Volume 15 Supplement 1

31st International Symposium on Intensive Care and Emergency Medicine

Open Access

Evaluation of eritoran tetrasodium (E5564), a TLR4 antagonist, on the QTc interval in healthy subjects

  • CF Nagy1,
  • M Lynn1 and
  • J Gogate1
Critical Care201115(Suppl 1):P264

https://doi.org/10.1186/cc9684

Published: 1 March 2011

Introduction

Eritoran tetrasodium (E), a TLR4 antagonist, is currently being evaluated in phase 3 as a treatment for severe sepsis and has been well tolerated in clinical trials [1]. The primary objective of this study was to evaluate the effect of E on QTc in healthy subjects.

Methods

This was a single 12-hour intravenous infusion, double-blind, placebo-comparator and active-comparator controlled, parallel-groupstudy. Subjects were randomized to: Arm A, E 2.3 mg/hour (a therapeutic(T) total dose of 28 mg); Arm B, E 7 mg/hour (a supratherapeutic (S) total dose of 84 mg); Arm C, placebo; or Arm D, placebo + moxifloxacin(M) 400 mg p.o. The primary outcome parameter was the placebo-corrected change from baseline in QTcF (ΔΔQTcF) based on the largest time-matched mean difference 10, 12, 14, 16, 18, 24, 36, and 48 hours after the start of infusion. Categorical and pharmacokinetic (PK)/pharmacodynamic (PD) evaluations were performed. Adverse events were reported.

Results

Two hundred subjects (mean age 33.4 years; 81.5% male) were randomized. In the M group, the increase in QTcF from baseline (ΔQTcF) consistently exceeded placebo (maximum ΔΔQTcF 11.4 ms at 4 hours postdose). The lower bound of the one-sided 95% confidence limit was >5 ms at each time point between 2 and 8 hours postdose, indicating the study's sensitivity to demonstrate small QTc effects. The largest mean ΔΔQTcF for E was 2.1 ms (84 mg, 12 hours) and 1.6 ms (28 mg, 48 hours). The upper limit of the two-sided 90% CI (one-sided 95% CI) for the mean difference did not exceed 4.6 ms and all 90% CIs were inclusive of zero. No subject in either E group had a ΔQTcF exceeding 30 ms and only one subject in the E 84 mg group had a single QTcF >450 ms at 16 hours. QTcB, QTci, categorical, and PK/PD results all confirmed those from the primary analysis. There was no obvious correlation between QTcF and plasma E concentration. E 28 mg or 84 mg was safe and well tolerated, with mild headache most frequently reported in the placebo (9.6%) and E 28 mg (8.7%) groups, injection site hemorrhage in the E 84 mg group (6.1%), and nausea in the M group (3.8%).

Conclusions

At either a T or S dose of E, a QTc effect exceeding 5 ms could be excluded. The upper bound of the 95% one-sided CI for ΔΔQTcF was <10 ms at both the S and T doses of E, indicating this is a negative thorough QT/QTc study.

Authors’ Affiliations

(1)
Eisai, Inc

References

  1. ACCESS: A Controlled Comparison of Eritoran Tetrasodium and Placebo in Patients with Severe Sepsis.[http://clinicaltrials.gov/ct2/show/NCT00334828?term=eritoran&rank=2]

Copyright

© Nagy et al. 2011

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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