Granulocyte-Macrophage Stimulating Factor (GM-CSF) in Peripheral Arterial Disease

Atherosclerotic peripheral artery disease (PAD) of the lower extremities afflicts up to 8% of
the U.S. population and lack of adequate sustainable therapies necessarily results in severe
morbidity and increased mortality. Both experimental and current clinical data indicate that
GM-CSF has the capacity to mobilize a variety of progenitor cells (PCs), including
endothelial PCs that appear to improve ischemia.

This study builds on the findings of prior research which showed improvements in claudication
symptoms after treatment with GM-CSF. This study aims to answer whether repeat administration
of GM-CSF at 3 months will further improve symptoms. The researchers will investigate in a
double-blind placebo-controlled randomized study whether 3 weeks of three-times-a-week
injection of GM-CSF will improve measures of ischemia in patients with intermittent
claudication.

This study will recruit 176 participants with atherosclerotic PAD and claudication. After
screening for inclusion and exclusion criteria, eligible subjects will be trained to perform
subcutaneous injections and instructed to walk until they develop claudication or symptomatic
limitation at least three times a day for 4 weeks. At the end of the 4-week period, subjects
will undergo baseline testing and will be randomized to receive 500 μg/day of GM-CSF thrice
weekly for 3 weeks (group A) or a placebo (group B). After 3 months, follow-up endpoint
testing will be performed. Subjects in group A will then receive the second administration of
500 μg/day of subcutaneous GM-CSF thrice weekly for another 3 weeks and be followed for
another 3 months for endpoint measurements, while Group B subjects will receive a matching
placebo. The primary outcome is change in walking performance in the active treatment group
after 6 months compared to the placebo group. The secondary outcome includes change in peak
walking time at 6 months, changes in circulating progenitor cell levels, ankle brachial index
(ABI), walking impairment questionnaire (WIQ) scores, and 36-item Short-Form Health Survey
(SF-36) scores. Long-term follow up, by way of a telephone call, will occur with each
participant one, two and three years after they enrolled in the study to administer
questionnaires and collect adverse event data.

Inclusion Criteria:

- Female subjects must be (a) post-menopausal, (b) surgically sterile or (c) use
adequate birth control and have a negative pregnancy test within 3 days prior to
administration of study drug and should not be breastfeeding

- Angiographically documented PAD

- Clinically stable (at least 2 months) history of intermittent claudication or walking
impairment (Rutherford Class II) with no change in symptom severity in the 2 months
prior to screening

- On stable statin therapy for previous 3 months

- Peak Walking Time (PWT) between 1 and 12 minutes on a standardized Gardner treadmill
protocol

- A Doppler-derived ankle-brachial index (ABI) of < 0.90 in the symptomatic limb after
10 minutes of rest at screening. For subjects with an ABI of >1.3 (non-compressible
arteries) a Toe-Brachial Index (TBI) of < 0.70 must be obtained for subject
qualification, or if ABI is > 0.9 to 1.0 , and a reduction of 20% in ABI measured
within 1 minute of treadmill testing.

- On appropriate and stable medical therapy for atherosclerosis for at least 2 months

- Able to give informed consent

- Diabetics with a dilated eye exam excluding proliferative retinopathy in the previous
12 months

Exclusion Criteria:

- Recent or current active infections (treated with antibiotics)

- Recent (3 months) change in statin or cilostazol therapy

- Critical limb ischemia either chronic (Rutherford Class >II) or acute ischemia
manifested by rest pain, ulceration, or gangrene

- Lower extremity vascular surgery, angioplasty or lumbar sympathectomy within 3 months
of enrollment

- Planned participation in a structured exercise treatment protocol in the future or
within period of study

- Prior myeloid malignancy

- Unstable angina, myocardial infarction, transient ischemic attack (TIA), stroke or
revascularization in the preceding 4 months

- Severe heart failure (Class III or IV), heart muscle disease or atrial fibrillation

- Limitation on exercise for symptoms other than intermittent claudication such as
arthritis or dyspnea

- Below- or above-knee amputation; wheelchair confinement

- Use of a walking aid other than a cane

- Walking impairment for reasons other than PAD eg. Parkinson's disease

- Uncontrolled diabetes mellitus (defined as HbA1c > 10.0)

- Chronic renal disease (creatinine of >2.5 mg/dl) or hepatic disease (> 3 X elevations
in aspartate aminotransferase (AST) and alanine aminotransferase (ALT))

- Ophthalmologic conditions associated with a neo-vascular response

- Alcohol or drug abuse, or any other disease process that, in the opinion of the PI,
will interfere with the ability of the patient to participate in the study

- Inability to attend study visits