Clinical trial NCT04196868: Methotrexate and Metformin in Rheumatoid Arthritis Patients
Official title: Randomized Placebo-controlled Trial Comparing Methotrexate vs. Methotrexate/Metformin Association in Rheumatoid Arthritis Patients
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Arthritis, Rheumatoid
Keywords: rheumatoid arthritis
methotrexate
metformin
clinical trial
Lead sponsor: University Hospital, Bordeaux
Sponsor class: OTHER
Collaborators: name: Ministry for Health and Solidarity, France
First posted: 2019-12-12
Enrollment: 128
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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).

Primary outcomes:
measure: Change of level of RA activity according to Disease Activity score on 28 joints (DAS28-ESR)
timeFrame: At baseline (Day 0) and 6 months after baseline
Secondary outcomes:
measure: Proportion of patients who reach remission
timeFrame: At 6 months, 12 months and 24 months after baseline (Day 0)
measure: Proportion of patients with low disease activity (DAS-ESR < 3,2)
timeFrame: At 6 months after baseline (Day 0)
measure: Proportion of patients for which a biologic treatment is introduced
timeFrame: At 6 months, 12 months and 24 months after baseline (Day 0)
measure: Mean dosage of Methotrexate in the two groups of randomization
timeFrame: At 6 months, 12 months and 24 months after baseline (Day 0)
measure: Proportion of patients who present a serious adverse event within the two groups
timeFrame: At 6 months after baseline (Day 0)
measure: Evolution of functional assessment according to Health Assessment Questionnaire (HAQ) within the two groups
timeFrame: At baseline (Day 0), 1 month, 3 months, 6 months, 12 months and 24 months after baseline
measure: Mean value of weight in kilograms in each randomization group
timeFrame: At baseline (Day 0), 6 months and 24 months after baseline
measure: Mean value of waist circumference in centimeters in each randomization group
timeFrame: At baseline (Day 0), 6 months and 24 months after baseline
measure: Mean value of fasting glycemia in g/l in each randomization group
timeFrame: At baseline (Day 0), 6 months and 24 months after baseline
measure: Mean value of hemoglobin A1c level (HbA1c) in percentage in each randomization group
timeFrame: At baseline (Day 0), 6 months and 24 months after baseline
measure: Mean value of cholesterol levels and triglycerides levels in g/l in each randomization group
timeFrame: At baseline (Day 0), 6 months and 24 months after baseline
measure: Mean value of insulinemia in µUI/ml in each randomization group
timeFrame: At baseline (Day 0), 6 months and 24 months after baseline
measure: Mean value of bilirubin in mg/l in each randomization group
timeFrame: At baseline (Day 0), 6 months and 24 months after baseline
Other outcomes:
Locations:
city: Bayonne
country: France
facility: CH de la Côte Basque - service de rhumatologie
city: Bordeaux
country: France
facility: CHU de Bordeaux - service de rhumatologie
city: Brest
country: France
facility: CHU de Brest - service de rhumatologie
city: Cahors
country: France
facility: CH de Cahors - service de rhumatologie
city: Caluire-et-Cuire
country: France
facility: Clinique de l'Infirmerie protestante de Lyon - service de rhumatologie
city: La Roche-sur-Yon
country: France
facility: CHD de Vendée - service de rhumatologie
city: Le Mans
country: France
facility: CH du Mans - service de rhumatologie
city: Libourne
country: France
facility: CH de Libourne - service de rhumatologie
city: Montpellier
country: France
facility: CHU de Montpellier - service de rhumatologie
city: Orléans
country: France
facility: CHR Orléans la Source - service de rhumatologie
city: Pau
country: France
facility: CH de Pau - service de rhumatologie
city: Toulouse
country: France
facility: CHU de Toulouse - service de rhumatolgie
Study officials:
affiliation: University Hospital, Bordeaux
name: Christophe RICHEZ, Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Bordeaux
name: Antoine BENARD, MD, PhD
role: STUDY_CHAIR
References: