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A phase III clinical trial did not demonstrate a significant impact of nelonemdaz on patients with acute ischemic stroke [1]. Although not prespecified in the original protocol, post-hoc analyses suggested potential interactions between treatment effects and time-related metrics, leading us to hypothesize that earlier drug administration may yield better outcomes. This study aimed to determine the treatment effect of nelonemdaz when administered early after emergency room (ER) arrival.
We conducted a post-hoc analysis using pooled data from two clinical trials investigating nelonemdaz in acute ischemic stroke: the phase II SONIC trial (Safety and Optimal Neuroprotection of Neu2000 in Acute Ischemic Stroke With Recanalization) and the phase III RODIN trial (Rescue on Reperfusion Damage in Cerebral Infarction by Nelonemdaz) (Supplementary Table 1) [1,2]. Both trials and the current study adhered to the Declaration of Helsinki principles. We combined the study populations after excluding the low-dose group from the SONIC trial. Our exploratory analysis revealed a significant interaction between treatment effect and the time from ER arrival to initial trial drug administration (Supplementary Figure 1). Based on subsequent subgroup analyses of time metrics, we established a 70-minute threshold from ER arrival to first trial drug infusion and included only patients who received treatment within this timeframe.
The efficacy of nelonemdaz was primarily assessed using the modified Rankin Scale (mRS) at 12 weeks post-treatment. Using ordinal logistic regression, the primary analysis evaluated a favorable shift in the distribution of mRS scores across the entire ordinal scale (0 [normal] to 6 [death]) at 12 weeks. As a secondary outcome measure, we analyzed the proportion of patients achieving functional independence, defined as mRS 0-2 at 12 weeks, using modified Poisson regression. Both regression models were adjusted for the following well-known major confounders: age, female sex, time from symptom onset to ER arrival (hours), baseline stroke severity (National Institutes of Health Stroke Scale [NIHSS] score), Alberta Stroke Program Early CT Score (ASPECTS), administration of intravenous alteplase, and achievement of successful reperfusion (modified Thrombolysis in Cerebral Infarction 2b-3).
The treatment effect was expressed as a common odds ratio (cOR) with the corresponding 95% confidence interval (CI) for mRS at 12 weeks and as a relative risk (RR) with 95% CI for mRS 0-2 at 12 weeks. Statistical significance was set at P<0.05 (two-sided) for all analyses. All statistical analyses were performed using SAS software, version 9.4 (SAS Institute Inc., Cary, NC, USA).
Baseline characteristics, treatment, and outcomes are summarized in Table 1. Regarding baseline characteristics, age was younger in the nelonemdaz group than in the placebo group (74.8±10.1 vs. 70.2±11.7, P=0.040). The baseline NIHSS score and ASPECTS did not differ between groups. Past stroke history tended to be more frequent in the nelonemdaz group than in the placebo group (12.5% vs. 27.5%, P=0.064). Variables regarding time metrics did not differ between groups. Regarding revascularization treatment, the frequency of intravenous alteplase infusion, endovascular thrombectomy (EVT) techniques, and successful post-EVT reperfusion did not differ between groups.
The regression analysis is presented in Table 2. The median score on the mRS at 12 weeks was 1 (interquartile range, 0 to 4) in the nelonemdaz group and 3 (interquartile range, 1 to 4) in the placebo group (adjusted cOR for a shift in the direction of a better outcome on the mRS, 2.22; 95% CI, 1.03 to 4.80; P=0.043). A favorable outcome (mRS 0-2) at 12 weeks occurred in 35 of 51 patients (68.6%) in the nelonemdaz group and in 24 of 48 patients (50.0%) in the placebo group (adjusted RR, 1.26; 95% CI, 0.95 to 1.69; P=0.112). Figure 1 shows the distribution of mRS scores in unadjusted and adjusted analyses, respectively.
Our post-hoc analysis demonstrated that early time from door to the 1st trial drug administration was associated with better treatment outcomes of nelonemdaz, aligning with the pathophysiological time window concept for neuroprotective therapy. This finding fits with current understandings of the underlying pathophysiological cascade in focal cerebral ischemia and the mechanism of action of neuroprotective agents, which is based on the concept of ischemic penumbra and infarct core.
