A Multi-Centre, Tolerability Study of a Cannabidiol-enriched Cannabis Herbal Extract for Chronic Headaches in Adolescents: the CAN-CHA Protocol
1Department of Pharmacology & Therapeutics, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
2Neurology Centre of Toronto, Toronto ON, Canada
3George and Fay Yee Centre for Healthcare Innovation, University of Manitoba, Winnipeg, Manitoba, Canada
4Quality Management in Clinical Research (QMCR), University of Alberta, Edmonton, AB, Canada
5Maternal Infant Child and Youth Research Network (MICYRN), Vancouver, British Columbia, Canada
6Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, Canada
7Youth research partners
8Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
9Department of Anesthesiology, Perioperative and Pain Medicine, University of Calgary, AB, Canada
10Department of Pediatrics, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
11University of California, San Francisco (UCSF) Child and Adolescent Headache Program. Department of Neurology, UCSF Weill Institute for Neurosciences, UCSF Benioff Children’s Hospitals.
12Division of Neurology, Children’s Hospital of Eastern Ontario, University of Ottawa ON, Canada
13Pediatric Neurosurgery, Department of Surgery, Sainte Justine Hospital, University of Montreal, Montreal, Quebec, Canada
14Department of Medicine, College of Medicine, University of Saskatchewan, Saskatchewan, Canada
15Department of Psychiatry, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
16Department of Anesthesia, Pain Management and Perioperative Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
17Center for Pediatric Pain Research, IWK Health, Halifax, Nova Scotia, Canada
18Cannabinoid Research Initiative of Saskatchewan, University of Saskatchewan, Saskatoon, SK, Canada
19College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada
20Department of Pediatrics, Royal University Hospital, University of Saskatchewan, Saskatoon, SK, Canada
*Corresponding Author: Lauren E Kelly PhD, MSc, BMedSci, CCRP, Assistant Professor, Dept. of Pharmacology and Therapeutics, University of Manitoba Scientific Director, Canadian Childhood Cannabinoid Clinical Trials (www.C4Trials.org) 417 – 753 McDermot Ave, Winnipeg Manitoba R3E0T6, Email: lauren.elyse.kelly@gmail.com Phone: 204 272 3190Abstract
Introduction
Cannabis products have been used in the management of headaches in adults and may play a role in pediatric chronic pain. Canadian pediatricians report increasing use of cannabis for the management of chronic headaches, despite no well-controlled studies to inform its dosing, safety, and effectiveness. The aim of our clinical trial is to determine the dosing and safety of a Cannabidiol (CBD)-enriched Cannabis Herbal Extract (CHE) for the treatment of chronic headaches in adolescents.
Methods and analysis
Youth, parents and an expert steering committee co-designed this tolerability study. Twenty adolescents (aged 14 to 17 years), with a chronic migraine diagnosis for more than 6 months that has not responded to other therapies, will be enrolled into an open label, dose escalation study across three Canadian sites. Study participants will receive escalating doses of a CBD-enriched CHE (MPL-001 with a THC:CBD of 1:25), starting at 0.2-0.4 mg/kg of CBD per day escalating monthly up to 0.8-1.0 mg/kg of CBD per day. The primary objective of this study is to determine the safety and tolerability of CBD-enriched CHE in adolescents with chronic migraine. Secondary objectives of this study will inform the development of subsequent randomized controlled trials and include investigating the relationship between the dose escalation and change in the frequency of headache, impact and intensity of pain, changes in sleep, mood, function, and quality of life. Exploratory outcomes include investigating steady-state trough plasma levels of bioactive cannabinoids and investigating how pharmacogenetic profiles affect cannabinoid metabolism among adolescents receiving CBD-enriched CHE.
Discussion
This protocol was co-designed with youth and describes a tolerability clinical trial of CBD-enriched CHE in adolescents with chronic headaches that have not responded to conventional therapies. This study is the first clinical trial on cannabis products in adolescents with chronic headaches and will inform the development of future comparative effectiveness clinical trials.
Trial registration: CAN-CHA trial is registered with ClinicalTrials.gov with a number of register NCT05337033.
