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

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

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.

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.

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.