Supplementary Appendix

This appendix has been provided by the authors to give readers additional information about their work.
Supplement to: Lembo AJ, Lacy BE, Zuckerman MJ, et al. Eluxadoline for irritable bowel syndrome with diarrhea.
N Engl J Med 2016;374:242-53. DOI: 10.1056/NEJMoa1505180

SUPPLEMENTARY APPENDIX

Eluxadoline Treatment for Irritable Bowel Syndrome with Diarrhea

Anthony J. Lembo, M.D.,1 Brian E. Lacy, Ph.D., M.D.,2 Marc J. Zuckerman, M.D.,3
Ron Schey, M.D.,4 Leonard S. Dove, Ph.D.,5 David A. Andrae, Ph.D.,5
J. Michael Davenport, Ph.D.,5 Gail McIntyre, Ph.D.,5 Rocio Lopez, Ph.D.,5
Lisa Turner, R.Ph.,5 and Paul S. Covington, M.D.5
1

Harvard Medical School, Boston, MA; 2Geisel School of Medicine at Dartmouth, Hanover,
NH; 3Texas Tech University Health Sciences Center, El Paso, TX; 4School of Medicine,
Temple University, Philadelphia, PA; 5Furiex Pharmaceuticals, Inc., an affiliate of Actavis,
Inc., Morrisville, NC

Table of Contents
SUPPLEMENTARY INFORMATION .................................................................................... 2
Adverse Cardiac Events ......................................................................................................... 2
Loperamide Rescue ................................................................................................................ 2
Adverse Events in Cholecystectomized Patients ................................................................... 2
SUPPLEMENTARY FIGURES ................................................................................................ 3
Figure S1. Study Design. ....................................................................................................... 3
Figure S2. Disposition of Patients. ........................................................................................ 4
Figure S3. Composite Responder Analysis of Eluxadoline Versus Placebo in
Subpopulations....................................................................................................................... 5
Figure S4. Assessment of IBS-D Symptom Rebound. .......................................................... 6
SUPPLEMENTARY TABLES ................................................................................................. 7
Table S1. CochranMantelHaenszel Analysis of Composite Responders by Interval
(Intent-to-treat Analysis Set): IBS-3001, IBS-3002, and Pooled Phase 3 Studies. ............... 7
Table S2. Pooled Secondary Efficacy Parameters (Weeks 1 to 12). ..................................... 8
Table S3. Secondary Efficacy Parameters Raw Scores (at Week 12).* ............................. 9
Table S4. Major Adverse Cardiac Events. ........................................................................... 10
Table S5. Selected Adverse Events Potentially Associated With Opiate Withdrawal or
Rebound, n (%). ................................................................................................................... 11
Table S6. Selected Adverse Events Potentially Associated With Opiate Withdrawal or
Rebound, n (%). ................................................................................................................... 11
Table S7. Pain-free Days. .................................................................................................... 12
Table S8. Numbers Needed to Treat / Numbers Needed to Harm....................................... 13
Table S9. Adverse Events in Patients With Prior Cholecystectomy. .................................. 13

SUPPLEMENTARY INFORMATION
Adverse Cardiac Events
Of eight patients with electrocardiogram findings suggestive of ischemia (i.e., T-wave
abnormalities, ST abnormalities, or myocardial ischemia), four received eluxadoline. Of
seven patients with findings consistent with prolonged cardiac repolarization, four received
eluxadoline. These latter four events occurred days after the study drug had been stopped,
were not different from baseline values, or were considered not clinically significant by the
investigator. Two patients in each of the eluxadoline 75 mg and placebo groups and three in
the eluxadoline 100 mg group experienced syncope. Major adverse cardiac events are
summarized in Table S4.
Loperamide Rescue
During the first 3 weeks of treatment, use of loperamide for diarrhea was uncommon and
averaged less than one unit dose per week for both eluxadoline treatment groups as well as
for placebo. From weeks 4 to 26, the average unit dose used per week was even lower.
Overall, 1748 (592, 600, and 556 patients in the eluxadoline 75 mg, eluxadoline 100 mg, and
placebo groups, respectively) of 2423 patients included in the intent-to-treat analysis set did
not use rescue medication. When a nonresponse was imputed for each day a patient took a
dose of loperamide rescue medication, the results of the CochranMantelHaenszel analysis
of composite response were nearly identical to the main CochranMantelHaenszel findings
for composite response over weeks 1 to 12.
Adverse Events in Cholecystectomized Patients
Ten percent of patients who had a cholecystectomy experienced a serious adverse event
compared with 2.9% of patients who had not had a cholecystectomy. The most frequent
adverse events among those who had had a cholecystectomy were nausea (10.5%),
constipation (8.5%), and bronchitis (6.7%). Adverse events and serious adverse events
stratified by cholecystectomy status are reported in Table S9.

