Nelonemdaz for Patients With Acute Ischemic Stroke Undergoing Endovascular Reperfusion Therapy

A Randomized Phase II Trial

Ji Man Hong, MD, PhD; Jin Soo Lee, MD, PhD; Yeong-Bae Lee, MD, PhD; Dong Hoon Shin, MD, PhD; Dong-Ick Shin, MD, PhD; Yang-Ha Hwang, MD, PhD; Seong Hwan Ahn, MD, PhD; Jae Guk Kim, MD, PhD; Sung-Il Sohn, MD, PhD; Sun U. Kwon, MD, PhD; Ji Sung Lee, PhD; Byoung Joo Gwag, PhD; Ángel Chamorro, MD, PhD; Dennis W. Choi, MD, PhD

Disclosures

Stroke. 2022;53(11):3250-3259. 

In This Article

Abstract and Introduction

Abstract

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.

Introduction

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.[1] 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.[4] However, numerous patients with stroke remain disabled despite the high reperfusion rate and striking improvements in clinical outcomes resulting from mechanical thrombectomy.[5] 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.[6] 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.

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