Effect of the Sequestrant Colesevelam in Bile Acid Diarrhoea

NCT03876717 | Completed Phase 4 DMC

• 1 other identifier: SJ-641
• Study Type: interventional
• Target: 255
• Locations: 1 country
• Sites: 4

Brief Summary

Bile acid diarrhoea is a chronic disease that impairs quality of life. One in 100 has the condition and many suffer from the disease without knowing. The current test is called SeHCAT and is expensive and time-consuming and is unavailable in many places, including the US. The disease is often misdiagnosed as irritable bowel syndrome and estimated one third of patients with irritable bowel syndrome of the mixed type and the diarrhoea predominant type suffer from bile acid diarrhoea without knowing. A blood test called 7α-hydroxy-4-cholestene-3-one (C4) could make it much easier to diagnose bile acid diarrhoea. To establish the new test, the results of both C4 and SeHCAT are compared with the treatment effect of the drug called colesevelam. We invite patients who are referred for the SeHCAT test to participate in the trial. The SeHCAT test takes two days that are one week apart. The study patients register stool habits with a diary in the week between the SeHCAT visits. Based on the diary results, we screen for eligibility; e.g. a certain degree/severity of diarrhoea is required for participation. We treat eligible study patients (i.e those with diarrhoea) with either colesevelam or placebo (medicine without effect) that is randomly assigned. 170 study patients need to complete the treatment. We aim to validate (ie. compare) both the C4-test and the SeHCAT test with the colesevelam treatment response as the reference.

Conditions

Bile Acid Malabsorption; Chronic Diarrhea

Outcome Measures

Primary Outcomes (1)

• Intention-to-treat diarrhoea remission rate defined by the Hjortswang criteria for colesevelam in patients with BAD defined by C4 > 46 ng/mL

  drop-outs are set as treatment failures in the ITT analysis if less than five of the last seven treatment days that comprise the endpoint assessment period are complete. If five or more of these days are complete, a mean of these days will be used for calculating the Hjortswang response criterium. We will fit an appropriate generalized linear mixed-effects model with an unstructured covariance pattern of the chance of response with colesevelam versus placebo. In addition, baseline adjustments for the severity of diarrhoea (mean per day sum of Bristol type 6 and 7 stools) and the severity of bile acid malabsorption (visit 2 C4 value) will be made

  Intervention days 6 through 12 (last seven intervention days)

Secondary Outcomes (6)

• Per protocol diarrhoea remission rate defined by the Hjortswang criteria for colesevelam in patients with BAD defined by C4 > 46 ng/mL

  Intervention days 6 through 12 (last seven intervention days)

• Intention-to-treat diarrhoea remission rate defined by the Hjortswang criteria for colesevelam in patients with BAD defined by SeHCAT <= 10%

  Intervention days 6 through 12 (last seven intervention days)

• Per protocol diarrhoea remission rate defined by the Hjortswang criteria for colesevelam in patients with BAD defined by SeHCAT <= 10%

  Intervention days 6 through 12 (last seven intervention days)

• placebo-controlled effect of colesevelam in patients with bile acid diarrhoea defined by C4 >46 ng/mL on the absolute number of stools as mean per day over 6 or 7 days

  Baseline period compared with Intervention days 6 through 12 (last seven intervention days)

• placebo-controlled effect of colesevelam in patients with bile acid diarrhoea defined by C4 >46 ng/mL on the total number of Bristol type 6 and 7 stools as a mean over 6 or 7 days

  Baseline period compared with Intervention days 6 through 12 (last seven intervention days)

Study Arms (2)

Colesevelam, active arm

EXPERIMENTAL

Colesevelam hydrochloride, 625mg tablets. Overencapsulated with DB caps AAA for blinding. Oral use. Dose: 1, 2, or 3 capsules twice daily. Starting dose 2 capsules twice daily. Dose titration by specific criteria by a central study nurse Treatment duration 12 days

Drug: Colesevelam Hydrochloride

Placebo

PLACEBO COMPARATOR

Inactive placebo tablets. Overencapsulated with DB caps AAA for blinding. Oral use. Dosage and treatment duration as specified for colesevelam

Drug: Placebo oral capsule

Interventions

Colesevelam Hydrochloride DRUG

Colesevelam is a sequestrant that binds bile acids in the intestinal lumen, the bile acids are then excreted with the feces. Colesevelam is registered for treating hypercholesterolemia but it is as other sequestrants (e.g. cholestyramine and colestipol) effective against bile acid diarrhoea.

