<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/NCT02971033</url>
  </required_header>
  <id_info>
    <org_study_id>INFA-015-16S</org_study_id>
    <nct_id>NCT02971033</nct_id>
  </id_info>
  <brief_title>Ezetimibe as a Safe and Efficacious Treatment for Chronic Hepatitis C</brief_title>
  <official_title>Ezetimibe as a Safe and Efficacious Treatment for Chronic Hepatitis C</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>VA Office of Research and Development</agency>
      <agency_class>U.S. Fed</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>VA Office of Research and Development</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      To address the need for more affordable hepatitis C virus (HCV) antivirals with high barriers&#xD;
      to viral resistance and strategies to shorten the current treatment duration, the goal is to&#xD;
      develop affordable therapeutic regimens to prevent HCV entry/spread and test the efficacy of&#xD;
      those inhibitors for treating HCV infection. The investigators recently discovered that a&#xD;
      major cholesterol uptake receptor is required for HCV entry into hepatocytes and that there&#xD;
      is already an FDA-approved drug that inhibits cholesterol uptake by this receptor.&#xD;
      Importantly the same drug also potently blocks HCV entry in human liver cells both in cell&#xD;
      culture and in a small animal model. Further, looking back at people who were previously&#xD;
      treated for HCV infection, the investigators found treatment response to be better (i.e.&#xD;
      larger viral log reduction) in patients who happened to be taking ezetimibe (EZE). Hence, the&#xD;
      objective of this study is to assess whether the FDA-approved drug (ezetimibe) is useful for&#xD;
      the treatment of chronic HCV. The investigators predict that when administered as monotherapy&#xD;
      ezetimibe will reduce HCV viremia perhaps allowing for viral clearance and that when included&#xD;
      in combination treatment regimens that EZE will increase HCV decline resulting in faster&#xD;
      viral clearance (i.e. shorter/cheaper direct-acting antiviral [DAA] therapy). To test these&#xD;
      hypotheses, the investigators will execute the following aims: (1) Assess the efficacy of EZE&#xD;
      monotherapy in chronically HCV infected and predict time to cure; (2) Assess the efficacy of&#xD;
      EZE as an adjunct therapy in chronically HCV infected patients undergoing currently approved&#xD;
      HCV DAA treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      To address the need for more affordable HCV antivirals with high barriers to viral resistance&#xD;
      and/or strategies to shorten the current treatment duration, the goal is to develop&#xD;
      affordable therapeutic regimens to prevent HCV entry/spread and test the efficacy of those&#xD;
      inhibitors for treating HCV infection. The investigators recently discovered that the&#xD;
      Niemann-Pick C1 Like-1 (NPC1L1) cellular cholesterol uptake receptor is required for HCV&#xD;
      entry into hepatocytes and that ezetimibe, an FDA-approved drug that inhibits NPC1L1-mediated&#xD;
      cholesterol uptake potently blocks HCV entry in human hepatoma cells and human hepatocytes&#xD;
      transplanted into urokinase-type plasminogen activator-severe combined immunodeficiency&#xD;
      (uPA-SCID) mice. Further, retrospective analysis of the National VA database using&#xD;
      multivariable logistic regression models to control for age, sex, race, alcohol use, drug&#xD;
      use, and other co-morbidities, the investigators found HCV prevalence to be lower (p &lt;.001)&#xD;
      and interferon/ribavirin (IFN/RBV) treatment response to be better (i.e. larger viral log&#xD;
      reduction) in patients taking ezetimibe. Hence, the specific objective of this application is&#xD;
      to assess the efficacy of EZE for the treatment of chronic HCV. Based on preliminary in&#xD;
      vitro, in vivo, clinical retrospective data and HCV/DAA modeling, the investigators&#xD;
      hypothesize that when administered as monotherapy EZE will reduce HCV viremia perhaps&#xD;
      allowing for viral clearance and that when included in combination treatment regimens that&#xD;
      EZE will augment 2nd phase HCV decline resulting in faster viral clearance (i.e.&#xD;
      shorter/cheaper DAA therapy). To test these hypotheses, the investigators will execute the&#xD;
