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

Overview

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.

Full Title of Study: “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”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Crossover Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: April 2021

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.

Interventions

  • Drug: Enteric-Coated Cholestyramine (ECC) Capsule
    • Enteric-Coated Delayed Release Cholestyramine Capsules
  • Drug: Placebo
    • Enteric-Coated Delayed Release Placebo Capsules

Arms, Groups and Cohorts

  • Experimental: “Low” Dose ECC Regimen
    • ECC at the 1.7 g daily dose, administered BID 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.
  • Experimental: “High” Dose ECC Regimen
    • ECC at the 4.25 g daily dose, administered BID as 5 capsules of ECC at least 30 minutes before breakfast and 5 capsules of ECC at least 30 minutes before evening meal.

Clinical Trial Outcome Measures

Primary Measures

  • Change in the weekly frequency of bowel movements measured between baseline and the second week of treatment
    • Time Frame: Days 8 to 14, and Days 36 to 42

Secondary Measures

  • Total number of bowel movements per week, after the first week of treatment
    • Time Frame: Days 1 to 7, and Days 29 to 35
  • Total number of bowel movements for the whole 2-week treatment period
    • Time Frame: Days 1 to 14 and Days 29 to 42
  • Mean daily stool form score according to the Bristol Stool Form Scale (BSFS), measured during the first week of treatment.
    • Time Frame: Days 1 to 7, and Days 29 to 35
    • The BSFS (Bristol Stool Form Scale) 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.
  • Mean daily stool form score according to the BSFS, measured during the second week of treatment
    • Time Frame: Days 8 to 14, and Days 36 to 42
    • The BSFS (Bristol Stool Form Scale) 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.
  • Mean daily stool form score according to the BSFS, measured during the whole 2-week treatment period
    • Time Frame: Days 1 to 14 and Days 29 to 42
    • The BSFS (Bristol Stool Form Scale) 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.
  • Total number of bowel movements with a BSFS score ≥ 6 during the first week of treatment
    • Time Frame: Days 1 to 7, and Days 29 to 35
    • The BSFS (Bristol Stool Form Scale) 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.
  • Total number of bowel movements with a BSFS score ≥ 6 during the whole 2-week treatment period
    • Time Frame: Days 1 to 14 and Days 29 to 42
    • The BSFS (Bristol Stool Form Scale) 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.
  • Mean daily dose of loperamide in mg, if used, during the second week of treatment
    • Time Frame: Days 8 to 14, and Days 36 to 42
  • Mean Diarrhea Composite Index ([weekly bowel movement frequency X mean daily BSFS score] + loperamide use [weekly mg X 3]) during the second week of treatment
    • Time Frame: Days 8 to 14, and Days 36 to 42
  • Safety – Hematology (Percentage of participants with clinically significant shift changes from baseline in hematology)
    • Time Frame: Screening (Day -15), Day 15, Day 28, Day 43 (end of study)
  • Safety – Serum Chemistry (Percentage of participants with clinically significant shift changes from baseline in serum chemistry)
    • Time Frame: Screening (Day -15), Day 15, Day 28, Day 43 (end of study)
  • Safety – Urinalysis (Percentage of participants with clinically significant shift changes from baseline in urinalysis)
    • Time Frame: Screening (Day -15), Day 15, Day 28, Day 43 (end of study)
  • Safety – Vital Signs (Percentage of participants with clinically significant shift changes from baseline in vital signs)
    • Time Frame: Screening (Day -15), Day 0, Day 15, Day 28, Day 43 (end of study)
  • Safety – Physical Examination (Percentage of participants with clinically significant shift changes from baseline in physical examination findings)
    • Time Frame: Screening (Day -15), Day 15, Day 28, Day 43 (end of study)
  • Safety – ECG (Percentage of participants with clinically significant shift changes from baseline in ECG findings)
    • Time Frame: Screening (Day -15), Day 43 (end of study)
  • Safety (to be evaluated through the assessment of adverse events (AE))
    • Time Frame: Through study completion (an average of 1 year)
  • Tolerability (to be evaluated through assessment of TEAEs and TESAEs)
    • Time Frame: Through study completion (an average of 1 year)
  • Evaluation of severity of diarrhea, abdominal pain, urgency and bloating using an 11-point Visual Analog Scale (VAS)
    • Time Frame: Days 0 (baseline), 15, 28 and 43
    • The VAS (Visual Analog Scale) is a continuous, linear scale from 0 to 10 where participants will indicate average symptom severity experienced over the past 24 hours. A score of 0 indicates “no symptom” and a score of 10 indicates “very severe”.

Participating in This Clinical Trial

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 4 times a week throughout the trial 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.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 80 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Pharmascience Inc.
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Marek Kunecki, MD, PhD, Principal Investigator, Wojewódzki Specjalistyczny Szpital im. M. Pirogowa w Łodzi
    • Konrad Matysiak, MD, PhD, Principal Investigator, Solumed Centrum Medyczne
    • Kinga Szczepanek, MD, Principal Investigator, Szpital Wielospecjalistyczny im. Stanleya Dudricka
  • Overall Contact(s)
    • Sophie Tanguay, M.Sc., 438-315-3593, stanguay@pharmascience.com

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