Peripheral artery disease (PAD) is a disease in which plaque builds up in the arteries that carry blood to the head, organs, and limbs. PAD usually occurs in the arteries in the legs, but can affect any arteries. Over time, plaque can harden and narrow the arteries which limits the flow of oxygen-rich blood to organs and other parts of the body. Blocked blood flow to the arteries can cause pain and numbness. The pain is usually worse with exercise and gets better with rest. PAD can raise the risk of getting an infection which could lead to tissue death and amputation. This study is investigating whether granulocyte-macrophage colony stimulating factor (GM-CSF) improves symptoms and blood flow in people with PAD. GM-CSF is a drug that is used to stimulate the bone marrow to release stem cells. Participants in the study will be randomly selected to receive GM-CSF or a placebo. After a four-week screening phase, participants will receive injections of GM-CSF or a placebo three times a week for three-weeks. Three months later, participants will again receive injections of GM-CSF or placebo three times a week for three-weeks. At six months, the study team will follow up to see if the group that received GM-CSF had more improvement than the group that received placebo.

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.

In response to the Coronavirus Disease 2019 (COVID-19) crisis on April 3, 2020 the Institutional Review Board (IRB) approved temporary modifications to this study to postpone study visits that do not involve active drug/placebo use.

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.
• Documented symptomatic PAD
• Clinically stable (at least 2 months prior to enrollment) history of intermittent claudication or walking impairment (Rutherford Class II) with no change in symptom severity in the 2 months prior to screening.
• On statin therapy for previous 3 months prior to enrollment, unless statin intolerant.
• Peak Walking Time (PWT) between 1 and 12 minutes on a standardized Gardner treadmill protocol or modified Gardner protocol or less than 12 minutes on a modified Bruce protocol in case PWT on Gardner protocol is more than 12 minutes.
• 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 prior to enrollment.
• Able to give informed consent.
• Diabetics with a dilated eye exam excluding proliferative retinopathy in the previous 12 months prior to enrollment.

Exclusion Criteria:

• Recent or current active infections (treated with antibiotics)
• Recent (6 months prior to randomization) or current active cancer undergoing treatment
• Recent (3 months prior to randomization) change in statin or cilostazol therapy
• Critical limb ischemia either chronic (Rutherford Class >II) or acute ischemia manifested by rest pain, ulceration, or gangrene
• Recent (3 months prior to randomization) lower extremity vascular surgery, angioplasty or lumbar sympathectomy
• Planned participation in a structured exercise treatment protocol in the future or within period of study
• Prior myeloid malignancy
• Recent (3 months prior to randomization) Unstable angina, myocardial infarction, transient ischemic attack (TIA), stroke or revascularization
• Severe heart failure (Class III or IV) or heart muscle disease
• 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 e.g. 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))
• White blood cell count < 3k/cmm
• Hemoglobin (HGB) < 10g/dL
• Blood Pressure Systolic >180 and/or Diastolic >100
• Taking Immunosuppressant drugs
• 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

Participants and the primary investigator will be blinded to group assignment. Blinding will be maintained by Investigational Pharmacy and blood counts will be reviewed by one of the study co-investigators who will make dose-modifications, when necessary.