinical Assessments
and Appendix A). Assessments will be carried out by Investigator (CEA) and
patient (PSA), both of which will determine a baseline score.
Randomized Treatment: Patients will be dispensed randomized study
medication with instructions for dose application at home, once daily during non-
clinic visit days. Patients will be administered the first application of blinded
study medication in the clinic by a designated site staff member. Patients will be
instructed not to apply the last dose until they arrive at the clinic for Visit 3.
Post-Treatment Clinical Assessment: 6 ( 10 minutes) hours following first
dose application, patients will be assessed for facial erythema as per baseline
Product Mirvaso


evaluation. Patients will remain in the clinic during the time interval between
their pre- and post-dose erythema evaluations.
End of Treatment, Visit 3 (Day 7 1)
Baseline: Patients will return to the clinic before dosing to be assessed for facial
erythema as per Day 1 baseline assessments.
Randomized Treatment: Patients will be administered the last application of
blinded study medication in the clinic by a designated site staff member.
Post-Treatment Clinical Assessment: 6 ( 10 minutes) hours following last
dose application, patients will be assessed for facial erythema as per baseline
evaluation. Patients will remain in the clinic during the time interval between
their pre- and post-dose erythema evaluations.
All other Visit 3 procedures (refer to section 9.5.4) will be conducted for all
patients who completed the study or terminated early.
9.2 Selection of Study Design
This study has been designed after a thorough review of a large number of clinical studies

in rosacea including those conducted as a part of the NDA for the Reference Listed Drug
(RLD) used in this study, Mirvaso

Laboratories), draft guidances for rosacea therapies (including those that treat erythema)
and results from a pilot study for the test formulation used in this study.
1-19, 24

9.3 Selection of Study Population
9.3.1 Inclusion Criteria
1. Male or non-pregnant, non-lactating female, 18 years of age or older.
2. Signed informed consent form, which meets all criteria of current FDA regulations.
3. Females of child bearing potential must not be pregnant or lactating at Screening and
Randomization (as confirmed by a negative urine pregnancy test with a sensitivity of
less than 25 mlU/mL or equivalent units of human chorionic gonadotropin). Women
of childbearing potential must agree to the use of a reliable method of contraception
(e.g., total abstinence, IUD, a double-barrier method [such as condom plus
diaphragm with spermicide], oral, transdermal, injected or implanted non- or
hormonal contraceptive), throughout the study. A sterile sexual partner is not
considered an adequate form of birth control.
All females will be considered to be of childbearing potential unless they:
Are post-menopausal, defined as women who have been amenorrheic for at
least 12 consecutive months, without other known or suspected primary
cause.
Product Mirvaso


Have been sterilized surgically or who are otherwise proven sterile (i.e., total
hysterectomy, or bilateral oophorectomy) with surgery at least 4 weeks prior
to Screening. Tubal ligation will not be considered a surgically sterile
method.
Female patients of childbearing potential are defined as:
Women without prior hysterectomy, or who have had any evidence of
menses in the past 12 months.
Females who have been amenorrheic for 12 months, but the amenorrhea is
possibly due to other causes, including prior chemotherapy, anti-estrogens, or
ovarian suppression.
4. Have a clinical diagnosis of facial rosacea and fewer than 3 inflammatory lesions on
the face at Screening and at Randomization (before drug application on Day 1).
5. Have moderate to severe facial erythema according to both CEA and PSA (i.e., an
erythema score of 3 or more for both CEA and PSA) at Screening and at
Randomization (before drug application on Day 1).
6. Free from any systemic or dermatologic disorder (other than rosacea) that, in the
opinion of the Investigator, will interfere with the study evaluations or increase the
risk of AEs.
7. Willing to minimize external factors that might trigger rosacea flare-ups (e.g., hot
environments, prolonged sun exposure, strong winds and emotional stress) within 24
hours of the Screening and Randomization visits.
8. Any skin type or race, providing the skin pigmentation will allow discernment of
erythema.
9. Willingness and capability to cooperate to the extent and degree required by the
protocol.
9.3.2 Exclusion Criteria
1. Patients with particular forms of rosacea (rosacea conglobata, rosacea fulminans,
isolated rhinophyma, isolated pustulosis of the chin) or other concomitant facial
dermatoses similar to rosacea, such as peri-oral dermatitis, demodicidosis, facial
keratosis pilaris, seborrheic dermatitis, acute lupus erythematosus, or actinic
telangiectasia, that are present on the face (i.e., 5 areas: chin, nose, both cheeks, and
forehead), that in the opinion of the Investigator would interfere with study
evaluations.
2. Have 3 or more facial inflammatory lesions of rosacea.
3. Have an erythema score of 2 (mild), 1 (almost clear), or 0 (clear) on the Clinicians
Erythema Assessment (CEA) and/or the Patients Self-Assessment (PSA) at
Screening and at Randomization (before drug application on Day 1).
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4. Patients with excessive facial hair (beards, sideburns, moustaches, etc.) that would
interfere with the diagnosis or assessment of rosacea.
5. Patients with moderate to severe telangiectasial masses in the 5 areas of the entire
face: forehead, chin, nose and each cheek, that would interfere with study
evaluations.
6. History of hypersensitivity or allergy to Mirvaso
including the active ingredient

brimonidine tartarate or other component within the formulation.
7. Facial laser surgery for telangiectasia (or other conditions) within 6 weeks prior to
randomization.
8. Exposed to excessive ultraviolet (UV) radiation within 1 week before Screening or
Randomization visit and/or patient was unwilling to refrain from excessive exposure
to UV radiation during the course of the study.
9. History of blood dyscrasia.
10. Current diagnosis of Raynauds syndrome, thromboangiitis obliterans, orthostatic
hypotension, severe cardiovascular disease, cerebral or coronary insufficiency, renal
or hepatic impairment, scleroderma, Sjgrens syndrome, or depression or any other
condition causing uncontrolled blood flow or blood pressure.
11. Females who are pregnant, lactating or likely to become pregnant during the study.
12. Significant history or current evidence of chronic infectious disease, system disorder,
organ disorder or other medical condition that in the Investigators opinion would
place the study patient at undue risk by participation.
13. Patients with severe, unstable or uncontrolled cardiovascular disease.
14. Patients who meet study restrictions at screening and/or unwillingness to comply
with all restricted treatments as detailed in section 9.3.3 of this protocol.
15. Receipt of any drug as part of a research study within 30 days before dosing.
16. Employees of the research center or Investigator.
17. Previous participation in this study.
18. Patients who are unable and/or unwilling to follow the study requirements, and
procedures.

