title: Baseline correction in parallel thorough QT studies.
abstract: BACKGROUND
  In parallel thorough QT (TQT) studies, it has been speculated that either baseline correction should be omitted, under the assumption that it only adds noise to the data, or a time-averaged baseline instead of a time-matched baseline correction should be considered in order to reduce the study variability.
  
  
  OBJECTIVE
  This study characterized the assumptions and implications of different baseline correction approaches in parallel TQT studies submitted for regulatory review.
  
  
  METHODS
  57 parallel TQT studies conducted between 2002 and 2009 in 5591 healthy volunteers were evaluated. Only moxifloxacin and placebo arms, including their baselines, were considered. The options of using no baseline correction, time-averaged baseline correction, and time-matched baseline correction were examined and compared.
  
  
  RESULTS
  QTc values exhibited a diurnal pattern, with longer QTc intervals during sleep preserved when correcting for a time-averaged baseline. Post-dose and baseline QTc values were highly correlated (mean ρ = 0.80, range 0.56-0.98 and mean ρ = 0.79, range 0.50-0.96 in the placebo and moxifloxacin groups, respectively). The variability of raw QTc values was substantially larger than that of baseline-adjusted QTc values. The difference in the point estimate of QTc differences between moxifloxacin and placebo differed by up to ± 4 ms between the time-averaged and the time-matched baseline corrections. Statistical tests indicate that assumptions of time-averaged baseline and no baseline correction are not appropriate.
  
  
  CONCLUSIONS
  Baseline correction in parallel TQT studies leads to more precise QTc estimates. Because of possible inaccuracy introduced by time-averaged baseline correction, the time-matched baseline correction appears to be preferable for a parallel TQT study to both reduce the intrinsic variability due to circadian patterns and obtain more accurate point estimates.
authors.affiliation: Division of Biometrics VI, Office of Biostatistics, Center of Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Bldg. #21 Room 4668, Silver Spring, MD 20993-0002, USA. Joanne.Zhang@fda.hhs.gov
authors.forename: Joanne
authors.initials: J
authors.lastname: Zhang
authors.forename: Qianyu
authors.initials: Q
authors.lastname: Dang
authors.forename: Marek
authors.initials: M
authors.lastname: Malik
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D001372:Aza Compounds / Q000009:adverse effects*; D054715:Cardiotoxins / Q000009:adverse effects; D002317:Cardiovascular Agents / Q000009:adverse effects*; D002940:Circadian Rhythm / Q000187:drug effects*; D003627:Data Interpretation, Statistical; D015716:Electrocardiography, Ambulatory / Q000187:drug effects*; D005260:Female; D024841:Fluoroquinolones; D006334:Heart Function Tests; D006801:Humans; D017387:Investigational New Drug Application; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D011804:Quinolines / Q000009:adverse effects*; D016032:Randomized Controlled Trials as Topic; D014481:United States; D014486:United States Food and Drug Administration; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D001372:Aza Compounds; D054715:Cardiotoxins; D002317:Cardiovascular Agents; D024841:Fluoroquinolones; D011804:Quinolines; D000077266:Moxifloxacin