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Cbd oil for epilepsy data

Medical Cannabis for Intractable Epilepsy in Childhood: A Review

This is an open-access article. All its content, except where otherwise noted, is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

In recent years, cannabis has been gaining increasing interest in both the medical research and clinical fields, with regard to its therapeutic effects in various disorders. One of the major fields of interest is its role as an anticonvulsant for refractory epilepsy, especially in the pediatric population. This paper presents and discusses the current accumulated knowledge regarding artisanal cannabis and Epidiolex®, a United States Food and Drug Administration (FDA)-approved pure cannabidiol (CBD), in epilepsy management in pediatrics, by reviewing the literature and raising debate regarding further research directions.

INTRODUCTION

Childhood epilepsy may be coarsely divided into (1) a large group (70%) of benign epileptic syndromes and easily controlled symptomatic epilepsies, and (2) a smaller but significant group of drug-resistant epilepsies which includes idiopathic and genetic epileptic encephalopathies and various symptomatic acquired epilepsies. The burden of intractable epilepsy on infants and children and their families is enormous, and in addition to the risks carried by the actual seizures it significantly affects the children’s development and quality of life. Most of these children are on polytherapy, which has its own consequences. This devastating situation has led to a quest for additional solutions. This quest, with regard to the use of cannabis, has been led by parents and caretakers in parallel to the medical authorities.

Various ancient cultures have mentioned cannabis as a useful tool to treat epileptic convulsions. There are historical records from ancient China dating back to 2700 BC 1 and tablets written by the Sumerian and Akkadian peoples in 1800 BC, 2 as well as other ancient historical records. In the nineteenth century several leading physicians published papers on its use as an anticonvulsant, presenting both case reports 3 and their general impression on its effectiveness when added to bromides. 4

Despite the Marijuana Tax Act of 1937, which led to the removal of cannabis from the US pharmacopeia in 1941, and its classification as a schedule 1 substance, several researchers and physicians renewed investigation on the biological effects and medicinal use of its various components in the 1970s. Several animal studies and small-scale clinical trials examined its use. Studies focusing mainly on purified cannabidiol (CBD) in epilepsy management in drug-resistant patients were published. 5 – 10 The above clinical studies were assessed in a 2012 Cochrane review stating that the trials were based on small samples with inconsistent products, dosages, dose frequencies, and treatment durations. These deficiencies led the Cochrane reviewers to conclude that CBD efficacy in the treatment of epilepsy could not be confirmed, but that a dosage within the range 200–300 mg daily was safe enough to be given over a short time period. 11

In the last decade social media, patient and family advocacy groups, and Internet activity have led to significant public interest in cannabis as an alternative treatment for those living with epilepsy. This public demand revived both basic and clinical research into cannabis and CBD use for epilepsy treatment particularly in the pediatric population. This review provides an overview and discussion of the current data relating to artisanal cannabis and pure CBD use in epilepsy.

CANNABIS AND CANNABIDIOL ANTIEPILEPTIC MECHANISM OF ACTION AND PHARMACOKINETICS

The marijuana plant, Cannabis sativa, and Cannabis indica contain up to 500 chemical species, with more than 100 different phytocannabinoid compounds. 12 The two main components of cannabis—Δ-9-tetrahydrocannabiniol (THC) and CBD—have generated the most interest in terms of their putative effectiveness as anti-seizure agents: THC is a psychoactive agent, with equivocal value for seizure control and a potential to trigger seizure activity; CBD is a non-psychoactive agent with both anecdotal and scientific evidence suggesting its usefulness as an antiepileptic medication. 13 , 14

Biologically, THC’s mechanism of action is primarily related to its effect on endogenous cannabinoid receptors in the brain, mainly cannabinoid receptor type 1 (CB1), and to the extra central nervous system (CNS) receptor, CB2. 15 Cannabidiol, on the other hand, has a relatively small direct affinity to the CB1 and CB2 receptors but has an inhibitory effect on THC binding to the CB1 receptors. 16 This inhibitory effect may lead to positive modulation (“fine tuning”) of CB1 activation by THC which may reduce anxiety and paranoia caused by its non-modulated activation. 17

The CBD anticonvulsant activity is most probably multifactorial and relates to: gamma-aminobutyric acid (GABA)-mediated inhibition of glutaminergic forebrain neurons 18 ; intracellular calcium current modulation through an effect on several transient receptor potential channels of the vanilloid subtype; its direct effect on the G-protein-coupled receptor GPR55; and the inhibition of adenosine reuptake and modulation of tumor necrosis factor (TNF)-alpha release, affecting the inflammatory related components of epileptiform activity. 19 The affinity of CBD for the 5-HT1A and 5-HT2A receptors is also considered a novel target for refractory epilepsy treatment. 20 In addition to its indirect antagonism on CB1, CBD may affect the seizure threshold as shown in several animal studies. 21

CANNABIDIOL ANTICONVULSANT EFFECTS IN ANIMAL MODELS

Cannabidiol has been tested in several animal epileptic models, including maximal electroshock, pentylenetetrazol, pilocarpine, penicillin, audiogenic seizures, 6-Hz, subcutaneous metrazol threshold test, and cobalt implantation, 22 – 26 and was found to have an anticonvulsant effect in all models. Its anticonvulsant profile was re-evaluated using the focused screening protocol developed by the National Institute of Neurological Disorders and Stroke (NINDS)-funded Epilepsy Therapy Screening Program. Intraperitoneal introduction of CBD produced a dose-dependent protection against maximal electroshock-induced seizures in mice and rats and was found to be effective in the 6 Hz, 44 mA seizure model and the corneal kindling model in mice. 27

