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 Medicine

Volumn 44, Issue 4, 2018, Pages 438-448

  Welte, Tobias ^a   Dellinger, R Phillip ^b   Ebelt, Henning ^c   Ferrer, Miguel ^d   Opal, Steven M ^e   Singer, Mervyn ^f   Vincent, Jean Louis ^g   Werdan, Karl ^c   Martin Loeches, Ignacio ^h,i   Almirall, Jordi ⁱ   Artigas, Antonio ⁱ   Ignacio Ayestarán, Jose ^j   Nuding, Sebastian ^c   Ferrer, Ricard ^k   Sirgo Rodríguez, Gonzalo ^l   Shankar Hari, Manu ^m   Álvarez Lerma, Francisco ⁿ   Riessen, Reimer ^o   Sirvent, Josep Maria ^p   Kluge, Stefan ^q   Zacharowski, Kai ^r   Bonastre Mora, Juan ^s   Lapp, Harald ^t   Wöbker, Gabriele ^u   Achtzehn, Ute ^v   Brealey, David ^w   Kempa, Axel ^x   Sánchez García, Miguel ^y   Brederlau, Jörg ^z   Kochanek, Matthias ^aa   Reschreiter, Henrik Peer ^ab   Wise, Matthew P ^ac   Belohradsky, Bernd H ^ad   Bobenhausen, Iris ^ae   Dälken, Benjamin ^ae   Dubovy, Patrick ^ae   Langohr, Patrick ^ae   Mayer, Monika ^ae   Schüttrumpf, Jörg ^ae   Wartenberg Demand, Andrea ^ae   Wippermann, Ulrike ^ae   Wolf, Daniele ^ae   Torres, Antoni ^d   more..

^a HANNOVER MEDICAL SCHOOL   (Germany)

^b Cooper University Health Care ^*  (United States)

^c MARTIN LUTHER UNIVERSITÄT HALLE WITTENBERG   (Germany)

^d UNIVERSITY OF BARCELONA   (Spain)

^e BROWN UNIVERSITY   (United States)

^f UNIVERSITY COLLEGE LONDON   (United Kingdom)

^g ERASME HOSPITAL   (Belgium)

^h ST JAMES S HOSPITAL   (Ireland)

ⁱ UNIVERSITAT AUTÒNOMA DE BARCELONA   (Spain)

^j HOSPITAL UNIVERSITARIO SON ESPASES   (Spain)

^k HOSPITAL MÚTUA DE TERRASSA   (Spain)

^l HOSPITAL UNIVERSITARI JOAN XXIII   (Spain)

^m GUY'S AND ST THOMAS' NHS FOUNDATION TRUST   (United Kingdom)

ⁿ HOSPITAL DEL MAR   (Spain)

^o UNIVERSITY HOSPITAL TÜBINGEN   (Germany)

^p HOSPITAL JOSEP TRUETA   (Spain)

^q UNIVERSITY MEDICAL CENTER HAMBURG EPPENDORF   (Germany)

^r UNIVERSITY HOSPITAL FRANKFURT   (Germany)

^s HOSPITAL CLÍNICO UNIVERSITARIO   (Spain)

^t HELIOS KLINIKUM ERFURT   (Germany)

^u Institute of Gynecology and Obstetrics   (Germany)

^v KLINIKUM CHEMNITZ   (Germany)

^w UNIVERSITY COLLEGE LONDON HOSPITALS   (United Kingdom)

^x KATHARINENHOSPITAL   (Germany)

^y HOSPITAL CLÍNICO SAN CARLOS   (Spain)

^z HELIOS KLINIKUM BERLIN BUCH   (Germany)

^aa UNIVERSITY HOSPITAL OF COLOGNE   (Germany)

^ab POOLE HOSPITAL NHS FOUNDATION TRUST   (United Kingdom)

^ac UNIVERSITY HOSPITAL OF WALES   (United Kingdom)

^ad LUDWIG MAXIMILIANS UNIVERSITY   (Germany)

^ae BIOTEST AG   (Germany)

more..

