Introduction

The Lennox–Gastaut syndrome is a severe developmental epileptic encephalopathy characterized by several seizure types, which begin to occur before the age of 8 years and persist into adulthood in more than 90% of patients, and severe cognitive impairment. Cannabidiol has been used for treatment-resistant seizures in patients with severe early-onset epilepsy.

Aim

To investigate the efficacy and safety of two doses of cannabidiol, as compared with placebo, added to a regimen of conventional antiepileptic medication to treat drop seizures in patients with the Lennox–Gastaut syndrome.

Patient Profile

225 patients with the Lennox–Gastaut syndrome (2 and 55 years of age;) who had had two or more drop seizures (an epileptic seizure involving the entire body, trunk, or head that leads or could lead to a fall, injury, or slumping in a chair) per week during a 28-day baseline period

Method

Study Design

• Multicenter, randomized, double-blind, placebo-controlled trial conducted at 30 clinical centers

• Patients were randomly assigned to receive cannabidiol oral solution at a dose of either 20 mg/kilogram of body weight (20-mg cannabidiol group) or 10 mg per kilogram (10-mg cannabidiol group) or matching placebo, administered in two equally divided doses daily for 14 weeks

Endpoints

• Primary outcome: the percentage change from baseline in the frequency of drop seizures (average per 28 days) during the treatment period
• Secondary outcomes: the percentage of patients who had at least a 50% reduction from baseline in drop-seizure frequency; the percentage change from baseline in the frequency of all types of seizures (total seizures); and the Patient or Caregiver Global Impression of Change from baseline in overall condition, as assessed on a 7-point scale that included three categories of improvement, three categories of worsening, and an option of “no change”; percentage of patients who had at least a 25%, at least a 75%, and a 100% reduction from baseline in drop-seizure frequency

Results

Efficacy

• The 20-mg cannabidiol group achieved a significant reduction of 41.9% from baseline in drop-seizure frequency versus 17.2% in the placebo group, with a median difference of 21.6 percentage points (P=0.005)
• The 10-mg cannabidiol group also achieved a significant reduction of 37.2% from baseline in drop-seizure frequency versus 17.2% in the placebo group with a median difference of 19.2 percentage points (P=0.002)
• Cannabidiol achieved significantly higher odds of at least a 50% reduction from their baseline in drop-seizure frequency versus the placebo group (odds ratio 3.85 with 20-mg, P<0.001 and 3.27 with 10-mg cannabidiol, P=0.003)
• Greater percentage of patients achieved at least a 75% reduction from baseline in drop-seizure frequency with 20-mg cannabidiol (25%) and 10-mg cannabidiol (11%) as compared to placebo (3%)
• Higher percentage of patients were free from drop seizures during the entire maintenance phase with 20-mg cannabidiol (7%) and 10-mg cannabidiol (4%) versus the placebo (1%)
• The estimated median difference in reduction from baseline in the frequency of all seizures per 28 days during the treatment period was significantly higher with 20-mg (18.8 percentage points, P=0.009) and 10-mg cannabidiol (19.5 percentage points, P=0.002) as compared to the placebo (38.4% with 20-mg, 36.4% with 10-mg cannabidiol and 18.5% with placebo)
• Significantly higher odds of improvement from baseline in overall condition (as per the Patient or Caregiver Global Impression of Change) at the last visit was achieved with 10 mg (66% patients; OR 2.57; P=0.002) and 20-mg cannabidiol (57% patients; OR 1.83; P=0.04) as compared to the placebo (44% patients)

Figure 1: Effect of cannabidiol (10 mg and 20 mg) and placebo on the primary outcome

Safety 

• The most common adverse events (somnolence, decreased appetite, and diarrhea) occurred more frequently in the high-dose cannabidiol group
• Adverse event related trial medication discontinuation and withdrawals were seen in 6 patients in 20-mg cannabidiol group and 1 patient in 10-mg cannabidiol group
• Elevated liver aminotransferase concentrations were seen in 9% patients on cannabidiol

Conclusion

• Addition of purified cannabidiol (10 mg or 20 mg/kilogram/day) to a conventional antiepileptic regimen resulted in significantly greater reductions in the frequency of drop seizures than placebo in children and adults with the Lennox–Gastaut syndrome
• Cannabidiol also significantly achieved the secondary outcome measures of at least a 50% reduction in the frequency of drop seizures, the reduction in the frequency of all seizures, and improvement in overall condition

N Engl J Med 2018; 378: 1888-97