IP 112. Cannabidiol Treatment Effect and Adverse Events in Patients with Lennox–Gastaut’s syndrome: Pooled Results from Two Trials

Background: Patients with Lennox–Gastaut’s syndrome (LGS) are frequently treatment resistant to available medications.

Aims: The efficacy and safety of CBD in the treatment of LGS-associated seizures were analyzed in two Phase 3 trials of similar design: GWPCARE3 (NCT02224560) and GWPCARE4 (NCT02224690).

Question: When CBD is added to existing antiepileptic drugs (AEDs), how early is the treatment effect observed, and when are adverse events (AEs) most likely to first occur?

Methods: Data were pooled from two randomized, multicenter, double-blind, placebo (PBO)-controlled trials of add-on CBD in patients aged 2 to 55 years with treatment-resistant LGS (≥2 drop seizures/week during 4-week baseline and failure of ≥1 AED). Patients were randomized to PBO or a plant-derived pharmaceutical formulation of CBD 10 mg/kg/d (CBD10) or 20 mg/kg/d (CBD20) in two equally divided doses over a 2-week titration followed by a 12-week maintenance period. Outcomes were median percent change from baseline in monthly drop seizure frequency during treatment and maintenance periods, and by time interval (titration, weeks 1–4, 5–8, 9–12). Times of AE onset and resolution were recorded during titration and maintenance periods.

Results: Overall, 396 patients were randomized (73 CBD10; 162 CBD20; 161 PBO). Baseline demographic characteristics were evenly distributed: mean age 15.5 years (32% ≥18 years); 55% male. Median percent changes from baseline in drop seizure frequency were CBD10 37 versus PBO 17% and CBD20 43 versus PBO 20% during the treatment period; CBD10 40 versus PBO 19% and CBD20 48 versus PBO 20% during the maintenance period. Greater reductions in monthly drop seizure frequency were evident during the 2-week titration period and each 4-week interval of the maintenance period for CBD versus PBO. More patients discontinued treatment owing to AEs in the CBD groups (CBD10 1%, CBD20 11%) versus PBO (1%). Onset of AEs was more common during titration (CBD10 46%, CBD20 52%, PBO 38%) versus the maintenance periods (weeks 1–4: CBD10 33%, CBD20 29%, PBO 16%; weeks 5–12: ≤10% all groups). The most common AEs were somnolence (CBD10 21%, CBD20 23%, PBO 7%), decreased appetite (CBD10 16%, CBD20 19%, PBO 5%), and diarrhea (CBD10 10%, CBD20 17%, PBO 8%). Overall, 48 and 57% of CBD10 and CBD20 patients had AEs that resolved during the study (most within 4 weeks of onset); 36 and 33% of CBD10 and CBD20 patients had ongoing AEs at the last visit. Elevated transaminases (>3× upper limit of normal range) were reported in 3 CBD10, 31 CBD20, and 1 PBO patient, most of whom (74%) were on concomitant valproic acid; some of these patients withdrew from treatment. All elevations resolved either spontaneously or with CBD/AED dose adjustment.

Conclusion: Reductions in monthly drop seizure frequency were greater with both CBD doses than with PBO; this treatment difference emerged during the titration period and persisted to the end of treatment. Onset of AEs for most patients occurred during titration or the first 4 weeks of maintenance; AEs were more frequent with CBD than PBO. Many AEs resolved within 4 weeks of onset and most resolved within the 14-week treatment period.

Funding: GW Research Ltd.