Because of the specific interest given to the positive effect of CBD in Dravet syndrome patients, this compound was studied in an SCN1A knockout mouse model showing decreased spontaneous seizure frequency and duration, as well as decreased severity of heat-induced seizures. Autistic-like social interaction deficits improved with low-dose CBD but failed to improve with the higher dosages required for seizure control. 28

Studying the effect of THC on seizures in various animal models showed conflicting results—including anticonvulsant, no effect, and proconvulsant responses—making it less attractive for clinical epilepsy treatment. 29

PHARMACOKINETICS

Cannabidiol has poor oral bioavailability of around 6%, which is related to its lipophilic structure, variable absorption rate, and extensive hepatic first-pass metabolism by isozymes CYP2C19 and CYP3A4. Its bioavailability can be increased or decreased by exposure to a strong enzyme inhibitor or inducer, respectively. 30 It is highly protein-bound and because of its lipophilic structure may accumulate in adipose tissues. The CBD peak plasma concentrations after oral administration in oily formula is about 2.5 hours, 31 with its biphasic elimination (initial half-life of 6 hours and terminal half-life of 18–32 hours) reflecting distributive processes into tissues. 32

CURRENT CLINICAL EXPERIENCE

Over the last six years, medical publications regarding epilepsy treatment with cannabis oil extracts and pure CBD can be divided into several groups: retrospective surveys and chart reviews of patients independently treated with artisanal cannabis by their caretakers which was reported to physicians; retrospective chart reviews of CBD-enriched cannabis oil use, as directed by physicians; and open-label followed by placebo-controlled prospective studies of US Food and Drug Administration (FDA)-approved pure CBD oil (Epidiolex®); in addition to anecdotal reports of other “pure CBD” compounds used. 33

Porter et al. surveyed parents who belong to a Facebook group that used CBD extracts to treat their children’s seizures. Nineteen out of 150 participants in the group responded: 84% reported a reduction in seizure frequency; of these, 11% (2/16) experienced a positive effect and became seizure-free. 34 Another online survey on CBD extract effect published by Hussain et al. included responses from 117 parents of children with epilepsy (more than 40% with intractable epileptic encephalopathies); the parents reported 85% responders, with 14% of the children achieving seizure freedom. 35 A third internet survey was reported from Mexico, 36 describing 53 patients, age range 9 months–18 years, using various cannabis extract compounds, mostly of unknown composition: 83% of patients experienced improved seizure control, and 16% became seizure-free, with only a 5% rate of seizure aggravation. However, for all these publications there is selection bias of the reports, and additionally the extract used, reported dosages, and lengths of treatment were inconsistent.

A retrospective medical chart review was performed on 75 children and adolescents who received various types and dosages of oral cannabis extracts to treat their epilepsy. Based on parental reports, within the subgroup of responders (33%), more than a 50% reduction of seizures was noted in children with Lennox–Gastaut syndrome (LGS) and Dravet syndrome. Interestingly there was a significantly higher response rate from families who had moved to Colorado in order access artisanal cannabis treatment for their child as compared to the families who were already Colorado residents (47% versus 22%), suggesting a higher placebo effect in those with higher treatment expectations. 37

A retrospective multicenter study was performed with data from three epilepsy clinics in Israel treating 74 children for intractable epilepsy with one of two well-controlled cannabis oil extracts (CBD:THC ratio, 20:1; dosage range 1–20 mg/kg/d for 3–12 months). The authors found that 52% of patients experienced more than 50% reduction in seizure frequency; only 7% of patients experienced seizure aggravation. 38 This study differs from the previous ones in that the cannabis oil treatment was directed by the pediatric neurologists responsible for all patient treatment decisions during the follow-up period. The largest chart review published so far on the effect of artisanal cannabis in pediatric epilepsy is by Sulak et al., reviewing information on 272 pediatric patients from Washington and California states who were followed for 3–30 months. They noted a more than 50% reduction in seizure frequency in 45% of patients, with 10% becoming seizure-free. 39

While the use of artisanal cannabis preparations can be criticized as being inaccurate and not as precise as expected for other drug treatments in the medical community, a more well-controlled process leading to FDA and European Medicines Agency (EMA) approval was performed for a pure CBD extract produced by GW Pharma called “Epidiolex.”

The first published study using Epidiolex as an add-on treatment for children with intractable epilepsy was by Devinsky et al. 40 This open-label multicenter efficacy and safety study included 214 patients (aged 1–30 years) with severe childhood-onset, drug-resistant epilepsy (33 patients had Dravet syndrome; 31 patients had LGS). A 36.5% median reduction in monthly motor seizures was found in the 137 patients eligible for analysis.

