A Simulation Study of Power in Thorough QT/QTc Studies and a Normal Approximation for Planning Purposes

Abstract

We report the results of a simulation study on power in a thorough QT/QTc study with a four-period crossover design in which the treatments are placebo, positive control, higher dose of investigational drug, and therapeutic dose of investigational drug. In the study, QTc interval values were obtained for several specified times during treatment. An assessment of noninferiority of the higher dose to placebo was performed by the intersection-union test within the framework of a linear mixed-effects analysis. With a noninferiority bound of 8 ms and a peak drug effect of 4 ms, it is found that 96 or more subjects would be required to have 80% power, but with a noninferiority bound of 10 ms, 48 subjects give more than an estimated 80% power if the number of times of measurement is 10 or fewer. For the purposes of planning such a study, a power approximation based on the multivariate normal distribution of the estimator of the difference in means of high dose of investigational drug and placebo is presented. The approximated power and the power estimate from the simulation study were quite close.