Obeticholic Acid in Bile Acid Diarrhoea

Phase 2

Completed

Conditions: Chronic Diarrhoea
Secondary Bile Acid Malabsorption
Primary Bile Acid Malabsorption

Interventions: Drug: Obeticholic acid

Registration Number: NCT01585025

Lead Sponsor: Imperial College Healthcare NHS Trust

Brief 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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 35

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Secondary BAD	Obeticholic acid	With Crohn's disease or ileal resection
Primary BAD	Obeticholic acid	Defined as SeHCAT \<10% without other causes such as Crohn's disease and/or ileal resection
Idiopathic Diarrhoea Controls	Obeticholic acid	Chronic diarrhoea with SeHCAT \>15% and no Crohn's or ileal resection

Primary Outcome Measures

Name	Time	Method
Changes in Fasting FGF19	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.

Secondary Outcome Measures

Name	Time	Method
Changes in Non-fasting Response of FGF19 to OCA	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.
Changes in Serum Total Bile Acids.	Day 0, Day 15	Dynamic changes of total bile acids over 6 hour period following OCA administration before and after 15 day OCA period.
Changes in Fasting 7α-hydroxy-4-cholesten-3-one	Day 0, Day 15	Change in fasting 7α-hydroxy-4-cholesten-3-one before and after 15 day administration of OCA.
Changes in Mean Stool Form	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).
Changes in Stool Frequency	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)
Change in Stool Index	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.

Trial Locations

Locations (2): Hammersmith Hospital, Imperial College Healthcare NHS Trust
🇬🇧
London, United Kingdom
Hammersmith Hospital
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London, United Kingdom