Article notes
Competing Interest Statement
I have read the journal's policy and the authors of this manuscript have the following competing interests: LEK is the Scientific Director for The Canadian Collaborative for Childhood Cannabinoid Therapeutics (C4T) academic research team. She holds funding from the Canadian Institutes of Health Research, Canadian Cancer Society, Research Manitoba, the Sick Kids Foundation, the Children?s Hospital Research Institute of Manitoba, the University of Manitoba and a Mitacs Accelerate award in partnership with Canopy Growth. Dr. Kelly is also a member of the Scientific Advisory Board for Health Products Containing Cannabis at Health Canada and a member of the Board of Directors of the Canadian Consortium for the Investigation of Cannabinoids (CCIC). RJH is a clinical lead for both the Cannabinoid Research Initiative of Saskatchewan and C4T. He is developing a research protocol in which cannabis products will be supplied in kind by JMCC Corporation. He is a co-chair of the Scientific Advisory Committee for Health Products Containing Cannabis at Health Canada. KEB's time is supported by a fellowship from the Canadian Child Health Clinician Scientist Program, and she currently holds unrelated funding from the Society of Pediatric Psychology, BC Children's Hospital Research Institute, Canadian Institutes of Health Research, ZonMw: The Netherlands Organization for Health Research and Development, and the CHILD-BRIGHT Network. ECL has received speaking honoraria from Spectrum Therapeutics, Biome Grow, MedReleaf and Miravo Healthcare. He holds a non-salaried position as the Chief Medical Advisor for the JMCC Group. He is the Vice President of Neurology Services for Numinus, a psychedelic medicine treatment and research company. He is a member of the Expert Committee of the Medical Cannabis Clinicians Society (MCCS) in the United Kingdom and sits on the Advisory Councils for Cannabis Patient Advocacy & Support Services (CPASS) and MedCan. SLI In the last 12 months, Dr. Irwin has received honoraria for authoring a chapter for the Canadian Pharmacy Association (CPhA) and for doing an online lecture for NeuroDiem. She also receives compensation for scientific consulting (Impel NeuroPharma Inc, Biohaven Pharmaceuticals and Lundbeck A/S) and has had research support from the Duke Clinical Research Institute. MC has been granted the 2022 Research Manitoba-George & Fay Yee Centre for Healthcare Innovation in Health Research PhD Studentship Award. RB, BS, TL, ZA, MCG, BID, GEB,KAB, VWLT, DP, AGW, ES, EP, ARM, SM, ZZ, SB, SG, JA, TFO, and GAF have no potential conflict of interest to declare.
Clinical Trial
CAN-CHA trial is registered with ClinicalTrials.gov with a number of register NCT05337033.
Funding Statement
This work was supported by the Hospital for Sick Children Foundation (https://www.sickkidsfoundation.com) and the Canadian Institutes of Health Research (https://cihr-irsc.gc.ca/) grant number N120-1028 as a team grant Dr Lauren Kelly is principal investigator for this grant. An investigational product for this trial has been purchased from MediPharm Labs. The funders did not and will not have a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Introduction
Globally, chronic headaches are one of the major causes of disability among adolescents. The World Health Organization classifies it under the top ten disabling health conditions,[1, 2] with a prevalence of 7.8% in adolescents 14 years of age or older [3–5]. In the US alone, the total annual cost incurred by pediatric headache is estimated around $1.1 billion [6]. Adolescents with chronic headaches often experience reduced quality of life, sleep disruption, anxiety, fatigue, limb pain, dizziness, overuse of medications and academic challenges [7]. Despite advancements in the therapeutic management of chronic pain, treatment of chronic headache disorders in adolescents remains challenging. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), triptans, gabapentin, neuromodulation devices and ergotamine are used for the acute treatment of migraine [8, 9]. Preventive migraine therapies are limited in availability, efficacy, and authorization for use in the adolescent population. Topiramate is the only FDA approved preventive treatment for migraine in adolescents [1, 10, 11]. In other areas of medicine, cannabinoids have shown therapeutic potential in adolescents where conventional medications fail, including treatment resistant epilepsy, and chemotherapy-induced nausea and vomiting [12]. In adults, use of cannabis products is increasing for the treatment of headaches and migraines [13]. An observational study reported that 36% of adult cannabis users are using cannabis to relieve symptoms related to migraine and/or headaches. Further, this study reported that the use of cannabis products in adults led to an average reduction of 3.6 points on a 10-point intensity of headache scale [14, 15]. Despite promising observational data in adults, a paucity of literature exists that demonstrates the tolerability of cannabis for the treatment of chronic headaches in adolescents. Cannabidiol (CBD) and Tetrahydrocannabinol (THC) are the principal active cannabinoids which have a number of potential therapeutic applications [16]. CBD, which is not associated with the same intoxicating effects of THC, acts as a negative allosteric modulator of CB1 receptors in the endocannabinoid system [17]. CBD potentiates anandamide-mediated intrinsic neurotransmission [18], and has antioxidant and anti-inflammatory activity [19].
Canadian studies have demonstrated the safety and tolerability of CBD-enriched CHE in children with refractory epilepsy [20, 21]. Huntsman et al reported on the preliminary results of the CARE-E trial where a 1:20 THC:CBD CHE oil was found to be well tolerated in children, and THC plasma concentrations were below levels associated with intoxication despite CBD doses of up to 12 mg/kg per day [21].
