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Quantitative Analysis of T-wave Morphology Increases Confidence in Drug-Induced Cardiac Repolarization Abnormalities: Evidence From the Investigational I_Kr Inhibitor Lu 35-138

From the Center for Sensory Motor Interaction (SMI), Department of Health Science and Technology, Aalborg University, Aalborg, Denmark (Mr Graff, Mr Andersen, Dr Toft, Mr Hardahl, Dr Struijk); H. Lundbeck A/S, Copenhagen, Denmark (Dr Matz, Ms Christensen); Department of Cardiology P, Gentofte University Hospital, Gentofte, Denmark (Dr Kanters); Danish National Research Foundation, Centre for Cardiac Arrhythmia (DARC), Laboratory of Experimental Cardiology, University of Copenhagen, Copenhagen, Denmark (Dr Kanters); Department of Cardiology S, Aalborg Hospital, Aarhus University Hospitals, Aalborg, Denmark (Dr Kanters, Dr Toft); Department of Cardiology B, Rigshospitalet, Copenhagen, Denmark (Dr Pehrson); and Unit for Psychiatric Research, Aalborg Psychiatric Hospital, Aarhus University Hospitals, Aalborg, Denmark (Dr Nielsen).

This study investigates repolarization changes induced by a new candidate drug to determine whether a composite electrocardiographic (ECG) measure of T-wave morphology could be used as a reliable marker to support the evidence of abnormal repolarization, which is indicated by QT interval prolongation. Seventy-nine healthy subjects were included in this parallel study. After a baseline day during which no drug was given, 40 subjects received an I_Kr-blocking antipsychotic compound (Lu 35-138) on 7 consecutive days while 39 subjects received placebo. Resting ECGs were recorded and used to determine a combined measure of repolarization morphology (morphology combination score [MCS]), based on asymmetry, flatness, and notching. Replicate measurements were used to determine reliable change and study power for both measures. Lu 35-138 increased the QTc interval with corresponding changes in T-wave morphology as determined by MCS. For subjects taking Lu 35-138, T-wave morphology was a more reliable indicator of I_Kr inhibition than QTcF (² = 20.3, P = .001). At 80% study power for identifying a 5-millisecond placebo-adjusted change from baseline for QTcF, the corresponding study power for MCS was 93%. As a covariate to the assessment of QT interval liability, MCS offered important additive information to the effect of Lu 35-138 on cardiac repolarization.

Key Words: T-wave morphology • QT interval • drugs • ECG • repolarization

Address for reprints: Claus Graff, MSc, SMI, Aalborg University, Fredrik Bajers Vej 7 E1-209, 9220 Aalborg, Denmark; e-mail: cgraff{at}hst.aau.dk.

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