Impact of Metformin on Immuno-virologic Parameters in HIV

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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HIV/AIDS

Intervention / Treatment
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* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Metformin vs Observation
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin<br>Metformin 500 mg Extended Release (ER) qd increasing to 1000 mg ER qd at week 4 and continued to week 48. | Drug: Metformin<br>* Metformin 500 mg Extended Release (ER) qd increasing to 1000 mg ER qd at week 4 and continued to week 48.<br>|
| No Intervention: Observation<br>Observed without metformin | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CD4 T cell PD1+TIGIT+ | 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 | Entry to week 72 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CD8 T cell PD1+TIGIT+ | Comparison of change over time in percentage of CD8 T cells bearing the PD1+TIGIT+ surface markers in PBMCs in the 2 study arms | Entry to week 72 | 
| Plasma levels of indoleamine 2,3-dioxygenase (IDO) | 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 | Entry to week 72 | 
| Peripheral blood CD4 T cell intracellular HIV DNA | 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 | Entry to week 72 | 
| Peripheral blood CD4 T cell intracellular HIV RNA | 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 | Entry to week 72 | 
| Peripheral blood monocyte intracellular HIV DNA | Comparison of change over time in the number of intracellular HIV DNA copies per million monocytes in PBMC in the 2 study arms | Entry to week 72 | 
| Peripheral blood monocyte intracellular HIV RNA | Comparison of change over time in the number of intracellular HIV RNA copies per million monocytes in PBMC in the 2 study arms | Entry to week 72 |