The goal of this clinical trial is to learn if cannabidiol ("CBD-oil") works to treat severe epilepsy in children. It will also learn about the safety of cannabidiol. The main questions it aims to answer are:
* Does cannabidiol lower the number of seizure in children with severe epilepsy? * Does cannabidiol effect other outcomes such as behaviour, sleep, communication, activities? * What medical problems do participants have when taking cannabidiol?
Researchers will compare cannabidiol to a placebo (a look-alike oil that contains no cannabidiol) to see if drug cannabidiol works to treat severe epilepsy. All participants will receive both the cannabidiol and the placebo during different periods. At the end of the trial, we will evaluate for each patient seperately, whether seizures were less or more frequent during cannabidiol periods or placebo periods, to see what works best for every patient seperately.
Participants will:
* Register their seizures in a digital application during 4 to 6 periods. During these periods, CBD oil of placebo will be provided * Take CBD oil during 2 to 3 periods. One period will last around 7 weeks. * Also take placebo oil during the other 2 to 3 periods * Have a blood test every 7 weeks to monitor for safety and possible adverse effects * Visit the clinic once every 15 weeks for checkups and tests * Fill in questionnaires about quality of life, functioning, sleep, behaviour, epilepsy severity every 7 weeks.
Minimum age of 1 year old and maximum age of 18 years old.
Confirmed diagnosis of refractory epilepsy according to ILAE criteria
At least 4 countable seizures (not all in one week) of epileptic origin, during the 4-week baseline period while receiving care as usual.
All medication doses or other interventions for epilepsy must have been stable for one month prior to screening and the participants/parents and treating physicians are willing to maintain the current treatment regimen throughout the trial.
Any known or suspected hypersensitivity to cannabinoids or any of the excipients of the Investigational Medicinal Product (cannabis extract and refined peanut oil, generally safe for patients with peanut allergy)
History or current signs of significantly impaired liver function, such as bilirubin level ≥ 2 x upper limit of normal, or presence of liver damage as indicated by levels of alanine aminotransferase and/or aspartate aminotransferase ≥ 3 x upper limit.
Pregnancy, breastfeeding, or intention to become pregnant throughout the trial or within 3 months of completing treatment
Cardiac disease including: Structural heart disease with hemodynamic significance, heart failure, ischemic heart disease, Brugada syndrome, long-QT syndrome, cardiac arrythmia
Crossover
Cannabidiol (CBD) oral solution
DrugBedrolite, which is a full spectrum cannabis extract with 10%CBD/0.4%THC. Cannabidiol will be titrated up to a dosage of 2.5-20mg/kg/day, dosed twice daily.
Placebo
Other interventionCannabis extract with less than 0.5% CBD/0.02%THC
Seizure frequency
The primary outcome measure is the change from baseline in daily seizure frequency during active treatment periods and placebo periods, at the individual level and the aggregated group level. This will be collected by the participants' caregivers using an electronic diary (app) developed specifically for epilepsy research, to register seizure frequency and -type, and the need for emergency medication, for up to 7 days in hindsight.
Seizure free days
At the individual level, key secondary outcomes include the change from baseline in number of seizure free days in the CBD periods, compared to the placebo periods.
Response rates
At the aggregated group level, key secondary outcome measures include: * The number of patients in which CBD is considered effective, which corresponds to the achieved 30% minimum clinically important difference (MCID) * The number of patients with a responder rate of \>50%, \>75% or 100% Mean change from baseline in seizure free days in the CBD periods compared to the placebo
Patient-centered outcome measures: QOLCE-55
By including an extensive set of patient-centered outcome measures, we aim to capture clinically relevant differences in life domains that significantly impact the patient's wellbeing but are challenging to measure in a generic manner using an online data capturing system (Castor Database). The Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55) is a validatedquestionnaire for use by parents of children with epilepsy. It consists of 55 items covering cognitive, emotional, social and physical wellbeing, resulting in a total score and a sub score per domain. It has been used in a number of previous trials testing both CBD as well as other ASM in children with epilepsy. Score range: 0-100 (domain and total scores are typically transformed to a 0-100 scale) Higher score: Better quality of life
Patient-centered outcome measures: GASE scale
The Global Assessment of Severity of Epilepsy (GASE) scale. The Global Assessment of Severity of Epilepsy (GASE) scale was chosen as a measure of epilepsy severity. It has been validated for use in pediatric patients, has proven correlation with clinical aspects of epilepsy such as seizure intensity, and has been shown to be responsive to changes. We therefore expect this scale to add valuable information to the effect of CBD on epilepsy characteristics. Score range: 1-7 Higher score: More severe epilepsy
Productivity Cost Questionnaire iPCQ
Change in caregivers' productivity loss will be measured by the Institute for Medical Consumption Questionnaire (iMTA) Productivity Cost Questionnaire (iPCQ), measuring lost productivity at paid work due to absenteeism and lost productivity at paid work due to presenteeism. The iPCQ will be collected for the main caregivers. Score range: No fixed total score (results expressed as number of hours of productivity loss and/or converted to monetary costs) Higher score: Greater productivity loss / higher indirect costs (worse outcome)
Medical Consumption Questionnaire iMCQ
Change in healthcare resources used will be measured by the iMTA Medical Consumption Questionnaire (iMCQ). The iMCQ is an often-used tool in the Netherlands and a version adapted to epilepsy in children will be used.The iMCQ will be used to measure all direct medical costs (healthcare and medication), and direct non-medical costs (for example, travelling costs). Healthcare resource use will be multiplied with Dutch unit costs to determine healthcare costs. Unit costs will be used as described in the Dutch Costing guideline or tariffs stablished by Dutch Care Authorities, or the participating centers if both are missing. Score range: No fixed total score (results expressed as counts of healthcare resource use per recall period, optionally converted to costs) Higher score: Higher healthcare utilization / greater healthcare burden (worse outcome)
Quality of life: EQ-5D-Y questionnaire
Change in health-related quality of life will be measured by the EuroQol Five-Dimensional Questionnaire Youth (EQ-5D-Y). The Dutch tariffs will be used to result in a utility score. Utility values at the end of a treatment or placebo period will be used to estimate mean utility values in the two groups. Descriptive system score range: 5 dimensions (mobility, looking after myself, doing usual activities, having pain or discomfort, feeling worried/sad), each scored 1-5. 1 = no problems, 5 = extreme problems EQ Visual Analogue Scale (EQ-VAS): 0-100 Higher score: Better perceived health Higher scores (descriptive system): Worse health state (more problems)
Click on the lead sponsor to view all of their trials.
UMC Utrecht
Lead sponsor
Stichting Epilepsie Instellingen Nederland
Collaborator
Epilepsiecentrum Kempenhaeghe
Collaborator
Erasmus Medical Center
Collaborator
Maastricht University Medical Center
Collaborator
ZonMw: The Netherlands Organisation for Health Research and Development
Collaborator
