<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/NCT02252081</url>
  </required_header>
  <id_info>
    <org_study_id>ENDA-014-13F</org_study_id>
    <secondary_id>1I01CX000982-01A1</secondary_id>
    <nct_id>NCT02252081</nct_id>
  </id_info>
  <brief_title>Metformin in Kidney Disease</brief_title>
  <official_title>Dysmetabolism of Chronic Kidney Disease and Vascular Health</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>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Chronic kidney disease (CKD) is a major global health problem associated with substantial&#xD;
      costs and resource utilization. Currently, CKD affects more than 500 million people&#xD;
      worldwide. Patients with CKD have unacceptably high mortality rates due to cardiovascular&#xD;
      (CV) causes, which are not entirely explained by traditional CV risk factors. The mortality&#xD;
      rates in advanced CKD are six times higher compared to the Medicare population, with CVD&#xD;
      accounting for the overwhelming majority of deaths. Insulin resistance (IR) is common in CKD&#xD;
      patients and may represent a central link between CKD and the increased CVD risk observed in&#xD;
      this population. Insulin resistance may increase CV risk by impairing and worsening&#xD;
      endothelial function, increasing reactive oxygen species, and exacerbating systemic&#xD;
      inflammation-hence, insulin resistance is considered a &quot;non-traditional CV risk factor&quot; in&#xD;
      CKD.&#xD;
&#xD;
      Obesity (defined by a body mass index [BMI] of at least 30 kg/m2) is a major public health&#xD;
      problem-the upward trend in obesity prevalence across regions and continents is a worldwide&#xD;
      concern. Obesity increases the risk for cardiovascular disease and death. In the general&#xD;
      population, obesity hastens death by 9.4 years. Obesity is an independent risk factor for&#xD;
      CKD. Besides its contribution to the development of diabetes and hypertension, increased fat&#xD;
      mass may also have a direct impact on kidney function.&#xD;
&#xD;
      In spite of the increasing prevalence of both obesity and CKD, the impact of obesity in the&#xD;
      CKD population is not known, especially in terms of the exaggerated metabolic disturbances&#xD;
      associated with their coexistence. It is highly likely that these two conditions have&#xD;
      profound interactions that exaggerate the severity of the metabolic derangements when they&#xD;
      coexist, particularly in regards to adipokine dysregulation, the risk of &quot;insulin&#xD;
      resistance&quot;, and downstream effects on vascular health. The current proposal will attempt to&#xD;
      characterize the relative and combined impact of both obesity and CKD on metabolic&#xD;
      disturbances, which may aid in risk stratification and identifying specific targets for&#xD;
      intervention.&#xD;
&#xD;
      The ultimate goal of this proposal is to understand the relative and combined impact of&#xD;
      obesity and CKD on the generation and maintenance of insulin resistance and their impact on&#xD;
      cardiovascular health.&#xD;
&#xD;
      Specific Aim 2: To study the effects of metformin, an AMPK activator, on metabolic&#xD;
      disturbances associated with obesity and moderate CKD.&#xD;
&#xD;
      S.A.2.a: To test if metformin will improve LAR in obese patients with moderate CKD compared&#xD;
      to placebo.&#xD;
&#xD;
      S.A.2.b: To test if metformin will improve markers of systemic inflammation, oxidative&#xD;
      stress, endothelial dysfunction in obese patients with moderate CKD compared to placebo.&#xD;
&#xD;
      S.A.2.c: To test if metformin will improve atherosclerosis markers and reduce clinical CVD&#xD;
      events in obese patients with moderate CKD compared to placebo.&#xD;
&#xD;
      Hypothesis: The investigators hypothesize that the administration of metformin in obese CKD&#xD;
      patients will significantly improve the adipokine profiles-particularly through a reduction&#xD;
      in LAR. Additionally, that it will improve systemic inflammation, oxidative stress and&#xD;
      endothelial function, which may or may not be mediated by changes in adipokines. Finally, the&#xD;
      investigators hypothesize that improvements in these markers of vascular health will&#xD;
      translate into reduced arterial stiffness and less clinical CV events&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 1, 2014</start_date>
  <completion_date type="Actual">December 31, 2019</completion_date>
  <primary_completion_date type="Actual">December 31, 2019</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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change is Leptin to Adiponectin Ratio (LAR)</measure>
