Exercise and Beetroot Juice for Peripheral Artery Disease

(RESIST Trial)

Recruiting at 1 trial location

Overseen By Kathryn Domanchuk, BS

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Northwestern University

Must not be taking: Oral nitrates, Beetroot supplements

Disqualifiers: Amputation, Ischemia, Ulcer, ESKD, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: 12 weeks

200 Participants Needed

Trial Summary

What is the purpose of this trial?

RESIST PAD is a randomized trial of 200 PAD patients to establish: 1) whether a 12-week exercise intervention significantly increases Δ nitrite at 12-week follow-up, compared to control; 2) whether exercise "responders" have greater Δ nitrite increases compared to "non-responders"; 3) among non-responders, whether supplementing exercise with nitrate-rich beetroot juice between weeks 13-24 increases Δ nitrite and improves 6-minute walk at 24-week follow-up.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must stop consuming beetroot juice, oral nitrate or nitrite, and beetroot supplements for 30 days before the trial and throughout the study.

What data supports the effectiveness of the treatment Nitrate-Rich Beetroot Juice + supervised exercise therapy for Peripheral Artery Disease?

Research shows that supervised exercise therapy (SET) improves walking ability in people with peripheral artery disease (PAD), and supervised treadmill-walking training enhances walking capacity and calf-muscle strength. These findings suggest that combining exercise with treatments like beetroot juice, which is known for its potential cardiovascular benefits, could be effective for PAD. ^{1 2 3 4 5}

Is supervised exercise therapy safe for people with peripheral artery disease?

Supervised exercise therapy (SET) is generally considered safe for people with peripheral artery disease, although there are concerns about cardiovascular risks. Guidelines recommend cardiac exercise testing before starting SET to ensure safety. ^{1 6 7 8 9}

How is supervised treadmill exercise different from other treatments for peripheral artery disease?

Supervised treadmill exercise (SET) is unique because it specifically focuses on improving walking capacity and calf muscle strength through guided walking sessions, which is different from other treatments like home-based exercise or surgical options. It involves regular, structured exercise sessions under professional supervision, which can enhance endurance and quality of life for patients with peripheral artery disease. ^{1 4 5 10 11}

Eligibility Criteria

This trial is for individuals with Peripheral Arterial Disease (PAD), specifically those who experience intermittent claudication, which is muscle pain during exercise due to poor blood flow. Participants should be able to perform treadmill exercises and have not been involved in regular exercise programs recently.

Inclusion Criteria

My ABI score drops significantly after a physical leg test.

An ABI less than or equal to 0.90 at baseline

I have been diagnosed with PAD based on vascular tests or angiography.

Exclusion Criteria

Abnormal baseline stress test without subsequent clearance for exercise by physician

I am not planning any major surgery or heart/leg artery procedures in the next 6 months.

I have a current foot ulcer on the bottom of my foot.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo a 12-week supervised treadmill exercise program or attend educational sessions

12 weeks

3 visits per week (in-person) for exercise group; 1 visit per week (in-person or virtual) for control group

Supplementation

Non-responders receive an additional 12 weeks of exercise with either nitrate-rich or placebo beetroot juice

12 weeks

3 visits per week (in-person)

Follow-up

Participants are monitored for changes in six-minute walk distance and other biomarkers

12 weeks

Treatment Details

Interventions

• Nitrate-Rich Beetroot Juice + supervised exercise therapy
• Placebo + supervised exercise therapy
• Supervised Treadmill Exercise

Trial Overview The RESIST PAD study tests if a 12-week supervised treadmill exercise program can increase nitric oxide levels compared to a control group. It also examines if adding nitrate-rich beetroot juice enhances benefits for those who don't initially respond well to the exercise alone.

Participant Groups

Group I: Supervised Treadmill Exercise Experimental Treatment 1 Intervention

This group will be participating in supervised treadmill exercise for 12 weeks. Participants will walk for exercise on a treadmill 3 times per week at a center while supervised by healthcare personnel.

Group II: Exercise Supplementation with Nitrate-Rich Beetroot Juice Experimental Treatment 1 Intervention

This group for "non-responders" will receive supervised exercise supplementation with nitrate-rich beetroot juice for an additional 12 weeks.

