Evaluation of Long-Term Safety and Tolerability of Pimavanserin Tartrate in Pediatric Patients with Irritability Associated with Autism Spectrum Disorder

The primary objective of this study is to evaluate the long-term **safety** and tolerability of **pimavanserin** after 52 weeks of treatment in children and adolescents with irritability associated with Autism Spectrum Disorder (ASD). This is clinically relevant as it aims to ensure that the therapeutic benefits of pimavanserin can be sustained over an extended period without compromising patient safety, which is crucial for managing chronic conditions such as ASD.

Secondary objectives include evaluating the continued response to long-term pimavanserin treatment in children and adolescents with ASD. This will help determine the efficacy of the treatment over time, providing insights into its potential as a sustained therapeutic option for managing symptoms associated with ASD.

The clinical trial involves a total of **37 participants** who are children and adolescents diagnosed with **autism spectrum disorder (ASD)**, specifically experiencing irritability associated with the condition. The study population includes both male and female subjects, aged between 2 and 17 years. Participants were selected based on their completion of a prior double-blind study and their ability to provide informed assent, with parental or legally authorized representative consent also required. The trial population is considered vulnerable, necessitating careful ethical considerations. Participants are required to be clinically stable, without imminent risk of self-harm or harm to others, and medically stable at the time of enrollment. Female participants of childbearing potential must adhere to specific contraceptive guidelines to ensure safety throughout the study. The trial aims to evaluate the long-term safety and tolerability of pimavanserin over a 52-week treatment period.

The clinical trial is designed to evaluate the long-term safety and tolerability of **pimavanserin** in children and adolescents with irritability associated with autism spectrum disorder (ASD). This is a Phase 4, open-label extension study, following the completion of an antecedent double-blind study. The trial will span a duration of 52 weeks, with the primary objective being the assessment of treatment-emergent adverse events (TEAEs) and other safety parameters such as vital signs, weight, body mass index (BMI), 12-lead electrocardiograms (ECGs), physical examination results, clinical laboratory tests, and specific rating scales.

The trial will involve the administration of **pimavanserin** in capsule form, with doses of 10 mg, 20 mg, or 34 mg, taken orally. Participants will be required to have completed the treatment period of the previous study and must provide informed consent, with assent from the child or adolescent if deemed able by the investigator. The study will include several visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to conclude participation. The expected length of participant involvement is 52 weeks, with conditions for early termination including non-compliance with study procedures or the emergence of significant safety concerns.

Inclusion criteria require participants to be clinically stable, not at imminent risk of harm, and medically stable at enrollment. Female participants of childbearing potential must agree to use two clinically acceptable methods of contraception during the study and for at least 45 days after the last dose. The primary endpoint focuses on safety, while secondary endpoints include the proportion of subjects achieving a significant reduction in irritability scores. The trial is not categorized as low intervention and is expected to conclude by October 2025, with recruitment having started in March 2023.

The clinical trial involves the administration of **Pimavanserin** in three different dosages, each formulated as a capsule for oral administration. The first experimental medication is Pimavanserin Capsules 10 mg, containing the active substance **pimavanserin tartrate**. This medication is manufactured by Acadia Pharmaceuticals and is of chemical origin. The maximum daily dose is 10 mg, with a treatment period extending up to 6 weeks. Participants are required to take the medication orally once daily, and compliance will be monitored throughout the study.

The second experimental medication is Pimavanserin 20 mg Capsule, also containing **pimavanserin tartrate** as the active ingredient. Similar to the 10 mg formulation, this capsule is produced by Acadia Pharmaceuticals and is chemically derived. The maximum daily dose for this formulation is 20 mg, administered orally once daily over a maximum treatment period of 6 weeks. Participant adherence to the dosing schedule will be closely monitored.

The third experimental medication is Pimavanserin 34 mg Capsule, which also contains **pimavanserin tartrate**. This formulation is provided by Acadia Pharmaceuticals and is of chemical origin. The maximum daily dose is 34 mg, with the medication being administered orally once daily for up to 6 weeks. Compliance with the dosing regimen will be assessed regularly to ensure adherence.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified for this study. The focus is on evaluating the long-term safety and tolerability of Pimavanserin in children and adolescents with irritability associated with Autism Spectrum Disorder (ASD) over a 52-week period. The study does not include any pediatric-specific formulations, and all medications are intended for oral administration.

The efficacy of the clinical trial will be assessed through both primary and secondary endpoints. The primary endpoint focuses on the evaluation of **treatment-emergent adverse events (TEAEs)**, with safety assessments including analyses of vital signs, weight and body mass index (BMI), 12-lead electrocardiograms (ECGs), physical examination results, clinical laboratory tests (including urinalysis) and hormonal assessments, the Columbia–Suicide Severity Rating Scale (C-SSRS), and the Extrapyramidal Symptom Rating Scale Abbreviated (ESRS-A).

The secondary endpoint involves measuring the proportion of subjects who achieve at least a 25% reduction in the Aberrant Behavior Checklist–Irritability (ABC-I) subscale score and a Clinical Global Impression–Improvement (CGI-I) of irritability score of 1 (very much improved) or 2 (much improved) compared to the antecedent study baseline status at Week 52. These assessments will be conducted at specified timepoints throughout the 52-week study period to ensure comprehensive evaluation of the treatment's efficacy in children and adolescents with irritability associated with Autism Spectrum Disorder (ASD).