Sample Size and Power Estimation in Thorough QT/QTc Studies with Parallel Group Design

Abstract

We developed analytical results for computing the power in a thorough QT/QTc study with a four-group parallel design in which the treatments are placebo, positive control, supratherapeutic dose of investigational drug, and therapeutic dose of investigational drug. An assessment of non-inferiority of the supratherapeutic dose to placebo is performed by the intersection–union test within the framework of a linear mixed effects analysis with baseline covariate. The power estimates obtained using analytical results and from the simulation study were presented and they are quite close and hence the analytical results could be used for computing power and sample size in the planning stage of a thorough QT/QTc study.

Key Words:

• Linear mixed model
• Parallel group designs
• Power and sample size

ACKNOWLEDGMENT

We thank the reviewers for suggestions on the earlier version of this paper.

Notes

∗Estimate of probability of getting claim of non-inferiority to placebo for drug with peak effect of 4 ms.

#The boundary for non-inferiority to placebo.

Note. For 5 times of measurement, assumed effects of the drug are 3, 4, 4, 3, and 2 ms. For 10 times of measurement, the drug effects were assumed to be 1, 2, 3, 3, 4, 4, 3, 3, 2, and 1 ms. For 15 times of measurement, the drug effects were assumed to be 1, 2, 2, 3, 3, 4, 4, 4, 3, 3, 2, 2, 2, 2, and 1 ms.

∗Estimate of probability of getting claim of non-inferiority to placebo for drug with peak effect of 4 ms.

#The boundary for non-inferiority to placebo.

Note. For 5 times of measurement, assumed effects of the drug are 3, 4, 4, 3, and 2 ms. For 10 times of measurement, the drug effects were assumed to be 1, 2, 3, 3, 4, 4, 3, 3, 2, and 1 ms. For 15 times of measurement, the drug effects were assumed to be 1, 2, 2, 3, 3, 4, 4, 4, 3, 3, 2, 2, 2, 2, and 1 ms.