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

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.