Conditions: Irritable Bowel Syndrome With Diarrhea
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 346
Healthy volunteers: no

Brief summary:
This study will evaluate the efficacy and safety of eluxadoline 100 milligrams (mg) twice a day (BID) versus placebo for the treatment of patients with Irritable Bowel Syndrome with Diarrhea (IBS-D) who report that the use of loperamide in the prior 12 months failed to provide control of their IBS-D symptoms.

Detailed description:

Arms:
arm 1: Eluxadoline 100 mg oral tablets twice daily (BID) with food for 12 weeks. arm 2: Placebo matching eluxadoline oral tablets BID with food for 12 weeks.

Interventions: intervention 1: Eluxadoline intervention 2: Placebo
Intervention descriptions: intervention 1: Eluxadoline 100 mg oral tablets BID with food. intervention 2: Placebo matching eluxadoline oral tablets BID with food.

Protocol document:
Prot_000.pdf: 
NCT02959983 
 
Study ID: CMO‐US‐GI‐0429 
 
Title: A Phase 4 Multicenter, Multinational, Prospective, Randomized, Placebo‐Controlled, Double‐
Blinded Parallel Group Study to Assess Efficacy of Eluxadoline in the Treatment of Irritable Bowel 
Syndrome with Diarrhea (IBS‐D) in Patients Who Report Inadequate Control of IBS‐D Symptoms with 
Prior Loperamide Use (RELIEF) 
 
 
Protocol Date: 12‐Aug‐2016 
 
 
 


CLINICAL STUDY PROTOCOL 
IND Number: 79,214 
A Phase 4 Multicenter, Multinational, Prospective, Randomized, 
Placebo-Controlled, Double-Blinded Parallel Group Study to Assess Efficacy of 
Eluxadoline in the Treatment of Irritable Bowel Syndrome with Diarrhea 
(IBS-D) in Patients Who Report Inadequate Control of IBS-D Symptoms with 
Prior Loperamide Use (RELIEF) 
PROTOCOL NUMBER: CMO-US-GI-0429 
Sponsor: 
Allergan  
Harborside Financial Center 
Plaza 5, Suite 1900 
Jersey City, NJ 07311, USA 
 
 
Sponsor Contact: 
 
 
 
 
 
  
Project Manager: 
 
 
 
 
 
 
Medical Safety Physician: 
 
 
 
Version of Protocol:  
1.0 (FINAL) 
Date of Protocol:  
12 August 2016 


CONFIDENTIAL  
All financial and nonfinancial support for this study will be provided by Allergan. The 
concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without the expressed, 
written consent of Allergan. 
The study will be conducted according to the International Council for Harmonisation 
harmonised tripartite guideline E6(R1): Good Clinical Practice. 
The following information can be found on US Food and Drug Administration Form 1572 
and/or study contacts page: Name and contact information of Allergan study personnel and 
Emergency Telephone Numbers; name, address, and statement of qualifications of each 
investigator; name of each subinvestigator working under the supervision of the investigator; 
name and address of the research facilities to be used; name and address of each reviewing 
Institutional Review Board; US Title 21 Code of Federal Regulations 312.23 section 6(iii)b. 






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Declaration of Investigator 
I have read and understood all sections of the protocol entitled “A Phase 4 Multicenter, 
Multinational, Prospective, Randomized, Placebo-Controlled, Double-Blinded Parallel Group 
Study to Assess Efficacy of Eluxadoline in the Treatment of Irritable Bowel Syndrome with 
Diarrhea (IBS-D) in Patients Who Report Inadequate Control of IBS-D Symptoms with Prior 
Loperamide Use (RELIEF)” and the accompanying eluxadoline Investigator’s Brochure (see 
Investigator’s Brochure signature page for version number and date). 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Final Protocol Version 1.0, dated 12 August 2016, the International 
Council for Harmonisation (ICH) harmonised tripartite guideline E6(R1): Good Clinical 
Practice (GCP), and all applicable government regulations. I will not make changes to the 
protocol before consulting with Allergan or implement protocol changes without Independent 
Ethics Committee (IEC) approval except to eliminate an immediate risk to patients. I agree to 
administer study treatment only to patients under my personal supervision or the supervision 
of a subinvestigator. 
I will not supply the investigational drug to any person not authorized to receive it. 
Confidentiality will be protected. Patient identity will not be disclosed to third parties or 
appear in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from Allergan. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Printed Name of Principal Investigator 
 
 
 
 


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Table of Contents 
Table of Contents ....................................................................................................................... 6 
List of Tables ............................................................................................................................ 10 
List of Figures .......................................................................................................................... 10 
Protocol Synopsis..................................................................................................................... 11 
List of Abbreviations................................................................................................................ 17 
1 
Introduction ...................................................................................................................... 19 
2 
Study Objectives ............................................................................................................... 22 
3 
Investigational Plan .......................................................................................................... 23 
3.1 
Study Design ........................................................................................................... 23 
3.1.1 
Rationale of Study Design ....................................................................... 25 
4 
Patient Selection and Withdrawal Criteria ....................................................................... 27 
4.1 
Selection of Study Population ................................................................................. 27 
4.1.1 
Inclusion Criteria ..................................................................................... 27 
4.1.2 
Exclusion Criteria .................................................................................... 29 
4.2 
Duration of Study .................................................................................................... 32 
4.2.1 
Withdrawal of Patients from the Study .................................................... 33 
4.2.2 
Handling of Withdrawals ......................................................................... 34 
4.2.3 
Replacements ........................................................................................... 34 
5 
Study Treatments .............................................................................................................. 35 
5.1 
Method of Assigning Patients to Treatment Groups ............................................... 35 
5.2 
Treatments Administered ........................................................................................ 35 
5.3 
Identity of Study Drug ............................................................................................ 36 
5.4 
Management of Clinical Supplies ........................................................................... 36 
5.4.1 
Study Drug Packaging and Storage ......................................................... 36 
5.4.2 
Test Article Accountability ...................................................................... 37 
5.4.3 
Other Supplies.......................................................................................... 37 
5.5 
Overdose Management ........................................................................................... 37 
5.5.1 
Treatment of Overdose ............................................................................ 37 
5.5.2 
Medication Errors .................................................................................... 38 


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5.5.3 
Treatment of Medication Errors ............................................................... 38 
5.6 
Blinding................................................................................................................... 38 
5.6.1 
Breaking the Blind ................................................................................... 38 
5.7 
Treatment Compliance ............................................................................................ 39 
5.8 
Prior and Concomitant Therapy .............................................................................. 39 
5.9 
Acute Loperamide Rescue Medication for Uncontrolled Diarrhea ........................ 40 
6 
Study Assessments and Procedures .................................................................................. 41 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2 
Efficacy Assessments .............................................................................................. 45 
6.2.1 
Daily IBS Symptoms ............................................................................... 45 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3.1 
Adverse Events ........................................................................................ 49 
6.3.1.1 
Definitions of Adverse Events ................................................................. 49 
6.3.1.2 
Serious Adverse Event: ............................................................................ 50 
6.3.1.3 
Reporting Adverse Events ....................................................................... 51 
6.3.1.4 
Reporting Serious Adverse Events .......................................................... 51 
6.3.1.5 
Assessment of Severity ............................................................................ 52 


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6.3.1.6 
Assessment of Causality .......................................................................... 52 
6.3.2 
Investigator Required Contact to Patient ................................................. 53 
6.3.2.1 
Investigator Required Contact to Patient for Diary-Confirmed 
Constipation ............................................................................................. 53 
6.3.2.2 
Investigator Required Contact to Patient for Frequent Use of Loperamide 
Rescue Medication ................................................................................... 53 
 
 
 
 
 
 
6.4 
Safety Monitoring Committee ................................................................................ 54 
6.5 
Pregnancy ................................................................................................................ 55 
6.6 
Laboratory Analyses ............................................................................................... 55 
6.7 
Sample Collections ................................................................................................. 56 
7 
Statistical and Analytical Plan .......................................................................................... 57 
7.1 
Primary Efficacy Endpoints .................................................................................... 57 
7.2 
Secondary Efficacy Endpoints ................................................................................ 57 
 
 
 
 
7.5 
Sample Size Calculations ........................................................................................ 60 
7.6 
Analysis Sets ........................................................................................................... 61 
7.7 
Statistical Analysis Methodology ........................................................................... 61 
7.7.1 
Analysis of Primary Efficacy Endpoint ................................................... 62 
7.7.2 
Analysis of Secondary Efficacy Endpoint ............................................... 62 
 
 
 
 
 
 
7.7.6 
Other Analyses ......................................................................................... 64 
7.7.7 
Interim Analyses ...................................................................................... 64 
7.8 
Handling of Missing Data ....................................................................................... 64 
7.9 
Data Quality Assurance........................................................................................... 64 
7.9.1 
Data Management .................................................................................... 64 
8 
Ethics ................................................................................................................................ 66 


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8.1 
Independent Ethics Committee or Institutional Review Board .............................. 66 
8.2 
Ethical Conduct of the Study .................................................................................. 66 
8.3 
Patient Information and Consent ............................................................................ 67 
9 
Investigator’s Obligations ................................................................................................ 68 
9.1 
Confidentiality ........................................................................................................ 68 
9.2 
Study Reporting Requirements ............................................................................... 68 
9.3 
Financial Disclosure and Obligations ..................................................................... 68 
9.4 
Investigator Documentation .................................................................................... 69 
9.5 
Study Conduct ......................................................................................................... 70 
9.6 
Adherence to Protocol............................................................................................. 70 
9.7 
Adverse Events and Study Report Requirements ................................................... 70 
9.8 
Investigator’s Final Report ..................................................................................... 70 
9.9 
Records Retention ................................................................................................... 70 
9.10 Publications ............................................................................................................. 71 
10 Study Management ........................................................................................................... 72 
10.1 Monitoring .............................................................................................................. 72 
10.1.1 
External Data Monitoring Committee ..................................................... 72 
10.1.2 
Monitoring of the Study ........................................................................... 72 
10.1.3 
Inspection of Records .............................................................................. 72 
10.2 Management of Protocol Amendments and Deviations.......................................... 73 
10.2.1 
Modification of the Protocol .................................................................... 73 
10.2.2 
Protocol Violations and Deviations ......................................................... 73 
10.3 Study Termination ................................................................................................... 74 
10.4 Final Report ............................................................................................................ 74 
11 Reference List................................................................................................................... 75 
12 Appendices ....................................................................................................................... 77 
 
 
12.3 Appendix: Bristol Stool Scale ................................................................................. 84 


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List of Tables 
 
 
 
 
List of Figures 
 
 


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Protocol Synopsis 
Protocol Number: CMO-US-GI-0429 
Title: 
A Phase 4 Multicenter, Multinational, Prospective, Randomized, 
Placebo-Controlled, Double-Blinded Parallel Group Study to Assess 
Efficacy of Eluxadoline in the Treatment of Irritable Bowel Syndrome 
with Diarrhea (IBS-D) in Patients Who Report Inadequate Control of 
IBS-D Symptoms with Prior Loperamide Use (RELIEF) 
Sponsor: 
Allergan 
Harborside Financial Center 
Plaza 5, Suite 1900 
Jersey City, NJ 07311, USA 
 
 
Study Phase: 
Phase 4 
Study Sites: 
The study will be conducted at approximately 75 sites in the United 
States, and approximately 10 sites in Canada. 
Indication: 
Treatment of patients with IBS-D. 
Rationale: 
In the Phase 3 studies that established the efficacy and safety of 
eluxadoline in the treatment of IBS-D, patients were prospectively 
asked about loperamide use in the prior 12 months for IBS-D and 
whether treatment with loperamide had adequately controlled their 
symptoms; 36% (N=873) of patients reported using loperamide in the 
prior 12 months for their IBS-D symptoms. Of these, approximately 
65% reported that use of loperamide failed to provide adequate control 
of their symptoms of IBS-D (N=538). Similar to the results in the 
overall intent-to-treat population, in patients who reported that 
loperamide did not provide adequate relief of their IBS-D symptoms, 
the proportion of composite responders was significantly greater in the 
eluxadoline treatment groups as compared with placebo (p < 0.05) for 
both eluxadoline 75 mg and 100 mg after 12 weeks of treatment. This 
prospective study is being conducted to further study the efficacy and 
safety of eluxadoline 100 mg twice daily (BID) in patients who 
self-report that loperamide failed to adequately control their IBS-D 
symptoms in the prior 12 months. 
The data from this study will enable Allergan to meet additional needs 
to understand the appropriate patient population for treatment of IBS-D 
symptoms with eluxadoline. 


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Objectives: 
The objectives of the study are: 
• To evaluate the efficacy of eluxadoline 100 mg BID versus placebo 
BID over 12 weeks of treatment in patients with IBS-D who report 
that use of loperamide in the prior 12 months failed to provide 
adequate control of their IBS-D symptoms. 
• To evaluate the safety and tolerability of eluxadoline 100 mg BID 
versus placebo BID over 12 weeks of treatment in patients with 
IBS-D who report that use of loperamide in the prior 12 months 
failed to provide adequate control of their IBS-D symptoms. 
 
