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The protocol for the Cannabidiol in children with refractory epileptic encephalopathy (CARE-E) study:… Reithmeier, Darren; Tang-Wai, Richard; Seifert, Blair; Lyon, Andrew W; Alcorn, Jane; Acton, Bryan; Corley, Scott; Prosser-Loose, Erin; Mousseau, Darrell D; Lim, Hyun J; Tellez-Zenteno, Jose; Huh, Linda; Leung, Edward; Carmant, Lionel; Huntsman, Richard J Jul 7, 2018

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STUDY PROTOCOL Open AccessThe protocol for the Cannabidiol inchildren with refractory epilepticencephalopathy (CARE-E) study: a phase 1dosage escalation studyDarren Reithmeier1,2, Richard Tang-Wai1,3,4, Blair Seifert1,5, Andrew W. Lyon1,6, Jane Alcorn1,2, Bryan Acton1,7,8,Scott Corley1,9, Erin Prosser-Loose1,10, Darrell D. Mousseau1,11, Hyun J. Lim1,12, Jose Tellez-Zenteno1,13, Linda Huh14,Edward Leung15, Lionel Carmant16 and Richard J. Huntsman1,17*AbstractBackground: Initial studies suggest pharmaceutical grade cannabidiol (CBD) can reduce the frequency of convulsiveseizures and lead to improvements in quality of life in children affected by epileptic encephalopathies. With limitedaccess to pharmaceutical CBD, Cannabis extracts in oil are becoming increasingly available. Physicians show reluctanceto recommend Cannabis extracts given the lack of high quality safety data especially regarding the potential for harmcaused by other cannabinoids, such as Δ9-tetrahydrocannabinol (Δ9-THC). The primary aims of the study presented inthis protocol are (i) To determine whether CBD enriched Cannabis extract is safe and well-tolerated for pediatricpatients with refractory epilepsy, (ii) To monitor the effects of CBD-enriched Cannabis extract on the frequency andduration 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 willbe recruited in four Canadian cities into an open-label, dose-escalation phase 1 trial. The primary objectives for the studyare (i) To determine if the CBD-enriched Cannabis herbal extract is safe and well-tolerated for pediatric patients withtreatment resistant epileptic encephalopathy and (ii) To determine the effect of CBD-enriched Cannabis herbal extract onthe frequency and duration of seizures. Secondary objectives include (i) To determine if CBD-enriched Cannabis herbalextracts alter steady-state levels of co-administered anticonvulsant medications. (ii) To assess the relation between doseescalation and quality of life measures, (iii) To determine the relation between dose escalation and steady state troughlevels 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 inchildren with treatment-resistant epileptic encephalopathy. This study will provide the first high quality analysis ofsafety of CBD-enriched Cannabis herbal extract in pediatric patients in relation to dosage and pharmacokinetics ofthe 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/NCT03024827Keywords: Cannabis, Cannabidiol, Pediatric epilepsy, CanniMed®* Correspondence: dr.huntsman@usask.ca1Cannabinoid Research Initiative of Saskatchewan (CRIS), University ofSaskatchewan, Saskatoon, Saskatchewan, Canada17Department of Pediatrics, Royal University Hospital, Rm 2744, 103 HospitalDrive, Saskatoon, SK S7N 0W8, CanadaFull list of author information is available at the end of the article© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Reithmeier et al. BMC Pediatrics  (2018) 18:221 https://doi.org/10.1186/s12887-018-1191-yBackgroundThe epileptic encephalopathies are a group ofchildhood-onset seizure disorders characterized by fre-quent seizures and markedly abnormal EEG patternsassociated with progressive disturbance of cerebralfunction that manifests as developmental stagnation orregression. These epilepsies are often resistant to con-ventional medical treatment regimens and childrenwith these conditions invariably experience neuro-logical and cognitive impairments that severely impairtheir quality of life (QoL) [1].In 2013 Porter and Jacobson reported the results of a24-point survey they posted on a Facebook-group com-posed of parents using CBD-enriched Cannabis prod-ucts to treat their children with refractory epilepsy. Ofthe 20 respondents, 84% reported the CBD-enrichedCannabis products resulted in a decrease in seizure fre-quency in their children and over half of their childreneither became seizure-free or had a greater than 80% re-duction in their seizure frequency. Just as importantly,most parents reported an improvement in QoL indicessuch as alertness, sleep, and mood [2]. Since that timeseveral open-label and randomized double-blind trials ofCBD-based treatments in children with epileptic enceph-alopathy including Dravet Syndrome and Lennox Gas-taut syndrome have been reported [3–6]. These studiesfound a reduced frequency of convulsive seizures andmild adverse events of somnolence and elevatedliver-enzyme activities. Unfortunately, there was consid-erable variation in the dosage and types of CBD formu-lation used; three studies using a purified CBD product(Epidiolex) and one using a whole plant Cannabis herbalextract. The considerable variation in CBD dosage andlack of pharmacokinetic data resulted in no guidance onappropriate dosage regimens in this pediatric patientpopulation.CBD can be derived from pure pharmaceuticalpreparations or in extracts of