Efficacy and Safety of Fenfluramine Hydrochloride in Pediatric and Adult Patients with CDKL5 Deficiency Disorder: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to demonstrate that the **efficacy** of fenfluramine (ZX008) at a dosage of 0.8 mg/kg/day is superior to placebo when used as an adjunctive therapy in pediatric and adult subjects with CDKL5 Deficiency Disorder (CDD). This is clinically relevant as it aims to establish fenfluramine as a more effective treatment option for managing symptoms associated with CDD, potentially improving patient outcomes.

Secondary objectives include characterizing the **safety** and tolerability of fenfluramine in both pediatric and adult subjects with CDD during Part 1 of the study. Additionally, the study seeks to assess the long-term effectiveness of fenfluramine as an adjunctive therapy in these populations during Part 2. These objectives are crucial for understanding the overall risk-benefit profile of fenfluramine in the treatment of CDD, ensuring that it is not only effective but also safe for long-term use.

The clinical trial involves a total of **38 participants** diagnosed with **CDKL5 Deficiency Disorder** (CDD), a condition characterized by epilepsy onset in the first year of life, along with motor and developmental delays. The study population includes both male and female subjects, aged 1 to 35 years. However, subjects aged 1 to less than 2 years are only permitted to enroll after a safety review. Participants have failed to achieve seizure control despite the use of two or more antiseizure treatments and are currently receiving at least one concomitant antiseizure treatment, such as antiseizure medication, vagus nerve stimulation, responsive neurostimulation, or a ketogenic diet. All treatments must be stable prior to screening and are expected to remain stable throughout the study. The trial population was selected based on the presence of a confirmed pathogenic mutation in the CDKL5 gene and a clinical diagnosis of CDD. Participants are required to have at least four countable motor seizures per week, as reported by a parent or caregiver. The study includes a vulnerable population, and informed consent is obtained from the subjects or their legal guardians. The trial aims to evaluate the efficacy and long-term safety of fenfluramine as an adjunctive therapy for CDD.

The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled, fixed-dose, multicenter study designed to evaluate the efficacy and safety of **fenfluramine hydrochloride** (ZX008) in subjects with **CDKL5 deficiency disorder** (CDD). The trial is structured in two main parts: an initial double-blind phase followed by an open-label extension. The primary objective is to demonstrate the superiority of fenfluramine at a dose of 0.8 mg/kg/day over placebo as an adjunctive therapy for both pediatric and adult subjects with CDD. The trial also aims to characterize the long-term safety and tolerability of fenfluramine in these populations.

The trial is expected to last until September 2026, with recruitment having commenced in July 2023. Participants will be involved in the study for a maximum treatment period of 74 weeks. The study includes several key visits: an initial screening visit to confirm eligibility, multiple follow-up visits to monitor efficacy and safety, and an end-of-study visit to assess final outcomes. The inclusion criteria require subjects to have a confirmed pathogenic mutation in the CDKL5 gene, a clinical diagnosis of CDD with epilepsy onset in the first year of life, and motor and developmental delays. Participants must be aged between 1 and 35 years and have failed to achieve seizure control despite previous or current use of two or more antiseizure treatments.

Study visits are sequenced to ensure comprehensive monitoring and data collection. The screening visit will confirm eligibility based on genetic and clinical criteria. Follow-up visits will occur at regular intervals to assess the primary endpoint, which is the percentage change from baseline in countable motor seizure frequency during the titration and maintenance periods. Secondary endpoints include achieving a significant reduction in seizure frequency and improvements in clinical global impression ratings. The end-of-study visit will evaluate long-term safety outcomes, including treatment-emergent adverse events and changes in laboratory parameters.

Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with study requirements, or if the study is terminated early for any reason. The trial is conducted under strict ethical guidelines, with informed consent obtained from all participants or their legal guardians. The study's design ensures that data collected will provide robust evidence on the efficacy and safety of fenfluramine as a treatment for CDD, contributing valuable insights into the management of this rare disorder.

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 administered orally. The dosage is set at a maximum of 0.8 mg/kg per day, with the treatment period extending up to 74 days. The primary objective of this treatment is to evaluate its efficacy and safety as an adjunctive therapy for seizures associated with Dravet and Lennox Gastaut syndrome. The medication is produced by UCB Pharma S.A. and is classified under the ATC code N03AX26.

In addition to the experimental medication, a **placebo** is used in the study. The placebo is designed to match the fenfluramine hydrochloride oral solution in appearance but does not contain any active substance. It serves as a comparator to assess the efficacy of the experimental treatment. The placebo is administered in the same manner as the active medication, ensuring that the study remains double-blind.

Another formulation of **fenfluramine hydrochloride** is also utilized in the trial, provided by Zogenix International Limited. This formulation is similarly presented as an oral solution and administered orally. The dosing regimen mirrors that of the Fintepla solution, with a maximum daily dose of 0.8 mg/kg and a treatment duration of up to 74 days. This formulation is also intended for the treatment of seizures associated with Dravet and Lennox Gastaut syndrome, and it is included in the study to further evaluate the long-term safety and tolerability of fenfluramine hydrochloride.

The efficacy of **fenfluramine hydrochloride** (ZX008) in the treatment of CDKL5 Deficiency Disorder (CDD) will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint is the percentage change from baseline in countable motor seizure frequency (CMSF) during the Titration and Maintenance Periods (T+M) of Part 1 of the trial. Secondary endpoints include the achievement of a ≥ 50% reduction from baseline in CMSF during T+M, the achievement of a Clinical Global Impression-Improvement (CGI-I) rating of much or very much improved as assessed by both the Investigator and the parent/caregiver at the end of T+M, and the percentage change from baseline in monthly generalized tonic-clonic (GTC) seizure frequency during T+M.

Additional secondary endpoints involve the achievement of categorized percentage changes in seizures from baseline in CMSF during T+M, the achievement of "near seizure freedom" (0 or 1 seizures) during T+M, and changes from baseline in the monthly frequency of CMS-free days during T+M. The trial will also monitor treatment-emergent adverse events (TEAEs) and changes from baseline in laboratory parameters, vital signs, body weight, and Tanner Staging. These efficacy parameters will be measured and collected at specified timepoints throughout the trial, using validated scales and assessments conducted by both investigators and caregivers.