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

Jennifer Madan Cohen, Daniel Checketts, Eduardo Dunayevich, Boudewijn Gunning, Ann Hyslop, Deepak Madhavan, Vicente Villanueva, Marta Zolnowska, Sameer M Zuberi, Jennifer Madan Cohen, Daniel Checketts, Eduardo Dunayevich, Boudewijn Gunning, Ann Hyslop, Deepak Madhavan, Vicente Villanueva, Marta Zolnowska, Sameer M Zuberi

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.

Keywords: antiepileptic drug; childhood onset epilepsy; convulsive seizures; efficacy onset.

Conflict of interest statement

J.M.C. has received speaker fees from Greenwich Biosciences, and has been a principal investigator for GW Research. D.C. is an employee of GW Research, and owns stock in GW Pharmaceuticals. E.D. is an employee of Greenwich Biosciences, and owns stock in GW Pharmaceuticals. B.G. has received consultancy fees from GW Pharmaceuticals, Ovid/Takeda and Zogenix, and has been a principal investigator for GW Research, Zogenix, LivaNova, and Marinus Pharmaceuticals. A.H. has received consultancy and/or speaker fees from Supernus Pharmaceuticals, Eisai, GW Pharmaceuticals, and Aquestive Pharmaceuticals, and has been a principal investigator for GW Research, Sage Therapeutics, Marinus Pharmaceuticals, Neurocrine Biosciences, and UCB Biosciences. D.M. has received speaker fees from Greenwich Biosciences, and has been a been a principal investigator for GW Research. V.V. has participated on advisory boards and in symposia organized by Angelini, Arvelle, Bial, Eisai, Esteve, GSK, GW Pharmaceuticals, Novartis, Sandoz, UCB, and Zogenix, and has been a principal investigator for GW Research. M.Z. has been a principal investigator for GW Research, Zogenix, Ovid/Takeda, Marinus, and Emalex Biosciences. S.M.Z. has received research support from Epilepsy Research UK, Glasgow Children's Hospital Charity, the Tenovus Foundation, and UCB Pharma; has received honoraria for advisory boards, consulting, and educational symposia from GW Pharmaceuticals, Zogenix, Arvelle Therapeutics, Stoke Therapeutics, and Encoded Genomics; and has been a principal investigator for GW Research. His institution has undertaken commercial trials for GW Research and Zogenix. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

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

Figures

FIGURE 1
FIGURE 1
Reduction in convulsive seizure frequency during the treatment period. (A) Percentage reduction from baseline in convulsive seizure frequency by cumulative day; nominally significant by Day 12 for cannabidiol 20 mg/kg/day (CBD20; p = .02) and Day 13 for cannabidiol 10 mg/kg/day (CBD10; p = .03). (B) Percentage of patients reporting ≥50% reduction in convulsive seizure frequency by cumulative day. aData censored until Day 3 because the seizure frequency was ≈1 seizure every 2–3 days. Data are from the efficacy analysis set
FIGURE 2
FIGURE 2
Adverse events (AEs) by time of onset. Onset of AEs occurred early in treatment for most patients: during the titration period in approximately half (165 of 318, 51.9%) and during the first 4 weeks of the maintenance period in approximately a quarter of patients (80 of 318, 25.2%). If a patient had multiple occurrences of an AE, then the AE was counted once for the first occurrence only. The 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. Three patients in the cannabidiol 10 mg/kg/day (CBD10) group and two patients in the placebo group first experienced an AE after the 14‐week treatment period. The titration period includes Days 1–14 of the treatment period (i.e., time taken to reach the target maintenance dose of 10 or 20 mg/kg/day). CBD20, cannabidiol 20 mg/kg/day
FIGURE 3
FIGURE 3
Time to first occurrence of the three most common adverse events by day: (A) somnolence/fatigue/lethargy/sedation, (B) decreased appetite, and (C) diarrhea. CBD, cannabidiol

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