Selfotel in acute ischemic stroke - Possible neurotoxic effects of an NMDA antagonist

Background and Purpose-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 greater than or equal to 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, neurotoxic effect in brain ischemia.