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: * Muscle biopsy: On the first day of the study, patients have a muscle biopsy. This procedure is done under local anesthesia with mild sedation. A 1-inch incision is cut into the skin over a calf muscle and a small amount of muscle tissue is removed for examination by a pathologist. * Drug treatment and tests: About 10 to 13 days after the biopsy, patients are admitted to the NIH Clinical Center for 3 to 5 days for drug treatment and tests. They receive 10 injections of either the study drug (EW-A-401) or placebo (an inactive substance) in each leg during a single session lasting about 1 hour. In addition, they have blood and urine tests, complete questionnaires about their symptoms, and undergo magnetic resonance imaging (MRI), a test that a magnetic field and radio waves to produce detailed images of body tissues and organs. For this procedure, the patient lies on a table that slides into the scanner (a large hollow tube) for imaging of the blood vessels in the legs. Patients wear headphones to muffle loud knocking and thumping sounds that occur during the scanning process. * 30-day follow-up: Patients return to the Clinical Center three times over 30 days following the hospital stay for a medical history, physical examination, and blood and urine tests to assess the safety of EW-A-401. * Extended follow-up: Patients return to the Clinical Center at 3, 6, and 12 months after hospitalization for a medical history and physical examination, blood and urine tests, two treadmill tests, questionnaires about symptoms, and MRI studies, including imaging for blood flow measurement. Blood flow to the legs is measured during MRI using large blood pressure cuffs inflated around the legs during the scanning. The cuffs are inflated very tightly for 5 minutes, and then a dye is injected into an arm vein to brighten the images. Additional pictures are taken over the next 5 to 10 minutes. At two of these follow-up visits, patients also have an eye examination, and at the 3- or 6-month visit they have a repeat muscle biopsy of the calf. 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.
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.
Study Type
INTERVENTIONAL
Purpose
TREATMENT
Enrollment
10
Baptist Health System, Inc.
Birmingham, Alabama, United States
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States
University of Wisconsin
Madison, Wisconsin, United States
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