Obeticholic Acid in Bile Acid Diarrhoea (OBADIAH1)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Imperial College London
ClinicalTrials.gov Identifier:
NCT01585025
First received: April 23, 2012
Last updated: September 5, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Primary Bile Acid Malabsorption
Secondary Bile Acid Malabsorption
Chronic Diarrhoea
Drug: Obeticholic acid
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacodynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Obeticholic Acid Treatment in Patients With Bile Acid Diarrhoea: an Open-label, Pilot Study of Mechanisms, Safety and Symptom Response.

Resource links provided by NLM:


Further study details as provided by Imperial College London:

Primary Outcome Measures:
  • Fasting FGF19 [ Time Frame: 15 days ] [ Designated as safety issue: No ]
    The primary outcome measure is the change over 2 weeks in fasting serum fibroblast growth factor (FGF19) in 3 groups of patients: primary bile acid diarrhoea, secondary bile acid diarrhoea, and a control population of patients with chronic diarrhoea but with normal bile acid retention.


Secondary Outcome Measures:
  • Non-fasting response of FGF19 to OCA [ Time Frame: 15 days ] [ Designated as safety issue: No ]
    Change in dynamic response of FGF19 in 6 hours following OCA administration; at start and end of 15 day OCA test period.

  • Fasting 7α-hydroxy-4-cholesten-3-one [ Time Frame: 15 days ] [ Designated as safety issue: No ]
    Change in fasting 7α-hydroxy-4-cholesten-3-one before and after 15 day administration of OCA.

  • Serum total bile acids. [ Time Frame: 15 days. ] [ Designated as safety issue: No ]
    Dynamic changes of total bile acids over 6 hour period following OCA administration before and after 15 day OCA period.


Enrollment: 28
Study Start Date: April 2012
Study Completion Date: February 2014
Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Obeticholic acid
Obeticholic acid 25mg once daily for 15 days.
Drug: Obeticholic acid
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.
Other Names:
  • INT-747
  • 6 ethyl chenodeoxycholic acid

Detailed Description:

Bile acid diarrhoea (BAD) is an under-recognised but common condition of chronic watery diarrhoea. BAD may be secondary to ileal disease affecting the reabsorption and the enterohepatic circulation of bile acids (bile acid malabsorption) or can be an idiopathic, primary BAD (PBAD). In work published in 2009, we described a new mechanism to explain this syndrome of primary BAD.

Blood levels of the hormone fibroblast growth factor 19 (FGF19) are reduced in primary and secondary BAD, producing impaired feedback inhibition of bile acid synthesis, leading to excess faecal bile acids, which then produce diarrhoea by stimulating colonic secretion. FGF19 is synthesised in the ileum and we have shown transcription is markedly induced by farnesoid X receptor(FXR) agonists such as chenodeoxycholic acid, an abundant natural bile acid. More potent FXR agonists are logical diagnostic and therapeutic agents for this condition, and obeticholic acid (OCA), which is 100x more potent than chenodeoxycholic acid, has recently been developed. It has been used in phase II studies in primary biliary cirrhosis and in non-alcoholic steatohepatitis where a relatively common side-effect was constipation.

We aim to investigate the effects of OCA in patients with primary and secondary BAD to determine whether FGF19 is able to be stimulated in these conditions. We will compare these responses to those in control patients with chronic diarrhoea but without evidence of BAD. It is possible in BAD that the defect in FGF19 levels is due to an inability to respond to FXR stimulation (particularly likely in secondary BAD after ileal resection). Patients with primary BAD may be able to respond and benefit from an increase in FGF19 levels.

This study aims to obtain pilot data on the effects of OCA on FGF19, other markers of bile acid metabolism and patient symptoms including diarrhoea. These are early phase II, proof of concept studies.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01585025

Locations
United Kingdom
Hammersmith Hospital
London, United Kingdom, W12 0HS
Hammersmith Hospital, Imperial College Healthcare NHS Trust
London, United Kingdom, W12 0HS
Sponsors and Collaborators
Imperial College London
Investigators
Principal Investigator: Julian RF Walters, MBBS MA FRCP Imperial College London
  More Information

Publications:

Responsible Party: Imperial College London
ClinicalTrials.gov Identifier: NCT01585025     History of Changes
Other Study ID Numbers: CRO1909, 2011-003777-28
Study First Received: April 23, 2012
Last Updated: September 5, 2014
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Imperial College London:
Primary bile acid malabsorption
Secondary bile acid malabsorption
Chronic diarrhoea
Obeticholic acid
SeHCAT
FXR
FGF19

Additional relevant MeSH terms:
Diarrhea
Malabsorption Syndromes
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Metabolic Diseases
Signs and Symptoms
Signs and Symptoms, Digestive
Bile Acids and Salts
Chenodeoxycholic Acid
Cathartics
Gastrointestinal Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 22, 2014