Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2012 Feb 17;16(1):R31.
doi: 10.1186/cc11203.

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

Peter E Morris  1 , Brian Zeno, Andrew C Bernard, Xiangning Huang, Shampa Das, Timi Edeki, Steven G Simonson, Gordon R Bernard
Affiliations
Clinical Trial

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

Peter E Morris et al. Crit Care. .

Abstract

Introduction: 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.

Methods: 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.

Results: 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 hours of commencing AZD9773 infusion. This suppression was maintained in most patients for the duration of treatment. AZD9773 was well tolerated. Most adverse events were of mild-to-moderate intensity and considered by the reporting investigator as unrelated to study treatment.

Conclusions: The safety, PK and PD data support the continued evaluation of AZD9773 in larger Phase IIb/III studies.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Patient disposition.
Figure 2
Figure 2
TNF-α serum concentrations following (A) single 250 U/kg dose of AZD9773; (B) multiple AZD9773 doses.
Figure 3
Figure 3
Exploratory analysis of TNF-α AUC over treatment: multiple AZD9773 dose cohorts vs placebo.
See this image and copyright information in PMC

References

    1. Dombrovskiy VY, Martin AA, Sunderram J, Paz HL. Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Crit Care Med. 2007;35:1244–1250. doi: 10.1097/01.CCM.0000261890.41311.E9. - DOI - PubMed
    1. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut J-F, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36:296–327. doi: 10.1097/01.CCM.0000298158.12101.41. - DOI - PubMed
    1. Sharma VK, Dellinger RP. Treatment options for severe sepsis and septic shock. Expert Rev Anti Infect Ther. 2006;4:395–403. doi: 10.1586/14787210.4.3.395. - DOI - PubMed
    1. Nawroth PP, Bank I, Handley D, Cassimeris J, Chess L, Stern D. Tumor necrosis factor/cachectin interacts with endothelial cell receptors to induce release of interleukin 1. J Exp Med. 1986;163:1363–1375. doi: 10.1084/jem.163.6.1363. - DOI - PMC - PubMed
    1. Spooner CE, Markowitz NP, Saravolatz LD. The role of tumor necrosis factor in sepsis. Clin Immunol Immunopathol. 1992;62:S11–S17. doi: 10.1016/0090-1229(92)90036-N. - DOI - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources