Cenobamate is a novel tetrazole-derived carbamate compound. |
Cenobamate acts as a modulator of voltage-gated sodium channels and GABA currents. |
Adjunctive cenobamate reduces the frequency of focal seizures in patients with uncontrolled epilepsy. |
The most common adverse events include somnolence, dizziness, fatigue, balance disorder, and diplopia. |
1 Introduction
2 Materials and Methods
2.1 Search Strategy
2.2 Eligibility Criteria
2.3 Outcome Measures
2.4 Study Selection, Data Extraction and Assessment of the Risk of Bias
2.5 Statistical Analysis
3 Results
3.1 Results of the Search and Characteristics of Included Studies
Study | Study design | Main inclusion/exclusion criteria | Treatment arms |
---|---|---|---|
Chung et al. [26] | Phase II Multicenter, multinational (India, Poland, Republic of Korea, US) Parallel-group, randomized, placebo-controlled trial: 8-week observational baseline period 6-week double-blind titration 6-week double-blind maintenance phase Open-label extension (optional) | Aged 18–65 years Diagnosis of treatment-resistant focal epilepsy History of epilepsy for at least 2 years At least 3 focal seizures (focal aware with motor component, focal impaired awareness, or focal to bilateral tonic–clonic) per month, with no consecutive 21-day seizure-free period, within the 2 months before randomization (baseline period) Current treatment on a stable dose of 1–3 ASMs for at least 12 weeks prior to randomization Patients taking phenytoin or phenobarbital were excluded due to the potential for drug–drug interaction with CNB | Oral placebo, once daily Oral CNB 200 mg once daily |
Krauss et al. [27] | Phase II Multicenter, multinational (Australia, Bulgaria, Czech Republic, France, Germany, Hungary, Israel, Poland, Romania, Serbia, South Korea, Spain, Thailand, Ukraine, UK, US) Parallel-group, randomized, placebo-controlled trial: 8-week observational baseline period 6-week double-blind titration 12-week double-blind maintenance phase Open-label extension (optional) | Aged 18–70 years Diagnosis of focal epilepsy uncontrolled despite treatment with at least one ASM within the past 2 years At least 8 focal seizures (focal aware with a motor component, focal impaired awareness, or focal to bilateral tonic–clonic) with a seizure-free interval of < 25 days during the 8-week baseline assessment with at least 3 of these seizures occurring during each of the two consecutive 4-week segments of the baseline period Current treatment on a stable dose of 1–3 ASMs for at least 4 weeks before screening Patients taking diazepam, phenytoin, or phenobarbital were excluded due to the potential for drug–drug interaction with CNB | Oral placebo, once daily Oral CNB 100, 200, 400 mg once daily |