In Canada, recreational markets have increased cannabis accessibility and there is increasing interest in managing chronic headaches off-label with cannabinoids, self-guided in the absence of evidence [22]. The paucity of clinical trial data in children is due to many historical challenges with studying cannabis products and cannabinoids, resulting from legal difficulties in obtaining products, variable product quality control and the stigma associated with illegal drug use, and particularly with children. The current reality warrants the need to conduct robust interventional studies establishing the tolerability, safety, and efficacy of cannabis in adolescents with chronic headaches. Here we describe a protocol for CAN-CHA (CANnabis for Chronic Headaches in Adolescents) trial, an open-label dose escalation study to establish the tolerability of a CBD-enriched Cannabis Herbal Extract (CHE) in adolescents with chronic headaches. CAN-CHA is funded by the SickKids Foundation, sponsored by the University of Manitoba and has received approvals from Health Canada and research ethics board. CAN-CHA is registered with ClinicalTrials.gov (NCT05337033).
Methods and analysis
Primary Objective
To determine the safety and tolerability of escalating doses of a CBD-enriched CHE in adolescents with chronic headaches.
Secondary Objectives
- To investigate the relationship between the dose-escalation with headache-free days.
- To monitor the effect of CBD-enriched CHE oil on the intensity of pain related to chronic headaches.
- To evaluate the effect of CBD-enriched CHE oil on sleep, mood, and function in adolescents with chronic headaches.
- To explore the impact of chronic headaches on quality of life.
Exploratory Objectives
- To investigate the relationship between the dose-escalation and steady-state trough levels of bioactive cannabinoids/endocannabinoids.
- To study pharmacogenetic variations among adolescents receiving CBD-enriched CHE oil.
Study Population
We will recruit 20 adolescents across three study sites: Halifax, Toronto, and Vancouver. To be eligible to participate in this study, an individual must meet all of the following criteria: Adolescents meeting any of the following criteria will be excluded from the study:
- Adolescents between 14-17 years of age at the time of screening
- Diagnosed with Chronic Migraine according to ICHD-3: headache (migraine-like or tension-type like) occurring on 15 or more days per month for more than 3 months, which on at least 8 days per month have features of migraine headache [23].
- Failed at least two preventive treatment options on the grounds of tolerability and/or efficacy, including but not limited to antidepressants (tricyclic antidepressant or selective norepinephrine reuptake inhibitor), magnesium, gabapentin, topiramate, beta-blockers, memantine, and/or non-pharmacological therapies including nutraceuticals and botox.
- Females who have reached menarche must have a negative serum pregnancy test during screening
- Must be willing to engage with psychology and physiotherapy throughout the trial as appropriate.
- As per the investigator judgment, the participant is not an ideal candidate due to a personal issue or medical condition that is likely to impede in the successful completion of the study
- Participants with a history of post-concussion headache or new daily persistent headache
- Participants with a diagnosis of medication overuse headache
- Participants with cardiac, renal, or hepatic disease (assessed by the site investigator)
- Participants with complex regional pain syndrome-II
- Participants with abnormal ECG findings at baseline (as determined by the investigator)
- Participants who are on the following medications: opioids, antipsychotics, antimanic, barbiturates, benzodiazepines, muscle relaxants, sedatives, or tramadol
- Participants with developmental delay or impairments including autism, cerebral palsy, or intellectual disability
- Participants with a personal or family history of schizophrenia or psychotic disorders
- Participants who are/plan to become pregnant within the study period or within three months of interventional product discontinuation
- Participants who cannot commit to using contraception, refraining from recreational cannabis use and driving throughout the study period
Withdrawal criteria
Study participants may withdraw from the study at any point. If a participant’s headaches worsen or they suffer from intolerable treatment related adverse effects, they will be withdrawn from the study. Participants who become pregnant during the study period, do not attend follow-up visits, or do not comply with the prescribed interventional drug regimen will be withdrawn from the study. Participants will be given the option to only withdraw from the study intervention, these participants will continue to be followed up for safety assessments till the end of study. All participants withdrawn from the study will be included in the final report at the end of the study for transparency.
Intervention
The investigational product for our study is a CBD-enriched CHE, MPL-001, purchased from MediPharm Labs. MPL-001 is a CBD-enriched CHE where each ml of oil contains 2 mg of THC and 50 mg of CBD dissolved in coconut/palm-based medium chain triglycerides (MCT) carrier oil. The MPL-001 (CBD:THC 25:1) oil used in this study contains lemon-peppermint flavoring agents. Manufacturing of MPL-001 occurs following Good Manufacturing Practices includes the following steps: harvesting of plant, followed by weighting, and drying. Further, dried plants are subjected to bucking, ethanolic extraction, filtration of cannabinoid ethanolic solution, and evaporation of ethanol, this leaves over acidic cannabis resin. Subsequently, cannabis resin is decarboxylated (activated) and mixed with oil. The oil is made available in a glass bottle sealed with child lock caps, stored and labeled at the study central pharmacy according in accordance with the Cannabis Act, 2018 and the Health Canada Division 5 Food and Drugs Act [24]. All the study participants will receive an escalating dose starting at 0.2-0.4 mg/kg of CBD per day with dose increases (0.2 mg/kg/day increments) happening monthly to a maximum of 0.8-1.0 mg/kg of CBD per day. This dosing strategy reflects the current clinical practice of study investigators and well below the maximum dose of CBD-enriched CHE of 10-12 mg/kg/day previously well tolerated in children with epilepsy [21]. Participants will be provided with dosing calendars (Fig 2) and be instructed to take their daily dose bid with 25% of the dose in the morning and 75% of the daily dose in the late afternoon to mimic the diurnal variation [25] in the endocannabinoids and prevents adolescents from having to take cannabis during school hours.