The importance of hyperacute treatment in acute ischemic stroke cannot be overstated. When intracranial large vessel occlusion occurs, an ischemic penumbra forms throughout the affected region, leading to loss of neuronal function [3]. During cerebral ischemia, glutamate is released and accumulated, resulting in Ca2+ overload through excess activation of postsynaptic Nmethyl-D-aspartate (NMDA) receptors and fulminant neuronal death [4]. Following recanalization, toxic free radicals produced in mitochondria contribute to additional neuronal death [3]. These progressive pathological processes result in irreversible neuronal death, and the affected brain region becomes the infarct core.
Neuroprotective agents represent substances that reduce ischemic brain damage by interrupting harmful molecular events rather than by improving cerebral blood flow. Their therapeutic potential primarily lies in the ischemic penumbra, the salvageable tissue, where molecular interventions can still effectively prevent cell death [3]. In this context, we investigated nelonemdaz (previously, Neu2000), which exhibits dual mechanisms of action: moderate NR2B-selective NMDA receptor antagonist and potent antioxidant [5-7]. These therapeutic mechanisms specifically target the critical pathways in the neuronal death cascade described above, supporting its potential efficacy as a neuroprotective agent when administered before the ischemic penumbra progresses to infarct core. In the phase III clinical trial, nelonemdaz failed to demonstrate efficacy in the main results when tested on patients who received EVT for acute ischemic stroke. However, in the current study using pooled data of phase II and III trials, beneficial effect of nelonemdaz was observed in cases where the time from ER to 1st trial drug infusion was early.
As time is brain, neuroprotective therapy may also be time-dependent. While a short door-to-needle time favorably modified nelonemdaz effect in exploratory analysis, no modification effect was seen with time from stroke onset to first trial drug infusion. This finding parallels previous EVT trials, where shorter times from ER arrival to EVT or shorter EVT procedural times were independently associated with good clinical outcomes, while time from stroke onset to ER arrival showed weaker statistical associations [8]. This phenomenon can be explained by two key factors. First, individual variations in collateral status significantly influence the rate of tissue damage, making the absolute time from symptom onset less predictive of salvageable tissue [9]. Some patients with good collaterals may maintain viable penumbra for extended periods, while others with poor collaterals might experience rapid infarct progression. Second, systematic patient selection occurs immediately after ER arrival: patients with established infarcts are excluded from EVT consideration, regardless of their onset-to-door time. This tissue-based selection process effectively creates a population with preserved tissue viability, making post-ER time metrics more directly relevant to outcomes than onset-to-door time alone. This clinical trial approach is particularly significant because the neuroprotective drug was tested under conditions that closely mirror those used for selecting EVT candidates, where tissue viability and collateral status, rather than absolute time from onset, guide patient selection.
Our time from ER arrival to the 1st trial drug infusion showed remarkable similarity to the ESCAPE trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times) [10], a landmark study in EVT. The ESCAPE trial intended to initiate treatment within 60 minutes of computed tomography (CT) completion. Considering that the entire process from ER arrival to CT image acquisition and processing typically takes 10 minutes, reducing treatment initiation to within 70 minutes of ER arrival might enable neuroprotective treatments to demonstrate efficacy similar to EVT. Therefore, future clinical trials of neuroprotective therapy with nelonemdaz should consider adopting similar in-hospital time-based protocols as the ESCAPE trial.
Several limitations warrant careful interpretation of our findings. First, this analysis was exploratory and post-hoc in nature, rather than a prespecified subgroup analysis. Although the original trials were randomized, our analysis focused on a selected subgroup where treatment effect was observed, potentially introducing selection bias that cannot be fully addressed through statistical adjustment. Second, while the treatment effect remained significant after regression analysis, lending support to our findings, the selective nature of our analysis (focusing only on patients receiving treatment within 70 minutes of ER arrival) may limit the external validity and generalizability of these results to the broader stroke population. Third, the relatively small sample size in this subgroup analysis necessitates careful interpretation of the observed treatment effects, despite statistical significance. Future prospective trials with prespecified time-dependent analyses are warranted to validate these preliminary findings regarding nelonemdaz efficacy. Given the operational challenges of achieving such rapid drug administration in clinical trials, identification of additional responder characteristics might help establish more feasible extended time windows while maintaining efficacy.
In conclusion, in acute ischemic stroke patients undergoing EVT, nelonemdaz administration within 70 minutes of ER arrival was associated with improved functional outcomes, suggesting its possible efficacy.
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