Evaluation of Methotrexate and Glucocorticoid Regimen with Optional Etanercept in Early Rheumatoid Arthritis: A Randomized, Multicenter Trial

The primary objective of this study is to evaluate the long-term effectiveness of accelerated access to a six-month course of anti-TNF therapy, specifically **etanercept**, in patients with early **Rheumatoid Arthritis** (RA) who exhibit an insufficient response to the COBRA-Slim remission induction strategy. This is assessed by comparing the area under the DAS28CRP curve from baseline until week 104, with the aim of understanding the overall evolution in disease burden over the first two years of treatment. This outcome is clinically significant as it considers the speed and stability of the response and the necessity for consecutive treatment adaptations.

The secondary objective is to investigate whether accelerated access to a six-month course of anti-TNF therapy, in insufficient responders to the COBRA-Slim regimen, leads to improved remission rates compared to conventional treatment adaptation according to the COBRA-Slim strategy, 28 weeks after randomization into one of two treatment arms.

The clinical trial focuses on individuals diagnosed with **Rheumatoid Arthritis** as defined by the ACR/EULAR2010 criteria for early RA, with a diagnosis made within one year. The study population includes both male and female participants, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants are not from a vulnerable population. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Selection criteria include the ability to understand and write in Dutch or French, and for women of childbearing potential, the use of a reliable method of contraception is required. Participants must be able and willing to give written informed consent. Lifestyle considerations such as diet, physical activity, or habits are not detailed in the available data.

The clinical trial is designed to evaluate the effectiveness of a combination therapy for **Rheumatoid Arthritis** (RA) using a randomized, double-blind, controlled methodology. The trial consists of two parts: a randomized controlled trial (RCT) and a long-term extension (LTE) observational follow-up. The RCT aims to assess the long-term effectiveness of accelerated access to a six-month course of anti-TNF therapy, specifically **etanercept**, compared to the standard COBRA-Slim strategy in patients with early RA who show insufficient response to initial treatment. The LTE part will observe the clinical disease course and safety over three years following the RCT.

The trial is expected to last until June 2025, with participant recruitment having started in June 2018. Participants will be involved for a maximum of 104 weeks in the RCT, with an additional 156 weeks for those continuing into the LTE phase. The study includes several key visits: an initial screening visit to confirm eligibility based on criteria such as a diagnosis of RA within the past year and the ability to provide informed consent. Follow-up visits will occur at regular intervals to monitor disease activity using the DAS28CRP score, assess treatment efficacy, and record any adverse events. The end-of-study visit will conclude the participant's involvement, unless early termination is warranted due to reasons such as significant adverse reactions or withdrawal of consent.

Participants will be randomly assigned to receive either the COBRA-Slim Bio-Induction or the Standard COBRA-Slim Induction. The primary endpoint for the RCT is the area under the DAS28CRP curve over 104 weeks, while secondary endpoints include remission rates and radiographic progression. For the LTE, the primary endpoint is the area under the DAS28CRP curve over 260 weeks. Conditions for early termination include failure to adhere to the study protocol, development of exclusion criteria, or significant adverse events. The trial is categorized as low-intervention, aligning with the marketing authorization for the use of **etanercept** and **leflunomide** in RA patients.

The clinical trial involves the administration of **Enbrel**, a 50 mg solution for injection in a pre-filled pen, containing the active substance **etanercept**. This medication is administered subcutaneously. The maximum daily dose is 50 mg, with a total maximum dose of 8.4 grams over a treatment period of 24 weeks. Enbrel is produced by Pfizer Europe MA EEIG and is classified under the ATC code L04AB01. The pharmaceutical form is a solution for injection, specifically designed for subcutaneous administration, ensuring precise dosing and ease of use for participants.

Another experimental medication used in the trial is **Benepali**, also a 50 mg solution for injection in a pre-filled pen, containing the active substance **etanercept**. Similar to Enbrel, Benepali is administered subcutaneously with a maximum daily dose of 50 mg and a total maximum dose of 8.4 grams over a 24-week treatment period. Benepali is manufactured by Samsung Bioepis NL B.V. and shares the same ATC classification as Enbrel, L04AB01. The use of a pre-filled pen facilitates accurate dosing and enhances participant compliance.

The trial also includes the administration of **Leflunomide**, which is provided in tablet form. The active substance is **leflunomide**, and it is administered orally. The maximum daily dose for Leflunomide is 20 mg, with a total maximum dose of 35.28 grams over a treatment period of 252 weeks. Leflunomide serves as a comparator treatment in the study, providing a standard-of-care therapy against which the effectiveness of the experimental treatments can be measured. The oral route of administration is chosen for its convenience and established efficacy in the management of rheumatoid arthritis.

Efficacy in this clinical trial will be assessed using the **DAS28CRP** (Disease Activity Score in 28 joints with C-reactive protein) as the primary endpoint. The primary objective is to evaluate the long-term effectiveness of accelerated access to a six-month course of anti-TNF therapy (etanercept) compared to the standard COBRA-Slim strategy in patients with early Rheumatoid Arthritis (RA) who have an insufficient response to initial treatment. The primary endpoint for the randomized controlled trial (RCT) part is the area under the DAS28CRP curve over 104 weeks, which reflects the overall evolution in disease burden, considering the speed and stability of the response and the need for consecutive treatment adaptations.

Secondary endpoints include the proportion of insufficient responders achieving remission (DAS28CRP<2.6) 28 weeks after randomization, clinical efficacy measures such as remission at week 104, EULAR response at 28 weeks and week 104, and HAQ response at the same time points. Radiographic progression will be assessed through X-ray evaluations at weeks 52 and 104 compared to baseline. Safety will be monitored by recording side effects and serious adverse reactions from baseline until week 104. Additionally, the primary outcome will be evaluated using the DAS28ESR (Erythrocyte Sedimentation Rate) instead of DAS28CRP.

For the long-term extension (LTE) part, the area under the DAS28CRP curve over 260 weeks will be assessed to determine long-term effectiveness. The LTE part will also evaluate the clinical efficacy and safety of the accelerated access to Etanercept strategy versus the classic COBRA Slim strategy over a three-year follow-up period. These assessments will provide comprehensive insights into the treatment's impact on disease progression and patient outcomes.