Concentration-QTc (C-QTc) modeling is being increasingly used in phase 1 studies. For studies without a placebo arm (single arm studies), the scientific whitepaper by Garnett et al. ( https://doi.org/10.1007/s10928-017-9558-5 ) states that time-matched baseline adjustments may minimize the effect of diurnal variation in QTc intervals, and categorical time effects are not needed in the model. However, how diurnal variations can be accounted for when only pre-dose baselines are available is unclear. This research investigates whether including categorical time effects in the model can adjust diurnal variation in single arm studies with pre-dose baselines, where QTc prolongation is evaluated at a concentration of interest based on ΔQTc at 24 h and ΔΔQTc (a model-derived difference in ΔQTc from concentration zero). To understand the operating characteristics for the models with and without categorical time effects, simulations were conducted under various scenarios considering oncology early phase studies. When the C-QTc relationship is linear, models without categorical time effects provided biased estimates for model parameters and inflated or decreased false negative rates (FNRs) depending on the pattern of diurnal variations in QTc intervals, whereas models with categorical time effects caused no biases and controlled the FNRs. For non-linear C-QTc relationships, ΔΔQTc estimations made using the model with categorical time effects were not robust. Thus, for single arm studies where only pre-dose baselines are available, we recommend collecting QTc measurements at 24 h and estimating ΔQTc at a concentration of interest at 24 h using the C-QTc model with categorical time effects.
Keywords: Concentration-QTc model; Diurnal variation; ICH E14; Mixed effects model; Single arm study.