Effect of Number of Replicate Electrocardiograms Recorded at Each Time Point in a Thorough QT Study on Sample Size and Study Cost

Abstract

In a "thorough QT/QTc" (TQT) study, several replicate electrocardiograms (ECGs) are recorded at each time point to reduce within-subject variability. This decreases the sample size but increases the cost of ECG analysis. To determine the most cost-effective number of ECG replicates, the authors retrospectively analyzed data from the placebo and moxifloxacin arms of a TQT study with crossover design. Six replicate ECGs were recorded at 7 time points on day -1 (baseline day), day 1, and day 3 in 124 normal healthy volunteers who were randomized to receive moxifloxacin or placebo on day 1 and the other treatment on day 3. QT interval was corrected for heart rate by the Fridericia (QTcF) and individual subject-specific (QTcI) formulas. Within-subject and between-subject standard deviations for QTcF obtained by repeated-measures analysis of covariance were 9.5 and 13.3 milliseconds with 1 replicate; 7.8 and 12.7 milliseconds with 2 replicates; 7.3 and 12.3 milliseconds with 3 replicates; 6.9 and 12.2 milliseconds with 4 replicates; 6.8 and 11.9 milliseconds with 5 replicates; and 6.6 and 11.8 milliseconds with 6 replicates. Within- and between-subject variance with QTcI also declined with increasing replicates. Sample size benefit based on these estimates was negligible beyond 4 replicates. The study cost was least with 3 or 4 replicates, depending on per-ECG and per-subject costs.

A thorough QT study to evaluate the QTc prolongation potential of two neuropsychiatric drugs, quetiapine and escitalopram, in healthy volunteers

“…The previous study calculated that the sample size in a TQT study with a four-period crossover design required 33-64 persons (Natekar et al, 2011). The previous study calculated that the sample size in a TQT study with a four-period crossover design required 33-64 persons (Natekar et al, 2011).…”

The sodium glucose cotransporter 2 inhibitor empagliflozin does not prolong QT interval in a thorough QT (TQT) study

“…Plasma concentrations of both empagliflozin and moxifloxacin were expected to reach peak levels within this three-hour window [10,25], ensuring the most relevant levels of drug exposure. Use of pre-dose period baseline ECGs has been shown to be the least variable method of baseline correction [30], and three triplicate ECG recordings were used in order to reduce the baseline variance further [31]. …”

Fast, accurate and easy-to-teach QT interval assessment: The triplicate concatenation method

“…Three main sources of variability of QT assessment have been identified: inter-reader variability, intra-reader variability and intrinsic beat-to-beat QT variability. Triplicate ECGs and median beat were introduced to reduce the intrinsic beat-tobeat variability [16,17] and ECG signal to noise ratio [18]. Finally, semi-automated computerassisted methods using the generation of a superimposed median beat have shown good reproducibility in terms of intra and inter-reader variability [19].…”