Previous Stroke Neuroprotective Trials

Over the past 15 years, over 85 phase II and phase III drug trials have been conducted to investigate the clinical efficacy of stroke neuroprotective drugs that target one or more pathways of cell death.5 These drugs were developed based on the promising results of over a thousand experimental studies in animal stroke models.6 Unfortunately, no drug has survived the challenge of clinical testing. The most notable failure is the SAINT-II trial of NXY-059, a free radical scavenger. Rodent and primate studies had shown remarkable efficacy with this drug, and the initial SAINT-I trial in Australasia and Europe showed that NXY-059 improved functional outcome after acute stroke and reduced the risk of thrombolytic-associated hemorrhage.7 The field of stroke neuroprotection was optimistic that SAINT-II, the largest ever acute stroke trial, would yield positive results. However, like numerous other trials of nonthrombolytic drugs, SAINT-II proved to be a negative trial and the company (Astra-Zeneca) terminated plans to further investigate the potential of this drug to treat stroke. Previous drugs that failed clinical trials include the lipid peroxidation inhibitor tirilazad mesylate,8 the ICAM-1 antibody enlimomab,9 the recombinant basic fibroblast growth factor Trafermin,10 the sodium channel blocker fosphenytoin, the calcium channel blocker nimodipine,11 the GABA agonist clomethiazole,12,13 the glutamate antagonist and sodium channel blocker lubeluzole,14 the competitive NMDA antagonist selfotel,15 and several noncompetitive NMDA antagonists (dextrorphan, gavestinel, aptiganel, and eliprodil).

The failure of these predominantly industry-sponsored clinical trials has been devastating for the field of stroke neuroprotection. Some of these failures may indeed be attributable to the lack of efficacy of the drug being tested. However, these past failures have also exposed the shortcomings of clinical trial designs, such as inadequate sample sizes, poor patient selection, and suboptimal choice of outcome measures. Efforts are underway to understand and address the reasons behind the failure of previous trials. The results of a recent meta-analysis6 indicate that the process of preclinical testing and drug selection for clinical trials was inadequate, and more stringent guidelines have been proposed.6,16,17 Neuroimaging is being advocated as a means to optimize patient selection, and attention is being paid to developing clinical outcome measures that are more sensitive and better suited for the drug being tested.18 The focus is shifting toward the use of drugs and physiological strategies as adjunctive therapies that expand the therapeutic time window for thrombolysis, and the development of combination therapies that target multiple rather than a single pathway of cell death. These and other advances provide reason to remain optimistic about the future of stroke neuroprotection. While a detailed review of past failures is beyond the scope of this chapter, the following sections provide a summary of a few highly promising drugs that failed clinical testing and a review of ongoing phase II and phase III clinical trials.

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