<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/NCT02244944</url>
  </required_header>
  <id_info>
    <org_study_id>13-0972-F1V</org_study_id>
    <nct_id>NCT02244944</nct_id>
  </id_info>
  <brief_title>Ezetimibe-Ursodiol Combination Therapy on Biomarkers of Liver Function and Sterol Balance in Subjects With NAFLD</brief_title>
  <official_title>The Effect of Ezetimibe-Ursodiol Combination Therapy on Biomarkers of Liver Function and Sterol Balance in Subjects With NAFLD</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Gregory Graf, PhD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Kentucky</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this research is to gather information on the combination Zetia® (Ezetimibe)&#xD;
      and Urso Forte® with respect to sterol balance and their effects on biomarkers of liver&#xD;
      function in subjects with nonalcoholic fatty liver disease (NAFLD).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study will be conducted as a prospective open label trial with pre- and post-treatment&#xD;
      measures for all dependent variables. This trial will enroll subjects with a clinical&#xD;
      diagnosis of nonalcoholic fatty liver disease (NAFLD) by magnetic resonance imaging (MRI),&#xD;
      computed tomography (CT) or ultrasound, including those diagnosed with nonalcoholic&#xD;
      steatohepatitis (NASH). Subjects will be consented, blood collected and a MRI conducted on&#xD;
      the first visit. Patients will be advised on the proper use of the study drug and given the&#xD;
      first three month's supply of the study drug to take home with them. For the remaining three&#xD;
      months, study drug will be delivered by US mail along with return packaging for the prior&#xD;
      three month's study medication in order to monitor compliance. Patients will be called&#xD;
      routinely to encourage compliance, retention, and monitor side effects or adverse events.&#xD;
      After six months of study drug administration, subjects will return for a follow-up visit.&#xD;
      Blood will be drawn, an MRI will be obtained and a post-study questionnaire will be&#xD;
      administered.&#xD;
&#xD;
      Duration of Patient Enrollment: 6 months Duration of Study: 18 months&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Failure to recruit&#xD;
  </why_stopped>
  <start_date>September 2014</start_date>
  <completion_date type="Actual">September 2015</completion_date>
  <primary_completion_date type="Actual">September 2015</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Reduction in Serum Alanine Transaminase (ALT)</measure>
    <time_frame>6 months</time_frame>
    <description>Determine if Ezetimibe-Ursodiol combination therapy improves liver function tests (ALT)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Increase in Plasma Lathosterol</measure>
    <time_frame>6 months</time_frame>
    <description>Determine if Ezetimibe-Ursodiol combination therapy promotes a net-negative sterol balance as evidenced by an increase in the cholesterol synthesis intermediate, lathosterol, in plasma.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Reduction in Hepatic Fat Fraction</measure>
    <time_frame>6 months</time_frame>
    <description>Determine if Ezetimibe-Ursodiol combination therapy reduces total fat in the liver as assessed by MRI</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">2</enrollment>
  <condition>Nonalcoholic Fatty Liver Disease (NAFLD)</condition>
  <arm_group>
    <arm_group_label>EZ-URSO Combination Therapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Ursodiol (URSO Forte) 13-15 mg per kg (250-500 mg b.i.d. or t.i.d depending on body weight) combined with Ezetimibe (Zetia) 10 mg o.p.d.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>EZ-Urso combination therapy</intervention_name>
    <description>Ursodiol 13-15 mg per kg per day combined with Ezetimibe (Zetia) 10 mg per day</description>
    <arm_group_label>EZ-URSO Combination Therapy</arm_group_label>
    <other_name>Ezetimibe (Zetia)</other_name>
    <other_name>Ursoldiol (URSO Forte)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Steatosis&#xD;
&#xD;
          -  ALT &gt;1.5 times normal&#xD;
&#xD;
          -  ALT/AST ratio &gt;1.0&#xD;
&#xD;
          -  Normal Kidney Function&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Normal ALT within last 6 months&#xD;
&#xD;
          -  Advanced fibrosis based on 1) biopsy, if available (Stage 3 or 4 NAFLD), 2) imaging,&#xD;
             or 3) lab (platelet count &lt;150,000)&#xD;
&#xD;
          -  Daily alcohol use above 20 g/day for women and 30 g/day for men&#xD;
&#xD;
          -  Prescription use of ursodiol, ezetimibe, vitamin E, fish oils, thiazolidinediones,&#xD;
             insulin, sulfonylureas, HMG-CoA reductase inhibitors&#xD;
&#xD;
          -  Weight loss greater than 15% in past 12 months&#xD;
&#xD;
          -  Pregnant or breastfeeding&#xD;
&#xD;
          -  Body Mass index greater than 50&#xD;
&#xD;
