Analysis of the TQT Study Results

The objective of the TQT study is to demonstrate that an NCE does not prolong the QTc interval by more than 5 ms, as evidenced by the upper bound (UB) of the 2-sided 90 % Cl of the placebo-adjusted change-from-baseline QTc (AAQTc) being below 10 ms. 

In crossover-designed TQT studies, the baseline assessment can be made either through time-matched recordings on a full baseline day before each treatment period (time-matched baseline) or through a limited number of recordings (e.g.. 

Initially, the IRT mandated blinding of the positive control, but this requirement was later dropped based on an internal IRT review of TQT smdies presented in 2008 (Garnett et al. 2008) and subsequent discussions in the E14 Implementation Working group [Question 7 in ICH E14 Questions Answers (2012)]. Exceptions exist when the nested crossover moxifloxacin/placebo comparison is used in parallel-designed TQT studies, moxifloxacin has to be blinded to protect the blinding of placebo. 

The difference in sample size is quite striking among smdies published in 2012 (see details in Table 1), ranging from 60 (Graham et al. 2013) to 352 subjects in parallel-designed smdies (Malik et al. 2012) and from 32 subjects for 2 treatment periods [(Taubel et al. 2013) methodology smdy] to 96 subjects for 4 periods (Morganroth et al. 2013) for crossover smdies. 

When calculating the sample size for a TQT smdy, the power of the smdy to exclude a QTc effect above 10 ms, the underlying assumed effect of the NCE (often 3-5 ms), and the variability of QTc are important factors that need to be factored into the equation. Using the same assumptions (90 % power and 3 ms assumed effect), the required sample size varies from approximately 50 subjects with a SD of AQTc of 8 ms to around 100 subjects with a SD of 12 ms, which underlines the importance of tightly controlled experimental conditions and ECG methodologies (Darpo et al. 2011). The variability of the moxifloxacin peak AQTc can be estimated using the width of the 90 % Cl, based on the assumptions that it was 

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