The following study 32 was already a double-blind placebo-controlled trial looking at the effectiveness of CBD oil (Epidiolex) as an add-on agent compared with placebo in 120 children and adolescents with treatment-resistant seizures related to Dravet syndrome (CBD dosage 20 mg/kg/d). After a four-week titration period, patients were followed for an additional 12 weeks. The main significant effect noted was the rate of reduction in convulsive seizures between CBD-treated patients (43% response rate) and the placebo group (27%), with 5% becoming seizure-free in the treatment versus placebo groups. The difference between groups for non-convulsive seizures was not significant. There was a larger drop-off (15%) in the treatment arm, compared to placebo (5%), as well as a higher rate of side effects (93% versus 85%). The response rate was higher in patients adding CBD to clobazam. 32 , 41

Two multicenter double-blind placebo-controlled trials investigated the short-term effect of CBD in LGS patients: the first one looked at the efficacy of CBD (20 mg/kg/day) as an add-on therapy for drop seizures in 171 patients (2–55 years) with treatment-resistant LGS and found a statistically significant reduction in drop seizure number in the CBD compared to the placebo group. 42 The second study compared two doses (20 mg/kg/day and 10 mg/kg/day) of purified CBD to placebo and demonstrated a significant reduction in drop seizures versus placebo with both dosages. 43

Equally important to double-blind placebo-controlled studies, which are usually short term, is investigation into a drug’s long-term effect on epilepsy. This collected data was lately reported by Szaflarski et al. 44 who reviewed the safety data of 607 patients, and the efficacy data of 580 patients, participating in the extended protocol Epidiolex studies. They found that the improvements experienced during the first 12 weeks of the study were sustained over the 96 weeks of the study, in most of the patients available for this analysis, with no aggravated side effects. The 76% study retention rate compares favorably to other antiepileptic drug trials.

Based on these positive trials the FDA approved pharmaceutical-grade CBD Epidiolex as an oral solution (100 mg CBD/mL) for treating seizures in LGS and Dravet syndrome patients over the age of two years. However, other CBD products remain as schedule I substances under the Controlled Substances Act. The above-mentioned approval was followed by EMA approval of Epidiolex for the same indications and age group, but only when added to clobazam, based on the assumption that because CBD increases blood levels of clobazam active metabolite, its antiepileptic effect in many patients in the randomized studies that led to the FDA approval could be attributed to this effect only.

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Smaller-scale studies looked at the effect of Epidiolex in other rare epileptic syndromes and disorders with severe epilepsy, including its positive effect on seizures in tuberous sclerosis patients 45 ; a higher response rate was noted when CBD (Epidiolex) was added to clobazam. A promising effect was also reported in an open-label study in 6/7 patients with febrile infection-related epilepsy syndrome, 46 as well as in Sturge–Weber syndrome. 47

CANNABIDIOL INTERACTIONS

Cannabidiol is a potent inhibitor of CYP2C19, CYP2D6, and CYP2C9, which leads to an increase in the level of several antiepileptic drugs, with the most significant effect being on clobazam and its metabolite N-desmethylclobazam, and a less prominent effect on topiramate, eslicarbazepine, zonisamide, rufinamide, and brivaracetam. 48 – 50

Abnormal elevation in liver enzymes (transaminases) can occur with concomitant use of valproate and CBD without significant changes in the valproate levels, suggesting a pharmacodynamic rather than a pharmacokinetic interaction. 32

CANNABIDIOL AND CANNABIDIOL-ENRICHED CANNABIS ADVERSE EVENTS AND POSITIVE NON-EPILEPSY-RELATED EFFECTS

The adverse events reported in the well-controlled trials of both artisanal cannabis use and Epidiolex were qualitatively similar and included fatigue, decreased appetite, somnolence, vomiting, diarrhea, and seizures. Somnolence was more frequently reported in patients treated with Epidiolex in addition to clobazam. 47 , 48 In the extensive chart review by Sulak et al., related to artisanal cannabis use, the main side effects were somnolence and fatigue in up to 20% of patients. 39 The same side effects with similar or slightly higher rates were reported in the other artisanal cannabis studies, 34 , 38 while various Epidiolex studies showed a significantly higher side effects rate. In the open-label study by Devinski et al., 40 a 79% adverse event rate was reported, with 25% somnolence, 19% decreased appetite, 19% diarrhea, 13% fatigue, and 11% convulsions; 3% of patients discontinued treatment because of an adverse event. Serious adverse events as defined by the research protocol were reported in 30% patients; in 12% these effects were possibly related to cannabidiol use, the most common of which was status epilepticus (6%). For LGS treatment, a comparison study of two CBD dosage groups, 10 mg and 20 mg, reported adverse events in 84% and 94%, respectively, but a significant adverse event rate of 72% was also reported in the placebo arm. The investigators judged 89% of the events to be of mild or moderate severity. The most common adverse events were, again, somnolence, decreased appetite, diarrhea, upper respiratory tract infection, pyrexia, and vomiting. 43

Elevations of liver transaminases were reported only in the Epidiolex studies, mainly during the first two months after treatment initiation, and were primarily dose-related; delayed transaminase elevations have also been noted, particularly with concomitant valproate use, and less frequently with concomitant clobazam use. The transaminase elevation was reversible with discontinuation or reduction of CBD oil and/or concomitant valproate. 32

The significantly higher rate of adverse events reported in the Epidiolex well-controlled trials compared to the open-label artisanal cannabis reports may be partially related to bias effect of the artisanal retrospective reports; the high rate of adverse events reported in the placebo group of the Epidiolex studies supports this assumption. But it could also be related to the much higher dose and rapid titration rate of CBD used in the Epidiolex studies as compared to artisanal cannabis use. The possibility that differing amounts of other constituents in artisanal cannabis oil, such as THC, other cannabinoids, and terpenes, have a protective effect merits further investigation.

