Abstracts

Rationale: Add-on CBD significantly reduced drop seizure frequency with an acceptable safety profile in patients with LGS in a phase 3 randomized controlled trial (RCT; GWPCARE3; NCT02224560). Long-term safety and efficacy of CBD was established in an OLE trial (GWPCARE5; NCT02224573) that enrolled patients who completed the RCT. In this post hoc analysis of GWPCARE3 and GWPCARE5, we evaluated the effect of dose adjustments on the efficacy and safety of CBD.

Methods: In GWPCARE3, eligible patients (2–55 yrs) who had ≥2 drop seizures per wk during the 4-wk baseline period were randomized to receive plant-derived highly purified CBD (Epidiolex®; 100 mg/mL oral solution) at 10 mg/kg/d (CBD10) or 20 mg/kg/d or matched placebo for 14 wks. Patients who completed the RCT were invited to enroll in the OLE trial. During the OLE, the dose was titrated to an initial target of 20 mg/kg/d in all patients. Based on response and tolerability, CBD could then be decreased or increased (up to a maximum of 30 mg/kg/d). These analyses included patients from the CBD10 group of GWPCARE3 whose dose was titrated up per OLE trial protocol and who maintained a modal dose of ≥12.5 mg/kg/d throughout the OLE treatment period. Efficacy was evaluated as the weekly median percent change from baseline in drop seizure frequency through 96 wks of treatment.

Results: Analyses included 43/71 OLE patients (28/71 [39%] did not maintain a modal dose ≥12.5mg/kg/d). Median (range) age was 12 (3–38) yrs. Patients had discontinued a median (range) of 7 (2–21) antiseizure medications (ASMs) and were currently taking a median of 3 (1–5) ASMs. In the 4-wk baseline period, median (range) drop seizure frequency was 83 (14–7494). At the end of the RCT, cumulative weekly median percent reduction from baseline was 47%. After entering the OLE portion, an additional 14% reduction in cumulative weekly seizure frequency was observed. Reduction in seizure frequency during the OLE was greater in patients (25/43 [58%]) who did not have ≥50% reduction in drop seizures during the RCT than in patients (18/43 [42%]) who had ≥50% reduction. Additional reduction in seizure frequency was maintained throughout the OLE. AEs were reported in 36/43 (84%) patients during the RCT and 42/43 (98%) patients during the OLE. For this subgroup, the most common AEs were somnolence, decreased appetite, and upper respiratory tract infection (8/43 patients [19%] each) during the RCT and convulsion (22/43 patients [51%]), diarrhea (18/43 [42%]), and pyrexia (16/43 [37%]) at any point during the OLE.

Conclusions: Additional reductions in drop seizure frequency were observed among patients in the CBD10 group of the RCT, whose dose was further titrated upon entering the OLE. The safety profile remained consistent with overall RCT and OLE trial populations. This post hoc analysis emphasizes the importance of titrating to each patient’s therapeutic dose, as dose adjustments may improve seizure reduction in some patients.

Funding: Please list any funding that was received in support of this abstract.: GW Research Ltd.