NXY-059 for the treatment of acute stroke: pooled analysis of the SAINT I and II Trials.
OBJECTIVE
In animal models of acute ischemic stroke (AIS), the free radical-trapping agent NXY-059 showed promise as a neuroprotectant. SAINT I and II were randomized, placebo-controlled, double-blind trials to investigate the efficacy of NXY-059 in patients with AIS.


METHODS
Patients with AIS received an infusion of intravenous NXY-059 or placebo within 6 hours from the onset of stroke symptoms. A pooled individual patient analysis was prespecified to assess the overall efficacy and to examine subgroups. The primary end point was the distribution of disability scores measured on the modified Rankin scale (mRS) at 90 days. Neurologic and activities of daily living scores were investigated as secondary end points. We also evaluated whether treatment with NXY-059 would reduce alteplase-related intracranial hemorrhages. Finally, we evaluated possible predictors of good or poor outcome.


RESULTS
An intent-to-treat efficacy analysis was based on 5028 patients. Baseline parameters and prognostic factors were well balanced between treatment groups. The distribution of scores on the mRS was not different in the group treated with NXY-059 (n=2438) compared with the placebo group (n=2456): odds ratio for limiting disability=1.02; 95% CI, 0.92 to 1.13 (P=0.682, Cochran-Mantel-Haenszel test). Comparisons at each level of the mRS confirmed an absence of benefit. There was no evidence of efficacy in prespecified subgroups or from the secondary outcome analyses. Mortality was equal in the 2 groups (16.7% vs 16.5%), and adverse event rates were similar. Among patients treated with alteplase, there was no decrease in rates of symptomatic or asymptomatic hemorrhage associated with NXY-059 treatment versus placebo. Subgroup analyses identified National Institutes of Health Stroke Scale score, age, markers of inflammation, blood glucose, and right-sided infarct as predictors of poor outcome.


CONCLUSIONS
NXY-059 is ineffective for treatment of AIS within 6 hours of symptom onset. This is also true for subgroups and the prevention of alteplase-associated hemorrhage.
Diener
Hans-Christoph
HC
Department of Neurology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany. hans.diener@uni-duisburg-essen.de
Lees
Kennedy R
KR
Lyden
Patrick
P
Grotta
Jim
J
Davalos
Antoni
A
Davis
Stephen M
SM
Shuaib
Ashfaq
A
Ashwood
Tim
T
Wasiewski
Warren
W
Alderfer
Vivian
V
Hårdemark
Hans-Goran
HG
Rodichok
Larry
L
D000367:Age Factors; D000368:Aged; D000975:Antioxidants / Q000008:administration & dosage* / Q000009:adverse effects; D001557:Benzenesulfonates / Q000008:administration & dosage* / Q000009:adverse effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002543:Cerebral Hemorrhage / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control; D002544:Cerebral Infarction / Q000453:epidemiology; D015897:Comorbidity; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004632:Emergency Medical Services / Q000379:methods; D004660:Encephalitis / Q000453:epidemiology; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000453:epidemiology; D007275:Injections, Intravenous; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000009:adverse effects; D010919:Placebos; D011379:Prognosis; D020521:Stroke / Q000188:drug therapy*; D017211:Treatment Failure
D000975:Antioxidants; D001557:Benzenesulfonates; D018696:Neuroprotective Agents; D010919:Placebos; C120851:disufenton sodium