Study of the Research Medicine CIN-103 in Adults With Irritable Bowel Syndrome With Predominant Diarrhea (IBS-D).

Study Overview
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Brief Summary
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The goal of this clinical trial is to evaluate if the study drug, CIN-103, can help reduce the symptoms associated with irritable bowel syndrome with predominant diarrhea (IBS-D) in adult patients. The main questions it aims to answer are: To evaluate the efficacy of CIN-103 on symptoms of IBS-D when given to patients with IBS-D compared to a placebo. To evaluate the safety and tolerability of CIN-103 when given to patients with IBS-D compared to a placebo Participants will attend the following visits: Screening Period (1 Visit) Baseline Period (1 Visit) Will complete daily diary and other Patient Reported Outcomes (PROs) as described in the protocol to assess eligibility for continued participation. 12-Week Treatment Period (5 Visits) Study drug taken twice daily by mouth. Will complete daily diaries and other PROs as described in the protocol. Follow- Up Period (1 Visit) Researchers will compare CIN-103 Dose 1, CIN-103 Dose 2, and placebo, to evaluate the clinical response to multiple dose strengths of CIN-103 relative to placebo on abdominal pain and stool consistency along with safety and tolerability.

Official Title
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A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Parallel-Group Study to Evaluate the Efficacy, Safety, and Tolerability of CIN-103 in Adults With Irritable Bowel Syndrome With Predominant Diarrhea (IBS-D)

Conditions
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Irritable Bowel Syndrome With Diarrhea

Intervention / Treatment
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* Drug: CIN-103
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Are adult male and female subjects ≥ 18 years of age; Have a body mass index between 18 and 40 kg/m2, inclusive at Screening; Meet Rome IV Criteria for IBS-D by subject self-report of recurrent abdominal pain that is associated with ≥ 2 of the following over the last ≥ 6 months, with frequency of at least 1 day per week over the last 3 months (on average) before enrollment: Related to defecation; Associated with a change in frequency of stool; and/or Associated with a change in form (appearance of stool). Based on Investigator interview of subject's symptoms over the last 3 months, have ≥ 25% of bowel movements (BMs) with Bristol Stool Scale (BSS) types 6 or 7 (loose or watery stools) and < 25% of BMs with BSS Type 1 or 2 (lumpy or hard stools) per the Rome IV Criteria for IBS-D; In the opinion of the Investigator, are on a stable diet for ≥ 4 weeks prior to Screening and are not planning to change lifestyle, exercise, and/or diet that may impact symptoms of IBS-D during study participation; Have a fecal calprotectin < 50 mcg/g at the Screening Visit or Visit 2; Have a serum tTG-IgA (tissue transglutaminase immunoglobulin A) ≤ 3 U/mL at the Screening Visit; Have undergone a colonoscopy examination within the designated time interval prior to randomization, if they meet any of the following criteria: Average risk, based on US Preventive Services Task Force Recommendation Statement for screening of colorectal cancer, with age ≥ 45 years (colonoscopy within 10 years); Personal history of completely removed adenomatous colorectal polyps (colonoscopy within 5 years for polyps >1 cm, within 10 years for polyps <1 cm); History of colorectal cancer or adenomatous polyps in a first-degree relative before age 60 (colonoscopy within 5 years); History of colorectal cancer or adenomatous polyps in ≥ 2 first-degree relatives at any age, or family history of hereditary colorectal cancer or polyposis (colonoscopy within 5 years); or History of or active inflammatory bowel disease in first-degree relative (colonoscopy any time). Exclusion Criteria: Have a diagnosis or suspected diagnosis of IBS with a subtype of constipation, IBS with mixed or alternating bowel habits, un-subtyped IBS, or functional constipation by the Rome IV Criteria; Have a history of or current inflammatory bowel disease (ie, Crohn's disease, ulcerative colitis, indeterminate colitis), microscopic colitis, lymphocytic colitis, celiac disease, non-celiac gluten sensitivity and non-compliant on a gluten-free diet, untreated lactose intolerance, carcinoid syndrome, Lynch syndrome, or familial polyposis; Note: Lactose intolerance and non-celiac gluten sensitivity will not exclude a subject from participation if the Investigator documents that the subject is compliant on a special diet (lactose-free diet or gluten-free diet, respectively) and/or for lactose intolerance is successfully treated with commercial lactase supplement(s). Have a known history of a pelvic floor disorder (unless successful treatment has been documented by a normal balloon expulsion test), refractory constipation not responsive to standard medical therapy, fecal impaction that required hospitalization, cathartic colon, and/or active proctological condition; Have a history of or current non-IBS chronic condition(s) with ongoing symptoms associated with abdominal pain or GI discomfort (eg, gastroparesis, functional dyspepsia, uncontrolled gastroesophageal reflux disease, polycystic kidney disease, ovarian cysts, urological pain, or endometriosis); Have a history of or current clinically significant arrhythmias as judged by the Investigator, including ventricular tachycardia, ventricular fibrillation, and Torsades de pointes. Subjects with any abnormal electrocardiogram (ECG) not considered clinically significant by the Investigator are not necessarily excluded; Have current or a history of diverticulitis, heme positive stool, or unexplained GI bleeding within 3 months prior to Screening Note: Surgically repaired diverticulitis > 3 months prior to Screening is permitted. Have a history of surgical resection of the stomach, small, or large intestine; Have had any major abdominal surgery within the 3 months prior to Screening; Note: Permitted procedures are uncomplicated appendectomy, cholecystectomy, and resection of benign polyps within the 3 months prior to Screening. Subjects who had an appendectomy that was associated with any related complications or sequelae are eligible if the procedure was performed at least 6 months prior to Screening. Have a history of intestinal obstruction, stricture, toxic megacolon, solitary rectal ulcer syndrome, GI perforation, intra-abdominal or pelvic adhesions, ischemic colitis, radiation proctitis, enteritis, colitis, or impaired intestinal circulation (eg, aortoiliac disease); Are currently undergoing or planning to initiate treatment with weight loss medication during study participation or prior weight loss surgery (eg, gastric bypass surgery, gastric banding); Have a planned invasive elective surgery during the period of anticipated study participation from the time of informed consent through the last study visit;