      following aims: (1) Assess the efficacy of EZE monotherapy in chronically HCV infected and&#xD;
      predict time to cure; (2) Assess the efficacy of EZE as an adjunct therapy in chronically HCV&#xD;
      infected patients undergoing currently approved HCV DAA treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Study Funding ended&#xD;
  </why_stopped>
  <start_date type="Actual">April 16, 2018</start_date>
  <completion_date type="Actual">March 31, 2021</completion_date>
  <primary_completion_date type="Actual">March 31, 2021</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Viral Load</measure>
    <time_frame>0 weeks, 8 weeks</time_frame>
    <description>Participants will have their HCV-RNA measured in international unit per milliliter at baseline and 8 weeks. HCV RNA international unit per milliliter ranges from 0 to infinity, with higher levels indicating HCV positivity. The change in international unit per milliliter will be compared among the three intervention groups (i.e., placebo or control cohort, those assigned to 20mg ezetimibe per day, and 40mg ezetimibe per day). Change is calculated based on 8 weeks minus baseline (0 weeks).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Second Phase Slope</measure>
    <time_frame>3 days through 4 weeks</time_frame>
    <description>HCV declines in a biphasic manner under HCV treatment. Here we are measuring the slope (i.e., rate) at which HCV is declining during the second slower phase of viral decline.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Alanine Aminotransferase (ALT)</measure>
    <time_frame>8 weeks</time_frame>
    <description>Participants will have their ALT levels measured in units per liter (U/L) at baseline and 8 weeks. ALT ranges from 0 to infinity with higher levels of ALT indicating hepatocyte death. The change in ALT levels will be compared among the three intervention groups (i.e., placebo or control cohort, those assigned to 20mg ezetimibe per day, and 40mg ezetimibe per day).</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">2</enrollment>
  <condition>Chronic Hepatitis C</condition>
  <arm_group>
    <arm_group_label>placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>placebo</description>
  </arm_group>
  <arm_group>
    <arm_group_label>20mg/day ezetimibe</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>20mg/day ezetimibe</description>
  </arm_group>
  <arm_group>
    <arm_group_label>40mg/day ezetimibe</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>40mg/day ezetimibe</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>20mg ezetimibe</intervention_name>
    <description>Participants assigned to this intervention will receive 20mg per day of ezetimibe for 12 weeks.</description>
    <arm_group_label>20mg/day ezetimibe</arm_group_label>
    <other_name>20mg Zetia</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Participants assigned to this intervention will receive placebo every day for 12 weeks</description>
    <arm_group_label>placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>40mg ezetimibe</intervention_name>
    <description>Participants assigned to this intervention will receive 40mg per day of ezetimibe for 12 weeks.</description>
    <arm_group_label>40mg/day ezetimibe</arm_group_label>
    <other_name>40mg Zetia</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Males/females 18 - 70 yrs of age&#xD;
&#xD;
          -  Serum HCV RNA &gt;2,000 IU/ml&#xD;
&#xD;
          -  Hepatitis C genotype 1&#xD;
&#xD;
          -  Other causes of chronic liver disease excluded by appropriate clinical, laboratory, or&#xD;
             histologic evaluation&#xD;
&#xD;
          -  The following hematological criteria must be met:&#xD;
&#xD;
               -  Hemoglobin &gt; 12 g/dl&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) &gt; 1.0x109 /L&#xD;
&#xD;
               -  Platelets 150 x 108 /L (i.e normal)&#xD;
&#xD;
          -  Serum creatinine &lt;1.5 times the upper limit of normal (ULN) at screening.&#xD;
&#xD;
          -  Fasting blood sugar normal for non-diabetics or hemoglobin A1C &lt; 8.5% with diabetes&#xD;
&#xD;
          -  Women of childbearing potential must have a negative pregnancy test prior to receiving&#xD;
             treatment. Sexually active women must take adequate precautions to prevent pregnancy&#xD;
             during the study. Pregnancy tests will be done at the final clinic visits and every 4&#xD;
             weeks&#xD;
&#xD;
