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)

Abstract

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.

Keywords: Add-on therapy; Immunoglobulin M; Polyclonal antibody; Severe community-acquired pneumonia; Trimodulin.

Conflict of interest statement

TW has served on advisory boards, received funding for institutional research, and honoraria from Biotest AG. RPD has received personal fees from Biotest AG for serving on the advisory board for this trial, institutional funding from Spectral Diagnostics, and personal fees for consulting from Merck, Bristol-Myers Squibb, and Spectral. HE has served on advisory boards for Biotest AG and received honoraria from Biotest AG. MF has served on advisory boards for Biotest AG. SMO has served on advisory boards for Aridis and Arsanis, and received institutional funding from Asahi Kasei and Ferring, and consultancy fees from Biotest AG. MS has received honoraria from Biotest AG for participation in advisory boards and satellite symposia. KW is a member of the Biotest BT086 Advisory Board and has received honoraria, research funding, consulting fees, and funding for travel from Biotest AG. IM-L has served on advisory boards for Biotest AG. AA has received institutional research funding and honoraria from GRIFOLS Co, and consulting fees from Asahi Kasei. RF has received honoraria from MSD, Pfizer, and Toray. MS-H has received travel costs for speaking at a Biotest seminar. FA-L has served on advisory boards for Gilead and MSD. SK has served on advisory boards for ANOMED, Astellas, Baxter, Fresenius, Gambro, Gilead, MSD, NovaLung, Novartis, and Pfizer; has received institutional research funding from NovaLung and Pfizer, and honoraria from ArjoHuntleigh, Astellas, Basilea, Baxter, Biotest AG, CSL Behring, Cytosorbents, Fresenius, Gilead, MSD, NovaLung, Pfizer, Orion, Sedana, Sorin, and Thermo Fisher Scientific. KZ has received research grants, honoraria, and financial support (education) for his department from Abbott, AbbVie Deutschland KG, Aesculap Akademie, AIT GmbH, Amomed GmbH, art tempi GmbH, Ashai Kasai Pharma, Astellas Pharma, B. Braun Avitum AG, B. Braun Melsungen AG, Bayer AG, Biotest AG, Codan PVB Medical, Covidien GmbH, CSL Behring, Delab GmbH, Dr. F. Köhler Chemie, Dr Rothenberger, Dräger Medical, ECCPS, Edward Life Science GmbH, Enterprise Analyses, Envico SRL, European Union, Ferring Arzneimittel, Forum Sanitas, Fresenius Kabi, Fresenius Medical Care, German Research Federation Gilead, Haemonetics Corporation, Hamilton Medical AG, Heinen + Löwenstein, Hepanet GmbH, Hexal AG, High Tech Grundungsford, INC Research, Josef Gassner, Karl Storz AG, Kentours Producciones, LOEWE TP 6, M&M Gesundheitsnetzwerk, Maquet GmbH, Marien-Akademie, Markus Lucke Kongress Organisation, Masimo, Massimo International, med-Update GmbH, Medtronic GmbH, MSD Sharp & Dohme, Mundipharma GmbH, Nordic Group, Novartis Pharma GmbH, Novo Nordisk Pharma GmbH, Orion Pharma GmbH, Pall GmbH, Pfizer, Photonics GmbH, Pulsion Medical Systems S.E., Radiometer GmbH, Ratiopharm GmbH, Reha Medi GmbH, Salvia Medical GmbH, Sarstedt GmbH, Schochl Medical Research Österreich, Serumwerke Berneburg, Siemens Healthcare, Smith Medical GmbH, Sorin Group, Sysmex, Teflex Medical GmbH, TEM International, Teva GmbH, Thieme Verlag, Verathon Medical, and Vifor Pharma. UA has received reimbursement for educational support and travel costs from Biotest AG. DB has received funding for institutional research at the trial site only. MK has served on advisory boards for MSD and Pfizer, and has received honoraria from Astellas, Gilead, MSD, and Pfizer. AT has served on advisory boards for Aridis, Bayer, GSK, Pfizer, Polyphor, and Roche. J-LV, JA, JIA, SN, GSR, RR, J-MS, JBM, HL, GW, AK, MSG, JB, HPR, MPW, and BHB have no interests to declare. IB, BD, PD, PL, MM, JS, AW-D, UW, and DW are employees of Biotest AG. UW, JS, and AW-D also hold stocks/shares in Biotest AG.

Figures

Fig. 1

Patient disposition and reasons for discontinuation during the study period

Fig. 2

Survival by treatment regimen

Fig. 3

Twenty-eight-day all-cause mortality in trimodulin and placebo treatment groups in all patients and in patient subsets. Mortality was assessed in all patients and in stratified patient populations based on baseline levels of C-reactive protein (CRP) ≥ 70 mg/L, immunoglobulin (Ig) M ≤ 0.8 g/L, or both criteria combined, or procalcitonin (PCT) ≥ 2.0 ng/mL. Actual numbers of deaths are given at the bottom of each column