Clinical trial NCT05132439: MetfOrmin BenefIts Lower Extremities With Intermittent Claudication
Official title: Metformin BenefIts Lower Extremities With Intermittent Claudication (MOBILE_IC)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Intermittent Claudication
Keywords: Peripheral artery disease
intermittent claudication
metformin
anti-inflammatory agents
clinical trial protocol
atherosclerosis
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
Collaborators: name: University of Pittsburgh
name: Northwestern University
name: San Francisco Veterans Affairs Medical Center
First posted: 2021-11-24
Enrollment: 200
Sex: ALL
Minimum age (years): 35
Maximum age (years): 89
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Maximal Walking distance on the 6 minute walk test
timeFrame: 6 month
Secondary outcomes:
measure: 6 minute walk test
timeFrame: 6 month
measure: 6 minute walk test
timeFrame: 12 month
measure: Cardiopulmonary exercise test
timeFrame: 6 month
measure: Cardiopulmonary exercise test
timeFrame: 12 month
measure: EndoPAT
timeFrame: 6 month
measure: Grip Strength
timeFrame: 6 month
measure: EndoPAT
timeFrame: 12 month
measure: Grip Strength
timeFrame: 12 month
measure: Ankle brachial index and pulse volume recording
timeFrame: 6 month
measure: Ankle brachial index
timeFrame: 12 month
measure: Health related quality of life questionnaire
timeFrame: 6 month
measure: Health related quality of life questionnaires
timeFrame: 12 month
measure: Walking Impairment Questionnaire
timeFrame: 6 month
measure: Walking Impairment Questionnaire
timeFrame: 12 month
measure: Freedom from major cardiac and major limb events
timeFrame: 12 month
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
state: Pennsylvania
Study officials:
affiliation: VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
name: Edith I. Tzeng, MD
role: PRINCIPAL_INVESTIGATOR
References: