A study on the effect of obetihcolic acid on bile composition in patients with PBC (chronic liver disease of the small bile ducts), NASH (chronic liver disease as a result of fatty liver) and healthy volunteers

• Register: EUCTR
• Last refreshed on: 17 July 2017
• Main ID: EUCTR2016-002965-67-NL
• Date of registration: 29/03/2017
• Prospective Registration: Yes
• Primary sponsor: AMC
• Public title: A study on the effect of obetihcolic acid on bile composition in patients with PBC (chronic liver disease of the small bile ducts), NASH (chronic liver disease as a result of fatty liver) and healthy volunteers
• Scientific title: An open, non-randomized, parallel-group pharmokinetic and -dynamic, investigator-initiated study on effects of obeticholic acid (OCA) in bile of patients with primary biliary cholangitis (PBC) and non-alcoholic steatohepatitis (NASH) in comparison to healthy controls - OCABILE
• Date of first enrolment: 07/07/2017
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-002965-67
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Netherlands

Contacts

• Name: E.S. de Vries
• Affiliation: AMC

• Name: E.S. de Vries
• Affiliation: AMC

Key inclusion & exclusion criteria

Inclusion criteria:
- Male or female patients / volunteers of 18 to 75 years of age.
- Body mass index within 18 to 40 kg/m2
- Positive AMA (anti-mitochondrial antibody) testing (for PBC patients).
- Proven non-cirrhotic liver disease compatible with PBC stage I, II, III or NASH, no reliable signs of portal hypertension such as esophageal varices or ascites and/or pylephlebectasia > 15 mm, and a fibroscan < 15 kPa.
- The diagnosis of NASH must be confirmed by a liver biopsy (e.g. according Brunt criteria) in the last 24 months
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 33
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
- Existing cardiac / hematological / renal / gastrointestinal diseases which might interfere with the drugs' safety, tolerability, absorption, pharmacokinetics and / or endoscopy.
- Other acute or chronic diseases which might affect absorption or metabolism of OCA
- Existing disorders of the coagulation system or treatment with anticoagulants or agents inhibiting thrombocyte aggregation
- Positive anti-HIV-test, HBsAg-test or anti-HCV-test.
- Acute inflammation of the gallbladder.
- Cholecystectomy
- Histologically proven cirrhotic liver disease or total bilirubin > 2 mg/dl or reliable signs of portal hypertension such as esophageal varices or ascites and/or pylephlebectasia > 15 mm and / or fibroscan > 15 kPa.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Primary biliairy cholangitis (PBC) Non-alcoholic steatohepatitis (NASH)
MedDRA version: 20.0 Level: SOC Classification code 10019805 Term: Hepatobiliary disorders System Organ Class: 10019805 - Hepatobiliary disorders

Therapeutic area: Diseases [C] - Digestive System Diseases [C06]

Intervention(s)

Product Name: OCA (INT-747)
Product Code: OCA (INT-747)
Pharmaceutical Form: Tablet

Primary Outcome(s)

Secondary Objective: Assess the effect of obeticholic acid (OCA) in patients with PBC [in combination with long-term UDCA treatment (15 mg/kg/d)], patients with NASH and healthy volunteers on the biliary and serum levels of cytokines (e.g., IL-6, IL-8, TNFa), chemokines and enterohepatic hormones (e.g., FGF-19)

Assess the effect of obeticholic acid (OCA) in patients with PBC [in combination with long-term UDCA treatment (15 mg/kg/d)], patients with NASH and healthy volunteers on the bile acid composition and microbiome in faeces

Assess the effect of obeticholic acid (OCA) in patients with PBC [in combination with long-term UDCA treatment (15 mg/kg/d)], patients with NASH and healthy volunteers on the expression of duodenal transport proteins and enzymes contributing to the biliary and intestinal detoxification machinery

Main Objective: To explore the exact working mechnism of OCA in PBC / NASH patients in comparison with healthy volunteers -->

Assess the effect of obeticholic acid (OCA) in patients with PBC [in combination with long-term UDCA treatment (15 mg/kg/d)], patients with NASH and healthy volunteers on the bile acid and lipid composition of bile and serum,

Primary end point(s): - Bile acids: Concentrations of UDCA, cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), glycoursodeoxycholic acid (GUDCA), glycocholic acid (GCA), glycochenodeoxycholic acid (GCDCA), glycodeoxycholic acid (GDCA), glycolithocholic acid (GLCA), tauroursodeoxycholic acid (TUDCA), taurocholic acid (TCA), taurochenodeoxycholic acid (TCDCA), taurodeoxycholic acid (TDCA), taurolithocholic acid (TLCA) and C4 will be determined in plasma and bile by liquid chromatography tandem mass spectrometry according to the principles of good laboratory practice.

Timepoint(s) of evaluation of this end point: Day 0, 29/30, day 35

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Day 0, 29/30, day 35

Secondary end point(s): - Lipids: The biliary lipid profile will be analyzed (before and 4 weeks after start of treatment with OCA) using a recently developed AMC lipidomics platform which allows to detect and quantify ~1000 different lipids in bile.

- Cyto- and chemokines and hormones: A panel of 27 cyto- and chemokines will be analyzed in bile after dilution (50-100 fold) using Luminex® technology (Merck Millipore, Milliplex Map Human Cytokine/Chemokine Panel). IL6, IL8 and TNFa levels in bile will be quantified by ELISA (R&D Systems, #DY-206, #DY-208 and #DY-210). FGF19 levels in bile and serum will be determined by sandwich ELISA; bile samples will be tested for proteolytic activity by spiking with FGF19.

Serum: CK-18 (a biomarker correlating with hepatocyte apoptosis)

- Total biliary levels of bile salts, phospholipids and cholesterol will be determined by enzymatic methods. Total bilirubin will be quantified by HPLC.

- Faeces: microbiome, bile acid composition

Secondary ID(s)

57877.018.016

Source(s) of Monetary Support

AMC