Time to onset of cannabidiol (CBD) treatment effect in Lennox–Gastaut syndrome: Analysis from two randomized controlled trials

Privitera, Michael; Bhathal, Hari; Wong, Matthew; Cross, J. Helen; Wirrell, Elaine; Marsh, Eric D.; Mazurkiewicz‐Bełdzińska, Maria; Villanueva, Vicente; Checketts, Daniel; Knappertz, Volker; VanLandingham, Kevan

doi:10.1111/epi.16878

Cited by 21 publications

(24 citation statements)

References 36 publications

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“…The interpretability and generalizability of the results are limited mostly because it was a post hoc analysis of pooled data from two trials with a rigid titration schedule. Although the observation of an early/clear separation from placebo may not prove to be statistically significant in a prospectively designed trial, the evidence of an early CBD antiseizure effect in two other post hoc analyses of trials in LGS 24 and TSC 25 robustly supports our results of an early antiseizure effect in DS. We could not evaluate the by‐day onset of efficacy for patients taking versus not taking clobazam due to the small number of patients not taking clobazam combined with the highly variable seizure data from just the first few days of treatment (compared to the full 14‐week treatment period); such an analysis would require a more appropriately powered study with balanced subgroups.…”

Section: Discussionsupporting

confidence: 69%

Time to onset of cannabidiol treatment effects in Dravet syndrome: Analysis from two randomized controlled trials

Cohen

Checketts

Dunayevich³

et al. 2021

Epilepsia

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Objective We conducted a post hoc analysis of two randomized controlled trials, GWPCARE1 (NCT02091375) and GWPCARE2 (NCT02224703), to estimate the time to onset of cannabidiol (CBD) treatment effects (seizure reduction and adverse events [AEs]) in patients with Dravet syndrome (DS). Methods Patients received either plant‐derived highly purified CBD (Epidiolex in the United States; 100 mg/ml oral solution) 10 mg/kg/day (CBD10; GWPCARE2) or 20 mg/kg/day (CBD20; GWPCARE1&2), or matching placebo for 14 weeks. Treatment started at 2.5 mg/kg/day, reached 10 mg/kg/day on Day 7, and went up to 20 mg/kg/day on Day 11 during the 14‐day titration period. Percentage change from baseline in convulsive seizure frequency was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were also evaluated. Results Overall, 124 patients received placebo and 194 received CBD (CBD10, n = 64; CBD20, n = 130). Mean age was 9.5 years (range = 2.2–18.9). Patients had discontinued a median of four antiepileptic drugs (range = 0–26) and were currently taking a median of three (range = 1–5). Differences in convulsive seizure reduction between placebo and CBD emerged during titration and became nominally significant by Day 12 for CBD20 (p = .02) and Day 13 for CBD10 (p = .03). Additionally, differences in the 50% responder rate between placebo and CBD became apparent during titration. Onset of the first reported AE occurred during the titration period in 48.4% of placebo patients and 54.1% of CBD patients. The three most common AEs of somnolence, decreased appetite, and diarrhea resolved within 4 weeks of onset in the majority of CBD‐treated patients (56.3%–72.9%). Significance The therapeutic effect of CBD in DS may start within 2 weeks of treatment in some patients. Although AEs lasted longer for CBD than placebo, most resolved within the 14‐week study period.

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Section: Discussionsupporting

confidence: 69%

Time to onset of cannabidiol treatment effects in Dravet syndrome: Analysis from two randomized controlled trials

Cohen

Checketts

Dunayevich³

et al. 2021

Epilepsia

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“…Although a nominally significant difference was observed in the antiseizure effect of placebo and CBD during the early time points, it may not prove to be statistically significant in a prospectively designed trial. However, early treatment effect is supported by data from CBD trials in patients with LGS and DS 20,21 …”

Section: Discussionmentioning

confidence: 99%

“…However, early treatment effect is supported by data from CBD trials in patients with LGS and DS. 20,21 The results of this analysis may differ from real-world use and for individual patients. Compared with what is prescribed in the US label, 17 the initial dose escalation in this trial was faster, which may have led to a relatively faster response.…”

Section: Discussionmentioning

confidence: 99%

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

Cock²,

Devinsky³

et al. 2022

Epilepsia

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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.

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“…Los aceites consumidos por los pacientes que los consideraron muy efectivos (62% en Figura 4), tenían CBD por debajo de su LCM a excepción de uno de origen importado. La elevada efectividad reportada supera ampliamente el efecto placebo presente al evaluar eficacia en ensayos clínicos que fue aproximadamente del 17% en ensayos con extractos de CBD (22,23) . Tampoco puede descartarse que otros medicamentos de uso concomitante u otras sustancias presentes en las muestras de aceite (no analizadas) hayan contribuido en la alta tasa de efectividad percibida.…”

Section: Discussionunclassified

“…Aunque se sostiene el requerimiento de un escrutinio riguroso de la evidencia, se sugiere un abordaje diferencial de las plantas medicinales respecto a otros ingredientes farmacéuticos activos, debido a su complejidad. Se plantea la batalla por el acceso al "cannabis" medicinal en términos de un derecho humano (23) . No obstante, persiste la preocupación por los eventos adversos a largo plazo, en particular aquellos irreversibles en el desarrollo del cerebro, la necesidad de continuar investigando otros usos, así como su comportamiento en síntomas de ansiedad y depresión de los usuarios y la evaluación sistemática del "cannabis" medicinal en problemas de salud mental (15,16,21) .…”

Section: Discussionunclassified

Caracterización de la problemática del uso terapéutico del Aceite de Cannabis en Córdoba, Argentina

Manzo

Martín

Uema

et al. 2022

Rev Fac Cien Med Univ Nac Cordoba

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El uso terapéutico del aceite de “cannabis” es una problemática social que pone en tensión aspectos legales, sanitarios, científicos y culturales. La dificultad en el acceso genera un vacío aprovechado por el mercado ilegal, al que recurren pacientes y familiares para mejorar su salud y calidad de vida. Estos aceites, de composición química desconocida, se emplean sin un seguimiento terapéutico. Un equipo interdisciplinario de la UNC se involucró en esta problemática con el objetivo de aportar elementos para su caracterización en nuestro medio. Metodología: Estudio observacional-descriptivo y transversal (aprobado por el CIEIS-HNC-UNC): entrevistas a pacientes/cuidadores mayores de edad que usaban el aceite (2019). Estudio experimental: análisis de muestras de aceites de los entrevistados para determinar su contenido de cannabinoides (THC y CBD), mediante HPLC. Resultados: Se realizaron 37 entrevistas y analizaron 48 muestras. El 73% fueron adultos y adultos-mayores. El 79% empiezan a usar el aceite por recomendación de parientes/amigos o por iniciativa propia, principalmente por falta de efectividad de otras terapias (54%) y por búsqueda de alternativas (33%). El 84% lo percibe efectivo (moderado-muy efectivo) y el 78% no manifestó eventos adversos. Usos principales: epilepsia refractaria 27% y artritis/artrosis 24%. El 15% de las muestras no presentaron contenidos cuantificables de CBD y THC, y el 67% presentó THC sin CBD. El contenido de cannabinoides cuantificables fue muy bajo. Conclusiones: Se obtuvo una aproximación sobre el uso terapéutico del aceite de “cannabis” en Córdoba y su calidad. Se observó discrepancia entre la efectividad percibida y el bajo contenido de cannabinoides detectados.

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Time to onset of cannabidiol (CBD) treatment effect in Lennox–Gastaut syndrome: Analysis from two randomized controlled trials

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 21 publications

References 36 publications

Time to onset of cannabidiol treatment effects in Dravet syndrome: Analysis from two randomized controlled trials

Time to onset of cannabidiol treatment effects in Dravet syndrome: Analysis from two randomized controlled trials

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

Caracterización de la problemática del uso terapéutico del Aceite de Cannabis en Córdoba, Argentina

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