Patient 
Population: 
Key Inclusion Criteria: 
• Patient is an adult aged 18 to 80 years (male or female), inclusive, 
at screening. 
• Patient has a diagnosis of IBS-D, defined by the Rome III criteria 
as loose (mushy) or watery stools ≥25% and hard or lumpy stools 
≤25% of bowel movements. 
•
 
 
• 
 
 
 
• Patient reports use of loperamide in the 12 months prior to 
screening for IBS-D symptoms and that loperamide did not provide 
adequate control of IBS-D symptoms. 
 
 
prior to randomization. Patients have 3 weeks to meet these criteria. 
• Patient has not used any loperamide rescue medication within 
14 days prior to randomization. 
Key Exclusion Criteria 
 
 
 
 
 
• Patient has a history or current evidence of laxative abuse within 
5 years prior to screening. 
• Patient has documented evidence of cirrhosis (Child-Pugh 
classification A, B, or C). 


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• 
 
 
. 
•
 
 
 
• Patient has used aspirin or aspirin-containing medications 
(>325 mg of aspirin per day) or nonsteroidal anti-inflammatory 
drugs, when taken specifically for the symptoms of IBS, within 
14 days of randomization. 
• Patient has surgical history of cholecystectomy or previously 
documented agenesis of gallbladder. 
• Patient has a history of cholecystitis within 6 months before 
Screening. 
• Patient has a history of pancreatitis or structural diseases of the 
pancreas, including known or suspected pancreatic duct 
obstruction. 
• Patient has a history of known or suspected biliary duct obstruction 
or sphincter of Oddi disease or dysfunction, excluding a history of 
gallstones. 
• Patient has a history of alcohol abuse, alcohol addiction, and 
alcoholism or drinks more than 3 alcoholic beverages per day. 
Study Design: 
This is a Phase 4, multicenter, multinational, randomized, double-blind, 
placebo-controlled, parallel group study to evaluate the efficacy, safety, 
and tolerability of eluxadoline 100 mg BID in patients with IBS-D who 
report that use of loperamide to treat their IBS-D symptoms in the prior 
12 months failed to adequately control their symptoms of IBS-D.  
Approximately 340 patients will be randomly assigned (in a 1:1 ratio) 
to 1 of 2 treatment groups: 
• Group 1: Eluxadoline 100 mg oral tablets BID with food 
• Group 2: Matching placebo oral tablets BID with food 
After screening procedures have been performed (up to 1 week), 
eligible patients will enter a pretreatment period of up to 3 weeks. At 
the beginning of the pretreatment period, patients will receive 
instructions for completing an ePRO diary to collect daily information 
related to their IBS-D symptoms and use of loperamide rescue 
medication. At the conclusion of the pretreatment period, patients who 
meet the study entry criteria related to ePRO diary compliance, stool 


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consistency (BSS), average WAP, and use of loperamide rescue 
medication will be randomized to a 12-week double-blind treatment 
period via central randomization. Patients randomized into the study 
will continue to record their IBS-D symptoms on a daily basis 
including WAP, stool consistency (BSS), abdominal discomfort, 
abdominal bloating, number of bowel movements, urgency, episodes of 
fecal incontinence, and use of loperamide rescue medication via an 
ePRO diary. A mandatory posttreatment visit will be performed 14 days 
after the last dose of study drug.  
Estimated Study 
Duration: 
The total duration of the study is up to 18 weeks, which includes a 
screening period (up to 1 week), pretreatment period (up to 3 weeks), 
12-week double-blind treatment period, and 2-week posttreatment 
follow-up period. A total of 7 study visits are planned for each patient: 
• Screening, week -4 (visit 1) 
• Pretreatment, week -3 to day 1 (visit 2) 
• Day 1 (visit 3; randomization and first administration of study 
drug) 
• Week 4 (visit 4) 
• Week 8 (visit 5) 
• Week 12 (visit 6; end of treatment) 
• Week 14 (visit 7; Posttreatment follow-up/exit) 
Efficacy 
Assessments: 
Daily IBS Symptoms: Patients will be required to access the ePRO 
diary each evening, preferably at the same time each day, to record 
their: stool consistency, WAP, abdominal discomfort, abdominal 
bloating, and information related to their bowel functioning (number of 
bowel movements, episodes of urgency and incontinence) over the past 
24 hours. 
 
 
 
Degree of Relief of IBS Symptoms: Patients will be asked to rate their 
overall degree of relief of IBS symptoms during the past 7 days 
compared with before they started this study on a weekly basis in the 
ePRO diary. 
 
 
 


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Safety 
Assessments: 
 
 
 
Study Drug, 
Dosage, and 
Route of 
Administration: 
Eluxadoline will be supplied as 100-mg, immediate release, film-coated 
(Opadry II) tablets. The excipients included in the formulation are 
microcrystalline cellulose, silicon dioxide, crospovidone, mannitol, and 
magnesium stearate. Placebo tablets of matching tablet image contain 
the same excipients. 
Eluxadoline 100 mg and placebo are taken orally BID with food. 
Sample Size: 
Assuming a placebo response for the primary efficacy endpoint 
(primary composite response in pain and stool consistency) of 13% and 
an approximate 14% treatment effect over placebo, a sample size of 
340 patients with 1:1 randomization ratio (eluxadoline: placebo, 
170 patients per arm) is required. This sample size will have 
approximately 90% power to detect the difference of the primary 
efficacy endpoint response proportion between eluxadoline and placebo 


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using a 2-sided chi-square test at significance level of 0.05. 
Statistical 
Methods: 
The comparison of proportion of primary composite responders in pain 
and stool consistency and the proportion in pain or stool consistency 
alone over 12 weeks between the eluxadoline and placebo groups will 
be performed using the chi-square test at a significance level of 0.05. 
Safety endpoint will be summarized descriptively. 
Date of Protocol: 
12 August 2016 
 


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List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BID 
twice daily 
BSS 
Bristol Stool Scale 
CFR 
Code of Federal Regulations 
CV 
curriculum vitae 
CDS-HRQOL-4 
Healthy Days Core Module 
δOR 
delta-opioid receptor 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ePRO 
electronic patient-reported outcome 
EQ-5D 
EuroQoL-5 Dimension 
FCS 
Fisher Clinical Services  
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HADS 
Hospital Anxiety and Depression Scale 
HEOR 
health economics and outcomes research 
IBS 
irritable bowel syndrome 
IBS-AR 
irritable bowel syndrome adequate relief 
IBS-D 
irritable bowel syndrome with diarrhea 
IBS-M 
irritable bowel syndrome with diarrhea and constipation (mixed) 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IxRS 
interactive response system 
κOR 
kappa-opioid receptor 
MedDRA 
Medical Dictionary for Regulatory Activities 


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Abbreviation 
Definition 
µOR 
mu-opioid receptor 
PI 
package insert 
SAE 
serious adverse event 
ULN 
upper limit of normal 
US 
United States 
WAP 
worst abdominal pain 
WPAI: IBS-D  
Work Productivity and Activity Impairment questionnaire: Irritable 
Bowel Syndrome with Diarrhea 


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1 
Introduction 
Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder characterized by 
symptoms of abdominal discomfort or pain associated with altered bowel habits 
(Drossman 2006). The 3 primary subtypes of IBS are characterized by predominant bowel 
habits: diarrhea (IBS-D), constipation (IBS-C), or mixed constipation and diarrhea (IBS-M). 
All forms of IBS have symptoms of abdominal pain or discomfort that may be linked to local 
reflexes within the bowel and visceral hypersensitivity (Drossman 2006). A recent 
meta-analysis of population-based studies yielded an international IBS prevalence of 11.2% 
(95% confidence interval, 9.8%–12.8%) in adults (≥15 years old). The prevalence varied 
according to country (from 1.1% to 45.0%), and was dependent on criteria used to define IBS 
(Lovell and Ford 2012). Irritable bowel syndrome is not life threatening but because of its 
chronic recurring course, often overlapping with other functional GI disorders, quality of life 
can be impaired. Irritable bowel syndrome is associated with high direct and indirect medical 
expenses (Thompson et al 1999). 
Pharmacologic options for treatment of IBS-D are limited. Alosetron, a selective serotonin 
5-HT3 receptor antagonist, is approved for severe IBS-D for female patients in the United 
States (US) (Talley 2003). The non-systemic antibiotic rifaximin was approved by US Food 
and Drug Administration (FDA) in May 2015 for treatment of IBS-D, and although effective 
in some patients, has shown high rates of symptom recurrence (Xifaxan® package insert [PI] 
2015). Loperamide, a peripherally restricted mu-opioid receptor (µOR) agonist, is widely 
used as an antidiarrheal, both over-the-counter and via prescription; however, loperamide is 
not indicated for chronic use, can result in constipation, and has not been shown to 
effectively treat the abdominal pain of IBS-D (Efskind et al 1996, Talley 2003, Loperamide 
PI 2015). Thus, there is a need for new agents with favorable safety and tolerability profiles 
that are effective in providing sustained relief of IBS-D. 
Eluxadoline is a locally active mixed µOR agonist, kappa-opioid receptor (κOR) agonist, and 
delta-opioid receptor (δOR) antagonist approved by FDA on 27 May 2015 for the treatment 
of IBS-D. Eluxadoline has GI transit-inhibiting activity that is consistent with its primary 
pharmacological profile as a µOR agonist. The additional δOR antagonist activity may 
mitigate against the constipating effects of unopposed peripherally acting µOR agonists (e.g., 
loperamide or diphenoxylate).  


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Eluxadoline was generally well tolerated in single- and multiple-dose animal studies. Across 
the Phase 1 studies and Phase 2 study, eluxadoline demonstrated an acceptable safety profile 
marked by the infrequent incidence of adverse events (AEs) (Eluxadoline Investigator’s 
Brochure). 
Efficacy and safety in IBS-D patients was demonstrated in 2 randomized, multicenter, 
multi-national, double-blind, placebo-controlled Phase 3 studies in a total of 2426 patients 
(studies IBS-3001 and IBS-3002; Lembo et al 2016 and VIBERZI™ PI 2015). The primary 
endpoint of the Phase 3 trials was defined by the simultaneous improvement in the daily 
worst abdominal pain (WAP) score by ≥30% compared with baseline weekly average and a 
reduction in the Bristol Stool Scale (BSS) to <5 on at least 50% of days within a 12-week 
treatment period (FDA endpoint) and a 26-week treatment period (European Medicines 
Agency endpoint). Eluxadoline 100 mg twice daily (BID) demonstrated significantly greater 
composite responder rates as compared with placebo over 12 weeks and 26 weeks of 
treatment. Eluxadoline 75 mg BID demonstrated significantly greater responder rates than 
placebo over 12 weeks in both studies, and greater responder rates than placebo over 
26 weeks of treatment in study IBS-3002, but not in study IBS-3001 (Lembo et al 2016, 
VIBERZI PI 2015). The treatment effect of eluxadoline over placebo was observed within 
the first week and was maintained throughout the 26-week assessment period. Based on 
efficacy of both eluxadoline 75 mg and 100 mg at 12 weeks of treatment, both doses were 
approved by FDA for treatment of adults with IBS-D.  
Other abdominal symptoms and measures of bowel function were also significantly 
improved with eluxadoline treatment as compared with placebo. Longitudinal analyses 
demonstrated that daily abdominal discomfort scores were significantly lower than placebo 
for both the 75-mg and 100-mg eluxadoline groups through week 26. Daily bloating scores 
were significantly lower than placebo with eluxadoline 100 mg after week 12 (weeks 16, 20, 
24, and 26). Risks for frequency of bowel movements and urgency episodes were also 
significantly lower than placebo for both eluxadoline doses through week 26 of treatment. 
Additionally, both doses of eluxadoline were significantly superior to placebo with respect to 
the endpoints of adequate relief of IBS symptoms, scores for global symptoms, and scores on 
the IBS-Quality of Life questionnaire. Eluxadoline was significantly superior to placebo in 
all subpopulations explored (Lembo et al 2016). 


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Overall, the clinical experience suggests that eluxadoline is a promising treatment for the 
symptoms of IBS-D, providing clinically important improvements in both abdominal pain 
and diarrhea. 


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2 
Study Objectives 
The objectives of this study are: 
• To evaluate the efficacy of eluxadoline 100 mg BID versus placebo BID over 12 weeks 
of treatment in patients with IBS-D who report that use of loperamide in the prior 
12 months failed to provide adequate control of their IBS-D symptoms. 
• To evaluate the safety and tolerability of eluxadoline 100 mg BID versus placebo BID 
over 12 weeks of treatment in patients with IBS-D who report that use of loperamide in 
the prior 12 months failed to provide adequate control of their IBS-D symptoms. 


