Orrin Devinsky, M.D., J. Helen Cross, Ph.D., F.R.C.P.C.H., Linda Laux, M.D., Eric Marsh, M.D., Ian Miller, M.D., Rima Nabbout, M.D., Ingrid E. Scheffer, M.B., B.S., Ph.D., Elizabeth A. Thiele, M.D., Ph.D., and Stephen Wright, M.D., for the Cannabidiol in Dravet Syndrome Study Group*
N Engl J Med 2017; 376:2011-2020
The Dravet syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet syndrome.
In this double-blind, placebo-controlled trial, we randomly assigned 120 children and young adults with the Dravet syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or placebo, in addition to standard antiepileptic treatment. The primary end point was the change in convulsive-seizure frequency over a 14-week treatment period, as compared with a 4-week baseline period.
The median frequency of convulsive seizures per month decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo (adjusted median difference between the cannabidiol group and the placebo group in change in seizure frequency, −22.8 percentage points; 95% confidence interval [CI], −41.1 to −5.4; P=0.01). The percentage of patients who had at least a 50% reduction in convulsive-seizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI, 0.93 to 4.30; P=0.08). The patient’s overall condition improved by at least one category on the seven-category Caregiver Global Impression of Change scale in 62% of the cannabidiol group as compared with 34% of the placebo group (P=0.02). The frequency of total seizures of all types was significantly reduced with cannabidiol (P=0.03), but there was no significant reduction in nonconvulsive seizures. The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo (P=0.08). Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests. There were more withdrawals from the trial in the cannabidiol group.
Among patients with the Dravet syndrome, cannabidiol resulted in a greater reduction in convulsive-seizure frequency than placebo and was associated with higher rates of adverse events. (Funded by GW Pharmaceuticals; ClinicalTrials.gov number, NCT02091375.)
Supported by GW Pharmaceuticals.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Dr. Devinsky reports receiving grant support from Novartis, PTC Therapeutics, and Zogenix and holding equity interest in Rettco, Pairnomix, Tilray, and Egg Rock Holdings. Dr. Cross reports receiving grant support, paid to her institution, from GW Pharmaceuticals, Zogenix, Sanofi, and Vitaflo; fees for serving on an advisory board, paid to her institution, from Eisai; lecture fees, paid to her institution, from Shire and Nutricia; and consulting fees, paid to her institution, from Takeda. Dr. Marsh reports serving as a site primary investigator for a trial supported by Neuren Pharmaceuticals and receiving consulting fees from Stanley Brothers Social Enterprises. Dr. Miller reports receiving honoraria and travel support from INSYS Therapeutics. Dr. Scheffer reports receiving travel support and fees for serving on a scientific advisory board from GlaxoSmithKline; receiving travel support and lecture fees from UCB and Sanofi; receiving lecture fees from Eisai and Transgenomic; holding a patent on diagnostic and therapeutic methods for epilepsy and mental retardation limited to female patients, for which a single royalty payment has been made to University of Melbourne Commercial (WO2009086591); and holding a patent on methods of treatment and diagnosis of epilepsy by detecting mutations in the SCN1A gene, which has been licensed by Bionomics (WO2006133508). Dr. Thiele reports receiving consulting fees from Eisai, grant support and consulting fees from Zogenix Pharmaceuticals, and grant support from Courtagen. Dr. Wright reports being an employee of GW Pharmaceuticals, holding a pending patent on the use of cannabinoids in the treatment of epilepsy (WO2015193667), and holding a patent on the use of phytocannabinoids in the treatment of epilepsy (EP2448637). No other potential conflict of interest relevant to this article was reported.
Drs. Devinsky and Cross contributed equally to this article.
From the New York University Langone Comprehensive Epilepsy Center, New York (O.D.); the University College London Great Ormond Street Institute of Child Health (J.H.C.) and GW Pharmaceuticals (S.W.) — both in London; Lurie Children’s Epilepsy Center, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago (L.L.); the Children’s Hospital of Philadelphia, Philadelphia (E.M.); Miami Children’s Hospital, Miami (I.M.); Hôpital Necker–Enfants Malades, Paris (R.N.); Florey Institute, Austin Health and Royal Children’s Hospital, University of Melbourne, Melbourne, VIC, Australia (I.E.S.); and Massachusetts General Hospital, Boston (E.A.T.).
Address reprint requests to Dr. Devinsky at the Department of Neurology, NYU Langone School of Medicine, 223 E. 34th St., New York, NY 10016, or at firstname.lastname@example.org.
A complete list of investigators in the Cannabidiol in Dravet Syndrome Study Group is provided in the Supplementary Appendix, available at NEJM.org.