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

Condition(s) targeted: Peripheral Arterial Disease

Intervention: Supervised Treadmill Exercise Therapy (Behavioral); Health education sessions (Control) (Other); granulocyte monocyte colony stimulating factor (GM-CSF) (Drug)

Phase: N/A

Status: Recruiting

Sponsored by: Northwestern University

Official(s) and/or principal investigator(s):
Mary M McDermott, MD, Principal Investigator, Affiliation: Northwestern University

Overall contact:
Kathryn Domanchuk, BS, Phone: 312-503-6438, Email: k-domanchuk@northwestern.edu

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 monocyte 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 GMCSF 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.

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.

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

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Factorial Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Change in Six-Minute Walk Performance at 12-week follow-up

Secondary outcome:

Change in Brachial Artery Flow-mediated Dilation (FMD) at 12-week follow-up

Change in Maximal treadmill walking time at 12-week follow-up

Change in CD34+ cells at 12-week follow-up

Minimum age: N/A. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

1. Participants with an ankle brachial index (ABI) ≤ 0. 90 will be eligible for participation.

2. 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.

3. 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.

4. Participants with an ABI > 0. 90 who have medical record evidence of a non-invasive vascular laboratory test result based on abnormal toe pressures consistent with PAD will be eligible (toe pressure < 0. 70 in either leg). Note that a screen-positive test from Lifeline Screening is not sufficient for inclusion in the study. Non-invasive vascular laboratory evidence of PAD must be obtained from an accredited vascular laboratory.

Exclusion Criteria:

The following exclusion criteria will be initially assessed by telephone:

1. Below or above-knee amputation.

2. Wheelchair confinement.

3. Use of a walking aid other than a cane (i. e. people using walkers).

4. Non-English speaking.

5. Significant hearing impairment.

6. Significant visual impairment.

7. Diagnosis of Parkinson's disease.

8. Inability to return to the medical center at the required visit frequency (three times per week).

9. > Class II New York Heart Association heart failure or angina (symptoms at rest or with minimal exertion).

10. Any increase in angina pectoris symptoms during the previous 6 months or angina at rest.

11. Foot ulcer. (Participants with a foot ulcer will be excluded by telephone and/or during a baseline study visit).

12. Lower extremity revascularization in the last nine months or major orthopedic surgery during the previous six months.

13. Myocardial infarction, stroke, or coronary artery bypass grafting during the previous 3 months.

14. 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.

15. 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.

16. Pre-menopausal women will be excluded because cyclic estrogen changes can influence progenitor cell levels.

17. Potential participants with diabetes and documented proliferative retinopathy will be excluded because GM-CSF may exacerbate this condition.

18. Potential participants with a history of myeloid malignancy will be excluded because GM-CSF may exacerbate these conditions.

19. Potential participants who have been treated for late stage cancer during the past three years, since GM-CSF may theoretically activate quiescent cancer cells.

20. Planned lower extremity revascularization within the next 6 months.

21. 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, participants who have taken part in another exercise trial within the last year will be excluded until six months have passed since they completed the last exercise trial.

22. Walking for exercise at a level comparable to that targeted in our intervention.

23. 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:

24. Severe aortic stenosis identified by physical exam at the study visit.

25. Critical limb ischemia identified by physical exam at the study visit.

26. 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.

27. 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.

28. 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.

29. Stopping during the six-minute walk test for symptoms other than ischemic leg symptoms.

30. Foot ulcer identified at the study visit.

31. Mini-Mental Status Examination (MMSE) score < 23 or disabling psychiatric disease.

32. Failure to complete a study run-in period.

33. 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.

Kathryn Domanchuk, BS, Phone: 312-503-6438, Email: k-domanchuk@northwestern.edu

Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States; Recruiting
Kathryn Domanchuk, BS, Phone: 312-503-6438, Email: k-domanchuk@northwestern.edu
Hyeji Na, BA, Phone: 312-503-3312, Email: h-na@northwestern.edu
Mary M McDermott, MD, Principal Investigator

Starting date: September 2011
Last updated: July 24, 2012