Cannabis sativa orCannabis indica [7]. The composition of Cannabisextracts can vary dramatically due to differences incultivars, growing conditions, and extraction and de-carboxylation processes. The lack of standardizationor quality assurance in the preparation and dose ad-ministration of these products severely limits the sci-entific study of herbal preparations of Cannabis. Therecent availability of commercial Cannabis extractsfrom a licensed medical marijuana producer that usesgood manufacturing processes (GMP) with assayedcannabinoid composition assures patient safety andreliable dosing and enables scientific evaluation [8, 9].We propose to conduct an open-label dose escalationstudy of CBD-enriched Cannabis herbal extract inpediatric patients with treatment resistant epilepticencephalopathy.Methods/DesignObjectivesThe primary objectives of the CARE-E study are:1) To determine if a CBD-enriched Cannabis herbalextract is safe and well-tolerated for pediatric pa-tients with treatment resistant epilepticencephalopathy.2) To monitor the effects of a CBD-enriched Cannabisherbal extract on the frequency and duration ofspecific seizure types.Secondary Objectives1) To determine whether CBD-enriched Cannabisherbal extract will alter steady-state levels of co-administered anticonvulsant medications.2) To assess how treatment of pediatric patients withtreatment refractory epileptic encephalopathy withCBD-enriched Cannabis herbal extract will affectthe patient’s QoL.3) To determine the relation between dose escalationand steady-state trough levels of bioactivecannabinoids.4) To determine the relation between dose escalationand improvement in seizure frequency, QoL andincidence of adverse effects.Study product The study product is an oil-based extractof Cannabis sativa purchased from CanniMed® Thera-peutics Incorporated (Saskatoon, Canada) named ‘Can-niMed® Oil 1:20’ with 1 mg/mL of Δ9-THC and 20 mg/mL of CBD. CanniMed® operates under the Access toCannabis for Medical Purposes Regulations governed byHealth Canada [10] using GMP. The general process forharvest, ethanol extraction, decarboxylation, concentra-tion and solution in olive oil is described by CanniMed®[11]. The concentrations of Δ9-THC and CBD in theproduct, and lack of mold, mycotoxins, and pesticidesare confirmed by a third party laboratory as mandatedby Health Canada. The product is purchased as 60 mLgraduated amber oval bottles (PETE) that are sealed withchild-proof caps, labeled according to local law andidentified by the protocol number and dosage. The Re-search Pharmacy at each site will receive the study prod-uct from CanniMed® for subsequent distribution to theirsite’s participants. As an oil-based suspension the prod-uct will be taken orally or by gastrostomy tube and thevolume varies according to the weight of the participant.A single lot number of product was provided by Can-niMed® for this study to ensure consistency of dosing.The product was purchased from CanniMed® at cost andthis research remained independent of the company bysecuring all funding through external research grants.Reithmeier et al. BMC Pediatrics  (2018) 18:221 Page 2 of 9Study population The study will recruit participants be-tween the ages of 1–10 years with an epileptic encephal-opathy resistant to standard medical treatment. Thestudy will aim to enroll 28 children from four Canadiancities (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 re-cruitment phase involves the selection of eligible partici-pants using pre-established exclusion and inclusioncriteria (described below). The baseline phase establishesbaseline values for each experimental measurement priorto treatment with the study product. During the treat-ment phase, caregivers of participants administer dos-ages of the CBD-enriched Cannabis herbal extract twicedaily to their children escalating at fixed one-month in-tervals over the course of four-months. Upon comple-tion of the treatment phase, participants will enter theweaning phase and caregivers will slowly taper the par-ticipants off of the CBD-enriched Cannabis herbal ex-tract using a one-month weaning schedule.During the study, caregivers will monitor the partici-pants for any potential side effects and will use a studydiary to record their child’s seizure activity by trackingseizure frequency and duration, and any use of rescuemedications to abort prolonged seizures. The partici-pant’s condition as well as drug levels and biomarkers oftoxicity will be monitored on a monthly basis. Testingwill include blood and urine analysis, QoL assessments,neurological and general pediatric assessments, and anelectroencephalogram (EEG) recorded for 2 h or untilsleep is obtained (Fig. 1).Recruitment Phase: Prospective participants will bedirectly identified and recruited through the caregiversby study physicians at each study site. Any potential par-ticipants’ caregiver will be contacted by the study phys-ician or pediatric neurology nurse either in-person at theFig. 