Peripheral Artery DiseasePhase 2RESISTNCT06657976
Response to Exercise and Nitric Oxide in PAD
A Phase 2 study testing Supervised Treadmill Exercise and Nitrate-Rich Beetroot Juice + supervised exercise therapy in people with Peripheral Artery Disease and Exercise, run by Northwestern University at 2 sites in United States.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 50 years and older
- Conditions the study is for
- Peripheral Artery Disease, Exercise, Intermittent Claudication
- What is being tested?
- Supervised Treadmill Exercise and Nitrate-Rich Beetroot Juice + supervised exercise therapy
- Type of treatment
- Lifestyle or therapy programme
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 200 participants
- Where
- 2 sitesUnited States
- Study dates
- 23 Jan 2025to 1 Oct 2029
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 50 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- An ABI less than or equal to 0.90 at baseline.
- Vascular lab evidence of PAD (such as a toe brachial pressure less than or equal to 0.70 or an ankle brachial index less than or equal to 0.90), or angiographic evidence of PAD defined as at least 70% stenosis of an artery supplying the lower extremities.
- An ABI of more than 0.90 and less than 1.00 who experience a 20% or greater drop in ABI in either leg after the heel-rise test.
Who cannot join
- Above- or below-knee amputation
- Limb-threatening ischemia defined as an ABI less than 0.40 with symptoms of rest pain
- Wheelchair confinement or requiring a walker to ambulate
- Walking is limited by a condition other than PAD
- Current foot ulcer on bottom of foot
- Failure to complete study-run
Show all 26Show fewer
- Unwilling to accept randomization into either group (supervised exercise or attention control)
- Planning to engage in new walking exercise outside of the study or unwilling to refrain from new walking exercise activity during the trial.
- Already exercising at a level consistent with exercise intervention, using investigator discretion.
- End-stage kidney disease (ESKD) that is treated with hemodialysis.
- Planned major surgery, coronary or leg revascularization during the next six months
- Major surgery, coronary or leg revascularization or major cardiovascular event in the previous three months
- Major medical illness including 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 require oxygen only at night may still qualify.]
- Mini-Mental Status Examination (MMSE) score less than 23 or dementia. If the MMSE is less than 23 and the Principal Investigator evaluation determines that the lower score is related to language barriers or education level, the Principal Investigator has discretion to allow a participant with MMSE less than 23 to participate, as appropriate. Dementia with sufficient impairment to prevent full engagement in all aspects of the trial will be an exclusion per the investigator's discretion.
- Allergy to beetroot juice
- 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 14 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.
- Currently consuming one cup or more of beets daily. Participants will be asked to discontinue beet ingestion of one cup or more of beets for 30 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.
- Unstable angina
- Abnormal baseline stress test without subsequent clearance for exercise by physician
- Non-English speaking. The RESIST PAD interventions are delivered by interventionists who do not speak non-English languages. The integrity of the clinical trial requires clear and effective communication for data collection and intervention delivery. The trial does not have staff members who are fluent in non-English languages nor does it have the ability to translate all study materials into other languages.
- 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.] Participants in a study that involved up to three single doses of nitrate-rich beetroot juice administered on separate days may participate if a month has passed since their last dose of nitrate-rich beetroot juice.
- Visual impairment that limits walking ability.
- Baseline blood pressure less than 100/45.
- Participation in a supervised treadmill exercise program in previous three months or planning to begin a supervised treadmill exercise program in the next six months.
- History of kidney stones that requires minimized intake of oxalate. Potential participants who need to minimize oxalate intake will be excluded from the trial.
- 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.
Trial locations and contacts
2 sites in 1 country. Contact the study team or a site near you to ask about taking part.
United States2 sites, 2 recruiting
- Recruiting
Northwestern University Feinberg School of Medicine
Chicago, Illinois, 60611
Kathryn Domanchuk, 312-503-6438, k-domanchuk@northwestern.edu
Mary M McDermott, MD
- Not yet recruiting
University of Chicago
Chicago, Illinois, 60637
Tamar Polonsky, MD, 773-702-6153, tpolonsky@bsd.uchicago.edu
Tamar Polonsky, MD
About this study
Official title: Response to Exercise and Nitric Oxide in Peripheral Artery Disease: The RESIST PAD 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.
Read the detailed description
Walking exercise is the only highly effective medical therapy for improving walking impairment in people disabled by lower extremity peripheral artery disease (PAD). However, approximately 45% of people with PAD do not meaningfully improve after an exercise intervention. Biologic pathways that mediate exercise response and biologic pathways that explain exercise non-response in PAD are unknown. Based on preliminary evidence, it is hypothesized that in PAD, exercise-induced arterial shear stress stimulates nitric oxide synthase (NOS) activity to increase nitric oxide bioavailability and improve leg perfusion, skeletal muscle mitochondrial activity, and walking ability. It is further hypothesized that exercise increases plasma nitric oxide during exercise in "responders" but does not meaningfully increase nitric oxide during exercise in "non-responders".
RESIST PAD is a randomized trial of 200 PAD patients that will 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.
- Being tested
- Supervised Treadmill Exercise, Attention Control, Nitrate-Rich Beetroot Juice + supervised exercise therapy, Placebo + supervised exercise therapy
- Keywords
- Peripheral artery disease, Claudication, Walking difficulty
- Medical subject headings
- Peripheral Arterial Disease, Motor Activity, Intermittent Claudication, Mobility Limitation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Supervised Treadmill ExerciseBehavioural
Also called Supervised Exercise Therapy
This is a 12 week intervention where participants will walk for exercise 3 times a week on a treadmill at a center while being supervised by healthcare personnel.
Attention ControlBehavioural
Also called Control
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.
Nitrate-Rich Beetroot Juice + supervised exercise therapyCombination product
Participants randomized to this group will drink nitrate-rich beetroot juice while engaged in supervised exercise.
Placebo + supervised exercise therapyCombination product
Participants randomized to this group will drink placebo while engaged in supervised exercise.
| Study group | Role | What they receive |
|---|---|---|
| Supervised Treadmill Exercise | Experimental | 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. Receives: Behavioral: Supervised Treadmill Exercise |
| Attention Control Group | Sham comparator | 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. Receives: Behavioral: Attention Control |
| Exercise Supplementation with Nitrate-Rich Beetroot Juice | Experimental | This group for "non-responders" will receive supervised exercise supplementation with nitrate-rich beetroot juice for an additional 12 weeks. Receives: Combination Product: Nitrate-Rich Beetroot Juice + supervised exercise therapy |
| Exercise Supplementation with Placebo Beetroot Juice | Placebo comparator | This group for "non-responders" will received supervised exercise supplementation with placebo beetroot juice for the additional 12 weeks. Receives: Combination Product: Placebo + supervised exercise therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Delta nitrite
Change in plasma nitrite from the beginning to the end of a maximal exercise stress test
Measured: Baseline to 12-week follow-up
Six-minute walk
Change in six-minute walk distance
Measured: From 12-weeks to 24-week follow-up
Secondary outcomes (5)
Calf muscle perfusion
Change in calf muscle perfusion, measured with arterial spin labeling MRI
Measured: Baseline to 12-week follow-up
Calf muscle perfusion
Change in calf muscle perfusion, measured with arterial spin labeling MRI
Measured: From 12-weeks to 24-week follow-up
Brachial artery flow-mediated dilation (FMD)
Change in brachial artery diameter in response to post-cuff occlusion hyperemia
Measured: Baseline to 12-week follow-up
Brachial artery flow-mediated dilation (FMD)
Change in brachial artery diameter in response to post-cuff occlusion hyperemia
Measured: From 12 weeks to 24-week follow-up
Delta nitrite
Change in plasma nitrite between the beginning and end of an exercise stress test.
Measured: From 12 weeks to 24-week follow-up
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Oct 2024
- Study start23 Jan 2025
- Primary completion1 Jul 2029 (estimated)
- Study completion1 Oct 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Peripheral Artery DiseaseStudies of the same condition, open and under way.
- More trials run by Northwestern UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 200 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Northwestern University
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute on Aging (NIA)
- Responsible party
- Principal investigator, Mary McDermott, Northwestern University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06657976
- Sponsor's protocol ID
- STU00220419
- Acronym
- RESIST
- Status last verified
- Jul 2026
- First submitted
- 23 Oct 2024
- Last updated
- 27 Jul 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
McDermott MM, Cetlin MD, Domanchuk KJ, Xu S, Whipple MO, Polonsky T, Criqui MH, Guralnik JM, Tian L, Zhao L, Ho KJ, Greenland P, Treat-Jacobson D. Community-based recruitment with ankle brachial index testing to identify peripheral artery disease participants for randomized clinical trials. Am Heart J. 2026 Oct;300:107450. doi: 10.1016/j.ahj.2026.107450. Epub 2026 Apr 24.