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9.3.3 Restrictions During The Study
The following will not be allowed before or during study participation as per the below
schedule:
Treatments Examples (not all inclusive)
Restriction
Period/Washout
Topical
Treatments
Prescription
medications for the
treatment of rosacea azelaic acid, metronidazole 4 weeks before Visit 1
Topical
Immunomodulators Tacrolimus, Pimecrolimus 4 weeks before Visit 1
Topical
Corticosteroids
Betamethasone, Clobetasol,
Fluocinonide, Triamcinolone,
Fluticasone, Hydrocortisone,
Alclomethasone 4 weeks before Visit 1
Topical Prescription
and OTC
medication treating
erythema and
inflammation Diclofenac, Indomethacin Within 24 hours of Visit 1
Topical antibiotics Neosporin, sulfacetamide sodium 2 weeks before Visit 1
OTC facial cosmetic
products
Make-up, lotion, oil, creams,
powder
12 hours before Clinic
Visits. Allowed on non-
visit days, if only applied
after study drug
application
OTC topical
medications for
treatment of acne
Benzoyl peroxide, salicylic acid
creams, face washes 1 week before Visit 1
Astringents or
abrasives Proactiv
, witch hazel lotion 2 days before Visit 1

Systemic
Treatments
Prescription
medications for the
treatment of rosacea
doxycycline, tetracycline,
macrolides 4 weeks before Visit 1
Prescription
medications for
treatment of acne corticosteroids 4 weeks before to Visit 1

Product Mirvaso


Treatments Examples (not all inclusive)
Restriction
Period/Washout
Systemic
Treatments

Corticosteroids,
Immunomodulators
Prednisone,
Methylprednisolone,
Hydrocortisone, Dexamethasone 12 weeks before Visit 1
Retinoids Isotretinoin 6 months before Visit 1
Antibiotics (effecting
Rosacea)
Tetracycline 4 weeks before Visit 1
OTC anti-
inflammatory drugs
(excluding low-dose,
e.g., 81 mg) Ibuprofen, Naproxen, Aspirin 1 week before Visit 1
Prescription anti-
inflammatory drugs
Ibuprofen, Naproxen, Aspirin,
Ketorolac, Celecoxib,
Indomethacin, Diclofenac,
Meloxicam 2 weeks before Visit 1
Cardiac glycosides,
alpha and beta
adrenergic blockers or
other antihypertensive
agents

Oxymetazoline, Nadolol,
Propranolol, Prazosin,
Doxazosin, Digoxin
Patients will be excluded,
if started these within <3
months prior to Visit 1.
For patients who have
been on a stable regimen
for 3 months, these
medications will be
allowed during the study,
as long as the patient
remains on the same
product/dosing regimen
throughout the study.
Tri cyclic anti-
depressants

Doxepin, Imipramine,
Desipramine, Amitriptyline
Barbiturates, opiates,
sedatives, systemic
anesthetics, or alpha-
agonists
Pentobarbital, morphine,
codiene, Diazepam, Propofol,
Phenylephrine, Oxymetazoline
Discontinued during
study duration
MAO Inhibitors Isocarboxazid, Phenelzine 30 days before Visit 1
Niacin ( 500 mg per
day )
vitamin B3 or nicotinic acid
supplements 1 week before Visit 1
Other
Phototherapy 4 weeks before Visit 1
Dermatologic/surgical
procedure on the face
Laser, Photodynamic Therapy
or IPL (intense pulsed light)
treatment; electrocoagulation;
Dermabrasion; Facial peels 4 weeks before Visit 1

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Patients will be asked to abstain from the following items 24 hours before clinic visits:
Caffeine (e.g., tea, coffee, caffeinated soft drinks including Pepsi, Coke)
Rosacea trigger foods (refer to Appendix B)
Patients will be allowed to consume these items on non-clinic visit days during the study,
but will be asked to minimize exposure in order to prevent rosacea flare-ups.
Patients will be questioned about all prescription and OTC concomitant medication use
(including vitamins or nutritional supplements) at each study visit. All concomitant
medications will be recorded in the patients source documents. Anyone who violates any
listed restrictions may be dropped from continued participation in the study by the
Investigator.
During confinement, patients will be required to remain in the ambulatory sitting and/or
standing position. No strenuous activities will be permitted during confinement.
9.3.4 Removal of Patients from the Study
Patients will be advised that they are free to withdraw from the study at any time for any
reason or, if necessary, the Investigator may withdraw a patient from the study to protect
the health of that patient. A patient may also be withdrawn for not complying with study
procedures. The clinical report will include all reasons for early withdrawals.
All patients who are randomized will be included in the safety monitoring tabulating all
adverse events experienced after dosing. If a randomized patient terminates from the
study early, all procedures performed up to that point will be used. In case of early
termination the Investigator shall fully document the reason for early termination.
9.4 Treatments
9.4.1 Treatments Administration
Patients will be instructed to apply study medication once a day, preferably in the
morning or early afternoon, at approximately the same time, each day of the study
duration.
The first and last doses will be applied in the clinic at Visit 2 and Visit 3, respectively, by
a blinded doser as outlined in steps below:
The patients will wash their face with Dove
facial soap and gently dry before

study gel application. Each treatment will be administered by a designated site
staff, Blinded Doser. The Blinded Doser will apply the study drug to the
patients entire face (i.e., chin, nose, forehead, and both cheeks) at Visits 2 and 3.
The Blinded Doser using gloves will gently and smoothly apply the gel in a thin
even layer to the entire face, avoiding contact with the eyes and lips. In order to
maintain consistency these application procedures will be followed for all
patients.
Product Mirvaso


The Blinded Doser will not be involved in any clinical assessments (i.e. CEA
assessment) and will be instructed not to discuss the appearance of the study drug
with any study personnel conducting evaluations. The Blinded Doser can be the
Independent Dispenser.
Each daily dose between Visits 2 and 3 will be applied by the patient, at home, according
to instructions provided (Refer to Sections 9.4.5 Compliance and 9.6.10 Dosing
Instructions and Diary). The last dose at home should be applied 24 ( 2) hours before
Visit 3 baseline erythema assessment.
9.4.2 Identity of Study Products
Test (A): Brimonidine Topical Gel, 0.33%, 30 gram fill (Watson Laboratories,
Inc., USA)
Reference (B): Mirvaso

Laboratories, L.P., USA)
Placebo (C): Topical gel base only (Watson Laboratories, Inc., USA)
All three study formulations will be supplied in 30 gram tubes with child resistant caps.
All randomized study medication will be blinded and packaged in blinded sealed boxes.
Each tube will be identified by a label bearing the protocol number, randomization
number, a statement that the study medication is for Investigational Use Only and the
Sponsors name. The delegated study staff will dispense the study medication tube only
to those patients identified by the Investigator as eligible participants. The study staff will
instruct the patients on the use and return of the study medication. The patient will be
instructed not to discuss the appearance of the study medication tube with any study
personnel conducting the study assessments i.e., the Investigator(s) or the Study
Coordinator(s).
Each study site will have at least one Independent Dispenser. The role of the
Independent Dispenser is to dispense and collect study medication to/from the patients,
maintain dispensing records, and ensure the study drug logs are complete and accurate.
Individual tubes of study medication will be packaged in blocks of 7 based on the 3:3:1
randomization (refer to section 9.4.3 of the protocol). The study medication will be
shipped to each Investigators site from a centralized location. The Principal Investigator
at each site is responsible for ensuring that all study medications are stored in a locked,
secure location, with access limited to the Investigator and his/her designee(s). An
accurate inventory of the study medication will be maintained in accordance with federal
regulations. For every study drug shipment received at the Investigator Site, the
Investigator (or designee) will randomly select at least one block of study drug for
retention, unless otherwise instructed by the Sponsor and/or Novum. The selection
process will ensure a sufficient amount of retention samples are retained as per Sponsor
requirement. These blocks will be affixed with a label provided by Novum to be clearly
Product Mirvaso


marked as retention samples and are not to be used for dispensing to study patients. The
selected retention samples will be retained at a third party storage facility (BioRepository
Resources, LLC) under FDA regulations as study retention samples.
21

