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Major study finds no benefit in experimental drug administered to stroke patients

New York, NY (April 4, 2001) -- A large clinical trial -- led by Dr. Ralph L. Sacco of Columbia Presbyterian Medical Center -- has found that stroke patients treated within six hours with an experimental drug called gavestinel show no improvement compared with placebo. This trial was the largest study in North America of a neuroprotective agent in acute stroke. While the finding is a disappointment -- in light of the growing belief that rapid action to counter the damage of acute stroke might improve outcomes for patients -- the strategy of neuroprotective drugs to treat ischemic stroke still remains a significant area for investigation.

Dr. Sacco, associate professor of neurology at Columbia University College of Physicians & Surgeons and associate chairman of neurology and associate director of the stroke division at Columbia Presbyterian Medical Center of NewYork-Presbyterian Hospital, and his collaborators have published their study in the April 4 issue of the Journal of the American Medical Association (JAMA). They report on the GAIN Americas Trial (for Glycine Antagonist In Neuroprotection) - a randomized, double-blind, placebo-controlled trial in which 1,367 patients with ischemic stroke at 132 hospital centers in the United States and Canada were tested.

"Recognition of the ischemic penumbra, a region of reduced cerebral blood flow in which cell death might be prevented, has focused attention on treatments that might minimize or reverse brain damage when administered soon after stroke onset," the researchers write. The glycine site of the N-methyl-D-aspartate (NMDA) receptor complex is one site that has appeared to be a promising target for drugs administered just after a stroke. Gavestinel (GV150526) was shown to have high affinity and high selectivity for this glycine site. In preclinical trials, the drug inhibited NMDA-induced damage, reducing infarct size by 50 percent in a rat model. Further studies showed the drug could be safely tolerated in humans.

In the GAIN Americas Trial, the patients were stratified by age (less than or greater than 75 years) and initial stroke severity, as measured by the National Institutes of Health Stroke Scale, to achieve balance in these characteristics across treatment groups.

In the trial 701 patients were randomly assigned to receive a full dose of gavestinel over three days, and 666 patients received placebo. Their functional ability was measured at three months by the Barthel Index (BI), a scale that assesses the patients' degree of independence or dependence on others for help with daily activities.

In the end, no significant differences were found between the treatment group and the control group. Thirty-nine percent of the gavestinel-treated patients were independent at three months, compared with 37 percent of the placebo-treated patients. Even among the 241 patients treated within four (rather than six) hours of stroke onset, no beneficial effect for gavestinel was found. On the other hand, neither did gavestinel have any serious adverse effects.

This study corroborates the results of a similar study of gavestinel in Europe, Australia, and Asia published last year.

Dr. Sacco and his colleagues conclude that while this agent was not effective, "We still believe neuroprotection remains a viable strategy for acute stroke treatment and should continue to be studied."

The other authors of the article are Janet T. DeRosa, M.P.H.; Bruce Levin, Ph.D.; Tanja Rundek, M.D., Ph.D.; and John L. P. Thompson, Ph.D., of Columbia University; E. Clarke Haley, Jr., M.D.; Paul Ordronneau, Ph.D.; Stephen J. Phillips, M.B.B.S, F.R.C.P.C.; Rose G. Snipes, M.D.; and the GAIN Americas investigative group.

The study was funded by GlaxoSmithKline, manufacturer of gavestinel (GV150526).

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