加拿大卡尔加里大学Michael D Hill团队研究了Nerinetide在接受血管内血栓切除术而未进行溶栓治疗的急性缺血性卒中患者中的疗效和安全性。这一研究成果于2025年2月15日发表在《柳叶刀》杂志上。

在ESCAPE-NA1试验中，对因大血管闭塞而行血管内取栓术的急性缺血性卒中患者进行nerinetide（一种干扰突触后密度蛋白95的20肽）治疗与改善功能预后相关，且不同时使用静脉溶栓剂。静脉溶栓剂联合治疗无明显疗效。研究组试图确认在没有静脉溶栓药物治疗的情况下使用nerinetide的临床益处。

在这项多中心、随机、双盲、安慰剂对照的研究中，研究组在加拿大（16）、美国（16）、德国（21）、意大利(4)、荷兰(3)、挪威(4)、瑞士(3)、澳大利亚(8)和新加坡(2)的77个中心进行了研究，纳入了发病后12小时内因前循环大血管闭塞而急性缺血性卒中的患者。符合条件的患者在随机化时年龄为18岁或以上，患有致残性缺血性卒中（国立卫生研究院卒中量表[NIHSS]基线评分>5），卒中前在社区独立生活（Barthel指数评分>90），阿尔伯塔卒中计划早期CT评分（ASPECTS）大于4，未接受纤溶酶原激活剂治疗。

根据估计或实际体重（如果已知），采用实时、动态、基于互联网的分层随机最小化程序，患者被随机分配（1:1）接受单次剂量2.6 mg/kg的nerinetide静脉输注，最大剂量为270 mg或生理盐水安慰剂。所有患者均行血管内取栓术。主要结局是随机化后90天的良好功能结局，定义为改良Rankin量表（mRS）评分0-2。分析是通过意向治疗和调整从卒中发作到随机化的时间（≤4.5 h[是或否]）、年龄、性别、基线NIHSS评分、闭塞位置、从合格成像到随机化的时间、基线方面和区域。次要结局是死亡率、中风恶化、功能独立性改善和神经功能障碍的测量。

从2020年12月6日到2023年1月31日，850名患者被分配接受nerinetide （n=454）或安慰剂（n=396）。Nerinetide组206名（45%）参与者和安慰剂组181名（46%）参与者在90天的mRS评分为0 - 2（优势比0.97,95% CI 0.72 - 0.30；p = 0·82）。严重不良事件在两组间发生率相等。

研究结果表明，虽然Nerinetide不能改善急性缺血性脑卒中患者的预后，但与过量不良事件无关。需要进一步的研究来确定理想的治疗时间和卒中患者亚群，这些患者可能从目前的再灌注治疗联合治疗中受益。

Title: Efficacy and safety of nerinetide in acute ischaemic stroke in patients undergoing endovascular thrombectomy without previous thrombolysis (ESCAPE-NEXT): a multicentre, double-blind, randomised controlled trial

Author: Michael D Hill, Mayank Goyal, Andrew M Demchuk, Bijoy K Menon, Thalia S Field, William C Guest, Jorg Berrouschot, Albrecht Bormann, Mirko Pham, Karl G Haeusler, Diedrick W J Dippel, Pieter J van Doormaal, Franziska Dorn, Felix J Bode, Brian A van Adel, Demetrios J Sahlas, Richard H Swartz, Leodante Da Costa, Johanna M Ospel, Rosalie V McDonough, Karla J Ryckborst, Mohammed A Almekhlafi, Kathy J Heard, David J Garman, Corey Adams, Yatika Kohli, Bridget A Schoon, Brian H Buck, Mario Muto, Atif Zafar, Hauke Schneider, Jonathan A Grossberg, Leonard L L Yeo, Jason W Tarpley, Marios-Nikos Psychogios, Jonathan M Coutinho, Nicola Limbucci, Volker Puetz, Michael E Kelly, Bruce C V Campbell, Sven Poli, Alexandre Y Poppe, Jai J Shankar, Ronil Chandra, Dar Dowlatshahi, George A Lopez, Luigi Cirillo, Aimen Moussaddy, Michael Devlin, Pablo Garcia-Bermejo, Jennifer L Mandzia, Mona Skjelland, Anne Hege Aamodt, Frank L Silver, Timothy J Kleinig, Guglielmo Pero, Jens Minnerup, Ryan A McTaggart, Ajit S Puri, Albert H Y Chiu, Gernot Reimann, Gordon J Gubitz, Marie-Christine Camden, Seon Kyu Lee, Eric Sauvageau, Sibu Mundiyanapurath, Donald F Frei, Hana Choe

Issue&Volume: 2025/02/15

Abstract:

Background

In the ESCAPE-NA1 trial, treatment with nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, was associated with improved functional outcome among patients with acute ischaemic stroke due to large vessel occlusion undergoing endovascular thrombectomy without co-treatment with an intravenous thrombolytic agent. There was no benefit when intravenous thrombolytic agent co-treatment was used. We sought to confirm the clinical benefit of nerinetide in the absence of previous intravenous thrombolytic drug treatment.

Methods

In this multicentre, randomised, double-blind, placebo-controlled study, done in 77 centres in Canada (16), the USA (16), Germany (21), Italy (four), the Netherlands (three), Norway (four), Switzerland (three), Australia (eight), and Singapore (two), we enrolled patients with acute ischaemic stroke due to anterior circulation large vessel occlusion within 12 h from onset. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation (baseline National Institutes of Health Stroke Scale [NIHSS] score >5), who had been functioning independently in the community (Barthel Index score >90) before the stroke, had Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and who were not treated with a plasminogen activator. Patients were randomly allocated (1:1) to receive intravenous infusion of nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, based upon estimated or actual weight (if known) or saline placebo using a real-time, dynamic, internet-based, stratified randomised minimisation procedure. All patients underwent endovascular thrombectomy. The primary outcome was a favourable functional outcome 90 days from randomisation, defined as a modified Rankin Scale (mRS) score of 0–2. The analysis was by intention to treat and adjusted for time from stroke onset to randomisation (≤4·5 h [yes or no]), age, sex, baseline NIHSS score, occlusion location, time from qualifying imaging to randomisation, baseline ASPECTS, and region. Secondary outcomes were measures of mortality, worsening of stroke, improved functional independence, and measures of neurological disability. This trial is registered with ClinicalTrials.gov, NCT04462536.

Findings

From Dec 6, 2020, to Jan 31, 2023, 850 patients were assigned to receive nerinetide (n=454) or placebo (n=396). 206 (45%) participants in the nerinetide group and 181 (46%) participants in the placebo group achieved an mRS score of 0–2 at 90 days (odds ratio 0·97, 95% CI 0·72–1·30; p=0·82). Serious adverse events occurred equally between groups.

Interpretation

While nerinetide did not improve outcomes in patients with acute ischaemic stroke, it was not associated with excess adverse events. Further study is needed to identify the ideal timing of treatment and the sub-population of stroke patients who might benefit from treatment combined with current reperfusion therapies.

DOI: 10.1016/S0140-6736(25)00194-1

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)00194-1/abstract