Cannabidiol as add-on Therapy for Children With Refractory Epilepsy (CBD-uN1que), a High-quality Individualized Approach: a Series of N-of-1 Trials

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.

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.

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

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

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

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)

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

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

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

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

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)

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)

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)

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)