Obeticholic Acid in Bariatric and Gallstone Disease

Phase 2

Completed

• Conditions: Gallstones; Obesity
• Interventions: Drug: Obeticholic acid; Drug: Placebo

• Registration Number: NCT01625026
• Lead Sponsor: Sahlgrenska University Hospital, Sweden

Brief Summary

By binding to the nuclear receptor FXR, bile acids not only regulate their own turn-over but presumably also pivotal steps in cholesterol, triglyceride and glucose metabolism as shown in laboratory animals. Obeticholic acid (OCA) is a semisynthetic bile acid with very high affinity to FXR. In a pharmacodynamic study the effects of OCA on bile acid, lipid and glucose turn-over are studied in 20 morbidly obese and 20 gallstones patents, respectively, that are administered OCA at 25 mg/day in three weeks before bariatric (BS) or gallstone (GS) surgery where in addition to blood samples also biopsies are taken from the liver and in the case of BS, omental and subcutaneous adipose tissue and in case of GS, gallbladder bile.

Detailed Description

In a placebo-controlled double-blind randomized trial, 20 otherwise healthy morbidly obese patients scheduled for bariatric surgery, and 20 otherwise healthy gallstone patients will be administered 25 mg/day INT-747 or placebo for three weeks until the day before surgery. Serum from days 1 and 21 will be analyzed for routine liver tests, bile acids, a complete lipid profile including FA and in addition for 7α-hydroxy-4-cholesten-3-one and FGF-19, markers for bile acid synthesis and its intestinal stimulation. For the evaluation of insulin resistance and possible pre-diabetes, plasma will be taken for the estimation of HOMA index and oral glucose tolerance test (OGTT) will be performed at days 1 and 21. At surgery, a liver biopsy (0.5-1 g) and a white adipose tissue (WAT) specimen (1 cm2) will be taken and immediately frozen in liquid nitrogen for mRNA and protein preparation for quantitative RT-PCR and Western analysis, respectively, histopathological NAFLD grading, and measuring of hepatic and WAT lipase activity. In gallstone patients, gallbladder bile will be sampled for the measurements of biliary lipids (cholesterol, phospholipids, bile acids) and the calculation of the cholesterol saturation index.

Study Timeline

• Study First Submitted: 2012-06-19
• Study First Submitted QC: 2012-06-20
• Study First Posted: 2012-06-21
• Study Start: 2013-09
• Primary Completion: 2016-04
• Study Completion: 2016-04
• Status Verified: 2016-10
• Last Update Submitted: 2016-10-15
• Last Update Posted: 2016-10-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

• In the obesity group: BMI ≥35 kg/m2
• In the gallstone group: symptomatic, ultrasound verified gallstone disease

Exclusion Criteria

• Chronic liver disease other than NAFLD (viral hepatitis, autoimmune liver disease, hemochromatosis, homozygous alpha1-antitrypsin deficiency and Wilson disease)
• Previous gastric or small bowel surgery
• Inflammatory bowel disease
• Uncontrolled diabetes mellitus (fasting blood glucose >6.7 mmol/L), hypothyroidism or hyperthyroidism, or other significant endocrine disease.
• Pregnancy. A urine pregnancy test will be performed the day before start of medication. Women of childbearing potential can only be included if a safe and reliable contraception is used, e.g., oral contraceptives.
• Elevations of transaminases (ALAT/ASAT) or alkaline phosphatase or bilirubin above 2xULN (upper limit of normal) the day before start of medication.
• Other serious disease, including depressive disorders treated by medication
• Patients who will not comply with the protocol.
• A subject who is euthyroid on a stable replacement dose of thyroid hormone is acceptable provided the TSH is within normal range.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Gallstones OCA	Obeticholic acid	Obeticholic acid 25 mg/day in three weeks
Gallstones Placebo	Placebo	Obeticholic acid 25 mg/day matching placebo in three weeks
Morbid Obesity Placebo	Placebo	Obeticholic acid 25 mg/day matching placebo in three weeks
Morbid Obesity OCA	Obeticholic acid	Obeticholic acid 25 mg/day in three weeks

Primary Outcome Measures

Name	Time	Method
Effects of OCA on FXR-dependent metabolism	Day 21	Primary endpoints; * relative changes in markers for insulin resistance; * relative changes in FA and TG; * relative changes in hepatic and adipose tissue lipase expression and activity; * relative changes in hepatic apical transport proteins ABCG5/8, BSEP, MDR3, MRP2; * relative changes in hepatic ER stress markers

Secondary Outcome Measures

Name	Time	Method
Effects of OCA on serum lipid levels	21 days	Secondary endpoints; * relative changes in m RNA expression levels of genes listed under 3.ix; * relative changes in hepatic basolateral transport proteins listed under 3.x; * relative change in serum bile acids as listed under 3.xii, including INT-747; * relative changes in biliary lipids (cholesterol, phospholipids, bile acids); * relative change in plasma 7α-hydroxy-4-cholesten-3-one and FGF-19; * relative changes in total cholesterol, LDL-C, HDL-C, Apo A1, Apo B, in Lp(A)

Trial Locations

Locations (1)

Hanns-Ulrich Marschall; 🇸🇪 Göteborg, Sweden