Introduction

Management of drug-resistant seizures is difficult in Dravet syndrome, which is a complex childhood epilepsy disorder associated with a high mortality rate. A series of in vitro and in vivo preclinical models of seizure showed that cannabidiol had activity against convulsive seizures.

Aim

To evaluate the efficacy of cannabidiol for the treatment of drug-resistant epilepsy in the Dravet syndrome in a randomized, double-blind, multinational, placebo-controlled trial

Patient Profile

• 120 patients (2-18 years of age) with Dravet syndrome whose seizures were not controlled by their current antiepileptic drug regimen
• Patients were taking >1 antiepileptic drugs, and had had >4 convulsive seizures during the 28-day baseline period
• All medications or interventions for epilepsy, including a ketogenic diet and vagus nerve stimulation, were stable for 4 weeks before screening and were to remain unchanged throughout the trial

Method

Study Design

• Multinational, randomized, double-blind, placebo-controlled trial
• Patients were randomly assigned to receive either adjunctive cannabidiol (oral solution of up to 20 mg/kilogram of body weight/day) or placebo, in addition to standard antiepileptic treatment.
• The trial comprised a 4-week baseline period, a 14-week treatment period (2 weeks of dose escalation and 12 weeks of dose maintenance), a 10-day taper period, and a 4-week safety follow-up period

Endpoints

• Primary end point: the percentage change per 28 days from the 4-week baseline period in convulsive-seizure frequency during the 14-week treatment period
• Secondary end-point: Caregiver Global Impression of Change (CGIC); the number of patients with a reduction in convulsive-seizure frequency of at least 25%, at least 50%, at least 75%, and 100%; reduction in total seizure frequency and reduction of seizure subtypes; the duration of seizure subtypes; sleep disruption; the change in the score on the Epworth Sleepiness Scale; the score on the Quality of Life in Childhood Epilepsy questionnaire; the age-standardized score on the Vineland Adaptive Behavior Scales, second edition; the number of hospitalizations due to epilepsy; the number of patients with the emergence of seizure types that had not occurred during the baseline period; and the use of rescue medication
• Safety assessments: basis of the number, type, and severity of adverse events as well as the Columbia Suicide Severity Rating Scale, vital signs, electrocardiographic variables, laboratory safety variables, and physical examination variables

Results

Efficacy

• Cannabidiol significantly reduced the median frequency of convulsive seizures per month (from 12.4 to 5.9) by −38.9 percentage points (P = 0.01) as compared to placebo (from 14.9 to 14.1) by -13.3 percentage points (Figure 1)
• Cannabidiol achieved at least a 50% reduction in convulsive seizure frequency in 43% of patients as compared to 27%patients with placebo (odds ratio, 2.00; P = 0.08)
• On the CGIC scale, 37 of 60 caregivers (62%) judged their child’s overall condition improved in the cannabidiol group, as compared with 20 of 58 caregivers (34%) in the placebo group (P=0.02)
• Cannabidiol significantly reduced the frequency of total seizures of all types (24 to 13.7 with a 28.6% reduction) versus placebo (41.5 to 31.1 with a 9.0% reduction); a significant adjusted median difference of −19.2 percentage points between groups (P = 0.03)
• Rescue medication was used by 36 patients (59%) in the cannabidiol group and by 41 patients (69%) in the control group

Figure 1: Effect of cannabidiol and placebo on the primary endpoint

Safety 

• The frequently reported adverse events in the cannabidiol group were the percentage change per 28 days from the 4-week baseline period in convulsive-seizure frequency during the 14-weektreatment period

• Study withdrawals occurred in 8 patients in the cannabidiol group as compared with 1 in the placebo group. The most common adverse event was somnolence (36% in the cannabidiol group and 10% in the placebo group)
• Serious adverse events were reported in 10 patients in the cannabidiol group and 3 in the placebo group

Conclusion

Cannabidiol achieved greater reduction in convulsive-seizure frequency as compared to placebo among children and young adults with the Dravet syndrome over a 14-week period but was associated with adverse events

N Engl J Med 2017; 376: 2011-20