Obeticholic Acid in Morbidly Obese Patients and Healthy Volunteers

Study Overview
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Brief Summary
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OCAPUSH (EudraCT 2014-002313-33) is a double-blind placebo-controlled parallel-arms study of the effects of obeticholic acid on farnesoid X receptor expression in jejunum and on gut microbiota in morbidly obese patients and healthy volunteers. Obeticholic acid (OCA, 6-ethyl-chenodeoxycholic acid, INT-747) is a semi-synthetic derivative of the major human bile acid chenodeoxycholic acid and will be administered orally at a dose of 25 mg/day during three weeks to 20 morbidly obese patients awaiting Roux-en-Y gastric bypass and to 20 healthy volunteers. On the days before the first and after the last dose faeces and blood are sampled for the analyses of bile acids and the gut microbiota. On the day after the last dose a push-enteroscopy is performed in conscious sedation for biopsy taking in the jejunum.These procedures are repeated 6 month after surgery in the morbid obese patients. Inclusion criteria are male or female gender, 20-65 years of age and morbid obesity (BMI >35 kg/m2) eligible for bariatric surgery. Exclusion criteria are liver diseases other that fatty liver disease, other significant morbidity, medications known to interact with OCA, pregnancy, uncertainty about safe and reliable contraception, and problems to understand or adhere to the protocol. The primary objectives of this pharmacodynamic trial are the study of the effect of OCA on the expression of FXR in the jejunum and small intestinal permeability, and on fecal bile acids and gut microbiota. The secondary objectives are the study of the effects of OCA on the genome-wide FXR DNA binding sites (cistromics) with the global gene expression profile (transcriptomics) in human jejunum.

Detailed Description
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Obeticholic acid will be administered orally at a dose of 25 mg/day during three weeks to 20 morbidly obese patients awaiting Roux-en-Y gastric bypass and to 20 healthy volunteers. On the days before the first and after the last dose faeces and blood are sampled for the analyses of bile acids and the gut microbiota. On the day after the last dose a push-enteroscopy is performed in conscious sedation for biopsy taking in the jejunum. These procedures are repeated 6 month after surgery in the morbid obese patients. Inclusion criteria are male or female gender, 20-65 years of age and morbid obesity (BMI >35 kg/m2) eligible for bariatric surgery. Exclusion criteria are liver diseases other that fatty liver disease, other significant morbidity, medications known to interact with OCA, pregnancy, uncertainty about safe and reliable contraception, and problems to understand or adhere to the protocol. The primary objectives of this pharmacodynamic trial are the study of the effect of OCA on the expression of FXR in the jejenum and small intestinal permeability, and on fecal bile acids and gut microbiota. The secondary objectives are the study of the effects of OCA on the genome-wide FXR DNA binding sites (cistromics) with the global gene expression profile (transcriptomics) in human jejunum.

Official Title
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Study of the Effects of Obeticholic Acid on Farnesoid X Receptor Expression in Jejunum and on Gut Microbiota in Morbidly Obese Patients and Healthy Volunteers

Conditions
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Obesity

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Morbid obesity awaiting gastric bypass surgery, ≥35 kg/m2 Male subjects, pre-, and post-menopausal female subjects Women of childbearing potential can only be included if a safe and reliable contraception is used, e.g., oral contraceptives Patients eligible to laparoscopic bariatric surgery Patients must give their signed and dated written consent to participate in this study based on written information of all pertinent aspects of the trial provided at least 24 hours before undertaking any trial related activity. 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. Hypothyroidism, unless the subject is clinically euthyroid, receiving a stable dose thyroid hormone replacement therapy and serum TSH is within the normal range.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Quadruple


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>* active drug<br>* Other names: INT-747;|
| Placebo Comparator: Morbid Obesity Placebo<br>Obeticholic acid 25 mg/day matching placebo in three weeks | Drug: Obeticholic acid<br>* active drug<br>* Other names: INT-747;Drug: Obeticholic acid placebo<br>* matching placebo<br>* Other names: INT-747 placebo;|
| Active Comparator: Healthy Volunteers OCA<br>Obeticholic acid Obeticholic acid 25 mg/day in three weeks | Drug: Obeticholic acid<br>* active drug<br>* Other names: INT-747;|
| Placebo Comparator: Healthy volunteers Placebo<br>Obeticholic acid 25 mg/day matching placebo in three weeks | Drug: Obeticholic acid<br>* active drug<br>* Other names: INT-747;Drug: Obeticholic acid placebo<br>* matching placebo<br>* Other names: INT-747 placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ChIP-assay in biopsies as a measure of Activation of FXR-dependent genes in small intestine | ChIP-assay in biopsies | Three weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Shot-gun metagenomics as a measure of Impact of FXR activation on gut microbiota | Shot-gun metagenomics | Three weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FXR, bile acids, FGF19, C4, gut microbiota, Pharmacodynamics of FXR activation in the small bowel