Insulin ResistancePhase 2NCT03733132
Metformin Effect on Brain Function in Insulin Resistant Elderly People
A Phase 2 study testing Metformin Hydrochloride in people with Insulin Resistance and Obesity, run by Mayo Clinic at 1 site in United States.
Trial summary
Alzheimer's disease (AD) and other forms of dementia are rapidly increasing with the aging of the population, and show a clear preponderance among people with insulin resistance. Metformin, an insulin sensitizer, is being examined in clinical trials as an anti-aging drug. Read more about this study
- Who is it for?
- Ages 65 years and olderHealthy volunteers can take part
- Conditions the study is for
- Insulin Resistance, Obesity, Obesity, Abdominal
- What is being tested?
- Metformin Hydrochloride
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 40 participants
- Where
- 1 siteUnited States
- Study dates
- 15 Mar 2019to 5 Apr 2023
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 65 years and older
- All sexes
- Healthy volunteers accepted
- Older adult
Who may be able to join
- Age >/= 65 years
- Abdominal girth > 102 cm in men and > 88 cm in women-
- Fasting glucose >/= 100-140 mg/dL
- Non-smoker
- English language proficiency
Who cannot join
- Coronary artery disease or heart failure
- A known medical condition that in the judgment of the investigator might interfere with the completion of the protocol such as the following examples:
- Inpatient psychiatric treatment in the past 6 months
- Presence of a known adrenal disorder
- Abnormal liver function test results (Transaminase >2 times the upper limit of normal); testing required for subjects taking medications known to affect liver function or with diseases known to affect liver function
- Abnormal renal function tests results (calculated GFR <60 mL/min/1.73m2); testing required for subjects with diabetes duration of greater than 5 years post onset of puberty
Show all 18Show fewer
- Active gastroparesis
- If on antihypertensive, thyroid, anti-depressant or lipid lowering medication, lack of stability on the medication for the past 2 months prior to enrollment in the study
- Uncontrolled thyroid disease (TSH undetectable or >10 mlU/L): testing required within here months prior to admission for subjects with a goiter, positive antibodies, or who are on thyroid hormone replacement, and within one year otherwise
- Abuse of alcohol or recreational drugs
- Infectious process not anticipated to resolve prior to study procedures (e.g. meningitis, pneumonia, osteomyelitis)
- Uncontrolled arterial hypertension (Resting diastolic blood pressure >90 mmHg and/or systolic blood pressure >160 mmHg) at the time of screening
- Oral steroids
- A recent injury to body or limb, muscular disorder, use of any medication, any carcinogenic disease, or other significant medical disorder if that injury, medication or disease in the judgment of the investigator will affect the completion of the protocol
- Any metal in the body that could interfere with magnetic resonance imaging (MRI) including pacemaker or implanted defibrillator, neurostimulators, ear implants, metal fragments within the body, metal joints, rods, pins, plates or screws
- Medications that may impact study end points such as mitochondrial biology eg. beta blockers
- Anti-hyperglycemic drugs including metformin
- Any other medication that the investigator believes is a contraindication to the subject's participation
Trial locations and contacts
1 site in 1 country.
United States1 site
Mayo Clinic in Rochester
Rochester, Minnesota, 55905
About this study
Alzheimer's disease (AD) and other forms of dementia are rapidly increasing with the aging of the population, and show a clear preponderance among people with insulin resistance. Metformin, an insulin sensitizer, is being examined in clinical trials as an anti-aging drug. However, very little objective data is available regarding metformin's effect on the brain, a major organ affected by aging.
Read the detailed description
Insulin resistance is highly prevalent with advancing age. Metformin is an insulin sensitizer and is currently being extensively investigated for its potential anti-aging effect. However, only very limited information is available on metformin effect on brain, which is a major organ affected by aging. With appropriate experimental design, the investigators are attempting to understand the mechanism of metformin treatment on the physiology of the brain as well as cognitive effects. These studies may uncover relationships that could be favorably manipulated to decrease health risks associated with insulin sensitivity and the effect on the brain.
The study results may lead to a breakthrough in providing either definitive data or sufficiently strong preliminary data regarding metformin's effect on elderly people with insulin resistance, on whether the drug enhances brain mitochondrial function in conjunction with improvement of brain functional network and cognitive function.
The overall hypothesis is that metformin administration to elderly people with insulin resistance enhances brain mitochondrial function in conjunction with improvement of brain function. To test this hypothesis, the investigators will address the following Specific Aims:
- Determine whether 40 weeks of metformin administration in elderly people (> 65 years) with insulin resistance enhances brain mitochondrial ATP production. The investigators will measure brain ATP production by 31P-MRS.
