CBD Oil Dosing Pediatrics

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Purpose: There is uncertainty regarding the appropriate dose of Cannabidiol (CBD) for childhood epilepsy. We present the preliminary data of seven participants from the Cannabidiol in Children with Refractory Epileptic Encephalopathy (CARE-E) study. Methods: The study is an open-label, prospective, dose-escalation trial. Participants received escalating doses of a Cannabis Herbal Extract (CHE) preparation of 1:20 9-tetrahydrocannabinol (THC):CBD up to 10-12 mg CBD/kg/day. Seizure frequency was monitored in daily logs, participants underwent regular electroencephalograms and parents filled out modified Quality of Life in Childhood Epilepsy (QOLCE) and Side Effect rating scale questionnaires. Steady-state trough levels (Css Min) of selected cannabinoids were quantified. Results: All seven participants tolerated the CHE up to 10-12 mg CBD/kg/day and had improvements in seizure frequency and QOLCE scores. CSS,Min plasma levels for CBD, THC, and cannabichromene (CBC) showed dose-independent pharmacokinetics in all but one participant. CSS,Min CBD levels associated with a greater than 50% reduction in seizures and seizure freedom were lower than those reported previously with purified CBD. In most patients, CSS,Min levels of THC remained lower than what would be expected to cause intoxication. Conclusion: The preliminary data suggest an initial CBD target dose of 5-6 mg/kg/day when a 1:20 THC:CBD CHE is used. Possible nonlinear pharmacokinetics of CBD and CBC needs investigation. The reduction in seizure frequency seen suggests improved seizure control when a whole plant CHE is used. Plasma THC levels suggest a low risk of THC intoxication when a 1:20 THC:CBD CHE is used in doses up to 12 mg/kg CBD/kg/day. Benefits of CBD use for children include the treatment of epilepsy, anxiety, and high blood pressure. But what about the dosage? Let's discuss it here. 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. 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. 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. 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

Dosage Related Efficacy and Tolerability of Cannabidiol in Children With Treatment-Resistant Epileptic Encephalopathy: Preliminary Results of the CARE-E Study

Richard J. Huntsman 1,2 * , Richard Tang-Wai 1,3 , Jane Alcorn 1,4 , Stephanie Vuong 4 , Bryan Acton 1,5 , Scott Corley 1,6 , Robert Laprairie 1,4 , Andrew W. Lyon 1,7 , Simona Meier 6 , Darrell D. Mousseau 1,8 , Doris Newmeyer 2 , Erin Prosser-Loose 2 , Blair Seifert 1,9 , Jose Tellez-Zenteno 1,10 , Linda Huh 11 , Edward Leung 12 and Philippe Major 13

  • 1 Cannabinoid Research Initiative of Saskatchewan, University of Saskatchewan, Saskatoon, SK, Canada
  • 2 Department of Pediatrics, Royal University Hospital, University of Saskatchewan, Saskatoon, SK, Canada
  • 3 Division of Child Neurology, Department of Pediatrics, Loma Linda University, San Bernardino, CA, United States
  • 4 College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada
  • 5 Saskatchewan Health Authority and Department of Psychology, University of Saskatchewan, Royal University Hospital, Saskatoon, SK, Canada
  • 6 Clinical Trial Support Unit, Royal University Hospital, University of Saskatchewan, Saskatoon, SK, Canada
  • 7 Department of Pathology and Laboratory Medicine, Royal University Hospital, Saskatchewan Health Authority, Saskatoon, SK, Canada
  • 8 Cell Signalling Laboratory, Departments of Psychiatry and Physiology, University of Saskatchewan, Saskatoon, SK, Canada
  • 9 Department of Pharmaceutical Services, Royal University Hospital, Saskatchewan Health Authority, Saskatoon, SK, Canada
  • 10 Division of Neurology, Department of Medicine, Royal University Hospital, University of Saskatchewan, Saskatoon, SK, Canada
  • 11 Division of Pediatric Neurology, Department of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, BC, Canada
  • 12 Division of Pediatric Neurology, Department of Pediatrics, Children’s Hospital, University of Manitoba, Winnipeg, MB, Canada
  • 13 Service de Neurologie Pédiatrique, Département de Neurosciences, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montreal, QC, Canada

Purpose: There is uncertainty regarding the appropriate dose of Cannabidiol (CBD) for childhood epilepsy. We present the preliminary data of seven participants from the Cannabidiol in Children with Refractory Epileptic Encephalopathy (CARE-E) study.

