Improving Mobility After Revascularization in Peripheral Artery Disease (IMPACT PAD)

IMProving Mobility After revasCularizaTion in Peripheral Artery Disease: The IMPACT PAD Trial

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. Investigators 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.

Investigators 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, the trial 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).

Study Overview

• Status: Recruiting
• Conditions: Intermittent Claudication; Peripheral Vascular Disease; Peripheral Artery Disease; Mobility Limitation; Revascularization
• Intervention / Treatment: Behavioral: Home Based Exercise; Drug: Nitrate Rich Beetroot Juice; Drug: Placebo Beetroot Juice Without Nitrate; Behavioral: Attention Control

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. Investigators 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.

Investigators 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, the trial 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, the trial 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, the trial 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.

• Study Type: Interventional
• Enrollment (Estimated): 386
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Mary M McDermott, MD; Phone Number: 312-503-6438; Email: mdm608@northwestern.edu

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • Not yet recruiting
      • University of Arizona
      • Contact: Wei Zhou, MD
  • California
    • Downey, California, United States, 90242
      • Recruiting
      • Rancho Research Institute
      • Contact: Tze-Woei Tan, MD
  • Georgia
    • Atlanta, Georgia, United States, 30307
      • Not yet recruiting
      • Emory University School of Medicine
      • Contact: Olamide Alabi, MD
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Recruiting
      • University of Chicago
      • Contact: Tamar Polonsky, MD; Phone Number: 773-702-6153
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Northwestern University Feinberg School of Medicine
      • Principal Investigator: Mary M McDermott, MD
      • Contact: Kathryn Domanchuk, BS; Phone Number: 312-503-6438; Email: k-domanchuk@northwestern.edu
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03766
      • Not yet recruiting
      • Dartmouth Hitchcock Medical Center
      • Contact: Philip P Goodney, MD
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Not yet recruiting
      • University of Pittsburgh
      • Contact: Ulka Sachdev, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Home based exercise + nitrate rich beetroot juice; This group will be participating in home based exercise and drinking nitrate rich beetroot juice for six months.	Behavioral: Home Based Exercise; This is a six month intervention where participants will walk at home for exercise with guidance from a study coach. They will attend two to four weekly meetings with the coach at the clinical site in the first 4 weeks following randomization, followed by once weekly telephone coaching calls for the remainder of the six-month intervention; Drug: Nitrate Rich Beetroot Juice; Participants will drink one shot of nitrate rich beet-root juice twice daily for six months.
Placebo Comparator: Home-based exercise + placebo; This group will be participating in home based exercise and drinking placebo beetroot juice with nitrate removed for six months.	Behavioral: Home Based Exercise; This is a six month intervention where participants will walk at home for exercise with guidance from a study coach. They will attend two to four weekly meetings with the coach at the clinical site in the first 4 weeks following randomization, followed by once weekly telephone coaching calls for the remainder of the six-month intervention; Drug: Placebo Beetroot Juice Without Nitrate; Participants will drink one shot of placebo beetroot without nitrate juice twice daily for six months.
Experimental: Attention control + nitrate-rich beetroot juice; This group will be participating in attention control and drinking nitrate rich beetroot juice for six months.	Drug: Nitrate Rich Beetroot Juice; Participants will drink one shot of nitrate rich beet-root juice twice daily for six months.; Behavioral: Attention Control; Participants will be asked to participate in weekly meetings with the coach in the attention control group for weeks 1-26. A staff member will present a topic from the National Institute on Aging "age pages" relevant to health, such as cancer screening or blood pressure treatment. Calls will last approximately 5-15 minutes and will focus on educational topics such as diabetes, healthy eating, and Medicare Part D.
Placebo Comparator: Attention control + placebo; This group will be participating in attention control and drinking placebo beetroot juice with nitrate removed for six months.	Drug: Placebo Beetroot Juice Without Nitrate; Participants will drink one shot of placebo beetroot without nitrate juice twice daily for six months.; Behavioral: Attention Control; Participants will be asked to participate in weekly meetings with the coach in the attention control group for weeks 1-26. A staff member will present a topic from the National Institute on Aging "age pages" relevant to health, such as cancer screening or blood pressure treatment. Calls will last approximately 5-15 minutes and will focus on educational topics such as diabetes, healthy eating, and Medicare Part D.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Six-Minute Walk Distance 6-month change	Distance walked in six minutes	Baseline to 6-month follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Walking Impairment Questionnaire (WIQ) Distance Score 6-month change	Patient reported ability to walk long distances. Score Range 0-100, 100 is best.	Baseline to 6-month follow-up.
Walking Impairment Questionnaire (WIQ) Distance Score 12-month change	Patient reported ability to walk long distances. Score Range 0-100, 100 is best.	Baseline to 12-month follow-up
PROMIS Mobility Questionnaire Score 6-month change	Patient report of mobility in daily living. Score range is from zero to infinity and a higher score means a better outcome.	Baseline to 6-month follow-up
PROMIS Mobility Questionnaire Score 12-month change	Patient report of mobility in daily living. Score range is from zero to infinity and a higher score means a better outcome.	Baseline to 12-month follow-up.
Prevention of Hemodynamic Failure of The Revascularized Vessel	Hemodynamic failure consists of loss of patency of the revascularized vessel. The outcome will be adjudicated as a categorical outcome. Medical records between randomization and final follow-up will be obtained and reviewed by the IMPACT PAD adjudication committee, consisting of field center investigators and an interventional cardiologist. Participants who meet pre-defined criteria for hemodynamic failure of the revascularized vessel.	Baseline to 12 month follow-up
Change in 6-minute walk distance	Change in 6-minute walk distance between baseline and 12-month follow-up	12 month follow-up

