Obeticholic Acid in Bile Acid Diarrhoea
Condition: Primary Bile Acid Malabsorption; Secondary Bile Acid Malabsorption; Chronic Diarrhoea
MeSH terms: Malabsorption Syndromes; Diarrhea
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): Obeticholic acid
Intervention type(s): Drug
Intervention description(s): 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 intervention name(s): INT-747; 6 ethyl chenodeoxycholic acid
Intervention MeSH terms: Chenodeoxycholic Acid
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Primary bile acid malabsorption; Secondary bile acid malabsorption; Chronic diarrhoea; Obeticholic acid; SeHCAT; FXR; FGF19