Efficacy and safety of trimodulin in patients with severe COVID-19: results from a randomised, placebo-controlled, double-blind, multicentre, phase II trial (ESsCOVID)

Background Trimodulin (human polyvalent immunoglobulin [Ig] M similar to 23%, IgA similar to 21%, IgG similar to 56% preparation) has previously been associated with a lower mortality rate in a subpopulation of patients with severe community-acquired pneumonia on invasive mechanical ventilation (IMV) and with clear signs of inflammation. The hypothesis for the ESsCOVID trial was that trimodulin may prevent inflammation-driven progression of severe coronavirus disease 2019 (COVID-19) to critical disease or even death. Methods Adults with severe COVID-19 were randomised to receive intravenous infusions of trimodulin or placebo for 5 consecutive days in addition to standard of care. The primary efficacy endpoint was a composite of clinical deterioration (Days 6-29) and 28-day all-cause mortality (Days 1-29). Results One-hundred-and-sixty-six patients received trimodulin (n = 84) or placebo (n = 82). Thirty-three patients died, nine during the treatment phase. Overall, 84.9% and 76.5% of patients completed treatment and follow-up, respectively. The primary efficacy endpoint was reported in 33.3% of patients on trimodulin and 34.1% of patients on placebo (P = 0.912). No differences were observed in the proportion of patients recovered on Day 29, days of invasive mechanical ventilation, or intensive care unit-free days. Rates of treatment-emergent adverse events were comparable. A post hoc analysis was conducted in patients with early systemic inflammation by excluding those with high CRP (> 150 mg/L) and/or D-dimer (>= 3 mg/L) and/or low platelet counts (< 130 x 10(9)/L) at baseline. Forty-seven patients in the trimodulin group and 49 in the placebo group met these criteria. A difference of 15.5 percentage points in clinical deterioration and mortality was observed in favour of trimodulin (95% confidence interval: -4.46, 34.78; P = 0.096). Conclusion Although there was no difference in the primary outcome in the overall population, observations in a subgroup of patients with early systemic inflammation suggest that trimodulin may have potential in this setting that warrants further investigation. ESsCOVID was registered prospectively at ClinicalTrials.gov on October 6, 2020. NCT04576728