PubMed 42035974
Study at a glance
From the registry record, last updated by the sponsor on 27 Jul 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Response to Exercise and Nitric Oxide in Peripheral Artery Disease: The RESIST PAD Trial
- ClinicalTrials.gov ID
- NCT06657976
- Acronym / sponsor ID
- RESIST / STU00220419
- Keywords
- Peripheral artery disease, Claudication, Walking difficulty
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 200 participants (estimated)
- Lead sponsor
- Northwestern UniversityUniversity, hospital or other
- Collaborators
- National Institute on Aging (NIA)
- Study start
- 23 Jan 2025 (actual)
- Primary completion
- 1 Jul 2029 (estimated)
- Study completion
- 1 Oct 2029 (estimated)
- First posted
- 26 Oct 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Walking exercise is the only highly effective medical therapy for improving walking impairment in people disabled by lower extremity peripheral artery disease (PAD). However, approximately 45% of people with PAD do not meaningfully improve after an exercise intervention. Biologic pathways that mediate exercise response and biologic pathways that explain exercise non-response in PAD are unknown. Based on preliminary evidence, it is hypothesized that in PAD, exercise-induced arterial shear stress stimulates nitric oxide synthase (NOS) activity to increase nitric oxide bioavailability and improve leg perfusion, skeletal muscle mitochondrial activity, and walking ability. It is further hypothesized that exercise increases plasma nitric oxide during exercise in "responders" but does not meaningfully increase nitric oxide during exercise in "non-responders".
RESIST PAD is a randomized trial of 200 PAD patients that will 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Supervised Treadmill Exercise | Experimental | Behavioral: Supervised Treadmill ExerciseThis 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. |
| Attention Control Group | Sham comparator | Behavioral: Attention ControlThis 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. |
| Exercise Supplementation with Nitrate-Rich Beetroot Juice | Experimental | Combination Product: Nitrate-Rich Beetroot Juice + supervised exercise therapyThis group for "non-responders" will receive supervised exercise supplementation with nitrate-rich beetroot juice for an additional 12 weeks. |
| Exercise Supplementation with Placebo Beetroot Juice | Placebo comparator | Combination Product: Placebo + supervised exercise therapyThis group for "non-responders" will received supervised exercise supplementation with placebo beetroot juice for the additional 12 weeks. |
Who may qualify
- Ages
- 50 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- An ABI less than or equal to 0.90 at baseline.
- Vascular lab evidence of PAD (such as a toe brachial pressure less than or equal to 0.70 or an ankle brachial index less than or equal to 0.90), or angiographic evidence of PAD defined as at least 70% stenosis of an artery supplying the lower extremities.
- An ABI of more than 0.90 and less than 1.00 who experience a 20% or greater drop in ABI in either leg after the heel-rise test.
Key exclusion criteria (26 listed)
- Above- or below-knee amputation
- Limb-threatening ischemia defined as an ABI less than 0.40 with symptoms of rest pain
- Wheelchair confinement or requiring a walker to ambulate
- Walking is limited by a condition other than PAD
- Current foot ulcer on bottom of foot
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Supervised Treadmill ExerciseAlso: Supervised Exercise TherapyThis is a 12 week intervention where participants will walk for exercise 3 times a week on a treadmill at a center while being supervised by healthcare personnel. | Behavioural | Supervised Treadmill Exercise |
| Attention ControlAlso: ControlThis 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. | Behavioural | Attention Control Group |
| Nitrate-Rich Beetroot Juice + supervised exercise therapyParticipants randomized to this group will drink nitrate-rich beetroot juice while engaged in supervised exercise. | Combination product | Exercise Supplementation with Nitrate-Rich Beetroot Juice |
| Placebo + supervised exercise therapyParticipants randomized to this group will drink placebo while engaged in supervised exercise. | Combination product | Exercise Supplementation with Placebo Beetroot Juice |
Primary outcome
Delta nitrite
Time frame: Baseline to 12-week follow-up
Change in plasma nitrite from the beginning to the end of a maximal exercise stress test
Six-minute walk
Time frame: From 12-weeks to 24-week follow-up
Change in six-minute walk distance
5 secondary outcomes
Calf muscle perfusion
Time frame: Baseline to 12-week follow-up
Calf muscle perfusion
Time frame: From 12-weeks to 24-week follow-up
Brachial artery flow-mediated dilation (FMD)
Time frame: Baseline to 12-week follow-up
Brachial artery flow-mediated dilation (FMD)
Time frame: From 12 weeks to 24-week follow-up
Delta nitrite
Time frame: From 12 weeks to 24-week follow-up
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Jul 2026.
- Derived from this study: PubMed 42035974McDermott MM, Cetlin MD, Domanchuk KJ, Xu S, Whipple MO, Polonsky T, Criqui MH, Guralnik JM, Tian L, Zhao L, Ho KJ, Greenland P, Treat-Jacobson D. Community-based recruitment with ankle brachial index testing to identify peripheral artery disease participants for randomized clinical trials. Am Heart J. 2026 Oct;300:107450. doi: 10.1016/j.ahj.2026.107450. Epub 2026 Apr 24.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Supervised Treadmill Exercise and Nitrate-Rich Beetroot Juice + supervised exercise therapy in people with Peripheral Artery Disease and Exercise, run by Northwestern University at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 27 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Mary M McDermott, MD (312-503-6419, mdm608@northwestern.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Delta nitrite (time frame: Baseline to 12-week follow-up). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06657976, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Jul 2026.