Effect of the Glycine Antagonist Gavestinel on cerebral infarcts in acute stroke patients, a randomized placebo-controlled trial: The GAIN MRI Substudy.
OBJECTIVE
Gavestinel, GV150526, is a selective antagonist at the glycine site of the N-methyl-D-aspartate receptor. The safety and efficacy of GV150526 were studied in two phase III randomized placebo-controlled clinical trials of acute ischemic stroke patients within 6 h from onset [The Glycine Antagonist in Neuroprotection (GAIN) International and GAIN Americas Trials]. A planned MRI substudy within these trials investigated the effect of gavestinel on infarct volume.


METHODS
Patients enrolled in the GAIN trials at designated MRI substudy sites were eligible if they had a pretreatment acute cortical lesion on diffusion-weighted MRI of at least 1.5 cm diameter or 5 cm(3). Final lesion assessment was performed on T(2)-weighted MRI at month 3. Blinded image analysis was performed centrally. The primary hypothesis was that gavestinel would attenuate lesion growth from baseline relative to placebo.


RESULTS
A total of 106 patients were eligible, 75 (34 gavestinel, 41 placebo) of whom had month 3 scans (primary analysis population). No effects of gavestinel on infarct volume were observed in the primary or other analyses. However, significant associations of lesion volume to clinical severity and outcomes were observed. Ischemic lesion volume decrease was predictive of substantial clinical improvement.


CONCLUSIONS
Consistent with the clinical outcomes in the GAIN trials, no effects of gavestinel on ischemic infarction was observed. Concordance of results of the clinical outcome trials with those of this infarct volume substudy as well the associations of infarct volume to clinical outcomes further support the potential role of infarct volume as a marker of outcome in dose finding and proof of principle acute stroke trials.
Warach
Steven
S
National Institute of Neurological Disorders and Stroke, Bethesda, Md 20892-1063, USA. warachs@ninds.njh.gov
Kaufman
David
D
Chiu
David
D
Devlin
Thomas
T
Luby
Marie
M
Rashid
Ajaz
A
Clayton
Linda
L
Kaste
Markku
M
Lees
Kennedy R
KR
Sacco
Ralph
R
Fisher
Marc
M
D002544:Cerebral Infarction / Q000150:complications / Q000188:drug therapy* / Q000473:pathology*; D004311:Double-Blind Method; D005500:Follow-Up Studies; D018684:Glycine Agents / Q000627:therapeutic use*; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D011446:Prospective Studies; D020521:Stroke / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D016896:Treatment Outcome
C105319:3-(2-((phenylamino)carbonyl)ethenyl)-4,6-dichloroindole-2-carboxylic acid; D018684:Glycine Agents; D007211:Indoles