<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/NCT01679197</url>
  </required_header>
  <id_info>
    <org_study_id>MCRU 2834</org_study_id>
    <secondary_id>R01DK088114-02</secondary_id>
    <nct_id>NCT01679197</nct_id>
  </id_info>
  <brief_title>Clinical Protocol to Investigate the Efficacy of Recombinant Human Leptin (Metreleptin) in Nonalcoholic Steatohepatitis (NASH) or Nonalcoholic Fatty Liver Disease (NAFLD) Associated With Lipodystrophy</brief_title>
  <official_title>Clinical Protocol to Investigate the Efficacy of Recombinant Human Leptin (Metreleptin) in Nonalcoholic Steatohepatitis (NASH) or Nonalcoholic Fatty Liver Disease (NAFLD) Associated With Lipodystrophy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Michigan</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Michigan</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study involves research about an investigational medicine called metreleptin. The reason&#xD;
      for this study is to find out how metreleptin can improve non-alcoholic steatohepatitis or&#xD;
      nonalcoholic fatty liver disease associated with lipodystrophy, a rare disorder associated&#xD;
      with abnormal loss of the body's fat tissue. In this study, metreleptin is considered to be&#xD;
      investigational for the treatment of lipodystrophy. Metreleptin will be given via injections&#xD;
      under the skin. We plan to continue therapy for a period of one year and evaluate the change&#xD;
      in liver disease by a liver biopsy. We will also follow the metabolic parameters (e.g. blood&#xD;
      cholesterol, liver function, insulin resistance) and body composition characteristics (e.g.&#xD;
      the pattern of fat distribution in the body).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The goal is to test the efficacy of restorative leptin therapy on the degree of hepatic&#xD;
      steatosis and on amelioration of pathological features of NASH/NAFLD. In addition, the study&#xD;
      will evaluate the impact of leptin therapy on total body insulin sensitivity and lipid levels&#xD;
      as well as energy expenditure. In order to accomplish this aim, we now propose an efficacy&#xD;
      study with recombinant human leptin therapy in patients with all forms of lipodystrophy who&#xD;
      also have NASH/NAFLD.&#xD;
&#xD;
        1. AIM 1: To determine the efficacy of leptin in promoting amelioration of body&#xD;
           composition, hepatic steatosis and histopathological scores in patients with all forms&#xD;
           of lipodystrophy and NAFLD/NASH. We will conduct a 1 year, open-label study, to assess&#xD;
           the metabolic effects of recombinant human leptin (METRELEPTIN, AztraZeneca, Wilmington,&#xD;
           DE). The primary outcome measure will be NASH scores. We will also explore body weight,&#xD;
           insulin sensitivity, glucose and lipid control, body composition, and free fatty acid&#xD;
           levels.&#xD;
&#xD;
        2. AIM 2: To Investigate molecular effects of leptin therapy. In parallel to our&#xD;
           preliminary studies, gene expression will be performed on individuals participating in&#xD;
           Aim 1 at baseline and following 1 year of leptin. We will combine this with measures of&#xD;
           liver metabolite levels to provide novel insights into alterations in metabolism that&#xD;
           occur secondary to leptin therapy. We will also measure plasma metabolites at baseline&#xD;
           and after 2 (optional), 24 and 48 weeks of therapy to assess the dynamic changes induced&#xD;
           by leptin and correlate these changes with phenotypic measures.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 8, 2012</start_date>
  <completion_date type="Actual">July 13, 2016</completion_date>
  <primary_completion_date type="Actual">July 13, 2016</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>Liver Histopathology</measure>
    <time_frame>1 year</time_frame>
    <description>Primary outcome will be the total non-alcoholic steatohepatitis (NASH) score read histopathologically from the liver biopsy samples. This outcome measure quantifies the severity of fatty liver disease. At baseline and at the end of the year, patients have undergone a transcutaneous liver biopsy and the specimens were graded for the severity of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) pathology. Histological features of NAFLD/NASH were scored using the validated NASH-CRN (NASH Clinical Research Network) scoring system. This scoring system is the total of 4 subscales: steatosis (0-3), lobular inflammation (0-3), hepatocellular ballooning (0-2) and fibrosis (0-4), which are evaluated semi-quantitatively. The total scale range for this scoring system is 0-12, with 0 representing no features of fatty liver disease, and 12 representing the highest degree of fatty liver disease.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Liver Fat by MRI and MR Spectroscopy</measure>
    <time_frame>1 year</time_frame>
    <description>All enrolled patients will have a baseline MRI of the liver to evaluate liver volume and liver fat. For determination of hepatic fat content by MRI and MR spectroscopy in patients, a series of out-phase and in-phase MRI at multiple flip angles are used. By combination of out-phase and in-phase MRI at multiple flip-angles and TE times, relaxation-time effects can be removed to yield quantitative intra-hepatic (and other organs') fractional fat content throughout the liver in a few breath-hold intervals.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Liver Function Tests</measure>
    <time_frame>1 year</time_frame>
    <description>AST and ALT are the liver function tests. We are reporting the liver function tests where the treatment group arm would normally be listed, though, we are looking at the same single arm population of 23 participants who received treatment in this study.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fasting Lipids</measure>