          -  Patient provides written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Evidence of liver disease other than HCV:&#xD;
&#xD;
               -  Antinuclear antibodies (ANA) &gt;1:160&#xD;
&#xD;
               -  Active alcoholic liver disease.&#xD;
&#xD;
               -  Hepatitis B surface antigen positive&#xD;
&#xD;
               -  Hemochromatosis&#xD;
&#xD;
               -  Wilson disease&#xD;
&#xD;
               -  Alpha-1-antitrypsin deficiency&#xD;
&#xD;
               -  Recent hepatotoxic drug exposure&#xD;
&#xD;
               -  Cirrhosis with complications of portal hypertension including esophageal varices&#xD;
                  (&gt; grade 1 by endoscopy), ascites, or hepatic encephalopathy, or bilirubin &gt;2.0&#xD;
                  mg/dl&#xD;
&#xD;
          -  Patients with advanced fibrosis (defined herein as decompensated cirrhosis, FIB4 &gt;&#xD;
             2.5, platelet count &lt;150 x 103/uL, clinical or radiographic evidence of cirrhosis)&#xD;
&#xD;
          -  Extrahepatic manifestations of liver disease or HIV co-infection&#xD;
&#xD;
          -  Use of fibric acid, Fenofibrate or cholestyramine&#xD;
&#xD;
          -  Active substance abuse including, but not limited to alcohol or i.v./inhaled drugs&#xD;
&#xD;
          -  Use of chemotherapy or systemic steroid therapy within 30 days prior to enrollment&#xD;
&#xD;
          -  Pregnancy, females who are breast feeding, or females of child bearing potential who&#xD;
             are not using adequate birth control measures&#xD;
&#xD;
          -  History of a medical condition that could interfere with participation or completion&#xD;
             of the protocol&#xD;
&#xD;
          -  Organ transplant recipient&#xD;
&#xD;
          -  History of hypersensitivity to ezetimibe&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Susan L. Uprichard, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Edward Hines Jr. VA Hospital, Hines, IL</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Edward Hines Jr. VA Hospital, Hines, IL</name>
      <address>
        <city>Hines</city>
        <state>Illinois</state>
        <zip>60141-5000</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2022</verification_date>
  <study_first_submitted>October 21, 2016</study_first_submitted>
  <study_first_submitted_qc>November 18, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 22, 2016</study_first_posted>
  <results_first_submitted>April 6, 2022</results_first_submitted>
  <results_first_submitted_qc>May 10, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">June 6, 2022</results_first_posted>
  <last_update_submitted>May 10, 2022</last_update_submitted>
  <last_update_submitted_qc>May 10, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">June 6, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>hepatitis C virus</keyword>
  <keyword>antiviral treatment</keyword>
  <keyword>viral entry inhibitor</keyword>
  <keyword>mathematical modeling</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hepatitis A</mesh_term>
    <mesh_term>Hepatitis C</mesh_term>
    <mesh_term>Hepatitis C, Chronic</mesh_term>
    <mesh_term>Hepatitis</mesh_term>
    <mesh_term>Hepatitis, Chronic</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ezetimibe</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>March 30, 2022</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/33/NCT02971033/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>Patients are enrolled, but then are not randomized until they pick up clinical and study medication with the investigational pharmacist at a subsequent visit. As such, one can be enrolled but never randomized if they patient does not return for the medication.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Placebo</title>
          <description>placebo&#xD;
Placebo: Participants assigned to this intervention will receive placebo every day for 8 weeks</description>
        </group>
        <group group_id="P2">
          <title>20mg/Day Ezetimibe</title>
          <description>20mg/day ezetimibe&#xD;
20mg ezetimibe: Participants assigned to this intervention will receive 20mg per day of ezetimibe for 8 weeks.</description>
        </group>
        <group group_id="P3">
          <title>40mg/Day Ezetimibe</title>
          <description>40mg/day ezetimibe&#xD;
40mg ezetimibe: Participants assigned to this intervention will receive 40mg per day of ezetimibe for 8 weeks.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>no patients were randomized to 40mg/day ezetimibe group</population>