Study design
CAN-CHA is a multicenter, open-label dose-escalation study to determine the tolerability of MPL-001 in adolescents with treatment refractory chronic migraine. A traditional 3+3 dose finding design was not practical as all participants would not receive the lowest cannabinoid dose and the recommended “start low and go slow” approach to titration. The trial will be conducted in three Canadian centers. CAN-CHA will consist of three different phases: baseline (1 month) without intervention, treatment (4 months of escalating doses) and weaning (1 month). All participants and their caregivers will be invited to complete a pre– and post-study survey about their experiences in the trial to inform future research.
Patient and public involvement
CAN-CHA trial was designed in collaboration with youth from the KidsCAN Young Persons’ Research Advisory Group (YRPAG) and from the Solutions for Kids in Pain (SKIP) network. The Canadian Collaborative for Childhood Cannabinoid Therapeutics (C4T) Parent Advisory Committee provided insight on the outcome measurement tools and the consent form. Three youth advisors (TL, ZA, MC-G) with chronic migraines have been involved throughout the study design process and will continue to advise on recruitment strategies, designing materials, reporting and dissemination.
Baseline Phase
Eligible adolescents will be asked by their healthcare providers if they are interested in learning more about this research study. A study team member, who is not involved in the patients’ care, will present the study, review the consent documents and answer any questions from the patients and their families. Adolescents who meet the inclusion criteria, assent, and whose caregiver’s consent to participate will then begin a baseline period. Baseline will consist of one month period without intervention to estimate headache frequency and severity, as well as mood, sleep, and pain before administering the intervention to the participants. Participants will be asked to maintain a daily electronic headache diary that will include reporting on the severity of headaches, associated pain, sleep, absences from work/school and adverse events. Participants will complete age-validated scales on sleep related impairment, anxiety, depression, positive mood, pain interference, family impact and goal attainment scaling [26–31] as described in the Fig 1. A blood sample will be drawn from the study participants to measure liver transaminases (ALT/AST) and creatinine, measure endocannabinoids and detect pregnancies, while saliva will be sampled for extraction of genomic DNA to allow for genotyping of pharmacogenetic variants. ECGs (within 3 months of screening or done at the time of screening) will be recorded at baseline to ensure there are no cardiac electrical activity concerns.
Treatment Phase
Following the one-month baseline period, study participants will receive CBD-enriched CHE oil, MPL-001with a dosing calendar and administration pamphlet shipped directly to their homes from the trial coordinating centre. A handout on cannabis oil administration co-created with the youth advisors and will be provided to all study participants and their families that will also have a video component. There will also be a demonstration by the research coordinator at the first study visit using olive oil in a product bottle. The study participants will be instructed to administer the investigational product at a starting dose of 0.2-0.4 mg/kg/day divided into two doses (BID, 25% in the morning and 75% in the evening after school) each day for one month.
Dose-escalation schedule during the treatment phase is described in Table 1. Participants will continue to complete a daily electronic headache diary to monitor symptoms and adverse effects. During all follow up visits, participants and their caregivers will be asked to complete validated outcome measurement tools alongside the PedsQL ™ Family Impact Module assessment, and Self-directed goal attainment. Blood samples will be collected prior to starting the next dose level, at study visits and will be used to evaluate changes and variability in cannabinoid pharmacokinetics with escalating doses, confirm pregnancies, and monitor liver enzymes and creatinine over time.
Weaning Phase: After the baseline phase (one month, no treatment) and the treatment phase (four months, escalating doses), participants will start the weaning schedule. Weaning includes incrementally reducing the dose (by 0.2 mg/kg CBD every week) leading to complete discontinuation of the study product. The complete weaning schedule is detailed in Table 2. The intervention will be discontinued by visit 7. If the parents, adolescents, and healthcare providers feel that there was improvement while on the intervention, participants will discuss the continued authorization of medical cannabis with the enrolling physician, caregivers and their healthcare team.
Dosing rationale and calculations
Data on the pharmacokinetics related to cannabinoids in adolescents are extremely lacking. In the current study, the CBD dose is extrapolated from safety data obtained in clinical trials in children and adults with refractory epilepsy [32–38]. CBD was found to be safe and well-tolerated in children with refractory epilepsy at a dose of up to 20 mg/kg/day [32, 33, 35, 38, 39]. We aim to keep the CBD dose as low as possible to limit adverse events and reduce costs for families should we confirm a tolerable dose is effective in future randomized controlled trials.
