Efficacy and Safety of Remimazolam Tosylate versus Propofol for Sedation of Postoperative Mechanically Ventilated Patients in Intensive Care Units: a Multicenter, Randomized, Single-blind, Non-inferiority, Phase 3 trial.

Abstract

Remimazolam tosylate, a novel short-acting benzodiazepine, has shown effective and safe sedation in mechanically ventilated patients in intensive care units (ICU) in a phase 2 trial. We conducted a multicenter, randomized, single-blind, actively controlled, phase 3 trial (NCT06222294) for further evaluation. Mechanically ventilated patients, requiring sedation for ≥6 h with a target Richmond Agitation-Sedation Scale (RASS) of -2 to 1, were randomized (1:1) to receive intravenous remimazolam tosylate (loading dose, 0.08 mg/kg; maintenance, 0-2.0 mg/kg/h) or propofol (loading dose, 0.3-0.5 mg/kg; maintenance, 0.3-4.0 mg/kg/h). Both allowed for adjusted infusion rates or additional doses to maintain target RASS. Maximum treatment duration was 24 h. Primary endpoint was proportion of patients achieving sedation success, defined as maintaining target sedation range for ≥70% of drug administration time without rescue sedation. Non-inferiority margin was -8%. Between Mar. 12, 2024 and Sep. 24, 2024, 211 patients (mean age, 61.1 years; 63.5% male; 99.1% postoperative) received remimazolam tosylate (n=106) or propofol (n=105). Mean (SD) treatment duration was 11.5±3.6 h for remimazolam tosylate and 11.1±3.1 h for propofol; mean (SD) total dose was 187.1±134.4 mg and 593.7±530.9 mg, respectively. Sedation success rate was 98.1% with remimazolam tosylate and 96.2% with propofol (difference 1.9%, 95% CI -3.3% to 7.8%); mean (SD) percentage of time in RASS target range was 95.1±13.8% vs 95.0±12.9%, and proportion of patients receiving rescue sedation was 0.0% (0/106) vs 1.0% (1/105). Mean (SD) additional doses required was 0.03±0.17 for remimazolam tosylate and 0.18±0.77 for propofol. Adverse event occurred in 81 (76.4%) patients with remimazolam tosylate and 77 (73.3%) with propofol; all were mild-moderate, except one severe with propofol. Mean terminal half-life (SD) of remimazolam tosylate was 1.97±1.62 h. Remimazolam tosylate demonstrated non-inferior efficacy and good tolerability compared with propofol for short-term sedation in postoperative mechanically ventilated ICU patients.