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  • Poster presentation
  • Open Access

Safety and tolerability of an ovine-derived polyclonal anti-TNFα Fab fragment (AZD9773) in patients with severe sepsis

  • 1,
  • 2,
  • 3,
  • 4,
  • 5 and
  • 6
Critical Care201115 (Suppl 1) :P263

https://doi.org/10.1186/cc9683

  • Published:

Keywords

  • Severe Sepsis
  • Placebo Administration
  • Laboratory Safety
  • Underlying Illness
  • Significant Medical Problem

Introduction

Sepsis remains a significant medical problem. TNFα is a central cytokine in sepsis pathophysiology. We conducted a phase IIa trial in patients with severe sepsis to assess the safety and tolerability of an intravenously infused ovine-derived polyclonal anti-TNFα Fab fragment (AZD9773).

Methods

This was a double-blind, placebo-controlled, dose-escalation trial (NCT00615017) with 2:1 randomisation (active:placebo). Two single-dose cohorts (50 units/kg and 250 units/kg) and three multiple-dose cohorts (250 units/kg followed by nine doses of 50 units/kg every 12 hours, 500 units/kg followed by nine doses of 100 units/kg, 750 units/kg followed by nine doses of 250 units/kg) were studied. Safety was assessed by monitoring adverse events (AEs), mortality, and laboratory safety measures, including formation of human anti-sheep antibodies (HASA) and their association with AEs.

Results

A total of 70 patients were studied. The mean age was 56 years, 46% were male, and the mean APACHE II score was 26. About 50% of patients had two organ failures (both respiratory and cardiovascular). Multiple doses of AZD9773 reduced circulating TNFα towards the limit of detection in most patients throughout the 5 days of dosing. The most common serious AEs were mainly related to the underlying illness and included: sepsis, pneumonia, septic shock and respiratory failure across all groups. Table 1 summarises the safety outcomes. Development of HASA did not appear to be associated with either decreased TNFα reduction or specific AEs.
Table 1

Safety outcomes with AZD9773 administration

 

Single-dose cohorts combined (n= 17)

Multiple-dose cohorts combined (n= 30)

Placebo (n= 23)

Mortality, n (%)

6 (35%)

7 (23%)

6 (26%)

Any treatment-emergent AEs

17 (100%)

27 (90%)

23 (100%)

Treatment-emergent AEs related to study drug

2 (12%)

7 (23%)

10 (43%)

Patients with any serious AEs

9 (53%)

14 (47%)

13 (57%)

Conclusions

Administration of AZD9773 in patients with severe sepsis reduced circulating TNFα levels and had a safety profile similar to placebo administration. A larger randomised phase IIb clinical trial (NCT01145560) is ongoing to further characterise the safety and efficacy of AZD9773 in patients with severe sepsis.

Authors’ Affiliations

(1)
Wake Forest University School of Medicine, Winston Salem, NC, USA
(2)
Riverside Methodist Hospital, Columbus, OH, USA
(3)
University of Kentucky, Lexington, KY, USA
(4)
AstraZeneca Charnwood, Loughborough, UK
(5)
AstraZeneca, Wilmington, DE, USA
(6)
Vanderbilt University, Nashville, TN, USA

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