Obeticholic Acid in Bariatric and Gallstone Disease (OCABSGS)
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Obesity Gallstones |
Drug: Obeticholic acid Drug: Placebo |
Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Pharmacodynamics Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Basic Science |
| Official Title: | Effects of Obeticholic Acid on Hepatic Fatty Acid/Triglyceride Metabolism and Hepatobiliary Detoxification/Elimination in Morbidly Obese and Gallstone Patients |
- Effects of OCA on FXR-dependent metabolism [ Time Frame: Day 21 ] [ Designated as safety issue: No ]
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
- Effects of OCA on serum lipid levels [ Time Frame: 21 days ] [ Designated as safety issue: No ]
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)
| Estimated Enrollment: | 40 |
| Study Start Date: | September 2012 |
| Estimated Study Completion Date: | December 2013 |
| Estimated Primary Completion Date: | June 2013 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Active Comparator: Obeticholic acid
Obeticholic acid 25 mg/day in three weeks
|
Drug: Obeticholic acid
Obeticholic acid 25 mg/day in three weeks
|
| Placebo Comparator: Placebo |
Drug: Placebo
Placebo to obeticholic acid
|
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| Ages Eligible for Study: | 20 Years to 65 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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.
Contacts and Locations| Contact: Hanns-Ulrich Marschall, MD, PhD | +46708774073 | hanns-ulrich.marschall@gu.se |
| Sweden | |
| Sahlgresnak University Hospital | Not yet recruiting |
| Gothenburg, Sweden, 41345 | |
| Principal Investigator: | Hanns-Ulrich Marschall, MD, PhD | Sahlgrenska University Hospital Gothenburg |
More Information
No publications provided
| Responsible Party: | Hanns-Ulrich Marschall, Professor of Clinical Hepatology, Sahlgrenska University Hospital, Sweden |
| ClinicalTrials.gov Identifier: | NCT01625026 History of Changes |
| Other Study ID Numbers: | OCABSGS |
| Study First Received: | June 19, 2012 |
| Last Updated: | June 27, 2012 |
| Health Authority: | Sweden: Medical Products Agency |
Keywords provided by Sahlgrenska University Hospital, Sweden:
|
Morbidly obesity Gastric bypass Cholecystolithiasis |
Additional relevant MeSH terms:
|
Gallstones Cholelithiasis Cholecystolithiasis Obesity Biliary Tract Diseases Digestive System Diseases Gallbladder Diseases |
Calculi Pathological Conditions, Anatomical Overnutrition Nutrition Disorders Overweight Body Weight Signs and Symptoms |
ClinicalTrials.gov processed this record on May 16, 2013