HIV/AIDS
Conditions
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.
Interventions
DRUGMetformin
Metformin 500 mg Extended Release (ER) qd increasing to 1000 mg ER qd at week 4 and continued to week 48.
Sponsors
Merck Sharp & Dohme LLC
University of Hawaii
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
DOUBLE (Subject, Investigator)
Intervention model description
Metformin vs Observation
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CD4 T cell PD1+TIGIT+ | 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
| Measure | Time frame | Description |
|---|---|---|
| CD8 T cell PD1+TIGIT+ | 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 |
| Plasma levels of indoleamine 2,3-dioxygenase (IDO) | 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 |
| Peripheral blood CD4 T cell intracellular HIV DNA | 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 |
| Peripheral blood CD4 T cell intracellular HIV RNA | 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 |
| Peripheral blood monocyte intracellular HIV DNA | 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 |
| Peripheral blood monocyte intracellular HIV RNA | 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
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability: # of grade 2 or greater adverse events in each arm | Entry to week 72 | Comparison of the # of grade 2 or greater adverse events in the 2 arms |
| Carotid intima-media thickness | 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 |
| Neuropsychological testing global Z score | 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 \[The z score has a mean of zero and a standard deviation of 1; higher than 0 is better cognitive performance and lower than 0 is lower performance than the mean\] |
| Beck's Depression Index II score | Entry to week 72 | Comparison of change over time in the Beck's Depression Index II score in the 2 study arms \[21-item rating scale with maximum score of 63; higher scores are indicative of worse depression\] |
| Total lean tissue by dual energy absorptiometry (DXA) | Entry to week 72 | Comparison of change over time in total lean tissue (kg) as assessed by DXA in the 2 study arms |
| Handgrip | Entry to week 72 | Comparison of change over time in handgrip strength (kg) as assessed by a handgrip dynamometer in the 2 study arms |
Countries
United States
Contacts
Primary ContactCecilia M Shikuma, MD
Backup ContactDebra Ogata-Arakaki, RN
Outcome results
None listed