PDF: Cannabidiol as Adjunct for LGS
(2018)Objective
Cannabidiol - To evaluate the efficacy and safety of cannabidiol (CBD) oral solution as adjunctive therapy for drop seizures in patients with Lennox–Gastaut syndrome.
Study Summary
Intervention
Adjunctive purified cannabidiol oral solution 10 mg/kg/day or 20 mg/kg/day vs. placebo, added to stable antiepileptic drug regimens.
Inclusion Criteria
Ages 2–55 years with Lennox–Gastaut syndrome, ≥2 drop seizures/week during baseline, and stable regimen of 1–4 AEDs.
Study Design
Arms: Placebo vs CBD 10 mg/kg/day vs CBD 20 mg/kg/day
Patients per Arm: Placebo: 76; CBD 10 mg/kg: 73; CBD 20 mg/kg: 76
Outcome
Bottom Line
Among children and adults with Lennox-Gastaut syndrome, cannabidiol at doses of 10mg or 20mg/kg/day added to conventional antiepileptic regimens resulted in significantly greater reductions in drop seizure frequency than placebo (median reductions 37-42% vs 17%), with dose-dependent adverse events including elevated liver aminotransferases in 9% of cannabidiol-treated patients.
Major Points
- 225 patients with LGS randomized 2:2:1:1 to cannabidiol 20mg/kg/day, 10mg/kg/day, or matching placebo volumes
- Median baseline drop seizures were 85 per 28 days across all groups
- Primary outcome: median percent reduction in drop seizures was 41.9% (20mg CBD), 37.2% (10mg CBD), vs 17.2% (placebo)
- Estimated median difference vs placebo: 21.6 percentage points (20mg) and 19.2 percentage points (10mg)
- ≥50% responder rate significantly higher with CBD: 39% (20mg), 36% (10mg) vs 14% placebo
- Total seizure frequency also significantly reduced with both CBD doses
- Patient/Caregiver Global Impression of Change showed improvement in 57-66% on CBD vs 44% placebo
- 14 patients (9%) on CBD had elevated aminotransferases >3x ULN; 79% were on concomitant valproate
- Somnolence occurred in 30% (20mg), 21% (10mg) vs 5% placebo
- 99% of completers entered open-label extension
Study Design
- Study Type
- Phase 3, multicenter, randomized, double-blind, placebo-controlled trial
- Randomization
- Yes
- Blinding
- Double-blind; patients, caregivers, investigators, and outcome assessors blinded; matching placebo volumes used
- Sample Size
- 225
- Follow-up
- Up to 24 weeks (4-week baseline, 14-week treatment [2-week titration + 12-week maintenance], up to 10-day taper, 4-week safety follow-up)
- Centers
- 30
- Countries
- United States, Spain, United Kingdom, France
Primary Outcome
Definition: Percentage change from baseline in the frequency of drop seizures (average per 28 days) during the treatment period
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 17.2% median reduction | 41.9% (20mg) and 37.2% (10mg) median reduction | - (Median difference 20mg vs placebo: 21.6 percentage points (6.7-34.8); 10mg vs placebo: 19.2 percentage points (7.7-31.2)) | P=0.005 (20mg vs placebo); P=0.002 (10mg vs placebo) |
Limitations & Criticisms
- Higher proportion of 20mg CBD group taking rufinamide (34% vs 26%) may confound results
- Short 14-week treatment period; long-term efficacy and safety not established
- Potential unblinding due to higher adverse event rates in CBD groups
- Drug-drug interactions with clobazam (increased active metabolite levels) may account for some efficacy
- Hepatotoxicity signal requires careful monitoring, particularly with valproate co-administration
- Three authors were employees of GW Pharmaceuticals
- Quality of life showed no significant difference despite seizure reductions
- Type 1 error not controlled for secondary outcomes other than key secondary outcomes
- No patients achieved complete seizure freedom during entire treatment period
- 2:2:1:1 randomization ratio resulted in unequal placebo group allocation
Citation
N Engl J Med 2018;378:1888-97