Efficacy of a sequential treatment strategy in Rheumatoid Arthritis. A randomized controlled trial with an independent efficacy assessor.

The primary objective of this study is to evaluate the **efficacy** of a sequential therapeutic strategy using abatacept compared to a routine strategy continuing TNF inhibitors (TNFi) in achieving remission in patients with **Rheumatoid Arthritis** (RA) who are ACPA positive and have responded to a first TNFi. Remission is defined as a DAS28-CRP score of less than 2.6, assessed over a 36-week period following randomization. This objective is clinically relevant as achieving remission in RA is crucial for improving patient outcomes and quality of life.

Secondary objectives include: - Comparing the proportion of patients in remission and low disease activity at 12, 24, and 36 weeks using different definitions. - Evaluating the proportion of responders based on EULAR response criteria. - Assessing variations in patient-reported outcomes and auto-antibody titers (RF and ACPA) compared to baseline, and their association with remission. - Comparing the number of flares using the FLARE self-questionnaire. - Analyzing the 36-week cumulative dose of steroids and serious adverse events, including severe infections. - Evaluating the 36-week cumulative cost-effectiveness. - Assessing radiographic progression and treatment retention at 48 weeks compared to baseline.

The clinical trial involves a total of **10 participants** diagnosed with **Rheumatoid Arthritis**. The study population includes both male and female subjects aged 18 years and above. Participants are required to have a diagnosis of Rheumatoid Arthritis according to the ACR-EULAR 2010 criteria and must be ACPA positive. All participants are under treatment with methotrexate or leflunomide for at least 3 months prior to the trial. The trial does not include a vulnerable population. Participants were selected based on their response to a first TNF inhibitor initiated 12 weeks before randomization, with a specific focus on those who have not previously been treated with targeted DMARDs. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection criteria ensure that participants have a DAS28-CRP score greater than 3.2 under methotrexate or leflunomide, calculated with CRP dated less than 7 days from baseline, and have shown an escape under synthetic background treatment as defined by an elevation of CRP or ESR within the last 6 months before baseline.

The clinical trial is designed to evaluate the **efficacy** of a sequential treatment strategy in patients with **Rheumatoid Arthritis**. This study is a randomized, controlled trial with an independent efficacy assessor, aiming to compare the percentage of remission achieved with a sequential therapeutic strategy using **abatacept** versus a routine strategy continuing TNF inhibitors in ACPA positive patients. The trial will span a total duration of 48 weeks, with the primary endpoint being the percentage of patients in remission, defined by a DAS28-CRP score of less than 2.6, during the 36 weeks following randomization.

Participants will be involved in the study for a maximum of 48 weeks, with the treatment period lasting 36 weeks. The trial will commence with an inclusion visit, where eligibility criteria such as age (18 years or above), diagnosis of **Rheumatoid Arthritis** according to ACR-EULAR 2010, and ACPA positivity will be confirmed. Participants must have been under methotrexate or leflunomide treatment for at least 3 months and must meet specific disease activity criteria. Following the inclusion visit, participants will be randomized to receive either the experimental treatment with **abatacept** or continue with their current TNF inhibitor.

Study visits will occur at baseline, and at 12, 24, and 36 weeks post-randomization, with additional follow-up visits extending to 48 weeks. These visits will assess various secondary endpoints, including remission rates using different criteria, patient-reported outcomes, and safety assessments. The end-of-study visit will occur at 48 weeks, marking the conclusion of participant involvement. Conditions that may lead to early termination from the study include the occurrence of serious adverse events or withdrawal of consent by the participant. The trial is structured to ensure rigorous assessment of the treatment's efficacy and safety, with data collected at each visit contributing to the overall analysis of the therapeutic strategy's impact on **Rheumatoid Arthritis** management.

The clinical trial involves the administration of **ORENCIA** 125 mg, a **solution for injection** in a pre-filled syringe, containing the active substance **abatacept**. This pharmaceutical form is specifically designed for **subcutaneous use**. The medication is administered at a maximum daily dose of 17.86 mg, with a total maximum dose of 4500 mg over the course of the study. The treatment period is set for a maximum of 36 weeks. Abatacept is a protein-based therapeutic agent, classified under the ATC code L04AA24, and is produced by Bristol-Myers Squibb Pharma EEIG. The administration schedule and participant compliance are closely monitored to ensure adherence to the dosing regimen.

In addition to the experimental treatment, the study includes a comparator treatment involving the continuation of **TNF inhibitors** (TNFi) as part of a routine strategy. This comparator is used to evaluate the efficacy of the sequential therapeutic strategy with abatacept in achieving remission in patients with **Rheumatoid Arthritis**. The trial aims to compare the percentage of remission, defined as DAS28-CRP<2.6, over the 36-week period following randomization. The study is designed to assess the effectiveness of abatacept in ACPA positive RA patients who have shown a response to a first TNFi initiated 12 weeks prior to randomization.

Efficacy in this clinical trial will be assessed by evaluating the percentage of patients achieving **remission** in Rheumatoid Arthritis, defined by a Disease Activity Score in 28 joints with C-reactive protein (DAS28-CRP) of less than 2.6. This primary endpoint will be measured over a 36-week period following randomization, utilizing a mixed logistic regression model for repeated data. Secondary endpoints include the percentage of patients in remission using alternative definitions such as DAS28-ESR<2.6, Clinical Disease Activity Index (CDAI) ≤2.8, Simplified Disease Activity Index (SDAI) ≤3.3, and Boolean criteria, assessed at 12, 24, and 36 weeks post-randomization. Additional secondary endpoints involve the proportion of responders according to the European League Against Rheumatism (EULAR) definition, variations in patient-reported outcomes like the Health Assessment Questionnaire (HAQ-DI), EQ5D, and SF-36, as well as changes in auto-antibody titers and their correlation with remission rates.

Patient-reported outcomes will be collected using validated instruments such as the HAQ-DI, EQ5D, and SF-36. The frequency of disease flares will be assessed using the FLARE-RA questionnaire, completed by patients between visits. Cumulative steroid doses will be documented in a booklet from 12 to 48 weeks. Safety will be monitored by recording serious adverse events, including severe infections, from the randomization visit at week 12 to week 48. A cost-efficacy analysis will be conducted based on direct and indirect costs and quality-adjusted life years (QALY) between the randomization visit and week 48. Radiographic progression will be evaluated using the Sharp modified by Van der Heidje score from baseline to 48 weeks. The percentage of patients remaining on abatacept in the sequential arm and on the first TNF inhibitor in the control arm at 48 weeks will also be assessed.