    <time_frame>1 year</time_frame>
    <description>Cholesterol, triglycerides, HDL cholesterol, and LDL together make up the lipid profile and must be reported together. We are reporting the lipid profile where the treatment group arm would normally be listed, though, we are looking at the same single arm population of 23 participants who received treatment in this study.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fasting Glucose</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Body Weight</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">23</enrollment>
  <condition>Fatty Liver Disease, Nonalcoholic</condition>
  <condition>Nonalcoholic Steatohepatitis</condition>
  <condition>Lipodystrophy</condition>
  <arm_group>
    <arm_group_label>Treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Metreleptin</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metreleptin</intervention_name>
    <arm_group_label>Treatment</arm_group_label>
    <other_name>(originally A100, recombinant-human-methionyl-leptin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Is male or female ≥ 5 years old at baseline.&#xD;
&#xD;
          -  Is male, female not of childbearing potential, or meets all the following criteria if&#xD;
             female of childbearing potential (including perimenopausal women who have had a&#xD;
             menstrual period within one year):&#xD;
&#xD;
               -  Not breastfeeding&#xD;
&#xD;
               -  Negative pregnancy test result (human chorionic gonadotropin, beta subunit&#xD;
                  [βhCG]) at baseline (not applicable to hysterectomized females).&#xD;
&#xD;
               -  Must practice and be willing to continue to practice appropriate birth control&#xD;
                  (defined as a method which results in a low failure rate when use consistently&#xD;
                  and correctly, such as implants, injectables, oral contraceptives, some&#xD;
                  intrauterine contraceptive devices, sexual abstinence, tubal ligation, or a&#xD;
                  vasectomized partner) during the entire duration of metreleptin treatment.&#xD;
&#xD;
          -  Has physician-confirmed lipodystrophy as defined by evidence of generalized (whole&#xD;
             body) or partial (limbs) loss of body fat outside the range of normal variation.&#xD;
&#xD;
          -  Alcohol consumption of less than 40 grams/week.&#xD;
&#xD;
          -  A liver ultrasound confirming non-alcoholic fatty liver disease, or previous liver&#xD;
             biopsy confirming NASH status.&#xD;
&#xD;
          -  If ≥ 18 years of age, is able to read, understand and sign the U of M IRBMED approved&#xD;
             informed consent form (ICF), communicate with study physician and study team,&#xD;
             understand and comply with protocol requirements.&#xD;
&#xD;
          -  If &lt; 18 and ≥ 7 years of age, is able to read, understand and sign the appropriate U&#xD;
             of M IRBMED approved assent form and has a parent or legal guardian that is able to&#xD;
             read, understand and sign the ICF.&#xD;
&#xD;
          -  If &lt; 7 and ≥ 5 years of age or unable to read, the appropriate assent form must be&#xD;
             explained to the child.&#xD;
&#xD;
          -  If previously treated with thiazolidinediones or Vitamin E, stable dose of these&#xD;
             medications for at least 3 months.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Presence of advanced liver disease (as evidenced by abnormal synthetic function,&#xD;
             abnormal PT or albumin).&#xD;
&#xD;
          -  Evidence of other etiologies of viral hepatitis.&#xD;
&#xD;
          -  Presence of clinically significant hematologic abnormalities (such as neutropenia&#xD;
             and/or lymphadenopathy).&#xD;
&#xD;
          -  Presence of HIV infection.&#xD;
&#xD;
          -  Very poorly controlled diabetes; HbA1c &gt;10%&#xD;
&#xD;
          -  Inability to give informed consent.&#xD;
&#xD;
          -  Presence of ESRD, any type of active cancer, or &gt;class 2 congestive heart failure&#xD;
             ((New York Heart Association Functional Classification System), based on medical&#xD;
             history and physical examination.&#xD;
&#xD;
          -  Active infection (may be transient).&#xD;
&#xD;
          -  Has known allergies to E. coli-derived proteins or hypersensitivity to any component&#xD;
             of metreleptin treatment.&#xD;
&#xD;
          -  Any other condition in the opinion of the investigators that may impede successful&#xD;
             data collection.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>5 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Elif A Oral, MD, MS</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Michigan</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Michigan</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2017</verification_date>
  <study_first_submitted>August 31, 2012</study_first_submitted>
  <study_first_submitted_qc>September 4, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 5, 2012</study_first_posted>
  <results_first_submitted>March 28, 2017</results_first_submitted>
  <results_first_submitted_qc>May 11, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">June 14, 2017</results_first_posted>
  <last_update_submitted>May 11, 2017</last_update_submitted>
  <last_update_submitted_qc>May 11, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">June 14, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Michigan</investigator_affiliation>
    <investigator_full_name>Elif Oral</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <keyword>Nonalcoholic fatty liver disease</keyword>