      <group_list>
        <group group_id="B1">
          <title>Placebo</title>
          <description>placebo&#xD;
Placebo: Participants assigned to this intervention will receive placebo every day for 8 weeks</description>
        </group>
        <group group_id="B2">
          <title>20mg/Day Ezetimibe</title>
          <description>20mg/day ezetimibe&#xD;
20mg ezetimibe: Participants assigned to this intervention will receive 20mg per day of ezetimibe for 8 weeks.</description>
        </group>
        <group group_id="B3">
          <title>40mg/Day Ezetimibe</title>
          <description>40mg/day ezetimibe&#xD;
40mg ezetimibe: Participants assigned to this intervention will receive 40mg per day of ezetimibe for 8 weeks.</description>
        </group>
        <group group_id="B4">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="1"/>
            <count group_id="B2" value="1"/>
            <count group_id="B3" value="0"/>
            <count group_id="B4" 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 group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </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="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>non-hispanic White</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>non-hispanic Black</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>HCV RNA</title>
          <description>HCV RNA is measured by clinical laboratories by reverse transcription quantitative PCR, which measures the number HCV genomes present. The results are reported as international units per milliliter (IU/mL). Higher HCV IU means higher levels of HCV in the blood.</description>
          <units>International Units per mL</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4030000" lower_limit="4030000" upper_limit="4030000"/>
                    <measurement group_id="B2" value="5860000" lower_limit="5860000" upper_limit="5860000"/>
                    <measurement group_id="B4" value="4945000" lower_limit="4030000" upper_limit="5860000"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>alanine transaminase (ALT)</title>
          <description>Participants will have their ALT levels measured in units per liter (U/L) at baseline. ALT ranges from 0 to infinity with higher levels of ALT indicating liver cells damage.</description>
          <units>Units/Liter</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="109" lower_limit="109" upper_limit="109"/>
                    <measurement group_id="B2" value="105" lower_limit="105" upper_limit="105"/>
                    <measurement group_id="B4" value="107" lower_limit="107" upper_limit="109"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in Viral Load</title>
        <description>Participants will have their HCV-RNA measured in international unit per milliliter at baseline and 8 weeks. HCV RNA international unit per milliliter ranges from 0 to infinity, with higher levels indicating HCV positivity. The change in international unit per milliliter will be compared among the three intervention groups (i.e., placebo or control cohort, those assigned to 20mg ezetimibe per day, and 40mg ezetimibe per day). Change is calculated based on 8 weeks minus baseline (0 weeks).</description>
        <time_frame>0 weeks, 8 weeks</time_frame>
        <population>Participants who were enrolled, were not randomized until they received their study medication. No one was randomized to the 40mg/day arm</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>placebo&#xD;
Placebo: Participants assigned to this intervention will receive placebo every day for 8 weeks</description>
          </group>
          <group group_id="O2">
            <title>20mg/Day Ezetimibe</title>
            <description>20mg/day ezetimibe&#xD;
20mg ezetimibe: Participants assigned to this intervention will receive 20mg per day of ezetimibe for 8 weeks.</description>
          </group>
          <group group_id="O3">
            <title>40mg/Day Ezetimibe</title>
            <description>40mg/day ezetimibe&#xD;
40mg ezetimibe: Participants assigned to this intervention will receive 40mg per day of ezetimibe for 8 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Viral Load</title>