    <time_frame>16 weeks after start of treatment</time_frame>
    <description>Change in leptin to adiponectin ratio (LAR) after 4 months of metformin vs. placebo will be assessed as a biomarker of insulin resistance in CKD</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Flow-mediated Dilation (FMD)</measure>
    <time_frame>16 weeks after the start of treatment</time_frame>
    <description>Change in FMD after 4 months of treatment with metformin will be compared to change in the placebo group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Aortic Pulse-wave Velocity (aPWV)</measure>
    <time_frame>16 weeks after starting treatment</time_frame>
    <description>is a measurement of stiffening of the large elastic arteries and atherosclerosis. It is a subclinical marker of cardiovascular disease</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Estimated Glomerular Filtration Rate (eGFR)</measure>
    <time_frame>baseline and 16 weeks after starting treatment</time_frame>
    <description>eGFR is a measurement of kidney function, this was a descriptive measurement</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">125</enrollment>
  <condition>Chronic Kidney Disease</condition>
  <condition>Cardiovascular Disease</condition>
  <condition>Metabolic Syndrome</condition>
  <arm_group>
    <arm_group_label>metformin</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>500 to 1500 mg orally per day for 16 weeks if eGFR &gt; 45 ml/min; 500 to 1000 mg orally per day for 16 weeks if eGFR =&lt; 45 ml/min</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>placebo pill(s) orally per day for 16 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>metformin</intervention_name>
    <description>500 to 1500 mg orally per day for 16 weeks if eGFR &gt; 45 ml/min; 500 to 1000 mg orally per day for 16 weeks if eGFR =&lt; 45 ml/min</description>
    <arm_group_label>metformin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>placebo pill(s) orally per day for 16 weeks</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age 18 years old;&#xD;
&#xD;
          -  Ability to give informed consent;&#xD;
&#xD;
          -  Life expectancy greater than 6 months;&#xD;
&#xD;
          -  Estimated GFR 30-59 ml/min/1.73m^2;&#xD;
&#xD;
          -  Overweight (BMI &gt;=25 to &lt; 30 kg/m^2) or obese (BMI &gt;=30 kg/m^2); or normal (BMI &gt;=18.5&#xD;
             to &lt;25 kg/m^2) if pre-diabetic or insulin resistant.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnancy or breast feeding;&#xD;
&#xD;
          -  Presence or history of Diabetes Mellitus type I or II&#xD;
&#xD;
          -  History of metformin use or any insulin sensitizer or any drug for the treatment of&#xD;
             metabolic syndrome over the last one year;&#xD;
&#xD;
          -  Any acute kidney injury episode in the last 4 months due to the risk of recurrent AKI;&#xD;
&#xD;
          -  Proteinuria of &gt; 5 g in 24 hours determined by a 24 hour urine collection or PCR &gt;&#xD;
             4.5;&#xD;
&#xD;
          -  Uncontrolled hypertension with systolic blood pressure 160 mmHg and diastolic blood&#xD;
             pressure 100 mmHg;&#xD;
&#xD;
          -  Patients with new changes to their antihypertensive regimen over the last 1 month;&#xD;
&#xD;
          -  Severe, unstable, or active inflammatory disease; active infection including&#xD;
             seropositive HIV, Hepatitis B or C; active connective tissue disorder; or moderate to&#xD;
             severe liver disease;&#xD;
&#xD;
          -  Decompensated heart failure;&#xD;
&#xD;
          -  Recent hospitalization or surgical procedure within 1 month prior to the study for any&#xD;
             cause;&#xD;
&#xD;
          -  Current active malignancy or cancer history in the prior 5 years (excluding squamous&#xD;
             cell and basal cell skin cancers);&#xD;
&#xD;
          -  Known intolerance to the study drug;&#xD;
&#xD;
          -  Patient receiving oral or injected steroids&#xD;
&#xD;
          -  Use of any investigational product or device within 30 days prior to screening, or&#xD;
             requirement for any investigational agent prior to completion of all scheduled study&#xD;
             assessments;&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Adriana M Hung, MD MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>Tennessee Valley Healthcare System Nashville Campus, Nashville, TN</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Tennessee Valley Healthcare System Nashville Campus, Nashville, TN</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37212-2637</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2021</verification_date>
  <study_first_submitted>September 25, 2014</study_first_submitted>
  <study_first_submitted_qc>September 25, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 29, 2014</study_first_posted>
