BACKGROUND: Dexamethasone 6 mg in patients with severe COVID-19 has been shown to decrease mortality and morbidity. The effects of higher doses of corticosteroid, that would further increase anti-inflammatory effects, are uncertain. The objective of our study was to assess the effect of 20 mg dexamethasone vs. 6 mg dexamethasone intravenously in patients with moderate-to-severe acute respiratory distress syndrome (ARDS) and COVID-19. METHODS: In a multicenter, open-label, randomized trial conducted in nine hospitals in the Czech Republic, we randomized adult patients with ARDS and COVID-19 requiring high-flow oxygen, noninvasive or invasive mechanical ventilation to receive either intravenous high-dose dexamethasone (20 mg/day on days 1-5, 10 mg/day on days 6-10) or standard-dose dexamethasone (6 mg/d, days 1-10). The primary outcome was 28-day ventilator-free days. The five secondary outcomes were 60-day mortality, C-reactive protein dynamics, 14-day WHO (World Health Organization) Clinical Progression Scale score, adverse events and 90-day Barthel index. The long-term outcomes were 180- and 360-day mortality and the Barthel index. The planned sample size was 300, with interim analysis after enrollment of 150 patients. RESULTS: The trial was stopped due to a lack of recruitment, and the follow-up was completed in February 2023. Among 234 randomized patients of 300 planned patients, the primary outcome was available for 224 patients (110 high-dose and 114 standard-dose dexamethasone; median [interquartile range (IQR)] age, 59.0 [48.5-66.0] years; 130 [58.0%] were receiving noninvasive or invasive mechanical ventilation at baseline). The mean number of 28-day ventilator-free days was 8.9 (± 11.5) days for high-dose dexamethasone and 8.0 (± 10.7) days for standard-dose dexamethasone, with an absolute difference of + 0.81 days (95% CI - 2.12-3.73 days). None of the prespecified secondary outcomes, including adverse events, differed between the groups. CONCLUSIONS: Despite not reaching its prespecified enrollment, there was no signal to either benefit or harm high-dose dexamethasone over standard-dose dexamethasone in patients with COVID-19 and moderate-to-severe ARDS. Trial registration Trial registration: ClinicalTrials.gov Identifier: NCT04663555. Registered 10 December 2020, https://clinicaltrials.gov/study/NCT04663555?term=NCT04663555&rank=1 and EudraCT: 2020-005887-70.

2nd Department of Anaesthesiology and Intensive Care Medicine University Hospital Brno Brno Czech Republic

Bloomsbury Institute of Intensive Care Medicine Division of Medicine University College London London UK

Department of Anaesthesia and Intensive Care General University Hospital Prague and the 1st Faculty of Medicine Charles University Prague Czech Republic

Department of Anaesthesia and Intensive Care University Hospital Královské Vinohrady and the 3rd Faculty of Medicine Charles University Šrobárova 1150 10034 Praha Czech Republic

Department of Anaesthesiology and Intensive Care Medicine St Anne's University Hospital and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Anaesthesiology and Intensive Care Medicine Tomáš Baťa Regional Hospital Zlín Czech Republic

Department of Anaesthesiology and Intensive Care Medicine University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Anaesthesiology and Intensive Care Medicine University Hospital Olomouc and Faculty of Medicine Palacky University Olomouc Czech Republic

Department of Anaesthesiology and Intensive Care Medicine University Hospital Pilsen and Faculty of Medicine in Pilsen Charles University Plzeň Czech Republic

Department of Anaesthesiology and Intensive Care Military University Hospital Praha and the 1st Faculty of Medicine Charles University Prague Czech Republic

Department of Anesthesiology and Intensive Care Medicine University Hospital Ostrava and Faculty of Medicine University Ostrava Ostrava Poruba Czech Republic

Department of Internal Medicine and Cardiology University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Paediatric Anaesthesiology and Intensive Care Medicine University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Pharmacology CZECRIN Faculty of Medicine Masaryk University Brno Czech Republic

Department of Simulation Medicine Faculty of Medicine Masaryk University Brno Czech Republic

International Clinical Research Centre at St Anne's University Hospital Brno Czech Republic

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