Once the site has been notified that they may do so, all unused study medication and
empty or partially used tubes of study medication, other than that randomly selected for
retention samples will be returned to the Sponsor (Watson) or designee. It is important
that retention samples not be returned to Novum, the Sponsor or the packaging company
during or at the end of the study. Sufficient study medication tubes must be retained
amongst the sites participating in the study to meet the sample retention requirements as
outlined by the FDA.
21

9.4.3 Method of Assigning Patients to Treatment Groups
In order to maintain the study blind, the study medication will be packaged and blinded
by an independent packaging company. The randomization will be generated in blocks of
7 (3 test medication: 3 reference medication: 1 placebo). Seven (7) patients worth of
study medication (3 tubes of test medication, 3 tubes of reference medication and 1 tube
of placebo) will be packed into a larger box. This larger box will be designated one
block of study medication. The study medication should be blinded, packaged and
delivered to the study site in blocks.
Randomization will be performed according to a computer-generated randomization
scheme. Prior to dispensing study treatment, patients will be randomized to a treatment
regimen in a blinded fashion by assigning randomization numbers in ascending
sequential order starting with the lowest available randomization number at each site.
The randomization number will consist of a 2-digit site number and 4-digit study drug kit
number. The 4-digit study drug kit number will be obtained from the individual study
drug box.
A perforated or two-part label will be attached to each of the small sized boxes of study
medication. Both pieces of the label will include the following information: Protocol
number, randomization number, space for patients initials, statement that the study
medication is for Investigational Use only, space for dispensing date and the Sponsors
name. In addition all patients will be provided with written instructions on how to use the
study medication. One part of the label shall remain attached to the box. The other part
will be removed prior to dispensing and attached to patients Source documentation.
Each patient will receive one box containing 1 x 30 gram tube of study medication; this
quantity will suffice for the entire study duration. Each patient will maintain the same
randomization number and treatment assignment throughout the study.
9.4.4 Study Blind
The Investigator, staff at the study site, study monitors, and data analysis/management
personnel will be blinded to the patient assignment. The patient will be requested not to
Product Mirvaso


discuss the appearance of the study medication tube with the Investigator or study staff
outside of the Independent Dispenser.
To ensure that information that could potentially bias handling of data is not disclosed,
the packaging company will hold the randomization scheme until after database lock. For
each patient a perforated tear-off label containing the unblinding information will be
placed in the patients chart, to be unblinded in case of medical emergency only. The
patients chart containing the occluded unblinding label should be stored in a secure
location at all times.
Where possible, the Sponsor and/or Novum medical monitor should be contacted before
breaking the blind for any patient. In the event the blind is broken for any reason Sponsor
and Novum will be notified as soon as possible in writing of the details of the occurrence.
At the conclusion of the study, after the database has been locked, each site will be sent a
sealed envelope containing the full study randomization scheme that should be retained
with the study documents in the event of an FDA Inspection.
The tubes of test, reference and placebo products will be blinded with identical labels.
This will allow the treatment phase of the study to be conducted under double-blind
conditions, such that neither the patient nor the Investigator or study staff members will
know the identity of the patients treatment.
9.4.5 Compliance
Patients will be provided with dosing instructions at Visit 2. One dose is equivalent to 1
application of study product to entire face (i.e. 5 areas of the face: nose, forehead, both
cheeks and chin), once a day.
Patient compliance with respect to study medication administration will be calculated by
analyzing the doses recorded in the provided dosing diary. Compliance criteria are as
outlined in the table below.
Compliance Criteria
Study period Duration
Scheduled
doses
not more than
125% (doses)
not less than
75% (doses)
Randomized
treatment 7 days 7 8 6

9.5 Study Conduct
9.5.1 Visit 1 (Day -14 to 1): Screening
1. Informed Consent: Patients who are willing to comply with study
procedures will read and sign the informed consent form.
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2. Baseline Demographics and Medical History: Confirm the patient has
a clinical diagnosis of rosacea. Review the patients demographic and
medical history.
3. Dermatological Assessment: Patients should have a clinical diagnosis
of rosacea with fewer than 3 inflammatory lesions on the face.
4. Erythema Assessment: The Investigator will perform the Clinicians
Erythema Assessment and confirm diagnosis of moderate to severe facial
erythema associated with rosacea. Patients will perform the Patients
Self-Assessment after appropriate instruction.
5. Lesion Count: Perform a count of the inflammatory rosacea lesions.
6. Vital Signs: Obtain the patients vital signs (blood pressure, pulse,
respiration rate and temperature).
7. Concomitant Medications: Review the patients use of concomitant
medication within the last 6 months.
8. Pregnancy Test: All females of child-bearing potential will have a urine
pregnancy test performed. The test must be negative for the patient to be
eligible for inclusion in the study.
9. Inclusion/Exclusion Criteria: Confirm the patient meets all the
inclusion/exclusion criteria.
10. Schedule Visit 2: Patients will be instructed to return to the clinic for
Visit 2 (as per the schedule determined by the site staff and patient).
9.5.2 Visit 2 (Day 1): Randomization
1. Medical History: Review and report any changes in the patients health
status since Visit 1.
2. Dermatological Assessment: Patients should have a clinical diagnosis
of rosacea with fewer than 3 inflammatory lesions on the face.
medication since Visit 1.
pregnancy test performed. The test must be negative for the patient to be
eligible for inclusion into the treatment phase of the study.
6. Pre-dose Erythema Assessment: The Investigator (who is not the
blinded doser/independent dispenser) will perform the Clinicians
Erythema Assessment. Confirm diagnosis of moderate to severe facial
Product Mirvaso


erythema associated with rosacea. Patients will perform the Patients
Self-Assessment after appropriate instruction.
7. Inclusion/Exclusion Criteria: Confirm the patient meets all the
inclusion/exclusion criteria, following which the patient may be enrolled
into the study and assigned a randomization number.
8. Dispense Study Medication and Dosing Diary: The independent
dispenser will dispense study drug. Patients will be provided their dosing
diary, and receive instruction on how to dose, and procedures for
recording doses, AEs and concomitant medications in their diary.
9. Administer First Dose: Patients will gently wash their face with a mild,
non medicated cleanser (e.g., Dove
soap), rinse with warm water and

