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The demonstration of the ischaemic penumbra in animal models and the effectiveness of reperfusion therapy in humans led to considerable optimism for neuroprotection in acute stroke. Initial experience with failure of phase II and III trials led to the STAIR recommendations for pre-clinical and clinical studies. Review of pre-clinical studies suggests that selection of agents for clinical development may not have been optimal. The neuroprotective agent NXY-059 fulfilled pre-clinical and many clinical STAIR criteria but a second large phase III study failed to demonstrate any benefit. Many of the STAIR criteria have not been fulfilled in the development of recent neuroprotective agents. Other issues not addressed include the use of animal models more reflective of older stroke patients with physiological derangement, demonstration of drug distribution to the proposed site of action in humans, selection of patients with salvageable tissue, achieving very early treatment, refinement of measurement of neurological impairment and disability, and physiological optimization in proof of concept human studies. Increasing the number and quality of clinical centres undertaking acute stroke research, use of surrogate imaging markers and adaptive dose designs in phase II trials could improve the likelihood of identifying an effective neuroprotective. Neuroprotection in acute stroke remains a significant challenge but has not been clearly shown to be ineffective. Given the profound burden of stroke and limited applicability of reperfusion to currently at best 10% patients, further proof of concept studies of neuroprotection remain indicated with careful review of pre-clinical data and more rigorous phase II trial design.

Original publication




Conference paper

Publication Date



153 Suppl 1


S112 - S119


Acute Disease, Animals, Biomarkers, Brain Ischemia, Clinical Trials as Topic, Drug Evaluation, Preclinical, Humans, Reperfusion Injury, Stroke