Irritable Bowel Syndrome With Diarrhea
Conditions
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.
Interventions
DRUGEluxadoline
Eluxadoline 100 mg oral tablets BID with food.
DRUGPlacebo
Placebo matching eluxadoline oral tablets BID with food.
Sponsors
Allergan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* 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. * 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: 1. Has documented weight loss within the past 6 months; or 2. Has nocturnal symptoms; or 3. Has a familial history of colon cancer; or 4. Has blood mixed with their stool (excluding any blood from hemorrhoids) * 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. * Has not used any loperamide rescue medication within 14 days prior to randomization.
Exclusion criteria
* Has a diagnosis of Irritable Bowel Syndrome (IBS) with a subtype of constipation IBS, mixed IBS, or unsubtyped IBS. * Has a history of inflammatory or immune-mediated gastrointestinal (GI) disorders including inflammatory bowel disease (i.e., Crohn's disease, ulcerative colitis), microscopic colitis, or celiac disease. * Has a history of diverticulitis within 3 months prior to screening. * Has a documented history of lactose intolerance. * Has a documented history of bile-acid malabsorption. * Has a history of chronic or severe constipation or intestinal obstruction, stricture, toxic megacolon, GI perforation, fecal impaction, gastric banding, bariatric surgery, adhesions. * Has any of the following surgical history: 1. Cholecystectomy or previously documented agenesis of gallbladder; or 2. Any abdominal surgery within the 3 months prior to screening; or 3. Major gastric, hepatic, pancreatic, or intestinal surgery (appendectomy, hemorrhoidectomy, or polypectomy greater than 3 months post-surgery are allowed). * Has a history of cholecystitis within 6 months before screening. * Has a history of pancreatitis or structural diseases of the pancreas, including known or suspected pancreatic duct obstruction. * Has a history of known or suspected biliary duct obstruction or sphincter of Oddi disease or dysfunction, excluding a history of gallstones. * Has a history or current evidence of laxative abuse within 5 years prior to screening. * Has documented evidence of cirrhosis. * Has a history of cardiovascular events, including stroke, myocardial infarction, congestive heart failure, or transient ischemic attack within 6 months prior to screening. * Has an unstable renal, hepatic, metabolic, or hematologic condition. * Has a history of malignancy within 5 years before screening (except squamous and basal cell carcinomas and cervical carcinoma in situ). * Has a history of human immunodeficiency virus infection. * 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. * Has a history of alcohol abuse, alcohol addiction, and alcoholism or drinks more than 3 alcoholic beverages per day. * 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. * 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. * 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. * Has an elective surgery planned or expects to need elective surgery at any time during the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Were Composite Responders Based on Improvements From Baseline in Daily Worst Abdominal Pain And Daily Stool Consistency Scores | Baseline, Weeks 1 to 12 | Percentage of primary composite responders is defined as the percentage of participants who meet both of the following daily composite criteria for at least 50% of the days with diary entry: 1)Worst Abdominal Pain (WAP) score improved by ≥40% compared to Baseline. The participant records their WAP score in the past 24 hours each day in a daily patient diary where: 0=no pain to 10=worst imaginable pain. 2) Bristol Stool Score (BSS) \<5; or the absence of a bowel movement if accompanied by ≥40% improvement in WAP compared to Baseline. The participant records their stool consistency each day in a daily patient diary using the BSS on a scale from 1 (hard stool) to 7 (watery stool). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Stool Consistency Responders | Weeks 1 to 12 and 4-week intervals (Weeks 1 to 4, Weeks 5 to 8 and Weeks 9 to 12) | Percentage of stool consistency responders is defined as the percentage of participants who meet the daily stool consistency response criteria: BSS \<5; or the absence of a bowel movement if accompanied by ≥40% improvement in WAP compared to Baseline for ≥50% of days with daily patient diary entries over a certain time period. The participant records their stool consistency each day in a daily patient diary using the BSS on a scale from 1 (hard stool) to 7 (watery stool). A participant must have had a minimum of 20 days of diary entries over any 4-week interval. |
| Percentage of Pain Responders | Baseline, Weeks 1 to 12 and 4-week intervals (Weeks 1 to 4, Weeks 5 to 8 and Weeks 9 to 12) | Percentage of pain responders is defined as the percentage of participants who meet the daily pain response criteria: WAP score improved by ≥40% compared to Baseline for ≥50% of days with diary entries over a certain time period. The participant records their WAP score in the past 24 hours each day in a daily diary where: 0=no pain to 10=worst imaginable pain. A participant must have had a minimum of 20 days of diary entries over any 4-week interval. |
| Percentage of Monthly Composite Responders | Weeks 1 to 4, 5 to 8, and 9 to 12 | Percentage of monthly composite responders is defined as the percentage of participants who meet the daily composite response criteria 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). Composite response includes both of the following criteria: 1) WAP score improved by ≥40% compared to Baseline. The participant records their WAP score in the past 24 hours each day in a daily patient diary where: 0=no pain to 10=worst imaginable pain. 2) BSS \<5; or the absence of a bowel movement if accompanied by ≥40% improvement in WAP compared to Baseline. The participant records their stool consistency each day in a daily patient diary using the BSS on a scale from 1 (hard stool) to 7 (watery stool). |
Countries
Canada, United States
Participant flow
Pre-assignment details
A total of 660 participants were screened; 346 participants were randomized; 344 participants received at least 1 dose of study drug which comprises the safety population. Randomization and treatment assignment were based on a randomization scheme prepared by Allergan Biostatistics prior to the start of the study.