Methods: The study is an open-label, prospective, dose-escalation trial. Participants received escalating doses of a Cannabis Herbal Extract (CHE) preparation of 1:20 Δ 9 -tetrahydrocannabinol (THC): CBD up to 10–12 mg CBD/kg/day. Seizure frequency was monitored in daily logs, participants underwent regular electroencephalograms, and parents filled out modified Quality of Life in Childhood Epilepsy (QOLCE) and Side Effect rating scale questionnaires. Steady-state trough levels (Css, Min) of selected cannabinoids were quantified.

Results: All seven participants tolerated the CHE up to 10–12 mg CBD/kg/day and had improvements in seizure frequency and QOLCE scores. CSS, Min plasma levels for CBD, THC, and cannabichromene (CBC) showed dose-independent pharmacokinetics in all but one participant. CSS, Min CBD levels associated with a >50% reduction in seizures and seizure freedom were lower than those reported previously with purified CBD. In most patients, CSS, Min levels of THC remained lower than what would be expected to cause intoxication.

Conclusion: The preliminary data suggest an initial CBD target dose of 5–6 mg/kg/day when a 1:20 THC:CBD CHE is used. Possible non-linear pharmacokinetics of CBD and CBC needs investigation. The reduction in seizure frequency seen suggests improved seizure control when a whole plant CHE is used. Plasma THC levels suggest a low risk of THC intoxication when a 1:20 THC:CBD CHE is used in doses up to 12 mg/kg CBD/kg/day.

Introduction

Recent trials with pharmaceutical grade cannabidiol (CBD) or CBD-enriched Cannabis Herbal Extract (CHE) support CBD’s ability to reduce seizure frequency in children with intractable epilepsy, including those with epileptic encephalopathy (1–5). Yet, there are significant knowledge gaps regarding the use of CBD and other cannabinoids in children, including the pharmacokinetics (PK), pharmacogenetics, and dose-concentration-effect relationships for these compounds (6). The resultant inability to provide evidence-based dosing and therapeutic monitoring of Cannabis-based products in children, combined with concerns regarding potential intoxicant effects of Δ 9 -tetrahydrocannabinol (THC), leads to a reluctance by many physicians to authorize CHE to these patients.

The age-related developmental changes that influence drug PK and pharmacodynamics (PD) complicate the development of appropriate dosing regimens for pediatric age groups (6). Without an understanding of dose concentration-effect relationship, a dosing regimen is largely empirical and/or anecdotal, and fraught with potential safety concerns.

CARE-E is a multi-center, phase 1, open-label, dosage escalation study using a Health Canada approved and Good Manufacturing Practices certified 1:20 THC:CBD CHE as adjunct therapy to treat children with epileptic encephalopathy. The primary objectives were to assess the safety and efficacy of CBD-enriched CHE, whereas secondary objectives included an analysis of trough steady state (CSS, Min) levels of CBD, THC, and cannabichromene (CBC); as well as an assessment of the correlation between cannabinoid levels and therapeutic effect. CBC levels were measured as the CHE used in this study contained 4% CBC by volume. We present results for seven CARE-E participants recruited at the University of Saskatchewan site.

Methods

Trial Design

The study is a phase 1, open-label, dosage-escalation clinical trial in which participants receive a 1:20 THC:CBD CHE in twice daily dosing. Upon enrollment (Visit 1) participants continue their current anticonvulsant regimen and baseline seizure frequency is determined for 1 month. At Visit 2 CHE dosing is initiated with a CBD dose of 2–3 mg/kg/day. At Visits 3–5 the CHE is increased at 1-month intervals with CBD doses of 5–6 mg/kg/day at Visit 3, 8–9 mg/kg/day at Visit 4, and 10–12 mg/kg/day at Visit 5. At Visit 6 the CHE is weaned over a 1-month period after which the participants have their end of study visit (Visit 7). Care-givers monitor and record seizure frequencies in daily seizure logs. The complete study design and methodology have been described previously (7).

Ethics

Prior to enrollment, written and informed consent was obtained from the child’s parents or legal guardian. This study received a No Objection Letter (NOL) from Health Canada, was approved by the University of Saskatchewan Biomedical Research Ethics Board and registered with ClinicalTrials.gov (NCT03024827).

