Abstract Body: Introduction: Nerinetide is a neuroprotectant intended to slow ischemic stroke progression. It was evaluated in ESCAPE-NEXT, a pivotal efficacy trial of nerinetide in participants with AIS selected for endovascular thrombectomy within 12 hours of symptoms. The primary endpoint was assessed at day 90 (D90) but the study also had a pre-planned one year (1Y) analysis. The study was terminated when it failed to meet its primary endpoint. However, 442 participants had completed both the D90 and 1Y visits. We examined whether the clinical benefits of nerinetide could be discerned at 1Y, and whether participants enrolled within the first three hours (“early window”) had different outcomes than those enrolled 3-12h (“late window”) after symptom onset.

Methods: The primary outcome was functional independence (mRS 0-2) with a key secondary analysis of mortality. D90 and 1Y outcomes were evaluated using the pre-specified logistic regression analyses for the trial. Additionally, the interaction between enrollment window stratum and treatment was examined. Analyses were stratified according to whether participants were enrolled within the early or late windows.

Results: Of 850 participants, 442 completed both the D90 and 1Y assessment. The adjusted odds ratio (aOR) of achieving mRS 0-2 at 1Y for the entire cohort (n=442) were aOR 1.08 (95% CI 0.71-1.63, p=0.718). There was a statistical interaction between enrollment window and treatment (p=0.025). Among early window participants (n=163), the aOR of achieving mRS 0-2 in participants treated with nerinetide increased from 1.13 (0.54-2.35, p=0.750) at D90 to 2.80 (1.18-6.66, p=0.019) at 1Y. Additionally, the aOR for reducing mortality increased from 1.97 (0.76-5.07, p=0.162) at D90 to 2.61(1.17-5.83, p=0.019) at 1Y. No clinical benefit was observed at 1Y on mRS 0-2 or mortality in the late window participants (n=279; mRS 0-2 aOR 0.81 (0.48-1.36, p=0.417); mortality aOR 1.09 (0.61-1.97, p=0.772)).

Conclusions: Late window participants may represent slow progressors who are least likely to benefit from treatments intended to slow stroke progression. For early window ESCAPE-NEXT participants, the benefit of nerinetide was more apparent at 1Y than D90. Early window patients may represent a population that could benefit from treatment with nerinetide. Long-term benefits of neuroprotection may emerge up to a year after stroke suggesting that 1Y outcomes could be useful in stroke neuroprotection trials.