SUPPLEMENTARY FIGURES
Figure S1. Study Design.

* Safety and quality of life evaluated after 26 weeks in IBS-3001.

Safety, quality of life, and symptom rebound evaluated after 26 weeks in IBS-3002.
Tx denotes treatment, and wks weeks.

Figure S2. Disposition of Patients.

BID denotes twice daily, and wks weeks.

Figure S3. Composite Responder Analysis of Eluxadoline Versus Placebo in

Subpopulations.

BID denotes twice daily, CI confidence interval, and Wks weeks.

Figure S4. Assessment of IBS-D Symptom Rebound.

BID denotes twice daily, and IBS-D irritable bowel syndrome with diarrhea.

SUPPLEMENTARY TABLES
Table S1. CochranMantelHaenszel Analysis of Composite Responders by Interval (Intent-to-treat Analysis Set): IBS-3001, IBS-3002,
and Pooled Phase 3 Studies.
IBS-3001
Interval
Weeks

Treatment*

1 to 4

5 to 8

9 to 12

13 to 16

17 to 20

21 to 24

IBS-3002

Pooled

Responder,
No. (%)

P Value

Responder,
No. (%)

P Value

Responder,
No. (%)

P Value

Placebo

427

55 (12.9)

382

46 (12.0)

809

101 (12.5)

75 mg

427

88 (20.6)

0.003

381

96 (25.2)

<0.001

808

184 (22.8)

<0.001

100 mg

426

96 (22.5)

<0.001

382

102 (26.7)

<0.001

806

198 (24.5)

<0.001

Placebo

427

85 (19.9)

382

76 (19.9)

809

161 (19.9)

75 mg

427

113 (26.5)

0.02

381

120 (31.5)

<0.001

808

233 (28.8)

<0.001

100 mg

426

123 (28.9)

0.002

382

128 (33.5)

<0.001

806

249 (30.9)

<0.001

Placebo

427

93 (21.8)

382

84 (22.0)

809

177 (21.9)

75 mg

427

101 (23.7)

0.51

381

123 (32.3)

0.001

808

224 (27.7)

0.007

100 mg

426

129 (30.3)

0.005

382

122 (31.9)

0.002

806

250 (31.0)

<0.001

Placebo

427

90 (21.1)

382

80 (20.9)

809

170 (21.0)

75 mg

427

97 (22.7)

0.56

381

117 (30.7)

0.002

808

214 (26.5)

0.01

100 mg

426

124 (29.1)

0.007

382

129 (33.8)

<0.001

806

253 (31.4)

<0.001

Placebo

427

93 (21.8)

382

86 (22.5)

809

179 (22.1)

75 mg

427

118 (27.6)

0.05

381

119 (31.2)

0.007

808

237 (29.3)

<0.001

100 mg

426

123 (28.9)

0.02

382

119 (31.2)

0.007

806

242 (30.0)

<0.001

Placebo

427

87 (20.4)

382

76 (19.9)

809

163 (20.1)

75 mg

427

117 (27.4)

0.02

381

110 (28.9)

0.004

808

227 (28.1)

<0.001

100 mg

426

120 (28.2)

0.008

382

124 (32.5)

<0.001

806

244 (30.3)

<0.001

* Study medication given twice a day; 75 and 100 mg doses refer to eluxadoline.
P value is based on Chi-square test statistic.
The pooled data include unique patient data. Data for patients randomized more than once in an individual study or who were randomized in both phase 3 studies were counted only once
(first randomization). Duplicate data were excluded from the intent-to-treat analysis set.
Composite responder indicates a patient who met the daily pain response AND the daily stool consistency criteria on 50% of days with diary entries during the interval and had a minimum of
20 days of diary data for the 4-week interval.

