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Adjunctive Cannabidiol in Patients with Dravet Syndrome: A Systematic Review and Meta-Analysis of Efficacy and Safety

Abstract

Background

Dravet syndrome (DS) is one of the most severe forms of drug-resistant epilepsy and available interventions fail to control seizures in most patients. Cannabidiol (CBD) is the first in a new class of antiepileptic drugs with a distinctive chemical structure and mechanism of action.

Objective

The aim of this systematic review was to evaluate the efficacy and safety of CBD as adjunctive treatment for seizures in patients with DS using meta-analytical techniques.

Methods

We searched for randomized, placebo-controlled, single- or double-blinded trials. Main outcomes included ≥ 50% reduction in baseline convulsive seizure frequency and the incidence of treatment withdrawal and adverse events (AEs). Risk ratios (RRs) with 95% confidence intervals (95% CIs) were estimated through the inverse variance method.

Results

Three trials were included involving 359 participants, 228 for CBD and 131 for placebo groups. In all trials, the active treatment was a plant-derived pharmaceutical formulation of purified CBD oral solution. The pooled RR for 50% response during the treatment was 1.69 (95% CI 1.21–2.36; p = 0.002). Across the trials, treatment was discontinued in 20 (9.0%) and 3 (2.3%) cases in the add-on CBD and placebo groups, respectively; the RR for CBD withdrawal was 3.12 (95% CI 1.07–9.10; p = 0.037). The RR to develop any AE during add-on CBD treatment was 1.06 (95% CI 0.87–1.28; p = 0.561). AEs significantly associated with adjunctive CBD were somnolence, decreased appetite, diarrhea, and increased serum aminotransferases.

Conclusions

Adjunctive CBD resulted in a greater reduction in convulsive seizure frequency than placebo and a higher rate of AEs in patients with DS presenting with seizures uncontrolled by concomitant antiepileptic therapy.

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References

  1. Fiest KM, Sauro KM, Wiebe S, Patten SB, Kwon CS, Dykeman J, Pringsheim T, Lorenzetti DL, Jetté N. Prevalence and incidence of epilepsy: a systematic review and meta-analysis of international studies. Neurology. 2017;88:296–303.

    Article  Google Scholar 

  2. Cagnetti C, Lattanzi S, Foschi N, Provinciali L, Silvestrini M. Seizure course during pregnancy in catamenial epilepsy. Neurology. 2014;83:339–44.

    Article  Google Scholar 

  3. Lattanzi S, Zaccara G, Giovannelli F, Grillo E, Nardone R, Silvestrini M, Trinka E, Brigo F. Antiepileptic monotherapy in newly diagnosed focal epilepsy. A network meta-analysis. Acta Neurol Scand. 2019;139:33–41.

    CAS  Article  Google Scholar 

  4. Lattanzi S, Cagnetti C, Foschi N, Provinciali L, Silvestrini M. Lacosamide monotherapy for partial onset seizures. Seizure. 2015;27:71–4.

    Article  Google Scholar 

  5. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342:314–9.

    CAS  Article  Google Scholar 

  6. Laxer KD, Trinka E, Hirsch LJ, Cendes F, Langfitt J, Delanty N, Resnick T, Benbadis SR. The consequences of refractory epilepsy and its treatment. Epilepsy Behav. 2014;37:59–70.

    Article  Google Scholar 

  7. Trinka E, Bauer G, Oberaigner W, Ndayisaba JP, Seppi K, Granbichler CA. Cause-specific mortality among patients with epilepsy: results from a 30-year cohort study. Epilepsia. 2013;54:495–501.

    Article  Google Scholar 

  8. Granbichler CA, Oberaigner W, Kuchukhidze G, Bauer G, Ndayisaba JP, Seppi K, Trinka E. Cause-specific mortality in adult epilepsy patients from Tyrol, Austria: hospital-based study. J Neurol. 2015;262:126–33.

    Article  Google Scholar 

  9. Granbichler CA, Zimmermann G, Oberaigner W, Kuchukhidze G, Ndayisaba JP, Taylor A, Luef G, Bathke AC, Trinka E. Potential years lost and life expectancy in adults with newly diagnosed epilepsy. Epilepsia. 2017;58:1939–45.

