Add-on CBD significantly reduced seizures associated with DS and LGS and was generally well tolerated in three Phase 3 randomized controlled trials.

To determine the time to onset of efficacy of add-on CBD treatment using a post-hoc analysis of efficacy by cumulative day during titration in three Phase 3 randomized controlled trials in patients with Dravet syndrome (DS) (GWPCARE1/NCT02091375) and Lennox-Gastaut syndrome (LGS) (GWPCARE3/NCT02224560; GWPCARE4/NCT02224690).

Patients received a plant-derived pharmaceutical formulation of highly purified CBD in oral solution (Epidiolex^®; 100 mg/mL) at 10 mg/kg/day (GWPCARE3) or 20 mg/kg/day (all trials), or placebo. CBD treatment started at 2.5 mg/kg/day and reached 10 mg/kg/day on Days 7/8 and 20 mg/kg/day by Day 11 in higher dose groups. Cumulative frequencies of convulsive (DS) and drop seizures (LGS) were calculated as 28-day averages for each titration day (including previous treatment days). Adverse events (AEs) were assessed.

Overall, 296 patients were randomized to CBD and 220 to placebo. Mean age was 9 years (DS; GWPCARE1) and 15 years (LGS; GWPCARE3/GWPCARE4). In GWPCARE1, nominal statistical significance vs placebo was achieved at day 10 (p=0.0261), and in GWPCARE3/GWPCARE4 (pooled data), at day 6 for the 20 mg/kg/d arm (p=0.0061) and at day 8 for the 10 mg/kg/d arm (p=0.0368). Of patients with AEs, 60% had their first during titration. Differences for CBD versus placebo in overall AEs and some common AEs were evident during titration but generally to a lesser degree than during the treatment period. Most common (≥10%) AEs: somnolence, decreased appetite, fatigue and diarrhea.

Findings suggest that the titration schedule used in the GWPCARE trials led to a significant treatment effect for CBD within 6–10 days during up titration.