A randomized, double-blind, placebo-controlled, phase 2b Study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and suspected disseminated intravascular coagulation

Critical Care Medicine

Volumn 41, Issue 9, 2013, Pages 2069-2079

  Vincent, Jean Louis ^a   Ramesh, Mayakonda K ^b   Ernest, David ^c   Larosa, Steven P ^d   Pachl, Jan ^e   Aikawa, Naoki ^f   Hoste, Eric ^g   Levy, Howard ^h   Hirman, Joe ⁱ   Levi, Marcel ^j   Daga, Mradul ^k   Kutsogiannis, Demetrios J ^l   Crowther, Mark ^m   Bernard, Gordon R ⁿ   Devriendt, Jacques ^o   Puigserver, Joan Vidal ^p   Blanzaco, Daniel U ^q   Esmon, Charles T ^r   Parrillo, Joseph E ^s   Guzzi, Louis ^t   Henderson, Seton J ^u   Pothirat, Chaicharn ^v   Mehta, Parthiv ^w   Fareed, Jawed ^x   Talwar, Deepak ^y   Tsuruta, Kazuhisa ^z   Gorelick, Kenneth J ^aa   Osawa, Yutaka ^z   Kaul, Inder ^z   more..

^a ERASME HOSPITAL   (Belgium)

^b Victoria Hospital   (India)

^c MONASH UNIVERSITY   (Australia)

^d Beverly Hospital   (United States)

^e CHARLES UNIVERSITY   (Czech Republic)

^f KEIO UNIVERSITY   (Japan)

^g GHENT UNIVERSITY HOSPITAL   (Belgium)

^h Howard Levy Consulting LLC   (United States)

ⁱ Pacific Northwest Statistical Consulting   (United States)

^j ACADEMIC MEDICAL CENTER   (Netherlands)

^k MAULANA AZAD MEDICAL COLLEGE   (India)

^l UNIVERSITY OF ALBERTA   (Canada)

^m ST JOSEPH S HOSPITAL   (Canada)

ⁿ VANDERBILT UNIVERSITY   (United States)

^o BRUGMANN UNIVERSITY HOSPITAL   (Belgium)

^p HOSPITAL UNIVERSITARIO SON ESPASES   (Spain)

^q HOSPITAL SAN MARTÍN   (Argentina)

^r HOWARD HUGHES MEDICAL INSTITUTE   (United States)

^s HACKENSACK UNIVERSITY MEDICAL CENTER   (United States)

^t FLORIDA HOSPITAL   (United States)

^u CHRISTCHURCH HOSPITAL   (New Zealand)

^v Faculty of Medicine Chiang Mai University   (Thailand)

^w Mehta Hospital and Cardiopulmonary Care Centre   (India)

^x LOYOLA UNIVERSITY MEDICAL CENTER   (United States)

^y Metro Hospitals   (India)

^z ASAHI KASEI PHARMA CORPORATION   (Japan)

^aa Zymo Consulting Group LLC   (United States)

more..

Author keywords

coagulopathy; organ dysfunction; sepsis

Indexed keywords

BIOLOGICAL MARKER; D DIMER; PLACEBO; PROTHROMBIN; RECOMBINANT THROMBOMODULIN;

ACUTE CORONARY SYNDROME; ANEMIA; ARTICLE; BLEEDING; BLOOD CLOTTING DISORDER; BRAIN ISCHEMIA; CONTROLLED STUDY; DEEP VEIN THROMBOSIS; DISSEMINATED INTRAVASCULAR CLOTTING; DOUBLE BLIND PROCEDURE; DRUG CLEARANCE; DRUG EFFICACY; DRUG FEVER; DRUG SAFETY; HOSPITAL ADMISSION; HUMAN; HYPOKALEMIA; LUNG EMBOLISM; MORTALITY; MULTICENTER STUDY; ORGAN; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; SCORING SYSTEM; SEPSIS;

ADOLESCENT; ADULT; AGED; AGED, 80 AND OVER; DISSEMINATED INTRAVASCULAR COAGULATION; DOUBLE-BLIND METHOD; FEMALE; HUMANS; INTENSIVE CARE UNITS; MALE; MIDDLE AGED; OUTCOME ASSESSMENT (HEALTH CARE); PLACEBOS; RECOMBINANT PROTEINS; SEPSIS; THROMBOMODULIN; YOUNG ADULT;

EID: 84883615933     PISSN: 00903493     EISSN: 15300293     Source Type: Journal    
DOI: 10.1097/CCM.0b013e31828e9b03     Document Type: Article

References (29)

