Supplementary Appendix

Transcription

1 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: DOI: /NEJMoa

2 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; 2 Geisel School of Medicine at Dartmouth, Hanover, NH; 3 Texas Tech University Health Sciences Center, El Paso, TX; 4 School of Medicine, Temple University, Philadelphia, PA; 5 Furiex 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 Figure S2. Disposition of Patients Figure S3. Composite Responder Analysis of Eluxadoline Versus Placebo in Subpopulations Figure S4. Assessment of IBS-D Symptom Rebound SUPPLEMENTARY TABLES... 7 Table S1. Cochran Mantel Haenszel Analysis of Composite Responders by Interval (Intent-to-treat Analysis Set): IBS-3001, IBS-3002, and Pooled Phase 3 Studies Table S2. Pooled Secondary Efficacy Parameters (Weeks 1 to 12) Table S3. Secondary Efficacy Parameters Raw Scores (at Week 12).*... 9 Table S4. Major Adverse Cardiac Events Table S5. Selected Adverse Events Potentially Associated With Opiate Withdrawal or Rebound, n (%) Table S6. Selected Adverse Events Potentially Associated With Opiate Withdrawal or Rebound, n (%) Table S7. Pain-free Days Table S8. Numbers Needed to Treat / Numbers Needed to Harm Table S9. Adverse Events in Patients With Prior Cholecystectomy

3 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 Cochran Mantel Haenszel analysis of composite response were nearly identical to the main Cochran Mantel Haenszel 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. 2

4 SUPPLEMENTARY FIGURES Figure S1. Study Design. * Safety and quality of life evaluated after 26 weeks in IBS Safety, quality of life, and symptom rebound evaluated after 26 weeks in IBS Tx denotes treatment, and wks weeks. 3

5 Figure S2. Disposition of Patients. BID denotes twice daily, and wks weeks. 4

6 Figure S3. Composite Responder Analysis of Eluxadoline Versus Placebo in Subpopulations. BID denotes twice daily, CI confidence interval, and Wks weeks. 5

7 Figure S4. Assessment of IBS-D Symptom Rebound. BID denotes twice daily, and IBS-D irritable bowel syndrome with diarrhea. 6

8 SUPPLEMENTARY TABLES Table S1. Cochran Mantel Haenszel Analysis of Composite Responders by Interval (Intent-to-treat Analysis Set): IBS-3001, IBS-3002, and Pooled Phase 3 Studies. Interval Weeks Treatment* N IBS-3001 IBS-3002 Pooled Responder, No. (%) P Value N Responder, No. (%) P Value N Responder, No. (%) 1 to 4 Placebo (12.9) (12.0) (12.5) - P Value 75 mg (20.6) (25.2) < (22.8) < mg (22.5) < (26.7) < (24.5) < to 8 Placebo (19.9) (19.9) (19.9) - 75 mg (26.5) (31.5) < (28.8) < mg (28.9) (33.5) < (30.9) < to 12 Placebo (21.8) (22.0) (21.9) - 75 mg (23.7) (32.3) (27.7) mg (30.3) (31.9) (31.0) < to 16 Placebo (21.1) (20.9) (21.0) - 75 mg (22.7) (30.7) (26.5) mg (29.1) (33.8) < (31.4) < to 20 Placebo (21.8) (22.5) (22.1) - 75 mg (27.6) (31.2) (29.3) < mg (28.9) (31.2) (30.0) < to 24 Placebo (20.4) (19.9) (20.1) - 75 mg (27.4) (28.9) (28.1) < mg (28.2) (32.5) < (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. 7

9 Table S2. Pooled Secondary Efficacy Parameters (Weeks 1 to 12). Pooled* Placebo 75 mg 100 mg End Point (N = 809) (N = 808) P Value (N = 806) P Value Responder Analyses (Weeks 1 to 12) Abdominal pain 40% responder no. (%) 290 (35.8) 324 (40.1) (43.2) % responder no. (%) 243 (30.0) 280 (34.7) (36.0) 0.01 Urgency Minimum 50% urgency-free days < <0.001 Minimum 75% urgency-free days < <0.001 * 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. 8

10 Table S3. Secondary Efficacy Parameters Raw Scores (at Week 12).* End Point Raw Score Analyses (at Week 12) Abdominal pain Placebo (N = 427) 75 mg (N = 427) IBS-3001 IBS-3002 Pooled P Value 100 mg (N = 426) P Value Placebo (N = 382) 75 mg (N = 381) Mean 3.62± ± ± ± ± ± ± ± ±2.4 - CFB <0.001 Stool consistency Mean 4.97± ± ± ± ± ± ± ± ±1.3 - CFB < <0.001 Frequency Mean 3.44± ± ± ± ± ± ± ± ±2.1 - CFB <0.001 Bloating Mean 3.91± ± ± ± ± ± ± ± ±2.5 - CFB IBS-D global symptom score Mean 1.72± ± ± ± ± ± ± ± ±1.0 - CFB <0.001 IBS Quality of Life questionnaire score Mean 61.72± ± ± ± ± ± ± ± ± CFB < <0.001 * Plus minus 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. P Value 100 mg (N = 382) P Value Placebo (N = 809) 75 mg (N = 808) P Value 100 mg (N = 806) P Value 9

11 Table S4. Major Adverse Cardiac Events. Dose / Study Event Details Placebo IBS-3001 IBS-3002 IBS-3002 Acute hemiparesis possibly secondary to hypertension. Troponin-negative stent required. 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 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 non- ST myocardial infarction with positive cardiac enzymes. However, due to normal coronary arteries and apical dyskinesia, the patient was subsequently diagnosed with stress cardiomyopathy 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

12 Table S5. Selected Adverse Events Potentially Associated With Opiate Withdrawal or Rebound, n (%). Placebo Eluxadoline 75 mg BID Eluxadoline 100 mg BID IBS-3001 (n=426) (n=426) (n=424) Abdominal pain (0.2) Abdominal pain upper 1 (0.2) 0 0 Abdominal tenderness 0 1 (0.2) 0 Diarrhea 0 1 (0.2) 1 (0.2) Nausea 0 1 (0.2) 1 (0.2) Stomach discomfort 0 1 (0.2) 0 Vomiting 1 (0.2) 0 0 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 IBS-3002 (n=381) (n=377) (n=379) Abdominal pain upper 1 (0.3) 1 (0.3) 0 Abdominal tenderness 0 1 (0.3) 0 Diarrhea (0.3) Vomiting (0.3) Viral diarrhea (0.3) BID denotes twice daily. 11

13 Table S7. Pain-free Days. Pain-free Days (0 or 1 on Pain Scale) Placebo Eluxadoline 75 mg Eluxadoline 100 mg % Mean Median % Mean Median % Mean Median Weeks 1 to 12 Pain-free days SD (min, max) 21.8 (0, 83) 24.2 (0, 83) 25 (0, 82) Weeks 1 to 26 Pain-free days SD (min, max) 49.8 (0, 181) 54.9 (0, 178) 56.3 (0, 176) Min denotes minimum, max maximum, and SD standard deviation. 12

14 Table S8. Numbers Needed to Treat / Numbers Needed to Harm. Weeks 1 to 12 Weeks 1 to 26 AE Prompting Discontinuation NNT 75 mg* NNH 75 mg* 25.2 NNT 100 mg* 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 SAE patients with prior cholecystectomy AE patients with no prior cholecystectomy SAE patients with no prior cholecystectomy AE denotes adverse event, and SAE serious adverse event. 13