Evaluation of Radiprodil's Safety, Tolerability, and Pharmacokinetics in Tuberous Sclerosis Complex and Focal Cortical Dysplasia Type II Patients

The primary objective of this study is to determine the **safety** and **tolerability** of multiple individually titrated doses of radiprodil in patients with Tuberous Sclerosis Complex (TSC) and Focal Cortical Dysplasia (FCD) Type II. Additionally, the study aims to assess the pharmacokinetics (PK) and plasma exposure of radiprodil. These objectives are clinically relevant as they provide critical information on the safe administration and systemic behavior of radiprodil, which is essential for its potential therapeutic use in these patient populations.

Secondary objectives include:

• Evaluating initial signs of efficacy on the frequency and severity of epileptic seizures in participants experiencing seizures.
• Assessing initial signs of efficacy of radiprodil on additional central nervous system (CNS) features, including behavior and quality of life.

The clinical trial involves a total of **10 participants** diagnosed with **Tuberous Sclerosis Complex (TSC)** or **Focal Cortical Dysplasia (FCD) Type II**. The study population includes both male and female subjects, with an age range from 6 months to 18 years. Participants were selected based on their failure to respond to at least two anti-seizure medications at appropriate dosages and durations. The trial does not involve a vulnerable population. All medical interventions for epilepsy or behavior, including the ketogenic diet and any neurostimulation devices, must be stable for 28 days prior to screening, with no more than six days per month use of rescue medication. Participants are required to maintain a stable regimen throughout the treatment period. The study does not specify any particular lifestyle considerations beyond the stability of medical interventions. Key inclusion criteria include having a diagnosis of FCD Type II confirmed by MRI or a diagnosis of TSC by clinical or genetic criteria, and experiencing a minimum of eight countable motor seizures during a four-week baseline period. Participants or their caregivers must be willing and able to complete daily entries in an eDiary.

The clinical trial is designed as a **multicenter, open-label study** to evaluate the safety, tolerability, pharmacokinetics, and effects of **Radiprodil** on seizures and behavioral symptoms in patients diagnosed with **Tuberous Sclerosis Complex (TSC)** or **Focal Cortical Dysplasia (FCD) Type II**. The trial will involve multiple individually titrated doses of Radiprodil, administered as an **oral suspension**. The study is expected to commence recruitment on December 15, 2023, and conclude by July 17, 2026. Participants will be involved in the study for a duration that includes a baseline period, treatment phases, and follow-up visits.

The trial will begin with a screening visit to confirm eligibility based on specific inclusion criteria, such as age range (≥ 6 months to 18 years), previous treatment history with anti-seizure medications, and stability of medical interventions for epilepsy. Participants must have a documented diagnosis of TSC or FCD Type II and meet seizure frequency requirements. Following the screening, eligible participants will enter the baseline period, during which seizure frequency will be monitored. The treatment phase will consist of Part A and Part B, with regular assessments to monitor adverse events, changes in vital signs, and other clinical parameters.

Study visits will be scheduled at predefined intervals to assess primary endpoints, including the frequency, type, severity, and duration of adverse events, as well as changes in vital signs and laboratory parameters. Secondary endpoints will evaluate changes in seizure frequency, seizure-free days, and behavioral features. Participants will be required to maintain a stable regimen of medical interventions throughout the treatment period. The end-of-study visit will include a comprehensive evaluation of the participant's response to the treatment and any long-term effects.

Participant involvement is expected to last until the end of the treatment period, with conditions for early termination including significant adverse events or non-compliance with study protocols. Participants or their caregivers must provide informed consent and be willing to complete daily entries in an electronic diary. The study aims to provide valuable insights into the safety and efficacy of Radiprodil in managing seizures and behavioral symptoms associated with TSC and FCD Type II.

The clinical trial involves the administration of **Radiprodil**, an experimental medication formulated as an **oral suspension**. Radiprodil is chemically synthesized and is provided by GRIN Therapeutics, Inc. The pharmaceutical form is specifically designed for **oral use**, and the formulation is suitable for pediatric patients. The study aims to evaluate the safety, tolerability, pharmacokinetics, and effects on seizures and behavioral symptoms in patients with Tuberous Sclerosis Complex (TSC) or Focal Cortical Dysplasia (FCD) Type II. The dosage of Radiprodil is individually titrated for each participant, although specific dosing schedules and maximum daily doses are not detailed in the provided data. The administration frequency is determined based on individual patient needs and study protocols.

In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are mentioned. The focus remains solely on the administration of Radiprodil. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol. The trial does not specify any additional devices or adjunctive therapies used in conjunction with Radiprodil. The study is open-label, meaning both the researchers and participants are aware of the treatment being administered. The trial's primary objective is to assess the safety and pharmacokinetic profile of Radiprodil in the specified patient population.

Efficacy in the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints include the evaluation of adverse events (AEs), serious adverse events (SAEs), and adverse drug reactions (ADRs) in terms of frequency, type, severity, and duration throughout the treatment phases (Part A and Part B). Additionally, changes in vital signs, physical examination findings, 12-lead electrocardiogram (ECG) results, clinically significant laboratory parameter changes, and the occurrence of suicidal ideation or behavior will be monitored. Plasma concentrations of **radiprodil** will be measured at predefined timepoints to assess pharmacokinetics.

Secondary endpoints focus on changes in seizure frequency and behavioral features. These include the change from baseline to the end of the Maintenance Period (Day 84) in seizure frequency as recorded in a daily seizure electronic diary (eDiary), and the percent change in video electroencephalogram (V-EEG) seizure burden, which encompasses seizure type, severity, and frequency. The number of seizure-free days and the longest period without seizures from baseline to the end of treatment will also be recorded. Behavioral changes will be measured using the Aberrant Behavior Checklist-Community (ABC-2C), Pediatric Quality of Life Inventory (PedsQL), Caregiver Burden Inventory (CBI), and global impression scales such as the Caregiver Global Impression of Change (CaGI-C) and Clinical Global Impression of Change (CGI-C).