PMID- 34477852 OWN - NLM STAT- MEDLINE DCOM- 20220110 LR - 20220110 IS - 2574-3805 (Electronic) IS - 2574-3805 (Linking) VI - 4 IP - 9 DP - 2021 Sep 1 TI - Safety and Tolerability of Transdermal Cannabidiol Gel in Children With Developmental and Epileptic Encephalopathies: A Nonrandomized Controlled Trial. PG - e2123930 LID - 10.1001/jamanetworkopen.2021.23930 [doi] LID - e2123930 AB - IMPORTANCE: Developmental and epileptic encephalopathies (DEEs) are the most severe group of drug-resistant epilepsies. Alternatives to oral therapies are urgently needed to reduce seizures and improve developmental outcomes and comorbidities in this medically complex population. OBJECTIVE: To assess the safety and tolerability of cannabidiol (CBD) transdermal gel in children with DEEs and to evaluate seizure frequency, sleep, and quality of life. DESIGN, SETTING, AND PARTICIPANTS: This nonrandomized controlled trial was conducted in 2 centers in Australia and New Zealand from April 2018 to July 2019. Children and adolescents aged 3 to 18 years with DEEs who were receiving a stable regimen of 1 to 4 antiseizure medications were eligible for this study. After 1-month baseline and titration periods, patients entered a 5.5-month flexible-dosing maintenance period for a total of 6.5 months of treatment. Data were analyzed throughout the 6.5-month treatment period. INTERVENTIONS: Twice-daily applications of CBD transdermal gel at doses of 125 to 500 mg for 6.5 months. MAIN OUTCOMES AND MEASURES: Safety and tolerability assessments included adverse events (AEs) and examination of skin. The outcome for seizures was the median percentage change from baseline in monthly (28-day) seizure frequency of focal impaired awareness seizures (FIAS) and tonic-clonic seizures (TCS) over 6.5 months. RESULTS: Of 48 patients (mean [SD] age, 10.5 [3.8] years; 26 [54%] boys), 29 (60%) had at least 1 treatment-related AE over 6.5 months; 44 of 46 treatment-related AEs (96%) were mild or moderate. Treatment-related AEs that occurred in at least 5% of patients were application-site dryness, application-site pain, and somnolence (each reported by 4 patients [8%]). The only treatment-related gastrointestinal AE was diarrhea, reported in a single patient. CBD treatment was associated with reductions in FIAS and TCS frequency. Analysis of the 33 patients with FIAS and TCS showed a median (interquartile range) monthly reduction in seizures of 58% (-5.3% to 81.8%) at 5 months and 43.5% (-23.8% to 57.5%) over the entire 6.5-month study period. Parents and caregivers noted improvements in social or interpersonal engagement and irritability (33 of 43 [77%] participants); alertness, energy, and sleep (23 of 43 [53%]); and cognition or concentration (20 of 43 [47%]). CONCLUSIONS AND RELEVANCE: In this study, CBD transdermal gel was safe, well tolerated, and was associated with reductions in FIAS and TCS frequency and disease burden. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: ACTRN12618000516280. FAU - Scheffer, Ingrid E AU - Scheffer IE AD - University of Melbourne, Austin Health and Royal Children's Hospital, Florey Institute, Melbourne, Victoria, Australia. AD - Murdoch Children's Research Institutes, Victoria, Australia. FAU - Hulihan, Joe AU - Hulihan J AD - Consultant, Newtown, Pennsylvania. FAU - Messenheimer, John AU - Messenheimer J AD - Consultant, Moncure, North Carolina. FAU - Ali, Shayma AU - Ali S AD - Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand. FAU - Keenan, Ngaire AU - Keenan N AD - Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand. FAU - Griesser, Jim AU - Griesser J AD - The Griesser