Dexamethasone 12 mg versus 6 mg for patients with COVID-19 and severe hypoxia: an international, randomized, blinded trial

IMPORTANCE Dexamethasone 6 mg daily is recommended for up to 10 days in patients with severe and critical COVID-19, but a higher dose may benefit those with more severe disease. OBJECTIVE To assess the effects of dexamethasone 12 mg versus 6 mg daily in patients with COVID-19 and severe hypoxia. DESIGN, SETTING, PARTICIPANTS We conducted a parallel-grouped, stratified, blinded randomized trial including 1000 adults with confirmed COVID-19 receiving at least 10 l/min of oxygen or mechanical ventilation in 26 hospitals in Europe and India from August 2020 to May 2021. INTERVENTIONS Patients were randomized 1:1 to masked intravenous dexamethasone 12 mg or dexamethasone 6 mg daily for up to 10 days. MAIN OUTCOME MEASURES The primary outcome was the number of days alive without life support (i.e. invasive mechanical ventilation, circulatory support or renal replacement therapy) at 28 days. The primary analysis was adjusted for the stratification variables (site, age above 70 years and invasive mechanical ventilation). RESULTS After exclusion of 18 patients who withdrew consent, there were 982 patients in the intention-to-treat population; 613 in Europe and 369 in India. We had primary outcome data for 971 patients; 491 assigned to dexamethasone 12 mg and 480 assigned to dexamethasone 6 mg. The median number of days alive without life support at 28 days was 22.0 days (interquartile range 6.0-28.0) in the 12 mg group and 20.5 days (4.0-28.0) in the 6 mg group (adjusted mean difference 1.3 days, 95% confidence interval (CI), 0.0-2.6; P=0.066). Mortality at 28 days was 27.1% and 32.3% in patients assigned to 12 mg and 6 mg, respectively (adjusted relative risk 0.86, 99% CI, 0.68-1.08). Serious adverse reactions, including septic shock and invasive fungal infections, occurred in 11.7% versus 13.6% of patients in the 12 mg group and 6 mg group, respectively (adjusted relative risk 0.85, 99% CI, 0.56-1.31). CONCLUSIONS AND RELEVANCE Among patients with COVID-19 and severe hypoxia, dexamethasone 12 mg did not result in statistically significant more days alive without life support at 28 days than dexamethasone 6 mg. However, the confidence interval around the point estimate should be considered when interpreting the importance of the trial.