Comparative Efficacy and Tolerability of Oral Versus Subcutaneous Methotrexate in Early Rheumatoid Arthritis: A Randomized Multicenter Study

The primary objective of this study is to evaluate the difference in **DAS28** (Disease Activity Score in 28 joints) over a 12-month follow-up period between patients with newly diagnosed **rheumatoid arthritis** (RA) who are randomized to receive either oral or subcutaneous **methotrexate**. This objective is clinically relevant as it aims to determine the most effective administration route for methotrexate, a cornerstone treatment in RA management, potentially influencing treatment guidelines and patient outcomes.

Secondary objectives include:

• Assessing drug retention after 24 months.
• Evaluating treatment efficacy in other aspects.
• Recording the number of adverse events.
• Investigating changes in gut microbiota driven by oral versus subcutaneous methotrexate.
• Understanding the trade-offs newly diagnosed RA patients are willing to make regarding methotrexate treatment.
• Determining the maximum acceptable levels of risks for newly diagnosed RA patients.
• Comparing health-related quality of life in patients treated with oral versus subcutaneous methotrexate during the first two years of treatment.
• Exploring the possibility of further modeling differences in health-related quality of life during extended follow-up.

The clinical trial involves participants diagnosed with **rheumatoid arthritis**, with an age range of 18 to 95 years. Both male and female subjects are included in the study, and the trial does not involve a vulnerable population. The sponsor has not provided the total number of participants. The study population was selected based on specific criteria, including a confirmed diagnosis of rheumatoid arthritis by a rheumatologist according to the 2010 Rheumatoid Arthritis Classification Criteria, and an indication for methotrexate treatment. Participants are required to have given written consent to participate. Women of childbearing capacity must adhere to highly effective contraception methods and have a negative pregnancy test, while male participants with fertile female partners must use adequate contraception. The trial does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the **efficacy** and tolerability of **methotrexate** in patients with early **rheumatoid arthritis**. This study is a randomized, double-blind, controlled trial comparing oral and subcutaneous administration of methotrexate. The trial is expected to last until December 31, 2026, with an estimated recruitment start date of April 28, 2022. Participants will be involved in the study for a maximum treatment period of 24 months, receiving methotrexate at doses ranging from 5 to 30 mg once weekly, either orally or subcutaneously.

The sequence of study visits includes an initial screening visit to confirm eligibility based on criteria such as age (18-95 years), diagnosis of rheumatoid arthritis, and consent to participate. Women of childbearing capacity must use effective contraception and have a negative pregnancy test, while male participants with fertile partners must also use adequate contraception. Following the screening, participants will undergo regular follow-up visits to monitor the primary endpoint, which is the change in DAS28 over 12 months. Secondary endpoints include the number of swollen and tender joints, HAQ, VAS pain, VAS general health, VAS fatigue, and other health assessments.

The end-of-study visit will assess the overall outcomes and any adverse events experienced by participants. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or any adverse events that pose a risk to the participant's health. The trial aims to provide comprehensive data on the preferences and outcomes of methotrexate administration routes in managing rheumatoid arthritis.

The clinical trial involves the administration of **methotrexate** in two different pharmaceutical forms to evaluate its efficacy, tolerability, and patient preferences in individuals with early rheumatoid arthritis. The first form of the experimental medication is **methotrexate** in a **tablet** form. This formulation is administered orally, with a dosage range of 5 to 30 mg taken once weekly. The maximum daily dose is 30 mg, and the total maximum dose over the treatment period is 3120 mg. The treatment duration is set for a maximum of 24 weeks. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

The second form of the experimental medication is **methotrexate** as a **solution for injection**. This formulation is administered subcutaneously, with the same dosage range of 5 to 30 mg once weekly. Similar to the oral form, the maximum daily dose is 30 mg, and the total maximum dose over the treatment period is 3120 mg. The treatment period is also set for a maximum of 24 weeks. Participant compliance with the subcutaneous administration is closely monitored to ensure accurate adherence to the prescribed dosing regimen.

Both forms of **methotrexate** are used as part of the standard treatment for rheumatoid arthritis, and no additional non-experimental treatments, such as placebo or comparator treatments, are included in this study. The trial aims to assess the difference in DAS28 scores over a 12-month follow-up period between patients receiving oral versus subcutaneous **methotrexate**. The study is designed to provide insights into the most effective and preferred method of administration for patients with newly diagnosed rheumatoid arthritis.

The efficacy of the clinical trial will be assessed by evaluating the primary endpoint, which is the difference in **DAS28** (Disease Activity Score in 28 joints) over a 12-month follow-up period between patients with newly diagnosed rheumatoid arthritis randomized to either oral or subcutaneous methotrexate. Secondary endpoints include a comprehensive set of parameters such as the number of swollen and tender joints, Health Assessment Questionnaire (HAQ) scores, Visual Analogue Scale (VAS) for pain, general health, and fatigue, as well as the doctor's global assessment. Additional secondary endpoints involve drug retention rates, including the number of individuals prescribed biologic treatment, patient contact with healthcare providers, and the use of other medications such as corticosteroids and biologics.

Further secondary endpoints include laboratory measures such as Erythrocyte Sedimentation Rate (ESR) and C-reactive protein (CRP) levels, the number of adverse events (AE), patient preferences, EQ5D scores, gut microbiota analysis, and questions on diet and alcohol consumption. These efficacy parameters will be collected and analyzed at specified time points throughout the trial duration, ensuring a robust assessment of the treatment's impact on disease activity and patient quality of life. The trial is designed as a randomized, register-based multicenter study, providing a comprehensive evaluation of methotrexate's efficacy in treating early rheumatoid arthritis.