LY315920NA/S-5920, a selective inhibitor of group IIA secretory phospholipase A2, fails to improve clinical outcome for patients with severe sepsis.

Abstract

OBJECTIVE:

Group IIA secretory phospholipase A2 (sPLA2-IIA), released during inflammation, is increased in severe sepsis, and plasma levels are inversely related to survival. In a previous study, a selective inhibitor of sPLA2-IIA (LY315920NA/S-5920) was well tolerated and appeared to improve survival in a subgroup of patients who received the drug within 24 hrs of first sepsis-induced organ failure. This study was designed to determine whether improvement in survival could be confirmed in a larger patient population meeting the characteristics of that subgroup.

DESIGN:

Multicenter, double-blind, placebo-controlled, parallel-group clinical trial of LY315920NA/S-5920 in patients with severe sepsis.

SETTING:

Seventy-five institutions worldwide.

PATIENTS:

A total of 373 patients with at least two sepsis-induced organ failures.

INTERVENTIONS:

Patients were randomized 1:1 to receive LY315920NA/S-5920 (target plasma concentration of 800 ng/mL; n = 188) or placebo (n = 185). Study medication was administered as a continuous intravenous infusion for 168 hrs.

MEASUREMENTS AND MAIN RESULTS:

The study was terminated after data on 250 patients suggested a significant improvement in 28-day all-cause mortality would not be found if the trial continued as planned. The mortality rate was 39.4% in the LY315920NA/S-5920 group, compared with 31.9% in the placebo group (p = .092). The negative trend in mortality was most pronounced among patients with cardiovascular failure at baseline (41.6% vs. 28.7%; p = .008) and patients whose culture data at baseline were negative (42.9% vs. 22.7%; p = .045). The negative trend in mortality is not explained by adverse events, microbiology, or laboratory data.

CONCLUSIONS:

Continuous 7-day infusion of an inhibitor of sPLA2-IIA had no beneficial effect on 28-day all-cause mortality among severe sepsis patients with at least two organ failures. This study did not confirm earlier promising subgroup results with LY315920NA/S-5920, which provides a reminder that subgroup effects should be viewed cautiously, especially when primary effects are not significant.

• Authors: Bernhardt G Zeiher, Jay Steingrub, Pierre-Francois Laterre, Alex Dmitrienko, Yonetaka Fukiishi, Edward Abraham, EZZI Study Group
• Journal: Critical care medicine (Crit Care Med) Vol. 33 Issue 8 Pg. 1741-8 (Aug 2005) ISSN: 0090-3493 [Print] United States
• PMID: 16096451 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Acetates
• Indoles
• Keto Acids
• varespladib
• Phospholipases A
• Group II Phospholipases A2
• Phospholipases A2

Topics

• Acetates (therapeutic use)
• Double-Blind Method
• Europe (epidemiology)
• Female
• Group II Phospholipases A2
• Humans
• Indoles (therapeutic use)
• Infusions, Intravenous
• Keto Acids
• Male
• Middle Aged
• Multiple Organ Failure (drug therapy, mortality)
• Phospholipases A (antagonists & inhibitors)
• Phospholipases A2
• Risk
• Sepsis (drug therapy, mortality)
• United States (epidemiology)