Peripheral Artery Disease
Conditions
Brief summary
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).
Detailed description
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.
Interventions
DRUGPlacebo
Sponsors
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age 40 years or greater * Intermittent claudication for 6 months or greater * Maximal walk time between 1-20 minutes on all ETTs * Resting ABI ≤ 0.9 in index leg at baseline * ABI falls ≥ 20% in index leg 1 minute post baseline ETT * MWT variability \< 20%
Exclusion criteria
* Type 1 or Type 2 Diabetes * Limb-threatening ischemia (rest pain, ulceration, gangrene) * Peripheral vascular surgery or PCI within 6 months * MI or CABG within 6 months * Carotid endarterectomy (CEA) within 6 months * Cerebrovascular accident or TIA within 6 months * Uncontrolled hypertension (SBP \> 140 mmHg, DBP \>90 mmHg) * Pentoxifylline/Cilostazol added/changed within 3 months * HMG-CoA reductase inhibitor added/changed within 3 months * Exercise limitations other than claudication (heart failure, angina, COPD, arthritis, neuropathy, etc.) * Serum creatinine ≥ 1.5 mg/dL * Pregnant or plans to become pregnant * 2 hour Oral Glucose Tolerance Test (OGTT) \> 200 mg/dL
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in PCr Recovery Time | baseline, 12 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Flow-mediated Dilation (FMD) | baseline, 12 weeks | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Maximal Treadmill Walking Time | baseline, 12 weeks | Maximal treadmill walking time is measured in minutes or seconds. Higher values indicate a better outcome. |
| Change in Pain-free Treadmill Walking Time | baseline, 12 weeks | Pain-free treadmill walking time is measured in minutes or seconds. Higher values indicate a better outcome. |
| Change in Oxygen Consumption | baseline, 12 weeks | Oxygen consumption is measured in ml/kg/min. Higher values indicate better outcomes. |
| Change in Six Minute Walk Test | baseline, 12 weeks | 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. |
Countries
United States
Participant flow
Pre-assignment details
Randomization blind was never broken, so only overall study participant flow is available.
Participants by arm
| Arm | Count |
|---|---|
| Overall Study Overall Study (Metformin and Placebo arms combined) | 2 |
| Total | 2 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | study was not funded and terminated | 2 |
Baseline characteristics
| Characteristic | Overall Study |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 79.5 years STANDARD_DEVIATION 4.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 1 Participants |
| Region of Enrollment United States | 2 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 |
Outcome results
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.
Time frame: baseline, 12 weeks
Population: Study was not funded and was terminated prematurely. Randomization blind was never broken, and data was not collected on the outcome measures.
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.
Time frame: baseline, 12 weeks
Population: Study was not funded and was terminated prematurely. Randomization blind was never broken, and data was not collected on the outcome measures.
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.
Time frame: baseline, 12 weeks
Population: Study was not funded and was terminated prematurely. Randomization blind was never broken, and data was not collected on the outcome measures.
Other Pre-specified
Change in Oxygen Consumption
Oxygen consumption is measured in ml/kg/min. Higher values indicate better outcomes.
Time frame: baseline, 12 weeks
Population: Study was not funded and was terminated prematurely. Randomization blind was never broken, and data was not collected on the outcome measures.
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.
Time frame: baseline, 12 weeks
Population: Study was not funded and was terminated prematurely. Randomization blind was never broken, and data was not collected on the outcome measures.
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.
Time frame: baseline, 12 weeks
Population: Study was not funded and was terminated prematurely. Randomization blind was never broken, and data was not collected on the outcome measures.