Participants

Inclusion criteria included pediatric patients between the ages of 1 to 10 years with epileptic encephalopathy resistant to standard medical treatment (as per International League Against Epilepsy definition of drug resistant epilepsy) and at minimum one major seizure per week or four major seizures per month (8). Seven participants from Saskatoon who met the inclusion criteria completed the study. All study data were collected and managed using the REDCap electronic data capture tool hosted at the University of Saskatchewan (9).

Efficacy Outcome Measures

Seizures occurring in a cluster were counted as a single seizure due to challenges arising from caregivers individually recording each seizure within a cluster. The data from the seizure logs was entered into REDCap (9) at each visit and underwent an independent audit performed by the University of Saskatchewan Clinical Trial Support Unit. To allow for variations in the length between study visits, the average daily number of seizures between visits was calculated by dividing the number of seizures recorded between each visit by the number of days between visits.

At Visits 2–6, participants underwent a 2-h EEG for assessment of degree of background slowing and spike index. The first EEG was performed prior to starting the CHE and each subsequent EEG was performed prior to a scheduled CHE dosage increase. To ensure consistency in EEG interpretation, an EEG rating scale for background slowing (encephalopathy) proposed by Lüders was used (10). A spike index ranked on a five-point scale ranging from 0 (= No Spikes) to 4 (= Continuous Spiking, defined as spikes occupying more than 70% of the EEG) was also calculated for each EEG.

At Visits 2–7, parents completed a modified Quality of Life in Childhood Epilepsy (QOLCE-55) survey which, in addition to questions assessing the domains including cognition, physical independence, social engagement, well-being, behavior (11), contained 13 additional items about sleep, verbal and non-verbal communication, interpersonal interactions, and irritability. Each item was rated from 1 (= Very Often) to 5 (= Never) or marked “Not Applicable.” The scores for reverse items were inverted and then all scores were transformed using (Score-1) × 25. The mean score for each subscale was calculated ignoring those marked “Not Applicable.”

Safety Outcome Measures

During the study caregivers recorded a description all adverse events associated with CHE in a participant diary. From Visit 3 to Visit 7, caregivers rated adverse effects previously described with CBD. Sleepiness/Lethargy and Irritability were rated from 0 (= Not Present) to 4 (= Present All The Time). Nausea/Vomiting and Diarrhea were rated from 0 (= Not Present) to 5 (= More Than Once Per Day). At each visit, the information for the preceding month was self-reported and provided to the study nurse.

At Visits 2–6, blood samples were collected for complete cell count and differential cell count, sodium, potassium, chloride, calcium, magnesium, phosphate, creatinine, urea, aspartate transaminase, alanine transaminase, alkaline phosphatase, and gamma glutamyltransferase, total and direct bilirubin, lipase, albumin, cholesterol, and triglycerides. Elevations in liver enzymes or lipase were considered significant if they were more than three times the upper limit of the normal reference range.

Quantification of Cannabinoids in Plasma and Steady State Trough Levels (CSS, Min)

To measure plasma trough steady-state (CSS, Min) cannabinoid levels, blood was collected on Visits 2–5 into lithium heparin Barricor vacutainers and centrifuged for 10 min in a clinical centrifuge (1,500 rpm) (12). These plasma samples (200 μL) were prepared and analyzed for CBD, CBC, and THC levels according to a validated liquid chromatography-mass spectrometry (LC-MS/MS) method that while developed independently in our lab is similar to a previously reported validated plasma cannabinoid assay (7, 13). All samples were stored at −70°C prior to analysis. Analytical method validation indicated the assay was specific and linear from 0.49 to 125 ng ml −1 , for THC and CBD, and 0.98–125 ng ml −1 CBC with r 2 > 0.998. Matrix effects ranged from 40 to 50% depending upon analyte resulting in extraction efficiencies in a similar range but recoveries were >88%. Intra- and inter-day precision and accuracy of the method was within ± 15%. The samples were analyzed in three batches (October 2017, May 2018, and March 2019). While most samples were analyzed within 3 months of collection, some were analyzed up to 8 months after collection. Stability analysis indicates stability of cannabinoids stored frozen for 3 months but stability beyond this is unknown. Full details of the quantification method of cannabinoids in plasma samples are available as Supplementary Protocol provided with this manuscript.

Steady-State Trough Anticonvulsant Levels

During the study, the participants’ anticonvulsant medications were not adjusted. The exception was clobazam, which was decreased if it was felt that clobazam side effects were being exacerbated by the known interaction between CBD and clobazam (14). Prior to decreasing the dose of clobazam, trough clobazam, and norclobazam levels were measured.

