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| ID | Type | Description | Link |
|---|---|---|---|
| 1R21AG060139-01 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute on Aging (NIA) | NIH |
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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.
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:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo | Placebo Comparator | Participants in placebo group will receive Placebo Oral Tablets identical to the metformin tablets for 10 months. |
|
| 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Metformin Hydrochloride | Drug | Metformin treatment of 2500mg for 10 months in the Metformin group |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 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 | Baseline, 10 months |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
Inpatient psychiatric treatment in the past 6 months
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| Name | Affiliation | Role |
|---|---|---|
| K Sreekumaran Nair, M.D., Ph.D. | Mayo Clinic | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Mayo Clinic in Rochester | Rochester | Minnesota | 55905 | United States |
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| Label | URL |
|---|---|
| Mayo Clinic Clinical Trials | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo | Participants in the placebo group received Placebo Oral Tablets identical to the metformin tablets for 10 months. Placebo Oral Tablet: Placebo treatment of identical tablets to metformin group |
| FG001 | Metformin | Participants in Metformin group received an escalating dose of Metformin hydrochloride tablets up to a dose of 2500mg for 10 months. Metformin Hydrochloride: Metformin treatment of 2500mg for 10 months in the Metformin group |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo | Participants in the placebo group received Placebo Oral Tablets identical to the metformin tablets for 10 months. Placebo Oral Tablet: Placebo treatment of identical tablets to metformin group |
| BG001 | Metformin |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | If PCr, γ-ATP, α-ATP, or β-ATP signals were indiscernible from the background noise after processing then those spectra were discarded. Spectra processing was performed by one person, and processing steps were checked for fidelity by a second person. Twelve patients in the placebo group and 15 in the metformin group meet quality control criteria for both the pre- and post-scans. | Posted | Mean | Standard Deviation | PCr/ATP ratio | Baseline, 10 months |
9 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo | Participants in the placebo group received Placebo Oral Tablets identical to the metformin tablets for 10 months. Placebo Oral Tablet: Placebo treatment of identical tablets to metformin group |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| COVID-19 infection | Infections and infestations | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Infections and infestations: Other | Infections and infestations | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| K Sreekumaran Nair, M.D., Ph.D. | Mayo Clinic | 507-255-2415 | Nair@mayo.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP_ICF | Yes | Yes | Yes | Study Protocol, Statistical Analysis Plan, and Informed Consent Form | Jun 22, 2021 | May 3, 2024 | Prot_SAP_ICF_001.pdf |
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| ID | Term |
|---|---|
| D007333 | Insulin Resistance |
| D009765 | Obesity |
| D056128 | Obesity, Abdominal |
| D060825 | Cognitive Dysfunction |
| ID | Term |
|---|---|
| D006946 | Hyperinsulinism |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D008687 | Metformin |
| ID | Term |
|---|---|
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
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Study will be a double-blind, placebo-controlled, randomized design.
| Placebo Oral Tablet | Drug | Placebo treatment of identical tablets to metformin group |
|
|
| 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. | 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. | Baseline, 10 months |
Participants in Metformin group received an escalating dose of Metformin hydrochloride tablets up to a dose of 2500mg for 10 months.
Metformin Hydrochloride: Metformin treatment of 2500mg for 10 months in the Metformin group
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
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|
|
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| Primary | 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 | Posted | Mean | Standard Deviation | t-score | Baseline, 10 months |
|
|
|
|
| Secondary | 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. | One participant in each group was not able to be analyzed due to lack of sufficent scan quality. | Posted | Mean | Standard Deviation | mm cubed | Baseline, 10 months |
|
|
|
|
| Secondary | 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. | 2 participants in each group were unable to be measured for mitochondrial respiration. 2 were due to instrumentation malfunction and 2 were due to inability to collect enough muscle tissue for mitochondrial isolation on one or both study dates. | Posted | Mean | Standard Deviation | pmol/sec/mL/mg tissue mass | Baseline, 10 months |
|
|
|
|
| Secondary | 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. | 5 participants in the placebo group and 6 in the metfomin group were unable to be analyzed. One in each group was due to the inability to collect enough muscle for mitochondrial isolation and the remainder were due to an equipment breakdown (power source - had to be externally source and repaired via service technician) that rendered the equipment unusable for multiple study days. | Posted | Mean | Standard Deviation | pmol/sec/ug mitochondrial protein | Baseline, 10 months |
|
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|
|
| 0 |
| 20 |
| 1 |
| 20 |
| 9 |
| 20 |
| EG001 | Metformin | Participants in Metformin group received an escalating dose of Metformin hydrochloride tablets up to a dose of 2500mg for 10 months. Metformin Hydrochloride: Metformin treatment of 2500mg for 10 months in the Metformin group | 0 | 20 | 0 | 20 | 12 | 20 |
| Pain | General disorders | Systematic Assessment |
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| Gastroesophageal reflux disease | Gastrointestinal disorders | Systematic Assessment |
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| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
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| Social circumstances | Social circumstances | Systematic Assessment |
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| Eye disorders | Eye disorders | Systematic Assessment |
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| COVID-19 Infection | Infections and infestations | Systematic Assessment |
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| Nausea | General disorders | Systematic Assessment |
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| Vomiting | Gastrointestinal disorders | Systematic Assessment |
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| Headache | General disorders | Systematic Assessment |
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| Stroke | Vascular disorders | Systematic Assessment |
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| Hypertension | Vascular disorders | Systematic Assessment |
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| Fall | Injury, poisoning and procedural complications | Systematic Assessment |
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| Anemia | Blood and lymphatic system disorders | Systematic Assessment |
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| Weight loss | General disorders | Systematic Assessment |
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| Flatulence | Gastrointestinal disorders | Systematic Assessment |
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| Hepatobiliary disorders | Hepatobiliary disorders | Systematic Assessment |
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| D050177 | Overweight |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D001835 | Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D003072 | Cognition Disorders |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |