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| Name | Class |
|---|---|
| Stichting Epilepsie Instellingen Nederland | OTHER |
| Epilepsiecentrum Kempenhaeghe | INDUSTRY |
| Erasmus Medical Center | OTHER |
| Maastricht University Medical Center |
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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:
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:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Active treatment with CBD oil | Active Comparator | All participants will undergo one to three treatment cycles. In each cycle, each participant will receive both the active comparator as the placebo comparator. The investigational medicinal product (IMP): Bedrolite, which is a full spectrum extract of Cannabis sativa L. "Rensina", with a CBD:THC ratio of approximately 26:1. Cannabidiol will be titrated up to a dosage of 2.5-20mg/kg/day, which is in line with previous clinical trials. There is scarce evidence in literature on optimal dosing of this specific CBD:THC preparation, therefore, directly after the baseline period, a titration phase is used to determine the maximum tolerated dose. The maximum daily dose is set at 1000mg CBD per day. Therefore, for patients weighing over 50 kg, a calculation weight of 50 kg will be used. |
|
| Placebo | Placebo Comparator | Placebo is identical to the IMP apart from the active ingredients (less than 0.5% CBD/0.02%THC ), with identical packaging. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cannabidiol (CBD) oral solution | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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) |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Marit van de Wiel, MD | Contact | 088 755 5555 | m.vandewiel@umcutrecht.nl |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Medical Center Utrecht | Recruiting | Utrecht | Utrecht | 3584 CX | Netherlands |
De-anonymized results of individual n-of-1 trials will be shared if participants have provided consent for that.
Protocol will be published before last inclusion of last patient. Informed consent, analytical code and individual data will be shared within one year of last visit of last participant.
Access will be granted to researchers affiliated with recognized academic or clinical institutions who submit a methodologically sound research proposal. Proposals will be reviewed by the researches involved in our CBD consortium. Approved applicants will be granted access through a secure remote data access environment or controlled data repository.
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| OTHER |
| ZonMw: The Netherlands Organisation for Health Research and Development | OTHER |
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.
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| Placebo | Other | Cannabis extract with less than 0.5% CBD/0.02%THC |
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| Response rates | At the aggregated group level, key secondary outcome measures include:
| 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. |
| 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 | - 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). |
| 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 | 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). |
| Patient-centered outcome measures: GCI scale | 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) | - 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). |
| Patient-centered outcome measures: ABC | 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 | - 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). |
| Patient-centered outcome measures: VABS-III | 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 | - 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). |
| Patient-centered outcome measures: SDSC | 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 | - 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). |
| Patient-centered outcome measures: GAS | 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 | - 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). |
| Patient-centered outcome measures: SSQ | 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) | - 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). |
| - 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). |
| 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) | - 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). |
| 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) | - 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). |
| ID | Term |
|---|---|
| D000069279 | Drug Resistant Epilepsy |
| D004827 | Epilepsy |
| D035583 | Rare Diseases |
| ID | Term |
|---|---|
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D002185 | Cannabidiol |
| ID | Term |
|---|---|
| D002186 | Cannabinoids |
| D013729 | Terpenes |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
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