Long-term Safety and Efficacy Data of Brivaracetam for the Treatment of Patients with Uncontrolled Epilepsy

10 May, 21

Introduction

Epilepsy generally requires long-term treatment with antiepileptic drugs (AEDs). It is therefore essential to evaluate the long-term safety of AEDs. Brivaracetam (BRV), an AED is indicated in patients aged ≥ 16 years focal seizures.

Aim

To evaluate the long-term safety and tolerability of BRV
To evaluate the maintenance of efficacy of BRV (including quality of life) over time

Patient Profile

Adult patients with focal or generalized-onset seizures (age ≥16 years, n=766)
All the study subjects had previously participated in one of the two placebo (PBO)-controlled trials of adjunctive BRV and had uncontrolled epilepsy despite treatment with one to two concomitant AEDs.

Methods

Study Design

An open-label, long-term follow-up (LTFU), multicenter, flexible-dose, single arm trial

Treatment Strategy

During LTFU, patients started on an oral BRV dose of 200 mg/day or 150 mg/day (as per the dosage during the previous placebo-controlled trial)
The dosage was maintained for at least 2 weeks unless the treatment was not tolerated.
The BRV dose could be adjusted subsequently based on each patient’s seizure control and tolerability, without exceeding 200 mg/day. Patients followed a flexible concomitant AED regimen.

Outcomes

Safety Outcomes

Treatment emergent adverse event (TEAE)
Withdrawal due to TEAE
Occurrence of serious TEAEs

Efficacy Outcomes

Percentage reduction in focal seizure frequency/28 days from ‘baseline’ of the previous trial to the evaluation period
Responder rate for the evaluation period’ (defined as ≥50% reduction in focal seizure frequency from baseline’ of the previous trial)
Percentage of patients remaining seizure-free continuously (all seizure types) for 6- or 12-month interval during the evaluation period’
Change in ‘Patient Weighted Quality of Life in Epilepsy Questionnaire 31’ (QOLIE-31-P) scores from baseline of the previous trial during the first 2 years of the evaluation period (scores range from 0 to 100 with higher scores corresponding to better functioning/health status)

Follow-up visits

One visit per month for first 3 months, and once in every 3 months thereafter

Results

Of the 766 patients included in the study, 753 had focal seizures and 13 had generalized-onset seizures. The mean age of the study population was 40 years, and 51.7% of them were females.
Overall, 48% patients completed the trial (368/766). Three hundred and ninety-eight (52.0%) patients discontinued, the reasons for discontinuation being lack of efficacy (21.4%), AE (12.5%), patient choice (11.6%), loss to follow-up (2.9%), or other reasons (3.5%).
As per a Kaplan–Meier analysis retention of BRV therapy was 71.9% at 12 months, and 53.7% at 36 months.
Treatment-emergent adverse events were reported by 83.9% patients (n=643), the most common being headache (13.6%) and dizziness (13.1%).
Drug-related TEAEs were reported in 33.6% patients (n=257), the most common being somnolence (6.4%) and dizziness (5.4%).
Permanent discontinuation of BRV due to TEAEs was reported in 11.9% patients (n=91).
Psychiatric TEAEs were reported by 25.3% patients, the most common being, depression and anxiety. Psychiatric TEAE leading to discontinuation of BRV was reported in 3.4% patients. Drug related psychiatric TEAEs were reported by 8.2% patients.
Patients with focal seizures had a median percentage reduction in focal seizure frequency by 52.0%. Overall, the 50% responder rate was 51.7%; 60% in patients with at least 12 months of treatment and 63.4% in those who completed 36 months of treatment (Fig. 1).

Fig. 1: 50% Responder rate during the study period

Nearly 26.0% patients remained seizure free continuously for 6 months, and 17.9% remained seizure free continuously for 12 months. Amongst patients who completed 12 months of treatment, continuous freedom from seizures was 17.8% and 6.3% at 6 and 12 months, respectively. The same was 29.5% and 18.2% amongst patients who completed the treatment for 36 months (Fig. 2).

Fig. 2: Proportion of patients with continuous seizure freedom

Clinically meaningful improvements in QOLIE-31-P total score at 12 months and 24 months was seen in 42.4% and 46.8% patients, respectively.

Conclusion

This LTFU provided long-term safety data on adjunctive therapy with BRV at flexible dose (up to 200 mg/day) for 8 years.
The results being consistent with the previous trials indicated that long-term treatment with BRV was generally effective, safe and well-tolerated for treating patients with focal seizures.

Epilepsy Behav. 2021 Mar 26 (Published Online);doi: 10.1016/j.yebeh.2021.107897.