Group III: Exercise Supplementation with Placebo Beetroot Juice Placebo Group 1 Intervention

This group for "non-responders" will received supervised exercise supplementation with placebo beetroot juice for the additional 12 weeks.

Group IV: Attention Control Group Placebo Group 1 Intervention

This group will attend weekly one-hour educational sessions either on Zoom or in-person for 12 weeks. These sessions are on topics of interest to the typical PAD patient and may be led by study staff, physicians, or other health care workers.

Supervised Treadmill Exercise is already approved in United States, European Union for the following indications:

Approved in United States as Supervised Exercise Therapy (SET) for:

• Lower Extremity Peripheral Artery Disease (PAD)

Approved in European Union as Supervised Exercise Therapy (SET) for:

• Lower Extremity Peripheral Artery Disease (PAD)

Who Is Running the Clinical Trial?

Northwestern University

Lead Sponsor

Trials

1,674

Recruited

989,000+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Findings from Research

In a study of 210 participants with peripheral artery disease (PAD), a 6-month supervised exercise therapy (SET) program significantly reduced systolic blood pressure by 12 mm Hg, pulse pressure by 9 mm Hg, and heart rate by 7 beats per minute during exercise compared to a control group.

The improvements in cardiovascular health metrics (blood pressure and heart rate) were associated with better walking performance, indicating that SET not only enhances walking ability but also positively impacts cardiovascular health in individuals with PAD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of supervised exercise therapy on blood pressure and heart rate during exercise, and associations with improved walking performance in peripheral artery disease: Results of a randomized clinical trial. Slysz, JT., Tian, L., Zhao, L., et al.[2021]

Only 30.4% of vascular surgeons reported access to supervised exercise programs (SEPs) for managing peripheral arterial disease (PAD), highlighting a significant accessibility issue.

Structured home-based exercise programs (HEPs) were found to be effective alternatives, significantly improving functional capacity and quality of life compared to standard advice, although SEPs were superior in some cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Availability of supervised exercise programs and the role of structured home-based exercise in peripheral arterial disease. Makris, GC., Lattimer, CR., Lavida, A., et al.[2018]

The Group Oriented Arterial Leg Study (GOALS) is a randomized controlled trial aimed at improving walking performance in individuals with lower extremity peripheral artery disease (PAD) through a Group-Mediated Cognitive Behavioral (GMCB) intervention, which encourages home-based walking exercises.

The primary outcome of the study is the change in six-minute walk performance after 6 months, with potential significant public health implications if the intervention proves effective in enhancing functional performance in PAD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Group Oriented Arterial Leg Study (GOALS) to improve walking performance in patients with peripheral arterial disease. McDermott, MM., Domanchuk, K., Liu, K., et al.[2021]

PoleStriding exercise significantly improved exercise tolerance and reduced claudication pain in patients with peripheral arterial disease (PAD), as shown by a randomized trial with 52 participants.

Vitamin E supplementation did not provide any additional benefits in terms of pain relief or exercise capacity compared to the PoleStriding exercise alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PoleStriding exercise and vitamin E for management of peripheral vascular disease. Collins, EG., Edwin Langbein, W., Orebaugh, C., et al.[2022]

A 12-week supervised treadmill-walking program significantly improved calf-muscle strength and endurance in 22 individuals with peripheral arterial disease (PAD), indicating its effectiveness as a treatment.

The study also found that improvements in calf-muscle endurance were correlated with enhanced walking capacity, suggesting that strengthening these muscles can help individuals with PAD walk better.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of supervised treadmill-walking training on strength and endurance of the calf muscles of individuals with peripheral arterial disease. Wang, J., Zhou, S., Bronks, R., et al.[2006]

In a study of 63 patients with peripheral artery disease (PAD) undergoing a 6-month supervised exercise therapy (SET) program, an increase in walking speed of 0.03 m/s or greater was identified as the minimal clinically important difference (MCID), indicating meaningful improvement in walking ability.

The study established specific thresholds for small and substantial improvements in walking speed, which can help clinicians set realistic goals and assess progress in claudicating patients with PAD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Claudicating patients with peripheral artery disease have meaningful improvement in walking speed after supervised exercise therapy. Rahman, H., Pipinos, II., Johanning, JM., et al.[2022]

Supervised exercise therapy (SET) has been effectively integrated into cardiopulmonary rehabilitation programs over a 3-year period, demonstrating its potential to improve walking distance for patients with symptomatic peripheral artery disease (PAD).

