Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: Results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial

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dc.contributor.authorOpal, S.
dc.contributor.authorLaterre, P-F.
dc.contributor.authorAbraham, E.
dc.contributor.authorFrancois, B.
dc.contributor.authorWittebole, X.
dc.contributor.authorLowry, S.
dc.contributor.authorDhainaut, J-F.
dc.contributor.authorWarren, B.
dc.contributor.authorDugernier, T.
dc.contributor.authorLopez, A.
dc.contributor.authorSanchez, M.
dc.contributor.authorDemeyer, I.
dc.contributor.authorJauregui, L.
dc.contributor.authorLorente, J. A.
dc.contributor.authorMcGee, W.
dc.contributor.authorReinhart, K.
dc.contributor.authorKljucar, S.
dc.contributor.authorSouza, S.
dc.contributor.authorPribble, J.
dc.contributor.authorOpal, S.
dc.contributor.authorLaterre, P-F.
dc.contributor.authorAbraham, E.
dc.contributor.authorFrancois, B.
dc.contributor.authorWittebole, X.
dc.contributor.authorLowry, S.
dc.contributor.authorDhainaut, J-F.
dc.contributor.authorWarren, B.
dc.contributor.authorDugernier, T.
dc.contributor.authorLopez, A.
dc.contributor.authorSanchez, M.
dc.contributor.authorDemeyer, I.
dc.contributor.authorJauregui, L.
dc.contributor.authorLorente, J. A.
dc.contributor.authorMcGee, W.
dc.contributor.authorReinhart, K.
dc.contributor.authorKljucar, S.
dc.contributor.authorSouza, S.
dc.contributor.authorPribble, J.
dc.date.accessioned2011-05-15T16:16:10Z
dc.date.accessioned2011-05-15T16:16:10Z
dc.date.available2011-05-15T16:16:10Z
dc.date.available2011-05-15T16:16:10Z
dc.date.issued2004
dc.date.issued2004
dc.description.abstractObjective: 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.
dc.description.abstractObjective: 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.
dc.description.versionArticle
dc.description.versionArticle
dc.identifier.citationCritical Care Medicine
dc.identifier.citation32
dc.identifier.citation2
dc.identifier.citationCritical Care Medicine
dc.identifier.citation32
dc.identifier.citation2
dc.identifier.issn00903493
dc.identifier.issn00903493
dc.identifier.other10.1097/01.CCM.0000108867.87890.6D
dc.identifier.other10.1097/01.CCM.0000108867.87890.6D
dc.identifier.urihttp://hdl.handle.net/10019.1/13662
dc.identifier.urihttp://hdl.handle.net/10019.1/13662
dc.subjectplacebo; 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
dc.subjectplacebo
dc.subjectadult
dc.subjectaged
dc.subjectarticle
dc.subjectbleeding
dc.subjectclinical trial
dc.subjectconfidence interval
dc.subjectcontrolled clinical trial
dc.subjectcontrolled study
dc.subjectdisease severity
dc.subjectdouble blind procedure
dc.subjectdrug monitoring
dc.subjectdrug safety
dc.subjectdrug tolerability
dc.subjectfemale
dc.subjecthuman
dc.subjectintensive care unit
dc.subjectmajor clinical study
dc.subjectmale
dc.subjectmortality
dc.subjectmulticenter study
dc.subjectpatient monitoring
dc.subjectphase 3 clinical trial
dc.subjectpriority journal
dc.subjectrandomized controlled trial
dc.subjectrisk assessment
dc.subjectsepsis
dc.subjectside effect
dc.subjectstatistical significance
dc.subject1-Alkyl-2-acetylglycerophosphocholine Esterase
dc.subjectDouble-Blind Method
dc.subjectFemale
dc.subjectHumans
dc.subjectMale
dc.subjectMiddle Aged
dc.subjectProspective Studies
dc.subjectRecombinant Proteins
dc.subjectSepsis
dc.subjectSeverity of Illness Index
dc.titleRecombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: Results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial
dc.titleRecombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: Results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial
dc.typeArticle
dc.typeArticle
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