  <keyword>NAFLD</keyword>
  <keyword>Nonalcoholic steatohepatitis</keyword>
  <keyword>NASH</keyword>
  <keyword>Lipodystrophy</keyword>
  <keyword>Leptin</keyword>
  <keyword>Metreleptin</keyword>
  <keyword>Hypertriglyceridemia</keyword>
  <keyword>Diabetes mellitus</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>
    <mesh_term>Lipodystrophy</mesh_term>
  </condition_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Treatment</title>
          <description>Metreleptin&#xD;
Metreleptin</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="23"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="19"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Treatment</title>
          <description>Metreleptin&#xD;
Metreleptin</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="23"/>
          </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="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                  </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>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="42.35" spread="15.82"/>
                  </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="18"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </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>Caucasian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>African American</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Asian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Native American</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Unknown</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Decline to answer</title>
              <category_list>
                <category>
                  <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="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Liver Histopathology</title>
        <description>Primary outcome will be the total non-alcoholic steatohepatitis (NASH) score read histopathologically from the liver biopsy samples. This outcome measure quantifies the severity of fatty liver disease. At baseline and at the end of the year, patients have undergone a transcutaneous liver biopsy and the specimens were graded for the severity of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) pathology. Histological features of NAFLD/NASH were scored using the validated NASH-CRN (NASH Clinical Research Network) scoring system. This scoring system is the total of 4 subscales: steatosis (0-3), lobular inflammation (0-3), hepatocellular ballooning (0-2) and fibrosis (0-4), which are evaluated semi-quantitatively. The total scale range for this scoring system is 0-12, with 0 representing no features of fatty liver disease, and 12 representing the highest degree of fatty liver disease.</description>
        <time_frame>1 year</time_frame>
        <population>The number of participants analyzed at month 12 differs from the overall number analyzed at baseline because 4 participants dropped from the study before their month 12 visit.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment</title>
            <description>Metreleptin&#xD;
Metreleptin</description>
          </group>
        </group_list>
        <measure>
          <title>Liver Histopathology</title>
          <description>Primary outcome will be the total non-alcoholic steatohepatitis (NASH) score read histopathologically from the liver biopsy samples. This outcome measure quantifies the severity of fatty liver disease. At baseline and at the end of the year, patients have undergone a transcutaneous liver biopsy and the specimens were graded for the severity of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) pathology. Histological features of NAFLD/NASH were scored using the validated NASH-CRN (NASH Clinical Research Network) scoring system. This scoring system is the total of 4 subscales: steatosis (0-3), lobular inflammation (0-3), hepatocellular ballooning (0-2) and fibrosis (0-4), which are evaluated semi-quantitatively. The total scale range for this scoring system is 0-12, with 0 representing no features of fatty liver disease, and 12 representing the highest degree of fatty liver disease.</description>
          <population>The number of participants analyzed at month 12 differs from the overall number analyzed at baseline because 4 participants dropped from the study before their month 12 visit.</population>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="23"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="23"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6" spread="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Month 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5" spread="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Liver Fat by MRI and MR Spectroscopy</title>
        <description>All enrolled patients will have a baseline MRI of the liver to evaluate liver volume and liver fat. For determination of hepatic fat content by MRI and MR spectroscopy in patients, a series of out-phase and in-phase MRI at multiple flip angles are used. By combination of out-phase and in-phase MRI at multiple flip-angles and TE times, relaxation-time effects can be removed to yield quantitative intra-hepatic (and other organs') fractional fat content throughout the liver in a few breath-hold intervals.</description>
        <time_frame>1 year</time_frame>
        <population>The number of participants analyzed at month 12 differs from the overall number analyzed at baseline because 4 participants dropped from the study before their month 12 visit.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment</title>
            <description>Metreleptin&#xD;
Metreleptin</description>
          </group>
        </group_list>
        <measure>
          <title>Liver Fat by MRI and MR Spectroscopy</title>
