Trial Design and Oversight

This was a multinational, randomized, double-blind trial of adjunctive cannabidiol versus placebo in children and young adults 2 to 18 years of age with the Dravet syndrome whose seizures were not controlled by their current antiepileptic-drug regimen. 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. The trial was approved by the review board or ethics committee at each participating institution and was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. All the patients or their parents or legal representatives provided written informed consent, and children mature enough to understand the trial provided assent. Patients could withdraw at any point without prejudice.

The funding source, GW Pharmaceuticals, was responsible for the trial design (with input from investigators and other experts), trial management, site monitoring, trial pharmacovigilance, data analysis, and statistical analysis. GW Pharmaceuticals prepared and provided the active treatment and placebo. Trial procedures were reviewed at multisite investigator meetings. Services were used for clinical laboratory testing; bioanalytical laboratory testing; design of the case-report form; data management; trial-agent distribution, returns, and destruction; the interactive voice-response system; diagnosis of the Dravet syndrome and seizure classification; and translation of documents. The authors vouch for the accuracy and completeness of the reported data and analyses and for the adherence of the trial to the protocol (available with the full text of this article at NEJM.org). The authors affirm that they approved the final draft of the manuscript.

Patients were eligible if they had an established diagnosis of the Dravet syndrome, were taking one or more antiepileptic drugs, and had had four or more convulsive seizures during the 28-day baseline period. An independent review of the previously documented diagnosis of the Dravet syndrome and the classification of seizure type was conducted for each patient by an independent panel appointed by the Epilepsy Study Consortium, under a standard protocol (see the protocol). 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. The dose of cannabidiol used in the trial was recommended by an independent data and safety monitoring committee (see the protocol), whose members reviewed data from a dose-ranging pharmacokinetic and safety evaluation of three doses of cannabidiol (5, 10, and 20 mg per kilogram of body weight per day) and identified the maximum dose that was safe and was not associated with unacceptable side effects.

Procedures

After informed consent was obtained, patients entered a 4-week baseline period. The investigator trained the caregiver to record daily seizure information. Patients who satisfied all eligibility criteria were randomly assigned in a 1:1 ratio to receive cannabidiol or matching placebo, in addition to their stable antiepileptic-drug regimens. Cannabidiol oral solution contained 100 mg of cannabidiol per milliliter. The placebo solution was identical to the cannabidiol solution except for the absence of cannabidiol. The dose was escalated up to 20 mg per kilogram per day (or the equivalent volume of placebo) with the use of a 14-day dosing regimen that was approved by the data and safety monitoring committee. All doses were administered twice daily. At the end of the treatment period, the cannabidiol and placebo solutions were tapered (10% each day) over a period of 10 days. After trial completion, all patients could enter a long-term open-label study.

Each day, patients or their caregivers recorded the number and type of convulsive seizures (tonic, clonic, tonic–clonic, or atonic) for the primary end-point measure of convulsive-seizure frequency, using an interactive voice-response system. Clinical laboratory assessments were performed at baseline and after 2, 4, 8, and 14 weeks of the trial regimen, as well as at the end of the taper period for those patients who did not enter the open-label extension study or who withdrew early and tapered the trial agent.

End Points

The primary end point was the percentage change per 28 days from the 4-week baseline period in convulsive-seizure frequency during the 14-week treatment period among patients who received cannabidiol as compared with placebo. The treatment period extended from randomization to the end of the 14-week trial or the date of the last dose. The maintenance period extended from the end of the 2-week dose-escalation period to the end of the 14-week trial or the date of the last dose. The intention-to-treat analysis set included all patients in the safety analysis set who had postbaseline efficacy data.

The secondary end-point measures were the Caregiver Global Impression of Change (CGIC), assessed on a 7-point Likert-like scale that used three categories of improvement (slightly improved, much improved, or very much improved), three categories of worsening (slightly worse, much worse, or very much worse), and an option of “no change”; 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, as assessed by the Caregiver Global Impression of Change in Seizure Duration (CGICSD) on a 3-point scale (decrease, no change, or increase in average duration); sleep disruption, assessed on a numerical rating scale from 0 to 10, with higher scores indicating greater disruption; the change in the score on the Epworth Sleepiness Scale (range, 0 to 24, with higher scores indicating greater daytime sleepiness); the score on the Quality of Life in Childhood Epilepsy questionnaire (range, 0 to 100, with higher scores indicating better function); the age-standardized score on the Vineland Adaptive Behavior Scales, second edition (Vineland-II; range, 20 to 160, with higher scores indicating better behavioral adaptation); 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.

The safety profile of cannabidiol was assessed on the basis of the number, type, and severity of adverse events as well as the Columbia Suicide Severity Rating Scale (for patients ≥6 years of age, when appropriate), vital signs, electrocardiographic variables, laboratory safety variables, and physical examination variables; safety end points were monitored at each visit. The palatability of the trial agents was assessed by caregivers on a 5-point scale, ranging from “liked it a lot” to “did not like it at all.”

Statistical Analysis

A total of 100 randomly assigned patients were planned. We calculated that this sample size would provide 80% power to detect an absolute difference of 32 percentage points between groups in the primary end point in an intention-to-treat analysis, with a standard deviation of 56% and a two-sided significance level of 5%. Randomization was performed and assigned independently, held centrally, and not divulged to any other person involved in the trial until after database lock.

Analysis of the primary end point was performed with the use of a Wilcoxon rank-sum test. An estimate of the median difference between cannabidiol and placebo, together with the 95% confidence interval, was calculated with the use of the Hodges–Lehmann approach. Sensitivity analyses of this primary end point were prespecified in the trial protocol and statistical analysis plan.

The percentage of patients with a reduction in convulsive-seizure frequency from baseline of at least 25%, at least 50%, at least 75%, or 100% was analyzed with the use of a Cochran–Mantel–Haenszel test and presented with odds ratios. The changes from baseline in the CGIC and the CGICSD were analyzed with the use of an ordinal logistic-regression model. For the secondary end points, there were no adjustments of P values for multiple comparisons.