Long-term cannabidiol treatment for seizures in patients with tuberous sclerosis complex: An open-label extension trial.
Thiele et al.·EpilepsiaImpact 4.1
Clear benefitGRADEModerate103 citations
Samplen = 199 Pat.
DurationMedian treatment time 267 days
EndpointSafety
Blindingoffen
DesignRCT
Cannabinoidcbd
Routeoral
”Key finding
CBD reduced seizure frequency by 54-68% across 12-week windows, 53-61% of patients achieved ≥50% seizure reduction, and 87% of patients/caregivers reported global improvement.
Summary
Open-label extension (n=199, median age 13 years, range 1-57) of the GWPCARE6 RCT on CBD in Tuberous Sclerosis Complex-associated epilepsy. Initial target dose 25 mg/kg/day (range up to 50 mg/kg/day), mean modal dose 27 mg/kg/day. Median seizure reduction 54-68% over 48 weeks (12-week windows). Responder rate ≥50% reduction: 53-61%, ≥75%: 29-45%, seizure-free: 6-11%. 1-year retention 79%. Most common adverse events: diarrhoea (42%), seizures (22%), decreased appetite (20%). Elevated transaminases in 9% (12 of 17 on valproate). Permanent discontinuation due to adverse events in 6%. 87% of patients/caregivers reported improvement on the S/CGIC scale after 26 weeks.
P
PopulationPatients with Tuberous Sclerosis Complex (TSC) and associated seizures who had completed the randomized phase, n=199, mean age 13 years (1–57 years)
OutcomeMedian seizure frequency reduction 54–68% across 12-week windows through week 48; responder rate (≥50% reduction) 53–61%; 87% of patients/caregivers reported global improvement (S/CGIC) at week 26
Confidence in the evidence
Very lowLowModerateHigh
Moderate
The third of four GRADE levels, the effect estimate is probably reliable.
Objective: To evaluate the long-term safety and efficacy of add-on cannabidiol (CBD) in patients with seizures associated with tuberous sclerosis complex (TSC) in the open-label extension (OLE) of the randomized, placebo-controlled phase 3 trial GWPCARE6 (NCT02544763). Results of an interim (February 2019 data cut) analysis are reported.
Methods: Patients who completed the randomized trial enrolled to receive CBD (Epidiolex((R)) in the United States; Epidyolex((R)) in the EU; 100 mg/mL oral solution). The initial target dose was 25 mg/kg/day, which, based on response and tolerability, could be decreased or increased up to 50 mg/kg/day. The primary end point was safety. Key secondary end points included percentage reduction in TSC-associated (countable focal and generalized) seizures, responder rates, and Subject/Caregiver Global Impression of Change (S/CGIC).
Results: Of 201 patients who completed the randomized phase, 199 (99%) entered the OLE. Mean age was 13 years (range, 1-57). At the time of analysis, 5% of patients had completed treatment, 20% had withdrawn, and 75% were ongoing. One-year retention rate was 79%. Median treatment time was 267 days (range, 18-910) at a 27 mg/kg/day mean modal dose. Most patients (92%) had an adverse event (AE). Most common AEs were diarrhea (42%), seizure (22%), and decreased appetite (20%). AEs led to permanent discontinuation in 6% of patients. There was one death that was deemed treatment unrelated by the investigator. Elevated liver transaminases occurred in 17 patients (9%) patients; 12 were taking valproate. Median percentage reductions in seizure frequency (12-week windows across 48 weeks) were 54%-68%. Seizure responder rates (>/=50%, >/=75%, 100% reduction) were 53%-61%, 29%-45%, and 6%-11% across 12-week windows for 48 weeks. Improvement on the S/CGIC scale was reported by 87% of patients/caregivers at 26 weeks.
Significance: In patients with TSC, long-term add-on CBD treatment was well tolerated and sustainably reduced seizures through 48 weeks, with most patients/caregivers reporting global improvement.