Comparison of Efficacy of Subcutaneous Abatacept Versus Adalimumab on Methotrexate in Early Seropositive Rheumatoid Arthritis with HLA Class II Risk Alleles

The primary objective of this study is to demonstrate the superiority in efficacy of **abatacept** compared with **adalimumab**, both administered with background methotrexate (MTX), in achieving a clinical response, specifically the ACR50 criteria, at Week 24. This is targeted at patients with early, seropositive rheumatoid arthritis (RA) who possess the "Shared Epitope" HLA Class II risk alleles (SE+). The clinical relevance of this objective lies in its potential to identify a more effective treatment regimen for this specific patient population, which could lead to improved management of RA symptoms and disease progression.

Secondary objectives include:

• Comparing the efficacy of abatacept with adalimumab, both on background MTX, in achieving clinical remission criteria (DAS28-CRP remission) at Week 24 in early, seropositive RA patients with SE+ alleles.
• Comparing the efficacy of abatacept with adalimumab, both on background MTX, in achieving clinical response (ACR50) at Week 24 in the entire study population of early, seropositive RA patients.
• Comparing the efficacy of abatacept with adalimumab, both on background MTX, in achieving clinical remission criteria (CDAI remission) at Week 24 in early, seropositive RA patients with SE+ alleles.
• Comparing the efficacy of abatacept with adalimumab, both on background MTX, in achieving improvement in pain at Week 24 in early, seropositive RA patients with SE+ alleles.
• Determining the efficacy over time by treatment in early, seropositive RA patients (SE+ subset and whole population).
• Determining the improvement in health-related quality of life over time by treatment in early, seropositive RA patients (SE+ subset and whole population).

The clinical trial involves a total of **259 participants** diagnosed with **Rheumatoid Arthritis**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific criteria, including early rheumatoid arthritis symptoms that began within 12 months prior to screening and meeting the American College of Rheumatology/European League Against Rheumatism 2010 criteria for RA classification. All participants are seropositive for rheumatoid factor and anti-cyclic citrullinated peptide-2, with a Disease Activity Score 28-joint count using C-reactive protein of at least 3.2. They have been treated with methotrexate for a minimum of 12 weeks, maintaining a stable dose for at least 4 weeks before randomization. The trial includes individuals with at least three tender and swollen joints at both screening and randomization. The study does not exclude vulnerable populations, and lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, head-to-head, single-blind study to evaluate the efficacy of subcutaneous **abatacept** compared to **adalimumab** in adults with early, seropositive **rheumatoid arthritis** who have an inadequate response to methotrexate. The trial aims to demonstrate the superiority of abatacept in achieving a clinical response, specifically an ACR50 response, at Week 24. The study will involve participants who meet specific inclusion criteria, such as having early rheumatoid arthritis symptoms that began within 12 months prior to screening and being naïve to any targeted disease-modifying antirheumatic drugs other than methotrexate. Participants must have been treated with methotrexate for at least 12 weeks with a stable dose for at least 4 weeks prior to randomization.

The trial will span an estimated duration from September 15, 2021, to July 24, 2025. Participants will be involved in the study for a maximum treatment period of 104 weeks. The study visits will include an initial screening visit to confirm eligibility based on the inclusion criteria, followed by randomization. Subsequent visits will occur at regular intervals to monitor the participants' response to treatment and assess primary and secondary endpoints, such as the proportion of participants achieving DAS28-CRP remission and changes in participant-reported pain. The end-of-study visit will conclude the trial, where final assessments will be conducted.

Participants may be withdrawn from the study if they experience adverse events that compromise their safety, fail to adhere to the study protocol, or withdraw consent. The trial is conducted under controlled conditions to ensure the reliability and validity of the results, with a focus on maintaining the integrity of the data collected throughout the study period.

The clinical trial involves the administration of two **experimental medications**: **Adalimumab** and **Abatacept**, both used in the treatment of early, seropositive **Rheumatoid Arthritis**. **Adalimumab** is provided as a 40 mg solution for injection in a pre-filled syringe, manufactured by AbbVie Deutschland GmbH & Co. KG. It is administered via **subcutaneous use**. The maximum daily dose is 40 mg, with a total maximum dose of 440 mg over a treatment period of 22 weeks. The pharmaceutical form is a solution for injection, and it is not a pediatric formulation. The active substance, **Adalimumab**, is a protein of non-human origin, classified under the ATC code L04AB04.

**Abatacept** is provided as a 125 mg/mL solution for injection, manufactured by Bristol-Myers Squibb International Corporation. It is also administered via **subcutaneous use**. The maximum daily dose is 125 mg, with a total maximum dose of 13,000 mg over a treatment period of 104 weeks. The pharmaceutical form is a solution for injection, and it is not a pediatric formulation. The active substance, **Abatacept**, is a fusion protein of non-human origin. The sponsor product code for Abatacept is BMS188667.

Both medications are administered in conjunction with background Methotrexate (MTX) therapy, which is considered the standard-of-care therapy in this study. The trial aims to compare the efficacy of Abatacept versus Adalimumab in achieving a clinical response at Week 24. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment protocol.

Efficacy in this clinical trial will be assessed by evaluating the primary and secondary endpoints related to the treatment of early, seropositive **rheumatoid arthritis** (RA). The primary endpoint is the proportion of participants with the shared epitope (SE+) achieving an ACR50 response at Week 24. Secondary endpoints include the proportion of SE+ participants achieving DAS28-CRP remission (DAS28-CRP < 2.6) at Week 24, the proportion of the entire study population meeting ACR50 response at Week 24, and the proportion of SE+ participants achieving CDAI remission (CDAI ≤ 2.8) at Week 24. Additionally, mean changes from baseline in SE+ participant-reported pain using the Visual Analog Scale (VAS) at Week 24 will be measured.

Further assessments will include the proportion of SE+ subset and whole population achieving ACR20/50/70 responses, DAS remission, CDAI remission, and SDAI remission over the study's blinded treatment period (SBTP) and open-label treatment period (OLTP). Mean changes from baseline in DAS28-CRP, CDAI, SDAI, and the 7 ACR core components over the SBTP and OLTP will also be evaluated. The mean change from baseline in the SF-36, covering 4 physical and 4 mental subscales, as well as the physical and mental component summaries, will be assessed at Week 24 and Week 104.