It is interesting to note that the artisanal cannabis reports and the short- and long-term Epidiolex studies reported other positive side effects not directly related to seizure control. The beneficial effects of CBD-enriched cannabis, other than reduced seizures, were reported in all studies related to artisanal cannabis use and included: increased alertness (>50%); improved sleep (25%–68%), behavior (33%), language (10%), and motor skills (10%–20%); and decreased self-stimulation (32%). 34 , 35 , 37 – 39 Although there is no specific reference to these effects in the Epidiolex studies, a recent report on quality of life (QoL) in pediatric patients enrolled in a CBD (via Epidiolex) study has shown significant improvement in caregiver-reported QoL in multiple domains, as well as in general. This may be related to both better seizure control as well as additional positive changes noted in the patients’ conditions. 51

THOUGHTS, PRECAUTIONS, AND CONCLUSIONS

Pure CBD (i.e. Epidiolex) and CBD-enriched cannabis oil extracts were found to be effective for epileptic seizure control in pediatric patients and young adults, particularly in the specific epileptic syndromes, Dravet syndrome and LGS, as was the case in larger more varied groups of patients with intractable epilepsy. Based on the current data, it is essential that drug formulations contain as low a THC content as possible, since the anti-seizure activity of THC is equivocal and it can potentially aggravate seizures; moreover, it can be associated with additional short- and long-term side effects, especially related to memory as well as other aspects of cognition and behavior. 52

We should be aware that artisanal and other commercially available products are currently not well controlled. This has been proven through in-depth chemical profiling of cannabinoids, terpenes, and oxidation products of commercially available CBD oils used for treating epilepsy in the United States, which found that 9/14 of the samples studied (64%) had concentrations that differed from the declared amount, with only five maintaining optimal concentrations. 53 Strict regulations for manufacturing, packaging, and labeling are warranted to ensure safe administration and efficient use of cannabis extracts, and would enable wider use for treatment of intractable epilepsy in the pediatric and possibly the adult population.

On the other hand, future research on the role of cannabis in epilepsy should keep in mind that the controlled, randomized trials have revealed that the actual reduction in seizure frequency in response to CBD is comparable to that achieved in response to other antiepileptic drugs, and have failed to meet the 60%–85% responder rates in unblended web-based surveys and chart reviews based on parental reports. In addition the rate of side effects was higher in the well-controlled Epidiolex studies compared to artisanal cannabis use. Although these differences may primarily be related to the positive bias of the open-label retrospective studies and higher CBD dosages used in the controlled pure CBD trials, there is still room for debate regarding the role of other phytocannabinoids present in artisanal cannabis extracts, which may have an “entourage effect” on both the anticonvulsant potency and their protective role, which points to the need for further research in this direction. 54

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

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 Δ 9 -tetrahydrocannabinol (Δ 9 -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

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 [3,4,5,6]. 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.

Methods/Design

Objectives

The primary objectives of the CARE-E study are:

To determine if a CBD-enriched Cannabis herbal extract is safe and well-tolerated for pediatric patients with treatment resistant epileptic encephalopathy.

To monitor the effects of a CBD-enriched Cannabis herbal extract on the frequency and duration of specific seizure types.

Secondary Objectives

To determine whether CBD-enriched Cannabis herbal extract will alter steady-state levels of co-administered anticonvulsant medications.

To assess how treatment of pediatric patients with treatment refractory epileptic encephalopathy with CBD-enriched Cannabis herbal extract will affect the patient’s QoL.

To determine the relation between dose escalation and steady-state trough levels of bioactive cannabinoids.

To determine the relation between dose escalation and improvement in seizure frequency, QoL and incidence of adverse effects.

Study product

The study product is an oil-based extract of Cannabis sativa purchased from CanniMed® Therapeutics Incorporated (Saskatoon, Canada) named ‘CanniMed® Oil 1:20’ with 1 mg/mL of Δ 9 -THC and 20 mg/mL of CBD. CanniMed® operates under the Access to Cannabis for Medical Purposes Regulations governed by Health Canada [10] using GMP. The general process for harvest, ethanol extraction, decarboxylation, concentration and solution in olive oil is described by CanniMed® [11]. The concentrations of Δ 9 -THC and CBD in the product, and lack of mold, mycotoxins, and pesticides are confirmed by a third party laboratory as mandated by Health Canada. The product is purchased as 60 mL graduated amber oval bottles (PETE) that are sealed with child-proof caps, labeled according to local law and identified by the protocol number and dosage. The Research Pharmacy at each site will receive the study product from CanniMed® for subsequent distribution to their site’s participants. As an oil-based suspension the product will be taken orally or by gastrostomy tube and the volume varies according to the weight of the participant. A single lot number of product was provided by CanniMed® for this study to ensure consistency of dosing. The product was purchased from CanniMed® at cost and this research remained independent of the company by securing all funding through external research grants.

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Study population

The study will recruit participants between the ages of 1–10 years with an epileptic encephalopathy resistant to standard medical treatment. The study will aim to enroll 28 children from four Canadian cities (anticipated seven participants per site).

