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This study will test the safety of a drug called EW-A-401 in patients with intermittent claudication - pain and discomfort in the legs due to blockages of the arteries. The study will also evaluate whether EW-A-401 improves blood flow to the legs. EW-A-401 contains genetic material (DNA) that instructs the body to produce specific proteins that promote the growth of new blood vessels and may, therefore, improve blood flow to the legs.
Patients 21 years of age and older with pain or discomfort of one or both legs due to blockages of the arteries below the groin may be eligible for this study. Candidates are screened with a medical history, physical examination, blood and urine tests, eye examination, chest x-ray and CT scan of the chest, and treadmill tests. Patients who are able to exercise more than 12 minutes on the treadmill may not enroll in the study.
Participants undergo the following procedures:
The study lasts 12 months. After 6 months, patients will be told whether they received EW-A-401 or placebo. Because EW-A-401 is so new, patients will continue to be contacted every year after the study is completed.
Full description
Lower limb intermittent claudication, muscular pain with exercise relieved promptly by rest, is a disabling syndrome affecting over 10 million patients in the United States. Intermittent claudication is caused by peripheral artery atherosclerosis, the same disease causing heart attack. Peripheral artery atherosclerosis impairs blood flow to skeletal muscles in the lower limbs. Growth factors, such as vascular endothelial growth factor (VEGF-A), have been shown in animal studies to improve blood flow the lower limbs by promoting the growth of new blood vessels.
This clinical study tests the safety and feasibility of gene transfer of an agent (EW-A-401) intended to improve blood flow in the skeletal muscle of subjects with intermittent claudication. The investigational agent is a circle of genetic material (plasmid DNA) that instructs the body to produce a genetically-engineered transcription factor, a protein that regulates expression of genes. This specific transcription factor has been shown in animal studies to increase expression of the VEGF-A gene, and to promote the growth of new blood vessels. The study agent will be delivered by injection into leg muscle during a single session. This is the first human experience using this transcription factor.
This study has a randomized, double-blind, dose-escalation, placebo-controlled design. The primary outcome measure will be safety and toxicity. In addition, we will collect exploratory effectiveness information including blood flow, walking capacity, quality of life, and inspection of blood vessels on samples of leg muscle.
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Inclusion and exclusion criteria
INCLUSION CRITERIA:
Resting or post-exercise ABI less than or equal to 0.9.
Typical intermittent claudication.
Infrainguinal obstructive atherosclerosis in a femoropopliteal and/or tibial artery greater than or equal to 70%.
Subjects enrolled into Strata A and B may have both unilateral or bilateral peripheral atherosclerotic disease.
EXCLUSION CRITERIA:
Any history of malignancy or a known genetic predisposition for developing cancer except for curatively resected basal cell carcinoma of skin, squamous cell carcinoma of skin, cervical carcinoma in situ, or resected benign colonic polyps.
Non-compressible arteries (resting ankle-brachial systolic blood pressure index (ABI) greater than 1.3 in the more-affected limb).
Evidence of malignancy after screening according to modified American Cancer Society Guidelines in the following organ systems (screening procedures in addition to history and physical exam are noted):
-Prostate: subjects with the following PSA levels above the recommended age-specific cut-points will be excluded
Age 50-59 greater than or equal to 3.7
Age 60-69 greater than or equal to 5.1
Age 70-79 greater than or equal to 7.0
Age 80 plus-greater than or equal to 7.2
Subjects with PSA values above the age-specific cut-points are eligible if a prostate biopsy, within 12 months, shows neither prostate cancer nor high-grade prostatic intraepithelial neoplasia (PIN).
Proliferative retinopathy, severe non-proliferative retinopathy, advanced age-related macular degeneration, especially subjects with chorodial neovascularization, diabetic retinopathy, macular edema, or intraocular surgery within 3 months.
Limiting symptom on Gardner Exercise Treadmill Examination other than intermittent claudication.
Co-morbid conditions that limit exercise capacity:
Cardiovascular surgery or percutaneous revascularization within 4 months.
Coagulopathy:
Women of childbearing potential.
Subjects unwilling to use barrier contraception during the study.
Subjects unsuitable for unilateral investigational thigh compression for perfusion measurements due to:
Immune compromise including chronic HIV, HBV, and HCV infection.
Contraindication to Magnetic Resonance Imaging:
Creatinine clearance less than or equal to 20 mL per minute. Creatinine clearance (CLcr) will be estimated using the Cockcroft-Gault formula.
Current alcohol, drug abuse, severe medical, psychiatric, behavioral, or emotional disorder of any other condition that may preclude a subject from complying with all requirement of the protocol.
Subjects receiving experimental medication or participating in another study receiving an experimental drug or procedure within 30 days prior to enrollment.
Unable or unwilling to provide written informed consent.
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Data sourced from clinicaltrials.gov
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