title: Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial.
abstract: BACKGROUND
  Drotrecogin alfa (activated) (DrotAA) is used for the treatment of adults with severe sepsis who have a high risk of dying. A phase 1b open-label study has indicated that the pharmacokinetics and pharmacodynamics of DrotAA are similar in children and adults. We initiated the RESOLVE (REsearching severe Sepsis and Organ dysfunction in children: a gLobal perspectiVE) trial to investigate the efficacy and safety of the drug in children.
  
  
  METHODS
  Children aged between 38 weeks' corrected gestational age and 17 years with sepsis-induced cardiovascular and respiratory failure were randomly assigned to receive placebo or DrotAA (24 microg/kg/h) for 96 h. We used a prospectively defined, novel primary endpoint of Composite Time to Complete Organ Failure Resolution (CTCOFR) score. Secondary endpoints were 28-day mortality, major amputations, and safety. Analysis was by intention-to-treat. This trial is registered with clinicaltrials.gov, number NCT00049764.
  
  
  RESULTS
  477 patients were enrolled; 237 received placebo, and 240 DrotAA. Our results showed no significant difference between groups in CTCOFR score (p=0.72) or in 28-day mortality (placebo 17.5%; DrotAA, 17.2%; p=0.93). Although there was no difference in overall serious bleeding events during the 28-day study period (placebo 6.8%; DrotAA 6.7%; p=0.97), there were numerically more instances of CNS bleeding in the DrotAA group (11 [4.6%], vs 5 [2.1%] in placebo, p=0.13), particularly in children younger than 60 days. For CTCOFR score days 1-14, correlation coefficient was -0.016 (95% CI -0.106 to 0.74); relative risk for 28-day mortality was 1.06 (95% CI 0.66 to 1.46) for DrotAA compared with placebo.
  
  
  CONCLUSIONS
  Although we did not record any efficacy of DrotAA in children with severe sepsis, serious bleeding events were similar between groups and the overall safety profile acceptable, except in children younger than 60 days. However, we gained important insights into clinical and laboratory characteristics of childhood severe sepsis, and have identified issues that need to be addressed in future trials in critically ill children.
authors.affiliation: St Mary's Hospital and Imperial College, London, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Nadel
authors.affiliation: Division of Pediatric Critical Care, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Brahm
authors.initials: B
authors.lastname: Goldstein
authors.affiliation: Lilly Research Laboratories, Indianapolis, IN, USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Williams
authors.affiliation: Children's National Medical Center, George Washington University, Washington DC, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Dalton
authors.affiliation: Great Ormond Street Hospital, Pediatric Intensive Care Unit, London, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Peters
authors.affiliation: Lilly Research Laboratories, Indianapolis, IN, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Macias
authors.affiliation: Loma Linda University Children's Hospital, Loma Linda, CA USA.
authors.forename: Shamel A
authors.initials: SA
authors.lastname: Abd-Allah
authors.affiliation: Lilly Research Laboratories, Indianapolis, IN, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Levy
authors.affiliation: Lilly Research Laboratories, Indianapolis, IN, USA.
authors.forename: Robinette
authors.initials: R
authors.lastname: Angle
authors.affiliation: Lilly Research Laboratories, Indianapolis, IN, USA.
authors.forename: Dazhe
authors.initials: D
authors.lastname: Wang
authors.affiliation: Lilly Research Laboratories, Indianapolis, IN, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Sundin
authors.affiliation: University of Texas Southwestern Medical Center, currently on loan to the Defense Advanced Research Projects Agency, Arlington, VA, USA. Electronic address: Brett.Giroir@darpa.mil.
authors.forename: Brett
authors.initials: B
authors.lastname: Giroir
mesh_terms: D000293:Adolescent; D000367:Age Factors; D000890:Anti-Infective Agents / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011486:Protein C / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012044:Regression Analysis; D012307:Risk Factors; D018805:Sepsis / Q000145:classification / Q000188:drug therapy*; D012720:Severity of Illness Index; D012737:Sex Factors; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000890:Anti-Infective Agents; D011486:Protein C; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated