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The investigators are doing this research study to find out if taking Metformin improves walking ability in patients with peripheral arterial disease (PAD). In PAD the arteries (blood vessels) in the legs are narrowed because of the build up of plaque. The leg muscle can hurt in patients with PAD and this is usually described as a cramp or tiredness. This pain is called intermittent claudication. Metformin is an FDA approved medication for the treatment of diabetes. The investigators believe that Metformin may help your leg muscles work better.
The investigators will enroll up to 100 subjects in order to find 60 subjects with PAD at Brigham and Women's Hospital (BWH).
Peripheral artery disease (PAD) is a manifestation of atherosclerosis that affects more than 7 million adults in the US. The prevalence of PAD increases with age and is estimated to be 15 20% among individuals 65 years of age and older. Patients with PAD have limited functional capacity; they walk more slowly and have less walking endurance than persons who do not have PAD, irrespective of whether they have classic symptoms of intermittent claudication or critical limb ischemia. This functional impairment adversely affects quality of life. Although flow limitation due to atherosclerotic stenosis is necessary for the development of symptoms in PAD, the lack of correlation between walking capacity and the degree of hemodynamic compromise raises the possibility that alternative mechanisms contribute to functional limitations in these patients. Putative mechanisms include inadequate skeletal muscle glucose uptake, altered skeletal muscle energetics, and impaired vasomotor tone and nutrient delivery mediated by endothelial dysfunction. Metformin, via AMPactivated protein kinase (AMPK)-dependent and independent mechanisms, can favorably affect skeletal muscle metabolic functions including glucose uptake, fatty acid oxidation, mitochondrial function, and consequently cellular energetics, and it also may have a direct salutary effect on vascular function via regulation of nitric oxide synthase. It is intriguing, therefore, to consider the possibility that metformin would improve skeletal muscle metabolic and vascular function in older patients with PAD and translate into functional benefits. Accordingly, the investigators seek to elucidate molecular mechanisms through which metformin affects skeletal muscle energetics and hypothesize that metformin will lead to advantageous metabolic, vascular, and physical functional changes in older patients with PAD.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Metformin 1000 mg | Experimental | metformin 1000 mg twice daily: In order to avoid gastrointestinal side effects, the starting dose of metformin will be 500 mg twice daily. After one week, the dose will be increased to 1000 mg twice daily (as two 500 mg tablets twice daily). Subjects will be instructed to take medications with breakfast and with dinner. |
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| Control | Placebo Comparator | placebo twice daily: In order to maintain blinding during the titration period, individuals randomized to placebo will receive one placebo tablet twice daily for one week, followed by an increase to 2 placebo tablets twice daily. Subjects will be instructed to take medications with breakfast and with dinner. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Metformin 1000 mg | Drug |
| ||
| Placebo |
| Measure | Description | Time Frame |
|---|---|---|
| Change in PCr Recovery Time | PCr recovery time, measured in seconds, is a measure of skeletal muscle metabolic function. PCr is a transport molecule and reservoir of high-energy phosphate bonds, which is important for cellular energetics. Phosphocreatine regeneration depends upon the skeletal muscle mitochondrial cells capacity for oxidative phosphorylation. We will measure PCr recovery time at baseline and after 12 weeks of treatment with metformin or placebo as an in vivo measure of mitochondrial function. Higher Pcr relative to P(i) during recovery is better and shorter recovery times are better. | baseline, 12 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Flow-mediated Dilation (FMD) | Flow mediated vasodilation of the brachial artery is a measure of endothelium-dependent vasodilation. Higher flow-mediated dilation (FMD), measured as the diameter of the brachial artery in millimeters, and reported as percent change after a flow stimulus compered to basal measurement, is better, indicative of better endothelial function. | baseline, 12 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Maximal Treadmill Walking Time | Maximal treadmill walking time is measured in minutes or seconds. Higher values indicate a better outcome. | baseline, 12 weeks |
| Change in Pain-free Treadmill Walking Time |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Mark A Creager, MD | Brigham and Women's Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Brigham and Women's Hospital | Boston | Massachusetts | 02115 | United States |
Randomization blind was never broken, so only overall study participant flow is available.
