Overview
The PROVE Trial is a randomized clinical trial that will determine whether a weight loss intervention combined with walking exercise achieves greater improvement or less decline in six-minute walk distance at 12 month follow-up than walking exercise alone in people with PAD and BMI>25 kg/m2. The intervention uses a Group Mediated Cognitive Behavioral framework, connective mobile technology, remote monitoring by a coach, and a calorie restricted Dietary Approaches to Stop Hypertension (DASH)-derived Optimal Macronutrient Intake Trial for Heart Health (OMNIHeart) diet.
212 participants with PAD and BMI > 25 kg/m2 will be randomized to one of two groups: weight loss + exercise (WL+EX) vs. exercise alone (EX). Participants will be randomized at Northwestern, Tulane University, and University of Minnesota. Our primary outcome is change in six-minute walk distance at 12-month follow-up. Secondary outcomes are change in 6-minute walk distance at 6-month follow-up and change in exercise adherence, physical activity, patient-reported walking ability (measured by the Walking Impairment Questionnaire (WIQ) distance score), and mobility (measured by the Patient-Reported Outcomes Measurement Information System [PROMIS] mobility questionnaire) at 12-month follow-up. Tertiary outcomes are perceived exertional effort (measured by the Borg scale at the end of the 6-minute walk at 12-month follow-up), and diet quality. Exploratory outcomes consist of change in the short physical performance battery (SPPB), the WIQ stair climbing and walking speed scores, and calf muscle biopsy measures at 12-month follow-up. Study investigators will perform calf muscle biopsies in 50 participants to compare changes in mitochondrial biogenesis and activity, capillary density, and inflammation between WL+EX vs. EX.
Eligibility
Inclusion criteria are a) presence of PAD; b) BMI> 25 kg/m2; c) Age >= 18. The diagnosis of
PAD will be based on the following. First, an ankle brachial index (ABI) value <= 0.90,
which is a well-accepted standard for diagnosing PAD. People with a toe brachial index of
<=0.70, performed at the study visit, will be eligible. Second, people with an ABI of >0.90
and <=1.00 who experience a 20% or greater drop in ABI in either leg after the heel-rise
test will also be included. Third, potential participants with an ABI > 0.90 who provide
vascular laboratory evidence or angiographic evidence of PAD will be included. Prior
vascular laboratory evidence consists of objective evidence of PAD including toe brachial
index (TBI) < 0.70, Duplex measure showing 70% stenosis or greater, a post-exercise ABI
drop in either leg of 20% or greater, or ABI values <= 0.90. Angiographic evidence of PAD
consists of a stenosis of 70% or greater in a lower extremity artery. Fourth, people 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 an exercise test will be eligible if
they have symptomatic PAD. Symptomatic PAD will be defined as leg symptoms associated with
exertion that resolved within 10 minutes of rest. The presence of symptomatic PAD will be
determined based on the claudication questionnaire, the six-minute walk, or principal
investigator interview/discussion with the potential participant. The post-exercise ABI
drop will be measured by obtaining an ABI, having the participant exercise, and then
immediately repeating the ABI. The exercise may consist of either the six-minute walk test
or the heel-rise test. The heel-rise test consists of 50 heel rises at a rate of one per
second. From the beginning of the trial until early 2023, we used the BMI inclusion
criterion of > 28 kg/m2 because overweight and obesity are defined as a BMI of 25 to 29
kg/m2 and > 30 kg/m2, respectively, and because in our PAD cohorts, those with BMI > 28
kg/m2 have significantly greater functional impairment and faster functional decline than
those with BMI of 20-28 kg/m2. In order to increase the rate of recruitment, on 1/19/2022,
investigators reduced the BMI inclusion criterion to > 25 kg/ m2. People with BMI above 25
are overweight or obese and therefore are expected to benefit from the healthy lifestyle
intervention.
Exclusion Criteria:
1. Above or below knee amputation, critical limb ischemia, or wheelchair confinement.
2. Walking is limited by a condition other than PAD.
3. Failure to complete the study run-in, defined as not entering at least 800 Kcal of
consumed calories per day for at least five days during the 14-day run-in*.
4. Major surgery, coronary or leg revascularization in the past 3 months or anticipated
in the next year.
5. Experienced a heart attack or stroke in the past 3 months.
6. Major medical illness including lung disease requiring oxygen or life-threatening
illness, 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.
7. Mini-Mental Status Examination (MMSE) score < 23, dementia and substance abuse.
Potential participants with an MMSE score of less than 23 may be eligible if the
principal investigator determines that their lower score is due to reasons other than
poor cognition. Other potential reasons for lower scores include poor literacy or that
English is not their first language.
8. History of being treated for new onset or an acute episode of schizophrenia or
psychosis in the past 6 months.
9. Hospitalization for a psychiatric disorder in the past 6 months.
10. BMI > 45 kg/m2
11. History of a significant eating disorder that has been active within the past 5 years
or any weight loss treatment in the past 6 months. Weight loss treatment includes
weight watchers, any history of weight loss surgery, and using weight loss medications
now or in the past six months.
12. Weight gain or loss of more than 25 pounds in the past six months
13. Potential participants unwilling/unable to use a smart phone and unwilling to attend
weekly study sessions.
14. Excessive alcohol use, defined as >14 drinks/week in men and > 10 alcoholic
drinks/week in women.
15. Current ulcer on bottom of foot
16. Current participation in supervised treadmill exercise, participation in supervised
treadmill exercise in the past three months, or planning to participate in supervised
treadmill exercise in the next year
17. Increase in angina or angina at rest. Potential participants may become eligible
following an abnormal baseline treadmill stress test if they have evidence of an
absence of coronary ischemia based on testing with their own physician.
18. Non-English speaking
19. Visual impairment that limits walking ability
20. Currently walking regularly for exercise at a level comparable to the amount of
exercise prescribed in the intervention
21. 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.]
22. 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
- The run-in will also be used to assist participants with learning the app.
However, they must demonstrate ability to enter at least 800 Kcal per day for at
least five days of the run-in.