Epidiolex (cannabidiol), as an add on-therapy administered at either a low or high dose, leads to similar clinically relevant reductions in the frequency of convulsive seizures in children with treatment-resistant Dravet syndrome,
Importantly, a lower Epidiolex dose shows a better safety and tolerability profile when compared to the higher dose.
Those results from the clinical trial “Dose-Ranging Effect of Adjunctive Oral Cannabidiol vs Placebo on Convulsive Seizure Frequency in Dravet SyndromeA Randomized Clinical Trial,” were published in the journal JAMA Neurology.
Epidiolex, developed by GW Pharmaceuticals, is a purified, oral form of cannabidiol (CBD), the most common non-psychoactive cannabinoid compound in the cannabis plant. CBD is able to mimic natural compounds by acting on brain receptors, which may cause seizures when faulty. It is thought to indirectly regulate the brain’s endocannabinoid system to suppress seizures in children and adults with Dravet syndrome and Lennox‑Gastaut syndrome (LGS).
Epidiolex was approved in the U.S. in June 2018 for the treatment of seizures associated with Dravet syndrome and LGS in patients age 2 and older. The European Commission approved it in September 2019 under the name Epidyolex.
In those trials, Epidiolex was efficient and had an acceptable safety profile as add-on anti-epileptic treatment in patients with Dravet at a dose of 20 mg/kg/d, and in patients with LGS at doses of 10 and 20 mg/kg/d.
Even though doses as high as 20 mg/kg/d are approved for Dravet syndrome and LGS, “the US prescribing information indicates 10 mg/kg/d as the recommended maintenance dose,” researchers noted.
However, clinical data on this lower dose were not available for Dravet syndrome.
Now, researchers report the results from the Phase 3 GWPCARE2 trial (NCT02224703) designed to evaluate the effectiveness and safety of the two doses of Epidiolex (10 and 20 mg/ kg/d) in children with Dravet syndrome.
The study enrolled 198 patients (average age 9.3 years, 104 girls and 94 boys) recruited across centers in the U.S, Spain, Poland, the Netherlands, Australia, and Israel.
Participants were assigned randomly to either a placebo (65 patients) or to one of the two doses of Epidiolex: 10 mg/kg/day (66 patients, called CBD10 group); and 20 mg/kg/day (65 patients, the CBD20 group) for 14 weeks. (A two-week dose escalation period, followed by 12 weeks of maintenance at the appropriate dose.) This was followed by a tapering-off period up to 10 days, and a four-week safety follow-up.
Epidiolex or placebo were given twice daily in two equivalent doses starting at 2.5 mg/kg/day and reaching the 10 mg/kg/day dose on day seven (in the CBD10 group) and the 20 mg/kg/day dose on day 11 (CBD20 group).
Patients in each group had been treated previously with a median of four (range, 0 to 19) anti-epileptic drugs (AEDs) and were currently taking a median of three (range, 1-5) AEDs. The most commonly used were Depacon (valproate) (139 patients) and Onfi (clobazam) (126 patients).
The study’s primary goal was to assess the changes from the start of the trial in the frequency of convulsive seizures. Secondary goals included changes in total seizure frequency, the proportion of patients with at least a 50% reduction in convulsive seizure activity, and clinically meaningful improvements in the Caregiver Global Impression of Change score.
A total of 190 patients completed the treatment period, and 186 (97.9%) entered an open-label extension study.
During the 14-week treatment period, the frequency of convulsive seizures was reduced by 48.7% in the CBD10 group, 45.7% in the CBD20 group, and 26.9% in the placebo group compared to the start (baseline) of the trial.
During the 12-week maintenance period, the frequency of convulsive seizures was reduced by 49.2% in the CBD10 group, 48.6% in the CBD20 group, and 28.6% in the placebo.
“The differences between treatment groups favored [Epidiolex] over placebo during the first 4 weeks of the maintenance period (…) and was maintained for the duration of treatment,” the researchers wrote.
The percentage reduction from baseline in total seizure frequency during the treatment period was 56.4% for the CBD10 group, 47.3% for the CBD20 group, an 29.7% for the placebo group. When compared to the placebo group, frequency of total seizures was reduced by 38% in the CBD10 group and 25.1% in the CBD20 group.
The proportion of patients achieving at least a 50% reduction from baseline in convulsive seizure frequency during the treatment period was 43.9% for the CBD10 group, 49.3% for the CBD20 group and 26.2% for the placebo group .
More patients in the CBD10 group achieved at least a 75% reduction (30.3%, 20 patients) in convulsive seizure frequency when compared to those in the CBD20 group (17.9%, 12 patients) or placebo (6.2%, four patients).
“Compared with placebo, caregivers of cannabidiol-treated patients were significantly more likely to report an improvement in overall condition,” the researchers wrote.
The number of patients reporting slightly improved, much improved, or very much improved, as shown by the CGIC scores, were significantly higher in the CBD10 (45 of 66 patients) and CBD20 (40 of 66 patients) groups than those who received placebo (27 of 65 patients).
Treatment-emergent adverse events (side effects) were detected in 88.9% of participants: 89.2% in the placebo group, 87.5% in the CBD10 group, and 89.9% in the CBD20 group.
The most common adverse events were decreased appetite, diarrhea, drowsiness, slight fever, and fatigue. Five patients in the CBD20 group discontinued the study due to side effects. Elevated liver transaminase levels — an indicator of possible liver damage — was more frequent in patients who received the higher dose of Epidiolex (13 patients) that in those who received the lower dose (three patients).
Overall, researchers wrote, the results show that add-on “cannabidiol at doses of 10 and 20 mg/kg/d led to similar clinically relevant reductions in convulsive seizure frequency with a better safety and tolerability profile for the 10-mg/kg/d dose in children with treatment-resistant Dravet syndrome.”
“Dose increases of cannabidiol to greater than 10 mg/kg/d should be tailored to individual efficacy and safety,” they added.