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Published in: Trials 1/2019

Open Access 01-12-2019 | Septicemia | Study protocol

Personalized medicine with IgGAM compared with standard of care for treatment of peritonitis after infectious source control (the PEPPER trial): study protocol for a randomized controlled trial

Authors: Christina Kalvelage, Kai Zacharowski, Artur Bauhofer, Ulrich Gockel, Michael Adamzik, Axel Nierhaus, Peter Kujath, Christian Eckmann, Mathias W. Pletz, Hendrik Bracht, Tim-Philipp Simon, Michael Winkler, Detlef Kindgen-Milles, Markus Albertsmeier, Markus Weigand, Björn Ellger, Maximilian Ragaller, Roman Ullrich, Gernot Marx

Published in: Trials | Issue 1/2019

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Abstract

Background

Peritonitis is responsible for thousands of deaths annually in Germany alone. Even source control (SC) and antibiotic treatment often fail to prevent severe sepsis or septic shock, and this situation has hardly improved in the past two decades. Most experimental immunomodulatory therapeutics for sepsis have been aimed at blocking or dampening a specific pro-inflammatory immunological mediator. However, the patient collective is large and heterogeneous. There are therefore grounds for investigating the possibility of developing personalized therapies by classifying patients into groups according to biomarkers. This study aims to combine an assessment of the efficacy of treatment with a preparation of human immunoglobulins G, A, and M (IgGAM) with individual status of various biomarkers (immunoglobulin level, procalcitonin, interleukin 6, antigen D-related human leucocyte antigen (HLA-DR), transcription factor NF-κB1, adrenomedullin, and pathogen spectrum).

Methods/design

A total of 200 patients with sepsis or septic shock will receive standard-of-care treatment (SoC). Of these, 133 patients (selected by 1:2 randomization) will in addition receive infusions of IgGAM for 5 days. All patients will be followed for approximately 90 days and assessed by the multiple-organ failure (MOF) score, by the EQ QLQ 5D quality-of-life scale, and by measurement of vital signs, biomarkers (as above), and survival.

Discussion

This study is intended to provide further information on the efficacy and safety of treatment with IgGAM and to offer the possibility of correlating these with the biomarkers to be studied. Specifically, it will test (at a descriptive level) the hypothesis that patients receiving IgGAM who have higher inflammation status (IL-6) and poorer immune status (low HLA-DR, low immunoglobulin levels) have a better outcome than patients who do not receive IgGAM. It is expected to provide information that will help to close the knowledge gap concerning the association between the effect of IgGAM and the presence of various biomarkers, thus possibly opening the way to a personalized medicine.