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3 
Investigational Plan 
3.1 
Study Design 
This is a Phase 4, multicenter, multinational, randomized, double-blind, placebo-controlled, 
parallel group study to evaluate the efficacy, safety, and tolerability of eluxadoline 100 mg 
BID in patients with IBS-D who report that use of loperamide to treat their IBS-D symptoms 
in the prior 12 months failed to adequately control their symptoms of IBS-D. 
Approximately 340 patients will be randomly assigned (in a 1:1 ratio) to 1 of 2 treatment 
groups: 
• Group 1: eluxadoline 100 mg oral tablets BID with food 
• Group 2: matching placebo oral tablets BID with food 
After screening procedures have been performed (up to 1 week), eligible patients will enter a 
Pretreatment period of up to 3 weeks. At the beginning of the pretreatment period, patients 
will receive instructions for completing an electronic patient-reported outcome (ePRO) diary 
to collect daily information related to their IBS-D symptoms and use of loperamide rescue 
medication. At the conclusion of the pretreatment period, patients who meet the study entry 
criteria related to ePRO diary compliance, stool consistency (BSS), average WAP, and use of 
loperamide rescue medication (refer to Section 4.1.1 for details) will be randomized to a 
12-week double-blind treatment period via central randomization. 
Patients randomized into the study will return to the clinic for study visits at week 4, week 8, 
week 12 (end-of-treatment study visit), and for a posttreatment follow-up study visit at 
week 14. A complete schedule of events is provided in Appendix 12.1, Table 12–1 and 
Table 12–2. Patients who discontinue from the study before the week 12 visit should return to 
the study site to complete the early withdrawal assessments as soon as possible after stopping 
the study drug. 
During the double-blind Treatment period, patients will record via the ePRO diary their daily 
IBS-D symptoms including stool consistency (BSS), WAP, abdominal discomfort, abdominal 
bloating, bowel movement frequency, number of episodes of urgency in a day, if any, number 
of episodes of fecal incontinence, and use of loperamide rescue medication. 


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The actual ePRO data entered by the patients will not be provided to the investigative site 
staff at the time of randomization or during the study to prevent any potential bias in 
subsequent patient entries. However, periodic notifications will be generated to inform the 
investigator of patients’ ongoing compliance with ePRO diary entries and to alert 
investigators if patients have experienced episodes of constipation or have required excessive 
loperamide rescue medication for acute treatment of uncontrolled diarrhea. 


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3.1.1 
Rationale of Study Design  
In the Phase 3 studies that established the efficacy and safety of eluxadoline in the treatment 
of IBS-D, patients were prospectively asked about loperamide use in the prior 12 months for 
IBS-D and whether treatment with loperamide had adequately controlled their symptoms; 
36% (N=872) of patients reported using loperamide in the prior 12 months for their IBS-D 
symptoms. Of these, approximately 65% reported that use of loperamide failed to provide 
adequate control of their IBS-D symptoms (N=538). Similar to the results in the overall 
intent-to-treat (ITT) population, in patients who reported that loperamide did not provide 
adequate relief of IBS-D symptoms, the proportion of composite responders was significantly 
greater in the eluxadoline treatment groups as compared with placebo (p < 0.05) for both 
eluxadoline 75 mg and 100 mg after 12 weeks of treatment. This prospective study is being 
conducted to further study the efficacy and safety of eluxadoline 100 mg BID in patients who 
self-report that loperamide failed to adequately control their IBS-D symptoms in the prior 
12 months.  
To be included in the trial, patients must have an average daily stool consistency score (BSS) 
of ≥5.5 and at least 5 days with a BSS score ≥5 on a 1-7 scale over the week prior to 
randomization and an average WAP score in the past 24 hours of >3.0 on a 0 to 10 scale over 
the week prior to randomization. Patients must report that use of loperamide in the 12 months 
to treat IBS symptoms prior to screening had failed to provide adequate control of their 
IBS-D symptoms. Additionally patients must have completed the ePRO diary on at least 5 of 
the 7 days during the week prior to randomization AND at least 10 of 14 days during the 
2 weeks prior to randomization. The patient population under study is considered as 
appropriate for achieving the study objectives. 
The screening and pretreatment periods permit evaluation of inclusion and exclusion criteria 
data (e.g., laboratory assessments, physical examination) and enables confirmation of 
eligibility of patients for inclusion in the study. Patients will be randomized to 1 of 2 
treatment groups (eluxadoline 100 mg or matching placebo BID with food). In order to 
ensure patient safety, a mandatory posttreatment visit will be performed 14 days after the last 
dose of study drug. Any ongoing AEs at the posttreatment visit must be followed until 
resolution, until the AE stabilizes, until it is determined to be non-clinically significant, or 
until the patient is lost to follow-up. 


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The 100-mg BID dose of eluxadoline to be administered in the present study is a marketed 
dose in the US and was shown to be generally well tolerated in prior studies with no evidence 
of a need for drug titration. Therefore, a fixed-dose design will be employed in this study. 
The placebo-control group has been included to establish the efficacy and safety of 
eluxadoline in this subset of patients. 
The treatment duration of 12 weeks has been chosen because this is considered an acceptable 
period to demonstrate efficacy and safety in this patient population. 
The data from this study will enable the sponsor to meet additional needs to understand the 
appropriate patient population for treatment of IBS-D symptoms with eluxadoline. 


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4 
Patient Selection and Withdrawal Criteria 
4.1 
Selection of Study Population 
Approximately 340 patients will be enrolled at approximately 75 sites in the US and 
approximately10 sites in Canada. Patients will be assigned to study treatment only if they 
meet all of the inclusion criteria and none of the exclusion criteria. 
Deviations from the inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability, or patient 
safety. Therefore, adherence to the criteria as specified in the protocol is essential. 
4.1.1 
Inclusion Criteria 
To be eligible for enrollment in this study, each of the following criteria must be satisfied 
with a “YES” answer (unless not applicable): 
1. Patient is an adult aged 18 to 80 years (male or female), inclusive, at Screening. 
2. Patient has a diagnosis of IBS-D, defined by the Rome III criteria as loose (mushy) or 
watery stools ≥25% and hard or lumpy stools ≤25% of bowel movements. 
3. Patient has had a colonoscopy performed within 5 years prior to Screening if they are 
at least 50 years of age, OR if they meet any of the following alarm features: 
a) 
Patient has documented weight loss within the past 6 months; or 
b) 
Patient has nocturnal symptoms; or 
c) 
Patient has a familial history of colon cancer; or 
d) 
Patient has blood mixed with their stool (excluding any blood from 
hemorrhoids) 
 
 


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. 
6. Patient reports use of loperamide in the 12 months prior to Screening for IBS-D 
symptoms and that loperamide did not provide adequate control of IBS-D symptoms.  
 
 
 
 
 
 
9. Patient has not used any loperamide rescue medication within 14 days prior to 
randomization. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.1.2 
Exclusion Criteria 
To be eligible for this study, each of the following criteria must be satisfied with a “NO” 
answer: 
1. Patient has a diagnosis of IBS with a subtype of constipation IBS, mixed IBS, or 
unsubtyped IBS by the Rome III criteria (refer to Appendix 12.2 for details). 
2. Patient has a history of inflammatory or immune-mediated GI disorders including 
inflammatory bowel disease (i.e., Crohn’s disease, ulcerative colitis), microscopic 
colitis, or celiac disease. 
3. Patient has a history of diverticulitis within 3 months prior to screening. 
4. Patient has a documented history of lactose intolerance. 
5. Patient has a documented history of bile-acid malabsorption. 
6. Patient has a history of chronic or severe constipation or intestinal obstruction, 
stricture, toxic megacolon, GI perforation, fecal impaction, gastric banding, bariatric 
surgery, adhesions, ischemic colitis, or impaired intestinal circulation (e.g., aortoiliac 
disease). 
7. Patient has any of the following surgical history: 


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a) 
Cholecystectomy or previously documented agenesis of gallbladder; or  
b) 
Any abdominal surgery within the 3 months prior to screening; or 
c) 
Major gastric, hepatic, pancreatic, or intestinal surgery (appendectomy, 
hemorrhoidectomy, or polypectomy greater than 3 months post-surgery are 
allowed). 
Note: For the purposes of this study, laparoscopic surgeries without 
complication are considered minor and non-exclusionary, provided the 
condition for which the surgery was performed was not exclusionary. 
8. Patient has a history of cholecystitis within 6 months before screening. 
9. Patient has a history of pancreatitis or structural diseases of the pancreas, including 
known or suspected pancreatic duct obstruction. 
10. Patient has a history of known or suspected biliary duct obstruction or sphincter of 
Oddi disease or dysfunction, excluding a history of gallstones. 
 
 
12. Patient has a history or current evidence of laxative abuse within 5 years prior to 
screening. 
13. Patient has documented evidence of cirrhosis (Child-Pugh classification A, B, or C). 
 
 
 
15. Patient has a history of cardiovascular events, including stroke, myocardial infarction, 
congestive heart failure, or transient ischemic attack within 6 months prior to 
screening. 
16. Patient has an unstable renal, hepatic, metabolic, or hematologic condition. 
17. Patient has a history of malignancy within 5 years before screening (except squamous 
and basal cell carcinomas and cervical carcinoma in situ). 


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18. Patient has a history of human immunodeficiency virus infection. 
19. Patient has a history of Diagnostic and Statistical Manual of Mental Disorders, 4th 
Edition, Text Revision-defined substance dependency, excluding nicotine and caffeine, 
within 2 years prior to screening. 
20. Patient has a history of alcohol abuse, alcohol addiction, and alcoholism or drinks 
more than 3 alcoholic beverages per day. 
 
 
 
 
 
 
 
 
 
25. Patient has used aspirin or aspirin-containing medications (>325 mg of aspirin per 
day) or nonsteroidal anti-inflammatory drugs, when taken specifically for the 
symptoms of IBS, within 14 days of randomization. 
26. Patient has current (within 14 days of randomization) or expected use of any narcotic 
or opioid-containing agents, tramadol, docusate, enemas, GI preparations (including 
antacids containing aluminum or magnesium, antidiarrheal agents [except loperamide 
rescue medication after randomization]), antinausea agents, antispasmodic agents, 
bismuth, or prokinetic agents. 


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27. Patient has current (within 28 days of randomization) use of rifaximin or other 
antibiotics (with the exception of topical antibiotics or a 1-day course with an 
antibiotic). Expected use of rifaximin or other antibiotics during the course of the 
study that is known at the time of randomization (e.g., for planned elective surgery) is 
also prohibited. However, a patient will be allowed to remain in the study should 
unplanned used of antibiotics other than rifaximin occur after the patient has been 
randomly assigned to study drug. 
 
 
 
 
 
 
31. Patient has an elective surgery planned or expects to need elective surgery at any time 
during the study. An elective procedure scheduled after the patient has been randomly 
assigned to study drug will not be considered a protocol violation. 
 
 
 
 
 
 
 
4.2 
Duration of Study 
The duration of the study is defined for each patient as the date signed written informed 
consent is provided through the posttreatment visit (visit 7) on day 126. 


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4.2.1 
Withdrawal of Patients from the Study 
All patients have the right to withdraw from the study at any time, for any reason, without 
prejudice. At any point, the investigator may discontinue the patient’s study participation at 
his/her discretion and ensure the patient receives appropriate medical care; the investigator 
may also consult the medical monitor to discuss out-of-range test results. The patient may 
also be withdrawn or terminated at the request of the sponsor. Additionally, although Allergan 
has every intention of completing the study, Allergan reserves the right to discontinue the 
study at any time for clinical or administrative reasons.  
As part of the clinical laboratory assessments, liver enzymes (ALT, AST, alkaline 
phosphatase), and total bilirubin values will be evaluated for all patients. In the event that a 
patient’s bilirubin level is elevated after the first dose of study drug, a fractionated bilirubin 
test should be performed if possible. In general, an increase in serum aminotransferases to 
greater than 3 times ULN after the first dose in patients who entered the study with normal 
baseline values should be followed by repeat testing within 48 to 72 hours of all 4 of the 
usual serum measures (ALT, AST, alkaline phosphatase, and total bilirubin) to confirm the 
abnormalities and to determine if they are increasing or decreasing. There also should be an 
inquiry made about symptoms. Patients should be observed for other possible causes of 
elevated liver function test results including acute viral hepatitis, alcoholic and autoimmune 
hepatitis, hepatobiliary disorders, nonalcoholic steatohepatitis, cardiovascular causes, or 
concomitant treatments. If baseline transaminases are found to be elevated above the ULN, 
the preceding guidance should be considered in patients who double their baseline value(s). 
If the repeat value for ALT or total bilirubin is unchanged or indicates decreasing activity, 
monitoring should continue at weekly intervals until the results are acceptable or normalized. 
If any value has increased further, immediate close observation is required. If close 
monitoring is not possible, the drug should be discontinued. 
Withdrawal from the study should be considered if any of the following occurs: 
• ALT or AST >8 × the ULN 
• ALT or AST >5 × ULN for more than 2 weeks 
• ALT or AST >3 × ULN and (total bilirubin >2 × ULN or international normalized ratio 
>1.5) 


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• ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
For complete information regarding withdrawal from the study in the event of a marked 
elevation of liver enzymes, refer to Pages 9-10 of Guidance for Industry – Drug-Induced 
Liver Injury: Premarketing Clinical Evaluation (US Department of health and Human 
Services 2009). 
4.2.2 
Handling of Withdrawals 
Patients who discontinue study treatment or active participation in the study will no longer 
receive study drug.  
When a patient withdraws from the study, the reason(s) for withdrawal shall be recorded by 
the investigator on the relevant page of the electronic case report form (eCRF). Whenever 
possible, for all patients who discontinue study treatment or withdraw from the study 
prematurely will undergo all end-of-treatment/early withdrawal visit assessments. Patients 
who fail to return for final assessments will be contacted by the site in an attempt to have 
them comply with the protocol. For patients that are considered to be lost to follow-up, the 
site should make every attempt possible to contact the patient (e.g., via documented phone 
call attempts and if necessary, a certified letter to the patient). 
It is vital to obtain follow-up data on any patient withdrawn because of an AE or serious AE 
(SAE). In every case, efforts must be made to undertake protocol-specified safety follow-up 
procedures until resolution or stabilization. 
4.2.3 
Replacements 
Patients who discontinue participation in the study for any reason after randomization will 
not be replaced. 


