ESCAPE-NEXT Trial: Nerinetide Fails to Improve Functional Outcomes in Acute Ischaemic Stroke Patients Undergoing Endovascular Thrombectomy Without Prior Thrombolysis

Highlight

• The ESCAPE-NEXT trial assessed nerinetide, a neuroprotective eicosapeptide, in acute ischaemic stroke patients undergoing endovascular thrombectomy without intravenous thrombolysis.
• No significant difference was found in achieving favorable functional outcomes (mRS 0-2 at 90 days) between nerinetide and placebo groups.
• Nerinetide exhibited a safety profile comparable to placebo without excess serious adverse events.
• Further research is needed to identify the ideal timing and patient subsets that could benefit from nerinetide alongside reperfusion therapies.

Background

Acute ischaemic stroke (AIS) caused by large vessel occlusion (LVO) accounts for significant neurological disability worldwide. Rapid restoration of cerebral blood flow through endovascular thrombectomy (EVT) improves outcomes in eligible patients. However, despite advances in mechanical reperfusion, many patients still suffer substantial neurological impairment. Adjunctive neuroprotective strategies have long been sought to enhance recovery by mitigating reperfusion injury and neuronal death.

Nerinetide is an eicosapeptide designed to disrupt post-synaptic density protein 95 (PSD-95) interactions that trigger excitotoxic neuronal injury after ischaemia. The ESCAPE-NA1 trial initially suggested that nerinetide improved functional outcomes in patients undergoing EVT without concurrent intravenous thrombolytic treatment but showed no benefit when thrombolytics were used. This raised the hypothesis that plasminogen activators might degrade nerinetide, abolishing its efficacy.

The ESCAPE-NEXT trial aimed to validate nerinetide’s efficacy and safety in AIS patients treated with EVT alone, without prior thrombolysis, thus confirming its potential role as a neuroprotective agent in this specific clinical context.

Study Design

ESCAPE-NEXT was a multicentre, randomized, double-blind, placebo-controlled trial conducted across 77 centers in Canada, the USA, Germany, Italy, the Netherlands, Norway, Switzerland, Australia, and Singapore. Participants were adults (≥18 years) with acute ischaemic stroke due to anterior circulation large vessel occlusion within 12 hours of symptom onset.

Inclusion criteria required a disabling stroke with a baseline National Institutes of Health Stroke Scale (NIHSS) score greater than 5, pre-stroke independence (Barthel Index >90), and an Alberta Stroke Program Early CT Score (ASPECTS) greater than 4. Crucially, patients had not received intravenous thrombolysis.

Participants were randomized 1:1 to receive a single intravenous dose of nerinetide (2.6 mg/kg, max 270 mg) or placebo, stratified by clinical variables including age, NIHSS score, and occlusion site. All patients subsequently underwent EVT. The primary endpoint was a favorable functional outcome defined as a modified Rankin Scale (mRS) score of 0–2 at 90 days post-randomization.

Secondary endpoints included mortality, neurological worsening, functional independence, and quantitative disability measures. Safety was rigorously monitored, focusing on adverse events and serious adverse events.

Key Findings

From December 2020 to January 2023, 850 patients were enrolled: 454 received nerinetide and 396 placebo. The proportion achieving the primary endpoint (mRS 0-2 at 90 days) was 45% in the nerinetide group versus 46% in the placebo group (odds ratio [OR] 0.97; 95% confidence interval [CI] 0.72–1.30; p=0.82), indicating no statistically significant difference.

Secondary outcomes, including mortality rates and neurological disability measures, showed no meaningful differences between groups. The incidence of serious adverse events was similar, with no excess safety concerns attributable to nerinetide.

These results contrast with the initial ESCAPE-NA1 findings where nerinetide showed benefit only in the subgroup of patients not receiving thrombolytics, thus challenging earlier expectations. The trial’s well-powered design and rigorous methodology provide strong evidence that nerinetide, as studied, does not confer clinical benefit when administered immediately before EVT in patients without previous thrombolysis.

Expert Commentary

The ESCAPE-NEXT trial contributes critical data on the role of nerinetide in modern stroke care. The lack of efficacy observed raises questions regarding the complex interplay between neuroprotection, reperfusion timing, and underlying pathophysiology. Post-hoc analyses may reveal patient subgroups or treatment windows where nerinetide might still offer benefit, but the current data do not support routine clinical use.

Potential limitations include heterogeneity in patient selection, differences in EVT procedural techniques across centers, and the inability to explore repeated dosing or combination with emerging therapies. Advances in neuroimaging biomarkers and mechanistic studies could refine selection criteria for neuroprotective agents in future trials.

Experts emphasize that the pursuit of effective adjunctive therapies remains vital, but stringent translational validation is necessary prior to widespread adoption. The ESCAPE-NEXT trial reinforces the importance of replicating promising early-phase results in large, carefully designed confirmatory studies for neuroprotection in stroke.

Conclusion

The ESCAPE-NEXT trial demonstrated that nerinetide did not improve functional outcomes at 90 days in patients with acute ischaemic stroke undergoing endovascular thrombectomy without prior intravenous thrombolysis. Nerinetide exhibited a favorable safety profile comparable to placebo.

These findings suggest no immediate role for nerinetide as a neuroprotective adjunct in this patient population. Future research should focus on identifying specific subpopulations, optimal therapeutic windows, or combination strategies to harness neuroprotection alongside reperfusion interventions.

The study underscores the challenges in translating neuroprotective strategies to clinical practice and the necessity of continued rigorous clinical investigation to improve stroke outcomes.

Funding and Trial Registration

This study was funded by the Canadian Institutes for Health Research and NoNO. The ESCAPE-NEXT trial is registered with ClinicalTrials.gov (NCT04462536).

Reference

Hill MD, Goyal M, Demchuk AM, Menon BK, Field TS, Guest WC, Berrouschot J, et al. 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. Lancet. 2025 Feb 15;405(10478):560-570. doi: 10.1016/S0140-6736(25)00194-1. PMID: 39955119.