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

Abstract

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; p values 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.

Clinicaltrialsgov 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.

Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Figures

Figure 1. Safety and Efficacy of Intravenous Natalizumab in Acute Ischemic Stroke (ACTION II) study design and patient disposition

(A) ACTION II study design and (B) patient disposition. *Number of patients withdrawn includes some patients who withdrew prior to receiving a full dose of study treatment. BDI-2 = Beck Depression Inventory 2; BI = Barthel Index; EQ-5D-3L = EuroQoL 5 dimensions/3 levels; FIM = Functional Independence Measure; FSS = Fatigue Severity Scale; HRU = healthcare resource utilization; LKN = last known normal; mITT = modified intent-to-treat; MoCA = Montreal Cognitive Assessment; mRS = modified Rankin Scale; NIHSS = NIH Stroke Scale; R = randomization; SDMT = Symbol Digit Modalities Test; SIS-16 = Stroke Impact Scale–16.

Figure 2. Subgroup analyses of the odds of an excellent outcome

Subgroup analyses of the odds of an excellent outcome on (A) the composite endpoint, (B) the modified Rankin scale (mRS), and (C) the Barthel Index (BI) at day 90 in the modified intent-to-treat population treated with natalizumab 300 mg or 600 mg vs placebo and (D) distributions of mRS scores at day 90. CI = confidence interval; OR = odds ratio; tPA = tissue plasminogen activator.

Figure 3. Pharmacokinetic and pharmacodynamic assessments

Pharmacokinetic and pharmacodynamic assessments of (A) serum natalizumab concentration (concentrations were below detectable levels in 1 natalizumab 600 mg patient at 24 hours, 6 natalizumab 300 mg patients and 4 natalizumab 600 mg patients at 30 days, and 59 natalizumab 300 mg patients and 60 natalizumab 600 mg patients at 90 days), (B) α4 integrin saturation (for α4 integrin saturation, median values were plotted over time instead of mean values due to outliers; 2 participants in the placebo group at 30 days and 1 participant in the placebo group at 90 days had extremely high α4 integrin saturation values due to laboratory errors), and (C) CD49d levels. Pharmacokinetic analyses were performed for 176 patients (87 in the natalizumab 300 mg group and 89 in the natalizumab 600 mg group) in the pharmacokinetic population, which included patients who had received the entire infusion of natalizumab at the baseline visit and had at least 1 measurable sample collected for the determination of natalizumab concentrations. The pharmacodynamic population included all patients who received the entire infusion of study treatment and had at least 1 postbaseline pharmacodynamic assessment (90 in the placebo group, 87 in the natalizumab 300 mg group, and 89 in the natalizumab 600 mg group). MFI = mean fluorescence intensity; SE = standard error.