Is Trimodulin a safe and beneficial adjuvant therapy for adult patients with sCAP?
EJRC Article Review
Severe community-acquired pneumonia (sCAP) remains associated with high mortality despite widespread use of supportive care and targeted antibiotic therapy. Evidence suggests that IgM-enriched Immunoglobulin preparations are associated with a decrease in mortality in severe sepsis and septic shock.
In this randomised double-blind phase II trial (1), Welte et al. aimed to evaluate the safety and efficacy of Trimodulin (a novel human plasma-derived native polyclonal preparation, containing 23% of IgM) as an adjuvant therapy in adult patients with sCAP requiring mechanical ventilation.
The primary endpoint was ventilator-free days (VFDs). Out of the 161 eligible patients, 160 were randomised: 81 to Trimodulin and 79 to receive human albumin as placebo. Trimodulin did not increase the number of VFDs (11.0 (9.5) vs 9.6 (9.4), p=0.173) and did not reduce the 28-day all-cause-mortality in the entire population. Using baseline levels of CRP and IgM to investigate the treatment effects in predefined subgroups, Trimodulin reduced the 28-day all cause-mortality in patients with high CRP and low IgM concentrations (11.8% vs 36.6%, p=0.006). Incidence of adverse effects was collected throughout the study and split after “System Organ Classes”. Trends for more “Renal and urinary disorders” (24.7% vs 15.2%, p=0.167) and “haepatobiliary disorders” (14.8% vs 5.1%, p=0.063) were found in the intervention group. However more “infections and infestations” were collected in the placebo group (33.3% vs 57.0% p=0.004).
These results should be interpreted with caution. First, the diagnosis of sCAP is hard to establish with certainty and only 50% of the randomised patients in this study had positive diagnosis by means of microbiological testing. Secondly, the only statistically significant results were derived from post-hoc analyses in which intervention and control groups were not utterly comparable.
The selection of the primary endpoint is not consensual in clinical trials evaluating treatment of pneumonia. All-cause of mortality has been recommended by American experts (2), but the study power of the studies using this outcome are low due to the low attributable mortality of hospital-acquired pneumonia. A European group of experts recently proposed to use other outcomes, notably VFD or the most-desirable outcomes (3), but their power and clinical meaning remains to be determined.
The development of host-targeted approaches to treat respiratory infection is urgently needed to win the fight again resistant bacteria. Stratification of patients into responders and non-responders will be critical to demonstrate the efficiency of such treatments since not the entire population will respond to specific immunotherapy. However, rather than proposing a never-ending list of predictive biomarkers in ICU, the first step will be the development of efficient therapy, with very few being available to date for critically ill patients.
In conclusion, Trimodulin did not reduce VFDs in the general population of this study. It appears however, safe to use in ICU settings and may benefit a targeted population. Further research is warranted to demonstrate its efficiency as one of the first stratified host-approaches to treat sCAP.
This article review was prepared and submitted by Alexandre Bourdiol and Antoine Roquilly (Anaesthesia and Critical Care Department, University Hospital of Nantes, Nantes, France) on behalf of the EJRC.
- Welte T, Dellinger RP, Ebelt H, Ferrer M, Opal SM, Singer M, et al. Efficacy and safety of trimodulin, a novel polyclonal antibody preparation, in patients with severe community-acquired pneumonia: a randomised, placebo-controlled, double-blind, multicentre, phase II trial (CIGMA study). Intensive Care Med. 2018;44(4):438–48. http://doi.org/10.1007/s00134-018-5143-7
- Talbot, G. H., Powers, J. H., Hoffmann, S. C., Biomarkers Consortium of the Foundation for the National Institutes of Health CABP-ABSSSI and HABP-VABP Project Teams. Developing Outcomes Assessments as Endpoints for Registrational Clinical Trials of Antibacterial Drugs: 2015 Update From the Biomarkers Consortium of the Foundation for the National Institutes of Health. Clinical Infectious Diseases: 2016;62(5), 603–607. https://academic.oup.com/cid/article/62/5/603/2462729
- Timsit, J.-F., de Kraker, M. E. A., Sommer, H., Weiss, E., Bettiol, E., et al. Appropriate endpoints for evaluation of new antibiotic therapies for severe infections: a perspective from COMBACTE’s STAT-Net. Intensive Care Medicine. 2017 ;43(7), 1002–1012. https://link.springer.com/article/10.1007%2Fs00134-017-4802-4