title: Timing of pre-dose baseline electrocardiograms in clinical trials: increased sampling over a prolonged baseline period worsens variance of QTc.
abstract: OBJECTIVE
  The US Food and Drug Administration (US FDA) currently recommends recording of electrocardiograms (ECGs) prior to drug administration in thorough QT studies over an hour or more time to improve reliability of baseline ECG values. However, the baseline period is usually in the morning during a period of intense trial activity and rapid circadian change in QTc. The purpose of this study was to determine if the practice of recording an extended baseline does, in fact, decrease QTc variance at baseline.
  
  
  METHODS
  ECG data from three thorough QT studies (TQTS) in which three ECGs (commonly referred to as triplicates) were recorded at each of three pre-specified time points during the 60 to 90 minutes before drug administration were analyzed by determining the intra-subject and inter-subject standard deviation (SD) of QTcF (Fridericia-correct QT) for each of the three pre-drug time points and for the three time points combined.
  
  
  RESULTS
  QTcF was relatively normally distributed in each study. Intra-subject variability of QTcF was greater for the combined triplicate recordings than for the individual triplicates at baseline treatment time points in 39 of 42 cases (93%). This was the case in 48% of the comparisons in the inter-subject analysis.
  
  
  CONCLUSIONS
  The practice of recording three sets of triplicate ECGs over an hour or more before drug administration in a TQTS increases variability of baseline QTcF consistently in cross-over designed trials, and in roughly half of parallel comparisons. Higher variability suggests that the three-triplicate approach does not provide a more reliable baseline value. Less variability of QTcF can be obtained by simply recording one triplicate prior to drug administration. This principal may apply to other ECG and other physiological variables that have a monotonic circadian trend or that may be affected by intense trial activity during the pre-drug hour.
authors: University of Utah, Salt Lake City, UT, USA. Electronic address: Jmason12@charter.net.
authors: Jay W
authors: JW
authors: Mason
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology*; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D015507:Drugs, Investigational / Q000008:administration & dosage*; D004562:Electrocardiography / Q000379:methods*; D024841:Fluoroquinolones / Q000008:administration & dosage*; D064368:Healthy Volunteers; D006801:Humans; D008875:Middle Aged; D000077266:Moxifloxacin; D010919:Placebos; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D015507:Drugs, Investigational; D024841:Fluoroquinolones; D010919:Placebos; D000077266:Moxifloxacin
keywords: Clinical trial; Electrocardiogram; Standard deviation; Thorough QT study