P23 Sample Size Determination for Cardiodynamic ECG Assessment Using the Concentration-QTc Analysis Method

Concentration-QTc (C-QTc) analysis was accepted to serve as an alternative to the by-time point analysis with intersection-union test (IUT) as the primary basis for decisions to classify the risk of a drug by E14 Q&As (R3) in December 2015. Since then, this analysis method has been widely applied by the industry, since it significantly reduces the sample size to achieve the same power as with IUT. It has the advantage of using the PK-ECG pair data from subjects across all dose levels and time points for the evaluation, while IUT is evaluated by dose and time point, separately. There is still no standard method to determine the sample size for C-QTc analysis to exclude a small effect on the QTc interval. Clario has developed a simple method to determine the sample size for different study designs using the C-QTc analysis and applied it to hundreds of studies.

At a 1-sided 5% significance level, an underlying effect of the study drug (or true mean difference in change-from-baseline QTcF [ΔQTcF] between the study drug and placebo) of 3 msec, a standard deviation (SD) of the ΔQTcF of 8 msec for both the study drug and placebo treatment groups, and the correlation (ρ) between ΔQTcF (study drug) and ΔQTcF (placebo) of zero are assumed. To achieve 90% power to exclude that the study drug causes ≥ 10 msec QTc effect at clinically relevant plasma levels, as shown by the upper bound of the 2-sided 90% confidence interval (CI) of the model-estimated QTc effect (placebo-corrected change-from-baseline QTcF: ∆∆QTcF) at the observed geometric mean Cmax of the study drug, a sample size of at least 24 evaluable subjects with continuous ECG data from all treatment periods is required for a crossover study. Considering a dropout rate of 15%-20%, a total of 28-30 subjects should be enrolled. This power is estimated using a paired-sample t-test at one time point. By using a highly precise ECG method, such as Early Precision QT Analysis (EPQT) at Clario, the SD of ΔQTc will be substantially lower and the sample size can be further reduced with maintained power.

Applying similar assumptions to a parallel study with nested crossover design or to a parallel TQT study, a sample size of 24 evaluable subjects per group will provide 91% power. For a standard single ascending dose (SAD) study, a sample size of 64 evaluable subjects (48 taking the study drug and 16 taking placebo) will provide 91% power. These powers are estimated using a two-sample t-test at one time point.

This calculation is conservative, since it does not take into account any gain in precision due to the use of all data from each subject across all time points in the linear mixed-effects model.

Clinical Trial Design (e.g., Innovative/Complex Design, Estimands, Master Protocol)

ASA Biopharmaceutical Section Regulatory-Industry Statistics Workshop 2024