Trough anticonvulsant levels were measured at Visits 2–6 to identify a possible drug interaction with CBD, a known competitive inhibitor of CYP2C and CYP3A isozymes (15). CSS, Min levels were obtained for valproic acid, lamotrigine, levetiracetam, topiramate, and clonazepam. CSS, Min levels for stiripentol were not obtained as this assay was not available to us through the Saskatchewan Provincial Health Laboratory or its partnering laboratories.

Statistical Analysis

Due to the small sample size reported a formal statistical analysis was not performed. Data are presented from individual participants and as the mean ± standard error of the mean (s.e.m.) (Figures 1, 3) and in a descriptive manner to illustrate trends emerging from the data (Figure 2). A formal analysis will be done when all patients are included in the trial.

Figure 1. (A) Percentage reduction in daily average seizure frequency as compared to baseline. The value shown at each visit represents the decrease in seizure frequency from baseline during the preceding month. (B) Average percentage reduction in daily average seizure frequency from baseline for all seven participants at each study visit. (C) Average percentage reduction in daily seizure frequency from baseline for all seven participants broken down into seizure type. Data are shown as mean ± s.e.m.

Figure 2. Pooled QOLCE-55 scores and subscores for all seven participants. The values shown at each visit represent the QOLCE-55 total and subscores for the preceding month. Data are mean from seven participants.

Figure 3. Participant minimum steady state (CSS,Min) plasma concentrations and average plasma CSS,Min levels for each cannabinoid of cannabidiol (CBD) (A,B), cannabichromene (CBC) (C,D), and Δ 9 -tetrahydrocannabinol (THC) (E,F) analyzed with LC-MS/MS. Values shown represent steady state levels after 1 month on the corresponding dosage of CBD measured just prior to a dose administration. Data are mean ± s.e.m.

Results

Demographic Characteristics and Compliance

At time of enrolment, all participants failed at least 2 appropriate anticonvulsants, and none were using the ketogenic diet or had a vagal nerve stimulator. All participants were fully compliant with all study protocols. Table 1 summarizes study participant characteristics. As per the publishing guidelines of this journal the participants’ gender is not included and age at recruitment is provided in ranges (1–3, 4–6, 7–10 years).

Table 1. Participant characteristics at time of recruitment into CARE-E including age, epilepsy diagnosis, and concomitant anticonvulsant medications.

Safety and Tolerability Outcome Measures

While all participants reported Sleepiness/Lethargy and Irritability during the study, no scores increased by more than two points. Irritability improved in two participants following a decrease in clobazam dosage. Occasional incidences of nausea and vomiting, diarrhea, increased appetite, difficulty sleeping and spasticity were reported. Changes in the side-effect rating scales were not consistent and, apart from nausea and vomiting, did not correlate with increased doses of the CHE. None of the side effects were severe enough to prompt withdrawal from the study. The side effects rating scale scores are provided in Supplementary Tables 1A–D.

No significant changes in complete blood count and differential, electrolytes, renal panels, triglyceride, cholesterol, albumin, or bilirubin levels were observed. All participants had elevated ALP at Visit 1; however, these levels did not increase with the introduction and titration of CHE, with the exception of participant A-07, whose ALP increased to 300 U/L (reference: 30–110 U/L) at Visit 4, but decreased back to 144 U/L at Visit 5.

Participant A-01 had a slight elevation of GGT at 44 U/L (reference 10–35 U/L) seen at Visit 3 only. Participant A-03 had a marked elevation of GGT to 738 U/L (10–50 U/L) during an admission to Pediatric Intensive Care for sepsis. GGT decreased to 73 U/L the following month and returned to normal on post-study follow up despite continuing CHE.

Participant A-04 had slight elevations of AST at Visits 3 and 6 (48 U/L and 44 U/L, respectively -reference: 10–40 U/L). GGT was elevated prior to, and remained elevated throughout, the study, reaching a peak of 88 U/L at Visit 4. Participant A-04’s serum lipase at 173 U/L (normal: 22–51 U/L) was significantly elevated at Visit 5. As he was asymptomatic and an abdominal ultrasound was normal, he continued to receive CHE. By Visit 6, lipase levels decreased to 83 U/L and returned to normal following the study after valproic acid dosing was decreased and CHE was continued at 10–12 mg/kg/day.

