Methotrexate and Metformin in Rheumatoid Arthritis Patients

Arthritis, Rheumatoid Clinical Trial

— METorMET²  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04196868
• Other study ID #: CHUBX 2016/44
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: December 3, 2020
• Est. completion date: June 2026

Study information

• Verified date: June 2024
• Source: University Hospital, Bordeaux
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 128
• Est. completion date: June 2026
• Est. primary completion date: June 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 ß-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).

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid

Intervention

Drug:
• Metformin treatment
1500 mg once a day, per os, during six months

Other:
• Placebo
per os, during six months

Drug:
• Methotrexate treatment
per os

Locations

Country	Name	City	State
France	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

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Bordeaux	Ministry for Health and Solidarity, France

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change of level of RA activity according to Disease Activity score on 28 joints (DAS28-ESR)		At baseline (Day 0) and 6 months after baseline
Secondary	Proportion of patients who reach remission		At 6 months, 12 months and 24 months after baseline (Day 0)
Secondary	Proportion of patients with low disease activity (DAS-ESR < 3,2)		At 6 months after baseline (Day 0)
Secondary	Proportion of patients for which a biologic treatment is introduced		At 6 months, 12 months and 24 months after baseline (Day 0)
Secondary	Mean dosage of Methotrexate in the two groups of randomization		At 6 months, 12 months and 24 months after baseline (Day 0)
Secondary	Proportion of patients who present a serious adverse event within the two groups		At 6 months after baseline (Day 0)
Secondary	Evolution of functional assessment according to Health Assessment Questionnaire (HAQ) within the two groups		At baseline (Day 0), 1 month, 3 months, 6 months, 12 months and 24 months after baseline
Secondary	Mean value of weight in kilograms in each randomization group		At baseline (Day 0), 6 months and 24 months after baseline
Secondary	Mean value of waist circumference in centimeters in each randomization group		At baseline (Day 0), 6 months and 24 months after baseline
Secondary	Mean value of fasting glycemia in g/l in each randomization group		At baseline (Day 0), 6 months and 24 months after baseline
Secondary	Mean value of hemoglobin A1c level (HbA1c) in percentage in each randomization group		At baseline (Day 0), 6 months and 24 months after baseline
Secondary	Mean value of cholesterol levels and triglycerides levels in g/l in each randomization group		At baseline (Day 0), 6 months and 24 months after baseline
Secondary	Mean value of insulinemia in µUI/ml in each randomization group		At baseline (Day 0), 6 months and 24 months after baseline
Secondary	Mean value of bilirubin in mg/l in each randomization group		At baseline (Day 0), 6 months and 24 months after baseline