A placebo-controlled, double-blind, dose-escalation study to assess the safety, tolerability and pharmacokinetics/pharmacodynamics of single and multiple intravenous infusions of AZD9773 in patients with severe sepsis and septic shock.

Critical Care : the Official Journal of the Critical Care Forum
Peter E MorrisGordon R Bernard

Abstract

Tumor necrosis factor-alpha (TNF-α), an early mediator in the systemic inflammatory response to infection, is a potential therapeutic target in sepsis. The primary objective of this study was to determine the safety and tolerability of AZD9773, an ovine, polyclonal, anti-human TNF-α Fab preparation, in patients with severe sepsis. Secondary outcomes related to pharmacokinetic (PK) and pharmacodynamic (PD) parameters. In this double-blind, placebo-controlled, multicenter Phase IIa study, patients were sequentially enrolled into five escalating-dose cohorts (single doses of 50 or 250 units/kg; multiple doses of 250 units/kg loading and 50 units/kg maintenance, 500 units/kg loading and 100 units/kg maintenance, or 750 units/kg loading and 250 units/kg maintenance). In each cohort, patients were randomized 2:1 to receive AZD9773 or placebo. Seventy patients received AZD9773 (n=47) or placebo (n=23). Baseline characteristics were similar across cohorts. Mean baseline APACHE score was 25.9. PK data demonstrated an approximately proportional increase in concentration with increasing dose and a terminal half-life of 20 hours. For the multiple-dose cohorts, serum TNF-α concentrations decreased to near-undetectable levels within two hour...Continue Reading

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Citations

Nov 19, 2013·Inflammation Research : Official Journal of the European Histamine Research Society ... [et Al.]·Peter NewhamJennifer S McKay
Feb 20, 2014·International Journal of Clinical Practice·S LvR Wang
Aug 26, 2015·Clinics in Chest Medicine·Peter BentzerKeith R Walley
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Jul 10, 2012·Nature Medicine·Sarah C P Williams
Dec 6, 2019·International Journal of Molecular Sciences·Kristopher TuttleEthan Anderson
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Feb 19, 2014·Critical Care Medicine·Tom van der Poll
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Sep 23, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Alexandre E Nowill, Pedro O de Campos-Lima

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Methods Mentioned

BETA
ELISA

Clinical Trials Mentioned

NCT00615017
NCT01145560
NCT01144624

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