PB125 + Exercise Rehabilitation for Peripheral Artery Disease

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

65 Participants Needed

Trial Summary

What is the purpose of this trial?

Physical activity is the most beneficial and cost-effective treatment for Veterans with PAD, however, issues with oxygen delivery and utilization dramatically impair exercise compliance. The cause of these oxygen delivery and utilization impairments is likely increased oxidative stress and inflammation. The proposed project will comprehensively examine the novel strategy of Nuclear Factor Erythroid-2-like 2 (Nrf2) activation using PB125, aimed at diminishing oxidative stress and inflammation, and thereby lessening the negative impacts of the disease. This therapeutic will be evaluated in isolation and in combination with exercise rehabilitation to determine if there is a complimentary benefit. The ultimate goal is to provide insight into a potential novel therapeutic treatment for this disease, therefore, improving exercise tolerance and quality of life in this growing population.

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.

What data supports the effectiveness of the treatment PB125 + Exercise Rehabilitation for Peripheral Artery Disease?

Research shows that exercise rehabilitation can significantly improve walking ability in patients with peripheral artery disease (PAD), and dietary supplements that increase nitric oxide, especially antioxidants, can improve walking distances in PAD patients. This suggests that combining exercise with a supplement like PB125, which may have antioxidant properties, could be beneficial. ^{1 2 3 4 5}

Is the combination of PB125 and exercise rehabilitation safe for humans?

Exercise rehabilitation is generally safe and can reduce inflammation and oxidative stress in patients with peripheral artery disease. While specific safety data for PB125 is not provided, exercise therapy has been shown to improve health outcomes without significant adverse effects. ^{1 6 7 8 9}

How does the PB125 + Exercise Rehabilitation treatment for peripheral artery disease differ from other treatments?

The PB125 + Exercise Rehabilitation treatment is unique because it combines a specific Nrf2 activator (PB125) with exercise rehabilitation, potentially reducing oxidative stress and enhancing the benefits of exercise for improving walking ability in peripheral artery disease. This approach is different from traditional treatments that focus solely on exercise or pharmacological interventions without targeting oxidative stress. ^{2 10 11 12 13}

Research Team

Jesse Craig, MBA

Principal Investigator

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

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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]

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]

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]

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 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]

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]

References

1. Switzerland 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. [2023]

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

Beet the Best? [2020]

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

Exercise rehabilitation programs for the treatment of claudication pain. A meta-analysis. [2022]

4. United States 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. [2021]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Peripheral artery disease, redox signaling, oxidative stress - Basic and clinical aspects. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Vascular surgical society of great britain and ireland: angioplasty reverses the systemic effects of exercise in intermittent claudication [2019]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Influence of Peripheral Transluminal Angioplasty Alongside Exercise Training on Oxidative Stress and Inflammation in Patients with Peripheral Arterial Disease. [2021]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Local Injections of Superoxide Dismutase Attenuate the Exercise Pressor Reflex in Rats with Femoral Artery Occlusion. [2020]

9. Japan 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? [2021]

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

Effects of exercise rehabilitation on cardiovascular risk factors in older patients with peripheral arterial occlusive disease. [2013]

11. United States 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. [2015]

12. Japan pubmed.ncbi.nlm.nih.gov

Training rather than walking: the test in -train out program for home-based rehabilitation in peripheral arteriopathy. [2019]

13. Netherlands 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. [2022]