Effect of the Sequestrant Colesevelam in Bile Acid Diarrhoea

Study Overview
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Brief Summary
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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.

Detailed Description
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ISSUE Bile Acid Diarrhoea (BAD) affects 1% of the general population and many people live with the disease and the impaired quality of life it causes without knowing it. The current scintigraphic seleno-homo-taurocholic acid retention test (SeHCAT) is time-consuming, expensive and causes a diagnostic bottleneck. the SeHCAT test is unavailable in many countries including the US. The biomarker 7α-hydroxy-4-cholesten-3-one (C4) could provide a cheap and available diagnostic option to surmount the issue of the many undiagnosed patients. The pivotal step for this is validation of the C4-test with the placebo-controlled treatment effect. PURPOSE To determine the efficacy and safety of colesevelam for treating Bile Acid Diarrhoea and 2. To correlate both the current scintigraphic 75-Selenium conjugated Tauro-homocholic acid retention test (SeHCAT) and the biochemical marker of BAD 7alpha-hydroxy-4-cholesten-3-one (C4) with colesevelam treatment response, and to validate the cut-off values determined in the 'VABAD' trial BACKGROUND Chronic diarrhoea affects 4-5% of the Western adult population and often results in specialist referral and endoscopies. Availability of the diagnostic SeHCAT test for BAD is limited, and BAD is often mistaken for the Irritable Bowel Syndrome (IBS). 32% of patients with two of the three IBS subtypes have BAD and the prevalence of BAD in the general population is thus approximately 1%. DIAGNOSIS of Bile Acid Diarrhoea The current diagnostic test for BAD is the SeHCAT scintigraphic retention test using 75Selenium labelled Homo-tauro-cholic acid. The γ-emission is measured on day 1 and again on day 8. Seven-day SeHCAT retention rates of <5% represent severe BAD, <10% moderate BAD, and <15% mild BAD. Although not properly validated, in observational studies 70-80% of patients with SeHCAT <10% report a good response to cholestyramine. SeHCAT is unavailable in many countries including the the US, and clinicians instead rely on the patient's response to a therapeutic trial. However, the non-specific action and multiple side effects of the first line treatment with cholestyramine gives rise to multiple diagnostic pitfalls. BIOMARKERS of Bile Acid Diarrhoea The recent increased insight into bile acid homeostasis and regulation has identified two biomarkers of BAD that may replace SeHCAT. 7α-hydroxy-4-cholestene-3-one (C4) is a bile acid precursor that correlates with bile acids synthesis rate. C4 is increased in BAD and has a sensitivity of 87% and specificity of 86% for diagnosing BAD defined by SeHCAT <10%. However, analysis of C4 is technically difficult and is thus primarily used at centres with special interest and no access to SeHCAT. Another biomarker Fibroblast Growth Factor 19 (FGF19) is released to the portal circulation from the terminal ileum in response to bile acid absorption. In the liver, FGF19 inhibits bile acid synthesis enticing a negative feedback loop. Fasting values of FGF19 correlate inversely with C4 and with SeHCAT, but the sensitivity of 67% and specificity of 77% for detecting even severe BAD is clinically insufficient. Performance of the biomarkers in a modern Danish population The investigators studied C4 and FGF19 in two pilot studies in selected populations and further established a Danish national collaboration with four university hospitals and prospectively recruited 71 subjects. The positive test cut-off C4 ≥ 46 ng/mL had 52% sensitivity and 91% specificity for detecting BAD defined by SeHCAT ≤ 10%. The analysis of these results and the literature suggest that taking account of liver cirrhosis, hyperbilirubinemia, and use of alcohol and statins may increase the diagnostic yield of C4. TREATMENT OF BILE ACID DIARRHOEA Sequestrants bind bile acids in the intestinal lumen and thus alleviate the diarrhoea symptoms. The first line therapy is cholestyramine, but this powder-formulation is distasteful with a low patient acceptability. Colesevelam tablets are much better tolerated, and therefore placebo-controlled studies of colesevelam for BAD are warranted. A systematic review found cholestyramine to be effective in 70% of BAD patients. A placebo-controlled trial of colesevelam in patients with suspected type 1 BAD. Diarrhoea intention-to-treat remission rates were 67% for colesevelam and 27% for placebo (p=0.057), but extreme selection criteria slowed recruitment and the study ended prematurely. Of note, only one of 19 dropped out due to side effects to colesevelam. In summary, colesevelam and cholestyramine have similar response rates of 70%. For a clinical trial, colesevelam is superior due to effective blinding and a much lower dropout rate. METHODS Effect parameters in chronic diarrhoea Symptoms reported by diary The Bristol stool form scale (BSFS) classifies stool from 1 (hard lumps) to 7 (completely watery). Clinical trials often use a seven-day diary. Patients with an organic cause of diarrhoea more often have ≥3 stools per day or a consistently watery stool consistency (BSF≥6) than those who have a functional cause of the diarrhoea. Criteria for activity and remission of diarrhoea (Hjortswang's criteria) Hjortswang correlated chronic diarrhoea symptoms with impact on quality of life for patients with microscopic colitis, and validated the definition of clinical activity as ≥ 3 stools per day or ≥ 1 watery stool (BSF 6-7) and remission as <3 stools per day and < 1 watery stool as a mean of the seven-day diary. MEDICINE Colesevelam The hospital pharmacy of the Capital Region over-encapsulates colesevelam tablets with Capsugel® DBcaps® Placebo Matrix placebo tablets, over-encapsulated as the colesevelam tablets. No side effects are expected. Dose: One, two or three capsules of 625mg twice daily. The dose is titrated by a central blinded study nurse without contact to the investigators. POWER CALCULATION Assumed remission rate of 67% for colesevelam and 27% for placebo. two-sided α = 0.05 and β = 0.20 (ie. 80% power). 1:1 allocation. This gives 23 subjects with BAD in each arm (G.Power 3.1: z-test of two independent proportions). 27% of subjects in our prospective pilot study that would be eligible for the SINBAD study had SeHCAT <10%. Thus, (2 x 23 / 27%) = 170 subjects. BIOCHEMISTRY C4 and bile acid species are analysed with liquid chromatography - tandem mass spectrometry. FGF19 is analysed with ELISA (R&D Systems, MN, USA). The hospital laboratories of the participating centres perform the routine biochemical analyses. STUDY PLAN Pre-screening We send a written invitation to eligible patients who already are referred for SeHCAT At the first SeHCAT visit, further information is provided and voluntary informed consent is obtained. Study visit 1 - Day 1: start of baseline registration The investigator creates an electronic Case Record Form (EasyTrial) including medical and surgical history, medication, and physical status. Baseline blood analyses include ALT, ALP, bilirubin, amylase; and on indication HCG. The investigator notifies the referring doctor. The participants start Study Diary 1 (screening+baseline). Study visit 2 - Day 8: Screening results - randomisation This is concurrent with the second SeHCAT visit. All subjects meet in the fasting for blood sampling. All subjects answer the baseline questionnaires (SHS, GSRS, SF36v2). The screening diary is assessed: Subjects without diarrhoea: cannot continue to randomisation. SeHCAT results are registered once available Result of the diagnostic work-up is registered at a six-month telephone follow-up. Subjects with diarrhoea: continue to randomisation. The subject is given a uniquely numbered treatment package starts Study Diary 2 is telephoned by the central study nurse for the planning of dose titration Telephone consultation - Day 9 (treatment day 2): The study nurse takes a history of adverse events and titres the dose Telephone consultation - day 13 (± 1 day): End of Run-in-period As on day 9. Ad hoc telephone consultations Any change in dose mandates a follow-up telephone consult after 2-3 days. Study visit 3 - Day 21 (+ 1-3 days) Intervention-End The intervention has ended on day 20. The investigator: Collects Study Diary 2 Takes a history of AEs Collects surplus medication to assess compliance Distributes questionnaires Orders follow-up blood analysis Schedules study-end telephone consultation Telephone consultation - Study day 26 (± 2 day): Clinical Study end AE registration continues three days after the end of treatment. The investigator: Assess biochemical AEs o Informs of results Takes a history of AEs Takes action if needed Six-month follow-up The questionnaires are redistributed. The patient's Medical file is checked and a telephone interview is done to note any conclusive diagnosis on the patients diarrhoea and (if any) anti-diarrhoea medication