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5 
Study Treatments 
5.1 
Method of Assigning Patients to Treatment Groups 
Approximately 340 patients will be randomly assigned (in a 1:1 ratio) to 1 of 2 treatment 
groups (eluxadoline 100 mg BID or matching placebo).  
The randomization schedule will be sequestered until the study is unblinded after database 
lock. It will also use an appropriate block size, which will not be revealed to the study sites. 
The randomization mechanism for the study will be deployed within an interactive response 
system (IxRS) and accessible 24 hours a day to authorized users. Study sites will access the 
IxRS to execute each randomization after a patient has met all prerequisites for 
randomization and has completed all scheduled procedures for day 1. Study site personnel, 
who are all blinded to treatment assignment, will receive a randomization notification 
indicating only the unique patient identifier and the date and time of randomization for each 
patient.  
All patients will be assigned a unique patient number by the randomization system. After a 
patient number has been assigned, the number will not be reused even if the patient 
withdraws before receiving any study drug. 
5.2 
Treatments Administered 
Patients will be randomly assigned to 1 of 2 treatment groups as follows: 
• Group 1: Eluxadoline 100 mg oral tablets BID with food 
• Group 2: Matching placebo oral tablets BID with food 
The study drug must be swallowed whole with liquid and not chewed, divided, dissolved, or 
crushed. 
In addition, patients will receive instructions for use of loperamide rescue medication for 
acute treatment of uncontrolled diarrhea (refer to Section 5.9 for details). 


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5.3 
Identity of Study Drug 
Eluxadoline will be supplied as 100-mg, immediate release, film-coated (Opadry II) tablets. 
The excipients included in the formulation are microcrystalline cellulose, silicon dioxide, 
crospovidone, mannitol, and magnesium stearate. Placebo tablets of matching tablet image 
contain the same excipients. 
, on behalf of the 
sponsor, will provide adequate supplies of eluxadoline and matching placebo tablets of 
identical size and shape to study sites. 
The following drug supplies will be used in the study:  
Product 
Supplied as: 
Eluxadoline 
100-mg tablets 
Placebo 
100-mg tablets 
 
Patients in each treatment group will receive a bottle containing 4-weeks’ worth of study 
drug at randomization (visit 3), week 4 (visit 4), and week 8 (visit 5). Patients will be 
instructed to take 1 tablet BID with food. 
5.4 
Management of Clinical Supplies 
5.4.1 
Study Drug Packaging and Storage 
The study drug will be packaged and labeled according to current Good Manufacturing 
Practices and local regulations. 
The study drug will be packaged in child-resistant 70-count bottles by 
 on 
behalf of the sponsor. The bottles will be labeled with double-blinded labels.  
Each bottle will contain a (randomized) dosage for 1 patient for 4 weeks of the 12-week 
double-blind treatment period and will be distributed at each of the scheduled visits during 
the treatment period: randomization (visit 3), week 4 (visit 4), and week 8 (visit 5). 
Recommended storage conditions for study drug are as per the commercial product. The 
study drug will be stored in controlled temperatures ranging from 
 
 
The storage conditions will be indicated on the label. Expiry dates will 


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be provided directly on the label or communicated to the sites with an expiry memo and/or 
managed electronically if drug distribution for the study is managed by IxRS. 
5.4.2 
Test Article Accountability 
The investigator will maintain accurate records of receipt of all test articles, including dates 
of receipt. In addition, accurate records will be kept regarding when and how much test 
article is dispensed and used by each patient in the study. Reasons for departure from the 
expected dispensing regimen must also be recorded. At the completion of the study, to satisfy 
regulatory requirements regarding drug accountability, all study drugs will be reconciled and 
retained or destroyed according to applicable regulations. 
5.4.3 
Other Supplies 
Patients will be provided with instructions on how to enter their diary data into the ePRO. 
Laboratory kits for assessments will be provided to the sites centrally. 
5.5 
Overdose Management 
An overdose is any dose of study treatment given to a patient or taken by a patient that 
exceeds the dose described in the protocol. Any overdose, with or without associated AEs, 
must be promptly reported to the medical monitor. Overdoses without signs or symptoms do 
not need to be recorded as AEs; in case of any AEs associated with the overdose, these 
should be reported on relevant AE/SAE sections in the eCRF. 
5.5.1 
Treatment of Overdose 
No reports of overdosage with eluxadoline have been reported. 
In the event of acute overdose, the stomach should be emptied and adequate hydration 
maintained. The patient should be carefully observed and given standard supportive 
treatment as required. Given eluxadoline’s action at opioid receptors, administration of a 
narcotic mu-opioid antagonist, such as naloxone, should be considered. Considering the short 
half-life of naloxone, repeated administration may be necessary. In the event of naloxone 
administration, patients should be monitored closely for the return of overdose symptoms, 
which may indicate need for repeated naloxone injection (VIBERZI PI 2015). 


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5.5.2 
Medication Errors 
Dispensing study treatment to be taken by patients in an outpatient study increases risk for 
medication errors. All errors in medication dispensing or administration must be carefully 
documented. These errors may include but are not limited to providing the wrong dose, 
losing medication, or administration at the wrong time of day. Medication adherence will be 
emphasized at every study visit. Additional adherence procedures and/or technology, such as 
a mobile device application, may be implemented. 
5.5.3 
Treatment of Medication Errors 
The treatment of medication errors should be discussed with the medical monitor on a case 
by case basis. In the case of overdose, refer to Section 5.5.1. 
5.6 
Blinding 
Patients will be randomly assigned to double-blind treatment of eluxadoline at a dose of 
100 mg BID or placebo BID. Blinding of the placebo tablets and eluxadoline tablets will be 
maintained throughout the study by using active and placebo tablets that are identical in 
appearance. The randomization schedules and treatment assignments will remain sequestered 
until the study blind is broken. 
5.6.1 
Breaking the Blind 
When necessary for the safety and proper treatment of the patient, the investigator can 
unblind the patient’s treatment assignment to determine which treatment has been assigned 
and institute appropriate follow-up care. When possible, the sponsor (Allergan Medical 
Safety Physician) should be notified prior to unblinding study drug. The investigator should 
inform the sponsor (Allergan Medical Safety Physician) of the unblinding if there is no 
notification prior to the unblinding. 
The treatment assignment for the patient can be determined by designated site personnel in 
the IxRS system via password protected access. The reason for breaking the code must be 
recorded in the patient’s source documents. 


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5.7 
Treatment Compliance 
Treatment compliance will be assessed at the study site by pill counts. This review will be 
documented in the source documents. 
5.8 
Prior and Concomitant Therapy  
All prescription drugs, herbal products, vitamins, minerals, and over-the-counter medications 
taken within 2 weeks prior to randomization will be recorded as prior medications. All 
medications taken after randomization and through the early termination or follow-up visit 
will be recorded as concomitant therapy. Use of all concomitant medications will be recorded 
in the patient’s eCRF. Any changes in concomitant medications will also be recorded in the 
patient’s eCRF. The minimum requirement is that drug name and the dates of administration 
are to be recorded. It will also be determined which prior medications were prescribed or 
taken over-the-counter by patients for the treatment of IBS-D. 
The following medications are prohibited before and during the study, as indicated: 
• 5-HT3 antagonists (e.g., alosetron or ondansetron); prohibition begins within 14 days of 
screening. 
• Aspirin or aspirin-containing medications (>325 mg of aspirin per day) or nonsteroidal 
anti-inflammatory drugs, when taken specifically for the symptoms of IBS; prohibition 
begins within 14 days of randomization. 
• Investigational drug or investigational medical device within 30 days prior to 
randomization. 
• Narcotics or opioid-containing agents, tramadol, docusate, enemas, or GI preparations 
(including antacids containing aluminum or magnesium, antidiarrheal agents [except 
loperamide rescue medication after randomization], antinausea agents, antispasmodic 
agents, bismuth, or prokinetic agents); prohibition begins within 14 days of 
randomization. 
• Rifaximin or other antibiotics (with the exception of topical antibiotics or a 1-day course 
with an antibiotic); prohibition begins within 28 days of randomization (see exclusion 
criteria number 27 for details). 


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Stable doses of antidepressants (i.e., for the 3 months prior to screening) can be taken during 
the study. Additionally, medications taken for the treatment of allergies, chronic medical 
conditions, and migraine headaches can be taken during this study (with the exception of 
opioids for acute treatment of migraines). Patients must be on a stable dose of medication for 
chronic migraines or preventive therapy for at least 1 month at screening. As-needed use of 
benzodiazepines for anxiety is permitted during the study. 
Any concomitant medication deemed necessary for the welfare of the patient during the 
study may be given at the discretion of the investigator. However, it is the responsibility of 
the investigator to ensure that details regarding the medication are recorded in full in the 
source documents as well as in the eCRF. 
5.9 
Acute Loperamide Rescue Medication for Uncontrolled Diarrhea 
Use of loperamide rescue medication for the acute treatment of uncontrolled diarrhea will not 
be allowed within 14 days prior to randomization. 
During the double-blind Treatment period and the Posttreatment period of the study, patients 
will be allowed to take loperamide rescue medication for the acute treatment of uncontrolled 
diarrhea. Loperamide at a unit dose of 2 mg may be taken once approximately every 6 hours 
with the following guidelines: 
• No more than 4 unit doses over a continuous 24-hour time period (8 mg/day) 
• No more than 7 unit doses over a continuous 48-hour time period (14 mg over 2 days) 
• No more than 11 unit doses over a continuous 7-day time period 
The use of loperamide rescue medication should be recorded by the patient in the ePRO 
diary. If a patient uses more than the allowed amount of loperamide rescue medication the 
ePRO system will generate a notification to alert the investigator. Excessive use of 
loperamide rescue medication may be cause for study discontinuation but will not be 
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6 
Study Assessments and Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.2 
Efficacy Assessments  
6.2.1 
Daily IBS Symptoms  
Patients will be required to access the ePRO diary each evening, preferably at the same time 
each day, to record daily IBS symptoms:  
• Stool Consistency: During their daily ePRO entry throughout the 12 weeks of 
double-blind treatment period, patients will be asked to rate the BSS most representative 
of the past 24 hours. The patient-reported BSS is a 1 to 7 scale where 1 corresponds to a 
hard stool and 7 corresponds to watery stool (Appendix 12.3): 
1=Separate hard lumps like nuts (difficult to pass) 
2=Sausage shaped but lumpy 
3=Like a sausage but with cracks on surface 
4=Like a sausage or snake, smooth and soft 


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5=Soft blobs with clear-cut edges (passed easily) 
6=Fluffy pieces with ragged edges, a mushy stool 
7=Watery, no solid pieces (entirely liquid)  
• Worst Abdominal Pain: During their daily ePRO entry throughout the 12 weeks of 
double-blind treatment period, patients will be asked to rate their WAP in the past 
24 hours. The patient-reported WAP in the past 24 hours will be recorded on a 0 to 10 
scale, where 0 corresponds to no pain and 10 corresponds to worst imaginable pain. 
• Abdominal Discomfort: During their daily ePRO entry throughout the 12 weeks of 
double-blind treatment period, patients will be asked to rate their abdominal discomfort 
in the past 24 hours. The patient-reported worst abdominal discomfort in the past 
24 hours will be recorded on a 0 to 10 scale, where 0 corresponds to no discomfort and 
10 corresponds to worst imaginable discomfort. 
• Abdominal Bloating: During their daily ePRO entry throughout the 12 weeks of 
double blind treatment period, patients will be asked to rate their abdominal bloating in 
the past 24 hours. The patient-reported worst abdominal bloating in the past 24 hours will 
be recorded on a 0 to 10 scale, where 0 corresponds to no bloating and 10 corresponds to 
worst imaginable bloating. 
• Frequency, Urgency and Incontinence: During their daily ePRO entry throughout the 
12 weeks of double-blind treatment period, patients will be asked to record the number of 
bowel movements (and characteristics, where applicable), number of urgency episodes, 
and number of episodes of fecal incontinence, over the past 24 hours. 
 
