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

ESCAPE-NA1 Investigators

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243 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)878-887
Number of pages10
JournalThe Lancet
Issue number10227
Publication statusPublished - 2020 Mar 14

Bibliographical note

Funding Information:
AB reports personal fees from Medtronic, outside the submitted work. SBC reports trial support from Boehringer Ingelheim, outside the submitted work. AMD reports grants from NoNO during the conduct of the study; a patent, Circle NVI, issued; and honoraria for continued medical education events from Medtronic. TGD reports grants from Medtronic; research support and consultancy fees from Medtronic, Viz.ai, and Neural Analytics; and equity interest from VIZ.AI and Neural Analytics, outside the submitted work; he also reports a patent neuronal protection device issued. JE reports personal fees from Stryker Neurovascular, outside the submitted work. TSF reports grants from Bayer Canada, and personal fees from BMS-Pfizer and Servier, outside the submitted work. DFF reports personal fees from Penumbra, Stryker, Genentech, and Siemens, outside the submitted work. DG is an officer of NoNO and is the inventor of three patents, owned by NoNO. MG reports personal fees from Medtronic, Stryker, Microvention, and Mentice, during the conduct of the study; unrestricted research grants to University of Calgary from NoNO, Stryker, and Medtronic; patents for a system of acute stroke diagnosis, with royalties paid to GE Healthcare, and a system of simulation for acute neurointervention, with royalties paid to Mentice; and ownership interest in Circle Neurovascular. RAH reports personal fees from Medtronic, Stryker, Microvention, and Cerenovous; in the scientific advisory board of Elum, MIVI, Three Rivers Medical, and Cerebrotech; and is a stockholder in Elum, Cerebrotech, Endostream, Scientia, Rist, Inneuroco, Deinde, Synchron, Three Rivers Medical, Serenity, and Bendit, outside the submitted work. DHa is a consultant for Stryker and Vesalio, and holds stock options from Viz.ai. KH holds stock options from NoNO. DHe reports personal fees from Stryker, outside the submitted work. MDH reports grants from Canadian Institutes for Health Research, Alberta Innovates, and NoNO, for the conduct of the study; reports personal fees from Merck; reports non-financial support from Hoffmann-La Roche Canada; reports grants from Covidien (Medtronic), Boehringer-Ingleheim, Stryker, and Medtronic, outside the submitted work; reports a patent for systems and methods for assisting in decision-making and triaging for acute stroke patients, issued to US Patent office Number 62/086,077; owns stock in Calgary Scientific; is a director of the Canadian Federation of Neurological Sciences and Circle NeuroVascular; and has received grant support from Alberta Innovates Health Solutions, CIHR, Heart & Stroke Foundation of Canada, and the National Institutes of Neurological Disorders and Stroke. CGM holds stock from NoNO. BKM holds shares in Circle NVI, and reports a patent for systems of triage in acute stroke. RGN reports personal fees from Stryker Neurovascular, Medtronic, Cerenovus/Neuravi, Phenox, Anaconda, Genentech, Biogen, Prolong Pharmaceuticals, Brainomix, Viz.ai, Corindus Vascular Robotics, Vesalio, and Ceretrieve; reports non-financial collaboration with Stryker Neurovascular, Medtronic, Penumbra, Cerenovus/Neuravi, and Phenox; reports financial compensation from research or trials from Stryker Neurovascular and Medtronic; reports consultancy fees from Stryker Neurovascular; and is a member of the Physician Advisory Board for Cerenovus/Neuravi, outside the submitted work. M-NP reports case fee paid to institution by NoNO, during the conduct of the study. ASP reports grants from Stryker Neurovascular and Medtronic; personal fees from Microvention, Cerenovus, CereVasc, and Merit; and stock options from InNeuroCo, outside the submitted work. SS reports grants from NoNO and University of Calgary, during the conduct of the study. JWT reports consultancy fees from Medtronic, outside the submitted work. GT reports grants and personal fees from Bayer and personal fees from Acandis, Portola, Stryker, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, and Daiichi Sankyo, outside the submitted work. JTh reports personal fees from Mircovetion, Cerenovus, and Perfuze, outside the submitted work. DT-P reports personal fees from Guidepoint, Mosaic Research Management, and Alphasights, outside the submitted work. MT is the CEO of NoNO and is the inventor of patents owned by NoNO. All other authors declare no competing interests.

Publisher Copyright:
© 2020 Elsevier Ltd

All Science Journal Classification (ASJC) codes

  • Medicine(all)


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