ESCAPE-NEXT
(2025)Objective
To confirm whether nerinetide, an eicosapeptide neuroprotectant targeting postsynaptic density protein 95, improves functional outcomes in patients with acute ischemic stroke due to large vessel occlusion undergoing endovascular thrombectomy who had not received intravenous thrombolytic therapy.
Study Summary
• No excess serious adverse events with nerinetide — drug was safe but ineffective (any SAE 41% nerinetide vs 34% placebo; mortality 19% vs 18%)
• Trial failed to confirm the benefit seen in the no-alteplase stratum of ESCAPE-NA1; possible explanations include secular improvements in stroke care, older patient age, COVID-19 effects, broader 12-hour enrollment window, and short interval between drug and reperfusion
Intervention
Nerinetide 2.6 mg/kg IV (maximum 270 mg) as a single 10-minute infusion administered before end of endovascular thrombectomy, versus saline placebo
Inclusion Criteria
Adults ≥18 years; acute ischemic stroke due to anterior circulation large vessel occlusion; onset within 12 hours; baseline NIHSS >5; pre-stroke Barthel Index >90; ASPECTS 5–10; ≥50% MCA pial collateral filling; NOT treated with any thrombolytic agent
Study Design
Arms: Nerinetide 2.6 mg/kg IV single dose (n=454) vs Saline placebo (n=396)
Patients per Arm: Nerinetide: 454; Placebo: 396
Outcome
• Mortality at 90 days: 19% nerinetide vs 18% placebo (OR 1.10, 95% CI 0.76–1.61, p=0.61)
• Serious adverse events: 41% nerinetide vs 34% placebo (numerically higher but not attributed to drug; no safety signal)
• All secondary outcomes were exploratory after non-significant primary; no benefit demonstrated on any hierarchical endpoint
Bottom Line
Nerinetide did not improve functional independence at 90 days in thrombolytic-naïve patients undergoing thrombectomy for large vessel occlusion stroke; it cannot be recommended for this population based on current evidence, though it was safe.
Major Points
- Nerinetide did not improve mRS 0–2 at 90 days: 45% vs 46% for placebo (OR 0.97, 95% CI 0.72–1.30, p=0.82) — the trial was neutral
- No excess mortality with nerinetide (19% vs 18% placebo; OR 1.10, 95% CI 0.76–1.61, p=0.61; adjusted HR 0.98, 95% CI 0.70–1.37, p=0.91)
- Serious adverse events were numerically higher in the nerinetide arm (41% vs 34%) but authors judged no true safety signal; angio-oedema/hives (AEs of special interest) did not occur in either group
- The trial failed to replicate the no-alteplase stratum benefit from ESCAPE-NA1 despite being specifically designed and powered for this purpose
- Possible explanations for the neutral result include secular improvements in thrombectomy outcomes raising the placebo response rate, enrollment of older patients with greater comorbidity burden, COVID-19 pandemic effects on patient selection, treatment at later time windows (up to 12h), and a short drug-to-reperfusion interval leaving little time for neuroprotective benefit
- The endovascular thrombectomy setting alone is insufficient to identify the ideal neuroprotection candidate population — additional selection criteria may be needed
- The accompanying FRONTIER trial and pooled analyses of nerinetide data are proposed as paths forward for identifying appropriate candidates for neuroprotection
Study Design
- Study Type
- Multicentre, randomised, double-blind, placebo-controlled, parallel-group, single-dose trial
- Randomization
- Yes
- Blinding
- Double-blind; patients and all trial personnel blinded via visually identical numbered vials
- Sample Size
- 850
- Follow-up
- 90 days
- Centers
- 77
- Countries
- Canada, USA, Germany, Italy, Netherlands, Norway, Switzerland, Australia, Singapore
Primary Outcome
Definition: Favourable functional outcome defined as modified Rankin Scale (mRS) score 0–2 at 90 days from randomisation, assessed in person or by telephone by certified personnel
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 181/398 (46%) achieved mRS 0–2 (per paper Table 2; ITT randomised placebo population per trial profile Figure 1 was n=396) | 206/454 (45%) achieved mRS 0–2 | 0.97 (0.72–1.30) | 0.82 |
Limitations & Criticisms
- The patient population may have been suboptimal for neuroprotective benefit: older patients with greater comorbidity burden and a higher proportion enrolled in later time windows (up to 12h) compared to ESCAPE-NA1
- COVID-19 pandemic likely affected patient selection and care pathways during enrollment (Dec 2020–Jan 2023), potentially altering baseline characteristics
- Secular improvements in thrombectomy care between ESCAPE-NA1 and ESCAPE-NEXT may have increased placebo response rates, reducing detectable treatment effect
- Short time from drug administration to reperfusion may have left insufficient ischemic exposure time for nerinetide's temporising mechanism to confer benefit
- No screening logs were kept, precluding assessment of selection bias or generalisability
- The asymmetric arm sizes (454 nerinetide vs 396 placebo) despite intended 1:1 allocation may reflect the dynamic minimisation algorithm; the paper does not explicitly explain this discrepancy
- Numerical excess of serious adverse events (41% vs 34%) and symptomatic ICH (6% vs 4%) in nerinetide arm, though authors argue no true safety signal and attribute to chance
- Internal denominator inconsistency in Table 2 (placebo n=398) versus trial profile Figure 1 (placebo ITT n=396) is unexplained
- The 12-hour enrollment window is broader than the primate models of efficacy, which did not test extended ischemic durations
Citation
Hill MD, Goyal M, Demchuk AM, 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;405(10478):560-570.