    Article  Google Scholar 

  10. Nabbout R, Gennaro E, Dalla Bernardina B, Dulac O, Madia F, Bertini E, Capovilla G, Chiron C, Cristofori G, Elia M, Fontana E, Gaggero R, Granata T, Guerrini R, Loi M, La Selva L, Lispi ML, Matricardi A, Romeo A, Tzolas V, Valseriati D, Veggiotti P, Vigevano F, Vallée L, Dagna Bricarelli F, Bianchi A, Zara F. Spectrum of SCN1A mutations in severe myoclonic epilepsy of infancy. Neurology. 2003;60:1961–7.

    CAS  Article  Google Scholar 

  11. Arzimanoglou A. Dravet syndrome: from electroclinical characteristics to molecular biology. Epilepsia. 2009;50(Suppl. 8):3–9.

    CAS  Article  Google Scholar 

  12. Dravet C, Oguni H. Dravet syndrome (severe myoclonic epilepsy in infancy). Handb Clin Neurol. 2013;111:627–33.

    Article  Google Scholar 

  13. Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014;55:791–802.

    CAS  Article  Google Scholar 

  14. Ibeas Bih C, Chen T, Nunn AV, Bazelot M, Dallas M, Whalley BJ. Molecular targets of cannabidiol in neurological disorders. Neurotherapeutics. 2015;12:699–730.

    Article  Google Scholar 

  15. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.

    Article  Google Scholar 

  16. European Medicines Agency. Assessment report: Epidiolex. International non-proprietary name: cannabidiol. https://www.ema.europa.eu/en/documents/assessment-report/epidyolex-epar-public-assessment-report_en.pdf. Accessed Oct 2019.

  17. FDA. Drug approval package: Epidiolex (Cannabidiol), NDA 210365, FDA Center for Drug Evaluation and Research. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210365Orig1s000TOC.cfm. Accessed Oct 2019.

  18. Lattanzi S, Trinka E, Russo E, Striano P, Citraro R, Silvestrini M, Brigo F. Cannabidiol as adjunctive treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome. Drugs Today (Barc). 2019;55:177–96.

    CAS  Article  Google Scholar 

  19. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. Higgins JPT and Green S, editors. The Cochrane Collaboration, 2011. http://handbook-5-1.cochrane.org/. Accessed Oct 2019.

  20. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58.

    Article  Google Scholar 

  21. Lattanzi S, Cagnetti C, Foschi N, Provinciali L, Silvestrini M. Brivaracetam add-on for refractory focal epilepsy: a systematic review and meta-analysis. Neurology. 2016;86:1344–52.

    Article  Google Scholar 

  22. Lattanzi S, Brigo F, Grillo E, Cagnetti C, Verrotti A, Zaccara G, Silvestrini M. Adjunctive eslicarbazepine acetate in pediatric patients with focal epilepsy: a systematic review and meta-analysis. CNS Drugs. 2018;32:189–96.

    CAS  Article  Google Scholar 

  23. Lattanzi S, Cagnetti C, Danni M, Provinciali L, Silvestrini M. Oral and intravenous steroids for multiple sclerosis relapse: a systematic review and meta-analysis. J Neurol. 2017;264:1697–704.

    CAS  Article  Google Scholar 

  24. Lattanzi S, Brigo F, Cagnetti C, Di Napoli M, Silvestrini M. Patent foramen ovale and cryptogenic stroke or transient ischemic attack: to close or not to close? A systematic review and meta-analysis. Cerebrovasc Dis. 2018;45:193–203.

    Article  Google Scholar 

  25. Lattanzi S, Grillo E, Brigo F, Silvestrini M. Efficacy and safety of perampanel in Parkinson’s disease. A systematic review with meta-analysis. J Neurol. 2018;265:733–40.

    CAS  Article  Google Scholar 

  26. Devinsky O, Patel AD, Thiele EA, Wong MH, Appleton R, Harden CL, GWPCARE1 Part A Study Group, et al. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology. 2018;90:e1204–11.

    CAS  Article  Google Scholar 

  27. Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, Cannabidiol in Dravet Syndrome Study Group, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet Syndrome. N Engl J Med. 2017;376:2011–20.

