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RecruitingNCT06657976RESISTUpdated Jul 27, 2026

Response to Exercise and Nitric Oxide in PAD

A Phase 2 interventional study of Supervised Treadmill Exercise and Attention Control in Peripheral Artery Disease, Exercise and Intermittent Claudication, sponsored by Northwestern University. Recruiting at 2 sites in United States. Open to participants aged 50 Years and older. Per ClinicalTrials.gov, last updated 2026-07-27.

Primary conditionIntermittent ClaudicationRegistry: Peripheral Arterial DiseaseReclassifiedWhy we changed it
Registry
Peripheral Arterial Disease — the first condition term the registry derived for this study.
ClinicalTrials.gg
Intermittent Claudication
Why
  1. The study's listed conditions name Intermittent Claudication, a narrower term within Peripheral Arterial Disease.
Confidence
High: the new condition is named in the study's own listed conditions. Of 351 hand-checked studies reclassified this way, 68% were exactly right and 84% in the right disease family; the registry's first term was right for 5% (measured 2026-10-21). How we classify →
Wrong?
Tell us the study's main condition →

Sponsored by Northwestern University · Phase 2, Interventional, and Treatment

From the registry’s dates

  • Started Jan 2025; still recruiting 1 year 9 months later.
Phase
Phase 2
Study type
Interventional
Enrollment
200
Allocation
Randomized
Ages
50 Years and older
Sex
All
01

Study 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 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.

02

Conditions studied

  • Peripheral Artery Disease
  • Exercise
  • Intermittent Claudication
  • Nitric Oxide

Keywords

  • Peripheral artery disease
  • Claudication
  • Walking difficulty
03

In context

Intermittent Claudication Reclassified

309 studies on the registry are indexed under Intermittent Claudication; 46 are open to participants now.

This study's planned enrollment of 200 is above the median of 74 across 242 interventional studies indexed under Intermittent Claudication.

Browse Intermittent Claudication studies →

Lead sponsor

Northwestern University is the lead sponsor of 1,423 studies on the registry; 198 are open to participants now.

Of its 105 completed or terminated interventional studies of FDA-regulated products, 78 (74%) have results posted.

Browse Northwestern University studies →

Compared within Intermittent Claudication, this study's primary condition as ClinicalTrials.gg classifies it; the registry's first condition term is Peripheral Arterial Disease. The counts are of registry records indexed under each term, refreshed daily. How we classify →

04

Who can participate

Ages eligible
50 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

Inclusion criteria

  1. An ABI less than or equal to 0.90 at baseline.
  2. 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.
  3. 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.

Exclusion criteria

Exclusion Criteria:

  1. Above- or below-knee amputation
  2. Limb-threatening ischemia defined as an ABI less than 0.40 with symptoms of rest pain
  3. Wheelchair confinement or requiring a walker to ambulate
  4. Walking is limited by a condition other than PAD
  5. Current foot ulcer on bottom of foot
  6. Failure to complete study-run
  7. Unwilling to accept randomization into either group (supervised exercise or attention control)
  8. Planning to engage in new walking exercise outside of the study or unwilling to refrain from new walking exercise activity during the trial.
  9. Already exercising at a level consistent with exercise intervention, using investigator discretion.
  10. End-stage kidney disease (ESKD) that is treated with hemodialysis.
  11. Planned major surgery, coronary or leg revascularization during the next six months
  12. Major surgery, coronary or leg revascularization or major cardiovascular event in the previous three months
  13. Major medical illness including lung disease requiring oxygen, Parkinson's disease, a life-threatening illness with 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.]
  14. Mini-Mental Status Examination () 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.
  15. Allergy to beetroot juice
  16. 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.
  17. 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.
  18. Unstable angina
  19. Abnormal baseline stress test without subsequent clearance for exercise by physician
  20. 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.
  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.] 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.
  22. Visual impairment that limits walking ability.
  23. Baseline blood pressure less than 100/45.
  24. 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.
  25. History of kidney stones that requires minimized intake of oxalate. Potential participants who need to minimize oxalate intake will be excluded from the trial.
  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.
Terms in these criteria, in plain language(2)

Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.

Life expectancy

The study doctor’s estimate of how long someone is likely to live. Criteria use it so that people can stay in the study long enough for it to answer its question.

MMSE and MoCA

Short tests of memory and thinking, each scored out of 30. Lower scores suggest more difficulty; criteria give a range, either to include people with memory problems or to leave them out.

05

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
200 participants (estimated)

Study arms

  • Experimental
    Supervised Treadmill Exercise

    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.

    Behavioral: Supervised Treadmill Exercise

  • Sham comparator
    Attention Control Group

    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.

    Behavioral: Attention Control

  • Experimental
    Exercise Supplementation with Nitrate-Rich Beetroot Juice

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

    Combination Product: Nitrate-Rich Beetroot Juice + supervised exercise therapy

  • Placebo comparator
    Exercise Supplementation with Placebo Beetroot Juice

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

    Combination Product: Placebo + supervised exercise therapy

Interventions

  • BehavioralSupervised Treadmill Exercise

    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.

    Also known as: Supervised Exercise Therapy

  • BehavioralAttention 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.

    Also known as: Control

  • Combination productNitrate-Rich Beetroot Juice + supervised exercise therapy

    Participants randomized to this group will drink nitrate-rich beetroot juice while engaged in supervised exercise.

  • Combination productPlacebo + supervised exercise therapy

    Participants randomized to this group will drink placebo while engaged in supervised exercise.