          <description>Participants will have their HCV-RNA measured in international unit per milliliter at baseline and 8 weeks. HCV RNA international unit per milliliter ranges from 0 to infinity, with higher levels indicating HCV positivity. The change in international unit per milliliter will be compared among the three intervention groups (i.e., placebo or control cohort, those assigned to 20mg ezetimibe per day, and 40mg ezetimibe per day). Change is calculated based on 8 weeks minus baseline (0 weeks).</description>
          <population>Participants who were enrolled, were not randomized until they received their study medication. No one was randomized to the 40mg/day arm</population>
          <units>international units per milliliter</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="1"/>
                <count group_id="O3" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-4030000" lower_limit="-4030000" upper_limit="-4030000"/>
                    <measurement group_id="O2" value="-5860000" lower_limit="-5860000" upper_limit="-5860000"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Second Phase Slope</title>
        <description>HCV declines in a biphasic manner under HCV treatment. Here we are measuring the slope (i.e., rate) at which HCV is declining during the second slower phase of viral decline.</description>
        <time_frame>3 days through 4 weeks</time_frame>
        <population>Participants who were enrolled, were not randomized until they received their study medication. No one was randomized to the 40mg/day arm</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>placebo&#xD;
Placebo: Participants assigned to this intervention will receive placebo every day for 8 weeks</description>
          </group>
          <group group_id="O2">
            <title>20mg/Day Ezetimibe</title>
            <description>20mg/day ezetimibe&#xD;
20mg ezetimibe: Participants assigned to this intervention will receive 20mg per day of ezetimibe for 8 weeks.</description>
          </group>
          <group group_id="O3">
            <title>40mg/Day Ezetimibe</title>
            <description>40mg/day ezetimibe&#xD;
40mg ezetimibe: Participants assigned to this intervention will receive 40mg per day of ezetimibe for 8 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Second Phase Slope</title>
          <description>HCV declines in a biphasic manner under HCV treatment. Here we are measuring the slope (i.e., rate) at which HCV is declining during the second slower phase of viral decline.</description>
          <population>Participants who were enrolled, were not randomized until they received their study medication. No one was randomized to the 40mg/day arm</population>
          <units>log(copies/mL)/day</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="1"/>
                <count group_id="O3" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value=".90" lower_limit=".90" upper_limit=".90"/>
                    <measurement group_id="O2" value=".98" lower_limit=".98" upper_limit=".98"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Alanine Aminotransferase (ALT)</title>
        <description>Participants will have their ALT levels measured in units per liter (U/L) at baseline and 8 weeks. ALT ranges from 0 to infinity with higher levels of ALT indicating hepatocyte death. The change in ALT levels will be compared among the three intervention groups (i.e., placebo or control cohort, those assigned to 20mg ezetimibe per day, and 40mg ezetimibe per day).</description>
        <time_frame>8 weeks</time_frame>
        <population>Participants who were enrolled, were not randomized until they received their study medication. No one was randomized to the 40mg/day arm</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>placebo&#xD;
Placebo: Participants assigned to this intervention will receive placebo every day for 8 weeks</description>
          </group>
          <group group_id="O2">
            <title>20mg/Day Ezetimibe</title>
            <description>20mg/day ezetimibe&#xD;
20mg ezetimibe: Participants assigned to this intervention will receive 20mg per day of ezetimibe for 8 weeks.</description>
          </group>
          <group group_id="O3">
            <title>40mg/Day Ezetimibe</title>
            <description>40mg/day ezetimibe&#xD;
40mg ezetimibe: Participants assigned to this intervention will receive 40mg per day of ezetimibe for 8 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Alanine Aminotransferase (ALT)</title>
