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

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

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.

Study Overview

• Status: Terminated
• Conditions: Short Bowel Syndrome
• Intervention / Treatment: Drug: Enteric-Coated Cholestyramine (ECC) Capsule; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 2

Contacts and Locations

Study Locations

• Poland
  • Poznań, Poland
    • Solumed Centrum Medyczne
  • Skawina, Poland
    • Szpital Wielospecjalistyczny im. Stanleya Dudricka
  • Łódź, Poland
    • Wojewódzki Specjalistyczny Szpital im. M. Pirogowa w Łodzi

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Adult, ambulatory male and female subjects
2. Provision of signed and dated informed consent form (ICF)
3. Age ≥ 18 years and ≤ 80 years

4. Stable SBS of:

   1. Non-surgical origin; OR
   2. Surgical origin where the last surgical ileal resection was performed at least 6 months prior to enrolment
5. 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
6. At least 50 % of the colon being intact
7. Intact duodenum
8. BMI ≥ 18
9. Presence of stable chronic diarrhea for at least 3 months prior to enrolment as evidenced by medical history

10. Presence of stable chronic diarrhea during the 2-week screening diary period before randomization, as evidenced by completion of a screening diary demonstrating:

    1. Mean daily production of at least 3 soft or watery stools (BSFS scores 6 or 7); or
    2. More than 3 bowel movements per day on average with >25% of them being BSFS type 6 or 7
11. 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
12. 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

13. 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:

    1. Abstinence from heterosexual intercourse
    2. Systemic contraceptives (combined birth control pills, injectable/implant/insertable hormonal birth control products, transdermal patch)
    3. Intrauterine device (with or without hormones)
    4. 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:

1. Patients with known or suspected intestinal strictures of clinical relevance as judged by the Investigator
2. Active inflammatory bowel disease (IBD) or fistula during the screening period as judged by the Investigator
3. Crohn's disease patients not being in clinical remission for the last 12 weeks prior to randomization
4. Diarrhea caused by other causes than SBS
5. Presence of clinically significant steatorrhea, requiring pancreatic enzymes supplementation
6. Presence of complete biliary obstruction
7. 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
8. History of allergic reaction to cholestyramine or any excipient of the investigational drug product or placebo, or packaging components
9. Females who are lactating at screening
10. Females who are pregnant according to the pregnancy test at screening or prior to the first study treatment administration
11. 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)
12. Subjects who took an Investigational Product (IP) in the 30 days prior to the first study drug administration
13. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: "Low" Dose ECC Regimen; 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; Enteric-Coated Delayed Release Cholestyramine Capsules; Drug: Placebo; Enteric-Coated Delayed Release Placebo Capsules
Experimental: "High" Dose ECC Regimen; 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; Enteric-Coated Delayed Release Cholestyramine Capsules

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Pharmascience Inc.
• Investigators: Principal Investigator: Marek Kunecki, MD, PhD, Wojewódzki Specjalistyczny Szpital im. M. Pirogowa w Łodzi; Principal Investigator: Konrad Matysiak, MD, PhD, Solumed Centrum Medyczne; Principal Investigator: Kinga Szczepanek, MD, Szpital Wielospecjalistyczny im. Stanleya Dudricka

Study record dates

Study Major Dates

• Study Start (Actual): October 15, 2019
• Primary Completion (Actual): December 22, 2021
• Study Completion (Actual): December 22, 2021

Study Registration Dates

• First Submitted: July 26, 2019
• First Submitted That Met QC Criteria: August 2, 2019
• First Posted (Actual): August 6, 2019

Study Record Updates

• Last Update Posted (Actual): July 19, 2022
• Last Update Submitted That Met QC Criteria: June 23, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Postoperative Complications; Disease; Gastrointestinal Diseases; Intestinal Diseases; Malabsorption Syndromes; Syndrome; Short Bowel Syndrome; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Cholestyramine Resin
• Other Study ID Numbers: PMS-2018-002; 2018-004419-32 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No