Medicinal Cannabis in Refractory Epilepsies

Research question: The primary question being addressed by this study is whether cannabidiol (CBD), and CBD with tetrahydrocannabinol (THC), reduce convulsive seizure frequency in a range of epilepsies more effectively than placebo, in the absence of any effect on neuropsychological function. Background: Epilepsy is a common neurological disorder affecting 1-2% of the population. Although anti-seizure medications (ASMs) successfully control epilepsy in around 70% of patients, approximately 30% will have seizures that are resistant to current treatments. Such individuals have a high risk of morbidity and a risk of early mortality, specifically sudden unexpected death in epilepsy. Historically there has been much interest in the use of cannabinoids for the treatment of the epilepsies. Recently there has been public and media interest in their use particularly in children with intractable seizures and learning impairment. The Cannabis plant produces in excess of 140 phyto-cannabinoids but almost all clinical research to date has focused on two: CBD and THC. There have been randomized controlled trials (RCTs) investigating the use of a pure CBD product (Epidyolex ®) in three rare conditions associated with difficult epilepsies: Dravet Syndrome, Lennox Gastaut Syndrome, and tuberous sclerosis complex. These trials have suggested benefit but there have been no RCTs in the broader group of children or adults with intractable epilepsy. Moreover, there have been no RCTs to determine the efficacy of products containing both CBD and THC or addressing the possibility of any cognitive effect of chronic exposure to THC. Aims and objectives: 1. To investigate whether CBD and CBD+THC are effective in reducing seizures in a broad range of epilepsies and across a broad range of seizure types 2. To investigate whether CBD and CBD+THC have any impact on cognition, quality of life, levels of behaviour and anxiety, sleep quality and parental stress 3. To estimate the cost-effectiveness of CBD and CBD+THC from the perspective of the National Health Service and Personal Social Services. Methods: Two double blind parallel arm studies; study 1 recruiting individuals with refractory early onset (<3 years) and cognitive impairment age 2-45 and study 2 individuals with refractory genetic generalised epilepsy of normal cognitive ability age 10-45. After a baseline period, they will be randomised to one of three treatment arms, and reviewed every month to 24 weeks (end of blind period/ primary outcome). Cognitive and/ or behaviour assessments will be conducted at baseline and 24 weeks. A total of 240 patients are required in each study. Timelines for delivery: After initial setup over 9 months, the first patient will enter screening for 2 months (8 weeks), and recruitment/randomisation will be conducted over 18 months. Final visit of last patient will be 32 weeks after final randomisation. Results will be analysed and written up over 6 months and available within 3.5 years of initiation of the study. Anticipated impact and dissemination: These studies will answer specific questions as to whether CBD and CBD with THC are safe and cost effective in the treatment of seizures in a range of epilepsies. Results will provide answers to current questions frequently asked by parents, carers, physicians, and politicians. Results will be disseminated through engagement with the epilepsy charities, as well as submitted for publication.