<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/NCT04500678</url>
  </required_header>
  <id_info>
    <org_study_id>H046</org_study_id>
    <nct_id>NCT04500678</nct_id>
  </id_info>
  <brief_title>Impact of Metformin on Immuno-virologic Parameters in HIV</brief_title>
  <official_title>A 72 Week, Randomized, Open-label vs Observation Study to Assess the Potential Immuno-virologic Benefit of Metformin in HIV-infected Individuals Receiving Antiretroviral Therapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Hawaii</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Merck Sharp &amp; Dohme LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Hawaii</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Non-diabetic, aviremic HIV-infected individuals on antiretroviral therapy (ART) will be&#xD;
      randomized to metformin therapy or to observation for 72 weeks. Primary objective is to&#xD;
      assess change over 72 weeks in CD4 T cell negative checkpoint receptors (PD-1 and TIGIT). As&#xD;
      secondary objectives the study will look at 72 week change in other immuno-virologic&#xD;
      parameters (CD8 T cell negative checkpoint receptors, plasma indoleamine 2,3-dioxygenase&#xD;
      (IDO) levels and CD4 T cell and monocyte intracellular HIV DNA and HIV RNA. The study will&#xD;
      also explore the 72 week impact of metformin on change in carotid intima-media thickness&#xD;
      (cIMT) as a surrogate marker of atherosclerosis, on neuropsychological (NP) performance,&#xD;
      strength, and change in body composition.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">February 1, 2019</start_date>
  <completion_date type="Anticipated">December 31, 2022</completion_date>
  <primary_completion_date type="Anticipated">February 1, 2022</primary_completion_date>
  <phase>Phase 2/Phase 3</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>
    <intervention_model_description>Metformin vs Observation</intervention_model_description>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>CD4 T cell PD1+TIGIT+</measure>
    <time_frame>Entry to week 72</time_frame>
    <description>Comparison of change over time in percentage of CD4 T cells bearing the PD1+TIGIT+ surface markers in peripheral blood mononuclear cells (PBMC) in the treatment (metformin) arm compared to the observation arm</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>CD8 T cell PD1+TIGIT+</measure>
    <time_frame>Entry to week 72</time_frame>
    <description>Comparison of change over time in percentage of CD8 T cells bearing the PD1+TIGIT+ surface markers in PBMCs in the 2 study arms</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma levels of indoleamine 2,3-dioxygenase (IDO)</measure>
    <time_frame>Entry to week 72</time_frame>
    <description>Comparison of change over time in the levels of IDO [assessed as a ratio of L-kynurenine (kyn) to substrate tryptophan (trp)] in mass spectrometry assays</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peripheral blood CD4 T cell intracellular HIV DNA</measure>
    <time_frame>Entry to week 72</time_frame>
    <description>Comparison of change over time in the number of intracellular HIV DNA copies per million CD4 T cells in PBMC in the 2 study arms</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peripheral blood CD4 T cell intracellular HIV RNA</measure>
    <time_frame>Entry to week 72</time_frame>
    <description>Comparison of change over time in the number of intracellular HIV RNA copies per million CD4 T cells in PBMC in the 2 study arms</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peripheral blood monocyte intracellular HIV DNA</measure>
    <time_frame>Entry to week 72</time_frame>
    <description>Comparison of change over time in the number of intracellular HIV DNA copies per million monocytes in PBMC in the 2 study arms</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peripheral blood monocyte intracellular HIV RNA</measure>
    <time_frame>Entry to week 72</time_frame>
    <description>Comparison of change over time in the number of intracellular HIV RNA copies per million monocytes in PBMC in the 2 study arms</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Safety and Tolerability: # of grade 2 or greater adverse events in each arm</measure>
    <time_frame>Entry to week 72</time_frame>