1 A flow chart of participant enrollment, treatment with CBD-Enriched Cannabis herbal extract, monitoring and weaningReithmeier et al. BMC Pediatrics  (2018) 18:221 Page 3 of 9study physician’s clinic or by telephone. Prospectivecaregivers of participants will be asked if they are inter-ested in having their child participate in the study. If theresponse is positive, a copy of the study brochure andconsent form will be provided to them. Caregivers ofprospective participants will be asked to attend a recruit-ment visit after they agree to participate in the study andprovide informed consent. During the recruitment visit,the participant will be screened for eligibility based onspecific inclusion and exclusion criteria. If the partici-pant qualifies for the study, the participants’ caregiverswill be instructed on use the study diary.Inclusion and exclusion criteria: Participation in thisstudy is inherent on meeting the following inclusioncriteria: (1) Participants must be between the ages of1 and 10 years of age with treatment-resistant epilep-tic encephalopathy including: Infantile Spasms, Con-tinuous Spike Wave in Sleep, Lennox Gastaut, Doose,Landau-Kleffner and Dravet Syndromes and Malig-nant Migrating Partial Seizures of Infancy. ‘Treatmen-t-resistant’ will be in keeping with the InternationalLeague Against Epilepsy (ILAE) definition of failingtwo appropriate anticonvulsant medications at thera-peutic doses. (2) Participants must experience a mini-mum of at least one major seizure per week or fourmajor seizures per month. For the purposes of thisstudy, 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 assess-ments regularly and enter data into the seizure moni-toring logs correctly. (4) Negative pregnancy test atscreening for females who have reached menarche.Exclusion criteria for the study include (1) Recent (<1 month) change in anticonvulsant therapies includinganticonvulsant medications, ketogenic diet or settings onVagal Nerve Stimulator (VNS) (2) Recent (< 6 months)change in intravenous immunoglobulin (IVIG) treat-ment. (3) Initiation of ketogenic diet within 6 months ofstudy enrollment. (4) Implantation and activation ofVNS within 12 months of study enrollment. (5) Use ofcannabis-based therapy within two months of study en-rollment. (6) Use of a Selective Serotonin Reuptake In-hibitor (SSRI), a tricyclic antidepressant, or an atypicalneuroleptic in the month prior to study enrollment. (7)Concomitant regular concomitant use of narcotics (useof narcotics in emergency situations under the supervi-sion of a physician is allowed). (8) Initiation or dosagechange in oral or injectable steroid therapy within threemonths of study enrollment. (9) Allergy or known in-tolerance to any ingredient in the study compound. (10)Inability to attend assessments on a monthly basis. (11)Clinically significant cardiac, renal or hepatic disease (asassessed by the site investigator).Subject Withdrawal Criteria: A participant may bewithdrawn from the study if: (1) The study drug is caus-ing intolerable side effects or a worsening in the partici-pant’s seizures; (2) The caregiver fails to give the studydrug to the participant as prescribed; (3) The caregiverdoes not bring the participant to appointments; (4) Thestudy at a particular site is cancelled by the principal in-vestigator, a site investigator or the institutional sponsorfor administrative or other reasons. Whenever possible,the participant withdrawn from the study will continueto receive a dosage schedule that gradually weans theparticipant off the study drug over a one-month period.However, if the site investigator deems it medicallynecessary for the participants’ safety, the participantcould be weaned off the study drug faster. All partici-pants that complete the study will be asked to returnfor an end of study visit (Visit 7). All data collectedabout the participant during enrolment will beretained for analysis and the participant will not bereplaced.Baseline Phase: Following the recruitment visit, partic-ipants will be sent home for one month with no changeto their current anticonvulsant therapy, ketogenic diet,or Vagal Nerve Stimulator settings. Caregivers will beasked to track their child’s seizure frequency, duration,and use of rescue medication during this month. Rescuemedications allowed for home-use include: Ativan (0.1–0.2 mg/kg PRN intrabucally, sublingual or IV), Midazo-lam (0.1–0.2 mg/kg PRN intranasally, intrabucally orIV), or Diazepam (0.2–0.5 mg/kg PRN rectally or IV).Other rescue medications may be administered by para-medics (under physician guidance) or physicians as perhospital guidelines or the child’s individual guidelines formanagement of status epilepticus. At the end of thismonth, participants and their caregivers will be requiredto visit the study clinic for a series of baseline tests in-cluding: blood and urine analyses, quality of life and cog-nitive/developmental assessments, neurological andgeneral pediatric assessment, and an EEG lasting 2 h oruntil the participant falls asleep. Data from the seizurediaries will be collected and a new diary will be providedfor the following month.Treatment phase: Initiation of therapy: Following base-line testing, caregivers of participants will receive a33-day supply of the 1:20 Δ9-THC:CBD Cannabis herbalextract from the site research pharmacist at visit 2. Care-givers of participants will be instructed to administer thestudy product at a 1:20 Δ9-THC:CBD Cannabis herbalextract dose of 2–3 mg/kg/day divided into two doses(BID). Caregivers will be further instructed to monitortheir child’s seizure activity as defined above. In addition,they will be asked to monitor their child for any poten-tial side effects such as drowsiness, ataxia, nausea,vomiting, worsening seizures, etc.Reithmeier et al. BMC Pediatrics  (2018) 18:221 Page 4 of 9Monthly follow-up: Caregivers will return to the clinicfor the monthly testing as described above. Data fromthe study diaries will be copied for analysis. Followingthe completion of testing, parents will receive a new33-day supply of the 1:20 THC:CBD Cannabis herbalextract from the research pharmacist. Parents will beinstructed to administer the extract at increasing dosesover the next 3 months; i.e. at 5–6 mg/kg/day dividedBID 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 par-ticipant experiences significant side-effects at a certaindose, the subsequent CBD dose will be adjusted to themid-point between their current dose and former dose.Parents will be instructed to continue tracking theirchild’s seizure activity and monitoring the child for po-tential side effects in the same manner as the initiationof therapy month.Dosage of 1:20 Δ9-THC:CBD Cannabis herbal extractRationale for escalating dose of CBD to 10–12 mg/kg/dayAs there is no available pediatric pharmacokinetic datafor the cannabinoids including CBD and THC, the dos-age regimen used in this study is extrapolated from CBDdosages previously described in the literature [2–6].Consideration is made of the fact that the study productis derived from a whole plant extract that containsΔ9-THC among other potentially biologically active can-nabinoids and terpines.In Jacobson and Porter’s report, most children whohad a positive response to CBD were taking a dose ran-ging from 8 to 14 mg/kg/day [2]. Devinsky and Thieleused a dose of 20 mg/kg/day in their participants ran-domized to receive study drug but this was a purifiedCBD product with negligible concentrations of Δ9-THC[5, 6]. Tzadok’s study participants received a CBD doseof either < 10 mg/kg/day or 10–20 mg/kg/day providedin the form a CBD-enriched Cannabis extract [4].Regarding calculation of dosage and distribution of 1:20Δ9-THC:CBD Cannabis herbal extract at each study visitTo ensure consistency between centers in the dosingregimen for their study participants, for each dosing in-crement for the participant, the mid-point value of thedosage range be chosen and the daily dosage berounded to the nearest 10 mg CBD (0.5 ml of CannabisExtract). This will also allow for greater ease and accur-acy in administering the study drug to the participantsby their caregivers. For example, a participant whoweighs 25 kg at Visit 1 would be prescribed a daily doseof 60 mg CBD (2.4 mg/kg/day) to commence on Visit2. The dosage for each visit would be calculated on thepreceding visit to allow time for the site’s researchpharmacy to order the study drug so it can be deliveredon time by the producer.Drug distribution and accountabilityIn order to comply with Health Canada requirementsfor a clinical study involving a Cannabis product, care istaken to ensure accountability with regards to theamount of 1:20 Δ9-THC:CBD Cannabis herbal extractdispensed to- and utilized by- the study participant.Proper disposal of unused or excess Cannabis herbal ex-tract must be ensured. For this reason, the Cannabisherbal extract will be distributed via the research phar-macies at each study site. This will allow for greater ac-countability with regards to the amount of Cannabisherbal extract dispensed to and used by the study partic-ipants. This will also prevent the possibility of Cannabisherbal extract being shipped to participants who havewithdrawn from the study or fail to attend study visits.As a total supply for 33 days will be allotted to each par-ticipant to allow some flexibility in scheduling studyvisits, Health Canada Section 56A Exemptions had to beobtained for the research pharmacy at each study site.Upon receipt of the 1:20 Δ9-THC:CBD Cannabis herbalextract by the research pharmacy, the quantity receivedwill be recorded in a drug receipt record and the 1:20Δ9-THC:CBD Cannabis herbal extract will be stored ina locked drug cabinet at the research pharmacy untilsuch time that it will be dispensed to the participant.Once dispensed by the research pharmacy to the partici-pant, the amount dispensed as well as the date and timewill be recorded in a drug dispensing log. When thestudy participant returns for their subsequent visit, theywill return all empty bottles as well as any unused 1:20Δ9-THC:CBD Cannabis herbal extract to the researchpharmacy. The amount of 1:20 Δ9-THC:CBD Cannabisherbal extract returned will be recorded in the drug dis-pensing log and a calculation will be performed to en-sure it matches the estimated amount that should havebeen returned based on the participant’s daily dose andthe date of return. To help contain costs of performingthis study, for visits 3–6, any unused 1:20 Δ9-THC:CBDCannabis herbal extract will be re-dispensed to thestudy participant and calculated into the total amountdispensed. At visit 7, any unused 1:20 Δ9-THC:CBDCannabis herbal extract will be recorded and storedalong with the unused 1:20 Δ9-THC:CBD Cannabisherbal extract for all participants at that site to bedestroyed as per the research pharmacy’s specificguidelines.