PB125 + Exercise Rehabilitation for Peripheral Artery Disease

No longer recruiting at 1 trial location

Overseen By P Jon White, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: VA Office of Research and Development

Must not be taking: Hormone therapy

Disqualifiers: Bleeding disorders, Complex atherosclerosis, others

Compensation: Varies

Number of Visits: 2

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new approach for individuals with peripheral artery disease (PAD), a condition that impairs blood flow and makes exercise difficult. The study tests whether a supplement called PB125, a Nuclear Factor Erythroid-2-like 2 (Nrf2) activator, can reduce inflammation and stress in the body, thereby easing physical activity, especially when combined with exercise rehabilitation. Participants will receive either PB125 or a placebo, along with exercise sessions, to determine the most effective combination. The trial seeks individuals aged 40 and older who have been diagnosed with PAD and find exercise challenging due to this condition.

As an unphased trial, this study provides a unique opportunity to contribute to groundbreaking research that could enhance exercise capacity for those with PAD.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you have a complex atherosclerotic lesion, you may not be able to stop certain medications due to increased risk.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that PB125 might reduce cell damage and inflammation by activating a protein called Nrf2, which protects cells. While detailed safety information for PB125 is not available, studies on similar substances suggest they are generally safe.

The other component of the treatment, exercise rehabilitation, is well-known for its health benefits and typically has few side effects. Those considering joining a trial should know that exercise programs are generally safe and can improve quality of life, especially for individuals with conditions like peripheral artery disease (PAD).

Interested participants should consult their healthcare provider for personalized advice. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about PB125 combined with exercise rehabilitation for peripheral artery disease because it offers a potentially novel approach to managing the condition. Unlike traditional treatments that focus primarily on improving blood flow and reducing symptoms through medication and lifestyle changes, PB125 is a supplement believed to target oxidative stress and inflammation at a cellular level. This could mean added benefits when paired with exercise, possibly enhancing overall treatment effectiveness. By addressing the underlying molecular contributors to the disease, PB125 might offer improvements beyond what standard therapies can achieve.

What evidence suggests that this trial's treatments could be effective for Peripheral Artery Disease?

Research has shown that activating Nrf2, a protein that helps cells manage stress, might reduce damage and inflammation caused by free radicals in people with Peripheral Artery Disease (PAD). PB125, one of the treatments in this trial, aims to activate Nrf2, potentially improving how oxygen is delivered and used during exercise.

Exercise rehabilitation, another treatment arm in this trial, is already a proven treatment for PAD. Studies have shown that structured exercise programs help people with PAD walk longer distances and improve their quality of life. This trial will test the combination of PB125 with exercise rehabilitation, which might offer extra benefits by addressing the root cause of exercise limitations in PAD, such as oxidative stress. ^{6 7 8 9 10}

Who Is on the Research Team?

David W. Wray, PhD

Principal Investigator

VA Salt Lake City Health Care System, Salt Lake City, UT

Are You a Good Fit for This Trial?

This trial is for Veterans aged 40+ with Peripheral Artery Disease (PAD), who understand the study and can consent, or have a caregiver to assist. It's open to women not pregnant or likely to become so within six months. Excluded are those with bleeding disorders, complex atherosclerotic lesions requiring medication, or on hormone replacement therapy.

Inclusion Criteria

Patients with mild cognitive impairment (i.e., montreal cognitive assessment (MOCA) <26) will be included but must have a responsible caregiver or spouse present during the informed consent

Must understand the study requirements and be willing and able to sign an informed consent document

I am not pregnant, breastfeeding, nor planning to become pregnant soon.

Exclusion Criteria

I have a serious blockage in my arteries that makes stopping my medication risky.

