Efficacy of tocilizumab in patients with rheumatoid arthritis

INTERVENTION: 1. Tocilizumab intravenous (IV), 4‐weekly for 48 weeks 2. Placebo IV, 4‐weekly for 12 weeks Then all patient receive tocilizumab/methotrexate, 2.5 mg or 10 mg tablets/7.5 ‐ 10 mg syringe. Weekly dose up to 25 mg. Total duration of treatment and follow‐up: 56 weeks CONDITION: Topic: Musculoskeletal; Subtopic: Musculoskeletal (all Subtopics); Disease: Musculoskeletal ; Musculoskeletal Diseases ; Rheumatoid arthritis PRIMARY OUTCOME: Changes in synovial tissue to identify onset and mechanism of action SECONDARY OUTCOME: 1. To evaluate the safety of tocilizumab and methotrexate combination for the treatment of rheumatoid arthritis by assessment of:; 1.1. Incidence, frequency of adverse events; 1.2. Vital signs; 1.3. Blood haematology, chemistry, urinalysis; 1.4. Electrocardiogram (ECG); 2. To evaluate efficacy of tocilizumab and methotrexate combination by:; 2.1. Clinical assessment:; 2.1.1. Composite scores: ACR and DAS28/EULAR response; 2.1.2. Patient pain visual analogue scale (VAS) and general health VAS; 2.1.3. Duration of morning stiffness; 2.1.4. Health Assessment Questionnaire (HAQ) and RAQol; 2.1.5. Physician Global VAS; 2.1.6. High sensitivity C‐reactive protein (hsCRP) and erythrocyte sedimentation rate (ESR); 2.2. Radiological assessment:; 2.2.1. MRI features (bone oedema and erosion score) in addition to synovial volume (primary outcome); 2.2.2. Ultrasonographical features (grey scale, power doppler and erosions); 2.2.3. Plain radiography; 2.2.4. Bone densitometry; 2.3. Synovial assessment:; 2.3.1. Macroscopic synovitis and vascularity scores; 2.3.2. Histological score and pro‐inflammatory cytokine expression in biopsies; 3. To evaluate predictive and mechanistic features of tocilizumab and methotrexate/disease‐modifying anti‐rheumatic drug (DMARD) combination by:; 3.1. Biomarker, cell biology and genetics studies:; 3.1.1. Predictive markers of response to tocilizumab; 3.1.2. Mechanistic studies; 3.1.3. Genetic studies to evaluate mechanism and response to tocilizumab INCLUSION CRITERIA: Subjects meeting all of the following criteria will be considered for enrolment into the study: 1. Male and female patients aged between 18 and 80 years 2. Diagnosis of rheumatoid arthritis (1987 revised American College of Rheumatology [ACR] criteria) confirmed at least 6 months prior to screening 3. Persistent RA disease activity with inadequate response whilst being treated with an anti‐TNF agent for at least 12 weeks, or patients who have previously discontinued anti‐TNF due to toxicity, or patients have previously qualified for anti‐TNF (NICE/BSR criteria) but therapy is contra‐indicated 4. Methotrexate dose stable for 12 weeks prior to screening and to be continued for the duration of the study 5. Subjects with active RA at baseline are defined as: Disease Activity Scale (DAS28) greater than 5.1 6. Patients on non‐steroidal anti‐inflammatory drugs (NSAIDs) and/or corticosteroids must have remained on an unchanged regimen for at least 28 days