Dose-Ranging Effect of Adjunctive Oral Cannabidiol vs Placebo on Convulsive Seizure Frequency in Dravet Syndrome: A Randomized Clinical Trial

Abstract

Importance: Clinical evidence supports effectiveness of cannabidiol for treatment-resistant seizures in Dravet syndrome, but this trial is the first to evaluate the 10-mg/kg/d dose.

Objective: To evaluate the efficacy and safety of a pharmaceutical formulation of cannabidiol, 10 and 20 mg/kg/d, vs placebo for adjunctive treatment of convulsive seizures in patients with Dravet syndrome.

Design, setting, and participants: This double-blind, placebo-controlled, randomized clinical trial (GWPCARE2) recruited patients from April 13, 2015, to November 10, 2017, with follow-up completed on April 9, 2018. Of 285 patients screened from 38 centers in the United States, Spain, Poland, the Netherlands, Australia, and Israel, 86 were excluded, and 199 were randomized. Patients were aged 2 to 18 years with a confirmed diagnosis of Dravet syndrome and at least 4 convulsive seizures during the 4-week baseline period while receiving at least 1 antiepileptic drug. Data were analyzed from November 16 (date of unblinding) to December 13 (date of final outputs), 2018, based on intention to treat and per protocol.

Interventions: Patients received cannabidiol oral solution at a dose of 10 or 20 mg/kg per day (CBD10 and CBD20 groups, respectively) or matched placebo in 2 equally divided doses for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were blinded to group assignment.

Main outcomes and measures: The primary outcome was change from baseline in convulsive seizure frequency during the treatment period. Secondary outcomes included change in all seizure frequency, proportion with at least a 50% reduction in convulsive seizure activity, and change in Caregiver Global Impression of Change score.

Results: Of 198 eligible patients (mean [SD] age, 9.3 [4.4] years; 104 female [52.5%]), 66 were randomized to the CBD10 group, 67 to the CBD20 group, and 65 to the placebo group, and 190 completed treatment. The percentage reduction from baseline in convulsive seizure frequency was 48.7% for CBD10 group and 45.7% for the CBD20 group vs 26.9% for the placebo group; the percentage reduction from placebo was 29.8% (95% CI, 8.4%-46.2%; P = .01) for CBD10 group and 25.7% (95% CI, 2.9%-43.2%; P = .03) for the CBD20 group. The most common adverse events were decreased appetite, diarrhea, somnolence, pyrexia, and fatigue. Five patients in the CBD20 group discontinued owing to adverse events. Elevated liver transaminase levels occurred more frequently in the CBD20 (n = 13) than the CBD10 (n = 3) group, with all affected patients given concomitant valproate sodium.

Conclusions and relevance: Adjunctive cannabidiol at doses of 10 and 20 mg/kg/d led to similar clinically relevant reductions in convulsive seizure frequency with a better safety and tolerability profile for the 10-mg/kg/d dose in children with treatment-resistant Dravet syndrome. Dose increases of cannabidiol to greater than 10 mg/kg/d should be tailored to individual efficacy and safety.

