MetfOrmin BenefIts Lower Extremities With Intermittent Claudication (MOBILE IC)

Metformin BenefIts Lower Extremities With Intermittent Claudication (MOBILE_IC)

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.

Study Overview

• Status: Recruiting
• Conditions: Intermittent Claudication
• Intervention / Treatment: Drug: Metformin ER; Drug: placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Edith I Tzeng, MD; Phone Number: (412) 360-1657; Email: Edith.Tzeng@va.gov

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15240
      • Recruiting
      • VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
      • Contact: Susan L Barr; Phone Number: 412-360-2387; Email: susan.barr2@va.gov
      • Contact: Samantha A Bonant, BS; Phone Number: (412) 360-3788; Email: samantha.bonant@va.gov
      • Principal Investigator: Edith I. Tzeng, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 89 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Collaborators: Northwestern University; University of Pittsburgh; San Francisco Veterans Affairs Medical Center
• Investigators: Principal Investigator: Edith I. Tzeng, MD, VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA

Publications and helpful links

General Publications

• Reitz KM, Althouse AD, Forman DE, Zuckerbraun BS, Vodovotz Y, Zamora R, Raffai RL, Hall DE, Tzeng E. MetfOrmin BenefIts Lower Extremities with Intermittent Claudication (MOBILE IC): randomized clinical trial protocol. BMC Cardiovasc Disord. 2023 Jan 21;23(1):38. doi: 10.1186/s12872-023-03047-8.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2022
• Primary Completion (Estimated): February 28, 2027
• Study Completion (Estimated): February 28, 2032

Study Registration Dates

• First Submitted: November 12, 2021
• First Submitted That Met QC Criteria: November 12, 2021
• First Posted (Actual): November 24, 2021

Study Record Updates

• Last Update Posted (Actual): April 21, 2026
• Last Update Submitted That Met QC Criteria: April 16, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: atherosclerosis; metformin; Peripheral artery disease; intermittent claudication; anti-inflammatory agents; clinical trial protocol
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Peripheral Vascular Diseases; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Peripheral Arterial Disease; Atherosclerosis; Intermittent Claudication; Organic Chemicals; Biguanides; Guanidines; Amidines; Metformin
• Other Study ID Numbers: CARB-012-20F; I01CX002150 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No