Evaluation of Methotrexate Efficacy in Achieving Clinical Disease Activity Index Remission in Patients with Active Rheumatoid Arthritis

The primary objective of the MethMax trial is to evaluate the proportion of patients with **rheumatoid arthritis** achieving Clinical Disease Activity Index (CDAI) remission, defined as a score of ≤2.8, at week 24. This objective is clinically relevant as achieving remission is a key goal in the management of rheumatoid arthritis, potentially leading to improved patient outcomes and quality of life.

Secondary objectives include assessing the proportion of patients achieving CDAI low disease activity, American College of Rheumatology (ACR) scores of ACR20%, ACR50%, and ACR70%, as well as patient-reported outcomes and inflammatory markers at various timepoints. Additionally, exploratory objectives involve the assessment of methotrexate-polyglutamates (MTX-PGs), sweat metabolites, treatment adherence, safety parameters, and cumulative glucocorticoid dose. These secondary and exploratory objectives aim to provide a comprehensive understanding of the treatment's efficacy and safety profile, as well as its impact on various clinical and biochemical parameters.

The clinical trial involves a total of **30 participants** diagnosed with **Rheumatoid Arthritis**. The study population includes both **men and women** aged **18 years and older**, who are capable of understanding and signing an informed consent. Participants are required to have been on a stable dose of oral methotrexate, ranging from 10mg to 25mg weekly, for at least three months, with clinical and laboratory tolerance for a minimum of 12 weeks. The trial does not include a vulnerable population. Participants must have a Clinical Disease Activity Index (CDAI) greater than 2.8 and at least one clinically swollen joint, as per the 28-Joint count. The selection criteria ensure that participants are willing to adjust their methotrexate dosing and administration route according to the study procedures. The trial does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed as a **randomized**, assessor-blinded, parallel-group study to evaluate the efficacy of **methotrexate** in patients with active **rheumatoid arthritis**. The trial will involve a low-intervention approach, focusing on optimizing the dose and route of administration of methotrexate. Participants will be randomly assigned to either a dose/route optimization group, where oral methotrexate (≥10mg weekly) is switched to 25mg subcutaneously weekly, or an oral dose optimization group, where the oral dose is increased to 25mg weekly. The primary endpoint is the achievement of remission, defined as a Clinical Disease Activity Index (CDAI) ≤2.8, assessed 24 weeks after randomization.

The trial is expected to commence recruitment on April 22, 2024, and conclude by March 30, 2026. Participants will be involved in the study for a maximum of 24 weeks. The study will include several key visits: an initial screening visit to confirm eligibility based on criteria such as age, diagnosis of rheumatoid arthritis, and current methotrexate therapy; baseline visit for randomization and initial assessments; follow-up visits at weeks 12 and 24 to monitor disease activity and treatment response; and an end-of-study visit to evaluate the primary and secondary endpoints. Secondary endpoints include assessments of CDAI low disease activity, American College of Rheumatology (ACR) response rates, and changes in patient-reported outcomes and inflammatory markers.

Participants may be withdrawn from the study if they experience significant adverse events, fail to adhere to the study protocol, or if the investigator deems it necessary for their safety. The trial will adhere to ethical standards, ensuring informed consent is obtained from all participants. The study aims to provide valuable insights into the optimization of methotrexate therapy, potentially improving treatment outcomes for patients with rheumatoid arthritis.

The clinical trial involves the administration of **methotrexate** in two pharmaceutical forms. The first form is **EBETREXAT 20mg/ml solution for injection**, provided in a pre-filled syringe. This formulation is intended for **subcutaneous** administration. The maximum daily dose is 25 mg, with a total maximum dose of 600 mg over a treatment period of up to 24 weeks. The solution is manufactured by EBEWE PHARMA and is classified under the ATC codes L01BA01 and L04AX03, indicating its use as an immunomodulatory medicinal product. Participant compliance with the dosing schedule will be monitored throughout the trial.

The second form of **methotrexate** used in the trial is **Ebetrexat 10 mg tablets**. These tablets are administered **orally**. Similar to the injectable form, the maximum daily dose is 25 mg, with a total maximum dose of 600 mg over a 24-week treatment period. The tablets are also produced by EBEWE PHARMA and share the same ATC classification as the injectable form. The trial will ensure adherence to the dosing regimen through regular monitoring of participant compliance.

Both forms of methotrexate are chemically derived and are not designated as orphan drugs. The trial does not include any non-experimental treatments such as placebo or comparator treatments. The primary objective of the trial is to evaluate the efficacy of methotrexate in achieving Clinical Disease Activity Index (CDAI) remission in patients with active rheumatoid arthritis by week 24.

Efficacy in the MethMax trial will be assessed primarily through the achievement of remission in patients with active rheumatoid arthritis, as defined by the **Clinical Disease Activity Index (CDAI)** score of ≤2.8 at week 24. This primary endpoint will compare patients undergoing dose/route optimization, where oral methotrexate (MTX) of ≥10 mg weekly is switched to 25 mg MTX subcutaneously weekly, against those with oral dose optimization, where the same oral dose is increased to 25 mg weekly.

Secondary endpoints include the proportion of subjects achieving CDAI low disease activity (≤10) and remission (≤2.8) at weeks 12 and 24. Additionally, the trial will evaluate the proportion of subjects achieving American College of Rheumatology (ACR) responses of 20%, 50%, and 70% at both week 12 and week 24. Patient-reported outcomes, such as pain, patient global assessment, and scores from the Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F), the 36-Item Short Form Survey version 1 (SF36v1), and the modified Health Assessment Questionnaire (mHAQ), will be analyzed for changes between baseline and weeks 12 and 24. Changes in swollen joint count, tender joint count, and C-reactive protein (CRP)/erythrocyte sedimentation rate (ESR) will also be assessed at these timepoints.

Exploratory endpoints will explore associations between methotrexate polyglutamates (MTX-PGs) levels and CDAI response, MTX dosage, and torque teno virus titer as potential markers for guiding immunosuppressive therapy. The study will also investigate the association of MTX-metabolites and inflammatory markers in finger sweat analysis, differences in cumulative glucocorticoid dose, and treatment adherence as measured by paper-based questionnaires, methotrexate metabolites, and electronic adherence monitoring. Safety profiles will be explored through the number of adverse events and affected organ systems, and disease activity trajectories will be analyzed in relation to predictors over all visits.