Abstract Rationale There are limited treatments for Acute Respiratory Distress Syndrome (ARDS), caused by pulmonary hyperinflammatory responses to viral, bacterial, chemical, or mechanical insults. Paridiprubart is a monoclonal antibody inhibitor of Toll-like Receptor 4 (TLR4), long implicated in ARDS pathogenesis. In a Phase 2 study, paridiprubart plus Standard of Care (SOC) was effective in treating critically ill patients with COVID-19-related ARDS receiving invasive mechanical ventilation (IMV) with additional organ support. This Phase 3 study compared paridiprubart plus SOC versus SOC alone in ICU patients receiving IMV. Methods Patients were enrolled from 38 hospitals in the USA, Canada and Colombia. Participants were 18 years or older, receiving IMV with or without additional organ support and had a laboratory-confirmed infection of SARS-CoV-2 at the time of hospitalization. They were randomly assigned (1:1) to SOC with paridiprubart (15mg/kg, maximum dose of 1400mg, N = 56), or SOC with placebo (N = 48). Efficacy outcomes were 28 and 60-day mortality and the proportion of patients with a decrease of ≥ 2 points in the WHO COVID-19 Severity Scale (WCSS) at 28-days to demonstrate improvement in disease severity. Results Patient demographics and baseline disease parameters were similar for the two groups with overall mean (SD) age: 52(14.7) years, 34% female, antiviral (9.6%), steroids (44.2%), immunomodulators (9.6%), IMV with additional organ support (64%). Multivariate logistic regression derived an adjusted estimated risk of 28-day mortality of 39% (95% CI: 35%-44%) in the paridiprubart group and 52% (95% CI: 47%-.58%) in the placebo group, for an adjusted difference of 13% (p 0.001). The adjusted estimated risk of 60-day mortality was 46% (95% CI: 42% - 50%) in the paridiprubart group and 59% (95% CI: 55% - 63%) in the placebo group, for an adjusted difference in risk of 13% (p 0.005). The adjusted rate of achieving ≥ 2-point reduction in WCSS was 38% (95% CI: 31%-45%) in the paridiprubart group and 27% (95% CI: 21%-33%) in the placebo group, for an adjusted difference in proportions of 11% (p 0.05). Conclusion In this randomized Phase 3 trial of critically ill patients, paridiprubart demonstrated clinically meaningful and statistically significant improvements in patient survival through 60 days and improvement in disease severity. The current SOC relies on supportive care, including IMV and organ support. Paridiprubart has the potential to offer safe and effective option for critically ill patients that may save lives and expedite patients’ recovery, allowing for earlier discharge from the ICU. This abstract is funded by: Strategic Innovation Fund (SIF) – Government of Canada
Steiner et al. (Fri,) studied this question.