Methotrexate and Metformin in Rheumatoid Arthritis Patients

NCT ID: NCT04196868

Last Updated: 2024-06-21

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 128 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-12-03
• Study Completion Date: 2026-06-30

Brief Summary

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.

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.

Conditions

Arthritis, Rheumatoid

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Experimental arm

Group Type: EXPERIMENTAL

Metformin treatment

Intervention Type: DRUG

1500 mg once a day, per os, during six months

Methotrexate treatment

Intervention Type: DRUG

per os

Control arm

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

per os, during six months

Methotrexate treatment

Intervention Type: DRUG

per os

Interventions

Metformin treatment

1500 mg once a day, per os, during six months

Intervention Type: DRUG

Placebo

per os, during six months

Intervention Type: OTHER

Methotrexate treatment

per os

Intervention Type: DRUG

Eligibility Criteria

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).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ministry for Health and Solidarity, France

OTHER_GOV

Sponsor Role: collaborator

University Hospital, Bordeaux

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Christophe RICHEZ, Prof

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Bordeaux

Antoine BENARD, MD, PhD

Role: STUDY_CHAIR

University Hospital, Bordeaux

Locations

CH de la Côte Basque - service de rhumatologie

Bayonne, , France

CHU de Bordeaux - service de rhumatologie

Bordeaux, , France

CHU de Brest - service de rhumatologie

Brest, , France

CH de Cahors - service de rhumatologie

Cahors, , France

Clinique de l'Infirmerie protestante de Lyon - service de rhumatologie

Caluire-et-Cuire, , France

CHD de Vendée - service de rhumatologie

La Roche-sur-Yon, , France

CH du Mans - service de rhumatologie

Le Mans, , France

CH de Libourne - service de rhumatologie

Libourne, , France

CHU de Montpellier - service de rhumatologie

Montpellier, , France

CHR Orléans la Source - service de rhumatologie

Orléans, , France

CH de Pau - service de rhumatologie

Pau, , France

CHU de Toulouse - service de rhumatolgie

Toulouse, , France

Countries

France

Other Identifiers

CHUBX 2016/44

Identifier Type: -

Identifier Source: org_study_id