Obeticholic Acid in Bile Acid Diarrhoea (OBADIAH1)
|Primary Bile Acid Malabsorption Secondary Bile Acid Malabsorption Chronic Diarrhoea||Drug: Obeticholic acid||Phase 2|
|Study Design:||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.|
- Fasting FGF19 [ Time Frame: 15 days ]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.
- Non-fasting response of FGF19 to OCA [ Time Frame: 15 days ]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 ]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. ]Dynamic changes of total bile acids over 6 hour period following OCA administration before and after 15 day OCA period.
|Study Start Date:||April 2012|
|Study Completion Date:||February 2014|
|Primary Completion Date:||January 2014 (Final data collection date for primary outcome measure)|
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.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01585025
|Hammersmith Hospital, Imperial College Healthcare NHS Trust|
|London, United Kingdom, W12 0HS|
|London, United Kingdom, W12 0HS|
|Principal Investigator:||Julian RF Walters, MBBS MA FRCP||Imperial College London|