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

doi:10.1111/epi.16974

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

Epilepsia. 2021 Sep;62(9):2218-2227. doi: 10.1111/epi.16974. Epub 2021 Jul 15.

Authors

Jennifer Madan Cohen¹, Daniel Checketts², Eduardo Dunayevich³, Boudewijn Gunning⁴, Ann Hyslop⁵, Deepak Madhavan⁶, Vicente Villanueva⁷, Marta Zolnowska⁸, Sameer M Zuberi⁹

Affiliations

¹ Department of Pediatrics, Division of Neurology at Connecticut Children's, University of Connecticut, Hartford, Connecticut, USA.
² GW Research, Cambridge, UK.
³ Greenwich Biosciences, Carlsbad, California, USA.
⁴ Stichting Epilepsie Instellingen Nederland, Zwolle, the Netherlands.
⁵ Nicklaus Children's Hospital, Miami, Florida, USA.
⁶ Boys Town National Research Hospital, Boys Town, Nebraska, USA.
⁷ University and Polytechnic Hospital La Fe, Valencia, Spain.
⁸ Medical Center Plejady, Krakow, Poland.
⁹ Paediatric Neurosciences Research Group, Royal Hospital for Children & College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, UK.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Anticonvulsants / therapeutic use
Cannabidiol / therapeutic use*
Child
Child, Preschool
Double-Blind Method
Epilepsies, Myoclonic* / drug therapy
Epileptic Syndromes
Humans
Randomized Controlled Trials as Topic
Seizures / drug therapy
Spasms, Infantile
Treatment Outcome

Substances

Anticonvulsants
Cannabidiol

Supplementary concepts

CDKL5 deficiency disorder

Associated data

ClinicalTrials.gov/NCT02091375
ClinicalTrials.gov/NCT02224703