Abstracts

Rationale: Nearly 20% of all patients with epilepsy have an intractable form with generalized seizure activity (IGE), with an early onset in children. With standard treatment frequently proven ineffective, we aim to determine the safety and efficacy of cannabidiol (CBD)(Epidiolex, GW Pharmaceuticals) on this specific epilepsy type. Methods: Through an open-label trial, children between 2 to 16 years with IGE were enrolled in an expanded-access program. Patients were given oil-based cannabidiol at 5 mg/kg/day, titrated up to a maximum dose 25 mg/kg/day. The primary outcomes were to determine the efficacy of CBD on median monthly seizure frequency, including its safety and tolerability after 12 months of treatment; the secondary outcome was quality of life changes. Non-parametric permutation tests were conducted with one million permutations each to obtain empirical p-values - three patients between the ages of 2 and 16 (average age 10.4 years) entered the study with an average of 220 seizures per month (range 7-3905). The 28 patients who completed the 12 months of CBD treatment were included in the efficacy, safety and tolerability analysis. The median monthly seizure frequency at baseline was 111.9, 47.4 after 3 months of treatment, 38.0 after 6 months, and 27.9 after 12 months. To monitor safety, blood draws, plasma levels, and vital signs were completed at each clinical visit.  Improvements in quality-of-life and sleep disruption were reported through clinical questionnaires. Results: The patients (n=33) experienced four different seizure types while using varying combinations of 12 different anti-epileptic drugs (AED) (average 2.8 AEDs each). Before CBD treatment, and again after 6 months, patients underwent assessments to track any adaptive behavior and daily function changes that may occur. Seven patients had an IQ score above 70 and 26 scored below 70 at the start of the study. Patients received CBD at a dose of 25 mg/kg/day in addition to their currently used AEDs for a total of 6 months, with all seizure activity recorded in diaries. Twenty-one of the 33 patients were considered responders, having a reduction of > 50% seizure activity. Fourteen had >80% seizure activity reduced, with three being completely seizure free. Assessments showed improvement in disruptive behavior, social interaction, and quality-of-life. No safety concerns from blood tests and vital signs were found, though there was notable interaction between CBD and other AEDs, particularly clobazam and clonazepam, resulting in some reported side effects. Ten patients had one-hour EEG recordings taken before starting the study and 6 months after CBD treatment began. Readings and quantitative analysis show a statistically significant reduction in epileptiform activity and discharges. These changes in brain electrical activity correspond to seizure reduction and cognitive transformations seen by the same patients.  The most common adverse events reported were diarrhea (32%), somnolence (25%), and weight loss (18%). Four (4) patients discontinued treatment unrelated to adverse events. Improvements in quality of life and sleep disruption were reported through clinical questionnaires. Conclusions: Cannabidiol results in a significant reduction in seizure frequency in children with IGE, with trends towards improving overall quality-of-life and behavior. Double-blinded trials are needed to identify the true efficacy of this treatment in IGE.  Funding: Florida Department of Health Grant Number EP501 (PRC)