Key result
Using ECG replicates reduces required sample size only when replicate correlation is near zero.
Why the study?
The impact of ECG recording replicates on power and sample size calculation for routine QT studies under parallel-group and crossover designs was not well characterized.
Provides statistical formulas and an approach to optimize the allocation between the number of subjects and ECG replicates per subject to maximize power or minimize cost in QT studies.
May inform QT study design by optimizing subject-replicate allocation when correlations are low; extends methodology but leaves open prospective validation.
The problem of the impact on power and sample size calculation for routine QT studies with ECG recording replicates under a parallel-group design and a crossover design is examined. Replicate ECGs are defined as single ECG recorded within several minutes of a nominal time (PhRMA, 2003 PhRMA ( 2003 ). Investigating drug-induced QT and QTc prolongation in the clinic: Statistical design and analysis considerations. Report from the Pharmaceutical Research and Manufacturers of America QT Statistics Expert Team, August 14, 2003 . [Google Scholar]). Formulas for sample size calculations with and without adjustment for covariates such as some pharmacokinetic responses (e.g., AUC or Cmax), which are known to be correlated to the QT intervals, were derived under both the parallel-group design and the crossover design. The results indicate that the approach of replicates may require a smaller sample size for achieving the same power when the correlation coefficient between the recording replicates (or repeated measures) is close to 0 (i.e., these replicate ECGs are almost independent). On the other hand, if the correlation coefficient is close to 1, then there is not much gain regardless of whether replicate ECGs are considered. In this paper, an approach to identifying optimal allocation between the number of subjects and the number of replicates per subject is proposed for achieving the maximum power under a fixed budget constraint. The proposed approach can also be applied to minimize the cost for a given power.
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Chow et al. (2008) studied Drug-induced QT and QTc prolongation. ECG recording replicates vs. No replicates was evaluated on Power and sample size. Using ECG recording replicates can reduce the required sample size for achieving the same power when the correlation coefficient between replicates is close to 0, but offers little gain if close to 1.
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