The use of THC is associated with some risk of developing adverse effects of the central nervous system, [40, 41] however, THC possesses its central pain-relieving potential at very low doses, much lower than would be expected from recreational cannabis exposures [42]. Previous studies on a 1:20 THC:CBD CHE oil in children reported that plasma THC levels following doses of up to 12 mg/kg/day suggested a low risk for THC intoxication [21]. The quantity of THC in our study product is 1 mg per mL with maximum THC doses only reaching 0.05 mg/kg/day, which we do not expect to be associated with any adverse psychoactive reactions. In this study, the maximum dose of CBD will be less than 10 percent of the recommended dose of CBD in the previous studies conducted in the pediatric population [43]. In order to maintain the accuracy and consistency in the dosing regimen of study participants across all the study centers, the mid-point of the dose range will be selected to calculate the desired dose based upon the weight of the participants. Participants will be weighed at each study visit to assist in tracking changes in appetite; however, the dose calculation will be based on the weight taken at baseline. The final dose will be calculated by rounding off (0.5 mL of MPL-001). This will help in achieving improved precision and will ease administration of the investigational product to the study participants. For example, an adolescent weighing 50 kg will receive a starting total daily dose containing 15 mg of CBD (0.3 mg/kg/day) and take 4 mLs in the morning and 11 mLs in the afternoon.
Dose limiting toxicities (DLTs)
Adverse events will be categorized using the Common Terminology Criteria for Adverse Events (CTCAE version 5.0 dated 27 Nov 2017). If any of the following DLTs occur the participant will not move up to the next dose level. Dose escalations will not be reattempted but the participant shall remain in CAN-CHA should no other DLTs occur. DLTs include:
- Parental/youth report complaints of moderate mood elevation defined as exaggerated feelings of well-being which is disproportionate to the events and stimuli (Euphoria Grade 2)
- Somnolence Grade 2 which includes moderate sedation (sleepiness and drowsiness) that limits instrumental activities of daily living
- Cannabis-attributed diarrhea, Grade 2 or more defined as an increase of 4 – 6 stools per day over baseline; moderate increase in ostomy output compared to baseline; limiting instrumental activities of daily living
- Unexplained tachycardia (w/out pain, fever, anemia etc.) requiring medical intervention
- Unexplained hypotension requiring medical intervention
- Non-infectious conjunctivitis Grade 2 defined as moderate decrease in visual acuity (best corrected visual acuity 20/40 and better or 3 lines or less decreased vision from known baseline) characterized by inflammation, swelling and redness to the conjunctiva of the eye.
- Serious adverse events requiring hospitalization
- Discretion of the participant, physician, or parents
Primary Outcome
The frequency and type of cannabis-related adverse events among study participants will be assessed daily throughout the study. Adverse events will be reported daily and reviewed at study visits.
Secondary Outcomes
- The frequency of headache measured using headache-free days [assessed: daily throughout the study]. Reported number of headache-free days per month during the study period
- The average intensity of pain due to chronic headaches as measured using an 11-point Numeric Rating Scale (NRS) [assessed: daily throughout the study] [44]. Reported for each study as a percentage change in average daily pain intensity due to chronic headaches on the numeric rating scale (NRS) from baseline to each follow up visit
- The impact of pain on participants’ quality of life using the PROMIS Pediatric Pain Interference– Short Form 8a [assessed: at visits 1,2,3,4,5,6 and 7] [26]. Reported as a percentage change in the scores from baseline value
- The quality of sleep will be recorded using the PROMIS Pediatric Sleep-Related Impairment– Short Form 8a scale [45]. [assessed: at visits 1,2,3,4,5,6 and 7] Reported as a percentage change in scores from baseline value
- Changes in anxiety will be measured using the PROMIS Pediatric Short Form v2.0 – Anxiety – 8a scale [46] [assessed: at visits 1,2,3,4,5,6 and 7]. Reported as percentage change in scores from the baseline value
- Change in mood will be evaluated using two tools PROMIS Pediatric Short Form v2.0 – Depressive Symptoms 8a scale and the PROMIS Pediatric Positive Affect – Short Form 8a. [29, 47] [assessed: at visits 1,2,3,4,5,6 and 7]. Reported as a percentage change in scores from baseline value
- Change in self-directed goal attainment (participant and parent reported) [assessed: monthly throughout the study] [30]. Reported as a percentage toward a physical, mental and social by participant at each monthly visit
- Change in scores of PedsQL ™ Family Impact Module, Version 2.0 [assessed: monthly throughout the study] [31]. Reported as percentage change in scores from the baseline value
- Steady-state trough plasma levels of bioactive cannabinoids THC, CBD, 11-OH-THC, 7-OH-CBD, and endocannabinoids [assessed: monthly throughout the study]. Reported as a plasma concentration relative to each dose increase/decrease and according to genotype
- Genetic polymorphisms within genes encoding for cytochrome P450 enzymes and the p-glycoprotein transporter and their association with plasma levels of THC, CBD, and their active metabolites in the study participants
Assessments
Participants will be enrolled in the study for six months. De-identified participant data will be collected electronically in a Research Electronic Data Capture (REDCap) database or paper copies will be provided based on participants’ preferences. Assessments completed on paper will be kept as source documents at each study site and entered into REDCap by study staff. The following includes a detailed description of all planned assessments.
