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Obeticholic Acid in Bariatric and Gallstone Disease (OCABSGS)

Primary Purpose

Obesity, Gallstones

Status

Completed

Phase

Phase 2

Locations

Sweden

Study Type

Interventional

Intervention

Obeticholic acid

Placebo

About this trial

This is an interventional basic science trial for Obesity focused on measuring Morbidly obesity, Gastric bypass, Cholecystolithiasis

Eligibility Criteria

20 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Hanns-Ulrich Marschall

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Placebo Comparator

Active Comparator

Placebo Comparator

Arm Label

Morbid Obesity OCA

Morbid Obesity Placebo

Gallstones OCA

Gallstones Placebo

Arm Description

Obeticholic acid 25 mg/day in three weeks

Obeticholic acid 25 mg/day matching placebo in three weeks

Obeticholic acid 25 mg/day in three weeks

Obeticholic acid 25 mg/day matching placebo in three weeks

Outcomes

Primary Outcome Measures

Effects of OCA on FXR-dependent metabolism

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

Effects of OCA on serum lipid levels

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)

Full Information

NCT ID

NCT01625026

First Posted

June 19, 2012

Last Updated

October 15, 2016

Sponsor

Sahlgrenska University Hospital, Sweden

Collaborators

Medical University of Vienna

1. Study Identification

Unique Protocol Identification Number

NCT01625026

Brief Title

Obeticholic Acid in Bariatric and Gallstone Disease

Acronym

OCABSGS

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

2. Study Status

Record Verification Date

October 2016

Overall Recruitment Status

Completed

Study Start Date

September 2013 (undefined)

Primary Completion Date

April 2016 (Actual)

Study Completion Date

April 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Sahlgrenska University Hospital, Sweden

Collaborators

Medical University of Vienna

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Obesity, Gallstones

Keywords

Morbidly obesity, Gastric bypass, Cholecystolithiasis

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

40 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Morbid Obesity OCA

Arm Type

Active Comparator

Arm Description

Obeticholic acid 25 mg/day in three weeks

Arm Title

Morbid Obesity Placebo

Arm Type

Placebo Comparator

Arm Description

Obeticholic acid 25 mg/day matching placebo in three weeks

Arm Title

Gallstones OCA

Arm Type

Active Comparator

Arm Description

Obeticholic acid 25 mg/day in three weeks

Arm Title

Gallstones Placebo

Arm Type

Placebo Comparator

Arm Description

Obeticholic acid 25 mg/day matching placebo in three weeks

Intervention Type

Drug

Intervention Name(s)

Obeticholic acid

Other Intervention Name(s)

INT-747

Intervention Description

Obeticholic acid 25 mg/day in three weeks

Intervention Type

Drug

Intervention Name(s)

Placebo

Other Intervention Name(s)

Placebo INT-747

Intervention Description

Placebo to obeticholic acid

Primary Outcome Measure Information:

Title

Effects of OCA on FXR-dependent metabolism

Description

Time Frame

Day 21

Secondary Outcome Measure Information:

Title

Effects of OCA on serum lipid levels

Description

Time Frame

21 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

20 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Hanns-Ulrich Marschall, MD, PhD

Organizational Affiliation

Sahlgrenska University Hospital Gothenburg

Official's Role

Principal Investigator

Facility Information:

Facility Name

Hanns-Ulrich Marschall

City

Göteborg

ZIP/Postal Code

411 31

Country

Sweden

12. IPD Sharing Statement

Citations:

PubMed Identifier

31254596

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.

Results Reference

derived

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Obeticholic Acid in Bariatric and Gallstone Disease

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