A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis

Critical Care Medicine

Volumn 38, Issue 8, 2010, Pages 1685-1694

  Rice, Todd W ^a   Wheeler, Arthur P ^a   Bernard, Gordon R ^a   Vincent, Jean Louis ^b   Angus, Derek C ^c   Aikawa, Naoki ^d   Demeyer, Ignace ^e   Sainati, Stephen ^f   Amlot, Nicholas ^g   Cao, Charlie ^f   Ii, Masayuki ^h   Matsuda, Hideyasu ^h   Mouri, Kouji ^h   Cohen, Jon ⁱ  

^a VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b ERASME HOSPITAL   (Belgium)

^c UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

^d KEIO UNIVERSITY SCHOOL OF MEDICINE   (Japan)

^e OLV HOSPITAL   (Belgium)

^f TAKEDA PHARMACEUTICALS   (United States)

^g Takeda Global Research and Development Centre (Europe) Ltd   (United Kingdom)

^h TAKEDA PHARMACEUTICAL COMPANY LIMITED   (Japan)

ⁱ UNIVERSITY OF SUSSEX   (United Kingdom)

Author keywords

cytokines; interleukin 6; mortality; severe sepsis; TAK 242; Toll like receptor 4; Toll like receptors

Indexed keywords

6 [N (2 CHLORO 4 FLUOROPHENYL)SULFAMOYL] 1 CYCLOHEXENE 1 CARBOXYLIC ACID ETHYL ESTER; INTERLEUKIN 6; METHEMOGLOBIN; PLACEBO;

ACUTE KIDNEY FAILURE; ADULT; AGITATION; ANEMIA; ARTICLE; BLOOD LEVEL; CLINICAL TRIAL; CONFUSION; CONSTIPATION; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; DECUBITUS; DIARRHEA; DOUBLE BLIND PROCEDURE; FEMALE; FEVER; GENERALIZED EDEMA; HEART ATRIUM FIBRILLATION; HUMAN; HYPERGLYCEMIA; HYPERNATREMIA; HYPERTENSION; HYPOGLYCEMIA; HYPOKALEMIA; HYPOTENSION; HYPOXIA; INSOMNIA; INTENSIVE CARE UNIT; MAJOR CLINICAL STUDY; MALE; METHEMOGLOBINEMIA; MORTALITY; MULTIPLE ORGAN FAILURE; NAUSEA; PERIPHERAL EDEMA; PLEURA EFFUSION; PNEUMONIA; PNEUMOTHORAX; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; RASH; RESPIRATORY FAILURE; SEPSIS; SHOCK; SIDE EFFECT; THROMBOCYTOPENIA; URINARY TRACT INFECTION; VOMITING;

EID: 77954953617     PISSN: 00903493     EISSN: 15300293     Source Type: Journal    
DOI: 10.1097/CCM.0b013e3181e7c5c9     Document Type: Article

References (54)

