Dose-Finding Study of Sarilumab in Pediatric Patients with Systemic Juvenile Idiopathic Arthritis

The primary objective of this study is to describe the **pharmacokinetic** (PK) profile of sarilumab in patients aged 1-17 years with Systemic Juvenile Idiopathic Arthritis (sJIA). This is crucial for identifying the appropriate dose and regimen necessary for the adequate treatment of this pediatric population, ensuring optimal therapeutic outcomes and minimizing potential adverse effects.

Secondary objectives include:

• Describing the pharmacodynamics (PD) profile of sarilumab in patients with sJIA.
• Evaluating the efficacy of sarilumab in this patient group.
• Assessing the long-term safety of sarilumab administration in children and adolescents with sJIA.

The clinical trial involves a total of **46 participants** diagnosed with **Systemic Juvenile Idiopathic Arthritis (sJIA)**. The study population comprises both male and female patients aged between 1 and 17 years, with specific age requirements for certain countries, such as 12-17 years for Russia. Participants were selected based on their diagnosis of the systemic JIA subtype according to the International Associations against Rheumatism (ILAR) 2001 Juvenile Idiopathic Arthritis Classification Criteria. Key features include having at least five active joints at screening or at least two active joints with systemic JIA fever exceeding 37.5°C in the days preceding baseline, despite stable glucocorticoid treatment. The trial targets patients with an inadequate response to current treatment, who are considered candidates for a biologic disease-modifying antirheumatic drug (DMARD) as per the investigator's judgment. The study includes a vulnerable population, and lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **pharmacokinetic** profile of **sarilumab** in pediatric patients aged 1 to 17 years diagnosed with **Systemic Juvenile Idiopathic Arthritis (sJIA)**. This study aims to identify the appropriate dose and regimen for effective treatment in this population. The trial follows an open-label, sequential, ascending, repeated dose-finding design, with an extension phase. The trial is expected to span from September 2018 to February 2029, encompassing both the core treatment and extension phases.

Participants will be administered **sarilumab** via subcutaneous injection, with a maximum daily dose of 300 mg and a total dose not exceeding 23,400 mg over a period of up to 156 weeks. The study includes several key visits: an initial screening visit to confirm eligibility based on criteria such as age, diagnosis, and response to current treatment, followed by regular follow-up visits to monitor the **pharmacokinetic** parameters and safety outcomes. The primary endpoints include the assessment of maximum serum concentration (Cmax), area under the curve (AUC0-t), and trough concentration (Ctrough) up to Week 12. Secondary endpoints involve evaluating adverse events, local tolerability, and various clinical response rates and changes in disease activity scores up to Week 156.

Participants are expected to be involved in the study for the entire duration of the core treatment phase, with the possibility of continuing into the extension phase. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or any adverse events that compromise participant safety. The study is conducted in accordance with ethical standards and regulatory requirements, ensuring the safety and well-being of all participants throughout the trial duration.

The clinical trial involves the administration of **sarilumab**, a **solution for injection** developed by Sanofi Aventis Recherche et Développement (SAR). Sarilumab is a protein-based therapeutic agent, specifically classified under "Protein - Other." The experimental medication is administered via **subcutaneous injection**. The dosing regimen for sarilumab involves a maximum daily dose of 300 mg, with a total maximum dose of 23,400 mg over the course of the treatment period, which spans up to 156 weeks. The study aims to determine the pharmacokinetic profile of sarilumab in pediatric patients aged 1 to 17 years diagnosed with Systemic Juvenile Idiopathic Arthritis (sJIA), to establish an appropriate dosing regimen for this population.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified for use in this study. The trial is designed as an open-label, sequential, ascending, repeated dose-finding study, followed by an extension phase. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen. The study does not include a pediatric formulation of sarilumab, and the product is not classified as an orphan drug. The sponsor product code for sarilumab is SAR153191/REGN88.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints focus on the pharmacokinetic (PK) parameters of **sarilumab** in patients with Systemic Juvenile Idiopathic Arthritis (sJIA). These include the maximum serum concentration observed (Cmax), the area under the serum concentration versus time curve (AUC0-t), and the concentration observed before treatment administration during repeated dosing (Ctrough). These parameters will be measured up to Week 12.

Secondary endpoints will evaluate various clinical outcomes and safety measures. These include the number of adverse events and acceptability assessments, which will be monitored during the core treatment phase up to Week 12 and the extension phase up to Week 162. The Juvenile Idiopathic Arthritis ACR30/50/70/90/100 response rate will be assessed in the absence of fever, with evaluations occurring at multiple timepoints: up to Week 12 during the core treatment phase and at Weeks 24, 48, and every 24 weeks up to Week 156 during the extension phase.

Additional secondary endpoints involve changes from baseline in several components of the JIA ACR, such as the physician's global assessment of disease activity, patient/parent assessment of overall wellbeing, the Childhood Health Assessment Questionnaire (CHAQ) – Disability Index, the number of joints with active arthritis, and the number of joints with limitation of motion. These will be assessed up to Week 12 in the core treatment phase and at specified intervals during the extension phase. Changes in high sensitivity C-reactive protein (hs-CRP), fever, and the Juvenile Arthritis Disease Activity Score-27 (JADAS) will also be evaluated.

Furthermore, changes in glucocorticoid use and IL-6 associated biomarkers, including IL6 and sIL-6 R, will be monitored up to Week 12. The proportion of patients receiving glucocorticoids by dose category and those free of glucocorticoids without JIA flare will be assessed at specified intervals up to Week 156. These comprehensive assessments will provide a detailed evaluation of the efficacy of sarilumab in the target population.