  
 
 
 


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. 
6.3.1 
Adverse Events 
Adverse events occurring during the study will be recorded in an AE eCRF. If AEs occur, the 
first concern will be the safety of the study participants. 
6.3.1.1 
Definitions of Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. In addition, during the screening period, AEs will be assessed 
regardless of the administration of a pharmaceutical product. 
Note: Adverse events must be collected once informed consent has been obtained, regardless 
of whether or not the patient has been administered study drug. Progression of treatment 


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indication including new or worsening of anticipated clinical signs or symptoms, which are 
collected as clinical efficacy variables and assessed as unequivocally associated with the 
disease progression and/or lack of efficacy, should NOT be reported as AEs unless the 
disease progression is greater than anticipated in the natural course of the disease. 
Adverse events will be assessed, documented, and recorded in the eCRF throughout the study 
(i.e., after informed consent has been obtained). At each visit, after the study assessments 
have been completed, the investigator will begin by querying for AEs by asking each subject 
a general, non-directed question such as “How have you been feeling since the last visit?” 
Directed questioning and examination will then be done as appropriate. All reported AEs will 
be documented in the appropriate eCRF. 
Any abnormal laboratory test results (hematology, serum chemistry, or serum lipase) or other 
safety assessments (e.g., vital sign measurements), including those that worsen from baseline, 
felt to be clinically significant in the medical and scientific judgment of the investigator are 
to be recorded as AEs or SAEs. See Section 4.2.1 for specific instructions for monitoring 
patients with abnormal liver function tests. 
However, any clinically significant safety assessments that are associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the patient’s 
condition, are not to be reported as AEs or SAEs. 
6.3.1.2 
Serious Adverse Event:  
An SAE is any AE occurring at any dose that results in any of the following outcomes: death, 
a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Important 
medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered an SAE when, based upon appropriate medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition (See Section 6.3.1.4 for procedures for reporting 
an SAE). 
Allergan considers all cancer AEs as SAEs. In addition, Allergan considers any abortion 
(spontaneous or nonspontaneous) as an SAE.  


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Pre-planned surgeries or procedures for pre-existing, known medical conditions for which a 
patient requires hospitalization is not reportable as an SAE. Any pre-planned surgery or 
procedure should be clearly documented in the site source documents by the medically 
qualified investigator at the time of the patient’s entry into the study. If it has not been 
documented at the time of the patient’s entry into the study, then it should be documented as 
an SAE and reported to Allergan. 
6.3.1.3 
Reporting Adverse Events 
Any AE must be recorded in the appropriate eCRF. 
All AEs that are drug-related and unexpected (not listed as treatment-related in the current 
Investigator’s Brochure) must be reported to the governing Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) as required by the IRB/IEC, local 
regulations, and the governing health authorities. Any AE that is marked “ongoing” at the 
posttreatment visit must be followed up as appropriate. 
6.3.1.4 
Reporting Serious Adverse Events 
Any SAE occurring during the study period (beginning with informed consent) and for at 
least 30 days after the last dose of study drug must be immediately reported but no later than 
24 hours after learning of an SAE. Serious AEs must be reported directly to Allergan in the 
US and Canada as listed on the Allergan Study Contacts Page and recorded on the SAE form. 
All subjects with an SAE must be followed up and the outcomes reported. The investigator 
must supply the sponsor and the IRB/IEC with any additional requested information (e.g., 
autopsy reports and discharge summaries). 
In the event of an SAE, the investigator must: 
1. Notify Allergan/
 immediately by fax or email using the SAE form (contact 
details can be found on page 1 of the SAE form); phone numbers and relevant Allergan 
personnel contacts are also on the front page of protocol and Study Contacts Page. 
2. Obtain and maintain in his/her files all pertinent medical records, information, and medical 
judgments from colleagues who assisted in the treatment and follow-up of the subject. 


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3. Provide Allergan/
 with a complete, written description of the AE(s) on the 
SAE form describing the event chronologically, including any treatment given (e.g., 
medications administered, procedures performed) for the AE(s). Summarize relevant clinical 
information about the event: signs, symptoms, diagnosis, clinical course and relevant clinical 
laboratory tests, etc. Include any additional or alternative explanation(s) for the causality 
which includes a statement as to whether the event was or was not related to the use of the 
investigational drug. 
4. Promptly inform the governing IRB/IEC of the SAE as required by the IRB/IEC, local 
regulations, and the governing health authorities. 
6.3.1.5 
Assessment of Severity 
A clinical determination will be made of the intensity of an AE. The severity assessment for a 
clinical AE must be completed using the following definitions as guidelines: 
Mild  
Awareness of sign or symptom, but easily tolerated. 
Moderate  
Discomfort enough to cause interference with usual activity. 
Severe  
Incapacitating with inability to work or do usual activity. 
Not applicable 
In some cases, an AE may be an “all or nothing” finding which 
cannot be graded. 
6.3.1.6 
Assessment of Causality 
A determination will be made of the relationship (if any) between an AE and the study drug 
or study procedure, as applicable. A causal relationship is present if a determination is made 
that there is a reasonable possibility that the AE may have been caused by the drug or study 
procedure. 
If an AE is deemed related to study treatment, the investigator will be asked to further 
delineate whether the AE was related to the administration procedure (versus the study drug). 


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Note: a study procedure occurring during the screening/baseline period can include a 
washout of medication or introduction of a run-in medication or study required diagnostic 
procedure. 
6.3.2 
Investigator Required Contact to Patient 
6.3.2.1 
Investigator Required Contact to Patient for Diary-Confirmed 
Constipation 
As previously noted, the ePRO system will notify the investigator if a patient reports not 
having a bowel movement for 4 consecutive days (i.e., diary-confirmed constipation). Once 
notified the investigator must contact the patient to review his/her status as soon as possible. 
An unscheduled visit to further evaluate the patient's status should be arranged if deemed 
warranted by the investigator. The decision to continue, interrupt or permanently discontinue 
study drug will be left to the discretion of the investigator on a patient-by-patient basis. 
The investigator should consider permanent discontinuation of study drug should a patient 
not have a bowel movement for more than 7 consecutive days or have more than one episode 
of diary-confirmed constipation. 
If a decision to permanently discontinue study drug due to diary-confirmed constipation is 
made, the patient should be brought in immediately for study termination procedures. 
6.3.2.2 
Investigator Required Contact to Patient for Frequent Use of 
Loperamide Rescue Medication 
During the double-blind Treatment period and the posttreatment period, patients may use 
loperamide rescue medication for the acute treatment of uncontrolled diarrhea as described in 
Section 5.9. The ePRO system will notify the investigator of patients requiring >4 unit doses 
over a continuous 24-hour time period (8 mg/day), >7 unit doses over a continuous 48-hour 
time period (14 mg over 2 days), or >11 unit doses over a continuous 7-day time period. 
Once notified the investigator must contact the patient to review his/her status as soon as 
possible. 
An unscheduled visit to further evaluate the patient's status should be arranged if deemed 
warranted by the investigator. A decision to permanently discontinue study drug due to 


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excessive use of loperamide rescue medication will be left to the discretion of the 
investigator on a patient-by-patient basis. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.4 
Safety Monitoring Committee 
No safety monitoring committee will be used for the study.  


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6.5 
Pregnancy 
Pregnancy tests will be performed for all women according to local procedures unless they 
are surgically sterile or there is a documented history of their postmenopausal status. A serum 
pregnancy test will be performed at screening and urine pregnancy tests will be performed at 
all other visits through week 12 (or early withdrawal visit), unless a serum pregnancy test is 
preferred at the discretion of the investigator or if required by local regulations. Additional 
serum or urine pregnancy tests may be conducted throughout the study in sufficient number, 
as determined by the investigator or required by local regulation, to establish the absence of 
pregnancy. If positive, the patient is not eligible to enter or continue in the study.  
Any pregnancy that occurs after the first dose of study drug or within 30 days of the last dose 
of study drug must be immediately reported, but no later than 24 hours, after learning of a 
pregnancy. Pregnancies must be reported directly to Allergan in the US and Canada, as listed 
on the Allergan Study Contacts Page and recorded on the Pregnancy Communication Form. 
Pregnancies in female partners of male patients occurring during the time frame described 
above must also be reported. The pregnancy will be followed until final outcome using the 
Pregnancy Notification Form and indicating that it is a follow-up report. The outcome, 
including any premature termination, must be reported directly to Allergan in the US and 
Canada. Pregnancy complications and elective terminations for medical reasons must be 
reported as an AE or SAE. Spontaneous abortions must be reported as an SAE. Any patient 
that becomes pregnant will be discontinued from the study.  
If the patient agrees to have her primary care physician informed, the investigator should 
notify the patient’s primary care physician that she was participating in a clinical study at the 
time that she became pregnant, and the investigator should provide the details of the 
treatment that the patient received (blinded or unblinded; [refer to Section 5.6.1 for 
information on unblinding], as applicable). 
6.6 
Laboratory Analyses 
The contract research organization central laboratory will perform all clinical laboratory 
tests, except urine pregnancy tests, which will be performed locally at the study site. The 
details related to sample handling, blood draw amounts, tubes, shipping, address, etc. are 
available in a separate laboratory manual. 


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Blood and urine samples for hematology, serum chemistry, serum lipase, and serum and urine 
pregnancy tests will be prepared using standard procedures. 
Hematology and serum chemistry testing will be completed at screening, baseline (day 1), 
week 4, and all subsequent study visits through week 14 (posttreatment follow-up visit). 
Serum lipase testing will be performed at screening and baseline (day 1). Unscheduled blood 
draws for additional serum chemistry testing (lipase specifically) should be completed when 
possible for any patients with confirmed or suspected AEs of pancreatitis. 
In addition, pregnancy tests will be performed for all women according to local procedures 
unless they are surgically sterile or there is a documented history of their postmenopausal 
status. A serum pregnancy test will be performed at screening and urine pregnancy tests will 
be performed at all other study visits through week 12 (or early withdrawal study visit), 
unless a serum pregnancy test is preferred at the discretion of the investigator or if required 
by local regulations. The serum pregnancy test will be performed by the central laboratory. 
The blood samples will be used for the following tests: 
Hematology: white blood cell count with differential, hemoglobin, hematocrit, platelet count, 
red blood cell count, mean corpuscular volume, mean corpuscular hemoglobin, and mean 
corpuscular hemoglobin concentration. 
Serum Chemistry: albumin, alkaline phosphatase, ALT, AST, blood urea nitrogen, carbon 
dioxide, calcium (albumin corrected), chloride, creatinine, glucose, lactate dehydrogenase, 
phosphorus, potassium, sodium, total bilirubin*, and total protein. Serum lipase will be tested 
at screening and baseline (day 1) only. Thyroid-stimulating hormone will be tested at 
screening only. 
*Note: If total bilirubin values are elevated in a patient who has received at least 1 dose of 
study drug, fractionated levels will also be determined if possible. 
6.7 
Sample Collections 
The details related to sample collection are provided in a separate laboratory manual. 


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7 
Statistical and Analytical Plan 
A statistical analysis plan (SAP) will be prepared and finalized before completion of the 
study. The plan document will provide further details regarding the definition of analysis 
variables and methodologies to meet all study objectives.  
7.1 
Primary Efficacy Endpoints 
The primary efficacy endpoint is the proportion of primary composite responders determined 
over the 12-week double-blind treatment period. A primary composite responder is defined as 
a patient who meets the daily composite response criteria for at least 50% of days with diary 
entry during the interval from weeks 1 to 12. 
A patient must meet BOTH of the following criteria on a given day to be a daily composite 
responder: 
• Daily pain response: WAP score in the past 24 hours improved by ≥40% compared to 
baseline pain (average of daily WAP in the week prior to randomization). 
• Daily stool consistency response: BSS score <5 (i.e., score of 1, 2, 3, or 4); or the 
absence of a bowel movement if accompanied by ≥40% improvement in WAP 
compared to baseline pain. 
To be eligible to be a primary composite responder, a patient must have a minimum of 
60 days of diary entries, including partial entries, over the interval from weeks 1 to 12. A 
partial diary entry consists of any of 3 data components: BSS score, WAP score, and bowel 
movement frequency. Partial entries will be used to determine whether or not a patient is a 
daily responder. Any patient with fewer than 60 days of diary entry will be considered a non-
primary composite responder, including patients in the ITT analysis who recorded no 
post-baseline diary data. 
7.2 
Secondary Efficacy Endpoints 
The following are the secondary efficacy endpoints:  


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• Proportion of stool consistency responders: defined as patients who meet the daily 
stool consistency response criteria (as defined in Section 7.1) for ≥50% of days with 
diary entries over a certain time period. This endpoint is defined for the 12-week 
treatment period, and for each 4-week interval (weeks 1 to 4, 5 to 8, and 9 to 12). For 
the weeks 1 to 12 time period, the ≥50% requirement is the same as specified for the 
primary efficacy endpoint in Section 7.1. For each of the 4-week periods, a responder 
must have a minimum of 20 days of diary entries over the 4 weeks. 
• Proportion of pain responders: defined as patients who meet the daily pain response 
criteria (as defined in Section 7.1) for ≥50% of days with diary entries over a certain 
time period. This endpoint is defined for the 12-week treatment period, and each 
4-week interval (weeks 1 to 4, 5 to 8, and 9 to 12). For the weeks 1 to 12 time period, 
the ≥50% requirement is the same as specified for the primary efficacy endpoint in 
Section 7.1. For each of the 4-week periods, a responder must have a minimum of 
20 days of diary entries over the 4 weeks. 
• Proportion of monthly composite responders: defined as patients who meet the daily 
composite response criteria (as defined in Section 7.1) for at least 50% of days with 
diary entry for a minimum of 20 days during each 4-week interval (weeks 1 to 4, 5 to 
8, and 9 to 12). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7.5 
Sample Size Calculations 
Assuming a placebo response for the primary efficacy endpoint, composite response in pain 
and stool consistency rate at 12 weeks, of 13% and an approximate 14% treatment effect of 
eluxadoline over placebo, a sample size of 340 patients is required (1:1 randomization ratio, 
eluxadoline: placebo, 170 patients per arm). (From the Integrated Summary of Efficacy 
Report, patients refractory to loperamide in the pooled studies IBS 3001 and 3002 had 13% 
and 27% composite response in pain and stool consistency rates in the placebo and 
eluxadoline groups, respectively. This set of response rates are the same when using 40% 