          <description>All enrolled patients will have a baseline MRI of the liver to evaluate liver volume and liver fat. For determination of hepatic fat content by MRI and MR spectroscopy in patients, a series of out-phase and in-phase MRI at multiple flip angles are used. By combination of out-phase and in-phase MRI at multiple flip-angles and TE times, relaxation-time effects can be removed to yield quantitative intra-hepatic (and other organs') fractional fat content throughout the liver in a few breath-hold intervals.</description>
          <population>The number of participants analyzed at month 12 differs from the overall number analyzed at baseline because 4 participants dropped from the study before their month 12 visit.</population>
          <units>%fat</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="23"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="23"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19.19" spread="11.11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Month 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13.47" spread="9.02"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Liver Function Tests</title>
        <description>AST and ALT are the liver function tests. We are reporting the liver function tests where the treatment group arm would normally be listed, though, we are looking at the same single arm population of 23 participants who received treatment in this study.</description>
        <time_frame>1 year</time_frame>
        <population>The number of participants analyzed at month 12 differs from the overall number analyzed at baseline because 4 participants dropped from the study before their month 12 visit.</population>
        <group_list>
          <group group_id="O1">
            <title>Liver Function AST</title>
          </group>
          <group group_id="O2">
            <title>Liver Function ALT</title>
          </group>
        </group_list>
        <measure>
          <title>Liver Function Tests</title>
          <description>AST and ALT are the liver function tests. We are reporting the liver function tests where the treatment group arm would normally be listed, though, we are looking at the same single arm population of 23 participants who received treatment in this study.</description>
          <population>The number of participants analyzed at month 12 differs from the overall number analyzed at baseline because 4 participants dropped from the study before their month 12 visit.</population>
          <units>IU/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="23"/>
                <count group_id="O2" value="23"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="23"/>
                    <count group_id="O2" value="23"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="41.52" spread="27.46"/>
                    <measurement group_id="O2" value="53.22" spread="37.03"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Month 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                    <count group_id="O2" value="19"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="30.37" spread="14.04"/>
                    <measurement group_id="O2" value="36" spread="22.84"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Fasting Lipids</title>
        <description>Cholesterol, triglycerides, HDL cholesterol, and LDL together make up the lipid profile and must be reported together. We are reporting the lipid profile where the treatment group arm would normally be listed, though, we are looking at the same single arm population of 23 participants who received treatment in this study.</description>
        <time_frame>1 year</time_frame>
        <population>The number of participants analyzed at month 12 differs from the overall number analyzed at baseline because 4 participants dropped from the study before their month 12 visit.</population>
        <group_list>
          <group group_id="O1">
            <title>Cholesterol, Total mg/dL</title>
            <description>Lipid measurement</description>
          </group>
          <group group_id="O2">
            <title>Triglycerides mg/dL</title>
            <description>Lipid measurement</description>
          </group>
          <group group_id="O3">
            <title>HDL Cholesterol mg/dL</title>
            <description>Lipid measurement</description>
          </group>
          <group group_id="O4">
            <title>LDL mg/dL</title>
            <description>Lipid measurement</description>
          </group>
        </group_list>
        <measure>
          <title>Fasting Lipids</title>
          <description>Cholesterol, triglycerides, HDL cholesterol, and LDL together make up the lipid profile and must be reported together. We are reporting the lipid profile where the treatment group arm would normally be listed, though, we are looking at the same single arm population of 23 participants who received treatment in this study.</description>
          <population>The number of participants analyzed at month 12 differs from the overall number analyzed at baseline because 4 participants dropped from the study before their month 12 visit.</population>
          <units>mg/dL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="23"/>
                <count group_id="O2" value="23"/>
                <count group_id="O3" value="23"/>
                <count group_id="O4" value="23"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="23"/>
                    <count group_id="O2" value="23"/>
                    <count group_id="O3" value="23"/>
                    <count group_id="O4" value="23"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="256.91" spread="136.87"/>
                    <measurement group_id="O2" value="1057.48" spread="1744.89"/>
                    <measurement group_id="O3" value="35.83" spread="11.01"/>
                    <measurement group_id="O4" value="95.39" spread="48.30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Month 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                    <count group_id="O2" value="19"/>
                    <count group_id="O3" value="19"/>
                    <count group_id="O4" value="19"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="189.11" spread="64.73"/>
                    <measurement group_id="O2" value="478.47" spread="790.85"/>
                    <measurement group_id="O3" value="33.42" spread="6.41"/>
                    <measurement group_id="O4" value="95.95" spread="32.64"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Fasting Glucose</title>
        <time_frame>1 year</time_frame>
        <population>The number of participants analyzed at month 12 differs from the overall number analyzed at baseline because 4 participants dropped from the study before their month 12 visit.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment</title>
            <description>Metreleptin&#xD;
Metreleptin</description>
          </group>
        </group_list>
        <measure>
          <title>Fasting Glucose</title>
          <population>The number of participants analyzed at month 12 differs from the overall number analyzed at baseline because 4 participants dropped from the study before their month 12 visit.</population>
          <units>mg/dL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="23"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="23"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="178.91" spread="82.36"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Month 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="163.53" spread="66.79"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Body Weight</title>
        <time_frame>1 year</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment</title>
            <description>Metreleptin&#xD;
Metreleptin</description>
          </group>
        </group_list>
        <measure>
          <title>Body Weight</title>
          <units>kg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="23"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="77.2" spread="21.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Month 12</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="75.0" spread="23.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>Treatment</title>
          <description>Metreleptin&#xD;
Metreleptin</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <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="23"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Left shoulder pain, atypical chest pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Epigastric pain, mild chest pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Granulomatous tissue reaction</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertriglyceridemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Secondary diabetes mellitus with keatoacidosis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Fall, hip fracture</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Chest pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Transient ischemic attack vs. cerebrovascular attack vs. complicated migraine</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Bell's palsy left side weakness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>UTI abdominal pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Bronchial pneumonia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Rectal prolapse surgery</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_assessment>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="22" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Hypoglycemia</sub_title>
                <counts group_id="E1" events="12" subjects_affected="7" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="6" subjects_affected="5" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Abdominal pain/discomfort</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" events="10" subjects_affected="9" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Cold/Flu-like symptoms</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Muscle cramping</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Hematuria</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Bronchitis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Asthma</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Injection site reaction</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT 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>Dr. Elif Oral</name_or_title>
      <organization>University of Michigan</organization>
      <phone>7346157271</phone>
      <email>eliforal@med.umich.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/NCT01679197
org study id: MCRU 2834
secondary id: R01DK088114-02
nct id: NCT01679197
lead sponsor: 
collaborator: 
has dmc: No
This study involves research about an investigational medicine called metreleptin. The reason
      for this study is to find out how metreleptin can improve non-alcoholic steatohepatitis or
      nonalcoholic fatty liver disease associated with lipodystrophy, a rare disorder associated
      with abnormal loss of the body's fat tissue. In this study, metreleptin is considered to be
      investigational for the treatment of lipodystrophy. Metreleptin will be given via injections
      under the skin. We plan to continue therapy for a period of one year and evaluate the change
      in liver disease by a liver biopsy. We will also follow the metabolic parameters (e.g. blood
      cholesterol, liver function, insulin resistance) and body composition characteristics (e.g.
      the pattern of fat distribution in the body).