          -  Largest body circumference greater than 160 cm&#xD;
&#xD;
          -  Claustrophobia&#xD;
&#xD;
          -  Allergy to ezetimibe or ursodiol&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Gregory Graf, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Kentucky</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Kentucky Medical Center</name>
      <address>
        <city>Lexington</city>
        <state>Kentucky</state>
        <zip>40536</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2018</verification_date>
  <study_first_submitted>September 10, 2014</study_first_submitted>
  <study_first_submitted_qc>September 17, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 19, 2014</study_first_posted>
  <results_first_submitted>September 20, 2017</results_first_submitted>
  <results_first_submitted_qc>January 11, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">February 7, 2018</results_first_posted>
  <last_update_submitted>January 11, 2018</last_update_submitted>
  <last_update_submitted_qc>January 11, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">February 7, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Kentucky</investigator_affiliation>
    <investigator_full_name>Gregory Graf, PhD</investigator_full_name>
    <investigator_title>PI</investigator_title>
  </responsible_party>
  <keyword>nonalcoholic fatty liver disease</keyword>
  <keyword>NAFLD</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liver Diseases</mesh_term>
    <mesh_term>Fatty Liver</mesh_term>
    <mesh_term>Non-alcoholic Fatty Liver Disease</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ezetimibe</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>EZ-URSO Combination Therapy</title>
          <description>Ursodiol (URSO Forte) 13-15 mg per kg (250-500 mg b.i.d. or t.i.d depending on body weight) combined with Ezetimibe (Zetia) 10 mg o.p.d.&#xD;
EZ-Urso combination therapy: Ursodiol 13-15 mg per kg per day combined with Ezetimibe (Zetia) 10 mg per day</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Study Terminated</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>EZ-URSO Combination Therapy</title>
          <description>Ursodiol (URSO Forte) 13-15 mg per kg (250-500 mg b.i.d. or t.i.d depending on body weight) combined with Ezetimibe (Zetia) 10 mg o.p.d.&#xD;
EZ-Urso combination therapy: Ursodiol 13-15 mg per kg per day combined with Ezetimibe (Zetia) 10 mg per day</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="2"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="43.5" lower_limit="33" upper_limit="54"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Reduction in Serum Alanine Transaminase (ALT)</title>
        <description>Determine if Ezetimibe-Ursodiol combination therapy improves liver function tests (ALT)</description>
        <time_frame>6 months</time_frame>
        <population>The trial was terminated early. No data was collected to analyze the primary outcome measure.</population>
        <group_list>
          <group group_id="O1">
            <title>EZ-URSO Combination Therapy</title>
            <description>Ursodiol (URSO Forte) 13-15 mg per kg (250-500 mg b.i.d. or t.i.d depending on body weight) combined with Ezetimibe (Zetia) 10 mg o.p.d.&#xD;
EZ-Urso combination therapy: Ursodiol 13-15 mg per kg per day combined with Ezetimibe (Zetia) 10 mg per day</description>
          </group>
        </group_list>
        <measure>
          <title>Reduction in Serum Alanine Transaminase (ALT)</title>
          <description>Determine if Ezetimibe-Ursodiol combination therapy improves liver function tests (ALT)</description>
          <population>The trial was terminated early. No data was collected to analyze the primary outcome measure.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Increase in Plasma Lathosterol</title>
        <description>Determine if Ezetimibe-Ursodiol combination therapy promotes a net-negative sterol balance as evidenced by an increase in the cholesterol synthesis intermediate, lathosterol, in plasma.</description>
        <time_frame>6 months</time_frame>
        <population>The trial was terminated early. No data was collected to analyze the secondary outcome measure.</population>
        <group_list>
          <group group_id="O1">
            <title>EZ-URSO Combination Therapy</title>
            <description>Ursodiol (URSO Forte) 13-15 mg per kg (250-500 mg b.i.d. or t.i.d depending on body weight) combined with Ezetimibe (Zetia) 10 mg o.p.d.&#xD;
EZ-Urso combination therapy: Ursodiol 13-15 mg per kg per day combined with Ezetimibe (Zetia) 10 mg per day</description>
          </group>
        </group_list>
        <measure>
          <title>Increase in Plasma Lathosterol</title>
          <description>Determine if Ezetimibe-Ursodiol combination therapy promotes a net-negative sterol balance as evidenced by an increase in the cholesterol synthesis intermediate, lathosterol, in plasma.</description>
