Efficacy of Add-On Cannabidiol and Dronabinol in Pediatric Refractory Epilepsy: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to evaluate the **efficacy** of add-on cannabidiol (CBD) compared to placebo in individuals with **refractory epilepsy**. This is clinically relevant as refractory epilepsy is a condition where seizures are not controlled by standard antiepileptic drugs, and finding effective treatments is crucial for improving patient outcomes.

Secondary objectives include:

• Assessing the effect of add-on CBD on the patient's and caregivers' quality of life and other patient-centered outcomes (PCOMs).
• Evaluating personalized biomarkers to improve the selection of patients who may benefit from and tolerate add-on CBD.
• Determining the cost-effectiveness of individualized CBD use compared to usual care in individuals with refractory epilepsy.

The clinical trial focuses on evaluating the efficacy of add-on **CBD** compared to placebo in individuals with **refractory epilepsy**. The study population includes both male and female participants, ranging in age from 1 to 18 years old. Participants must have a confirmed diagnosis of refractory epilepsy according to ILAE criteria and experience at least four countable seizures during the 4-week baseline period while on at least one anti-seizure medication (ASM). All medications or interventions for epilepsy must have been stable for one month prior to screening, and participants must be willing to maintain their current ASM regimen throughout the trial. The trial requires informed consent or assent from legal representatives or parents, and the presence of a consistently available patient caregiver for proxy-reports. The sponsor has not provided information regarding the total number of participants. The trial includes a vulnerable population, emphasizing the need for careful ethical considerations. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **efficacy** of add-on cannabidiol (CBD) compared to placebo in individuals with **refractory epilepsy**. This study employs a randomized, double-blind, controlled trial design to ensure the reliability and validity of the results. The trial is expected to commence recruitment on June 1, 2024, and conclude by June 1, 2027. Participants will be randomly assigned to receive either the active treatment, TA-CBD 10, or a placebo cannabis oil, both administered orally in liquid form. The maximum daily dose is 10 ml, with a total treatment period of up to 12 weeks.

The study will include several key visits: an initial screening visit, regular follow-up visits, and an end-of-study visit. During the screening visit, eligibility will be confirmed based on criteria such as age (1 to 18 years), a confirmed diagnosis of refractory epilepsy, and a stable antiepileptic medication regimen. Informed consent from legal representatives and the presence of a caregiver for proxy-reports are also required. Follow-up visits will monitor seizure frequency, adverse events, and other clinical parameters. The end-of-study visit will assess the primary endpoint, which is the change in daily seizure frequency from baseline during placebo versus active treatment periods.

Participant involvement is expected to last for the duration of the treatment period, approximately 12 weeks, with additional time for follow-up assessments. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with the study protocol, or withdrawal of consent. Secondary endpoints will evaluate changes in quality of life, global assessment of epilepsy severity, and other clinical and behavioral measures. The trial will also include pharmacogenetic assessments and measurements of neuronal excitability to provide comprehensive insights into the treatment's impact.

The clinical trial involves the administration of **TA-CBD 10**, an experimental medication formulated as an **oral liquid**. This investigational product contains the active substances **dronabinol** and **cannabidiol**, both of which are chemically derived. The medication is administered orally with a maximum daily dose of 10 ml, and the total dose over the treatment period should not exceed 840 ml. The treatment duration is set for a maximum of 12 weeks. The product is developed by Universitair Medisch Centrum Utrecht and is intended to evaluate its efficacy as an add-on therapy in individuals with refractory epilepsy.

In addition to the experimental medication, a **placebo** is utilized in the study. The placebo is a cannabis oil composed of cannabis granulated flos after ethanol extraction of cannabinoids, combined with arachidis oleum raffinatum. It is also administered orally, mirroring the dosage and administration schedule of the experimental treatment, with a maximum daily dose of 10 ml and a total dose not exceeding 840 ml over a 12-week period. The use of a placebo allows for a controlled comparison to assess the true efficacy of the TA-CBD 10 treatment.

Efficacy in the clinical trial will be assessed by evaluating the **change from baseline in daily seizure frequency** during placebo periods compared to the change from baseline in daily seizure frequency during active treatment periods. This primary endpoint will provide a direct measure of the treatment's impact on seizure reduction in individuals with refractory epilepsy. Secondary endpoints will include changes in scores from baseline during placebo versus CBD treatment using several validated scales: Quality of Life in Childhood Epilepsy (QoLCE-55), Global Assessment of Severity of Epilepsy (GASE), Clinical Global Impression of Change (CGI-C), Aberrant Behavior Checklist (ABC), Vineland Adaptive Behavior Score III (VABS-III), Sleep Disturbances Scale for Children (SDSC), and Goal attainment scaling (GAS). Additionally, the number of serious adverse events, clinical characteristics, and measurements of neuronal excitability will be assessed. Neuronal excitability will be measured using EEG and TMS-EMG, focusing on epileptic discharges, background activity, resting motor threshold, and cortical silent period. Pharmacogenetic assessments of CYP-enzymes such as CYP2C19, CYP2C9, and CYP3A4 will also be conducted. Changes in productivity loss, healthcare resources used, and health-related quality of life will be measured using the iMTA Productivity Cost Questionnaire, iMTA Treatment Inventory of Costs in Patients with psychiatric disorders for Children, and EuroQol Five-Dimensional Questionnaire, Youth version, respectively. These assessments will be conducted at specified intervals throughout the trial to ensure comprehensive data collection and analysis.