Safety and Tolerability of Transdermal Cannabidiol Gel in Children With Developmental and Epileptic Encephalopathies: A Nonrandomized Controlled Trial.

Abstract

Developmental and epileptic encephalopathies (DEEs) are the most severe group of drug-resistant epilepsies. Alternatives to oral therapies are urgently needed to reduce seizures and improve developmental outcomes and comorbidities in this medically complex population. To assess the safety and tolerability of cannabidiol (CBD) transdermal gel in children with DEEs and to evaluate seizure frequency, sleep, and quality of life. This nonrandomized controlled trial was conducted in 2 centers in Australia and New Zealand from April 2018 to July 2019. Children and adolescents aged 3 to 18 years with DEEs who were receiving a stable regimen of 1 to 4 antiseizure medications were eligible for this study. After 1-month baseline and titration periods, patients entered a 5.5-month flexible-dosing maintenance period for a total of 6.5 months of treatment. Data were analyzed throughout the 6.5-month treatment period. Twice-daily applications of CBD transdermal gel at doses of 125 to 500 mg for 6.5 months. Safety and tolerability assessments included adverse events (AEs) and examination of skin. The outcome for seizures was the median percentage change from baseline in monthly (28-day) seizure frequency of focal impaired awareness seizures (FIAS) and tonic-clonic seizures (TCS) over 6.5 months. Of 48 patients (mean [SD] age, 10.5 [3.8] years; 26 [54%] boys), 29 (60%) had at least 1 treatment-related AE over 6.5 months; 44 of 46 treatment-related AEs (96%) were mild or moderate. Treatment-related AEs that occurred in at least 5% of patients were application-site dryness, application-site pain, and somnolence (each reported by 4 patients [8%]). The only treatment-related gastrointestinal AE was diarrhea, reported in a single patient. CBD treatment was associated with reductions in FIAS and TCS frequency. Analysis of the 33 patients with FIAS and TCS showed a median (interquartile range) monthly reduction in seizures of 58% (-5.3% to 81.8%) at 5 months and 43.5% (-23.8% to 57.5%) over the entire 6.5-month study period. Parents and caregivers noted improvements in social or interpersonal engagement and irritability (33 of 43 [77%] participants); alertness, energy, and sleep (23 of 43 [53%]); and cognition or concentration (20 of 43 [47%]). In this study, CBD transdermal gel was safe, well tolerated, and was associated with reductions in FIAS and TCS frequency and disease burden. ClinicalTrials.gov Identifier: ACTRN12618000516280.