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.
Drug Saf. 2013 Jun;36(6):441-53. doi: 10.1007/s40264-013-0040-z.
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.
This study characterized the assumptions and implications of different baseline correction approaches in parallel TQT studies submitted for regulatory review.
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.
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.
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.
在平行的全面 QT（TQT）研究中，人们推测，基线校正要么应该省略，因为它只会给数据增加噪声，要么应该考虑时间平均基线而不是时间匹配的基线校正，以减少研究的变异性。
本研究描述了在提交给监管部门审查的平行 TQT 研究中，不同基线校正方法的假设和影响。
评估了 2002 年至 2009 年间在 5591 名健康志愿者中进行的 57 项平行 TQT 研究。仅考虑莫西沙星和安慰剂组，包括它们的基线。检查并比较了不使用基线校正、时间平均基线校正和时间匹配基线校正的选项。
QTc 值呈现出昼夜节律模式，用时间平均基线校正时，睡眠期间的 QTc 间隔较长。给药后和基线 QTc 值高度相关（安慰剂组和莫西沙星组的平均 ρ 值分别为 0.80（范围 0.56-0.98）和 0.79（范围 0.50-0.96））。原始 QTc 值的变异性明显大于基线调整后的 QTc 值。莫西沙星和安慰剂之间的 QTc 差异的点估计值在时间平均和时间匹配的基线校正之间最大差异可达±4ms。统计检验表明，时间平均基线和无基线校正的假设是不合适的。
在平行 TQT 研究中，基线校正可导致更精确的 QTc 估计。由于时间平均基线校正可能引入的不准确性，时间匹配的基线校正似乎更适合平行 TQT 研究，以减少由于昼夜节律模式引起的固有变异性，并获得更准确的点估计。
