Study register · detailopen-label extension · Epilepsy · 2021
Add-on cannabidiol in patients with Dravet syndrome: Results of a long-term open-label extension trial.
Scheffer et al.·EpilepsiaImpact 4.1
Clear benefitGRADEModerate91 citations
Samplen = 315 Pat.
DurationMedian treatment duration 444…
EndpointSeizure frequency
Blindingn.a.
Designopen-label extension
Cannabinoidcbd
Routeoral
”Key finding
CBD led to sustained, clinically meaningful reductions in seizure frequency (45%-74% for convulsive seizures, 49%-84% for total seizures) and ≥83% of patients/caregivers reported improvement in overall condition.
Summary
n=315 Dravet patients (open-label extension study GWPCARE5, up to 1535 days); CBD add-on therapy reduced convulsive seizures by median 45–74 % and total seizures by 49–84 % in 12-week windows up to week 156; ≥83 % of patients/caregivers reported improvement on the Global Impression of Change; tolerable safety profile (9 % discontinuations due to AEs, transaminase increase >3× ULN in 22 %, mainly under valproate).
P
PopulationChildren and adults with Dravet syndrome (treatment-resistant), n=315
OutcomeMedian reduction in monthly convulsive seizure frequency versus baseline of 45–74 % (weeks 1–156); ≥83 % of patients/caregivers reported improvement on the S/CGIC
Confidence in the evidence
Very lowLowModerateHigh
Moderate
The third of four GRADE levels, the effect estimate is probably reliable.
Downgraded for
Risk of bias
Quality profile
Sample size★★★★★
Blinding—
Effect sizeClear benefit
Citations / year★★★★★
Authors
Scheffer IE, Halford JJ, Miller I, Nabbout R, Sanchez-Carpintero R, Shiloh-Malawsky Y, Wong M, Zolnowska M, Checketts D, Dunayevich E, Devinsky O
Add-on cannabidiol (CBD) reduced seizures associated with Dravet syndrome (DS) in two randomized, double-blind, placebo-controlled trials: GWPCARE1 Part B (NCT02091375) and GWPCARE2 (NCT02224703). Patients who completed GWPCARE1 Part A (NCT02091206) or Part B, or GWPCARE2, were enrolled in a long-term open-label extension trial, GWPCARE5 (NCT02224573). We present an interim analysis of the safety, efficacy, and patient-reported outcomes from GWPCARE5. Patients received a pharmaceutical formulation of highly purified CBD in oral solution (100 mg/ml), titrated from 2.5 to 20 mg/kg/day over a 2-week period, added to their existing medications. Based on response and tolerance, CBD could be reduced or increased to 30 mg/kg/day. Of the 330 patients who completed the original randomized trials, 315 (95%) enrolled in this open-label extension. Median treatment duration was 444 days (range = 18-1535), with a mean modal dose of 22 mg/kg/day; patients received a median of three concomitant antiseizure medications. Adverse events (AEs) occurred in 97% patients (mild, 23%; moderate, 50%; severe, 25%). Commonly reported AEs were diarrhea (43%), pyrexia (39%), decreased appetite (31%), and somnolence (28%). Twenty-eight (9%) patients discontinued due to AEs. Sixty-nine (22%) patients had liver transaminase elevations >3 x upper limit of normal; 84% were on concomitant valproic acid. In patients from GWPCARE1 Part B and GWPCARE2, the median reduction from baseline in monthly seizure frequency assessed in 12-week periods up to Week 156 was 45%-74% for convulsive seizures and 49%-84% for total seizures. Across all visit windows, >=83% patients/caregivers completing a Subject/Caregiver Global Impression of Change scale reported improvement in overall condition. We show that long-term CBD treatment had an acceptable safety profile and led to sustained, clinically meaningful reductions in seizure frequency in patients with treatment-resistant DS.