No clinically significant adverse events directly attributed to the CHE were encountered. Two participants had serious adverse events requiring hospitalization, but these were not related to the study drug. During their hospitalizations, both remained on their routine anticonvulsants and CHE.

Efficacy Outcome Measures

The average reduction in daily seizure frequency between visits for each participant is displayed in Figure 1A. Over the study period, all seven participants had an improvement in seizure frequency with CHE. One participant (A-04) had a transient worsening of seizures at a CBD equivalent dose of 2–3 mg/kg/day. All participants had a reduction in average daily seizure frequency at a CBD equivalent dose of 5–6 mg/kg/day with six participants having a decrease >25% and four participants having a decrease >50%. After increasing to 10–12 mg/kg/day, the average reduction across all participants was 74% (Figure 1B) with all participants having a >25% reduction in daily seizure frequency, five participants having a decrease >50%, and three participants being seizure free. One participant was seizure free on an 8–9 mg/kg/day CBD equivalent dose.

During the final month of the study, when CHE was weaned off completely in the first three weeks, the reduction in seizure frequency was maintained in all participants and continued to improve in three participants (A-02, A-04, A-05) despite no changes to their anticonvulsant regimens.

While there was a reduction in daily seizure frequency between visits for all seizure types recorded, the greatest reduction was seen in atonic and versive seizures while epileptic spasms increased in frequency (Figure 1C). The percentage reduction in frequency of reported seizure types compared to baseline for all seven participants at each visit are also provided as Supplementary Figures 1A–G.

By the time the CBD dose was increased to 10–12 mg/kg/day, all participants -except for participant A-07, who had a normal background activity on the initial EEG– had an improvement in their EEG encephalopathy rating scale with most improving by one point on the rating scale. Participant A-03 had an improvement by two points. During the course of the study, three participants had an improvement in their EEG Spike Index scores. Participants A-03 and A-04 had resolution of their continuous spike activity in sleep. Full details of EEG results are provided in Supplementary Figures 2A,B.

An improvement in the total QOLCE-55 scores was observed in all participants with the greatest improvements were found on the Cognitive, Social and Emotional Functioning subscales (Figure 2). While the improvements in the QOLCE scores decreased during the weaning period following Visit 6 the scores remained improved over the baseline scores.

Plasma Cannabinoid Plasma Levels in Relation to Dosage Escalation and Decrease in Seizure Frequency

Cannabinoid CSS, Min plasma concentrations were measured at the end of each subsequent month’s dosage escalation (Figures 3A–F). With each dosage escalation, CBD and CBC CSS, Min values generally increased proportionally with dose in all participants, except for participant A-04, whose last dose escalation resulted in non-proportional increases in both CBD and CBC CSS, Min values (Figures 3A–C).

Following a month of CBD at 5–6 mg/kg/day, the four participants with a >50% reduction in average daily seizure frequency, had CSS, Min CBD levels ranging from 14.8 to 24.4 ng/mL. After a month of CBD at 10–12 mg/kg/day, the five participants with a >50% reduction in average daily seizure frequency, had CSS, Min CBD level ranging from 42.5 to 124.7 ng/mL. The CSS, Min CBD levels corresponding with the CBD dosage at which the three participants became seizure free, ranged from 54.8 to 78.9 ng/mL (Figure 3A).

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In all but two participants (A-04 and A-07), CSS, Min THC levels were detectable at 2–3 mg/kg/day. Even at the highest dose of CHE, the CSS, Min THC levels were low—below 4 ng/mL in all but two participants with the highest level being 4.34 ng/mL (Figure 3E).

Effect of CHE on Steady State Levels of Anticonvulsants

Apart from clobazam, CSS, Min anticonvulsant levels did not change significantly and remained within therapeutic limits with the following exceptions. Valproic acid levels for participant A-07 doubled between visits 2 and 6 but remained within therapeutic range (350–700 umol/L). For participant A-06, Valproic acid levels decreased to below therapeutic range at 16 umol/L between visits 4 and 5 suggesting medication non-compliance. CSS, Min clobazam and norclobazam levels of the four participants taking clobazam during the study are provided in Supplementary Table 2. For participants A-02 and A-03 these levels are not available for visit 6 due to the samples being misplaced in our hospital central laboratory. Three participants (A-01, A-02, and A-03) experienced side effects felt to be secondary to clobazam prompting a decrease in their clobazam dosage. In all three participants, these apparent side-effects of clobazam resolved with a decrease in clobazam dosing. Co-administration of clobazam did not appear to correlate with higher levels of CBD or CBC at each dosage escalation.

