PMID- 34265088 OWN - NLM STAT- MEDLINE DCOM- 20220303 LR - 20240403 IS - 1528-1167 (Electronic) IS - 0013-9580 (Print) IS - 0013-9580 (Linking) VI - 62 IP - 9 DP - 2021 Sep TI - Time to onset of cannabidiol treatment effects in Dravet syndrome: Analysis from two randomized controlled trials. PG - 2218-2227 LID - 10.1111/epi.16974 [doi] AB - 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. CI - (c) 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy. FAU - Madan Cohen, Jennifer AU - Madan Cohen J AUID- ORCID: 0000-0002-7087-1448 AD - Department of Pediatrics, Division of Neurology at Connecticut Children's, University of Connecticut, Hartford, Connecticut, USA. FAU - Checketts, Daniel AU - Checketts D AD - GW Research, Cambridge, UK. FAU - Dunayevich, Eduardo AU - Dunayevich E AD - Greenwich Biosciences, Carlsbad, California, USA. FAU - Gunning, Boudewijn AU - Gunning B AD - Stichting Epilepsie Instellingen Nederland, Zwolle, the Netherlands. FAU - Hyslop, Ann AU - Hyslop A AD - Nicklaus Children's Hospital, Miami, Florida, USA. FAU - Madhavan, Deepak AU - Madhavan D AD - Boys Town National Research Hospital, Boys Town, Nebraska, USA. FAU - Villanueva, Vicente AU - Villanueva V AD - University and Polytechnic Hospital La Fe, Valencia, Spain. FAU - Zolnowska, Marta AU - Zolnowska M AD - Medical Center Plejady, Krakow, Poland. FAU - Zuberi, Sameer M AU - Zuberi SM AD - Paediatric Neurosciences Research Group, Royal Hospital for Children & College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, UK. LA - eng SI - ClinicalTrials.gov/NCT02091375 SI - ClinicalTrials.gov/NCT02224703 PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210715 PL - United States TA - Epilepsia JT - Epilepsia JID - 2983306R RN - 0 (Anticonvulsants) RN - 19GBJ60SN5 (Cannabidiol) RN - CDKL5 deficiency disorder SB - IM MH - Adolescent MH - Anticonvulsants/therapeutic use MH - Cannabidiol/*therapeutic use MH - Child MH - Child, Preschool MH - Double-Blind Method MH - *Epilepsies, Myoclonic/drug therapy MH - Epileptic Syndromes MH - Humans MH - Randomized Controlled Trials as Topic MH - Seizures/drug therapy MH - Spasms, Infantile MH - Treatment Outcome PMC - PMC8456817 OTO - NOTNLM OT - antiepileptic drug OT - childhood onset epilepsy OT - convulsive seizures OT - efficacy onset COIS- J.M.C. has received speaker fees from Greenwich Biosciences, and has been a principal investigator for GW Research. D.C. is an employee of GW Research, and owns stock in GW Pharmaceuticals. E.D. is an employee of Greenwich Biosciences, and owns stock in GW Pharmaceuticals. B.G. has received consultancy fees from GW Pharmaceuticals, Ovid/Takeda and Zogenix, and has been a principal investigator for GW Research, Zogenix, LivaNova, and Marinus Pharmaceuticals. A.H. has received consultancy and/or speaker fees from Supernus Pharmaceuticals, Eisai, GW Pharmaceuticals, and Aquestive Pharmaceuticals, and has been a principal investigator for GW Research, Sage Therapeutics, Marinus Pharmaceuticals, Neurocrine Biosciences, and UCB Biosciences. D.M. has received speaker fees from Greenwich Biosciences, and has been a been a principal investigator for GW Research. V.V. has participated on advisory boards and in symposia organized by Angelini, Arvelle, Bial, Eisai, Esteve, GSK, GW Pharmaceuticals, Novartis, Sandoz, UCB, and Zogenix, and has been a principal investigator for GW Research. M.Z. has been a principal investigator for GW Research, Zogenix, Ovid/Takeda, Marinus, and Emalex Biosciences. S.M.Z. has received research support from Epilepsy Research UK, Glasgow Children's Hospital Charity, the Tenovus Foundation, and UCB Pharma; has received honoraria for advisory boards, consulting, and educational symposia from GW Pharmaceuticals, Zogenix, Arvelle Therapeutics, Stoke Therapeutics, and Encoded Genomics; and has been a principal investigator for GW Research. His institution has undertaken commercial trials for GW Research and Zogenix. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. EDAT- 2021/07/16 06:00 MHDA- 2022/03/04 06:00 PMCR- 2021/09/22 CRDT- 2021/07/15 17:55 PHST- 2021/06/08 00:00 [revised] PHST- 2021/04/20 00:00 [received] PHST- 2021/06/08 00:00 [accepted] PHST- 2021/07/16 06:00 [pubmed] PHST- 2022/03/04 06:00 [medline] PHST- 2021/07/15 17:55 [entrez] PHST- 2021/09/22 00:00 [pmc-release] AID - EPI16974 [pii] AID - 10.1111/epi.16974 [doi] PST - ppublish SO - Epilepsia. 2021 Sep;62(9):2218-2227. doi: 10.1111/epi.16974. Epub 2021 Jul 15.