Steroid, Thiamine, and Ascorbic Acid for Comatose Out-of-hospital Cardiac Arrest Survivors (STAR): a Randomised, Placebo-Controlled, Phase 2 Trial

Background Pharmacologic neuroprotection for out-of-hospital cardiac arrest (OHCA) remains elusive. We evaluated whether early hydrocortisone, ascorbic acid, and thiamine reduced neuronal injury in comatose OHCA survivors. Methods In this multicentre, placebo-controlled trial across four South Korean hospitals, comatose adult OHCA survivors undergoing targeted temperature management were randomly assigned (1:1) to intravenous hydrocortisone (100 mg), ascorbic acid (50 mg/kg), and thiamine (200 mg) every 12 h for 3 days, or placebo. Randomisation was computer-generated. Bedside clinicians were aware of treatment allocation, whereas laboratory personnel and independent outcome assessors were masked. The primary outcome was peak neuron-specific enolase (NSE) concentration, defined as the highest available value measured at 48 h or 72 h after return of spontaneous circulation. Efficacy was analysed using a modified intention-to-treat (mITT) principle, with multiple imputation for the full intention-to-treat (ITT) population. The completed trial was registered with ClinicalTrials.gov on June 4, 2021 (NCT04921189). Findings Between Dec 31, 2021, and Dec 7, 2024, 160 participants (123 male, 37 female) were assigned (80 per group); 147 were included in the mITT analysis (74 treatment, 73 placebo). Peak NSE levels were 47·4 ng/mL (interquartile range [IQR] 22·4–262·6) in the treatment group and 53·3 ng/mL (IQR 26·6–244·2) in the placebo group (median difference −5·9 ng/mL; 95% confidence interval [CI] −34·5–40·8; p = 0·54). ITT sensitivity findings were consistent (geometric mean ratio 0·94; 95% CI 0·61–1·46; p = 0·80). At 180 days, survival (63·5% vs 69·9%) and good neurological outcome (54·1% vs 56·2%) were similar. Serious adverse events were comparable in the ITT population (52·5% vs 50·0%), with none deemed related to the study medication. Interpretation Early administration of hydrocortisone, ascorbic acid, and thiamine did not reduce neuronal injury or improve 6-month clinical outcomes. The findings do not support empiric neuroprotective use in comatose OHCA survivors. Funding National Research Foundation of Korea and Korea Health Technology R&D Project.