Physical examination
During the baseline and close out visits (visit 7), participants will undergo physical assessments, but weight will be reported at every visit to potentially signal changes in appetite. Blood work will assess liver function and renal safety, plasma concentration of cannabinoids, and pregnancy status. At the time of screening, participants will receive an electrocardiogram as per standard practice at each site should they not have had one in the previous 3 months.
Electronic headache diary
The daily diary was developed in collaboration with the youth advisors as described above. Administration will incorporate best practices in the use of daily diaries in adolescents, and feedback from patients with chronic pain and families interviewed about the use of in-home longitudinal ecological momentary assessment tools [48]. The purpose of the diary is to monitor and report headache characteristics, including intensity (Numeric Rating Scale; NRS), headache-free days, use of the rescue medication, and potential headache triggers (e.g., low sleep). Electronic diaries will be completed by the participants using REDCap. Adverse events will be assessed daily with flags to research coordinators to review changes. The NRS is a validated tool that will be used to record daily self-reports of headache intensity from visit 1 until the end of the study [49]. Participants will rate the intensity of pain from 0 to 10, 0 means no hurt, 10 means the worst hurt you could ever imagine. The efficacy of the investigational product in treating the chronic headaches will be assessed in reducing the intensity of headache from baseline to each follow-up visit. Daily data from the electronic headache diaries will be transferred to the server. Based on pain intensity reported on the NRS, the study participant will be categorized into the severity of the headaches. Mild headache will vary in intensity between 1-5, moderate between 6-8, and severe between 9-10 [50]. A complete list of the daily headache diary questions are provided in Table 3. All the study participants will be given an option of using an electronic wrist worn device (actigraphy), provided at no cost to them by the study team, to help keep track of the number of hours slept per night.
PROMIS measures
Patient-Reported Outcomes Measurement Information System (PROMIS) evaluates social, mental, and physical health of adults and children [51]. We will be using the PROMIS tools to measure pain interference, sleep, depressive symptoms, emotions, and family’s quality of life. These tools will be completed by the study participants. The following PROMIS measure will be administered by the study participants.
Pediatric Pain Interference – Short Form 8a scale
The Pediatric Pain Interference PROMIS tool assesses the self-reported consequences of pain on the essential aspects of a participant’s life. It measures the extent to which pain interferes with cognitive, emotional, social, physical, and recreational activities. The pediatric pain interference scale is non-disease specific, and the items utilize a 7–day recall period (items include the phrase “the past 7 days”). Varni et al. describe the strong psychometric properties of the PROMIS Pediatric Pain Interference Scale [26].
Pediatric Depressive Symptoms – Short Form 8a scale v2.0
Pediatric Short Form v2.0 – Depressive Symptoms 8a is a PROMIS tool which is used for assessment of negative mood states, including sadness or guilt, self-criticism, self-perceived worthlessness, loneliness, interpersonal alienation (social cognition) and decreased positive affect and engagement. However, this scale does not assess somatic symptoms associated with depression, such as changes in appetite and sleeping patterns. Pediatric Short Form v2.0 – Depressive Symptoms 8a scale has demonstrated good test-retest reliability, and validity of administration across groups [28].
Pediatric Positive Affect – Short Form 8a scale
The Pediatric Positive Affect scale is PROMIS tool used for the assessment of positive or rewarding feelings and moods, including elation, pride, affection, pleasure, joy, engagement, excitement, happiness, and contentment. The short form of Pediatric Positive Affect scale is an efficient, accurate, and valid assessment of positive affect in adolescents and good reliability has been reported [47].
Pediatric Anxiety Symptoms-Short Form 8a scale v.2.0
The pediatric short form v2.0 Anxiety scale is a PROMIS tool used to assess the self-reported fear (fearfulness, panic), anxious misery (worry, dread), hyperarousal (tension, nervousness, restlessness), and somatic symptoms related to arousal (racing heart, dizziness). The literature reports excellent reliability and validity of the Pediatric Short Form v2.0 – Anxiety – 8a scale [29].
Goal attainment Scaling
Goal attainment scaling is a patient-derived and reported outcome measure in which participants select their goals in areas where they would like to improve function [30]. Participants will be asked to select three goals at their screening appointment which could include physical, social, academic, or personal goals that they hope to improve on throughout the study period. In this, scaling goals are weighted with the importance (on a 0-10 scale) and difficulty (also on a 0-10 scale).
PedsQL™ Family Impact Module
Pediatric quality of life family impact module aims to measure the effect of the child’s chronic health condition on the family and parents. The PedsQL examines the domains of physical, emotional, social, cognitive, worry and communication to provide an overview of quality of life and impact on families. The PedsQL scale has demonstrated well defined validity and reliability [31].
