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Impact of Metformin on Immuno-virologic Parameters in HIV

Primary Purpose

HIV/AIDS

Status
Unknown status
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Metformin
Sponsored by
University of Hawaii
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for HIV/AIDS

Eligibility Criteria

40 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • John A. Burns School of Medicine, University of Hawaii - ManoaRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Metformin

Observation

Arm Description

Metformin 500 mg Extended Release (ER) qd increasing to 1000 mg ER qd at week 4 and continued to week 48.

Observed without metformin

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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
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
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
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
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
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

Full Information

First Posted
July 31, 2020
Last Updated
August 4, 2020
Sponsor
University of Hawaii
Collaborators
Merck Sharp & Dohme LLC
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1. Study Identification

Unique Protocol Identification Number
NCT04500678
Brief Title
Impact of Metformin on Immuno-virologic Parameters in HIV
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
Study Type
Interventional

2. Study Status

Record Verification Date
August 2020
Overall Recruitment Status
Unknown status
Study Start Date
February 1, 2019 (Actual)
Primary Completion Date
February 1, 2022 (Anticipated)
Study Completion Date
December 31, 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Hawaii
Collaborators
Merck Sharp & Dohme LLC

4. Oversight

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
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV/AIDS

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Model Description
Metformin vs Observation
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
38 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Metformin
Arm Type
Experimental
Arm Description
Metformin 500 mg Extended Release (ER) qd increasing to 1000 mg ER qd at week 4 and continued to week 48.
Arm Title
Observation
Arm Type
No Intervention
Arm Description
Observed without metformin
Intervention Type
Drug
Intervention Name(s)
Metformin
Intervention Description
Metformin 500 mg Extended Release (ER) qd increasing to 1000 mg ER qd at week 4 and continued to week 48.
Primary Outcome Measure Information:
Title
CD4 T cell PD1+TIGIT+
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
Time Frame
Entry to week 72
Secondary Outcome Measure Information:
Title
CD8 T cell PD1+TIGIT+
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
Time Frame
Entry to week 72
Title
Plasma levels of indoleamine 2,3-dioxygenase (IDO)
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
Time Frame
Entry to week 72
Title
Peripheral blood CD4 T cell intracellular HIV DNA
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
Time Frame
Entry to week 72
Title
Peripheral blood CD4 T cell intracellular HIV RNA
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
Time Frame
Entry to week 72
Title
Peripheral blood monocyte intracellular HIV DNA
Description
Comparison of change over time in the number of intracellular HIV DNA copies per million monocytes in PBMC in the 2 study arms
Time Frame
Entry to week 72
Title
Peripheral blood monocyte intracellular HIV RNA
Description
Comparison of change over time in the number of intracellular HIV RNA copies per million monocytes in PBMC in the 2 study arms
Time Frame
Entry to week 72
Other Pre-specified Outcome Measures:
Title
Safety and Tolerability: # of grade 2 or greater adverse events in each arm
Description
Comparison of the # of grade 2 or greater adverse events in the 2 arms
Time Frame
Entry to week 72
Title
Carotid intima-media thickness
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
Time Frame
Entry to week 72
Title
Neuropsychological testing global Z score
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]
Time Frame
Entry to week 72
Title
Beck's Depression Index II score
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]
Time Frame
Entry to week 72
Title
Handgrip
Description
Comparison of change over time in handgrip strength (kg) as assessed by a handgrip dynamometer in the 2 study arms
Time Frame
Entry to week 72
Title
Total lean tissue by dual energy absorptiometry (DXA)
Description
Comparison of change over time in total lean tissue (kg) as assessed by DXA in the 2 study arms
Time Frame
Entry to week 72

10. Eligibility

Sex
All
Minimum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
Eligibility 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Cecilia M Shikuma, MD
Phone
808 692-1328
Email
shikuma@hawaii.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Debra Ogata-Arakaki, RN
Phone
808 692-1332
Email
ogataara@hawaii.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Cecilia M Shikuma, MD
Organizational Affiliation
University of Hawaii
Official's Role
Principal Investigator
Facility Information:
Facility Name
John A. Burns School of Medicine, University of Hawaii - Manoa
City
Honolulu
State/Province
Hawaii
ZIP/Postal Code
96813
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Cecilia Shikuma, MD
Phone
808-692-1328
Email
shikuma@hawaii.edu
First Name & Middle Initial & Last Name & Degree
Debra Ogata-Arakaki, RN
Phone
808 692-1332
Email
ogataara@hawaii.edu

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Dataset will be available to other researchers upon request once the primary manuscript is written
IPD Sharing Time Frame
After the study analyses are completed and primary manuscript is published, and for a duration of at least 5 years afterwards
IPD Sharing Access Criteria
De-identified dataset will be provided upon request to legitimate researchers

Learn more about this trial

Impact of Metformin on Immuno-virologic Parameters in HIV

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