Author keywords

Add on therapy; Immunoglobulin M; Polyclonal antibody; Severe community acquired pneumonia; Trimodulin

Indexed keywords

BETA LACTAM ANTIBIOTIC; BT 086; C REACTIVE PROTEIN; IMMUNOGLOBULIN M; MACROLIDE; POLYCLONAL ANTIBODY; PROCALCITONIN; QUINOLINE DERIVED ANTIINFECTIVE AGENT; TRIMODULIN; UNCLASSIFIED DRUG; ANTIINFECTIVE AGENT; IMMUNOGLOBULIN CLASS; IMMUNOLOGIC FACTOR;

ADD ON THERAPY; ADULT; AGED; ALL CAUSE MORTALITY; ANTIBIOTIC THERAPY; APACHE; ARTICLE; ARTIFICIAL VENTILATION; COMBINATION DRUG THERAPY; COMMUNITY ACQUIRED PNEUMONIA; CONNECTIVE TISSUE DISEASE; CONTROLLED STUDY; CRITICAL ILLNESS; DOUBLE BLIND PROCEDURE; DRUG EFFICACY; DRUG INTOXICATION; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; FEMALE; GASTROINTESTINAL DISEASE; HEADACHE; HEART DISEASE; HEMATOLOGIC DISEASE; HEPATOBILIARY DISEASE; HOSPITALIZATION; HUMAN; IMMUNOGLOBULIN BLOOD LEVEL; IMMUNOTHERAPY; INCIDENCE; INFECTION; INFESTATION; INJURY; KIDNEY DISEASE; LYMPHATIC SYSTEM DISEASE; MAJOR CLINICAL STUDY; MALE; MEDIASTINUM DISEASE; MENTAL DISEASE; METABOLIC DISORDER; MORTALITY; MULTICENTER STUDY; MUSCULOSKELETAL DISEASE; NEUROLOGIC DISEASE; NUTRITIONAL DISORDER; PHASE 2 CLINICAL TRIAL; POLYNEUROPATHY; RANDOMIZED CONTROLLED TRIAL; RESPIRATORY TRACT DISEASE; SKIN DISEASE; SUBCUTANEOUS TISSUE DISORDER; THORAX DISEASE; UROGENITAL TRACT DISEASE; VASCULAR DISEASE; VOCAL CORD PARALYSIS; CLINICAL TRIAL; COMMUNITY ACQUIRED INFECTION; MIDDLE AGED; MULTIMODALITY CANCER THERAPY; NEWBORN; PNEUMONIA; TREATMENT OUTCOME; VERY ELDERLY;

AGED; AGED, 80 AND OVER; ANTI-BACTERIAL AGENTS; COMBINED MODALITY THERAPY; COMMUNITY-ACQUIRED INFECTIONS; DOUBLE-BLIND METHOD; FEMALE; HUMANS; IMMUNOGLOBULIN ISOTYPES; IMMUNOLOGIC FACTORS; INFANT, NEWBORN; MALE; MIDDLE AGED; PNEUMONIA; RESPIRATION, ARTIFICIAL; TREATMENT OUTCOME;

EID: 85045110708     PISSN: 03424642     EISSN: 14321238     Source Type: Journal    
DOI: 10.1007/s00134-018-5143-7     Document Type: Article

References (33)

1. Torres A, Peetermans WE, Viegi G, Blasi F (2013) Risk factors for community-acquired pneumonia in adults in Europe: a literature review. Thorax 68:1057–1065
2. Jain S, Self WH, Wunderink RG, Fakhran S, Balk R, Bramley AM, Reed C, Grijalva CG, Anderson EJ, Courtney DM, Chappell JD, Qi C, Hart EM, Carroll F, Trabue C, Donnelly HK, Williams DJ, Zhu Y, Arnold SR, Ampofo K, Waterer GW, Levine M, Lindstrom S, Winchell JM, Katz JM, Erdman D, Schneider E, Hicks LA, McCullers JA, Pavia AT, Edwards KM, Finelli L (2015) Community-acquired pneumonia requiring hospitalization among U.S. adults. N Engl J Med 373:415–427
3. Woodhead M, Welch CA, Harrison DA, Bellingan G, Ayres JG (2006) Community-acquired pneumonia on the intensive care unit: secondary analysis of 17,869 cases in the ICNARC Case Mix Programme Database. Crit Care 10(Suppl 2):S1
4. Kellum JA, Kong L, Fink MP, Weissfeld LA, Yealy DM, Pinsky MR, Fine J, Krichevsky A, Delude RL, Angus DC (2007) Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) study. Arch Intern Med 167:1655–1663
5. Calfee CS, Delucchi K, Parsons PE, Thompson BT, Ware LB, Matthay MA (2014) Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials. Lancet Respir Med 2:611–620
6. Alejandria MM, Lansang MA, Dans LF, Mantaring JB III (2013) Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock. Cochrane Database Syst Rev. 10.1002/14651858.CD001090.pub2
7. Kreymann KG, de Heer G, Nierhaus A, Kluge S (2007) Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock. Crit Care Med 35:2677–2685
8. Sibila O, Rodrigo-Troyano A, Torres A (2016) Nonantibiotic adjunctive therapies for community-acquired pneumonia (corticosteroids and beyond): where are we with them? Semin Respir Crit Care Med 37:913–922
9. Torres A, Sibila O, Ferrer M, Polverino E, Menendez R, Mensa J, Gabarrus A, Sellares J, Restrepo MI, Anzueto A, Niederman MS, Agusti C (2015) Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial. JAMA 313:677–686
10. de la Torre MC, Toran P, Serra-Prat M, Palomera E, Guell E, Vendrell E, Yebenes JC, Torres A, Almirall J (2016) Serum levels of immunoglobulins and severity of community-acquired pneumonia. BMJ Open Respir Res 3:e000152
11. Giamarellos-Bourboulis EJ, Apostolidou E, Lada M, Perdios I, Gatselis NK, Tsangaris I, Georgitsi M, Bristianou M, Kanni T, Sereti K, Kyprianou MA, Kotanidou A, Armaganidis A (2013) Kinetics of circulating immunoglobulin M in sepsis: relationship with final outcome. Crit Care 17:R247
12. Justel M, Socias L, Almansa R, Ramirez P, Gallegos MC, Fernandez V, Gordon M, Andaluz-Ojeda D, Nogales L, Rojo S, Valles J, Estella A, Loza A, Leon C, Lopez-Mestanza C, Blanco J, Berezo JA, Rosich S, Cilloniz C, Torres A, de Lejarazu RO, Martin-Loeches I, Bermejo-Martin JF (2013) IgM levels in plasma predict outcome in severe pandemic influenza. J Clin Virol 58:564–567
13. Ehrenstein MR, Notley CA (2010) The importance of natural IgM: scavenger, protector and regulator. Nat Rev Immunol 10:778–786
14. Esen F, Tugrul S (2009) IgM-enriched immunoglobulins in sepsis. In: Vincent JL (ed) Yearbook of intensive care and emergency medicine. Springer, New York, pp 102–110
15. Rieben R, Roos A, Muizert Y, Tinguely C, Gerritsen AF, Daha MR (1999) Immunoglobulin M-enriched human intravenous immunoglobulin prevents complement activation in vitro and in vivo in a rat model of acute inflammation. Blood 93:942–951
16. Duerr C, De Martin A, Sachet M, Konrad T, Baumann S, Spittler A (2011) Influence of an immunoglobulin-enriched (IgG, IgA, IgM) solution on activation and immunomodulatory functions of peripheral blood mononuclear cells in a LPS second-hit model. Crit Care 15(Suppl 1):P244
17. Shmygalev S, Damm M, Knels L, Strassburg A, Wunsche K, Dumke R, Stehr SN, Koch T, Heller AR (2016) IgM-enriched solution BT086 improves host defense capacity and energy store preservation in a rabbit model of endotoxemia. Acta Anaesthesiol Scand 60:502–512
18. Welte T, Dellinger RP, Ebelt H, Ferrer M, Opal SM, Schliephake DE, Wartenberg-Demand A, Werdan K, Loffler K, Torres A (2015) Concept for a study design in patients with severe community-acquired pneumonia: a randomised controlled trial with a novel IGM-enriched immunoglobulin preparation—the CIGMA study. Respir Med 109:758–767
19. Welte T, Almirall J, Ayesteran JI, Artigas A, Nuding S, Rodriguez G, Ferrer R, Shankar-Hari M, Alvarez Lerma F, Riessen R, Sirvent J-M, Kluge S, Lapp H, Wobker G, Zacharowksi K, Bonastre Mora J, Wartenburg-Demand A, Langohr P, Daelken B, Torres A (2018) Reduction in mortality with a novel polyclonal antibody preparation in patients with severe community-acquired pneumonia. https://www.escmid.org/escmid_publications/escmid_elibrary/?q=welte&id=2173&L=0&tx_solr%5Bsort%5D=relevance%2Basc&tx_solr%5Bfilter%5D%5B0%5D=main_filter_eccmid%253Atrue&tx_solr%5Bfilter%5D%5B1%5D=pub_date%253A201701010000-201712312359&x=0&y=0. Accessed 26 Jan 2018
20. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File TM Jr, Musher DM, Niederman MS, Torres A, Whitney CG (2007) Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 44(Suppl 2):S27–S72
21. Schoenfeld DA, Bernard GR (2002) Statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome. Crit Care Med 30:1772–1777
22. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF III, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J (2009) A new equation to estimate glomerular filtration rate. Ann Intern Med 150:604–612
23. Becze Z, Molnar Z, Fazakas J (2015) Can procalcitonin levels indicate the need for adjunctive therapies in sepsis? Int J Antimicrob Agents 46(Suppl 1):S13–S18
24. Oxford University Hospitals NHS Foundation Trust (2017) Immunoglobulins. http://www.ouh.nhs.uk/immunology/diagnostic-tests/tests-catalogue/immunoglobulins.aspx. Accessed 22 Mar 2017
25. de la Torre MC, Bolibar I, Vendrell M, de Gracia J, Vendrell E, Rodrigo MJ, Boquet X, Torrebadella P, Yebenes JC, Serra-Prat M, Rello J, Torres A, Almirall J (2013) Serum immunoglobulins in the infected and convalescent phases in community-acquired pneumonia. Respir Med 107:2038–2045
26. Bermejo-Martin JF, Rodriguez-Fernandez A, Herran-Monge R, Andaluz-Ojeda D, Muriel-Bombin A, Merino P, Garcia-Garcia MM, Citores R, Gandia F, Almansa R, Blanco J (2014) Immunoglobulins IgG1, IgM and IgA: a synergistic team influencing survival in sepsis. J Intern Med 276:404–412
27. Chalmers JD, Singanayagam A, Hill AT (2008) C-reactive protein is an independent predictor of severity in community-acquired pneumonia. Am J Med 121:219–225
28. Bloos F, Marshall JC, Dellinger RP, Vincent JL, Gutierrez G, Rivers E, Balk RA, Laterre PF, Angus DC, Reinhart K, Brunkhorst FM (2011) Multinational, observational study of procalcitonin in ICU patients with pneumonia requiring mechanical ventilation: a multicenter observational study. Crit Care 15:R88
29. Povoa P, Coelho L, Almeida E, Fernandes A, Mealha R, Moreira P, Sabino H (2005) C-reactive protein as a marker of infection in critically ill patients. Clin Microbiol Infect 11:101–108
30. Ugarte H, Silva E, Mercan D, De Mendonca A, Vincent JL (1999) Procalcitonin used as a marker of infection in the intensive care unit. Crit Care Med 27:498–504
31. Le Bel J, Hausfater P, Chenevier-Gobeaux C, Blanc FX, Benjoar M, Ficko C, Ray P, Choquet C, Duval X, Claessens YE (2015) Diagnostic accuracy of C-reactive protein and procalcitonin in suspected community-acquired pneumonia adults visiting emergency department and having a systematic thoracic CT scan. Crit Care 19:366
32. Dantal J (2013) Intravenous immunoglobulins: in-depth review of excipients and acute kidney injury risk. Am J Nephrol 38:275–284
33. Bacci MR, Leme RC, Zing NP, Murad N, Adami F, Hinnig PF, Feder D, Chagas AC, Fonseca FL (2015) IL-6 and TNF-alpha serum levels are associated with early death in community-acquired pneumonia patients. Braz J Med Biol Res 48:427–432