Pharmacogenomic analyses
Genomic DNA will be extracted from saliva samples using a QIAmp DNA extraction kit at the University of Manitoba and genotyping will be performed using the Illumina Global Screening Array (GSA) v3 array on the iScan array scanner. The GSAv3 GWAS arrays have been designed to capture both common and rare genetic variation, including all variants that have been shown by the Clinical Pharmacogenetics Implementation Consortium to affect the function of the selected candidate genes [54]. Genotyped variants and samples will undergo standard quality control procedures in PLINK 1.9 [55]. Imputation of non-genotyped variants will be performed using the Michigan Imputation Server, including the Haplotype Reference Consortium data as a reference and genetically-determined ancestry will be assessed with EIGENSOFT v5 [56]. Association between these variants and response outcomes will be performed using logistic regression.
Health care utilization
Costs are an important consideration for families caring for an adolescent with a chronic illness, and are especially concerning for families accessing cannabis oils [57]. Participants in this study will provide consent to access their administrative health records for a pre and post study of healthcare utilization to be designed, reviewed and approved in the future. During CAN-CHA, measures of absences from school and work for participants and caregivers, hospitalizations and the use of rescue medicines will be captured to inform building blocks for future health technology assessment. To reduce participant burden, access to health records will also ensure that the use of all rescue medications is documented should there be an admission to the emergency department or inpatient unit.
Sample size
CAN-CHA is a tolerability study, designed to evaluate the safety of escalating doses of a cannabidiol-enriched CHE. Given the within-participant study design, a sample size of 20 study participants (common for early phase trials) should provide a reasonable characterization of the pattern of adverse event frequency and severity as dosing increases. To provide more generalizable data we will recruit these participants across three pediatric chronic pain/headache programs in Halifax, Vancouver, and Toronto, Canada.
Data collection, management and sharing
Data collection will be the responsibility of the study team at each site under the supervision of the site investigators (TFO, ECL, GAF) and trial sponsor (LEK, University of Manitoba).
Investigators and research coordinators will be responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data reported. All source documents will be completed in a neat, legible manner to ensure accurate interpretation of data. Hardcopies of the study visit measurement tool will be provided as source documents for each participant enrolled in the study. Data recorded in the electronic case report form (eCRF) derived from source documents should be consistent with source documents. Clinical and laboratory data will be entered into REDCap (Research Electronic Data Capture), [58] a 21 CFR Part 11-compliant data capture system provided by the Women and Children’s Health Research Institute at the University of Alberta, Edmonton. REDCap includes password protection and internal data quality checks, such as automatic range checking, to identify data that appear inconsistent, incomplete, or inaccurate to the study team for verification. Clinical data will be entered directly from the source documents. Full de-identified datasets will be available from the corresponding author upon reasonable request and review by the trial steering committee.
Statistical analysis
The primary statistical analyses will be a descriptive summary of the pattern of incidence and severity of adverse events across dosage levels. Adverse event severity grading is assigned using CTCAE definitions as described above. Conventional summary statistics will be used to describe baseline characteristics and other outcomes (means, standard deviations, as well as medians, range, and interquartile range (IQR) for numerical variables; counts and percentages for categorical variables). Adverse events will be reported overall (duration of the study period) and by dosage level (study month). Medians, ranges and IQR will be provided for the concentrations of CBD, THC, and the major metabolites at each sampling point. The ratio of concentration of parent compound to metabolites and endocannabinoids will also be summarized to explore variability in cannabinoid metabolism. Severity, frequency, and relationship of treatment emergent AEs to study intervention will be presented by system organ class and MEDRa coded. All serious adverse events will be reported to pharmacovigilance programs including Health Canada and the Canadian Paediatric Surveillance Program along with regulatory bodies including research ethics boards, the data safety monitoring board and trial steering committee. The secondary outcomes including pain, sleep impairment, depression, positive affect, anxiety, and goal attainment scores will be summarized at each timepoint; within-participant change from baseline of these measures will also be summarized (both absolute and percentage change) but this trial is underpowered, and not designed to evaluate efficacy.
Ethics and dissemination
CAN-CHA received a No Objection Letter from Health Canada (Dec 2022), registered with ClinicalTrials.gov (NCT05337033). The study was approved by the University of Manitoba Health Research Ethics Board (HS25503-B2022:037. An institutional cannabis research license is received in Sep 2022, and we expect to enroll our first participant in Spring 2023. Written informed consent will be taken from all the participants and from the legal guardians for the participants who will be below 16 years of age. We plan to disseminate our findings of the CAN-CHA trial by presenting them to conferences and publishing them in an open-access journal.
