(Devinsky, et al. 2017) The long-anticipated results from the first randomized, double blind, placebo controlled trial of cannabidiol (CBD) in Dravet syndrome show that cannabidiol can help alleviate seizures in this syndrome. While there have been anecdotal stories of success with CBD in Dravet syndrome since as early as 2012, this trial represents the first and largest study in which the participants were randomized (assigned to either the group receiving 20mg/kg/day of cannabidiol or the placebo group), double blind (neither the treating physician nor the patient knew whether the patient was receiving cannabidiol or placebo) and reported seizures daily (as opposed to retrospective caregiver reports of seizure counts). This is a rigorous study method because it eliminates many sources of bias, ensures statistically significant group sizes, eliminates variables such as medication, diet, and other changes to treatment during the study, and systematically measures side effects.
A total of 108 patients successfully completed the 14-week treatment period that included “randomization” (50% entered the placebo group and 50% entered the cannabidiol group), a 2-week titration up to the desired dose, and a 12 week maintenance period. After this blind portion of the study, patients were offered the option of entering into a long-term open-label study, in which all patients received cannabidiol. In clinical trials, “endpoints” are established during trial design to prevent post-experimental justification or misdirected conclusions from occurring. Primary endpoints measure the most important outcome of the trial, and if a primary endpoint is not met, the trial is usually considered a failure. In this trial, the primary endpoint was the percentage change per 28 days from the 4-week baseline period in convulsive seizure frequency during the 14-week treatment period compared to placebo. In the cannabidiol group, median convulsive seizure frequency (the primary endpoint) decreased from 12.4 seizures per month during baseline to 5.9 seizures per month during treatment (-39%), compared to the placebo group whose median convulsive seizure frequency decreased from 14.9 seizures per month during baseline to 14.1 seizures per month during treatment (-13%).
The secondary endpoints included caregiver impression of change (as measured by a repeated questionnaire with seven options of improvement, worsening, or no change), reduction of convulsive seizure frequency, reduction in total seizure frequency, duration of seizures, sleep disruption (measured on a 10 point scale), sleepiness (measured on 24 point scale), quality of life (measured in a standard questionnaire with a range of 0-100), the Vineland Adaptive Behavior Scale, number of hospitalizations due to epilepsy, new seizure types, and rescue medication use. The secondary endpoints had varying results. 43% of the cannabidiol group experienced a 50% reduction in convulsive seizures compared to 27% of the placebo group. There was little to no difference between the two groups in terms of nonconvulsive seizures, rescue medication use, sleep disruption or sleepiness scores, quality of life scores, or Vineland-II scores, but 62% of caregivers rated their child’s overall condition improved in the cannabidiol group compared to 34% in the placebo group.
The most common adverse event was somnolence, followed by diarrhea, decreased appetite, and fatigue. Dose adjustment reduced these events in many patients. Serious adverse events occurred in 16% of the cannabidiol group and 5% of the placebo group and included status epilepticus (equal frequency of occurrence in both groups, deemed unrelated to the medication) and elevated levels of liver aminotransferase enzymes in patients taking some form of valproate.