Effect of the Sequestrant Colesevelam in Bile Acid Diarrhoea
Condition: Bile Acid Malabsorption; Chronic Diarrhea
MeSH terms: Malabsorption Syndromes; Diarrhea
Study type: Interventional
Phase: Phase 4

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.
    

Detailed description: 
      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

        1. To determine the efficacy and safety of colesevelam for treating Bile Acid Diarrhoea

           and

        2. 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

        1. We send a written invitation to eligible patients who already are referred for SeHCAT

        2. 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.

        1. SeHCAT results are registered once available

        2. 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
    

Intervention name(s): Colesevelam Hydrochloride; Placebo oral capsule
Intervention type(s): Drug; Drug
Intervention description(s): 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.; Inactive placebo tablets over-encapsulated with DB caps AAA
Other intervention name(s): Cholestagel; Inactive placebo
Intervention MeSH terms: Colesevelam Hydrochloride
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Parallel arms, randomized 1:1 allocation.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment