Obeticholic Acid in Bile Acid Diarrhoea (OBADIAH1)

March 8, 2023 updated by: Imperial College Healthcare NHS Trust

Obeticholic Acid Treatment in Patients With Bile Acid Diarrhoea: an Open-label, Pilot Study of Mechanisms, Safety and Symptom Response.

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.

Study Overview

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.

Study Type

Interventional

Enrollment (Actual)

35

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • London, United Kingdom, W12 0HS
        • Hammersmith Hospital
      • London, United Kingdom, W12 0HS
        • Hammersmith Hospital, Imperial College Healthcare NHS Trust

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Primary BAD
Defined as SeHCAT <10% without other causes such as Crohn's disease and/or ileal resection
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
Experimental: Secondary BAD
With Crohn's disease or ileal resection
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
Experimental: Idiopathic Diarrhoea Controls
Chronic diarrhoea with SeHCAT >15% and no Crohn's or ileal resection
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Changes in Fasting FGF19
Time Frame: Day 0, Day 15
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.
Day 0, Day 15

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Changes in Non-fasting Response of FGF19 to OCA
Time Frame: Day 0, Day 15
Change in dynamic response of FGF19 in 6 hours following OCA administration; at start and end of 15 day OCA test period.
Day 0, Day 15
Changes in Fasting 7α-hydroxy-4-cholesten-3-one
Time Frame: Day 0, Day 15
Change in fasting 7α-hydroxy-4-cholesten-3-one before and after 15 day administration of OCA.
Day 0, Day 15
Changes in Serum Total Bile Acids.
Time Frame: Day 0, Day 15
Dynamic changes of total bile acids over 6 hour period following OCA administration before and after 15 day OCA period.
Day 0, Day 15
Changes in Stool Frequency
Time Frame: Week 2, Week 4
Change in total number of stool episodes reported per week between week 2 (baseline) and week 4 (week 2 of treatment)
Week 2, Week 4
Changes in Mean Stool Form
Time Frame: Week 2, Week 4
Change in mean stool form reported per week between week 2 (baseline) and week 4 (week 2 of treatment) using the Bristol Stool Form Scale (range of scores 1 to 7). High scores are a worse outcome (7=liquid stools).
Week 2, Week 4
Change in Stool Index
Time Frame: Week 2, Week 4

Change in index calculated on a weekly basis, between week 2 (baseline) and week 4 (week 2 of treatment).

Index calculated as ([weekly stool frequency x mean Bristol Stool Form Scale score] = Loperamide use [weekly mg x 3]).

Individual scores ranged from 25 to 1095, with higher scores being worst.

Week 2, Week 4

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Julian RF Walters, MBBS MA FRCP, Imperial College London

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2012

Primary Completion (Actual)

January 1, 2014

Study Completion (Actual)

February 1, 2014

Study Registration Dates

First Submitted

April 23, 2012

First Submitted That Met QC Criteria

April 24, 2012

First Posted (Estimate)

April 25, 2012

Study Record Updates

Last Update Posted (Estimate)

March 10, 2023

Last Update Submitted That Met QC Criteria

March 8, 2023

Last Verified

March 1, 2023

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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