1. Martin GS, Mannino DM, Eaton S, et al: The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003; 348:1546-1554
2. Levi M, Ten Cate H: Disseminated intravascular coagulation. N Engl J Med 1999; 341:586-592
3. Zeerleder S, Hack CE, Wuillemin WA: Disseminated intravascular coagulation in sepsis. Chest 2005; 128:2864-2875
4. Fourrier F, Chopin C, Goudemand J, et al: Septic shock, multiple organ failure, and disseminated intravascular coagulation. Compared patterns of antithrombin III, protein C, and protein S deficiencies. Chest 1992; 101:816-823
5. Bakhtiari K, Meijers JC, de Jonge E, et al: Prospective validation of the International Society of Thrombosis and Haemostasis scoring system for disseminated intravascular coagulation. Crit Care Med 2004; 32:2416-2421
6. Levi M, Toh CH, Thachil J, et al: Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol 2009; 145:24-33
7. Nagato M, Okamoto K, Abe Y, et al: Recombinant human soluble thrombomodulin decreases the plasma high-mobility group box-1 protein levels, whereas improving the acute liver injury and survival rates in experimental endotoxemia. Crit Care Med 2009; 37:2181-2186
8. Abeyama K, Stern DM, Ito Y, et al: The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. J Clin Invest 2005; 115:1267-1274
9. Shi CS, Shi GY, Hsiao SM, et al: Lectin-like domain of thrombomodulin binds to its specific ligand Lewis Y antigen and neutralizes lipopolysaccharide-induced inflammatory response. Blood 2008; 112:3661-3670
10. Saito H, Maruyama I, Shimazaki S, et al: Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: Results of a phase III, randomized, doubleblind clinical trial. J Thromb Haemost 2007; 5:31-41
11. Yamakawa K, Fujimi S, Mohri T, et al: Treatment effects of recombinant human soluble thrombomodulin in patients with severe sepsis: A historical control study. Crit Care 2011; 15:R123
12. Bone RC, Balk RA, Cerra FB et al: Definition for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992; 101:1644-1655
13. Taylor FB Jr, Toh CH, Hoots WK, et al; Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH): Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 2001; 86:1327-1330
14. Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16:31-41
15. Fleming TR, Richardson BA: Some design issues in trials of microbicides for the prevention of HIV infection. J Infect Dis 2004; 190:666-674
16. Nakashima M, Kanamaru M, Umemura K, et al: Pharmacokinetics and safety of a novel recombinant soluble human thrombomodulin, ART-123, in healthy male volunteers. J Clin Pharmacol 1998; 38:40-44
17. Moll S, Lindley C, Pescatore S, et al: Phase I study of a novel recombinant human soluble thrombomodulin, ART-123. J Thromb Haemost 2004; 2:1745-1751
18. Bernard GR, Vincent JL, Laterre PF, et al; Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344:699-709
19. Dhainaut JF, Yan SB, Joyce DE, et al: Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation. J Thromb Haemost 2004; 2:1924-1933
20. Ranieri VM, Thompson BT, Barie PS, et al: Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med 2012; 366:2055-2064
21. Faust SN, Heyderman RS, Levin M: Coagulation in severe sepsis: A central role for thrombomodulin and activated protein C. Crit Care Med 2001; 29(7 Suppl):S62-7; discussion S67
22. Esmon CT: The interactions between inflammation and coagulation. Br J Haematol 2005; 131:417-430
23. Iba T, Yagi Y, Kidokoro A, et al: Increased plasma levels of soluble thrombomodulin in patients with sepsis and organ failure. Surg Today 1995; 25:585-590
24. Lin SM, Wang YM, Lin HC, et al: Serum thrombomodulin level relates to the clinical course of disseminated intravascular coagulation, multiorgan dysfunction syndrome, and mortality in patients with sepsis. Crit Care Med 2008; 36:683-689
25. Borgel D, Bornstain C, Reitsma PH, et al: A comparative study of the protein C pathway in septic and nonseptic patients with organ failure. Am J Respir Crit Care Med 2007; 176:878-885
26. Faust SN, Levin M, Harrison OB, et al: Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N Engl J Med 2001; 345:408-416
27. Aikawa N, Shimazaki S, Yamamoto Y, et al: Thrombomodulin alfa in the treatment of infectious patients complicated by disseminated intravascular coagulation: Subanalysis from the phase 3 trial. Shock 2011; 35:349-354
28. Wada H, Gabazza EC, Asakura H, et al: Comparison of diagnostic criteria for disseminated intravascular coagulation (DIC): Diagnostic criteria of the International Society of Thrombosis and Hemostasis and of the Japanese Ministry of Health and Welfare for overt DIC. Am J Hematol 2003; 74:17-22
29. Gando S, Iba T, Eguchi Y, et al; Japanese Association for Acute Medicine Disseminated Intravascular Coagulation (JAAM DIC) Study Group: A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: Comparing current criteria. Crit Care Med 2006; 34:625-631