Factors Influencing Nerinetide Effect on Clinical Outcome in Patients Without Alteplase Treatment in the ESCAPE-NA1 Trial

Article information

J Stroke. 2025;27(1):95-101

Publication date (electronic) : 2025 January 31

doi : https://doi.org/10.5853/jos.2024.03139

Mayank Goyal^,1,2, Bijoy K. Menon^1,2, Johanna Ospel^1,2, Mohammed Almekhlafi^1,2, Charlotte Zerna³, Raul Nogueira⁴, Ryan McTaggart⁵, Andrew M. Demchuk^1,2, Alexandre Y. Poppe⁶, Brian Buck⁷, Kathy Heard⁸, Manish Joshi^1,2, Diogo Haussen⁸, Shawna Cutting⁵, Shelagh B. Coutts², Daniel Roy⁶, Jeremy L. Rempel⁷, Thalia S. Field⁹, Dar Dowlatshahi¹⁰, Brian van Adel¹¹, Richard Swartz¹², Ruchir Shah¹³, Eric Sauvageau¹⁴, Volker Puetz¹⁵, Frank L. Silver¹⁶, Bruce Campbell¹⁷, René Chapot¹⁸, Michael Tymianski⁸, Michael D. Hill^1,2, on Behalf of the ESCAPE-NA1 Investigators

¹Department of Diagnostic Imaging, Cumming School of Medicine, University of Calgary, Calgary, Canada

²Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Canada

³Städtisches Klinikum Dresden, Dresden, Germany

⁴Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

⁵Warren Alpert School of Medicine, Brown University, Providence, RI, USA

⁶Centre Hospitalier de l’Université de Montréal, Montreal, QC, Canada

⁷University of Alberta Hospital, Edmonton, Alberta, Canada

⁸NoNO Inc., Toronto, Canada

⁹University of British Columbia, Vancouver, BC, Canada

¹⁰Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada

¹¹McMaster University, Hamilton, ON, Canada

¹²Sunnybrook Health Sciences Centre, Toronto, Canada

¹³Erlanger Hospital, Chattanooga, TN, USA

¹⁴Lyerly Neurosurgery, Baptist Hospital, Jacksonville, FL, USA

¹⁵University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden Neurovascular Center, Dresden, Germany

¹⁶University Health Network, University of Toronto, Toronto, Canada

¹⁷The Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia

¹⁸Neuroradiology, Alfried Krupp Krankenhaus, Essen, Germany

Correspondence: Mayank Goyal Departments of Diagnostic Imaging and Clinical Neurosciences, Foothills Medical Centre, 1403 29th St. NW, Calgary, AB, T2N2T9, University of Calgary, Calgary, AB, Canada Tel: +1-(403)-9443379 E-mail: mgoyal@ucalgary.ca

Received 2024 August 5; Revised 2024 December 16; Accepted 2025 January 2.

Abstract

Introduction

Acute ischemic stroke due to large vessel occlusion (LVO) is a severely disabling and fatal disease. Endovascular treatment (EVT) improves the prognosis of patients with LVO strokes, but despite EVT, less than 50% of patients achieve an independent outcome at 90 days [1]. The prognosis is even worse when concurrent treatment with intravenous alteplase is contraindicated [1].

Nerinetide is an eicosapeptide that disrupts the post-synaptic density protein 95 signaling pathway, attenuating excitotoxic cell death in acute ischemic stroke [2,3]. In a temporary middle cerebral artery ischemia-reperfusion model in primates, nerinetide has been shown to significantly improve functional outcomes [4]. The ESCAPE-NA1 (Efficacy and Safety of Nerinetide for the Treatment of Acute Ischaemic Stroke) trial was a multicenter, double-blind, randomized, placebo-controlled trial that assessed the efficacy and safety of nerinetide in human acute ischemic stroke patients with LVO who underwent EVT [5]. In patients who were concurrently treated with intravenous alteplase, nerinetide was not associated with improved outcomes, possibly because the nerinetide effect was nullified by a drug–drug interaction with intravenous alteplase, as suggested by pharmacokinetic data from a trial patient subset (see supplementary figure 2 of the ESCAPE-NA1 main paper [5]). In patients who did not receive intravenous alteplase, nerinetide was associated with improved outcomes and reduced mortality.

We compared the effect of nerinetide on clinical outcomes in patients not concurrently treated with intravenous alteplase across different patient subgroups and assessed for evidence of treatment effect modification.

Methods

ESCAPE-NA1 was a multicenter randomized, double-blinded, placebo-controlled trial that evaluated the efficacy and safety of nerinetide [5] in patients with acute ischemic stroke due to LVO treated with EVT. The trial was approved by the research ethics board of the coordinating centre (University of Calgary, REB15-3029) and by the research ethics boards/ethics committees at each participating site. Patients were randomized to a single, 2.6 mg/kg dose of intravenous nerinetide or placebo. All patients received EVT and best medical care, including intravenous alteplase as indicated. Non-contrast computed tomography (NCCT) and multiphase computed tomography angiography (mCTA) were performed at baseline. Patients were eligible for the trial if they had an LVO (intracranial internal carotid artery, M1 occlusion or functional M1 occlusion [occlusion of both M2 branches]), moderate or good collaterals (defined as filling ≥50% of the middle cerebral artery territory), and an Alberta Stroke Program Early CT Score (ASPECTS) of 5 or higher. The clinical inclusion criteria were as follows: (1) age of 18 years or older, (2) baseline National Institutes of Health Stroke Scale (NIHSS) >5, functional independence prior to the ischemic stroke (Barthel Index score >90), and (3) time since last known well <12 hours. This analysis included only patients who did not receive intravenous alteplase (n=446).

All imaging data (baseline NCCT, mCTA, catheter angiography, follow-up NCCT, and diffusion-weighted magnetic resonance imaging [DWI-MRI]) were reviewed in consensus readings by an independent core lab that was blinded both to clinical outcomes and to follow-up images when assessing baseline images. The primary endpoint was independent functional outcome, defined as modified Rankin Scale (mRS) score 0–2 at 90 days.

Results

A total of 446 patients who did not receive intravenous alteplase were included in this analysis. Patient baseline characteristics have been previously published, and baseline characteristics of patients in nerinetide and control arms, without concurrent alteplase treatment, included in this analysis are shown in Table 1 [5]. Overall, 243 (54.5%) patients achieved a good outcome at 90 days. In the nerinetide arm, 130/219 (59.4%) patients achieved a good outcome, and in the control arm, 113/227 (49.8%) achieved a good outcome. Variables that were predictive of outcome are shown in Table 2, with their effect size estimates and a univariable test for heterogeneity of treatment effect (interaction). Figure 1 shows the unadjusted absolute risk difference for nerinetide for each subgroup. Parsimonious multivariable models are shown in Supplementary Table 1 (based upon variables known prior to randomization) and Supplementary Table 2 (based upon variables known at the end of the EVT procedure) and provide adjusted estimates of effect.

Table 1.

Baseline characteristics of the included patient sample without concurrent alteplase treatment

Table 2.

Univariable predictors of outcome

Figure 1.

Absolute risk difference (unadjusted) by patient characteristics. CI, confidence interval; NIHSS, National Institutes of Health Stroke Scale; AFIB, atrial fibrillation; MCA, middle cerebral artery; ICA, internal carotid artery; ASPECTS, Alberta Stroke Program Early CT Score; eTICI, expanded Thrombolysis In Cerebral Infarction.

In short, nerinetide was a predictor of favorable outcome (risk ratio 1.17, 95% confidence interval 1.01–1.36). Several baseline variables were associated with favorable outcome, whereby the larger prognostic effect sizes were seen in patients with baseline ASPECTS 8–10 compared to those with baseline ASPECTS 5–7.

Furthermore, higher prognostic effect sizes were also seen in those patients in whom no procedural sedation or conscious sedation rather than general anesthesia was used.

There was possible effect modification of the nerinetide treatment effect by ASPECTS score. Patients with higher ASPECTS scores had a significantly larger effect size compared to patients with moderate or low ASPECTS scores (P_interaction=0.0141) (Supplementary Table 1). The direction of effect of the interaction is shown graphically in Figure 2, whereby probabilities of achieving 90-day mRS 0–2 are shown on the y-axis and patient categories on the x-axis. Larger nominal effect sizes of nerinetide treatment were observed among patients with higher ASPECTS (ASPECTS 9–10) and there was a direction of effect favoring placebo among patients with lower ASPECTS scores. Supplementary Figure 1 shows the number of patients with good outcomes in the nerinetide and control arms for each individual ASPECTS category. Note that comparisons in individual ASPECTS groups are limited by low subgroup sample sizes.

Figure 2.

Interaction between ASPECTS scores and nerinetide treatment (NA1) on functional outcomes at 90 days. Patients with higher ASPECTS scores showed a larger treatment effect with nerinetide compared to those with lower scores (P_interaction=0.0141; Table 2). ASPECTS, Alberta Stroke Program Early CT Score; mRS, modified Rankin Scale.

Discussion

In this subgroup analysis of the randomized ESCAPE-NA1 trial, proportions of good outcomes in patients without concurrent alteplase treatment were higher in those randomized to the nerinetide arm compared to the control arm (mRS 0–2: 59.4% vs. 49.8%). There was possible treatment effect modification by ASPECTS score, whereby patients with ASPECTS 8–10 showed a larger treatment effect compared to patients with lower ASPECTS. Of note, this result was driven primarily by patients with ASPECTS 9 and 10, while in those with ASPECTS 8, patients who received nerinetide had slightly worse outcomes compared to those randomized to placebo (Supplementary Figure 1), perhaps related to the small sample size in individual ASPECTS subgroups, which likely resulted in imbalances in baseline characteristics.

The magnitude of the observed improvement in clinical outcome in these patients with nerinetide (9.5% absolute risk difference, as reported previously [5]) is clinically significant and slightly less than half (45%) of the benefit (21.2% absolute risk difference) observed in the HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) pooled individual patient meta-analysis of EVT trials [1]. The safety and efficacy of nerinetide were assessed in two other trials, namely the ESCAPE-NEXT (Efficacy and Safety of Nerinetide in Participants With Acute Ischemic Stroke Undergoing Endovascular Thrombectomy Excluding Thrombolysis) and FRONTIER (Field Randomization of NA-1 Treatment In Early Responders) trials. The results of these trials were conflicting. While in ESCAPE-NA1, improved outcomes with nerinetide were seen in the no-alteplase stratum only [5], ESCAPE-NEXT showed no treatment effect, and FRONTIER (clinicaltrials.gov NCT02315443) showed improved outcomes with nerinetide in the entire modified intention to treat sample, which was even more pronounced in patients with confirmed ischemic stroke and subsequent vessel recanalization. A preliminary pooled analysis of the trials indicates a possible higher benefit in patients who are enrolled in the very early time window (presented at the 2024 International Stroke Conference; Michael Tymianski, unpublished data).

In the current study, which is based on ESCAPE-NA1 data, the benefit of treatment was modified by baseline ASPECTS score. Patients with higher ASPECTS (score 8–10 vs. 5–7) showed a larger treatment effect after adjusting for other key variables. Affected ASPECTS regions have a high fidelity with permanent infarction observed on follow-up imaging. It is, therefore, not surprising that a peptide designed to prevent cell death, but not reverse cell death, is found to be most effective in situations where there is limited evidence of permanent tissue damage. In general, the treatment effect of nerinetide was not statistically different across other subgroups, including demographic, physiological, and imaging variables (other than ASPECTS score). Of note, the observed possible interaction will need to be confirmed in future clinical trials such as the NoNO-42 (NoNO-42 Trial in Acute Ischemic Stroke Patients Selected for Thrombolysis with or Without Endovascular Thrombectomy) trial, which will begin enrollment soon (clinicaltrials.gov NCT06403267).

Key prognostic variables (age, NIHSS score, glucose, atrial fibrillation, ASPECTS score, occlusion location, use of conscious or no sedation vs. use of general anesthesia, and speed of treatment) identified are consistent with prior knowledge and therefore confirmatory. It is notable that the use of general anesthesia remains a strong negative prognostic factor, consistent with other studies but not confirmed in randomized trials. We also remark that speed of treatment is an important prognostic factor but that the magnitude of the effect is quite small. We believe this is because the effect of time is a biased assessment, as patient selection by imaging excluded those with extensive early infarction, who, by definition, show rapid progression of infarction.

This study has several limitations. First, we did not capture the specific reasons why the patients in our study sample were not treated with intravenous alteplase and therefore cannot describe alternate patient classification groups. Second, some subgroups included only few patients, which might limit the generalizability of our results. Third, this analysis contains only patient data from one of three randomized controlled trials on the safety and efficacy of nerinetide, and we emphasize that these analyses are exploratory and must be confirmed, ideally in a pooled analysis of all three trials.

Conclusions

Patients in the nerinetide arm of the ESCAPE-NA1 trial without concurrent alteplase treatment showed improved clinical outcomes compared to patients who were randomized to the control arm. There was a possible treatment effect modification by ASPECTS score. Patients with higher ASPECT scores may show larger treatment benefits.

Supplementary materials

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