Biomarker-Guided Anakinra Tapering Strategy in Pediatric Systemic Juvenile Idiopathic Arthritis: A Randomized Controlled Trial

The primary objective of this study is to evaluate whether the use of the **biomarker IL-18** can reduce the average number of injections of recombinant IL-1 receptor antagonist (rIL-1RA) required to achieve and maintain clinically inactive disease in patients with systemic Juvenile Idiopathic Arthritis (sJIA) during the first year of treatment. This is compared to a historical cohort where treatment decisions were based solely on the clinical judgment of the treating physician. The clinical relevance of this objective lies in potentially minimizing the treatment burden and improving patient outcomes by tailoring therapy based on biomarker guidance.

Secondary objectives include:

• The number of patients with clinically inactive disease without medication at the 1-year mark.
• The total number of disease flares during or after tapering and stopping therapy in the first year.
• The number of patients achieving remission off medication at the 2-year mark.
• The number of patients needing to switch treatment due to treatment failure during the first year, which will aid in calculating the reduction in treatment costs.
• The number of (serious) adverse events occurring in the first year.

The clinical trial involves a study population comprising both **male** and **female** participants, specifically children and adolescents diagnosed with systemic juvenile idiopathic arthritis (sJIA), as per the ILAR 2004 classification criteria. The age range of the participants is from 8 months to 16 years. The trial does not involve a vulnerable population. Participants were selected based on their diagnosis of sJIA and their initial beneficial response to rIL-1RA monotherapy, with the absence of fever on day 7 of treatment being a key indicator. The trial population was not specified in terms of total number, as the sponsor did not provide this information. Lifestyle considerations such as diet and physical activity were not detailed in the available data. The study aims to evaluate the efficacy of rIL-1RA in achieving and maintaining clinically inactive disease, utilizing the biomarker IL-18 to potentially reduce the number of injections required. The trial does not include any specific exclusion criteria beyond those implied by the inclusion criteria.

The clinical trial is designed to evaluate a **biomarker-guided treatment-and-stop strategy** for the recombinant IL-1 receptor antagonist, **anakinra**, in patients with systemic Juvenile Idiopathic Arthritis (sJIA). This study is structured as a randomized, open-label trial with a focus on reducing the number of injections required to achieve and maintain clinically inactive disease. The trial will span approximately nine months, with the estimated end date set for July 1, 2025. Participants will be involved in the study from the initial screening visit through to the end-of-study visit, with the possibility of early termination if specific conditions are met, such as adverse events or lack of efficacy.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility is confirmed based on criteria such as age (8 months to 16 years) and diagnosis of sJIA. Following the screening, participants will enter an open-label lead-in phase, where they will receive anakinra as a first-line therapy. The primary endpoint is the total number of anakinra injections needed to maintain clinically inactive disease during the first year of treatment. Secondary endpoints include the number of patients achieving remission off medication at one and two years, the incidence of disease flares, and the occurrence of serious adverse events.

Participants will attend follow-up visits to monitor their response to treatment and adjust the dosing strategy as needed. The intervention part of the trial involves tapering and stopping anakinra based on the patient's response, with the use of the biomarker IL-18 to guide decisions. The end-of-study visit will assess the overall outcomes and document any long-term effects. Conditions for early termination from the study include the development of serious adverse events or failure to achieve the desired clinical response. The trial aims to provide insights into optimizing treatment strategies for sJIA, potentially reducing the treatment burden on patients.

The clinical trial involves the administration of **Kineret**, a recombinant interleukin-1 receptor antagonist, with the active substance **anakinra**. The pharmaceutical form of the experimental medication is a **solution for injection** provided in a pre-filled syringe. Each syringe contains 100 mg of anakinra in 0.67 ml of solution. The medication is administered via **subcutaneous injection**. The maximum daily dose is 100 mg, and the treatment period is limited to a maximum of 9 months. The dosing schedule is determined based on the study protocol, which aims to achieve and maintain clinically inactive disease in patients with systemic Juvenile Idiopathic Arthritis. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the treatment protocol.

In this clinical trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of Kineret, with the primary objective being to evaluate the efficacy of a biomarker-guided treatment-and-stop strategy. This strategy utilizes the biomarker IL-18 to potentially reduce the number of injections required to maintain disease inactivity compared to historical cohorts where treatment decisions were based solely on clinical judgment. The trial does not include any additional medications or interventions beyond the administration of Kineret.

Efficacy in this clinical trial will be assessed through both primary and secondary endpoints. The primary endpoint is the total (mean/median) number of injections of **anakinra** per patient necessary to achieve and maintain clinically inactive disease during the first year of treatment. This will provide a quantitative measure of the treatment's effectiveness in managing systemic Juvenile Idiopathic Arthritis (sJIA).

Secondary endpoints include several key measures: the number of patients with clinically inactive disease without medication at the 1-year time point, the total number of disease flares during or after tapering and stopping therapy in the first year, the number of patients with remission off medication at the 2-year time point, the number of patients needing to switch treatment due to treatment failure within the first year, and the number of (serious) adverse events in the first year. These endpoints will help evaluate the broader impact of the treatment strategy, including its sustainability and safety.

The trial will utilize a biomarker-guided treatment-and-stop strategy, specifically using the biomarker IL-18, to potentially reduce the number of injections required compared to historical cohorts where decisions were based solely on clinical judgment. The efficacy assessments will be conducted at specified time points, including 1 year and 2 years, to capture both immediate and longer-term outcomes of the treatment strategy.