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


METHODS
Double-blind, randomized, placebo-controlled, multicenter, dose-ranging (sequential), phase II clinical trial.


METHODS
Forty community or academic medical institutions in United States and Canada.


METHODS
One hundred thirty-one adult patients with severe sepsis.


METHODS
Intravenous infusion of rhAPC (12, 18, 24, or 30 microg/kg/hr) or placebo for 48 or 96 hrs.


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.
Bernard
G R
GR
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
Ely
E W
EW
Wright
T J
TJ
Fraiz
J
J
Stasek
J E
JE
Russell
J A
JA
Mayers
I
I
Rosenfeld
B A
BA
Morris
P E
PE
Yan
S B
SB
Helterbrand
J D
JD
D003422:Critical Care; D004211:Disseminated Intravascular Coagulation / Q000145:classification / Q000150:complications / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D017052:Hospital Mortality; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011486:Protein C / Q000008:administration & dosage / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use*; D018805:Sepsis / Q000145:classification / Q000150:complications / Q000188:drug therapy*; D012720:Severity of Illness Index
D005338:Fibrin Fibrinogen Degradation Products; D011486:Protein C; D011994:Recombinant Proteins; C036309:fibrin fragment D