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

Objective. Group IIA secretory phospholipase A(2) (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 (LY31592ONA/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 LY31592ONA/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 LY31592ONA/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 LY31592ONA/S-5920, which provides a reminder that subgroup effects should be viewed cautiously, especially when primary effects are not significant.