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

Darren Reithmeier, Richard Tang-Wai, Blair Seifert, Andrew W. Lyon, Jane Alcorn, Bryan Acton, Scott Corley, Erin Prosser-Loose, Darrell D. Mousseau, Hyun J. Lim, Jose Tellez-Zenteno, Linda Huh, Edward Leung, Lionel Carmant and Richard J. Huntsman

BMC Pediatrics, 2018, 18:221

https://doi.org/10.1186/s12887-018-1191-y

 

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 : Cannabis, Cannabidiol, Pediatric epilepsy, CanniMed®

 

Background

The epileptic encephalopathies are a group of childhood-onset seizure disorders characterized by frequent seizures and markedly abnormal EEG patterns associated with progressive disturbance of cerebral function that manifests as developmental stagnation or regression. These epilepsies are often resistant to conventional medical treatment regimens and children with these conditions invariably experience neurological and cognitive impairments that severely impair their quality of life (QoL) [1].

In 2013 Porter and Jacobson reported the results of a 24-point survey they posted on a Facebook-group composed of parents using CBD-enriched Cannabis products to treat their children with refractory epilepsy. Of the 20 respondents, 84% reported the CBD-enriched Cannabis products resulted in a decrease in seizure frequency in their children and over half of their children either became seizure-free or had a greater than 80% reduction in their seizure frequency. Just as importantly, most parents reported an improvement in QoL indices such as alertness, sleep, and mood [2]. Since that time several open-label and randomized double-blind trials of CBD-based treatments in children with epileptic encephalopathy including Dravet Syndrome and Lennox Gastaut syndrome have been reported [3–6]. These studies found a reduced frequency of convulsive seizures and mild adverse events of somnolence and elevated liver-enzyme activities. Unfortunately, there was considerable variation in the dosage and types of CBD formulation used; three studies using a purified CBD product (Epidiolex) and one using a whole plant Cannabis herbal extract. The considerable variation in CBD dosage and lack of pharmacokinetic data resulted in no guidance on appropriate dosage regimens in this pediatric patient population.

CBD can be derived from pure pharmaceutical preparations or in extracts of Cannabis sativa or
Cannabis indica [7]. The composition of Cannabis extracts can vary dramatically due to differences in cultivars, growing conditions, and extraction and decarboxylation processes. The lack of standardization
or quality assurance in the preparation and dose administration of these products severely limits the scientific study of herbal preparations of Cannabis. The recent availability of commercial Cannabis extracts from a licensed medical marijuana producer that uses good manufacturing processes (GMP) with assayed cannabinoid composition assures patient safety and reliable dosing and enables scientific evaluation [8, 9]. We propose to conduct an open-label dose escalation study of CBD-enriched Cannabis herbal extract in pediatric patients with treatment resistant epileptic encephalopathy.

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