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GAIN Americas: A Randomized Controlled Trial

Ralph L. Sacco, MD,MS; Janet T. DeRosa, MPH; E. Clarke Haley, Jr, MD; Bruce Levin, PhD; Paul Ordronneau, PhD; Stephen J. Phillips, MBBS,FRCPC; Tanja Rundek, MD,PhD; Rose G. Snipes, MD; John L. P. Thompson, PhD; for the GAIN Americas Investigators

JAMA. 2001;285:1719-1728.

Context  Elucidation of the ischemic cascade has helped stimulate development of neuroprotective drugs aimed at limiting brain injury in the hours following an ischemic stroke. To date, none of these drugs has shown clinical efficacy.

Objective  To examine the efficacy of gavestinel (GV150526), an antagonist of the glycine site of the N-methyl-D-aspartate receptor, as a neuroprotective therapy for acute ischemic stroke when administered within 6 hours of symptom onset.

Design  The Glycine Antagonist in Neuroprotection (GAIN) Americas trial, a randomized, double-blind placebo-controlled trial with enrollment from April 1998 to October 1999.

Setting  One hundred thirty-two hospital centers across the United States and Canada.

Patients  The primary efficacy population consisted of 1367 ischemic stroke patients with a predefined level of limb weakness and functional independence prior to stroke, stratified at randomization by age (75 vs >75 years) and initial stroke severity (National Institutes of Health [NIH] Stroke Scale scores of 2-5, 6-13, or 14).

Intervention  Patients were randomly assigned to receive an intravenous loading dose (800 mg) plus 5 maintenance doses (200 mg every 12 hours) of gavestinel (n = 701) or placebo (n = 666) for 3 days.

Main Outcome Measure  Functional capability at 3 months, measured by the Barthel Index (BI), with scores trichotomized as dead/0-55, 60-90, and 95-100, compared between the gavestinel and placebo groups.

Results  Treatment groups were well matched for baseline characteristics. For each group, median NIH Stroke Scale was 12, median age was 72 years, and median time to treatment was 5.2 hours. No statistically significant improvement on the 3-month BI trichotomy was demonstrated for gavestinel (P = .79). The proportion who were functionally independent (BI score = 95-100) was 39% in the gavestinel group and 37% in the placebo group. No statistically significant difference in 3-month survival was observed using Kaplan-Meier curves (P = .11). No other secondary end point suggested an advantage for gavestinel. Among the 333 patients (24%) who received recombinant tissue-type plasminogen activator, there was also no benefit for gavestinel (P = .53). There were no serious safety issues.

Conclusion  In this study, gavestinel administered up to 6 hours after an acute ischemic stroke did not improve functional outcome at 3 months.

Author Affiliations: Columbia University and the New York-Presbyterian Hospital, New York, NY (Drs Sacco, Levin, Rundek, Thompson, and Ms DeRosa); University of Virginia Health System, Charlottesville (Dr Haley); Glaxo Wellcome Inc, Research Triangle Park, NC (Drs Ordronneau and Snipes); and Dalhousie University, Halifax, Nova Scotia (Dr Phillips).

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