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

Bernard GR, Ely EW, Wright TJ, Fraiz J, Stasek JE, Russell JA, Mayers I, Rosenfeld BA, Morris PE, Yan SB, Helterbrand JD
Crit Care Med. 2001 29 (11): 2051-9

PMID: 11700394 · 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.

MeSH Terms (16)

Critical Care Disseminated Intravascular Coagulation Dose-Response Relationship, Drug Double-Blind Method Drug Administration Schedule Female Fibrin Fibrinogen Degradation Products Hospital Mortality Humans Infusions, Intravenous Male Middle Aged Protein C Recombinant Proteins Sepsis Severity of Illness Index

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