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WAP improvement to replace the 30% in the primary efficacy composite responder criteria.) 
This sample size will have approximately 90% power to detect the difference of the primary 
efficacy endpoint response proportion between eluxadoline and placebo using a 2-sided 
chi-square test at a significance level of 0.05. 
7.6 
Analysis Sets 
The following analysis sets will be used in the statistical analyses. 
Intent-to-Treat Population (ITT): The ITT population will include all randomized patients. 
Patient disposition, demographics, and baseline characteristics and efficacy and HEOR data 
will be analyzed on the ITT population. Patients will be analyzed according to their 
randomization assignment, regardless of the actual treatment received. In this study, only 
randomized patients are considered as enrolled. 
Safety Population: The Safety Population will include all patients enrolled who received at 
least 1 dose of study drug. Safety data will be analyzed using the safety population. Patients 
will be grouped and analyzed according to the treatment they will actually receive. 
7.7 
Statistical Analysis Methodology 
Statistical analysis will be performed using 
 
 Continuous variables will be summarized using mean, standard 
deviation, median, minimum value, and maximum value. Categorical variables will be 
summarized using frequency counts and percentages. Data will be listed in patient listings. 
All statistical tests will be 2-sided at significance level of 0.05.  
No adjustment for the multiplicity of the endpoints will be performed since there is only a 
primary efficacy endpoint and no interim analyses have been planned. 
Statistical analysis and methodologies will be briefly discussed in sections below. All details 
of the statistical analyses, methods, and missing data handling strategy will be described in 
the study SAP. 


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7.7.1 
Analysis of Primary Efficacy Endpoint 
The primary study analysis will be to evaluate the proportions of primary composite 
responders (defined in Section 7.1) over 12 weeks of treatment between the eluxadoline and 
placebo groups. These 2 proportions are represented as π eluxadoline and π Placebo. The primary 
hypotheses for this study are described below: 
H0: π eluxadoline - π Placebo = 0 
 Vs 
HA: π eluxadoline - π Placebo ≠ 0  
The numbers of responder and non-responder patients and corresponding percentages will be 
summarized and presented in a summary table by treatment group. Treatment effect will be 
assessed using the chi-square test. 
As supportive analysis, the primary endpoint will be analyzed using logistic regression model 
that will include treatment group as a factor and baseline pain score and stool consistency 
score as covariates. 
7.7.2 
Analysis of Secondary Efficacy Endpoint 
The proportions of stool consistency responders and pain responders (defined in Section 7.2) 
over the 12-week treatment period and at each 4-week interval (weeks 1 to 4, 5 to 8, and 9 to 
12) will be analyzed similar to the primary endpoint analysis. 
The proportion of monthly composite responders (defined in Section 7.2) at each 4-week 
interval (weeks 1 to 4, 5 to 8, and 9 to 12) will be analysed similar to the primary endpoint 
analyses. 
 
 
 
 
 
 


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7.7.6 
Other Analyses 
Not applicable. 
7.7.7 
Interim Analyses 
There will be no interim analysis for this study. 
7.8 
Handling of Missing Data 
Based upon interactive voice response compliance data from the completed Phase 3 trials in 
patients with IBS-D, we are anticipating on the order of 15% to 20% missed ePRO diary 
entry days for those patients who have not discontinued. For this study, missed daily ePRO 
diary entries will not be considered as protocol violations. Adequacy of non-missing diary 
entries for each study endpoint has been defined specifically in the primary, secondary, and 
additional endpoints sections of this protocol; patients will be considered as non-responders 
for the corresponding endpoints if the adequacy criteria are not met. 
Detailed missing data strategies will be defined in the study SAP. 
7.9 
Data Quality Assurance 
To ensure compliance with Good Clinical Practice (GCP) and all applicable regulatory 
requirements, Allergan may conduct a quality assurance audit of the site records and 
regulatory agencies may conduct a regulatory inspection at any time during or after the study. 
In the event of an audit or inspection, the investigator (and institution) must agree to grant the 
auditor(s) and inspector(s) direct access to all relevant documents and to allocate their time 
and the time of their staff to discuss any findings/relevant issues. 
7.9.1 
Data Management 
As part of the responsibilities assumed by participating in the study, the principal investigator 
or subinvestigator agrees to maintain adequate case histories for the patients treated as part of 
the research under this protocol. The investigator agrees to maintain source documentation as 
part of the case histories. These source documents may include patient’s medical records, 
hospital charts, clinic charts, the investigator’s patient study files, patient diaries, as well as 
diagnostics tests such as laboratory reports, etc. 


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Allergan/
 will supply the eCRF. 
The principal investigator or designee(s) must enter study data required by the protocol into 
an electronic data capture (EDC) system. All eCRF fields are to be filled in. If an item is not 
available or is not applicable, this fact should be indicated. Blank fields should not be present 
unless otherwise directed. The analysis data sets will be a combination of these data and data 
from other sources (e.g., laboratory data).  
Guidelines for completion of eCRFs will be reviewed with study site personnel at the 
investigators’ meeting/site initiation visits. The principal investigator is responsible for 
approval of the entered/corrected data. The eCRF responsibilities of the site personnel will be 
documented on the site delegation log, which will be collected at the closeout visits. Principal 
investigators or designees must review and approve the data before database lock. 
The clinical research associate will visit each study site, at a frequency documented in the 
monitoring plan, to review eCRFs for completeness and accuracy. Any discrepancies found 
between source documents and completed eCRFs will be entered as a discrepancy in the 
EDC system by the clinical research associate. Appropriate study site personnel should then 
address those discrepancies in the EDC system. Uniform procedures for eCRF correction 
(queries) will be discussed at the investigators’ meeting and during the study site initiation 
visits. 
Data from eCRFs and other external data sources will be entered into a clinical database as 
specified in the data management plan. Quality control and data validation procedures will be 
applied to ensure the validity and accuracy of the clinical database. 
Computerized and manual procedures should be used to review and check data from eCRFs 
and data from other external sources for omissions, apparent errors, and values that may 
require further clarification. Data queries requiring clarification should be documented, and 
the study site should be requested to review and resolve the queries. Only authorized 
personnel can make corrections to the clinical database, and all corrections should be 
documented in an audit trail. A quality assurance audit should be performed before database 
lock. 
After database lock, each study site will receive a CD-ROM containing all of their 
site-specific eCRF data as entered into EDC for the study, including full discrepancy and 


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audit history. Additionally, a CD-ROM copy of all of the study site’s data from the study will 
be created and sent to the sponsor for storage. 
8 
Ethics 
8.1 
Independent Ethics Committee or Institutional Review Board 
The US federal regulations (and applicable local country regulations) and the International 
Council for Harmonisation (ICH) guidelines require that approval be obtained from an 
IRB/IEC before participation of human patients in research studies. Before study onset, the 
protocol, informed consent, advertisements to be used for the recruitment of study patients, 
and any other written information regarding this study to be provided to the patient or the 
patient’s legal guardian must be approved by the IRB/IEC. Documentation of all IRB/IEC 
approvals and of the IRB/IEC compliance with ICH harmonised tripartite guideline E6(R1): 
GCP will be maintained by the site and will be available for review by the sponsor or its 
designee. 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must 
identify the IRB/IEC name and address, the clinical protocol by title or protocol number or 
both, and the date approval or a favorable opinion was granted. 
The principal investigator or subinvestigator is responsible for providing written summaries 
of the progress and status of the study at intervals not exceeding 1 year or otherwise specified 
by the IRB/IEC. The principal investigator or subinvestigator must promptly supply the 
sponsor or its designee, the IRB/IEC, and, where applicable, the institution, with written 
reports on any changes significantly affecting the conduct of the study or increasing the risk 
to patients. 
8.2 
Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki, ICH GCP, and all applicable regulations. 


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8.3 
Patient Information and Consent 
A written informed consent in compliance with US Title 21 Code of Federal Regulations 
(CFR) Part 50 (and applicable local country regulations) shall be obtained from each patient 
before entering the study or performing any unusual or nonroutine procedure that involves 
risk to the patient. An informed consent template may be provided by the sponsor to 
investigative sites. If any institution-specific modifications to study-related procedures are 
proposed or made by the site, the consent should be reviewed by the sponsor or its designee 
or both before IRB/IEC submission. Once reviewed, the consent will be submitted by the 
investigator to his or her IRB/IEC for review and approval before the start of the study. If the 
ICF is revised during the course of the study, all active participating patients must sign the 
revised form, if applicable, especially if the rights, well-being, and the safety of the patient 
are impacted by the revision. 
Before recruitment and enrollment, each prospective patient will be given a full explanation 
of the study and be allowed to read the approved ICF. Once the investigator is assured that 
the patient understands the implications of participating in the study, the patient will be asked 
to give consent to participate in the study by signing the ICF. 
The investigator shall retain the signed original ICF(s) and give a copy of the signed original 
form to the patient. 


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9 
Investigator’s Obligations 
The following administrative items are meant to guide the investigator (principal investigator 
or subinvestigator) in the conduct of the study but may be subject to change based on 
industry and government standard operating procedures, working practice documents, or 
guidelines. Changes will be reported to the IRB/IEC but will not result in protocol 
amendments. 
9.1 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain patient confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the patient, except as necessary for monitoring and auditing by the sponsor, its 
designee, the local regulatory authorities, or ethics committees. 
The principal investigator or subinvestigator and all employees and coworkers involved with 
this study may not disclose or use for any purpose other than performance of the study any 
data, record, or other unpublished, confidential information disclosed to those individuals for 
the purpose of the study. Prior written agreement from the sponsor or its designee must be 
obtained for the disclosure of any said confidential information to other parties. 
9.2 
Study Reporting Requirements 
By participating in this study, the principal investigator or subinvestigator agrees to submit 
reports of SAEs according to the timeline and method outlined in the protocol. In addition, 
the principal investigator or subinvestigator agrees to submit annual reports to his/her 
IRB/IEC as appropriate. 
9.3 
Financial Disclosure and Obligations 
Principal investigators or subinvestigators are required to provide financial disclosure 
information to allow the sponsor to submit the complete and accurate certification or 
disclosure statements required under 21 CFR 54 (and applicable local country regulations). 
In addition, the investigator (principal investigator or any subinvestigators) must provide to 


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the sponsor a commitment to promptly update this information if any relevant changes occur 
during the course of the investigation and for 1 year following the completion of the study. 
Neither the sponsor nor 
 is financially responsible for further testing or 
treatment of any medical condition that may be detected during the screening process. In 
addition, in the absence of specific arrangements, neither the sponsor nor 
 is 
financially responsible for further treatment of the patient’s disease. 
9.4 
Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH E6(R1) 8.2, 
21 CFR (Parts 50, 54, 56, and 312), and applicable local country regulations by providing the 
following essential documents, including but not limited to: 
• An original investigator-signed investigator agreement page of the protocol 
• An IRB/IEC approved informed consent, samples of site advertisements for recruitment 
for this study, and any other written information regarding this study that is to be 
provided to the patient 
• IRB/IEC approval 
• Form FDA 1572, fully executed, and all updates on a new fully executed Form FDA 1572 
• Laboratory certifications and normal ranges for any local laboratories used by the site, in 
accordance with 42 CFR 493 
• Curriculum vitae (CV) for the principal investigator and each subinvestigator listed on 
Form FDA 1572. Current licensure must be noted on the CV or a copy of current 
licensure provided along with the CV. They will be signed and dated by the principal 
investigators and subinvestigators, indicating that they are accurate and current 
• Financial disclosure information to allow the sponsor to submit complete and accurate 
certification or disclosure statements required under 21 CFR 54. In addition, the 
investigators must provide to the sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and for 
1 year after the completion of the study. 


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9.5 
Study Conduct 
The principal investigator agrees that the study will be conducted according to the principles 
of ICH E6(R1). The principal investigator will conduct all aspects of this study in accordance 
with all national, state, and local laws or regulations. Study information from this protocol 
will be posted on publicly available clinical trial registers before enrollment of patients 
begins. 
9.6 
Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH E6(R1) and all applicable guidelines and government regulations. 
9.7 
Adverse Events and Study Report Requirements 
By participating in this study, the principal investigator or subinvestigator agrees to submit 
reports of SAEs according to the time line and method outlined in the protocol. In addition, 
the investigator agrees to submit annual reports to the study site IRB/IEC as appropriate. 
9.8 
Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the 
institution; the investigator/institution should provide the IRB/IEC with a summary of the 
study’s outcome and the sponsor and regulatory authority(ies) with any reports required. 
9.9 
Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study drug. These documents should be 
retained for a longer period, however, if required by the applicable regulatory requirements 
or by an agreement with the sponsor. It is the responsibility of the sponsor to inform the 
principal investigator or subinvestigator/institution as to when these documents no longer 
need to be retained. 


