Evaluation of Dose Tapering Versus Continuation of JAK Inhibitors Baricitinib, Upadacitinib, Tofacitinib, and Filgotinib in Low Disease Activity Rheumatoid Arthritis

The primary objective of this study is to compare a **dose-tapering strategy** versus therapy continuation in patients with **rheumatoid arthritis** who are in low disease activity and treated with JAK inhibitors. The focus is on assessing the risk of losing low disease activity despite rescue therapy over a 12-month period. This is clinically relevant as it aims to optimize treatment regimens, potentially reducing medication exposure and associated side effects while maintaining disease control.

Secondary objectives include:

• Comparing tapering or spacing dose strategies versus therapy continuation on disease activity over time.
• Evaluating the delay before a first flare with different dosing strategies.
• Assessing the cumulative glucocorticoid dose at 12 months.
• Comparing patient-reported outcomes such as pain, function, fatigue, and quality of life at 12 months.
• Describing structural progression over 12 months in both groups.
• Describing the risk of adverse events, including serious infections and major cardiovascular events, at 12 months.
• Describing the proportion of patients in low disease activity at 12 months who could reduce the JAK inhibitor dose.
• Assessing risk factors for achieving low disease activity with a reduced JAK inhibitor dose.
• Evaluating the cost-utility and cost-effectiveness of the dose-tapering strategy versus continuous therapy from a collective perspective.
• Assessing the impact of socioeconomic characteristics on the cost of care and quality of life in each group at 12 months.

The clinical trial involves participants diagnosed with **rheumatoid arthritis**, as defined by the ACR/EULAR criteria. The study population includes both male and female subjects aged 18 years and older. Participants are required to have been treated with a JAK inhibitor at full dose for a minimum of six months, either as monotherapy or in combination with a csDMARD, with a stable dosage for at least three months prior to inclusion. All participants must have maintained low disease activity (CDAI ≤ 10) for at least six months and have a CRP level below the laboratory standard within the month before the inclusion visit. Women of childbearing potential are required to have a negative pregnancy test before starting the study. The sponsor has not provided information regarding the total number of participants. The trial does not include a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are highlighted in the selection criteria.

The clinical trial is designed to evaluate a **dose-tapering strategy** versus therapy continuation in patients with **rheumatoid arthritis** who are in low disease activity and treated with JAK inhibitors. This study is a randomized, double-blind, controlled trial with an estimated duration of four years, concluding in May 2028. Participants will be randomly assigned to either continue their current JAK inhibitor therapy or undergo a dose-tapering strategy. The primary endpoint is the proportion of patients maintaining low disease activity at 12 months, as measured by the Clinical Disease Activity Index (CDAI).

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening visit, will confirm eligibility based on criteria such as age (≥18 years), diagnosis of rheumatoid arthritis per ACR/EULAR criteria, and stable low disease activity for at least six months. Participants must have been on a full dose of a JAK inhibitor for at least six months prior to inclusion. Follow-up visits will occur at regular intervals to assess disease activity, adverse events, and other secondary endpoints, including patient-reported outcomes and quality of life measures. The end-of-study visit will evaluate the long-term effects of the dose-tapering strategy.

Participant involvement is expected to last for 12 months, with conditions for early termination including significant adverse events or withdrawal of consent. The trial will utilize oral administration of JAK inhibitors, including **baricitinib**, **upadacitinib**, **tofacitinib**, and **filgotinib**, with maximum daily doses specified for each. The study aims to provide insights into the efficacy and safety of dose reduction in maintaining low disease activity, potentially influencing future treatment guidelines for rheumatoid arthritis.

The clinical trial involves the administration of several **experimental medications** to evaluate a dose-tapering strategy in patients with low disease activity rheumatoid arthritis. The first medication, **Baricitinib**, is provided in the form of a film-coated tablet. The active substance, baricitinib, is of chemical origin. The maximum daily dose is 4 mg, administered orally. The treatment period for baricitinib is up to 12 months. Participants' compliance with the dosing schedule will be monitored throughout the study.

Another medication used in the trial is **Upadacitinib**, which is administered as a prolonged-release tablet. The active substance, upadacitinib, is also of chemical origin. The maximum daily dose for upadacitinib is 15 mg, taken orally. The treatment duration is set for a maximum of 12 months. Adherence to the dosing regimen will be closely observed to ensure participant compliance.

**Tofacitinib** is included in the study as a film-coated tablet. The active substance, tofacitinib, is chemically derived. The maximum daily dose is 10 mg, administered orally. The treatment period for tofacitinib is up to 12 months. Participant compliance with the dosing schedule will be systematically monitored.

The trial also involves the administration of **Filgotinib**, provided as a film-coated tablet. The active substance, filgotinib, is of chemical origin. The maximum daily dose is 200 mg, taken orally. The treatment duration is set for a maximum of 12 months. Compliance with the dosing regimen will be monitored to ensure adherence.

All medications in the trial are synthetic and are administered orally. The study does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The primary objective is to assess the risk of losing low disease activity despite rescue therapy at 12 months when employing a dose-tapering strategy with these JAK inhibitors.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints designed to evaluate the impact of a dose-tapering strategy versus therapy continuation in patients with **rheumatoid arthritis** who are in low disease activity. The primary endpoint is the proportion of patients still receiving a JAK inhibitor and maintaining low disease activity, as measured by the Clinical Disease Activity Index (CDAI), at 12 months. Secondary endpoints include disease activity over time assessed by CDAI, Simplified Disease Activity Index (SDAI), and Disease Activity Score 28 (DAS28) scores. Additionally, the delay between the inclusion visit and the first flare diagnosed by a physician will be measured, with flares defined by specific criteria including CDAI > 10 or an increase in DAS28-ESR scores.

Patient-reported outcomes will be collected over 12 months, including pain assessed by a visual analog scale (VAS), function by the Health Assessment Questionnaire (HAQ), flares by the FLARE questionnaire, fatigue by VAS and the FACIT-F questionnaire, and quality of life by the EQ-5D-5L and the Rheumatoid Arthritis Impact of Disease (RAID) score. The modified van der Heijde Total Sharp Score will be used to assess radiographic progression between baseline and the 12-month visit. The trial will also record the number of adverse events and severe adverse events at 12 months, as well as the number and percentage of patients in CDAI low disease activity who could reduce the JAK inhibitor dosage in the dose-tapering arm.

Economic evaluations will be conducted, including incremental cost-utility and cost-effectiveness ratios (ICUR and ICER) from a collective perspective, expressed in terms of cost per quality-adjusted life year (QALY) and cost per patient without major flares at 12 months. Socioeconomic characteristics such as occupation, level of income, and education will be recorded to assess their impact on care costs and efficiency. The trial is designed to provide comprehensive data on the efficacy and economic implications of dose-tapering strategies in maintaining low disease activity in rheumatoid arthritis patients treated with JAK inhibitors.