title: Randomized trial evaluating serial protein C levels in severe sepsis patients treated with variable doses of drotrecogin alfa (activated).
abstract: BACKGROUND
  Serial alterations in protein C levels appear to correlate with disease severity in patients with severe sepsis, and it may be possible to tailor severe sepsis therapy with the use of this biomarker. The purpose of this study was to evaluate the dose and duration of drotrecogin alfa (activated) treatment using serial measurements of protein C compared to standard therapy in patients with severe sepsis.
  
  
  METHODS
  This was a phase 2 multicenter, randomized, double-blind, controlled study. Adult patients with two or more sepsis-induced organ dysfunctions were enrolled. Protein C deficient patients were randomized to standard therapy (24 μg/kg/hr infusion for 96 hours) or alternative therapy (higher dose and/or variable duration; 24/30/36 μg/kg/hr for 48 to 168 hours). The primary outcome was a change in protein C level in the alternative therapy group, between study Day 1 and Day 7, compared to standard therapy.
  
  
  RESULTS
  Of 557 patients enrolled, 433 patients received randomized therapy; 206 alternative, and 227 standard. Baseline characteristics of the groups were largely similar. The difference in absolute change in protein C from Day 1 to Day 7 between the two therapy groups was 7% (P = 0.011). Higher doses and longer infusions were associated with a more pronounced increase in protein C level, with no serious bleeding events. The same doses and longer infusions were associated with a larger increase in protein C level; higher rates of serious bleeding when groups received the same treatment; but no clear increased risk of bleeding during the longer infusion. This group also experienced a higher mortality rate; however, there was no clear link to infusion duration.
  
  
  CONCLUSIONS
  The study met its primary objective of increased protein C levels in patients receiving alternative therapy demonstrating that variable doses and/or duration of drotrecogin alfa (activated) can improve protein C levels, and also provides valuable information for incorporation into potential future studies.
  
  
  BACKGROUND
  ClinicalTrials.gov identifier: NCT00386425.
authors.affiliation: Washington Hospital Center, 110 Irving Street NW, Washington DC 20010, USA. afshorr@dnamail.com
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Shorr
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Janes
authors.forename: Antonio
authors.initials: A
authors.lastname: Artigas
authors.forename: Jyrki
authors.initials: J
authors.lastname: Tenhunen
authors.forename: Duncan L A
authors.initials: DL
authors.lastname: Wyncoll
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Mercier
authors.forename: Bruno
authors.initials: B
authors.lastname: Francois
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Vincent
authors.forename: Burkhard
authors.initials: B
authors.lastname: Vangerow
authors.forename: Darell
authors.initials: D
authors.lastname: Heiselman
authors.forename: Amy G
authors.initials: AG
authors.lastname: Leishman
authors.forename: Yajun E
authors.initials: YE
authors.lastname: Zhu
authors.forename: Konrad
authors.initials: K
authors.lastname: Reinhart
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011486:Protein C / Q000008:administration & dosage / Q000378:metabolism*; D011994:Recombinant Proteins / Q000008:administration & dosage; D018805:Sepsis / Q000097:blood / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D011486:Protein C; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated