Ischemic stroke continues to be a major public health problem, and is the third leading cause of death and the leading cause of disability in adults over age 45 in the United States. To date, no treatment has been proven to be useful in limiting the amount of ischemic brain injury and improving outcome following acute cerebral infarction. Tirilazad mesylate, a 21-aminosteroid lipid peroxidase inhibitor, has shown great promise in reducing infarct size in experimental models of focal brain ischemia and has an excellent record of safety in human trials. The enclosed proposal outlines the details of a large-scale, multi-center, randomized, double-blind, placebo-controlled trial of tirilazad mesylate in patients with symptoms of acute cerebral infarction of less than 6 hours' duration. To expedite the initiation of treatment with study drug as soon as possible after the onset of symptoms, treatment will be initiated before full eligibility is determined, thereby saving valuable minutes during which irreversible changes in brain tissue may be occurring. Fully eligible patients will continue treatment for 72 hours, while all randomized patients will be followed-up at 7-10 days and 3 months. The primary endpoint for the trial will be the proportion of patients (both all randomized and fully eligible) achieving an independent recovery at three months following the stroke. Assuming that 50% of randomized patients may not be fully eligible, we estimate that 2244 patients (1122 in each treatment group) will need to be randomized to detect an absolute improvement rate of 12% in independent recovery in the fully eligible tirilazad group with two tailed alpha=0.05 and power=0.80.