Participants by arm
| Arm | Count |
|---|---|
| Eluxadoline Eluxadoline 100 mg oral tablets twice daily (BID) with food for 12 weeks. | 172 |
| Placebo Placebo matching eluxadoline oral tablets BID with food for 12 weeks. | 174 |
| Total | 346 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 1 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Lost to Follow-up | 12 | 9 |
| Overall Study | Other | 1 | 1 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 7 | 12 |
Baseline characteristics
| Characteristic | Eluxadoline | Placebo | Total |
|---|---|---|---|
| Age, Customized <65 | 158 Participants | 161 Participants | 319 Participants |
| Age, Customized ≥65 | 14 Participants | 13 Participants | 27 Participants |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Asian | 7 Participants | 3 Participants | 10 Participants |
| Race/Ethnicity, Customized Black or African American | 20 Participants | 26 Participants | 46 Participants |
| Race/Ethnicity, Customized Caucasian | 144 Participants | 141 Participants | 285 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 33 Participants | 41 Participants | 74 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 139 Participants | 133 Participants | 272 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Female | 124 Participants | 119 Participants | 243 Participants |
| Sex: Female, Male Male | 48 Participants | 55 Participants | 103 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 171 | 0 / 173 |
| other Total, other adverse events | 10 / 171 | 5 / 173 |
| serious Total, serious adverse events | 1 / 171 | 3 / 173 |
Outcome results
Primary
Percentage of Participants Who Were Composite Responders Based on Improvements From Baseline in Daily Worst Abdominal Pain And Daily Stool Consistency Scores
Percentage of primary composite responders is defined as the percentage of participants who meet both of the following daily composite criteria for at least 50% of the days with diary entry: 1)Worst Abdominal Pain (WAP) score improved by ≥40% compared to Baseline. The participant records their WAP score in the past 24 hours each day in a daily patient diary where: 0=no pain to 10=worst imaginable pain. 2) Bristol Stool Score (BSS) \<5; or the absence of a bowel movement if accompanied by ≥40% improvement in WAP compared to Baseline. The participant records their stool consistency each day in a daily patient diary using the BSS on a scale from 1 (hard stool) to 7 (watery stool).
Time frame: Baseline, Weeks 1 to 12
Population: The Intent-to-Treat population includes all randomized patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eluxadoline | Percentage of Participants Who Were Composite Responders Based on Improvements From Baseline in Daily Worst Abdominal Pain And Daily Stool Consistency Scores | 22.7 percentage of participants |
| Placebo | Percentage of Participants Who Were Composite Responders Based on Improvements From Baseline in Daily Worst Abdominal Pain And Daily Stool Consistency Scores | 10.3 percentage of participants |
Comparison: Overall Weeks 1-12p-value: 0.0022Chi-squared
Secondary
Percentage of Monthly Composite Responders
Percentage of monthly composite responders is defined as the percentage of participants who meet the daily composite response criteria 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). Composite response includes both of the following criteria: 1) WAP score improved by ≥40% compared to Baseline. The participant records their WAP score in the past 24 hours each day in a daily patient diary where: 0=no pain to 10=worst imaginable pain. 2) BSS \<5; or the absence of a bowel movement if accompanied by ≥40% improvement in WAP compared to Baseline. The participant records their stool consistency each day in a daily patient diary using the BSS on a scale from 1 (hard stool) to 7 (watery stool).
