• G R Bernard, E W Ely, T J Wright, J Fraiz, J E Stasek, J A Russell, I Mayers, B A Rosenfeld, P E Morris, S B Yan, and J D Helterbrand.
• Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-2650, USA. gordon.bernard@mcmail.vanderbilt.edu
• Crit. Care Med. 2001 Nov 1;29(11):2051-9.

ObjectivesTo 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.DesignDouble-blind, randomized, placebo-controlled, multicenter, dose-ranging (sequential), phase II clinical trial.SettingForty community or academic medical institutions in United States and Canada.PatientsOne hundred thirty-one adult patients with severe sepsis.InterventionsIntravenous infusion of rhAPC (12, 18, 24, or 30 microg/kg/hr) or placebo for 48 or 96 hrs.Measurements And Main ResultsNo 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.ConclusionsrhAPC 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.

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