  <results_first_submitted>July 20, 2021</results_first_submitted>
  <results_first_submitted_qc>October 5, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">November 4, 2021</results_first_posted>
  <last_update_submitted>October 5, 2021</last_update_submitted>
  <last_update_submitted_qc>October 5, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">November 4, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>metformin</keyword>
  <keyword>cardiovascular disease</keyword>
  <keyword>Chronic Kidney Disease</keyword>
  <keyword>Metabolic Syndrome</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Kidney Diseases</mesh_term>
    <mesh_term>Renal Insufficiency, Chronic</mesh_term>
    <mesh_term>Cardiovascular Diseases</mesh_term>
    <mesh_term>Metabolic Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Metformin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>No we do not plan to make individual level data available.&#xD;
This is a pilot mechanistic study.</ipd_description>
  </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>September 26, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/81/NCT02252081/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>65 patients did not meet inclusion criteria (normal GFR or to low GFR, new diabetes diagnosis, uncontrolled hypertension) or decline to participate.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Metformin</title>
          <description>500 to 1500 mg orally per day for 16 weeks if eGFR &gt; 45 ml/min; 500 to 1000 mg orally per day for 16 weeks if eGFR =&lt; 45 ml/min&#xD;
metformin: 500 to 1500 mg orally per day for 16 weeks if eGFR &gt; 45 ml/min; 500 to 1000 mg orally per day for 16 weeks if eGFR =&lt; 45 ml/min</description>
        </group>
        <group group_id="P2">
          <title>Placebo</title>
          <description>placebo pill(s) orally per day for 16 weeks&#xD;
Placebo: placebo pill(s) orally per day for 16 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="30"/>
                <participants group_id="P2" count="30"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="24"/>
                <participants group_id="P2" count="26"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>non compliance &amp; others</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Metformin</title>
          <description>500 to 1500 mg orally per day for 16 weeks if eGFR &gt; 45 ml/min; 500 to 1000 mg orally per day for 16 weeks if eGFR =&lt; 45 ml/min&#xD;
metformin: 500 to 1500 mg orally per day for 16 weeks if eGFR &gt; 45 ml/min; 500 to 1000 mg orally per day for 16 weeks if eGFR =&lt; 45 ml/min</description>
        </group>
        <group group_id="B2">
          <title>Placebo</title>
          <description>placebo pill(s) orally per day for 16 weeks&#xD;
Placebo: placebo pill(s) orally per day for 16 weeks</description>
        </group>
        <group group_id="B3">
          <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="30"/>
            <count group_id="B2" value="30"/>
            <count group_id="B3" value="60"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="69" lower_limit="64" upper_limit="72"/>
                    <measurement group_id="B2" value="66" lower_limit="58" upper_limit="72"/>
                    <measurement group_id="B3" value="67" lower_limit="60" upper_limit="72"/>
                  </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="6"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="24"/>
                    <measurement group_id="B2" value="24"/>
                    <measurement group_id="B3" value="48"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="23"/>
                    <measurement group_id="B2" value="25"/>
                    <measurement group_id="B3" value="48"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change is Leptin to Adiponectin Ratio (LAR)</title>
        <description>Change in leptin to adiponectin ratio (LAR) after 4 months of metformin vs. placebo will be assessed as a biomarker of insulin resistance in CKD</description>
        <time_frame>16 weeks after start of treatment</time_frame>
        <population>analyzed as log transformed using ANCOVA of change, ng/µg (log transformed value)</population>
        <group_list>
          <group group_id="O1">
            <title>Metformin</title>
            <description>metformin 500 to 1500 mg orally per day for 16 weeks if eGFR &gt; 45 ml/min/1.73m^2; 500 to 1000 mg orally per day for 16 weeks if eGFR =&lt; 45 ml/min/1.73m^2&#xD;
Placebo: placebo pill(s) orally per day for 16 weeks</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>placebo pill(s) orally per day for 16 weeks&#xD;
Placebo: placebo pill(s) orally per day for 16 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Change is Leptin to Adiponectin Ratio (LAR)</title>
          <description>Change in leptin to adiponectin ratio (LAR) after 4 months of metformin vs. placebo will be assessed as a biomarker of insulin resistance in CKD</description>
          <population>analyzed as log transformed using ANCOVA of change, ng/µg (log transformed value)</population>
          <units>ng/micrograms</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="26"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.2" lower_limit="1.5" upper_limit="3.2"/>
                    <measurement group_id="O2" value="1.3" lower_limit="0.6" upper_limit="3.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 16</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.3" lower_limit="1.0" upper_limit="2.6"/>
                    <measurement group_id="O2" value="1.4" lower_limit="0.5" upper_limit="3.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Flow-mediated Dilation (FMD)</title>
        <description>Change in FMD after 4 months of treatment with metformin will be compared to change in the placebo group.</description>
        <time_frame>16 weeks after the start of treatment</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Metformin</title>
            <description>500 to 1500 mg if eGFR &gt; 45 ml/min; 500 to 1000 mg if eGFR =&lt; 45 ml/min&#xD;
metformin: 500 to 1500 mg if eGFR &gt; 45 ml/min; 500 to 1000 mg if eGFR =&lt; 45 ml/min</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>placebo pill(s) orally per day for 16 weeks&#xD;
Placebo: placebo pill(s) orally per day for 16 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Flow-mediated Dilation (FMD)</title>
          <description>Change in FMD after 4 months of treatment with metformin will be compared to change in the placebo group.</description>
          <units>change in percent</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="26"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.1" lower_limit="3.2" upper_limit="8.4"/>
                    <measurement group_id="O2" value="5.0" lower_limit="3.7" upper_limit="8.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>week 16</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.5" lower_limit="5.4" upper_limit="18.8"/>
                    <measurement group_id="O2" value="6.2" lower_limit="4.2" upper_limit="11.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Aortic Pulse-wave Velocity (aPWV)</title>
        <description>is a measurement of stiffening of the large elastic arteries and atherosclerosis. It is a subclinical marker of cardiovascular disease</description>
        <time_frame>16 weeks after starting treatment</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Metformin</title>
            <description>500 to 1500 mg orally per day for 16 weeks if eGFR &gt; 45 ml/min; 500 to 1000 mg orally per day for 16 weeks if eGFR =&lt; 45 ml/min</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>500 to 1500 mg orally per day for 16 weeks if eGFR &gt; 45 ml/min; 500 to 1000 mg orally per day for 16 weeks if eGFR =&lt; 45 ml/min</description>
          </group>
        </group_list>
        <measure>
          <title>Aortic Pulse-wave Velocity (aPWV)</title>
          <description>is a measurement of stiffening of the large elastic arteries and atherosclerosis. It is a subclinical marker of cardiovascular disease</description>
          <units>cm/s</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="26"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>baseline aPWV (cm/s)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.6" lower_limit="8.2" upper_limit="11.4"/>
                    <measurement group_id="O2" value="9.8" lower_limit="8.4" upper_limit="12.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week16 aPWC (cm/s)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.9" lower_limit="8.9" upper_limit="10.9"/>
                    <measurement group_id="O2" value="9.9" lower_limit="8.6" upper_limit="11.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Estimated Glomerular Filtration Rate (eGFR)</title>
        <description>eGFR is a measurement of kidney function, this was a descriptive measurement</description>
        <time_frame>baseline and 16 weeks after starting treatment</time_frame>
        <population>kidney function measurement</population>
        <group_list>
          <group group_id="O1">
            <title>Metformin</title>
            <description>metformin: 500 to 1500 mg orally per day if eGFR &gt; 45 ml/min/1.73m^2; 500 to 1000 mg orally per day if eGFR =&lt; 45 ml/min/1.73m^2 orally per day for 16 weeks</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>matching placebo pill(s) 500 to 1500 mg orally per day if eGFR &gt; 45 ml/min/1.73m^2; 500 to 1000 mg orally per day if eGFR =&lt; 45 ml/min/1.73m^2 orally per day for 16 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Estimated Glomerular Filtration Rate (eGFR)</title>
