<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03253276</url>
  </required_header>
  <id_info>
    <org_study_id>OCAPBC</org_study_id>
    <nct_id>NCT03253276</nct_id>
  </id_info>
  <brief_title>Effect of Obeticholic Acid on Transport of Bile Acids in PBC Examined by 11C-cholyl-sarcosine PET/CT</brief_title>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Aarhus</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Aarhus</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is an investigator-initiated, double-blind crossover study on the mechanism of OCA&#xD;
      treatment of patients with PBC.&#xD;
&#xD;
      Hypothesis and significance&#xD;
&#xD;
      The investigators will test the hypothesis that OCA administration to patients with PBC&#xD;
      increases hepatobiliary secretion of cholylsarcosine assessed by PET/CT using 11C-labeled&#xD;
      cholylsarcosine (11C-CSar) as tracer.&#xD;
&#xD;
      The results of this research project will elucidate the mechanism of the effect of using OCA&#xD;
      therapeutically in patients with PBC.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background&#xD;
&#xD;
      Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by&#xD;
      cholestasis and cirrhosis. Pathogenesis comprises impaired hepatobiliary secretion of bile&#xD;
      acids to the bile. As a result bile flow reduces and diminished content of bile acids in the&#xD;
      intestines leads to impaired absorption of lipids and lipid-soluble vitamins, diarrhea,&#xD;
      general pruritus, and fatigue.&#xD;
&#xD;
      Bile acids are transported from blood to hepatocytes by the transporter proteins&#xD;
      Na+-taurocholate co-transporting polypeptide (NTCP) and Organic anion-transporting&#xD;
      polypeptide (OATP) and secreted from hepatocyte to bile canaliculi by the Bile salt export&#xD;
      pump (BSEP) and Multidrug resistance protein type 3 (MDR3). Dysfunction of BSEP most probably&#xD;
      plays a key pathogenic role in PBC.&#xD;
&#xD;
      Ursodeoxycholic acid (UDCA) is a dihydroxylated bile acid and the only approved drug for&#xD;
      treatment of PBC today. In most cases UDCA can delay or prevent disease progression. However,&#xD;
      a subgroup of patients does not respond adequately to UDCA and for these patients new&#xD;
      therapies are needed.&#xD;
&#xD;
      BSEP is induced by the nuclear bile acid receptor (BAR), also known as farnesoid X receptor&#xD;
      (FXR). Obeticholic Acid (INT-747, Intercept) (OCA) is a FXR agonist and induces BSEP.&#xD;
&#xD;
      OCA administration therefore may increase the hepatobiliary secretion of bile acids, being&#xD;
      the mechanism behind beneficial therapeutic effects in PBC.&#xD;
&#xD;
      Cholylsarcosine is a synthetic conjugated bile acid (sarcosine = methyl-glycine) that is&#xD;
      non-toxic, not metabolized in the gut or liver, and transported by BSEP. The trans-hepatic&#xD;
      transport of bile acids can be assessed in humans by PET/CT of the liver using 11C-labeled&#xD;
      cholylsarcosine (11C-CSar) as tracer. 11C-CSar is handled by the liver as a natural bile acid&#xD;
      in pig studies (1). Studies in humans (2) show that&#xD;
&#xD;
        -  11C-CSar is taken up avidly by the liver and flow-determined&#xD;
&#xD;
        -  11C-CSar secretion from hepatocytes to bile is reduced during cholestasis, and&#xD;
&#xD;
        -  11C-CSar back flux from hepatocytes to blood during cholestasis&#xD;
&#xD;
      Patients&#xD;
&#xD;
      8 patients with PBC&#xD;
&#xD;
        -  who are not responding adequately to treatment with UDCA, defined as ALP &gt; 2 times upper&#xD;
           normal level during a time period of 6 months&#xD;
&#xD;
        -  Patients are recruited from Aarhus University Hospital, Department of Hepatology and&#xD;
           Gastroenterology.&#xD;
&#xD;
      Paired study design&#xD;
&#xD;
        -  11C-CSar PET/CT before and after 3 months treatment with OCA or placebo.&#xD;
&#xD;
      Methods&#xD;
&#xD;
      PET/CT: Initial low-dose CT for anatomical definition of the PET findings and for attenuation&#xD;
      correction of PET data. Dynamic 60-min PET recording of the tissue radioactivity&#xD;
      concentration over time following iv bolus injection of 100 MBq 11C-CSar and iv infusion of&#xD;
      100 MBq 11C-CSar. During the PET study, ICG is given as a constant iv infusion for&#xD;
      measurements of hepatic blood flow, used in the kinetic analysis, and blood samples are&#xD;
      collected from catheters in a radial artery and a liver vein (blood 11C-CSar concentrations&#xD;
      for kinetic calculations, ICG, and blood gasses for monitoring purposes).&#xD;
&#xD;
      Liver tests at the time points of the PET/CT study: Plasma ALT, ALP, GGT, bilirubin, bile&#xD;
      salts, IRN, platelets, hemoglobin, mitochondrial antibodies; ICG clearance.&#xD;
&#xD;
      Raw data comprise time-courses of the 11C-CSar concentrations in liver tissue and common&#xD;
      hepatic bile duct (PET recordings) and blood concentrations of 11C-CSar in arterial and liver&#xD;
      vein blood (blood samples); hepatic blood flow, hepatic venous pressure gradient (HVPG),&#xD;
      splanchnic oxygen uptake.&#xD;
&#xD;
      11C-CSar data comprise clearances of 11C-CSar from blood-to-hepatocytes and from&#xD;