- Determine the effect of 40 weeks of metformin administration in elderly people (> 65 years) with insulin resistance on blood flow and functional network in different areas of brain. As a secondary outcome, the investigators will measure structural changes in white and grey matter areas of brain to determine whether metformin has any effect on brain structure.
- Determine the effect of 40 weeks of metformin administration in elderly people (> 65 years) with insulin resistance on cognitive function. The investigators will utilize the computerized NIH Toolbox to measure cognitive outcomes.
The investigators will also associate outcomes from our specific aims with improvements in whole-body insulin sensitivity and skeletal muscle mitochondrial function.
The investigators propose to complete 40 weeks of study in 40 elderly (> 65 years) participants with fasting glucose between 100 to 140 mg/dl and abdominal girth of >102 cm in men and > 88 cm in women. All participants will be those who are not oral hypoglycemic agents including metformin. In this double-blind placebo trial, the investigators will randomly assign the participants to placebo or metformin in an escalated dose to reach a maximum of 2500 mg per day.
- Conditions
- Insulin Resistance, Obesity, Obesity, Abdominal
- Being tested
- Metformin Hydrochloride, Placebo Oral Tablet
- Keywords
- Insulin Resistance, Cognition, Cognitive Impairment, Brain Function
- Medical subject headings
- Insulin Resistance, Obesity, Obesity, Abdominal, Cognitive Dysfunction
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Metformin HydrochlorideDrug
Also called Metformin
Metformin treatment of 2500mg for 10 months in the Metformin group
Placebo Oral TabletDrug
Also called Placebo
Placebo treatment of identical tablets to metformin group
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo comparator | Participants in placebo group will receive Placebo Oral Tablets identical to the metformin tablets for 10 months. Receives: Drug: Placebo Oral Tablet |
| Metformin | Active comparator | Participants in placebo group will receive an escalating dose of Metformin hydrochloride tablets up to a dose of 2500mg for 10 months. Receives: Drug: Metformin Hydrochloride |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change From Baseline in Brain PCr/ATP Ratio as Measured by Phosphorus Magnetic Spectroscopy (31P-MRS) After 10 Months of Metformin Administration
Multivoxel spectroscopic imaging of the brain will be performed using our dual-tuned single-channel-proton eight-channel-phosphorus head coil. A single 2.5 cm thick slice will be prescribed to encompass the temporal and occipital lobes, and weighted MRSI will be performed using a 16x16 matrix to acquire nominal 2.5 cm3 voxels. Multivoxel phosphorus magnetic resonance spectroscopic imaging data were reconstructed and quantified using jMRUI 6.0. Spectra were preprocessed by (a) truncating the data to 768 points, then 0-filling to 1024 points; (b) apodizing with a 5 Hz Lorenzian; and (c) aligning the data such that the PCr peak was set to 0 Hz. Next, 2 voxels from occipital lobe were selected, extracted, and averaged together into a single free induction decay in order to reduce noise. The outcome measure PCr/ATP ratio is a marker of ATP resynthesis potential and is reported as a change from pre- to post-treatment.
Measured: Baseline, 10 months
Change From Baseline in Cognitive Function as Measured by NIH Toolbox After 10 Months of Metformin Administration
The NIH Toolbox will be utilized to measure cognitive outcomes. The NIH Toolbox-Cognition Battery is composed of 7 tests (~30 minutes) and our primary outcome measure will be the Total Cognition Composite score comprised from these 7 tests. Results are presented as a fully-adjusted T-score. For a single timepoint, T-scores are expected to have a population mean of 50, standard deviation of 10. For a single timepoint, higher T-scores indicate better cognitive test performance. An increase in T-score over time is considered a better outcome. At the individual level, a T-score < 40 is considered low test performance. There were no clear clinically relevant thresholds for a change in T-score over 10 months at the start of this study. Comparison of the mean change in T-score over time in the Metformin treatment group to placebo is our analysis of interest
Measured: Baseline, 10 months
Secondary outcomes (3)
Change From Baseline in Brain Structure as Measured by MRI After 10 Months of Metformin Administration
AA sagittal 3D MPRAGE sequence with 0.7mm isotropic voxels (TR=2400, TE=2.57, TI=1100, FA=8) will be used to acquire high-resolution structural data for volumetric analysis of brain region changes related to metformin. To measure white matter information: An axial 2D symmetric multi-slice (SMS) diffusion tensor imaging (DTI) sequence with 60 diffusion directions, 5 B0 acquisitions and 2mm isotropic voxels (TR=3000, TE=73, FA=90, ETL 43, both A-P and P-A phase encoding for B0 images) will be used to acquire white matter integrity data related to metformin.