Ages Eligible for Study
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Minimum Age: 18 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CIN-103 BID Dose 1<br>CIN-103 Dose 1, administered as 2 x CIN-103 capsules and 2 x matching placebo per dose. Two doses per day. | Drug: CIN-103<br>* CIN-103 BID<br>|
| Experimental: CIN-103 BID Dose 2<br>CIN-103 Dose 2, administered as 4 x CIN-103 capsules per dose. Two doses per day. | Drug: CIN-103<br>* CIN-103 BID<br>|
| Placebo Comparator: Placebo for CIN-103 BID<br>Placebo for CIN-103, administered as 4 x matching placebo capsules per dose. Two doses per day. | Drug: Placebo<br>* Placebo for CIN-103 BID<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of meeting Study Composite Responder status for an adult subject with IBS-D. | A subject is defined as a Study Composite Responder if he or she meets the Daily Composite Responder criteria for at least 50% of days with diary entry during the 12-week Double-Blind Treatment Period. A subject is defined as a Daily Composite Responder if he or she meets both the pain intensity and stool consistency criteria as follows: Improvement in the mean daily worst abdominal pain (WAP) score by ≥ 30% compared to the mean daily WAP score from the Baseline Period (the average of the daily measurements over the 14 days prior to randomization); AND Improvement in stool consistency based on the Bristol Stool Scale (BSS) score < 5 or the absence of a bowel movement (BM) over the past 24 hours. Note: If a subject did not have a BM, an improvement of at least 30% in the WAP score is sufficient for a response on that day. The proportion of subjects with a primary outcome within each dose of CIN-103 will be compared to the proportion of subjects in the placebo arm. | 12 weeks of Double Blind Treatment Period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The occurrence of meeting Weekly Composite Responder status |  | 12-week of Double-Blind Treatment Period | 
| The occurrence of meeting Weekly Composite Responder status over 4-weekly intervals (1 to 4, 5 to 8, and 9 to 12 weeks). | A subject is defined as a Weekly Composite Responder if he or she meets both abdominal pain and stool consistency criteria as follows: An Abdominal Pain Intensity Weekly Responder is defined as a subject who experiences a decrease in the weekly average of WAP in the past 24 hours score of at least 30% compared with Baseline; AND A Stool Consistency Weekly Responder is defined as a subject who experiences a 50% or greater reduction in the number of days per week with at least 1 stool that has a consistency of Type 6 or 7 compared with Baseline. | 12 weeks of Double Blind Treatment Period | 
| The change in a composite of the daily mean and weekly mean of daily WAP score and stool consistency score as compared to Baseline | The subject-reported WAP in the past 24 hours will be recorded on an 11-point (ie, 0 to 10) numeric rating scale, where 0 corresponds to no pain and 10 corresponds to worst imaginable pain. The stool consistency will be measured using the Bristol Stool Score, based on a 1 to 7 scale where 1 corresponds to a hard stool and 7 corresponds to watery diarrhea. | 12-week of Double-Blind Treatment Period | 
