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

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, 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

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).

Keywords: Biomarkers; IgGAM; Pentaglobin; Peritonitis; Personalized medicine; Sepsis; Severe bacterial infection.

Conflict of interest statement

Ethics approval and consent to participate

Approval for the study has been obtained from the ethics committee responsible for the sponsor and from the responsible German federal agency (the Paul-Ehrlich-Institut) and from local ethics committees as appropriate. No invasive study procedure will be commenced if written informed consent to participate in the trial has not been obtained from the subject, a legal representative, a court-appointed carer or a study-independent consultant physician. A list of the ethics committees involved can be made available on request.

Important protocol modifications will be made public on clinicaltrials.gov.

Consent for publication

Not applicable.

Competing interests

AB and UG are employees of Biotest AG, manufacturer of Pentaglobin® (IgGAM). CK is an employee of the RWTH Aachen University. KZ has received various research stipends, honoraria and lecturer’s fees, including from Biotest AG. There are no other actual or potential competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Course of the study. ICU intensive care unit, IgGAM preparation containing immunoglobulins G, A, and M, MOF multiple organ failure, OP operation , QoL quality of life
Fig. 2
Fig. 2
SPIRIT figure. For abbreviations see text

References

    1. Statistisches Bundesamt . Gesundheit: Diagnosedaten der Patienten und Patientinnen in Krankenhäusern (einschl. Sterbe- und Stundenfälle) 2015. Wiesbaden: Statistisches Bundesamt; 2016.
    1. Kujath P, Rodloff AC. Peritonitis. Bremen: UNI-MED; 2001.
    1. Montravers P, Leroy O, Eckmann C. Intraabdominal candidiasis: it’s still a long way to get unquestionable data. Intensive Care Med. 2015;41:1682–1684.
    1. Weber GF, Swirski FK. Immunopathogenesis of abdominal sepsis. Langenbeck’s Arch Surg. 2014;399:1–9.
    1. 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;31:1560–1567.
    1. 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;28:977–983.
    1. 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.
    1. Maruna P, Nedelnikova K, Gurlich R. Physiology and genetics of procalcitonin. Physiol Res. 2000;49(Suppl 1):S57–S61.
    1. 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):102–107.
    1. 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;36:67–68.
    1. Brunkhorst FM. Sepsismarker – what is useful? Dtsch Med Wochenschr. 2008;133:2512–2515.
    1. 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.
    1. 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;16:819–827.
    1. Van Snick J. Interleukin-6: an overview. Annu Rev Immunol. 1990;8:253–278.
    1. 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;352:1271–1277.
    1. 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;32:2173–2182.
    1. 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;28:418–425.
    1. 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;180:640–648.
    1. 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;27:616–622.
    1. 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;276:404–412.
    1. 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.
    1. 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;133:1298–1304.
    1. Koo DJ, Zhou M, Chaudry IH, Wang P. The role of adrenomedullin in producing differential hemodynamic responses during sepsis. J Surg Res. 2001;95:207–218.
    1. 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.
    1. 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;160:132–136.
    1. 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;114:912–917.
    1. 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;71:872–877.
    1. 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;186:2321–2328.
    1. 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.
    1. Busani S, et al. Mortality in patients with septic shock by multidrug resistant bacteria. J Intensive Care Med. 2017;34:48–54.
    1. Beyer K, Menges P, Keßler W, Heidecke CD. Pathophysiologie der Peritonitis [Pathology of pritonitis] Chirurg. 2016;87:5–12.
    1. 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.
    1. 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;35:2677–2685.
    1. 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.
    1. 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.
    1. Alejandria MM, Lansang MA, Dans LF, Mantaring JB 3rd. Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock. Cochrane Database Syst Rev. 2013;9. 10.1002/14651858.
    1. 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;40:1888–1896.
    1. McClelland DB, Yap PL. Clinical use of immunoglobulins. Clin Haematol. 1984;13(1):39–74.
    1. 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;22:707–710.
    1. Biotest Pharma GmbH. Fachinformation Pentaglobin 50 mg/ml Infusionslösung. . Accessed 20 Feb 2019
    1. Goris RJ, te Boekhorst TP, Nuytinck JK, Gimbrère JS. Multiple-organ failure. Generalized autodestructive inflammation? Arch Surg. 1985;120:1109–1115.
    1. Lefering R, Goris RJ, van Nieuwenhoven EJ, Neugebauer E. Revision of the multiple organ failure score. Langenbeck's Arch Surg. 2002;387:14–20.
    1. 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;1:169–177.
    1. 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;13:54–59.
    1. 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.
    1. 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):801–810.
    1. 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.
    1. 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;24:663–672.
    1. 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;29:765–769.
    1. 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.
    1. 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;152:224–232.

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