Rationale and methods of the Antioxidant and NMDA receptor blocker Weans Anoxic brain damage of KorEa OHCA patients (AWAKE) trial

Abstract

Background: Ischemic brain injury is a major hurdle that limits the survival of resuscitated out-of-hospital cardiac arrest (OHCA).

Methods: The aim of this study is to assess the feasibility and potential for reduction of ischemic brain injury in adult OHCA patients treated with high- or low-dose Neu2000K, a selective blocker of N-methyl-D-aspartate (NMDA) type 2B receptor and also a free radical scavenger, or given placebo. This study is a phase II, multicenter, randomized, double-blinded, prospective, intention-to-treat, placebo-controlled, three-armed, safety and efficacy clinical trial. This trial is a sponsor-initiated trial supported by GNT Pharma. Successfully resuscitated OHCA patients aged 19 to 80 years would be included. The primary outcome is blood neuron-specific enolase (NSE) level on the 3rd day. The secondary outcomes are safety, efficacy defined by study drug administration within 4 h in > 90% of participants, daily NSE up to 5th day, blood S100beta, brain MRI apparent diffusion coefficient imaging, cerebral performance category (CPC), and Modified Rankin Scale (mRS) at 5th, 14th, and 90th days. Assuming NSE of 42 ± 80 and 80 ± 80 μg/L in the treatment (high- and low-dose Neu2000K) and control arms with 80% power, a type 1 error rate of 5%, and a 28% of withdrawal prior to the endpoint, the required sample size is 150 patients.

Discussion: The AWAKE trial explores a new multi-target neuroprotectant for the treatment of resuscitated OHCA patients.

Trial registration: ClinicalTrials.gov NCT03651557 . Registered on August 29, 2018.

Keywords: Free radical scavenger; Ischemic-reperfusion brain injury; NMDA antagonist; Neu2000K; Out-of-hospital cardiac arrest; Randomized controlled trial.

Conflict of interest statement

J.L., G.L., J.J., C.A., and B.G. are employees of GNT Pharma. All the other authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1

Mechanism of Neu2000K as a dual-target neuroprotectant for ischemic and reperfusion brain injury. In patients suffering from cardiac arrest, oxygen and glucose are deprived from the brain, which results in glutamate release and accumulation at the synaptic cleft. Excess glutamate causes acute and fulminant neuronal death through the overactivation of calcium ion-permeable NMDA receptors. Free radicals such as superoxide and hydrogen peroxide are produced in the mitochondria over hours and days after the return of spontaneous circulation. Such prolonged and excessive oxidative stress causes delayed cell death including the neurons and glia. Neu2000K moderately and selectively blocks the NR2B subtype of NMDA receptor, which activates pro-survival signaling pathways without causing excessive calcium influx, which can reduce acute neuronal death. Neu2000K also functions as a potent reactive oxygen species scavenger and reduces oxidative stress or reperfusion injury, which can reduce delayed brain cell death

Fig. 2

Study flow. OHCA, out-of-hospital cardiac arrest; ROSC, return of spontaneous circulation; ECMO, extracorporeal membranous oxygenation; TTM, targeted temperature management; CT, computed tomography; NSE, neuron-specific enolase; MRI, magnetic resonance imaging; CPC, cerebral performance category; mRS, Modified Rankin Scale