Abstracts

Rationale: Add-on CBD significantly reduced frequency of convulsive seizures associated with Dravet syndrome (DS), with an acceptable safety profile, in two phase 3, randomized, placebo-controlled trials, GWPCARE1 (NCT02091375) and GWPCARE2 (NCT02224703). To estimate the time to onset of efficacy across treatments and safety in the overall DS population, we conducted a post hoc pooled analysis of GWPCARE1 and 2. Methods: Patients were randomized to receive a plant-derived pharmaceutical formulation of highly purified CBD in oral solution (Epidiolex®100 mg/mL) at a 10 mg/kg/d (CBD10; GWPCARE2) or 20 mg/kg/d (CBD20; both trials) dose or placebo for 14 weeks (2-week titration and 12-week maintenance phase). Both dose groups of CBD started at 2.5 mg/kg/d and reached 10 mg/kg/d on day 7 of the titration period; 20 mg/kg/d was reached on day 11. Seizures were reported daily using an interactive voice response system. Percent reduction in cumulative convulsive seizure frequency for each treatment day (ie, including all previous treatment days) was calculated. Incidence of adverse events (AEs) and their time to onset and resolution during the treatment period were also assessed. Results: Across the 2 trials, 194 patients were randomized to CBD and 124 to placebo. Mean age of patients was 9 years. Patients had previously tried and discontinued a median of 4 antiepileptic drugs (AEDs) and were taking a median of 3 concurrent AEDs during the trial, with valproate (VPA; 66%) and clobazam (CLB; 64%) as the most common. The median baseline monthly convulsive seizure frequency was 11 for the CBD group and 16 for placebo. In the individual studies, CBD led to significantly greater percent reductions in convulsive seizure frequency than placebo: 39% for CBD20 vs 13% for placebo (p=0.0123) in GWPCARE1; 49% for CBD10 (p=0.0095) and 46% for CBD20 (p=0.0299) vs 27% for placebo in GWPCARE2. In the pooled data, differences in the percent reduction in seizure frequency between CBD and placebo emerged during the titration phase and were maintained throughout the study, with nominal significance (p<0.05) achieved by day 13 for CBD10 and day 12 for CBD20. Onset of the first reported AE occurred during the titration period in 60% of patients with AEs (CBD10, 50%; CBD20, 65%; placebo, 59%). Overall, AEs resolved within 4 weeks of onset in 40% of patients and by end of study (14 weeks) in 60%. Of the 3 most common AEs—somnolence, decreased appetite, and diarrhea—diarrhea was the only one with a notable difference in time to resolution between treatment groups (all cases resolved within 4 weeks for placebo and CBD10 vs 65% of cases for CBD20). Increases in ALT/AST (>