Study | ||||||
---|---|---|---|---|---|---|
Chung et al. [26] | Krauss et al. [27] | |||||
CNB 200 mg/day (n = 113) | Placebo (n = 109) | CNB 100 mg/day (n = 108) | CNB 200 mg/day (n = 110) | CNB 400 mg/day (n = 111) | Placebo (n = 108) | |
Age, years | 36 [range: 18, 61] | 38 [range: 18, 59] | 39.0 (12.1) | 40.9 (12.4) | 39.6 (10.3) | 39.6 (12.4) |
Male sex, n (%) | 55 (48.7) | 58 (53.2) | 57 (52.8) | 54 (49.1) | 52 (46.8) | 58 (53.7) |
Race | ||||||
Caucasian/White | 57 (50.4) | 58 (53.2) | 89 (82.4) | 94 (85.5) | 96 (86.5) | 93 (86.1) |
Asian | 49 (43.4) | 45 (41.3) | 10 (9.3) | 11 (10.0) | 11 (9.9) | 9 (8.3) |
Black/African American | 3 (2.7) | 2 (1.8) | 4 (3.7) | 3 (2.7) | 1 (0.9) | 4 (3.7) |
Other/unknown | 4 (3.5) | 4 (3.7) | 5 (4.6) | 2 (1.8) | 3 (2.7) | 2 (1.9) |
Baseline seizure frequencya | 7.5 [range: 0b, 187] | 5.5 [range: 2, 237] | 9.5 [6.0–19.8] | 11.0 [6.0–26.0] | 9.0 [6.0–21.5] | 8.4 [6.0–19.0] |
Number of concomitant ASMs, n (%) | ||||||
One | 19 (16.8) | 12 (11.0) | 25 (23.1) | 39 (35.5) | 24 (21.6) | 27 (25.0) |
Two | 53 (46.9) | 52 (47.7) | 48 (44.5) | 47 (42.7) | 62 (55.9) | 54 (50.0) |
Three or more | 41 (36.3) | 45 (41.3) | 35 (32.9)c | 24 (21.8) | 25 (22.6)c | 27 (25.0) |
Concomitant ASMs, n (%) | ||||||
Levetiracetam | 51 (45.1) | 53 (48.6) | 47 (43.5) | 48 (43.6) | 50 (45.0) | 41 (38.0) |
Lamotrigine | 41 (36.3) | 34 (31.2) | 44 (40.7) | 27 (24.5) | 36 (32.4) | 31 (28.7) |
Carbamazepine | 38 (33.6) | 43 (39.4) | 29 (26.9) | 29 (26.4) | 25 (22.5) | 39 (36.1) |
Oxcarbazepine | 24 (21.2) | 26 (23.9) | 15 (13.9) | 17 (15.5) | 19 (17.1) | 13 (12.0) |
Valproate or valproic acid | 30 (26.5) | 31 (28.4) | 23 (21.3) | 28 (25.5) | 28 (25.2) | 31 (28.7) |
Clobazam | 22 (19.5) | 16 (14.7) | 17 (15.7) | 12 (10.9) | 17 (15.3) | 5 (4.6) |
Lacosamide | 27 (23.9) | 21 (19.3) | ||||
Topiramate | 25 (22.1) | 21 (19.3) |
3.2 Proportions of Patients with ≥ 50, ≥ 75, ≥ 90 and 100% Reduction in Baseline Seizure Frequency
3.3 Treatment Withdrawal
Outcome or subgroup | Number of studies [References] | Number of events/participants (%) | I2 (%) | Risk ratio (95% CI) | p Value | |
---|---|---|---|---|---|---|
CNB | Placebo | |||||
Treatment withdrawal | ||||||
Any dose | 74/442 (16.7) | 24/217 (11.1) | 0.0 | 1.34 (0.85–2.09) | 0.205 | |
CNB 100 mg/day | 1 [27] | 13/108 (12.0) | 14/108 (13.0) | 0.93 (0.46–1.88) | 0.837 | |
CNB 200 mg/day | 31/223 (13.9) | 24/217 (11.1) | 0.0 | 1.26 (0.77–2.08) | 0.357 | |
CNB 400 mg/day | 1 [27] | 30/111 (27.0) | 14/108 (13.0) | 2.09 (1.17–3.71) | 0.012 | |
Treatment withdrawal due to AEs | ||||||
Any dose | 54/442 (12.2) | 9/217 (4.1) | 54.0 | 2.27 (1.08–4.79) | 0.031 | |
CNB 100 mg/day | 1 [27] | 12/108 (11.1) | 5/108 (4.6) | 2.40 (0.88–6.58) | 0.089 | |