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
BH4/BH2 6-month change	Change in BH4/BH2 ratio	Baseline to 6-month follow-up
Six-Minute Walk Distance	Change in six-minute walk distance 24 hours after the final study beverage	Baseline to six-month follow-up at the time point that is twenty-four hours after the final study drink
Plasma Nitrite Levels	Change in plasma nitrite levels in the blood at 6-month follow-up	Baseline to 6-month follow-up
Progression of PAD	Determine whether home-based walking exercise, compared to attention control prevents progression of PAD, defined by any new lower extremity revascularization, acute limb ischemia, or amputation of either lower extremity between baseline and 12-month follow-up.	Baseline to 12-month follow-up

Collaborators and Investigators

• Sponsor: Northwestern University
• Collaborators: University of Chicago; Emory University; Dartmouth-Hitchcock Medical Center; University of Arizona; University of Pittsburgh Medical Center; Wake Forest University; Rancho Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): August 4, 2025
• Primary Completion (Estimated): February 1, 2032
• Study Completion (Estimated): August 1, 2032

Study Registration Dates

• First Submitted: November 8, 2024
• First Submitted That Met QC Criteria: November 12, 2024
• First Posted (Actual): November 13, 2024

Study Record Updates

• Last Update Posted (Estimated): August 26, 2025
• Last Update Submitted That Met QC Criteria: August 23, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: Oxidative stress; Revascularization; Mobility; Peripheral artery disease; Behavior Change; Patient Reported Outcome Measures; 6-minute walk; Intermittent claudication
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Atherosclerosis; Arteriosclerosis; Arterial Occlusive Diseases; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Peripheral Arterial Disease; Mobility Limitation; Peripheral Vascular Diseases; Intermittent Claudication; Organic Chemicals; Inorganic Chemicals; Nitrogen Compounds; Anions; Ions; Electrolytes; Nitric Acid; Nitrates
• Other Study ID Numbers: STU00222333

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Time Frame: Data will be available at the time the primary outcome manuscript is submitted for publication and will be available for up to 10 years.
• IPD Sharing Access Criteria: Per BioLINCC
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No