title: Recombinant human activated protein C for adults with septic shock: a randomized controlled trial.
abstract: BACKGROUND
  A decade after drotrecogin alfa (activated) (DAA) was released on the market worldwide, its benefit-to-risk ratio remains a matter of debate.
  
  
  OBJECTIVE
  The current investigator-led trial was designed to evaluate the efficacy and safety of DAA, in combination with low-dose steroids, in adults with persistent septic shock.
  
  
  METHODS
  This was a multicenter (24 intensive care units), placebo-controlled, double-blind, 2 × 2 factorial design trial in which adults with persistent septic shock and no contraindication to DAA were randomly assigned to DAA alone (24 μg/kg/h for 96 h), hydrocortisone and fludrocortisone alone, their respective combinations, or their respective placebos. Primary outcome was mortality rate on Day 90.
  
  
  RESULTS
  On October 25, 2011, the trial was suspended after the withdrawal from the market of DAA. The Scientific Committee decided to continue the trial according to a two parallel group design comparing low-dose steroids with their placebos and to analyze the effects of DAA on patients included before trial suspension. At the time trial was suspended, 411 patients had been recruited, 208 had received DAA, and 203 had received its placebo. There was no significant interaction between DAA and low-dose steroids (P = 0.47). On Day 90, there were 99 deaths (47.6%) among the 208 patients receiving DAA and 94 deaths (46.3%) among the 203 patients receiving placebo (P = 0.79). There was no evidence of a difference between DAA and its placebo for any secondary outcomes or serious adverse events.
  
  
  CONCLUSIONS
  In adults with established and severe septic shock, DAA showed no evidence of benefit or harm. Clinical trial registered with www.clinicaltrials.gov (NCT00625209).
authors.affiliation: Department of Intensive Care, Raymond Poincaré University Hospital, Versailles Saint-Quentin University, Garches, France. djillali.annane@rpc.aphp.fr
authors.forename: Djillali
authors.initials: D
authors.lastname: Annane
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Timsit
authors.forename: Bruno
authors.initials: B
authors.lastname: Megarbane
authors.forename: Claude
authors.initials: C
authors.lastname: Martin
authors.forename: Benoit
authors.initials: B
authors.lastname: Misset
authors.forename: Bruno
authors.initials: B
authors.lastname: Mourvillier
authors.forename: Shidasp
authors.initials: S
authors.lastname: Siami
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Chagnon
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Constantin
authors.forename: Franck
authors.initials: F
authors.lastname: Petitpas
authors.forename: Bertrand
authors.initials: B
authors.lastname: Souweine
authors.forename: Roland
authors.initials: R
authors.lastname: Amathieu
authors.forename: Xavier
authors.initials: X
authors.lastname: Forceville
authors.forename: Claire
authors.initials: C
authors.lastname: Charpentier
authors.forename: Antoine
authors.initials: A
authors.lastname: Tesnière
authors.forename: Jean
authors.initials: J
authors.lastname: Chastre
authors.forename: Julien
authors.initials: J
authors.lastname: Bohe
authors.forename: Gwenhael
authors.initials: G
authors.lastname: Colin
authors.forename: Alain
authors.initials: A
authors.lastname: Cariou
authors.forename: Alain
authors.initials: A
authors.lastname: Renault
authors.forename: Christian
authors.initials: C
authors.lastname: Brun-Buisson
authors.forename: Eric
authors.initials: E
authors.lastname: Bellissant
mesh_terms: D000890:Anti-Infective Agents / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D004311:Double-Blind Method; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D005438:Fludrocortisone / Q000627:therapeutic use; D006801:Humans; D006854:Hydrocortisone / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011486:Protein C / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D056737:Safety-Based Drug Withdrawals; D012772:Shock, Septic / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D000890:Anti-Infective Agents; D000893:Anti-Inflammatory Agents; D011486:Protein C; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated; D005438:Fludrocortisone; D006854:Hydrocortisone