CNB 200 mg/day | 19/223 (8.5) | 9/217 (4.1) | 41.4 | 2.02 (0.91–4.46) | 0.083 | |
CNB 400 mg/day | 1 [27] | 23/111 (20.7) | 5/108 (4.6) | 0.002 |
3.4 Adverse Events
Outcome | Number of studies [References] | Number of events/participants (%) | I2 (%) | Risk ratio (99% CI) | p Value | |
---|---|---|---|---|---|---|
CNB | Placebo | |||||
Any AE | 340/442 (76.9) | 115/217 (53.0) | 0.0 | 1.14 (0.99–1.31) | 0.021 | |
Treatment-related AE | 293/442 (66.3) | 96/217 (44.2) | 37.2 | 1.46 (1.17–1.83) | < 0.001 | |
Any SAE | 24/442 (5.4) | 10/217 (4.6) | 0.0 | 0.99 (0.36–2.75) | 0.978 | |
Somnolence | 109/442 (24.7) | 22/217 (10.1) | 16.7 | 2.35 (1.31–4.24) | < 0.001 | |
Dizziness | 103/442 (23.3) | 33/217 (15.2) | 0.0 | 1.53 (0.94–2.49) | 0.026 | |
Headache | 49/442 (11.1) | 20/217 (9.2) | 34.5 | 1.27 (0.63–2.57) | 0.374 | |
Nausea | 31/442 (7.0) | 6/217 (2.8) | 0.0 | 2.98 (0.92–9.61) | 0.017 | |
Fatigue | 71/442 (16.1) | 16/217 (7.4) | 0.0 | 1.96 (0.97–3.95) | 0.014 | |
Nystagmus | 25/442 (5.7) | 1/217 (0.5) | 0.0 | 7.83 (0.91–67.64) | 0.014 | |
Balance disorder | 24/442 (5.4) | 1/217 (0.5) | 0.0 | 9.19 (1.04–80.96) | 0.009 | |
Upper respiratory infection | 18/442 (4.1) | 11/217 (5.1) | 47.8 | 0.88 (0.34–2.29) | 0.721 | |
Constipation | 21/442 (4.8) | 1/217 (0.5) | 0.0 | 6.71 (0.77–58.40) | 0.024 | |
Vomiting | 17/442 (3.8) | 2/117 (0.9) | 0.0 | 3.64 (0.60–22.27) | 0.066 | |
Urinary tract infection | 1 [26] | 9/113 (8.0) | 2/109 (1.8) | 4.34 (0.60–31.56) | 0.057 | |
Tremor | 1 [26] | 7/113 (6.2) | 3/109 (2.8) | 2.25 (0.39–12.87) | 0.231 | |
Nasopharyngitis | 1 [26] | 7/113 (6.2) | 1/109 (0.9) | 6.75 (0.44–103.73) | 0.072 | |
Diarrhea | 1 [26] | 6/113 (5.3) | 0/109 (0.0) | 12.54 (0.29–541.21) | 0.084 | |
Anxiety | 1 [26] | 1/113 (0.9) | 6/109 (5.5) | 0.16 (0.01–2.54) | 0.088 | |
Ataxia | 1 [27] | 13/329 (4.0) | 1/108 (0.9) | 4.27 (0.30–60.87) | 0.160 | |
Dysarthria | 1 [27] | 12/329 (3.6) | 0/108 (0.0) | 8.26 (0.20–335.34) | 0.142 | |
Diplopia | 1 [27] | 36/329 (10.9) | 2/108 (1.9) | 5.91 (0.93–37.56) | 0.013 | |
Fall | 1 [27] | 10/329 (3.0) | 6/108 (5.6) | 0.55 (0.15–2.01) | 0.232 | |
Back pain | 1 [27] | 11/329 (3.3) | 3/108 (2.8) | 1.20 (0.23–6.29) | 0.773 | |
Vertigo | 1 [27] | 10/329 (3.0) | 3/108 (2.8) | 1.09 (0.21–5.82) | 0.890 | |
Decreased appetite | 1 [27] | 10/329 (3.0) | 1/108 (0.9) | 3.28 (0.22–48.19) | 0.254 | |
Gait disturbance | 1 [27] | 16/329 (4.9) | 3/108 (2.8) | 1.75 (0.36–8.63) | 0.366 |
Outcome or subgroup | Number of studies [Reference] | Number of events/participants (%) | I2 (%) | Risk ratio (99% CI) | p Value | |
---|---|---|---|---|---|---|
CNB | Placebo | |||||
CNB 100 mg/day | ||||||
Any AE | 1 [27] | 70/108 (64.8) | 76/108 (70.4) | 0.92 (0.72–1.18) | 0.384 | |
Treatment-related AE | 1 [27] | 62/108 (57.4) | 46/108 (42.6) | 1.35 (0.94–1.93) | 0.032 | |
Any SAE | 1 [27] | 10/108 (9.3) | 6/108 (5.6) | 1.67 (0.46–6.01) | 0.305 | |
Somnolence | 1 [27] | 20/108 (18.5) | 9/108 (8.3) | 2.22 (0.84–5.88) | 0.034 | |
Dizziness | 1 [27] | 19/108 (17.6) | 15/108 (13.9) | 1.27 (0.56–2.87) | 0.456 | |
Headache | 1 [27] | 11/108 (10.2) | 6/108 (5.6) | 1.83 (0.52–6.46) | 0.215 | |
Nausea | 1 [27] | 7/108 (6.5) | 1/108 (0.9) | 7.00 (0.46–107.47) | 0.066 | |
Fatigue | 1 [27] | 13/108 (12.0) | 9/108 (8.3) | 1.44 (0.50–4.17) | 0.372 | |
Nystagmus | 1 [27] | 3/108 (2.8) | 1/108 (0.9) | 3.00 (0.16–57.52) | 0.338 | |
Balance disorder | 1 [27] | 3/108 (2.8) | 0/108 (0.0) | 7.00 (0.15–338.50) | 0.196 | |
Upper respiratory infection | 1 [27] | 3/108 (2.8) | 6/108 (5.6) | 0.50 (0.08–2.99) | 0.318 | |
Constipation | 1 [27] | 2/108 (1.9) | 1/108 (0.9) | 2.00 (0.09–45.99) | 0.569 | |
Vomiting | 1 [27] | 2/108 (1.9) | 0/108 (0.0) | 5.00 (0.09–266.30) | 0.297 | |
Ataxia | 1 [27] | 2/108 (1.9) | 1/108 (0.9) | 2.00 (0.09–45.99) | 0.569 | |
Dysarthria | 1 [27] | 2/108 (1.9) | 0/108 (0.0) | 5.00 (0.09–266.30) | 0.297 | |
Diplopia | 1 [27] | 8/108 (7.4) | 2/108 (1.9) | 4.00 (0.54–29.73) | 0.075 | |
Fall | 1 [27] | 2/108 (1.9) | 6/108 (5.6) | 0.33 (0.04–2.65) | 0.172 | |
Back pain | 1 [27] | 4/108 (3.7) | 3/108 (2.8) | 1.33 (0.19–9.24) | 0.702 | |
Vertigo | 1 [27] | 1/108 (0.9) | 3/108 (2.8) | 0.33 (0.02–6.39) | 0.338 | |
Decreased appetite | 1 [27] | 3/108 (2.8) | 1/108 (0.9) | 3.00 (0.16–57.52) | 0.338 | |
Gait disturbance | 1 [27] | 1/108 (0.9) | 3/108 (2.8) | 0.33 (0.02–6.39) | 0.338 | |
CNB 200 mg/day | ||||||
Any AE | 170/223 (76.2) | 145/217 (66.8) | 0.0 | 1.14 (0.97–1.33) | 0.034 | |
Treatment-related AE | 139/223 (62.3) | 96/217 (44.2) | 0.0 | 1.41 (1.11–1.79) | < 0.001 | |
Any SAE | 6/223 (2.7) | 10/217 (4.6) | 0.0 | 0.59 (0.16–2.18) | 0.295 | |
Somnolence | 48/223 (21.5) | 22/217 (10.1) | 0.0 | 2.11 (1.14–3.90) | 0.002 | |
Dizziness | 47/223 (21.1) | 33/217 (15.2) | 0.0 | 1.38 (0.81–2.35) | 0.115 | |
Headache | 26/223 (11.7) | 20/217 (9.2) | 29.4 | 1.24 (0.59–2.58) | 0.455 | |
Nausea | 14/223 (6.3) | 6/217 (2.8) | 0.0 | 2.25 (0.66–7.72) | 0.090 | |
Fatigue | 31/223 (13.9) | 16/217 (7.4) | 0.0 | 1.89 (0.89–4.01) | 0.030 | |
Nystagmus | 15/223 (6.7) | 1/217 (0.5) | 0.0 | 7.49 (0.78–72.06) | 0.022 | |
Balance disorder | 11/223 (4.9) | 1/217 (0.5) | 0.0 | 7.26 (0.78–67.46) | 0.022 | |
Upper respiratory infection | 12/223 (5.4) | 11/217 (5.1) | 4.1 | 1.06 (0.36–3.11) | 0.884 | |
Constipation | 9/223 (4.0) | 1/217 (0.5) | 0.0 | 5.12 (0.50–52.26) | 0.070 | |
Vomiting | 9/223 (4.0) | 2/217 (0.9) | 0.0 | 3.51 (0.56–21.85) | 0.077 | |
Urinary tract infection | 1 [26] | 9/113 (8.0) | 2/109 (1.8) | 4.34 (0.60–31.56) | 0.057 | |
