Oxygen-guided Supervised Exercise Therapy

NCT06003855 | Recruiting

• 1 other identifier: E4632-P
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

Peripheral artery disease (PAD) is a cardiovascular disease manifesting from systemic atherosclerosis, which blocks the leg arteries and results in insufficient blood flow to the lower extremities. Limb ischemia from PAD is the most common disorder treated within the vascular surgery service at the Omaha Veterans' Affairs Medical Center. PAD also accounts for one-third of the operations performed in the VA Medical Centers nationwide. This project aims to establish the feasibility and acceptability of a muscle oxygen-guided supervised exercise program for patients with PAD. The investigators will determine the potential benefits of using this intervention over standard supervised exercise therapy. This modified intervention may enable patients to increase overall physical activity without the negative impacts on muscle structure and function. Increasing physical activity will decrease cardiovascular morbidity and mortality. If proven beneficial, the findings will lead to an improved exercise program that directly benefits veterans nationwide.

Conditions

Peripheral Artery Disease

Keywords

peripheral arterial disease; atherosclerosis; arterial occlusive disease; gait

Outcome Measures

Primary Outcomes (9)

• Distance walked

  Total distance walked during the exercise session (standard or M-SET) will be determined using the total time of walking multiplied by the walking speed.

  Before and after 12 week exercise program

• Energy expenditure

  Energy expenditure57 will be assessed via oxygen consumption as measured by a metabolic cart (K5, Cosmed USA, Inc., Chicago, IL). Subjects will stand quietly for five minutes to collect resting energy expenditure. Standing steady state energy expenditure will be calculated for each subject by plotting VO2 and assigning a sliding best fit line over a two-minute window. Steady-state oxygen consumption in ml/kg/min will be calculated during the exercise session. Energy cost of transport will be calculated by subtracting the energy consumption values at standing from walking to achieve net metabolic cost for each bout of exercise.

  Before and after 12 weeks after the exercise program

• Reactive oxygen species

  Quantification of reactive oxygen species (ROS) related markers and free radicals: Electron paramagnetic resonance (EPR), which has been known as a gold standard for free radical assessment, will be used to quantify free radicals such as superoxide as we have previously performed (1-3). Plasma samples will be used for measuring ROS-related markers such as TAC, SOD, GSH:GSSG, ONOO- and MDA with commercially available and previously validated ELISA Assay Kits (CAT#s ab65329, ab65354, ab138881, ab233469, and ab233471 Abcam, UK) according to the manufacturer's instructions60. The average intra-assay variability measured as the coefficient of variation for each sample was 2.9%, 3.8%, and 3.3% for SOD, TAC, and MDA, respectively.

  Before exercise, immediately after exercise, 30 minutes after exercise, and 1 hour after exercise

• Protein expression of ROS-related enzymes

  Protein expression of ROS-related enzymes: Enzymes related to ROS will be quantified with western blots of isolated PBMCs analyzed for catalase, 4 hydroxynonenal (4HNE), and glutathione peroxidase 1 (GPX) (4). All samples will be homogenized in RIPA buffer (Boston Bioproducts) and 100X protease inhibitor (Sigma Aldrich). A 150-volt electrical potential will be applied to the gel for 1 hr to separate proteins based on mass. A 250-volt electrical potential will then be applied to the gel for 7 min to transfer protein bands to transfer paper with TurboTransfer (Biorad). Primary antibodies for catalase, 4HNE, and GPX will be recombinant anti-catalase antibody (ab209211), anti-4 hyroxynonenal antibody (ab243070), and recombinant anti-glutathione peroxidase 1 antibody (ab108429), respectively.

  Before exercise, immediately after exercise, 30 minutes after exercise, and 1 hour after exercise

• Markers of systemic inflammation

  Markers of systemic inflammation: Standard ELISA kits will be used to test blood samples for interleukin 6, tumor necrosis factor-a, vascular cell adhesion protein 1, and vascular endothelial growth factor-a (Cat#s, ab178013, ab285312, ab223591, ab119566). Oxidized low density lipoproteins (LDL) will be measured with an oxidized LDL assay kit (ab242302). All measurements will be made per validated manufacturer specifications.

