title: Systematic decrements in QTc between the first and second day of contiguous daily ECG recordings under controlled conditions.
abstract: BACKGROUND
  Many thorough QT (TQT) studies use a baseline day and double delta analysis to account for potential diurnal variation in QTc. However, little is known about systematic changes in the QTc across contiguous days when normal volunteers are brought into a controlled inpatient environment.
  
  
  METHODS
  Two separate crossover TQT studies included 2 days of no treatment lead-in days with ECG collection preceding periods of drug treatment . In the first study, there were two pairs of such contiguous days with 10 replicate electrocardiograms (ECGs) collected at six time points, and in the second study, there were four pairs of contiguous days with nine replicate ECGs collected at five time points. These lead-in day pairs provided the opportunity to evaluate any systematic changes across contiguous first and second days of an inpatient environment. Within-patient consistency of change across pairs of days as well as within day, diurnal variation could also be evaluated.
  
  
  RESULTS
  Modest (4.2 ms [range 1.9-6.5 ms]) but consistent decreases (significant [P < 0.05] for all 32 comparisons) were observed (probability: ≤5.4 × 10(-16)). Although group behavior with respect to QTc was consistent, individual subjects demonstrated substantial variability across pairs of days. Evidence of diurnal variation was weak and inconsistent. Magnitude of any diurnal variation was less than magnitude of change across days.
  
  
  CONCLUSIONS
  Subjects show a systematic decrease in QTc from first day to second day of inpatient status and do not demonstrate a significant diurnal pattern. The magnitude of this systematic change is sufficient to influence QTc study interpretation.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. cmbeasleyj@lilly.com
authors.forename: Charles M
authors.initials: CM
authors.lastname: Beasley
authors.forename: Charles
authors.initials: C
authors.lastname: Benson
authors.forename: Jessie Q
authors.initials: JQ
authors.lastname: Xia
authors.forename: S Stanley
authors.initials: SS
authors.lastname: Young
authors.forename: Harry
authors.initials: H
authors.lastname: Haber
authors.forename: Malcolm I
authors.initials: MI
authors.lastname: Mitchell
authors.forename: Corina
authors.initials: C
authors.lastname: Loghin
mesh_terms: D000293:Adolescent; D000328:Adult; D002940:Circadian Rhythm / Q000502:physiology*; D004562:Electrocardiography / Q000379:methods*; D006321:Heart / Q000502:physiology*; D006339:Heart Rate / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015203:Reproducibility of Results; D055815:Young Adult