title: 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.
abstract: OBJECTIVE
  To determine the safety and efficacy of recombinant thrombomodulin (ART-123) in patients with suspected sepsis-associated disseminated intravascular coagulation.
  
  
  METHODS
  Phase 2b, international, multicenter, double-blind, randomized, placebo-controlled, parallel group, screening trial.
  
  
  METHODS
  Two hundred and thirty-three ICUs in 17 countries.
  
  
  METHODS
  All adult patients admitted with sepsis and suspected disseminated intravascular coagulation as assessed using a modified International Society on Thrombosis and Hemostasis score.
  
  
  METHODS
  Patients were randomized to receive IV ART-123 (0.06 mg/kg/d) for 6 days or placebo, in addition to standard of care. The primary endpoint was reduction in mortality. Secondary endpoints included reversal of overt disseminated intravascular coagulation and reduction in disease severity.
  
  
  RESULTS
  A total of 750 patients were randomized, nine of whom did not receive the allocated treatment so that 371 patients received ART-123 and 370 received placebo. There were no meaningful differences between the two groups in any of the baseline variables. Twenty-eight-day mortality was 17.8% in the ART-123 group and 21.6% in the placebo group (Cochran-Mantel-Haenszel two-sided p value of 0.273 in favor of ART-123, which met the predefined statistical test for evidence suggestive of efficacy). There were no statistically significant differences in event-free and alive days between the two groups. d-dimer, prothrombin fragment F1.2 and TATc concentrations were lower in the ART-123 group than in the placebo group. There were no differences between the two groups in organ function, inflammatory markers, bleeding or thrombotic events or in the development of new infections. In post hoc analyses, greatest benefit from ART-123 was seen in patients with at least one organ system dysfunction and an international normalized ratio greater than 1.4 at baseline.
  
  
  CONCLUSIONS
  ART-123 is a safe intervention in critically ill patients with sepsis and suspected disseminated intravascular coagulation. The study provided evidence suggestive of efficacy supporting further development of this drug in sepsis-associated coagulopathy including disseminated intravascular coagulation. Future study should focus on using ART-123 in the subgroup of patients most likely to respond to this agent.
authors: Department of Intensive Care, Erasme Hospital, Université libre de Bruxelles, Brussels, Belgium. jlvincen@ulb.ac.be
authors: Jean-Louis
authors: JL
authors: Vincent
authors: Mayakonda K
authors: MK
authors: Ramesh
authors: David
authors: D
authors: Ernest
authors: Steven P
authors: SP
authors: LaRosa
authors: Jan
authors: J
authors: Pachl
authors: Naoki
authors: N
authors: Aikawa
authors: Eric
authors: E
authors: Hoste
authors: Howard
authors: H
authors: Levy
authors: Joe
authors: J
authors: Hirman
authors: Marcel
authors: M
authors: Levi
authors: Mradul
authors: M
authors: Daga
authors: Demetrios J
authors: DJ
authors: Kutsogiannis
authors: Mark
authors: M
authors: Crowther
authors: Gordon R
authors: GR
authors: Bernard
authors: Jacques
authors: J
authors: Devriendt
authors: Joan Vidal
authors: JV
authors: Puigserver
authors: Daniel U
authors: DU
authors: Blanzaco
authors: Charles T
authors: CT
authors: Esmon
authors: Joseph E
authors: JE
authors: Parrillo
authors: Louis
authors: L
authors: Guzzi
authors: Seton J
authors: SJ
authors: Henderson
authors: Chaicharn
authors: C
authors: Pothirat
authors: Parthiv
authors: P
authors: Mehta
authors: Jawed
authors: J
authors: Fareed
authors: Deepak
authors: D
authors: Talwar
authors: Kazuhisa
authors: K
authors: Tsuruta
authors: Kenneth J
authors: KJ
authors: Gorelick
authors: Yutaka
authors: Y
authors: Osawa
authors: Inder
authors: I
authors: Kaul
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004211:Disseminated Intravascular Coagulation / Q000188:drug therapy* / Q000209:etiology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D010919:Placebos; D011994:Recombinant Proteins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D018805:Sepsis / Q000150:complications / Q000188:drug therapy*; D018180:Thrombomodulin / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: C472045:ART123; D010919:Placebos; D011994:Recombinant Proteins; D018180:Thrombomodulin