Effect of Obeticholic Acid on Transport of Bile Acids in PBC Examined by 11C-cholyl-sarcosine PET/CT

October 31, 2019 updated by: University of Aarhus

Effect of Obeticholic Acid (INT-747, Intercept) on the Hepatobiliary Transport of Bile Acids in Patients With PBC Examined by 11C-cholyl-sarcosine PET/CT

This is an investigator-initiated, double-blind crossover study on the mechanism of OCA treatment of patients with PBC.

Hypothesis and significance

The investigators will test the hypothesis that OCA administration to patients with PBC increases hepatobiliary secretion of cholylsarcosine assessed by PET/CT using 11C-labeled cholylsarcosine (11C-CSar) as tracer.

The results of this research project will elucidate the mechanism of the effect of using OCA therapeutically in patients with PBC.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Background

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by cholestasis and cirrhosis. Pathogenesis comprises impaired hepatobiliary secretion of bile acids to the bile. As a result bile flow reduces and diminished content of bile acids in the intestines leads to impaired absorption of lipids and lipid-soluble vitamins, diarrhea, general pruritus, and fatigue.

Bile acids are transported from blood to hepatocytes by the transporter proteins Na+-taurocholate co-transporting polypeptide (NTCP) and Organic anion-transporting polypeptide (OATP) and secreted from hepatocyte to bile canaliculi by the Bile salt export pump (BSEP) and Multidrug resistance protein type 3 (MDR3). Dysfunction of BSEP most probably plays a key pathogenic role in PBC.

Ursodeoxycholic acid (UDCA) is a dihydroxylated bile acid and the only approved drug for treatment of PBC today. In most cases UDCA can delay or prevent disease progression. However, a subgroup of patients does not respond adequately to UDCA and for these patients new therapies are needed.

BSEP is induced by the nuclear bile acid receptor (BAR), also known as farnesoid X receptor (FXR). Obeticholic Acid (INT-747, Intercept) (OCA) is a FXR agonist and induces BSEP.

OCA administration therefore may increase the hepatobiliary secretion of bile acids, being the mechanism behind beneficial therapeutic effects in PBC.

Cholylsarcosine is a synthetic conjugated bile acid (sarcosine = methyl-glycine) that is non-toxic, not metabolized in the gut or liver, and transported by BSEP. The trans-hepatic transport of bile acids can be assessed in humans by PET/CT of the liver using 11C-labeled cholylsarcosine (11C-CSar) as tracer. 11C-CSar is handled by the liver as a natural bile acid in pig studies (1). Studies in humans (2) show that

  • 11C-CSar is taken up avidly by the liver and flow-determined
  • 11C-CSar secretion from hepatocytes to bile is reduced during cholestasis, and
  • 11C-CSar back flux from hepatocytes to blood during cholestasis

Patients

8 patients with PBC

  • who are not responding adequately to treatment with UDCA, defined as ALP > 2 times upper normal level during a time period of 6 months
  • Patients are recruited from Aarhus University Hospital, Department of Hepatology and Gastroenterology.

Paired study design

  • 11C-CSar PET/CT before and after 3 months treatment with OCA or placebo.

Methods

PET/CT: Initial low-dose CT for anatomical definition of the PET findings and for attenuation correction of PET data. Dynamic 60-min PET recording of the tissue radioactivity concentration over time following iv bolus injection of 100 MBq 11C-CSar and iv infusion of 100 MBq 11C-CSar. During the PET study, ICG is given as a constant iv infusion for measurements of hepatic blood flow, used in the kinetic analysis, and blood samples are collected from catheters in a radial artery and a liver vein (blood 11C-CSar concentrations for kinetic calculations, ICG, and blood gasses for monitoring purposes).

Liver tests at the time points of the PET/CT study: Plasma ALT, ALP, GGT, bilirubin, bile salts, IRN, platelets, hemoglobin, mitochondrial antibodies; ICG clearance.

Raw data comprise time-courses of the 11C-CSar concentrations in liver tissue and common hepatic bile duct (PET recordings) and blood concentrations of 11C-CSar in arterial and liver vein blood (blood samples); hepatic blood flow, hepatic venous pressure gradient (HVPG), splanchnic oxygen uptake.

11C-CSar data comprise clearances of 11C-CSar from blood-to-hepatocytes and from hepatocytes-to-bile canaliculi, vascular extraction fractions, biliary secretion fraction, transit times, etc.

Study Type

Interventional

Enrollment (Actual)

8

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Denmark
      • Aarhus, Denmark, 8000
        • Susanne Keiding

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 85 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • patients with PBC
  • who are not responding adequately to treatment with UDCA, defined as ALP > 2 times upper normal level during a time period of 6 months

Exclusion Criteria:

  • Itching that requires medical treatment

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: BASIC_SCIENCE
  • Allocation: RANDOMIZED
  • Interventional Model: CROSSOVER
  • Masking: DOUBLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
ACTIVE_COMPARATOR: Obeticholic Acid
Patients with primary biliary cirrhosis are treated 3 months with OCA (active drug) or placebo in a double-blind cross-over study design.
Drug: Obeticholic acid
Placebo-controlled
Other Names:
  • placebo
PLACEBO_COMPARATOR: placebos
Patients with primary biliary cirrhosis are treated 3 months with OCA (active drug) or placebo in a double-blind cross-over study design.
Drug: Placebos
Other Names:
  • Obeticholic acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Effect of OCA on bile flow
Time Frame: Measured after 3 months of treatment with Obeticholic Acid or placebo
Bile flow measured by PET
Measured after 3 months of treatment with Obeticholic Acid or placebo

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Aarhus

Investigators

  • Principal Investigator: Susanne Keiding, prof, University of Aarhus

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

May 19, 2016

Primary Completion (ACTUAL)

September 20, 2018

Study Completion (ACTUAL)

September 20, 2018

Study Registration Dates

First Submitted

May 28, 2017

First Submitted That Met QC Criteria

August 16, 2017

First Posted (ACTUAL)

August 17, 2017

Study Record Updates

Last Update Posted (ACTUAL)

November 1, 2019

Last Update Submitted That Met QC Criteria

October 31, 2019

Last Verified

October 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • OCAPBC

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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