Clinical trial NCT06686121: Improving Mobility After Revascularization in Peripheral Artery Disease
Official title: IMProving Mobility After revasCularizaTion in Peripheral Artery Disease: The IMPACT PAD Trial
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Peripheral Artery Disease
Intermittent Claudication
Peripheral Vascular Disease
Mobility Limitation
Revascularization
Keywords: Behavior Change
Patient Reported Outcome Measures
Mobility
Revascularization
Peripheral artery disease
Intermittent claudication
6-minute walk
Oxidative stress
Lead sponsor: Northwestern University
Sponsor class: OTHER
Collaborators: name: Rancho Research Institute
name: University of Chicago
name: Wake Forest University
name: University of Pittsburgh Medical Center
name: Emory University
name: University of Arizona
name: Dartmouth-Hitchcock Medical Center
First posted: 2024-11-13
Enrollment: 386
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: Two x two factorial design
Primary purpose: TREATMENT

Brief summary: Lower extremity revascularization combined with supervised exercise significantly improves walking performance compared to revascularization alone in people who have PAD without limb threatening ischemia. However, supervised exercise is inaccessible or burdensome for most PAD patients. We hypothesize that home-based exercise combined with lower extremity revascularization will significantly improve walking performance compared to revascularization alone in patients with PAD undergoing revascularization for disabling PAD.

We further hypothesize that inorganic nitrate, a major source of nitric oxide (NO) abundant in beetroot juice, will improve walking performance after lower extremity revascularization, compared to placebo. In preclinical models, NO inhibits inflammation, neointimal hyperplasia, thrombosis, and vascular smooth muscle cell migration at sites of revascularization. NO increases angiogenesis and perfusion, repairs skeletal muscle damaged by ischemia, and stimulates mitochondrial activity.

In a randomized clinical trial with a 2 x 2 factorial design, we will test the following two primary hypotheses in 386 patients randomized within three months of a successful lower extremity revascularization for disabling PAD: First, that home-based exercise combined with lower extremity revascularization will improve six-minute walk distance more than revascularization alone at 6-month follow-up (Primary Aim #1). Second, that nitrate-rich beetroot juice combined with lower extremity revascularization will improve six-minute walk, compared to placebo combined with revascularization at 6-month follow-up (Primary Aim #2).

Detailed description: More than 300,000 surgical or endovascular lower extremity revascularization procedures are performed annually for Medicare beneficiaries who have lower extremity peripheral artery disease (PAD) without limb threatening ischemia, and rates of these procedures are increasing. In these patients, revascularization typically improves, but does not eliminate, PAD related walking impairment. Lower extremity revascularization combined with supervised exercise significantly improves walking performance compared to revascularization alone in people who have PAD without limb threatening ischemia. However, supervised exercise is inaccessible or burdensome for most PAD patients. We hypothesize that home-based exercise combined with lower extremity revascularization will significantly improve walking performance compared to revascularization alone in patients with PAD undergoing revascularization for disabling PAD.

We further hypothesize that inorganic nitrate, a major source of nitric oxide (NO) abundant in beetroot juice, will improve walking performance after lower extremity revascularization, compared to placebo. In preclinical models, NO inhibits inflammation, neointimal hyperplasia, thrombosis, and vascular smooth muscle cell migration at sites of revascularization. NO increases angiogenesis and perfusion, repairs skeletal muscle damaged by ischemia, and stimulates mitochondrial activity. A large body of evidence, assembled over more than 25 years, supports our hypothesis that inorganic nitrate (such as that in nitrate-rich beetroot juice) will improve walking performance and other lower extremity outcomes after lower extremity revascularization.

Effective, accessible, and safe therapies are needed to enhance the benefits and improve durability of lower extremity revascularization. Therefore, in a randomized clinical trial with a 2 x 2 factorial design, we will test the following two primary hypotheses in 386 patients randomized within three months of a successful lower extremity revascularization for disabling PAD: First, that home-based exercise combined with lower extremity revascularization will improve six-minute walk distance more than revascularization alone at 6-month follow-up (Primary Aim #1). Second, that nitrate-rich beetroot juice combined with lower extremity revascularization will improve six-minute walk, compared to placebo combined with revascularization at 6-month follow-up (Primary Aim #2). In Secondary Aims, we will establish whether home-based exercise, compared to control, and whether nitrate-rich beetroot juice, compared to placebo, improve the Walking Impairment Questionnaire and the PROMIS Mobility Questionnaire and prevent hemodynamic failure of the revascularized vessel. In exploratory aims, we will test the effects of the interventions on plasma nitric oxide bioavailability. If our hypotheses are correct, results of this trial will have a major impact on improving mobility in the large and growing number of people undergoing revascularization for disabling PAD.

