Metabolic SyndromePhase 2SMARTNCT05571319
A Pilot Study of Metformin to Reduce Cerebrovascular Dysfunction in Participants With HIV and Metabolic Syndrome.
A Phase 2 study testing Metformin Extended Release Oral Tablet in people with Metabolic Syndrome and HIV Seropositivity, run by University of Stellenbosch at 1 site in South Africa.
Trial summary
Metabolic syndrome is a constellation of risk factors for cardiovascular disease and type 2 diabetes mellitus which frequently occur together. Data is emerging suggesting metabolic syndrome causes brain disease by contributing to blood vessel damage and inflammation. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Metabolic Syndrome, HIV Seropositivity
- What is being tested?
- Metformin Extended Release Oral Tablet
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 1 siteSouth Africa
- Study dates
- 11 Aug 2022to 28 Mar 2025
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Adult (>18 years);
- HIV+ on antiretroviral therapy for at least 12 months prior to study entry;
- Viral load ≤50 copies/mL;
- Able to provide informed consent;
- Metabolic syndrome as per the harmonized criteria;
- Women of child-bearing potential willing to use adequate contraception (defined as either an intra-uterine contraceptive device or hormonal contraceptive);
Who cannot join
- Treated with metformin as part of care;
- History of drug or alcohol abuse within 3 months before screening;
- Known neurosyphilis;
- Known vitamin B12 deficiency;
- Known neuropsychiatric disorders or serious psychiatric symptoms;
- Significant head trauma with imaging structural abnormalities;
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- Renal impairment (estimated glomerular filtration < 60 mL/min/1.73m2);
- Type I or type II diabetes (fasting plasma glucose >7mmol/L and/or HbA1c >6.5%);
- Hypersensitivity to metformin;
- Any contraindication or special precaution in the metformin package insert which may put the participant at a safety risk;
- Cationic drugs (as listed in the metformin package insert) that may increase metformin concentrations significantly;
- Claustrophobia, metal implants or any other condition that prevents performing MR scan;
- Pregnant / breastfeeding;
Trial locations and contacts
1 site in 1 country.
South Africa1 site
Desmond Tutu Health Foundation: Gugulethu Research Site
Cape Town, Western Cape, 8001
About this study
Official title: Study of Metformin to Reduce Cerebrovascular Dysfunction in South African Patients With HIV and Metabolic syndRome: a Pilot Trial.
Metabolic syndrome is a constellation of risk factors for cardiovascular disease and type 2 diabetes mellitus which frequently occur together. Data is emerging suggesting metabolic syndrome causes brain disease by contributing to blood vessel damage and inflammation. People living with HIV (PLWH) are at high risk and the investigators will perform a pilot study of the well-known type 2 diabetes drug metformin to treat this blood vessel damage and inflammation in PLWH.
Read the detailed description
Background: Metabolic syndrome (MetS) is a constellation of risk factors for cardiovascular disease and type 2 diabetes mellitus (T2D) which frequently occur together. The consequences of MetS extend beyond the increased risk of vascular-metabolic disease. Data is emerging suggesting causality between MetS and cerebral small vessel disease. MetS is associated with an increased incidence of vascular dementia and progression from mild cognitive impairment to dementia. MetS cause endothelial dysfunction and low-level inflammation of adipose tissue. MetS-associated endothelial dysfunction is independent of obesity status with an increased number of MetS abnormalities correlating with more endothelial dysfunction. Middle cerebral artery stiffening with impaired blood flow is associated with a higher MetS score.
Enhanced access to effective combination antiretroviral therapy (cART) improved the life expectancy of people living with HIV (PLWH) substantially. Longevity, however, presents unique health challenges, one being the development of non-communicable diseases including MetS. Emerging data from sub-Saharan Africa indicate a higher prevalence of MetS among PLWH compared with their HIV-negative counterparts. The incidence of MetS in PLWH is predicted to increase. Abdominal obesity is reaching alarming proportions in sub-Saharan Africa with the prevalence similar to that of high-income countries. Older antiretroviral regimens are associated with higher treatment-emergent MetS. Given the growing HIV-positive population with MetS, and that both MetS and HIV are chronic inflammatory conditions, there is an urgent need to identify effective and affordable pharmacotherapy that addresses modifiable aspects of vascular disease.