The goal is to test the efficacy of restorative leptin therapy on the degree of hepatic
      steatosis and on amelioration of pathological features of NASH/NAFLD. In addition, the study
      will evaluate the impact of leptin therapy on total body insulin sensitivity and lipid levels
      as well as energy expenditure. In order to accomplish this aim, we now propose an efficacy
      study with recombinant human leptin therapy in patients with all forms of lipodystrophy who
      also have NASH/NAFLD.

        1. AIM 1: To determine the efficacy of leptin in promoting amelioration of body
           composition, hepatic steatosis and histopathological scores in patients with all forms
           of lipodystrophy and NAFLD/NASH. We will conduct a 1 year, open-label study, to assess
           the metabolic effects of recombinant human leptin (METRELEPTIN, AztraZeneca, Wilmington,
           DE). The primary outcome measure will be NASH scores. We will also explore body weight,
           insulin sensitivity, glucose and lipid control, body composition, and free fatty acid
           levels.

        2. AIM 2: To Investigate molecular effects of leptin therapy. In parallel to our
           preliminary studies, gene expression will be performed on individuals participating in
           Aim 1 at baseline and following 1 year of leptin. We will combine this with measures of
           liver metabolite levels to provide novel insights into alterations in metabolism that
           occur secondary to leptin therapy. We will also measure plasma metabolites at baseline
           and after 2 (optional), 24 and 48 weeks of therapy to assess the dynamic changes induced
           by leptin and correlate these changes with phenotypic measures.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Liver Histopathology
time frame: 1 year
description: Primary outcome will be the total non-alcoholic steatohepatitis (NASH) score read histopathologically from the liver biopsy samples. This outcome measure quantifies the severity of fatty liver disease. At baseline and at the end of the year, patients have undergone a transcutaneous liver biopsy and the specimens were graded for the severity of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) pathology. Histological features of NAFLD/NASH were scored using the validated NASH-CRN (NASH Clinical Research Network) scoring system. This scoring system is the total of 4 subscales: steatosis (0-3), lobular inflammation (0-3), hepatocellular ballooning (0-2) and fibrosis (0-4), which are evaluated semi-quantitatively. The total scale range for this scoring system is 0-12, with 0 representing no features of fatty liver disease, and 12 representing the highest degree of fatty liver disease.
measure: Liver Fat by MRI and MR Spectroscopy
time frame: 1 year
description: All enrolled patients will have a baseline MRI of the liver to evaluate liver volume and liver fat. For determination of hepatic fat content by MRI and MR spectroscopy in patients, a series of out-phase and in-phase MRI at multiple flip angles are used. By combination of out-phase and in-phase MRI at multiple flip-angles and TE times, relaxation-time effects can be removed to yield quantitative intra-hepatic (and other organs') fractional fat content throughout the liver in a few breath-hold intervals.
measure: Liver Function Tests
time frame: 1 year
description: AST and ALT are the liver function tests. We are reporting the liver function tests where the treatment group arm would normally be listed, though, we are looking at the same single arm population of 23 participants who received treatment in this study.
measure: Fasting Lipids
time frame: 1 year
description: Cholesterol, triglycerides, HDL cholesterol, and LDL together make up the lipid profile and must be reported together. We are reporting the lipid profile where the treatment group arm would normally be listed, though, we are looking at the same single arm population of 23 participants who received treatment in this study.
measure: Fasting Glucose
time frame: 1 year
measure: Body Weight
time frame: 1 year
arm group label: Treatment
arm group type: Experimental
description: Metreleptin
intervention type: Drug
intervention name: Metreleptin
arm group label: Treatment
other name: (originally A100, recombinant-human-methionyl-leptin
criteria: 
gender: All
minimum age: 5 Years
maximum age: N/A
healthy volunteers: No
last name: Elif A Oral, MD, MS
role: Principal Investigator
affiliation: University of Michigan
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Michigan
investigator full name: Elif Oral
investigator title: Associate Professor
mesh term: Liver Diseases
mesh term: Fatty Liver
mesh term: Non-alcoholic Fatty Liver Disease
mesh term: Lipodystrophy
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 