Peripheral Artery DiseaseMOMETNCT06003855
Oxygen-guided Supervised Exercise Therapy
A study testing Supervised exercise therapy in people with Peripheral Artery Disease, run by VA Office of Research and Development at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Peripheral Artery Disease
- What is being tested?
- Supervised exercise therapy
- Type of treatment
- Lifestyle or therapy programme
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Oct 2023to 30 Dec 2026
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE
Omaha, Nebraska, 68105-1850
Frederick G Hamel, PhD, 402-995-3540, Frederick.Hamel@va.gov
Amy M Patten, (402) 995-3541, amy.patten@va.gov
About this study
Official title: Oxygen-guided Supervised Exercise Therapy in Peripheral Artery Disease
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.
Read the detailed description
The long-term goal of this research is to improve mobility, functional independence, and quality of life in patients with peripheral artery disease (PAD) by developing conservative interventions. PAD is a manifestation of atherosclerosis, which produces blockages in the leg arteries, and results in insufficient blood flow to the legs. PAD results in significant gait deficits and an overall sedentary lifestyle. The investigators' prior work showed that the biochemical (oxidative stress and mitochondrial dysfunction) and histological (myofiber degeneration and fibrosis) characteristics of PAD muscles are altered compared to controls. These myopathic changes are due to cycles of ischemia and reperfusion, and they correlate to functional limitations (walking distance and calf muscle strength). Limb ischemia from PAD is the most common disorder treated within the vascular surgery service of the Omaha Veterans Affairs Medical Center. The most effective treatment for increasing the distances that patients with PAD can walk is supervised exercise therapy (SET). However, SET uses pain onset to guide exercise intensity and rest cycles. These repeated bouts of ischemia/reperfusion could cause further pathological damage to muscle myofibers and oxidative processes. Such adverse effects of ischemia may explain why not all patients improve with SET. Preventing cycles of ischemia-reperfusion during SET can improve walking performance without further muscle biochemistry damage in patients with PAD. The investigators propose using hemodynamic responses to modulate exercise intensity and prevent ischemia during SET. Muscle oxygen-guided supervised exercise therapy (M-SET) can prevent ischemia onset and thus preserve muscle mass and function during exercise therapy in patients with PAD. The aims are:
Aim 1: To determine the exercise outcomes of an M-SET versus a standard SET session in patients with PAD. Aim 2: To determine the acute effect of M-SET versus standard SET on oxidative stress and inflammation in patients with PAD. Aim 3: To determine the effect of 12 weeks of M-SET versus standard SET on exercise outcomes, muscle biochemistry, and subject-reported preference in patients with PAD.
The investigators will measure exercise outcomes during one session each of M-SET (using StO2 on the calf to modulate exercise) and SET, in 12 patients with PAD using a cross-over design. Exercise outcomes will be assessed by the total distance patients walked during the session, metabolic cost, metabolic equivalents of the task, physical activity enjoyment, and rate of perceived exertion. In Aim 2, oxidative stress will be measured using peripheral blood mononuclear cells before and after each exercise session (SET and M-SET) in all patients. During the standard SET session, subjects will walk until claudication pain becomes severe and the participant needs to stop. Then subjects will rest until claudication pain subsides. Afterward, subjects will walk again, repeating the cycle for up to 50 minutes. M-SET will use an StO2 threshold that is 15% lower level than baseline StO2 levels. Subjects will stop walking once they reach the threshold and rest until StO2 levels return to baseline. Then, subjects will begin walking again, repeating this cycle for 50 total minutes (including walking and rest). Patients from Aims 1 and 2 will be randomly assigned to either a 12-week M-SET or standard SET (6 per group) program. Training will be performed three times weekly as described above. Subjects will be evaluated before and after the intervention to capture initial and absolute walking distances and 7-day physical activity. Muscle biochemistry will be quantified using mitochondrial function, mitochondrial oxidative dynamics, and reactive oxygen species production before and after training. Results will support a full clinical trial and rehabilitation recommendations.
- Conditions
- Peripheral Artery Disease
- Being tested
- Supervised exercise therapy
- Keywords
- peripheral arterial disease, atherosclerosis, arterial occlusive disease, gait
- Medical subject headings
- Peripheral Arterial Disease, Atherosclerosis, Arterial Occlusive Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Supervised exercise therapyBehavioural
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Behavioral: Supervised exercise therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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.
Measured: 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.
Measured: Before and after 12 week supervised exercise program
Secondary outcomes (8)
Metabolic equivalents of task
Metabolic equivalents of task (MET) will be used to quantify exercise dose accumulated over the course of the SET or M-SET session. The MET value (measured by metabolic cart) will be multiplied by the number of minutes exercised during each bout. Session MET/min will be summed to quantify total dose (Exercise intensity).
Measured: Immediate
Physical activity enjoyment scale
Physical activity enjoyment scale is an 18-item measure developed to assess the extent to which an individual enjoys a given physical activity. Ratings span from 1(most enjoyment) to 7 (least enjoyment) and the questionnaire has been extensively validated1. The scale will be given at the end of each exercise session.
