Long-Term Safety Assessment of Fenfluramine Hydrochloride as Adjunctive Therapy in Patients with Dravet or Lennox-Gastaut Syndrome

The primary objective of this study is to evaluate the **long-term safety** and tolerability of ZX008 (fenfluramine hydrochloride) as an adjunctive therapy for seizures in patients with rare seizure disorders, specifically **Dravet syndrome** and **Lennox-Gastaut syndrome**. This is clinically relevant as these conditions are severe forms of epileptic encephalopathies, and long-term safety data is crucial for understanding the risk-benefit profile of fenfluramine hydrochloride in this patient population.

Secondary objectives include assessing the effect of ZX008 on various effectiveness measures:

• Investigator assessment of convulsive seizure response, categorized by percentage improvement (<25%, ≥25%, ≥50%, ≥75%, or 100% improvement, indicating seizure-free status).
• Clinical Global Impression – Improvement (CGI-I) rating, both global and symptomatic, as assessed by the investigator.
• CGI-I rating, global and symptomatic, as assessed by the parent or caregiver.

The clinical trial involves a total of **221 participants** diagnosed with **Dravet syndrome** or **Lennox-Gastaut syndrome**, both of which are rare seizure disorders. The study population includes both male and female subjects, with an age range that encompasses children and adolescents. Participants were selected based on their satisfactory completion of a core study and previous successful participation in other Zogenix-sponsored clinical trials with ZX008. The trial population is characterized by individuals who have a rare seizure disorder, such as epileptic encephalopathy. Caregivers of the participants are required to be compliant with study procedures, visit schedules, and study drug accountability. The trial includes a vulnerable population, indicating that special considerations are in place to ensure the safety and well-being of the participants throughout the study.

The clinical trial is designed as an **open-label extension** study to evaluate the long-term safety and tolerability of **fenfluramine hydrochloride** oral solution as an adjunctive therapy for seizures in patients with rare seizure disorders, specifically **Dravet syndrome** and **Lennox-Gastaut syndrome**. The trial is not randomized or blinded, allowing all participants to receive the investigational product. The study is expected to span a duration of approximately 36 months, with the estimated end date set for June 30, 2025.

Participants eligible for inclusion are those who have satisfactorily completed a core study and have a rare seizure disorder such as epileptic encephalopathy. The study involves a series of visits, beginning with a screening visit to confirm eligibility based on the inclusion criteria. Subsequent follow-up visits are scheduled to monitor safety endpoints, which include adverse events, laboratory safety assessments, vital signs, physical and neurological examinations, electrocardiograms, and other relevant tests. The end-of-study visit will conclude the participant's involvement, ensuring all safety and efficacy data are collected.

The expected length of participant involvement is up to 36 months, contingent upon continued compliance with study procedures and visit schedules. Conditions that may lead to early termination from the study include non-compliance with study requirements, withdrawal of consent, or any safety concerns that arise during the trial. The primary endpoints focus on safety assessments, while secondary endpoints evaluate the effectiveness of the treatment in reducing seizure burden and improving clinical global impressions as assessed by both caregivers and investigators.

The clinical trial involves the administration of **Fintepla 2.2 mg/ml oral solution**, which contains the active substance **fenfluramine hydrochloride**. This experimental medication is provided in the form of an oral solution and is intended for the treatment of seizures associated with rare seizure disorders such as Dravet Syndrome and Lennox-Gastaut Syndrome. The medication is administered orally, with a maximum daily dose of 0.8 mg/kg and a maximum total dose of 30 mg. The treatment period can extend up to 36 months. The pharmaceutical product is manufactured by UCB PHARMA S.A. and is classified under the ATC code N03AX26. The formulation is not specifically designed for pediatric use, and the active substance is of chemical origin.

In this open-label extension trial, the primary objective is to assess the long-term safety and tolerability of ZX008, the sponsor product code for Fintepla. The trial does not include any non-experimental treatments such as a placebo or comparator treatment. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen. The trial is conducted under the authorization of the European Union, with the marketing authorization number EU/1/20/1491/002 and orphan drug designation number DS: EU/3/13/1219.

Efficacy in this clinical trial will be assessed using several endpoints. The primary effectiveness endpoints include the Clinical Global Impression-Improvement (CGI-I) scale, which will be evaluated both globally and symptomatically by the parent or caregiver, as well as by the investigator or their designee. Additionally, the percent improvement in seizure burden will be assessed by the investigator or their designee. These measures will provide a comprehensive evaluation of the treatment's impact on seizure frequency and overall patient condition.