Outcome measures
death, lung injury, inflammation, VFD, VFDs
INFLAMMATION, ADVERSE EVENT
Primary endpoint was the number of days of survival free from mechanical ventilation (VFDs) during the first 28 days after administration of study treatment. VFDs were calculated based on the time and date of extubation and re-intubation; one VFD was defined as a day free from the ventilator for 24 h. If death occurred before day 28 after administration, or mechanical ventilation continued after day 28, then VFDs were zero. If mechanical ventilation was discontinued before day 28, with X as the cumulative number of days with mechanical ventilation, then VFD was equal to 28 minus X. For patients who discontinued within 28 days for reasons other than death, VFDs were calculated assuming that a patient was on a ventilator on the day of discontinuation and onwards. Secondary efficacy endpoints included ventilator weaning rate on day 28, re-intubation rate, mortality on days 28, 60, 90, and 180 after treatment administration, and progression of chest imaging findings (radiographic and HRCT changes) through day 90 (obtained at screening, once between the time of ventilator weaning and discharge from hospital, and on days 14, 60, and 90). Procedures for confirmation and implementation of ventilator weaning are provided in Additional file Exploratory endpoints included parameters of inflammation and lung injury and the EuroQol 5-Dimension 5-Level (EQ-5D-5L) [Safety endpoints included AEs from informed consent to day 180 of follow-up or discontinuation. AE severity was assessed by the investigator as mild (sign or symptom easily tolerable and not interfering with daily life activities), moderate (significant discomfort and interfering with daily life activities), or severe (incapacitating or significantly interfering with daily life activities); infusion-related AEs were graded according to the Common Terminology Criteria for Adverse Events v4.0. Treatment-emergent AEs (TEAEs) were summarized by preferred term according to the Medical Dictionary for Regulatory Activities/Japanese edition Version 24.1. Any causal relationship was determined by the attending physician. Vital signs were collected throughout the study period at screening, 1 h (± 15 min) before, at the time of (0 min), and every 15 min (± 5 min) until 2 h after the start of administration, 3 h (± 15 min) and 4 h (± 15 min) after the start of administration, twice daily from day 1 until ventilator weaning, once daily from ventilator weaning until discharge, and if possible, on days 60, 90, and 180 after discharge. Laboratory test values were collected, including hematology, blood chemistry, and urinalysis, at screening, on days 1, 2, 3, and 7, and then every 7 days until discharge, at ventilator weaning, at discharge, and on days 60, 90, and 180 when possible.