and SCI.24 An initial North American trial of 1100 TBI patients compared tirilazad treatment with placebo for 5 days, both initiated with 4h postinjury. The trial ended with such a confounding randomization imbalance that no meaningful efficacy analysis could be extracted. In contrast, a European phase III trial was successfully completed, but failed to show an overall effect in moderate and severely injured patients. However, post hoc analysis revealed that the new compound entity significantly improved survival in both moderately and severely injured male patients with tSAH.22 This beneficial effect in the tSAH subgroup, representing about half of the severe TBIs, was not surprising, in that the new compound entity had previously been shown to improve recovery and survival in a phase III trial in aneurysmal SAH patients.23 Interestingly, this effect in tSAH and aneurysmal SAH was mainly apparent in males. This gender difference was partially due to a faster rate of metabolism of the drug in females. Nevertheless, subsequent female-only trials with higher tirilazad doses that were calculated to duplicate the exposure levels in males failed to demonstrate the same level of efficacy as seen in male patients, although beneficial effects were apparent in females with the more severe SAH. Thus the issue of gender differences in neuroprotective drug responsiveness clouds the interpretation of the neuroprotective efficacy of tirilazad.

Tirilazad was also extensively evaluated in four different phase III stroke trials.15'16 The first two (TESS I in Europe, and RANTTAS I in the USA) evaluated the effects of 6mgkg_ 1 intravenous (i.v.) per day for 3 days, with treatment beginning within 6h of stroke onset. No effect was seen on 3- or 6-month outcomes. Two subsequent higher dose trials (10mgkg_ 1 per day in males; 15mgkg_ 1 per day in females) were conducted. The first, the European

TESS II, which included patients enrolled within the first 6h of the stroke occurring, was stopped prematurely due to a significant increase in morbidity and mortality in the high-dose tirilazad group. Prudence dictated the simultaneous cessation of the parallel US high-dose RANTTAS II trial. However, subsequent analysis of the 3-month recovery scores of the approximately 100 patients enrolled in RANTTAS II revealed a nearly significant improvement in neurological recovery. The only difference between the two trials was that in TESS II the enrollment window was 6 h, whereas in RANTTAS II treatment began within 4h. The contrasting results of TESS II and RANTTAS II indicate that tirilazad may be effective in stroke patients if given in the first 4h, but may in fact be harmful if delayed until 6 h. Another issue besides therapeutic window is the issue of how long to maintain treatment. The decision to treat stroke patients in all of the tirilazad trials for 72 h was based on the limits of safety rather than on a demonstration of the benefits of such lengthy treatment in preclinical stroke models.20 The toxicity of the drug in TESS II indicates that it is possible to overtreat with tirilazad. Thus, the possibility exists that a shorter treatment duration may have yielded more positive results. The fact that neither the optimum therapeutic window nor the optimal treatment duration were ever determined for tirilazad or any other neuroprotective drug prior to their being advanced into clinical trials for TBI or stroke may have played a role in the failures of NMDA antagonists, the calcium channel blocker nimodipine, and the antioxidants PEG-SOD and tirilazad in achieving an overall beneficial effect.

Currently, however, the nitroxide free radical 'spin trapping' agent NXY-059 is being tested in phase III stroke trials.27

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