title: Evaluating the efficacy and safety of two doses of the polyclonal anti-tumor necrosis factor-α fragment antibody AZD9773 in adult patients with severe sepsis and/or septic shock: randomized, double-blind, placebo-controlled phase IIb study*.
abstract: OBJECTIVE
  This trial compared the efficacy/safety of two IV doses of AZD9773, a polyclonal antibody to tumor necrosis factor-α, in adult patients with severe sepsis/septic shock.
  
  
  METHODS
  Multicenter, randomized, double-blind, placebo-controlled phase IIb trial.
  
  
  METHODS
  ICUs in seven countries (Australia, Belgium, Canada, Czech Republic, Finland, France, and Spain).
  
  
  METHODS
  Patients 18 years old or older with severe sepsis and/or septic shock. Patients were required to have 1) objective clinical evidence of infection; 2) at least two of four systemic inflammatory response syndrome criteria; and 3) cardiovascular and/or respiratory sepsis-related failure.
  
  
  METHODS
  Patients were randomized 1:1:1 to a single loading infusion of AZD9773 250 U/kg followed by 50 U/kg every 12 hours (low dose, n = 100), a single loading infusion of AZD9773 500 U/kg followed by 100 U/kg every 12 hours (high dose, n = 100), or placebo (n = 100) for 5 days. Follow-up assessments were performed up to day 90.
  
  
  RESULTS
  Mean number of ventilator-free days (primary endpoint) did not differ between low-dose (19.7 d) or high-dose AZD9773 (17.3 d) and placebo (18.3 d) (one-sided p = 0.18 and 0.74, respectively). Mortality rates were comparable across treatment groups; relative risk of death versus placebo at day 29 was 0.80 for low-dose AZD9773 (one-sided p = 0.25) and 1.64 for high-dose AZD9773 (p = 0.97). Most patients experienced at least one treatment-emergent adverse event (87.8% in AZD9773-treated patients, 92.9% in placebo patients) although most were mild/moderate in nature. No differences in the incidence of adverse events or laboratory or vital sign abnormalities were observed between groups.
  
  
  CONCLUSIONS
  AZD9773 rapidly and efficiently decreased plasma tumor necrosis factor-α concentration in patients with severe sepsis/septic shock, but this effect did not translate into clinical benefit.
authors: 1Division of Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN. 2Service de Réanimation Polyvalente, CIC-P 0801, CHU Dupuytren, Limoges, Cedex, France. 3Hôpitaux Paris Centre, AP-HP; Université Paris Descartes, Faculté de médecine, Paris, France and Cochin Institute, INSERM U567, CNRS UMR 8104, Paris, France. 4Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium. 5Department of Medicine, Cooper University Hospital, Camden, NJ. 6Centre for Heart Lung Innovation, University of British Columbia, Vancouver, BC, Canada. 7Division of Infectious Diseases, Beverly Hospital, Beverly, MA. 8Critical Care Department, St Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium. 9Department of Medicine, Brown University, Providence, RI. 10Worldwide Medical Services Department, PAREXEL International, Durham, NC. 11AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors: Gordon R
authors: GR
authors: Bernard
authors: Bruno
authors: B
authors: Francois
authors: Jean-Paul
authors: JP
authors: Mira
authors: Jean-Louis
authors: JL
authors: Vincent
authors: R Phillip
authors: RP
authors: Dellinger
authors: James A
authors: JA
authors: Russell
authors: Steven P
authors: SP
authors: Larosa
authors: Pierre-Francois
authors: PF
authors: Laterre
authors: Mitchell M
authors: MM
authors: Levy
authors: Wayne
authors: W
authors: Dankner
authors: Nicola
authors: N
authors: Schmitt
authors: Justin
authors: J
authors: Lindemann
authors: Xavier
authors: X
authors: Wittebole
mesh_terms: D000328:Adult; D000368:Aged; D016001:Confidence Intervals; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005069:Evaluation Studies as Topic; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage*; D007262:Infusions, Intravenous; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D018570:Risk Assessment; D018805:Sepsis / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D012772:Shock, Septic / Q000175:diagnosis / Q000188:drug therapy / Q000401:mortality; D018709:Statistics, Nonparametric; D015996:Survival Rate; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000037:antagonists & inhibitors*
chemical_list: D007140:Immunoglobulin Fab Fragments; D014409:Tumor Necrosis Factor-alpha