Methotrexate and Metformin in Rheumatoid Arthritis Patients (METorMET²)

January 30, 2026 updated by: University Hospital, Bordeaux

Randomized Placebo-controlled Trial Comparing Methotrexate vs. Methotrexate/Metformin Association in Rheumatoid Arthritis Patients

Methotrexate (MTX) is the anchor drug for patients with rheumatoid arthritis (RA). Despite its marked efficacy and acceptable side effect profile, about 1/3 of patients failed to reach RA remission. Metformin is the first-line therapy for type 2 diabetes. Its antioxidative and anti-inflammatory properties make it a good candidate for the treatment of inflammatory diseases such as rheumatoid arthritis.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Active, not recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Methotrexate is usually the first-line disease modifying antirheumatic drugs (DMARD) for the treatment of RA. The main goal of its treatment is to reach disease remission but, despite its good efficacy, 1/3 of patients failed to achieve it. This could lead to the introduction of a biologic therapy which is more expensive and exposes the patient to a greater infection risk. Neutrophils through expulsion of neutrophil extracellular traps (NETs), were found to be important in RA pathogenesis (source of anti-citrullinated protein antibodies, activation of fibroblast-like synoviocytes…). The formation of NETs is reactive oxygen species (ROS) dependent, while metformin can selectivity inhibit mitochondrial respiratory chain complex I and decrease NADPH oxidase activity, thus leading to a decrease in ROS production.

Metformin is the first-line therapy for type 2 diabetes. Recently, a study presented its potential impact in the treatment of systemic lupus erythematosus according to its metabolic properties and the inhibition of NETosis.

The aim of this study is to compare the efficacy of Methotrexate/Metformin vs. Methotrexate alone on the decrease of RA activity in MTX-naive patients, after 6 months of treatment.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
128

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • France
      • Bayonne, France
        • CH de la Côte Basque - service de rhumatologie
      • Bordeaux, France
        • CHU de Bordeaux - service de rhumatologie
      • Brest, France
        • CHU de Brest - Service de rhumatologie
      • Cahors, France
        • CH de Cahors - service de rhumatologie
      • Caluire-et-Cuire, France
        • Clinique de l'Infirmerie protestante de Lyon - service de rhumatologie
      • La Roche-sur-Yon, France
        • CHD de Vendée - service de rhumatologie
      • Le Mans, France
        • CH du Mans - service de rhumatologie
      • Libourne, France
        • CH de Libourne - service de rhumatologie
      • Montpellier, France
        • CHU de Montpellier - service de rhumatologie
      • Orléans, France
        • CHR Orléans la Source - service de rhumatologie
      • Pau, France
        • CH de Pau - service de rhumatologie
      • Toulouse, France
        • CHU de Toulouse - service de rhumatolgie

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Patients aged over 18 years old,
  • Patient affected by RA according to American College of Rheumatology (ACR) 2010 criteria
  • DAS28-ESR > 3.2
  • Methotrexate naïve patients, or without any methotrexate intake for more than six months.
  • Men who accept to take active contraception during the study and during six months after the end of the Methotrexate treatment. Partner of patient will be informed of teratogenicity of MTX and will be advised to be on effective contraceptives for all the study duration.

OR

  • Women with a negative test of β-human chorionic gonadotropin (HCG) who accept to take active contraception during the study and during six months after the end of the Methotrexate treatment
  • Patients without any Metformin previous therapy.
  • Being affiliated to a health insurance system
  • Having signed an informed consent form (later than the day of inclusion and before any examination required by the research)

Exclusion Criteria:

