PDF: Cenobamate C013
(2021)Objective
Cenobamate - To assess the long-term safety and retention of adjunctive cenobamate in adults with uncontrolled focal seizures over a 7.8-year follow-up.
Study Summary
Intervention
Adjunctive oral cenobamate (50–400 mg/day), with flexible dosing and adjustments to concomitant ASMs as clinically indicated.
Inclusion Criteria
Adults aged 18–65 with treatment-resistant focal epilepsy who completed the preceding double-blind trial (NCT01397968).
Study Design
Arms: Single-arm open-label extension
Patients per Arm: 149 patients
Outcome
Bottom Line
Long-term retention in the C013 open-label extension demonstrated sustained safety and tolerability of adjunctive cenobamate treatment up to 7.8 years in adults with treatment-resistant focal seizures, with 57% of patients remaining in the study at data cutoff and high retention rates among those continuing at 1 year (79% after median 6.8 years).
Major Points
- This was an open-label extension of study YKP3089C013, a 12-week double-blind, randomized, placebo-controlled Phase 2 study
- 149 patients entered the OLE with median cenobamate treatment duration of 6.25 years
- 57% of patients (85/149) remained in the OLE at data cutoff with median treatment duration of 6.8 years (range 6.4-7.8 years)
- Retention rates at 1-6 years were 73%, 67%, 63%, 61%, 60%, and 59% respectively
- Among patients who continued at 1 year (n=107), retention at Years 2-5 was 92%, 87%, 83%, and 82%
- Median modal daily cenobamate dose was 200 mg (range 50-400 mg)
- Most common discontinuation reasons: patient withdrawal (19.5%), adverse events (10.1%), lack of efficacy (5.4%)
- Most frequent adverse events: dizziness (32.9%), headache (26.8%), somnolence (21.5%)
- Adverse events were primarily mild or moderate in severity
- 53.7% of patients discontinued and remained off one or more concomitant ASMs during the OLE
- Flexible dosing of both cenobamate and concomitant ASMs was allowed, reflecting real-world clinical practice
Study Design
- Study Type
- Multicenter, multinational, single-arm, open-label extension
- Randomization
- No
- Blinding
- None - open-label
- Sample Size
- 149
- Follow-up
- Up to 7.8 years (median 6.25 years)
- Countries
- United States, Republic of Korea, Poland
Primary Outcome
Definition: Long-term retention rate and continuation in the open-label extension study
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 57% of patients (85/149) remained in OLE at data cutoff with median treatment duration of 6.8 years. Probability of continuation at 1-6 years: 73%, 67%, 63%, 61%, 60%, 59% respectively. | - |
Limitations & Criticisms
- No control comparison group (inherent limitation of open-label extension design)
- Reduced sample size over time due to discontinuations
- Potential confounders including changes in concomitant ASM therapy during the study
- No collection of seizure data to directly assess efficacy during the OLE
- Retention analysis began at start of OLE rather than double-blind phase, which could overestimate retention rate as patients who discontinued during double-blind are not included
- Loss of patients from India sites who could not participate in OLE may affect generalizability
- Most patients had cenobamate discontinuation for approximately 3 weeks between double-blind and OLE periods
- No specific reasons recorded for 'withdrawal by patient' category (19.5% of discontinuations)
Citation
Epilepsia. 2021;62:2142-2150