Efficacy, Safety, and Tolerability of Eluxadoline in the Treatment of Participants With Diarrhea-Predominant Irritable Bowel Syndrome (IBS-d)

Study Overview
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Brief Summary
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The purpose of this study is to determine the efficacy, safety, and tolerability of different doses of eluxadoline (JNJ-27018966) compared with placebo in the treatment of participants with diarrhea-predominant irritable bowel syndrome.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Phase 3 Study to Evaluate the Efficacy, Safety, and Tolerability of JNJ-27018966 in the Treatment of Patients With Diarrhea-Predominant Irritable Bowel Syndrome

Conditions
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Irritable Bowel Syndrome

Intervention / Treatment
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* Drug: Eluxadoline
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant has a diagnosis of irritable bowel syndrome (IBS) with a subtype of diarrhea defined by the Rome III criteria. Participant has had a colonoscopy performed: Within 10 years prior to Prescreening if participant is at least 50 years of age (sigmoidoscopy, double contrast barium enema, or computed tomography (CT) colonography within the past 5 years is acceptable) Since the onset (if applicable) of any of the following alarm features for participants of any age: Participant has documented weight loss within the past 6 months Participant has nocturnal symptoms Participant has a familial history of first-degree relatives with colon cancer or Participant has blood mixed with their stool (excluding blood from hemorrhoids). Female participants must be: Postmenopausal, defined as 52 years or older and amenorrheic for at least 2 years at Prescreening, Surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy), Abstinent, or If sexually active, be practicing an effective method of birth control. Exclusion Criteria: Participant has a diagnosis of IBS with a subtype of constipation, mixed IBS, or unsubtyped IBS by the Rome III criteria. Participant has a history of inflammatory or immune-mediated gastrointestinal (GI) disorders including inflammatory bowel disease (ie, Crohn's disease, ulcerative colitis) and celiac disease. Participant has a history of diverticulitis within 3 months prior to Prescreening. Participant has a history of intestinal obstruction, stricture, toxic megacolon, GI perforation, fecal impaction, gastric banding, bariatric surgery, adhesions, ischemic colitis, or impaired intestinal circulation (eg, aortoiliac disease). Participant has any of the following surgical history: Cholecystectomy with any history of post cholecystectomy biliary tract pain Any abdominal surgery within the 3 months prior to Prescreening Participant has a history of major gastric, hepatic, pancreatic, or intestinal surgery (appendectomy, hemorrhoidectomy, or polypectomy greater than 3 months post surgery are allowed) Other protocol-specific eligibility criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eluxadoline 75 mg<br>Eluxadoline 75 mg tablets, orally, twice daily for up to 52 weeks period. | Drug: Eluxadoline<br>* Oral tablets twice daily<br>* Other names: JNJ-27018966;|
| Experimental: Eluxadoline 100 mg<br>Eluxadoline 100 mg tablets, orally, twice daily for up to 52 weeks period. | Drug: Eluxadoline<br>* Oral tablets twice daily<br>* Other names: JNJ-27018966;|
| Placebo Comparator: Placebo<br>Eluxadoline placebo matching tablets, orally, twice daily for up to 52 weeks period. | Drug: Placebo<br>* Oral tablets twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Were Composite Responders Based on Improvements From Baseline in Daily Worst Abdominal Pain And Daily Stool Consistency Scores | Composite responders were defined as a participant who met the daily response criteria for at least 50% of the days with diary entries during the interval of interest. A participant must had met both of the following criteria on a given day to be a daily responder: 1) Daily pain response: worst abdominal pain scores in the past 24 hours improved by ≥30% compared to baseline (average of daily worst abdominal pain the week prior to randomization). 2) Daily stool consistency response: Bristol Stool Scale (BSS) score <5 (ie, score of 1, 2, 3, or 4) or the absence of a bowel movement if accompanied by ≥30% improvement in worst abdominal pain compared to baseline pain. Bristol stool scale was defined as 7-point Scale in which a score of 1 = separate hard lumps, 2 = sausage shaped but lumpy, 3 = sausage-like with cracks on the surface, 4 = sausage-like but smooth and soft, 5 = soft blobs with clear cut edges, 6 = fluffy pieces with ragged edges, and 7 = watery with no solid pieces. | Up to 12 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Were Composite Responders Based on Improvements From Baseline in Daily Worst Abdominal Pain And Daily Stool Consistency Scores | Composite responders were defined as a participant who met the daily response criteria for at least 50% of the days with diary entries during the interval of interest. A participant must had met both of the following criteria on a given day to be a daily responder: 1) Daily pain response: worst abdominal pain scores in the past 24 hours improved by ≥30% compared to baseline (average of daily worst abdominal pain the week prior to randomization). 2) Daily stool consistency response: Bristol Stool Scale (BSS) score <5 (ie, score of 1, 2, 3, or 4) or the absence of a bowel movement if accompanied by ≥30% improvement in worst abdominal pain compared to baseline pain. Bristol stool scale was defined as 7-point Scale in which a score of 1 = separate hard lumps, 2 = sausage shaped but lumpy, 3 = sausage-like with cracks on the surface, 4 = sausage-like but smooth and soft, 5 = soft blobs with clear cut edges, 6 = fluffy pieces with ragged edges, and 7 = watery with no solid pieces. | Up to 26 Weeks | 
| Percentage of Participants Who Were Pain Responders In Daily Worst Abdominal Pain Scores by Intervals | Pain responders were defined as participants who met the daily pain response criteria (ie, the worst abdominal pain score in the past 24 hours improved by ≥30% compared to baseline) for at least 50% of days with diary entries during each interval. A participant must have had a minimum of 20 days of diary entries over any 4-week interval, a minimum of 60 days of diary entries over the 12-week interval, and a minimum of 110 days of diary entries over the 26-week interval to be a responder. | 12-week interval (Weeks 1-12), 26-week interval (Weeks 1-26), and 4-week interval (Weeks 1-4, 5-8, 9-12, 13-16, 17-20, and 21-24) | 
| Percentage of Participants Who Were Responders In Daily Stool Consistency Scores by Intervals | Stool consistency responders: participants who met daily stool consistency response criterion (ie,score of 1, 2, 3, or 4 or absence of bowel movement if accompanied by ≥30% improvement in worst abdominal pain compared to baseline pain) for at least 50% of days with diary entries during each interval. BSS was defined as 7-point Scale in which score of 1= separate hard lumps, 2= sausage shaped but lumpy, 3= sausage-like with cracks on the surface, 4= sausage-like but smooth and soft, 5= soft blobs with clear cut edges, 6= fluffy pieces with ragged edges, and 7= watery with no solid pieces. A participant must have had a minimum of 20 days of diary entries over any 4-week interval, a minimum of 60 days of diary entries over 12-week interval, and a minimum of 110 days of diary entries over 26-week interval to be a responder. | 12-week interval (Weeks 1-12), 26-week interval (Weeks 1-26), and 4-week interval (Weeks 1-4, 5-8, 9-12, 13-16, 17-20, and 21-24) | 
| Percentage of Participants Who Were Responders In Irritable Bowel Syndrome, Diarrhea Predominant (IBS-d) Global Symptom Scale by Intervals | IBS-d global symptom responders were defined as those participants who met the daily IBS-d global symptom response criteria (ie, IBS-d global symptom score of 0 [none] or 1 [mild]; or a daily IBS-d global symptom score improved by ≥2.0 compared to the baseline average) for at least 50% of days with diary entries during each interval. IBS-d Global Symptom Scale was a 5 point scale, score ranging from 0 to 4. 0= no symptoms, 1= mild symptoms, 2= moderate symptoms, 3= severe symptoms and 4 = very severe symptoms. A participant must have had a minimum of 20 days of diary entries over any 4-week interval, a minimum of 60 days of diary entries over the 12-week interval, and a minimum of 110 days of diary entries over the 26-week interval to be a responder. | 12-week interval (Weeks 1-12), 26-week interval (Weeks 1-26), and 4-week interval (Weeks 1-4, 5-8, 9-12, 13-16, 17-20, and 21-24) | 
| Percentage of Participants Who Were Responders to the Irritable Bowel Syndrome Quality of Life Measure (IBS-QoL) Scale | IBS-QoL responders were defined as participants who achieved at least a 14-point improvement in IBS-QoL total score from baseline to the applicable visit. The IBS-QoL consists of 34 items each with a 5-point response scale, where 1 generally represents better responses on items and 5 represents worse responses. The individual responses to the answered items were summed and standardized for a total score and then transformed to a 0- to 100-point (0= worst; 100=better) scale for ease of interpretation. | Weeks 4, 8, 12, 18, 26, 36, 44, and 52 (End of Treatment [EOT]) | 
| Percentage of Participants With Irritable Bowel Syndrome - Adequate Relief (IBS-AR) Scale | Adequate relief of IBS symptoms was assessed once weekly by participants answering the IBS-AR item in the electronic diary. IBS-AR responders were defined as participants with a weekly response of Yes to adequate relief of their IBS symptoms for at least 50% of the total weeks during the interval. A participant must have had a positive response on ≥6 weeks for the 12-week interval and ≥13 weeks for the 26-week interval, regardless of diary compliance, to be a responder. | 12-week interval (Weeks 1-12) and 26-week interval (Weeks 1-26) | 
| Change From Baseline in Daily Abdominal Discomfort Scores | Symptoms of abdominal discomfort were recorded on a 0 to 10 scale, where 0 corresponded to no discomfort and 10 corresponded to worst imaginable discomfort. A negative change from Baseline indicates the discomfort decreased. | Baseline, Weeks 4, 12 and 26 | 
| Change From Baseline in Daily Abdominal Bloating Scores | Symptoms of abdominal bloating were recorded on a 0 to 10 scale, where 0 corresponded to no bloating and 10 corresponded to worst imaginable bloating. A negative change from Baseline indicates the bloating decreased. | Baseline, Weeks 4, 12 and 26 | 
| Number of Bowel Movements Per Day | Participants recorded the number of bowel movements over 24 hours daily throughout the treatment. | Weeks 4, 12 and 26 | 
| Number of Bowel Incontinence Episodes | Participants recorded the number of incontinence episodes over 24 hours daily throughout the treatment. | Weeks 4, 12 and 26 | 
| Number of Bowel Incontinence Free Days | An incontinence free day was one where the participant reports zero incontinence episodes. The number of incontinence free days for a participant was assessed each week based on the number of reported days. | Weeks 4, 12 and 26 | 
| Number of Urgency Episodes Per Day | Participants recorded the number of urgency episodes over 24 hours daily throughout the treatment. | Weeks 4, 12 and 26 | 
| IBS-QoL Total Scores | The IBS-QoL consists of 34 items each with a 5-point response scale, where 1 generally represents better responses on items and 5 represents worse responses. The individual responses to the answered items were summed and standardized for a total score and then transformed to a 0- to 100- point scale (0=worst; 100=better) for ease of interpretation. | Weeks 4, 8, 12, 18, 26, 36, 44, and 52 (EOT) | 
| Change From Baseline in IBS-QoL Total Scores | The IBS-QoL consists of 34 items each with a 5-point response scale, where 1 generally represents better responses on items and 5 represents worse responses. The individual responses to the answered items were summed and standardized for a total score and then transformed to a 0- to 100- point scale (0=worst; 100=better) for ease of interpretation. A positive change from Baseline indicates that quality of life improved. | Baseline, Weeks 4, 8, 12, 18, 26, 36, 44, and 52/EOT |