Treadmill Exercise and GM-CSF Study to Improving Functioning in Peripheral Artery Disease (PAD)

Study Overview
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Brief Summary
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The PROPEL study will test the hypothesis that GM-CSF combined with supervised treadmill exercise will significantly improve functional performance in patients with PAD more than GM-CSF alone or supervised treadmill exercise alone. In addition to identifying novel therapeutic options for patients with PAD, the current proposal is expected to identify mechanisms by which functional impairment is improved in patients with PAD.

Detailed Description
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Eight million men and women in the United States have lower extremity peripheral arterial disease (PAD). PAD is expected to be increasingly common as the population survives longer with chronic disease. Patients with PAD have greater functional impairment and faster functional decline compared to those without PAD. However, currently there are only two FDA approved medications for improving functional performance in patients with PAD. Furthermore, these FDA approved medications are only modestly beneficial for improving walking performance in patients with PAD. Preliminary evidence suggests that increasing circulating levels of CD34+ cells with granulocyte macrophage colony stimulating factor (GM-CSF) or other therapies may improve walking performance in patients with PAD. However, results of small clinical trials testing the ability of GM-CSF to improve walking performance in patients with PAD are mixed. The association of GM-CSF with improved walking performance in PAD is not definitively established. Preliminary data also suggest that lower extremity ischemia, induced during walking exercise, may increase circulating CD34+ cell levels, enhance homing of CD34+ cells to ischemic sites, and augment the ability of GMCSF to improve walking performance in PAD. However, it is currently unknown whether the combination of GM-CSF and supervised treadmill exercise significantly improve functional performance more than either therapy alone.

Official Title
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PROgenitor Cell Release Plus Exercise to Improve functionaL Performance in PAD: The PROPEL Study

Conditions
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Peripheral Arterial Disease

Intervention / Treatment
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* Behavioral: Supervised Treadmill Exercise Therapy
* Other: Health education sessions (Control)
* Drug: granulocyte macrophage colony stimulating factor (GM-CSF)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with an ankle brachial index (ABI) ≤ 0.90 will be eligible for participation. Participants with an ABI > 0.90 but ≤ 1.00 who experience a 20% drop in ankle pressure after the heel-rise exercise will be eligible. Participants with an ABI > 0.90 who have medical record evidence of prior lower extremity revascularization and experience a 20% drop in ankle pressure after the heel-rise exercise will be eligible for inclusion. Participants with an ABI > 0.90 who have medical record evidence of a non-invasive vascular laboratory test result consistent with PAD. Note that a screen-positive test from Lifeline Screening is not sufficient for inclusion in the study. Exclusion Criteria: The following exclusion criteria will be initially assessed by telephone: Below or above-knee amputation. Wheelchair confinement. Use of a walking aid other than a cane (i.e. people using walkers). Non-English speaking. Significant hearing impairment. Significant visual impairment. Diagnosis of Parkinson's disease. Inability to return to the medical center at the required visit frequency (three times per week). > Class II New York Heart Association heart failure or angina (symptoms at rest or with minimal exertion). Any increase in angina pectoris symptoms during the previous 6 months or angina at rest. Foot ulcer. (Participants with a foot ulcer will be excluded by telephone and/or during a baseline study visit). Lower extremity revascularization in the last three months or major orthopedic surgery during the previous three months. Myocardial infarction, stroke, or coronary artery bypass grafting during the previous 3 months. Major medical illnesses including end stage renal disease requiring dialysis and chronic lung disease requiring oxygen, since these individuals may not be able to adhere to study requirements. Participants who only use oxygen at night may still qualify. Potential participants who have received G-CSF, GM-CSF, or erythropoietin within the past year will be excluded because these interventions may influence study outcomes independently of the interventions. Pre-menopausal women will be excluded because cyclic estrogen changes can influence progenitor cell levels. Potential participants with diabetes and documented proliferative retinopathy will be excluded because GM-CSF may exacerbate this condition. Potential participants with a history of myeloid malignancy will be excluded because GM-CSF may exacerbate these conditions. Potential participants who have been treated for late stage cancer during the past three years, since GM-CSF may theoretically activate quiescent cancer cells. Planned lower extremity revascularization within the next 6 months. Current participation in another clinical trial. If a participant recently completed a clinical trial, at least three months must have passed before they can be considered for the PROPEL Trial. However, for a clinical trial of stem cell or gene therapy intervention, potential participants will be potentially eligible immediately after the final study visit of the stem cell or gene therapy clinical trial, so long as at least six months has passed since the participant received their final treatment in the stem cell or gene therapy intervention. Walking for exercise at a level comparable to that targeted in our intervention. Current participation in or completion of a cardiac rehabilitation program within the last six months. The following exclusion criteria will be assessed at the time of the study visit or later: Severe aortic stenosis identified by physical exam at the study visit. Critical limb ischemia identified by physical exam at the study visit. Coronary ischemia during exercise, defined as ST segment depression > 1 mm during the baseline exercise treadmill test, with or without associated chest discomfort, without a perfusion stress test demonstrating no reversible ischemia within the previous 3 months. Left-bundle branch block or significant ST-T wave changes on the baseline ECG without a perfusion stress test demonstrating no reversible ischemia within the previous 3 months. Stopping during the treadmill stress test for shortness of breath, chest pain, hip pain, knee pain, or another symptom that may not represent ischemic leg pain. Stopping during the six-minute walk test for symptoms other than ischemic leg symptoms. Foot ulcer identified at the study visit. Mini-Mental Status Examination (MMSE) score < 23 or disabling psychiatric disease. Failure to complete a study run-in period. Walking impairment due to a cause other than PAD. In addition to the exclusion criteria listed above, individuals thought to be poorly suited to the intervention (i.e. not a good fit) can be excluded at the discretion of the principal investigator.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A: GM-CSF + supervised treadmill exercise therapy<br> | Behavioral: Supervised Treadmill Exercise Therapy<br>* Exercise intervention will be delivered three times weekly for 26 weeks. In the first week, participants will be asked to exercise 15 minutes per session (excluding rest periods). Walking exercise duration will be increased to 25 minutes minutes per session during week 2. Week 3 and 4 sessions will also be 25 minutes long, but the intensity will be increased either to produce leg symptoms or at a target rate of perceived exertion (RPE)of 12-14 on the Borg's 6-20 scale. For weeks 5-8, walking duration will be increased to 40 to 50 minutes while maintaining intensity. For weeks 9-26, exercise duration will continue to be 40 to 50 minutes but we will increase intensity up to a maximum of 4.0 miles per hour at 10% grade.<br>* Other names: treadmill exercise;Drug: granulocyte macrophage colony stimulating factor (GM-CSF)<br>* The dose of GM-CSF will be 250 ug/M^2 subcutaneously three times weekly for two weeks.<br>* Other names: leukine;|