  Before exercise, immediately after exercise, 30 minutes after exercise, and 1 hour after exercise

• Initial and absolute walking distances

  Initial and absolute walking distances will be determined from the progressive-load treadmill test. Subjects will walk on a treadmill that starts at 0% grade and 2.0 mph. Every two minutes, the grade will be increased by 2% up to a maximum of 15% grade, and the speed held constant throughout the test. Initial claudication distance is the distance walked prior to claudication pain onset. Absolute claudication distance is the total distance walked before subjects had to stop walking due to claudication pain.

  Before and after 12 week supervised exercise program

• Comprehensive mitochondrial respiratory complex function

  Comprehensive mitochondrial respiratory complex function (complex I, II, III, IV, and V) will be completed with previously validated high resolution respirometry with complex agonists/antagonists. Skeletal muscle tissue will be manually teased and permeabilized with 15 l of digitonin for 30 min. Samples will then be rinsed twice in 2 ml of MIRO5 for 10-min. 3-5 mg (dry weight) of tissue will then be isolated and placed in the high-resolution respirometer with 2 ml of MIRO5 solution. The order and quantity of each agonist and antagonist will be applied as follows: 5 l malate and 10 l glutamate (complex I agonist), 20 l adenosine diphosphate (complex V agonist), 20 l succinate (complex II agonist), 1 l rotenone (complex I antagonist), 1 l oligomycin (complex V antagonist), 1 l antimycin A (complex III antagonist), and 5 l ascorbate + 5 l TMPD (complex IV agonist).

  Before and after 12 week supervised exercise program

• Mitochondrial dynamics

  Specific proteins we will assess are Fis-1 and DRP-1 (fission), Mfn-1, Mfn-2 and OPA-1 (fusion), and UPC-1 and UCP-2 (dynamics). We will perform the same Western Blot technique mentioned in Aim #262. Primary antibodies for Fis-1, DRP-1, Mfn-1, Mfn-2, OPA-1, UPC-1, and UCP-2 will be recombinant anti- TTC11/FIS1 (ab156865), recombinant anti-DRP1 (ab184247), anti-mitofusin 1 antibody-N-terminal (ab191853), recombinant anti-mitofusin 2 (ab205236), recombinant anti-OPA1 (ab157457), anti-UCP1 (ab155117), and anti-UCP2 (ab247184), respectively.

  Before and after 12 week supervised exercise program

• Mitochondrial reactive oxygen species production

  Mitochondrial reactive oxygen species production will be assessed with fluorescent imaging of skeletal muscle biopsy samples treated with H2DCFDA (D399, ThermoFisher), which is validated to detect ROS within cells. The validated mitochondrial targeted antioxidant MitoTempo (SML0737, Sigma-Aldrich) will be used to confirm the presence of mitochondrial ROS. EPR will be used to quantify free radicals such as superoxide.

  Before and after 12 week supervised exercise program

Secondary Outcomes (8)

• Metabolic equivalents of task

  Immediate

• Physical activity enjoyment scale

  Immediate

• Rating of perceived exertion

  Immediate

• Physical activity average steps/day

  Before and after 12 week supervised exercise program

• Muscle strength

  Before and after 12 week supervised exercise program

Study Arms (2)

Oxygen guided supervised exercise

EXPERIMENTAL

Modified-SET parameters will be determined from resting StO2 during 10 minutes of sitting. The StO2 threshold will be set at 15% lower than baseline StO2 levels. After warm-up, the subjects will walk until they reach the StO2 threshold. The subjects will be instructed to stop walking once they reach the threshold and to rest until the StO2 level returns to the baseline level. Then, subjects will be instructed to begin walking again and this cycle will be repeated for 50 total minutes. The threshold was selected to be above the 31% drop associated with claudication onset time. If subjects experience pain earlier than the 15% drop, the threshold will be progressively decreased by 5%, as needed. Subjects will repeat this for up to 50 minutes (including walking and rest). Walking speed and treadmill incline will be adjusted to allow for 5-10 minutes of walking before reaching the threshold. Subjects will complete 3 sessions/week for 12 weeks.

