Obeticholic Acid in Bile Acid Diarrhoea
Condition: Primary Bile Acid Malabsorption; Secondary Bile Acid Malabsorption; Chronic Diarrhoea
MeSH terms: Malabsorption Syndromes; Diarrhea
Intervention: Obeticholic acid
Intervention description: Day -14 to Day 0 subjects will stop their usual diarrhoeal medication. Day 1 to Day 15 Obeticholic acid 25mg tablet will be administered to subjects once daily in the morning. Day 16 to day 28 normal diarrhoeal medication may be re-commenced.
Intervention MeSH terms: Chenodeoxycholic Acid
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 35.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Primary bile acid malabsorption; Secondary bile acid malabsorption; Chronic diarrhoea; Obeticholic acid; SeHCAT; FXR; FGF19

Summary:

      The investigators propose to develop studies of obeticholic acid (OCA) in patients with bile
      acid diarrhoea. OCA is a semisynthetic bile acid, also known as 6αethylchenodeoxycholic acid
      or INT747,and is a potent farnesoid X receptor (FXR) agonist. Preliminary data suggests that
      patients with bile acid diarrhoea have impaired production of the ileal hormone Fibroblast
      Growth Factor 19 (FGF19). FGF19 is stimulated by FXR agonists, and regulates bile acid
      synthesis. This study is a pilot, proof-of-concept, open-label study to investigate whether
      OCA can stimulate FGF19 in bile acid diarrhoea patients to provide a safe and effective
      treatment.
    

Eligibility criteria:

        Inclusion Criteria Patients aged 18 - 80 who present at routine Gastrointestinal Outpatient
        Clinics at Hammersmith and Charing Cross Hospitals with chronic diarrhoea, defined as an
        average stool frequency of at least three per day, of Bristol Stool Type 6 or 7, for at
        least 3 months. Previous routine SeHCAT testing to establish the presence or absence of
        bile acid diarrhoea (BAD) unless there is evidence of TI disease/ resection. BAD will be
        defined as SeHCAT 7-day retention of less than 15% or diarrhoea in presence of TI disease/
        resection. Study subjects will be grouped as having secondary BAD, due to ileal resection
        or Crohn's disease, or primary BAD, with no obvious cause. The third, control group having
        chronic diarrhoea but with normal SeHCAT retention (greater than 15%).

        Female patients must be postmenopausal, surgically sterile, or if premenopausal, be
        prepared to use ≥ 1 effective (≤ 1% failure rate) method of contraception during the trial
        and for 15 days after the last dose of OCA. Male subjects with female partners of
        childbearing potential must use ≥ 1 effective method of contraception. Effective methods of
        contraception are considered to be: 1. Established use of oral, injected or implanted
        hormonal methods of contraception. 2. Placement of an intrauterine device (IUD) or
        intrauterine system (IUS). 3. Barrier methods of contraception: Condom or Occlusive cap
        (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository. 4.
        Male sterilisation (with the appropriate post-vasectomy documentation of the absence of
        sperm in the ejaculate). 5. True abstinence: When this is in line with the preferred and
        usual lifestyle of the subject.

        Exclusion Criteria

          -  Patients with other diagnoses leading to diarrhoea, including colorectal neoplasia,
             ulcerative colitis, coeliac disease, chronic pancreatitis, drug-induced diarrhoea or
             active infection.

          -  Patients who have not been investigated by standard clinical assessments to exclude
             these disorders.

          -  Treatment with bile acid sequestrants (colestyramine, colestipol, colesevelam) for 2
             weeks before the first dose of OCA. Loperamide use will be allowed up to 16mg/d in
             divided doses.

          -  Previous biliary surgery, excluding cholecystectomy.

          -  Abnormal bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST)
             or alkaline phosphatase on more than 1 occasion.

          -  Chronic liver disease

          -  Chronic kidney disease

          -  Active, serious medical disease with likely life expectancy less than 5 years

          -  Active substance abuse including inhaled or injection drugs in the year prior to
             screening

          -  Allergy to obeticholic acid.

          -  Pregnancy, planned pregnancy, potential for pregnancy and unwillingness to use
             effective birth control during the trial, breast feeding. Pregnancy will be assessed
             with urinary β-hCG pregnancy test.

          -  Participation in an investigational new drug trial in the 30 days before randomisation

          -  Any other condition which, in the opinion of the investigator, would impede compliance
             or hinder completion of the study

          -  Failure to give informed consent