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Evaluating the Efficacy and Safety of Two Doses of the Polyclonal Anti-Tumor Necrosis Factor- Fragment Antibody AZD9773 in Adult Patients With Severe Sepsis and/or Septic Shock: Randomized, Double-Blind, Placebo-Controlled Phase IIb Study*

Bernard, Gordon R. MD1; Francois, Bruno MD2; Mira, Jean-Paul MD3; Vincent, Jean-Louis MD, PhD, FCCM4; Dellinger, R. Phillip MD5; Russell, James A. MD6; LaRosa, Steven P. MD7; Laterre, Pierre-Francois MD8; Levy, Mitchell M. MD9; Dankner, Wayne MD10; Schmitt, Nicola MPhil11; Lindemann, Justin MBChB11; Wittebole, Xavier MD8

Critical Care Medicine:
doi: 10.1097/CCM.0000000000000043
Feature Articles
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.

Design: Multicenter, randomized, double-blind, placebo-controlled phase IIb trial.

Setting: ICUs in seven countries (Australia, Belgium, Canada, Czech Republic, Finland, France, and Spain).

Patients: 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.

Interventions: 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.

Measurements and Main 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.

Author Information

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.

* See also p. 724.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Supported, in part, by AstraZeneca.

Dr. Bernard received a grant from AstraZeneca to his home institution, Vanderbilt University, to support his effort on this project. Dr. Bernard’s institution received grant support, support for participation in review activities, support for writing the article, and provision of assistance from AstraZeneca. Dr. Francois served as board member for KentaBiotech; consulted for KentaBiotech, Sanofi, and GlaxoSmithKline; and received grant support from Biomérieux. Dr. Mira served as member of the scientific board for AstraZeneca and Merch Sharp and Dohme, served as member of scientific committee for LFB Pharmaceutical Group (LFB), consulted for Astellas, provided expert testimony for Thermo Scientific B·R·A·H·M·S Biomarkers, and lectured for LFB. Dr. Mira’s institution received grant support from Biomérieux (Exome sequencing project). Dr. Vincent received grant support from AstraZeneca for work presented in this article. Dr. Dellinger’s institution received grant support from AstraZeneca (earlier phase 2a study with similar compound). Dr. Dellinger received consulting fees from AstraZeneca. Dr. Russell consulted for AstraZeneca (advisory committee), received support for travel from AstraZeneca (advisory committee for current trial), and consulted for Ferring Grifols and Sirius Genomics. Dr. Russell received consulting fees from AstraZeneca and received a grant from AstraZeneca to his home institution, the University of British Columbia, as a participating site in this study. Dr. LaRosa served as scientific advisory board member for ExThera Medical. Dr. LaRosa’s institution received grant support from the Ocean State Clinical Coordinating Center. Dr. LaRosa received grant support from AstraZeneca for work performed by the Ocean State Clinical Coordinating Center. Dr. Laterre’s institution consulted for St. Luc University Clinical Coordinating Center (Clinical Coordinating Center). Dr. Laterre received grant support from AstraZeneca for work performed by the Saint Luc Clinical Coordinating Center. Dr. Levy’s institution received grant support from Lifespan Corporation (site for clinical trial). Dr. Levy received grant support from AstraZeneca for work performed by the Ocean State Clinical Coordinating Center. Dr. Dankner received stock options from PAREXEL as part of employment. Dr. Dankner is an employee of PAREXEL (contracted by AstraZeneca to monitor the trial). Dr. Dankner’s institution received support for participation in review activities from PAREXEL International, received clinical trial support from PAREXEL (phase 2b trial), and is employed by PAREXEL International (holds position of Global Therapeutic Area Lead-Infectious Diseases at PAREXEL). Ms. Schmitt is employed by and is a stockholder of AstraZeneca. Mr. Lindemann is employed by and has stock with AstraZeneca (part of employment). Dr. Wittebole is a member of the St Luc University Hospital Coordinating Center and principal investigator at St Luc University Hospital. Dr. Wittebole’s institution consulted for AstraZeneca.

Address requests for reprints to: Gordon R. Bernard, MD, Vanderbilt Institute for Clinical and Translational Research, Room T-1208 Medical Center North, Vanderbilt University, Nashville, TN 37232. E-mail: gordon.bernard@vanderbilt.edu

© 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins