Sivelestat Sodium in the Treatment of Patients with Acute Respiratory Distress Syndrome Combined with Systemic Inflammatory Response Syndrome

Abstract Objectives Neutrophil elastase (NE) plays an important role in the pathogenesis of acute respiratory distress syndrome (ARDS). Sivelestat sodium, an NE inhibitor, has been approved in Japan for the treatment of patients with ARDS combined with systemic inflammatory response syndrome (SIRS). This trial was designed to evaluate the role of sivelestat sodium in mild-to-moderate ARDS combined with SIRS. Methods We conducted a multicentre, double-blind, randomized, placebo-controlled trial enrolling patients diagnosed with mild-to-moderate ARDS combined with SIRS admitted within 72 hours of ARDS onset ( clinicaltrials.gov , NCT04909697 ). Patients were randomized in a 1:1 fashion to sivelestat or placebo. Trial drugs were administrated as a 24-hour continuous intravenous infusion at a rate of 0.2 mg/kg/h for 5 days. The primary outcome was PaO 2 /FiO 2 ratio change on day 3 after randomization, which was defined as (PaO 2 /FiO 2 ratio on day 3 – baseline PaO 2 /FiO 2 ratio)/baseline PaO 2 /FiO 2 ratio. Results The study was stopped early at the recommendation of an independent Data and Safety Monitoring Board, which noted a between-group difference in mortality. A total of 162 patients were randomized, of whom 81 were assigned to receive sivelestat sodium and 81 placebo. On day 3, the PaO 2 /FiO 2 ratio improved by 36% in the sivelestat group compared to 3% in the placebo group (difference, 0.27; 95% CI, 0.13 to 0.41, p < 0.001). In addition, The invasive mechanical ventilation-free days within 28 days was significantly longer in the sivelestat sodium group compared to the placebo group (median 26.9 days vs. 21.0 days, p = 0.004). The Kaplan-Meier curves showed a significant reduction in 90-day mortality in patients receiving sivelestat compared to those not receiving sivelestat (hazard ratio, 0.51; 95% CI, 0.26 to 0.99; log-rank p = 0.044). Conclusion In patients with mild-to-moderate ARDS combined with SIRS, sivelestat sodium may improve oxygenation on day3, increase invasive mechanical ventilation-free days, and was associated with improved survival.