PMID- 33797076 OWN - NLM STAT- MEDLINE DCOM- 20210930 LR - 20240402 IS - 1528-1167 (Electronic) IS - 0013-9580 (Print) IS - 0013-9580 (Linking) VI - 62 IP - 5 DP - 2021 May TI - Time to onset of cannabidiol (CBD) treatment effect in Lennox-Gastaut syndrome: Analysis from two randomized controlled trials. PG - 1130-1140 LID - 10.1111/epi.16878 [doi] AB - OBJECTIVE: To estimate time to onset of cannabidiol (CBD) treatment effect (seizure reduction and adverse events [AEs]), we conducted post hoc analyses of data from two randomized, placebo-controlled, Phase 3 trials, GWPCARE3 (NCT02224560) and GWPCARE4 (NCT02224690), of patients with Lennox-Gastaut syndrome. METHODS: Patients received plant-derived pharmaceutical formulation of highly purified CBD (Epidiolex, 100 mg/ml oral solution) at 10 mg/kg/day (CBD10; GWPCARE3) or 20 mg/kg/day (CBD20; both trials) or placebo for 14 weeks. Treatment started at 2.5 mg/kg/day for all groups and reached 10 mg/kg/day on Day 7 and 20 mg/kg/day (CBD20 and matching placebo only) on Day 11. Percentage change from baseline in drop seizure frequency was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were evaluated. RESULTS: Overall, 235 patients received CBD (CBD10 [GWPCARE3 only], n = 67; CBD20 [pooled GWPCARE3&4], n = 168) and 161 received placebo. Mean (range) age was 15.3 years (2.6-48.0). Patients had previously discontinued a median (range) of six (0-28) antiepileptic drugs (AEDs) and were currently taking a median of three (0-5) AEDs. Differences in drop seizure reduction between placebo and CBD emerged during the titration period and became nominally significant by Day 6 (p = .008) for pooled CBD treatment groups. Separation between placebo and CBD in >/=50% responder rate emerged by Day 6. Onset of the first reported AE occurred during the titration period in 45% of patients (CBD10, 46%; CBD20, 52%; placebo, 38%). In patients with AEs, resolution occurred within 4 weeks of onset in 53% of placebo and 39% of CBD patients and by end of study in 63% of placebo and 61% of CBD patients. SIGNIFICANCE: Treatment effect (efficacy and AEs) of CBD may occur within 1 week of starting treatment. Although AEs lasted longer for CBD than placebo, most resolved within the 14-week period. CI - (c) 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy. FAU - Privitera, Michael AU - Privitera M AUID- ORCID: 0000-0002-0862-5975 AD - University of Cincinnati Medical Center, Cincinnati, OH, USA. FAU - Bhathal, Hari AU - Bhathal H AD - Neurocenter Barcelona, Teknon Medical Center, Barcelona, Spain. FAU - Wong, Matthew AU - Wong M AD - Wake Forest Baptist Medical Center, Winston-Salem, NC, USA. FAU - Cross, J Helen AU - Cross JH AUID- ORCID: 0000-0001-7345-4829 AD - University College London National Institute for Health Research Biomedical Research Center Great Ormond Street Institute of Child Health, London, UK. FAU - Wirrell, Elaine AU - Wirrell E AUID- ORCID: 0000-0003-3015-8282 AD - Mayo Clinic, Rochester, MN, USA. FAU - Marsh, Eric D AU - Marsh ED AUID- ORCID: 0000-0003-3264-0902 AD - Children's Hospital of Philadelphia, Philadelphia, PA, USA. FAU - Mazurkiewicz-Beldzinska, Maria AU - Mazurkiewicz-Beldzinska M AUID- ORCID: 0000-0002-9405-5066 AD - Medical University of Gdansk, Gdansk, Poland. FAU - Villanueva, Vicente AU - Villanueva V AUID- ORCID: 0000-0003-2080-8042 AD - University and Polytechnic Hospital La Fe, Valencia, Spain. FAU - Checketts, Daniel AU - Checketts D AD - GW Research Ltd., Cambridge, UK. FAU - Knappertz, Volker AU - Knappertz V AD - Greenwich Biosciences, Inc., Carlsbad, CA, USA. FAU - VanLandingham, Kevan AU - VanLandingham K AD - Greenwich Biosciences, Inc., Carlsbad, CA, USA. LA - eng SI - ClinicalTrials.gov/NCT02224690 SI - ClinicalTrials.gov/NCT02224560 PT - Clinical Trial, Phase III PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20210402 PL - United States TA - Epilepsia JT - Epilepsia JID - 2983306R RN - 0 (Anticonvulsants) RN - 19GBJ60SN5 (Cannabidiol) SB - IM MH - Adolescent MH - Adult MH - Anticonvulsants/*therapeutic use MH - Cannabidiol/*therapeutic use MH - Child MH - Child, Preschool MH - Double-Blind Method MH - Female MH - Humans MH - Lennox Gastaut Syndrome/*drug therapy MH - Male MH - Middle Aged MH - Seizures/etiology/therapy MH - Time Factors MH - *Treatment Outcome MH - Young Adult PMC - PMC8252057 OTO - NOTNLM OT - antiepileptic drug OT - antiseizure medication OT - childhood onset epilepsy OT - drop seizures OT - treatment-resistant epilepsy COIS- M.P. has received research grants from SK Life Science, Xenon Pharmaceuticals, Epilepsy Foundation, and GW Pharmaceuticals, and has served as a consultant for SK Life Science, GW Pharmaceuticals, and Neurelis. H.B. was an investigator on trials sponsored by GW Research. M.W. received funds from GW Pharmaceuticals associated with conducting this study. J.H.C.'s institution received grants from Zogenix, Marinius, and Vitaflo and other support from GW Pharmaceuticals, Nutricia, and Biomarin. Her research is supported by the National Institute of Health Research Biomedical Research Centre at Great Ormond Street Hospital. E.W. has participated on advisory boards for Biomarin and Sunovian and has received personal fees from UpToDate. E.M. has served as a consultant for Eisai Pharma and Cydan, and as a study investigator for GW Pharmaceuticals. M.M.-B. has served as a study investigator for GW Pharmaceuticals. V.V. has received grants from Eisai and UCB, and has participated on advisory boards for Eisai, UCB, Bial, Esteve, GW Pharmaceuticals, Arvelle Therapeutics, and Novartis. D.C. is a full-time employee of GW Research. V.K. is a full-time employee of Greenwich Biosciences and owns shares in the company. K.V. was an employee of Greenwich Biosciences at the time this study was conducted. EDAT- 2021/04/03 06:00 MHDA- 2021/10/01 06:00 PMCR- 2021/07/02 CRDT- 2021/04/02 06:48 PHST- 2021/02/19 00:00 [revised] PHST- 2020/11/24 00:00 [received] PHST- 2021/03/03 00:00 [accepted] PHST- 2021/04/03 06:00 [pubmed] PHST- 2021/10/01 06:00 [medline] PHST- 2021/04/02 06:48 [entrez] PHST- 2021/07/02 00:00 [pmc-release] AID - EPI16878 [pii] AID - 10.1111/epi.16878 [doi] PST - ppublish SO - Epilepsia. 2021 May;62(5):1130-1140. doi: 10.1111/epi.16878. Epub 2021 Apr 2.