Time frame: Weeks 1 to 4, 5 to 8, and 9 to 12
Population: The Intent-to-Treat population includes all randomized patients.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eluxadoline | Percentage of Monthly Composite Responders | Weeks 1-4 | 14 Percentage of Participants |
| Eluxadoline | Percentage of Monthly Composite Responders | Weeks 5-8 | 26.7 Percentage of Participants |
| Eluxadoline | Percentage of Monthly Composite Responders | Weeks 9-12 | 30.8 Percentage of Participants |
| Placebo | Percentage of Monthly Composite Responders | Weeks 1-4 | 6.9 Percentage of Participants |
| Placebo | Percentage of Monthly Composite Responders | Weeks 5-8 | 14.9 Percentage of Participants |
| Placebo | Percentage of Monthly Composite Responders | Weeks 9-12 | 16.7 Percentage of Participants |
Comparison: Weeks 1-4p-value: 0.033Chi-squared
Comparison: Weeks 5 to 8p-value: 0.0063Chi-squared
Comparison: Weeks 9 to 12p-value: 0.0018Chi-squared
Secondary
Percentage of Pain Responders
Percentage of pain responders is defined as the percentage of participants who meet the daily pain response criteria: WAP score improved by ≥40% compared to Baseline for ≥50% of days with diary entries over a certain time period. The participant records their WAP score in the past 24 hours each day in a daily diary where: 0=no pain to 10=worst imaginable pain. A participant must have had a minimum of 20 days of diary entries over any 4-week interval.
Time frame: Baseline, Weeks 1 to 12 and 4-week intervals (Weeks 1 to 4, Weeks 5 to 8 and Weeks 9 to 12)
Population: The Intent-to-Treat population includes all randomized patients.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eluxadoline | Percentage of Pain Responders | Weeks 1 to 4 | 30.2 Percentage of Participants |
| Eluxadoline | Percentage of Pain Responders | Weeks 5 to 8 | 45.9 Percentage of Participants |
| Eluxadoline | Percentage of Pain Responders | Overall Weeks 1 to 12 | 43.6 Percentage of Participants |
| Eluxadoline | Percentage of Pain Responders | Weeks 9 to 12 | 44.8 Percentage of Participants |
| Placebo | Percentage of Pain Responders | Overall Weeks 1 to 12 | 31.0 Percentage of Participants |
| Placebo | Percentage of Pain Responders | Weeks 1 to 4 | 25.9 Percentage of Participants |
| Placebo | Percentage of Pain Responders | Weeks 5 to 8 | 31.6 Percentage of Participants |
| Placebo | Percentage of Pain Responders | Weeks 9 to 12 | 35.1 Percentage of Participants |
Comparison: Overall Weeks 1 to 12p-value: 0.0174Chi-squared
Comparison: Weeks 1 to 4p-value: 0.3832Chi-squared
Comparison: Weeks 5 to 8p-value: 0.0052Chi-squared
Comparison: Weeks 9 to 12p-value: 0.0619Chi-squared
Secondary
Percentage of Stool Consistency Responders
Percentage of stool consistency responders is defined as the percentage of participants who meet the daily stool consistency response criteria: BSS \<5; or the absence of a bowel movement if accompanied by ≥40% improvement in WAP compared to Baseline for ≥50% of days with daily patient diary entries over a certain time period. The participant records their stool consistency each day in a daily patient diary using the BSS on a scale from 1 (hard stool) to 7 (watery stool). A participant must have had a minimum of 20 days of diary entries over any 4-week interval.
Time frame: Weeks 1 to 12 and 4-week intervals (Weeks 1 to 4, Weeks 5 to 8 and Weeks 9 to 12)
Population: The Intent-to-Treat population includes all randomized patients.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eluxadoline | Percentage of Stool Consistency Responders | Overall Weeks 1 to 12 | 27.9 Percentage of Participants |
| Eluxadoline | Percentage of Stool Consistency Responders | Weeks 1 to 4 | 24.4 Percentage of Participants |
| Eluxadoline | Percentage of Stool Consistency Responders | Weeks 5 to 8 | 30.8 Percentage of Participants |
| Eluxadoline | Percentage of Stool Consistency Responders | Weeks 9 to 12 | 29.7 Percentage of Participants |
| Placebo | Percentage of Stool Consistency Responders | Weeks 9 to 12 | 25.3 Percentage of Participants |
| Placebo | Percentage of Stool Consistency Responders | Overall Weeks 1 to 12 | 16.7 Percentage of Participants |
| Placebo | Percentage of Stool Consistency Responders | Weeks 5 to 8 | 20.1 Percentage of Participants |
| Placebo | Percentage of Stool Consistency Responders | Weeks 1 to 4 | 12.6 Percentage of Participants |
Comparison: Overall Weeks 1 to 12p-value: 0.0119Chi-squared
Comparison: Weeks 1 to 4p-value: 0.0048Chi-squared
Comparison: Weeks 5 to 8p-value: 0.0207Chi-squared
Comparison: Weeks 9 to 12p-value: 0.37Chi-squared