Exciting times for trimodulin

<title>Extract</title> Trimodulin is a human plasma-derived polyclonal antibody preparation for intravenous use that contains 21% IgA, 23% IgM and 56% IgG, and which was initially proposed as an IgM-enriched intravenous immunoglobulin therapy for use in the management of sepsis [1]. The efficacy and safety of trimodulin as adjunctive therapy has now been assessed in patients with severe community-acquired pneumonia in a randomised, placebo-controlled, double-blind, multicentre phase 2 trial (the CIGMA study; <ext-link>NCT01420744</ext-link>), where no differences in ventilator-free days or mortality were noted comparing the trimodulin and placebo groups [2]. Subsequently, the safety and efficacy of trimodulin was also assessed in patients with severe COVID-19 in another randomised, placebo-controlled, double-blind, multicentre phase 2 trial (the ESsCOVID trial; <ext-link>NCT04576728</ext-link>), where, again, no impact of trimodulin on the primary outcome in the overall population was noted [3]. However, notwithstanding the negative outcomes reported in both studies – which included patients with bacterial and viral pneumonia – <italic>post hoc</italic> analyses revealed a potential role for trimodulin in patients with a hyperinflammatory phenotype and patients with low IgM levels [2–4]. That observation led to the initiation of two phase 3 trials, including the now-completed ESsCAPE trial (<ext-link>NCT04576728</ext-link>), which considered trimodulin in patients with severe community-acquired pneumonia requiring invasive mechanical ventilation, and the now-terminated TRICOVID trial (<ext-link>NCT05531149</ext-link>), which considered hospitalised patients with either non-severe community-acquired pneumonia or moderate or severe COVID-19 pneumonia.