Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial.
OBJECTIVE
Platelet-activating factor (PAF) and structurally-related oxidized phospholipids are proinflammatory mediators in systemic inflammatory states such as severe sepsis. The enzyme platelet-activating factor acetylhydrolase (PAF-AH) rapidly degrades PAF and oxidized phospholipids into inactive metabolites. Reduced PAF-AH activity has been observed in patients with severe sepsis and may contribute to their systemic inflammatory response and organ dysfunction. A previous clinical trial with recombinant human PAF-AH (rPAF-AH, Pafase) suggested that this treatment may decrease 28-day all-cause mortality in patients with severe sepsis. The current study was undertaken to confirm this result.


METHODS
A prospective, randomized, double-blind, placebo-controlled, multicenter, international trial.


METHODS
One hundred forty-six intensive care units from nine countries.


METHODS
Approximately 2,522 patients were planned to be enrolled < or =12 hrs after the onset of severe sepsis. Eligible patients were randomized to receive either rPAF-AH 1.0 mg/kg or placebo administered intravenously once daily for five consecutive days.


RESULTS
The study was terminated based on the recommendation of an independent data and safety monitoring committee after the second of three planned interim analyses, and the enrollment of 1,425 patients. rPAF-AH treatment was well tolerated among the 1,261 patients included in the interim analysis (643 rPAF-AH and 618 placebo), but did not decrease 28-day all-cause mortality compared with placebo (25% for rPAF-AH vs. 24% for placebo; relative risk, 1.03; 95% confidence interval, 0.85-1.25; p =.80). There were no statistically significant differences between treatment groups in any of the secondary efficacy end points. The overall incidence of adverse events was similar among rPAF-AH and placebo-treated patients, and no rPAF-AH-treated patients developed antibodies to PAF-AH.


CONCLUSIONS
rPAF-AH was well tolerated and not antigenic, but did not decrease 28-day all-cause mortality in patients with severe sepsis.
Opal
Steven
S
Division of Infectious Diseases, Brown Medical School, Providence, RI, USA.
Laterre
Pierre-Francois
PF
Abraham
Edward
E
Francois
Bruno
B
Wittebole
Xavier
X
Lowry
Stephen
S
Dhainaut
Jean-Francois
JF
Warren
Brian
B
Dugernier
Thierry
T
Lopez
Angel
A
Sanchez
Miguel
M
Demeyer
Ignace
I
Jauregui
Luis
L
Lorente
Jose Angel
JA
McGee
William
W
Reinhart
Konrad
K
Kljucar
Sascha
S
Souza
Sonia
S
Pribble
John
J
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000627:therapeutic use; D018805:Sepsis / Q000188:drug therapy*; D012720:Severity of Illness Index
D011994:Recombinant Proteins; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase