Obeticholic Acid in Morbidly Obese Patients and Healthy Volunteers (OCAPUSH)

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

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.

Study Overview

• Status: Unknown
• Conditions: Obesity
• Intervention / Treatment: Drug: Obeticholic acid; Drug: Obeticholic acid placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Hanns-Ulrich Marschall, MD, PhD, MSc; Phone Number: +46708774073; Email: hanns-ulrich.marschall@gu.se

Study Locations

• Sweden
  • Göteborg, Sweden, 411 31
    • Recruiting
    • Hanns-Ulrich Marschall
    • Contact: Hanns-Ulrich Marschall; Phone Number: +4670774073; Email: hanns-ulrich.marschall@gu.se
    • Principal Investigator: Hanns-Ulrich Marschall, MD, PhD
  • Göteborg, Sweden
    • Enrolling by invitation
    • Sahlgrenska Academy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Morbid Obesity OCA; Obeticholic acid 25 mg/day in three weeks	Drug: Obeticholic acid; active drug; Other Names: INT-747
Placebo Comparator: Morbid Obesity Placebo; Obeticholic acid 25 mg/day matching placebo in three weeks	Drug: Obeticholic acid; active drug; Other Names: INT-747; Drug: Obeticholic acid placebo; matching placebo; Other Names: INT-747 placebo
Active Comparator: Healthy Volunteers OCA; Obeticholic acid Obeticholic acid 25 mg/day in three weeks	Drug: Obeticholic acid; active drug; Other Names: INT-747
Placebo Comparator: Healthy volunteers Placebo; Obeticholic acid 25 mg/day matching placebo in three weeks	Drug: Obeticholic acid; active drug; Other Names: INT-747; Drug: Obeticholic acid placebo; matching placebo; Other Names: INT-747 placebo

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Sahlgrenska University Hospital, Sweden
• Investigators: Principal Investigator: Hanns-Ulrich Marschall, Sahlgrenska University Hospital, Sweden

Study record dates

Study Major Dates

• Study Start: August 1, 2015
• Primary Completion (Anticipated): December 1, 2020
• Study Completion (Anticipated): June 1, 2021

Study Registration Dates

• First Submitted: August 21, 2015
• First Submitted That Met QC Criteria: August 24, 2015
• First Posted (Estimate): August 25, 2015

Study Record Updates

• Last Update Posted (Actual): August 25, 2020
• Last Update Submitted That Met QC Criteria: August 22, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: gut microbiota; bile acids; FGF19; FXR; C4; Pharmacodynamics of FXR activation in the small bowel
• Additional Relevant MeSH Terms: Gastrointestinal Agents; Cathartics; Chenodeoxycholic Acid
• Other Study ID Numbers: OCAPUSH

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO