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

Abstract

Background: Trimodulin (human polyvalent immunoglobulin [Ig] M ~ 23%, IgA ~ 21%, IgG ~ 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 × 10⁹/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.

Keywords: COVID-19; Early systemic inflammation; Immunoglobulin; Immunomodulation; Trimodulin.

Fig. 1

Pharmacokinetics of IgM, IgA and IgG in COVID-19 patients (PK set). Serum concentrations (mean ± SD) for IgM (A), IgA (B) and IgG (C) were assessed in patients in the PK set. Graphs show PK assessments from samples taken pre-dose on Day 1 (trimodulin, n = 73; placebo, n = 73) and post-dose on Day 5 (trimodulin, n = 53; placebo, n = 63) and Day 29 (trimodulin, n = 7; placebo, n = 8). Dotted line: normal reference ranges [31]. COVID-19 coronavirus disease 2019, Ig immunoglobulin, PK pharmacokinetics, SD standard deviation

Fig. 2

Impact on clinical deterioration and 28-day mortality (overall population [FAS]). A Bar graph represents the proportion of patients achieving the composite endpoint (patients who clinically deteriorated [between Days 6 and 29] plus patients who died [between Days 1 and 29]) and the individual components of this composite endpoint. P values calculated by chi-square test. Error bars denote 95% CIs. B Kaplan–Meier of probability of survival without an event (defined as deterioration or mortality between Days 1 and 29) in the FAS. P value was calculated by log-rank test. CI confidence interval, FAS full analysis set

Fig. 3

Impact on clinical deterioration and 28-day mortality (early systemic inflammation subgroup [FAS]). Post hoc analysis of the primary endpoint in the subgroup of patients with early systemic inflammation who had not yet reached the advanced-stage thresholds (C-reactive protein > 150 mg/L and/or D-dimer ≥ 3 mg/L and/or platelet count < 130 × 10⁹/L). A Bar graph represents the proportion of patients that clinically deteriorated (between Days 6 and 29) plus those that died (between Days 1 and 29) and the individual components of this endpoint. P values calculated by chi-square test. Error bars denote 95% CI. B Kaplan–Meier plot showing the probability of survival with an event (defined as deterioration or mortality between Days 1 and 29). P value was calculated by log-rank test. CI confidence interval, FAS full analysis set, n number of patients