Discussion
In Canada, adolescents with refractory headache disorders are using cannabis products off-label to manage their symptoms, self-guided in the absence of evidence [59]. Chronic headaches are often resistant to standard drug therapies in adolescents, resulting in school absenteeism, withdrawal from social activities and can cause significant stress for families [60]. Based on anecdotal reports, parents of children with chronic headaches found cannabinoids to be effective for the management of headache[1], but there remains minimal data available to inform dosing or safety. CAN-CHA is a tolerability study designed with youth and parents that will investigate the safety of escalating doses up to 1mg/kg/day of CBD-enriched CHE in adolescents. This represents the first study evaluating a cannabis product, providing valuable knowledge on the safety and dosing of a CBD-enriched CHE in children with chronic pain. The CAN-CHA trial is an open label with a small sample size, underpowered to evaluate efficacy. This study will inform dose selection for a larger scale randomized clinical trial comparing a CBD-enriched CHE oil to placebo (on top of standard of care) for adolescents with chronic headache. Given the high prevalence of chronic headaches, severe morbidity, and current lack of effective treatment options, the successful outcomes from this research project will have the potential to create meaningful impact for the lives of Canadian adolescents.
Supporting information
S1. SPIRIT checklist: Recommended items to address in a clinical trial protocol and related documents.
S2. Approval by ethics committee.
S3. Study protocol reviewed by ethics committee.
Abbreviations
AE: Adverse Events; BMI: Body Mass Index; CBD: Cannabidiol; CHE: Cannabis Herbal Extract; CNS: Central Nervous System; eCRF: electronic case report form; GMP: Good Manufacturing Practices; NRS: Numeric Rating Scale; NSAIDs: Non-steroidal Anti-inflammatory Drugs; REDCap: Research Electronic Data Capture; THC: delta 9 – Tetrahydrocannabinol
Ethics and dissemination
The study was approved by the University of Manitoba Health Research Ethics Board (HS25503-B2022:037). We plan to disseminate our findings of the CAN-CHA trial open-access publication.
Availability of data and material
Access to the protocol and a deidentified dataset may be provided upon reasonable request to LEK and approval by the Clinical Trial Steering Committee.
Funding
This work was supported by the Hospital for Sick Children Foundation and the Canadian Institutes of Health Research grant number N120-1028. An investigational product for this trial has been purchased from MediPharm Labs. This organization has played no role in the design, conduct or reporting of the trial.
Competing interest
LEK is the Scientific Director for The Canadian Collaborative for Childhood Cannabinoid Therapeutics (C4T) academic research team. She holds funding from the Canadian Institutes of Health Research, Canadian Cancer Society, Research Manitoba, the Sick Kids Foundation, the Children’s Hospital Research Institute of Manitoba, the University of Manitoba and a Mitacs Accelerate award in partnership with Canopy Growth. Dr. Kelly is also a member of the Scientific Advisory Board for Health Products Containing Cannabis at Health Canada and a member of the Board of Directors of the Canadian Consortium for the Investigation of Cannabinoids (CCIC). RJH is a clinical lead for both the Cannabinoid Research Initiative of Saskatchewan and C4T. He is developing a research protocol in which cannabis products will be supplied in kind by JMCC Corporation. He is a co-chair of the Scientific Advisory Committee for Health Products Containing Cannabis at Health Canada. KEB’s time is supported by a fellowship from the Canadian Child Health Clinician Scientist Program, and she currently holds unrelated funding from the Society of Pediatric Psychology, BC Children’s Hospital Research Institute, Canadian Institutes of Health Research, ZonMw: The Netherlands Organization for Health Research and Development, and the CHILD-BRIGHT Network. ECL has received speaking honoraria from Spectrum Therapeutics, Biome Grow, MedReleaf and Miravo Healthcare. He holds a non-salaried position as the Chief Medical Advisor for the JMCC Group. He is the Vice President of Neurology Services for Numinus, a psychedelic medicine treatment and research company. He is a member of the Expert Committee of the Medical Cannabis Clinicians Society (MCCS) in the United Kingdom and sits on the Advisory Councils for Cannabis Patient Advocacy & Support Services (CPASS) and MedCan. SLI In the last 12 months, Dr. Irwin has received honoraria for authoring a chapter for the Canadian Pharmacy Association (CPhA) and for doing an online lecture for NeuroDiem. She also receives compensation for scientific consulting (Impel NeuroPharma Inc, Biohaven Pharmaceuticals and Lundbeck A/S) and has had research support from the Duke Clinical Research Institute. MC has been granted the 2022 Research Manitoba-George & Fay Yee Centre for Healthcare Innovation in Health Research PhD Studentship Award. RB, BS, TL, ZA, MCG, BID, GEB,KAB, VWLT, DP, AGW, ES, EP, ARM, SM, ZZ, SB, SG, JA, TFO, and GAF have no potential conflict of interest to declare.
Data Availability
Deidentified research data will be made publicly available when the study is completed and published.
Acknowledgements
We are thankful to Dr Thierry Lacaze-Masmoniteil for providing insights during the design of the study and all of the C4T members who have been consulted on protocol development and mentorship.