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Highly Automated QT Measurement Techniques in 7 Thorough QT Studies Implemented under ICH E14 Guidelines

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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.

Ann Noninvasive Electrocardiol 2011;16(1):13–24
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Keywords: QT interval; drug cardiotoxicity; drug safety; electrocardiogram; moxifloxacin; thorough QT study

Document Type: Research Article

Affiliations: 1: Heart Research Follow-up Program, Cardiology Department, University of Rochester Medical Center, Rochester, NY 2: Division of Cardiovascular and Renal Products, Office of New Drugs, Center for Drug Evaluation and Research, FDA, Silver Spring, MD 3: School of Biomedical Engineering, University of Rochester, NY

Publication date: January 1, 2011

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