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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Primary Biliary Cirrhosis

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


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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: Crossover Assignment
Interventional Model Description: Double blind placebo-controlled crossover
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Obeticholic Acid<br>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<br>* Placebo-controlled<br>* Other names: placebo;|
| Placebo Comparator: placebos<br>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<br> <br> * Other names: Obeticholic acid;|

What is the study measuring?
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Primary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bile Acid Transporter