Introduction

Patients with Lennox-Gastaut syndrome are frequently treatment resistant to available medications. Cannabidiol has been shown to be safe and efficacious in patients with drug-resistant epilepsy and in Dravet syndrome (severe, treatment-resistant, genetic epilepsy syndrome)

Aim

To assess the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy compared with placebo for the treatment of seizures associated with Lennox-Gastaut syndrome

Patient Profile

• 171 Lennox-Gastaut syndrome patients (aged 2–55 years), including a history of slow (<3 Hz) spike-and-wave patterns on electroencephalogram, evidence of >1 type of generalised seizure for at least 6 months, >2 drop seizures/week during the 4-week baseline period, and had not responded to treatment with >2 antiepileptic drugs

  Method

  Study Design

• Randomised, double-blind, placebo-controlled phase 3 trial
• Patients were randomly assigned to receive 20 mg/kg oral cannabidiol daily or matched placebo for 14 weeks
• All patients received treatment for 14 weeks, which included 2 weeks of dose escalation (starting at a daily dose of 2.5 mg/kg, followed by 12 weeks of stable dosing [maintenance]), a tapering period of up to 10 days, and a 4-week safety follow-up period

Endpoints

• Primary endpoint: percentage change from baseline in monthly frequency of drop seizures
• Secondary endpoints: Percentage of patients had showed 50% or more reduction in monthly frequency of drop seizures, percent change in total seizure frequency, change from baseline in patient & caregiver global impression of change (GIC) and frequency of non-drop seizures
• Safety endpoints: proportion of patients with adverse events

Results

Efficacy

• Addition of cannibidiol to existing antiepileptic drug regimens achieved significantly higher percentage reduction of 43.9% in monthly drop seizure frequency during the 14-week treatment period as compared to 21.8% with placebo with a significant median difference of −17.21 (p=0.0135) during the 14-week treatment period and −19.45 (p=0.0096) during the 12-week maintenance period alone (Figure 1)
• Cannabidiol efficacy was established as early as the first 4 weeks of the maintenance period, and was maintained for the full treatment period
• Significantly higher percentages of patients in the cannabidiol group achieved >25%, >50% (44% vs. 24%), and >75% reductions in monthly frequency of drop seizures versus placebo group
• Three patients in the cannabidiol group versus none in placebo group were free of drop seizures during the entire 12-week maintenance period
• Cannabidiol significantly reduced the median frequency of total seizures (41.2% vs. 13.7%) with a significant median difference of –21.1 (p=0.0005) during treatment period and –23.3 (p=0.0004) during the 12-week maintenance period

   

  Figure 1: Comparison of add-on cannabidiol and placebo on reduction in monthly drop seizure frequency

  

  Safety 

• Patients in the cannabidiol group or their caregivers were significantly more likely than patients in the placebo group or their caregivers to report an improvement in the patient’s overall condition compared with baseline (odds ratio 2.54, p=0.0012); three times as many patients reported overall improvement in cannabidiol group than placebo group
• Cannabidiol significantly reduced median monthly non-drop seizure frequency by 49.4% versus 22.9% in the placebo group; difference was −26.1 (p=0.0044) during the treatment period and −31% (p=0.0008) during the 12-week maintenance period

• Add-on cannabidiol was well tolerated

• Cannabidiol was associated with more adverse events (86%) than placebo (69%), most events were mild or moderate, resolved on treatment (61% patients in cannabidiol and 64% in placebo), and were consistent with previous clinical trial reports of the use of cannabidiol in patients with epilepsy
• Most commons adverse events were diarrhoea, somnolence, pyrexia, decreased appetite and vomiting
• Adverse event related study withdrawals were 14% in cannabidiol group and 1% in placebo group; transient elevations in liver enzymes were most frequent

Conclusion

• A 20 mg/kg daily dose of add-on cannabidiol to existing antiepileptic drugs, is clinically effective for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated
• The study suggested that cannabidiol might have broad spectrum effects on seizure reduction

Lancet 2018; 391: 1085-96