Glycine antagonist in neuroprotection for patients with acute stroke gain americas: A randomized controlled trial

Ralph L Sacco, Janet T. DeRosa, E. Clarke Haley, Bruce Levin, Paul Ordronneau, Stephen J. Phillips, Tatjana Rundek, Rose G. Snipes, John L P Thompson

Research output: Contribution to journalArticle

230 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1719-1728
Number of pages10
JournalJournal of the American Medical Association
Volume285
Issue number13
StatePublished - Apr 4 2001
Externally publishedYes

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Glycine
Randomized Controlled Trials
Stroke
Placebos
National Institutes of Health (U.S.)
Neuroprotection
3-(2-((phenylamino)carbonyl)ethenyl)-4,6-dichloroindole-2-carboxylic acid
Neuroprotective Agents
Tissue Plasminogen Activator
Random Allocation
N-Methyl-D-Aspartate Receptors
Brain Injuries
Canada
Therapeutics
Extremities
Outcome Assessment (Health Care)
Safety
Survival
Pharmaceutical Preparations
Population

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Sacco, R. L., DeRosa, J. T., Haley, E. C., Levin, B., Ordronneau, P., Phillips, S. J., ... Thompson, J. L. P. (2001). Glycine antagonist in neuroprotection for patients with acute stroke gain americas: A randomized controlled trial. Journal of the American Medical Association, 285(13), 1719-1728.

Glycine antagonist in neuroprotection for patients with acute stroke gain americas : A randomized controlled trial. / Sacco, Ralph L; DeRosa, Janet T.; Haley, E. Clarke; Levin, Bruce; Ordronneau, Paul; Phillips, Stephen J.; Rundek, Tatjana; Snipes, Rose G.; Thompson, John L P.

In: Journal of the American Medical Association, Vol. 285, No. 13, 04.04.2001, p. 1719-1728.

Research output: Contribution to journalArticle

Sacco, RL, DeRosa, JT, Haley, EC, Levin, B, Ordronneau, P, Phillips, SJ, Rundek, T, Snipes, RG & Thompson, JLP 2001, 'Glycine antagonist in neuroprotection for patients with acute stroke gain americas: A randomized controlled trial', Journal of the American Medical Association, vol. 285, no. 13, pp. 1719-1728.
Sacco, Ralph L ; DeRosa, Janet T. ; Haley, E. Clarke ; Levin, Bruce ; Ordronneau, Paul ; Phillips, Stephen J. ; Rundek, Tatjana ; Snipes, Rose G. ; Thompson, John L P. / Glycine antagonist in neuroprotection for patients with acute stroke gain americas : A randomized controlled trial. In: Journal of the American Medical Association. 2001 ; Vol. 285, No. 13. pp. 1719-1728.
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abstract = "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.",
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AU - Sacco, Ralph L

AU - DeRosa, Janet T.

AU - Haley, E. Clarke

AU - Levin, Bruce

AU - Ordronneau, Paul

AU - Phillips, Stephen J.

AU - Rundek, Tatjana

AU - Snipes, Rose G.

AU - Thompson, John L P

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N2 - 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.

AB - 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.

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