Efficacy and safety of trimodulin, a novel polyclonal antibody preparation, in patients with severe community-acquired pneumonia: a randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study)

Tobias Welte, R. Phillip Dellinger, Henning Ebelt, Miguel Ferrer, Steven M. Opal, Mervyn Singer, Jean Louis Vincent, Karl Werdan, Ignacio Martin-Loeches, Jordi Almirall, Antonio Artigas, Jose Ignacio Ayestarán, Sebastian Nuding, Ricard Ferrer, Gonzalo Sirgo Rodríguez, Manu Shankar-Hari, Francisco Álvarez-Lerma, Reimer Riessen, Josep Maria Sirvent, Stefan KlugeKai Zacharowski, Juan Bonastre Mora, Harald Lapp, Gabriele Wöbker, Ute Achtzehn, David Brealey, Axel Kempa, Miguel Sánchez García, Jörg Brederlau, Matthias Kochanek, Henrik Peer Reschreiter, Matthew P. Wise, Bernd H. Belohradsky, Iris Bobenhausen, Benjamin Dälken, Patrick Dubovy, Patrick Langohr, Monika Mayer, Jörg Schüttrumpf, Andrea Wartenberg-Demand, Ulrike Wippermann, Daniele Wolf, Antoni Torres

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40 Citations (Scopus)

Abstract

© 2018, The Author(s). Purpose: The CIGMA study investigated a novel human polyclonal antibody preparation (trimodulin) containing ~ 23% immunoglobulin (Ig) M, ~ 21% IgA, and ~ 56% IgG as add-on therapy for patients with severe community-acquired pneumonia (sCAP). Methods: In this double-blind, phase II study (NCT01420744), 160 patients with sCAP requiring invasive mechanical ventilation were randomized (1:1) to trimodulin (42 mg IgM/kg/day) or placebo for five consecutive days. Primary endpoint was ventilator-free days (VFDs). Secondary endpoints included 28-day all-cause and pneumonia-related mortality. Safety and tolerability were monitored. Exploratory post hoc analyses were performed in subsets stratified by baseline C-reactive protein (CRP; ≥ 70 mg/L) and/or IgM (≤ 0.8 g/L). Results: Overall, there was no statistically significant difference in VFDs between trimodulin (mean 11.0, median 11 [n = 81]) and placebo (mean 9.6; median 8 [n = 79]; p = 0.173). Twenty-eight-day all-cause mortality was 22.2% vs. 27.8%, respectively (p = 0.465). Time to discharge from intensive care unit and mean duration of hospitalization were comparable between groups. Adverse-event incidences were comparable. Post hoc subset analyses, which included the majority of patients (58–78%), showed significant reductions in all-cause mortality (trimodulin vs. placebo) in patients with high CRP, low IgM, and high CRP/low IgM at baseline. Conclusions: No significant differences were found in VFDs and mortality between trimodulin and placebo groups. Post hoc analyses supported improved outcome regarding mortality with trimodulin in subsets of patients with elevated CRP, reduced IgM, or both. These findings warrant further investigation. Trial registration: NCT01420744.
Original languageEnglish
Pages (from-to)438-448
JournalIntensive Care Medicine
Volume44
Issue number4
DOIs
Publication statusPublished - 1 Apr 2018

Keywords

  • Add-on therapy
  • Immunoglobulin M
  • Polyclonal antibody
  • Severe community-acquired pneumonia
  • Trimodulin

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