Table 1.
Advanced RCTs on new drugs for epilepsy treatment.
| References | Type of RCT and treatment | Study population (n° of pts, type of epilepsy, mean age ± SD) | Previously tested vs. concomitant ASMs (n°) | Primary end point | Outcomes |
|---|---|---|---|---|---|
| Devinsky et al. (17) | Double-blind, placebo-controlled RCT 20 mg/kg/d CBD oral solution |
214 DS pts M 9.8 ± 4.8 years |
4.0 3.0 |
Change in CSF | - 38.9% reduction in CSF in the CBD group vs. 13.3% in reduction in the placebo group - ≥50% reduction in CSF in 43% pts in the CBD group vs. in 27% pts in the placebo group - 5% pts sz-free in the CBD group vs. 0% sz-free in the placebo group |
| Thiele et al. (18) | Double-blind, placebo-controlled, phase 3 RCT 20 mg/kg/d CBD oral solution |
171 LGS pts M 15.4 ± 9.25 years |
6.0 3.0 |
Change in monthly frequency of drop sz | - 43.9% reduction in monthly drop sz frequency in the CBD group vs. 21.8% reduction in the placebo group - ≥50% reduction in drop sz frequency in 44% pts in the CBD group vs. in 24% pts in the placebo group - Improved overall condition in 58% pts in the CBD group vs. in 34% pts in the placebo group |
| Devinsky et al. (19) | Multicenter, double-blind, placebo-controlled, phase 3 RCT 10 or 20 mg/kg/d CBD oral solution |
225 LGS pts M 15.6 ± 9.9 years |
6.0 3.0 |
Average change in drop sz frequency | −41.9% reduction in drop sz frequency in the 20 mg CBD group vs. 37.2% reduction in the 10 mg group vs. 17.2% reduction in the placebo group - 50% reduction in drop sz frequency in 39% pts in the 20 mg CBD group vs. in 36% pts in the 10 mg group vs. in 14% pts in the placebo group - Improved PGIC in 57% pts in the 20 mg CBD group vs. in 66% pts in the 10 mg group vs. in 44% pts in the placebo group |
| Devinsky et al. (20) | OLE 20 up to 30 mg/kg/d CBD oral solution |
264 DS pts M 9.8 ± 4.4 years |
na 3.0 |
Long-term safety and tolerability of CBD | - 37.5% reduction in CSF retained for up to 48 w; - 4.8% pts were convulsive sz free and 2.9% pts were totally sz-free in the last 12 w of treatment - ≥50% reduction in CSF observed in more than 40% of pts - 93.2% of pts reported AEs: 36.7% mild; 39.0% moderate; 29.2% severe |
| Lagae et al. (23) | Double-blind, placebo-controlled RCT 0.2 or 0.7 mg/kg/d of fenfluramine HCl oral solution |
119 DS pts M 9.0 ± 4.7 years |
na M 2.4 ± 1.0 |
Change in monthly CSF | - 74.9% reduction in CSF in the 0.7 mg/kg/d group vs. 42.3% reduction in the 0.2 mg/kg/d group vs. 19.2% reduction in the placebo group - ≥50% reduction in CSF observed in 68% pts in the 0.7 mg/kg/d group vs. in 38% pts in the 0.2 mg/kg/d group vs. in 12% pts in the placebo group - 8% pts were sz-free in the 0.7 mg/kg/d group vs. 8% in the 0.2 mg/kg/d group vs. 0% in the placebo group - Improved CaGI in 55% pts in the 0.7 mg/kg/d vs. in 41% pts in the 0.2 mg/kg/d vs. in 10% pts in the placebo group |
| Lai et al. (25) | OLE 0.2 up to 0.7 mg/kg/d of fenfluramine HCl oral solution (up to 0.4 mg/kg/d if concomitant STP) |
232 DS pts M 9.1 ± 4.7 years |
na na |
Number of pts with VHD or PAH during treatment (median 256 d) | - No pts developed VHD or PAH - 23% pts showed trace of mitral regurgitation (mostly transient) |
| Krauss et al. (27) | Multicentre, double-blind, placebo-controlled, dose-response RCT 100–200–400 mg/d cenobamate oral solution |
437 pts with drug-R focal epilepsy M 39.8 ± 11.8 years |
2.0–3.0 2.0–3.0 |
Change in monthly focal sz frequency | - 55.0% reduction in focal sz frequency in the 200 and 400 mg/d group vs. 35.5% reduction in the 100 mg/d group vs. 24.0% reduction in the placebo group - ≥50% reduction in sz frequency observed in 64% pts in the 400 mg/d group vs. in 56% pts in the 200 mg/d group vs. in 40% pts in the 100 mg/d group vs. in 25% pts in the placebo group |
| Sperling et al. (28) | Multicenter, ongoing, phase 3, OLE 12.5 up to 400 mg/d cenobamate oral solution |
1,339 pts with drug-R focal epilepsy M 39.7 ± 12.84 years |
2.0–3.0 2.0–3.0 |
Long-term safety of cenobamate | - At least one AE was reported in 84.2% of pts: 77.8% were mild-moderate - At least one serious AE was reported in 8.1% of pts: seizures; pneumonia; fall; dizziness - No cases of DRESS were identified when starting at low dose and titrating every 2 w |
AEs, adverse events; ASMs, antiseizure medications; BDI, beck depression inventory; CaGI, caregiver global impression; CBD, cannabidiol; CSF, convulsive seizure frequency; d, day; drug-R, drug-resistant; DS, Dravet syndrome; LGS, Lennox-Gastaut syndrome; LINCL, late infantile neuronal ceroid lipofuscinoses; M, mean; n°, number; na, not assessed; OLE, open label extension; PAH, pulmonary arterial hypertension; PGIC, patient global impression of change; Pts, patients; RCT, randomized clinical trial; Ref, reference; SD, standard deviation; SF, seizure frequency; SUDEP, sudden unexpected death in epilepsy; STP, stiripentol; sz, seizures; VHD, valvular heart disease; w, weeks; y, years.