pat dry. A designated member of staff will apply the first dose of
blinded, randomized medication to patients with a gloved hand, in the
clinic.
10. 6 Hour Confinement Period: Patients will be asked to remain at the
clinic for 6 hours following first dose application. They may be provided
with a standard light meal (i.e., snacks and/or small meal) and
refreshments during this period. All food provided will be in accordance
with dietary restrictions in Appendix B.
11. Post-dose Erythema Assessment: Following 6 hours ( 10 minutes) of
the first dose, patients will undergo a post-dose erythema assessment
(CEA and PSA) in a manner similar to the pre-dose assessment.
12. Scheduled Adverse Events Assessment: Prior to release from
confinement, an assessment of changes in patients health (since the
application of the study medication) will be performed.
13. Adverse Events: Review any adverse events reported by patient during
the 6 hours after study medication application.
15. Schedule Visit 3: Patients will be instructed to return to the clinic for
Visit 3 (as per the schedule determined by the site staff and patient) and
not apply the last dose until they are in the clinic. Patients will be
instructed to bring their study medication tube to the clinic for Visit 3.
9.5.3 Visit 3 (Day 7 1): Study Completion or Early Discontinuation
2. Collect Dosing Diary: Review for dosing compliance.
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medication since Visit 2.
4. Adverse Events: Review any adverse events reported by patient since
Visit 2.
pregnancy test performed.
6. Pre-dose Erythema Assessment: The Investigator (who is not the
blinded doser/independent dispenser) will perform the Clinicians
Erythema Assessment. Patients will perform the Patients Self-
Assessment after appropriate instruction. CEA and PSA assessments at
baseline should not be conducted 24 ( 2) hours before last study
medication application at home (i.e., last dose before Visit 3).
7. Administer Last Dose: Patients will gently wash their face with a mild,
non medicated cleanser (e.g., Dove

soap) rinse with warm water and pat
dry. A designated member of staff will apply the last dose of blinded,
randomized medication to patients with a gloved hand, in the clinic.
8. Study Drug: Collect the study drug after the last dose has been
administered.
9. 6 Hour Confinement Period: Patients will be asked to remain at the
clinic for 6 hours following last dose application. They may be provided
with a standard light meal (i.e., snacks and/or small meal) and
refreshments during this period. All food provided will be in accordance
with dietary restrictions in Appendix B.
10. Post-dose Erythema Assessment: Following 6 hours ( 10 minutes) of
the last dose, patients will undergo a post-dose erythema assessment
(CEA and PSA) in a manner similar to the pre-dose assessment.
11. Scheduled Adverse Events Assessment: Prior to release from
confinement, an assessment of changes in patients health (since the
application of the study medication) will be performed.
12. Adverse Events: Review any adverse events reported by patient during
the 6 hours after study medication application.
14. Release: Discharge patient from study.
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9.6 Study Procedures
9.6.1 Informed Consent
At Visit 1, each patient shall be required to read and sign the IRB approved Informed
Consent Form. No patient will be entered into the study without reading, understanding,
and signing an informed consent. For illiterate patients, verbal consent should be obtained
in the presence of and be countersigned by a literate witness. If any other language is
required, translation will be performed by a certified translator.
9.6.2 Demographics
At Visit 1, each patient shall be required to provide basic demographic information: date
of birth, gender, ethnicity, race, and tobacco usage.
9.6.3 Medical History
At Visit 1, patients will be questioned about their rosacea history and must provide
information on all symptoms and rosacea medications. The patients medical history,
including any acute and/or chronic medical conditions and concomitant medication use
(used within the last 6 months) will be recorded. At Visit 2 a review of the patients
medical history and concomitant medication use since the previous visit will be
performed and updates will be recorded. At Visits 1 and 2 medical history and
concomitant medication recorded will be reviewed to determine eligibility for inclusion
into the study.
9.6.4 Vital Signs
The patients vital signs will be recorded (pulse, blood pressure, temperature and
respiration rate) at all three visits.
9.6.5 Lesion Count
At Visits 1 and 2 a dermatological exam will be performed by an Investigator to count the
inflamed facial lesions of rosacea and will determine eligibility for inclusion into the
study. At Visit 3 the Investigator will continue to perform lesion counts.
9.6.6 Concomitant Medication Use
At Visit 1 patients will be questioned about current and concomitant medication use over
the previous 6 months. At Visits 2 and 3, patients will be questioned about ongoing or
new concomitant medication use.
9.6.7 Pregnancy Test
All females of child-bearing potential will have a urine pregnancy test performed at
Visits 1, 2 and 3. The test must be negative at Visits 1 and 2 for the patient to be eligible
for inclusion in the study. If the patient is female and not considered to be of child-
bearing potential, then the reason for non child-bearing potential must be documented in
the patients source documents.
Product Mirvaso


Any patient who becomes pregnant during the study must be discontinued and applicable
End of Study/Visit 3 procedures (i.e., vitals, lesion count, pregnancy test, collection of
study medication, and dosing diary, concomitant medication and AE review) completed.
Only those female patients, who are randomized and treated with study drug, will require
applicable End of Study/Visit 3 procedures completed. The outcome of the pregnancy
will be followed by the Investigator to birth or termination as appropriate.
9.6.8 Dispensing Study Drug
The Independent Dispenser will dispense study drug at Randomization (Visit 2), after the
Investigator has determined the patient meets the inclusion/exclusion criteria for the
study. Patients will be instructed to gently wash the face with the provided mild non-
medicated cleanser (e.g., Dove
soap), rinse with warm water and pat dry prior to each
dose application.
9.6.9 Collecting Study Drug
Used or unused study drug tubes will be collected at study completion visit (Visit 3) or
early termination visit.
9.6.10 Dosing Instructions and Diary
At Visit 2, the site will provide instructions on the procedures for washing the face prior
to dosing. A mild, non-medicated cleanser (e.g., Dove
soap) will be provided to the

patients. The patient will wash and dry his/her face prior to study drug application. On
Visit 2, a designated member of staff will administer to the patient the first dose of
blinded, randomized study medication (a thin application of pea-sized amount to each of
the 5 areas of the entire face, including forehead, chin, nose and both cheeks) with a
gloved hand, avoiding application to broken or irritated skin, open wounds, eyes or lips.
Patients will be asked to dose at home for non-clinic days (between Visits 2 and 3), one
application daily, at approximately the same time each day, per dosing instructions
provided. Hands should be washed immediately after applying the product.
Patients will be given a dosing diary with instructions on recording the time and date of
each dose, AEs, and concomitant medications throughout the study. The diary will be
reviewed at each visit by the study staff.
The last dose at home should be applied 24 ( 2) hours before Visit 3 baseline erythema
assessments.
Patients will be instructed not to apply the last dose at home. On Visit 3, a blinded doser,
as designated by the investigator, will administer the last dose of blinded, randomized
study medication at the clinic.
Product Mirvaso


