search
Back to results

Methotrexate and Metformin in Rheumatoid Arthritis Patients (METorMET²)

Primary Purpose

Arthritis, Rheumatoid

Status
Recruiting
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Metformin treatment
Placebo
Methotrexate treatment
Sponsored by
University Hospital, Bordeaux
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Arthritis, Rheumatoid focused on measuring rheumatoid arthritis, methotrexate, metformin, clinical trial

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients aged over 18 years old,
  • Patient affected by RA according to American College of Rheumatology (ACR) 2010 criteria
  • DAS28 > 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).

Sites / Locations

  • CH de la Côte Basque - service de rhumatologie
  • CHU de Bordeaux - service de rhumatologieRecruiting
  • CHU de Brest - service de rhumatologieRecruiting
  • CH de Cahors - service de rhumatologieRecruiting
  • Clinique de l'Infirmerie protestante de Lyon - service de rhumatologie
  • CHD de Vendée - service de rhumatologie
  • CH du Mans - service de rhumatologieRecruiting
  • CH de Libourne - service de rhumatologieRecruiting
  • CHU de Montpellier - service de rhumatologieRecruiting
  • CH des Pays de Morlaix - service de rhumatologie
  • CHR Orléans la Source - service de rhumatologieRecruiting
  • CH de Pau - service de rhumatologieRecruiting
  • CHU de Toulouse - service de rhumatolgieRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Experimental arm

Control arm

Arm Description

Outcomes

Primary Outcome Measures

Change of level of RA activity according to Disease Activity score on 28 joints (DAS28-ESR)

Secondary Outcome Measures

Proportion of patients who reach remission
Proportion of patients with low disease activity (DAS-ESR < 3,2)
Proportion of patients for which a biologic treatment is introduced
Mean dosage of Methotrexate in the two groups of randomization
Proportion of patients who present a serious adverse event within the two groups
Evolution of functional assessment according to Health Assessment Questionnaire (HAQ) within the two groups
Mean value of weight in kilograms in each randomization group
Mean value of waist circumference in centimeters in each randomization group
Mean value of fasting glycemia in g/l in each randomization group
Mean value of hemoglobin A1c level (HbA1c) in percentage in each randomization group
Mean value of cholesterol levels and triglycerides levels in g/l in each randomization group
Mean value of insulinemia in µUI/ml in each randomization group
Mean value of bilirubin in mg/l in each randomization group

Full Information

First Posted
December 5, 2019
Last Updated
August 29, 2023
Sponsor
University Hospital, Bordeaux
Collaborators
Ministry for Health and Solidarity, France
search

1. Study Identification

Unique Protocol Identification Number
NCT04196868
Brief Title
Methotrexate and Metformin in Rheumatoid Arthritis Patients
Acronym
METorMET²
Official Title
Randomized Placebo-controlled Trial Comparing Methotrexate vs. Methotrexate/Metformin Association in Rheumatoid Arthritis Patients
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 3, 2020 (Actual)
Primary Completion Date
December 2025 (Anticipated)
Study Completion Date
December 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Bordeaux
Collaborators
Ministry for Health and Solidarity, France

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Arthritis, Rheumatoid
Keywords
rheumatoid arthritis, methotrexate, metformin, clinical trial

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
Participant
Masking Description
placebo-controlled trial
Allocation
Randomized
Enrollment
128 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Experimental arm
Arm Type
Experimental
Arm Title
Control arm
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Metformin treatment
Intervention Description
1500 mg once a day, per os, during six months
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
per os, during six months
Intervention Type
Drug
Intervention Name(s)
Methotrexate treatment
Intervention Description
per os
Primary Outcome Measure Information:
Title
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
Secondary Outcome Measure Information:
Title
Proportion of patients who reach remission
Time Frame
At 6 months, 12 months and 24 months after baseline (Day 0)
Title
Proportion of patients with low disease activity (DAS-ESR < 3,2)
Time Frame
At 6 months after baseline (Day 0)
Title
Proportion of patients for which a biologic treatment is introduced
Time Frame
At 6 months, 12 months and 24 months after baseline (Day 0)
Title
Mean dosage of Methotrexate in the two groups of randomization
Time Frame
At 6 months, 12 months and 24 months after baseline (Day 0)
Title
Proportion of patients who present a serious adverse event within the two groups
Time Frame
At 6 months after baseline (Day 0)
Title
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
Title
Mean value of weight in kilograms in each randomization group
Time Frame
At baseline (Day 0), 6 months and 24 months after baseline
Title
Mean value of waist circumference in centimeters in each randomization group
Time Frame
At baseline (Day 0), 6 months and 24 months after baseline
Title
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
Title
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
Title
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
Title
Mean value of insulinemia in µUI/ml in each randomization group
Time Frame
At baseline (Day 0), 6 months and 24 months after baseline
Title
Mean value of bilirubin in mg/l in each randomization group
Time Frame
At baseline (Day 0), 6 months and 24 months after baseline

