Third-Generation Antiseizure Medications for Adjunctive Treatment of Focal-Onset Seizures in Adults: A Systematic Review and Network Meta-analysis

Abstract

Background: Brivaracetam (BRV), cenobamate (CNB), eslicarbazepine acetate (ESL), lacosamide (LCM) and perampanel (PER) are antiseizure medications (ASMs) approved for adjunctive treatment of focal-onset seizures. So far, no randomised controlled trial directly compared the efficacy and safety of these drugs.

Objective: We estimated the comparative efficacy and safety of these ASMs for the treatment of focal-onset seizures in adults with epilepsy using a network meta-analysis (NMA).

Methods: We systematically searched (June week 4, 2021) MEDLINE (accessed by PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and the US National Institutes of Health Clinical Trials Registry ( http://www.clinicaltrials.gov ). There were no date limitations or language restrictions. Randomised, double-blinded, controlled, parallel-group, add-on studies that compared oral BRV, CNB, ESL, LCM, and PER versus any comparator over maintenance periods of at least 12 weeks and included adult patients with focal seizures uncontrolled by concomitant ASMs were identified. The efficacy outcomes were the proportions of patients with ≥ 50% and 100% reduction in baseline seizure frequency during the maintenance period. The tolerability outcomes were the proportions of participants who experienced at least one treatment-emergent adverse event (TEAE) and experienced at least one TEAE leading to discontinuation. Effect sizes were estimated by network meta-analyses within a frequentist framework. The hierarchy of competing interventions was established using the surface under the cumulative ranking curve (SUCRA).

Results: Sixteen trials (BRV: n = 3, CNB: n = 1, ESL: n = 4, LCM: n = 4, PER: n = 4) were included, overall enrolling 4507 patients randomised to add-on active treatments (BRV = 803, CNB = 221, ESL =9 90, LCM = 1104, and PER = 1389) and 2246 to add-on placebo. Cenobamate was associated with a higher rate of ≥ 50% seizure frequency reduction than BRV [odds ratio (OR) 2.02, 95% confidence interval (CI) 1.11-3.66], ESL (OR 1.93, 95% CI 1.07-3.48), LCM (OR 1.86, 95% CI 1.04-3.32), and PER (OR 2.07, 95% CI 1.16-3.70). There was a not statistically significant trend favouring CNB over ESL, LCM and PER for the seizure freedom outcome. Brivaracetam (OR 0.61, 95% CI 0.44-0.86) and LCM (OR 0.60, 95% CI 0.40-0.88) were associated with a lower proportion of participants experiencing TEAEs compared to ESL, and patients treated with PER were associated with a higher risk to experience at least one TEAE (OR 1.42, 95% CI 1.02-1.96) than BRV. According to SUCRA, CNB had the greatest likelihood of being the best option for the ≥ 50% and 100% seizure frequency reduction, and BRV and LCM had the highest probabilities of being the best-tolerated treatments.

Conclusions: Cenobamate ranked best for efficacy, and BRV and LCM were best tolerated over the other comparators. Although NMAs cannot replace direct comparisons, they may support physicians in clinical decision making.

Fig. 1

Study flow diagram. CENTRAL Cochrane Central Register of Controlled Trials

Fig. 2

Interval plot for the efficacy outcome: seizure response. BRV brivaracetam, CNB cenobamate, CI confidence interval, ESL eslicarbazepine acetate, LCM lacosamide, PBO placebo, PER perampanel

Fig. 3

Interval plot for the efficacy outcome: seizure freedom. BRV brivaracetam, CNB cenobamate, CI confidence interval, ESL eslicarbazepine acetate, LCM lacosamide, PBO placebo, PER perampanel

Fig. 4

Interval plot for the tolerability outcome: at least one treatment-emergent adverse event. BRV brivaracetam, CNB cenobamate, CI confidence interval, ESL eslicarbazepine acetate, LCM lacosamide, PBO placebo, PER perampanel

Fig. 5

Interval plot for the tolerability outcome: at least one treatment-emergent adverse event leading to discontinuation. BRV brivaracetam, CNB cenobamate, CI confidence interval, ESL eslicarbazepine acetate, LCM lacosamide, PBO placebo, PER perampanel

Fig. 6

Clustered ranking plot of the antiseizure medications network for the efficacy and tolerability outcomes: seizure response and occurrence of at least one treatment-emergent adverse event. Ranking plots are based on cluster analysis of SUCRA values for two different outcomes: efficacy and tolerability. Note: Y and X axes represent the cumulative ranking curve (SUCRA) to rank each intervention—i.e., probability between 0 to 1 of an intervention being superior in efficacy (X axis) or tolerability (Y axis). Higher SUCRA values correspond to higher probabilities of better efficacy/tolerability. Each colour represents a group of treatments that belong to the same cluster. BRV brivaracetam, CNB cenobamate, CI confidence interval, ESL eslicarbazepine acetate, LCM lacosamide, PBO placebo, PER perampanel, SUCRA surface under the cumulative ranking curve

Fig. 7

Clustered ranking plot of the antiseizure medications network for the efficacy and tolerability outcomes: seizure response and occurrence of at least one treatment-emergent adverse event leading to treatment discontinuation. Ranking plots are based on cluster analysis of SUCRA values for two different outcomes: efficacy and tolerability. Note: Y and X axes represent the cumulative ranking curve (SUCRA) to rank each intervention—i.e., probability between 0 to 1 of an intervention being superior in efficacy (X axis) or tolerability (Y axis). Higher SUCRA values correspond to higher probabilities of better efficacy/tolerability. Each colour represents a group of treatments that belong to the same cluster. BRV brivaracetam, CNB cenobamate, CI confidence interval, ESL eslicarbazepine acetate, LCM lacosamide, PBO placebo, PER perampanel, SUCRA surface under the cumulative ranking curve

Fig. 8

Clustered ranking plot of the antiseizure medications network for the efficacy and tolerability outcomes: seizure freedom and occurrence of at least one treatment-emergent adverse event. Ranking plots are based on cluster analysis of SUCRA values for two different outcomes: efficacy and tolerability. Note: Y and X axes represent the cumulative ranking curve (SUCRA) to rank each intervention—i.e., probability between 0 to 1 of an intervention being superior in efficacy (X axis) or tolerability (Y axis). Higher SUCRA values correspond to higher probabilities of better efficacy/tolerability. Each colour represents a group of treatments that belong to the same cluster. BRV brivaracetam, CNB cenobamate, CI confidence interval, ESL eslicarbazepine acetate, LCM lacosamide, PBO placebo, PER perampanel, SUCRA surface under the cumulative ranking curve

Fig. 9

Clustered ranking plot of the antiseizure medications network for the efficacy and tolerability outcomes: seizure freedom and occurrence of at least one treatment-emergent adverse event leading to treatment discontinuation. Ranking plots are based on cluster analysis of SUCRA values for two different outcomes: efficacy and tolerability. Note: Y and X axes represent the cumulative ranking curve (SUCRA) to rank each intervention—i.e., probability between 0 to 1 of an intervention being superior in efficacy (X axis) or tolerability (Y axis). Higher SUCRA values correspond to higher probabilities of better efficacy/tolerability. Each colour represents a group of treatments that belong to the same cluster. BRV brivaracetam, CNB cenobamate, CI confidence interval, ESL eslicarbazepine acetate, LCM lacosamide, PBO placebo, PER perampanel, SUCRA surface under the cumulative ranking curve