A multicenter, randomized open-label study to assess the efficacy, safety, and pharmacokinetics of upadacitinib with a tocilizumab reference arm in subjects from 1 year to less than 18 years old with active systemic juvenile idiopathic arthritis.

The primary objective of this study is to evaluate the **efficacy**, safety, and pharmacokinetics of **upadacitinib** in comparison to a **tocilizumab** reference arm in pediatric and adolescent subjects aged 1 to less than 18 years with active systemic juvenile idiopathic arthritis (sJIA). This is clinically relevant as it aims to determine the therapeutic potential and safety profile of upadacitinib, which could offer an alternative treatment option for managing sJIA, a condition characterized by inflammation and joint pain in children.

The secondary objectives focus on assessing the proportion of subjects who achieve the dichotomous secondary endpoints and the mean of continuous endpoints, as specified in the protocol, based on the intention-to-treat (ITT) population. These objectives are crucial for understanding the broader impact of the treatment on various clinical outcomes and patient subgroups.

The clinical trial involves a total of **65 participants** diagnosed with **juvenile idiopathic arthritis**, specifically focusing on children and adolescents aged 1 to less than 18 years. The study population includes both male and female subjects, ensuring a diverse representation of genders. Participants were selected based on specific inclusion criteria, which required them to have a total body weight of 10 kg or higher and meet certain laboratory value thresholds, such as serum aspartate transaminase (AST) and alanine aminotransferase (ALT) levels, estimated glomerular filtration rate (eGFR), and blood cell counts. The trial population is considered vulnerable due to the inclusion of minors, necessitating informed consent from legally authorized representatives. The study does not specify any particular lifestyle considerations such as diet or physical activity. The selection process ensures that participants are in a general state of health that allows for the safe administration of the study drugs, upadacitinib and tocilizumab, to assess their efficacy, safety, and pharmacokinetics in treating active systemic juvenile idiopathic arthritis (sJIA).

The clinical trial is designed as a **randomized**, open-label study to evaluate the efficacy, safety, and pharmacokinetics of **upadacitinib** with a **tocilizumab** reference arm in pediatric and adolescent subjects aged 1 to less than 18 years with active systemic **juvenile idiopathic arthritis** (sJIA). The trial is expected to last until February 8, 2029, with recruitment starting on December 6, 2023. The study involves two cohorts, with Cohort 1 focusing on subjects aged 2 to less than 18 years in regions where subcutaneous tocilizumab is not approved for sJIA. The trial will include multiple study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as age, weight, and laboratory values. Participants will be randomly assigned to receive either upadacitinib or tocilizumab, with the treatment period lasting up to 52 weeks.

Study visits will be scheduled at regular intervals to monitor the participants' health, assess the primary and secondary endpoints, and ensure adherence to the protocol. The primary endpoint for Cohort 1 is the achievement of an adapted sJIA ACR 30 response at Week 12, defined by the absence of fever and improvement in specific clinical variables. Secondary endpoints include achieving higher levels of response (ACR 50/70/90/100) and changes in core sJIA components. The end-of-study visit will occur after the completion of the treatment period, where final assessments will be conducted to evaluate the long-term effects of the treatment.

Participants are expected to be involved in the study for the entire duration of the treatment period, with the possibility of early termination if they experience significant adverse events, fail to adhere to the study protocol, or withdraw consent. The trial is not categorized as low intervention and is classified as a phase 3 trial. The study aims to provide valuable data on the comparative efficacy and safety of upadacitinib and tocilizumab in managing active sJIA in the pediatric population.

The clinical trial involves the administration of **RoActemra** (tocilizumab) in various pharmaceutical forms. The first form is a 162 mg solution for injection in a pre-filled pen. This solution is administered via **injection** and is not a pediatric formulation. The maximum daily dose is 23.14 mg, with a total maximum dose of 8424 mg over a treatment period of up to 52 weeks. The product is manufactured by Roche Registration GmbH and is classified under the ATC code L04AC07. The active substance, tocilizumab, is a protein of non-human origin.

Another form of RoActemra used in the trial is a 162 mg solution for injection in a pre-filled syringe. Similar to the pre-filled pen, this form is administered via injection, with the same dosing parameters: a maximum daily dose of 23.14 mg and a total maximum dose of 8424 mg over 52 weeks. This formulation is also produced by Roche Registration GmbH and contains the active substance tocilizumab, a protein of non-human origin.

Additionally, RoActemra is available as a 20 mg/mL concentrate for solution for infusion. This form is administered as a solution for infusion, with a maximum daily dose of 23 mg and a total maximum dose of 8424 mg over a 52-week period. The concentrate is also manufactured by Roche Registration GmbH and contains the active substance tocilizumab, classified as a protein of non-human origin.

The trial also includes the administration of **Upadacitinib**, which is provided in two forms. The first form is an oral solution, and the second is a modified-release tablet. Both forms are administered orally. Upadacitinib is a chemical substance produced by AbbVie Deutschland GmbH & Co. KG. The dosing parameters for Upadacitinib are not specified in terms of maximum daily or total dose, but the treatment period is up to 52 weeks. The oral solution and modified-release tablet forms are not pediatric formulations.

The efficacy of the clinical trial will be assessed through a series of predefined endpoints. The primary endpoint focuses on the achievement of an adapted systemic juvenile idiopathic arthritis (sJIA) ACR 30 response at Week 12. This response is defined by the absence of fever (temperature > 38°C) in the week preceding evaluation and an improvement of at least 30% in three or more of the six variables of the JIA core set, with no more than one variable worsening by more than 30%.

Secondary endpoints will also be evaluated at Week 12 and include the achievement of adapted sJIA ACR 50/70/90/100 responses. Additionally, changes from baseline in each core adapted sJIA ACR component will be measured. These components include the number of joints with active arthritis, the number of joints with limitation of motion, the Childhood Health Assessment Questionnaire-Disability Index (CHAQ-DI), the Patient/Parent Global Assessment (Pt/ParentGA), the Physician's Global Assessment of disease activity (PhGA), and high-sensitivity C-reactive protein levels.