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

Abstract

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

Figure 1

Summary of patients treated. A total of 2340 patients were screened; 379 were eligible and 291 were randomised. One patient withdrew after randomisation. Treatment allocations, exclusions, and non-attributable deaths showing the basis for analysis of outcome by intention to treat, complications, and attributable mortality.

Figure 2

Mean organ failure scores (OFS) in the placebo and lexipafant groups (mean (SEM)). Values observed on day 3 were significantly different in the placebo and treatment groups (p=0.039).

Figure 3

Median (interquartile range) changes in interleukin 8 (IL-8) levels from baseline values given in the text. Values observed 12 hours after the start of therapy were significantly different (p=0.006, Wilcoxon rank sum test). Median area under the curve (AUC) for placebo was 0 (−499 to 9820) and for lexipafant -1.53 (−3890 to 1190) (p=0.003).

Figure 4

Median (interquartile range) changes in E-selectin levels from the baseline values given in the text. Values observed 12 hours after the start of therapy were significantly different (p=0.005, Wilcoxon rank sum test). Median area under the curve (AUC) for placebo was −0.0 (−24 to 130) and for lexipafant −1.3 (−95 to 77) (p=0.03).

Figure 5

Relationship between duration of symptoms before treatment and risk of death, expressed as log odds ratio of death in the lexipafant group compared with the placebo group. Solid line, estimated ratio; broken lines, 95% confidence intervals.