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9.10 Publications 
After completion of the study, the data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal. In these cases, the sponsor will be 
responsible for these activities and will work with the investigators to determine how the 
manuscript is written and edited, the number and order of authors, the publication to which it 
will be submitted, and other related issues. The sponsor has final approval authority over all 
such issues. 
Data are the property of the sponsor and cannot be published without prior authorization 
from the sponsor, but data and publication thereof will not be unduly withheld. 


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10 Study Management 
10.1 Monitoring 
10.1.1 
External Data Monitoring Committee 
There will not be an external data monitoring committee for this study. 
10.1.2 
Monitoring of the Study 
The clinical research associate, as a representative of the sponsor, has the obligation to follow 
the study closely. In doing so, the clinical research associate will visit the principal 
investigator or subinvestigator at periodic intervals, in addition to maintaining necessary 
telephone and letter contact. The monitor will maintain current personal knowledge of the 
study through observation, review of study records and source documentation, and discussion 
of the conduct of the study with the principal investigator or subinvestigator and study site 
personnel. 
All aspects of the study will be carefully monitored, by the sponsor or its designee, for 
compliance with applicable government regulation with respect to current ICH E6(R1) and 
current standard operating procedures. 
10.1.3 
Inspection of Records 
Principal investigators or subinvestigators and institutions involved in the study will permit 
study-related monitoring, audits, IRB/IEC review, and regulatory inspections by providing 
direct access to all study records. In the event of an audit, the principal investigator or 
subinvestigator agrees to allow the sponsor, representatives of the sponsor, or a regulatory 
agency (e.g., FDA or other regulatory agency) access to all study records. 
The principal investigator or subinvestigator should promptly notify the sponsor and 
 
 of any audits scheduled by any regulatory authorities and promptly forward copies 
of any audit reports received to the sponsor. 


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10.2 Management of Protocol Amendments and Deviations 
10.2.1 
Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, 
immediate hazard to the patient, must be reviewed and approved by the sponsor or its 
designee. Amendments to the protocol must be submitted in writing to the principal 
investigator’s or subinvestigator’s IRB/IEC for approval before patients are enrolled into an 
amended protocol. 
10.2.2 
Protocol Violations and Deviations 
The principal investigator or subinvestigator or designee must document and explain in the 
patient’s source documentation any deviation from the approved protocol. The principal 
investigator or subinvestigator may implement a deviation from, or a change of the protocol 
to eliminate an immediate hazard to study patients without prior IRB/IEC approval. As soon 
as possible after such an occurrence, the implemented deviation or change, the reasons for it, 
and any proposed protocol amendments should be submitted to the IRB/IEC for review and 
approval, to the sponsor for agreement, and to the regulatory authorities, if required. 
A deviation from the protocol is an unintended and/or unanticipated departure from the 
procedures or processes approved by the sponsor and the IRB/IEC and agreed to by the 
principal investigator or subinvestigator. Deviations usually have an impact on individual 
patients or a small group of patients and do not involve inclusion/exclusion or primary 
endpoint criteria. 
A protocol violation occurs when there is nonadherence to the protocol that results in a 
significant, additional risk to the patient, when the patient or principal investigator or 
subinvestigator has failed to adhere to significant protocol requirements (e.g., 
inclusion/exclusion criteria) and the patient was enrolled without prior sponsor approval, or 
when there is nonadherence to federal regulations and/or ICH E6(R1) guidelines. 
Protocol violations and deviations will be documented by the clinical research associate 
throughout the course of monitoring visits. Principal investigators will be notified in writing 
by the clinical research associate of deviations. Investigators should notify their IRB/IEC of 
all protocol violations and deviations in a timely manner. 


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10.3 Study Termination 
Although Allergan has every intention of completing the study, Allergan reserves the right to 
discontinue the study at any time for clinical or administrative reasons. 
The end of the study is defined as the date on which the last patient completes the last visit 
(includes follow-up visit). 
10.4 Final Report 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the 
clinical study report is prepared and provided to the regulatory agency(ies) as required by the 
applicable regulatory requirement(s). The sponsor will also ensure that the clinical study 
report in marketing applications meet the standards of the ICH harmonised tripartite 
guideline E3: Structure and content of clinical study reports. 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results. 
Upon completion of the clinical study report, the sponsor will provide the investigator with 
the full summary of the study results. The investigator is encouraged to share the summary 
results with the study patients, as appropriate. The study results will be posted on publicly 
available clinical trial registers. 


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11 Reference List 
US Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research 
(CBER). Guidance for Industry – Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation. July 2009. Available at: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM174090.pdf. 
Drossman DA. The functional gastrointestinal disorders and the Rome III process. 
Gastroenterology. 2006;130(5):1377-90. 
Efskind PS, Bernklev T, Vatn MH. A double-blind placebo-controlled trial with loperamide in 
irritable bowel syndrome. Scand J Gastroenterol. 1996;31(5):463-8. 
Eluxadoline [Investigator’s Brochure] Forest Pharmaceuticals Inc. Cincinnati (Ohio); 
03/2016. 
EuroQol Group. EuroQol--a new facility for the measurement of health-related quality of 
life. Health Policy. 1990;16(3):199-208. 
Lembo AJ, Lacy BE, Zuckerman MJ, Schey Ret al. Eluxadoline for irritable bowel syndrome 
with diarrhea. N Engl J Med. 2016;374(3):242-53. 
Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders. 
Gastroenterology 2006;130(5):1480-91. 
Loperamide [package insert]. Teva Pharmaceuticals Inc, North Wales(PA); 01/2015. 
Lovell RM, Ford AC. Global prevalence of and risk factors for irritable bowel syndrome: a 
meta-analysis. Clin Gastroenterol Hepatol. 2012;10(7):712-721.e4. 
Reilly MC, Bracco A, Ricci JF, et al. The validity and accuracy of the Work Productivity and 
Activity Impairment questionnaire—irritable bowel syndrome version (WPAI: IBS). Aliment 
Pharmacol Ther. 2004;20(4):459-67. 
Talley NJ. Evaluation of drug treatment in irritable bowel syndrome. Br J Clin Pharmacol. 
2003;56(4):362-9. 


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Thompson WG, Longstreth GF, Drossman DA, et al. Functional bowel disorders and 
functional abdominal pain. Gut. 1999;45(Suppl 2):1143-7. 
US Department of Health and Human Services, Centers for Disease Control and Prevention, 
National Center for Chronic Disease Prevention and Health Promotion, Division of Adult and 
Community Health. Measuring Healthy Days, Population Assessment of Health-Related 
Quality of Life. Atlanta, GA: November 2000. Available at: 
http://www.cdc.gov/hrqol/pdfs/mhd.pdf. 
VIBERZI [package insert]. Forest Pharmaceuticals Inc. Cincinnati (Ohio); 05/2015. 
Xifaxan [package insert]. Salix Pharmaceuticals Inc. Morrisville (NC); 05/2015.  
Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 
1983;67(6):361-70. 


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12 Appendices 


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Subtyping IBS by Predominant Stool Pattern 
(Longstreth et al, 2006) 
 
 
 
 


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12.3 Appendix: Bristol Stool Scale 
 
  
Type 1 - Separate hard lumps like nuts 
(difficult to pass) 
Type 2 - Sausage shaped but lumpy 
Type 3 - Like a sausage but with cracks on 
surface 
Type 4 - Like a sausage or snake, smooth and 
soft 
Type 5 - Soft blobs with clear-cut edges 
(passed easily) 
Type 6 - Fluffy pieces with ragged edges, a 
mushy stool 
Type 7 - Watery, no solid pieces (entirely 
liquid) 
 


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SAP_001.pdf: 
NCT02959983 
 
Study ID: CMO‐US‐GI‐0429 
 
Title: A Phase 4 Multicenter, Multinational, Prospective, Randomized, Placebo‐Controlled, Double‐
Blinded Parallel Group Study to Assess Efficacy of Eluxadoline in the Treatment of Irritable Bowel 
Syndrome with Diarrhea (IBS‐D) in Patients Who Report Inadequate Control of IBS‐D Symptoms with 
Prior Loperamide Use (RELIEF) 
 
 
Statistical Analysis Plan Date: 18‐Oct‐2017 
 
 
 


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6.1.9 Statistical Methods 
 
Allergan 
Biostatistics 
Analysis Plan – Clinical Stud y Report 
 
Study ID: CMO-US-GI-0429 
 
Study Title: A Phase 4 Multicenter, Multinational, Prospective, Randomized, Placebo-
Controlled, Double-Blinded Parallel Group Study to Assess Efficacy of Eluxadoline in the 
Treatment of Irritable Bowel Syndrome with Diarrhea (IBS-D) in Patients Who Report 
Inadequate Control of IBS-D Symptoms with Prior Loperamide Use (RELIEF)  
 
 
Study Phase: 
IV 
Sponsor: 
Allergan LLC 
Harborside Financial Center 
Plaza 5, Suite 1900 
Jersey City, NJ 07311, USA 
 
 
Biostatistician: 
Allergan LLC 
Somerset Corporate Blvd.                            
Bridgewater, NJ 08807, USA 
Version: 
1.0 
Issue Date: 
October 18, 2017 
 


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List of Abbreviations 
 
Abbreviation  
Definition  
AE  
adverse event  
BID  
twice daily  
BSS  
Bristol Stool Scale  
CDS-HRQOL-4  
Healthy Days Core Module  
eCRF  
electronic case report form  
ePRO  
electronic patient-reported outcome  
EQ-5D  
EuroQoL-5 Dimension  
GI  
gastrointestinal  
HADS  
Hospital Anxiety and Depression Scale  
HEOR  
health economics and outcomes research  
IBS  
irritable bowel syndrome  
IBS-AR  
irritable bowel syndrome adequate relief  
IBS-D  
irritable bowel syndrome with diarrhea  
ICF  
informed consent form  
ITT  
intent-to-treat  
IxRS  
interactive response system  
MedDRA  
Medical Dictionary for Regulatory Activities 
SAE  
serious adverse event  


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US  
United States  
WAP  
worst abdominal pain  
WPAI: IBS-D  
Work Productivity and Activity Impairment questionnaire: Irritable 
Bowel Syndrome with Diarrhea 


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Table of Content s 
1. 
Introduction ........................................................................................................................ 6 
1.1 
Primary Study Objective .......................................................................................... 7 
1.2 
Secondary Objectives ............................................................................................... 8 
2. 
Analysis Populations and Data Conventions ..................................................................... 8 
2.1 
Analysis Populations ................................................................................................ 8 
2.2 
Baseline Definition and Visit Window for Analysis ................................................ 8 
2.3 
Data Conventions ..................................................................................................... 9 
3. 
Disposition and Exit Status ................................................................................................ 9 
3.1 
Screening Log Data .................................................................................................. 9 
3.2 
Disposition and Exit Status .................................................................................... 10 
4. 
Demographics and Other Baseline Characteristics .......................................................... 10 
4.1 
Demographics and Baseline Characteristics .......................................................... 10 
4.2 
Medical History ...................................................................................................... 10 
4.3 
Prior Medications ................................................................................................... 10 
4.4 
Concomitant Medications ...................................................................................... 10 
4.5 
Prior IBS-D Symptom Management Questionnaire .............................................. 10 
5. 
Duration to Study Treatment(s) and Compliance of Treatment ....................................... 11 
14 
6.3 
Primary Efficacy Analyses ..................................................................................... 14 
6.3.1 Primary Analyses for Primary Efficacy Endpoint ...................................... 15 


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6.3.2 Other Analysis for Primary Efficacy Endpoint .......................................... 15 
6.4 
Secondary Efficacy Analyses ................................................................................. 15 
8. 
Interim Analyses .............................................................................................................. 22 
9. 
Deviations from Protocol ................................................................................................. 22 
10. Appendices ...................................................................................................................... 24 
10.2 Bristol Stool Scale .................................................................................................. 28 
11. Signature Page ................................................................................................................. 70 
 


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1. 
Introduction 
The analyses described in the SAP are based upon the final protocol dated 12 August 2016. Where differences 
exist between analyses specified in the protocol and this SAP, the SAP will be followed.  
 
This is a Phase 4, multicenter, multinational, randomized, double-blind, placebo-controlled, parallel group study 
to evaluate the efficacy, safety, and tolerability of eluxadoline 100 mg BID in patients with IBS-D who report 
that use of loperamide to treat their IBS-D symptoms in the prior 12 months failed to adequately control their 
symptoms of IBS-D. (RELIEF) 
 
Approximately 340 patients will be randomly assigned (in a 1:1 ratio) to 1 of 2 treatment groups below:  
 
• Group 1: eluxadoline 100 mg oral tablets BID with food  
• Group 2: matching placebo oral tablets BID with food  
 
During the screening period (up to 1 week), screening procedures, including Prior Symptoms Management 
Questionnaire (refer to Appendix 10.7), will be performed. After that, eligible patients will enter a pretreatment 
period (up to 3 weeks). At the beginning of the pretreatment period, patients will receive instructions for 
completing an electronic patient-reported outcome (ePRO) diary to collect daily information related to their IBS-
D symptoms and use of loperamide rescue medication. At the end of the pretreatment period, patients who meet 
the study inclusion criteria related to ePRO diary compliance, stool consistency (Bristol Stool Scale [BSS]) , 
average worst abdominal pain (WAP) score , and use of loperamide rescue medication will be randomized into a 
12-week double-blind treatment period via central randomization.  
 
