Obeticholic Acid in Bariatric and Gallstone Disease

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Obesity, Gallstones

Intervention / Treatment
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* Drug: Obeticholic acid
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Morbid Obesity OCA<br>Obeticholic acid 25 mg/day in three weeks | Drug: Obeticholic acid<br>* Obeticholic acid 25 mg/day in three weeks<br>* Other names: INT-747;|
| Placebo Comparator: Morbid Obesity Placebo<br>Obeticholic acid 25 mg/day matching placebo in three weeks | Drug: Placebo<br>* Placebo to obeticholic acid<br>* Other names: Placebo INT-747;|
| Active Comparator: Gallstones OCA<br>Obeticholic acid 25 mg/day in three weeks | Drug: Obeticholic acid<br>* Obeticholic acid 25 mg/day in three weeks<br>* Other names: INT-747;|
| Placebo Comparator: Gallstones Placebo<br>Obeticholic acid 25 mg/day matching placebo in three weeks | Drug: Placebo<br>* Placebo to obeticholic acid<br>* Other names: Placebo INT-747;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Day 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 21 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Morbidly obesity, Gastric bypass, Cholecystolithiasis