Choice of baseline in a multiple-dose thorough QT study (TQTS) – effect on analysis of moxifloxacin-induced QTc prolongation

Abstract

Background:

The primary endpoint of a thorough QT study (TQTS) is the change from baseline in QT corrected (QTc) measured on electrocardiograms (ECG) tracings. It has been suggested that during a crossover study, the time-matched or predose baseline could be recorded. The choice of method for baseline ECG collection may influence the results and the cost of the TQTS.

Objective:

The objective of our study was to compare the collection of a time-matched baseline before each period (TM_EACH), an average of all the time-matched baseline (TM_MEAN), a time-matched baseline before period 1 (TM_P1) and a predose baseline (PD_EACH) on QT interval prolongation induced by moxifloxacin, in a 30 subjects, 5 arm cross-over TQTS.

Results:

Moxifloxacin induced a similar significant increase in QT corrected using Fridericia’s formula (QTc) (lower limit of the confidence interval excluded 5 ms) at all time-points between 0.5 hours and 12 hours with all baseline methods. TM_EACH was associated with a lower within subject variability (SD 5.59 ms) than TM_MEAN and TM_P1 (5.90 and 6.90 ms, respectively). PD_EACH was associated with the highest variability (7.41 ms).

Conclusion:

The collection of ECG tracings during a full baseline day before each period was associated with the lowest variability. However, the two more cost effective designs (TM_P1 and PD_EACH) were sufficient, in this small TQTS, to significantly detect moxifloxacin.

Keywords::

• thorough QT study
• QT correction
• baseline
• design
• superimposed representative complex
• moxifloxacin