          <description>eGFR is a measurement of kidney function, this was a descriptive measurement</description>
          <population>kidney function measurement</population>
          <units>ml/min</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="26"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>baseline GFR</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="49.5" lower_limit="46.5" upper_limit="54.2"/>
                    <measurement group_id="O2" value="48.5" lower_limit="45.4" upper_limit="56.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 16 GFR</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="52" lower_limit="45.25" upper_limit="54.9"/>
                    <measurement group_id="O2" value="48.7" lower_limit="43.9" upper_limit="56.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>16 weeks</time_frame>
      <desc>clinicaltrials.gov definitions</desc>
      <group_list>
        <group group_id="E1">
          <title>Metformin</title>
          <description>500 to 1500 mg orally per day for 16 weeks if eGFR &gt; 45 ml/min; 500 to 1000 mg orally per day for 16 weeks if eGFR =&lt; 45 ml/min&#xD;
metformin: 500 to 1500 mg orally per day for 16 weeks if eGFR &gt; 45 ml/min; 500 to 1000 mg orally per day for 16 weeks if eGFR =&lt; 45 ml/min</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>placebo pill(s) orally per day for 16 weeks&#xD;
Placebo: placebo pill(s) orally per day for 16 weeks</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="18" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>acute coronary syndrome</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Pericarditis &amp; chest pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>pneumonia &amp; pneumonia related complications</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="30"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>3</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperlactetemia without acidosis &gt;3.5 mmol/L</sub_title>
                <assessment>Systematic Assessment</assessment>
                <description>safety labs at baseline, 2,4,8,12 &amp;16 weeks</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>diarrhea/loose stools/flatulence</sub_title>
                <assessment>Systematic Assessment</assessment>
                <counts group_id="E1" events="8" subjects_affected="8" subjects_at_risk="30"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>left lower quadrant pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="30"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Generalized fatigue</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Upper respiratory infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Asthma</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="30"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Adriana Hung</name_or_title>
      <organization>Nashville Campus TVHS</organization>
      <phone>6153274751 ext 6731</phone>
      <email>adriana.hung@va.goc</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/NCT02252081
org study id: ENDA-014-13F
secondary id: 1I01CX000982-01A1
nct id: NCT02252081
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
Chronic kidney disease (CKD) is a major global health problem associated with substantial
      costs and resource utilization. Currently, CKD affects more than 500 million people
      worldwide. Patients with CKD have unacceptably high mortality rates due to cardiovascular
      (CV) causes, which are not entirely explained by traditional CV risk factors. The mortality
      rates in advanced CKD are six times higher compared to the Medicare population, with CVD
      accounting for the overwhelming majority of deaths. Insulin resistance (IR) is common in CKD
      patients and may represent a central link between CKD and the increased CVD risk observed in
      this population. Insulin resistance may increase CV risk by impairing and worsening
      endothelial function, increasing reactive oxygen species, and exacerbating systemic
      inflammation-hence, insulin resistance is considered a "non-traditional CV risk factor" in
      CKD.

      Obesity (defined by a body mass index [BMI] of at least 30 kg/m2) is a major public health
      problem-the upward trend in obesity prevalence across regions and continents is a worldwide
      concern. Obesity increases the risk for cardiovascular disease and death. In the general
      population, obesity hastens death by 9.4 years. Obesity is an independent risk factor for
      CKD. Besides its contribution to the development of diabetes and hypertension, increased fat
      mass may also have a direct impact on kidney function.

