Highly automated QT measurement techniques in 7 thorough QT studies implemented under ICH E14 guidelines

  • Couderc J
  • Garnett C
  • Li M
 et al. 
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Abstract

Thorough QT (TQT) studies are designed to evaluate potential effect of a novel drug on the ventricular repolarization process of the heart using QTc prolongation as a surrogate marker for torsades de pointes. The current process to measure the QT intervals from the thousands of electrocardiograms is lengthy and expensive. In this study, we propose a validation of a highly automatic-QT interval measurement (HA-QT) method. We applied a HA-QT method to the data from 7 TQT studies. We investigated both the placebo and baseline-adjusted QTc interval prolongation induced by moxifloxacin (positive control drug) at the time of expected peak concentration. The comparative analysis evaluated the time course of moxifloxacin-induced QTc prolongation in one study as well. The absolute HA-QT data were longer than the FDA-approved QTc data. This trend was not different between ECGs from the moxifloxacin and placebo arms: 9.6 +/- 24 ms on drug and 9.8 +/- 25 ms on placebo. The difference between methods vanished when comparing the placebo-baseline-adjusted QTc prolongation (1.4 +/- 2.8 ms, P = 0.4). The differences in precision between the HA-QT and the FDA-approved measurements were not statistically different from zero: 0.1 +/- 0.1 ms (P = 0.7). Also, the time course of the moxifloxacin-induced QTc prolongation adjusted for placebo was not statistically different between measurements methods.

Author-supplied keywords

  • QT interval
  • drug cardiotoxicity
  • drug safety
  • electrocardiogram
  • moxifloxacin
  • thorough QT study

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Authors

  • Jean Philippe Couderc

  • Christine Garnett

  • Mike Li

  • Robert Handzel

  • Scott McNitt

  • Xiajuan Xia

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