Discussion
death, pneumonia, pulmonary fibroproliferation, TEAEs, ARDS, pyrexia, organ failure
EVENTS, DISEASE, ARDS, PNEUMONIA
This is the first study to evaluate the efficacy and safety of multipotent adult progenitor cells (invimestrocel) in a clearly defined set of patients with ARDS. In this study, invimestrocel was evaluated in patients with ARDS caused by pneumonia and with severity defined by the APACHE II score and HRCT score. Patients who were likely to die of severe systemic organ failure within a few days were specifically excluded by an APACHE II score ≥ 27, while those at a high risk of progressive pulmonary fibroproliferation based on an HRCT score ≥ 211, which is considered optimal for examining the repair effect of MSCs on injured lungs, were included [Although corticosteroids have been shown to improve survival in patients with ARDS caused by COVID-19 [The number of TEAEs was similar between the invimestrocel and standard treatment groups, and the number of TEAEs possibly related to invimestrocel was small, with all events being resolved or resolving at the time of data cutoff. The safety profile observed in this study aligns with that of the MUST-ARDS trial, in which pyrexia was the only possibly related TEAE observed in patients treated with invimestrocel [The limitations of this study are that it was open-label, the number of patients was small (especially in the standard group), and statistically significant differences could not be determined. An open-label, comparator-controlled study design using standard treatment as a control was chosen because the administration of placebo may be associated with a risk of aggravation of the disease due to fluid loading. Although the study was open-label, quality was enhanced by the use of a predefined ventilator weaning protocol with confirmation by physicians that extubation proceeded without concerns. In addition, physician discretion was minimized where possible, e.g., by using multiple evaluators for HRCT score, and a third evaluator was included in ventilator weaning to confirm the appropriateness of weaning and whether extubation was not arbitrarily delayed or hastened. Furthermore, HRCT score used as part of the patient selection in this study is validated only in the Japanese population, which limits the generalizability of the study. We included patients with high HRCT scores to select patients with ARDS at a high risk of progressive pulmonary fibroproliferation, and we specifically excluded patients at risk of early death using APACHE II scores; however, these criteria will make it more difficult to directly compare our data with other clinical studies.