Safety and dose relationship of recombinant human activated protein C for coagulopathy in severe sepsis

Gordon R. Bernard, E. Wesley Ely, Theressa J. Wright, Joseph Fraiz, Jerome E. Stasek, James A. Russell, Irvin Mayers, Brian A. Rosenfeld, Peter E. Morris, S. Betty Yan, Jeffery D. Helterbrand

Research output: Contribution to journalArticlepeer-review

261 Scopus citations


Objectives: To assess the safety and effect on coagulopathy of a range of doses of recombinant human activated protein C (rhAPC). To determine an effective dose and duration of rhAPC for use in future clinical trials. Design: Double-blind, randomized, placebo-controlled, multicenter, dose-ranging (sequential), phase II clinical trial. Setting: Forty community or academic medical institutions in United States and Canada. Patients: One hundred thirty-one adult patients with severe sepsis. Interventions: Intravenous infusion of rhAPC (12, 18, 24, or 30 μg/kg/hr) or placebo for 48 or 96 hrs. Measurements and Main Results: No significant differences in incidence of serious bleeding events (4% rhAPC, 5% placebo, p > .999) or incidence of serious adverse events (39% rhAPC, 46% placebo, p = 0.422) between rhAPC- and placebo-treated patients were observed. One of 53 rhAPC-treated patients with suitable immunogenicity samples had a low level, transient, non-neutralizing anti-APC antibody response not associated with any clinical adverse event. Significant dose-dependent decreases in both D-dimer (p <0.001) and end of infusion interleukin 6 levels (p = .021) were demonstrated. No statistically significant effects on fibrinogen or platelet counts were observed. A nonstatistically significant 15% relative risk reduction in 28-day all-cause mortality was observed between rhAPC- and placebo-treated patients. Conclusions: rhAPC was safe and well-tolerated and demonstrated a dose-dependent reduction in D-dimer and interleukin 6 levels relative to placebo. The dose of 24 μg/kg/hr for 96 hrs was selected for use in future clinical studies.

Original languageEnglish
Pages (from-to)2051-2059
Number of pages9
JournalCritical Care Medicine
Issue number11
StatePublished - 2001


  • Activated protein C
  • Critical care
  • D-dimer
  • Disseminated intravascular coagulopathy
  • Inflammation
  • Phase II clinical trial
  • Randomized controlled trial
  • Recombinant proteins
  • Sepsis
  • Septic shock
  • Severe sepsis

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine


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