Time to onset of cannabidiol treatment effect and resolution of adverse events in tuberous sclerosis complex: Post hoc analysis of randomized controlled phase 3 trial GWPCARE6.
Wu et al.·EpilepsiaImpact 4.1
Klarer NutzenGRADEHoch47 Zitate
Stichproben = 224 Pat.
Dauer16 Wochen
KontrollePlacebo
EndpunktAnfallsreduktion
Verblindungdoppelblind
DesignRCT
Cannabinoidcbd
Applikationoral
”Kernaussage
CBD zeigte Anfang der Seizure-Reduktion ab Tag 6 mit nominaler Signifikanz ab Tag 10 im Vergleich zu Placebo, wobei die Wirkung bei höheren Dosen größer war.
Zusammenfassung
Post-hoc-Analyse der Phase-III-RCT GWPCARE6 zu CBD bei Tuberöser Sklerose-assoziierter Epilepsie, n=224 (CBD 25 mg/kg/Tag n=75, CBD 50 mg/kg/Tag n=73, Placebo n=76). Behandlungseffekt (Anfallsreduktion) trat ab Tag 6 (15 mg/kg/Tag) auf, statistisch signifikant ab Tag 10 (p<0,049). ≥50%-Responder-Rate separierte sich ebenfalls ab Tag 10 von Placebo. Nebenwirkungen begannen bei 61% der Patienten (CBD25: 61%, CBD50: 67%, Placebo: 54%) innerhalb der ersten 2 Wochen; Resolution bei CBD-Patienten innerhalb 4 Wochen bei 27%, bis Studienende bei 51%.
P
PopulationPatienten mit arzneimittelresistenter Epilepsie bei tuberöser Sklerose (TSC), n=224, medianes Alter 11,3 Jahre (1,1–56,8)
OutcomeSignifikante Anfallsreduktion vs. Placebo ab Tag 10 (p<0,049); ≥50%-Responderrate ebenfalls ab Tag 10 differenziert; UAW traten bei 61–67% (CBD) vs. 54% (Placebo) in den ersten 2 Wochen auf und lösten sich bis Studienende bei 51% (CBD) vs. 78% (Placebo) auf
Vertrauen in die Evidenz
Sehr niedrigNiedrigModeratHoch
Hoch
Höchste von vier GRADE-Stufen, die Effektschätzung ist sehr verlässlich.
Qualitätsprofil
Größe★★★★★
VerblindungDoppelblind
EffektstärkeKlarer Nutzen
Zitate / Jahr★★★★★
Autoren
Wu JY, Cock HR, Devinsky O, Joshi C, Miller I, Roberts CM, Sanchez-Carpintero R, Checketts D, Sahebkar F
Objective: To estimate the timing of cannabidiol (CBD) treatment effect (seizure reduction and adverse events [AEs]) onset, we conducted a post hoc analysis of GWPCARE6 (NCT02544763), a randomized, placebo-controlled, phase 3 trial in patients with drug-resistant epilepsy associated with tuberous sclerosis complex (TSC).
Methods: Patients received plant-derived pharmaceutical formulation of highly purified CBD (Epidiolex; 100 mg/ml oral solution) at 25 mg/kg/day (CBD25) or 50 mg/kg/day (CBD50) or placebo for 16 weeks (4-week titration, 12-week maintenance). Treatment started at 5 mg/kg/day for all groups and reached 25 mg/kg/day on Day 9 and 50 mg/kg/day on Day 29. Percentage change from baseline in TSC-associated seizure (countable focal or generalized) count was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were evaluated.
Results: Of 224 patients, 75 were randomized to CBD25, 73 to CBD50, and 76 to placebo. Median (range) age was 11.3 (1.1-56.8) years. Patients had discontinued a median (range) of 4 (0-15) antiseizure medications and were currently taking 3 (0-5). Difference in seizure reduction between CBD and placebo emerged on Day 6 (titrated dose, 15 mg/kg/day) and became nominally significant (p < .049) by Day 10. Separation between placebo and CBD in >/=50% responder rate also emerged by Day 10. Onset of AEs occurred during the first 2 weeks of the titration period in 61% of patients (CBD25, 61%; CBD50, 67%; placebo, 54%). In patients with an AE, resolution occurred within 4 weeks of onset in 42% of placebo and 27% of CBD patients and by end of trial in 78% of placebo and 51% of CBD patients.
Significance: Onset of treatment effect occurred within 6-10 days. AEs lasted longer for CBD than placebo, but the most common (diarrhea, decreased appetite, and somnolence) resolved during the 16-week trial in most patients.