Efficacy and safety of LY315920Na/S-5920, a selective inhibitor of 14-kDa group IIA secretory phospholipase A₂, in patients with suspected sepsis and organ failure

Objective: Concentrations of group IIA secretory phospholipase A₂, an inflammatory response mediator, are increased in the plasma of patients with sepsis and septic shock, and the extent of elevation is correlated with mortality. LY315920Na/S-5920 is a selective inhibitor of group IIA secretory phospholipase A₂ that has been shown to inhibit serum group IIA secretory phospholipase A₂ enzyme activity in patients with severe sepsis. The primary objectives of this study were to determine whether there was a dose-response relationship between two doses of LY315920Na/S-5920 compared with placebo in the reduction of 28-day all-cause mortality in patients with severe sepsis and to determine whether LY315920Na/S-5920 had an acceptable safety profile. Design: Multicenter, double-blind, placebo-controlled trial of two doses of LY315920Na/S-5920 in a parallel design. Patients: A total of 586 patients with severe sepsis at 72 institutions in the United States. Interventions: Patients enrolled within 72 hrs from onset of first sepsis-induced organ failure were randomized (1:1:1) to low-dose LY315920Na/S-5920 (target plasma concentration of 200 ng/mL, n = 196), high-dose LY315920Na/S-5920 (800 ng/mL, n = 194), or placebo (n = 196). Study medication was administered as a constant-rate intravenous infusion for 168 hrs. Measurements and Main Results: The study was stopped prematurely because it was unlikely that a statistically significant difference in mortality between LY315920Na/S-5920 and placebo would be found. There was no effect of LY315920Na/S-5920 on the primary end point of 28-day all-cause mortality across the entire study population. The 28-day all-cause mortality was distributed as follows: placebo group, 33.2% (65/196 patients); low-dose LY315920Na/S-5920, 37.2% (73/196); and high-dose LY315920Na/S-5920, 36.1% (70/194); p = .525. However, in a prospectively planned analysis, there was a favorable overall dose-response effect on 28-day all-cause mortality in patients administered LY315920Na/S-5920 within 18 hrs of onset of the first sepsis-induced organ failure. Among these patients, 28-day all-cause mortality was distributed as follows: placebo group, 43.5% (20/46 patients); low-dose LY315920Na/S-5920, 31.4% (16/ 51); and high-dose LY315920Na/S-5920, 20.8% (10/48); p = .018. Conclusions: Administration of LY315920Na/S-5920 had an acceptable safety profile in patients with severe sepsis. There was no overall survival benefit associated with the use of LY315920Na/S-5920 in this study. However, prospectively planned secondary analyses suggested that treatment with LY315920Na/ S-5920 was associated with an improvement in survival in patients treated within 18 hrs of the first sepsis-induced organ failure.