Abstract and Introduction
Background: Nelonemdaz is a multitarget neuroprotectant that selectively blocks N-methyl-D-aspartate receptors and scavenges free radicals, as proven in preclinical ischemia-reperfusion studies. We aimed to evaluate the safety and efficacy of nelonemdaz in patients with acute ischemic stroke receiving endovascular reperfusion therapy.
Methods: This phase II randomized trial involved participants with large-artery occlusion in the anterior circulation at baseline who received endovascular reperfusion therapy <8 hours from symptom onset at 7 referral stroke centers in South Korea between October 29, 2016, and June 1, 2020. Two hundred thirteen patients were screened and 209 patients were randomly assigned at a 1:1:1 ratio using a computer-generated randomization system. Patients were divided into 3 groups based on the medication received—placebo, low-dose (2750 mg) nelonemdaz, and high-dose (5250 mg) nelonemdaz. The primary outcome was the proportion of patients with modified Rankin Scale scores of 0–2 at 12 weeks.
Results: Two hundred eight patients were assigned to the placebo (n=70), low-dose (n=71), and high-dose (n=67) groups. The groups had similar baseline characteristics. The primary outcome was achieved in 183 patients, and it did not differ among the groups (33/61 [54.1%], 40/65 [61.5%], and 36/57 [63.2%] patients; P=0.5578). The common odds ratio (90% CI) indicating a favorable shift in the modified Rankin Scale scores at 12 weeks was 1.55 (0.92–2.60) between the placebo and low-dose groups and 1.61 (0.94–2.76) between the placebo and high-dose groups. No serious adverse events were reported.
Conclusions: The study arms showed no significant difference in the proportion of patients achieving modified Rankin Scale scores of 0–2 at 12 weeks. Nevertheless, nelonemdaz-treated patients showed a favorable tendency toward achieving these scores at 12 weeks, without serious adverse effects. Thus, a large-scale phase III trial is warranted.
Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT02831088.
Graphic Abstract: A graphic abstract is available for this article.
Nelonemdaz, previously known as Neu2000, is a derivative of aspirin and sulfasalazine and is a multitarget neuroprotective agent with potent inhibitory effects against Ca2+ permeability of the NMDA (N-methyl-D-aspartate) receptor. Moreover, the drug with high selectivity inhibits the NR2B subunit of the NMDA receptor, strongly scavenges reactive oxygen species, and prevents blood-brain barrier disruption.[1–3] Studies have demonstrated the therapeutic potential of nelonemdaz in preclinical animal stroke models subjected to ischemia and reperfusion; they have shown the excellent efficacy and wide therapeutic time window of the drug.[1–3]
Recent clinical trials have shown that endovascular reperfusion therapy (ERT) has remarkable benefits in terms of the outcome of patients presenting with acute ischemic stroke in the proximal anterior circulation. However, numerous patients with stroke remain disabled despite the high reperfusion rate and striking improvements in clinical outcomes resulting from mechanical thrombectomy. The potential of neuroprotective agents as a promising treatment in patients with acute ischemic stroke is being revisited in the ERT era, owing to the optimization of preclinical efficacy in ischemia and reperfusion models. The above preclinical results and good patient tolerance to and lack of serious adverse effects of nelonemdaz in phase I trials performed in the United States and China have warranted a phase II randomized clinical trial.
The current SONIC trial (Safety and Optimal Neuroprotection of Neu2000 in Acute Ischemic Stroke With Recanalization) was designed as a phase II trial aiming to evaluate the safety and efficacy of nelonemdaz. This trial was a proof-of-concept study on adjuvant neuroprotection beyond state-of-the-art treatments such as ERT. The aim of this study was to test whether the potential therapeutic benefits of nelonemdaz observed in preclinical studies can be translated to clinical practice.
Stroke. 2022;53(11):3250-3259. © 2022 American Heart Association, Inc.