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Effect of Number of Replicate Electrocardiograms Recorded at Each Time Point in a Thorough QT Study on Sample Size and Study Cost
Author(s) -
Natekar Mili,
Hingorani Pooja,
Gupta Pallavi,
Karnad Dilip R.,
Kothari Snehal,
Vries Michiel,
ZumBrunnen Troy,
Narula Dhiraj
Publication year - 2011
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270010376962
Subject(s) - replicate , moxifloxacin , sample size determination , medicine , placebo , time point , crossover study , qt interval , statistics , repeated measures design , confidence interval , cardiology , mathematics , biology , philosophy , alternative medicine , aesthetics , pathology , microbiology and biotechnology , antibiotics
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.