Any other condition or event considered exclusionary by the PI and faculty physician

I do not have a bleeding disorder that prevents muscle biopsy.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline

Initial assessments of functional capacity, cognitive function, vascular function, and mitochondrial respiration

1 week

1 visit (in-person)

Supplement Loading

Participants receive PB125 or placebo supplementation

4 weeks

1 visit (in-person)

Exercise Rehabilitation

Participants undergo 12 weeks of exercise rehabilitation with continued supplementation

12 weeks

Monthly assessments (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Exercise Rehabilitation
• PB125
• Placebo

Trial Overview The trial tests PB125, a drug aimed at reducing oxidative stress and inflammation in PAD patients. It will be evaluated alone and alongside exercise rehabilitation to see if they work better together. The goal is improving exercise tolerance and life quality by addressing oxygen delivery issues.

How Is the Trial Designed?

Group I: Exercise Rehabilitation+PB125 Experimental Treatment 2 Interventions

Participants will be assigned to the Exercise+Placebo or Exercise+PB125 rehabilitation interventions using block randomization.

Group II: Exercise Rehabilitation with Placebo Placebo Group 2 Interventions

Participants will be assigned to the Exercise+Placebo rehabilitation interventions using block randomization.

Exercise Rehabilitation is already approved in United States for the following indications:

Approved in United States as Exercise Rehabilitation for:

• Peripheral Artery Disease (PAD)
• Claudication
• Vascular Health Improvement

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Published Research Related to This Trial

In a study of 35 men with symptomatic peripheral artery disease (PAD), a single bout of maximal walking exercise led to increased inflammation and changes in muscle and blood markers, indicating potential local and systemic impairments.

The findings suggest that high-intensity exercise may not be beneficial for PAD patients, and that exercise strategies should focus on avoiding maximal effort to reduce damage and improve health outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Local and Systemic Inflammation and Oxidative Stress After a Single Bout of Maximal Walking in Patients With Symptomatic Peripheral Artery Disease. Andrade-Lima, A., da Silva Junior, N., Chehuen, M., et al.[2021]

A short course of supervised treadmill training in 24 patients with peripheral artery disease (PAD) significantly improved walking distances and reduced cell damage, indicating enhanced resistance to ischemia-reperfusion injuries.

The training led to increased expression of protective pathways (UPR and Nrf2) in peripheral blood mononuclear cells, suggesting that treadmill training may induce a protective adaptation similar to ischemic conditioning, which helps cells survive oxidative stress.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Physical Exercise Reduces Cytotoxicity and Up-Regulates Nrf2 and UPR Expression in Circulating Cells of Peripheral Artery Disease Patients: An Hypoxic Adaptation? Fratta Pasini, AM., Stranieri, C., Rigoni, AM., et al.[2021]

A systematic review of 34 randomized controlled trials involving 3472 participants found that dietary upregulators of nitric oxide, particularly antioxidants, significantly improved initial claudication distance in patients with peripheral artery disease (PAD).

While antioxidants also enhanced maximum walking distances, the overall dietary interventions did not show improvements in quality of life, physical function, or risks of adverse events, indicating a need for larger, high-quality studies to better understand their benefits and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Dietary Supplements Which Upregulate Nitric Oxide on Walking and Quality of Life in Patients with Peripheral Artery Disease: A Meta-Analysis. Wong, SA., Drovandi, A., Jones, R., et al.[2023]

Reactive oxygen and nitrogen species (ROS and RNS) play a crucial role in the progression of peripheral artery disease (PAD) by contributing to oxidative stress and inflammation, which can worsen symptoms like intermittent claudication and critical limb ischemia.

Therapeutic strategies, including pharmacological treatments (like statins and ACE inhibitors) and non-pharmacological approaches (like exercise), can help manage PAD by reducing oxidative stress and inflammation, potentially improving complications and slowing disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Peripheral artery disease, redox signaling, oxidative stress - Basic and clinical aspects. Steven, S., Daiber, A., Dopheide, JF., et al.[2018]

A systematic review of 21 studies showed that exercise rehabilitation significantly improves claudication pain symptoms in patients with peripheral arterial disease, with walking distances to the onset of pain increasing by 179% after rehabilitation.

