Evaluation of Disease Activity-Guided Dose Reduction of Janus Kinase Inhibitors Filgotinib, Tofacitinib, Upadacitinib, and Baricitinib in Inflammatory Rheumatic Diseases

The primary objective of this study is to evaluate whether a **disease activity** guided dose reduction strategy for Janus Kinase inhibitors (JAKi) is not inferior in terms of efficacy compared to the continuation of JAKi in patients with **rheumatoid arthritis**, **psoriatic arthritis**, and **axial spondyloarthritis** who are currently in a low disease activity or remission state. This is clinically relevant as it may allow for reduced medication exposure while maintaining disease control, potentially minimizing side effects and healthcare costs.

Secondary objectives include:

• Assessing differences in disease activity between groups, subdivided by disease.
• Determining the number of participants able to reduce or discontinue their JAKi dose.
• Evaluating differences in safety endpoints between study groups.
• Investigating differences in the incidence of flares between groups.
• Quantifying the use of NSAIDs, corticosteroids, and csDMARDs among participants.
• Assessing the cost-effectiveness of the proposed dose reduction strategy compared to usual care.
• Identifying predictive biomarkers for successful or unsuccessful dose reduction or discontinuation.

The clinical trial involves participants diagnosed with **rheumatoid arthritis**, psoriatic arthritis, or axial spondyloarthritis. The study population includes both male and female subjects aged 16 years and older. Participants are required to have been treated with a Janus kinase inhibitor (JAKi), either as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), at a dose of at least 50% of the authorized amount. They must also be in a state of low disease activity or remission for a minimum of six months, as determined by specific criteria for each condition or the judgment of the treating rheumatologist and patient. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of a **disease activity** guided dose reduction strategy for Janus Kinase inhibitors (JAKi) in patients with **rheumatoid arthritis**, **psoriatic arthritis**, and **axial spondyloarthritis**. This is a randomized, double-blind, controlled trial with a primary objective to determine if the dose reduction strategy is not inferior to the continuation of the current JAKi dose in patients who are in a low disease activity or remission state. The trial is categorized as a low intervention phase IV study, with an estimated duration from May 2025 to May 2028.

Participants will be involved in the study for a maximum of 12 months. The trial will include several key visits: an initial screening visit to confirm eligibility based on criteria such as age (≥16 years), clinical diagnosis, and current treatment status. Follow-up visits will occur at regular intervals to monitor disease activity and adjust treatment as necessary. The primary endpoint is the proportion of patients maintaining low disease activity at 12 months, with secondary endpoints including mean disease activity scores, incidence of adverse events, and quality of life assessments.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit will involve detailed assessments to confirm eligibility, including disease activity scores and current medication regimens. Follow-up visits will be scheduled at 6 and 12 months to evaluate primary and secondary endpoints. The end-of-study visit will conclude the participant's involvement, with a final assessment of disease activity and any adverse events.

Participants may be withdrawn from the study if they experience significant adverse events, fail to adhere to the study protocol, or if the treating physician deems it necessary for their safety. The trial aims to provide valuable insights into the cost-effectiveness and safety of dose reduction strategies in managing inflammatory rheumatic diseases.

The clinical trial involves the administration of several **experimental medications** to evaluate their efficacy in patients with inflammatory rheumatic diseases. The first medication is **Jyseleca**, which contains the active substance **filgotinib**. It is available in two dosages: 100 mg and 200 mg, both in the form of film-coated tablets. The medication is administered orally with a maximum daily dose of 200 mg. The total maximum dose over the treatment period is 73,000 mg, and the treatment duration is up to 12 months.

Another medication used in the trial is **XELJANZ**, which contains the active substance **tofacitinib**. It is available in two formulations: 11 mg prolonged-release tablets and 5 mg film-coated tablets. Both forms are administered orally. The maximum daily dose for the 11 mg prolonged-release tablet is 11 mg, with a total maximum dose of 4,015 mg over the treatment period. For the 5 mg film-coated tablet, the maximum daily dose is 10 mg, with a total maximum dose of 3,650 mg over the treatment period. The treatment duration for both formulations is up to 12 months.

**RINVOQ**, containing the active substance **upadacitinib**, is also part of the trial. It is provided as 15 mg prolonged-release tablets, administered orally. The maximum daily dose is 15 mg, with a total maximum dose of 5,475 mg over the treatment period. The treatment duration is up to 12 months.

Additionally, the trial includes **Olumiant**, which contains the active substance **baricitinib**. It is available in two dosages: 4 mg and 2 mg, both in the form of film-coated tablets. The medication is administered orally with a maximum daily dose of 4 mg. The total maximum dose over the treatment period is 1,460 mg, and the treatment duration is up to 12 months.

All medications are administered orally, and participant compliance is monitored throughout the trial. The trial aims to assess the efficacy of a disease activity-guided dose reduction strategy for Janus Kinase inhibitors compared to the continuation of the current dosage in patients with rheumatoid arthritis, psoriatic arthritis, or axial spondyloarthritis who are in a low disease activity or remission state.

The efficacy of the clinical trial titled "REDO-JAK: Dose REDuction Of JAnus Kinase inhibitors in patients with inflammatory rheumatic diseases" will be assessed using specific primary and secondary endpoints. The primary endpoint is the proportion of patients in low disease activity (LDA) at 12 months of follow-up in each study group. LDA is defined by disease-specific criteria: for rheumatoid arthritis (RA) patients, a **DAS28-CRP** score of less than 2.9; for psoriatic arthritis (PsA) patients, a **PASDAS** score of less than 3.2 and psoriasis mBSA involvement of 3% or less; and for axial spondyloarthritis (axSpA) patients, an **ASDAS** score of less than 2.1 with no active extra musculoskeletal symptoms.

Secondary endpoints include the mean DAS28-CRP for RA patients, PASDAS for PsA patients, and ASDAS for axSpA patients at 6 and 12 months of follow-up. Additionally, the trial will evaluate the proportion of patients in the intervention group at each dose reduction step, including discontinuation, at 6 and 12 months. The study will also monitor the cumulative incidence and incidence density of treatment-related adverse events, focusing on infections, anemia, cardiovascular events, venous thromboembolism (VTE), and malignancies. Other secondary endpoints include the cumulative incidence of flares, the proportion of patients using csDMARDs, corticosteroids, or NSAIDs at baseline and during follow-up, and quality of life and cost comparisons between study groups. The incremental cost-effectiveness ratio will be calculated using incremental costs and quality of life, compared with different willingness-to-pay thresholds. The study will also explore associations between possible predictors, such as baseline peak and trough JAKi concentrations and whole blood/PBMC immunophenotyping, and outcomes.