Obeticholic Acid in Bariatric and Gallstone Disease (OCABSGS)

October 15, 2016 updated by: Hanns-Ulrich Marschall, Sahlgrenska University Hospital, Sweden

Effects of Obeticholic Acid on Hepatic Fatty Acid/Triglyceride Metabolism and Hepatobiliary Detoxification/Elimination in Morbidly Obese and Gallstone Patients

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

40

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Sweden
      • Göteborg, Sweden, 411 31
        • Hanns-Ulrich Marschall

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

20 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Morbid Obesity OCA
Obeticholic acid 25 mg/day in three weeks
Drug: Obeticholic acid
Obeticholic acid 25 mg/day in three weeks
Other Names:
  • INT-747
Placebo Comparator: Morbid Obesity Placebo
Obeticholic acid 25 mg/day matching placebo in three weeks
Drug: Placebo
Placebo to obeticholic acid
Other Names:
  • Placebo INT-747
Active Comparator: Gallstones OCA
Obeticholic acid 25 mg/day in three weeks
Drug: Obeticholic acid
Obeticholic acid 25 mg/day in three weeks
Other Names:
  • INT-747
Placebo Comparator: Gallstones Placebo
Obeticholic acid 25 mg/day matching placebo in three weeks
Drug: Placebo
Placebo to obeticholic acid
Other Names:
  • Placebo INT-747

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Effects of OCA on FXR-dependent metabolism
Time Frame: 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
Day 21

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Effects of OCA on serum lipid levels
Time Frame: 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)
21 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sahlgrenska University Hospital, Sweden

Collaborators

Medical University of Vienna

Investigators

  • Principal Investigator: Hanns-Ulrich Marschall, MD, PhD, Sahlgrenska University Hospital Gothenburg

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2013

Primary Completion (Actual)

April 1, 2016

Study Completion (Actual)

April 1, 2016

Study Registration Dates

First Submitted

June 19, 2012

First Submitted That Met QC Criteria

June 20, 2012

First Posted (Estimate)

June 21, 2012

Study Record Updates

Last Update Posted (Estimate)

October 18, 2016

Last Update Submitted That Met QC Criteria

October 15, 2016

Last Verified

October 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • OCABSGS

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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