Discussion

CARE-E is an open label dosage finding study designed to assess the safety and efficacy of a CBD-Enriched Cannabis Herbal Extract (CHE) in children with intractable epileptic encephalopathy. The study involved measurement of CSS, Min levels of CBD, THC, and CBC and their relationship with safety, tolerability, and efficacy outcome measures in hopes to identify appropriate doses of similar Cannabis products in children. This study is the first to report pediatric CSS, Min levels of CBD, THC, and CBC in any pediatric dosage escalation study and provide guidance on initial dosing of CBD-enriched CHEs.

Escalating doses of CBD-enriched CHE from 2–3 mg/kg/day to 10–12 mg/kg/day resulted in no serious adverse events related to the CHE. Parents reported sleepiness/lethargy and irritability in most participants, but these side effects were assessed after starting the study drug and were likely pre-existing. Transient increases in sleepiness and irritability in three participants taking clobazam resolved after clobazam dose was decreased, suggesting these side-effects could be secondary to an interaction between the CHE and clobazam (14). Laboratory monitoring noted significant elevations in GGT, AST, and lipase levels in two participants, both of whom were also taking valproic acid. Participant A-03’s marked elevation of GGT was likely secondary to sepsis, which occurred during the study. Participant A-04’s transient and non-significant elevation of AST and significant elevation of lipase levels were likely secondary to a predisposition to hepatic and pancreatic dysfunction from high-dose valproic acid and corroborates observations reported elsewhere (3, 16). The fact that this participant had a preexisting elevated GGT suggests that liver enzymes should be screened prior to starting CHE, especially if the child is already prescribed valproic acid.

The concentrations of CBD, THC, and CBC appeared to increase linearly with dosage in six of the seven participants, suggesting dose-independent pharmacokinetics for these participants within this dosage escalation trial. The greater than proportional increase in CSS, Min CBD with the final dosage increase in participant A-04 may suggest dose-dependent pharmacokinetics with saturation of first-pass metabolism and an increase in the oral bioavailability. Participant A-04 did not exhibit any change in clinical status or in anticonvulsant therapy to explain this disproportional increase in CSS, Min. To confirm the possible non-linear pharmacokinetics in children, a dosage escalation study involving a larger sample size and a higher dose beyond the doses used in the current trial will be necessary. The possibility of dose-dependent PK, though, raises a safety concern, which also warrants further investigation in pediatric patients and suggests a need to limit dose sizes and not to simply continue increasing doses until an appropriate effect is observed.

CBD and THC both inhibit enzymes involved in the metabolism of many anticonvulsants including CYP2C and CYP3A isoenzymes (17). While increases in Clobazam and norClobazam levels were seen in some participants taking clobazam, overall co-administration of CHE did not significantly affect Css, min levels of the other concomitant anticonvulsants. It would have been of interest to measure Css, min levels of stiripentol given that many children with Dravet syndrome would also be taking this medication and stiripentol is metabolized by CYP2C19 and CYP3A4 isoenzymes. At present it is unknown if there is a pharmacokinetic interaction between CBD and Stiripentol. Although an assay to measure stiripentol levels is described, it is not indicated for therapeutic purposes by the manufacturer or regulatory bodies such as Health Canada, FDA or the EU. As such, it was not available for us for the purposes of this study (18).

The potential intoxicating effects of any THC present in CHE remain a concern for pediatric patients. Oral consumption of Cannabis products results in lower peak levels of THC as compared to smoking due to a high first-pass effect and slow erratic absorption from the gastrointestinal tract. However, intoxication can still occur because of greater distribution into the central nervous system and conversion to 11-hydroxy-THC, which is also intoxicating and has a half-life as long as, or longer, than THC (17, 19, 20). The CSS, Min levels of THC increased in a seemingly linear relationship to dosage, and with the exception of two participants at the highest dosage level, these remained lower than levels that have been reported to cause intoxication (19). Tachycardia and conjunctival injection—felt to be reliable markers of intoxication from THC—were not seen during the study. The lack of intoxication seen in our participants whose plasma THC levels exceeded 4 ng/mL may have been due to the reported CBD-mediated attenuation of the intoxicant effects of THC (21).

