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 A, 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 A that has been shown to inhibit serum group IIA secretory phospholipase A 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.(2) (2) (2)


METHODS
Multicenter, double-blind, placebo-controlled trial of two doses of LY315920Na/S-5920 in a parallel design.


METHODS
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.


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.
Abraham
Edward
E
University of Colorado Health Sciences Center, Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, Denver 80262, USA.
Naum
Chris
C
Bandi
Venkata
V
Gervich
Daniel
D
Lowry
Stephen F
SF
Wunderink
Richard
R
Schein
Roland M
RM
Macias
William
W
Skerjanec
Simona
S
Dmitrienko
Alex
A
Farid
Nagy
N
Forgue
S Thomas
ST
Jiang
Frank
F
D000085:Acetates / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology; D000368:Aged; D002423:Cause of Death; D016638:Critical Illness; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D016903:Drug Monitoring; D005260:Female; D054501:Group II Phospholipases A2; D017052:Hospital Mortality; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology; D007249:Inflammation; D007262:Infusions, Intravenous; D007651:Keto Acids; D008297:Male; D008875:Middle Aged; D008970:Molecular Weight; D009102:Multiple Organ Failure / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000401:mortality; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000276:immunology; D054467:Phospholipases A2; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012449:Safety; D016019:Survival Analysis; D018746:Systemic Inflammatory Response Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000401:mortality; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States / Q000453:epidemiology
D000085:Acetates; D007211:Indoles; D007651:Keto Acids; C117948:varespladib; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2