Also known as: Cholestagel

Colesevelam, active arm

Placebo oral capsule DRUG

Inactive placebo tablets over-encapsulated with DB caps AAA

Also known as: Inactive placebo

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient referred to Clinical Physiological/Nuclear Medicine departments for SeHCAT
• Suspected Bile acid diarrhoea
• Age \> 18 years and under 80 years
• women of fertile age must use safe contraception during the treatment part of the study
• Ability to give informed consent after written and oral information in Danish language

You may not qualify if:

• Inflammatory bowel disease, including microscopic colitis
• Investigator assessed debilitating chronic disease e.g. World Health Organisation performance score 3-5
• Prior treatment with colesevelam
• Treatment with laxatives or anti-diarrhoeal drugs during the study
• Except for stable dose the last four weeks of psyllium husk and opioids for pain
• Breastfeeding women
• Crucial medication that cannot be separated appropriately from colesevelam
• i.e. taken one hour before or 4 hours after colesevelam
• Oral anticoagulation, both warfarin, and new oral anticoagulation
• Treatment with cyclosporine within two months
• Bowel obstruction (subileus or ileus)
• Biliary obstruction
• Short bowel syndrome
• Bowel ostomy
• Allergy to colesevelam or its constituents

Sponsors & Collaborators

• Lars Kristian Munck: lead
• Pierre and Marie Curie University: collaborator

Study Sites (4)

Aalborg University Hospital

Aalborg, 9000, Denmark

Location

Aarhus University Hospital

Aarhus, 8200, Denmark

Location

Hvidovre University Hospital

Hvidovre, 2650, Denmark

Location

Zealand University Hospital

Køge, 4600, Denmark

Location

Related Publications (2)

• Borup C, Vinter-Jensen L, Jorgensen SPG, Wildt S, Graff J, Gregersen T, Zaremba A, Andersen TB, Nojgaard C, Timm HB, Lamaziere A, Rainteau D, Hansen SH, Rumessen JJ, Munck LK. Prospective comparison of diagnostic tests for bile acid diarrhoea. Aliment Pharmacol Ther. 2024 Jan;59(1):39-50. doi: 10.1111/apt.17739. Epub 2023 Oct 5.

  PMID: 37794830 DERIVED

• Borup C, Vinter-Jensen L, Jorgensen SPG, Wildt S, Graff J, Gregersen T, Zaremba A, Borup Andersen T, Nojgaard C, Timm HB, Rainteau D, Hansen SH, Rumessen JJ, Munck LK. Efficacy and safety of colesevelam for the treatment of bile acid diarrhoea: a double-blind, randomised, placebo-controlled, phase 4 clinical trial. Lancet Gastroenterol Hepatol. 2023 Apr;8(4):321-331. doi: 10.1016/S2468-1253(22)00401-0. Epub 2023 Feb 6.

  PMID: 36758570 DERIVED

MeSH Terms

Interventions

Colesevelam Hydrochloride

Intervention Hierarchy (Ancestors)

Allylamine; Amines; Organic Chemicals; Allyl Compounds; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Study subjects and all investigators are blinded. As effect and side effects of the active drug may demask the blinding, a central study nurse is the primary contact for the subjects during the intervention periode regarding everything except suspected/possible serious events.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Senior Physician, Clinical Associate Professor, Sponsor-Investigator

Model Details: Parallel arms, randomized 1:1 allocation.

Study Record Dates

• First Submitted: January 9, 2019
• First Posted: March 15, 2019
• Study Start: October 25, 2018
• Primary Completion: July 1, 2021
• Study Completion: February 13, 2022
• Last Updated: August 23, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR, ANALYTIC CODE
• Time Frame: De-identified data will be made available without restrictions after articles from the study have been published
• Access Criteria: Data access is unrestricted and indefinite and with investigator assistance for the first 36 months. Publications need proper citing.

Locations

DK (4)