Group, Conshohocken, Pennsylvania. FAU - Gutterman, Donna L AU - Gutterman DL AD - Zynerba Pharmaceuticals Inc, Devon, Pennsylvania. FAU - Sebree, Terri AU - Sebree T AD - Zynerba Pharmaceuticals Inc, Devon, Pennsylvania. FAU - Sadleir, Lynette G AU - Sadleir LG AD - Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand. LA - eng PT - Clinical Trial PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20210901 PL - United States TA - JAMA Netw Open JT - JAMA network open JID - 101729235 RN - 0 (Anticonvulsants) RN - 0 (Gels) RN - 19GBJ60SN5 (Cannabidiol) SB - IM MH - Administration, Cutaneous MH - Adolescent MH - Anticonvulsants/administration & dosage/*therapeutic use MH - Australia MH - Cannabidiol/administration & dosage/*therapeutic use MH - Child MH - Child, Preschool MH - *Developmental Disabilities MH - Drug Resistant Epilepsy/*drug therapy MH - Female MH - Gels MH - Humans MH - Male MH - New Zealand MH - Seizures/*drug therapy MH - Treatment Outcome PMC - PMC8417764 COIS- Conflict of Interest Disclosures: Dr Scheffer reported service on the editorial boards of the Annals of Neurology, Neurology, and Epileptic Disorders; she reported patents held or pending for therapeutic compounds, testing methods, and molecular diagnostic targets for infantile epilepsy, some of which are licensed and have paid royalties. She reported service on scientific advisory boards for UCB Pharmaceuticals, Eisai Co Ltd, GlaxoSmithKline, BioMarin Pharmaceutical, Nutricia, Rogcon Inc, Chiesi, Encoded Therapeutics, Xenon Pharmaceuticals, Zynerba Pharmaceuticals, and Knopp Biosciences; she reported receiving speaker honoraria from GlaxoSmithKline, UCB Pharmaceuticals, BioMarin, Athena Diagnostics, Liva Nova, Biocodex, and Eisai; she reported receiving funding for travel from UCB Pharmaceuticals, Biocodex, GlaxoSmithKline, Biomarin Pharmaceutical, National Research Foundation Singapore, and Eisai Co Ltd; she reported service as an investigator for Zogenix, Zynerba Pharmaceuticals, Ultragenyx, GW Pharmaceuticals, UCB Pharmaceuticals, Eisai Co Ltd, Anavex Life Sciences, Ovid Therapeutics, Epigenyx, Encoded Therapeutics, and Marinus; and she reported consulting work for Zynerba Pharmaceuticals, Athena Diagnostics, Atheneum Partners, Ovid Therapeutics, Care Beyond Diagnosis, Epilepsy Consortium, and UCB Pharmaceuticals. She reported receiving research support from the National Health and Medical Research Council of Australia, the Australian Medical Research Future Fund, Health Research Council of New Zealand, Citizens United for Research in Epilepsy, Australian Epilepsy Research Fund, and the National Institute of Neurological Disorders and Stroke outside the submitted work. Dr Sadleir reported consulting work for Zynerba Pharmaceuticals Inc, and reported receiving honoraria from Eisai Co Ltd. Drs Hulihan and Messenheimer and Mr Griesser reported consulting work for Zynerba Pharmaceuticals Inc. Dr Gutterman and Ms Sebree reported employment with Zynerba Pharmaceuticals Inc and reported stock options from Zynerba Pharmaceuticals Inc; they reported holding patents for treatment methods using cannabidiol and CBD. Ms Sebree reported stock ownership of Zynerba Pharmaceuticals Inc. No other conflicts were reported. EDAT- 2021/09/04 06:00 MHDA- 2022/01/11 06:00 PMCR- 2021/09/03 CRDT- 2021/09/03 12:24 PHST- 2021/09/03 12:24 [entrez] PHST- 2021/09/04 06:00 [pubmed] PHST- 2022/01/11 06:00 [medline] PHST- 2021/09/03 00:00 [pmc-release] AID - 2783716 [pii] AID - zoi210698 [pii] AID - 10.1001/jamanetworkopen.2021.23930 [doi] PST - epublish SO - JAMA Netw Open. 2021 Sep 1;4(9):e2123930. doi: 10.1001/jamanetworkopen.2021.23930.