Patients randomized into the study will return to the clinic for study visits at week 4, week 8, week 12 (end-of-
treatment study visit), and for a post-treatment follow-up visit at week 14. A complete schedule of events is 
provided in Appendix 10.1, Table 10–1 and Table 10–2. Patients who discontinue from the study before the 
week 12 visit should return to the study site to complete the early withdrawal assessments as soon as possible 
after stopping the study drug.  
 
During the double-blind Treatment period, patients will record via the ePRO diary their daily IBS-D symptoms 
including BSS, WAP, abdominal discomfort, abdominal bloating, bowel movement frequency, number of 
episodes of urgency in a day, if any, number of episodes of fecal incontinence, and use of loperamide rescue 
medication. 
 
The actual ePRO data entered by the patients will not be provided to the investigative site staff at the time of 
randomization or during the study to prevent any potential bias in subsequent patient entries. However, periodic 
notifications will be generated to inform the investigator of patients’ ongoing compliance with ePRO diary 
entries and to alert investigators if patients have experienced episodes of constipation or have required excessive 
loperamide rescue medication for acute treatment of uncontrolled diarrhea.  


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1.1 
Primary Study Objective 
The primary objective of this study is to evaluate the efficacy of eluxadoline 100 mg BID versus placebo BID 
over 12 weeks of treatment in patients with IBS-D who report that use of loperamide in the prior 12 months 
failed to provide adequate control of their IBS-D symptoms. 
  


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1.2 
Secondary Objectives 
The secondary objectives are to evaluate the safety and tolerability of eluxadoline 100 mg BID versus placebo 
BID over 12 weeks of treatment in patients with IBS-D who report that use of loperamide in the prior 12 months 
failed to provide adequate control of their IBS-D symptoms. 
 
2. 
Analysis Populations and Data Conventions 
2.1 
Analysis Populations 
The following analysis sets will be used in the statistical analyses.  
 
Intent-to-Treat Population (ITT): The ITT population will include all randomized patients. Patient disposition, 
demographics, baseline characteristics, efficacy, and HEOR data will be analyzed using the ITT population. 
Patients will be analyzed according to their randomization assignment, regardless of the actual treatment 
received. In this study, only randomized patients are considered as enrolled.  
 
Safety Population: The Safety Population will include all patients enrolled who received at least 1 dose of study 
drug. Safety data will be analyzed using the safety population. Patients will be grouped and analyzed according 
to the treatment they actually received.  
2.2 
Baseline Definition and Visit Window for Analysis 
For the score of BSS, WAP, abdominal discomfort, and abdominal bloating, the baseline value is defined as 
the weekly average in the week prior to randomization.  
 
For bowel movement, urgency episodes, and episodes of fecal incontinence, the baseline value is defined as 
the average number per day in the week prior to randomization. 
 
For all other variables, the baseline value is the last observation prior to receiving the first dose of study 
medication as usual. 
 
 


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For weekly assessment such as treatment satisfaction and degree of relief of IBS symptoms, the visit 
window is defined as target day ± 3 days. For example, the treatment satisfaction assessment is collected 
weekly, starting from end of Week 1, the visit window will be day 4 (- 3 days) -- day 7 (target day) -- day 10 
(+ 3 days). 
2.3 
Data Conventions 
Based upon interactive voice response compliance data from the completed Phase 3 trials in patients with 
IBS-D, we are anticipating 15% to 20% missed ePRO diary entry days for those patients who were not 
discontinued. For this study, missed daily ePRO diary entries will not be considered as protocol violations. 
The minimum of the non-missing diary entries for each study endpoint will be specified in corresponding 
sections and the method of handling missing data for each endpoint is described in corresponding sections. 
Only observed data (i.e., no imputation) will be used for analyses except for the second definition of weekly 
composite responder (details are described in Section 6.5.1 14)).  
 
If there is more than one visit within a visit window (e.g., unscheduled visits), the visit closest to the target 
date of the visit will be used for analyses. If two visits are equidistant from the target date, then the data 
from the later visit will be used for analyses.  
If the date of a visit is out of the visit window, the data will only be displayed in listings. 
All data collected will be displayed in listings. 
 
3. 
Disposition and Exit Status 
3.1 
Screening Log Data 
A summary table will be provided for the number of screen failures for study enrollment and the break-
down of screen failures by failure reasons.  


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3.2 
Disposition and Exit Status 
The number of patients in ITT population and Safety population in each treatment group will be 
summarized for overall and by site. Another table will summarize the number of completers and non-
completers with sub-categorization of reason for discontinuation and p-value for comparison between 
treatment groups.    
A listing for patients who prematurely discontinued during double-blind treatment period will be provided.   
4. 
Demographics and Other Baseline Characteristics 
4.1 
Demographics and Baseline Characteristics 
A demographic and baseline disease characteristic table will be provided with p-values for testing 
differences between treatment groups.  
4.2 
Medical History 
Medical history will be coded by MedDRA 20.0. The medical history data will be summarized by SOC and 
preferred term in MedDRA and by treatment groups. 
 
4.3 
Prior Medications 
Prior medications are defined as any medication taken between Day -14 to Day -1. 
Medications are to be coded by WHO DDE B2. The prior medication records will be summarized by 
preferred drug name under ATC level 2 classification and by treatment groups. 
 
4.4 
Concomitant Medications 
Concomitant medications are defined as any medication that are ongoing or start after the first dose of study 
drug has been administrated and through the early termination or follow-up visit. 
Medications are to be coded by WHO DDE B2. The concomitant medication records will be summarized by 
preferred drug name under ATC level 2 classification and by treatment groups. 
 
4.5 
Prior IBS-D Symptom Management Questionnaire 
The number and percentage of patient’s taking each category of medication (Loperamide, Antidiarrheals 
(other than loperamide), Antidepressants, Anticholinergics/Antispasmodics) will be summarized with p-
values for testing differences between treatment groups. Furthermore, the responses to follow-up questions 
will be summarized by each category of medication and by questions.  
 


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Further text answers will be provided in a listing. 
 
5. 
Duration to Study Treatment(s) and Compliance of Treatment 
Duration of treatment is defined as: [(last dose date - first dose date) + 1].  
 
The duration of treatment will be summarized by descriptive statistics. A listing will present the first dose 
date and the last dose date, the dates and days of interruption, and the overall days of exposure.  
 
The total dose for a patient is defined as the sum of the patient reported dose on each day with dosing 
information (i.e., without any imputation) during 12-week treatment period. The total dose will be 
summarized by descriptive statistics. 
Study drug compliance will be calculated as the number of tablets taken divided by the target number of 
tablets to be taken during 12-week treatment period. 
 
Overall Compliance (%) =      (Number of tablets taken) x 100 %     
                                               Target number of tablets to be taken 
 
The target number of tablets to be taken is calculated as: (last dose date – first dose date + 1) x 2, since the 
dose is 1 tablet BID. The number of tablets taken is obtained by:  (no. dispensed – no. returned).  
If the drug is not returned at one visit for a patient, the compliance for the patient will be set to missing and 
the patient will be excluded from the analysis. 
 
Treatment compliance will be summarized by descriptive statistics and also as frequency counts and 
percentages for the following categories (<80 % vs ≥80%). 
 
The diary entry compliance will be summarized by compliance days categories (< 60 days vs > = 60 days) 
during the 12-week treatment period (84 days). For partial diary entry, the diary entry compliance is defined 
as if a patient’s diary entry has EITHER WAP score and BSS score OR WAP score and bowel movement 
frequency data for a day, this patient will be considered as diary entry compliance for the day.  
 
A listing will be provided for drug administration data, including number of tablets dispensed, returned, and 
the number not returned also not taken, etc. 
 


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6. 
Efficacy Analyses 


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6.3 
Primary Efficacy Analyses 
The primary efficacy endpoint is the proportion of primary composite responders determined over the 12-week 
double-blind treatment period. A primary composite responder is defined as a patient who meets the daily 
composite response criteria for at least 50% of days with diary entry during the interval of week 1-12.  
 
A patient must meet BOTH of the following criteria on a given day to be a daily composite responder:  
 
• 
Daily pain response: WAP score in the past 24 hours improved by ≥40% compared to baseline pain 
(average of daily WAP in the week prior to randomization).  


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• 
Daily stool consistency response: BSS score <5 (i.e., score of 1, 2, 3, or 4); or the absence of a bowel 
movement if accompanied by ≥40% improvement in WAP compared to baseline pain.   
 
To be eligible to be a primary composite responder, a patient must have a minimum of 60 days of diary entries, 
including partial entries, over the interval of week 1-12. A partial diary entry should consist of EITHER WAP 
score and BSS score OR WAP score and bowel movement frequency equals 0 to determine whether a patient is a 
daily responder. Any patient with fewer than 60 days of diary entry will be considered as a non-responder. 
 
6.3.1 
Primary Analyses for Primary Efficacy Endpoint 
The primary analysis is to evaluate the proportions of primary composite responders between the 
eluxadoline and placebo groups. These 2 proportions are represented as πEluxadoline and πPlacebo. The 
primary hypotheses for this study are described below: 
 
H0: πEluxadoline - πPlacebo = 0 
vs 
HA: πEluxadoline - πPlacebo ≠0 
 
The number and the percentage of responders and non-responders will be summarized in a table with p-value 
from chi-square test to test the different response rates between treatment groups.  
 
6.3.2 
Other Analysis for Primary Efficacy Endpoint 
As a supportive analysis, the primary endpoint will also be analyzed using logistic regression model with 
treatment group, the baseline pain score, and the baseline stool consistency score as exploratory variables. 
 
6.4 
Secondary Efficacy Analyses 
The following are the secondary efficacy endpoints: 
 
• Proportion of stool consistency responders: defined as patients who meet the daily stool consistency 
response criteria (BSS <5, or absence of a bowel movement) for ≥50% of days with diary entries 
over a certain time period. This endpoint is defined for the 12-week treatment period and for each 4-
week interval (week 1 to 4, 5 to 8, and 9 to 12). For the 12-week treatment period, the ≥50% 
requirement is the same as specified for the primary efficacy endpoint in Section 6.3. For each of the 
4-week intervals, a responder must have a minimum of 20 days of diary entries over the 4 weeks. 
Any patient with fewer than 60 days (for 12-week period) or with fewer than 20 days (for 4-week 
interval) of diary entries will be considered as a non-responder. 


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• 
Proportion of pain responders: defined as patients who meet the daily pain response criteria (as defined in 
Section 6.3) for ≥50% of days with diary entries over a certain time period. This endpoint is defined for 
the 12-week treatment period and for each 4-week interval (week 1 to 4, 5 to 8, and 9 to 12). For the 12-
week treatment period, the ≥50% requirement is the same as specified for the primary efficacy endpoint 
in Section 6.3. For each of the 4-week intervals, a responder must have a minimum of 20 days of diary 
entries over the 4 weeks. Any patient with fewer than 60 days (for 12-week period) or with fewer than 
20 days (for 4-week interval) of diary entries will be considered as a non-responder. 
• 
Proportion of monthly composite responders: defined as patients who meet the daily composite response 
criteria (as defined in Section 6.3) for at least 50% of days with diary entry for each 4-week interval 
(week 1 to 4, 5 to 8, and 9 to 12). For each of the 4-week intervals, a responder must have a minimum of 
20 days of diary entries over the 4 weeks. Any patient with fewer than 20 days of diary entries for the 
4-week interval will be considered as a non-responder. 
The secondary endpoints will be analyzed by the number and percentage of the corresponding responders 
with p-value from chi-square test to test the different response rates between treatment groups. No adjustment for 
the multiplicity of the endpoints will be performed. 


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8. 
Interim Analyses 
There will be no interim analysis for this study. 
 
9. 
Deviations from Protocol  
This analysis mentioned in protocol section 7.7.3, “The mixed-effect model for repeated measures method will 
be used to analyze these endpoints with treatment group as the factor and baseline endpoint values as covariate.” 
is not performed.


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10.2 Bristol Stool Scale 
 
  
Type 1 - Separate hard lumps like nuts (difficult to 
pass) 
Type 2 - Sausage shaped but lumpy 
Type 3 - Like a sausage but with cracks on surface 
Type 4 - Like a sausage or snake, smooth and soft 
Type 5 - Soft blobs with clear-cut edges (passed 
easily) 
Type 6 - Fluffy pieces with ragged edges, a mushy 
stool 
Type 7 - Watery, no solid pieces (entirely liquid) 


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5 = It costs too much


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5 = It costs too much


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11. 
Signature Page 
 
Study ID:  
CMO-US-GI-0429 
 
Version:  
1.0 
 
Issue Date:  
October 18, 2017