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

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

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.

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Correspondence to P Morris.

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Morris, P., Zeno, B., Bernard, A. et al. Safety and tolerability of an ovine-derived polyclonal anti-TNFα Fab fragment (AZD9773) in patients with severe sepsis. Crit Care 15, P263 (2011). https://doi.org/10.1186/cc9683

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Keywords

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