9.6.11 Dosing Compliance
Compliance criteria for dosing are described in section 9.4.5. Diaries should be reviewed
at Visit 3 to determine compliance. The patient diary should be collected at Visit 3 and
retained in the patients file as source documentation.
9.6.12 Clinical Assessments
Clinical assessments (CEA and PSA) will be performed by the clinical Investigator and
patient, evaluations will be performed in the dosing area. Baseline and post-dose
erythema assessments should reflect an overall severity in erythema across the entire face
including the 5 areas i.e., forehead, nose, both cheeks and chin.
Clinicians Erythema Assessment (CEA)
The Investigator/evaluator (or a board-certified dermatologist) will evaluate the
patients rosacea-associated facial erythema by performing a static (snap-shot)
evaluation of erythema severity using the CEA (Appendix A), and report the one
integer that best describes the overall severity.
Patients Self-Assessment (PSA)
Patients will perform static (snap-shot) evaluations of their rosacea-associated
facial erythema severity at all clinic visits using the PSA scale (Appendix A), and
report the one integer that best describes the overall severity of their facial
redness as seen in a mirror at the time of the evaluation.
9.7 Adverse Events
The patients will be monitored throughout the study for any AEs. A scheduled AE
assessment will be performed prior to the patients release from confinement at Visit 2
and 3. At each Visit 2 and 3 patients will be questioned regarding any changes in their
medical status since their previous visit. Observed changes during the dermatology exam
and/or clinical assessment at each visit, (i.e., changes in lesion count) should be assessed
by the Investigator to determine (in their opinion) to report the change as an adverse
event or not.
Patients will be specifically questioned about whether they have experienced symptoms
of burning, itching, stinging, and flushing. If a patient reports signs or symptoms of
irritation such as burning, itching, stinging or pain, these will be reviewed by an
Investigator to determine if the reported change is an AE or not.
AEs will be collected through both solicited and unsolicited means and subsequently
coded in tabular form using the MedDRA version 17 (or higher) AE Dictionary. Patients
will be encouraged to report signs, symptoms and any changes in health to the clinic
staff. Severity of each AE will be determined based on observation and questioning of
the patient. The Investigator will judge the relationship of the event to the study
treatments.
Product Mirvaso


9.7.1 Definitions
Adverse Event
Any untoward medical occurrence in a patient or clinical investigation patient
administered a pharmaceutical product and which does not necessarily have a causal
relationship with treatment. An AE can therefore be any unfavorable and unintended
sign, symptom, or disease, temporally associated with the use of a medicinal
(investigational) product, whether or not related to this product. This includes events not
seen at screening or worsened even if present at screening.

Adverse Drug Reaction
All noxious and unintended responses to a medical product related to any dose should be
considered adverse drug reactions. The response to a medical product means that a
causal relationship between a medicinal product and an adverse event is at least a
reasonable possibility.
Unexpected Adverse Reaction
An adverse event where the nature or severity of is not consistent with the applicable
product information (e.g., Investigators Brochure for an unapproved investigational
product or package insert/summary of product characteristics for an approved product).
9.7.2 Severity of Adverse Events
Severity of AE
The severity of the adverse event will be graded by the Investigator using the following
criteria as guidelines:
Mild: Awareness of symptom but does not interfere with routine activities
Moderate: Discomfort sufficient to interfere with routine activities
Severe: Impossible to perform routine activities
9.7.3 Causality Assessment
Relationship to the Study Product
SUSPECTED: A reasonable possibility exists that the investigational product
caused or contributed to an adverse event.
NOT SUSPECTED: The Investigator does not feel that the investigational
product caused or contributed to the adverse event in any way.
Product Mirvaso


9.8 Serious Adverse Events
9.8.1 Definition of a Serious Adverse Event
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose suggests
a medically significant hazard, including any event that:
Results in death -- includes all deaths, even those that appear to be completely
unrelated to study treatment (e.g., car accident where patient is a passenger).
Is life-threatening -- in the view of the Investigator, the patient is at immediate
risk of death at the time of the event.
Results in persistent or significant disability or incapacity (substantial disruption
of ones ability to conduct normal life).
Requires inpatient hospitalization or prolongation of existing hospitalization
causes congenital anomaly or birth defect.
Is an important medical event that may not be immediately life-threatening or
result in death or hospitalization, but may jeopardize the patient or may require
medical or surgical intervention to prevent one of the other serious outcomes
listed above (e.g., intensive treatment in an emergency room, convulsions that do
not result in hospitalizations). Emergency Room visits that require medical or
surgical intervention to prevent one of the other serious outcomes listed above
are considered a serious adverse event.
9.8.2 Reporting Serious Adverse Events
Investigator Reporting of SAEs
Adverse events which are evaluated by the Investigator as "Serious" will be reported to
the Sponsor and IRB within 24 hours of notice whether or not they are considered
expected or drug-related. All Serious Adverse Events will be reported as per FDA
regulations. All Adverse Events encountered during the study will be reported on the
appropriate form and summarized in the final report.
Any serious or unexpected adverse events should be reported to Novum within 24
hours. Following is the contact information:
Gail Gongas
Vice President, Clinical Trials
Cell Phone: 412-606-1603
Phone: 412-363-3300 x 522
Fax: (412) 291-3171

Or

Darin Brimhall, DO, FACP, CPI
Medical Monitor
Product Mirvaso


Phone: 702-435-3739 x 370
Fax: (412) 291-3171
Novum will report any Serious Adverse Event to Watson.
Watson Study Manager
Nageshwar Thudi, PhD
Director, Biopharmaceutics
Phone: 862-261-7548
Fax: 862-261-7911
Email: nageshwar.thudi@actavis.com

And
Drug Safety Department
ATTN: INTAKE
Actavis
Building B, 1
st
floor
Phone: 800-432-8534 Fax: 908-248-0805
Email: PVNJIntake@actavis.com
Under 21 CFR 320.31(d)(3), the Sponsor or CRO must inform other Investigators
involved in the study plus the FDA within 15 days of becoming aware of the occurrence
of the SAE.
10.0 STATISTICAL METHODS
10.1 Statistical Plan
All statistical analysis will be conducted using SAS
, Version 9.3 or higher.

10.2 Determination of Sample Size
The primary statistical analysis of interest is the proportion of patients in the PP
population with a clinical response of treatment success (at least a 2-grade improvement
on CEA and PSA over 6 hours) at study Day 7 ( 1 day) (end of 7-day treatment period).
The sample size estimations are based on data from two sources:
1. The observed response rate data from Watson's pilot study 71304909. Study
71304909 evaluated a single-dose of placebo test formulation of Brimonidine
Topical Gel (Watson Laboratories, Inc., USA) and a single-dose of the marketed
US reference product Mirvaso
(brimonidine) topical gel 0.33% (Galderma

Laboratories, L.P., USA) in the treatment of patients facial erythema associated
Product Mirvaso


with rosacea. The rates of treatment success (at least a 2 grade improvement in
CEA and PSA over 6 hours) were 45% and 0% for patients treated with
Mirvaso

on one half of the face and vehicle gel on the other half, respectively.
24

2. The observed response rate data for the once-daily multiple-dose placebo and
active treatments in the innovator's studies to support approval of Mirvaso
NDA 204708.
11, 16-17