Trial registration: ClinicalTrials.gov Identifier: NCT02224703.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Miller reported receiving grants and other compensation from Greenwich Biosciences during the conduct of the study and grants, personal fees, and other compensation from Greenwich Biosciences, nonfinancial support and other compensation from Dravet Syndrome Foundation, grants and nonfinancial support from Insys Pharmaceuticals, personal fees and nonfinancial support from BioMarin Pharmaceutical, Inc, and Upshire-Smith Laboratories, LLC, and grants, personal fees, and nonfinancial support from Zogenix, Inc, outside the submitted work. Dr Scheffer reported receiving other compensation from GW Pharmaceuticals during the conduct of the study; other from Zynerba Pharmaceuticals, Inc, Zogenix, Inc, Ovid Therapeutics, Inc, Marinus, and Ultragenyx Pharmaceutical, Inc, personal fees and other compensation from UCB, personal fees from GlaxoSmithKline, Eisai Co, Ltd, BioMarin Pharmaceutical, Inc, Nutricia, and Xenon Pharmaceuticals, outside the submitted work; a patent to WO06/133508 issued; and research funding from the National Health and Medical Research Council, Health Research Council of New Zealand, and National Institutes of Health. Dr Gunning reported serving on scientific advisory boards of GW Pharmaceuticals, Zogenix, Inc, and Ovid Therapeutics, Inc/Takeda Pharmaceutical Company Limited; serving on the speaker’s bureau for LivaNova plc; and serving as the principal investigator for trials sponsored by GW Research, Ltd, and Zogenix, Inc. Dr Sanchez-Carpintero reported receiving research support from GW Pharmaceuticals and Zogenix for clinical trials; serving on advisory boards for Novartis International AG, GW Pharmaceuticals, and Zogenix, Inc; and serving as a trial investigator for GW Research, Ltd and Ovid Therapeutics, Inc/Takeda Pharmaceutical Company Limited. Dr Gil-Nagel reported serving as an investigator, speaker, and advisory board member for Bial, Eisai Co, Ltd, Esteve, UCB, GW Pharmaceuticals, GW Research, Ltd, Zogenix, Inc, Stoke Therapeutics, Sanofi, and Arvelle Therapeutics. Dr Perry reported participating on advisory boards for Upsher-Smith Laboratories, LLC, and Zogenix, Inc, as a consultant for Encoded Therapeutics, Inc, and as a trial investigator for GW Research, Ltd, and Zogenix, Inc. Dr Saneto reported serving as a principal investigator on the GW Research, Ltd, trials for Dravet Syndrome Foundation and TSC; on the data safety monitoring board for a clinical study sponsored by Reata Pharmaceuticals for Friedreich ataxia; as principal investigator on a study sponsored by Stealth Pharmaceutical for primary mitochondrial myopathy; as principal investigator on a study sponsored by Zogenix, Inc, in patients with Dravet syndrome; and on the speaker’s bureau for GW Pharmaceuticals. No other disclosures were reported.

Figures

Figure 1.. Flow of Patients Through the GWPCARE2 Trial

Patients in the placebo group were pooled for a combined total of 65 patients; 32 were assigned to receive a volume equivalent to the 10-mg/kg/d cannabidiol dose and 33 were assigned to receive a volume equivalent to the 20-mg/kg/d cannabidiol dose. Among the 86 patients excluded, 3 had multiple reasons for exclusion. One patient randomized to the 10-mg/kg/d dose was not treated and was subsequently withdrawn by the investigator.

Figure 2.. Percentage Reductions in Convulsive and Total Seizure Frequency During the Treatment Period

The estimated percentage reduction in seizure frequency and 95% CIs are shown for each treatment group. Cannabidiol doses of 10 mg/kg/d (CBD10 group) and 20 mg/kg/d (CBD20 group) were associated with greater reductions in convulsive (primary end point) and total seizure frequency compared with placebo. Convulsive seizures include tonic, clonic, tonic-clonic, and atonic types; total seizures include convulsive and nonconvulsive seizures (myoclonic, countable partial, and other partial or absence types). The percentage reduction in convulsive seizures from placebo was 29.8% (95% CI, 8.4%-46.2%; P = .01) for the CBD10 group and 25.7% (95% CI, 2.9%-43.2%; P = .03) for the CBD20 group; for total seizures, 38.0% for the CBD10 group (95% CI, 20.1%-51.9%; P < .001) and 25.1% for the CBD20 group (95% CI, 3.5%-41.9%; P = .03).

Figure 3.. Reduction in Convulsive Seizure Frequency During the Treatment Period

Cannabidiol doses of 10 mg/kg/d (CBD10 group) and 20 mg/kg/d (CBD20 group) resulted in a higher proportion of patients achieving at least a 50% reduction in convulsive seizure frequency compared with placebo, and the differences were statistically significant (odds ratio [OR] for CBD10 group, 2.21 [95% CI, 1.06-4.62; P = .03]; OR for CBD20 group, 2.74 [95% CI, 1.32-5.70; P = .007]). A higher proportion of patients treated with cannabidiol compared with placebo achieved at least a 75% reduction in convulsive seizure frequency (OR for CBD10 group, 6.63 [95% CI, 2.12-20.73]; OR for CBD20 group, 3.33 [95% CI, 1.10-10.92]; P values are not shown because this was not a key secondary outcome and type I error was not controlled for).