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Effect of the Sequestrant Colesevelam in Bile Acid Diarrhoea (SINBAD)

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ClinicalTrials.gov Identifier: NCT03876717
Recruitment Status : Recruiting
First Posted : March 15, 2019
Last Update Posted : March 15, 2019
Sponsor:
Collaborator:
Pierre and Marie Curie University
Information provided by (Responsible Party):
Lars Kristian Munck, Zealand University Hospital

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. 140 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.


Condition or disease Intervention/treatment Phase
Bile Acid Malabsorption Chronic Diarrhea Drug: Colesevelam Hydrochloride Drug: Placebo oral capsule Phase 4

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 140 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Parallel arms, randomized 1:1 allocation.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: 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.
Primary Purpose: Treatment
Official Title: Treatment Effect of Colesevelam for Bile Acid Diarrhoea - a Randomised Placebo-controlled Trial
Actual Study Start Date : January 1, 2019
Estimated Primary Completion Date : September 30, 2020
Estimated Study Completion Date : March 1, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Diarrhea

Arm Intervention/treatment
Experimental: Colesevelam, active arm

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
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.
Other Name: Cholestagel

Placebo Comparator: Placebo
Inactive placebo tablets. Overencapsulated with DB caps AAA for blinding. Oral use. Dosage and treatment duration as specified for colesevelam
Drug: Placebo oral capsule
Inactive placebo tablets over-encapsulated with DB caps AAA
Other Name: Inactive placebo




Primary Outcome Measures :
  1. Intention-to-treat diarrhoea remission rate defined by the Hjortswang criteria for colesevelam in patients with BAD defined by C4 ≥ 15.4 ng/mL [ Time Frame: Intervention days 6 through 12 (last seven intervention days) ]

Secondary Outcome Measures :
  1. Per protocol diarrhoea remission rate defined by the Hjortswang criteria for colesevelam in patients with BAD defined by C4 ≥ 15.4 ng/mL [ Time Frame: Intervention days 6 through 12 (last seven intervention days) ]
  2. Intention-to-treat diarrhoea remission rate defined by the Hjortswang criteria for colesevelam in patients with BAD defined by SeHCAT <= 10% [ Time Frame: Intervention days 6 through 12 (last seven intervention days) ]
  3. Per protocol diarrhoea remission rate defined by the Hjortswang criteria for colesevelam in patients with BAD defined by SeHCAT <= 10% [ Time Frame: Intervention days 6 through 12 (last seven intervention days) ]
  4. placebo-controlled effect of colesevelam in patients with bile acid diarrhoea defined by C4 on the absolute number of stools as mean per day over 6 or 7 days [ Time Frame: Baseline period compared with Intervention days 6 through 12 (last seven intervention days) ]
  5. placebo-controlled effect of colesevelam in patients with bile acid diarrhoea defined by C4 on the total number of Bristol type 6 and 7 stools as a mean over 6 or 7 days [ Time Frame: Baseline period compared with Intervention days 6 through 12 (last seven intervention days) ]
  6. Intention-to-treat diarrhoea remission rate defined by the Hjortswang criteria for colesevelam in patients with BAD defined by FGF19 <= 85 pg/mL [ Time Frame: Baseline period compared with Intervention days 6 through 12 (last seven intervention days) ]
  7. Difference in change in Health related quality of life (HRQoL) in the primary endpoint population by the Short Form 36 version 2 (SF36v2) Physical component score (colesevelam vs. placebo) [ Time Frame: Change from baseline period compared with Intervention days 6 through 12 (last seven intervention days) ]
  8. Difference in change in Health related quality of life (HRQoL) in the primary endpoint population by the Short Form 36 version 2 (SF36v2) Mental component score (colesevelam vs. placebo) [ Time Frame: Change from baseline period compared with Intervention days 6 through 12 (last seven intervention days) ]
  9. Placebo-controlled subject assessed "good response" ITT rate in the primary endpoint population [ Time Frame: Baseline period compared with Intervention days 6 through 12 (last seven intervention days) ]
  10. Placebo-controlled ITT diarrhoea remission rate defined by the Hjortswang criteria for colesevelam in patients with non-BAD, ie. defined by C4 < 15.4 ng/mL [ Time Frame: Baseline period compared with Intervention days 6 through 12 (last seven intervention days) ]

Other Outcome Measures:
  1. Placebo-controlled remission rates (ITT+ PP) for colesevelam defined by the Hjortswang criteria in patients with BAD defined by SeHCAT <=5% [ Time Frame: Baseline period compared with Intervention days 6 through 12 (last seven intervention days) ]
  2. Placebo-controlled remission rates (ITT+ PP) for colesevelam defined by the Hjortswang criteria in patients with BAD defined by SeHCAT <=15% [ Time Frame: Baseline period compared with Intervention days 6 through 12 (last seven intervention days) ]
  3. Intention-to-treat and per-protocol diarrhoea remission rate defined by the Hjortswang criteria for colesevelam in non-BAD [ Time Frame: Baseline period compared with Intervention days 6 through 12 (last seven intervention days) ]
    Separately for non-BAD defined by 1) C4 < 15.4 ng/mL and by 2) SeHCAT > 10%

