Abstract
Background
Acute respiratory distress syndrome (ARDS) remains associated with substantial mortality. The 2023 global definition includes non-intubated patients, creating an opportunity to evaluate therapies earlier in the disease course.Research question
Is TISA-818 safe and potentially efficacious in patients with ARDS, particularly those who are non-intubated?Study design and methods
This randomized, double-blind, placebo-controlled, multicenter phase 2 trial was, to our knowledge, the first in China to use the 2023 global ARDS definition. Fifty-eight patients were randomized 1:1:1 to intravenous TISA-818 6 mg twice daily (BID), 12 mg once daily (QD), or matched placebo for 14 days. The primary endpoint was safety. Key secondary endpoints included respiratory support-free days (RSFDs) through day 28, proportion of patients alive and free from respiratory support at day 14, clinical improvement rate at day 14, and length of stay through 28 days.Results
TISA-818 demonstrated an acceptable safety profile with comparable rates of treatment-emergent adverse events (AEs) and no unexpected safety signals. Treatment-related AEs were mild-to-moderate and occurred in 5.3%, 36.8%, and 21.1% of patients in the placebo, 6 mg BID, and 12 mg QD groups, respectively. Day-28 mortality was 5.3%, 10.5%, and 26.3%, whereas day-60 mortality was 26.3%, 21.1%, and 31.6% for placebo, 6 mg BID, and 12 mg QD, respectively. No drug-related serious AEs or deaths occurred. In the prespecified non-intubated subgroup (n=27, 9 per arm), exploratory analyses numerically favored 6 mg BID over placebo, with more RSFDs (difference, 6 days; 95% confidence interval, -3 to 15) and consistent numerical improvements across all secondary outcomes.Interpretation
TISA-818 was generally well tolerated. Day-28 mortality was numerically imbalanced but not sustained, likely reflecting small-sample variability; cautious interpretation is warranted. Consistent improvements across all efficacy endpoints, particularly with 6 mg BID in non-intubated patients, support further investigation in adequately powered trials.