Study design

The CARE-E trial is a phase 1, open-label, dose-escalation study consisting of 4 separate phases: recruitment, baseline, treatment, and weaning. The recruitment phase involves the selection of eligible participants using pre-established exclusion and inclusion criteria (described below). The baseline phase establishes baseline values for each experimental measurement prior to treatment with the study product. During the treatment phase, caregivers of participants administer dosages of the CBD-enriched Cannabis herbal extract twice daily to their children escalating at fixed one-month intervals over the course of four-months. Upon completion of the treatment phase, participants will enter the weaning phase and caregivers will slowly taper the participants off of the CBD-enriched Cannabis herbal extract using a one-month weaning schedule.

During the study, caregivers will monitor the participants for any potential side effects and will use a study diary to record their child’s seizure activity by tracking seizure frequency and duration, and any use of rescue medications to abort prolonged seizures. The participant’s condition as well as drug levels and biomarkers of toxicity will be monitored on a monthly basis. Testing will include blood and urine analysis, QoL assessments, neurological and general pediatric assessments, and an electroencephalogram (EEG) recorded for 2 h or until sleep is obtained (Fig. 1).

A flow chart of participant enrollment, treatment with CBD-Enriched Cannabis herbal extract, monitoring and weaning

Recruitment Phase: Prospective participants will be directly identified and recruited through the caregivers by study physicians at each study site. Any potential participants’ caregiver will be contacted by the study physician or pediatric neurology nurse either in-person at the study physician’s clinic or by telephone. Prospective caregivers of participants will be asked if they are interested in having their child participate in the study. If the response is positive, a copy of the study brochure and consent form will be provided to them. Caregivers of prospective participants will be asked to attend a recruitment visit after they agree to participate in the study and provide informed consent. During the recruitment visit, the participant will be screened for eligibility based on specific inclusion and exclusion criteria. If the participant qualifies for the study, the participants’ caregivers will be instructed on use the study diary.

Inclusion and exclusion criteria: Participation in this study is inherent on meeting the following inclusion criteria: (1) Participants must be between the ages of 1 and 10 years of age with treatment-resistant epileptic encephalopathy including: Infantile Spasms, Continuous Spike Wave in Sleep, Lennox Gastaut, Doose, Landau-Kleffner and Dravet Syndromes and Malignant Migrating Partial Seizures of Infancy. ‘Treatment-resistant’ will be in keeping with the International League Against Epilepsy (ILAE) definition of failing two appropriate anticonvulsant medications at therapeutic doses. (2) Participants must experience a minimum of at least one major seizure per week or four major seizures per month. For the purposes of this study, major seizures will be motor seizures including: atonic, tonic, clonic, tonic-clonic, major myoclonic, myoclonic astatic seizures and epileptic spasms. (3) Participants must be available to attend study assessments regularly and enter data into the seizure monitoring logs correctly. (4) Negative pregnancy test at screening for females who have reached menarche.

Subject Withdrawal Criteria: A participant may be withdrawn from the study if: (1) The study drug is causing intolerable side effects or a worsening in the participant’s seizures; (2) The caregiver fails to give the study drug to the participant as prescribed; (3) The caregiver does not bring the participant to appointments; (4) The study at a particular site is cancelled by the principal investigator, a site investigator or the institutional sponsor for administrative or other reasons. Whenever possible, the participant withdrawn from the study will continue to receive a dosage schedule that gradually weans the participant off the study drug over a one-month period. However, if the site investigator deems it medically necessary for the participants’ safety, the participant could be weaned off the study drug faster. All participants that complete the study will be asked to return for an end of study visit (Visit 7). All data collected about the participant during enrolment will be retained for analysis and the participant will not be replaced.

Baseline Phase: Following the recruitment visit, participants will be sent home for one month with no change to their current anticonvulsant therapy, ketogenic diet, or Vagal Nerve Stimulator settings. Caregivers will be asked to track their child’s seizure frequency, duration, and use of rescue medication during this month. Rescue medications allowed for home-use include: Ativan (0.1–0.2 mg/kg PRN intrabucally, sublingual or IV), Midazolam (0.1–0.2 mg/kg PRN intranasally, intrabucally or IV), or Diazepam (0.2–0.5 mg/kg PRN rectally or IV). Other rescue medications may be administered by paramedics (under physician guidance) or physicians as per hospital guidelines or the child’s individual guidelines for management of status epilepticus. At the end of this month, participants and their caregivers will be required to visit the study clinic for a series of baseline tests including: blood and urine analyses, quality of life and cognitive/developmental assessments, neurological and general pediatric assessment, and an EEG lasting 2 h or until the participant falls asleep. Data from the seizure diaries will be collected and a new diary will be provided for the following month.

Treatment phase: Initiation of therapy: Following baseline testing, caregivers of participants will receive a 33-day supply of the 1:20 Δ 9 -THC:CBD Cannabis herbal extract from the site research pharmacist at visit 2. Caregivers of participants will be instructed to administer the study product at a 1:20 Δ 9 -THC:CBD Cannabis herbal extract dose of 2–3 mg/kg/day divided into two doses (BID). Caregivers will be further instructed to monitor their child’s seizure activity as defined above. In addition, they will be asked to monitor their child for any potential side effects such as drowsiness, ataxia, nausea, vomiting, worsening seizures, etc.

