Oral Melatonin in Critically Ill Patients With COVID‐19: A Quasi‐Experimental Pragmatic Trial

Melatonin has demonstrated antioxidant, anti‐inflammatory, and potential antiviral properties. Its therapeutic role in critically ill COVID‐19 patients admitted to intensive care was underexplored at the start of the pandemic. We conducted a quasi‐experimental, pragmatic study over 4 consecutive uninterrupted time periods alternating control groups receiving standard of care (SoC) with treatment groups receiving SoC plus high‐dose oral bedtime melatonin (50–200 mg) (OBM). The primary endpoint was 90‐day mortality; secondary outcomes included sequential organ failure assessment (SOFA) scores at 4, 7, 14, and 30 days and pre‐defined severe adverse events (SAEs). A total of 335 of 339 consecutive patients with a predicted stay > 48 h were enrolled; 202 received OBM with SoC and 133 received SoC alone. OBM was dispensed during the second (n = 162) and fourth (n = 40) study periods after the first (n = 40) and third (n = 93) control group periods, respectively. Melatonin therapy was associated with significantly lower 90‐day mortality (20.8% vs. 36.1%, OR 0.46, 95% CI 0.28–0.76). Subjects receiving melatonin had lower SOFA scores on Day 4 and subsequent study visits. SAEs occurred in 84 (41.6%) subjects on OBM and in 80 (60.2%) receiving SoC (risk ratio 0.68, 95% CI 0.54–0.87; p = 0.001). High‐dose oral melatonin was safe and associated with improved clinical outcomes. Further evaluation of melatonin and its potential antiviral effects in future epidemics is warranted.