Official Title
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Treatment Effect of Colesevelam for Bile Acid Diarrhoea - a Randomised Placebo-controlled Trial

Conditions
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Bile Acid Malabsorption, Chronic Diarrhea

Intervention / Treatment
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* Drug: Colesevelam Hydrochloride
* Drug: Placebo oral capsule


Participation Criteria
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Eligibility Criteria
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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

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: Parallel Assignment
Interventional Model Description: Parallel arms, randomized 1:1 allocation.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Colesevelam, active arm<br>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<br>* 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.<br>* Other names: Cholestagel;|
| Placebo Comparator: Placebo<br>Inactive placebo tablets. Overencapsulated with DB caps AAA for blinding. Oral use. Dosage and treatment duration as specified for colesevelam | Drug: Placebo oral capsule<br>* Inactive placebo tablets over-encapsulated with DB caps AAA<br>* Other names: Inactive placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Per protocol diarrhoea remission rate defined by the Hjortswang criteria for colesevelam in patients with BAD defined by C4 > 46 ng/mL | this is an efficacy (de jure) estimand for colesevelam. Modelling as for the primary endpoint but with imputation of missing data as if all patients had adhered. This includes all patients with bile acid diarrhoea and complies with a per protocol principle. | 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% | Statistical analysis: as the primary endpoint but with baseline adjustment for SeHCAT, not C4. Sensitivity analyses: as for the primary endpoint. Instead of differing C4 cutoffs, the SeHCAT cutoffs ≤ 5%, and ≤ 15% will be assessed | 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% | Statistical analysis: this is an efficacy (de jure) estimand for colesevelam. Modelling as for the primary endpoint with baseline adjustment for SeHCAT and with imputation of missing data as if all patients had adhered. | 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 | Statistical analysis: as for the primary endpoint but instead of the binary Hjortswang response criteria as outcome, continuous variables will be modelled with suiting baseline adjustment | 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 | Statistical analysis: as for the primary endpoint but instead of the binary Hjortswang response criteria as outcome, continuous variables will be modelled with suiting baseline adjustment | Baseline period compared with Intervention days 6 through 12 (last seven intervention days) | 
| The de facto effectiveness of colesevelam on health related quality of life assessed as the sum of Short Health Scale scores | Statistical analysis: modelling with adjustment for baseline SHS score | Baseline period compared with Intervention days 6 through 12 (last seven intervention days) |