PDF: Cenobamate C017
(2022)Objective
Cenobamate - To assess the long-term efficacy and safety of adjunctive cenobamate in adults with uncontrolled focal seizures over a nearly 6-year open-label extension.
Study Summary
Intervention
Adjunctive cenobamate (target 300 mg/day; range 50–400 mg/day) with flexible dose adjustments and background ASM changes.
Inclusion Criteria
Adults 18–70 with focal epilepsy who completed the prior 18-week double-blind trial and continued into the open-label extension.
Study Design
Arms: Single-arm open-label extension
Patients per Arm: 355 patients (265 from CNB group, 90 transitioned from placebo)
Outcome
Bottom Line
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, confirming findings from the double-blind study and supporting the potential long-term clinical benefit of cenobamate.
Major Points
- This was an open-label extension of an 18-week double-blind, randomized, placebo-controlled phase 2 study (NCT01866111)
- 355 patients entered the OLE safety population (265 originally randomized to cenobamate, 90 to placebo)
- Median duration of OLE exposure was 53.9 months (range 1.1-68.7 months)
- As of July 2019, 58.9% of patients (209/355) were continuing cenobamate treatment
- Retention rates: 83% at 12 months, 71% at 24 months, 65% at 36 months, 62% at 48 months
- Among patients who completed 12 months (n=294), 73% remained on treatment through 48 months
- Median percent seizure frequency reduction increased progressively, reaching 76.1% at months 43-48
- Among observed patients during months 36-48: 16.4% achieved 100% seizure reduction, 39.1% achieved ≥90% reduction, 51.8% achieved ≥75% reduction, 76.4% achieved ≥50% reduction
- Using initial mITT population as denominator: 10.2% achieved 100% seizure reduction and 24.3% achieved ≥90% reduction during months 36-48
- Any consecutive ≥12-month duration of 100% seizure reduction occurred in 18.4% of patients (65/354)
- Any consecutive ≥24-month duration of 100% seizure reduction occurred in 11.9% of patients (42/354)
- Median duration of 100% seizure reduction was 45.1 months (IQR 27.4)
- Median modal daily cenobamate dose was 300 mg (IQR 100 mg; range 50-400 mg)
- Discontinuation reasons: lack of efficacy (16.6%), withdrawal by patient (8.7%), adverse events (7.6%)
- Adverse events were primarily mild (21.7%) or moderate (45.4%) in severity
- Most common adverse events occurred during the first month of OLE treatment
Study Design
- Study Type
- Multicenter, open-label extension
- Randomization
- No
- Blinding
- 2-week blinded conversion period to cenobamate, then open-label
- Sample Size
- 355
- Follow-up
- Up to 68.7 months (median 53.9 months)
- Countries
- United States, Germany, Spain
Primary Outcome
Definition: Median percent change in focal seizure frequency over baseline by 6-month intervals
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 65.4% reduction at months 1-6, progressively increasing to 76.1% reduction at months 43-48. Similar results for patients originally treated with cenobamate or placebo in double-blind study. | - |
Limitations & Criticisms
- Uncontrolled study design (inherent limitation of open-label extension)
- Potential confounders including use of and changes in concomitant ASM therapy and changes in cenobamate dose
- Potential differences due to prior treatment with cenobamate in double-blind period may confound seizure reduction results
- Reduced sample size over time and potential selection bias for remaining cohort
- Lack of standardization of long-term efficacy reporting across studies makes comparisons difficult
- No direct comparison to other antiseizure medications
- Potential for drug-drug interactions between cenobamate and certain ASMs (phenytoin, clobazam)
- Study population may not be representative of all patients with focal epilepsy due to inclusion/exclusion criteria
Citation
Neurology. 2022;99:e989-e998