Obeticholic Acid in Bile Acid Diarrhoea (OBADIAH1)

• ClinicalTrials.gov Identifier: NCT01585025
• Recruitment Status: Completed
• First Posted: April 25, 2012
• Results First Posted: September 13, 2019
• Last Update Posted: March 10, 2020
• Sponsor: Imperial College London
• Information provided by (Responsible Party): Imperial College London

Tracking Information

• First Submitted Date: April 23, 2012
• First Posted Date: April 25, 2012
• Results First Submitted Date: March 20, 2019
• Results First Posted Date: September 13, 2019
• Last Update Posted Date: March 10, 2020
• Study Start Date: April 2012
• Actual Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 8, 2019)

Changes in Fasting FGF19 [ Time Frame: 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.

Original Primary Outcome Measures (submitted: April 24, 2012)

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.

Current Secondary Outcome Measures (submitted: August 8, 2019)

• Changes in Non-fasting Response of FGF19 to OCA [ Time Frame: 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 Fasting 7α-hydroxy-4-cholesten-3-one [ Time Frame: Day 0, Day 15 ]
  Change in fasting 7α-hydroxy-4-cholesten-3-one before and after 15 day administration of OCA.
• Changes in Serum Total Bile Acids. [ Time Frame: 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 Stool Frequency [ Time Frame: 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)
• Changes in Mean Stool Form [ Time Frame: 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).
• Change in Stool Index [ Time Frame: 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.

Original Secondary Outcome Measures (submitted: April 24, 2012)

• 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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Primary Bile Acid Malabsorption
• Secondary Bile Acid Malabsorption
• Chronic Diarrhoea

Intervention

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.

Other Names:

• INT-747
• 6 ethyl chenodeoxycholic acid

Study Arms

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

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. Review.
• Hofmann AF. The syndrome of ileal disease and the broken enterohepatic circulation: cholerheic enteropathy. Gastroenterology. 1967 Apr;52(4):752-7. Review.
• 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.
• 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.
• Montagnani M, Love MW, Rössel 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.
• 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.
• 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.
• Lundåsen T, Gälman 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. 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.
• 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. Review.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 8, 2019): 35
• Original Estimated Enrollment (submitted: April 24, 2012): 30
• Actual Study Completion Date: February 2014
• Actual Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United Kingdom

Administrative Information

• NCT Number: NCT01585025
• Other Study ID Numbers: CRO1909; 2011-003777-28 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Imperial College London
• Study Sponsor: Imperial College London
• Collaborators: Not Provided

Investigators

• Principal Investigator: Julian RF Walters, MBBS MA FRCP; Imperial College London

• PRS Account: Imperial College London
• Verification Date: March 2020