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

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.

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 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:

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 three months or major orthopedic surgery
during the previous three 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. Participants who only use oxygen at night may still
qualify.

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, 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.

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.