Monthly follow-up: Caregivers will return to the clinic for the monthly testing as described above. Data from the study diaries will be copied for analysis. Following the completion of testing, parents will receive a new 33-day supply of the 1:20 THC:CBD Cannabis herbal extract from the research pharmacist. Parents will be instructed to administer the extract at increasing doses over the next 3 months; i.e. at 5–6 mg/kg/day divided BID at visit 3, 8–10 mg/kg/day divided BID at visit 4, and 10–12 mg/kg/day divided BID at visit 5. If the participant experiences significant side-effects at a certain dose, the subsequent CBD dose will be adjusted to the mid-point between their current dose and former dose. Parents will be instructed to continue tracking their child’s seizure activity and monitoring the child for potential side effects in the same manner as the initiation of therapy month.

Dosage of 1:20 Δ 9 -THC:CBD Cannabis herbal extract

Rationale for escalating dose of CBD to 10–12 mg/kg/day

As there is no available pediatric pharmacokinetic data for the cannabinoids including CBD and THC, the dosage regimen used in this study is extrapolated from CBD dosages previously described in the literature [2,3,4,5,6]. Consideration is made of the fact that the study product is derived from a whole plant extract that contains Δ 9 -THC among other potentially biologically active cannabinoids and terpines.

In Jacobson and Porter’s report, most children who had a positive response to CBD were taking a dose ranging from 8 to 14 mg/kg/day [2]. Devinsky and Thiele used a dose of 20 mg/kg/day in their participants randomized to receive study drug but this was a purified CBD product with negligible concentrations of Δ 9 -THC [5, 6]. Tzadok’s study participants received a CBD dose of either < 10 mg/kg/day or 10–20 mg/kg/day provided in the form a CBD-enriched Cannabis extract [4].

Regarding calculation of dosage and distribution of 1:20 Δ 9 -THC:CBD Cannabis herbal extract at each study visit

To ensure consistency between centers in the dosing regimen for their study participants, for each dosing increment for the participant, the mid-point value of the dosage range be chosen and the daily dosage be rounded to the nearest 10 mg CBD (0.5 ml of Cannabis Extract). This will also allow for greater ease and accuracy in administering the study drug to the participants by their caregivers. For example, a participant who weighs 25 kg at Visit 1 would be prescribed a daily dose of 60 mg CBD (2.4 mg/kg/day) to commence on Visit 2. The dosage for each visit would be calculated on the preceding visit to allow time for the site’s research pharmacy to order the study drug so it can be delivered on time by the producer.

Drug distribution and accountability

In order to comply with Health Canada requirements for a clinical study involving a Cannabis product, care is taken to ensure accountability with regards to the amount of 1:20 Δ 9 -THC:CBD Cannabis herbal extract dispensed to- and utilized by- the study participant. Proper disposal of unused or excess Cannabis herbal extract must be ensured. For this reason, the Cannabis herbal extract will be distributed via the research pharmacies at each study site. This will allow for greater accountability with regards to the amount of Cannabis herbal extract dispensed to and used by the study participants. This will also prevent the possibility of Cannabis herbal extract being shipped to participants who have withdrawn from the study or fail to attend study visits. As a total supply for 33 days will be allotted to each participant to allow some flexibility in scheduling study visits, Health Canada Section 56A Exemptions had to be obtained for the research pharmacy at each study site. Upon receipt of the 1:20 Δ 9 -THC:CBD Cannabis herbal extract by the research pharmacy, the quantity received will be recorded in a drug receipt record and the 1:20 Δ 9 -THC:CBD Cannabis herbal extract will be stored in a locked drug cabinet at the research pharmacy until such time that it will be dispensed to the participant. Once dispensed by the research pharmacy to the participant, the amount dispensed as well as the date and time will be recorded in a drug dispensing log. When the study participant returns for their subsequent visit, they will return all empty bottles as well as any unused 1:20 Δ 9 -THC:CBD Cannabis herbal extract to the research pharmacy. The amount of 1:20 Δ 9 -THC:CBD Cannabis herbal extract returned will be recorded in the drug dispensing log and a calculation will be performed to ensure it matches the estimated amount that should have been returned based on the participant’s daily dose and the date of return. To help contain costs of performing this study, for visits 3–6, any unused 1:20 Δ 9 -THC:CBD Cannabis herbal extract will be re-dispensed to the study participant and calculated into the total amount dispensed. At visit 7, any unused 1:20 Δ 9 -THC:CBD Cannabis herbal extract will be recorded and stored along with the unused 1:20 Δ 9 -THC:CBD Cannabis herbal extract for all participants at that site to be destroyed as per the research pharmacy’s specific guidelines.

Weaning phase: Termination of treatment: At visit 6 (after completing 1 month of CBD at 10–12 mg/kg/day) participants will return to the clinic for a final series of tests which include: blood and urine analyses, quality of life and cognitive/developmental assessments, neurological and general pediatric assessments, and EEG. Participants will be provided with a one-month weaning schedule which incrementally decreases the dose of the 1:20 Δ 9 -THC:CBD Cannabis herbal extract administered (CBD at 8–9 mg/kg/day for 1 week then 5–6 mg/kg/day for 1 week then 2–3 mg/kg/day for 1 week prior to discontinuing the study product).

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Final Assessment: Participants will return to the clinic upon completion of the one-month weaning period. Caregivers will provide observations of any side-effects noted during the weaning period and will complete a final quality of life questionnaire. Data from the seizure monitoring diaries will be collected and caregivers will be asked to return any leftover study drug.

