Time to onset of cannabidiol treatment effect and resolution of adverse events in tuberous sclerosis complex: Post hoc analysis of randomized controlled phase 3 trial GWPCARE6.
Wu et al.·EpilepsiaImpact 4.1
Clear benefitGRADEHigh47 citations
Samplen = 224 Pat.
Duration16 weeks
ControlPlacebo
EndpointSeizure reduction
Blindingdoppelblind
DesignRCT
Cannabinoidcbd
Routeoral
”Key finding
CBD showed onset of seizure reduction from day 6 with nominal significance from day 10 compared to placebo, with the effect being greater at higher doses.
Summary
Post-hoc analysis of the phase III RCT GWPCARE6 on CBD in tuberous sclerosis complex-associated epilepsy, n=224 (CBD 25 mg/kg/day n=75, CBD 50 mg/kg/day n=73, placebo n=76). Treatment effect (seizure reduction) occurred from day 6 (15 mg/kg/day), statistically significant from day 10 (p<0,049). ≥50% responder rate also separated from placebo from day 10. Adverse events began in 61% of patients (CBD25: 61%, CBD50: 67%, placebo: 54%) within the first 2 weeks; resolution in CBD patients within 4 weeks in 27%, by end of study in 51%.
P
PopulationPatients with drug-resistant epilepsy associated with tuberous sclerosis complex (TSC), n=224, median age 11,3 years (1,1–56,8)
OutcomeSignificant seizure reduction vs. placebo from day 10 (p<0,049); ≥50% responder rate also differentiated from day 10; AEs occurred in 61–67% (CBD) vs. 54% (placebo) in the first 2 weeks and resolved by end of study in 51% (CBD) vs. 78% (placebo)
Confidence in the evidence
Very lowLowModerateHigh
High
The highest of four GRADE levels, the effect estimate is very reliable.
Quality profile
Sample size★★★★★
BlindingDouble-blind
Effect sizeClear benefit
Citations / year★★★★★
Authors
Wu JY, Cock HR, Devinsky O, Joshi C, Miller I, Roberts CM, Sanchez-Carpintero R, Checketts D, Sahebkar F
Objective: To estimate the timing of cannabidiol (CBD) treatment effect (seizure reduction and adverse events [AEs]) onset, we conducted a post hoc analysis of GWPCARE6 (NCT02544763), a randomized, placebo-controlled, phase 3 trial in patients with drug-resistant epilepsy associated with tuberous sclerosis complex (TSC).
Methods: Patients received plant-derived pharmaceutical formulation of highly purified CBD (Epidiolex; 100 mg/ml oral solution) at 25 mg/kg/day (CBD25) or 50 mg/kg/day (CBD50) or placebo for 16 weeks (4-week titration, 12-week maintenance). Treatment started at 5 mg/kg/day for all groups and reached 25 mg/kg/day on Day 9 and 50 mg/kg/day on Day 29. Percentage change from baseline in TSC-associated seizure (countable focal or generalized) count was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were evaluated.
Results: Of 224 patients, 75 were randomized to CBD25, 73 to CBD50, and 76 to placebo. Median (range) age was 11.3 (1.1-56.8) years. Patients had discontinued a median (range) of 4 (0-15) antiseizure medications and were currently taking 3 (0-5). Difference in seizure reduction between CBD and placebo emerged on Day 6 (titrated dose, 15 mg/kg/day) and became nominally significant (p < .049) by Day 10. Separation between placebo and CBD in >/=50% responder rate also emerged by Day 10. Onset of AEs occurred during the first 2 weeks of the titration period in 61% of patients (CBD25, 61%; CBD50, 67%; placebo, 54%). In patients with an AE, resolution occurred within 4 weeks of onset in 42% of placebo and 27% of CBD patients and by end of trial in 78% of placebo and 51% of CBD patients.
Significance: Onset of treatment effect occurred within 6-10 days. AEs lasted longer for CBD than placebo, but the most common (diarrhea, decreased appetite, and somnolence) resolved during the 16-week trial in most patients.