Measured: Immediate
Rating of perceived exertion
Rating of perceived exertion will be recorded using the Borg Scale, which ranges from 6 (no exertion) to 20 (maximal exertion) at the end of exercise session.
Measured: Immediate
Physical activity average steps/day
Physical activity will be measured with an accelerometer (Actigraph GT3X, Actigraph, FL, USA) placed on subjects' hip for seven days after the intervention but prior to the assessment visit. Average steps/day will be calculated. Accelerometers will be given to patients at their last exercise session prior to the assessment data collection.
Measured: Before and after 12 week supervised exercise program
Muscle strength
Muscle strength will be measured with an isokinetic dynamometer (Biodex 4 Medical Systems, Inc. USA). Peak isokinetic strength (torque) of the ankle and hip of the more symptomatic leg will be measured. Subjects will perform one trial of five repetitions at 60 degrees/second to assess strength.
Measured: Before and after 12 week supervised exercise program
Acceptability
In each intervention group, patients will be interviewed after completing the 12 week intervention. Interviews will provide the potential feasibility of exercise by identifying acceptability (satisfaction, intent to continue participation), perceived demand, and practicality (positive/negative effects).
Measured: Before and after 12 week supervised exercise program
Maximum cadence/day
Physical activity will be measured with an accelerometer (Actigraph GT3X, Actigraph, FL, USA) placed on subjects' hip for seven days after the intervention but prior to the assessment visit. Accelerometers will be given to patients at their last exercise session prior to the assessment data collection. Cadence is the number of steps per minute and the maximum cadence in a 24 hour period will be recorded as the maximum cadence/day.
Measured: Before and after 12 week supervised exercise program
Muscle endurance
Muscle endurance will be measured with an isokinetic dynamometer (Biodex 4 Medical Systems, Inc. USA). Peak isokinetic torque of the ankle and hip of the more symptomatic leg will be measured. Subjects will perform one trial of 15 repetitions at 120 degrees/second to assess endurance.
Measured: Before and after 12 weeks supervised exercise program.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Aug 2023
- Study start1 Oct 2023
- Primary completion30 Dec 2026 (estimated)
- Study completion30 Dec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Peripheral Artery DiseaseStudies of the same condition, open and under way.
- More trials run by VA Office of Research and DevelopmentThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- 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.
- Masking
- None (open label)
- Enrolment
- 12 participants (estimated)
Sponsor and investigators
- Lead sponsor
- VA Office of Research and Development
- Sponsor type
- US federal agency
- Collaborators
- University of Nebraska
- Responsible party
- Sponsor
- Investigators
- Iraklis I Pipinos, MD, Principal investigator, Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06003855
- Sponsor's protocol ID
- E4632-P
- Acronym
- MOMET
- Status last verified
- Jan 2026
- First submitted
- 25 Jul 2023
- Last updated
- 13 Jan 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: A de-identified, anonymized dataset will be created for sharing purposes. All the outcomes and results will be published in peer-reviewed journals and conference proceedings. The raw data will be shared in a de identified, anonymized dataset upon request with a written agreement from recipient. Therefore, the recipient will be able to complete follow-up and perform new analyses of the raw data.
Study at a glance
From the registry record, last updated by the sponsor on 13 Jan 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Oxygen-guided Supervised Exercise Therapy in Peripheral Artery Disease
- ClinicalTrials.gov ID
- NCT06003855
- Acronym / sponsor ID
- MOMET / E4632-P
- Conditions
- Peripheral Artery Disease
- Keywords
- peripheral arterial disease, atherosclerosis, arterial occlusive disease, gait
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 12 participants (estimated)
- Lead sponsor
- VA Office of Research and DevelopmentUS federal agency
- Collaborators
- University of Nebraska
- Study start
- 1 Oct 2023 (actual)
- Primary completion
- 30 Dec 2026 (estimated)
- Study completion
- 30 Dec 2026 (estimated)
- First posted
- 22 Aug 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
The long-term goal of this research is to improve mobility, functional independence, and quality of life in patients with peripheral artery disease (PAD) by developing conservative interventions. PAD is a manifestation of atherosclerosis, which produces blockages in the leg arteries, and results in insufficient blood flow to the legs. PAD results in significant gait deficits and an overall sedentary lifestyle. The investigators' prior work showed that the biochemical (oxidative stress and mitochondrial dysfunction) and histological (myofiber degeneration and fibrosis) characteristics of PAD muscles are altered compared to controls. These myopathic changes are due to cycles of ischemia and reperfusion, and they correlate to functional limitations (walking distance and calf muscle strength). Limb ischemia from PAD is the most common disorder treated within the vascular surgery service of the Omaha Veterans Affairs Medical Center. The most effective treatment for increasing the distances that patients with PAD can walk is supervised exercise therapy (SET). However, SET uses pain onset to guide exercise intensity and rest cycles. These repeated bouts of ischemia/reperfusion could cause further pathological damage to muscle myofibers and oxidative processes. Such adverse effects of ischemia may explain why not all patients improve with SET. Preventing cycles of ischemia-reperfusion during SET can improve walking performance without further muscle biochemistry damage in patients with PAD. The investigators propose using hemodynamic responses to modulate exercise intensity and prevent ischemia during SET. Muscle oxygen-guided supervised exercise therapy (M-SET) can prevent ischemia onset and thus preserve muscle mass and function during exercise therapy in patients with PAD. The aims are:
Aim 1: To determine the exercise outcomes of an M-SET versus a standard SET session in patients with PAD. Aim 2: To determine the acute effect of M-SET versus standard SET on oxidative stress and inflammation in patients with PAD. Aim 3: To determine the effect of 12 weeks of M-SET versus standard SET on exercise outcomes, muscle biochemistry, and subject-reported preference in patients with PAD.