The treatment success rate for the reference treatment group at the end of the 7-day
treatment period is assumed to be 45% in the PP population. Assuming that the treatment
success rate for the test treatment group will be an absolute difference of 5% higher than
the reference success rate in this study, a sample size of 159 patients per active group will
provide at least 82% power to demonstrate bioequivalence (i.e., the 90% confidence
interval (Yates continuity-corrected) of the absolute difference between the test and
reference composite success rate rates is within a defined equivalence range [-20%,
+20%]).
The rates of treatment success for the placebo and active treatment groups at the end of
the 7-day treatment period are assumed to be 10% and at least 40%, respectively, in the
mITT population. Therefore, one-third of the number of patients will be enrolled in the
placebo group as in each of the two active treatment groups to maintain an adequate
sample size in the placebo treatment group. Assuming the conversion rate from mITT to
PP will be about 90%, 177 patients in each of active groups and 59 patients in the placebo
group of the mITT population will provide at least 98% power to demonstrate superiority
of active over placebo. Under the above assumptions, the overall global study power to
demonstrate bioequivalence and superiority is estimated to be at least 80% (0.82 x 0.98),
assuming 100% correlation between the two superiority tests. To allow for about 10% of
patients who may drop out from the study or are otherwise non-evaluable, up to 462
patients may be enrolled (198 in each active group and 66 in the placebo group).
If the response rate of the reference treatment decreases to 30% in the mITT and PP
populations (as observed in one of the innovator's studies), and assuming no difference in
response rates between test and reference treatments, then the randomization scheme of
177:177:59 patients in the mITT population and 159:159:53 in the PP population would
have at least 82% power to demonstrate superiority of each of the active treatments
against placebo and 96% power to show bioequivalence. The overall global study power
would still be maintained at about 80%.
10.3 Study Populations
10.3.1 Per Protocol (PP) Population
Patients are eligible for inclusion in the PP population if they:
Met all inclusion/exclusion criteria at Visits 1 and 2.
Product Mirvaso


Returned to the study site for Visit 3 within the specified window (Day 7 1
day) and completed all primary endpoint assessments (baseline and 6 hours [ 10
min] post-dose).
Were compliant with study treatment dosing (i.e., administered 75%-125% of
scheduled doses) during the study.
Complied with all study restrictions including concomitant medications.
Did not have any other significant protocol violations that would affect the
treatment evaluation.
Patients who discontinued because of lack of treatment effect will be included in
the PP population as treatment failures and did not have any protocol violations
that would affect treatment evaluation and provided the patient has been
administered at least 1 dose of study medication.
Patients whose condition worsened and required alternate or supplemental
therapy for the treatment of rosacea during the study should be discontinued and
included in the PP population as treatment failures and provided with alternative
therapy provided the patient has taken at least 1 dose of study medication.
10.3.2 Modified Intent-to-Treat (mITT) Population
The mITT population will include all patients in the PP population and if they:
Had at least one dose of randomized study medication.
Had both pre and post-dose erythema assessments on Visit 2 or Visit 3. Visit 2 data
would be LOCF to Visit 3 if Visit 3 data are missing, and if treatment success rate is
evaluable for Visit 2.
Met all inclusion/exclusion criteria (at Visits 1 and 2).
10.3.3 Safety Population
The safety population includes all randomized patients who received study treatment.
10.4 Baseline Comparability
Baseline comparability of all treatment groups will be evaluated separately in the PP, mITT and
Safety populations. The following baseline demographics (determined from their initial study
visit) will be evaluated:
Age (years)
Gender (male/female)
Ethnicity (Hispanic/non Hispanic)
Race (White, Black/African American, Native Hawaiian or Other Pacific Islander, Asian,
American Indian or Alaska Native, Other)
Tobacco use (yes/no)
Erythema assessment score at screening
Product Mirvaso


Descriptive statistics by treatment group will be presented.
10.5 Efficacy Endpoints
Primary efficacy endpoint
Proportion of patients with a clinical response of treatment success on Day 7 ( 1). Treatment
success is defined as at least a 2-grade improvement on both CEA and PSA scores from baseline
(pre-dose) on Day 7 ( 1) to 6 hours post-application on Day 7 ( 1).
Secondary efficacy endpoints
Proportion of patients with a clinical response of treatment success on Day 1. Treatment success
is defined as at least a 2-grade improvement on both CEA and PSA scores from baseline (pre-
dose) on Day 1 to 6 hours post-application on Day 1.
10.6 Bioequivalence
Therapeutic equivalence of the test product to the reference product will be evaluated in the PP
population. If the 90% confidence interval (calculated using Yates continuity correction) for the
absolute difference between the proportion of patients considered a treatment success (at least a
2-grade improvement on CEA and PSA over 6 hours) in the test and reference groups is
contained within the range [-20%, +20%] then bioequivalence of the test product to the reference
product will be considered to have been demonstrated.
10.7 Superiority to Placebo Analysis
Superiority of the test and reference gels against the placebo will be tested at the 5% significance
level (p < 0.05; using two-sided, continuity-corrected Z-test) in the mITT population using last
observation carried forward. The superiority of test and reference treatments over the placebo will
be evaluated identically in separate Z-Test analyses.
10.8 Safety Analysis
Adverse events will be classified using standard MedDRA terminology Version 17.0 or higher
and summarized by treatment group. Summary tables comparing the type, incidence, severity and
Investigators opinion of relationship to the study medication will be prepared by treatment
group. Signs and symptoms of rosacea will not be considered adverse events, unless in the
Investigators opinion, they have increased in frequency and/or severity to such an extent that the
Investigator/patient considers that it is in the patients best interest to be dropped from continued
participation in the study and given alternative therapy for their rosacea.
Should sufficient data exist, adverse event frequencies will be compared between treatments
using Fishers exact test or a similar test.
Concomitant medication use during the study period will be tabulated by patient. All patients who
are randomized to the active treatment period of the study will be included in the comparative
safety analysis.
Product Mirvaso


Adverse events reported during the study will be tabulated in summary tables listing the type,
incidence, severity and Investigators opinion of relationship to the study medication.

11.0 REGULATORY OBLIGATIONS
11.1 Institutional Review Board
The study protocol, informed consent form, Investigator's Brochure, or package insert (as
applicable), and any specific advertising will be submitted to, and approved by, an Institutional
Review Board (IRB) before the start of the study. A form must be signed by the chairman or
designee of the IRB noting the approvals. This notification of the board's approval along with a
description by profession and gender of the board's composition will be provided to the Sponsor.
11.2 Study Documentation
This study will be conducted in compliance with the protocol, Good Clinical Practices (GCPs)
and all applicable regulations, including the Federal Food, Drug and Cosmetics Act, US
applicable Code of Federal Regulations (title 21), parts 50, 56, 312, 320 and any IRB
requirements relative to clinical studies and the Declaration of Helsinki, June 1964, as modified
by the 59
th
World Medical Association General Assembly, October 2008.
The Investigator will permit trial-related monitoring, audits, IRB review and regulatory
inspections providing direct access to source data/documents.
11.2.1 Protocol
The Investigator indicated on FDA Form 1572 will act as the Principal Investigator at each study
site. Protocols will be noted as approved by placement of the Novum Representatives signature
on the cover page. The Sponsor of the study will also approve the protocol by having a study-
responsible individual sign the protocol cover page.
11.2.2 Informed Consent
An Informed Consent Form (ICF) that includes all of the relevant elements currently required by
FDA and local State regulations will be provided to each prospective study patient before
enrollment into the study. The type and method of study, tests to be administered, any potential or
possible hazards, and the patient's right to withdraw from the study at any time will be explained
to the patients by the Investigator or designee. Once the Investigator or designee is assured that an
individual candidate understands the implications of participating in this study, the patient will be
asked to give consent by signing and dating in the appropriate areas of the ICF. The Investigator
or designee will also sign and date the form, along with a staff member who will sign the ICF as a
witness to verify that the patient has indeed received information. For illiterate patients, verbal
consent should be obtained in the presence of and be countersigned by a literate witness. If any
other language is required, translation will be performed by a certified translator. A copy of the
ICF will be provided to the patient.
Product Mirvaso


