Comparative Efficacy of Methotrexate and Methotrexate/Metformin in Methotrexate-Naive Rheumatoid Arthritis Patients: A Randomized, Placebo-Controlled Trial

The primary objective of this randomized placebo-controlled trial is to compare the efficacy of a **Methotrexate/Metformin** combination versus Methotrexate alone in reducing the activity of **rheumatoid arthritis** (RA) in Methotrexate-naive patients after 6 months of treatment. This is clinically relevant as it may offer insights into optimizing treatment regimens for RA, potentially improving patient outcomes by identifying more effective therapeutic strategies.

Secondary objectives include:

• Describing the proportion of patients achieving remission (DAS28-ESR ≤ 2.6) at 6, 12, and 24 months in both randomization groups.
• Describing the proportion of patients achieving a low level of activity (DAS28-ESR ≤ 3.2) at 6 months in both randomization groups.
• Describing the mean dose of Methotrexate prescribed at 6, 12, and 24 months in both randomization groups.
• Describing clinical and laboratory parameters related to metabolism in both randomization groups.
• Describing the frequency of occurrence of serious adverse events in both randomization groups.
• Describing the quality of life of patients in both randomization groups.

The clinical trial focuses on individuals diagnosed with **rheumatoid arthritis (RA)**, aiming to evaluate the efficacy of Methotrexate/Metformin compared to Methotrexate alone in reducing RA activity over a six-month period. The study population includes both male and female participants, aged over 18 years, who are Methotrexate-naive or have not taken Methotrexate for more than six months. Participants must meet the American College of Rheumatology (ACR) 2010 criteria for RA and have a Disease Activity Score (DAS28-ESR) greater than 3.2. The trial includes a vulnerable population, and all participants are required to be affiliated with a health insurance system and have signed an informed consent form. The sponsor has not provided the total number of participants involved in the study. Key lifestyle considerations include the requirement for active contraception for both male and female participants during the study and for six months following the conclusion of Methotrexate treatment, due to the teratogenic potential of the medication.

The clinical trial is designed to evaluate the efficacy of a **Methotrexate**/**Metformin** combination compared to **Methotrexate** alone in patients with **rheumatoid arthritis**. This study is a randomized, placebo-controlled, double-blind trial, ensuring that neither the participants nor the researchers know which treatment the participants are receiving, thus minimizing bias. The trial is set to last for a total duration of 24 months, with the primary objective being the assessment of the decrease in rheumatoid arthritis activity after 6 months of treatment.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to determine eligibility based on specific criteria, such as being over 18 years old, having a **Disease Activity Score** (DAS28-ESR) greater than 3.2, and being **Methotrexate**-naïve. Following the screening, eligible participants will be randomized into one of the treatment groups. Follow-up visits will occur at regular intervals to monitor the participants' health, assess the primary and secondary endpoints, and ensure adherence to the study protocol. The primary endpoint is the level of rheumatoid arthritis activity as measured by the DAS28 score. Secondary endpoints include the proportion of patients achieving remission, changes in metabolic parameters, and the occurrence of serious adverse events.

The expected length of participant involvement is up to 24 months, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. Participants are required to adhere to specific conditions, such as using effective contraception during and after the study, to ensure safety and compliance with the study protocol. The end-of-study visit will involve a comprehensive assessment to evaluate the overall outcomes and any long-term effects of the treatment. This trial aims to provide valuable insights into the potential benefits of combining **Methotrexate** with **Metformin** in managing rheumatoid arthritis.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Calcium folinate**, also known as leucovorin calcium, is utilized in the study as an auxiliary treatment. It is administered orally in a pharmaceutical form designated as PHF00169MIG. The maximum daily dose is 10 mg, with a treatment period limited to one day. This compound is classified under the ATC code B03BB01, indicating its role as an anti-anemic agent.

**Metformin hydrochloride** is employed as a test treatment in the trial. It is provided in the form of a film-coated tablet, specifically METFORMINE ARROW LAB 500 mg. The administration route is oral, with a maximum daily dose of 1500 mg. The treatment duration extends up to six months. Metformin is categorized under the ATC code A10BA02, which identifies it as a medication used in the management of diabetes.

**Methotrexate** is included in the study in two forms: as a tablet and as an injection. Both forms are used as test treatments. The tablet form is administered orally, while the injection form is delivered via injection. The maximum daily dose for both forms is 25 mg, with a treatment period of up to 24 months. Methotrexate is recognized for its immunosuppressive properties and is used in the management of various autoimmune conditions.

**Prednisolone** is another auxiliary treatment in the trial, administered orally in a pharmaceutical form identified as PHF00245MIG. The maximum daily dose is 7.5 mg, with a treatment period of up to five days. Prednisolone is classified under the ATC code H02AB07, indicating its use as a corticosteroid for anti-inflammatory and immunosuppressive purposes.

The trial also includes a placebo, designated as PL1, which serves as a comparator treatment. The placebo is utilized to assess the efficacy of the experimental treatments by providing a baseline for comparison. The administration details for the placebo are not specified in the data provided.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the level of rheumatoid arthritis (RA) activity, measured using the **Disease Activity Score on 28 joints (DAS28)**. This score will be used to determine the effectiveness of the Methotrexate/Metformin combination compared to Methotrexate alone in reducing RA activity in patients who are naive to Methotrexate treatment over a period of 6 months.

Secondary endpoints include several parameters: the proportion of patients achieving remission, defined as a DAS28 score of less than 2.6, after 6, 12, and 24 months of treatment; the proportion of patients with low disease activity, indicated by a DAS28 score of less than 3.2, after 6 months; and the proportion of patients requiring the introduction of biologic treatment after 6, 12, and 24 months. Additionally, metabolic parameters such as weight loss, waist circumference, fasting glycemia, hemoglobin A1c (HbA1c) levels, cholesterol levels, triglycerides, insulinemia, and bilirubin will be described within the two treatment groups. The occurrence of serious adverse events within the two groups during the 6 months of treatment will also be monitored. Furthermore, the evolution of functional assessment will be described using the Health Assessment Questionnaire (HAQ) within the two groups during the 6 months of treatment.