Multicenter SPAN Trial of Fasudil in Ischemic Stroke

Abstract

BACKGROUND: The SPAN (Stroke Preclinical Assessment Network) is a confirmatory multicenter trial network to test cerebroprotective interventions in experimental acute stroke. In a first-of-its-kind trial, SPAN tested 6 interventions in a rodent model of transient focal ischemic stroke. Here, we report the efficacy of fasudil, an isoform-nonselective rho-associated kinase inhibitor, on primary and secondary outcomes in the SPAN trial. METHODS: Fasudil was administered at 10 mg/kg intraperitoneally every 12 hours for 6 doses starting 5 minutes before reperfusion in a 60-minute endovascular filament middle cerebral artery occlusion model. The active treatment arm (n=345) was compared with the pooled intraperitoneal and intravenous vehicle arms (n=344). In addition to healthy young mice, the trial included aging mice (16±1 months), diet-induced obese mice, and spontaneously hypertensive rats. The a priori fasudil substudy design stipulated the modified corner test performance on day 28 as the primary end point and separate analyses for mice and spontaneously hypertensive rats using the modified intention-to-treat cohort. RESULTS: Fasudil improved the primary outcome end point in mice (probabilistic index point estimate, 0.57; P=0.022). The effect appeared stronger in aging mice and when ischemia was induced during the active circadian stage. Fasudil did not show any benefit in the spontaneously hypertensive rats. Alternative analyses using the per-protocol population and imputation generally yielded similar conclusions. CONCLUSIONS: Our results reveal a favorable therapeutic profile for fasudil, supporting future translational development of rho-associated kinase inhibitors in ischemic stroke.