Experimental measurements

Bioactive cannabinoid plasma concentrations

A secondary study objective is to determine the relationship between dose escalation and steady state trough concentrations of bioactive cannabinoids, and if possible, relate these levels with therapeutic and adverse effects. To achieve this objective a liquid chromatography-mass spectrometry (LC-MS/MS) method was validated in accordance with the United States FDA guidelines [12, 13]. Blood collected into lithium heparin Barricor vacutainers ® (BD Canada, Mississauga, ON) at each visit will be centrifuged (10 min at 1500 rpm), the plasma aliquoted into clearly labeled microcentrifuge tubes, and placed at − 80 °C until analysis. Plasma concentrations of THC, CBD and THC-OH (11-hydroxy-THC) in participant plasma samples will be determined by LC-MS/MS analysis. Briefly, stock solutions (1 mg mL − 1 ) of cannabinoids and their respective stable isotope labeled internal standards (Cerilliant Corp., Round Rock, TX) will be prepared in methanol and stored at − 20 °C. Working solutions will be prepared by serial dilution of the stock solution in blank human plasma to produce appropriate standard calibration curves. Acceptance criteria for each analytical run will be based on low, medium, and high concentration quality control (QC) standards. Calibration and QC samples will be prepared on each day of sample analysis. A linear least-squares regression analysis using 1/X 2 as weighting factor will be conducted to determine the linearity of the calibration curve. Plasma sample extraction involves the addition of 10 μL of the internal standard working solution and 600 μL of cold acetonitrile to 200 μL plasma, followed by vortex-mixing and centrifugation at 20,000 g for 10 min at 4 °C. 700 μL of supernatant is dried under filtered air for 15 min at 37 °C. Samples are reconstituted using 200 μL mobile phase. Supernatant will be transferred to HPLC inserts and 5 μL injected onto a Zorbax Eclipse XDB-C18 narrow bore 2.1 × 12.5 mm 5 μm guard column and Zorbax Eclipse XDB-C8 narrow bore 2.1 × 12.5 mm 5 μm guard column with column temperature maintained at 30 °C. The cannabinoids are separated using an Agilent series 1290 binary pump (Agilent Technologies, Mississauga, ON, Canada) with an online degasser and auto sampler set at 4° and a mobile phase of 80% methanol and 20% Solution B (0.1 mM ammonium formate) at a flow rate of 250 μL/min. Injections will occur at 13.5 min intervals and will include linear gradients to 90% methanol 10% Solution B at 3.5 min to 10 min and return to 80% methanol: 20% Solution B from 10 min to 10.5 min.

The cannabinoids will be detected with an ABSciex 6500 QTRAP mass spectrometer (AB Sciex, Concord, ON, Canada) in positive ion mode. Multiple reaction monitoring (MRM) will be used to quantify the cannabinoids and the peak areas will be summed through use of MultiQuant 3.0.1 Software. The ratio of peak areas of the cannabinoids to their respective internal standards will be plotted against the nominal concentrations to construct the calibration curve and the concentrations of the cannabinoids determined by interpolation.

Complete blood counts and clinical chemistry

At each visit participants will have laboratory assessment of blood components to evaluate hepatic, renal, or hematopoietic toxicity performed at their local hospital laboratory. The tests performed include: a complete blood cell count panel with automated three or five part cell differential, electrolytes, glucose, creatinine, urea, alanine transaminase, aspartate transaminase, albumin, gamma glutamyl transferase and lipase. Adverse events from each participant will be assessed as laboratory results that exceed the local laboratory age-specific reference intervals. If participants are on a ketogenic diet during the study, then urine ketone testing will be performed to assess the consistency of the ketosis at each visit.

Trough levels of anticonvulsants

Participants will remain on pre-existing anticonvulsant medications throughout the cannabis oil study period. Serum specimens will be collected from participants at each visit and trough levels of serum anticonvulsant medications will be determined by LC-MS/MS by the Roy Romano Provincial Laboratory Regina, SK, Canada. Serum specimens were collected and stored at − 20 °C prior to analysis. Adverse events will be counted if participants require a change in anticonvulsant medication during the trial either to maintain trough levels in the therapeutic range.

Quality of life assessment

The instrument we have chosen is the Quality of Life in Childhood Epilepsy (QOLCE-55) [14]. The QOLCE is a parent/proxy-completed measure of health-related quality of life specifically developed for children with epilepsy. It has several subsections containing multiple items, as well as a series of global ratings. The original tool was designed for individuals between 4 and 18 years of age which is one of the broadest age ranges for a tool of this kind. The tool allows for the rater to indicate that an item is not applicable if its content is above the age or developmental level of the child being rated. This makes the QOLCE potentially robust in the face of issues such as lower age and intellectual disability.

The QOLCE-55 shows good internal consistency and criterion-related validity as well as adequate to good test-retest reliability, depending on the subtest or item involved [14,15,16]. Areas covered include physical features (including physical limitations and fatigue), well-being (including depression, anxiety, helplessness and self-esteem), cognition (including attention, memory, language and general cognition), social engagement (including interactions, activities and stigma), and behavior. The QOLCE has also been shown to be sensitive to seizure activity and other clinical and psychosocial variables associated with epilepsy [14] and to benefits from treatments such as surgery [17]. Finally, the QOLCE has been used in the study of epileptic conditions with associated cognitive delays and Intellectual Disability and has already shown its utility in samples with Intellectual Disabilities [18]. While the QOLCE-55 was not exclusively positive in the wording of its items, most items were positively stated, making for less distress on the side of those completing the measure [19].

