A Randomized, Open-Label, Superiority Trial Comparing Subcutaneous Abatacept and Tocilizumab in Rheumatoid Arthritis Patients with Inadequate Response to Targeted Therapies

The primary objective of this study is to compare the **efficacy** of subcutaneously administered tocilizumab versus abatacept in patients with rheumatoid arthritis who have shown inadequate response to one or two targeted treatments. This comparison is clinically relevant as it aims to identify a more effective treatment option for patients who do not respond adequately to existing therapies, potentially improving patient outcomes and quality of life.

Secondary objectives include:

• Comparing disease progression between the treatment groups.
• Assessing treatment response and tolerance.
• Evaluating radiobiological criteria to provide pathophysiological explanations for differential responses between the drugs.
• Comparing treatment failure rates between the groups.

The clinical trial involves **adult patients** diagnosed with **rheumatoid arthritis** who have shown an inadequate response to one or two targeted treatments. The study population includes both male and female participants over the age of 18, with no upper age limit specified. Participants are required to have a moderate to high disease activity, as defined by a DAS28-ESR score greater than 3.2 and a CDAI score greater than 10, after at least three months of treatment with a first-line or second-line targeted therapy. The trial population was selected based on these criteria, and all participants must be beneficiaries of the French National Health Insurance Fund and have provided signed informed consent. Women of childbearing age are required to use effective contraception during the treatment period and for 14 weeks following the last administration. The sponsor has not provided information regarding the total number of participants. The trial includes a vulnerable population, indicating additional ethical considerations in the study design.

The clinical trial is designed to evaluate the efficacy of **tocilizumab** versus **abatacept** administered subcutaneously in adult patients with rheumatoid arthritis who have shown an inadequate response to one or two targeted treatments. This is a randomized, open-label, superiority trial. The trial is expected to last for approximately eight years, with an estimated recruitment start date of October 2, 2017, and an estimated end date of October 2, 2025. Participants will be involved in the study for a maximum treatment period of 12 months.

The trial includes several key study visits. The initial visit is the inclusion (screening) visit, where eligibility criteria are assessed, including age over 18 years, diagnosis of rheumatoid arthritis according to ACR/EULAR 2010 criteria, and inadequate response to previous treatments. Following the screening, participants will be randomized to receive either **tocilizumab** or **abatacept**. Subsequent follow-up visits are scheduled at 3, 6, and 12 months to assess primary and secondary endpoints, including the evolution of the Clinical Disease Activity Index (CDAI) and other measures of treatment response and tolerance.

The end-of-study visit will occur at the 12-month mark, where final assessments will be conducted. Participants may be withdrawn from the study early if they experience significant side effects, require a change in treatment, or fail to adhere to the study protocol. The primary endpoint is the change in CDAI at 6 months, while secondary endpoints include various measures of disease activity, quality of life, and treatment tolerance. The trial aims to provide a comprehensive evaluation of the comparative efficacy and safety of the two treatments in this patient population.

The clinical trial involves the administration of two experimental medications for the treatment of **rheumatoid arthritis** in patients who are inadequate responders to one or two targeted treatments. The first experimental medication is **ORENCIA** (abatacept), which is provided as a 125 mg solution for injection in a pre-filled syringe. This pharmaceutical form is a solution for injection, and the route of administration is subcutaneous. The maximum daily dose of abatacept is 17.86 mg, with a total maximum dose of 6500 mg over a treatment period of up to 12 months. The administration frequency is determined by the study protocol, and participant compliance is monitored throughout the trial. The active substance, abatacept, is a protein of other origin, and the product is manufactured by Bristol-Myers Squibb Pharma EEIG.

The second experimental medication is **RoActemra** (tocilizumab), which is provided as a 162 mg solution for injection in a pre-filled syringe. Similar to abatacept, this medication is also administered subcutaneously. The maximum daily dose for tocilizumab is 23.14 mg, with a total maximum dose of 8424 mg over a 12-month treatment period. The administration schedule is outlined in the study protocol, and adherence to the dosing regimen is closely monitored. Tocilizumab is also a protein of other origin, and the product is manufactured by Roche Registration GmbH.

Both medications are used in the trial to compare their efficacy in treating rheumatoid arthritis in patients who have not adequately responded to previous targeted treatments. The trial is designed as a randomized, open-label, superiority trial to evaluate the effectiveness of these medications when administered subcutaneously. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are mentioned in the trial data provided.

The efficacy of the clinical trial comparing **tocilizumab** and **abatacept** for the treatment of rheumatoid arthritis will be assessed using several primary and secondary endpoints. The primary endpoint is the evolution of the Clinical Disease Activity Index (CDAI) at 6 months. The CDAI is a composite score that includes Tender 28-joint count, Swollen 28-joint count, Patient Global Disease (PGA), and Evaluator's Global Disease Activity (EGA), providing a numerical assessment of disease activity independently of acute phase reactants.

Secondary endpoints will evaluate treatment response at baseline (M0) and at 3, 6, and 12 months. These include assessments of DAS28-ESR, DAS28-CRP, SDAI, HAQ, SF-36 FLARE-RA quality of life score, PGA and EGA VAS, CDAI, and DAS28-ESR LDA. The proportion of patients achieving good or moderate European League Against Rheumatism (EULAR) therapeutic response (DS28-ESR) and those achieving ACR20, ACR50, and ACR70 response will also be measured.

Additional secondary outcomes include tolerance observed at 3, 6, and 12 months, with the proportion of patients presenting at least one side effect according to the NCI-CTCAE v4.0 scale, rates of treatment withdrawals for intolerance, and the rate of rescue medication use. Radiobiological criteria will be assessed through changes in joint US-Doppler synovitis, Doppler hyperemia grade, Sharp score of radiographs, and levels of Vascular Endothelial Growth Factor (VEGF) and interleukin-6 plasma levels at specified time points.

The treatment failure rate will be defined at 3, 6, and 12 months by changes in treatment, CDAI > 10, corticosteroid therapy > 10 mg/d, and cortisone derivative infiltration prior to the assessment visit. These comprehensive assessments will provide a detailed evaluation of the efficacy of the treatments under investigation.