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Is add-on cannabidiol superior to placebo in reducing the number of seizures associated with tuberous sclerosis complex?
In this randomized clinical trial, 224 patients with tuberous sclerosis complex were treated with cannabidiol (25 or 50 mg/kg/day) or matched placebo for 16 weeks. The percentage reduction in the type of seizures regarded as the primary end point was 27% for placebo, 49% for 25 mg/kg/day of cannabidiol, and 48% for 50 mg/kg/day of cannabidiol; a dosage of 25 mg/kg/day led to fewer adverse events than the 50-mg/kg/day dosage.
In this study, both cannabidiol dosages were equally efficacious in reducing tuberous sclerosis complex–associated seizures compared with placebo, but the smaller dosage led to fewer adverse events.
Efficacy of cannabidiol has been demonstrated in seizures associated with Lennox-Gastaut and Dravet syndromes but appears not yet to have been established in conditions with primarily focal seizures, such as tuberous sclerosis complex (TSC).
To evaluate efficacy and safety of 25-mg/kg/day and 50-mg/kg/day cannabidiol dosages vs placebo against seizures associated with TSC.
Design, Setting, and Participants
This double-blind, placebo-controlled randomized clinical trial (GWPCARE6) enrolled patients between April 6, 2016, and October 4, 2018; follow-up was completed on February 15, 2019. The trial was conducted at 46 sites in Australia, Poland, Spain, the Netherlands, United Kingdom, and United States. Eligible patients (aged 1-65 years) were those with a clinical diagnosis of TSC and medication-resistant epilepsy who had had at least 8 TSC-associated seizures during the 4-week baseline period, with at least 1 seizure occurring in at least 3 of the 4 weeks, and were currently taking at least 1 antiepileptic medication.
Patients received oral cannabidiol at 25 mg/kg/day (CBD25) or 50 mg/kg/day (CBD50) or a matched placebo for 16 weeks.
Main Outcomes and Measures
The prespecified primary outcome was the change from baseline in number of TSC-associated seizures for cannabidiol vs placebo during the treatment period.
Of 255 patients screened for eligibility, 31 were excluded and 224 were randomized. Of the 224 included patients (median [range] age, 11.4 [1.1-56.8] years; 93 female patients [41.5%]), 75 were randomized to CBD25, 73 to CBD50, and 76 to placebo, with 201 completing treatment. The percentage reduction from baseline in the type of seizures considered the primary end point was 48.6% (95% CI, 40.4%-55.8%) for the CBD25 group, 47.5% (95% CI, 39.0%-54.8%) for the CBD50 group, and 26.5% (95% CI, 14.9%-36.5%) for the placebo group; the percentage reduction from placebo was 30.1% (95% CI, 13.9%-43.3%; P < .001) for the CBD25 group and 28.5% (95% CI, 11.9%-42.0%; nominal P = .002) for the CBD50 group. The most common adverse events were diarrhea (placebo group, 19 [25%]; CBD25 group, 23 [31%]; CBD50 group, 41 [56%]) and somnolence (placebo group, 7 [9%]; CBD25 group, 10 [13%]; CBD50 group, 19 [26%]), which occurred more frequently with cannabidiol than placebo. Eight patients in CBD25 group, 10 in CBD50 group, and 2 in the placebo group discontinued treatment because of adverse events. Twenty-eight patients taking cannabidiol (18.9%) had elevated liver transaminase levels vs none taking placebo.
Conclusions and Relevance
Cannabidiol significantly reduced TSC-associated seizures compared with placebo. The 25-mg/kg/day dosage had a better safety profile than the 50-mg/kg/day dosage.
ClinicalTrials.gov Identifier: NCT02544763
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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Accepted for Publication: October 4, 2020.
Published Online: December 21, 2020. doi:10.1001/jamaneurol.2020.4607
Corresponding Author: Elizabeth A. Thiele, MD, PhD, Pediatric Epilepsy Program, Massachusetts General Hospital, 175 Cambridge St, Ste 340, Boston, MA 02114 (firstname.lastname@example.org).
Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2020 Thiele EA et al. JAMA Neurology.
Author Contributions: Drs Thiele and Knappertz had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Thiele, Jansen, Kotulska, O'Callaghan, Checketts.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Bhathal, Jansen, Lawson, Wong, Sahebkar, Checketts, Knappertz.
Critical revision of the manuscript for important intellectual content: Thiele, Bebin, Bhathal, Jansen, Kotulska, Lawson, O'Callaghan, Wong, Sahebkar, Knappertz.
Statistical analysis: Checketts, Knappertz.
Administrative, technical, or material support: Jansen, Sahebkar.
Supervision: Thiele, Bhathal, Jansen, Sahebkar, Knappertz.
Conflict of Interest Disclosures: Dr Thiele received support from GW Research Ltd as a site principal investigator during the conduct of the trial; outside of the current work, Dr Thiele serves as a principal investigator on clinical trials for GW Research Ltd and Zogenix and as a consultant for Aquestive Therapeutics, Biocodex, West Therapeutics, Greenwich Biosciences, and Zogenix. Dr Bebin received support from GW Research Ltd as a site principal investigator during the conduct of the trial and serves as a consultant for Greenwich Biosciences and Biocodex. Dr Jansen was a site principal investigator on this trial. Dr Bhathal reported having participated as a principal investigator in the clinical trials used as data for this article. Dr Kotulska reported personal fees and nonfinancial support from GW Pharmaceutical Companies during the conduct of the study. Dr Lawson reported grants from GW Pharmaceutical Companies during the conduct of the study. Dr O'Callaghan reported personal fees from GW Pharmaceutical Companies during the conduct of the study and personal fees from Novartis outside the submitted work. Dr Wong was a site principal investigator on this trial, for which his institution received support from GW Research Ltd. Dr Sahebkar is a full-time employee of Greenwich Biosciences. Mr Checketts is a full-time employee of GW Research Ltd and reports other support from GW Pharmaceutical Companies outside the submitted work. Dr Knappertz is a full-time employee of Greenwich Biosciences and owns shares in the company. In addition, Dr Knappertz had a patent to Use of Cannabinoids in the Treatment of Epilepsy issued and had additional related patents pending (WO2019097238, WO2019106386, WO2019064031, and WO2019145700, as well as unpublished patent documents PCT/GB2019/051173, GB1818935.7, GB1819573.5, GB1900797.0, GB1902427.2, GB1906261.1, GB1907283.4, and GB1910803.4). No other disclosures were reported.
Funding/Support: The study was supported by GW Research Ltd.
Role of the Funder/Sponsor: GW Research Ltd was responsible for the design and conduct of the study (following input from investigators and other experts); the collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. This included management, monitoring, pharmacovigilance, data analysis, and study medication supply. The trial protocol and procedures were reviewed prior to trial start at investigators’ meetings. Third-party services were used for clinical and bioanalytical laboratory analyses; case report form design; data management; trial medication distribution, returns, and destruction; an interactive voice-response system; seizure type classification; and translation of documents.
Group Information: Members of the GWPCARE6 Study Group are listed in Supplement 3.
Meeting Presentation: Data from this study were previously presented at the American Epilepsy Society Annual Meeting; December 7, 2019; Baltimore, Maryland.
Data Sharing Statement: See Supplement 4.
Additional Contributions: The authors would like to thank the patients, their families, and the sites that participated in this trial sponsored by GW Research Ltd, a GW Pharmaceuticals PLC company. Medical writing and editorial support were provided by Ritu Pathak, PhD, and Mary Kacillas, Ashfield Healthcare Communications, and was funded by GW Research Ltd.
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