OBJECTIVES: 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 (QTc(SS) ). MAIN OUTCOME MEASURES: The primary endpoint was the largest time-matched mean difference of QTc(SS) change from baseline between drug and placebo (maximum DeltaDeltaQTc(SS)). The same approach was adopted using the Fridericia's correction (QTc(F)). The relationships between DeltaQTc(SS) and plasma concentration of brivaracetam and moxifloxacin were fitted to a straight line using linear least-squares regression. RESULTS:Mean maximum DeltaDeltaQTc(SS) 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 QTc(SS) intervals > 480 ms or changes from baseline of > 60 ms were observed. DeltaQTc(SS) 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.
RCT Entities:
OBJECTIVES: 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 (QTc(SS) ). MAIN OUTCOME MEASURES: The primary endpoint was the largest time-matched mean difference of QTc(SS) change from baseline between drug and placebo (maximum DeltaDeltaQTc(SS)). The same approach was adopted using the Fridericia's correction (QTc(F)). The relationships between DeltaQTc(SS) and plasma concentration of brivaracetam and moxifloxacin were fitted to a straight line using linear least-squares regression. RESULTS: Mean maximum DeltaDeltaQTc(SS) 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 QTc(SS) intervals > 480 ms or changes from baseline of > 60 ms were observed. DeltaQTc(SS) 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.