Evaluation of Perampanel Efficacy and Safety in Behavioral Symptom Management for White-Sutton Syndrome: A Multicentric, Self-Controlled Case Series Trial

The primary objective of this clinical trial is to assess the **efficacy** of Perampanel in improving behavioral symptoms in patients with White-Sutton syndrome (POGZ-Related Disorder). This will be measured by the improvement in scores on the Child Behavior Checklist (CBCL) and the Vineland Adaptive Behavior Scales (VABS) between baseline and 6 months post-treatment. Clinically, this is significant as it aims to demonstrate the potential of Perampanel to enhance behavioral outcomes and adaptive functioning in affected individuals, which could lead to improved quality of life.

Secondary objectives include:

• Evaluating the improvement in CBCL and VABS scores at 12 or 18 months post-treatment.
• Assessing improvements in neuropsychological test scores and questionnaires related to cognitive, motor, speech, language, emotional, social interaction, attention, executive function, aggressive behavior, quality of life, and psychopathology.
• Analyzing the frequency and severity of adverse events, with a focus on safety, using CTCAE v5.0 criteria.
• Investigating the association between genotype and therapeutic outcomes.
• Studying the epigenetic signature before and during Perampanel treatment.
• Collecting and analyzing molecular and clinical data of POGZ-affected subjects to expand knowledge about this syndromic intellectual disability and further explore genotype-phenotype associations.

The clinical trial involves participants diagnosed with **White-Sutton syndrome** (POGZ-Related Disorder), characterized by a molecular identification of a mutation in POGZ and a clinical diagnosis consistent with a neurodevelopmental disorder. The study population includes both pediatric and young adult individuals, with an age range from 4 to 25 years. The trial is open to both male and female participants. Females of childbearing potential are required to use medically acceptable contraception throughout the study and for 30 days after discontinuation of the study drug. The trial population was selected based on the presence of either de novo or familial POGZ mutation. Participants are required to provide written informed consent, either personally if capable or through a parent or legal representative if minors or otherwise unable. The sponsor has not provided information regarding the total number of participants. The trial includes a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are mentioned.

The clinical trial is designed to evaluate the efficacy and safety of **perampanel** in improving behavioral symptoms and increasing the quality of life in patients with White-Sutton syndrome, a POGZ-related disorder. This is a multicentric, drug-repositioning, self-controlled case series (SCCS) trial. The study is structured as a Phase IV trial, with a randomized, double-blind, and controlled design. The trial is expected to last until December 31, 2025, with recruitment having commenced on June 8, 2023. Participants will be involved for a maximum of 18 months, depending on their response to the treatment.

The trial involves several study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, gender, and a confirmed diagnosis of White-Sutton syndrome. Participants must be between 4 and 25 years old, and both male and female subjects are eligible, with specific requirements for females of childbearing potential. Following the screening, participants will undergo baseline assessments, including the Child Behavior Checklist (CBCL) and Vineland Adaptive Behavior Scales (VABS), to establish initial scores.

Subsequent follow-up visits will occur at 6, 12, and 18 months. The primary endpoint is the evaluation of differences in total CBCL scores from baseline to month 6. Secondary endpoints include differences in scores of all neuropsychological scales at months 12 or 18. Participants showing improvement in CBCL or VABS scores will continue with the same dosage of perampanel until month 12. Those without positive effects will have their dosage doubled until month 18. The end-of-study visit will involve a comprehensive assessment to evaluate the overall impact of the treatment.

Participants may be terminated early from the study if they experience adverse effects, fail to comply with study procedures, or withdraw consent. The trial aims to provide valuable insights into the potential benefits of perampanel for individuals with White-Sutton syndrome, contributing to the understanding and management of this rare disorder.

The clinical trial involves the administration of **Perampanel**, an active substance used in the treatment of White-Sutton syndrome. The experimental medication is provided in the form of **Fycompa 4 mg film-coated tablets**. These tablets are designed for **oral use** and are manufactured by EISAI GMBH. The maximum daily dose of Fycompa 4 mg is 8 mg, with a total treatment period extending up to 18 months. The administration schedule involves a daily intake, with the dosage adjusted based on the participant's response to the treatment. Compliance with the dosing regimen is monitored throughout the study to ensure adherence and evaluate the efficacy of the treatment.

Additionally, the study utilizes **Fycompa 2 mg film-coated tablets**, also containing the active substance **Perampanel**. Similar to the 4 mg formulation, these tablets are intended for **oral use** and are produced by EISAI GMBH. The maximum daily dose for the 2 mg tablets is also 8 mg, with the same maximum treatment duration of 18 months. Participants are required to follow a daily dosing schedule, and their adherence is closely monitored to assess the impact of the treatment on behavioral symptoms and quality of life in patients with White-Sutton syndrome. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment.

Efficacy in this clinical trial will be assessed by evaluating the improvement in behavioral symptoms and quality of life in patients with White-Sutton syndrome, a **POGZ-related disorder**. The primary efficacy endpoint is the change in scores on the Child Behavior Checklist (CBCL) and the Vineland Adaptive Behavior Scales (VABS) from baseline to six months after treatment initiation. Improvement on the CBCL is defined as a shift from 'Clinical' to 'Borderline clinical' or from 'Borderline clinical' to 'Normal' in at least one of the subscales, which include 'Internalization', 'Exteriorization', 'Other problems', and 'Total'. For the VABS, improvement is defined as a shift from 'Low' to 'Moderately low' or from 'Moderately low' to 'Normal' in at least one of the subscales, which include 'Communication', 'Daily living skills', 'Socialization', 'Motor skills', and 'Total'.

The primary endpoint will be measured at baseline and at month 6 during the intake of Perampanel at the minimum dosage. Secondary endpoints include the evaluation of differences in scores of all neuropsychological scales administered at baseline and during treatment at month 12 or 18. Additional data collection will include medical history, clinical features, pharmacological history, physical examination, instrumental evaluation, and neuropsychological assessment. Subjects showing improvement will continue with the same dosage of Perampanel until month 12, while those without positive effects will have their dosage doubled until month 18.