Table 5.
Clinical studies CO13, CO17, and CO21 of adjunctive cenobamate efficacy and safety.
| Reference | Study CO13, NCT01397968, Chung et al. [60] | Study CO17, NCT01866111, Krauss et al. [61] |
Study CO21, NCT02535091, Sperling et al. [62] | |
|---|---|---|---|---|
| Type of study | Phase II, R, DB, followed by OLE | Phase II, R, DB, DR, followed by OLE | Phase III, open-label | |
| Seizure type | Focal, uncontrolled a | Focal, uncontrolled b | Focal, uncontrolled b | |
| CNB starting dose mg/day | 50 | 50 c | 12.5 | |
| Titration schedule | Increase by 50 mg every two weeks | Increase by 50 mg every week up to 200 mg, then 100 mg/week thereafter c | Increase to 25 mg for weeks 3 and 4, 50 mg for weeks 5 and 6, and then by 50 mg every 2 weeks thereafter | |
| Titration phase, weeks | 6 | 6 | 12 | |
| CNB target dose for maintenance phase mg/day (N of participants) | 200 (n = 113) | 100 (n = 108); 200 (n = 110); 400 (n = 111) | 200, could be increased to a maximum dose of 400 (n = 1339) | |
| Maintenance phase, weeks | 6 | 12 | ≥40 | |
| Compared group | Placebo (n = 109) | Placebo (n = 108) | NA | |
| Inclusion criteria | Common | 1. Taking 1–3 concomitant ASMs at stable doses; 2. EEG confirming the diagnosis of focal epilepsy; 3. prior neuroimaging | ||
| Specific | 4. Adults 18–65 years old 5. ≥3 focal seizures per month (baseline period 8 weeks) 6. No consecutive 21-day seizure-free interval |
4. Adults 18–70 years old 5. ≥3 focal seizures per month (baseline period 8 weeks), with ≥8 focal seizures during baseline 6. No consecutive 25-day seizure-free interval |
4. Adults 18–70 years old | |
| Exclusion criteria | Common | 1. Taking FBM for <18 continuous months; 2. history of status epilepticus, alcoholism, drug abuse, or psychiatric illness; 3. taking VGB within the past year | ||
| Specific | 4. Taking intermittent rescue benzodiazepines more than once per month within the past month 5. Taking PHT or PB 6. History of >2 allergic reactions to prior ASMs 7. History of 1 serious hypersensitivity reaction |
4. Taking intermittent rescue benzodiazepines more than once per month within the past month 5. Taking diazepam, PHT, or PB 6. History of a serious drug-induced hypersensitivity reaction or drug-related rash requiring treatment in a hospital, ASM drug-associated rash involving conjunctiva or mucosa, or >1 maculopapular rash requiring discontinuation |
4.Taking retigabine (ezogabine) within the past year 5. History of any drug-induced rash or hypersensitivity reaction 6. First-degree relatives with a serious cutaneous, drug-induced adverse reaction |
|
| Median % seizure reduction from baseline d |
ITT population (primary endpoint) CNB 200 mg (↓55%) * vs. placebo (↓21%) |
mITT population (FDA primary endpoint) CNB 400 mg (↓55%) * vs. CNB 200 mg (↓55%) * vs. CNB 100 mg (↓35%) * vs. placebo (↓24%) |
NA | |
| Responder rate, % of patients e |
• ITT population (secondary endpoint) CNB 200 mg (50%) * vs. placebo (22%) • Post hoc analysis (maintenance phase) CNB 200 mg (62%) * vs. placebo (32%) |
mITT-M population (EMA primary endpoint) CNB 400 mg (64%) * vs. CNB 200 mg (56%) * vs. CNB 100 mg (40%) * vs. placebo (25%) |
NA | |
| 100% seizure reduction during maintenance phase, % of patients |
Post hoc analysis CNB 200 mg (28%) * vs. placebo (8%) |
Secondary endpoint CNB 400 mg (21%) * vs. CNB 200 mg (11%) * vs. CNB 100 mg (3%) vs. placebo (1%) |
NA | |
| Median % seizure reduction by seizure subtype from baseline |
ITT population (secondary endpoint) • Focal aware motor seizures CNB 200 mg (↓76%) * vs. placebo (↓27%) • Focal impaired awareness seizures CNB 200 mg (↓55%) * vs. placebo (↓21%) • Focal to bilateral tonic-clonic seizures CNB 200 mg (↓77%) * vs. placebo (↓33%) |
mITT-M population (post-hoc analysis) • Focal aware motor seizures CNB 400 mg (69%) * vs. CNB 200 mg (62%) * vs. CNB 100 mg (49%) * vs. placebo (↑11%) • Focal impaired awareness seizures CNB 400 mg (61%) * vs. CNB 200 mg (55%%) * vs. CNB 100 mg (32%) vs. placebo (29%) • Focal to bilateral tonic-clonic seizures CNB 400 mg (83%) * vs. CNB 200 mg (92%) * vs. CNB 100 mg (51%) vs. placebo (33%) |
NA | |
| Most common TEAEs, % of CNB patients (occurring in ≥10% of patients with any dose) | • 22% somnolence • 22% dizziness • 12% headache • 11% nausea • 10% fatigue |
• 18% (100 mg), 20% (200 mg), 36% (400 mg) somnolence • 17%, 20%, 33% dizziness • 10%, 10%, 10% headache • 12%, 17%, 24% fatigue • 7%, 10%, 15% diplopia |
• 28% somnolence • 23% dizziness • 16% fatigue • 11% headache |
|
| Serious TEAEs, % of patients |
CNB (1.8%) vs. placebo (3.7%) | CNB 400 mg (7.2%), 200 mg (3.6%), 100 mg (9.3%) vs. placebo (5.6%) | 8.1% | |
| Hypersensitivity reactions in CNB-treated patients, n of patients | 1 (reddening of palms and soles and itching of ears) | 3 (1 non-serious pruritic rash with fever, 1 non-serious rash and facial swelling, 1 DRESS) | 1 | |
| DRESS, n of patients | 0 | 1 (randomized to 200 mg cenobamate with weekly titration) | 0 | |
| Deaths, n of patients (relationship to study drug) |
1 (unrelated, occurred prior to randomization) | 0 | 4 (3 unrelated; 1 remotely related) | |
Abbreviations: ASM: antiseizure medication; CNB: cenobamate; DB: double-blind; DR: dose-response; DRE: drug-resistant epilepsy; EEG: electroencephalogram; FBM: felbamate; FDA: U.S. Food and Drug Administration; ITT: intention-to-treat; m-ITT: modified intention-to-treat; mITT-M = modified intention-to-treat-maintenance phase; NA: not available/not reported; OLE: open-label extension; PB: phenobarbital; PHT: phenytoin; R: randomized; TEAE: treatment-emergent adverse event; VGB: vigabatrin. a Treatment-resistant (≥3 seizures per month) despite treatment with one to three ASMs. b Seizures despite treatment with at least one ASM within the past two years and taking stable doses of one to three concomitant ASMs. c Initial starting dose of 100 mg/day with a faster titration schedule of 100 mg increments weekly was amended to an initial starting dose of 50 mg/day with a slower up-titration after a blinded review of the first nine patients. d Based on seizure frequency per 28 days. e Responder rate defined as ≥50% reduction in seizure frequency. * Significant at 0.05 level.