The most effective exercise program included walking for over 30 minutes per session, at least three times a week, and lasting more than 6 months, with training to near-maximal pain as a key component.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exercise rehabilitation programs for the treatment of claudication pain. A meta-analysis. Gardner, AW., Poehlman, ET.[2022]

In patients with peripheral artery disease (PAD), muscle oxidative stress leads to decreased levels of superoxide dismutase (SOD), which contributes to an exaggerated exercise pressor reflex, worsening blood flow to the limbs.

Administering tempol, a SOD mimetic, significantly reduced the enhanced pressor response during exercise in a rat model of PAD, suggesting that improving SOD levels could help manage blood flow issues in PAD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Local Injections of Superoxide Dismutase Attenuate the Exercise Pressor Reflex in Rats with Femoral Artery Occlusion. Xing, J., Lu, J., Liu, J., et al.[2020]

In a study involving 62 patients with claudication, combining propionyl-L-carnitine (PLC) with monitored home-based exercise training did not significantly improve peak walking time compared to exercise training alone after 6 months.

Both treatment groups showed improvements in walking performance, indicating that the monitored exercise training itself was effective, but the addition of PLC did not provide a statistically significant advantage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of propionyl-L-carnitine on a background of monitored exercise in patients with claudication secondary to peripheral artery disease. Hiatt, WR., Creager, MA., Amato, A., et al.[2015]

The Ti-To program, which involved structured home-based walking sessions and monthly check-ups, significantly improved perceived claudication and functional parameters in patients with peripheral arterial disease (PAD) compared to the traditional free walking exercise program.

Patients in the Ti-To group experienced better hemodynamic improvements, including lower resting heart rates and better ankle-brachial index scores, indicating enhanced cardiovascular health alongside improved walking ability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Training rather than walking: the test in -train out program for home-based rehabilitation in peripheral arteriopathy. Manfredini, F., Malagoni, AM., Mascoli, F., et al.[2019]

Daily oral administration of RTA-dh404, an Nrf2 activator with antioxidant properties, significantly reduced oxidative stress in ischemic limbs of mice, leading to improved survival of injected adipose-derived regenerative cells (ADRCs).

In the RTA-dh404-treated mice, there was a 10% increase in neovascularization and a 63% increase in the salvage ratio of ischemic limbs 14 days after ADRC injection, suggesting that RTA-dh404 enhances the therapeutic effects of cell-based treatments for peripheral artery disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

RTA-dh404 decreased oxidative stress in mice ischemic limbs and augmented efficacy of therapeutic angiogenesis by intramuscular injection of adipose-derived regenerative cells in the limbs. Ishizaki, Y., Sasaki, KI., Yoshikawa, T., et al.[2022]

A 12-week exercise rehabilitation program combined with oral inorganic nitrate (beetroot juice) significantly improved claudication onset time and walking distance in patients with peripheral artery disease (PAD), with the beetroot juice group showing a 180.3 seconds increase in claudication onset time compared to 59.2 seconds in the placebo group.

The study also demonstrated that nitrate supplementation enhanced skeletal muscle perfusion during exercise, as indicated by significant improvements in measures like peak reactive hyperemic blood flow, suggesting that it may help PAD patients exercise with less pain and at higher intensities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beet the Best? Woessner, M., VanBruggen, MD., Pieper, CF., et al.[2020]

In a study of 10 patients with intermittent claudication, successful percutaneous transluminal angioplasty (PTA) reversed exercise-induced changes in kidney function markers, indicating that PTA can effectively restore normal physiological responses after exercise.

PTA also reduced total antioxidant capacity (TAC) levels, suggesting that it may lower oxidative stress in patients, which could be beneficial for their overall health following exercise.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vascular surgical society of great britain and ireland: angioplasty reverses the systemic effects of exercise in intermittent claudication Lewis, DR., Day, A., Baird, RN., et al.[2019]

In a study of 41 patients with intermittent claudication, combining endovascular revascularization (ER) with home-based exercise training significantly reduced oxidative stress and improved blood flow, as indicated by increased ankle-brachial index (ABI) measurements in the ER group.

Both groups showed improvements in walking distances (absolute and initial claudication distances), but the ER group had a greater reduction in reactive oxygen species (ROS) production, suggesting that this combination therapy may enhance the benefits of exercise training in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of Peripheral Transluminal Angioplasty Alongside Exercise Training on Oxidative Stress and Inflammation in Patients with Peripheral Arterial Disease. Koppe-Schmeißer, F., Schwaderlapp, M., Schmeißer, J., et al.[2021]

A 6-month exercise rehabilitation program significantly improved functional performance in patients with peripheral arterial occlusive disease (PAOD), increasing treadmill times to claudication pain by 106% and peak oxygen uptake by 7%.

The program also led to favorable changes in cardiovascular risk factors, including a 5.2% reduction in total cholesterol and an 8% reduction in LDL cholesterol, highlighting its efficacy in managing PAOD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of exercise rehabilitation on cardiovascular risk factors in older patients with peripheral arterial occlusive disease. Izquierdo-Porrera, AM., Gardner, AW., Powell, CC., et al.[2013]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39755577

Effectiveness of home-based walking exercise for patients ... Home-based exercise interventions for patients with PAD and IC were beneficial in improving pain-free walking distance and maximal walking distance.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3061490/

Exercise Rehabilitation in Peripheral Artery Disease Exercise therapy combined with comprehensive secondary prevention has the potential to benefit patients with PAD by preserving or improving functional capacity.

3. acc.org acc.org/Latest-in-Cardiology/Articles/2025/04/02/13/44/Exercise-Therapy-in-Symptomatic-Peripheral-Artery-Disease

Exercise Therapy in Symptomatic Peripheral Artery Disease Structured exercise programs have been shown to improve walking performance, functional status, and QOL in patients with symptomatic PAD.

4. sciencedirect.com sciencedirect.com/science/article/pii/S2542454823000565

Exercise Therapy in the Management of Peripheral Arterial ... The estimated 5-year outcomes for patients with PAD with intermittent claudication include progression to CLTI in 1%-2% and development of nonfatal myocardial ...

5. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2809783

Home-Based Walking Exercise and Supervised Treadmill ... Supervised treadmill exercise is first-line therapy for walking impairment among people with lower extremity peripheral artery disease (PAD).

6. withpower.com withpower.com/trial/phase-peripheral-artery-disease-d058729-6-2023-0012c

PB125 + Exercise Rehabilitation for Peripheral Artery ... While specific safety data for PB125 is not provided, exercise therapy has been shown to improve health outcomes without significant adverse effects. Show more.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT06319339

Study Details | NCT06319339 | Impact of Nrf2 Activation on ... A potentially effective pharmacological target for oxidative stress management in those with PAD may be the nuclear factor erythroid 2-related factor 2 (Nrf2)- ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10669303/

A Review of the Potential of Nuclear Factor [Erythroid-Derived 2] The evidence supporting a correlation between Nrf2 signaling and the most common autoimmune diseases is reviewed here.

9. trialx.com trialx.com/clinical-trials/listings/324928/impact-of-nrf2-activation-on-macrovascular-microvascular-leg-function-walking-capacity-in-peripheral-artery-disease/

Impact of Nrf2 Activation on Macrovascular, Microvascular ... Peripheral artery disease (PAD) is associated with elevated oxidative stress, and oxidative stress has been implicated as the cause of reduced ...

10. sciencedirect.com sciencedirect.com/science/article/pii/S089158492200199X

Protective actions of nuclear factor erythroid 2-related ... In this review, we describe protective actions of NRF2-mediated pathways against environmental stressors such as noise, air pollution, heavy metals, UV ...