Randomized Placebo-controlled Trial Comparing Methotrexate vs. Methotrexate/Metformin Association in Rheumatoid Arthritis Patients
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 128
- 试验地点
- 12
- 主要终点
- Change of level of RA activity according to Disease Activity score on 28 joints (DAS28-ESR)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Participant)
盲法说明
placebo-controlled trial
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •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)
排除标准
- •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).
研究组 & 干预措施
Control arm
干预措施: Placebo (Other)
Control arm
干预措施: Methotrexate treatment (Drug)
Experimental arm
干预措施: Metformin treatment (Drug)
Experimental arm
干预措施: Methotrexate treatment (Drug)
结局指标
主要结局
Change of level of RA activity according to Disease Activity score on 28 joints (DAS28-ESR)
时间窗: At baseline (Day 0) and 6 months after baseline
Change of level of RA activity according to Disease Activity Score on 28 joints (DAS28-CRP)
时间窗: At baseline (Day 0) and 6 months after baseline
次要结局
- Proportion of patients who reach remission(At 6 months, 12 months and 24 months after baseline (Day 0))
- Proportion of patients with low disease activity (DAS-ESR < 3,2)(At 6 months after baseline (Day 0))
- Proportion of patients for which a biologic treatment is introduced(At 6 months, 12 months and 24 months after baseline (Day 0))
- Mean dosage of Methotrexate in the two groups of randomization(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(At 6 months after baseline (Day 0))
- 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)
- Mean value of weight in kilograms in each randomization group(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(At baseline (Day 0), 6 months and 24 months after baseline)
- Mean value of insulinemia in µUI/ml in each randomization group(At baseline (Day 0), 6 months and 24 months after baseline)
- Mean value of waist circumference in centimeters in each randomization group(At baseline (Day 0), 6 months and 24 months after baseline)
- Mean value of fasting glycemia in g/l in each randomization group(At baseline (Day 0), 6 months and 24 months after baseline)
- Mean value of hemoglobin A1c level (HbA1c) in percentage in each randomization group(At baseline (Day 0), 6 months and 24 months after baseline)
- Mean value of bilirubin in mg/l in each randomization group(At baseline (Day 0), 6 months and 24 months after baseline)
- Secondary Outcome Measures " : Change of level of RA according to Disease Activity Score on 28 joints (DAS28-ESR)(At baseline (Day 0), 1 month, 3 months, 6 months, 12 months and 24 months)