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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
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, quality of life, and symptom rebound evaluated after 26 weeks in IBS-3002.
Tx denotes treatment, and wks weeks.
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.
75 mg
(N = 809)
(N = 808)
P Value
(N = 806)
P Value
290 (35.8)
324 (40.1)
0.08
348 (43.2)
0.003
243 (30.0)
280 (34.7)
0.05
290 (36.0)
0.01
0.29
0.42
<0.001
0.42
<0.001
0.12
0.22
<0.001
0.21
<0.001
End Point
100 mg
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
* 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.
Event Details
Placebo
IBS-3001
IBS-3002
IBS-3002
75 mg eluxadoline
IBS-3001
100 mg eluxadoline
IBS-3001
IBS-3001
10
Table S5. Selected Adverse Events Potentially Associated With Opiate Withdrawal or
Rebound, n (%).
Placebo
Eluxadoline 75 mg BID
(n=426)
(n=426)
(n=424)
1 (0.2)
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
(n=381)
(n=377)
(n=379)
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
11
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
34.6
22.9
41.2
54.9 (0, 178)
25 (0, 82)
8.0
23.8
43.1
7.0
12
Weeks 1 to 12
Weeks 1 to 26
NNT 75 mg*
10.5
13.9
NNH 75 mg*
25.2
9.7
8.7
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.
Eluxadoline 75 mg BID
77.2
72.1
71.6
8.2
6.1
12.6
50.5
57.2
54.6
1.7
3.7
2.7
13