PMID- 35175622 OWN - NLM STAT- MEDLINE DCOM- 20220509 LR - 20220731 IS - 1528-1167 (Electronic) IS - 0013-9580 (Print) IS - 0013-9580 (Linking) VI - 63 IP - 5 DP - 2022 May TI - 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. PG - 1189-1199 LID - 10.1111/epi.17199 [doi] 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. CI - (c) 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy. FAU - Wu, Joyce Y AU - Wu JY AUID- ORCID: 0000-0003-3502-788X AD - Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. FAU - Cock, Hannah R AU - Cock HR AUID- ORCID: 0000-0002-5656-0141 AD - St George's University Hospitals National Health Service Foundation Trust, St George's University of London, London, UK. FAU - Devinsky, Orrin AU - Devinsky O AUID- ORCID: 0000-0003-0044-4632 AD - Comprehensive Epilepsy Center, NYU Langone Health, New York, New York, USA. FAU - Joshi, Charuta AU - Joshi C AUID- ORCID: 0000-0003-4502-7242 AD - Children's Hospital Colorado, Aurora, Colorado, USA. FAU - Miller, Ian AU - Miller I AUID- ORCID: 0000-0003-0416-1015 AD - Nicklaus Children's Hospital, Miami, Florida, USA. FAU - Roberts, Colin M AU - Roberts CM AD - Oregon Health and Science University, Portland, Oregon, USA. FAU - Sanchez-Carpintero, Rocio AU - Sanchez-Carpintero R AUID- ORCID: 0000-0002-5058-0686 AD - University of Navarra Clinic, Pamplona, Spain. FAU - Checketts, Daniel AU - Checketts D AD - GW Research, Cambridge, UK. FAU - Sahebkar, Farhad AU - Sahebkar F AD - Greenwich Biosciences, Carlsbad, California, USA. LA - eng SI - ClinicalTrials.gov/NCT02544763 PT - Clinical Trial, Phase III PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20220304 PL - United States TA - Epilepsia JT - Epilepsia JID - 2983306R RN - 0 (Anticonvulsants) RN - 19GBJ60SN5 (Cannabidiol) SB - IM MH - Adolescent MH - Adult MH - Anticonvulsants/adverse effects MH - *Cannabidiol/adverse effects MH - Child MH - Double-Blind Method MH - Humans MH - Middle Aged MH - Seizures/chemically induced/etiology MH - Treatment Outcome MH - *Tuberous Sclerosis/complications/drug therapy MH - Young Adult PMC - PMC9314914 OTO - NOTNLM OT - antiseizure medication OT - cannabidiol OT - epilepsy OT - focal seizures OT - medication-resistant seizures OT - tuberous sclerosis complex COIS- J.Y.W. has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Novartis Pharmaceuticals and GW Pharmaceuticals and has received research support from both. She has also received support from the National Institutes of Health and TSC Alliance. H.R.C. has received research support as a site investigator from GW Research and from Novartis during the conduct of the study; grant support from the National Institute of Neurological Disorders and Stroke (NINDS); nonfinancial support from the International League Against Epilepsy and European Academy of Neurology; and personal fees for consulting from Bial Pharma and in relation to medicolegal expert witness reports from civil court proceedings in the UK for personal injury cases (via solicitors). O.D. has equity interests in Qstate Biosciences, Tevard Biosciences, Regel Therapeutics, Script Biosciences, Privateer Holdings, Tilray, Receptor Life Sciences, Empatica, Engage, Egg Rock/Papa & Barkley, Rettco, SilverSpike, and California Cannabis Enterprises and receives grant support from NINDS, National Institute of Mental Health, Multidisciplinary University Research Initiative, US Centers for Disease Control and Prevention, and National Science Foundation. He is an investigator for PTC Therapeutics, Stoke Therapeutics, Marinus, Ovid, and GW Pharmaceuticals. C.J. has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Zogenix. I.M. has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with GW Pharmaceuticals, TS Alliance, DS Foundation, lnsys, Biomarin, Upsher-Smith, Visualase, Neuroblate, Zogenix, and Ultragenyx. He has received personal compensation in an editorial capacity for Insys Pharmaceuticals, GW Pharmaceuticals, TS Alliance, DS Foundation, Visualase, Neuroblate, Zogenix, and Ultragenyx and has received research support from GW Pharmaceuticals, TS Alliance, DS Foundation, lnsys, Biomarin, Upsher-Smith, Visualase, Neuroblate, Zogenix, and Ultragenyx. C.M.R. has nothing to disclose. R.S.-C. has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with scientific advisory boards of GW Pharmaceuticals, Zogenix, and Novartis; is a member of the speaker's bureau of GW Pharmaceuticals; and has received research support as a principal investigator for GW Pharmaceuticals-, Zogenix-, and Takeda-initiated trials. D.C. is an employee of GW Research. F.S. is an employee of Greenwich Biosciences. 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- 2022/02/18 06:00 MHDA- 2022/05/10 06:00 PMCR- 2022/07/26 CRDT- 2022/02/17 12:29 PHST- 2022/02/11 00:00 [revised] PHST- 2021/12/22 00:00 [received] PHST- 2022/02/14 00:00 [accepted] PHST- 2022/02/18 06:00 [pubmed] PHST- 2022/05/10 06:00 [medline] PHST- 2022/02/17 12:29 [entrez] PHST- 2022/07/26 00:00 [pmc-release] AID - EPI17199 [pii] AID - 10.1111/epi.17199 [doi] PST - ppublish SO - Epilepsia. 2022 May;63(5):1189-1199. doi: 10.1111/epi.17199. Epub 2022 Mar 4.