Add-on Cannabidiol Treatment for Drug-Resistant Seizures in Tuberous Sclerosis Complex: A Placebo-Controlled Randomized Clinical Trial
Elizabeth A Thiele, E Martina Bebin, Hari Bhathal, Floor E Jansen, Katarzyna Kotulska, John A Lawson, Finbar J O'Callaghan, Michael Wong, Farhad Sahebkar, Daniel Checketts, Volker Knappertz, GWPCARE6 Study Group, John Archer, Daniel H Arndt, Todd Barron, E Martina Bebin, Hari Bhathal, Verónica Cantarín-Extremera, Rocio Sanchez-Carpintero, Michael A Ciliberto, Hannah Cock, Marie-Claire Y De Wit, Orrin Devinsky, Merce Falip, Francis M Filloux, Nathan B Fountain, Jacek Gawlowicz, Robert S Greenwood, Khalid Hamandi, Floor E Jansen, Charuta Joshi, Sergiusz Jóźwiak, Pavel Klein, Katarzyna Kotulska, Patrick Kwan, John A Lawson, Pawel Lisewski, Ian O Miller, Richard P Morse, Ali S Mostajelean, Danielle A Nolan, Terence J O'Brien, Finbar J O'Callaghan, Fernando Paredes, M Scott Perry, Federico J Ramos, David Reutens, Colin M Roberts, Russell P Saneto, Gregory B Sharp, Anurag Saxena, Steven P Sparagana, Priyamvada Tatachar, Elizabeth A Thiele, James W Wheless, Elaine C Wirrell, Matthew H Wong, Michael Wong, Joyce Y Wu, Marta Żołnowska, Elizabeth A Thiele, E Martina Bebin, Hari Bhathal, Floor E Jansen, Katarzyna Kotulska, John A Lawson, Finbar J O'Callaghan, Michael Wong, Farhad Sahebkar, Daniel Checketts, Volker Knappertz, GWPCARE6 Study Group, John Archer, Daniel H Arndt, Todd Barron, E Martina Bebin, Hari Bhathal, Verónica Cantarín-Extremera, Rocio Sanchez-Carpintero, Michael A Ciliberto, Hannah Cock, Marie-Claire Y De Wit, Orrin Devinsky, Merce Falip, Francis M Filloux, Nathan B Fountain, Jacek Gawlowicz, Robert S Greenwood, Khalid Hamandi, Floor E Jansen, Charuta Joshi, Sergiusz Jóźwiak, Pavel Klein, Katarzyna Kotulska, Patrick Kwan, John A Lawson, Pawel Lisewski, Ian O Miller, Richard P Morse, Ali S Mostajelean, Danielle A Nolan, Terence J O'Brien, Finbar J O'Callaghan, Fernando Paredes, M Scott Perry, Federico J Ramos, David Reutens, Colin M Roberts, Russell P Saneto, Gregory B Sharp, Anurag Saxena, Steven P Sparagana, Priyamvada Tatachar, Elizabeth A Thiele, James W Wheless, Elaine C Wirrell, Matthew H Wong, Michael Wong, Joyce Y Wu, Marta Żołnowska
Abstract
Importance: 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).
Objective: 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.
Interventions: 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.
Results: 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.
Trial registration: ClinicalTrials.gov Identifier: NCT02544763.
Conflict of interest statement
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.
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Source: PubMed