Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial

Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial thumbnail
Summary Background Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke. Methods For this…


Summary

Background

Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95,
is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion.
In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion
that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic
stroke.

Methods

For this multicentre, double-blind, randomised, placebo-controlled study done in 48
acute care hospitals in eight countries, we enrolled patients with acute ischaemic
stroke due to large vessel occlusion within a 12 h treatment window. Eligible patients
were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation,
had been functioning independently in the community before the stroke, had an Alberta
Stroke Program Early CT Score (ASPECTS) greater than 4, and vascular imaging showing
moderate-to-good collateral filling, as determined by multiphase CT angiography. Patients
were randomly assigned (1:1) to receive intravenous nerinetide in a single dose of
2·6 mg/kg, up to a maximum dose of 270 mg, on the basis of estimated or actual weight
(if known) or saline placebo by use of a real-time, dynamic, internet-based, stratified
randomised minimisation procedure. Patients were stratified by intravenous alteplase
treatment and declared endovascular device choice. All trial personnel and patients
were masked to sequence and treatment allocation. All patients underwent endovascular
thrombectomy and received alteplase in usual care when indicated. The primary outcome
was a favourable functional outcome 90 days after randomisation, defined as a modified
Rankin Scale (mRS) score of 0–2. Secondary outcomes were measures of neurological
disability, functional independence in activities of daily living, excellent functional
outcome (mRS 0–1), and mortality. The analysis was done in the intention-to-treat
population and adjusted for age, sex, baseline National Institutes of Health Stroke
Scale score, ASPECTS, occlusion location, site, alteplase use, and declared first
device. The safety population included all patients who received any amount of study
drug. This trial is registered with
ClinicalTrials.gov,
NCT02930018.

Findings

Between March 1, 2017, and Aug 12, 2019, 1105 patients were randomly assigned to receive
nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide
and 329 (59·2%) of 556 with placebo achieved an mRS score of 0–2 at 90 days (adjusted
risk ratio 1·04, 95% CI 0·96–1·14; p=0·35). Secondary outcomes were similar between
groups. We observed evidence of treatment effect modification resulting in inhibition
of treatment effect in patients receiving alteplase. Serious adverse events occurred
equally between groups.

Interpretation

Nerinetide did not improve the proportion of patients achieving good clinical outcomes
after endovascular thrombectomy compared with patients receiving placebo.

Funding

Canadian Institutes for Health Research, Alberta Innovates, and NoNO.

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Article Info

Publication History

Published: February 20, 2020

Identification

DOI: https://doi.org/10.1016/S0140-6736(20)30258-0

Copyright

© 2020 Elsevier Ltd. All rights reserved.

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