Chronic Diarrhoea Clinical Trial
— OBADIAH1Official title:
Obeticholic Acid Treatment in Patients With Bile Acid Diarrhoea: an Open-label, Pilot Study of Mechanisms, Safety and Symptom Response.
Verified date | March 2023 |
Source | Imperial College Healthcare NHS Trust |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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.
Status | Completed |
Enrollment | 35 |
Est. completion date | February 2014 |
Est. primary completion date | January 2014 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years to 80 Years |
Eligibility | 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 ß-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 |
Country | Name | City | State |
---|---|---|---|
United Kingdom | Hammersmith Hospital | London | |
United Kingdom | Hammersmith Hospital, Imperial College Healthcare NHS Trust | London |
Lead Sponsor | Collaborator |
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Imperial College Healthcare NHS Trust |
United Kingdom,
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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. — View Citation
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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. — View Citation
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. — View Citation
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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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
* Note: There are 11 references in all — Click here to view all references
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | 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 | 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 | |
Secondary | Changes in Fasting 7a-hydroxy-4-cholesten-3-one | Change in fasting 7a-hydroxy-4-cholesten-3-one before and after 15 day administration of OCA. | Day 0, Day 15 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 | |
Secondary | 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 |
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