Evaluation of Pitolisant Efficacy and Safety in Pediatric Autism Spectrum Disorders: A Randomized, Double-Blind, Placebo-Controlled Multicenter Study

The primary objective of this study is to evaluate the effect of **pitolisant** treatment on the core symptom of social communication and interaction deficit in children and adolescents with Autism Spectrum Disorders (ASD), as assessed by the Social Responsiveness Scale-2 (SRS-2) Total score. This is clinically relevant as it addresses a fundamental challenge in ASD, potentially improving social functioning and quality of life for affected individuals.

Secondary objectives include:

• Evaluating the effect of pitolisant on social communication and interaction deficits through SRS-2 sub-domains, social communication and daily living skills via Vineland Adaptive Behavior Scales III (VABS III), quality of sleep using the Child's Sleep Habits Questionnaire (CSHQ), hyperactivity and attention assessed by Conners 4 ADHD Index (Conners 4 AI), and improvement in Clinical Global Impression as measured by CGI-I.
• Investigating the pharmacokinetics of pitolisant and its metabolites.
• Assessing the safety and tolerability of a 3-month treatment with pitolisant, including monitoring adverse events, adverse events of special interest, suicidal risk via the Columbia-Suicide Severity Scale (C-SSRS), vital signs, 12-lead ECG, and routine safety laboratory tests.

The clinical trial involves a total of **12 participants** diagnosed with **autism spectrum disorders**. The study population comprises both male and female children and adolescents aged between 6 to 17 years. Participants are required to have an Intelligence Quotient (IQ) of 70 or above, as confirmed by the Wechsler Intelligence Scale, and a Social Responsiveness Scale Second Edition (SRS-2) total T-score of 66 or higher at screening and baseline. The trial population was selected based on their ability to provide informed assent and consent, with the support of their parent(s) or legal guardian(s). Participants must have a care provider who can ensure compliance with study requirements and maintain stable ongoing medications or interventions for ASD-related symptoms. The study does not include a vulnerable population, and participants' language, hearing, and vision must be compatible with the study assessments. The ability to swallow the investigational medicinal product is also a prerequisite for participation.

The clinical trial is designed as an exploratory, multicenter, **randomized**, double-blind, placebo-controlled study to evaluate the effect and safety of **pitolisant** in children and adolescents with **autism spectrum disorders**. The primary objective is to assess the impact of pitolisant on the social communication and interaction deficits, a core symptom of autism spectrum disorders, as measured by the Social Responsiveness Scale Second Edition (SRS-2) Total score. The trial is expected to commence recruitment on October 2, 2023, and conclude by July 30, 2025, with a maximum treatment period of 12 weeks for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and cognitive abilities. Following successful screening, participants will be randomly assigned to receive either pitolisant or a placebo. The study will include regular follow-up visits to monitor safety, efficacy, and adherence to the treatment regimen. The end-of-study visit will occur at the conclusion of the 12-week treatment period, where final assessments will be conducted to evaluate changes from baseline in various endpoints, including the SRS-2 sub-domain scores and the Vineland Adaptive Behavior Scale III (VABS III) scores.

Participant involvement is expected to last approximately 12 weeks, with conditions for early termination including the occurrence of serious adverse events, non-compliance with the study protocol, or withdrawal of consent. The trial will adhere to rigorous ethical standards, ensuring informed consent is obtained from participants and their guardians. The study aims to provide valuable insights into the potential benefits of pitolisant for improving social communication and interaction in children and adolescents with autism spectrum disorders.

The clinical trial involves the administration of **Wakix 18 mg film-coated tablets**, which contain the active substance **pitolisant**. These tablets are manufactured by BIOPROJET PHARMA and are classified under the ATC code N07XX11. The pharmaceutical form is a film-coated tablet, intended for **oral use**. The maximum daily dose is 40 mg, with a total maximum dose of 2765 mg over a treatment period of up to 12 weeks. The tablets are administered once daily, and participant compliance is monitored through regular assessments and pill counts.

Additionally, the trial includes the use of **Wakix 4.5 mg film-coated tablets**, also containing **pitolisant** as the active ingredient. These tablets share the same manufacturer, BIOPROJET PHARMA, and are similarly classified under the ATC code N07XX11. The pharmaceutical form is identical, being a film-coated tablet for **oral use**. The dosing schedule and compliance monitoring are consistent with the 18 mg formulation, with a maximum daily dose of 40 mg and a total maximum dose of 2765 mg over a 12-week period.

The study also employs **matching pitolisant film-coated tablets** as a placebo control. These tablets are designed to be indistinguishable from the active treatment in appearance and administration route, ensuring the double-blind nature of the trial. The placebo is administered in the same manner as the active treatments, with compliance monitored through similar methods.

The efficacy of pitolisant in children and adolescents with Autism Spectrum Disorders (ASD) will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline in the Social Responsiveness Scale Second Edition (SRS-2) total score at the end of the treatment period. This scale is a validated tool used to measure social communication and interaction deficits, which are core symptoms of ASD.

Secondary endpoints include changes from baseline to the end of the treatment period in various sub-domain scores of the SRS-2, such as Social Awareness, Social Cognition, Social Communication, Social Motivation, and Restricted Interests and Repetitive Behavior. Additionally, the Vineland Adaptive Behavior Scale III (VABS III) will be used to assess changes in total score and sub-domains like Communication, Daily Living Skills, and Socialization. Other secondary measures include the Child’s Sleep Habits Questionnaire (CSHQ) total score, Conners 4 ADHD Index (Conners 4 AI) total score, and the Clinical Global Impression – Improvement (CGI-I) score at week 12 of treatment.

Pharmacokinetic assessments will include the trough serum level of **pitolisant** prior to the last investigational medicinal product (IMP) intake after 12 weeks of treatment. Safety and tolerability will be monitored through the incidence of treatment discontinuation due to adverse events (AEs) and adverse drug reactions (ADRs), serious AEs, and AEs of special interest (AESI). The Columbia-Suicide Severity Scale (C-SSRS) will be used to measure the incidence of emergence or worsening of symptoms. Vital signs, 12-lead ECG parameters, and laboratory parameters will be evaluated for clinically significant abnormalities.