An overall trend for improvement in seizure control and QOLCE scores was observed with increasing CHE dosage and CSS, Min CBD levels. A >50% reduction in average daily seizure frequency occurred in four of seven participants at a CBD dose of 5–6 mg/kg/day, and all participants had a >25% reduction in seizures at a CBD dose of 10–12 mg/kg/day. In the QOLCE scores, there was a trend toward improvements in cognitive, social, and emotional function in relation to CBD dosage. These data suggest that the initial target dose of CBD should be 5–6 mg/kg/day when a 1:20 THC:CBD whole plant extract is used and can be increased as needed up to 10–12 mg/kg/day with careful consideration of potential non-linear pharmacokinetics at higher doses.

Trembly and Sherman reported that adult patients taking purified CBD had no improvement in seizure control when their plasma CBD levels ranged from 20 to 30 ng/mL, while a significant decrease in seizure control occurred when plasma CBD levels increased above 150 ng/mL (22). While it is challenging to correlate CSS, Min levels of CBD and CBC with efficacy in reducing seizure frequency based on our data, we do note that the CSS, Min CBD levels associated with a >50% reduction in average daily seizure frequency and seizure freedom in this study were lower. Further analysis with larger sample sizes are needed to delineate which CSS, Min level of CBD is associated with optimal seizure control and improved QOLCE scores.

Two recent systematic reviews of clinical trials assessing pharmaceutical grade CBD in children with treatment epilepsy provide insight into the expected outcomes at the CBD doses used in these trials. In pooled data of 17 observational studies, Stockings et al. found that CBD at 20 mg/kg/day resulted in 48.5% of patients having a 50% reduction in seizures and QoLCE scores improved in 55.8% (23). Lattanzi et al. also performed a systematic review of the four clinical trials assessing pharmaceutical grade CBD in children with treatment resistant Lennox Gastaut and Dravet Syndromes. They reported that the pooled average difference in seizure frequency between CBD and placebo with CBD at 10 mg/kg/day was 19.5% while that with CBD at 20 mg/kg/day was 19.9% both in favor of CBD. A seizure frequency reduction of 50% (for all seizure types) was 37.2% with CBD at 20 mg/kg/day and 21.2% with placebo (24).

An “entourage” effect in which the clinical efficacy of cannabinoids when used in combination are greater than when used individually has been demonstrated in several animal models of epilepsy but has yet to be reported for human trials (25–27). While we saw clinical efficacy with regards to reduction in seizure frequency and improvements in QoL scores with CBD doses lower than those reported in studies using pharmaceutical grade CBD, the small number of participants reported require caution when interpreting the results and preclude drawing definite conclusions in particular with regards to possible entourage effect. Additionally, CARE-E was not designed to compare efficacy of CHE to pharmaceutical grade CBD. This can only be addressed in a head to head comparative study.

The preliminary findings presented in this manuscript are however, in keeping with the results of a metanalysis of clinical studies comparing whole plant Cannabis CHE to pharmaceutical grade CBD in children with refractory epilepsy. This metanalysis found that while there was no significant difference between the CHE and pharmaceutical grade CBD in attaining 50% reduction in seizures, 71% of children taking CHE had improvement in seizure frequency compared to 46% taking purified CBD (p < 0.0001). The average CBD dose for children taking CHE was 6 mg/kg/day (28).

The three participants who became seizure free were taking long acting benzodiazepines (clobazam or clonazepam) but clobazam and clonazepam levels did not increase for two of these participants. This suggests that, while CBD and long acting benzodiazepines likely have a synergistic effect, this is not necessarily due to an increase in plasma benzodiazepine levels.

The reported half-life of CBD ranges from 9 to 32 h; however, the influence of age and concomitant anticonvulsants on the half-life remain largely unknown (29). These influences on half-life, however, would not explain the month-long continued improvements in seizure control and QOLCE scores observed in our three participants during the wean-off CHE. Such sustained effects often involve epigenetic changes and therefore it is possible that any long-term beneficial effect of CBD may reflect, in part, an as-of-yet unrecognized epigenetic effect (30). In order to assess if any long-lasting effect might be mediated through an active metabolite of CBD, we will measure participants’ plasma levels of CBD, CBC, THC, and their metabolites upon completion of the 1-month weaning period in subsequent participants who are enrolled in CARE-E.

While an improvement in background EEG activity was seen in four participants, there was no correlation between CBD dosing and improvements on the background score. A more complete examination of a potential relationship between the improvement in cognitive functioning seen in the QOLCE scores and improved background activity seen on EEG is warranted. The reduction in spike count following CBD treatment in three participants is reminiscent of the effect observed with broad-spectrum anticonvulsants such as benzodiazepines and valproic acid (31).

