Epilepsy, Refractory Epilepsy, Refractory Epilepsy in Children
Conditions
Keywords
Refractory epilepsy, rare diseases, Cannabidiol., bedrolite, n-of-1 trial, medicinal cannabis
Brief summary
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.
Interventions
Bedrolite, 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.
OTHERPlacebo
Cannabis extract with less than 0.5% CBD/0.02%THC
Sponsors
UMC Utrecht
Stichting Epilepsie Instellingen Nederland
Epilepsiecentrum Kempenhaeghe
Erasmus Medical Center
Maastricht University Medical Center
ZonMw: The Netherlands Organisation for Health Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
The CBD-uN1que trial is designed as a series of 50 double-blind randomized placebo-controlled multiple crossover superiority trials. Each n-of-1 trial consists of 1-3 treatment "cycles", each with 2 treatment "periods" in which the participant is randomized to one of the two treatment arms (cannabidiol or placebo in a 1:1 ratio. Before starting the trial, each patient will start with a 4-week baseline period to assess main baseline outcome measures, and a 19-days dose-titration phase to assess an individualized optimal tolerated dosage (titrated to a dosage of 2.5-20mg/kg/day CBD), administered twice daily. Each period consists of a 7-day run-in period to reduce risk of adverse effects, 4-week treatment period (CBD or placebo), a 10-day taper period to reduce withdrawal symptoms and a 7-day washout period with no intervention to reduce carryover effects. If efficacy is shown in the n-of-1 trial , participants can choose to enter an open-label extension phase of 6 months.
Eligibility
Sex/Gender
ALL
Age
1 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* 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. * Informed consent/ of legal representative/ parents. * Presence of a consistently available patient caregiver for proxy-reports.
Exclusion criteria
* 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 * Glaucoma * Ongoing evaluation for epilepsy surgery * Implementation of vagal nerve stimulation within 3 months prior to screening and unwillingness to delay inclusion until stable settings of vagal nerve stimulation are reached * Starting a ketogenic diet within 3 months prior to screening and unwillingness to delay inclusion until a stable ketogenic diet is reached * Unstable medical condition, other than refractory epilepsy, that is of significant influence on participation in the trial; significance to be determined with the treating physician/pediatric neurologist * History of recreational or medicinal cannabis use, or cannabinoid-based medications, within three months prior to screening and the patient is unwilling to abstain for the duration of the study * Planned intervention under general anesthesia interfering with the baseline period; or any planned major surgery within the duration of the trial * Expected inability to undergo blood sampling due to anxiety or resistance * Use of clobazam dosage of \> 0,5 mg/kg/day in the last month
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Seizure frequency | Daily, from start of baseline after enrollment to the end of the last treatment cycle (each cycle - consisting of two periods with run in, taper and washout phases - is 15 weeks). Adittionally, untill up to 6 months during open label extension phase. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Seizure free days | Registered daily using a seizure diary. Analysis endpoints specifically after completion of cycle 2 and (if applicable) cycle 3 and after 6 months of open label extension (if applicable), or else at withdrawal. Each cycle (two periods) lasts 15 weeks. | 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 | Seizures will be registered daily using a seizure diary. Analysis endpoints after cycle 2 and (if applicable) cycle 3 and after 6 months of open label extension (if applicable), or else at withdrawal. Each cycle (two periods) lasts 15 weeks. | 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 | - Once durine the 4-week baseline - Once every period (up to maximum of 6 periods), one period lasts 7 weeks. - At the and of the open label extension phase after 6 months (if applicable). | 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 | Once durine the 4-week baseline - Once every period (up to maximum of 6 periods), one period lasts 7 weeks. - At the and of the open label extension phase after 6 months (if applicable). | 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 |