Trial registration

EudraCT, 2016–001788-34; ClinicalTrials.gov, NCT03334006. Registered on 17 Nov 2017.
Trial sponsor: RWTH Aachen University, represented by the Center for Translational & Clinical Research Aachen (contact Dr. S. Isfort).
Appendix
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Literature
1.
Statistisches Bundesamt. Gesundheit: Diagnosedaten der Patienten und Patientinnen in Krankenhäusern (einschl. Sterbe- und Stundenfälle) 2015. Wiesbaden: Statistisches Bundesamt; 2016.
2.
Kujath P, Rodloff AC. Peritonitis. Bremen: UNI-MED; 2001. ISBN 3-8999-549-5
3.
Montravers P, Leroy O, Eckmann C. Intraabdominal candidiasis: it’s still a long way to get unquestionable data. Intensive Care Med. 2015;41:1682–4.PubMed
4.
Weber GF, Swirski FK. Immunopathogenesis of abdominal sepsis. Langenbeck’s Arch Surg. 2014;399:1–9.
5.
Marshall JC, Vincent JL, Fink MP, Cook DJ, Rubenfeld G, Foster D, et al. Measures, markers, and mediators: toward a staging system for clinical sepsis. A report of the Fifth Toronto Sepsis Round Table, Toronto, Ontario, Canada, October 25–26, 2000. Crit Care Med. 2003;31:1560–7.PubMed
6.
Müller B, Becker KL, Schächinger H, Rickenbacher PR, Huber PR, Zimmerli W, Ritz R. Calcitonin precursors are reliable markers of sepsis in a medical intensive care unit. Crit Care Med. 2000;28:977–83.PubMed
7.
Harbarth S, Holeckova K, Froidevaux C, Pittet D, Ricou B, Grau GE, et al. Diagnostic value of procalcitonin, interleukin-6, and interleukin-8 in critically ill patients admitted with suspected sepsis. Am J Respir Crit Care Med. 2001;164:396–402.PubMed
8.
Maruna P, Nedelnikova K, Gurlich R. Physiology and genetics of procalcitonin. Physiol Res. 2000;49(Suppl 1):S57–61.PubMed
9.
Clec'h C, Fosse JP, Karoubi P, Vincent F, Chouahi I, Hamza L, Cupa M, Cohen Y. Differential diagnostic value of procalcitonin in surgical and medical patients with septic shock. Crit Care Med. 2006;34(1):102–7.PubMed
10.
Monneret G, Doche C, Durand DV, Lepape A, Bienvenu J. Procalcitonin as a specific marker of bacterial infection in adults. Clin Chem Lab Med. 1998;36:67–8.PubMed
11.
Brunkhorst FM. Sepsismarker – what is useful? Dtsch Med Wochenschr. 2008;133:2512–5.PubMed
12.
Christ-Crain M, Stolz D, Bingisser R, Müller C, Miedinger D, Huber PR, Zimmerli W, Harbarth S, Tamm M, Müller B. Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial. Am J Respir Crit Care Med. 2006;174:84–93.PubMed
13.
de Jong E, van Oers JA, Beishuizen A, Vos P, Vermeijden WJ, Haas LE, et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis. 2016;16:819–27.PubMed
14.
Van Snick J. Interleukin-6: an overview. Annu Rev Immunol. 1990;8:253–78.PubMed
15.
Küster H, Weiss M, Willeitner AE, Detlefsen S, Jeremias I, Zbojan J, et al. Interleukin-1 receptor antagonist and interleukin-6 for early diagnosis of neonatal sepsis 2 days before clinical manifestation. Lancet. 1998;352:1271–7.PubMed
16.
Panacek EA, Marshall JC, Albertson TE, Johnson DH, Johnson S, MacArthur RD, et al. Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab')2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels. Crit Care Med. 2004;32:2173–82.PubMed
17.
Schefold JC, von Haehling S, Corsepius M, Pohle C, Kruschke P, Zuckermann H, et al. A novel selective extracorporeal intervention in sepsis: immunoadsorption of endotoxin, interleukin 6, and complement-activating product 5a. Shock. 2007;28:418–25.PubMed
18.
Meisel C, Schefold JC, Pschowski R, Baumann T, Hetzger K, Gregor J, et al. Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial. Am J Respir Crit Care Med. 2009;180:640–8.PubMed
19.
Tamayo E, Fernández A, Almansa R, Carrasco E, Goncalves L, Heredia M, et al. Beneficial role of endogenous immunoglobulin subclassesand isotypes in septic shock. J Crit Care. 2012;27:616–22.PubMed
20.
Bermejo-Martín JF, Rodriguez-Fernandez A, Herrán-Monge R, Andaluz-Ojeda D, Muriel-Bombín A, Merino P, García-García MM, Citores R, Gandía F, Almansa R, Blanco J, GRECIA Group. Immunoglobulins IgG1, IgM and IgA: a synergistic team influencing survival in sepsis. J Intern Med. 2014;276:404–12.PubMed
21.
Giamarellos-Bourboulis EJ, Apostolidou E, Lada M, Perdios I, Gatselis NK, Tsangaris I, et al. Kinetics of circulating immunoglobulin M in sepsis: relationship with final outcome. Crit Care. 2013;17:R247.PubMedPubMedCentral
22.
Wang P, Ba ZF, Cioffi WG, Bland KI, Chaudry IH. The pivotal role of adrenomedullin in producing hyperdynamic circulation during the early stage of sepsis. Arch Surg. 1998;133:1298–304.PubMed
23.
Koo DJ, Zhou M, Chaudry IH, Wang P. The role of adrenomedullin in producing differential hemodynamic responses during sepsis. J Surg Res. 2001;95:207–18.PubMed
24.
Marino R, Struck J, Maisel AS, Magrini L, Bergmann A, Di Somma S. Plasma adrenomedullin is associated with short-term mortality and vasopressor requirement in patients admitted with sepsis. Crit Care. 2014;18:R34.PubMedPubMedCentral
25.
Ueda S, Nishio K, Minamino N, Kubo A, Akai Y, Kangawa K, et al. Increased plasma levels of adrenomedullin in patients with systemic inflammatory response syndrome. Am J Respir Crit Care Med. 1999;160:132–6.PubMed
26.
Adamzik M, Frey UH, Möhlenkamp S, Scherag A, Waydhas C, Marggraf G, Dammann M, Steinmann J, Siffert W, Peters J. Aquaporin 5 gene promoter--1364A/C polymorphism associated with 30-day survival in severe sepsis. Anesthesiol. 2011;114:912–7.