    <description>Comparison of the # of grade 2 or greater adverse events in the 2 arms</description>
  </other_outcome>
  <other_outcome>
    <measure>Carotid intima-media thickness</measure>
    <time_frame>Entry to week 72</time_frame>
    <description>Comparison of change over time in the thickness of the right carotid intima-media thickness (mm) as assessed by carotid ultrasound in the 2 study arms</description>
  </other_outcome>
  <other_outcome>
    <measure>Neuropsychological testing global Z score</measure>
    <time_frame>Entry to week 72</time_frame>
    <description>Comparison of change over time in the age, gender and education-adjusted neuropsychological testing global Z score in the 2 study arms [The z score has a mean of zero and a standard deviation of 1; higher than 0 is better cognitive performance and lower than 0 is lower performance than the mean]</description>
  </other_outcome>
  <other_outcome>
    <measure>Beck's Depression Index II score</measure>
    <time_frame>Entry to week 72</time_frame>
    <description>Comparison of change over time in the Beck's Depression Index II score in the 2 study arms [21-item rating scale with maximum score of 63; higher scores are indicative of worse depression]</description>
  </other_outcome>
  <other_outcome>
    <measure>Handgrip</measure>
    <time_frame>Entry to week 72</time_frame>
    <description>Comparison of change over time in handgrip strength (kg) as assessed by a handgrip dynamometer in the 2 study arms</description>
  </other_outcome>
  <other_outcome>
    <measure>Total lean tissue by dual energy absorptiometry (DXA)</measure>
    <time_frame>Entry to week 72</time_frame>
    <description>Comparison of change over time in total lean tissue (kg) as assessed by DXA in the 2 study arms</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">38</enrollment>
  <condition>HIV/AIDS</condition>
  <arm_group>
    <arm_group_label>Metformin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Metformin 500 mg Extended Release (ER) qd increasing to 1000 mg ER qd at week 4 and continued to week 48.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Observation</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Observed without metformin</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metformin</intervention_name>
    <description>Metformin 500 mg Extended Release (ER) qd increasing to 1000 mg ER qd at week 4 and continued to week 48.</description>
    <arm_group_label>Metformin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  HIV+&#xD;
&#xD;
          -  On suppressive ART stable for &gt; 1 year&#xD;
&#xD;
          -  Plasma HIV RNA &lt; 50 copies/mL within 3 months of entry, with no HIV RNA &gt; 200&#xD;
             copies/mL within the past 6 months prior to entry&#xD;
&#xD;
          -  Age &gt;40 years&#xD;
&#xD;
          -  Ability and willingness to provide written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Uncontrolled chronic medical condition or cancer&#xD;
&#xD;
          -  Acute illness within 2 weeks of entry&#xD;
&#xD;
          -  Diagnosis of diabetes by history, fasting blood glucose &gt;126, or by HgbA1c &gt; 6.5&#xD;
&#xD;
          -  Chronic, uncontrolled diarrhea&#xD;
&#xD;
          -  Known hypersensitivity or contraindication to metformin use&#xD;
&#xD;
          -  Current presence of hepatitis C including currently on or intent to start therapy for&#xD;
             hepatitis C within the 48 week duration of study.&#xD;
&#xD;
          -  Serum B12 level below the reference normal range as listed by the commercial lab&#xD;
             utilized for this study (Diagnostic Laboratory Services)&#xD;
&#xD;
          -  Pregnancy, or intent to become pregnant or nursing an infant&#xD;
&#xD;
          -  Any immunomodulator, HIV vaccine, any other vaccine, or investigational therapy within&#xD;
             30 days of study entry.&#xD;
&#xD;
          -  Current uncontrolled coronary artery disease or NYHA Class 3 or 4 congestive heart&#xD;
             failure&#xD;
&#xD;
          -  History of liver cirrhosis&#xD;
&#xD;
          -  Current use of zidovudine, stavudine or didanosine&#xD;
&#xD;
          -  The following lab values&#xD;
&#xD;
               -  Hemoglobin &lt; 9.0 g/dL&#xD;
&#xD;
               -  Absolute neutrophil count &lt; 1000/μL&#xD;
&#xD;