  • Patient who present contraindications to treatment with Methotrexate or Metformin
  • Patient with type 1 or type 2 diabetes
  • Patient with daily corticosteroid treatment at a dosage ≥ 15 mg/day within four weeks before the inclusion
  • History of allergy or intolerance to biguanide
  • Presence of anemia (hemoglobin < 80 g/l), neutropenia (neutrophils count < 1500 mm3), lymphopenia (lymphocytes count < 750 mm3), thrombopenia (platelets < 100 000/mm3) or bone marrow hypoplasia.
  • Renal insufficiency with clearance < 50 ml/mn
  • Decompensated heart failure
  • Uncontrolled heart history
  • Severe respiratory insufficiency
  • Hepatic insufficiency, or bilirubin level upper than 5mg/dl (85,5 µmol/l), or aspartate transaminase (ASAT) / alanine aminotransferase (ALAT) more than twice the standard level.
  • Acute or chronic infection, such as tuberculosis or HIV
  • Critical ischemia of the lower limbs
  • Recent stroke
  • Patient with pleural effusion, or ascites
  • Patient with stomatitis, mouth ulcers, or active gastrointestinal ulcer.
  • Patient with alcohol intoxication
  • B12 Vitamin deficiency
  • Patient performing or planning to perform a long-fasting period
  • Pregnant or breastfeeding women
  • Patient concerned by articles L 1121-5 to L 1121-8 (persons deprived of their liberty by a judicial or administrative decision, minors, persons of legal age who are the object of a legal protection measure or unable to express their consent).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Experimental arm
Drug: Metformin treatment
1500 mg once a day, per os, during six months
Drug: Methotrexate treatment
per os
Placebo Comparator: Control arm
Drug: Methotrexate treatment
per os
Other: Placebo
per os, during six months

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Time Frame
Change of level of RA activity according to Disease Activity score on 28 joints (DAS28-ESR)
Time Frame: At baseline (Day 0) and 6 months after baseline
At baseline (Day 0) and 6 months after baseline

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Time Frame
Proportion of patients who reach remission
Time Frame: At 6 months, 12 months and 24 months after baseline (Day 0)
At 6 months, 12 months and 24 months after baseline (Day 0)
Proportion of patients for which a biologic treatment is introduced
Time Frame: At 6 months, 12 months and 24 months after baseline (Day 0)
At 6 months, 12 months and 24 months after baseline (Day 0)
Mean dosage of Methotrexate in the two groups of randomization
Time Frame: At 6 months, 12 months and 24 months after baseline (Day 0)
At 6 months, 12 months and 24 months after baseline (Day 0)
Proportion of patients who present a serious adverse event within the two groups
Time Frame: At 6 months after baseline (Day 0)
At 6 months after baseline (Day 0)
Evolution of functional assessment according to Health Assessment Questionnaire (HAQ) within the two groups
Time Frame: At baseline (Day 0), 1 month, 3 months, 6 months, 12 months and 24 months after baseline
At baseline (Day 0), 1 month, 3 months, 6 months, 12 months and 24 months after baseline
Mean value of weight in kilograms in each randomization group
Time Frame: At baseline (Day 0), 6 months and 24 months after baseline
At baseline (Day 0), 6 months and 24 months after baseline
Mean value of waist circumference in centimeters in each randomization group
Time Frame: At baseline (Day 0), 6 months and 24 months after baseline
At baseline (Day 0), 6 months and 24 months after baseline
Mean value of fasting glycemia in g/l in each randomization group
Time Frame: At baseline (Day 0), 6 months and 24 months after baseline
At baseline (Day 0), 6 months and 24 months after baseline
Mean value of hemoglobin A1c level (HbA1c) in percentage in each randomization group
Time Frame: At baseline (Day 0), 6 months and 24 months after baseline
At baseline (Day 0), 6 months and 24 months after baseline
Mean value of cholesterol levels and triglycerides levels in g/l in each randomization group
Time Frame: At baseline (Day 0), 6 months and 24 months after baseline
At baseline (Day 0), 6 months and 24 months after baseline
Mean value of insulinemia in µUI/ml in each randomization group
Time Frame: At baseline (Day 0), 6 months and 24 months after baseline
At baseline (Day 0), 6 months and 24 months after baseline
Mean value of bilirubin in mg/l in each randomization group
Time Frame: At baseline (Day 0), 6 months and 24 months after baseline
At baseline (Day 0), 6 months and 24 months after baseline
Proportion of patients with low disease activity (DAS-ESR < 3,2)
Time Frame: At 6 months after baseline (Day 0)
At 6 months after baseline (Day 0)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University Hospital, Bordeaux

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Ministry for Health and Solidarity, France

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Chair: Antoine BENARD, MD, PhD, University Hospital, Bordeaux
  • Principal Investigator: Christophe RICHEZ, Prof, University Hospital, Bordeaux

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
December 3, 2020

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 19, 2024

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
June 1, 2026

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
December 5, 2019

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 10, 2019

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
December 12, 2019

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
February 3, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 30, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
January 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • CHUBX 2016/44

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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