Introduction

Efficacy of cannabidiol has not yet been established in conditions with primarily focal seizures, such as tuberous sclerosis complex (TSC).

Aim

To assess efficacy and safety of add-on cannabidiol (25 mg/kg/day and 50 mg/kg/day dosages) for the treatment of TSC-associated seizures in children and adults.

Patient Profile

• 224 patients (aged 1-65 years) with TSC and medication-resistant epilepsy with at least 8 TSC-associated seizures during the 4-week baseline period with at least 1 seizure occurring in at least 3 of the 4 weeks and were taking at least 1 antiepileptic medication

  Method

  Study Design

• Phase 3, international, double-blind, placebo-controlled parallel-group randomized clinical trial (conducted at 46 sites in Australia, Poland, Spain, the Netherlands, United Kingdom and United States)
• Patients received add-on oral cannabidiol at 25 mg/kg/day (CBD25) or 50 mg/kg/day (CBD50) as twice daily in equally divided doses (dose initiation at 5 mg/kg/day, then 25 mg/kg/day on day 9 and 50 mg/kg/day on day 29) or a matched placebo for 16 weeks
• The trial consisted of a 4-week baseline period, a 16-week treatment period (4 weeks for dose escalation [titration period] followed by 12 weeks of stable dosing [maintenance period]), a taper period of up to 10 days, and a 4-week safety follow-up

Endpoints

• Primary outcome: change from baseline in number of TSC-associated seizures
• Secondary outcomes: proportion of patients who had at least a 50% reduction from baseline in primary– end-point seizures; the participants’ or caregivers’ global impressions of change from baseline in overall condition and the change from baseline in total seizures

Results

Efficacy

• Add-on cannabidiol significantly reduced the primary end point by 48.6% in CBD25 group, 47.5% in CBD50 group and 26.5% in the placebo group (Figure 1)
• Cannabidiol caused a significant percentage reduction in primary endpoint from placebo (30.1% in CBD25 group, P<0.001 and 28.5% in CBD50 group, P=0.002)
• During the maintenance period, cannabidiol (CBD25 & CBD50 groups) led to a 36.9% reduction in primary–end-point seizures versus placebo; reduction was regardless of concomitant clobazam use
• Cannabidiol achieved the secondary outcome, of at least 50% reduction from baseline in primary–end-point seizures, in 36% patients in CBD25 group, 40% patients in CBD50 group, and 22% in placebo group
• It led to a 75% reduction in seizures in 16.9% patients vs none in placebo
• Freedom from seizures was seen in one patient in CBD25 group for full treatment period; 4 patients in CBD25 group, 2 in CBD50 group, and none in placebo group during the maintenance period
• Cannabidiol improved the overall condition from baseline with an odds ratios of 2.25 for CBD25 (69% patients) and 1.77 for CBD50 (62% patients) vs placebo (39% patients)
• Significant percentage reduction from baseline in total seizures was seen with cannabidiol during treatment as well as maintenance periods (48.1% & 35.6% CBD25 group; 47.6% & 37% CBD50 group, respectively) versus placebo (26.9%)
• During the 12-week maintenance period, cannabidiol treated patients gained a mean of 10 or 8 additional seizure-free days (CBD25/CBD50 groups, resp.) vs. placebo

Figure 1: Reduction from baseline in the frequency of primary–end-point

Safety 

• Diarrhea (placebo group, 25%; CBD25 group, 31%; CBD50 group, 56%) and somnolence (placebo group, 9%; CBD25 group, 13%; CBD50 group, 26%) occurred more frequently with cannabidiol than placebo
• An elevation in liver transaminase levels was seen in 18.9% patients on cannabidiol vs. none on placebo

Conclusion

• Add-on cannabidiol significantly reduced seizure frequency in patients with TSC; 25-mg/kg/day dosage had a better safety profile than the 50-mg/kg/day dosage
• This is the first randomized clinical trial to assess add-on cannabidiol in a disorder with primarily focal seizures
• The safety profile in this study is consistent with prior studies, with confirmation of cannabidiol-associated risks of transaminase level elevations (especially in the presence of valproate) and somnolence and sedation (especially in the presence of clobazam)