The joint modeling of drug and positive control effects to estimate sample size and power in crossover "thorough" QT/QTc studies.

ABSTRACT

We present analytical results for computing the power and sample size in a thorough QT/QTc study with a four-period crossover design in which the treatments are placebo, positive control, supratherapeutic dose of investigational drug, and therapeutic dose of investigational drug. An assessment of noninferiority of the supratherapeutic dose to placebo is performed by the intersection-union test and assay sensitivity is tested (union-intersection test) at prespecified time points using positive control within the framework of a linear mixed-effects analysis. The power and sample size estimates are obtained using the joint distribution of statistics to test noninferiority of the supratherapeutic dose to placebo and to test assay sensitivity using positive control.