Evaluation of Safety, Pharmacokinetics, and Efficacy of Cannabidiol Oral Solution in Pediatric Patients with Tuberous Sclerosis Complex, Dravet Syndrome, or Lennox-Gastaut Syndrome

The primary objective of this study is to evaluate the **safety** and tolerability of adjunctive GWP42003-P, assessed over a 52-week treatment period. This is clinically relevant as it aims to ensure that the treatment is safe for use in young patients with Dravet Syndrome, Tuberous Sclerosis Complex, and Lennox-Gastaut Syndrome, who experience inadequately controlled seizures. Additionally, the study seeks to investigate the exposure of GWP42003-P and its major metabolites following multiple doses, and to evaluate the efficacy of GWP42003-P in reducing the frequency of indication-specific countable seizures.

Secondary objectives include: - Evaluating the efficacy of GWP42003-P in reducing the frequency of total countable seizures. - Assessing the retention of participants receiving GWP42003-P. - Exploratory: Evaluating the efficacy of GWP42003-P based on video electroencephalogram (VEEG). - Exploratory: Evaluating the effects of GWP42003-P on quality of life (QoL). - Exploratory: Evaluating the time of dosing relative to food intake time.

The clinical trial involves a total of **17 participants** diagnosed with **Dravet Syndrome**, **Tuberous Sclerosis Complex**, or **Lennox-Gastaut Syndrome**. The study population includes both male and female subjects, with an age range from 1 month to less than 2 years. Participants were selected based on their diagnosis, which must align with established guidelines, and they must have uncontrolled seizures despite current treatment with one or more anti-seizure medications (ASMs). The trial does not focus on a vulnerable population. Participants' general health status is characterized by the presence of inadequately controlled seizures, and they are required to maintain stable ASM dosages prior to and during the trial. Lifestyle considerations such as diet and physical activity are not specified as part of the selection criteria. The trial aims to evaluate the safety, tolerability, and efficacy of the investigational product, GWP42003-P, over a 52-week treatment period.

The clinical trial is designed as an **open-label**, single-arm study to evaluate the safety, pharmacokinetics, and efficacy of an adjunctive **cannabidiol** oral solution in participants with **Dravet Syndrome**, **Tuberous Sclerosis Complex**, or **Lennox-Gastaut Syndrome** who experience inadequately controlled seizures. The trial will span a total duration of 52 weeks, with the primary objective being to assess the safety and tolerability of the treatment, as well as to investigate the exposure of the drug and its major metabolites following multiple doses. The study will also evaluate the efficacy of the treatment in reducing the frequency of indication-specific countable seizures.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, including age and diagnosis according to established guidelines. Following the screening, participants will enter a baseline period where caregivers are required to complete electronic patient-reported outcome diaries. The treatment phase will involve regular follow-up visits every four weeks to monitor adverse events, vital signs, and seizure frequency, as well as to conduct comprehensive neurodevelopmental assessments. The end-of-study visit will occur at the conclusion of the 52-week treatment period, where final assessments will be conducted to evaluate the overall impact of the treatment.

Participant involvement is expected to last for the entire 52-week duration unless conditions arise that necessitate early termination, such as significant adverse events or non-compliance with study requirements. The study will include primary endpoints such as the frequency, type, and severity of adverse events, changes in vital signs, and the percentage change from baseline in seizure frequency. Secondary endpoints will focus on the number and percentage of participants considered treatment responders, as well as exploratory endpoints related to seizure frequency and caregiver-reported outcomes. The trial is not categorized as low intervention and is classified as a Phase 3 trial, emphasizing its focus on evaluating the therapeutic efficacy and safety of the investigational product.

The clinical trial involves the administration of **Epidyolex 100 mg/ml oral solution**, an experimental medication containing the active substance **cannabidiol**. This pharmaceutical form is an oral solution, designed for oral administration. The dosage is determined based on the participant's weight, with a maximum daily dose of 25 mg/kg and a total maximum dose of 8775 mg/kg over the course of the study. The treatment period is set for a maximum of 52 weeks. The medication is provided by GW Pharma (International) B.V., and it is classified under the ATC code N03AX24. The formulation is not specifically pediatric, although it is used in a pediatric population in this study. The packaging and labeling have been modified for use in this clinical trial.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the administration of the experimental medication, Epidyolex. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The study aims to evaluate the safety, pharmacokinetics, and efficacy of the adjunctive cannabidiol oral solution in reducing the frequency of seizures in participants with Tuberous Sclerosis Complex, Dravet Syndrome, or Lennox-Gastaut Syndrome, who experience inadequately controlled seizures.

The efficacy of the adjunctive **cannabidiol** oral solution (GWP42003-P) will be assessed in participants with Tuberous Sclerosis Complex, Dravet Syndrome, or Lennox-Gastaut Syndrome who experience inadequately controlled seizures. The primary efficacy endpoint is the percentage change from baseline in indication-specific countable seizures, as recorded by caregivers on seizure diaries. This will be measured at Week 12, every 4 weeks thereafter, and during the 4-week period prior to the end of treatment. Secondary efficacy endpoints include the total countable seizures (average per 28 days) and the number and percentage of participants considered treatment responders, defined as those with a ≥50% reduction from baseline in total countable seizures. Seizure freedom, defined as a 100% reduction from baseline, will also be evaluated. Exploratory endpoints involve the percent change in seizure frequency from baseline to the end of treatment as captured by prolonged multichannel VEEG recordings, and changes in VEEG seizure burden. Additionally, the correlation between multichannel VEEG-recorded seizures and seizure frequency recorded by investigators and caregivers will be explored. The percentage of participants still taking GWP42003-P at Week 12 and every 4 weeks thereafter will also be assessed. The efficacy assessments will be conducted using validated seizure diaries and VEEG recordings, ensuring comprehensive evaluation of the treatment's impact on seizure frequency and burden.