11.2.3 Protocol and Informed Consent Changes
Sponsor approved revisions to the original protocol will be documented in amendments,
incorporated as a preface to the new version and approved by the IRB. Any revision that
substantially alters the study design or increases potential risk to the patient requires the patients
consent to continue in the study. Revisions to the original ICF will also be approved by the IRB.
The approvals will be processed in accordance with the established IRB procedures. Copies of all
protocol and ICF amendments/revisions, along with letters noting IRB approval, will be
submitted to the Sponsor.
11.2.4 Source Documents and Case Report Forms
All patients will be identified by initials and a unique patient/randomization number. Source
documents will be used to record all study-related data. Source document entries will be used to
complete Case Report Forms (CRFs). A set of CRFs will be completed for each patient
randomized into the study at Visit 2. All data and CRFs will be reviewed, evaluated and signed
by the Investigator, as required.
The original source documents and a copy of the corresponding CRFs will be retained by the
Investigator. Patients who terminate early from the study will have the applicable end of study
source/CRF completed.
11.2.5 Drug Accountability
All drug receipt, inventory, dispensing, dosing and reconciliation records will be maintained in
compliance with Federal Regulations. The study drug will be dispensed by the Investigator
designated Independent Dispenser to qualified study patients according to established procedures.
At the end of the study all used and unused study drug will be returned to the Sponsor (Watson)
or designee for destruction.
11.2.6 Drug Storage
All study drug will be stored at controlled room temperature 20-25C (68-77F) excursions
permitted between 15-30C (59-86F), in a secure place with access by authorized individuals
only. The Investigator will be responsible for maintaining accurate records of drug receipt,
dispensing, collecting, and shipping. At the end of the study, all partially used and unused study
drug will be returned to the Sponsor (Watson) or designee for destruction.
11.2.7 Retention of Reserve Samples
For every study drug shipment received at the Investigator site, the Investigator (or designee) will
randomly select at least one block of study drug for retention, unless otherwise instructed by the
Sponsor and/or Novum. The selection process will ensure a sufficient amount of retention
samples are retained as per Sponsor requirement. A block contains 7 patient kits (as the study is
randomized in a 3:3:1 ratio). The number of each patient kit in each block kept for retention will
be noted on the drug accountability form, as a retention sample, in addition to the retention
sample log. These retention samples should be stored under the appropriate storage conditions for
a minimum of 5 years following the application approval or, if not approved, at least 5 years after
Product Mirvaso


the completion of the study.
22
Retention samples should not be returned to sponsor at any time.
The retention samples will be shipped to a third party storage facility:
BioRepository Resources, LLC
755 Central Ave, Unit 3
New Providence, NJ 07974
Office: 908-790-8890
Mobile: 908-635-3777
www.brr.us.com

11.2.8 Return of Clinical Supplies
With the exception of the retention samples, all unused kits of Investigational Product will be
returned to Watsons Drug Labeling, Packaging and Shipping Facility:
Denis Bartle
Manager, R&D Support
Watson Laboratories, Inc.
577 Chipeta Way
Salt Lake City, UT 84108-1222
Phone: 801.588.6500

11.2.9 Pregnancies
Patients with a positive pregnancy test at Screening (Visit 1) and Randomization (Visit 2) will not
be enrolled in the study. Patients who report that they have become pregnant during the study
will be discontinued from the study and have all applicable Visit 3 procedures conducted
(including vitals, pregnancy test, lesion count, drug and diary collection, AE and concomitant
medication review); or have a positive pregnancy test at Visit 3, will have the outcome of the
pregnancy followed by the Investigator to the conclusion of the pregnancy. The pregnancy will be
reported as an AE.
11.2.10 Withdrawals due to Adverse Events
All AEs, both serious and non-serious, that result in the patients early withdrawal from the study
(either by the patient request or Investigator decision) will be reported to the Novum Medical
Monitor, when deemed necessary by Novum or Sponsor.
11.2.11 Reporting Safety Information to the IRB
The Investigator must promptly report to Novum all unanticipated problems involving risks to
patients. Thereafter Novum will route all applicable information to the IRB. This includes death
from any cause and all serious adverse events occurring during the study, regardless of the
assessed causality. SAEs must be reported within 24 hrs (business day) of being notified of the
event. The Investigative Site has one business day to report the event to Novum, once notified of
the SAE. Novum has one business day (after notification) to report the event to the IRB.
Per 21 CFR 312.32 (IND Safety Reporting), AEs that are evaluated by the Investigator as
"serious" (e.g., fatal, life-threatening, requiring in-patient hospitalization or extended
hospitalization, persistent or resulting in disabling incapacity, congenital anomaly/birth defect)
Product Mirvaso


will be reported to Novum and the respective IRB within 24 hours, whether or not the event is
considered expected or drug-related. All AEs and SAEs reported during the study will be
summarized in the final report.
23

As per 21 CFR, the Sponsor (Watson Laboratories, Inc., USA) or Novum must inform other
Investigators involved in the study and the FDA within 15 days of becoming aware of the
occurrence of the serious AEs. Serious AEs that occur with the test, reference or placebo product
must be reported.
23

11.2.12 Record Retention
All drug accountability records, CRFs, source data and related regulatory documents must be
retained for at least ten years following completion of the study or for two years after the test
product has been approved for marketing by the Food and Drug Administration. Sites must obtain
authorization from Novum or Sponsor (Watson) prior to destruction.
11.2.13 Study Monitoring and Auditing
Novum will be responsible for monitoring the study according to Good Clinical Practice and
applicable regulations. Monitoring visits are for the purpose of confirming adherence to the
protocol and to verify complete and accurate data collection. The clinical site will make all
records associated with the study available to Novums representative during such visits and
audits.
The study may be subject to audit by the Sponsor, Sponsor Representative or by regulatory
authorities. If such an audit occurs the Investigator must agree to allow access to required patient
records. By signing this protocol, the Investigator grants permission to personnel from the
Sponsor, its representatives and appropriate regulatory authorities for on-site monitoring of all
appropriate study documentation, as well as on-site review of study procedures.
11.2.14 End of the Trial
The end of the trial is defined as the time at which the last patient has completed his/her last visit
in the study. Upon completion of the study, the study drug will no longer be available to the
patient but the Investigator can, at his/her discretion, discuss alternative treatments with the
patient.
11.2.15 Clinical Study Report
At the end of the study a full report per requirements of Sponsor and regulatory authorities will be
prepared which will include a narrative of the clinical conduct and results of the study, a
statistical report including a description of the analysis performed, and other documentation as
may be appropriate. The report will be in electronic format according to eCTD and ICH
formatting standards and guidelines. FDA ANDA summary tables will also be generated. Data
sets will be provided in SAS
transport (.xpt) format with appropriate description (Read Me) files

as required by FDA.
23
Product Mirvaso


11.2.16 Termination of the Study
The Sponsor reserves the right to terminate the study at any time for administrative reasons.