The investigators will measure exercise outcomes during one session each of M-SET (using StO2 on the calf to modulate exercise) and SET, in 12 patients with PAD using a cross-over design. Exercise outcomes will be assessed by the total distance patients walked during the session, metabolic cost, metabolic equivalents of the task, physical activity enjoyment, and rate of perceived exertion. In Aim 2, oxidative stress will be measured using peripheral blood mononuclear cells before and after each exercise session (SET and M-SET) in all patients. During the standard SET session, subjects will walk until claudication pain becomes severe and the participant needs to stop. Then subjects will rest until claudication pain subsides. Afterward, subjects will walk again, repeating the cycle for up to 50 minutes. M-SET will use an StO2 threshold that is 15% lower level than baseline StO2 levels. Subjects will stop walking once they reach the threshold and rest until StO2 levels return to baseline. Then, subjects will begin walking again, repeating this cycle for 50 total minutes (including walking and rest). Patients from Aims 1 and 2 will be randomly assigned to either a 12-week M-SET or standard SET (6 per group) program. Training will be performed three times weekly as described above. Subjects will be evaluated before and after the intervention to capture initial and absolute walking distances and 7-day physical activity. Muscle biochemistry will be quantified using mitochondrial function, mitochondrial oxidative dynamics, and reactive oxygen species production before and after training. Results will support a full clinical trial and rehabilitation recommendations.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- 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.
| Arm | Type | Receives |
|---|---|---|
| Oxygen guided supervised exercise | Experimental | Behavioral: Supervised exercise therapyModified-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. |
| Standard supervised exercise | Active comparator | Behavioral: Supervised exercise therapyAfter 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. |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (4 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Supervised exercise therapySubjects 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. | Behavioural | Oxygen guided supervised exercise, Standard supervised exercise |
Primary outcome
Distance walked
Time frame: Before and after 12 week exercise program
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.
Energy expenditure
Time frame: Before and after 12 weeks after the exercise program
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.
Reactive oxygen species
Time frame: Before exercise, immediately after exercise, 30 minutes after exercise, and 1 hour after exercise
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.
Protein expression of ROS-related enzymes
Time frame: Before exercise, immediately after exercise, 30 minutes after exercise, and 1 hour after exercise
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.
Markers of systemic inflammation
Time frame: Before exercise, immediately after exercise, 30 minutes after exercise, and 1 hour after exercise
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.
Initial and absolute walking distances
Time frame: Before and after 12 week supervised exercise program
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.
Comprehensive mitochondrial respiratory complex function
Time frame: Before and after 12 week supervised exercise program
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).
Mitochondrial dynamics
Time frame: Before and after 12 week supervised exercise program
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.
Mitochondrial reactive oxygen species production
Time frame: Before and after 12 week supervised exercise program
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.
8 secondary outcomes
Metabolic equivalents of task
Time frame: Immediate
Physical activity enjoyment scale
Time frame: Immediate
Rating of perceived exertion
Time frame: Immediate
Physical activity average steps/day
Time frame: Before and after 12 week supervised exercise program
Muscle strength
Time frame: Before and after 12 week supervised exercise program
Acceptability
Time frame: Before and after 12 week supervised exercise program
Maximum cadence/day
Time frame: Before and after 12 week supervised exercise program
Muscle endurance
Time frame: Before and after 12 weeks supervised exercise program.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Jan 2026.
- Individual participant dataSharing planned: Yes. A de-identified, anonymized dataset will be created for sharing purposes. All the outcomes and results will be published in peer-reviewed journals and conference proceedings. The raw data will be shared in a de identified, anonymized dataset upon request with a written agreement from recipient. Therefore, the recipient will be able to complete follow-up and perform new analyses of the raw data.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Iraklis I Pipinos, MD principal investigator
Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Supervised exercise therapy in people with Peripheral Artery Disease, run by VA Office of Research and Development at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 13 Jan 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Farahnaz Fallahtafti, PhD ((402) 995-3542, ffallahtafti@unomaha.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Distance walked (time frame: Before and after 12 week exercise program). The study lists 9 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Jan 2026.