          <description>Participants will have their ALT levels measured in units per liter (U/L) at baseline and 8 weeks. ALT ranges from 0 to infinity with higher levels of ALT indicating hepatocyte death. The change in ALT levels will be compared among the three intervention groups (i.e., placebo or control cohort, those assigned to 20mg ezetimibe per day, and 40mg ezetimibe per day).</description>
          <population>Participants who were enrolled, were not randomized until they received their study medication. No one was randomized to the 40mg/day arm</population>
          <units>units per Liter</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="1"/>
                <count group_id="O3" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-75" lower_limit="-75" upper_limit="-75"/>
                    <measurement group_id="O2" value="-73" lower_limit="-73" upper_limit="-73"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>12 weeks</time_frame>
      <desc>there were no patients randomized to the 40mg/day ezetimibe arm</desc>
      <group_list>
        <group group_id="E1">
          <title>Placebo</title>
          <description>placebo&#xD;
Placebo: Participants assigned to this intervention will receive placebo every day for 8 weeks</description>
        </group>
        <group group_id="E2">
          <title>20mg/Day Ezetimibe</title>
          <description>20mg/day ezetimibe&#xD;
20mg ezetimibe: Participants assigned to this intervention will receive 20mg per day of ezetimibe for 8 weeks.</description>
        </group>
        <group group_id="E3">
          <title>40mg/Day Ezetimibe</title>
          <description>40mg/day ezetimibe&#xD;
40mg ezetimibe: Participants assigned to this intervention will receive 40mg per day of ezetimibe for 8 weeks.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="0"/>
              </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>
    <limitations_and_caveats>A major limitation is that the study was that it was interrupted by the CoVID-19 pandemic and then was terminated early leading to small numbers of subjects analyzed. It is not possible to derive conclusions comparing the single patients enrolled in arms 1 and 2.&#xD;
The patient in arm 2 had study medication remaining at the first pill count indicating that EZE dosing was lower than 20mg/day during at least part of the treatment period.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Susan L. Uprichard</name_or_title>
      <organization>Edward Hines Jr. Veterans Administration Hospital</organization>
      <phone>(336) 402-1086</phone>
      <email>susan.uprichard@va.gov</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/NCT02971033
org study id: INFA-015-16S
nct id: NCT02971033
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
To address the need for more affordable hepatitis C virus (HCV) antivirals with high barriers
      to viral resistance and strategies to shorten the current treatment duration, the goal is to
      develop affordable therapeutic regimens to prevent HCV entry/spread and test the efficacy of
      those inhibitors for treating HCV infection. The investigators recently discovered that a
      major cholesterol uptake receptor is required for HCV entry into hepatocytes and that there
      is already an FDA-approved drug that inhibits cholesterol uptake by this receptor.
      Importantly the same drug also potently blocks HCV entry in human liver cells both in cell
      culture and in a small animal model. Further, looking back at people who were previously
      treated for HCV infection, the investigators found treatment response to be better (i.e.
      larger viral log reduction) in patients who happened to be taking ezetimibe (EZE). Hence, the
      objective of this study is to assess whether the FDA-approved drug (ezetimibe) is useful for
      the treatment of chronic HCV. The investigators predict that when administered as monotherapy
      ezetimibe will reduce HCV viremia perhaps allowing for viral clearance and that when included
      in combination treatment regimens that EZE will increase HCV decline resulting in faster
      viral clearance (i.e. shorter/cheaper direct-acting antiviral [DAA] therapy). To test these
      hypotheses, the investigators will execute the following aims: (1) Assess the efficacy of EZE
      monotherapy in chronically HCV infected and predict time to cure; (2) Assess the efficacy of
      EZE as an adjunct therapy in chronically HCV infected patients undergoing currently approved
      HCV DAA treatment.