Although the reported improvement in seizure control and quality of life are promising, these findings must be interpreted with caution as there are several limitations in this preliminary report, in particular the small sample size and potential reporting bias inherent with open label studies. The lack of a placebo group and self-reporting of outcomes may limit the ability to discern any placebo effect which is seen in many drug trials. Reporting fatigue experienced by caregivers also may be a confounder, in particular for seizure frequency data.

Conclusion

The preliminary results of seven participants from the CARE-E study suggest CBD-enriched CHE up to 10–12 mg/kg/day is generally well tolerated. All participants had improvements in seizure frequency, modified Quality of Life in Childhood Epilepsy (QOLCE), and electroencephalogram (EEG) rating scores. Steady state CSS, Min data for CBD, THC, and CBC suggest linear PK, although one participant gave possible evidence of non-linear PK at higher doses. The preliminary data suggest an initial CBD target dose of 5–6 mg/kg/day when using a 1:20 THC:CBD CHE in children with treatment resistant epileptic encephalopathy. CSS, Min CBD levels suggest that dosing with a CHE containing THC and other cannabinoids may be more effective than purified CBD alone. Based on clinical observations and measurement of plasma THC levels, intoxication from THC is unlikely to occur when a 1:20 THC:CBD CHE is used within therapeutic doses. The anticonvulsant effect of CHE persisted after it was weaned off, suggesting an enduring anticonvulsant effect.

Data Availability

The datasets generated for this study are available on request to the corresponding author.

Ethics Statement

This study was carried out in accordance with the University of Saskatchewan Biomedical Research Ethics Review Board with written informed consent from the parents/legal guardians of all subjects. The parents/legal guardians of all subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the University of Saskatchewan Biomedical Research Ethics Review Board.

Author Contributions

RH, RT-W, JA, BA, SC, RL, AL, SM, DM, DN, EP-L, BS, and JT-Z contributed to the design of the study protocol. RH, LH, EL, and PM are site investigators for CARE-E. SC analyzed the data. RH, RT-W, JA, RL, and AL interpreted the data. SV assisted with the development and validation of the plasma cannabinoid assay used in this study. RH drafted the manuscript. All authors contributed to the revision of the manuscript and approved it for submission.

Funding

This study was funded through research grants from the Saskatchewan Health Research Foundation, the Jim Pattison Children’s Hospital Foundation, the Durwood Seafoot Estate, and the Savoy Foundation. As grant numbers were not provided with these awards, copies of the award letters from these granting agencies to our research team are available upon request. The granting agencies and CanniMed, from whom we purchased the study drug at cost, had no influence on study design, or the collection, interpretation, and/or reporting of data.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

The authors would like to acknowledge the financial support to perform this study received from the Jim Pattison Children’s Hospital Foundation, the Durwood Seafoot Estate, the Saskatchewan Health Research Foundation and the Savoy Foundation. We also acknowledge the operational support provided by the Department of Pediatrics, University of Saskatchewan and the Saskatchewan Health Authority.

Supplementary Material

References

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Keywords: cannabidiol, Δ 9 -tetrahydrocannabinol, cannabis, epileptic encephalopathy, cannabinoid plasma levels

Citation: Huntsman RJ, Tang-Wai R, Alcorn J, Vuong S, Acton B, Corley S, Laprairie R, Lyon AW, Meier S, Mousseau DD, Newmeyer D, Prosser-Loose E, Seifert B, Tellez-Zenteno J, Huh L, Leung E and Major P (2019) Dosage Related Efficacy and Tolerability of Cannabidiol in Children With Treatment-Resistant Epileptic Encephalopathy: Preliminary Results of the CARE-E Study. Front. Neurol. 10:716. doi: 10.3389/fneur.2019.00716

Received: 01 May 2019; Accepted: 17 June 2019;
Published: 03 July 2019.

Pasquale Striano, University of Genoa, Italy

Ugo De Grazia, Istituto Neurologico Carlo Besta (IRCCS), Italy
Simona Lattanzi, Marche Polytechnic University, Italy

Copyright © 2019 Huntsman, Tang-Wai, Alcorn, Vuong, Acton, Corley, Laprairie, Lyon, Meier, Mousseau, Newmeyer, Prosser-Loose, Seifert, Tellez-Zenteno, Huh, Leung and Major. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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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.

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.

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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).

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.

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