Abstracts

This is a Late Breaking abstract

Rationale: Dravet syndrome (DS) is a rare developmental and epileptic encephalopathy associated with severe, treatment-resistant seizures. The natural history of DS is variable and imprecisely characterized. Since seizures and seizure clusters are linked to morbidity, reduced quality of life, and premature mortality, a greater understanding of the natural history could improve trial designs. This analysis explored seizure types, seizure clusters and factors affecting seizure cluster variability in DS patients.

Methods: Pooled post-hoc analyses were performed on data from placebo-treated patients from the GWPCARE 1B and GWPCARE 2 randomized controlled phase III trials comparing cannabidiol and placebo in DS patients aged 2–18 years.^1,2 Seizure clusters were defined as either ≥2 or ≥3 seizures occurring within 24 hours. Multivariate stepwise analysis of covariance (ANCOVA) of log-transformed seizure cluster frequency during the 14-week treatment period (2 weeks dose escalation; 12 weeks dose maintenance) was performed; explanatory variables included body weight and body mass index (BMI), antiseizure medication use, sex, race, geographic region, baseline seizure cluster frequency, DS history and age group (2–5; 6–12; 13–18 years). Incidence of adverse events (AEs) was assessed during the treatment period.

Results: The analysis included 124 placebo-treated patients across both studies (2–5 years: n=35; 6–12 years: n=52; 13–18 years: n=37). Generalized tonic-clonic seizures followed by myoclonic seizures were the most frequent seizure types. Mean and median convulsive seizure cluster frequency overall decreased between the baseline and maintenance period but did not change significantly during the maintenance period; variation in the mean and median seizure cluster frequency across the different age groups was observed. Multivariate analysis revealed an association of age (positive correlation) and BMI (negative correlation) with seizure cluster frequency (when defined as ≥3 seizures in 24 hours). AEs were generally infrequent, with “somnolence, fatigue, lethargy and sedation” being the most common across the three age groups.

Conclusions: This study identified a potential link between age, BMI and seizure cluster frequency. Our results suggest that seizure cluster frequency may be a valuable outcome measure in future trials. Further research to assess the natural history of DS, ideally with larger cohorts and objective measures, is needed to confirm our findings.
_x000D_ References:_x000D_ _x000D_ 1. Devinsky O, Cross JH, Wright S. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N Engl J Med. 2017;377:699-700._x000D_ 2. Miller I, Scheffer IE, Gunning B, Sanchez-Carpintero R, Gil-Nagel A, Perry MS et al. Dose-Ranging Effect of Adjunctive Oral Cannabidiol vs Placebo on Convulsive Seizure Frequency in Dravet Syndrome: A Randomized Clinical Trial. JAMA Neurol. 2020;77:613-621._x000D_
Funding: This study was funded by Jazz Pharmaceuticals. Editorial and medical writing services were provided by Costello Medical.