Time to onset of cannabidiol (CBD) treatment effect in Lennox-Gastaut syndrome: Analysis from two randomized controlled trials.
Privitera et al.·EpilepsiaImpact 4.1
Clear benefitGRADEHigh59 citations
Samplen = 396 Pat.
Duration14 weeks
ControlPlacebo over 14 weeks
EndpointDrop seizure frequency
Blindingdoppelblind
DesignRCT
Cannabinoidcbd
Routeoral
”Key finding
CBD showed a nominally significant reduction in drop seizures versus placebo as early as day 6, with differences in responder rate (≥50% reduction) from day 6.
Summary
Post-hoc analysis of GWPCARE3/4 (n=396; 235 CBD, 161 placebo) in Lennox-Gastaut syndrome; CBD 10 or 20 mg/kg/day. Significant reduction in drop seizures from day 6 (p=0,008). ≥50% responder rate separation visible from day 6. Adverse events occurred in 45% during titration (CBD10: 46%, CBD20: 52%, placebo: 38%); 61% of CBD patients showed adverse event resolution by end of study.
P
PopulationPatients with Lennox-Gastaut syndrome, n=396 (CBD n=235, placebo n=161), mean age 15,3 years, median pretreatment with 6 antiepileptic drugs
ControlPlacebo (matching oral solution) over 14 weeks
O
OutcomeSignificant separation of drop seizure reduction between CBD and placebo from day 6 (p=0,008, pooled CBD groups); ≥50% responder rate also diverging from day 6
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
Privitera M, Bhathal H, Wong M, Cross JH, Wirrell E, Marsh ED, Mazurkiewicz-Beldzinska M, Villanueva V, Checketts D, Knappertz V
Objective: To estimate time to onset of cannabidiol (CBD) treatment effect (seizure reduction and adverse events [AEs]), we conducted post hoc analyses of data from two randomized, placebo-controlled, Phase 3 trials, GWPCARE3 (NCT02224560) and GWPCARE4 (NCT02224690), of patients with Lennox-Gastaut syndrome.
Methods: Patients received plant-derived pharmaceutical formulation of highly purified CBD (Epidiolex, 100 mg/ml oral solution) at 10 mg/kg/day (CBD10; GWPCARE3) or 20 mg/kg/day (CBD20; both trials) or placebo for 14 weeks. Treatment started at 2.5 mg/kg/day for all groups and reached 10 mg/kg/day on Day 7 and 20 mg/kg/day (CBD20 and matching placebo only) on Day 11. Percentage change from baseline in drop seizure frequency was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were evaluated.
Results: Overall, 235 patients received CBD (CBD10 [GWPCARE3 only], n = 67; CBD20 [pooled GWPCARE3&4], n = 168) and 161 received placebo. Mean (range) age was 15.3 years (2.6-48.0). Patients had previously discontinued a median (range) of six (0-28) antiepileptic drugs (AEDs) and were currently taking a median of three (0-5) AEDs. Differences in drop seizure reduction between placebo and CBD emerged during the titration period and became nominally significant by Day 6 (p = .008) for pooled CBD treatment groups. Separation between placebo and CBD in >/=50% responder rate emerged by Day 6. Onset of the first reported AE occurred during the titration period in 45% of patients (CBD10, 46%; CBD20, 52%; placebo, 38%). In patients with AEs, resolution occurred within 4 weeks of onset in 53% of placebo and 39% of CBD patients and by end of study in 63% of placebo and 61% of CBD patients.
Significance: Treatment effect (efficacy and AEs) of CBD may occur within 1 week of starting treatment. Although AEs lasted longer for CBD than placebo, most resolved within the 14-week period.