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

Edward Abraham, Chris Naum, Venkata Bandi, Daniel Gervich, Stephen F. Lowry, Richard Wunderink, Roland Schein, William Macias, Simona Skerjanec, Alex Dmitrienko, Nagy Farid, S. Thomas Forgue, Frank Jiang

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)718-728
Number of pages11
JournalCritical Care Medicine
Volume31
Issue number3
DOIs
StatePublished - Mar 1 2003

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varespladib
Group II Phospholipases A2
Sepsis
Safety
Placebos
Mortality

Keywords

  • Group IIA secretory phospholipase
  • LY315920Na/S-5920
  • Organ failure
  • Severe sepsis

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

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. / Abraham, Edward; Naum, Chris; Bandi, Venkata; Gervich, Daniel; Lowry, Stephen F.; Wunderink, Richard; Schein, Roland; Macias, William; Skerjanec, Simona; Dmitrienko, Alex; Farid, Nagy; Forgue, S. Thomas; Jiang, Frank.

In: Critical Care Medicine, Vol. 31, No. 3, 01.03.2003, p. 718-728.

Research output: Contribution to journalArticle

Abraham, E, Naum, C, Bandi, V, Gervich, D, Lowry, SF, Wunderink, R, Schein, R, Macias, W, Skerjanec, S, Dmitrienko, A, Farid, N, Forgue, ST & Jiang, F 2003, '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', Critical Care Medicine, vol. 31, no. 3, pp. 718-728. https://doi.org/10.1097/01.CCM.0000053648.42884.89
Abraham, Edward ; Naum, Chris ; Bandi, Venkata ; Gervich, Daniel ; Lowry, Stephen F. ; Wunderink, Richard ; Schein, Roland ; Macias, William ; Skerjanec, Simona ; Dmitrienko, Alex ; Farid, Nagy ; Forgue, S. Thomas ; Jiang, Frank. / 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. In: Critical Care Medicine. 2003 ; Vol. 31, No. 3. pp. 718-728.
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abstract = "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.",
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TY - JOUR

T1 - 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

AU - Abraham, Edward

AU - Naum, Chris

AU - Bandi, Venkata

AU - Gervich, Daniel

AU - Lowry, Stephen F.

AU - Wunderink, Richard

AU - Schein, Roland

AU - Macias, William

AU - Skerjanec, Simona

AU - Dmitrienko, Alex

AU - Farid, Nagy

AU - Forgue, S. Thomas

AU - Jiang, Frank

PY - 2003/3/1

Y1 - 2003/3/1

N2 - 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.

AB - 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.

KW - Group IIA secretory phospholipase

KW - LY315920Na/S-5920

KW - Organ failure

KW - Severe sepsis

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