title: 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.
authors.affiliation: Quintiles Cardiac Safety Services, Research Section, 502A, Leela Business Park, M.V Road, Andheri East, Mumbai, India.
authors.forename: Mili
authors.initials: M
authors.lastname: Natekar
authors.forename: Pooja
authors.initials: P
authors.lastname: Hingorani
authors.forename: Pallavi
authors.initials: P
authors.lastname: Gupta
authors.forename: Dilip R
authors.initials: DR
authors.lastname: Karnad
authors.forename: Snehal
authors.initials: S
authors.lastname: Kothari
authors.forename: Michiel
authors.initials: M
authors.lastname: de Vries
authors.forename: Troy
authors.initials: T
authors.lastname: Zumbrunnen
authors.forename: Dhiraj
authors.initials: D
authors.lastname: Narula
mesh_terms: D000328:Adult; D001372:Aza Compounds / Q000009:adverse effects*; D003362:Cost-Benefit Analysis; D004562:Electrocardiography / Q000187:drug effects / Q000191:economics* / Q000706:statistics & numerical data*; D005260:Female; D024841:Fluoroquinolones; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D011804:Quinolines / Q000009:adverse effects*; D018401:Sample Size; D023382:Toxicity Tests, Acute / Q000191:economics* / Q000379:methods
chemical_list: D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D000077266:Moxifloxacin