An efficient analysis of covariance model for crossover thorough QT studies with period-specific pre-dose baselines.

Baseline adjustment is an important consideration in thorough QT studies for non-antiarrhythmic drugs. For crossover studies with period-specific pre-dose baselines, we propose a by-time-point analysis of covariance model with change from pre-dose baseline as response, treatment as a fixed effect, pre-dose baseline for current treatment and pre-dose baseline averaged across treatments as covariates, and subject as a random effect. Additional factors such as period and sex should be included in the model as appropriate. Multiple pre-dose measurements can be averaged to obtain a pre-dose-averaged baseline and used in the model. We provide conditions under which the proposed model is more efficient than other models. We demonstrate the efficiency and robustness of the proposed model both analytically and through simulation studies. The advantage of the proposed model is also illustrated using the data from a real clinical trial.