Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: Results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial
Date
2004, 2004
Authors
Opal, S.
Laterre, P-F.
Abraham, E.
Francois, B.
Wittebole, X.
Lowry, S.
Dhainaut, J-F.
Warren, B.
Dugernier, T.
Lopez, A.
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
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. Design: A prospective, randomized, double-blind, placebo-controlled, multicenter, international trial. Setting: One hundred forty-six intensive care units from nine countries. Patients: Approximately 2,522 patients were planned to be enrolled ≤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. Measurements and Main 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.
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. Design: A prospective, randomized, double-blind, placebo-controlled, multicenter, international trial. Setting: One hundred forty-six intensive care units from nine countries. Patients: Approximately 2,522 patients were planned to be enrolled ≤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. Measurements and Main 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.
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. Design: A prospective, randomized, double-blind, placebo-controlled, multicenter, international trial. Setting: One hundred forty-six intensive care units from nine countries. Patients: Approximately 2,522 patients were planned to be enrolled ≤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. Measurements and Main 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.
Description
Keywords
placebo; adult; aged; article; bleeding; clinical trial; confidence interval; controlled clinical trial; controlled study; disease severity; double blind procedure; drug monitoring; drug safety; drug tolerability; female; human; intensive care unit; major clinical study; male; mortality; multicenter study; patient monitoring; phase 3 clinical trial; priority journal; randomized controlled trial; risk assessment; sepsis; side effect; statistical significance; 1-Alkyl-2-acetylglycerophosphocholine Esterase; Double-Blind Method; Female; Humans; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Sepsis; Severity of Illness Index, placebo, adult, aged, article, bleeding, clinical trial, confidence interval, controlled clinical trial, controlled study, disease severity, double blind procedure, drug monitoring, drug safety, drug tolerability, female, human, intensive care unit, major clinical study, male, mortality, multicenter study, patient monitoring, phase 3 clinical trial, priority journal, randomized controlled trial, risk assessment, sepsis, side effect, statistical significance, 1-Alkyl-2-acetylglycerophosphocholine Esterase, Double-Blind Method, Female, Humans, Male, Middle Aged, Prospective Studies, Recombinant Proteins, Sepsis, Severity of Illness Index
Citation
Critical Care Medicine
32
2
Critical Care Medicine
32
2
32
2
Critical Care Medicine
32
2