Measured: Baseline, 10 months
Change From Baseline in Muscle Mitochondrial Respiration as Measured by High-resolution Respirometry Following 10 Months of Metformin Administration
High-resolution respirometry will be used to analyze oxygen consumption in isolated mitochondria from skeletal muscle biopsy samples while simultaneously quantifying reactive oxygen species (ROS) production using amplex red. An increase in mitochondrial respiration is indicative of increased mitochondrial function which is a positive outcome.
Measured: Baseline, 10 months
Change From Baseline in Muscle Mitochondrial ATP Production as Measured by Fluorometry Following 10 Months of Metformin Administration
Concurrent to mitochondrial respiration, muscle mitochondrial ATP production will be measured using high-sensitivity fluorometry. An increase in mitochondrial ATP production shows increase mitochondrial efficiency which is a positive outcome.
Measured: Baseline, 10 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Nov 2018
- Study start15 Mar 2019
- Primary completion5 Apr 2023
- Study completion5 Apr 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Insulin ResistanceStudies of the same condition, open and under way.
- More trials run by Mayo ClinicThe sponsor's other registered studies.
- 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
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 40 participants (actual)
Sponsor and investigators
- Lead sponsor
- Mayo Clinic
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute on Aging (NIA)
- Responsible party
- Principal investigator, K. Sreekumaran Nair, Mayo Clinic
- Investigators
- K Sreekumaran Nair, M.D., Ph.D., Principal investigator, Mayo Clinic
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03733132
- Sponsor's protocol ID
- 18-004012
- Other IDs
- 1R21AG060139-01
- Status last verified
- May 2024
- First submitted
- 16 Oct 2018
- Last updated
- 18 Jun 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 18 Jun 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Metformin Effect on Brain Function in Insulin Resistant Elderly People
- ClinicalTrials.gov ID
- NCT03733132
- Acronym / sponsor ID
- 18-004012
- Conditions
- Insulin Resistance, Obesity, Obesity, Abdominal
- Keywords
- Insulin Resistance, Cognition, Cognitive Impairment, Brain Function
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 40 participants (actual)
- Lead sponsor
- Mayo ClinicUniversity, hospital or other
- Collaborators
- National Institute on Aging (NIA)
- Study start
- 15 Mar 2019 (actual)
- Primary completion
- 5 Apr 2023 (actual)
- Study completion
- 5 Apr 2023 (actual)
- First posted
- 7 Nov 2018 (actual)
- Results
- Posted 18 Jun 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Alzheimer's disease (AD) and other forms of dementia are rapidly increasing with the aging of the population, and show a clear preponderance among people with insulin resistance. Metformin, an insulin sensitizer, is being examined in clinical trials as an anti-aging drug. However, very little objective data is available regarding metformin's effect on the brain, a major organ affected by aging.
Detailed description
Insulin resistance is highly prevalent with advancing age. Metformin is an insulin sensitizer and is currently being extensively investigated for its potential anti-aging effect. However, only very limited information is available on metformin effect on brain, which is a major organ affected by aging. With appropriate experimental design, the investigators are attempting to understand the mechanism of metformin treatment on the physiology of the brain as well as cognitive effects. These studies may uncover relationships that could be favorably manipulated to decrease health risks associated with insulin sensitivity and the effect on the brain.
The study results may lead to a breakthrough in providing either definitive data or sufficiently strong preliminary data regarding metformin's effect on elderly people with insulin resistance, on whether the drug enhances brain mitochondrial function in conjunction with improvement of brain functional network and cognitive function.
The overall hypothesis is that metformin administration to elderly people with insulin resistance enhances brain mitochondrial function in conjunction with improvement of brain function. To test this hypothesis, the investigators will address the following Specific Aims:
- Determine whether 40 weeks of metformin administration in elderly people (> 65 years) with insulin resistance enhances brain mitochondrial ATP production. The investigators will measure brain ATP production by 31P-MRS.
- Determine the effect of 40 weeks of metformin administration in elderly people (> 65 years) with insulin resistance on blood flow and functional network in different areas of brain. As a secondary outcome, the investigators will measure structural changes in white and grey matter areas of brain to determine whether metformin has any effect on brain structure.
- Determine the effect of 40 weeks of metformin administration in elderly people (> 65 years) with insulin resistance on cognitive function. The investigators will utilize the computerized NIH Toolbox to measure cognitive outcomes.
The investigators will also associate outcomes from our specific aims with improvements in whole-body insulin sensitivity and skeletal muscle mitochondrial function.
The investigators propose to complete 40 weeks of study in 40 elderly (> 65 years) participants with fasting glucose between 100 to 140 mg/dl and abdominal girth of >102 cm in men and > 88 cm in women. All participants will be those who are not oral hypoglycemic agents including metformin. In this double-blind placebo trial, the investigators will randomly assign the participants to placebo or metformin in an escalated dose to reach a maximum of 2500 mg per day.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Placebo | Placebo comparator | Drug: Placebo Oral TabletParticipants in placebo group will receive Placebo Oral Tablets identical to the metformin tablets for 10 months. |
| Metformin | Active comparator | Drug: Metformin HydrochlorideParticipants in placebo group will receive an escalating dose of Metformin hydrochloride tablets up to a dose of 2500mg for 10 months. |
Who may qualify
- Ages
- 65 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Older adult
Key inclusion criteria (5 listed)
- Age >/= 65 years
- Abdominal girth > 102 cm in men and > 88 cm in women-
- Fasting glucose >/= 100-140 mg/dL
- Non-smoker
- English language proficiency
Key exclusion criteria (18 listed)
- Coronary artery disease or heart failure
- A known medical condition that in the judgment of the investigator might interfere with the completion of the protocol such as the following examples:
- Inpatient psychiatric treatment in the past 6 months
- Presence of a known adrenal disorder
- Abnormal liver function test results (Transaminase >2 times the upper limit of normal); testing required for subjects taking medications known to affect liver function or with diseases known to affect liver function
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 HydrochlorideAlso: MetforminMetformin treatment of 2500mg for 10 months in the Metformin group | Drug | Metformin |
| Placebo Oral TabletAlso: PlaceboPlacebo treatment of identical tablets to metformin group | Drug | Placebo |
Primary outcome
Change From Baseline in Brain PCr/ATP Ratio as Measured by Phosphorus Magnetic Spectroscopy (31P-MRS) After 10 Months of Metformin Administration
Time frame: Baseline, 10 months
Multivoxel spectroscopic imaging of the brain will be performed using our dual-tuned single-channel-proton eight-channel-phosphorus head coil. A single 2.5 cm thick slice will be prescribed to encompass the temporal and occipital lobes, and weighted MRSI will be performed using a 16x16 matrix to acquire nominal 2.5 cm3 voxels. Multivoxel phosphorus magnetic resonance spectroscopic imaging data were reconstructed and quantified using jMRUI 6.0. Spectra were preprocessed by (a) truncating the data to 768 points, then 0-filling to 1024 points; (b) apodizing with a 5 Hz Lorenzian; and (c) aligning the data such that the PCr peak was set to 0 Hz. Next, 2 voxels from occipital lobe were selected, extracted, and averaged together into a single free induction decay in order to reduce noise. The outcome measure PCr/ATP ratio is a marker of ATP resynthesis potential and is reported as a change from pre- to post-treatment.
Change From Baseline in Cognitive Function as Measured by NIH Toolbox After 10 Months of Metformin Administration
Time frame: Baseline, 10 months
The NIH Toolbox will be utilized to measure cognitive outcomes. The NIH Toolbox-Cognition Battery is composed of 7 tests (~30 minutes) and our primary outcome measure will be the Total Cognition Composite score comprised from these 7 tests. Results are presented as a fully-adjusted T-score. For a single timepoint, T-scores are expected to have a population mean of 50, standard deviation of 10. For a single timepoint, higher T-scores indicate better cognitive test performance. An increase in T-score over time is considered a better outcome. At the individual level, a T-score < 40 is considered low test performance. There were no clear clinically relevant thresholds for a change in T-score over 10 months at the start of this study. Comparison of the mean change in T-score over time in the Metformin treatment group to placebo is our analysis of interest
3 secondary outcomes
Change From Baseline in Brain Structure as Measured by MRI After 10 Months of Metformin Administration
Time frame: Baseline, 10 months
Change From Baseline in Muscle Mitochondrial Respiration as Measured by High-resolution Respirometry Following 10 Months of Metformin Administration
Time frame: Baseline, 10 months
Change From Baseline in Muscle Mitochondrial ATP Production as Measured by Fluorometry Following 10 Months of Metformin Administration
Time frame: Baseline, 10 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jun 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Mayo Clinic Clinical TrialsLink provided by the sponsor.
- Individual participant dataSharing planned: No
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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.
K Sreekumaran Nair, M.D., Ph.D. principal investigator
Mayo Clinic
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 Hydrochloride in people with Insulin Resistance and Obesity, run by Mayo Clinic at 1 site in United States.
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 5 inclusion and 18 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 18 Jun 2024. 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 United States. 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. Some participants in this study may receive a placebo. 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?
Yes. Results are posted in the registry (first posted 18 Jun 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Change From Baseline in Brain PCr/ATP Ratio as Measured by Phosphorus Magnetic Spectroscopy (31P-MRS) After 10 Months of Metformin Administration (time frame: Baseline, 10 months). The study lists 2 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 18 Jun 2024.