Systematic decrements in QTc between the first and second day of contiguous daily ECG recordings under controlled...

Many thorough QT (TQT) studies use a baseline day and double delta analysis to account for potential diurnal variation in QTc. However, little is known about systematic changes in the QTc across contiguous days when normal volunteers are brought into a controlled inpatient environment.

Two separate crossover TQT studies included 2 days of no treatment lead-in days with ECG collection preceding periods of drug treatment . In the first study, there were two pairs of such contiguous days with 10 replicate electrocardiograms (ECGs) collected at six time points, and in the second study, there were four pairs of contiguous days with nine replicate ECGs collected at five time points. These lead-in day pairs provided the opportunity to evaluate any systematic changes across contiguous first and second days of an inpatient environment. Within-patient consistency of change across pairs of days as well as within day, diurnal variation could also be evaluated.

Modest (4.2 ms [range 1.9-6.5 ms]) but consistent decreases (significant [P < 0.05] for all 32 comparisons) were observed (probability: ≤5.4 × 10(-16)). Although group behavior with respect to QTc was consistent, individual subjects demonstrated substantial variability across pairs of days. Evidence of diurnal variation was weak and inconsistent. Magnitude of any diurnal variation was less than magnitude of change across days.

Subjects show a systematic decrease in QTc from first day to second day of inpatient status and do not demonstrate a significant diurnal pattern. The magnitude of this systematic change is sufficient to influence QTc study interpretation.