Efficacy and tolerability of brivaracetam monotherapy in childhood and juvenile absence epilepsy: An innovative adaptive trial design

Abstract

Objective: Despite introduction of several antiseizure medications over the past two decades, treatment options for childhood absence epilepsy (CAE) and juvenile absence epilepsy (JAE) remain limited. We report the innovative adaptive design of an ongoing phase 2/3 trial to evaluate efficacy, safety, and tolerability of brivaracetam (BRV) monotherapy in patients 2-25 years of age with CAE or JAE.

Methods: N01269 (ClinicalTrials.gov: NCT04666610; start: July 2021; expected completion: 2024) is a randomized, dose-finding and confirmatory, double-blind, placebo-controlled, parallel-group, multicenter trial. The trial consists of a dose-selection and assessment for futility stage, followed by an optimal-dose stage after interim analysis. Both stages include an up to 2-week screening period, a 2-week placebo-controlled period, and an 11-week active treatment period (10 weeks of initial treatment followed by a 24-hour electroencephalogram [EEG] and an additional week of active treatment for 24-hour EEG assessment). Patients who are absence seizure-free will enter an up to 4-week randomized withdrawal period. Efficacy assessments will be based on 24-hour EEG and seizure diaries.

Significance: This two-stage adaptive trial design allows investigation of two potentially efficacious BRV doses, where one dose is dropped in favor of the other dose with a better benefit-risk profile. This allows for a combined phase 2 dose-finding and phase 3 confirmatory efficacy trial, which reduces the number of patients needed to be recruited and reduces trial duration. A randomized withdrawal period is included to evaluate sustainability of treatment effect over time and to allow for placebo control while minimizing placebo exposure. Use of EEG capture in addition to seizure diaries offers a robust mechanism of detecting seizure activity and measuring treatment effect. Positive efficacy and safety/tolerability data may support the use of BRV as monotherapy for CAE or JAE, providing another treatment option and representing long-delayed progress in the treatment of absence seizures in these populations.

Keywords: antiseizure medication; double-blind placebo-controlled; electroencephalogram; randomized withdrawal; seizures.

FIGURE 1

Trial design. EEG, electroencephalogram; h, hour; RDW, randomized withdrawal.

FIGURE 2

Treatment during Stage 1 and Stage 2. Down‐titration followed by 2 weeks safety follow‐up can occur at any time after first dose of trial drug. 100 mg BRV corresponds to 2 mg/kg/day BRV for patients <50 kg body weight; 200 mg BRV corresponds to 4 mg/kg/day BRV for patients <50 kg body weight. AT, active treatment; BRV, brivaracetam; EEG, electroencephalogram; h, hour; PC, placebo‐controlled; RDW, randomized withdrawal.

FIGURE 3

Potential patient scenarios (A) during the placebo‐controlled and active treatment periods or (B) during the randomized withdrawal period. AT, active treatment; BRV, brivaracetam; COVID‐19, coronavirus disease 2019; EEG, electroencephalogram; h, hour; PC, placebo‐controlled; RDW, randomized withdrawal. ^aA safety follow‐up visit will occur 14 days after the last dose of the down‐titration scheme; ^bPatient will enter unblinded down‐titration if still on BRV at the time (first 2 weeks of the randomized withdrawal), otherwise the patient will directly enter the safety follow‐up period.