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 oftests which include: blood and urine analyses, quality oflife and cognitive/developmental assessments, neuro-logical and general pediatric assessments, and EEG. Par-ticipants will be provided with a one-month weaningschedule which incrementally decreases the dose of theReithmeier et al. BMC Pediatrics  (2018) 18:221 Page 5 of 91:20 Δ9-THC:CBD Cannabis herbal extract administered(CBD at 8–9 mg/kg/day for 1 week then 5–6 mg/kg/dayfor 1 week then 2–3 mg/kg/day for 1 week prior to dis-continuing the study product).Final Assessment: Participants will return to the clinicupon completion of the one-month weaning period.Caregivers will provide observations of any side-effectsnoted during the weaning period and will complete afinal quality of life questionnaire. Data from the seizuremonitoring diaries will be collected and caregivers willbe asked to return any leftover study drug.Experimental measurementsBioactive cannabinoid plasma concentrationsA secondary study objective is to determine the relation-ship between dose escalation and steady state troughconcentrations of bioactive cannabinoids, and if possible,relate these levels with therapeutic and adverse effects.To achieve this objective a liquid chromatography-massspectrometry (LC-MS/MS) method was validated inaccordance with the United States FDA guidelines[12, 13]. Blood collected into lithium heparin Barricorvacutainers ® (BD Canada, Mississauga, ON) at each visitwill be centrifuged (10 min at 1500 rpm), the plasmaaliquoted into clearly labeled microcentrifuge tubes, andplaced at − 80 °C until analysis. Plasma concentrationsof THC, CBD and THC-OH (11-hydroxy-THC) inparticipant plasma samples will be determined by LC-MS/MS analysis. Briefly, stock solutions (1 mg mL− 1) ofcannabinoids and their respective stable isotope labeledinternal standards (Cerilliant Corp., Round Rock, TX) willbe prepared in methanol and stored at − 20 °C. Workingsolutions will be prepared by serial dilution of the stocksolution in blank human plasma to produce appropriatestandard calibration curves. Acceptance criteria for eachanalytical run will be based on low, medium, and highconcentration quality control (QC) standards. Calibrationand QC samples will be prepared on each day of sampleanalysis. A linear least-squares regression analysis using1/X2 as weighting factor will be conducted to determinethe linearity of the calibration curve. Plasma sampleextraction involves the addition of 10 μL of the internalstandard working solution and 600 μL of cold acetonitrileto 200 μL plasma, followed by vortex-mixing and centrifu-gation at 20,000 g for 10 min at 4 °C. 700 μL of super-natant 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 μLinjected onto a Zorbax Eclipse XDB-C18 narrow bore2.1 × 12.5 mm 5 μm guard column and Zorbax EclipseXDB-C8 narrow bore 2.1 × 12.5 mm 5 μm guard columnwith column temperature maintained at 30 °C. The canna-binoids are separated using an Agilent series 1290 binarypump (Agilent Technologies, Mississauga, ON, Canada)with an online degasser and auto sampler set at 4° and amobile 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 includelinear gradients to 90% methanol 10% Solution B at3.5 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 ABSciex6500 QTRAP mass spectrometer (AB Sciex, Concord,ON, Canada) in positive ion mode. Multiple reactionmonitoring (MRM) will be used to quantify the cannabi-noids and the peak areas will be summed through use ofMultiQuant 3.0.1 Software. The ratio of peak areas ofthe cannabinoids to their respective internal standardswill be plotted against the nominal concentrations toconstruct the calibration curve and the concentrationsof the cannabinoids determined by interpolation.Complete blood counts and clinical chemistryAt each visit participants will have laboratory assessmentof blood components to evaluate hepatic, renal, orhematopoietic toxicity performed at their local hospitallaboratory. The tests performed include: a completeblood cell count panel with automated three or five partcell differential, electrolytes, glucose, creatinine, urea,alanine transaminase, aspartate transaminase, albumin,gamma glutamyl transferase and lipase. Adverse eventsfrom each participant will be assessed as laboratory re-sults that exceed the local laboratory age-specific refer-ence intervals. If participants are on a ketogenic dietduring the study, then urine ketone testing will be per-formed to assess the consistency of the ketosis at eachvisit.Trough levels of anticonvulsantsParticipants will remain on pre-existing anticonvulsantmedications throughout the cannabis oil study period.Serum specimens will be collected from participants ateach visit and trough levels of serum anticonvulsantmedications will be determined by LC-MS/MS by theRoy Romano Provincial Laboratory Regina, SK, Canada.Serum specimens were collected and stored at − 20 °Cprior to analysis. Adverse events will be counted if par-ticipants require a change in anticonvulsant medicationduring the trial either to maintain trough levels in thetherapeutic range.Quality of life assessmentThe instrument we have chosen is the Quality of Life inChildhood Epilepsy (QOLCE-55) [14]. The QOLCE is aparent/proxy-completed measure of health-related qual-ity of life specifically developed for children with epi-lepsy. It has several subsections containing multipleitems, as well as a series of global ratings. The originalReithmeier et al. BMC Pediatrics  (2018) 18:221 Page 6 of 9tool was designed for individuals between 4 and 18 yearsof age which is one of the broadest age ranges for a toolof this kind. The tool allows for the rater to indicate thatan item is not applicable if its content is above the ageor developmental level of the child being rated. Thismakes the QOLCE potentially robust in the face of is-sues such as lower age and intellectual disability.The QOLCE-55 shows good internal consistency andcriterion-related validity as well as adequate to goodtest-retest reliability, depending on the subtest or iteminvolved [14–16]. Areas covered include physical fea-tures (including physical limitations and fatigue),well-being (including depression, anxiety, helplessnessand self-esteem), cognition (including attention, mem-ory, language and general cognition), social engagement(including interactions, activities and stigma), and behav-ior. The QOLCE has also been shown to be sensitive toseizure activity and other clinical and psychosocial vari-ables associated with epilepsy [14] and to benefits fromtreatments such as surgery [17]. Finally, the QOLCE hasbeen used in the study of epileptic conditions with asso-ciated cognitive delays and Intellectual Disability andhas already shown its utility in samples with IntellectualDisabilities [18]. While the QOLCE-55 was not exclu-sively positive in the wording of its items, most itemswere positively stated, making for less distress on theside of those completing the measure [19].Ratings on the QOLCE are made on a 5-point scalewith 1 titled “very often” and 5 titled “never.” Reverseditems are recoded when scoring such that higher scoresmean more positive outcomes. These scores are thenrecoded as follows: 1 = 0, 2 = 25, 3 = 50, 4 = 75, and 5 =100. The mean for each of the subscales is then foundby adding these values together and dividing by thenumber of items not marked Not Appropriate. The totalscore for the scale is the unweighted mean of the foursubscales.As well, for the purposes of our study we added 13additional items based on reports from parents. Add-itional items covered sleep (including being drowsy), ver-bal and nonverbal communication, use of books,awareness of surroundings, interpersonal interactionswith children and adults, and irritability. These add-itional items are scored as other QOLCE items and aresummed into their own total score as well as beinglooked at individually.Seizure monitoringSeizure monitoring will be used to determine how treat-ment with the study compound affects seizure frequencyduration. Caregivers will be asked to track the frequencyand duration of their child’s three most frequent types ofseizures on a daily basis using a study diary. In order forthe study to remain consistent, the caregivers will trackthe same three types of seizures throughout the study.Seizures that occur in a cluster will be counted as oneseizure although the duration of the cluster and numberof seizures per cluster will be recorded. Although dialep-tic seizures are not included as part of the inclusion cri-teria for the study, caregivers will be encouraged torecord the frequency of dialeptic seizures if their childexperienced them frequently.Use of rescue medicationCaregivers will be asked to track their child’s use of res-cue medication. This will determine whether treatmentwith the study compound has any influence on use ofrescue medication. Caregivers will record the medicationused, the dosage used, and the number of times it wasadministered.Sample size determinationAs CARE-E is a phase I dose escalation safety and toler-ability study designed to find the most appropriate doseof CBD in a pediatric population it was felt that poweranalysis was not required to calculate sample size. Thesample size of 28 participants each receiving 4 separatedosage escalations is within usual guidelines for standardphase I clinical trial designs. In this multi-site dose escal-ation study, we chose to escalate within the same partici-pant with 7 participants at each site because the lowpediatric population incidence of epileptic encephalop-athy (the inclusion criterion), precluded ability to escal-ate in cohorts of 6, where a new cohort of six would beadministered the next dosing level [20, 21]. Any patientexhibiting a dose limiting toxicity will not receive thenext dose escalation.Data analysisStudy data will be collected and managed using REDCapelectronic data capture tools hosted at the University ofSaskatchewan [22]. REDCap (Research Electronic DataCapture) is a secure, web-based application designed tosupport data capture for research studies, providing 1)an intuitive interface for validated data entry; 2) audittrails for tracking data manipulation and export proce-dures; 3) automated export procedures for seamless datadownloads to common statistical packages; and 4) pro-cedures for importing data from external sources.Statistical analysisAll data will be descriptively analyzed using means,standard deviations, frequencies (where appropriate),and 95% confidence intervals. The sample size of 28 par-ticipants is sufficient for an initial phase 1 safety and tol-erability study, but is too small for precise estimation ofsteady state levels of biologically active cannabinoids ateach dose and for definitive assessments of efficacy.Reithmeier et al. BMC Pediatrics  (2018) 18:221 Page 7 of 9Trends will be examined and a medical statistician willassist with statistical and trend analysis of the data.Complete, specific details of the statistical analysis willbe described and fully documented in the StatisticalAnalysis Plan (SAP) after completion of data collection.Study funding:Given the potential controversy surrounding the studyof Cannabis products in children, CARE-E was fundedentirely through external funding in order to minimizethe potential for perceived bias in our study results.Funding was obtained through research grants from theJim Pattison Children’s Hospital Foundation (formerlythe Children’s Hospital Foundation of Saskatchewan),the Saskatchewan Health Research Foundation and theSavoy Foundation as well as a donation from the Dur-wood Seafoot Estate (administered through the Jim Pat-tison Children’s Hospital Foundation).DiscussionChildren with epileptic encephalopathies resistant tostandard therapy are at considerable risk for long-termneurocognitive impairment and poor quality of life.CBD-enriched Cannabis based therapies have beenshown in several studies to provide a reduction in seiz-ure frequencies and improvements in sleep patterns,mood, and alertness. Such favorable reports in the med-ical literature and social media have prompted parentswho are desperate to help their children to combineCannabis products with current medical treatments inchildren with refractory epilepsy. However, the encour-aging publicity surrounding medical marijuana is not ac-companied by strong scientific and rigorousinvestigation. This is particularly true for this vulnerablepediatric population.As a Phase I dose escalation study, the CARE-E studyis primarily designed to assess safety of a high CBD, lowΔ9-THC Cannabis oil preparation. However, it is antici-pated that the study can begin to address other major is-sues associated with Cannabis use in pediatric epilepticencephalopathies, namely the lack of an accepted dosageregimen, the relationship between steady state plasmaconcentrations and efficacy or adverse effects, its efficacyto reduce seizure frequency and improve quality of life,and potential drug-drug interactions with standard med-ical treatments for pediatric epilepsy. Successful imple-mentation of the CARE-E study will lay foundation for alarger Phase II efficacy trial of a high CBD, low Δ9-THCCannabis oil product. Such studies are imperative to al-leviate the lack of clinical information on medical Can-nabis in children with refractory seizures and givepractitioners confidence to prescribe Cannabis-derivedproducts to their patients.While CARE-E has a small sample size and open labeldesign, there are several strengths that differentiateCARE-E from other studies. The multicenter design al-lows for a wider range of study participants and preventsintrinsic bias in interpretation of study results. The re-cording of EEG activity in participants allows for an ob-jective measurement of efficacy of the Cannabis herbalextract in relation to dosage and steady state pharmaco-kinetics. Procurement of external funding to performthis study also prevents perception of bias in the collec-tion and reporting of study results.AbbreviationsCARE-E: Cannabidiol in Children with Refractory Epileptic Encephalopathy;CBD: Cannabidiol; EEG: Electroencephalogram; QoL: Quality of life; Δ9-THC: Δ9-tetrahydrocannabinolAcknowledgementsThe authors would like to thank Ms. Simona Meier for assistance in obtainingHealth Canada approval for this study and Ms. Stephanie Vuong for herassistance in developing the assay used to measure cannabinoids. We wouldalso like to acknowledge the financial support received from the Jim PattisonChildren’s Hospital Foundation, the Durwood Seafoot Estate, theSaskatchewan Health Research Foundation and the Savoy Foundation.FundingThis study was supported by grants from the Jim Pattison Children’s HospitalFoundation (formerly the Children’s Hospital Foundation of Saskatchewan),the Saskatchewan Health Research Foundation, the Savoy Foundation and aprivate donation from the Durwood Seafoot Estate. All grants were awardedfollowing a peer review by the funding agencies. The funding agencies werenot involved in the development of this study nor will they play a role in thedata collection and/ or analysis. The Cannabis Herbal Extract used in thisstudy was purchased at cost of production from the producer (Cannimed ®),who also provided technical information necessary to write an Investigator’sBrochure. Cannimed® had no influence in the design of the study nor willthey have any influence in the interpretation and publication of studyresults.Availability of data and materialsAll data collected from this study will be maintained at the University ofSaskatchewan and are available from the corresponding author onreasonable request and in accordance with the regulations of theSaskatchewan Health Information Protection and Access Act (HIPAA).Authors’ contributionsAll authors participated in the writing and editing of this manuscript. RJHand RT-W are co-principal investigators of CARE-E. BS, AWL, JA, BA, SC, EP-L,DDM, HJL and JT-Z all contributed to the development of the design of thestudy. LH, EL and LC are site investigators. All authors read and approved thefinal manuscript.Ethics approval and consent to participateEthical approval was obtained from the University of Saskatchewan EthicsReview Board for Biomedical Research in Human Subjects and operationalapproval to conduct this study was obtained from the Saskatchewan HealthAuthority. Similar Biomedical Ethics approvals have been obtained from theparticipating sites (University of British Columbia, Universite de Montreal,University of Manitoba). Approval from Health Canada was obtained for useof the study product and to conduct this study.Prior to enrollment informed consent will be obtained from the participant’sparents or legal guardians. Participants who were felt to be capable ofproviding assent were asked to provide their written and verbal assent toparticipate in the study.Consent for publicationNot applicable.Reithmeier et al. BMC Pediatrics  (2018) 18:221 Page 8 of 9Competing interestsAll authors declare no competing interests.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1Cannabinoid Research Initiative of Saskatchewan (CRIS), University ofSaskatchewan, Saskatoon, Saskatchewan, Canada. 2College of Pharmacy andNutrition, University of Saskatchewan, Room E3210 Health Sciences 104Clinic Place, Saskatoon, SK S7N-2Z4, Canada. 3Department of Pediatrics,Division of Child Neurology, Loma Linda University, Loma Linda, California,USA. 4Division of Pediatric Neurology, Department of Pediatrics, University ofAlberta, 11405-87 Avenue, 4th Floor, Edmonton, AB T6G-1C9, Canada.5Department of Pharmaceutical Services, Saskatchewan Health Authority,Saskatoon Health Region, Royal University Hospital, 103 Hospital Drive,Saskatoon, SK S7N-0W8, Canada. 6Department of Pathology and LaboratoryMedicine, Saskatchewan Health Authority, St. Paul’s Hospital, 1702 20th StreetWest, Saskatoon, SK S7M-0Z9, Canada. 7Saskatchewan Health Authority andDepartment of Psychology, University of Saskatchewan, Saskatoon,Saskatchewan, Canada. 8Department of Clinical Health Psychology, RoyalUniversity Hospital, 103 Hospital Drive, Saskatoon, SK S7N 0W8, Canada.9Clinical Trial Support Unit, University of Saskatchewan, Royal UniversityHospital, Room 5676, 103 Hospital Drive, Saskatoon, SK S7N 0W8, Canada.10Department of Pediatrics, University of Saskatchewan, Royal UniversityHospital, Room 2665, 103 Hospital Drive, Saskatoon, SK S7N 0W8, Canada.11Cell Signalling Laboratory, Departments of Psychiatry and Physiology,University of Saskatchewan, GB41, HSB 107 Wiggins Ave, Saskatoon, SK S7N5E5, Canada. 12Department of Community Health and Epidemiology,University of Saskatchewan, Room E3222 Health Sciences, 104 Clinic Place,Saskatoon, SK S7N-2Z4, Canada. 13Department of Medicine, Division ofNeurology, University of Saskatchewan, Royal University Hospital, Room 1622,103 Hospital Drive, Saskatoon, SK S7N 0W8, Canada. 14Division of PediatricNeurology, Department of Pediatrics, University of British Columbia, BCChildren’s Hospital, Room 2D19, 4480 Oak Street, Vancouver, BC V6H-3V4,Canada. 15Division of Pediatric Neurology, Room CE208, Department ofPediatrics 5, University of Manitoba, Children’s Hospital, 840 SherbrookeStreet, Winnipeg, MB R3A-1S1, Canada. 16Division of Pediatric Neurology,Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine,Universite de Montreal, Room 5-4, 3175 Chemin de la Cote Ste-Catherine,Montreal, QC H3T-1C5, Canada. 17Department of Pediatrics, Royal UniversityHospital, Rm 2744, 103 Hospital Drive, Saskatoon, SK S7N 0W8, Canada.Received: 18 May 2018 Accepted: 24 June 2018References1. Hani AJ, Mikati MA. Current and emerging therapies of severe epilepticencephalopathies. Semin Pediatr Neurol. 2016;23:180–6.2. Porter BE, Jacobson C. Report of a parent survey of cannabidiol-enrichedcannabis use in pediatric treatment-resistant epilepsy. Epilepsy Behav. 2013;29:574–7.3. Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, Miller I, FlaminiR, Wilfong A, Filloux F, Wong M, Tilton N, Bruno P, Bluvstein J, Hedlund J,Kamens R, Maclean J, Nangia S, Singhal NS, Wilson CA, Patel A, Cilio MR.Cannabidiol in patients with treatment-resistant epilepsy: an open-labelinterventional trial. Lancet Neurol. 2016;15:270–8.4. Tzadok M, Uliel-Siboni S, Linder I, Kramer U, Epstein O, Menascu S, et al.CBD enriched medical cannabis for intractable pediatric epilepsy: thecurrent Israeli experience. Seizure. 2016;35:41–4.5. Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, Scheffer IE, ThieleEA, Wright S, Cannabidiol in Dravet Syndrome Study Group. 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Accelerated titration designs forphase I clinical trials in oncology. J Natl Cancer I. 1997;89:1138–47.21. Wang Y, Jadhav PR, Lala M, Gobburu JV. Clarification on precision criteria toderive sample size when designing pediatric pharmacokinetic studies. J ClinPharmacol. 2012;52:1601–6.22. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Researchelectronic data capture (REDCap) – a metadata-driven methodology andworkflow process for providing translational research informatics support.J Biomed Inform. 2009;42:377–81.Reithmeier et al. BMC Pediatrics  (2018) 18:221 Page 9 of 9

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