Natalizumab in acute ischemic stroke (ACTION II) A randomized, placebo-controlled trial

Objective We evaluated the effect of 2 doses of natalizumab on functional outcomes in patients with acute ischemic stroke (AIS). Methods In this double-blind phase 2b trial, patients with AIS aged 18-80 years with NIH Stroke Scale scores of 5-23 from 53 US and European sites were randomized 1:1:1 to receive a single dose of 300 or 600 mg IV natalizumab or placebo, with randomization stratified by treatment window (<= 9 or >9 to <= 24 hours from patient's last known normal state). The primary endpoint was a composite measure of excellent outcome (modified Rankin Scale score <= 1 and Barthel Index score >= 95) at day 90 assessed in all patients receiving a full dose. Sample size was estimated from a Bayesian model;pvalues were not used for hypothesis testing. Results An excellent outcome was less likely with natalizumab than with placebo (natalizumab 300 or 600 mg odds ratio 0.60; 95% confidence interval 0.39-0.93). There was no effect modification by time to treatment or use of thrombolysis/thrombectomy. For natalizumab 300 mg, 600 mg, or placebo, there were no differences in incidence of adverse events (90.0%, 92.1%, and 92.3%, respectively), serious adverse events (25.6%, 32.6%, and 20.9%, respectively), or deaths (6.7%, 4.5%, and 5.5%, respectively). Conclusions Natalizumab administered <= 24 hours after AIS did not improve patient outcomes. ClinicalTrials.gov identifier NCT02730455 Classification of evidence This study provides Class I evidence that for patients with AIS, an excellent outcome was less likely in patients treated with natalizumab than with placebo.