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

Crit Care Med. 2001 Nov;29(11):2051-9. doi: 10.1097/00003246-200111000-00003.


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 microg/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 microg/kg/hr for 96 hrs was selected for use in future clinical studies.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Critical Care
  • Disseminated Intravascular Coagulation / classification
  • Disseminated Intravascular Coagulation / complications
  • Disseminated Intravascular Coagulation / drug therapy*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Administration Schedule
  • Female
  • Fibrin Fibrinogen Degradation Products / metabolism
  • Hospital Mortality
  • Humans
  • Infusions, Intravenous
  • Male
  • Middle Aged
  • Protein C / administration & dosage
  • Protein C / therapeutic use*
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / therapeutic use*
  • Sepsis / classification
  • Sepsis / complications
  • Sepsis / drug therapy*
  • Severity of Illness Index


  • Fibrin Fibrinogen Degradation Products
  • Protein C
  • Recombinant Proteins
  • fibrin fragment D