      In spite of the increasing prevalence of both obesity and CKD, the impact of obesity in the
      CKD population is not known, especially in terms of the exaggerated metabolic disturbances
      associated with their coexistence. It is highly likely that these two conditions have
      profound interactions that exaggerate the severity of the metabolic derangements when they
      coexist, particularly in regards to adipokine dysregulation, the risk of "insulin
      resistance", and downstream effects on vascular health. The current proposal will attempt to
      characterize the relative and combined impact of both obesity and CKD on metabolic
      disturbances, which may aid in risk stratification and identifying specific targets for
      intervention.

      The ultimate goal of this proposal is to understand the relative and combined impact of
      obesity and CKD on the generation and maintenance of insulin resistance and their impact on
      cardiovascular health.

      Specific Aim 2: To study the effects of metformin, an AMPK activator, on metabolic
      disturbances associated with obesity and moderate CKD.

      S.A.2.a: To test if metformin will improve LAR in obese patients with moderate CKD compared
      to placebo.

      S.A.2.b: To test if metformin will improve markers of systemic inflammation, oxidative
      stress, endothelial dysfunction in obese patients with moderate CKD compared to placebo.

      S.A.2.c: To test if metformin will improve atherosclerosis markers and reduce clinical CVD
      events in obese patients with moderate CKD compared to placebo.

      Hypothesis: The investigators hypothesize that the administration of metformin in obese CKD
      patients will significantly improve the adipokine profiles-particularly through a reduction
      in LAR. Additionally, that it will improve systemic inflammation, oxidative stress and
      endothelial function, which may or may not be mediated by changes in adipokines. Finally, the
      investigators hypothesize that improvements in these markers of vascular health will
      translate into reduced arterial stiffness and less clinical CV events
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Change is Leptin to Adiponectin Ratio (LAR)
time frame: 16 weeks after start of treatment
description: Change in leptin to adiponectin ratio (LAR) after 4 months of metformin vs. placebo will be assessed as a biomarker of insulin resistance in CKD
measure: Change in Flow-mediated Dilation (FMD)
time frame: 16 weeks after the start of treatment
description: Change in FMD after 4 months of treatment with metformin will be compared to change in the placebo group.
measure: Aortic Pulse-wave Velocity (aPWV)
time frame: 16 weeks after starting treatment
description: is a measurement of stiffening of the large elastic arteries and atherosclerosis. It is a subclinical marker of cardiovascular disease
measure: Estimated Glomerular Filtration Rate (eGFR)
time frame: baseline and 16 weeks after starting treatment
description: eGFR is a measurement of kidney function, this was a descriptive measurement
arm group label: metformin
arm group type: Active Comparator
description: 500 to 1500 mg orally per day for 16 weeks if eGFR > 45 ml/min; 500 to 1000 mg orally per day for 16 weeks if eGFR =< 45 ml/min
arm group label: Placebo
arm group type: Placebo Comparator
description: placebo pill(s) orally per day for 16 weeks
intervention type: Drug
intervention name: metformin
description: 500 to 1500 mg orally per day for 16 weeks if eGFR > 45 ml/min; 500 to 1000 mg orally per day for 16 weeks if eGFR =< 45 ml/min
arm group label: metformin
intervention type: Drug
intervention name: Placebo
description: placebo pill(s) orally per day for 16 weeks
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Adriana M Hung, MD MPH
role: Principal Investigator
affiliation: Tennessee Valley Healthcare System Nashville Campus, Nashville, TN
facility: 
country: United States
responsible party type: Sponsor
mesh term: Kidney Diseases
mesh term: Renal Insufficiency, Chronic
mesh term: Cardiovascular Diseases
mesh term: Metabolic Syndrome
mesh term: Metformin
sharing ipd: No
ipd description: No we do not plan to make individual level data available.
This is a pilot mechanistic study.
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 