Cardiovascular Intervention Program
Gene Transfer for Therapeutic Angiogenesis: 04-H-0143
Title: Modulation of Vascular Endothelial Growth Factor (VEGF) Using an Engineered Zinc-Finger Transcription Factor to Treat Lower Limb Intermittent Claudication
Summary: 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.
MORE INFORMATION
What is EW-A-401 (ZFP-VEGF)?
This is the first human trial of a new agent for gene transfer. The gene, called ZFP-VEGF, does not exist in nature. EW-A-401 is a circle of genetic material (plasmid DNA) that instructs the cells of your body to manufacture ZFP-VEGF and thereby several natural forms of vascular endothelial growth factor, a protein that may improve blood flow by helping to grow new arteries.
About Intermittent Claudication
Intermittent claudication (from the latin claudus, lame) is muscular leg pain during exercise that is relieved promptly at rest. It should not be confused with joint pain, or with pain from spinal nerve root impingement. Intermittent claudication is usually caused by artery blockages due to atherosclerosis, the same disease that causes heart attacks and many strokes. Patients with intermittent claudication should be evaluated by a physician to determine how to prevent heart disease and or stroke by smoking cessation, treatment of high cholesterol, hypertension, and diabetes. Symptoms of intermittent claudication may be improved by supervised exercise training and to some extent by the drug cilostazol in suitable patients. In certain patients, symptoms can be significantly improved by improving blood flow with minimally-invasive angioplasty and stenting or by bypass surgery.
Major inclusion criteria (Who is eligible?)
Adults with moderate-severe intermittent claudication due to atherosclerotic peripheral artery disease.
There should be clinical, hemodynamic, or angiographic evidence of bilateral involvement.
Major exclusion criteria (Who is Not Eligible?)
Candidates with “critical limb ischemia” (pain at rest, non-healing ulcer, gangrene)
Candidates with cancer.
Candidates whose walking is limited by a symptom other than claudication.
Candidates with severe kidney disease
Candidates with severe eye disease due to diabetes.
Candidates who clearly would be better treated by conventional means (for example, by angioplasty or by bypass surgery).
Women of childbearing potential.
Is there a Placebo group?
Yes. One-third of subjects will receive “dummy injections” of placebo into both legs. Neither the subjects nor the investigators will know who receives what treatment.
Can I receive the study drug outside of the trial?
No. ZFP-VEGF is only being offered to candidates randomized to receive it as part of this clinical trial.
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