Abstracts

Rationale: Two trials (GWPCARE 3 [NCT02224560]; GWPCARE 4 [NCT02224690]) of similar design established the efficacy and safety of CBD treatment for LGS-associated seizures. To understand the course of seizure reduction and the onset and resolution of AEs in CBD-treated pts, pooled data from these trials were analyzed. Methods: Data were pooled from 2 randomized, multicenter, double-blind, placebo (PBO)-controlled trials of CBD as add-on therapy in pts aged 2-55 years (y) with treatment-resistant LGS (defined as =2 drop seizures/week [wk] during 4-wk baseline, and failure of =1 antiepileptic drug [AED]). Pts were randomized to PBO or a plant-derived pharmaceutical formulation of CBD (100 mg/mL) in oral solution, dosed at 10 mg/kg/day (CBD10) or 20 mg/kg/day (CBD20) in 2 equally divided doses, over a 2-wk titration period followed by a 12-wk maintenance period. Outcomes were median percent change from baseline in monthly drop and total seizures during the treatment period and across the maintenance period (Wks 1-4, 5-8, and 9-12). Times of AE onset and resolution were recorded during the titration and maintenance periods. Results: A total of 396 pts were randomized (73 CBD10; 162 CBD20; 161 PBO). Baseline demographic characteristics were evenly distributed: mean age 15 y (32% =18 y), 55% male. Median percent change from baseline in drop seizure frequency for CBD10 and CBD20 vs PBO was 37% and 43% vs 20% during the treatment period, and 40% and 48% vs 20% during the maintenance period; between-group differences were significant by Wk 4 of maintenance and remained stable (Table 1). Median percent changes from baseline in total seizure frequency were also greater for CBD10 and CBD20 than PBO during both the treatment (36% and 39% vs 17%) and maintenance (40% and 44% vs 17%) periods; differences between groups were significant by Wk 4 and were consistent over time (Table 1). More pts discontinued treatment due to AEs in the CBD groups (2% for CBD10 and 11% for CBD20 vs 1% for PBO). AE onset was more common during titration vs maintenance (Table 2). The most common AEs were somnolence (21% CBD10, 23% CBD20, 8% PBO), decreased appetite (16% CBD10, 19% CBD20, 5% PBO), and diarrhea (10% CBD10, 17% CBD20, 8% PBO). Forty-eight percent and 57% of CBD10 and CBD20 pts had AEs that resolved during the study (most within 4 wks of onset) and 36% and 33% of CBD10 and CBD20 pts had AEs that were ongoing at last visit (Table 2). Elevated transaminases (>3x ULN) were reported in 3 CBD10, 31 CBD20, and 1 PBO pt, most of whom were on concomitant valproic acid; some of these pts withdrew from treatment, and all elevations resolved either spontaneously or with CBD/AED dose adjustment. Conclusions: Significant reductions in both drop and total seizures were observed during the first 4 wks of maintenance treatment with add-on CBD. These effects persisted to the end of treatment. About half of the pts in the CBD groups had AEs that first occurred during titration, and the majority resolved during the study. Funding: GW Research Ltd