Long-Term Efficacy and Safety From an Open-Label Extension of Adjunctive Cenobamate in Patients With Uncontrolled Focal Seizures

Abstract

Objective: Evaluate long-term efficacy (percent seizure frequency reduction and responder rates), safety, and tolerability of adjunctive cenobamate in an open-label extension (OLE) of the randomized, double-blind, placebo-controlled study.

Methods: Patients (aged 18-70 years) with uncontrolled focal seizures despite treatment with 1-3 antiseizure medications who completed the 18-week double-blind study (n=360) could enter the OLE, where they underwent a 2-week blinded conversion to cenobamate (target dose, 300 mg/day; min/max, 50/400 mg/day).

Results: Three hundred fifty-five patients were included in the OLE safety population (265 originally randomized to cenobamate, 90 originally randomized to placebo), and 354 were included in the OLE modified intent-to-treat population. As of July 2019, 58.9% (209/355) of patients were continuing cenobamate treatment and 141 had discontinued, including 16.6% (59/355) due to lack of efficacy, 8.7% (31/355) due to withdrawal by patient, and 7.6% (27/355) due to adverse events. Median (range) duration of OLE exposure was 53.9 (1.1-68.7) months. Retention rates at 12, 24, 36, and 48 months were 83%, 71%, 65%, and 62%, respectively. Median percent seizure frequency reduction over baseline increased with each 6-month OLE interval, up to 76.1% at months 43-48. Among observed patients, 16.4% (36/220) achieved 100% and 39.1% (86/220) achieved ≥90% seizure reduction during >36-48 months. Among the initial OLE mITT population, 10.2% (36/354) of patients achieved 100% and 24.3% (86/354) achieved ≥90% seizure reduction during >36-48 months. Similar to the double-blind study, adverse events (AEs) included dizziness, somnolence, fatigue, and headache. Serious AEs occurred in 20.3% (72/355) of patients.

Conclusion: Long-term efficacy, including 100% and ≥90% seizure reduction, was sustained during 48 months of cenobamate treatment, with 71% retention at 24 months. No new safety issues were identified. These results confirm the findings of the double-blind study and support the potential long-term clinical benefit of cenobamate.

Registration: ClinicalTrials.gov NCT01866111.

Classification of evidence: This study provides Class IV evidence that oral Cenobamate 50-400 mg/day is effective as an adjunctive treatment for the long-term management of patients with uncontrolled focal seizures previously treated with 1 to 3 ASMs.

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Figures

Figure 1. Patient Disposition and Reason for Discontinuation (OLE Population)

aStudy completion as reported on the end-of-study subject disposition case report form. mITT = modified intent-to-treat; OLE = open-label extension.

Figure 2. Kaplan-Meier Plot of Time to Discontinuation During OLE

Event = early discontinuation from OLE. Patients who completed the study and patients ongoing at the date of data cutoff are considered as censored. OLE = open-label extension.

Figure 3. Median Percent Change in Seizure Frequency/28 Days by 6-Month Intervals During OLE (mITT Population)

Median (IQR) baseline seizure frequency/28 days during the double-blind study for the 354 patients in the mITT population was 9.5 (16.0). CNB = cenobamate; DB = double-blind; IQR = interquartile range; mITT = modified intent-to-treat; OLE = open-label extension; PBO = placebo.

Figure 4. 100% Reduction in Seizure Frequency by 12-Month Intervals During OLE (mITT Population)

mITT = modified intent-to-treat; OLE = open-label extension; SE = standard error.

Figure 5. ≥50%, ≥75%, and ≥90% Reduction in Seizure Frequency by 12-Month Intervals During OLE (mITT Population)

(A) Observed patients at each time point and (B) initial OLE mITT population. mITT = modified intent-to-treat; OLE = open-label extension.