27.
Ma P, Zhu Y, Qiu H, Liu J, Wang Y, Zeng L. Endothelial nitric oxide synthase 894G→T but not –786T→C gene polymorphism is associated with organ dysfunction and increased mortality in patients with severe sepsis. J Trauma. 2011;71:872–7.PubMed
28.
Thair SA, Walley KR, Nakada TA, McConechy MK, Boyd JH, Wellman H, Russell JA. A single nucleotide polymorphism in NF-κB inducing kinase is associated with mortality in septic shock. J Immunol. 2011;186:2321–8.PubMed
29.
De Waele J, Lipman J, Sakr Y, Marshall JC, Vanhems P, Barrera Groba C, Leone M, Vincent JL, EPIC II Investigators. Abdominal infections in the intensive care unit: characteristics, treatment and determinants of outcome. BMC Infect Dis. 2014;14:420.PubMedPubMedCentral
30.
Busani S, et al. Mortality in patients with septic shock by multidrug resistant bacteria. J Intensive Care Med. 2017;34:48–54.
31.
Beyer K, Menges P, Keßler W, Heidecke CD. Pathophysiologie der Peritonitis [Pathology of pritonitis]. Chirurg. 2016;87:5–12.PubMed
32.
Rodríguez A, Rello J, Neira J, Maskin B, Ceraso D, Vasta L, Palizas F. Effects of high-dose of intravenous immunglobulin and antibiotics on survival for severe sepsis undergoing surgery. Shock. 2005;23:298–304.PubMed
33.
Kreymann KG, de Heer G, Nierhaus A, Kluge S. Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock. Crit Care Med. 2007;35:2677–85.PubMed
34.
Andaluz-Ojeda D, Iglesias V, Bobillo F, Nocito M, Loma AM, Nieto C, Ramos E, Gandía F, Rico L, Bermejo-Martin JF. Early levels in blood of immunoglobulin M and natural killer cells predict outcome in nonseptic critically ill patients. J Crit Care. 2013;28:1110.e7–1110.e10.
35.
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 randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study). Intensive Care Med. 2018;44:438–48.
36.
37.
Cavazzuti I, Serafini G, Busani S, Rinaldi L, Biagioni E, Buoncristiano M, Girardis M. Early therapy with IgM-enriched polyclonal immunoglobulin in patients with septic shock. Intensive Care Med. 2014;40:1888–96.PubMed
38.
McClelland DB, Yap PL. Clinical use of immunoglobulins. Clin Haematol. 1984;13(1):39–74.PubMed
39.
Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. Intensive Care Med. 1996;22:707–10.PubMed
40.
41.
Goris RJ, te Boekhorst TP, Nuytinck JK, Gimbrère JS. Multiple-organ failure. Generalized autodestructive inflammation? Arch Surg. 1985;120:1109–15.PubMed
42.
Lefering R, Goris RJ, van Nieuwenhoven EJ, Neugebauer E. Revision of the multiple organ failure score. Langenbeck's Arch Surg. 2002;387:14–20.
43.
Wacha H, Linder MM, Feldman U, Wesch G, Gundlach E, Steifensand RA. Mannheim peritonitis index – prediction of risk of death from peritonitis: construction of a statistical and validation of an empirically based index. Theoretical Surg. 1987;1:169–77.
44.
Neri A, Marrelli D, Scheiterle M, Di Mare G, Sforza S, Roviello F. Re-evaluation of Mannheim prognostic index in perforative peritonitis: prognostic role of advanced age. A prospective cohort study. Int J Surg. 2015;13:54–9.PubMed
45.
Heyland DK, Muscedere J, Drover J, Jiang X, Day AG, Canadian Critical Care Trials G. Persistent organ dysfunction plus death: a novel, composite outcome measure for critical care trials. Crit Care. 2011;15:R98.PubMedPubMedCentral
46.
Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801–10.PubMedPubMedCentral
47.
Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med. 2017;45:486–552.PubMed
48.
Eisele B, Lamy M, Thijs LG, Keinecke HO, Schuster HP, Matthias FR, et al. Antithrombin III in patients with severe sepsis. A randomized, placebo-controlled, double-blind multicenter trial plus a meta-analysis on all randomized, placebo-controlled, double-blind trials with antithrombin III in severe sepsis. Intensive Care Med. 1998;24:663–72.PubMed
49.
Reinhart K, Menges T, Gardlund B, Harm Zwaveling J, Smithes M, Vincent JL, et al. Randomized, placebo-controlled trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory response during severe sepsis: The RAMSES Study. Crit Care Med. 2001;29:765–9.PubMed
50.
Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344:699–709.PubMed
51.
Solomkin J, Evans D, Slepavicius A, Lee P, Marsh A, Tsai L, Sutcliffe JA, Horn P. Assessing the efficacy and safety of eravacycline vs. ertapenem in complicated intra-abdominal infections in the investigating gram-negative infections treated with eravacycline (IGNITE 1) trial: a randomized clinical trial. JAMA Surg. 2017;152:224–32.PubMed
Metadata
Title
Personalized medicine with IgGAM compared with standard of care for treatment of peritonitis after infectious source control (the PEPPER trial): study protocol for a randomized controlled trial
Authors
Christina Kalvelage
Kai Zacharowski
Artur Bauhofer
Ulrich Gockel
Michael Adamzik
Axel Nierhaus
Peter Kujath
Christian Eckmann
Mathias W. Pletz
Hendrik Bracht
Tim-Philipp Simon
Michael Winkler
Detlef Kindgen-Milles
Markus Albertsmeier
Markus Weigand
Björn Ellger
Maximilian Ragaller
Roman Ullrich
Gernot Marx
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Trials / Issue 1/2019
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/s13063-019-3244-4

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