Selfotel in acute ischemic stroke : possible neurotoxic effects of an NMDA antagonist.
OBJECTIVE
Based on neuroprotective efficacy in animal models, we evaluated the N-methyl D-aspartate antagonist Selfotel in patients with ischemic stroke, after doses up to 1.5 mg/kg were shown to be safe in phase 1 and phase 2a studies.


METHODS
Two pivotal phase 3 ischemic stroke trials tested the hypothesis, by double-blind, randomized, placebo-controlled parallel design, that a single intravenous 1.5 mg/kg dose of Selfotel, administered within 6 hours of stroke onset, would improve functional outcome at 90 days, defined as the proportion of patients achieving a Barthel Index score of >/=60. The trials were performed in patients aged 40 to 85 years with acute ischemic hemispheric stroke and a motor deficit.


RESULTS
The 2 trials were suspended on advice of the independent Data Safety Monitoring Board because of an imbalance in mortality after a total enrollment of 567 patients. The groups were well matched for initial stroke severity and time from stroke onset to therapy. There was no difference in the 90-day mortality rate, with 62 deaths (22%) in the Selfotel group and 49 (17%) in the placebo-treated group (RR=1.3; 95% CI 0.92 to 1.83; P=0.15). However, early mortality was higher in the Selfotel-treated patients (day 30: 54 of 280 versus 37 of 286; P=0.05). In patients with severe stroke, mortality imbalance was significant throughout the trial (P=0.05).


CONCLUSIONS
Selfotel was not an effective treatment for acute ischemic stroke. Furthermore, a trend toward increased mortality, particularly within the first 30 days and in patients with severe stroke, suggests that the drug might have a neurotoxic effect in brain ischemia.
Davis
S M
SM
Departments of Neurology, Royal Melbourne Hospital and University of Melbourne, Australia. sdavis@ariel.its.unimelb.edu.au
Lees
K R
KR
Albers
G W
GW
Diener
H C
HC
Markabi
S
S
Karlsson
G
G
Norris
J
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004311:Double-Blind Method; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D010875:Pipecolic Acids / Q000008:administration & dosage*; D020521:Stroke / Q000188:drug therapy* / Q000503:physiopathology; D016896:Treatment Outcome
D018691:Excitatory Amino Acid Antagonists; D010875:Pipecolic Acids; C053672:selfotel