Efficacy, Safety and Tolerability of Enteric-Coated Cholestyramine Capsules for Adult Short Bowel Syndrome

Study Overview
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Brief Summary
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A new Enteric-Coated Cholestyramine (ECC) capsule has been developed to manage diarrhea associated with Short Bowel Syndrome (SBS) in adults. The formulation is expected to release cholestyramine in the remaining segment of the small intestine in SBS patients, thus binding bile acids after fat digestion, but before induction of diarrhea in the colon. The delayed-release profile is also expected to help reduce the potential for drug-drug interactions occurring in the proximal small intestine. Two doses of ECC will be studied for efficacy, safety and tolerability in this Phase IIa trial.

Detailed Description
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A new Enteric-Coated Cholestyramine (ECC) capsule has been developed to manage diarrhea associated with Short Bowel Syndrome (SBS). SBS is usually caused by the significant resection or loss of function of the ileum, leading to reduced reabsorption of bile acids and subsequent osmotic diarrhea. The new ECC formulation could release cholestyramine in the remaining segment of the small intestine in SBS patients, delivering and binding bile acids before they induce diarrhea in the colon. The proposed advantages of this formulation are: a) to prevent drug-drug interactions in the proximal GI tract, b) to preserve the fat digestive properties of bile acids in the duodenum and 3) to offer a more palatable dosage form to patients. Moreover, since distal delivery of cholestyramine is expected to be more effective in diarrhea prevention/reduction in SBS, lower doses than the ones used with non-enteric coated cholestyramine may be sufficient. Two doses of ECC will be studied for efficacy, safety and tolerability in well-defined non fully-colectomized, adult SBS patients suffering from diarrhea.

Official Title
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A Phase IIa, Proof of Concept, Randomized, Double-Blind, Dose-Finding, Cross-Over Study of the Efficacy, Safety and Tolerability of a New Enteric-Coated Cholestyramine Capsule in Adult Short Bowel Syndrome Patients

Conditions
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Short Bowel Syndrome

Intervention / Treatment
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* Drug: Enteric-Coated Cholestyramine (ECC) Capsule
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult, ambulatory male and female subjects Provision of signed and dated informed consent form (ICF) Age ≥ 18 years and ≤ 80 years Stable SBS of: Non-surgical origin; OR Surgical origin where the last surgical ileal resection was performed at least 6 months prior to enrolment Partial, Home Parenteral Nutrition and/or parenteral fluids are allowed, at a maximum frequency of 6 times a week throughout the trial, as long as the regimen has been stable for at least 2 weeks prior to screening and is expected to remain unchanged during the study At least 50 % of the colon being intact Intact duodenum BMI ≥ 18 Presence of stable chronic diarrhea for at least 3 months prior to enrolment as evidenced by medical history Presence of stable chronic diarrhea during the 2-week screening diary period before randomization, as evidenced by completion of a screening diary demonstrating: Mean daily production of at least 3 soft or watery stools (BSFS scores 6 or 7); or More than 3 bowel movements per day on average with >25% of them being BSFS type 6 or 7 Stated willingness and ability to comply with all study procedures, including daily recording of bowel movements and BSFS in the patient diaries, and availability for the duration of the study Clinical laboratory values within the laboratory's stated normal range; if not within this range, they must be without clinical significance, as determined by the investigator Female subjects must meet one of the following criteria: a) Participant is of childbearing potential and agrees to use one of the accepted contraceptive regimens from at least 30 days prior to the first study treatment administration through to at least 30 days after the last dose of the study treatment. An acceptable method of contraception includes one of the following: Abstinence from heterosexual intercourse Systemic contraceptives (combined birth control pills, injectable/implant/insertable hormonal birth control products, transdermal patch) Intrauterine device (with or without hormones) Condom with spermicide b) Participants of non-childbearing potential, defined as surgically sterile (i.e. has undergone complete hysterectomy or bilateral oophorectomy) or is in a menopausal state (i.e. at least 1 year without menses prior to the first study drug administration) are eligible Exclusion Criteria: Patients with known or suspected intestinal strictures of clinical relevance as judged by the Investigator Active inflammatory bowel disease (IBD) or fistula during the screening period as judged by the Investigator Crohn's disease patients not being in clinical remission for the last 12 weeks prior to randomization Diarrhea caused by other causes than SBS Presence of clinically significant steatorrhea, requiring pancreatic enzymes supplementation Presence of complete biliary obstruction Presence of active cancer (except resected cutaneous basal or squamous cell carcinoma and except in situ cervical cancer) and/or need to receive chemotherapy or radiotherapy during the study History of allergic reaction to cholestyramine or any excipient of the investigational drug product or placebo, or packaging components Females who are lactating at screening Females who are pregnant according to the pregnancy test at screening or prior to the first study treatment administration Significant history (at least 3 consecutive months in the year prior to Screening) of drug dependency or alcohol abuse (> 3 units of alcohol per day, intake of excessive alcohol, acute or chronic) Subjects who took an Investigational Product (IP) in the 30 days prior to the first study drug administration Any other clinically significant condition that is considered by the principal investigator as being susceptible to put the patient at greater safety risk, influence response to study product, or interfere with study assessments.

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: Crossover Assignment
Interventional Model Description: Multiple-center, randomized, double-blind, double dummy, 2-period, 2-sequence cross-over design
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low Dose ECC Regimen<br>ECC at the 1.7 g daily dose, administered BID (twice daily) as 2 capsules of ECC, plus 3 capsules of placebo, at least 30 minutes before breakfast and 2 capsules of ECC, plus 3 capsules of placebo at least 30 minutes before evening meal. | Drug: Enteric-Coated Cholestyramine (ECC) Capsule<br>* Enteric-Coated Delayed Release Cholestyramine Capsules<br>Drug: Placebo<br>* Enteric-Coated Delayed Release Placebo Capsules<br>|
| Experimental: High Dose ECC Regimen<br>ECC at the 4.25 g daily dose, administered BID (twice daily) as 5 capsules of ECC at least 30 minutes before breakfast and 5 capsules of ECC at least 30 minutes before evening meal. | Drug: Enteric-Coated Cholestyramine (ECC) Capsule<br>* Enteric-Coated Delayed Release Cholestyramine Capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Weekly Frequency of Bowel Movements Measured Between Baseline and the Second Week of Treatment | Change in the weekly frequency of bowel movements measured between baseline and the second week of treatment. Baseline is defined as the second week of screening for treatment period 1 and second week of washout for treatment period 2. | Baseline and Week 2 of treatment (Days 8 to 14, and Days 36 to 42) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Number of Bowel Movements for the Whole 2-week Treatment Period |  | Days 1 to 14 and Days 29 to 42 | 
| Mean Daily Stool Form Score According to the BSFS (Bristol Stool Form Scale), Measured During the Second Week of Treatment | The BSFS classifies the form of human feces into seven categories (Type 1 to Type 7) based on stool shape and consistency. Types or scores of 1 and 2 indicate constipation, with 3 and 4 being the ideal stools as they are easy to defecate while not containing excess liquid, 5 tending towards diarrhea, and 6 and 7 indicate diarrhea. | Days 8 to 14, and Days 36 to 42 | 
| Mean Daily Dose of Loperamide in mg, if Used, During the Second Week of Treatment |  | Days 8 to 14, and Days 36 to 42 |