Randomized Trial of Early Versus Late Withdrawal of Etanercept, Baricitinib, and Tocilizumab in Juvenile Idiopathic Arthritis Remission Using Imaging and Multi-Omics

The primary objective of this study is to demonstrate that early **biomarker**-guided withdrawal of antirheumatic agents in patients with juvenile idiopathic arthritis (JIA) who have achieved 6 months of clinical inactive disease (CID) with medication and do not exhibit subclinical inflammation is both safe and more effective compared to the standard practice of maintaining stable treatment intensity over 12 months. This is clinically relevant as it aims to optimize treatment strategies, potentially reducing medication exposure and associated side effects while maintaining disease remission.

Secondary objectives include the collection and analysis of biological (blood) samples using multi-Omics approaches. The goal is to accelerate the discovery of novel biomarkers that can predict disease flare after treatment withdrawal. Enhanced access to these immunologic and transcriptomic profiling technologies could significantly aid clinicians in identifying patients who are suitable candidates for successful medication withdrawal.

The clinical trial focuses on participants diagnosed with **juvenile idiopathic arthritis** (JIA), encompassing various subtypes such as oligoarthritis, rheumatoid factor-negative polyarthritis, rheumatoid factor-positive polyarthritis, psoriatic arthritis, and enthesitis-related arthritis. The study population includes both male and female subjects, with an age range corresponding to categories 2 and 3, indicating a pediatric population. Participants are required to have achieved clinical inactive disease status for a minimum of six continuous months while on medication. The trial involves a vulnerable population, necessitating informed consent from parents or legal guardians. Female participants of child-bearing potential must have a negative pregnancy test at the trial's onset and must not intend to conceive while on antirheumatic treatment. The sponsor has not provided the total number of participants involved in the study. The selection criteria ensure that participants can comply with study procedures and communicate effectively with the investigational staff.

The clinical trial is designed to evaluate the safety and efficacy of early biomarker-guided withdrawal of antirheumatic agents in children with **juvenile idiopathic arthritis** (JIA) who have achieved clinical inactive disease (CID) for at least six months while on medication. This trial is a randomized, controlled, double-blind study comparing early versus late drug withdrawal. The trial is categorized as low-intervention, as the investigational medicinal products are authorized and used according to their marketing authorization, with minimal additional risk or burden to participants. The trial is expected to commence recruitment on August 31, 2024, and conclude by September 1, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on the principal inclusion criteria, which include a diagnosis of JIA according to the ILAR classification and the ability to comply with study procedures. Following randomization, participants will attend regular follow-up visits to monitor disease activity and assess for any flares. The primary endpoint is the rate of flares, while the secondary endpoint is the time to flare from randomization. The end-of-study visit will occur at the conclusion of the participant's involvement, which is anticipated to last up to 21 weeks, depending on the treatment arm.

Participants may be withdrawn from the study early if they experience a disease flare or are unable to comply with study procedures. Female participants of child-bearing potential must have a negative pregnancy test at the start of the trial and agree to use effective contraception throughout the study. The trial aims to provide evidence that early withdrawal of antirheumatic agents, guided by biomarkers, is a safe and effective strategy for managing JIA in clinical remission.

The clinical trial involves several experimental medications, each with specific administration protocols. **Enbrel** (etanercept) is provided as a 25 mg or 50 mg solution for injection in pre-filled syringes or pens. It is administered subcutaneously with a maximum daily dose of 0.11 mg/kg and a total dose of 0.8 mg/kg over a 21-day period. The pharmaceutical form is a solution for injection, and participant compliance is monitored through regular assessments.

**Olumiant** (baricitinib) is available in 1 mg, 2 mg, and 4 mg film-coated tablets. The medication is administered orally with a maximum daily dose of 4 mg and a total dose of 4 mg over a 21-day period. The dosing schedule is designed to ensure optimal therapeutic levels, and adherence is tracked through pill counts and patient diaries.

**RoActemra** (tocilizumab) is provided as a 20 mg/mL concentrate for solution for infusion or a 162 mg solution for injection in pre-filled pens. The intravenous form is administered with a maximum daily dose of 0.36 mg/kg and a total dose of 10 mg/kg over 21 days, while the subcutaneous form has a maximum daily dose of 11.57 mg and a total dose of 162 mg. Infusion schedules are carefully managed to maintain consistent drug levels.

**ORENCIA** (abatacept) is available as a 250 mg powder for concentrate for solution for infusion and a 125 mg solution for injection in pre-filled syringes. The intravenous form is administered with a maximum daily dose of 0.36 mg/kg and a total dose of 10 mg/kg over 21 days, while the subcutaneous form has a maximum daily dose of 17.86 mg and a total dose of 125 mg. Administration is monitored to ensure proper infusion rates and patient safety.

**Reumaflex** (methotrexate) is provided as a 50 mg/mL solution for injection in pre-filled syringes and as a 2.5 mg film-coated tablet. The subcutaneous form is administered with a maximum daily dose of 3.57 mg and a total dose of 15 mg over 12 days, while the oral form has a maximum daily dose of 2.5 mg. Compliance is assessed through regular blood tests and patient logs.

**Humira** (adalimumab) is available as a 40 mg solution for injection in pre-filled pens and syringes. It is administered subcutaneously with a maximum daily dose of 2.86 mg and a total dose of 40 mg over a 21-day period. The administration schedule is designed to maintain therapeutic levels, and adherence is monitored through patient self-reports and clinical evaluations.

**Simponi** (golimumab) is provided as a 50 mg solution for injection in pre-filled pens and syringes, and a 45 mg/0.45 mL solution in pre-filled pens. It is administered subcutaneously with a maximum daily dose of 1.61 mg and a total dose of 45 mg over 21 days. Compliance is tracked through patient diaries and regular clinical assessments.

**XELJANZ** (tofacitinib) is available as a 5 mg film-coated tablet and a 1 mg/mL oral solution. The oral form is administered with a maximum daily dose of 10 mg and a total dose of 5 mg over 21 days. Adherence is monitored through pill counts and patient self-reports.

**Cosentyx** (secukinumab) is provided as a 75 mg or 150 mg solution for injection in pre-filled syringes and pens. It is administered subcutaneously with a maximum daily dose of 5.36 mg and a total dose of 150 mg over 21 days. The administration schedule is designed to ensure consistent drug levels, and compliance is assessed through patient logs and clinical evaluations.

**Jylamvo** (methotrexate) is available as a 2 mg/mL oral solution. It is administered with a maximum daily dose of 2 mg and a total dose of 15 mg over 12 days. Adherence is monitored through patient self-reports and regular clinical assessments.

The efficacy of the clinical trial will be assessed using specific endpoints to evaluate the outcomes of early biomarker-guided withdrawal of antirheumatic agents in children with juvenile idiopathic arthritis (JIA) who have achieved clinical inactive disease (CID) for at least six months. The primary endpoint for efficacy assessment is the rate of flares, which refers to the proportion of patients experiencing a disease flare at any point during the study period. This will be compared between the two study arms to determine the effectiveness of the intervention.

Additionally, a secondary endpoint will be the time to flare, which measures the duration from randomization to the occurrence of a flare. These endpoints will provide insights into the safety and effectiveness of the early withdrawal strategy compared to the standard practice of maintaining stable treatment intensity. The trial is designed to ensure that the investigational medicinal products are used in accordance with their marketing authorization, and the procedures involved do not pose more than minimal additional risk to the participants.