| Abstract: | ABSTRACTObjectives: To assess the effect on cardiac repolarisation of the investigational synaptic vesicle protein 2A (SV2A) ligand brivaracetam.Research design and methods: Subjects received double-blind, multiple bid doses of placebo (n?=?53), brivaracetam 75?mg (n?=?39) or brivaracetam 400?mg (n?=?40), or open-label single-dose moxifloxacin 400?mg (positive control, n?=?52). Continuous 12-lead ECG recordings were performed at baseline and after last dosing, using a Mortara Holter device. Plasma samples were obtained before and up to 12?h after last dosing for drug determination. Triplicate ECGs were extracted before each sample, and read centrally in a blinded manner. QT was corrected using a centre- and gender-specific correction (QTcSS).Main outcome measures: The primary endpoint was the largest time-matched mean difference of QTcSS change from baseline between drug and placebo (maximum ΔΔQTcSS). The same approach was adopted using the Fridericia's correction (QTcF). The relationships between ΔQTcSS and plasma concentration of brivaracetam and moxifloxacin were fitted to a straight line using linear least-squares regression.Results: Mean maximum ΔΔQTcSS for brivaracetam 75 and 400?mg bid, and moxifloxacin 400?mg was 0.2?ms, ?1.1?ms and 12.4?ms, respectively. The one-sided 95% upper limit for 75?mg and 400?mg brivaracetam was 4.3?ms and 3.0?ms, respectively; the one-sided 95% lower limit for moxifloxacin was 8.6?ms. After brivaracetam no QTcSS intervals >480?ms or changes from baseline of >60?ms were observed. ΔQTcSS did not increase with plasma concentration of brivaracetam, whereas there was a statistically significant rise with increasing moxifloxacin concentrations.Conclusions: The study was found to be valid in terms of assay sensitivity and the results demonstrated the absence of effects of brivaracetam on cardiac repolarisation. These results suggest that no intensive cardiac monitoring is required during the subsequent stages of brivaracetam development. |