| Active Comparator: B: GM-CSF + attention control group<br> | Other: Health education sessions (Control)<br>* Participants randomized to the attention control group will attend weekly one-hour educational sessions at Northwestern University for six months. These educational sessions are on topics of interest to the typical PAD patient and are led by physicians and other health care workers. Topics include Medicare Part D, nutritional supplements, C-reactive protein, and hypertension. Sessions do not include information about exercise.<br>* Other names: attention control group;Drug: granulocyte macrophage colony stimulating factor (GM-CSF)<br>* The dose of GM-CSF will be 250 ug/M^2 subcutaneously three times weekly for two weeks.<br>* Other names: leukine;|
| Active Comparator: C: placebo + supervised exercise therapy<br> | Behavioral: Supervised Treadmill Exercise Therapy<br>* Exercise intervention will be delivered three times weekly for 26 weeks. In the first week, participants will be asked to exercise 15 minutes per session (excluding rest periods). Walking exercise duration will be increased to 25 minutes minutes per session during week 2. Week 3 and 4 sessions will also be 25 minutes long, but the intensity will be increased either to produce leg symptoms or at a target rate of perceived exertion (RPE)of 12-14 on the Borg's 6-20 scale. For weeks 5-8, walking duration will be increased to 40 to 50 minutes while maintaining intensity. For weeks 9-26, exercise duration will continue to be 40 to 50 minutes but we will increase intensity up to a maximum of 4.0 miles per hour at 10% grade.<br>* Other names: treadmill exercise;|
| Placebo Comparator: D: placebo + attention control group<br> | Other: Health education sessions (Control)<br>* Participants randomized to the attention control group will attend weekly one-hour educational sessions at Northwestern University for six months. These educational sessions are on topics of interest to the typical PAD patient and are led by physicians and other health care workers. Topics include Medicare Part D, nutritional supplements, C-reactive protein, and hypertension. Sessions do not include information about exercise.<br>* Other names: attention control group;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Six-Minute Walk Performance at 12-week Follow-up | In the six-minute walk, participants walk back and forth along a 100-ft hallway for six minutes after standardized instructions to complete as many laps as possible. Distance covered in six minutes is recorded. | change from baseline to week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Brachial Artery Flow-mediated Dilation (FMD) at 12-week Follow-up | The brachial artery is imaged 5 to 9 cm above the antecubital fossa using a linear array vascular ultrasound transducer. Three video sequences are obtained. The first verifies the location and baseline hemodynamic state of the brachial artery. The second begins 20 seconds before cuff inflation and continues for 10 seconds after inflation. The third begins 15 seconds before cuff release and continues for 90 seconds after deflation. Brachial artery FMD is calculated as the percent change in brachial artery diameter at 60 seconds and at 90 seconds after the release of the cuff. | change from baseline to week 12 | 
| Change in Maximal Treadmill Walking Time at 12-week Follow-up | The Gardner graded treadmill exercise test is the standard, accepted treadmill protocol for measuring change in maximal treadmill walking time in response to interventions among PAD participants. In the Gardner exercise protocol, speed is maintained at 2.0 miles per hour (mph) and treadmill grade increases by 2.0% every two minutes. If patients cannot begin walking at 2.0 mph, treadmill speed is started at 0.50 mph and increased by 0.50 mph every 2 minutes until the participant reaches 2.0 mph, after which the treadmill grade is increased every two minutes. | change from baseline to week 12 | 
| Change in CD34_CD45lo at 12-week Follow-up | Red blood cells are lysed twice with freshly prepared lysis buffer. Remaining cells are stained with LIVE/DEAD® Fixable Dead Cell Stains for 20 minutes at room temperature and Fc receptors are blocked by incubating with Fc receptor blocking reagent for 10 minutes at 4oC. Samples are then stained with the following antibody cocktail for 30 minutes at 4oC: CD34 VioBlue, CD133-APC , CD45 AlexaFluor 700, and CD31 (PECAM-1) APC-eFluor® 780. Stained samples are acquired using a BD LSRII and analyzed using Flowjo software. The outcome is the absolute change in the percentages of cells. | change from baseline to week 12 | 
| Change in CD34_CD45loCD133_ at 12-week Follow-up | Red blood cells are lysed twice with freshly prepared lysis buffer. Remaining cells are stained with LIVE/DEAD® Fixable Dead Cell Stains for 20 minutes at room temperature and Fc receptors are blocked by incubating with Fc receptor blocking reagent for 10 minutes at 4oC. Samples are then stained with the following antibody cocktail for 30 minutes at 4oC: CD34 VioBlue, CD133-APC , CD45 AlexaFluor 700, and CD31 (PECAM-1) APC-eFluor® 780. Stained samples are acquired using a BD LSRII and analyzed using Flowjo software. The outcome is the absolute change in the percentages of cells. | change from baseline to week 12 | 
| Change in CD34_CD45lo_CD31_ at 12-week Follow-up | Red blood cells are lysed twice with freshly prepared lysis buffer. Remaining cells are stained with LIVE/DEAD® Fixable Dead Cell Stains for 20 minutes at room temperature and Fc receptors are blocked by incubating with Fc receptor blocking reagent for 10 minutes at 4oC. Samples are then stained with the following antibody cocktail for 30 minutes at 4oC: CD34 VioBlue, CD133-APC , CD45 AlexaFluor 700, and CD31 (PECAM-1) APC-eFluor® 780. Stained samples are acquired using a BD LSRII and analyzed using Flowjo software. The outcome is the absolute change in the percentages of cells. | change from baseline to week 12 | 
| Change in CD34_CD45lo_CD31_CD133_ at 12-week Follow-up | Red blood cells are lysed twice with freshly prepared lysis buffer. Remaining cells are stained with LIVE/DEAD® Fixable Dead Cell Stains for 20 minutes at room temperature and Fc receptors are blocked by incubating with Fc receptor blocking reagent for 10 minutes at 4oC. Samples are then stained with the following antibody cocktail for 30 minutes at 4oC: CD34 VioBlue, CD133-APC , CD45 AlexaFluor 700, and CD31 (PECAM-1) APC-eFluor® 780. Stained samples are acquired using a BD LSRII and analyzed using Flowjo software. The outcome is the absolute change in the percentages of cells. | change from baseline to week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PAD, peripheral arterial disease, granulocyte macrophage colony stimulating factor, GM-CSF, sargramostim, leukine, treadmill exercise