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

TY - JOUR

T1 - Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial

AU - Hill, Michael D

AU - Goyal, Mayank

AU - Menon, Bijoy K

AU - Nogueira, Raul G

AU - McTaggart, Ryan A

AU - Demchuk, Andrew M

AU - Poppe, Alexandre Y

AU - Buck, Brian H

AU - Field, Thalia S

AU - Dowlatshahi, Dar

AU - van Adel, Brian A

AU - Swartz, Richard H

AU - Shah, Ruchir A

AU - Sauvageau, Eric

AU - Zerna, Charlotte

AU - Ospel, Johanna M

AU - Joshi, Manish

AU - Almekhlafi, Mohammed A

AU - Ryckborst, Karla J

AU - Lowerison, Mark W

AU - Heard, Kathy

AU - Garman, David

AU - Haussen, Diogo

AU - Cutting, Shawna M

AU - Coutts, Shelagh B

AU - Roy, Daniel

AU - Rempel, Jeremy L

AU - Rohr, Axel Cr

AU - Iancu, Daniela

AU - Sahlas, Demetrios J

AU - Yu, Amy Y X

AU - Devlin, Thomas G

AU - Hanel, Ricardo A

AU - Puetz, Volker

AU - Silver, Frank L

AU - Campbell, Bruce C V

AU - Chapot, René

AU - Teitelbaum, Jeanne

AU - Mandzia, Jennifer L

AU - Kleinig, Timothy J

AU - Turkel-Parrella, David

AU - Heck, Donald

AU - Kelly, Michael E

AU - Bharatha, Aditya

AU - Bang, Oh Young

AU - Jadhav, Ashutosh

AU - Gupta, Rishi

AU - Frei, Donald F

AU - Tarpley, Jason W

AU - McDougall, Cameron G

AU - Holmin, Staffan

AU - Rha, Joung-Ho

AU - Puri, Ajit S

AU - Camden, Marie-Christine

AU - Thomalla, Götz

AU - Choe, Hana

AU - Phillips, Stephen J

AU - Schindler, Joseph L

AU - Thornton, John

AU - Nagel, Simon

AU - Heo, Ji Hoe

AU - Sohn, Sung-Il

AU - Psychogios, Marios-Nikos

AU - Budzik, Ronald F

AU - Starkman, Sidney

AU - Martin, Coleman O

AU - Burns, Paul A

AU - Murphy, Seán

AU - Lopez, George A

AU - English, Joey

AU - Tymianski, Michael

AU - ESCAPE-NA1 Investigators

AU - Deb-Chatterji, Milani

N1 - Copyright © 2020 Elsevier Ltd. All rights reserved.

PY - 2020/3/14

Y1 - 2020/3/14

N2 - 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.

AB - 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.

KW - Acute Disease

KW - Aged

KW - Aged, 80 and over

KW - Brain Ischemia/complications

KW - Disks Large Homolog 4 Protein/drug effects

KW - Double-Blind Method

KW - Endovascular Procedures

KW - Female

KW - Humans

KW - Male

KW - Middle Aged

KW - Neuroprotective Agents/adverse effects

KW - Peptides/adverse effects

KW - Stroke/drug therapy

KW - Thrombectomy

KW - Treatment Outcome

U2 - 10.1016/S0140-6736(20)30258-0

DO - 10.1016/S0140-6736(20)30258-0

M3 - SCORING: Journal article

C2 - 32087818

VL - 395

SP - 878

EP - 887

JO - LANCET

JF - LANCET

SN - 0140-6736

IS - 10227

ER -