Time to onset of cannabidiol treatment effects in Dravet syndrome: Analysis from two randomized controlled trials

Abstract

Objective We conducted a post hoc analysis of two randomized controlled trials, GWPCARE1 (NCT02091375) and GWPCARE2 (NCT02224703), to estimate the time to onset of cannabidiol (CBD) treatment effects (seizure reduction and adverse events [AEs]) in patients with Dravet syndrome (DS). Methods Patients received either plant‐derived highly purified CBD (Epidiolex in the United States; 100 mg/ml oral solution) 10 mg/kg/day (CBD10; GWPCARE2) or 20 mg/kg/day (CBD20; GWPCARE1&2), or matching placebo for 14 weeks. Treatment started at 2.5 mg/kg/day, reached 10 mg/kg/day on Day 7, and went up to 20 mg/kg/day on Day 11 during the 14‐day titration period. Percentage change from baseline in convulsive seizure frequency was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were also evaluated. Results Overall, 124 patients received placebo and 194 received CBD (CBD10, n = 64; CBD20, n = 130). Mean age was 9.5 years (range = 2.2–18.9). Patients had discontinued a median of four antiepileptic drugs (range = 0–26) and were currently taking a median of three (range = 1–5). Differences in convulsive seizure reduction between placebo and CBD emerged during titration and became nominally significant by Day 12 for CBD20 (p = .02) and Day 13 for CBD10 (p = .03). Additionally, differences in the 50% responder rate between placebo and CBD became apparent during titration. Onset of the first reported AE occurred during the titration period in 48.4% of placebo patients and 54.1% of CBD patients. The three most common AEs of somnolence, decreased appetite, and diarrhea resolved within 4 weeks of onset in the majority of CBD‐treated patients (56.3%–72.9%). Significance The therapeutic effect of CBD in DS may start within 2 weeks of treatment in some patients. Although AEs lasted longer for CBD than placebo, most resolved within the 14‐week study period.

Time to onset of cannabidiol treatment effect and resolution of adverse events in tuberous sclerosis complex: Post hoc analysis of randomized controlled phase 3 trial GWPCARE6

“…28,29 Both vigabatrin 30 and CBD 31 reach steady state after approximately 2 days, supporting their early onset of treatment effect. The early onset of CBD's treatment effect in terms of efficacy was also observed in clinical trials of patients with LGS and DS, 20,21 during which a significant difference in seizure reduction between placebo and CBD was observed within 2 weeks of starting treatment, demonstrating a consistent effect of CBD treatment across several treatment-resistant epilepsies.…”

“…Although a nominally significant difference was observed in the antiseizure effect of placebo and CBD during the early time points, it may not prove to be statistically significant in a prospectively designed trial. However, early treatment effect is supported by data from CBD trials in patients with LGS and DS 20,21 …”

Long‐term cannabidiol treatment for seizures in patients with tuberous sclerosis complex: An open‐label extension trial

“…Although the etiology is not known, diarrhea has been reported as the most frequent AE in other clinical trials of CBD; in most cases, however, the severity was mild or moderate and resolved before the end of treatment. 30 , 31 Permanent treatment discontinuation because of an AE was low (6%) despite some patients being on treatment for up to 130 weeks, supporting a favorable safety profile of CBD for long‐term use in patients with TSC‐associated seizures.…”

Cannabidiol and epilepsy in Brazil: a current review

“…Fifty two percent of patients displayed side effects within two weeks of dose titration. Most common side effects were drowsiness, hyporexia and diarrhea, which were resolved within four weeks in most patients 43 .…”

“…Internationally, cannabidiol use for refractory epilepsy was evaluated by Agencies in England (National Institute for Health and Care Excellence - NICE), Scotland (Scottish Medicines Consortium - SMC) and Argentina (Administracion Nacional de Medicamentos, Alimentos y Tecnologia Médica - ANMAT) 43 . Following approval of Epidiolex , these agencies strongly recommended its exclusive use for Dravet 38 , 39 and Lennox-Gastaut syndromes 38 , 40 .…”