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Improving Exercise Rehabilitation Efficacy Outcomes Veterans Peripheral Artery Disease

Primary Purpose

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

Status
Recruiting
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
PB125
Placebo
Exercise Rehabilitation
Sponsored by
VA Office of Research and Development
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Peripheral Artery Disease (D058729) focused on measuring inflammation (D007249), Skeletal muscle (D018482), Antioxidants (D000975)

Eligibility Criteria

40 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

  • University of Utah Dept of Vascular Surgery
  • VA Salt Lake City Health Care System, Salt Lake City, UTRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Exercise Rehabilitation+PB125

Exercise Rehabilitation with Placebo

Arm Description

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

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

Outcomes

Primary Outcome Measures

Six-minute Walk Test (6MWT) Change
6MWT will be quantified with total distance, last minute speed, and claudication onset time. Greater distance and higher speed indicates better functional capacity and greater change over time suggests improvement.
Exercise pressor response (EPR) Change
EPR will be quantified with the change in mean arterial blood pressure from rest to exercise. A greater EPR indicates elevated cardiovascular risk and a reduction in the EPR over time suggests improvement.
Intramuscular maximal bioenergetics (Vmax) Change
Vmax will be quantified as the rate of intramuscular phosphocreatine replenishment following exercise. A greater Vmax indicates better mitochondrial and hemodynamic function and greater change over time suggests improvement.

Secondary Outcome Measures

Full Information

First Posted
November 4, 2022
Last Updated
August 8, 2023
Sponsor
VA Office of Research and Development
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1. Study Identification

Unique Protocol Identification Number
NCT05648630
Brief Title
Improving Exercise Rehabilitation Efficacy Outcomes Veterans Peripheral Artery Disease
Official Title
Improving Exercise Rehabilitation Efficacy and Outcomes in Veterans With Peripheral Artery Disease: Targeting Oxidative Stress and Inflammation
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
July 3, 2023 (Actual)
Primary Completion Date
June 1, 2028 (Anticipated)
Study Completion Date
June 1, 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
VA Office of Research and Development

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Peripheral Artery Disease (D058729), Oxidative Stress (D018384), Inflammation (D007249)
Keywords
inflammation (D007249), Skeletal muscle (D018482), Antioxidants (D000975)

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
Two separate groups of subjects (patients with PAD) receiving PB125 or Placebo
Masking
None (Open Label)
Masking Description
Two separate groups of subjects (patients with PAD) receiving PB125 or Placebo
Allocation
Randomized
Enrollment
65 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Exercise Rehabilitation+PB125
Arm Type
Experimental
Arm Description
Participants will be assigned to the Exercise+Placebo or Exercise+PB125 rehabilitation interventions using block randomization.
Arm Title
Exercise Rehabilitation with Placebo
Arm Type
Placebo Comparator
Arm Description
Participants will be assigned to the Exercise+Placebo rehabilitation interventions using block randomization.
Intervention Type
Dietary Supplement
Intervention Name(s)
PB125
Intervention Description
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
Intervention Name(s)
Placebo
Intervention Description
A placebo will be used in combination with exercise rehabilitation allowing for a double blinded placebo controlled design.
Intervention Type
Behavioral
Intervention Name(s)
Exercise Rehabilitation
Intervention Description
A 12-week treadmill based supervised rehabilitation
Primary Outcome Measure Information:
Title
Six-minute Walk Test (6MWT) Change
Description
6MWT will be quantified with total distance, last minute speed, and claudication onset time. Greater distance and higher speed indicates better functional capacity and greater change over time suggests improvement.
Time Frame
Baseline, month 1, month 2, month 3, month 4
Title
Exercise pressor response (EPR) Change
Description
EPR will be quantified with the change in mean arterial blood pressure from rest to exercise. A greater EPR indicates elevated cardiovascular risk and a reduction in the EPR over time suggests improvement.
Time Frame
Baseline, month 1, month 2, month 3, month 4
Title
Intramuscular maximal bioenergetics (Vmax) Change
Description
Vmax will be quantified as the rate of intramuscular phosphocreatine replenishment following exercise. A greater Vmax indicates better mitochondrial and hemodynamic function and greater change over time suggests improvement.
Time Frame
Baseline, month 1, month 4

10. Eligibility

Sex
All
Minimum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Paul J White, MD
Phone
(801) 582-1565
Ext
4897
Email
Paul.White2@va.gov
First Name & Middle Initial & Last Name or Official Title & Degree
Misti R Seppi, MBA BS AAS
Phone
(801) 582-1565
Ext
4860
Email
Misti.Seppi@va.gov
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jesse Craig, MBA
Organizational Affiliation
VA Salt Lake City Health Care System, Salt Lake City, UT
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Utah Dept of Vascular Surgery
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jesse Craig, PhD
Phone
801-582-1565
Email
jesse.craig@utah.edu
Facility Name
VA Salt Lake City Health Care System, Salt Lake City, UT
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84148-0001
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Paul J White, MD
Phone
801-582-1565
Ext
4897
Email
Paul.White2@va.gov
First Name & Middle Initial & Last Name & Degree
Misti R Seppi, MBA BS AAS
Phone
(801) 582-1565
Ext
4860
Email
Misti.Seppi@va.gov
First Name & Middle Initial & Last Name & Degree
Jesse Craig, MBA

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
Upon written request, a limited, de-identified, anonymized dataset will be created pursuant to the Data Use Agreement. This DUA will limit the use of the dataset and prohibit the recipient from taking steps to identify individuals whose data is included in the dataset. This dataset will be provided through a password-protected, machine-readable database format. Whenever possible, the dataset will be delivered through physical transfer of the storage medium.

Learn more about this trial

Improving Exercise Rehabilitation Efficacy Outcomes Veterans Peripheral Artery Disease

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