PDF: GWPCARE1
(2017)Objective
To evaluate the efficacy and safety of cannabidiol oral solution as adjunctive therapy for drug-resistant convulsive seizures in children and young adults with the Dravet syndrome
Study Summary
• Adjusted median difference in convulsive-seizure reduction: –22.8 percentage points (95% CI –41.1 to –5.4; P=0.01)
• 43% of cannabidiol patients had ≥50% reduction in convulsive seizures vs 27% with placebo (OR 2.00; P=0.08)
• 5% of cannabidiol patients became seizure-free vs 0% with placebo
• Caregiver Global Impression of Change improved in 62% of cannabidiol group vs 34% of placebo group (P=0.02)
• Total seizure frequency also significantly reduced (P=0.03), but nonconvulsive seizures showed no significant difference
Intervention
Cannabidiol oral solution 20 mg/kg/day (escalated over 2 weeks) added to stable antiepileptic drug regimen vs matching placebo, for 14 weeks treatment period
Inclusion Criteria
• Ages 2–18 years
• Established diagnosis of Dravet syndrome confirmed by independent panel
• Taking ≥1 antiepileptic drug
• ≥4 convulsive seizures during 28-day baseline period
• Stable medication doses for ≥4 weeks before screening
Study Design
Arms: Array
Patients per Arm: Cannabidiol: 61; Placebo: 59
Outcome
• ≥50% reduction in convulsive seizures: 43% vs 27% (OR 2.00; 95% CI 0.93–4.30; P=0.08)
• Seizure-free: 5% vs 0% (P=0.08)
• Total seizure reduction: –28.6% vs –9.0% (P=0.03)
• CGIC improved: 62% vs 34% (P=0.02)
• Adverse events more common with cannabidiol: diarrhea, vomiting, fatigue, pyrexia, somnolence, elevated LFTs
Bottom Line
Cannabidiol at 20 mg/kg/day significantly reduced convulsive-seizure frequency by 39% compared to 13% with placebo in patients with Dravet syndrome. The NNT for ≥50% seizure reduction was approximately 6. However, cannabidiol was associated with higher rates of adverse events including somnolence, diarrhea, decreased appetite, and elevated liver enzymes. This trial led to the FDA approval of Epidiolex as the first cannabis-derived medication approved for any condition.
Major Points
- First randomized, placebo-controlled trial of pharmaceutical-grade cannabidiol (Epidiolex) in Dravet syndrome
- Median convulsive-seizure frequency decreased from 12.4 to 5.9/month with CBD vs 14.9 to 14.1/month with placebo (adjusted median difference −22.8 pp; P=0.01)
- 43% of CBD patients achieved ≥50% seizure reduction vs 27% placebo (OR 2.00; P=0.08)
- 5% of CBD patients became seizure-free vs 0% placebo, though this did not reach significance
- Significant reduction in total seizures (P=0.03) but not in nonconvulsive seizures alone (P=0.88)
- Caregiver Global Impression of Change favored CBD: 62% improved vs 34% placebo (P=0.02)
- Common adverse events with CBD: diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal liver function tests
- Most patients (65%) were taking clobazam concomitantly — CBD inhibits CYP2C19 and raises N-desmethylclobazam levels, which may have contributed to both efficacy and somnolence
Study Design
- Study Type
- Multicenter, randomized, double-blind, placebo-controlled trial
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 120
- Follow-up
- 14 weeks treatment (2-week escalation + 12-week maintenance) plus 4-week safety follow-up
- Centers
- 23
- Countries
- United States, United Kingdom, France, Australia, Poland
Primary Outcome
Definition: Percentage change from baseline in convulsive-seizure frequency per 28 days during treatment period
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| −13.3% | −38.9% | - (−41.1 to −5.4 (adjusted median difference)) | 0.01 |
Limitations & Criticisms
- Relatively small sample size (n=120)
- Short treatment duration (14 weeks)
- 65% on concomitant clobazam — difficult to separate CBD efficacy from clobazam interaction effect
- CBD raises N-desmethylclobazam levels via CYP2C19 inhibition, potentially confounding efficacy results
- Functional unblinding possible due to side effects (somnolence, GI symptoms)
- Only one dose tested (20 mg/kg/day); dose-response not evaluated
- No EEG confirmation of seizure types
- Industry funded (GW Pharmaceuticals)
Citation
N Engl J Med 2017;376:2011-2020