Improve PAD PERformance With METformin

Study Overview
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Brief Summary
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The PERMET trial will determine whether metformin daily for six months improves six-minute walk performance in individuals with peripheral artery disease compared to placebo.

Official Title
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Improve PAD Performance With Metformin: The PERMET Trial

Conditions
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Peripheral Artery Disease

Intervention / Treatment
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* Drug: Metformin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All participants will have PAD. PAD will be defined as follows: First, an ankle brachial index (ABI) <=0.90 at the baseline study visit is an inclusion criterion for PAD. Second, potential participants who have an ABI > 0.90 but ≤ 1.00 and experience a 20% or higher drop in ABI after heel-rise exercise will be eligible. Third, potential participants with an ABI > 0.90 who have vascular lab evidence of PAD or angiographic evidence of PAD who have ischemic symptoms during the six-minute walk and/or treadmill exercise stress test will be eligible. Fourth, potential participants with a history of lower extremity revascularization who do not meet the criterion above and have an ABI > 0.90 with a 20% or higher drop in ABI after heel-rise exercise will be eligible. Exclusion Criteria: Above- or below-knee amputation. Critical limb ischemia. Wheelchair-bound or requiring a walker to ambulate. Walking is limited by a symptom other than PAD. Current foot ulcer on bottom of foot. Diabetes mellitus defined as one or more of a) patient report of physician diagnosed diabetes mellitus, b) use of one or more diabetes medications, c) two baseline hemoglobinA1C values of >6.5, d) two fasting glucose values >126 mg/dl. [NOTE: the second fasting glucose value and hemoglobin A1C values will be at the discretion of the principal investigator. For example, if the first glucose value is >300 or the first A1C value is >6.9, then investigators may decide not to repeat the value.] Chronic kidney disease defined as GFR <=45. [NOTE: if GFR is 40-44, investigator discretion will be used to determine if a repeat test may be performed. If the second GFR value is >45, the participant may be included.] Chronic liver disease defined as two or more hepatic function tests >=2.0 times the upper limit of normal. [NOTE: participants who meet this criterion may undergo a re-test of hepatic function tests to determine whether initially elevated hepatic enzymes represented a transient or spurious phenomenon.] Failure to successfully complete the 2-week study run-in, defined as unable to tolerate metformin and/or failing to take the medication daily for 10 or more days in the two-week period. Planned lower extremity revascularization, orthopedic surgery, or other major surgery during the next six months. Lower extremity revascularization, orthopedic surgery, cardiovascular event, coronary revascularization, or other major surgery in the previous three months. Major medical illness including renal disease requiring dialysis, lung disease requiring oxygen, Parkinson's disease, a life-threatening illness with life expectancy less than six months, or cancer requiring treatment in the previous two years. [NOTE: potential participants may still qualify if they have had treatment for an early stage cancer in the past two years and the prognosis is excellent. Participants who only use oxygen at night may still qualify.] Mini-Mental Status Examination (MMSE) score <23 or dementia. However, investigator discretion may be used to allow some people below this threshold to participate, if the investigator determines there is another reason for their lower score, including lack of familiarity with the English language or lack of sufficient education to achieve a score of 23 or higher. Note that the MMSE include some spelling and English writing proficiency. Participation in or completion of a clinical trial in the previous three months. [NOTE: after completing a stem cell or gene therapy intervention, participants will become eligible after the final study follow-up visit of the stem cell or gene therapy study so long as at least six months have passed since the final intervention administration. After completing a supplement or drug therapy (other than stem cell or gene therapy), participants will be eligible after the final study follow-up visit as long as at least three months have passed since the final intervention of the trial.] Currently taking metformin or has taken metformin in past six months. Increase in angina or angina at rest Non-English speaking. Visual impairment that limits walking ability. In addition to the above criteria, investigator discretion will be used to determine if the trial is unsafe or not a good fit for the potential participant. Vulnerable populations (fetuses, pregnant women, children, prisoners, and institutionalized persons) and adults unable to consent will not be included in the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Metformin<br>Metformin daily | Drug: Metformin<br>* Participants will be prescribed up to 2,000 mgs daily of metformin<br>|
| Placebo Comparator: Placebo<br>Placebo daily for six months. | Drug: Placebo<br>* Placebo pills will appear identical to the metformin to maintain blinding of participants and investigators.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Six-minute walk performance | Participants walking up and down a 100 foot hallway for six minutes following a standardized protocol. The goal is for them to walk as far as possible in six minutes | Change from baseline to six-month follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal treadmill walking time | A Gardner treadmill exercise protocol will be used | Change from baseline to six-month follow-up | 
| Brachial artery flow-mediated dilation | Upper brachial artery flow-mediated dilation will be assessed using a standard protocol | Change from baseline to six-month follow-up | 
| The Walking Impairment Questionnaire | The well validated Walking Impairment Questionnaire will be used to measure patient- perceived walking performance. | Change from baseline to six-month follow-up | 
| The SF-36 Physical Functioning Score | This well validated quality of life measure will be used to assess changes in patient perceived quality of life. | Change from baseline to six-month follow-up | 
| Calf muscle biopsy biochemical measures | A skeletal muscle sample will be obtained from the gastrocnemius muscle. | Change from baseline to six-month follow-up |