Clinical trial NCT01625026: Obeticholic Acid in Bariatric and Gallstone Disease
Official title: Effects of Obeticholic Acid on Hepatic Fatty Acid/Triglyceride Metabolism and Hepatobiliary Detoxification/Elimination in Morbidly Obese and Gallstone Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Obesity
Gallstones
Keywords: Morbidly obesity
Gastric bypass
Cholecystolithiasis
Lead sponsor: Sahlgrenska University Hospital
Sponsor class: OTHER
Collaborators: name: Medical University of Vienna
First posted: 2012-06-21
Enrollment: 40
Sex: ALL
Minimum age (years): 20
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Effects of OCA on FXR-dependent metabolism
timeFrame: Day 21
Secondary outcomes:
measure: Effects of OCA on serum lipid levels
timeFrame: 21 days
Other outcomes:
Locations:
city: Göteborg
country: Sweden
facility: Hanns-Ulrich Marschall
Study officials:
affiliation: Sahlgrenska University Hospital Gothenburg
name: Hanns-Ulrich Marschall, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Al-Dury S, Wahlstrom A, Panzitt K, Thorell A, Stahlman M, Trauner M, Fickert P, Backhed F, Fandriks L, Wagner M, Marschall HU. Obeticholic acid may increase the risk of gallstone formation in susceptible patients. J Hepatol. 2019 Nov;71(5):986-991. doi: 10.1016/j.jhep.2019.06.011. Epub 2019 Jun 27.