The ECG effects of moxifloxacin in thorough QT trials: Updated systematic review.

L Ashkir1, T Morris2, Y Loke1, A Ring2,3. 1University of East Anglia, Norwich, UK, 2University of Leicester, Leicester, UK, 3University of Ulm, Ulm, Germany

Background:

An uncommon side effect on of an increasing number of non-cardiovascular drugs is a delay in ventricular repolarization leading to a prolonged QT (QTc) interval that has the potential to induce fatal tachyarrythmias. As a result, the ‘International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use’ created a guideline (ICH E14) outlining strategies to investigate these effects. A key component of this guideline is the ‘thorough QT/QTc study’ (TQT), which utilises a positive control.

Aims:

Since the commencement of the guideline in 2005, moxifloxacin has been widely accepted as the ideal positive control. However, previous TQT trials looking primarily at the QT effects of moxifloxacin have shown a significant variability in the prolongation of the QT interval. This uncertainty may prove challenging when planning future TQT trials. Hence, we aimed to update a systematic review that had previously been presented in August 2013 [1]. Our main focus was on factors associated with variability including the role of study design, study population and baseline characteristics.

Methods: We systematically reviewed all publications retrieved through a SCOPUS search of abstracts in peer reviewed journals, using the key words “moxifloxacin”, “placebo” and “QT”. All articles flagged by this search were manually reviewed to exclude trials which do not meet the standards of ICH E14 (quality assured ECG recording and interval measurement), or which described meta-analyses of other trials. The selection was quality checked by a second reviewer. Data were abstracted using a standardized form, including trial and demographic characteristics, and ECG measurements at baseline and on-treatment. The standard error was obtained at set time points in order to create funnel plots.

Results: 250 possibly relevant abstracts were identified in the key word search up to July 2013, of which 150 had to be excluded. From July 2013 to July 2014 a further 71 abstracts were identified, of which 48 were excluded. Thus, in total 123 articles were identified, comprising 23 from the recent year and 100 from before July 2013. Most of these articles (100/123 - 76%) were published after 2009. Of the 123 included trials, 90 (73%) employed a crossover design, 28 (23%) were parallel group and 5 (4%) a mixed design. Further results will be presented at the conference.

Conclusion: This systematic review will identify possible factors contributing to the variation of the QT prolongation in TQT trials, which could lead to more efficient trial designs in future TQT trials.

Reference:

Ring A. Schall R, Yu LM. A systematic review of the ECG effects of moxifloxacin in thorough QT trials. Int Soc Clin Biostat Annual meeting, Munich 2013. P25.