Table S2. Pooled Secondary Efficacy Parameters (Weeks 1 to 12).

Pooled*
Placebo

75 mg

(N = 809)

(N = 808)

P Value

(N = 806)

P Value

40% responder no. (%)

290 (35.8)

324 (40.1)

0.08

348 (43.2)

0.003

50% responder no. (%)

243 (30.0)

280 (34.7)

0.05

290 (36.0)

0.01

Minimum 50% urgency-free days

0.29

0.42

<0.001

0.42

<0.001

Minimum 75% urgency-free days

0.12

0.22

<0.001

0.21

<0.001

End Point

100 mg

Responder Analyses (Weeks 1 to 12)

Abdominal pain

Urgency

* Study medication given twice a day; 75 and 100 mg doses refer to eluxadoline.
A pain responder was defined as a patient who met the daily pain response criterion (worst abdominal pain score in the past 24 hours improved
by 30%, 40%, or 50% compared with baseline pain) on 50% of days with diary entries during the interval and had a minimum of 60 days
of diary data from weeks 1 to 12.
An urgency-free responder was defined as a patient who reported no urgency episodes on 50% of days within an interval.
Incidence was defined as the inverse link of the least-squares mean estimate for each treatment group.

Table S3. Secondary Efficacy Parameters Raw Scores (at Week 12).*
IBS-3001

Pooled

IBS-3002

Placebo
(N = 427)

75 mg
(N = 427)

P
Value

100 mg
(N = 426)

P
Value

Placebo
(N = 382)

75 mg
(N = 381)

P
Value

100 mg
(N = 382)

P
Value

Placebo
(N = 809)

75 mg
(N = 808)

P
Value

100 mg
(N = 806)

P
Value

Mean

3.622.4

3.362.4

3.142.5

3.442.4

3.082.5

2.872.3

3.532.4

3.232.4

3.012.4

CFB

2.7

2.7

3.0

2.6

2.9

3.0

2.6

2.8

0.06

3.0

<0.001

Mean

4.971.2

4.801.3

4.771.3

5.021.2

4.551.4

4.461.3

4.991.2

4.681.4

4.621.3

CFB

1.3

1.5

1.5

1.2

1.7

1.7

1.2

1.6

<0.001

1.6

<0.001

Mean

3.442.0

3.122.1

3.092.3

3.152.0

2.89 2.1

2.801.7

3.302.0

3.012.1

2.962.1

CFB

1.5

1.7

1.8

1.4

1.8

2.0

1.5

1.8

0.002

1.8

<0.001

Mean

3.912.7

3.452.4

3.282.6

3.552.6

3.492.6

3.212.4

3.742.7

3.472.5

3.252.5

CFB

2.2

2.4

2.5

2.1

2.2

2.4

2.1

2.3

0.10

2.5

0.003

Mean

1.721.0

1.621.0

1.521.0

1.661.0

1.420.9

1.390.9

1.691.0

1.521.0

1.461.0

CFB

1.2

1.2

1.4

1.2

1.3

1.4

1.2

1.3

0.008

1.4

<0.001

Mean

61.7225.6

66.8024.1

68.9323.9

66.3924.5

73.8121.3

71.0923.6

63.925.1

70.123.1

70.023.8

CFB

17.8

20.3

22.8

19.5

22.7

22.6

17.8

22.1

<0.001

22.8

<0.001

End Point
Raw Score Analyses
(at Week 12)
Abdominal pain

Stool consistency

Frequency

Bloating

IBS-D global
symptom score

IBS Quality of Life

questionnaire
score

* Plusminus values are mean standard deviation. CFB denotes change from baseline.
Study medication given twice a day; 75 and 100 mg doses refer to eluxadoline.
Estimated counts of the number of bowel movements from the longitudinal model.
Bloating score is based on a scale of 0 to 10, with 0 indicating no bloating and 10 the worst bloating imaginable. Patients who responded to the interactive voice-response system or interactive web-response system
items in Spanish did not have the bloating item presented.
IBS-D global symptom score is based on a scale of 0 to 4, with 0 indicating no symptoms and 4 very severe symptoms.
IBS Quality of Life questionnaire has a maximum score of 100, with higher scores indicating better quality of life.

Table S4. Major Adverse Cardiac Events.

Dose / Study

Event Details

Placebo
IBS-3001

Acute hemiparesis possibly secondary to hypertension.