06

What researchers measure

Primary outcomes

  1. Delta nitrite

    Change in plasma nitrite from the beginning to the end of a maximal exercise stress test

    Time frame: Baseline to 12-week follow-up

  2. Six-minute walk

    Change in six-minute walk distance

    Time frame: From 12-weeks to 24-week follow-up

Secondary outcomes

  1. Calf muscle perfusion

    Change in calf muscle perfusion, measured with arterial spin labeling MRI

    Time frame: Baseline to 12-week follow-up

  2. Calf muscle perfusion

    Change in calf muscle perfusion, measured with arterial spin labeling MRI

    Time frame: From 12-weeks to 24-week follow-up

  3. Brachial artery flow-mediated dilation (FMD)

    Change in brachial artery diameter in response to post-cuff occlusion hyperemia

    Time frame: Baseline to 12-week follow-up

  4. Brachial artery flow-mediated dilation (FMD)

    Change in brachial artery diameter in response to post-cuff occlusion hyperemia

    Time frame: From 12 weeks to 24-week follow-up

  5. Delta nitrite

    Change in plasma nitrite between the beginning and end of an exercise stress test.

    Time frame: From 12 weeks to 24-week follow-up

Other outcomes

  1. Dihydrobiopterin (BH2)

    Change in plasma levels of BH2

    Time frame: From baseline to 12-week follow-up

  2. Dihydrobiopterin (BH2)

    Change in plasma levels of BH2

    Time frame: From 12 week to 24-week follow-up

  3. Tetrahydrobiopterin (BH4)

    Change in plasma levels of BH4

    Time frame: From baseline to 12-week follow-up

  4. Tetrahydrobiopterin (BH4)

    Change in plasma levels of BH4

    Time frame: From 12 week to 24-week follow-up

  5. BH4/BH2

    Change in ratio of plasma levels of BH4 to plasma levels of BH2

    Time frame: From baseline to 12-week follow-up

  6. BH4/BH2

    Change in ratio of plasma levels of BH4 to plasma levels of BH2

    Time frame: From 12 week to 24-week follow-up

  7. Cyclic Guanosine Monophosphate (cGMP)

    Change in plasma levels of cGMP

    Time frame: From baseline to 12-week follow-up

  8. Cyclic Guanosine Monophosphate (cGMP)

    Change in plasma levels of cGMP

    Time frame: From 12 week to 24-week follow-up

  9. 4 hydroxynonenal (4HNE)

    Change in plasma levels of 4HNE

    Time frame: From baseline to 12-week follow-up

  10. 4 hydroxynonenal (4HNE)

    Change in plasma levels of 4HNE

    Time frame: From 12 week to 24-week follow-up

  11. Nitrite

    Change in gastrocnemius (calf) muscle levels of nitrite, obtained from participants who undergo gastrocnemius muscle biopsy

    Time frame: From baseline to 12-week follow-up

  12. Mitochondrial Activity

    Change in gastrocnemius (calf) muscle levels of mitochondrial activity (measured with respirometry), obtained from participants who undergo gastrocnemius muscle biopsy

    Time frame: From baseline to 12-week follow-up

  13. Capillary Density

    Change in gastrocnemius muscle capillary density, obtained from participants who undergo gastrocnemius muscle biopsy

    Time frame: From baseline to 12-week follow-up

  14. Myofiber Size

    Change in gastrocnemius muscle myofiber size, obtained from participants who undergo gastrocnemius muscle biopsy

    Time frame: From baseline to 12-week follow-up

  15. Satellite Cell Abundance

    Change in gastrocnemius muscle levels of satellite cell abundance, obtained from participants who undergo gastrocnemius muscle biopsy

    Time frame: From baseline to 12-week follow-up

07

Study locations

1 of 2 sites recruiting
08

References and documents

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 ↗
09

Timeline

Tracking since Sep 25, 2026
ElapsedEstimatedEstimated, not yet reached

Started Jan 2025 (actual). Primary completion is estimated for Jul 2029, 53 months after the start.

How these figures are worked out, and which studies are left out of them.

Registered
Oct 23, 2024
First posted
Oct 26, 2024
StartActual
Jan 23, 2025
Primary completionEst.
Jul 1, 2029
CompletionEst.
Oct 1, 2029
Last update
Jul 27, 2026
What these dates mean
Start.
When the first participant enrolled; while estimated, when the study expects to open to recruitment.
Primary completion.
When the last participant was examined or treated to collect data for the study's main question, its primary outcome. A study that stopped early gives the date its data collection stopped.
Completion.
When the last participant's last visit took place, for every outcome, secondary ones and side effects included: the end of the study. Often later than primary completion, sometimes the same day.
Actual and Est.
Actual means the registry says the date has happened. Est. (estimated) is a date the sponsor plans or expects. It can still move, and the sponsor is expected to change it to actual once it has passed.
No changes since tracking began. The registry record was last updated on Jul 27, 2026, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
10

Registry details

Key details

Study ID
NCT06657976
Lead sponsor
Northwestern University
Collaborators
National Institute on Aging (NIA)
Responsible party
Mary McDermott (Professor, Northwestern University) — Principal investigator
First posted
Oct 26, 2024
Start date
Jan 23, 2025
Primary completion
Jul 1, 2029 (estimated)
Completion
Oct 1, 2029 (estimated)
Last update
Jul 27, 2026

Study contacts

Mary M McDermott, MD
Contact
mdm608@northwestern.edu
312-503-6419
Kathryn Domanchuk, BS
Contact
k-domanchuk@northwestern.edu
312-503-6438

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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