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

ObjectiveConcentrations 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. DesignMulticenter, double-blind, placebo-controlled trial of two doses of LY315920Na/S-5920 in a parallel design. PatientsA total of 586 patients with severe sepsis at 72 institutions in the United States. InterventionsPatients 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 ResultsThe 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. ConclusionsAdministration 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.

[1]  E. Draper,et al.  APACHE II: A severity of disease classification system , 1985, Critical care medicine.

[2]  P. Vadas,et al.  Pathogenesis of hypotension in septic shock: correlation of circulating phospholipase A2 levels with circulatory collapse. , 1988, Critical care medicine.

[3]  G. Clermont,et al.  Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care , 2001, Critical care medicine.

[4]  P. Malfertheiner,et al.  Serum phospholipase A2 in intensive care patients with peritonitis, multiple injury, and necrotizing pancreatitis , 1989, Klinische Wochenschrift.

[5]  J. Carlet,et al.  INTERSEPT: an international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-alpha in patients with sepsis. International Sepsis Trial Study Group. , 1996, Critical care medicine.

[6]  N. Roehm,et al.  Pharmacology of LY315920/S-5920, [[3-(aminooxoacetyl)-2-ethyl-1- (phenylmethyl)-1H-indol-4-yl]oxy] acetate, a potent and selective secretory phospholipase A2 inhibitor: A new class of anti-inflammatory drugs, SPI. , 1999, The Journal of pharmacology and experimental therapeutics.

[7]  T. van der Poll,et al.  Activation of coagulation after administration of tumor necrosis factor to normal subjects. , 1990, The New England journal of medicine.

[8]  Increase in National Hospital Discharge Survey rates for septicemia--United States, 1979-1987. , 1990, MMWR. Morbidity and mortality weekly report.

[9]  E. Moore,et al.  Phospholipase A2 regulates critical inflammatory mediators of multiple organ failure. , 1994, The Journal of surgical research.

[10]  J Ean,et al.  Efficacy and safety of recombinant human activated protein C for severe sepsis. , 2001, The New England journal of medicine.

[11]  J. Parrillo.  Management of septic shock: present and future. , 1991, Annals of internal medicine.

[12]  T. Clemmer,et al.  Sepsis syndrome: a valid clinical entity , 1989 .

[13]  J. Vincent,et al.  The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure , 1996, Intensive Care Medicine.

[14]  G. Béréziat,et al.  Secretory non-pancreatic phopholipase A2 in severe sepsis: Relation to endotoxin, cytokines and thromboxane B2 , 1996, Infection.

[15]  S. Eckstein.  Ethical principles for medical research involving human subjects. , 2001, European journal of emergency medicine : official journal of the European Society for Emergency Medicine.

[16]  M. Boermeester,et al.  Interleukin-1 blockade attenuates mediator release and dysregulation of the hemostatic mechanism during human sepsis. , 1995, Archives of surgery.

[17]  T. Clemmer,et al.  A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. , 1987, The New England journal of medicine.

[18]  S. Nasraway,et al.  Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. , 1995, JAMA.

[19]  Christiane,et al.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. , 2004, Journal international de bioethique = International journal of bioethics.

[20]  A. Matsukawa,et al.  Therapeutic time-window of a group IIA phospholipase A2 inhibitor in rabbit acute lung injury: Correlation with lung surfactant protection , 2001, Critical care medicine.

[21]  P. Vadas,et al.  Influence of plasma proteins on activity of proinflammatory enzyme phospholipase A2 , 1986, Inflammation.

[22]  P. Stanley,et al.  Inhibitor of phospholipase A2 blocks eicosanoid and platelet activating factor biosynthesis and has topical anti-inflammatory activity. , 1994, The Journal of pharmacology and experimental therapeutics.

[23]  F. Ognibene,et al.  Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. , 1990, Annals of internal medicine.

[24]  R. Nemenoff,et al.  Activation of a novel form of phospholipase A2 during liver regeneration , 1995, FEBS letters.

[25]  P. Vadas,et al.  Acute lung injury induced by phospholipase A2. Structural and functional changes. , 1991, The American review of respiratory disease.

[26]  S. Katz,et al.  STUDIES OF ILLNESS IN THE AGED. THE INDEX OF ADL: A STANDARDIZED MEASURE OF BIOLOGICAL AND PSYCHOSOCIAL FUNCTION. , 1963, JAMA.

[27]  F. Ognibene,et al.  Septic shock in humans , 2020 .

[28]  D. Pittet,et al.  The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. , 1995, JAMA.

[29]  M. Büchler,et al.  Serum phospholipase A2 in patients with multiple injuries. , 1990, The Journal of trauma.

[30]  S. Opal,et al.  Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. , 1994, JAMA.

[31]  Epidemiology of sepsis syndrome in 8 academic medical centers. , 1998, JAMA.

[32]  O. Arrieta,et al.  Pharmacological treatment of septic shock , 2000 .

[33]  S. Opal,et al.  Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. , 1997, Critical care medicine.

[34]  E. Dennis,et al.  Group-specific assays that distinguish between the four major types of mammalian phospholipase A2. , 1999, Analytical biochemistry.

[35]  H. Bruining,et al.  p55 Tumor Necrosis Factor Receptor Fusion Protein in the Treatment of Patients With Severe Sepsis and Septic Shock: A Randomized Controlled Multicenter Trial , 1997 .

[36]  R. F. Johnston,et al.  Recombinant Human Interleukin 1 Receptor Antagonist in the Treatment of Patients With Sepsis Syndrome: Results From a Randomized, Double-blind, Placebo-Controlled Trial , 1994 .

[37]  C. Sprung,et al.  Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. A randomized, double-blind, placebo-controlled trial. The HA-1A Sepsis Study Group. , 1991 .

[38]  C. Sprung,et al.  Clinical expert round table discussion (session 3) at the Margaux Conference on Critical Illness: the role of activated protein C in severe sepsis. , 2001, Critical care medicine.

[39]  Chaby.  Strategies for the control of LPS-mediated pathophysiological disorders. , 1999, Drug discovery today.

[40]  M. Yoshida,et al.  Plasma levels of type II phospholipase A2 and cytokines in patients with sepsis. , 1995, Research communications in molecular pathology and pharmacology.

[41]  H. Bruining,et al.  p55 Tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock. A randomized controlled multicenter trial. Ro 45-2081 Study Group. , 1997, JAMA.

[42]  G. Koch,et al.  Efficacy and Safety of Monoclonal Antibody to Human Tumor Necrosis Factor α in Patients With Sepsis Syndrome: A Randomized, Controlled, Double-blind, Multicenter Clinical Trial , 1995 .