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Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial

Thiele, Elizabeth A, Marsh, Eric D, French, Jacqueline A, Mazurkiewicz-Beldzinska, Maria, Benbadis, Selim R, Joshi, Charuta, Lyons, Paul D, Taylor, Adam, Roberts, Claire, Sommerville, Kenneth, Gunning, Boudewjin, Gawlowicz, Jacek, Lisewski, Pawel, Mazurkiewicz Beldzinska, Maria, Mitosek Szewczyk, Krystyna, Steinborn, Barbara, Zolnowska, Marta, Hughes, Elaine, McLellan, Ailsa, Benbadis, Selim, Ciliberto, Michael, Clark, Gary, Dlugos, Dennis, Filloux, Francis, Flamini, Robert, French, Jacqueline, Frost, Michael, Haut, Sheryl, Joshi, Charuta, Kapoor, Siddarth, Kessler, Sudha, Laux, Linda, Lyons, Paul, Marsh, Eric, Moore, David, Morse, Richard, Nagaraddi, Venkatesh, Rosenfeld, William, Seltzer, Laurie, Shellhaas, Renée, Sullivan, Joseph, Thiele, Elizabeth, Thio, Liu Lin, Wang, David, Wilfong, Angus·2018·The Lancet
DOI 10.1016/s0140-6736(18)30136-3
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Abstract

Background Patients with Lennox-Gastaut syndrome, a rare, severe form of epileptic encephalopathy, are frequently treatment resistant to available medications. No controlled studies have investigated the use of cannabidiol for patients with seizures associated with Lennox-Gastaut syndrome. We therefore assessed the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy in this population of patients.Methods In this randomised, double-blind, placebo-controlled trial done at 24 clinical sites in the USA, the Netherlands, and Poland, we investigated the efficacy of cannabidiol as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome. Eligible patients (aged 2-55 years) had Lennox-Gastaut syndrome, including a history of slow (<3 Hz) spike-and-wave patterns on electroencephalogram, evidence of more than one type of generalised seizure for at least 6 months, at least two drop seizures per week during the 4-week baseline period, and had not responded to treatment with at least two antiepileptic drugs. Patients were randomly assigned (1:1) using an interactive voice response system, stratified by age group, to receive 20 mg/kg oral cannabidiol daily or matched placebo for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were masked to group assignment. The primary endpoint was percentage change from baseline in monthly frequency of drop seizures during the treatment period, analysed in all patients who received at least one dose of study drug and had post-baseline efficacy data. All randomly assigned patients were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02224690.Findings Between April 28, 2015, and Oct 15, 2015, we randomly assigned 171 patients to receive cannabidiol (n=86) or placebo (n=85). 14 patients in the cannabidiol group and one in the placebo group discontinued study treatment; all randomly assigned patients received at least one dose of study treatment and had post-baseline efficacy data. The median percentage reduction in monthly drop seizure frequency from baseline was 43·9% (IQR -69·6 to -1·9) in the cannibidiol group and 21·8% (IQR -45·7 to 1·7) in the placebo group. The estimated median difference between the treatment groups was -17·21 (95% CI -30·32 to -4·09; p=0·0135) during the 14-week treatment period. Adverse events occurred in 74 (86%) of 86 patients in the cannabidiol group and 59 (69%) of 85 patients in the placebo group; most were mild or moderate. The most common adverse events were diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting. 12 (14%) patients in the cannabidiol group and one (1%) patient in the placebo group withdrew from the study because of adverse events. One patient (1%) died in the cannabidiol group, but this was considered unrelated to treatment.Interpretation Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated. The long-term efficacy and safety of cannabidiol is currently being assessed in the open-label extension of this trial.Funding GW Pharmaceuticals.

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Authors
Thiele, E. A., Marsh, E. D., French, J. A., Mazurkiewicz-Beldzinska, M., Benbadis, S. R., Joshi, C., Lyons, P. D., Taylor, A., Roberts, C., Sommerville, K., Gunning, B., Gawlowicz, J., Lisewski, P., Mazurkiewicz Beldzinska, M., Mitosek Szewczyk, K., Steinborn, B., Zolnowska, M., Hughes, E., McLellan, A., Benbadis, S., Ciliberto, M., Clark, G., Dlugos, D., Filloux, F., Flamini, R., French, J., Frost, M., Haut, S., Joshi, C., Kapoor, S., Kessler, S., Laux, L., Lyons, P., Marsh, E., Moore, D., Morse, R., Nagaraddi, V., Rosenfeld, W., Seltzer, L., Shellhaas, R., Sullivan, J., Thiele, E., Thio, L. L., Wang, D., & Wilfong, A.
Affiliations
  • GW Pharmaceuticals (United Kingdom) (GB)
  • Duke University (US)
ORCID
Venue
The Lancet
Publisher
Elsevier BV
Published
2018-03
Volume
391
Issue
10125
Pages
1085-1096
ISSN
  • 0099-5355 (ISSN-L)
  • 0140-6736
DOI
10.1016/s0140-6736(18)30136-3
OpenAlex
W2785059893
Cited by
905
References
27
Citations by year
2026: 51 · 2025: 114 · 2024: 63 · 2023: 103 · 2022: 110 · 2021: 108 · 2020: 171 · 2019: 116 · 2018: 68
FWCI
91.09
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • The Lancet (publishedVersion)
  • PubMed (publishedVersion)
Funders
GW Pharmaceuticals
Topics
  • Health Sciences › Medicine › Clinical Neurology › Epilepsy research and treatment
  • Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
  • Health Sciences › Medicine › Physiology (medical) › Diet and metabolism studies
Keywords
cannabidiol, Lennox-Gastaut syndrome, drop seizures, drug-resistant epilepsy, seizure frequency reduction, drug safety, adverse events, pediatric and adult patients, generalized seizures, antiepileptic drugs, treatment efficacy and safety
MeSH terms
Adolescent, Adult, Anticonvulsants, Cannabidiol, Child, Child, Preschool, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Male, Middle Aged, Seizures, Treatment Outcome, Young Adult, Lennox Gastaut Syndrome

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