- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01585025
Obeticholic Acid in Bile Acid Diarrhoea (OBADIAH1)
Obeticholic Acid Treatment in Patients With Bile Acid Diarrhoea: an Open-label, Pilot Study of Mechanisms, Safety and Symptom Response.
Study Overview
Status
Intervention / 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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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London, United Kingdom, W12 0HS
- Hammersmith Hospital
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London, United Kingdom, W12 0HS
- Hammersmith Hospital, Imperial College Healthcare NHS Trust
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
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
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 |
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Experimental: Primary BAD
Defined as SeHCAT <10% without other causes such as Crohn's disease and/or ileal resection
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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:
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Experimental: Secondary BAD
With Crohn's disease or ileal resection
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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:
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Experimental: Idiopathic Diarrhoea Controls
Chronic diarrhoea with SeHCAT >15% and no Crohn's or ileal resection
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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:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Changes in Fasting FGF19
Time Frame: Day 0, Day 15
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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.
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Day 0, Day 15
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Changes in Non-fasting Response of FGF19 to OCA
Time Frame: Day 0, Day 15
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Change in dynamic response of FGF19 in 6 hours following OCA administration; at start and end of 15 day OCA test period.
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Day 0, Day 15
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Changes in Fasting 7α-hydroxy-4-cholesten-3-one
Time Frame: Day 0, Day 15
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Change in fasting 7α-hydroxy-4-cholesten-3-one before and after 15 day administration of OCA.
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Day 0, Day 15
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Changes in Serum Total Bile Acids.
Time Frame: Day 0, Day 15
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Dynamic changes of total bile acids over 6 hour period following OCA administration before and after 15 day OCA period.
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Day 0, Day 15
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Changes in Stool Frequency
Time Frame: Week 2, Week 4
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Change in total number of stool episodes reported per week between week 2 (baseline) and week 4 (week 2 of treatment)
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Week 2, Week 4
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Changes in Mean Stool Form
Time Frame: Week 2, Week 4
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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).
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Week 2, Week 4
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Change in Stool Index
Time Frame: Week 2, Week 4
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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
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Collaborators and Investigators
Investigators
- Principal Investigator: Julian RF Walters, MBBS MA FRCP, Imperial College London
Publications and helpful links
General Publications
- Wedlake L, A'Hern R, Russell D, Thomas K, Walters JR, Andreyev HJ. Systematic review: the prevalence of idiopathic bile acid malabsorption as diagnosed by SeHCAT scanning in patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2009 Oct;30(7):707-17. doi: 10.1111/j.1365-2036.2009.04081.x. Epub 2009 Jun 30.
- Hofmann AF. The syndrome of ileal disease and the broken enterohepatic circulation: cholerheic enteropathy. Gastroenterology. 1967 Apr;52(4):752-7. No abstract available.
- Walters JR, Tasleem AM, Omer OS, Brydon WG, Dew T, le Roux CW. A new mechanism for bile acid diarrhea: defective feedback inhibition of bile acid biosynthesis. Clin Gastroenterol Hepatol. 2009 Nov;7(11):1189-94. doi: 10.1016/j.cgh.2009.04.024. Epub 2009 May 6.
- Hofmann AF, Mangelsdorf DJ, Kliewer SA. Chronic diarrhea due to excessive bile acid synthesis and not defective ileal transport: a new syndrome of defective fibroblast growth factor 19 release. Clin Gastroenterol Hepatol. 2009 Nov;7(11):1151-4. doi: 10.1016/j.cgh.2009.07.026. Epub 2009 Aug 7. No abstract available.
- Oelkers P, Kirby LC, Heubi JE, Dawson PA. Primary bile acid malabsorption caused by mutations in the ileal sodium-dependent bile acid transporter gene (SLC10A2). J Clin Invest. 1997 Apr 15;99(8):1880-7. doi: 10.1172/JCI119355.
- Montagnani M, Love MW, Rossel P, Dawson PA, Qvist P. Absence of dysfunctional ileal sodium-bile acid cotransporter gene mutations in patients with adult-onset idiopathic bile acid malabsorption. Scand J Gastroenterol. 2001 Oct;36(10):1077-80. doi: 10.1080/003655201750422693.
- Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, Hull MV, Lustig KD, Mangelsdorf DJ, Shan B. Identification of a nuclear receptor for bile acids. Science. 1999 May 21;284(5418):1362-5. doi: 10.1126/science.284.5418.1362.
- Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG, Luo G, Jones SA, Goodwin B, Richardson JA, Gerard RD, Repa JJ, Mangelsdorf DJ, Kliewer SA. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2005 Oct;2(4):217-25. doi: 10.1016/j.cmet.2005.09.001.
- Lundasen T, Galman C, Angelin B, Rudling M. Circulating intestinal fibroblast growth factor 19 has a pronounced diurnal variation and modulates hepatic bile acid synthesis in man. J Intern Med. 2006 Dec;260(6):530-6. doi: 10.1111/j.1365-2796.2006.01731.x. Erratum In: J Intern Med. 2008 Apr;263(4):459.
- Brydon WG, Nyhlin H, Eastwood MA, Merrick MV. Serum 7 alpha-hydroxy-4-cholesten-3-one and selenohomocholyltaurine (SeHCAT) whole body retention in the assessment of bile acid induced diarrhoea. Eur J Gastroenterol Hepatol. 1996 Feb;8(2):117-23. doi: 10.1097/00042737-199602000-00005.
- Johnston I, Nolan J, Pattni SS, Walters JR. New insights into bile acid malabsorption. Curr Gastroenterol Rep. 2011 Oct;13(5):418-25. doi: 10.1007/s11894-011-0219-3.
- Walters JR, Johnston IM, Nolan JD, Vassie C, Pruzanski ME, Shapiro DA. The response of patients with bile acid diarrhoea to the farnesoid X receptor agonist obeticholic acid. Aliment Pharmacol Ther. 2015 Jan;41(1):54-64. doi: 10.1111/apt.12999. Epub 2014 Oct 20.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- CRO1909
- 2011-003777-28 (EudraCT Number)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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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