Peripheral Artery Disease
Conditions
Brief summary
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.
Interventions
DRUGMetformin
Participants will be prescribed up to 2,000 mgs daily of metformin
DRUGPlacebo
Placebo pills will appear identical to the metformin to maintain blinding of participants and investigators.
Sponsors
Northwestern University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Six-minute Walk Performance | Change from baseline to six-month follow-up | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximal Treadmill Walking Time | Change from baseline to six-month follow-up | A Gardner treadmill exercise protocol will be used |
| Brachial Artery Flow-mediated Dilation | Percent change from baseline to six-month follow-up | Upper brachial artery flow-mediated dilation was evaluated by measuring percent change in the brachial artery diameter in response to reactive hyperemia, induced by inflating a blood pressure cuff for five minutes over the brachial artery. |
| The Walking Impairment Questionnaire - Distance Score | Change from baseline to six-month follow-up | The Walking impairment questionnaire is a patient reported outcome measure, in which participants indicate the ease of walking distances ranging from across the room to up to approximately 1500 feet. The score is calculated on a 0-100 scale, where 0 indicates the in ability to walk any of the distances and 100 indicates no difficulty walking any of the distances. |
| The SF-36 Physical Functioning Score | Change from baseline to six-month follow-up | This outcome is a patient reported quality of life measure. The score ranges from 0 to 100, where 0 indicates extremely poor functioning and 100 indicates the best possible functioning, |
| Calf Muscle Biopsy Biochemical Measures - Capillary Density | Change from baseline to six-month follow-up | Capillary density was measured as the number of capillaries per mm2 of muscle. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORMary McDermott, MD
Northwestern University
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 69.6 years STANDARD_DEVIATION 8.4 |
| Ankle brachial index, consisting of a ratio of Doppler recorded pressures. | 0.63 Ratio STANDARD_DEVIATION 0.16 |
| Body mass index | 28.7 kg/m^2 STANDARD_DEVIATION 6.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 188 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 41 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) White | 116 Participants |
| Sex: Female, Male Female | 32 Participants |
| Sex: Female, Male Male | 65 Participants |
| Six-minute walking distance | 357.0 meters STANDARD_DEVIATION 105.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 97 | 1 / 105 |
| other Total, other adverse events | 76 / 97 | 72 / 105 |
| serious Total, serious adverse events | 11 / 97 | 14 / 105 |
Outcome results
None listed