Improving Exercise Rehabilitation Efficacy Outcomes Veterans Peripheral Artery Disease

NCT ID: NCT05648630

Last Updated: 2025-11-10

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: NA
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-07-03
• Study Completion Date: 2025-10-01

Brief Summary

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.

Detailed Description

Peripheral artery disease (PAD) is a debilitating atherosclerotic disease caused by plaque development in the arteries leading to diminished skeletal muscle blood flow, oxygen delivery, and metabolic dysfunction during ambulation causing marked exercise intolerance. Veterans have a disproportionate risk of developing PAD compared to the general population because of higher levels of smoking, hypertension, diabetes, and obesity. Worryingly, the mortality rate for PAD in Veterans (~30%) is nearly double that of the general population. Currently, the best treatment of PAD is exercise rehabilitation, however, issues with patient motivation and pain reduce the effectiveness of this treatment. There is a pressing, and unmet need to identify the sites and underlying mechanisms of the systemic dysfunction leading to exercise intolerance induced by PAD. Oxidative stress and inflammation play important roles in the development and progression of PAD. Critically, the peripheral vasculature (diminished blood flow) and mitochondria (diminished respiration) are primary determinants/mechanisms responsible for exercise intolerance in health and disease that are particularly vulnerable to elevations in oxidative stress and inflammation, making these likely sites of systemic dysfunction leading to exercise intolerance in Veterans with PAD. Any vascular or mitochondrial dysfunction would further augment oxidative stress and inflammation initiating a vicious cycle. It is the central hypothesis that increased endogenous antioxidant capacity and diminished inflammation will improve oxygen delivery and utilization during exercise, thus, increasing the efficacy of exercise rehabilitation due to increased adherence and exercise capacity. To test this hypothesis, the investigators will utilize the naturally-derived Nuclear Factor Erythroid-2-like 2 (Nrf2; the "master regulator of antioxidant enzymes") activator, PB125, to stimulate induction of endogenous antioxidants and decrease the activity of inflammatory pathways. Veterans with PAD will be randomly assigned to receive either PB125 or Placebo supplementation. Each Veteran will undergo three phases of testing: 1) baseline, 2) post 1 month of supplement loading, and 3) post 12 weeks of exercise rehabilitation with continued supplementation. Functional capacity and cognitive function (Aim 1), Vascular function and exercising hemodynamics (Aim 2), and in vivo and ex vivo mitochondrial respiration (Aim 3) will be assessed each phase. Monthly assessments of functional capacity, behavioral regulation, quality of life, and physical activity will track improvements across the trial. At the conclusion of these studies, the investigators will have expanded the knowledge of the mechanisms underlying exercise intolerance in Veterans suffering from PAD, and, more importantly from a clinical perspective, provided insight into a potential novel therapeutic treatment to improve exercise rehabilitation efficacy for this population. It is anticipated this advancement will contribute to advancing clinical practice in rehabilitative medicine, and ultimately, improving the quality of life for Veterans living with PAD.

Conditions

Peripheral Artery Disease (D058729); Oxidative Stress (D018384); Inflammation (D007249)

Keywords

inflammation (D007249); Skeletal muscle (D018482); Antioxidants (D000975)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Exercise Rehabilitation+PB125

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

Group Type: EXPERIMENTAL

PB125

Intervention Type: DIETARY_SUPPLEMENT

PB125 is a naturally-derived plant-based supplement that activates the Nuclear Factor Erythroid-2-like 2 (Nrf2) system to stimulate induction of endogenous antioxidants and anti-inflammatory pathways.

Exercise Rehabilitation

Intervention Type: BEHAVIORAL

A 12-week treadmill based supervised rehabilitation

Exercise Rehabilitation with Placebo

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DIETARY_SUPPLEMENT

A placebo will be used in combination with exercise rehabilitation allowing for a double blinded placebo controlled design.

Exercise Rehabilitation

Intervention Type: BEHAVIORAL

A 12-week treadmill based supervised rehabilitation

Interventions

PB125

PB125 is a naturally-derived plant-based supplement that activates the Nuclear Factor Erythroid-2-like 2 (Nrf2) system to stimulate induction of endogenous antioxidants and anti-inflammatory pathways.

Intervention Type: DIETARY_SUPPLEMENT

Placebo

A placebo will be used in combination with exercise rehabilitation allowing for a double blinded placebo controlled design.

Intervention Type: DIETARY_SUPPLEMENT

Exercise Rehabilitation

A 12-week treadmill based supervised rehabilitation

Intervention Type: BEHAVIORAL

Eligibility Criteria

Inclusion Criteria

• Age 40 and older with clinically diagnosed femoropopliteal PAD (ankle-brachial index < 0.9)
• Must understand the study requirements and be willing and able to sign an informed consent document
• 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
• Women that are not pregnant, breastfeeding, or likely to become pregnant within the next 6 months

Exclusion Criteria

• Patients with a bleeding disorder that would contraindicate the performance of a muscle biopsy, such as a history of clinically significant bleeding diathesis (i.e., Hemophilia A or B, Von Willebrand's Disease, or congenital Factor VII deficiency)
• Patients with a complex atherosclerotic lesion such that withholding medication creates disproportionate risk
• Women currently taking hormone replacement therapy
• Any other condition or event considered exclusionary by the PI and faculty physician

• Minimum Eligible Age: 40 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

VA Office of Research and Development

FED

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

David W. Wray, PhD

Role: PRINCIPAL_INVESTIGATOR

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

Locations

University of Utah Dept of Vascular Surgery

Salt Lake City, Utah, United States

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

Salt Lake City, Utah, United States

Countries

United States

Other Identifiers

RX003913

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

E3913-W

Identifier Type: -

Identifier Source: org_study_id