• Gordon R Bernard, Bruno Francois, Jean-Paul Mira, Jean-Louis Vincent, R Phillip Dellinger, James A Russell, Steven P Larosa, Pierre-Francois Laterre, Mitchell M Levy, Wayne Dankner, Nicola Schmitt, Justin Lindemann, and Xavier Wittebole.
• 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.
• Crit. Care Med.. 2014 Mar 1;42(3):504-11.

ObjectiveThis 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.DesignMulticenter, randomized, double-blind, placebo-controlled phase IIb trial.SettingICUs in seven countries (Australia, Belgium, Canada, Czech Republic, Finland, France, and Spain).PatientsPatients 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.InterventionsPatients 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.Measurements And Main ResultsMean 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.ConclusionsAZD9773 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.

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