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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).
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Christophe RICHEZ, Prof
Phone
(0)556795556
Ext
+33
Email
christophe.richez@chu-bordeaux.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Thomas BARNETCHE, PhD
Phone
(0)557820493
Ext
+33
Email
thomas.barnetche@chu-bordeaux.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Christophe RICHEZ, Prof
Organizational Affiliation
CHU Bordeaux
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Antoine BENARD, MD, PhD
Organizational Affiliation
University Hospital, Bordeaux
Official's Role
Study Chair
Facility Information:
Facility Name
CH de la Côte Basque - service de rhumatologie
City
Bayonne
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alexia HOURDILLE, MD
Email
alexia.hourdille@hotmail.fr
First Name & Middle Initial & Last Name & Degree
Alexia HOURDILLE, MD
Facility Name
CHU de Bordeaux - service de rhumatologie
City
Bordeaux
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Christophe RICHEZ, Prof
Email
christophe.richez@chu-bordeaux.fr
First Name & Middle Initial & Last Name & Degree
Thomas BARNETCHE, PhD
Email
thomas.barnetche@chu-bordeaux.fr
First Name & Middle Initial & Last Name & Degree
Christophe RICHEZ, Prof
Facility Name
CHU de Brest - service de rhumatologie
City
Brest
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alain SARAUX, Prof
Email
alain.saraux@chu-brest.fr
First Name & Middle Initial & Last Name & Degree
Alain SARAUX, Prof
Facility Name
CH de Cahors - service de rhumatologie
City
Cahors
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Slim LASSOUED, MD
Email
lassoued3@ch-cahors.fr
First Name & Middle Initial & Last Name & Degree
Slim LASSOUED, MD
Facility Name
Clinique de l'Infirmerie protestante de Lyon - service de rhumatologie
City
Caluire-et-Cuire
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
André BASCH, MD
Email
recherche-clinique@infirmerieprotestante.com
First Name & Middle Initial & Last Name & Degree
André BASCH, MD
Facility Name
CHD de Vendée - service de rhumatologie
City
La Roche-sur-Yon
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Grégoire CORMIER, MD
Email
gregoire.cormier@ght85.fr
First Name & Middle Initial & Last Name & Degree
Grégoire CORMIER, MD
Facility Name
CH du Mans - service de rhumatologie
City
Le Mans
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Emmanuelle DERNIS, MD
Email
edernis@ch-lemans.fr
First Name & Middle Initial & Last Name & Degree
Emmanuelle DERNIS, MD
Facility Name
CH de Libourne - service de rhumatologie
City
Libourne
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Stéphanie DUBLANC, MD
Email
stephanie.dublanc@ch-libourne.fr
First Name & Middle Initial & Last Name & Degree
Stéphanie DUBLANC, MD
Facility Name
CHU de Montpellier - service de rhumatologie
City
Montpellier
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jacques MOREL, Prof
Email
j-morel@chu-montpellier.fr
First Name & Middle Initial & Last Name & Degree
Jacques MOREL, Prof
Facility Name
CH des Pays de Morlaix - service de rhumatologie
City
Morlaix
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
LE HENAFF-BOURHIS Catherine, MD
Email
CLehenaff@ch-morlaix.fr
First Name & Middle Initial & Last Name & Degree
LE HENAFF-BOURHIS Catherine
Facility Name
CHR Orléans la Source - service de rhumatologie
City
Orléans
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Carine SALLIOT, MD
Email
carine.salliot@chr-orleans.fr
First Name & Middle Initial & Last Name & Degree
Carine SALLIOT, MD
Facility Name
CH de Pau - service de rhumatologie
City
Pau
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
GERMAIN Vincent, MD
Email
vincent.germain@ch-pau.fr
First Name & Middle Initial & Last Name & Degree
GERMAIN Vincent, MD
Facility Name
CHU de Toulouse - service de rhumatolgie
City
Toulouse
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Adeline RUYSSEN-WITRAND, MD
Email
ruyssen-witrand.a@chu-toulouse.fr
First Name & Middle Initial & Last Name & Degree
Adeline RUYSSEN-WITRAND, MD

12. IPD Sharing Statement

Learn more about this trial

Methotrexate and Metformin in Rheumatoid Arthritis Patients

We'll reach out to this number within 24 hrs