Ratings on the QOLCE are made on a 5-point scale with 1 titled “very often” and 5 titled “never.” Reversed items are recoded when scoring such that higher scores mean more positive outcomes. These scores are then recoded as follows: 1 = 0, 2 = 25, 3 = 50, 4 = 75, and 5 = 100. The mean for each of the subscales is then found by adding these values together and dividing by the number of items not marked Not Appropriate. The total score for the scale is the unweighted mean of the four subscales.

As well, for the purposes of our study we added 13 additional items based on reports from parents. Additional items covered sleep (including being drowsy), verbal and nonverbal communication, use of books, awareness of surroundings, interpersonal interactions with children and adults, and irritability. These additional items are scored as other QOLCE items and are summed into their own total score as well as being looked at individually.

Seizure monitoring

Seizure monitoring will be used to determine how treatment with the study compound affects seizure frequency duration. Caregivers will be asked to track the frequency and duration of their child’s three most frequent types of seizures on a daily basis using a study diary. In order for the study to remain consistent, the caregivers will track the same three types of seizures throughout the study. Seizures that occur in a cluster will be counted as one seizure although the duration of the cluster and number of seizures per cluster will be recorded. Although dialeptic seizures are not included as part of the inclusion criteria for the study, caregivers will be encouraged to record the frequency of dialeptic seizures if their child experienced them frequently.

Use of rescue medication

Caregivers will be asked to track their child’s use of rescue medication. This will determine whether treatment with the study compound has any influence on use of rescue medication. Caregivers will record the medication used, the dosage used, and the number of times it was administered.

Sample size determination

As CARE-E is a phase I dose escalation safety and tolerability study designed to find the most appropriate dose of CBD in a pediatric population it was felt that power analysis was not required to calculate sample size. The sample size of 28 participants each receiving 4 separate dosage escalations is within usual guidelines for standard phase I clinical trial designs. In this multi-site dose escalation study, we chose to escalate within the same participant with 7 participants at each site because the low pediatric population incidence of epileptic encephalopathy (the inclusion criterion), precluded ability to escalate in cohorts of 6, where a new cohort of six would be administered the next dosing level [20, 21]. Any patient exhibiting a dose limiting toxicity will not receive the next dose escalation.

Data analysis

Study data will be collected and managed using REDCap electronic data capture tools hosted at the University of Saskatchewan [22]. REDCap (Research Electronic Data Capture) is a secure, web-based application designed to support data capture for research studies, providing 1) an intuitive interface for validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data downloads to common statistical packages; and 4) procedures for importing data from external sources.

Statistical analysis

All data will be descriptively analyzed using means, standard deviations, frequencies (where appropriate), and 95% confidence intervals. The sample size of 28 participants is sufficient for an initial phase 1 safety and tolerability study, but is too small for precise estimation of steady state levels of biologically active cannabinoids at each dose and for definitive assessments of efficacy. Trends will be examined and a medical statistician will assist with statistical and trend analysis of the data. Complete, specific details of the statistical analysis will be described and fully documented in the Statistical Analysis Plan (SAP) after completion of data collection.

Study funding:

Given the potential controversy surrounding the study of Cannabis products in children, CARE-E was funded entirely through external funding in order to minimize the potential for perceived bias in our study results. Funding was obtained through research grants from the Jim Pattison Children’s Hospital Foundation (formerly the Children’s Hospital Foundation of Saskatchewan), the Saskatchewan Health Research Foundation and the Savoy Foundation as well as a donation from the Durwood Seafoot Estate (administered through the Jim Pattison Children’s Hospital Foundation).

Discussion

Children with epileptic encephalopathies resistant to standard therapy are at considerable risk for long-term neurocognitive impairment and poor quality of life. CBD-enriched Cannabis based therapies have been shown in several studies to provide a reduction in seizure frequencies and improvements in sleep patterns, mood, and alertness. Such favorable reports in the medical literature and social media have prompted parents who are desperate to help their children to combine Cannabis products with current medical treatments in children with refractory epilepsy. However, the encouraging publicity surrounding medical marijuana is not accompanied by strong scientific and rigorous investigation. This is particularly true for this vulnerable pediatric population.

As a Phase I dose escalation study, the CARE-E study is primarily designed to assess safety of a high CBD, low ∆ 9 -THC Cannabis oil preparation. However, it is anticipated that the study can begin to address other major issues associated with Cannabis use in pediatric epileptic encephalopathies, namely the lack of an accepted dosage regimen, the relationship between steady state plasma concentrations and efficacy or adverse effects, its efficacy to reduce seizure frequency and improve quality of life, and potential drug-drug interactions with standard medical treatments for pediatric epilepsy. Successful implementation of the CARE-E study will lay foundation for a larger Phase II efficacy trial of a high CBD, low ∆ 9 -THC Cannabis oil product. Such studies are imperative to alleviate the lack of clinical information on medical Cannabis in children with refractory seizures and give practitioners confidence to prescribe Cannabis-derived products to their patients.

While CARE-E has a small sample size and open label design, there are several strengths that differentiate CARE-E from other studies. The multicenter design allows for a wider range of study participants and prevents intrinsic bias in interpretation of study results. The recording of EEG activity in participants allows for an objective measurement of efficacy of the Cannabis herbal extract in relation to dosage and steady state pharmacokinetics. Procurement of external funding to perform this study also prevents perception of bias in the collection and reporting of study results.