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Impact of Metformin on Immuno-virologic Parameters in HIV

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04500678
Recruitment Status : Recruiting
First Posted : August 5, 2020
Last Update Posted : August 5, 2020
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Cecilia Shikuma, University of Hawaii

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
HIV/AIDS Drug: Metformin Phase 2 Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 38 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Metformin vs Observation
Masking: Double (Participant, Investigator)
Primary Purpose: Diagnostic
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
Actual Study Start Date : February 1, 2019
Estimated Primary Completion Date : February 1, 2022
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: Metformin
Metformin 500 mg Extended Release (ER) qd increasing to 1000 mg ER qd at week 4 and continued to week 48.
Drug: Metformin
Metformin 500 mg Extended Release (ER) qd increasing to 1000 mg ER qd at week 4 and continued to week 48.

No Intervention: Observation
Observed without metformin



Primary Outcome Measures :
  1. CD4 T cell PD1+TIGIT+ [ Time Frame: Entry to week 72 ]
    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


Secondary Outcome Measures :
  1. CD8 T cell PD1+TIGIT+ [ Time Frame: Entry to week 72 ]
    Comparison of change over time in percentage of CD8 T cells bearing the PD1+TIGIT+ surface markers in PBMCs in the 2 study arms

  2. Plasma levels of indoleamine 2,3-dioxygenase (IDO) [ Time Frame: Entry to week 72 ]
    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

  3. Peripheral blood CD4 T cell intracellular HIV DNA [ Time Frame: Entry to week 72 ]
    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

  4. Peripheral blood CD4 T cell intracellular HIV RNA [ Time Frame: Entry to week 72 ]
    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

  5. Peripheral blood monocyte intracellular HIV DNA [ Time Frame: Entry to week 72 ]
    Comparison of change over time in the number of intracellular HIV DNA copies per million monocytes in PBMC in the 2 study arms

  6. Peripheral blood monocyte intracellular HIV RNA [ Time Frame: Entry to week 72 ]
    Comparison of change over time in the number of intracellular HIV RNA copies per million monocytes in PBMC in the 2 study arms


Other Outcome Measures:
  1. Safety and Tolerability: # of grade 2 or greater adverse events in each arm [ Time Frame: Entry to week 72 ]
    Comparison of the # of grade 2 or greater adverse events in the 2 arms

  2. Carotid intima-media thickness [ Time Frame: Entry to week 72 ]
    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

  3. Neuropsychological testing global Z score [ Time Frame: Entry to week 72 ]
    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]

  4. Beck's Depression Index II score [ Time Frame: Entry to week 72 ]
    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]

  5. Handgrip [ Time Frame: Entry to week 72 ]
    Comparison of change over time in handgrip strength (kg) as assessed by a handgrip dynamometer in the 2 study arms

  6. Total lean tissue by dual energy absorptiometry (DXA) [ Time Frame: Entry to week 72 ]
    Comparison of change over time in total lean tissue (kg) as assessed by DXA in the 2 study arms



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Ages Eligible for Study:   40 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • HIV+
  • On suppressive ART stable for > 1 year
  • Plasma HIV RNA < 50 copies/mL within 3 months of entry, with no HIV RNA > 200 copies/mL within the past 6 months prior to entry
  • Age >40 years
  • Ability and willingness to provide written informed consent

Exclusion Criteria:

  • Uncontrolled chronic medical condition or cancer
  • Acute illness within 2 weeks of entry
  • Diagnosis of diabetes by history, fasting blood glucose >126, or by HgbA1c > 6.5
  • Chronic, uncontrolled diarrhea
  • Known hypersensitivity or contraindication to metformin use
  • Current presence of hepatitis C including currently on or intent to start therapy for hepatitis C within the 48 week duration of study.
  • Serum B12 level below the reference normal range as listed by the commercial lab utilized for this study (Diagnostic Laboratory Services)
  • Pregnancy, or intent to become pregnant or nursing an infant
  • Any immunomodulator, HIV vaccine, any other vaccine, or investigational therapy within 30 days of study entry.
  • Current uncontrolled coronary artery disease or NYHA Class 3 or 4 congestive heart failure
  • History of liver cirrhosis
  • Current use of zidovudine, stavudine or didanosine
  • The following lab values

    • Hemoglobin < 9.0 g/dL
    • Absolute neutrophil count < 1000/μL
    • Platelet count < 50,000/μL
    • AST (SGOT) and ALT (SGPT) > 5x upper limit of normal (ULN)
    • Calculated creatinine clearance (Cockcroft and Gault) < 50 ml/min
  • Active or recent past history (within past 2 years) of illicit substance or alcohol use or abuse which, in the judgment of the Investigator, will interfere with the patient's ability to comply with the protocol requirements
  • Patients, who, in the opinion of the Investigator, are unable to comply with the dosing schedule and protocol evaluation or for whom the study may not be advisable

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04500678


Contacts
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Contact: Cecilia M Shikuma, MD 808 692-1328 shikuma@hawaii.edu
Contact: Debra Ogata-Arakaki, RN 808 692-1332 ogataara@hawaii.edu

Locations
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United States, Hawaii
John A. Burns School of Medicine, University of Hawaii - Manoa Recruiting
Honolulu, Hawaii, United States, 96813
Contact: Cecilia Shikuma, MD    808-692-1328    shikuma@hawaii.edu   
Contact: Debra Ogata-Arakaki, RN    808 692-1332    ogataara@hawaii.edu   
Sponsors and Collaborators
University of Hawaii
Merck Sharp & Dohme Corp.
Investigators
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Principal Investigator: Cecilia M Shikuma, MD University of Hawaii
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Responsible Party: Cecilia Shikuma, Professor, Medicine, University of Hawaii
ClinicalTrials.gov Identifier: NCT04500678    
Other Study ID Numbers: H046
First Posted: August 5, 2020    Key Record Dates
Last Update Posted: August 5, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Dataset will be available to other researchers upon request once the primary manuscript is written
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: After the study analyses are completed and primary manuscript is published, and for a duration of at least 5 years afterwards
Access Criteria: De-identified dataset will be provided upon request to legitimate researchers

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Acquired Immunodeficiency Syndrome
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs