TY - JOUR
T1 - 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)
AU - Welte, Tobias
AU - Dellinger, R. Phillip
AU - Ebelt, Henning
AU - Ferrer, Miguel
AU - Opal, Steven M.
AU - Singer, Mervyn
AU - Vincent, Jean Louis
AU - Werdan, Karl
AU - Martin-Loeches, Ignacio
AU - Almirall, Jordi
AU - Artigas, Antonio
AU - Ignacio Ayestarán, Jose
AU - Nuding, Sebastian
AU - Ferrer, Ricard
AU - Sirgo Rodríguez, Gonzalo
AU - Shankar-Hari, Manu
AU - Álvarez-Lerma, Francisco
AU - Riessen, Reimer
AU - Sirvent, Josep Maria
AU - Kluge, Stefan
AU - Zacharowski, Kai
AU - Bonastre Mora, Juan
AU - Lapp, Harald
AU - Wöbker, Gabriele
AU - Achtzehn, Ute
AU - Brealey, David
AU - Kempa, Axel
AU - Sánchez García, Miguel
AU - Brederlau, Jörg
AU - Kochanek, Matthias
AU - Reschreiter, Henrik Peer
AU - Wise, Matthew P.
AU - Belohradsky, Bernd H.
AU - Bobenhausen, Iris
AU - Dälken, Benjamin
AU - Dubovy, Patrick
AU - Langohr, Patrick
AU - Mayer, Monika
AU - Schüttrumpf, Jörg
AU - Wartenberg-Demand, Andrea
AU - Wippermann, Ulrike
AU - Wolf, Daniele
AU - Torres, Antoni
PY - 2018/4/1
Y1 - 2018/4/1
N2 - © 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.
AB - © 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.
KW - Add-on therapy
KW - Immunoglobulin M
KW - Polyclonal antibody
KW - Severe community-acquired pneumonia
KW - Trimodulin
U2 - https://doi.org/10.1007/s00134-018-5143-7
DO - https://doi.org/10.1007/s00134-018-5143-7
M3 - Article
VL - 44
SP - 438
EP - 448
JO - Intensive Care Medicine
JF - Intensive Care Medicine
SN - 0342-4642
IS - 4
ER -