Obeticholic Acid in Bile Acid Diarrhoea

Study Overview
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Brief Summary
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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
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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.

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

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

Intervention / Treatment
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* Drug: Obeticholic acid


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Primary BAD<br>Defined as SeHCAT <10% without other causes such as Crohn's disease and/or ileal resection | Drug: Obeticholic acid<br>* 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.<br>* Other names: 6 ethyl chenodeoxycholic acid;|
| Experimental: Secondary BAD<br>With Crohn's disease or ileal resection | Drug: Obeticholic acid<br>* 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.<br>* Other names: 6 ethyl chenodeoxycholic acid;|
| Experimental: Idiopathic Diarrhoea Controls<br>Chronic diarrhoea with SeHCAT >15% and no Crohn's or ileal resection | Drug: Obeticholic acid<br>* 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.<br>* Other names: 6 ethyl chenodeoxycholic acid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Fasting FGF19 | 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 | 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 | 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. | 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 | 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 | 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 | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Secondary bile acid malabsorption, FXR, Primary bile acid malabsorption, Chronic diarrhoea, Obeticholic acid, SeHCAT, FGF19