Abstracts

Rationale: Epilepsy is the most common neurologic manifestation of tuberous sclerosis complex (TSC) and is resistant to therapy in up to 60% of patients. Here we report the efficacy and safety results from GWPCARE6 (NCT02544763), the first trial to evaluate adjunctive CBD in patients with drug-resistant epilepsy associated with TSC. Methods: This was a randomized, double-blind, controlled trial conducted at 46 sites in 6 countries. Patients were randomized (2:2:1:1) to receive a plant-derived pharmaceutical formulation of highly purified CBD in oral solution (Epidiolex®; 100 mg/mL) at 25 mg/kg/d (CBD25) or 50 mg/kg/d (CBD50) dose or matched placebo for 16 wks (4-wk titration and 12-wk maintenance phase). Eligible patients were 1–65 y old with a clinical diagnosis of TSC, had ≥8 TSC-associated focal and generalized seizures (excluding absence, myoclonic, focal sensory, and infantile/epileptic spasms) during the 4-wk baseline period with ≥1 seizure/wk in ≥3 out of 4 wks, and were taking ≥1 antiepileptic drug (AED). The primary endpoint was percent change from baseline in TSC-associated focal and generalized seizure frequency for CBD vs placebo over the treatment period, calculated using a negative binomial regression analysis. Key secondary endpoints were ≥50% responder rate, percent reduction in total seizure frequency (including focal sensory and epileptic spasms), and subject/caregiver global impression of change (S/CGIC) in overall condition. Results: A total of 224 patients were randomized to CBD25 (n=75), CBD50 (n=73), or placebo (n=76) with 201 completing the study. The median (range) age was 11 (1–57) y. Patients had previously tried and discontinued a median of 4 AEDs and were currently taking a median of 3 AEDs. Valproate (45%), vigabatrin (33%), levetiracetam (29%), and clobazam (27%) were the most common concomitant AEDs. The median (interquartile range) baseline monthly TSC-associated seizure frequency was 56 (21–101) for CBD25, 61 (36–117) for CBD50, and 54 (26–102) for placebo. CBD produced a significantly greater percent reduction in TSC-associated seizure frequency vs placebo: 49% for CBD25, p=0.0009; 48% for CBD50, p=0.0018; 27% for placebo. More patients taking CBD25 (36%; p=0.0692) and CBD50 (40%; p=0.0245) had a ≥50% reduction in seizures vs placebo (22%). CBD also produced a significantly greater reduction in total seizure frequency vs placebo: 48% for CBD25, p=0.0013; 48% for CBD50, p=0.0018; 27% for placebo. Improvement in overall condition on S/CGIC was reported by 69% (odds ratio [OR]=2.25; p=0.0074) of patients/caregivers for CBD25 and 62% (OR=1.77; p=0.0580) for CBD50 vs 40% for placebo. Overall 93% of patients in CBD25, 100% in CBD50, and 95% in placebo groups had an adverse event (AE); most were mild or moderate. The most common AEs were diarrhea (CBD25, 31%; CBD50, 56%; placebo, 25%), decreased appetite (CBD25, 20%; CBD50, 23%; placebo, 12%), and somnolence (CBD25, 13%; CBD50, 26%; placebo, 9%). Eight patients in CBD25, 10 in CBD50, and 2 in placebo groups discontinued treatment due to an AE. ALT/AST increases (>3× ULN) occurred in 9 (12%) patients in CBD25, 18 (25%) in CBD50, and none in placebo groups; 81% of patients with elevations were on concomitant valproate. Conclusions: CBD reduced TSC-associated seizures vs placebo with similar efficacy between the 25 and 50 mg/kg/d doses. Given that the safety profile of 25 mg/kg/d was superior to 50 mg/kg/d, the lower dose range confers a superior benefit to risk ratio. Funding: GW Research Ltd