Eligibility criteria: Inclusion Criteria:

Successful lower extremity revascularization for disabling PAD performed at least 30 days before baseline testing and between 30 and 100 days before randomization.

Exclusion Criteria:

1. History of leg amputation, not including toe and partial foot amputation
2. Active gangrene
3. Active limb threatening ischemia
4. Already exercising at a level consistent with exercise intervention, using investigator discretion.
5. Unstable angina
6. Unwilling to drink study beverages
7. Unwilling to adhere to the interventions and complete follow-up testing
8. Currently taking sildenafil, tadalafil, or related drugs.
9. Unwilling to accept randomization into either group (home-based exercise or attention control)
10. Currently consuming beetroot juice, oral nitrate or nitrite, or a beetroot supplement and/or unwilling to avoid beetroot juice during the study. Participants will be asked to discontinue these items for 30 days before baseline testing and throughout the clinical trial. If the potential participant is unwilling to refrain from taking these items, they will not be eligible for the clinical trial.
11. History of kidney stones that requires minimized intake of oxalate. Potential participants who need to minimize oxalate intake will be excluded from the trial.
12. Baseline blood pressure \<100/45.
13. Wheelchair confinement or requiring a walker to ambulate
14. Walking is limited by a condition other than PAD
15. Current foot ulcer
16. Planned major surgery, coronary revascularization, or lower extremity revascularization during the next 12 months
17. Major medical illness including lung disease requiring oxygen, Parkinson's disease, or a life-threatening illness with life expectancy less than six months.
18. Allergy to beetroot juice
19. Currently consuming one cup or more of beets daily. Participants will be asked to decrease beet consumption to less than one cup of beets per day for 14 days before baseline testing and throughout the clinical trial. If the potential participant is unwilling to refrain from daily beet consumption of one cup or more for 30 days before the trial and during the trial, they will not be eligible for the clinical trial.
20. Participation in or completion of a clinical trial in the previous three months, using investigator discretion for trials that may not impact study participation or outcome measures of the IMPACT PAD Trial.
21. Visual impairment that limits walking ability.
22. Unable to communicate in English, unless the participant communicates in Spanish and is enrolled at a site that can deliver the intervention in Spanish. All sites with a Spanish speaking coordinator and interventionist will be able to enroll Spanish-speaking participants. While investigators aim to be as inclusive as possible, resources are not available to allow inclusion of people speaking languages that are not Spanish or English.
23. Using a mouthwash containing chlorhexidine or cetylpyridinium chloride or a mouthwash determined to be bactericidal and unwilling to discontinue.
24. Planning to begin a supervised treadmill exercise program in the next 12 months.
25. Heart attack or stroke in previous three months prior to baseline testing.
26. 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.

Primary outcomes:
measure: Six-Minute Walk Distance 6-month change
timeFrame: Baseline to 6-month follow-up
Secondary outcomes:
measure: Walking Impairment Questionnaire (WIQ) Distance Score 6-month change
timeFrame: Baseline to 6-month follow-up.
measure: Walking Impairment Questionnaire (WIQ) Distance Score 12-month change
timeFrame: Baseline to 12-month follow-up
measure: PROMIS Mobility Questionnaire Score 6-month change
timeFrame: Baseline to 6-month follow-up
measure: PROMIS Mobility Questionnaire Score 12-month change
timeFrame: Baseline to 12-month follow-up.
measure: Prevention of Hemodynamic Failure of The Revascularized Vessel
timeFrame: Baseline to 12 month follow-up
measure: Change in 6-minute walk distance
timeFrame: 12 month follow-up
Other outcomes:
measure: Six-Minute Walk Distance
timeFrame: Baseline to six-month follow-up at the time point that is twenty-four hours after the final study drink
measure: Plasma Nitrite Levels
timeFrame: Baseline to 6-month follow-up
measure: BH4/BH2 6-month change
timeFrame: Baseline to 6-month follow-up
measure: Progression of PAD
timeFrame: Baseline to 12-month follow-up
Locations:
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: Downey
country: United States
facility: Rancho Research Institute
state: California
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Chicago
country: United States
facility: Northwestern University Feinberg School of Medicine
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center
state: New Hampshire
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
Study officials:
References: