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

Joyce Y. Wu; Hannah R. Cock; Orrin Devinsky; Charuta Joshi; Ian Miller; Colin M. Roberts; Rocio Sanchez-Carpintero; Daniel Checketts; Farhad Sahebkar

doi:10.1111/epi.17199

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

Joyce Y. Wu^*, Hannah R. Cock, Orrin Devinsky, Charuta Joshi, Ian Miller, Colin M. Roberts, Rocio Sanchez-Carpintero, Daniel Checketts, Farhad Sahebkar

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	1189-1199
Number of pages	11
Journal	Epilepsia
Volume	63
Issue number	5
DOIs	https://doi.org/10.1111/epi.17199
State	Published - May 2022

Funding

The authors would like to thank the patients, their families, and the staff at sites that participated in this trial. Medical writing support for the development of this article, under the direction of the authors, was provided by Ritu Pathak, PhD, and editing support by Dena McWain, both of Ashfield MedComms, an Ashfield Health company, and funded by Greenwich Biosciences. This trial was sponsored by GW Research, Cambridge, UK.

Keywords

antiseizure medication
cannabidiol
epilepsy
focal seizures
medication-resistant seizures
tuberous sclerosis complex

ASJC Scopus subject areas

Neurology
Clinical Neurology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1111/epi.17199

Cite this

Wu, J. Y., Cock, H. R., Devinsky, O., Joshi, C., Miller, I., Roberts, C. M., Sanchez-Carpintero, R., Checketts, D., & Sahebkar, F. (2022). 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. Epilepsia, 63(5), 1189-1199. https://doi.org/10.1111/epi.17199

@article{d0def0ac129d4d0aa2c12f5e8e07a7b1,

title = "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",

abstract = "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.",

keywords = "antiseizure medication, cannabidiol, epilepsy, focal seizures, medication-resistant seizures, tuberous sclerosis complex",

author = "Wu, {Joyce Y.} and Cock, {Hannah R.} and Orrin Devinsky and Charuta Joshi and Ian Miller and Roberts, {Colin M.} and Rocio Sanchez-Carpintero and Daniel Checketts and Farhad Sahebkar",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.",

year = "2022",

month = may,

doi = "10.1111/epi.17199",

language = "English (US)",

volume = "63",

pages = "1189--1199",

journal = "Epilepsia",

issn = "0013-9580",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "5",

}

Wu, JY, Cock, HR, Devinsky, O, Joshi, C, Miller, I, Roberts, CM, Sanchez-Carpintero, R, Checketts, D & Sahebkar, F 2022, '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', Epilepsia, vol. 63, no. 5, pp. 1189-1199. https://doi.org/10.1111/epi.17199

TY - JOUR

T1 - Time to onset of cannabidiol treatment effect and resolution of adverse events in tuberous sclerosis complex

T2 - Post hoc analysis of randomized controlled phase 3 trial GWPCARE6

AU - Wu, Joyce Y.

AU - Cock, Hannah R.

AU - Devinsky, Orrin

AU - Joshi, Charuta

AU - Miller, Ian

AU - Roberts, Colin M.

AU - Sanchez-Carpintero, Rocio

AU - Checketts, Daniel

AU - Sahebkar, Farhad

PY - 2022/5

Y1 - 2022/5

N2 - 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.

AB - 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.

KW - antiseizure medication

KW - cannabidiol

KW - epilepsy

KW - focal seizures

KW - medication-resistant seizures

KW - tuberous sclerosis complex

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JO - Epilepsia

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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

Abstract

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UN SDGs

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