Novel concentration-QTc models for early clinical studies with parallel placebo controls: A simulation study.

The QTc interval of the electrocardiogram is a pharmacodynamic biomarker for drug-induced cardiac toxicity. The ICH E14 guideline Questions and Answers offer a solution for evaluating a concentration-QTc relationship in early clinical studies as an alternative to conducting a thorough QT/QTc study. We focused on covariance structures of QTc intervals on the baseline day and dosing day (two-day covariance structure,) and proposed a two-day QTc model to analyze a concentration-QTc relationship for placebo-controlled parallel phase 1 single ascending dose studies. The proposed two-day QTc model is based on a constrained longitudinal data analysis model and a mixed effects model, thus allowing various variance components to capture the two-day covariance structure. We also propose a one-day QTc model for the situation where no baseline day or only a pre-dose baseline is available and models for multiple ascending dose studies where concentration and QTc intervals are available over multiple days. A simulation study shows that the proposed models control the false negative rate for positive drugs and have both higher accuracy and power for negative drugs than existing models in a variety of settings for the two-day covariance structure. The proposed models will promote early and accurate evaluation of the cardiac safety of new drugs.