Jean T Barbey1, Margaret Connolly2, Brenda Beaty3, Mori J Krantz4,5. 1. Social & Scientific Systems, Inc, Silver Spring, MD. 2. PAREXEL International Corp, Waltham, MA. 3. University of Colorado, Aurora, Colorado. 4. Denver Health and Hospitals, Denver, CO. 5. CPC Clinical Research, Aurora, CO.
Abstract
BACKGROUND:Electrocardiographic (ECG) safety evaluation is a required element of drug development. Performance characteristics of ECG measurement methodologies have rarely been studied prospectively. METHODS: We conducted a randomized, placebo-controlled, crossover study in 24 subjects to evaluate effects of moxifloxacin on the Fridericia rate-corrected QT (QTcF) interval. Five ECG replicates were obtained at 30 time points. Change from baseline QTcF (ΔQTcF) was fit by mixed-model analysis of variance to evaluate residual standard deviation. Precision was defined as intrasubject QTcF variance. Two core lab approaches were compared: QTinno, fully automated, 5 replicates and HeartSignals, computer-assisted manual, 3 replicates. Core lab values were then compared to an automated commercial algorithm (VERITAS). RESULTS: Twenty-three subjects provided 3450 ECGs potentially available for analysis. QTinnoQTcF values were based upon 3419 ECGs, HeartSignals data on 2028 ECGs. Variance was similar between the QTinno and HeartSignals approaches (41.5 and 44 ms(2)). After excluding VERITAS QTcF measurements that deviated by >40 ms on visual review, variance in a set of 1907 common ECGs was lowest for HeartSignal, followed by QTinno and VERITAS (43.8, 52.6, 89.4 ms(2)) P = 0.02 HeartSignals versus QTinno, P < 0.0001 for both HeartSignals and QTinno versus VERITAS. CONCLUSIONS: A fully automated core lab approach using 5 replicates and a computer-assisted manual approach using 3 replicates were equally precise. When an identical number of ECGs were compared, the computer-assisted manual method was most precise, while the commercial algorithm was relatively imprecise. Although suitable for clinical assessment the standard commercial algorithm cannot be recommended for regulated safety research.
RCT Entities:
BACKGROUND: Electrocardiographic (ECG) safety evaluation is a required element of drug development. Performance characteristics of ECG measurement methodologies have rarely been studied prospectively. METHODS: We conducted a randomized, placebo-controlled, crossover study in 24 subjects to evaluate effects of moxifloxacin on the Fridericia rate-corrected QT (QTcF) interval. Five ECG replicates were obtained at 30 time points. Change from baseline QTcF (ΔQTcF) was fit by mixed-model analysis of variance to evaluate residual standard deviation. Precision was defined as intrasubject QTcF variance. Two core lab approaches were compared: QTinno, fully automated, 5 replicates and HeartSignals, computer-assisted manual, 3 replicates. Core lab values were then compared to an automated commercial algorithm (VERITAS). RESULTS: Twenty-three subjects provided 3450 ECGs potentially available for analysis. QTinno QTcF values were based upon 3419 ECGs, HeartSignals data on 2028 ECGs. Variance was similar between the QTinno and HeartSignals approaches (41.5 and 44 ms(2)). After excluding VERITAS QTcF measurements that deviated by >40 ms on visual review, variance in a set of 1907 common ECGs was lowest for HeartSignal, followed by QTinno and VERITAS (43.8, 52.6, 89.4 ms(2)) P = 0.02 HeartSignals versus QTinno, P < 0.0001 for both HeartSignals and QTinno versus VERITAS. CONCLUSIONS: A fully automated core lab approach using 5 replicates and a computer-assisted manual approach using 3 replicates were equally precise. When an identical number of ECGs were compared, the computer-assisted manual method was most precise, while the commercial algorithm was relatively imprecise. Although suitable for clinical assessment the standard commercial algorithm cannot be recommended for regulated safety research.
Authors: Pentti M Rautaharju; Borys Surawicz; Leonard S Gettes; James J Bailey; Rory Childers; Barbara J Deal; Anton Gorgels; E William Hancock; Mark Josephson; Paul Kligfield; Jan A Kors; Peter Macfarlane; Jay W Mason; David M Mirvis; Peter Okin; Olle Pahlm; Gerard van Herpen; Galen S Wagner; Hein Wellens Journal: Circulation Date: 2009-02-19 Impact factor: 29.690
Authors: Katerina Hnatkova; Peter Smetana; Ondrej Toman; Axel Bauer; Georg Schmidt; Marek Malik Journal: Pacing Clin Electrophysiol Date: 2009-01 Impact factor: 1.976