| Patient-centered outcome measures: GCI scale | - Once durine the 4-week baseline. - Once every period (up to maximum of 6 periods), one period lasts 7 weeks. - At the and of the open label extension phase after 6 months (if applicable). | The Clinical Global Impressions (CGI) scale. The Clinical Global Impressions (CGI) scale is a well-established, brief assessment of the patient's global functioning prior to and after initiating a study medication, applicable to patients with central nervous system disorders. As such, it is universally regarded as a useful scale for measuring the efficacy of ASM for assessing the patient's general condition. Previous randomized clinical trials have shown improvement on the CGI scale after treatment with CBD, and we therefore expect it to be both a responsive tool as well as useful for comparison of results to previous research. CGI-Severity score range: 1-7 Higher score: Greater illness severity CGI-Improvement score range: 1-7 Higher score: Worse change (less improvement / greater worsening) |
| Patient-centered outcome measures: ABC | - Once durine the 4-week baseline. - Once every period (up to maximum of 2 periods), one period lasts 7 weeks. - At the and of the open label extension phase after 6 months (if applicable). | The Aberrant Behaviour Checklist (ABC). The Aberrant Behavior Checklist (ABC) will be used to measure the effect of CBD on behavioral challenges associated with epilepsy. It is a proxy-rated scale for assessing various domains of problematic behavior, and has been validated for the pediatric population, including children with a developmental delay. It has also previously been used as an outcome measure in studies with CBD and clobazam Score range: 0-174 (58 items scored 0-3) Higher score: More severe behavioral problems |
| Patient-centered outcome measures: VABS-III | - Once durine the 4-week baseline. - Once every period (up to maximum of 2 periods), one period lasts 7 weeks. - At the and of the open label extension phase after 6 months (if applicable). | The Vineland Adaptive Behavior Scale (VABS-III), We will include the Vineland Adaptive Behavior Scale (VABS-III) - Parent/Caregiver Form as a measurement of adaptive functioning. It has good psychometric properties in the pediatric population with development delay and has been extensively used for research concerning pediatric epilepsy, including the previous randomized clinical trials with CBD. Score range: Standard scores typically 20-160 (domain and composite scores; mean = 100, SD = 15) Higher score: Better adaptive functioning |
| Patient-centered outcome measures: SDSC | - Once durine the 4-week baseline. - Once every period (up to maximum of 6 periods), one period lasts 7 weeks. - At the and of the open label extension phase after 6 months (if applicable). | The Sleep Disturbance Scale for Children (SDSC).The Sleep Disturbance Scale for Children (SDSC) is a caregiver-completed rating tools validated for the pediatric population. It has been previously used in assessing the impact of epilepsy on sleep in children with epilepsy Score range: 26-130 Higher score: Greater sleep disturbance / worse sleep quality |
| Patient-centered outcome measures: GAS | - Once durine the 4-week baseline. - Once every period (up to maximum of 6 periods), one period lasts 7 weeks. - At the and of the open label extension phase after 6 months (if applicable). | Goal Attainment Scaling (GAS). Lastly, Goal Attainment Scaling (GAS) will be performed to enable the clinician and patient to measure effectiveness of CBD on personalized treatment goals. GAS has been developed to specify individual goals along with a standardized outcome scale, thereby enabling the calculation of personalized results in a standardized manner. It has been shown to be a reliable and responsive measurement instrument, particularly suitable for measuring treatment effect in small and heterogenous patient populations. Score range: Individual goal scores typically range from -2 to +2 per goal (often transformed into a standardized T-score with mean = 50, SD = 10, range approximately 0-100 in aggregated analyses) Higher score: Greater achievement of individualized treatment goals |
| Patient-centered outcome measures: SSQ | - Once durine the 4-week baseline. - Once every period (up to maximum of 6 periods), one period lasts 7 weeks. - At the and of the open label extension phase after 6 months (if applicable). | The Seizure Severity Questionnaire (SSQ).The Seizure Severity Questionnaire will be used to determine seizure severity including questions on pre- inter- and post-ictal symptoms Score range: 1-7 for each question Higher score: Greater seizure severity (more severe pre-ictal, ictal, and post-ictal symptom burden) |
Countries
Netherlands
Contacts
CONTACTMarit van de Wiel, MD
Outcome results
None listed