Product Mirvaso


12.0 REFERENCES

1. National Rosacea Society. Patient Home Page. http://www.rosacea.org/patient/index.php.
2. National Rosacea Society. All About Redness. http://www.rosacea.org/patients/index.php.
3. National Rosacea Society. Frequently Asked Questions.
http://www.rosacea.org/patients/faq.php.
4. Drummond P et al. Blushing in Rosacea Sufferers. Journal of Psyschosomatic Research.
2012; 72: 153-158.
5. National Rosacea Society. Essential Steps Help Keep Rosacea at Bay.
http://rosacea.org/rr/2009/spring/article_2.php.
6. Crawford GH, Pelle MT, James WD. Rosacea: I. Etiology, pathogenesis, and subtype
classification. J Am Acad Dermatol. 2004; 51: 327-41.
7. Gupta AK, Chaudhry MM. Rosacea and its management: an overview. J Eur Acad Dermatol
Venereol. 2005; 19: 273-285. [PubMed: 15857452]
8. Odom R, Dahl M, Dover J, et al. Standard management options for rosacea, Part II: option
according to subtype. Cutis. 2009; 84:97-104. [PubMed: 19746768]
9. Singer MI. Drug therapy of rosacea: a problem-directed approach. J Cutan Med Surg. 1998;
2(Suppl. 4): 20-23.
10. Powell FC. Rosacea. N Engl J Med. 2005; 352:792-803. [PubMed: 15728812].
11. Prescribing Information for MIRVASO
Topical Gel 0.33%.

12. Wilkin JK. Rosacea: pathophysiology and treatment. Arch Dermatol. 1994; 130: 359-62.
13. Del Rosso JQ. Advances in understanding and managing rosacea: part1: connecting the dots
between pathophysiological mechanisms and common clinical features of rosacea with
emphasis on vascular changes and facial erythema. J Clin Aesthet Dermatol. 2012; 5: 16-25.
14. Steinhoff H, Buddenkotte J, Aubert J, Sulk M, Novak P, Schwab VD, et al. Clinical, cellular
and molecular aspects in the pathophysiology of Rosacea. J Invest Dermatol Symp Proc.
2011; 15:2-11.
15. Fowler J, Jarratt M, Moore A, et al. Once-daily topical brimonidine tartrate gel 0.5% is a
novel treatment of moderate to severe facial rosacea: results of two multicenter, randomized
and vehicle-controlled studies. Br J Dermatol. 2012 March; 166 (3): 633-641.
16. Mirvaso
medical review NDA 204708, June 24, 2013.

17. Fowler J Jr, Jackson JM, Moore AM, et al. Efficacy and Safety of Once-Daily Topical
Brimonidine Tartrate Gel 0.5% for the Treatment of Moderate to Severe Facial Erythema of
Rosacea: Results of Two Randomizaed, Double-Blind, Vehicle-Controlled Pivotal Studies.
Journal of Drugs in Dermatology. 2013; 12:650-656.
Product Mirvaso


18. Draft Guidance on Metronidazole Gel/Topical, Office of Generic Drugs, March 2010.
19. Draft Guidance on Azelaic Acid Gel/Topical, Office of Generic Drugs, May 2010; Revised
Sep 2012.
20. Penslar RL, Porter JP. (1993) IRB Guidebook, Office for Human Rights Protection, US
Department of Health and Human Services.
21. Guidance for Industry. Handling and Retention of BA and BE Testing Samples U.S. (2004,
May) Department of Health and Human Services, Food and Drug Administration, Center for
Drug Evaluation and Research (CDER).
22. Guidance for Industry. ICH Topic E3 (1996, July) Structure and Content of Clinical Study
Reports. CPMP/ICH/137/95.
23. 21 CFR, 312.2 IND Safety Reporting: http://www.ecfr.gov/cgi-bin/text-
idx?SID=85f6b2cb9f503701d84347f38474660f&node=21:5.0.1.1.3.2.1.7&rgn=div8
24. Pilot Study 71304909. A Randomized, Double Blind, Study Evaluating the Reduction in
Erythema by Mirvaso
(brimonidine)Topical Gel 0.33% (Galderma) and Placebo Topical Gel

in Patients with Moderate to Severe Facial Erythema of Rosacea. Data on File.
Product Mirvaso


13.0 APPENDICES
13.1 Appendix A
Clinicians Erythema Assessment (CEA) and Patients Self-Assessment (PSA)

Score Grade CEA PSA
0 Clear Clear skin with no
signs of erythema
Clear of unwanted
redness
1 Almost clear Almost clear; slight
redness
Nearly clear of
unwanted redness
2 Mild Mild erythema;
definite redness
Somewhat more
redness than I prefer
3 Moderate Moderate erythema;
marked redness
More redness than I
prefer
4 Severe Severe erythema;
fiery redness
Completely
unacceptable redness
Product Mirvaso


13.2 Appendix B
Rosacea Trigger Foods and Beverages Tabulation (not all inclusive)
Foods Beverages
Liver
Yogurt
Sour cream
Aged cheese (i.e. brie and blue cheese)
Chocolate
Vanilla bean
Soy sauce
Yeast extract (bread is OK)
Vinegar
Eggplant
Avocados
Spinach
Broad-leaf beans and pods,
including lima, navy or pea
Citrus fruits, tomatoes, bananas,
red plums, raisins or figs
Spicy foods
Foods high in histamine
Hot spices (i.e. cayenne, red pepper,
chili powder)
Aged foods
Mustard, tomatoes, ketchup
Alcohol, especially red wine,
beer, bourbon, gin, vodka or
champagne

Hot drinks, including hot
cider, hot chocolate, coffee or
tea

Product Mirvaso


13.3 Appendix C
Mirvaso

Product Insert

Product Mirvaso


13.4 Appendix D
Amendments to the protocol:
Revision Date
1 07.02.2014
The following revisions were made to the protocol dated 07.02.2014:

The protocol was revised to update the retention sample selection requirements and
location of where selected retention samples will be stored.
The protocol was revised to make modifications to the Inclusion and Exclusion
criteria.
The protocol was revised to include the contact name and address of the location
where the used and unused study drug will be sent after study completion.
The protocol was revised to make minor administrative changes.

Protocol Rev 1

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CONFIDENTIAL PROTOCOL

(brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in

(brimonidine) topical gel, 0.33% (Galderma Laboratories, L.P., USA) in

(brimonidine) topical gel, 0.33% (Galderma

including the active

facial soap and gently dry before each

(brimonidine) topical gel

, maximal treatment success was observed about 6

and vehicle gel,

indicated that a similar treatment response was

NDA showed similar rates of

including the active ingredient

, witch hazel lotion 2 days before Visit 1

facial soap and gently dry before

(brimonidine) topical gel, 0.33% (Galderma

soap), rinse with warm water and

soap) will be provided to the

, Version 9.3 or higher.

(brimonidine) topical gel 0.33% (Galderma

transport (.xpt) format with appropriate description (Read Me) files

Topical Gel 0.33%.

medical review NDA 204708, June 24, 2013.

(brimonidine)Topical Gel 0.33% (Galderma) and Placebo Topical Gel

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