| The change in a composite of the daily mean and weekly mean of daily WAP score, stool consistency score, and abdominal bloating score as compared to Baseline | The subject-reported WAP in the past 24 hours will be recorded on an 11-point (ie, 0 to 10) numeric rating scale, where 0 corresponds to no pain and 10 corresponds to worst imaginable pain. The stool consistency will be measured using the Bristol Stool Score, based on a 1 to 7 scale where 1 corresponds to a hard stool and 7 corresponds to watery diarrhea. The subject-reported abdominal bloating in the past 24 hours will be recorded on an 11-point (ie, 0 to 10) numeric rating scale, where 0 corresponds to no bloating and 10 corresponds to worst imaginable bloating. | 12-week of Double-Blind Treatment Period | 
| The change in daily mean and weekly mean number of BMs per day compared to Baseline |  | 12-week of Double-Blind Treatment Period | 
| The occurrence of meeting Stool Consistency Responder status | A participant is considered a Stool Consistency Responder if there is an improvement in stool consistency based on the BSS score < 5 or the absence of a bowel movement over the past 24 hours. | 12-week of Double-Blind Treatment Period | 
| The change in the daily mean and weekly mean of stool consistency measured with the Bristol Stool Scale (BSS) as compared to Baseline | The subject-reported BSS consistency score is based on a 1 to 7 scale where 1 corresponds to a hard stool and 7 corresponds to watery diarrhea. | 12-week of Double-Blind Treatment Period | 
| The occurrence of meeting Pain Responder status | A participant is considered a Pain Responder if there is an improvement in the mean daily WAP score by ≥ 30% compared to the mean daily WAP score from the Baseline Period (the average of the daily measurements over the 14 days prior to randomization). | 12-week of Double-Blind Treatment Period | 
| The change in the daily mean and weekly mean of daily WAP as compared to Baseline |  | 12-week of Double-Blind Treatment Period | 
| The change in the daily mean and weekly mean of daily abdominal bloating score as compared to Baseline. | The subject-reported abdominal bloating in the past 24 hours will be recorded on an 11-point (ie, 0 to 10) numeric rating scale, where 0 corresponds to no bloating and 10 corresponds to worst imaginable bloating. | 12-week of Double-Blind Treatment Period | 
| The change in daily mean and weekly mean of daily urgency score compared to Baseline. | Daily urgency score is measured on a numeric rating scale from 0 (no urgency) to 10 (worst possible urgency). | 12-week of Double-Blind Treatment Period | 
| The change in daily mean and weekly mean fecal incontinence episodes compared to Baseline | Subjects will receive daily automatic reminders on eDiary to record the number of fecal incontinence episodes over the past 24 hours. | 12-week of Double-Blind Treatment Period | 
| Incidence of clinically significant changes, in the Investigator's opinion, in vital signs, physical examinations, ECGs, and clinical laboratory evaluations. | Including standard safety chemistry panel, hematology, coagulation, lipids, and urinalysis. | Through study completion, up to 19 weeks. | 
| Occurrence of Treatment-Emergent Adverse Events (TEAEs). |  | Through study completion, up to 19 weeks. | 
| Occurrence of treatment-emergent serious adverse events. |  | Through study completion, up to 19 weeks. | 
| Occurrence of TEAEs leading to premature discontinuation of the study drug. |  | Through study completion, up to 19 weeks. | 
| Occurrence of treatment-emergent marked laboratory abnormalities. |  | Through study completion, up to 19 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Irritable Bowel Syndrome, IBS-D, IBS, IBS with diarrhea, Abdominal pain with diarrhea, IBS with loose stool