The recent decision by the Centers for Medicare and Medicaid to cover SET could significantly enhance its adoption in clinical practice, providing a structured approach for rehabilitation therapists to implement SET in their programs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experience Implementing Supervised Exercise Therapy for Peripheral Artery Disease. Salisbury, DL., Whipple, MO., Burt, M., et al.[2022]

Supervised exercise therapy (SET) for patients with intermittent claudication (IC) is very safe, with only eight adverse events reported over 82,725 hours of training, resulting in a complication rate of just one event per 10,340 patient-hours.

The study suggests that routine cardiac screening before starting SET is unnecessary, which may encourage more healthcare providers to recommend this effective treatment for IC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of supervised exercise therapy in patients with intermittent claudication. Gommans, LN., Fokkenrood, HJ., van Dalen, HC., et al.[2022]

A survey of 91 Dutch vascular surgeons revealed that 75.4% would refer newly diagnosed patients with intermittent claudication for supervised exercise therapy (SET), indicating a strong belief in its importance as a treatment for peripheral arterial occlusive disease (PAOD).

Surgeons expressed that SET should be combined with lifestyle management and emphasized that despite its recognized benefits, SET is underutilized in clinical practice, particularly for patients with co-morbidities or significant artery stenosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

When is supervised exercise therapy considered useful in peripheral arterial occlusive disease? A nationwide survey among vascular surgeons. Lauret, GJ., van Dalen, HC., Hendriks, HJ., et al.[2018]

A supervised exercise therapy (SET) program for patients with intermittent claudication showed a 20% improvement in walking distance, increasing from an average of 298.5 meters to 360 meters, based on a study involving 155 patients over nearly two years.

The program is cost-effective compared to traditional physiotherapy and is designed to be accessible, with efforts made to increase participation through additional classes and venues, demonstrating the potential for successful implementation of community-based health interventions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Implementation of a supervised exercise therapy programme. Murgitroyd, E., Fraser, S., Hebson, A., et al.[2020]

Supervised exercise therapy (SET) significantly increases daily physical activity in patients with intermittent claudication (IC), with an average increase of about 803 steps per day compared to usual care.

Home-based exercise therapy (HBET) also shows a positive effect on physical activity, with an increase of approximately 980 steps per day, while endovascular revascularization (ER) did not demonstrate a statistically significant improvement over control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effect of Supervised Exercise, Home Based Exercise and Endovascular Revascularisation on Physical Activity in Patients With Intermittent Claudication: A Network Meta-analysis. van den Houten, MML., Hageman, D., Gommans, LNM., et al.[2020]

References

1. United States pubmed.ncbi.nlm.nih.gov

Effects of supervised exercise therapy on blood pressure and heart rate during exercise, and associations with improved walking performance in peripheral artery disease: Results of a randomized clinical trial. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Availability of supervised exercise programs and the role of structured home-based exercise in peripheral arterial disease. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

The Group Oriented Arterial Leg Study (GOALS) to improve walking performance in patients with peripheral arterial disease. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

PoleStriding exercise and vitamin E for management of peripheral vascular disease. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Effects of supervised treadmill-walking training on strength and endurance of the calf muscles of individuals with peripheral arterial disease. [2006]

6. United States pubmed.ncbi.nlm.nih.gov

Claudicating patients with peripheral artery disease have meaningful improvement in walking speed after supervised exercise therapy. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Experience Implementing Supervised Exercise Therapy for Peripheral Artery Disease. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Safety of supervised exercise therapy in patients with intermittent claudication. [2022]

9. England pubmed.ncbi.nlm.nih.gov

When is supervised exercise therapy considered useful in peripheral arterial occlusive disease? A nationwide survey among vascular surgeons. [2018]

10. England pubmed.ncbi.nlm.nih.gov

Implementation of a supervised exercise therapy programme. [2020]

11. England pubmed.ncbi.nlm.nih.gov

The Effect of Supervised Exercise, Home Based Exercise and Endovascular Revascularisation on Physical Activity in Patients With Intermittent Claudication: A Network Meta-analysis. [2020]