Jan. 11, 2000 DURHAM, N.C. - Like hearts, legs can also suffer from "attacks" when too little blood flows through clogged and narrowed arteries. And like angina in a heart, this lack of oxygen-rich blood to muscles that need it produces pain. Leg by-pass surgery and angioplasty can help some patients, but most people with leg clots walk as little as possible to avoid the pain.
Now, a novel therapy is being tested to treat this condition, known medically as "intermittent claudication." Researchers are using an "angiogenesis growth factor" to create new blood vessels around clogged leg arteries. Tests of these factors in heart disease have been ongoing, but this trial, led by physicians from Duke University Medical Center and the University of Michigan, is by far the largest study of angiogenesis in leg arteries.
The biologic drug being studied, called recombinant basic fibroblast growth factor (rFGF-2), has the potential to promote the growth of blood vessels around blockages, said Duke cardiologist Dr. Brian Annex.
"Potentially, this investigational drug may increase blood flow to the legs, which would increase exercise capacity and improve patients' quality of life," Annex said. He added that use of such angiogenesis factors in the legs "may even be more straightforward than in the heart where the circulation and delivery can be more complicated."
Annex and co-principal investigator, Dr. Robert Lederman, from Michigan, are organizing a 22-hospital, 180-patient trial that is randomized and placebo controlled. That means that neither the patients nor the physicians involved know who is receiving the drug or a "dummy" substance delivered twice, one month apart, by injection into arteries in both legs near the patient's hipbone.
Chiron Corp., makers of rFGF-2, is funding the Phase II clinical trial, which is being dubbed "TRAFFIC" - Therapeutic Angiogenesis with FGF For Intermittent Claudication. The study is being coordinated by the Duke Clinical Research Institute.
Patients with clogged blood vessels in their legs suffer from what is known as peripheral artery disease. This chronic, progressive condition is similar to heart disease in that arteries become obstructed with a buildup of plaque. This results in a dearth of oxygen to leg muscles, which causes pain or "claudication" - the same process by which an oxygen-starved heart produces angina.
"It's a straightforward supply-and-demand problem," Annex said. "Walking increases the demand for oxygen in leg muscles, so walking is painful. This discomfort only gets better with rest."
Some patients can be treated with leg by-pass surgery or angioplasty, a procedure that flattens plaque inside the artery, but for many, the disease is too extensive for such options. Those are the kind of patients participating in this trial, Annex said. "There are lots of branches in a leg artery, which can have multiple blockages. The trial is designed to help a group of patients who cannot readily be treated in other ways."
The drug being tested is a recombinant protein made in bacteria that is nearly identical to one produced naturally in humans. While investigators don't know how it works in the body, in a test tube Annex said the protein "is a potent angiogenic agent that promotes the grow of endothelial or blood vessel cells." He theorizes that a dose delivered into the top of the leg artery (the femoral artery near the hipbone) flows down through blood vessels to the place or places where clogs exist. "The agent could be going to the muscle that is starved for oxygen to help produce new vessels around the blockage or it could be making collateral vessels that already exist work better. We just don't know."
Patients enrolled in the study will be followed for six months to measure changes in their capacity to exercise and their quality of life.
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