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). 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 PaO2/FiO2 ratio improved by 41% in the sivelestat group compared to 16% in the placebo group (difference, 0.25; 95% CI, 0.10 to 0.40, p=0.001). In addition, the duration of invasive mechanical ventilation was significantly shorter in the sivelestat group compared to the placebo group (median 104.0 hours versus 170.3 hours, p=0.006). 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; p=0.044). Conclusion: In patients with mild to moderate ARDS combined with SIRS, sivelestat sodium may improve oxygenation on day3, shorten the duration of mechanical ventilation, and was associated with reduced 90 day mortality.

The authors have declared no competing interest.

NCT04909697

This study was funded by Shanghai Huilun (Jiangsu) Pharmaceutical Co., Ltd., which is also responsible for the supply of the study drug andplacebo as well as distribution to the participating centers. Funding agencyhad no input into the design, conduct, data collection, statistical analysis, orwriting of the manuscript.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

(1)Ethics committee of sichuan people's hospital gave ethical approval for this work. (2)Ethics committee of affiliated hospital of chengdu university of traditional chinese medicine gave ethical approval for this work. (3)Ethics committee of chengdu shuangliu district first people's hospital gave ethical approval for this work. (4)Ethics committee of chengdu second people's hospital gave ethical approval for this work. (5)Ethics committee of chengdu fifth people's hospital gave ethical approval for this work. (6)Ethics committee of affiliated hospital of chengdu university gave ethical approval for this work. (7)Ethics committee of chengdu third people's hospital gave ethical approval for this work. (8)Ethics committee of sichuan cancer hospital gave ethical approval for this work.

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