Primary Bile Acid Malabsorption | Obeticholic Acid in Bile Acid Diarrhoea
Primary Bile Acid Malabsorption research study
What is the primary objective of this study?
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.
Who is eligible to participate?
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
Which medical condition, disease, disorder, syndrome, illness, or injury is researched?
Primary Bile Acid Malabsorption
Secondary Bile Acid Malabsorption
Interventions can include giving participants drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available or noninvasive approaches such as surveys, education, and interviews.
Drug:Obeticholic acidDay -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.
Research studies and clinical trials typically have two or more research arms. An arm is a group of people who receive the same treatment in the study.
Obeticholic acidObeticholic acid 25mg once daily for 15 days.
Start Date: April 2012
Completed Date: February 2014
Phase: Phase 2
Primary Outcome: Fasting FGF19
Secondary Outcome: Non-fasting response of FGF19 to OCA
Study sponsors, principal investigator, and references
Principal Investigator: Julian RF Walters, MBBS MA FRCP
Lead Sponsor: Imperial College London
Wedlake L, A'Hern R, Russell D, Thomas K, Walters JR, Andreyev HJ. Systematic review: the prevalence of idiopathic bile acid malabsorption as diagnosed by SeHCAT scanning in patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2009 Oct;30(7):707-17. doi: 10.1111/j.1365-2036.2009.04081.x. Epub 2009 Jun 30. Review.