Document Detail

Double blind, randomised, placebo controlled study of a platelet activating factor antagonist, lexipafant, in the treatment and prevention of organ failure in predicted severe acute pancreatitis.
MedLine Citation:
PMID:  11115824     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Platelet activating factor (PAF) is believed to amplify the activity of key mediators of the systemic inflammatory response syndrome (SIRS) in acute pancreatitis, resulting in multiorgan dysfunction syndrome. We tested the hypothesis that a potent PAF antagonist, lexipafant, could dampen SIRS and reduce organ failure in severe acute pancreatitis. METHODS: We conducted a randomised, double blind, placebo controlled, multicentre trial of lexipafant (100 mg/24 hours intravenously for seven days commenced within 72 hours of the onset of symptoms) involving 290 patients with an APACHE II score >6. Power calculations assumed that complications would be reduced from 40% to 24%. Secondary end points studied included severity of organ failure, markers of the inflammatory response, and mortality rate. FINDINGS: Overall, 80/138 (58%) patients in the placebo group and 85/148 (57%) in the lexipafant group developed one or more organ failures. The primary hypothesis was invalidated by the unexpected finding that 44% of patients had organ failure on entry into the study; only 39 (14%) developed new organ failure. Organ failure scores were reduced in the lexipafant group only on day 3: median change -1 (range -4 to +8) versus 0 (-4 to +10) in the placebo group (p=0.04). Systemic sepsis affected fewer patients in the lexipafant group (13/138 v 4/148; p=0.023). Local complications occurred in 41/138 (30%) patients in the placebo group and in 30/148 (20%) in the lexipafant group (20%; p=0.065); pseudocysts developed in 19 (14%) and eight (5%) patients, respectively (p=0.025). Deaths attributable to acute pancreatitis were not significantly different. Interleukin 8, a marker of neutrophil activation, and E-selectin, a marker of endothelial damage, decreased more rapidly in the lexipafant group (both p<0.05); however, absolute values were not different between the two groups. INTERPRETATION: The high incidence of organ failure within 72 hours of the onset of symptoms undermined the primary hypothesis, and power calculations for future studies in severe acute pancreatitis will need to allow for this. Lexipafant had no effect on new organ failure during treatment. This adequately powered study has shown that antagonism of PAF activity on its own is not sufficient to ameliorate SIRS in severe acute pancreatitis
C D Johnson; A N Kingsnorth; C W Imrie; M J McMahon; J P Neoptolemos; C McKay; S K Toh; P Skaife; P C Leeder; P Wilson; M Larvin; L D Curtis
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Publication Detail:
Type:  Clinical Trial; Clinical Trial, Phase III; Journal Article; Multicenter Study; Randomized Controlled Trial    
Journal Detail:
Title:  Gut     Volume:  48     ISSN:  0017-5749     ISO Abbreviation:  Gut     Publication Date:  2001 Jan 
Date Detail:
Created Date:  2001-01-30     Completed Date:  2001-02-22     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  2985108R     Medline TA:  Gut     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  62-9     Citation Subset:  AIM; IM    
University Surgical Unit, F Level, Centre Block, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK.
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MeSH Terms
Acute Disease
Biological Markers / blood
Double-Blind Method
E-Selectin / blood
Imidazoles / therapeutic use*
Interleukin-8 / blood
Length of Stay
Leucine / analogs & derivatives*,  therapeutic use*
Logistic Models
Middle Aged
Multiple Organ Failure / drug therapy*,  mortality,  prevention & control
Pancreatitis / drug therapy*,  mortality
Platelet Activating Factor / antagonists & inhibitors*
Prospective Studies
Reg. No./Substance:
0/Biological Markers; 0/E-Selectin; 0/Imidazoles; 0/Interleukin-8; 0/Placebos; 0/Platelet Activating Factor; 139133-26-9/lexipafant; 61-90-5/Leucine

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