The protocol for the Cannabidiol in children with refractory epileptic encephalopathy (CARE-E) study: a phase 1 dosage escalation study.

BMC Pediatr. 2018 Jul 7;18(1):221. doi: 10.1186/s12887-018-1191-y. Reithmeier D1,2, Tang-Wai R1,3,4, Seifert B1,5, Lyon AW1,6, Alcorn J1,2, Acton B1,7,8, Corley S1,9, Prosser-Loose E1,10, Mousseau DD1,11, Lim HJ1,12, Tellez-Zenteno J1,13, Huh L14, Leung E15, Carmant L16, Huntsman RJ17,18. Author information 1 Cannabinoid Research Initiative of Saskatchewan (CRIS), University of Saskatchewan, Saskatoon, Saskatchewan, Canada. 2 College of Pharmacy and Nutrition, University of Saskatchewan, Room E3210 Health Sciences 104 Clinic Place, Saskatoon, SK, S7N-2Z4, Canada. 3 Department of Pediatrics, Division of Child Neurology, Loma Linda University, Loma Linda, California, USA. 4 Division of Pediatric Neurology, Department of Pediatrics, University of Alberta, 11405-87 Avenue, 4th Floor, Edmonton, AB, T6G-1C9, Canada. 5 Department of Pharmaceutical Services, Saskatchewan Health Authority, Saskatoon Health Region, Royal University Hospital, 103 Hospital Drive, Saskatoon, SK, S7N-0W8, Canada. 6 Department of Pathology and Laboratory Medicine, Saskatchewan Health Authority, St. Paul's Hospital, 1702 20th Street West, Saskatoon, SK, S7M-0Z9, Canada. 7 Saskatchewan Health Authority and Department of Psychology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. 8 Department of Clinical Health Psychology, Royal University Hospital, 103 Hospital Drive, Saskatoon, SK, S7N 0W8, Canada. 9 Clinical Trial Support Unit, University of Saskatchewan, Royal University Hospital, Room 5676, 103 Hospital Drive, Saskatoon, SK, S7N 0W8, Canada. 10 Department of Pediatrics, University of Saskatchewan, Royal University Hospital, Room 2665, 103 Hospital Drive, Saskatoon, SK, S7N 0W8, Canada. 11 Cell Signalling Laboratory, Departments of Psychiatry and Physiology, University of Saskatchewan, GB41, HSB 107 Wiggins Ave, Saskatoon, SK, S7N 5E5, Canada. 12 Department of Community Health and Epidemiology, University of Saskatchewan, Room E3222 Health Sciences, 104 Clinic Place, Saskatoon, SK, S7N-2Z4, Canada. 13 Department of Medicine, Division of Neurology, University of Saskatchewan, Royal University Hospital, Room 1622, 103 Hospital Drive, Saskatoon, SK, S7N 0W8, Canada. 14 Division of Pediatric Neurology, Department of Pediatrics, University of British Columbia, BC Children's Hospital, Room 2D19, 4480 Oak Street, Vancouver, BC, V6H-3V4, Canada. 15 Division of Pediatric Neurology, Room CE208, Department of Pediatrics 5, University of Manitoba, Children's Hospital, 840 Sherbrooke Street, Winnipeg, MB, R3A-1S1, Canada. 16 Division of Pediatric Neurology, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, Universite de Montreal, Room 5-4, 3175 Chemin de la Cote Ste-Catherine, Montreal, QC, H3T-1C5, Canada. 17 Cannabinoid Research Initiative of Saskatchewan (CRIS), University of Saskatchewan, Saskatoon, Saskatchewan, Canada. dr.huntsman@usask.ca. 18 Department of Pediatrics, Royal University Hospital, Rm 2744, 103 Hospital Drive, Saskatoon, SK, S7N 0W8, Canada. dr.huntsman@usask.ca. Abstract BACKGROUND: Initial studies suggest pharmaceutical grade cannabidiol (CBD) can reduce the frequency of convulsive seizures and lead to improvements in quality of life in children affected by epileptic encephalopathies. With limited access to pharmaceutical CBD, Cannabis extracts in oil are becoming increasingly available. Physicians show reluctance to recommend Cannabis extracts given the lack of high quality safety data especially regarding the potential for harm caused by other cannabinoids, such as Δ9-tetrahydrocannabinol (Δ9-THC). The primary aims of the study presented in this protocol are (i) To determine whether CBD enriched Cannabis extract is safe and well-tolerated for pediatric patients with refractory epilepsy, (ii) To monitor the effects of CBD-enriched Cannabis extract on the frequency and duration of seizure types and on quality of life. METHODS: Twenty-eight children with treatment resistant epileptic encephalopathy ranging in age from 1 to 10 years will be recruited in four Canadian cities into an open-label, dose-escalation phase 1 trial. The primary objectives for the study are (i) To determine if the CBD-enriched Cannabis herbal extract is safe and well-tolerated for pediatric patients with treatment resistant epileptic encephalopathy and (ii) To determine the effect of CBD-enriched Cannabis herbal extract on the frequency and duration of seizures. Secondary objectives include (i) To determine if CBD-enriched Cannabis herbal extracts alter steady-state levels of co-administered anticonvulsant medications. (ii) To assess the relation between dose escalation and quality of life measures, (iii) To determine the relation between dose escalation and steady state trough levels of bioactive cannabinoids. (iv) To determine the relation between dose escalation and incidence of adverse effects. DISCUSSION: This paper describes the study design of a phase 1 trial of CBD-enriched Cannabis herbal extract in children with treatment-resistant epileptic encephalopathy. This study will provide the first high quality analysis of safety of CBD-enriched Cannabis herbal extract in pediatric patients in relation to dosage and pharmacokinetics of the active cannabinoids. TRIAL REGISTRATION: http://clinicaltrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2016 Dec 16. Identifier NCT03024827, Cannabidiol in Children with Refractory Epileptic Encephalopathy: CARE-E; 2017 Jan 19 [cited 2017 Oct]; Available from: http://clinicaltrials.gov/ct2/show/NCT03024827. KEYWORDS: Cannabidiol; Cannabis; CanniMed®; Pediatric epilepsy PMID: 29981580 PMCID: PMC6035794 DOI: 10.1186/s12887-018-1191-y Free PMC Article Share on FacebookShare on TwitterShare on Google+