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Study register · detail Meta-Analyse (4 Phase-3-RCTs) · Epilepsy · 2020

Cannabidiol in conjunction with clobazam: analysis of four randomized controlled trials.

Gunning et al. ·Acta Neurologica Scandinavica Impact 0.5
Clear benefit GRADE High 47 citations
Samplek = 4 Studien
n = 714 Pat.
Duration14 weeks
ControlPlacebo
EndpointSeizure frequency
Blindingdoppelblind
DesignMeta-Analyse (4 Phase-3-RCTs)
Cannabinoidcbd
Routeoral
Key finding

CBD significantly reduced primary seizure frequency vs. placebo in LGS and Dravet syndrome, both in the overall population and in patients under clobazam; secondary endpoints confirmed seizure control.

Summary

Meta-analysis across 4 phase 3 RCTs (k=4, n=714; LGS n=396, DS n=318); add-on CBD 10/20 mg/kg/day vs. placebo. Primary seizure frequency reduced: LGS Treatment Ratio 0,70 [95% CI 0,62–0,80], DS 0,71 [95% CI 0,60–0,83]; under co-medication with clobazam even stronger (LGS 0,56 [95% CI 0,47–0,67], DS 0,63 [95% CI 0,52–0,77]). More frequent somnolence/sedation in the CBD+clobazam group.

P
PopulationChildren and adults with Lennox-Gastaut syndrome (n=396) and Dravet syndrome (n=318), pooled analysis of four phase 3 RCTs, subgroup: patients under co-medication with clobazam
I
InterventionPlant-derived, highly purified cannabidiol (Epidiolex/Epidyolex, 100 mg/ml oral) 10 or 20 mg/kg/day as add-on
C
ControlPlacebo
O
OutcomeReduction in primary seizure frequency: LGS overall Treatment Ratio 0,70 (95% CI 0,62–0,80); DS overall 0,71 (95% CI 0,60–0,83); under clobazam: LGS 0,56 (95% CI 0,47–0,67), DS 0,63 (95% CI 0,52–0,77)
Confidence in the evidence
High

The highest of four GRADE levels, the effect estimate is very reliable.

Quality profile
Sample size ★★★★★
Blinding Double-blind
Effect size Clear benefit
Citations / year ★★★★★
Authors
Gunning B, Mazurkiewicz-Beldzinska M, Chin RFM, Bhathal H, Nortvedt C, Dunayevich E, Checketts D
DOI 10.1111/ane.13351↗
Design: Meta-Analyse (4 Phase-3-RCTs)
Share
Abstract
To assess the efficacy and safety profile of add-on cannabidiol (CBD) in patients with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) on clobazam and in the overall population of four randomized, controlled phase 3 trials. Patients received plant-derived, highly purified CBD medicine (Epidiolex in the USA; Epidyolex in Europe; 100 mg/ml oral solution) at a dose of 10 or 20 mg/kg/day, or placebo for 14 weeks. A subgroup analysis of patients on clobazam and meta-analysis by syndrome were conducted. The primary endpoint was percentage reduction in primary seizure type during the treatment period. 396 patients with LGS (49% on clobazam) and 318 patients with DS (64% on clobazam) were included. CBD treatment resulted in a reduction in primary seizure frequency vs placebo in the overall population (treatment ratio [95% confidence interval]: LGS, 0.70 [0.62-0.80]; DS, 0.71 [0.60-0.83]) and in patients receiving clobazam (LGS, 0.56 [0.47-0.67]; DS, 0.63 [0.52-0.77]). The antiseizure efficacy of CBD was also demonstrated across other endpoints vs placebo (≥50% responder rate, total seizure frequency, number of seizure-free days, and Subject/Caregiver Global Impression of Change scores) in the overall populations and in patients receiving clobazam. There were higher incidences of somnolence and sedation in patients on CBD and clobazam. Most incidences of elevated transaminases occurred in patients on concomitant valproate and, to a lesser extent, clobazam. Add-on CBD was effective in reducing seizures in the overall populations and in conjunction with clobazam. Somnolence and sedation occurred more frequently in patients on CBD and clobazam.
Indication
Further studies on Epilepsy
All studies →
S Devinsky et al. · 2018 · The New England journal of medicine
973 citations
Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome.
Clear benefit RCT

Multizentrische Phase-III-RCT bei Lennox-Gastaut-Syndrom (n=225, Alter 2-55 Jahre, 30 Zentren), Cannabidiol 20 mg/kg vs. 10 mg/kg vs. Placebo (14 Wochen). Baseline: median 85 Drop-Seizures/28 Tage. Mediane Reduktion der Drop-Seizure-Frequenz: 41,9% (20 mg/kg, p=0,005 vs. Placebo), 37,2% (10 mg/kg, p=0,002 vs. Placebo), 17,2% (Placebo). Häufigste Nebenwirkungen: Somnolenz, verminderter Appetit, Diarrhö (dosisabhängig); 6 Patienten (20 mg/kg-Gruppe) und 1 Patient (10 mg/kg-Gruppe) brachen wegen Nebenwirkungen ab.

10.1056/nejmoa1714631 View study →
S Devinsky et al. · 2017 · New England Journal of Medicine
1652 citations
Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome
Clear benefit RCT

n=120 Dravet-Syndrom (therapierefraktär), CBD 20mg/kg/d vs. Placebo über 14 Wochen; median konvulsive Anfallsreduktion 38,9% (CBD) vs. 13,3% (Placebo), adjustierte Differenz -22,8 Prozentpunkte (95%-CI -41,1 bis -5,4; p=0,01); 5% anfallsfrei (CBD) vs. 0% (Placebo).

10.1056/nejmoa1611618 View study →
S Thiele et al. · 2018 · The Lancet
881 citations
Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial
Clear benefit RCT

Phase-III-RCT (GWPCARE4) bei Lennox-Gastaut-Syndrom, n=171 (2–55 Jahre), randomisiert zu CBD 20 mg/kg/d vs. Placebo über 14 Wochen. Primärer Endpunkt: prozentuale Reduktion der monatlichen Drop-Seizure-Frequenz. Multizentrisch (24 Zentren USA, Niederlande, Polen). 14 Patienten in CBD-Gruppe, 1 in Placebo-Gruppe brachen ab. [Numerische Outcomes im Abstract abgeschnitten; Volltext zeigt signifikante Drop-Seizure-Reduktion vs. Placebo].

10.1016/s0140-6736(18)30136-3 View study →

The impediment to action advances action. — Marcus Aurelius