Tremor | 1 [26] | 7/113 (6.2) | 3/109 (2.8) | 2.25 (0.39–12.87) | 0.231 | |
Nasopharyngitis | 1 [26] | 7/113 (6.2) | 1/109 (0.9) | 6.75 (0.44–103.73) | 0.072 | |
Diarrhea | 1 [26] | 6/113 (5.3) | 0/109 (0.0) | 12.54 (0.29–541.21) | 0.084 | |
Anxiety | 1 [26] | 1/113 (0.9) | 6/109 (5.5) | 0.16 (0.01–2.54) | 0.088 | |
Ataxia | 1 [27] | 4/110 (3.6) | 1/108 (0.9) | 3.93 (0.23–68.48) | 0.218 | |
Dysarthria | 1 [27] | 3/110 (2.7) | 0/108 (0.0) | 6.87 (0.14–332.45) | 0.200 | |
Diplopia | 1 [27] | 11/110 (10.0) | 2/108 (1.9) | 5.40 (0.77–37.92) | 0.026 | |
Fall | 1 [27] | 4/110 (3.6) | 6/108 (5.6) | 0.66 (0.13–3.33) | 0.502 | |
Back pain | 1 [27] | 1/110 (0.9) | 3/108 (2.8) | 0.33 (0.02–6.28) | 0.330 | |
Vertigo | 1 [27] | 3/110 (2.7) | 3/108 (2.8) | 0.98 (0.12–7.81) | 0.982 | |
Decreased appetite | 1 [27] | 1/110 (0.9) | 1/108 (0.9) | 0.98 (0.03–36.88) | 0.990 | |
Gait disturbance | 1 [27] | 6/110 (5.5) | 3/108 (2.8) | 1.96 (0.33–11.73) | 0.331 | |
CNB 400 mg/day | ||||||
Any AE | 1 [27] | 110/111 (99.1) | 76/108 (70.4) | 1.28 (1.07–1.53) | < 0.001 | |
Treatment-related AE | 1 [27] | 92/111 (82.9) | 46/108 (42.6) | 1.95 (1.43–2.65) | < 0.001 | |
Any SAE | 1 [27] | 8/111 (7.2) | 6/108 (5.6) | 1.30 (0.34–4.99) | 0.619 | |
Somnolence | 1 [27] | 41/111 (36.9) | 9/108 (8.3) | 4.43 (1.84–10.71) | < 0.001 | |
Dizziness | 1 [27] | 37/111 (33.3) | 15/108 (13.9) | 2.40 (1.18–4.87) | 0.001 | |
Headache | 1 [27] | 12/111 (10.8) | 6/108 (5.6) | 1.95 (0.56–6.72) | 0.167 | |
Nausea | 1 [27] | 10/111 (9.0) | 1/108 (0.9) | 9.73 (0.67–141.77) | 0.029 | |
Fatigue | 1 [27] | 27/111 (24.3) | 9/108 (8.3) | 2.92 (1.15–7.39) | 0.003 | |
Nystagmus | 1 [27] | 7/111 (6.3) | 1/108 (0.9) | 6.81 (0.44–104.60) | 0.070 | |
Balance disorder | 1 [27] | 10/111 (9.0) | 0/108 (0.0) | 20.44 (0.50–836.92) | 0.036 | |
Upper respiratory infection | 1 [27] | 3/111 (2.7) | 6/108 (5.6) | 0.49 (0.08–2.91) | 0.299 | |
Constipation | 1 [27] | 10/111 (9.0) | 1/108 (0.9) | 9.73 (0.67–141.77) | 0.029 | |
Vomiting | 1 [27] | 6/111 (5.4) | 0/108 (0.0) | 12.65 (0.29–545.75) | 0.082 | |
Ataxia | 1 [27] | 7/111 (6.3) | 1/108 (0.9) | 6.81 (0.44–104.60) | 0.070 | |
Dysarthria | 1 [27] | 7/111 (6.3) | 0/108 (0.0) | 14.60 (0.34–618.40) | 0.065 | |
Diplopia | 1 [27] | 17/111 (15.3) | 2/108 (1.9) | 8.27 (1.25–54.95) | 0.004 | |
Fall | 1 [27] | 4/111 (3.6) | 6/108 (5.6) | 0.65 (0.13–3.30) | 0.493 | |
Back pain | 1 [27] | 6/111 (5.4) | 3/108 (2.8) | 1.95 (0.33–11.63) | 0.337 | |
Vertigo | 1 [27] | 6/111 (5.4) | 3/108 (2.8) | 1.95 (0.33–11.63) | 0.337 | |
Decreased appetite | 1 [27] | 6/111 (5.4) | 1/108 (0.9) | 5.84 (0.37–92.27) | 0.100 | |
Gait disturbance | 1 [27] | 9/111 (8.1) | 3/108 (2.8) | 2.92 (0.54–15.69) | 0.101 |