Elsevier

The Lancet

Volume 391, Issue 10125, 17–23 March 2018, Pages 1085-1096
The Lancet

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

https://doi.org/10.1016/S0140-6736(18)30136-3Get rights and content

Summary

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.

Introduction

Lennox-Gastaut syndrome is a rare, severe form of epileptic encephalopathy with early childhood onset. The syndrome typically manifests by 8 years of age with peak incidence between age 3 and 5 years.1 Lennox-Gastaut syndrome is characterised by the occurrence of multiple seizure types, including so-called drop attacks (ie, sudden falls due to seizures), slow spike-and-wave activity on electroencephalograms, and cognitive impairment. Lennox-Gastaut syndrome is typically a lifelong condition in which the phenotype and nature of seizures often vary with age.2 Although 20–60% of patients with Lennox-Gastaut syndrome have delayed cognitive development at disease onset,3 75–95% of patients become cognitively impaired with increasing age.3 Few robust, population-based epidemiological studies of Lennox-Gastaut syndrome have been done, but regional studies4, 5 have reported that Lennox-Gastaut syndrome accounts for 1–4% of cases of paediatric epilepsy.

The drugs approved for Lennox-Gastaut syndrome in the USA and Europe include felbamate, lamotrigine, topiramate, rufinamide, clobazam, and clonazepam.6 Although not approved for Lennox-Gastaut syndrome, valproate is also used on the basis of clinical experience and study data.7 Hancock and Cross8 identified nine randomised controlled trials of monotherapies for Lennox-Gastaut syndrome to assess treatment effects on specific seizure types, adverse events, and mortality. Although a meta-analysis was not possible because of different patient populations and outcome measures, the authors concluded that adjunctive therapy with felbamate, lamotrigine, topiramate, and rufinamide might be beneficial, and clobazam might be efficacious for drop seizures.8 In a separate randomised, placebo-controlled trial of more than 200 patients, Ng and colleagues9 showed that clobazam significantly decreased drop seizure frequency. Non-pharmacological treatments, including a ketogenic diet,10 vagus nerve stimulation,11, 12 and surgery, including resective surgery and corpus callosotomy,13 have been shown to be effective in some patients.14 However, despite the number of available treatments, less than 10% of patients become seizure free with existing treatments.15

Research in context

Evidence before this study

We searched PubMed for English-language studies published between Jan 1, 1973, and June 1, 2017, using the search terms “cannabidiol” AND “(epilepsy OR seizures OR anticonvulsant)”. Preclinical data have shown that cannabidiol has activity against seizures in in-vitro and in-vivo models. An open-label expanded access programme has indicated that GW Pharmaceutical's (Cambridge, UK) specific formulation of cannabidiol might be safe and efficacious in children and young adults with drug-resistant epilepsy, and results from a previous multicentre, randomised, placebo-controlled trial have suggested the formulation might also be safe and efficacious in children with Dravet syndrome.

Added value of this study

This is the first randomised, placebo-controlled trial to assess the efficacy and safety of a pharmaceutical formulation of purified cannabidiol as add-on therapy to existing antiepileptic drugs for the treatment of seizures associated with Lennox-Gastaut syndrome in children and adults.

Implications of all the available evidence

In addition to the available evidence, the results of this randomised, placebo-controlled trial suggest that the use of cannabidiol (20 mg/kg daily) as an add-on therapy for existing antiepileptic drug regimens might significantly reduce the frequency of seizures in patients with Lennox-Gastaut syndrome. The results also indicate that cannabidiol might lead to additional adverse events, but in general it appears to be well tolerated.

In comparison to approved antiepileptic drugs, cannabidol is structurally unique and has potentially novel multimodal mechanisms of action.16, 17 Preclinical data have shown cannabidiol to have activity against seizures in in-vitro and in-vivo models.18 Results of an open-label expanded access programme19 in 214 children and young adults suggested that cannabidiol might be safe and efficacious in patients with drug-resistant epilepsy, and results from a randomised, controlled trial20 in 120 children indicated that cannabidiol might be safe and efficacious in Dravet syndrome. Dravet syndrome is a severe, treatment-resistant, and rare genetic epilepsy syndrome with childhood onset that is associated with life-long seizures and considerable intellectual and physical disabilities. The GWPCARE4 study was designed to assess the efficacy and safety of cannabidiol compared with placebo as add-on therapy to existing antiepileptic drugs for the treatment of seizures associated with Lennox-Gastaut syndrome in children and adults.

Section snippets

Study design and patients

We did a randomised, double-blind, placebo-controlled, phase 3 trial at 24 clinical sites in the USA (n=17), the Netherlands (n=1), and Poland (n=6). Eligible patients were aged between 2 and 55 years, with a clinical diagnosis of Lennox-Gastaut syndrome (including documented history of slow [<3·0 Hz] spike-and-wave electroencephalograms), and evidence of more than one type of generalised seizure, including drop seizures, for at least 6 months. The definition of Lennox-Gastaut syndrome chosen

Results

Between April 28, 2015, and Oct 15, 2015, 200 patients were screened for eligibility, of whom 171 were randomly assigned to receive add-on cannabidiol (n=86) or add-on placebo (n=85; figure 1) at 24 study sites. The proportion of patients who were ineligible after screening was half of what was expected. Additionally, after notification of pending recruitment closure to sites, the number of patients referred for screening increased. These two factors contributed to more patients being

Discussion

This is the first randomised, double-blind trial to assess the efficacy and safety of cannabidiol as add-on anticonvulsant therapy for patients with Lennox-Gastaut syndrome. Patients in this study were highly treatment resistant; at baseline, they had previously not responded to a median of six antiepileptic drugs, were taking a median of three concomitant antiepileptic drugs, and had a median of 73·8 drop seizures every 28 days. The urgent need for novel treatment options for patients with

References (28)

  • JH Doring et al.

    Thirty years of orphan drug legislation and the development of drugs to treat rare seizure conditions: a cross sectional analysis

    PLoS One

    (2016)
  • GD Montouris et al.

    The efficacy and tolerability of pharmacologic treatment options for Lennox-Gastaut syndrome

    Epilepsia

    (2014)
  • EC Hancock et al.

    Treatment of Lennox-Gastaut syndrome

    Cochrane Database Syst Rev

    (2013)
  • YT Ng et al.

    Randomized, phase III study results of clobazam in Lennox-Gastaut syndrome

    Neurology

    (2011)
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