1. Bone RC, Balk RA, Cerra FB, et al: American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992; 101:1644-1655
2. Janeway CA Jr, Medzhitov R: Innate immune recognition. Annu Rev Immunol 2002; 20: 197-216
3. Grannuci F, Foti M, Ricciardi-Castagnoli P: Dendritic cell biology. Adv Immunol 2005; 88:193-233
4. Cohen J: The immunopathogenesis of sepsis. Nature 2002; 420:885-891
5. Singh S, Evans TW: Organ dysfunction during sepsis. Intensive Care Med 2006; 32:349-360
6. Rittirsch D, Flierl MA, Ward PA: Harmful molecular mechanisms in sepsis. Nat Rev Immunol 2008; 8:776-787
7. Hotchkiss RS, Karl IE: The pathophysiology and treatment of sepsis. N Engl J Med 2003; 348:138-150
8. Cinel I, Opal SM: Molecular biology of in-flammation and sepsis: A primer. Crit Care Med 2009; 37:291-304
9. Medzhitov R, Preston-Hurlburt R, Janeway CA Jr: A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 1997; 388:394-397
10. Tsujimoto H, Ono S, Efron PA, et al: Role of Toll-like receptors in the development of sepsis. Shock 2008; 29:315-321
11. Levy RM, Prince JM, Yang R, et al: Systemic inflammation and remote organ damage following bilateral femur fracture requires Tolllike receptor. Am J Physiol Regul Integr Comp Physiol 2006; 291:R970-R976
12. Mollen KP, Levy RM, Prince JM, et al: Systemic inflammation and end organ damage following trauma involves functional TLR-4 signaling in both bone-marrow derived cells and parenchymal cells. J Leukoc Biol 2008; 83:80-88
13. Benhamou Y, Favre J, Musette P, et al: Tolllike receptors 4 contribute to endothelial injury and inflammation in hemorrhagic shock in mice. Crit Care Med 2009; 37:1724-1728
14. Ii M, Matsunaga N, Hazeki K, et al: A novel cyclohexene derivative, ethyl (6R)-6-[N-(2-Chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), selectively inhibits Toll-like receptor 4-mediated cytokine production through suppression of intracellular signaling. Mol Pharmacol 2006; 69: 1288-1295
15. Kawamoto T, Ii M, Kitazaki T, et al: TAK-242 selectively suppresses Toll-like receptor 4-signaling mediated by the intracellular domain. Eur J Pharmacol 2008; 584:40-48
16. Sha T, Sunamoto M, Kitazaki T, et al: Therapeutic effects of TAK-242, a novel selective Toll-like receptor 4 signal transduction inhibitor, in mouse endotoxin shock model. Eur J Pharmacol 2007; 571:231-239
17. Zanotti-Cavazzoni SL, Goldfarb RD, Dellinger RP, et al: A cytokine production inhibitor (TAK-242) improves cardiovascular performance, inhibits cytokine release and increases survival in a porcine model of gram negative sepsis. Crit Care Med 2004; 32(Suppl):A15
18. Knaus WA, Draper EA, Wagner DP, et al: APACHE II: A severity of disease classification system. Crit Care Med 1985; 38:818-829
19. Vincent JL, Moreno R, Takala J, et al: The SOFA (Sepsis-Related Organ Failure Assessment) score to describe organ dysfunction/failure. Intensive Care Med 1996; 22:707-710
20. Ulloa L, Tracey KJ: The "cytokine profile": A code for sepsis. Trends Mol Med 2005; 11: 56-63
21. Marshall JC, Reinhart K: International Sepsis Forum: Biomarkers of sepsis. Crit Care Med. 2009; 37:3193
22. Xing Z, Gauldie J, Cox G, et al: IL-6 is an anti-inflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest 1998; 101:311-320
23. Dhainaut JF, Yan SB, Margolis BD, et al: Drotrecogin alfa (activated) (recombinant human activated protein C) reduced host coagulopathy response in patients with severe sepsis. Thromb Haemost 2003; 90:642-653
24. Rice TW, Wheeler AP, Morris PE, et al: Safety and efficacy of affinity-purified, anti-tumor necrosis factor-, ovine fab for injection (CytoFab) in severe sepsis. Crit Care Med 2006; 34:2271-2281
25. Abraham E, Wunderink R, Silverman H, et al: Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. JAMA 1995; 273:934-941
26. Cohen J, Carlet J: INTERSEPT: An international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-alpha in patients with sepsis. INTERSEPT Study Group. Crit Care Med 1996; 24:1431-1440
27. Abraham E, Anzueto A, Gutierrez G, et al: Double-blind randomized controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. Lancet 1998; 351:929-933
28. Fisher CJ Jr, Agosti JM, Opal SM, et al: Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein: The Soluble TNF Receptor Sepsis Study Group. N Engl J Med 1996; 334:1697-1702
29. Abraham E, Glauser MP, Butler T, et al: p55 tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock. JAMA 1997; 277: 1531-1538
30. Reinhart K, Menges T, Gardlund B, 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
31. Kiechl S, Lorenz E, Reindl M, et al: Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med 2002; 347:185-192
32. Agnese DM, Calvano JE, Hahm SJ, et al: Human Toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of gram-negative infections. J Infect Dis 2002; 186:1522-1525
33. Lorenz E, Mira JP, Frees KL, et al: Relevance of mutations in the TLR-4 receptor in patients with Gram-negative septic shock. Arch Intern Med 2002; 162:1028-1032
34. Tsujimoto H, Ono S, Majima T, et al: Neutrophil elastase, MIP-2, and TLR-4 expression during human and experimental sepsis. Shock 2005; 23:39-44
35. Feterowski C, Emmanuilidis K, Miethke T, et al: Effects of functional Toll-like receptor-4 mutations on the immune response to human and experimental sepsis. Immunology 2003; 169:2823-2827
36. Opal SM, Cohen J: Clinical gram-positive sepsis: Does it fundamentally differ from Gram-negative bacterial sepsis? Crit Care Med 1999; 27:1608-1616
37. Feezor RJ, Oberholzer C, Baker HV, et al: Molecular characterization of the acute in-flammatory response to infections with Gram-negative versus gram-positive bacteria. Infect Immun 2003; 71:5803-5813
38. Gao H, Evans TW, Finney SJ: Bench-tobedside review: Sepsis, severe sepsis and septic shock\Does the nature of the infecting organism matter? Crit Care 2008; 12:213
39. Hoogerwerf JJ, de Vos AF, Bresser P, et al: Lung inflammation induced by lipoteichoic acid or lipopolysaccharide in humans. Am J Respir Crit Care Med 2008; 178:34-41
40. Cinel I, Opal SM: Molecular biology of in-flammation and sepsis: A primer. Crit Care Med 2009; 37:291-304
41. Chow JC, Young DW, Golenbock DT, et al: Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction. J Biol Chem 1999; 274:10689-10692
42. Schroder NW, Morath S, Alexander C, et al: Lipoteichoic acid (LTA) of Streptococcus pneumoniae and Staphylococcus aureus activates immune cells via Toll-like receptor (TLR)-2, lipopolysaccharide-binding protein (LBP), and CD14, whereas TLR-4 and MD-2 are not involved. J Biol Chem 2003; 278:15587-15594
43. Ellingsen E, Morath S, Flo T, et al: Induction of cytokine production in human T cells and monocytes by highly purified lipoteichoic acid: Involvement of Toll-like receptors and CD Med Sci Monit 2002; 8:BR149-BR156
44. Takashima K, Matsunaga N, Yoshimatsu M, et al: Analysis of binding site for the novel small-molecule TLR4 signal transduction inhibitor TAK-242 and its therapeutic effect on mouse sepsis model. Br J Pharmacol 2009; 157:1250-1262
45. Ziegler EJ, Fisher CJ Jr, Sprung CL, et al: Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin: A randomized, double-blind, placebo-controlled trial. The HA-1A Sepsis Study Group. N Engl J Med 1991; 324:429-436
46. Dierkes C, Ehrenstein B, Siebig S, et al: Clinical impact of a commercially available multiplex PCR system for rapid detection of pathogens in patients with presumed sepsis. BMC Infect Dis 2009; 9:126
47. Westh H, Lisby G, Breysse F, et al: Multiplex real-time PCR and blood culture for identifi-cation of bloodstream pathogens in patients with suspected sepsis. Clin Microbiol Infect 2009; 15:544-551
48. Bernard GR, Vincent JL, Laterre PF, et al: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344:699-709
49. Knaus WA, Harrell FE Jr, LaBrecque JF, et al: Use of predicted risk of mortality to evaluate the efficacy of anticytokine therapy in sepsis. The rhIL-Ira Phase III Sepsis Study Group. Crit Care Med 1996; 24:46-56
50. Eichacker PQ, Parent C, Kalil A, et al: Risk and the efficacy of anti-inflammatory agents: Retrospective and confirmatory studies of sepsis. Am J Respir Crit Care Med 2002; 166:1197-1205
51. Bernard GR: Drotrecogin alfa (activated) (recombinant human activated protein C) for the treatment of severe sepsis. Crit Care Med 2003; 31(Suppl):S85-S93
52. Krafte-Jacobs B, Brilli R, Szabo C: Circulating methemoglobin and nitrite/nitrate concentrations as indicators of nitric oxide overproduction in critically ill children with septic shock. Crit Care Med 1997; 25:1588-1593
53. Ohashi K, Yukioka H, Hayashi M, et al: Elevated methemoglobin in patients with sepsis. Acta Anaesthesiol Scand 1998; 42:713-716
54. Memis D, Karamanlioglu B, Yuksel M, et al: The influence of methylene blue infusion on cytokine levels during severe sepsis. Anaesth Intensive Care 2002; 30:755-762