  4. The placebo-controlled effect of colesevelam in non BAD-patients on the absolute number of stools [ Time Frame: Baseline period compared with Intervention days 6 through 12 (last seven intervention days) ]
    Separately for non-BAD defined by 1) C4 < 15.4 ng/mL and by 2) SeHCAT > 10%

  5. ROC analysis (dichotomous positive/negative) of C4, SeHCAT, FGF19, subject assessed "good response", with response by Hjortswang criteria as gold standard. [ Time Frame: Baseline period compared with Intervention days 6 through 12 (last seven intervention days) ]
    Positive tests: for C4 ≥ 15.4ng/mL, for SeHCAT ≤ 10%, for FGF19 ≤ 85pg/mL.

  6. Validation of C4 cut-off ≥ 15.4ng/mL with SeHCAT ≤ 10% for diagnosing BAD [ Time Frame: Baseline period compared with Intervention days 6 through 12 (last seven intervention days) ]
  7. Test-retest variability of baseline C4 assessed with a Bland-Altman plot [ Time Frame: Baseline day 1 vs day 8 (before treatment start) ]
  8. Test-retest variability of baseline FGF19 assessed with a Bland-Altman plot [ Time Frame: Baseline day 1 vs day 8 (before treatment start) ]
  9. Exploratory assessment of the effect on C4 test-retest variability assessed with a Bland-Altman plot comparing C4 measured on baseline day 1 possibly affected by different factors compared with 'gold standard' C4 measured on day 8. [ Time Frame: Baseline day 1 versus day 8 ]
    Possible day 1 factors: 1) late sampling time, 2) statin use, and 3) alcohol intake.

  10. Health-related quality of life Short Form 36 v.2 item 'Physical Component Score (range 0-100)' correlated with diarrhoea symptoms [ Time Frame: Baseline, last seven treatment days and six-month follow-up. ]
  11. Health-related quality of life Short Form 36 v.2 item 'Mental Component Score (range 0-100)' correlated with diarrhoea symptoms [ Time Frame: Baseline, last seven treatment days and six-month follow-up. ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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
  • Allergy to placebo constituents (excluding lactose)
  • Investigator assessed high risk of non-compliance
  • If on statin/fibrate medication, unwilling to pause medication between study visits 1 and 2

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03876717


Contacts
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Contact: Lars K Munck, DMSci +45 47322400 lkmu@regionsjaelland.dk
Contact: Christian Borup, MD +45 23328035 chrbo@regionsjaelland.dk

Locations
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Denmark
Aalborg University Hospital Enrolling by invitation
Aalborg, Denmark, 9000
Aarhus University Hospital Enrolling by invitation
Aarhus, Denmark, 8200
Hvidovre University Hospital Recruiting
Hvidovre, Denmark, 2650
Contact: Christian Borup, MD       chrbo@regionsjaelland.dk   
Zealand University Hospital Recruiting
Køge, Denmark, 4600
Contact: Christian Borup, MD    +45 23328035    chrbo@regionsjaelland.dk   
Principal Investigator: Christian Borup, MD         
Sponsors and Collaborators
Lars Kristian Munck
Pierre and Marie Curie University
  Study Documents (Full-Text)

Documents provided by Lars Kristian Munck, Zealand University Hospital:

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Responsible Party: Lars Kristian Munck, Senior Physician, Clinical Associate Professor, Sponsor-Investigator, Zealand University Hospital
ClinicalTrials.gov Identifier: NCT03876717     History of Changes
Other Study ID Numbers: SJ-641
First Posted: March 15, 2019    Key Record Dates
Last Update Posted: March 15, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

An electronic Data Management Plan has been created on dmponline.dcc.ac.uk with details on management of raw data, refined data, metadata, organising, storing, backup, sharing, and curation of the data The biological material is saved anonymously and destroyed 15 years after study end.

Positive and negative results will be published in an international peer-reviewed journal. We regard the study protocol, consent form, questionnaires, statistical analysis plan, raw data, refined data, statistical code, and metadata as long-term valuable data to be shared after de-identification in the repository of the Danish National Archives to be available after the primary article is published. Data access is unrestricted and indefinite and with investigator assistance for the first 36 months.

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (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.
URL: https://dmponline.dcc.ac.uk/

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Diarrhea
Malabsorption Syndromes
Signs and Symptoms, Digestive
Signs and Symptoms
Intestinal Diseases
Gastrointestinal Diseases
Digestive System Diseases
Metabolic Diseases
Colesevelam Hydrochloride
Bile Acids and Salts
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Gastrointestinal Agents