Abstract
Background. This study investigates whether exploitation of circadian variation in heart rate-adjusted QT interval (QTc) is an alternative to the inclusion of a positive control as a method for demonstrating assay sensitivity in a phase 1 clinical trial.Methods. Electrocardiograms (ECGs) from a dose-escalating placebo-controlled phase 1 clinical trial were analyzed. The trial included 63 healthy young males in 7 cohorts; each had 17 ECGs recorded. The 21 subjects receiving placebo were studied: hierarchical linear model analysis was conducted with the measurements across a 43-hour time period nested within subjects. Separate analyses were conducted with QTcBazett, QTcFridericia, QTcFramingham, and a QT-heart rate z score as the dependent variable.Results. Pairwise contrasts between the time points 6 and 10 hours after the administration of the placebo showed a difference of 15.97 ms (CI 9.58-22.37), 8.17 ms (CI 3.47-12.88), 10.77 ms (CI 5.70-15.84), and 0.39 (equivalent to 8 ms CI 0.16-0.62) for QTcBazett...
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