Nelonemdaz Treatment for Patients With Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial

OBJECTIVES:Nelonemdaz is a N-methyl d-aspartate receptor subtype 2B-selective N-methyl-D-aspartate receptor antagonist and a potent free-radical scavenger that might ameliorate hypoxic-ischemic brain injury after out-of-hospital cardiac arrest (OHCA). We investigated the efficacy of nelonemdaz for patients with OHCA. DESIGN:A double-blind, placebo-controlled, randomized, multicenter phase II trial. SETTING:This trial enrolled 105 patients at five sites in South Korea between November 18, 2018, and February 23, 2023. PARTICIPANTS:OHCA patients undergoing targeted temperature management. INTERVENTIONS:Patients were randomly assigned to high-dose (5250 mg), low-dose (3250 mg), and placebo groups at a 1:1:1 ratio. MEASUREMENTS AND MAIN RESULTS:Patients with a median age of 61 years (82% male) were assigned to the high-dose (n = 37), low-dose (n = 35), and placebo (n = 33) groups. The primary outcome, the serum level of neuron-specific enolase (NSE) at 48-52 hours, was evaluated in 93 patients. There was no difference in serum NSE between high-dose (median and interquartile range; 23.7, 15.0-69.9) and placebo (17.5, 13.6-113.0) groups, or between low-dose (26.6, 16.2-83.4) and placebo groups (p > 0.05). Brain MRI fractional anisotropy was significantly higher in the high-dose group compared with the placebo group (0.465, 0.449-0.485 vs. 0.441, 0.431-0.464; p = 0.028), but not between low-dose (0.462, 0.439-0.480) and placebo groups (p > 0.05). At day 90, the common odds ratio (95% CI) indicating a numerically favorable shift in the modified Rankin Scale was 1.25 (0.48-3.24) and 1.22 (0.47-3.20) in the high-dose and low-dose groups, respectively, compared with placebo group (p > 0.05). No serious adverse events were reported. CONCLUSIONS:Nelonemdaz treatment of patients after OHCA did not reduce serum NSE levels compared with controls. Patients treated with high-dose nelonemdaz showed higher brain MRI fractional anisotropy suggesting less cerebral white matter damage.