IBS-3002

Troponin-negative stent required.

IBS-3002

Elective coronary artery bypass graft required.

75 mg eluxadoline
IBS-3001

Acute myocardial infarction in a 79-year-old male with medical

history of cerebrovascular accident, myocardial infarction, coronary
artery stent placement, coronary artery bypass draft, hypertension,
hypercholesterolemia, peripheral vascular disease, and diabetes
mellitus.

100 mg eluxadoline
IBS-3001

A 71-year-old female was hospitalized 79 days after her first dose

of 100 mg eluxadoline for acute exacerbation of bronchial asthma
which was associated with increasing use of beta agonists; ultimately
acute respiratory failure ensued. Additionally, she experienced a nonST myocardial infarction with positive cardiac enzymes. However,
due to normal coronary arteries and apical dyskinesia, the patient was
subsequently diagnosed with stress cardiomyopathy

IBS-3001

A 70-year-old female with a medical history significant for

hypertension, coronary artery disease since 2005, and hyperlipidemia
developed angina pectoris on five occasions while on 100 mg
eluxadoline over a period of 7 months; the first episode occurred
88 days after her first dose. Serial cardiac enzymes were always
negative; however, the patient was found to have significant
stenoses, resulting in four stents placed over a series of three separate
cardiac catheterizations.

10

Table S5. Selected Adverse Events Potentially Associated With Opiate Withdrawal or
Rebound, n (%).
Placebo

Eluxadoline 75 mg BID

Eluxadoline 100 mg BID

(n=426)

(n=426)

(n=424)

1 (0.2)

Abdominal pain upper

1 (0.2)

Abdominal tenderness

1 (0.2)

Diarrhea

1 (0.2)

1 (0.2)

Nausea

1 (0.2)

1 (0.2)

Stomach discomfort

1 (0.2)

1 (0.2)

IBS-3001
Abdominal pain

Vomiting
BID denotes twice daily.

Table S6. Selected Adverse Events Potentially Associated With Opiate Withdrawal or
Rebound, n (%).
Placebo

Eluxadoline 75 mg BID

Eluxadoline 100 mg BID

(n=381)

(n=377)

(n=379)

Abdominal pain upper

1 (0.3)

1 (0.3)

Abdominal tenderness

1 (0.3)

Diarrhea

1 (0.3)

Vomiting

1 (0.3)

Viral diarrhea

1 (0.3)

IBS-3002

BID denotes twice daily.

11

Table S7. Pain-free Days.

Pain-free Days (0 or 1 on Pain Scale)
Placebo

Weeks 1 to 12

Pain-free days

Pain-free days
SD (min, max)

Eluxadoline 100 mg

Mean

Median

Mean

Median

Mean

Median

16.5

14.4

2.0

20.4

17.5

2.0

21.2

18.2

3.0

SD (min, max)
Weeks 1 to 26

Eluxadoline 75 mg

21.8 (0, 83)

18.8

34.6

24.2 (0, 83)

4.0

49.8 (0, 181)

22.9

41.2
54.9 (0, 178)

25 (0, 82)
8.0

23.8

43.1

7.0

56.3 (0, 176)

Min denotes minimum, max maximum, and SD standard deviation.

12

Table S8. Numbers Needed to Treat / Numbers Needed to Harm.

AE Prompting
Discontinuation

Weeks 1 to 12

Weeks 1 to 26

NNT 75 mg*

10.5

13.9

NNH 75 mg*

25.2

NNT 100 mg*

9.7

8.7

NNH 100 mg*

23.3

* 75 mg and 100 mg doses refer to eluxadoline. AE denotes adverse event, NNT numbers needed to treat, and
NNH numbers needed to harm.

Table S9. Adverse Events in Patients With Prior Cholecystectomy.

AEs/SAEs by Prior Cholecystectomy, %
Placebo

Eluxadoline 75 mg BID

Eluxadoline 100 mg BID

AE patients with prior

cholecystectomy

77.2

72.1

71.6

SAE patients with prior

cholecystectomy

8.2

6.1

12.6

AE patients with no prior

cholecystectomy

50.5

57.2

54.6

SAE patients with no prior

cholecystectomy

1.7

3.7

2.7

AE denotes adverse event, and SAE serious adverse event.

13