To address the need for more affordable HCV antivirals with high barriers to viral resistance
      and/or strategies to shorten the current treatment duration, the goal is to develop
      affordable therapeutic regimens to prevent HCV entry/spread and test the efficacy of those
      inhibitors for treating HCV infection. The investigators recently discovered that the
      Niemann-Pick C1 Like-1 (NPC1L1) cellular cholesterol uptake receptor is required for HCV
      entry into hepatocytes and that ezetimibe, an FDA-approved drug that inhibits NPC1L1-mediated
      cholesterol uptake potently blocks HCV entry in human hepatoma cells and human hepatocytes
      transplanted into urokinase-type plasminogen activator-severe combined immunodeficiency
      (uPA-SCID) mice. Further, retrospective analysis of the National VA database using
      multivariable logistic regression models to control for age, sex, race, alcohol use, drug
      use, and other co-morbidities, the investigators found HCV prevalence to be lower (p <.001)
      and interferon/ribavirin (IFN/RBV) treatment response to be better (i.e. larger viral log
      reduction) in patients taking ezetimibe. Hence, the specific objective of this application is
      to assess the efficacy of EZE for the treatment of chronic HCV. Based on preliminary in
      vitro, in vivo, clinical retrospective data and HCV/DAA modeling, the investigators
      hypothesize that when administered as monotherapy EZE will reduce HCV viremia perhaps
      allowing for viral clearance and that when included in combination treatment regimens that
      EZE will augment 2nd phase HCV decline resulting in faster viral clearance (i.e.
      shorter/cheaper DAA therapy). To test these hypotheses, the investigators will execute the
      following aims: (1) Assess the efficacy of EZE monotherapy in chronically HCV infected and
      predict time to cure; (2) Assess the efficacy of EZE as an adjunct therapy in chronically HCV
      infected patients undergoing currently approved HCV DAA treatment.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Change in Viral Load
time frame: 0 weeks, 8 weeks
description: Participants will have their HCV-RNA measured in international unit per milliliter at baseline and 8 weeks. HCV RNA international unit per milliliter ranges from 0 to infinity, with higher levels indicating HCV positivity. The change in international unit per milliliter will be compared among the three intervention groups (i.e., placebo or control cohort, those assigned to 20mg ezetimibe per day, and 40mg ezetimibe per day). Change is calculated based on 8 weeks minus baseline (0 weeks).
measure: Second Phase Slope
time frame: 3 days through 4 weeks
description: HCV declines in a biphasic manner under HCV treatment. Here we are measuring the slope (i.e., rate) at which HCV is declining during the second slower phase of viral decline.
measure: Change in Alanine Aminotransferase (ALT)
time frame: 8 weeks
description: Participants will have their ALT levels measured in units per liter (U/L) at baseline and 8 weeks. ALT ranges from 0 to infinity with higher levels of ALT indicating hepatocyte death. The change in ALT levels will be compared among the three intervention groups (i.e., placebo or control cohort, those assigned to 20mg ezetimibe per day, and 40mg ezetimibe per day).
arm group label: placebo
arm group type: Placebo Comparator
description: placebo
arm group label: 20mg/day ezetimibe
arm group type: Experimental
description: 20mg/day ezetimibe
arm group label: 40mg/day ezetimibe
arm group type: Experimental
description: 40mg/day ezetimibe
intervention type: Drug
intervention name: 20mg ezetimibe
description: Participants assigned to this intervention will receive 20mg per day of ezetimibe for 12 weeks.
arm group label: 20mg/day ezetimibe
other name: 20mg Zetia
intervention type: Drug
intervention name: Placebo
description: Participants assigned to this intervention will receive placebo every day for 12 weeks
arm group label: placebo
intervention type: Drug
intervention name: 40mg ezetimibe
description: Participants assigned to this intervention will receive 40mg per day of ezetimibe for 12 weeks.
arm group label: 40mg/day ezetimibe
other name: 40mg Zetia
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Susan L. Uprichard, PhD
role: Principal Investigator
affiliation: Edward Hines Jr. VA Hospital, Hines, IL
facility: 
country: United States
responsible party type: Sponsor
mesh term: Hepatitis A
mesh term: Hepatitis C
mesh term: Hepatitis C, Chronic
mesh term: Hepatitis
mesh term: Hepatitis, Chronic
mesh term: Ezetimibe
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: A major limitation is that the study was that it was interrupted by the CoVID-19 pandemic and then was terminated early leading to small numbers of subjects analyzed. It is not possible to derive conclusions comparing the single patients enrolled in arms 1 and 2.
The patient in arm 2 had study medication remaining at the first pill count indicating that EZE dosing was lower than 20mg/day during at least part of the treatment period.
point of contact: 