Effect of Obeticholic Acid on Transport of Bile Acids in PBC Examined by 11C-cholyl-sarcosine PET/CT
Primary Purpose
Primary Biliary Cirrhosis
Status
Completed
Phase
Early Phase 1
Locations
Denmark
Study Type
Interventional
Intervention
Obeticholic acid
Placebos
Sponsored by
About this trial
This is an interventional basic science trial for Primary Biliary Cirrhosis focused on measuring Bile Acid Transporter
Eligibility Criteria
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
Sites / Locations
- Susanne Keiding
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
Obeticholic Acid
placebos
Arm Description
Patients with primary biliary cirrhosis are treated 3 months with OCA (active drug) or placebo in a double-blind cross-over study design.
Patients with primary biliary cirrhosis are treated 3 months with OCA (active drug) or placebo in a double-blind cross-over study design.
Outcomes
Primary Outcome Measures
Effect of OCA on bile flow
Bile flow measured by PET
Secondary Outcome Measures
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03253276
Brief Title
Effect of Obeticholic Acid on Transport of Bile Acids in PBC Examined by 11C-cholyl-sarcosine PET/CT
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
October 2019
Overall Recruitment Status
Completed
Study Start Date
May 19, 2016 (Actual)
Primary Completion Date
September 20, 2018 (Actual)
Study Completion Date
September 20, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Aarhus
4. Oversight
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
Data Monitoring Committee
No
5. Study Description
Brief Summary
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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Primary Biliary Cirrhosis
Keywords
Bile Acid Transporter
7. Study Design
Primary Purpose
Basic Science
Study Phase
Early Phase 1
Interventional Study Model
Crossover Assignment
Model Description
Double blind placebo-controlled crossover
Masking
ParticipantInvestigator
Masking Description
Codes (OCA or placebo) will be opened after final examination of final patient
Allocation
Randomized
Enrollment
8 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Obeticholic Acid
Arm Type
Active Comparator
Arm Description
Patients with primary biliary cirrhosis are treated 3 months with OCA (active drug) or placebo in a double-blind cross-over study design.
Arm Title
placebos
Arm Type
Placebo Comparator
Arm Description
Patients with primary biliary cirrhosis are treated 3 months with OCA (active drug) or placebo in a double-blind cross-over study design.
Intervention Type
Drug
Intervention Name(s)
Obeticholic acid
Other Intervention Name(s)
placebo
Intervention Description
Placebo-controlled
Intervention Type
Drug
Intervention Name(s)
Placebos
Other Intervention Name(s)
Obeticholic acid
Primary Outcome Measure Information:
Title
Effect of OCA on bile flow
Description
Bile flow measured by PET
Time Frame
Measured after 3 months of treatment with Obeticholic Acid or placebo
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Susanne Keiding, prof
Organizational Affiliation
University of Aarhus
Official's Role
Principal Investigator
Facility Information:
Facility Name
Susanne Keiding
City
Aarhus
ZIP/Postal Code
8000
Country
Denmark
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
28249726
Citation
Orntoft NW, Munk OL, Frisch K, Ott P, Keiding S, Sorensen M. Hepatobiliary transport kinetics of the conjugated bile acid tracer 11C-CSar quantified in healthy humans and patients by positron emission tomography. J Hepatol. 2017 Aug;67(2):321-327. doi: 10.1016/j.jhep.2017.02.023. Epub 2017 Feb 27.
Results Reference
result
PubMed Identifier
26966160
Citation
Sorensen M, Munk OL, Orntoft NW, Frisch K, Andersen KJ, Mortensen FV, Alstrup AK, Ott P, Hofmann AF, Keiding S. Hepatobiliary Secretion Kinetics of Conjugated Bile Acids Measured in Pigs by 11C-Cholylsarcosine PET. J Nucl Med. 2016 Jun;57(6):961-6. doi: 10.2967/jnumed.115.171579. Epub 2016 Mar 10.
Results Reference
result
PubMed Identifier
22454486
Citation
Frisch K, Jakobsen S, Sorensen M, Munk OL, Alstrup AK, Ott P, Hofmann AF, Keiding S. [N-methyl-11C]cholylsarcosine, a novel bile acid tracer for PET/CT of hepatic excretory function: radiosynthesis and proof-of-concept studies in pigs. J Nucl Med. 2012 May;53(5):772-8. doi: 10.2967/jnumed.111.098731. Epub 2012 Mar 27.
Results Reference
result
PubMed Identifier
32717289
Citation
Kjaergaard K, Frisch K, Sorensen M, Munk OL, Hofmann AF, Horsager J, Schacht AC, Erickson M, Shapiro D, Keiding S. Obeticholic acid improves hepatic bile acid excretion in patients with primary biliary cholangitis. J Hepatol. 2021 Jan;74(1):58-65. doi: 10.1016/j.jhep.2020.07.028. Epub 2020 Jul 25.
Results Reference
derived
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Effect of Obeticholic Acid on Transport of Bile Acids in PBC Examined by 11C-cholyl-sarcosine PET/CT
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