The investigtors hypothesise that metformin is effective in treating endothelial dysfunction and thus ameliorating cerebrovascular function in HIV-positive patients with metabolic syndrome. Metformin has been shown to affect endothelial cells by inhibiting several inflammatory molecules. Pilot clinical trial data support that metformin significantly improves endothelial function, even in short-term treatment. Metformin is a low-cost and well-known drug used for the management of abnormal glucose homeostasis in people with T2D. Metformin is widely available in public service settings and is considered to have a clinical effect beyond glucose lowering. Based on the rationale above, the investigators propose to study metformin in HIV-positive participants with MetS who are virologically suppressed by standard of care cART to receive open-label metformin to assess its effect on cerebrovascular function.
Objective: The investigators propose to address the Specific Aims listed below in HIV-positive participants with metabolic syndrome virologically suppressed on standard of care cART receiving open-label metformin 12 weeks. Aim 1: To obtain preliminary data on the effect of metformin on cerebral vascular reactivity and cerebral blood flow in HIV positive participants with metabolic syndrome. Aim 2: To assess whether metformin associated changes in cerebral vascular reactivity and cerebral blood flow (CBF) are mediated via improvements in endothelial function.
Methods: The investigators will enroll 30 participants in an open-label study of metformin treatment for 12 weeks with a 4-week washout period and a final evaluation. Comprehensive metabolic, laboratory and neuroimaging evaluation will be performed at screening and 12 weeks with selected procedures repeat after the 4 weeks washout period at week 16. Whole body dual-energy X-ray absorptiometry (DEXA) at study entry will be used to assess adipose tissue location.
Outcome: The purpose of this pilot study in PLWH with MetS is to obtain preliminary data on the effect of metformin on cerebrovascular function using non-invasive neuroimaging biomarkers. Furthermore, the investigators will test the hypothesis that metformin mediates the cerebrovascular changes in part via endothelial regulation by using a comprehensive panel of endothelial functional and soluble markers which will be correlated with the imaging metrics. The results of the study will form the basis for a future clinical trial that will assess the beneficial effect of metformin in reducing the burden of cerebral small vessel disease in PLWH.
- Conditions
- Metabolic Syndrome, HIV Seropositivity
- Being tested
- Metformin Extended Release Oral Tablet
- Keywords
- pilot open label trial, cerebrovascular dysfunction, endothelial function
- Medical subject headings
- Metabolic Syndrome, HIV Seropositivity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Metformin Extended Release Oral TabletDrug
Glucophage XR 500 mg
| Study group | Role | What they receive |
|---|---|---|
| Open-label arm | Experimental | All participants to receive metformin extended-release 1000mg to 2000mg daily for 12 weeks. Receives: Drug: Metformin Extended Release Oral Tablet |
What is being measured
The primary outcome is the main question the study is designed to answer.
Outcome: cerebral reactivity.
We will measure changes in cerebrovascular reactivity (percentage change of BOLD signal during resting state fMRI) from baseline to 12 weeks.
Measured: 12 weeks
Outcome: cerebral blood flow.
We will measure changes in cerebral blood flow (mL/100mL/min, via arterial spin labeling) from baseline to 12 weeks.
Measured: 12 weeks
Outcome: peripheral vascular reactivity.
We will measure changes in finger reactive hyperemia index from baseline to 12 weeks.
Measured: 12 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Oct 2022
- Study start11 Aug 2022
- Primary completion24 Mar 2025
- Study completion28 Mar 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Metabolic SyndromeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- We will enroll 30 participants in an open-label study of metformin treatment for 12 weeks with a 4-week washout period and a final evaluation. The 4-week washout period was chosen to assess the post-treatment effect of metformin on peripheral markers of endothelial function, with expectation that those measurements will trend toward the baseline values.
- Masking
- None (open label)
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Stellenbosch
- Sponsor type
- University, hospital or other
- Collaborators
- University of Rochester, Fogarty International Center of the National Institute of Health
- Responsible party
- Principal investigator, Eric Decloedt, University of Stellenbosch
- Investigators
- Eric Decloedt, MBChB, PhD, Principal investigator, University of Stellenbosch
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05571319
- Sponsor's protocol ID
- M21/10/024
- Other IDs
- R21TW012185-01
- Acronym
- SMART
- Status last verified
- May 2025
- First submitted
- 28 Jun 2022
- Last updated
- 6 Oct 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: The raw study data will be made available to individuals or organisations who make legitimate and appropriate requests, provided that permission from the collaborators and their institutions, sponsor, funder and the Stellenbosch University Human Research Ethics Committee have been obtained.
Study at a glance
From the registry record, last updated by the sponsor on 6 Oct 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Study of Metformin to Reduce Cerebrovascular Dysfunction in South African Patients With HIV and Metabolic syndRome: a Pilot Trial.
- ClinicalTrials.gov ID
- NCT05571319
- Acronym / sponsor ID
- SMART / M21/10/024
- Conditions
- Metabolic Syndrome, HIV Seropositivity
- Keywords
- pilot open label trial, cerebrovascular dysfunction, endothelial function
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants (actual)
- Lead sponsor
- University of StellenboschUniversity, hospital or other
- Collaborators
- University of Rochester, Fogarty International Center of the National Institute of Health
- Study start
- 11 Aug 2022 (actual)
- Primary completion
- 24 Mar 2025 (actual)
- Study completion
- 28 Mar 2025 (actual)
- First posted
- 7 Oct 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Metabolic syndrome is a constellation of risk factors for cardiovascular disease and type 2 diabetes mellitus which frequently occur together. Data is emerging suggesting metabolic syndrome causes brain disease by contributing to blood vessel damage and inflammation. People living with HIV (PLWH) are at high risk and the investigators will perform a pilot study of the well-known type 2 diabetes drug metformin to treat this blood vessel damage and inflammation in PLWH.
Detailed description
Background: Metabolic syndrome (MetS) is a constellation of risk factors for cardiovascular disease and type 2 diabetes mellitus (T2D) which frequently occur together. The consequences of MetS extend beyond the increased risk of vascular-metabolic disease. Data is emerging suggesting causality between MetS and cerebral small vessel disease. MetS is associated with an increased incidence of vascular dementia and progression from mild cognitive impairment to dementia. MetS cause endothelial dysfunction and low-level inflammation of adipose tissue. MetS-associated endothelial dysfunction is independent of obesity status with an increased number of MetS abnormalities correlating with more endothelial dysfunction. Middle cerebral artery stiffening with impaired blood flow is associated with a higher MetS score.
Enhanced access to effective combination antiretroviral therapy (cART) improved the life expectancy of people living with HIV (PLWH) substantially. Longevity, however, presents unique health challenges, one being the development of non-communicable diseases including MetS. Emerging data from sub-Saharan Africa indicate a higher prevalence of MetS among PLWH compared with their HIV-negative counterparts. The incidence of MetS in PLWH is predicted to increase. Abdominal obesity is reaching alarming proportions in sub-Saharan Africa with the prevalence similar to that of high-income countries. Older antiretroviral regimens are associated with higher treatment-emergent MetS. Given the growing HIV-positive population with MetS, and that both MetS and HIV are chronic inflammatory conditions, there is an urgent need to identify effective and affordable pharmacotherapy that addresses modifiable aspects of vascular disease.
The investigtors hypothesise that metformin is effective in treating endothelial dysfunction and thus ameliorating cerebrovascular function in HIV-positive patients with metabolic syndrome. Metformin has been shown to affect endothelial cells by inhibiting several inflammatory molecules. Pilot clinical trial data support that metformin significantly improves endothelial function, even in short-term treatment. Metformin is a low-cost and well-known drug used for the management of abnormal glucose homeostasis in people with T2D. Metformin is widely available in public service settings and is considered to have a clinical effect beyond glucose lowering. Based on the rationale above, the investigators propose to study metformin in HIV-positive participants with MetS who are virologically suppressed by standard of care cART to receive open-label metformin to assess its effect on cerebrovascular function.
Objective: The investigators propose to address the Specific Aims listed below in HIV-positive participants with metabolic syndrome virologically suppressed on standard of care cART receiving open-label metformin 12 weeks. Aim 1: To obtain preliminary data on the effect of metformin on cerebral vascular reactivity and cerebral blood flow in HIV positive participants with metabolic syndrome. Aim 2: To assess whether metformin associated changes in cerebral vascular reactivity and cerebral blood flow (CBF) are mediated via improvements in endothelial function.
Methods: The investigators will enroll 30 participants in an open-label study of metformin treatment for 12 weeks with a 4-week washout period and a final evaluation. Comprehensive metabolic, laboratory and neuroimaging evaluation will be performed at screening and 12 weeks with selected procedures repeat after the 4 weeks washout period at week 16. Whole body dual-energy X-ray absorptiometry (DEXA) at study entry will be used to assess adipose tissue location.
Outcome: The purpose of this pilot study in PLWH with MetS is to obtain preliminary data on the effect of metformin on cerebrovascular function using non-invasive neuroimaging biomarkers. Furthermore, the investigators will test the hypothesis that metformin mediates the cerebrovascular changes in part via endothelial regulation by using a comprehensive panel of endothelial functional and soluble markers which will be correlated with the imaging metrics. The results of the study will form the basis for a future clinical trial that will assess the beneficial effect of metformin in reducing the burden of cerebral small vessel disease in PLWH.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- We will enroll 30 participants in an open-label study of metformin treatment for 12 weeks with a 4-week washout period and a final evaluation. The 4-week washout period was chosen to assess the post-treatment effect of metformin on peripheral markers of endothelial function, with expectation that those measurements will trend toward the baseline values.
| Arm | Type | Receives |
|---|---|---|
| Open-label arm | Experimental | Drug: Metformin Extended Release Oral TabletAll participants to receive metformin extended-release 1000mg to 2000mg daily for 12 weeks. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Adult (>18 years);
- HIV+ on antiretroviral therapy for at least 12 months prior to study entry;
- Viral load ≤50 copies/mL;
- Able to provide informed consent;
- Metabolic syndrome as per the harmonized criteria;
Key exclusion criteria (13 listed)
- Treated with metformin as part of care;
- History of drug or alcohol abuse within 3 months before screening;
- Known neurosyphilis;
- Known vitamin B12 deficiency;
- Known neuropsychiatric disorders or serious psychiatric symptoms;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Metformin Extended Release Oral TabletGlucophage XR 500 mg | Drug | Open-label arm |
Primary outcome
Outcome: cerebral reactivity.
Time frame: 12 weeks
We will measure changes in cerebrovascular reactivity (percentage change of BOLD signal during resting state fMRI) from baseline to 12 weeks.
Outcome: cerebral blood flow.
Time frame: 12 weeks
We will measure changes in cerebral blood flow (mL/100mL/min, via arterial spin labeling) from baseline to 12 weeks.
Outcome: peripheral vascular reactivity.
Time frame: 12 weeks
We will measure changes in finger reactive hyperemia index from baseline to 12 weeks.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Oct 2025.
- Individual participant dataSharing planned: Yes. The raw study data will be made available to individuals or organisations who make legitimate and appropriate requests, provided that permission from the collaborators and their institutions, sponsor, funder and the Stellenbosch University Human Research Ethics Committee have been obtained.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Eric Decloedt, MBChB, PhD principal investigator
University of Stellenbosch
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Metformin Extended Release Oral Tablet in people with Metabolic Syndrome and HIV Seropositivity, run by University of Stellenbosch at 1 site in South Africa.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Oct 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in South Africa. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Outcome: cerebral reactivity. (time frame: 12 weeks). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Oct 2025.