               -  Platelet count &lt; 50,000/μL&#xD;
&#xD;
               -  AST (SGOT) and ALT (SGPT) &gt; 5x upper limit of normal (ULN)&#xD;
&#xD;
               -  Calculated creatinine clearance (Cockcroft and Gault) &lt; 50 ml/min&#xD;
&#xD;
          -  Active or recent past history (within past 2 years) of illicit substance or alcohol&#xD;
             use or abuse which, in the judgment of the Investigator, will interfere with the&#xD;
             patient's ability to comply with the protocol requirements&#xD;
&#xD;
          -  Patients, who, in the opinion of the Investigator, are unable to comply with the&#xD;
             dosing schedule and protocol evaluation or for whom the study may not be advisable&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Cecilia M Shikuma, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Hawaii</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Cecilia M Shikuma, MD</last_name>
    <phone>808 692-1328</phone>
    <email>shikuma@hawaii.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Debra Ogata-Arakaki, RN</last_name>
    <phone>808 692-1332</phone>
    <email>ogataara@hawaii.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>John A. Burns School of Medicine, University of Hawaii - Manoa</name>
      <address>
        <city>Honolulu</city>
        <state>Hawaii</state>
        <zip>96813</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Cecilia Shikuma, MD</last_name>
      <phone>808-692-1328</phone>
      <email>shikuma@hawaii.edu</email>
    </contact>
    <contact_backup>
      <last_name>Debra Ogata-Arakaki, RN</last_name>
      <phone>808 692-1332</phone>
      <email>ogataara@hawaii.edu</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2020</verification_date>
  <study_first_submitted>July 31, 2020</study_first_submitted>
  <study_first_submitted_qc>August 4, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 5, 2020</study_first_posted>
  <last_update_submitted>August 4, 2020</last_update_submitted>
  <last_update_submitted_qc>August 4, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">August 5, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Hawaii</investigator_affiliation>
    <investigator_full_name>Cecilia Shikuma</investigator_full_name>
    <investigator_title>Professor, Medicine</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acquired Immunodeficiency Syndrome</mesh_term>
    <mesh_term>HIV Infections</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>Yes</sharing_ipd>
    <ipd_description>Dataset will be available to other researchers upon request once the primary manuscript is written</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>After the study analyses are completed and primary manuscript is published, and for a duration of at least 5 years afterwards</ipd_time_frame>
    <ipd_access_criteria>De-identified dataset will be provided upon request to legitimate researchers</ipd_access_criteria>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04500678
org study id: H046
nct id: NCT04500678
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
Non-diabetic, aviremic HIV-infected individuals on antiretroviral therapy (ART) will be
      randomized to metformin therapy or to observation for 72 weeks. Primary objective is to
      assess change over 72 weeks in CD4 T cell negative checkpoint receptors (PD-1 and TIGIT). As
      secondary objectives the study will look at 72 week change in other immuno-virologic
      parameters (CD8 T cell negative checkpoint receptors, plasma indoleamine 2,3-dioxygenase
      (IDO) levels and CD4 T cell and monocyte intracellular HIV DNA and HIV RNA. The study will
      also explore the 72 week impact of metformin on change in carotid intima-media thickness
      (cIMT) as a surrogate marker of atherosclerosis, on neuropsychological (NP) performance,
      strength, and change in body composition.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Metformin vs Observation
primary purpose: Diagnostic
masking: Double (Participant, Investigator)
measure: CD4 T cell PD1+TIGIT+
time frame: Entry to week 72
description: Comparison of change over time in percentage of CD4 T cells bearing the PD1+TIGIT+ surface markers in peripheral blood mononuclear cells (PBMC) in the treatment (metformin) arm compared to the observation arm
measure: CD8 T cell PD1+TIGIT+
time frame: Entry to week 72
description: Comparison of change over time in percentage of CD8 T cells bearing the PD1+TIGIT+ surface markers in PBMCs in the 2 study arms
measure: Plasma levels of indoleamine 2,3-dioxygenase (IDO)
time frame: Entry to week 72
description: Comparison of change over time in the levels of IDO [assessed as a ratio of L-kynurenine (kyn) to substrate tryptophan (trp)] in mass spectrometry assays
measure: Peripheral blood CD4 T cell intracellular HIV DNA
time frame: Entry to week 72
description: Comparison of change over time in the number of intracellular HIV DNA copies per million CD4 T cells in PBMC in the 2 study arms
measure: Peripheral blood CD4 T cell intracellular HIV RNA
time frame: Entry to week 72
description: Comparison of change over time in the number of intracellular HIV RNA copies per million CD4 T cells in PBMC in the 2 study arms
measure: Peripheral blood monocyte intracellular HIV DNA
time frame: Entry to week 72
description: Comparison of change over time in the number of intracellular HIV DNA copies per million monocytes in PBMC in the 2 study arms
measure: Peripheral blood monocyte intracellular HIV RNA
time frame: Entry to week 72
description: Comparison of change over time in the number of intracellular HIV RNA copies per million monocytes in PBMC in the 2 study arms
measure: Safety and Tolerability: # of grade 2 or greater adverse events in each arm
time frame: Entry to week 72
description: Comparison of the # of grade 2 or greater adverse events in the 2 arms
measure: Carotid intima-media thickness
time frame: Entry to week 72
description: Comparison of change over time in the thickness of the right carotid intima-media thickness (mm) as assessed by carotid ultrasound in the 2 study arms
measure: Neuropsychological testing global Z score
time frame: Entry to week 72
description: Comparison of change over time in the age, gender and education-adjusted neuropsychological testing global Z score in the 2 study arms [The z score has a mean of zero and a standard deviation of 1; higher than 0 is better cognitive performance and lower than 0 is lower performance than the mean]
measure: Beck's Depression Index II score
time frame: Entry to week 72
description: Comparison of change over time in the Beck's Depression Index II score in the 2 study arms [21-item rating scale with maximum score of 63; higher scores are indicative of worse depression]
measure: Handgrip
time frame: Entry to week 72
description: Comparison of change over time in handgrip strength (kg) as assessed by a handgrip dynamometer in the 2 study arms
measure: Total lean tissue by dual energy absorptiometry (DXA)
time frame: Entry to week 72
description: Comparison of change over time in total lean tissue (kg) as assessed by DXA in the 2 study arms
arm group label: Metformin
arm group type: Experimental
description: Metformin 500 mg Extended Release (ER) qd increasing to 1000 mg ER qd at week 4 and continued to week 48.
arm group label: Observation
arm group type: No Intervention
description: Observed without metformin
intervention type: Drug
intervention name: Metformin
description: Metformin 500 mg Extended Release (ER) qd increasing to 1000 mg ER qd at week 4 and continued to week 48.
arm group label: Metformin
criteria: 
gender: All
minimum age: 40 Years
maximum age: N/A
healthy volunteers: No
last name: Cecilia M Shikuma, MD
role: Principal Investigator
affiliation: University of Hawaii
last name: Cecilia M Shikuma, MD
phone: 808 692-1328
email: shikuma@hawaii.edu
last name: Debra Ogata-Arakaki, RN
phone: 808 692-1332
email: ogataara@hawaii.edu
facility: 
status: Recruiting
contact: 
contact backup: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Hawaii
investigator full name: Cecilia Shikuma
investigator title: Professor, Medicine
mesh term: Acquired Immunodeficiency Syndrome
mesh term: HIV Infections
mesh term: Metformin
sharing ipd: Yes
ipd description: Dataset will be available to other researchers upon request once the primary manuscript is written
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd time frame: After the study analyses are completed and primary manuscript is published, and for a duration of at least 5 years afterwards
ipd access criteria: De-identified dataset will be provided upon request to legitimate researchers