Evaluation of Methotrexate and Tumor Necrosis Factor Inhibitor Withdrawal Strategies in Juvenile Idiopathic Arthritis Remission: A Randomized Multicenter Trial

The primary objective of this study is to evaluate the effect of two different **treatment withdrawal** strategies compared to a stable dose of **methotrexate** and **tumor necrosis factor inhibitor** (TNFi) on the risk of flares in children and adolescents with **Juvenile Idiopathic Arthritis** (JIA) who are in sustained inactive disease. This is clinically relevant as it aims to optimize treatment strategies for maintaining remission in JIA, potentially reducing medication exposure and associated side effects while preventing disease flares.

Secondary objectives include:

• Assessing the risk of flares between the two different treatment withdrawal strategies.
• Evaluating the time to flare and the time to regain inactive disease after a flare.
• Comparing changes in disease activity across different treatment arms.
• Assessing overall safety of the treatment strategies.

The clinical trial focuses on evaluating treatment withdrawal strategies in children and adolescents diagnosed with **Juvenile Idiopathic Arthritis**. The study population includes both male and female participants aged between 2 to less than 18 years. Participants are required to have sustained clinical remission for at least 12 months, documented at a minimum of two visits during the last 18 months, and must exhibit Wallace inactive disease at the time of inclusion. Additionally, they should have no active uveitis for at least 24 months and must be on stable treatment with a tumor necrosis factor inhibitor and methotrexate for at least three months. The trial involves a vulnerable population, and the sponsor has not provided the total number of participants. The selection criteria ensure that participants are in a state of sustained inactive disease, as clinically judged by their treating physician, at all appointments for at least 12 months prior to inclusion. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of two different treatment withdrawal strategies compared to continued stable treatment with **methotrexate** and tumor necrosis factor inhibitors (TNFi) in children and adolescents with **Juvenile Idiopathic Arthritis** (JIA) in sustained remission. This is an open, randomized, multicenter trial, categorized as a Phase IV clinical trial, and is considered low-intervention due to the established safety and efficacy of the medications involved. The trial will commence on October 24, 2024, with an estimated end date of August 31, 2030, and recruitment is expected to start on September 1, 2024.

Participants will be randomly assigned to one of three arms: two drug withdrawal strategies or a stable treatment arm. The primary objective is to assess the risk of disease flares during the first 12 months of follow-up. The trial will include several study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, sustained clinical remission, and stable treatment with TNFi and **methotrexate**. Follow-up visits will occur regularly to monitor disease activity, adverse events, and any signs of disease flare, defined by specific clinical criteria. The end-of-study visit will conclude the participant's involvement, assessing the overall outcomes and any long-term effects of the treatment strategies.

Participant involvement is expected to last up to 36 months, depending on the treatment arm and individual response. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or a decision by the investigator that continued participation is not in the participant's best interest. The trial will collect data on primary and secondary endpoints, including the proportion of participants experiencing a disease flare, time to flare, time to regain inactive disease, and changes in disease activity measures. Safety will be monitored through reports of adverse events, serious adverse events, and suspected unexpected adverse reactions.

The clinical trial involves the administration of several **experimental medications** to evaluate their efficacy in treating **juvenile idiopathic arthritis**. The primary experimental medication is **METHOTREXATE**, which is provided in three different pharmaceutical forms: oral solution, tablets, and solution for injection in a pre-filled syringe. The oral solution is administered orally with a maximum daily dose of 3.6 mg and a total maximum dose of 3900 mg over a treatment period of up to 36 months. The tablet form is administered subcutaneously with a maximum daily dose of 3.57 mg and the same total maximum dose and treatment period as the oral solution. The solution for injection in a pre-filled syringe is also administered subcutaneously, with a maximum daily dose of 3.6 mg and a total maximum dose of 3900 mg over 36 months.

Another experimental medication used in the trial is **GOLIMUMAB**, provided as a solution for injection in a pre-filled pen. This medication is administered subcutaneously with a maximum daily dose of 3.3 mg and a total maximum dose of 3600 mg over a 36-month treatment period.

**ADALIMUMAB** is also included in the trial as a solution for injection. It is administered subcutaneously with a maximum daily dose of 5.7 mg and a total maximum dose of 6240 mg over a treatment period of up to 36 months.

Lastly, **ETANERCEPT** is administered as a solution for injection, delivered subcutaneously. The maximum daily dose for this medication is 7.2 mg, with a total maximum dose of 7800 mg over a 36-month period.

All medications are administered according to the specified dosing schedules, and participant compliance is monitored throughout the trial. The trial aims to compare the effects of these medications on the risk of flares in children and adolescents with juvenile idiopathic arthritis in sustained inactive disease. No non-experimental treatments, such as standard-of-care therapy or placebo, are mentioned in the trial data provided.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints related to **Juvenile Idiopathic Arthritis**. The primary endpoint is the proportion of study participants experiencing a disease flare during the first 12 months of follow-up. This will be compared between each of the two drug withdrawal arms and the stable treatment arm. A disease flare is defined as a clinically significant increase in the Juvenile Arthritis Disease Activity Score 27 (JADAS-27) of ≥1.7 from baseline, along with at least one active joint (swollen, or tender with limited range of motion), or a consensus between the treating physician and participant/parents that a clinically significant flare has occurred, necessitating the intensification of antirheumatic (DMARD) treatment.

Secondary endpoints include the proportion of participants with a disease flare during the first 12 months of follow-up compared between the two drug withdrawal arms, time to flare, and time to regain inactive disease after a flare. Additionally, changes in validated measures of disease activity will be monitored, along with reports of adverse events, serious adverse events, and suspected unexpected adverse reactions. These efficacy parameters will be collected and analyzed throughout the trial duration, with specific timepoints and methods for measurement not detailed in the provided data.