Obeticholic Acid in Bile Acid Diarrhoea

NCT01585025 | Completed Phase 2 Results DMC

• 2 other identifiers: CRO19092011-003777-28
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 2

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.

Conditions

Primary Bile Acid Malabsorption; Secondary Bile Acid Malabsorption; Chronic Diarrhoea

Keywords

Primary bile acid malabsorption; Secondary bile acid malabsorption; Chronic diarrhoea; Obeticholic acid; SeHCAT; FXR; FGF19

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Changes in Non-fasting Response of FGF19 to OCA

  Day 0, Day 15

• Changes in Fasting 7α-hydroxy-4-cholesten-3-one

  Day 0, Day 15

• Changes in Serum Total Bile Acids.

  Day 0, Day 15

• Changes in Stool Frequency

  Week 2, Week 4

• Changes in Mean Stool Form

  Week 2, Week 4

Study Arms (3)

Primary BAD

EXPERIMENTAL

Defined as SeHCAT \<10% without other causes such as Crohn's disease and/or ileal resection

Drug: Obeticholic acid

Secondary BAD

EXPERIMENTAL

With Crohn's disease or ileal resection

Drug: Obeticholic acid

Idiopathic Diarrhoea Controls

EXPERIMENTAL

Chronic diarrhoea with SeHCAT \>15% and no Crohn's or ileal resection

Drug: Obeticholic acid

Interventions

Obeticholic acid DRUG

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.

Also known as: INT-747, 6 ethyl chenodeoxycholic acid

Idiopathic Diarrhoea Controls; Primary BAD; Secondary BAD

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Imperial College Healthcare NHS Trust: lead

Study Sites (2)

Hammersmith Hospital, Imperial College Healthcare NHS Trust

London, W12 0HS, United Kingdom

Location

Hammersmith Hospital

London, W12 0HS, United Kingdom

Location

Related Publications (12)

• 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.

  PMID: 19570102 BACKGROUND

• Hofmann AF. The syndrome of ileal disease and the broken enterohepatic circulation: cholerheic enteropathy. Gastroenterology. 1967 Apr;52(4):752-7. No abstract available.

  PMID: 5337211 BACKGROUND

• 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.

  PMID: 19426836 BACKGROUND

• 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.

  PMID: 19665580 BACKGROUND

• 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.

  PMID: 9109432 BACKGROUND

• 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.

  PMID: 11589382 BACKGROUND

• 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.

  PMID: 10334992 BACKGROUND

• 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.

  PMID: 16213224 BACKGROUND

• 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.

  PMID: 17116003 BACKGROUND

• 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.

  PMID: 8723414 BACKGROUND

• 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.

  PMID: 21805078 BACKGROUND

• 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.

  PMID: 25329562 DERIVED

MeSH Terms

Conditions

Bile Acid Malabsorption, Primary

Interventions

obeticholic acid

Limitations and Caveats

Recruitment in the idiopathic chronic diarrhoea control group did not reach the prespecified number of 10 due to dropouts. Of the 8 subjects recruited, one failed to return diaries that could be analysed.

Results Point of Contact

• Title: Prof Julian Walters
• Organization: Imperial College London

julian.walters@imperial.ac.uk

+442033132361

Study Officials

• Julian RF Walters, MBBS MA FRCP

  Imperial College London

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 23, 2012
• First Posted: April 25, 2012
• Study Start: April 1, 2012
• Primary Completion: January 1, 2014
• Study Completion: February 1, 2014
• Last Updated: March 10, 2023
• Results First Posted: September 13, 2019

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

GB (2)