    CAS  Article  Google Scholar 

  28. ClinicalTrials.gov. GWPCARE2. A study to investigate the efficacy and safety of Cannabidiol (GWP42003-P) in children and young adults with Dravet Syndrome. https://clinicaltrials.gov/ct2/NCT02224703. Accessed Oct 2019.

  29. Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug–drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56:1246–51.

    CAS  Article  Google Scholar 

  30. Anderson LL, Absalom NL, Abelev SV, Low IK, Doohan PT, Martin LJ, Chebib M, McGregor IS, Arnold JC. Coadministered cannabidiol and clobazam: preclinical evidence for both pharmacodynamic and pharmacokinetic interactions. Epilepsia. 2019;60:2224–34.

    CAS  Article  Google Scholar 

  31. Wallace A, Wirrell E, Kenney-Jung DL. Pharmacotherapy for Dravet Syndrome. Paediatr Drugs. 2016;18:197–208.

    Article  Google Scholar 

  32. Lattanzi S, Brigo F, Cagnetti C, Trinka E, Silvestrini M. Efficacy and safety of adjunctive cannabidiol in patients with Lennox-Gastaut syndrome: a systematic review and meta-analysis. CNS Drugs. 2018;32:905–16.

    CAS  Article  Google Scholar 

  33. Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016;15:270–8.

    CAS  Article  Google Scholar 

  34. Morrison G, Crockett J, Blakey G, Sommerville K. A phase 1, open-label, pharmacokinetic trial to investigate possible drug–drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects. Clin Pharmacol Drug Dev. 2019;8:1009–31.

    CAS  Article  Google Scholar 

  35. Lattanzi S, Brigo F, Trinka E, Zaccara G, Cagnetti C, Del Giovane C, Silvestrini M. Efficacy and safety of cannabidiol in epilepsy: a systematic review and meta-analysis. Drugs. 2018;78:1791–804.

    CAS  Article  Google Scholar 

  36. Devinsky O, Nabbout R, Miller I, Laux L, Zolnowska M, Wright S, Roberts C. Long-term cannabidiol treatment in patients with Dravet syndrome: an open-label extension trial. Epilepsia. 2019;60:294–302.

    CAS  Article  Google Scholar 

  37. Szaflarski JP, Bebin EM, Comi AM, Patel AD, Joshi C, Checketts D, CBD EAP Study Group, et al. Long-term safety and treatment effects of cannabidiol in children and adults with treatment resistant epilepsies: expanded access program results. Epilepsia. 2018;59:1540–8.

    CAS  Article  Google Scholar 

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Correspondence to Simona Lattanzi.

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Funding

No funding has been received for the conduct of this study.

Conflict of interest

Simona Lattanzi, Cinzia Del Giovane and Mauro Silvestrini have no conflicts of interest directly relevant to the content of this study. Francesco Brigo acted as a consultant for Eisai. Eugen Trinka has received speaker’s honoraria from UCB, Biogen, Gerot-Lannach, Bial, Eisai, Takeda, Newbridge, Sunovion Pharmaceuticals Inc., LivaNova and Novartis; consultancy funds from UCB, Biogen, Gerot-Lannach, Bial, Eisai, Takeda, Newbridge, GW Pharmaceuticals, Sunovion Pharmaceuticals Inc., and Novartis; directorship funds from Neuroconsult GmbH. E. Trinka’s Institution received grants from Biogen, Red Bull, Merck, UCB, European Union, FWF Österreichischer Fond zur Wissenschaftsförderung, and Bundesministerium für Wissenschaft und Forschung. Gaetano Zaccara has received speaker’s or consultancy fees from Eisai, Sanofi-Aventis, and UCB Pharma. Pasquale Striano has received speaker fees and participated at advisory boards for Biomarin, Zogenyx and GW Pharmaceuticals, and received research funding by ENECTA srl, GW Pharmaceuticals, Kolfarma srl. and Eisai.

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Lattanzi, S., Brigo, F., Trinka, E. et al. Adjunctive Cannabidiol in Patients with Dravet Syndrome: A Systematic Review and Meta-Analysis of Efficacy and Safety. CNS Drugs 34, 229–241 (2020). https://doi.org/10.1007/s40263-020-00708-6

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  • DOI: https://doi.org/10.1007/s40263-020-00708-6