A Comparison of the Effects of ORP-101 Versus Placebo in Adult Patients With Irritable Bowel Syndrome With Diarrhea (IBS-D)

Study Overview
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Brief Summary
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This study will evaluate the effects of ORP-101 versus placebo on stool consistency and abdominal pain in patients with Irritable Bowel Syndrome with Diarrhea (IBS-D). It will also assess the safety and tolerability of ORP-101 in patients with IBS-D.

Detailed Description
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The objectives of this study are to evaluate the efficacy, safety and tolerability of ORP-101 in patients with IBS-D. This is a randomized, double-blind, placebo-controlled, 3-arm, 12-week, parallel proof-of-concept study with 2 active arms (50 mg and 100 mg ORP-101, QD) and 1 matching placebo arm, using a responsive adaptive randomization approach. After screening, patients who qualify will enter the baseline symptom assessment period, during which they will be instructed on completion of an electronic diary for daily collection of data related to their IBS symptoms, bowel function and loperamide rescue usage (not allowed during baseline). Patients who meet all entry criteria will be randomized to receive one of two different doses of ORP-101 tablets or placebo for 12 weeks. The study drug will be taken once daily, approximately 30 minutes prior to breakfast. Patients will return to the clinic on Days 14, 28, 56, 84 (12 weeks) and 2 weeks after dosing has completed (Day 98) for a follow-up visit. Study subjects will include both male and female adults. Approximately 320 patients with IBS-D will be randomized to receive study drug or placebo. Randomization will be stratified by history of cholecystectomy/gallbladder agenesis.

Official Title
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A Double-Blind, Placebo-Controlled, Phase 2, Responsive Adaptive Randomization Study of ORP-101 in Patients With Irritable Bowel Syndrome With Diarrhea (IBS-D)

Conditions
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Irritable Bowel Syndrome With Diarrhea

Intervention / Treatment
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* Drug: ORP-101
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to comply with protocol, including completion of electronic daily diary as required. Has a diagnosis of IBS-D (Irritable Bowel Syndrome with Diarrhea) and meets the Rome IV Criteria, by history, for both IBS and IBS-D. Has abdominal pain intensity score, and stool consistency as determined by protocol and assessed by Investigator for the week prior to randomization. Has not used loperamide within the 14 days prior to randomization. Is on a stable diet for the past 12 weeks and is not planning to change lifestyle and/or diet during study. Exclusion Criteria: History of clinically relevant pancreatic conditions including pancreatitis, pancreas divisum, or Sphincter of Oddi (SO) dysfunction with pancreatic manifestations. History of biliary pathology including acute cholecystitis within 6 months or biliary pain including post-cholecystectomy pain. Patients who have had biliary sphincterotomy with post-procedure persistent abnormal liver function transaminases (LFTs). Planned elective surgery within the next 4 months. Significant and/or severe medical illnesses such as cardiovascular, neurological, infectious, renal, hepatic or respiratory disorders that would interfere with the patient's medical care, participation in, or conduct of the study. History of intestinal obstruction, stricture, toxic megacolon, GI (gastro-intestinal) perforation, fecal impaction, gastric banding, bariatric surgery, adhesions, ischemic colitis, or impaired intestinal circulation (e.g. aorto-iliac disease). History of lactose intolerance uncontrolled on a lactose-free diet, or other malabsorption syndromes (e.g. fructose malabsorption). Dysphagia or difficulty swallowing pills. History of inflammatory bowel disease, celiac disease, Clostridium difficile colitis or have had recent unexplained GI bleeding within 3 months prior to screening. History of major gastric, hepatic, pancreatic or intestinal surgery (appendectomy, hemorrhoidectomy, or polypectomy allowed as long as occurred > 3 months prior to trial screening; uncomplicated laparoscopic or open cholecystectomy is allowed if no history of post-operative biliary tract pain and surgery occurred > 3 months prior to screening). Patients >40 years of age at high risk for colon cancer must have had a screening colonoscopy within the past 3 years prior to trial screening visit or > 50 years of age, must have had a normal screening colonoscopy within the past 10 years prior to trial screening visit. Patients with Lynch Syndrome or Familial Polyposis are excluded from the study. Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Sequential Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ORP-101 50 mg<br>ORP-101 (50 mg) once daily | Drug: ORP-101<br>* Oral tablet<br>* Other names: dibuprenorphine-ethyl-ether;|
| Experimental: ORP-101 100 mg<br>ORP-101 (100 mg), once daily | Drug: ORP-101<br>* Oral tablet<br>* Other names: dibuprenorphine-ethyl-ether;|
| Placebo Comparator: Placebo<br>Matching placebo, once daily | Drug: Placebo<br>* Oral tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Are Composite Responders Based on Improvements From Baseline in Daily Worst Abdominal Pain and Daily Stool Consistency Scores | Composite responders are defined as participants who met the daily response criteria for at least 50% of the days with diary entries over the 12-week interval. A participant must meet 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) Average of daily stool consistency response for all reported bowel movements on the specific day: 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. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Are Responders in Daily Worst Abdominal Pain Scores | Pain responders over the interval from Weeks 1-12 are defined as those patients who meet the daily pain response criteria for at least 50% of days with diary entry during the interval. To be eligible to be a responder, a patient must have a minimum of 60 days of diary entries over the 12-week interval. | Week 12 | 
| Percentage of Participants Who Are Responders in Daily Stool Consistency Scores | Stool consistency responders over the interval from Weeks 1-12 are defined as those patients who meet the daily stool consistency response criteria for at least 50% of days with diary entry during the interval. To be eligible to be a responder, a patient must have a minimum of 60 days of diary entries over the 12-week interval. | Baseline to Week 12 | 
| Percentage of Participants Who are Responders in IBS Global Symptom Scores | IBS Global Symptom Score: Change from baseline for interval from Weeks 1-12: A responder is defined as a patient who has an IBS global symptom score of 0 (none) or 1 (mild) or daily IBS symptom score improved by ≥ 2.0 compared to the average in the week prior to randomization. A minimum of 60 days of diary entries over the 12-week interval is required for responders. | Week 12 | 
| Percentage of Participants Who are Responders in IBS Adequate Relief Scores | IBS Adequate Relief: Percent of responders over the interval from Weeks 1-12. Responders are defined as those patients with a weekly response of Yes to adequate relief of their IBS symptoms for at least 50% of the total weeks during the interval. | Week 12 | 
| Percentage of Participants Who Are Modified Composite Responders Based on Responder Endpoints | A modified composite responder endpoint in which a daily responder will be defined as having both: 1) Pain response: worst abdominal pain score in the past 24 hours improved ≥ 30% compared to the average in the week prior to randomization. 2) Stool consistency response: all bowel movements on the specific day must have BSFS score < 5 or the absence of a bowel movement if accompanied by ≥ 30% improvement in worst abdominal pain. | Week 12 | 
| Change from Baseline in Daily Abdominal Discomfort Scores | Discomfort: Change from baseline in daily abdominal discomfort scores | Week 12 | 
| Change from Baseline in Daily Abdominal Bloating Scores | Bloating: Change from baseline in daily abdominal bloating scores | Week 12 | 
| Number of Bowel Movements Per Day | Frequency: Change from baseline in mean number of bowel movements per day | Week 12 | 
| Number of Bowel Incontinence Free Days | Change from baseline in mean number of bowel incontinence episodes per day as well as the number of incontinence-free days | Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IBS, Irritable Bowel Syndrome