Abstracts

Rationale: Treatment-emergent adverse events (TEAEs) in clinical trials are typically reported for the duration of the treatment period. Some TEAEs (e.g. central nervous system [CNS]-related events) occur early and may habituate with time. Almost all trials of antiepileptic drugs (AEDs) initially titrate doses upwards to reduce the incidence of CNS-related TEAEs, such as fatigue, somnolence, dizziness and headaches. However, this approach obscures whether, and exactly how much, habituation to TEAEs occurs over time. Brivaracetam (BRV) is a selective, high-affinity ligand for synaptic vesicle protein 2A. In clinical trials leading to the approval of BRV for the adjunctive treatment of focal (partial-onset) seizures, the drug was administered without titration at the target dose (50–200 mg/day). This allowed for examination of the timing of TEAE onset and habituation. Methods: Data were pooled from three studies (NCT00490035, NCT00464269, NCT01261325) of adult patients with focal seizures, uncontrolled by 1–2 other AEDs. This analysis reports data on the incidence of the most common TEAEs over time in patients who received BRV doses ranging 50–200 mg/day or placebo during a 12-week treatment period. The safety population comprised those taking ≥1 dose of study drug. Results: A total of 1,262 patients received the following treatments: placebo (n=459), BRV 50 mg/day (n=200), BRV 100 mg/day (n=353), and BRV 200 mg/day (n=250). Overall, the majority of incidences of common TEAEs (frequency of >5%) had their onset in Week 1 for the total BRV-treated population, compared with the whole treatment period (22.4% vs 34.4%). This effect was most marked in the BRV 200 mg/day treatment group where 30.0% of TEAE onsets occurred in Week 1, compared with 38.0% during the whole treatment period. In contrast, less than half of TEAE onsets associated with placebo treatment occurred in the first week (10.2% vs 22.9% total). TEAEs for placebo were lower when compared with BRV overall therapeutic doses during the treatment period (22.9% vs 34.4%). However, most of the TEAEs with onset during the first week of treatment were resolved over the first 3?6 weeks of the treatment period. All of these observations were particularly noticeable for the TEAEs of somnolence/sedation (Figure 1) and dizziness (Figure 2); fatigue showed a similar pattern (data not shown). Conclusions: In both placebo and BRV treatment groups, the majority of common TEAEs, especially events such as fatigue, somnolence/sedation, and dizziness, occurred early in the course of treatment. TEAEs in the BRV group habituated over time (3?6 weeks). TEAEs of AEDs might be better represented by division into early and late (persistent and delayed) onset, to guide clinician monitoring and patient expectations. The overall safety and tolerability profile of BRV identified by this temporal analysis is consistent with previous safety findings reported in the labeling. Taking these data into consideration with other BRV safety information, titration to a therapeutic range is not required. Funding: Studies supported by UCB Pharma