Comparison between leflunomide or methotrexate plus subcutaneous tumour necrosis factor-alpha (TNF-alpha) blocking agents in rheumatoid arthritis: a two year open label study
To compare the effectiveness and safety of a therapeutic regimen associating subcutaneous anti-tumour necrosis factor-alpha (anti-TNF-alpha) agents etanercept (ETN) and adalimumab (ADA) with leflunomide (LEF) or methotrexate (MTX), in a two year open-label study performed in clinical practice.
New biological disease-modifying antirheumatic drugs (DMARDs) became available in 1999, including agents targeting anti-TNF-alpha agents. Among these, infliximab (INF), etanercept (ETN) and adalimumab (ADA) have been shown to reduce signs and symptoms of RA and to protect joints from structural damage in double-blind placebo-controlled randomised trials. Certain anti-TNF-alpha agents can be prescribed alone, but randomised trials have consistently demonstrated that the efficacy of these biological agents is significantly increased by concomitant MTX. However, not all patients tolerate or respond to MTX, and anti-TNF-alpha agents are commonly prescribed with DMARDs other than MTX in clinical routine.
Local ethical committee of ASL10 Florence approved in 2005 (ref: CTS/2005/31057)
Randomised open label active controlled trial
Primary study design
Secondary study design
Randomised controlled trial
Patient information sheet
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Rheumatoid arthritis (RA)
Leflunomide 20 mg/ day or methotrexate 10-15 mg/ once week plus etanercept 50 mg /once week or adalimumab 14 mg/ every other week.
Total duration 104 weeks.
Etanercept, adalimumab, leflunomide, methotrexate
Primary outcome measure
All patients were assessed at the beginning of the study (baseline) and every 3 months for 2 years by measuring 28-item Disease Activity Scale (DAS-28) score and DAS-CRP score. Remission was considered for a value less than 2.6 while low disease activity was considered for a value between 2.6 and 3.2.
Secondary outcome measures
Effectiveness and safety of both groups assessed using the value of DAS 28 and DAS-CRP score every 6 months.
Overall trial start date
Overall trial end date
Reason abandoned (if study stopped)
Participant inclusion criteria
1. Adult patients (aged between 26 and 86 years, either sex) with active rheumatoid arthritis (RA) defined as follows: greater than or equal to 6 swollen joints and greater than or equal to 6 painful joints and at least two of the following:
1.1. Morning stiffness greater than or equal to 45 minutes
1.2. Erythrocyte sedimentation rate (ESR) greater than or equal to 28 mm/first hour
1.3. C-reactive protein (CRP) greater than or equal to 2.0 mg/dL
2. Stabilised low-dose of prednisone (less than or equal to 7.5 mg )
3. Stable dose of non-steroidal anti-inflammatory drugs (NSAIDs)
4. Intrarticular injections of corticosteroids not allowed
Target number of participants
96 undifferentiated Caucasian patients
Participant exclusion criteria
Patients in stable therapy with LEF or MTX with a non-controlled disease activity with association therapy using a biological infusion (infliximab, rituximab, abatacept) or with a high dose of prednisone (greater than 10 mg)
Recruitment start date
Recruitment end date
Countries of recruitment
Trial participating centre
Ospedale S. Giovanni di Dio
St John of God Hospital (Ospedale S. Giovanni di Dio) (Italy)
Funding Body Type
Funding Body Subtype
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)