Open-label, Single-arm, Phase 3 Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Fenfluramine (Hydrochloride) in Infants 1 Year to less Than 2 Years of Age with Dravet Syndrome

The primary objective of this study is to evaluate the **safety** and tolerability of fenfluramine hydrochloride (HCl) at doses ranging from 0.2 to 0.8 mg/kg/day in infants aged 1 to less than 2 years with Dravet syndrome. This is clinically relevant as it aims to ensure that the treatment is safe for this vulnerable population, potentially providing a therapeutic option for managing seizures associated with Dravet syndrome.

Secondary objectives include:

• Assessing the effectiveness of fenfluramine HCl in the same age group with Dravet syndrome.
• Determining the pharmacokinetic profile of fenfluramine HCl and its metabolite, norfenfluramine, at steady state in these infants.

The clinical trial involves a total of **6 participants** diagnosed with **Dravet syndrome**, a severe form of epilepsy. The study population consists of infants aged 1 to less than 2 years, including both male and female subjects. Participants are required to have a documented or likely diagnosis of Dravet syndrome according to the International League Against Epilepsy criteria. All participants must be on at least one stable dose of concomitant antiseizure medication for a minimum of four weeks prior to the screening visit and are expected to maintain this stability throughout the study. The trial includes individuals with drug-resistant epilepsy, characterized by a history of unsuccessful trials with at least two antiepileptic drug schedules. Participants must have experienced at least one countable motor seizure during the baseline period. The study population is considered vulnerable due to the young age of the participants. The selection criteria ensure that participants have a body weight of at least 8 kg. The trial does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed as an open-label, single-arm, Phase 3 study to evaluate the **safety**, tolerability, and pharmacokinetics of **fenfluramine hydrochloride** in infants aged 1 to less than 2 years with **Dravet syndrome**. The trial will involve administering fenfluramine hydrochloride at doses ranging from 0.2 to 0.8 mg/kg/day. The study is expected to last until March 2027, with participant recruitment starting in October 2023. The trial will include a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, diagnosis, and current treatment regimen. Participants must have a documented diagnosis of Dravet syndrome and be on a stable dose of at least one antiseizure medication for at least four weeks prior to the screening visit.

Following the screening, participants will undergo a baseline period to assess seizure frequency, which may be extended if necessary. The treatment period will consist of regular follow-up visits to monitor primary endpoints, including changes in QT interval, body weight, and the occurrence of valvular heart disease. Secondary endpoints will assess changes in seizure frequency and the pharmacokinetic profile of fenfluramine. The end-of-study visit will evaluate the overall safety and efficacy of the treatment. Participants are expected to be involved in the study for up to 52 weeks, with conditions for early termination including significant adverse events or withdrawal of consent. The study aims to provide comprehensive data on the use of fenfluramine in this pediatric population, contributing to the understanding of its therapeutic potential in managing Dravet syndrome.

The clinical trial involves the administration of **Fintepla 2.2 mg/ml oral solution**, which contains the active substance **fenfluramine hydrochloride**. This medication is provided in the form of an oral solution and is administered orally. The dosage ranges from 0.2 to 0.8 mg/kg/day, with a maximum treatment period of 52 weeks. The primary objective of the trial is to evaluate the safety and tolerability of fenfluramine hydrochloride in infants aged 1 to less than 2 years with Dravet syndrome. The medication is classified under the ATC code N03AX26 and is authorized for the treatment of seizures associated with Dravet and Lennox Gastaut syndrome. Participant compliance with the dosing schedule is monitored throughout the study.

In addition to the experimental treatment, the trial includes auxiliary substances classified under the ATC codes N05BA, N03AE, and N05CD, which are benzodiazepine derivatives. These substances are not specified in detail due to the diversity of the ATC level selected. They are provided in various pharmaceutical forms, denoted as PHF00006MIG, PHF00221MIG, and PHF00245MIG, respectively. The route of administration for these auxiliary substances is unspecified, and they are not the primary focus of the trial. The maximum treatment period for these substances is limited to 1 week, and they are not intended for pediatric formulation. The role of these auxiliary substances in the trial is to support the primary investigation of fenfluramine hydrochloride.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints include the change from baseline in QT interval corrected by Fridericia (QTcF) at Visit 13, the occurrence of treatment-emergent results meeting the FDA case definition of drug-associated valvulopathy, the occurrence of clinically confirmed valvular heart disease (VHD), changes from baseline in body weight (Z-score) and recumbent length (Z-score) at each visit, and the occurrence of clinically significant abnormalities on neurological examinations at each visit.

Secondary endpoints focus on the percentage change from baseline in monthly countable motor seizure frequency (CMSF) during specified periods, including Weeks 9 through 20 and the entire treatment period. Additionally, the achievement of a Clinical Global Impression – Improvement (CGI-I) rating of "much improved" or "very much improved" as assessed by both the Principal Investigator and the parent/caregiver at Week 20 will be evaluated. Pharmacokinetic parameters such as the steady-state maximum plasma concentration (Cmax) and minimum plasma concentration (Cmin) of **fenfluramine** and norfenfluramine at Week 12, as well as the area under the plasma concentration time curve from time zero to 24 hours (AUC0-24) for steady-state fenfluramine and norfenfluramine at Week 12, will also be assessed.