Behavioral: Supervised exercise therapy

Standard supervised exercise

ACTIVE COMPARATOR

After the warmup, subjects will walk until claudication pain becomes severe and needs to stop. Then subjects will rest until claudication pain subsides. Afterwards, subjects will walk again, repeating the cycle for up to 50 minutes (including walking and rest). Walking speed and treadmill incline will be adjusted during the SET session to allow individuals with PAD to walk for 5-10 minutes before claudication symptoms arise. Time at each speed and incline, along with rest times will be recorded during each exercise session. Subjects will complete 3 sessions/week for 12 weeks.

Behavioral: Supervised exercise therapy

Interventions

Supervised exercise therapy BEHAVIORAL

Subjects will be enrolled in a 12-week intervention program of either modified supervised exercise therapy or standard supervised exercise therapy. The program will be 3 sessions/week for 12 weeks. Each session will consist of 50 minutes plus 5 minutes warm up and cool down.

Oxygen guided supervised exercise; Standard supervised exercise

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• At entry into the study, all subjects must:
• Be able to give written, informed consent
• Have documented lower extremity arterial occlusive disease based on ankle/brachial index measurements and/or arterial imaging
• Demonstrate positive history of chronic claudication
• Have a stable blood pressure regimen, stable lipid regimen, stable diabetes regimen and risk factor control for 6 weeks

You may not qualify if:

• Any potential subjects will be excluded if they have:
• Rest pain or tissue loss due to PAD (Fontaine stage III and IV)
• Acute lower extremity ischemic event secondary to thromboembolic disease or acute trauma
• Walking capacity limited by conditions other than claudication including leg (joint/musculoskeletal, neurologic) and systemic (heart, lung disease) pathology

Sponsors & Collaborators

• VA Office of Research and Development: lead
• University of Nebraska: collaborator

Study Sites (1)

Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE

Omaha, Nebraska, 68105-1850, United States

RECRUITING

MeSH Terms

Conditions

Peripheral Arterial Disease; Atherosclerosis; Arterial Occlusive Diseases

Condition Hierarchy (Ancestors)

Arteriosclerosis; Vascular Diseases; Cardiovascular Diseases; Peripheral Vascular Diseases

Study Officials

• Iraklis I Pipinos, MD

  Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Farahnaz Fallahtafti, PhD

CONTACT

(402) 995-3542; ffallahtafti@unomaha.edu

Sara A Myers, PhD

CONTACT

(402) 554-3246; Sara.Myers2@va.gov

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Model Details: Two groups will complete 12 weeks (36 sessions) of supervised exercise therapy. One group will complete the standard of care and the other group will complete the muscle oxygen guided supervised exercise therapy. Subjects will be randomly assigned to one of the two groups.

Study Record Dates

• First Submitted: July 25, 2023
• First Posted: August 22, 2023
• Study Start: October 1, 2023
• Primary Completion (Estimated): December 30, 2026
• Study Completion (Estimated): December 30, 2026
• Last Updated: January 13, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ANALYTIC CODE
• Time Frame: The de-identified, anonymized dataset will only be shared after the completion of the study and publishing the outcomes in peer-reviewed journals and conference proceedings.
• Access Criteria: All data obtained from the research study will be securely stored in a VA Data Repository system. Only the PI and authorized VA personnel will have the access to the data. A de-identified, anonymized dataset will be created for sharing purposes. The study data will be shared upon request for potential future uses with a written agreement from the recipient complying with VA guidelines for data sharing.

Locations

US (1)