          <population>The trial was terminated early. No data was collected to analyze the secondary outcome measure.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Reduction in Hepatic Fat Fraction</title>
        <description>Determine if Ezetimibe-Ursodiol combination therapy reduces total fat in the liver as assessed by MRI</description>
        <time_frame>6 months</time_frame>
        <population>The trial was terminated early. No data was collected to analyze the primary outcome measure.</population>
        <group_list>
          <group group_id="O1">
            <title>EZ-URSO Combination Therapy</title>
            <description>Ursodiol (URSO Forte) 13-15 mg per kg (250-500 mg b.i.d. or t.i.d depending on body weight) combined with Ezetimibe (Zetia) 10 mg o.p.d.&#xD;
EZ-Urso combination therapy: Ursodiol 13-15 mg per kg per day combined with Ezetimibe (Zetia) 10 mg per day</description>
          </group>
        </group_list>
        <measure>
          <title>Reduction in Hepatic Fat Fraction</title>
          <description>Determine if Ezetimibe-Ursodiol combination therapy reduces total fat in the liver as assessed by MRI</description>
          <population>The trial was terminated early. No data was collected to analyze the primary outcome measure.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>EZ-URSO Combination Therapy</title>
          <description>Ursodiol (URSO Forte) 13-15 mg per kg (250-500 mg b.i.d. or t.i.d depending on body weight) combined with Ezetimibe (Zetia) 10 mg o.p.d.&#xD;
EZ-Urso combination therapy: Ursodiol 13-15 mg per kg per day combined with Ezetimibe (Zetia) 10 mg per day</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>diarrhea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Gregory Graf</name_or_title>
      <organization>University of Kentucky</organization>
      <phone>8592574749</phone>
      <email>Gregory.Graf@uky.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT02244944
org study id: 13-0972-F1V
nct id: NCT02244944
lead sponsor: 
has dmc: Yes
The purpose of this research is to gather information on the combination Zetia® (Ezetimibe)
      and Urso Forte® with respect to sterol balance and their effects on biomarkers of liver
      function in subjects with nonalcoholic fatty liver disease (NAFLD).
The study will be conducted as a prospective open label trial with pre- and post-treatment
      measures for all dependent variables. This trial will enroll subjects with a clinical
      diagnosis of nonalcoholic fatty liver disease (NAFLD) by magnetic resonance imaging (MRI),
      computed tomography (CT) or ultrasound, including those diagnosed with nonalcoholic
      steatohepatitis (NASH). Subjects will be consented, blood collected and a MRI conducted on
      the first visit. Patients will be advised on the proper use of the study drug and given the
      first three month's supply of the study drug to take home with them. For the remaining three
      months, study drug will be delivered by US mail along with return packaging for the prior
      three month's study medication in order to monitor compliance. Patients will be called
      routinely to encourage compliance, retention, and monitor side effects or adverse events.
      After six months of study drug administration, subjects will return for a follow-up visit.
      Blood will be drawn, an MRI will be obtained and a post-study questionnaire will be
      administered.

      Duration of Patient Enrollment: 6 months Duration of Study: 18 months
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Reduction in Serum Alanine Transaminase (ALT)
time frame: 6 months
description: Determine if Ezetimibe-Ursodiol combination therapy improves liver function tests (ALT)
measure: Increase in Plasma Lathosterol
time frame: 6 months
description: Determine if Ezetimibe-Ursodiol combination therapy promotes a net-negative sterol balance as evidenced by an increase in the cholesterol synthesis intermediate, lathosterol, in plasma.
measure: Reduction in Hepatic Fat Fraction
time frame: 6 months
description: Determine if Ezetimibe-Ursodiol combination therapy reduces total fat in the liver as assessed by MRI
arm group label: EZ-URSO Combination Therapy
arm group type: Experimental
description: Ursodiol (URSO Forte) 13-15 mg per kg (250-500 mg b.i.d. or t.i.d depending on body weight) combined with Ezetimibe (Zetia) 10 mg o.p.d.
intervention type: Drug
intervention name: EZ-Urso combination therapy
description: Ursodiol 13-15 mg per kg per day combined with Ezetimibe (Zetia) 10 mg per day
arm group label: EZ-URSO Combination Therapy
other name: Ezetimibe (Zetia)
other name: Ursoldiol (URSO Forte)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Gregory Graf, PhD
role: Principal Investigator
affiliation: University of Kentucky
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: University of Kentucky
investigator full name: Gregory Graf, PhD
investigator title: PI
mesh term: Liver Diseases
mesh term: Fatty Liver
mesh term: Non-alcoholic Fatty Liver Disease
mesh term: Ezetimibe
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 