      hepatocytes-to-bile canaliculi, vascular extraction fractions, biliary secretion fraction,&#xD;
      transit times, etc.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 19, 2016</start_date>
  <completion_date type="Actual">September 20, 2018</completion_date>
  <primary_completion_date type="Actual">September 20, 2018</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <intervention_model_description>Double blind placebo-controlled crossover</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
    <masking_description>Codes (OCA or placebo) will be opened after final examination of final patient</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Effect of OCA on bile flow</measure>
    <time_frame>Measured after 3 months of treatment with Obeticholic Acid or placebo</time_frame>
    <description>Bile flow measured by PET</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">8</enrollment>
  <condition>Primary Biliary Cirrhosis</condition>
  <arm_group>
    <arm_group_label>Obeticholic Acid</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients with primary biliary cirrhosis are treated 3 months with OCA (active drug) or placebo in a double-blind cross-over study design.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>placebos</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Patients with primary biliary cirrhosis are treated 3 months with OCA (active drug) or placebo in a double-blind cross-over study design.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Obeticholic acid</intervention_name>
    <description>Placebo-controlled</description>
    <arm_group_label>Obeticholic Acid</arm_group_label>
    <other_name>placebo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebos</intervention_name>
    <arm_group_label>placebos</arm_group_label>
    <other_name>Obeticholic acid</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  patients with PBC&#xD;
&#xD;
          -  who are not responding adequately to treatment with UDCA, defined as ALP &gt; 2 times&#xD;
             upper normal level during a time period of 6 months&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Itching that requires medical treatment&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Susanne Keiding, prof</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Aarhus</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Susanne Keiding</name>
      <address>
        <city>Aarhus</city>
        <zip>8000</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <results_reference>
    <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.</citation>
    <PMID>28249726</PMID>
  </results_reference>
  <results_reference>
    <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.</citation>
    <PMID>26966160</PMID>
  </results_reference>
  <results_reference>
    <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.</citation>
    <PMID>22454486</PMID>
  </results_reference>
  <verification_date>October 2019</verification_date>
  <study_first_submitted>May 28, 2017</study_first_submitted>
  <study_first_submitted_qc>August 16, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 17, 2017</study_first_posted>
  <last_update_submitted>October 31, 2019</last_update_submitted>
  <last_update_submitted_qc>October 31, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">November 1, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Bile Acid Transporter</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liver Cirrhosis, Biliary</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Chenodeoxycholic Acid</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03253276
org study id: OCAPBC
nct id: NCT03253276
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
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.
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.
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: Double blind placebo-controlled crossover
primary purpose: Basic Science
masking: Double (Participant, Investigator)
masking description: Codes (OCA or placebo) will be opened after final examination of final patient
measure: Effect of OCA on bile flow
time frame: Measured after 3 months of treatment with Obeticholic Acid or placebo
description: Bile flow measured by PET
arm group label: Obeticholic Acid
arm group type: Active Comparator
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 group label: placebos
arm group type: Placebo Comparator
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: Obeticholic acid
description: Placebo-controlled
arm group label: Obeticholic Acid
other name: placebo
intervention type: Drug
intervention name: Placebos
arm group label: placebos
other name: Obeticholic acid
criteria: 
gender: All
minimum age: 18 Years
maximum age: 85 Years
healthy volunteers: No
last name: Susanne Keiding, prof
role: Principal Investigator
affiliation: University of Aarhus
facility: 
country: Denmark
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.
PMID: 28249726
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.
PMID: 26966160
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.
PMID: 22454486
responsible party type: Sponsor
mesh term: Liver Cirrhosis, Biliary
mesh term: Chenodeoxycholic Acid
sharing ipd: No