Time to onset of cannabidiol (CBD) treatment effect in Lennox-Gastaut syndrome: Analysis from two randomized controlled trials

Abstract

Objective: To estimate time to onset of cannabidiol (CBD) treatment effect (seizure reduction and adverse events [AEs]), we conducted post hoc analyses of data from two randomized, placebo-controlled, Phase 3 trials, GWPCARE3 (NCT02224560) and GWPCARE4 (NCT02224690), of patients with Lennox-Gastaut syndrome.

Methods: Patients received plant-derived pharmaceutical formulation of highly purified CBD (Epidiolex, 100 mg/ml oral solution) at 10 mg/kg/day (CBD10; GWPCARE3) or 20 mg/kg/day (CBD20; both trials) or placebo for 14 weeks. Treatment started at 2.5 mg/kg/day for all groups and reached 10 mg/kg/day on Day 7 and 20 mg/kg/day (CBD20 and matching placebo only) on Day 11. Percentage change from baseline in drop seizure frequency was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were evaluated.

Results: Overall, 235 patients received CBD (CBD10 [GWPCARE3 only], n = 67; CBD20 [pooled GWPCARE3&4], n = 168) and 161 received placebo. Mean (range) age was 15.3 years (2.6-48.0). Patients had previously discontinued a median (range) of six (0-28) antiepileptic drugs (AEDs) and were currently taking a median of three (0-5) AEDs. Differences in drop seizure reduction between placebo and CBD emerged during the titration period and became nominally significant by Day 6 (p = .008) for pooled CBD treatment groups. Separation between placebo and CBD in ≥50% responder rate emerged by Day 6. Onset of the first reported AE occurred during the titration period in 45% of patients (CBD10, 46%; CBD20, 52%; placebo, 38%). In patients with AEs, resolution occurred within 4 weeks of onset in 53% of placebo and 39% of CBD patients and by end of study in 63% of placebo and 61% of CBD patients.

Significance: Treatment effect (efficacy and AEs) of CBD may occur within 1 week of starting treatment. Although AEs lasted longer for CBD than placebo, most resolved within the 14-week period.

Keywords: antiepileptic drug; antiseizure medication; childhood onset epilepsy; drop seizures; treatment-resistant epilepsy.

Conflict of interest statement

M.P. has received research grants from SK Life Science, Xenon Pharmaceuticals, Epilepsy Foundation, and GW Pharmaceuticals, and has served as a consultant for SK Life Science, GW Pharmaceuticals, and Neurelis. H.B. was an investigator on trials sponsored by GW Research. M.W. received funds from GW Pharmaceuticals associated with conducting this study. J.H.C.'s institution received grants from Zogenix, Marinius, and Vitaflo and other support from GW Pharmaceuticals, Nutricia, and Biomarin. Her research is supported by the National Institute of Health Research Biomedical Research Centre at Great Ormond Street Hospital. E.W. has participated on advisory boards for Biomarin and Sunovian and has received personal fees from UpToDate. E.M. has served as a consultant for Eisai Pharma and Cydan, and as a study investigator for GW Pharmaceuticals. M.M.‐B. has served as a study investigator for GW Pharmaceuticals. V.V. has received grants from Eisai and UCB, and has participated on advisory boards for Eisai, UCB, Bial, Esteve, GW Pharmaceuticals, Arvelle Therapeutics, and Novartis. D.C. is a full‐time employee of GW Research. V.K. is a full‐time employee of Greenwich Biosciences and owns shares in the company. K.V. was an employee of Greenwich Biosciences at the time this study was conducted.

© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.

Figures

FIGURE 1

Efficacy outcomes: cumulative percentage reduction from baseline in drop seizure frequency by day (A) and percentage of patients with ≥50% reduction in drop seizure frequency by day (B). *Difference between pooled cannabidiol (CBD) groups and placebo became nominally significant on Day 6 at p = .008. The dotted line for each dose group represents the data until Day 9, when all patients were receiving the same dose of study drug, reflecting small variations in response not attributable to difference in dosage. The solid purple line represents all CBD patients until Day 9, at which point patients in CBD10 remained on 10 mg/kg/day and those in CBD20 continued titration up to 20 mg/kg/day. CBD10, cannabidiol 10 mg/kg/day; CBD20, cannabidiol 20 mg/kg/day

FIGURE 2

Adverse events by time of onset. If a patient had multiple occurrences of an adverse event (AE), then the AE was counted once for the first occurrence only. Percentage of patients was calculated based on the number of patients in the safety analysis set who had a visit or follow‐up call within each time period. One patient in the placebo group first experienced an AE after the 14‐week treatment period. CBD, cannabidiol

FIGURE 3

Time to first occurrence of somnolence or sedation (A), decreased appetite (B), and diarrhea (C) by day. The arrow in panel A shows the time (Day 2) when a clear separation in the time to first occurrence between placebo and cannabidiol (CBD) was observed. During the first 2 days of treatment, 10 patients taking CBD and one patient taking placebo had a treatment‐emergent adverse event of somnolence; seven of 10 patients on CBD were also taking clobazam. No incidence of sedation was reported during Days 1–2