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| ID | Title | Description |
|---|---|---|
| FG000 | Overall Study | Overall Study (Metformin and Placebo arms combined) |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Randomization blind was never broken, so only overall study participant baseline measures are available.
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| ID | Title | Description |
|---|---|---|
| BG000 | Overall Study | Overall Study (Metformin and Placebo arms combined) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| 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 in PCr Recovery Time | PCr recovery time, measured in seconds, is a measure of skeletal muscle metabolic function. PCr is a transport molecule and reservoir of high-energy phosphate bonds, which is important for cellular energetics. Phosphocreatine regeneration depends upon the skeletal muscle mitochondrial cells capacity for oxidative phosphorylation. We will measure PCr recovery time at baseline and after 12 weeks of treatment with metformin or placebo as an in vivo measure of mitochondrial function. Higher Pcr relative to P(i) during recovery is better and shorter recovery times are better. | Study was not funded and was terminated prematurely. Randomization blind was never broken, and data was not collected on the outcome measures. | Posted | baseline, 12 weeks |
|
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"0" Total Number of Participants at Risk (e.g., "All-Cause Mortality, Serious, and Other [Not Including Serious] Adverse Events) were not monitored/assessed.
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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 | Overall Study | Overall Study (Metformin and Placebo arms combined) |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Mark A. Creager, MD | Brigham and Women's Hospital | 603-650-8283 | mark.a.creager@hitchcock.org |
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| ID | Term |
|---|---|
| D058729 | Peripheral Arterial Disease |
| ID | Term |
|---|---|
| D050197 | Atherosclerosis |
| D001161 | Arteriosclerosis |
| D001157 | Arterial Occlusive Diseases |
| D014652 | Vascular Diseases |
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| ID | Term |
|---|---|
| D008687 | Metformin |
| ID | Term |
|---|---|
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
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Pain-free treadmill walking time is measured in minutes or seconds. Higher values indicate a better outcome.
| baseline, 12 weeks |
| Change in Oxygen Consumption | Oxygen consumption is measured in ml/kg/min. Higher values indicate better outcomes. | baseline, 12 weeks |
| Change in Six Minute Walk Test | The 6-min walk test (6 MWT) is a submaximal exercise test that entails measurement of distance walked over a span of 6 minutes.The 6 MWT is measured in meters, and higher values indicate better outcomes. | baseline, 12 weeks |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
|
| Secondary | Change in Flow-mediated Dilation (FMD) | Flow mediated vasodilation of the brachial artery is a measure of endothelium-dependent vasodilation. Higher flow-mediated dilation (FMD), measured as the diameter of the brachial artery in millimeters, and reported as percent change after a flow stimulus compered to basal measurement, is better, indicative of better endothelial function. | Study was not funded and was terminated prematurely. Randomization blind was never broken, and data was not collected on the outcome measures. | Posted | baseline, 12 weeks |
|
|
| Other Pre-specified | Change in Maximal Treadmill Walking Time | Maximal treadmill walking time is measured in minutes or seconds. Higher values indicate a better outcome. | Study was not funded and was terminated prematurely. Randomization blind was never broken, and data was not collected on the outcome measures. | Posted | baseline, 12 weeks |
|
|
| Other Pre-specified | Change in Pain-free Treadmill Walking Time | Pain-free treadmill walking time is measured in minutes or seconds. Higher values indicate a better outcome. | Study was not funded and was terminated prematurely. Randomization blind was never broken, and data was not collected on the outcome measures. | Posted | baseline, 12 weeks |
|
|
| Other Pre-specified | Change in Oxygen Consumption | Oxygen consumption is measured in ml/kg/min. Higher values indicate better outcomes. | Study was not funded and was terminated prematurely. Randomization blind was never broken, and data was not collected on the outcome measures. | Posted | baseline, 12 weeks |
|
|
| Other Pre-specified | Change in Six Minute Walk Test | The 6-min walk test (6 MWT) is a submaximal exercise test that entails measurement of distance walked over a span of 6 minutes.The 6 MWT is measured in meters, and higher values indicate better outcomes. | Study was not funded and was terminated prematurely. Randomization blind was never broken, and data was not collected on the outcome measures. | Posted | baseline, 12 weeks |
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| D002318 |
| Cardiovascular Diseases |
| D016491 | Peripheral Vascular Diseases |