Evaluation of Therapeutic Drug Monitoring in Mitigating Risperidone and Aripiprazole-Induced Weight Gain in Pediatric Autism Spectrum Disorder

The primary objective of this study is to evaluate the **effectivity** of therapeutic drug monitoring (TDM) in preventing or mitigating side effects associated with the use of risperidone and aripiprazole in children and adolescents diagnosed with autism spectrum disorder. This is clinically relevant as it aims to optimize treatment regimens and improve patient outcomes by minimizing adverse effects, which are a significant concern in pediatric psychopharmacology. The study will specifically assess differences in weight gain six months after the initiation of treatment between a group receiving TDM-based dosing advice and a group receiving standard clinical care.

Secondary objectives include: - Studying the differences in weight gain one year after the start of treatment. - Comparing drug effectivity between groups based on the severity of irritability and aggression, as measured by the Aberrant Behavior Checklist (ABC). - Comparing safety parameters between groups, including levels of glucose, cholesterol, lipoproteins, triglycerides, and hormones such as ghrelin, prolactin, and leptin. Additionally, the study will assess extrapyramidal side effects using the Abnormal Involuntary Movement Scale (AIMS) and evaluate quality of life using the Pediatric Quality of Life Inventory (PedsQL), EuroQol-5D-Y (EQ-5D-Y), and Treatment Inventory of Costs in Patients with psychiatric disorders (TIC-P).

The clinical trial involves participants diagnosed with **autism spectrum disorder** and comorbid behavioral problems, aged between 6 to 18 years. The study population includes both male and female subjects, and it is noted that the participants are considered a vulnerable population. The trial aims to evaluate the effectiveness of therapeutic drug monitoring in managing side effects associated with risperidone and aripiprazole treatment. Participants are required to begin treatment with either of these medications. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. The selection criteria include a documented clinical diagnosis according to DSM IV or DSM V standards. The trial does not specify additional lifestyle factors or habits that may influence participation.

The clinical trial is designed to evaluate the **safety** and pharmacokinetics of **antipsychotics** in children and adolescents diagnosed with **autism spectrum disorder**. This study is a randomized, double-blind, controlled trial with a primary objective to assess the effectiveness of therapeutic drug monitoring (TDM) in mitigating side effects associated with the use of **risperidone** and **aripiprazole**. The trial will compare weight gain differences over six months between a group receiving TDM-based dosing advice and a group receiving standard clinical care. The trial is expected to last until November 2025, with participant recruitment having commenced in November 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (6 to 18 years) and a documented clinical diagnosis of autism spectrum disorder with comorbid behavioral problems. Following the screening, participants will be randomized into one of the two study groups. Regular follow-up visits will be scheduled to monitor treatment effects, collect data on primary and secondary endpoints, and ensure participant safety. The primary endpoint is the change in body mass index z-scores (BMI-Z) after six months of treatment. Secondary endpoints include changes in BMI-Z after 12 months, assessments using the Aberrant Behavior Checklist, EuroQol-5D Youth, Pediatric Quality of Life Inventory, and other health-related measures.

The expected length of participant involvement is up to 24 months, with conditions for early termination including adverse events, withdrawal of consent, or non-compliance with study procedures. The end-of-study visit will involve a comprehensive evaluation of the participant's health status and the collection of final data points. Throughout the trial, the maximum daily dose of **aripiprazole** is 10 mg, and for **risperidone**, it is 0.08 mg/kg, both administered orally. The trial is categorized as a phase IV low interventional study, focusing on the long-term safety and efficacy of these medications in the pediatric population.

The clinical trial involves the administration of **Aripiprazole**, a chemical compound classified under the ATC code N05AX12. Aripiprazole is provided in an oral pharmaceutical form, identified by the code PHF00245MIG. The maximum daily dose for participants is set at 10 mg, with the same amount being the maximum total dose. The treatment period is limited to 24 weeks. The administration of Aripiprazole is conducted orally, and the formulation is not specifically designed for pediatric use. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

**Risperidone** is the second experimental medication used in this trial, also a chemical compound, and is classified under the ATC code N05AX08. Risperidone is administered orally in a pharmaceutical form denoted by the code PHF00082MIG. The dosing regimen for Risperidone is weight-based, with a maximum daily dose of 0.08 mg/kg, which is also the maximum total dose. The treatment duration is similarly capped at 24 weeks. As with Aripiprazole, the formulation of Risperidone is not tailored for pediatric patients. Participant compliance with the dosing schedule is closely monitored to ensure accurate adherence to the treatment protocol.

In this clinical trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The primary objective is to evaluate the effectiveness of therapeutic drug monitoring in mitigating side effects associated with the use of Aripiprazole and Risperidone in children and adolescents. The study focuses on assessing weight gain differences over a six-month period between groups receiving therapeutic drug monitoring-based dosing advice and those receiving standard clinical care.

Efficacy in this clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the difference between the groups in change in body mass index z-scores (BMI-Z) after 6 months of treatment. Secondary endpoints include the change in BMI-Z after 12 months, as well as assessments using the Aberrant Behavior Checklist, which is a parental symptom checklist for evaluating problem behavior in children, particularly focusing on aggression and irritability in those with autism spectrum disorder. Additional secondary endpoints involve the EuroQol-5D Youth, a descriptive system for health-related quality of life, and the Pediatric Quality of Life Inventory, which measures health-related quality of life in children and adolescents. Other secondary endpoints include Clinical Global Improvement, the Treatment Inventory of Costs in Patients with psychiatric disorders, and various laboratory measures such as levels of glucose, cholesterol, lipoproteins, triglycerides, and hormones like ghrelin, prolactin, and leptin. The Abnormal Involuntary Movement Scale will be used to detect extrapyramidal side effects, and blood pressure will also be monitored.