MetfOrmin BenefIts Lower Extremities With Intermittent Claudication

Study Overview
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Brief Summary
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Peripheral arterial disease (PAD) affects over 20% of aged adults and is very common among Veterans due significant tobacco use. PAD is due to the progressive blockage of peripheral arteries, predominantly to the legs, and results in intermittent claudication (IC) or recurrent muscle pain with activity secondary to insufficient blood supply. Those with PAD and IC experience a progressive decline in walking and poor quality of life. There is no effective medical treatment for PAD and IC. Metformin is a safe and effective treatment for Type 2 diabetes but it can also reduce inflammation, oxidative stress, and improve energy requirements as well as improve blood flow to the legs. Therefore, the investigators will test the ability of Metformin to improve overall functional status, reduce PAD progression, and reduce systemic inflammation in Veterans suffering from PAD and IC in a randomized, placebo controlled trial: Metformin BenefIts Lower Extremities with Intermittent Claudication (MOBILE IC) Trial. The success of this trial may identify a safe and effective treatment for PAD and IC.

Detailed Description
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This is a quadruple blinded randomized controlled trial. Therefore, the allocation of participants to either placebo or metformin is unknown by the participant, research personnel, investigator, or blinded statistician. A total of 200 participants will be randomized over the course of 3 years. Study drug is administered to participants after all inclusion and no exclusion criteria is confirmed, informed consent is completed, and they are randomized. Study drug is continued throughout for 6 months following randomization. Participants are prospectively observed and monitored for 12 months after randomization. The patients' involvement (study visits/study phone calls) will last 12 months. Then, for 5 years, the study team will do a medical chart review as outlined in the ICF and protocol. All main study endpoints are within the 12-month time point. Secondary endpoints including MACE and MALE - major adverse cardiac and major adverse limb events - are time to event end points which can continue beyond the 12-month study time frame and will inform not only the effect of metformin on IC but also the natural history of IC among patients enrolled in the study.

Official Title
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Metformin BenefIts Lower Extremities With Intermittent Claudication (MOBILE_IC)

Conditions
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Intermittent Claudication

Intervention / Treatment
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* Drug: Metformin ER
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and Female Veteran >35 & <89 Symptoms of Intermittent claudication Medically stable, optimal medical therapy (for >3 months prior to randomization which includes - statin and anti-platelet therapy, blood pressure control, smoking cessation and physical activity counseling) a. Participants may not comply with the above measures to meet inclusion criteria, but investigator driven attempts to maximize the optimal medical therapy, as tolerated, for each participant prior to trial enrollment PAD as defined by ABI <0.9 or >0.9 with evidence of PAD as documented by pulse volume recordings (within 6 months prior to expected randomization date) Maximum Walking Distance (MWD) on the 6-minute walk test (6MWT) of greater than or equal to 50 meters with onset of pain before or at 400 meters without the use of a walker (cane is acceptable; within 6 months of expected randomization date) Exclusion Criteria: Diabetes (Type I or II) or Hemoglobin A1c>6.5 (within 6 months of expected randomization) Currently Taking metformin or have previously taken metformin (within 6 months of enrollment) Medical condition that limit their ability to ambulate other than PAD (i.e., Angina, CHF, pulmonary disease requiring oxygen, malignancy requiring treatment, etc.) Prior above or below knee amputation Critical limb threatening ischemia (i.e., non-healing wounds or rest pain) Planned hospital admission, major operation, or lower extremity revascularization to be completed (within 12 months after expected randomization date) Prior major operation or lower extremity revascularization (within the 3 months before expected randomization) Unable to complete quality of life testing due to Non-English Speaking and/or Dementia Kidney disease - dialysis or eGFR<45 (within 6 months of expected randomization date)* Planned iodinated contrasted study (within 6 months of expected randomization date) Evidence current or history of hepatic failure Women who are pregnant or breast feeding Unable to swallow uncrushed pills Investigator expects inclusion could cause harm to subject

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 89 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
Interventional Model Description: Two arm randomization to 1000mg metformin ER or placebo daily with 1:1 parallel randomization, Randomization stratification will be based on baseline Maximum Walking Distance on the 6 Minute Walk Test and smoking status
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin ER 1000mg<br>daily by mouth | Drug: Metformin ER<br>* Oral medication typically used for Type 2 diabetes with presumed anti-inflammatory properties<br>* Other names: Glucophage;|
| Placebo Comparator: Matching placebo<br>daily by mouth | Drug: placebo<br>* Matched to active study drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal Walking distance on the 6 minute walk test | This validated measure of functional status in PAD and IC is highly reproducible and the ideal measure of real-life walking capacity | 6 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6 minute walk test | This validated measure of functional status in PAD and IC is highly reproducible and the ideal measure of real-life walking capacity. The six minute walk test includes maximal walking distance, pain free walking distance, time to pain onset. | 6 month | 
| 6 minute walk test | This validated measure of functional status in PAD and IC is highly reproducible and the ideal measure of real-life walking capacity. The six minute walk test includes maximal walking distance, pain free walking distance, time to pain onset. | 12 month | 
| Cardiopulmonary exercise test | The CPET is a well validated, reproducible measure symptom-limited (maximal) aerobic and anaerobic capacity in patients with PAD and IC and correlates with systemic disease severity and outcome | 6 month | 
| Cardiopulmonary exercise test | The CPET is a well validated, reproducible measure symptom-limited (maximal) aerobic and anaerobic capacity in patients with PAD and IC and correlates with systemic disease severity and outcome | 12 month | 
| EndoPAT | Systemic endothelial cell function and health will be evaluated by EndoPAT, measuring peripheral artery tonometry and generates reproducible digital pulse wave amplitude before and during reactive hyperemia induced by brachial artery occlusion with a blood pressure cuff | 6 month | 
| Grip Strength | Grip strength with a dynamometer provides a digital reading of force | 6 month | 
| EndoPAT | Systemic endothelial cell function and health will be evaluated by EndoPAT, measuring peripheral artery tonometry and generates reproducible digital pulse wave amplitude before and during reactive hyperemia induced by brachial artery occlusion with a blood pressure cuff | 12 month | 
| Grip Strength | Grip strength with a dynamometer provides a digital reading of force | 12 month | 
| Ankle brachial index and pulse volume recording | The ABI and PVR assess regional lower extremity blood supply in large-vessels and contribution of collaterals | 6 month | 
| Ankle brachial index | The ABI assesses regional lower extremity blood supply in large-vessels and contribution of collaterals | 12 month | 
| Health related quality of life questionnaire | Functionality outcomes will be supported by the general (SF-36) and disease specific (Vascular Quality of Life Questionnaire [VascQol6]) health related quality of life questionnaires. | 6 month | 
| Health related quality of life questionnaires | Functionality outcomes will be supported by the general (SF-36) and disease specific (Vascular Quality of Life Questionnaire [VascQol6]) health related quality of life questionnaires. | 12 month | 
| Walking Impairment Questionnaire | A subjective measure of patient-reported walking performance developed for PAD | 6 month | 
| Walking Impairment Questionnaire | A subjective measure of patient-reported walking performance developed for PAD | 12 month | 
| Freedom from major cardiac and major limb events | Major cardiac events include: composite of CVD mortality, myocardial ischemia, coronary revascularization, hospitalization for heart failure, non-fatal stroke, and transient ischemic attack. Major adverse limb events include: composite of minor and major amputations, revascularization | 12 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Peripheral artery disease, intermittent claudication, metformin, anti-inflammatory agents, clinical trial protocol, atherosclerosis