Rheumatoid arthritis Musculoskeletal Diseases Rheumatoid arthritis
Conditions
Interventions
Part 1 open-label study (first two doses of IMP):
2 doses x 1 g rituximab infusion (with methylpred pre-infusion) plus methotrexate as standard treatment dictates.
Part 2 double-blind, placebo-cont
Sponsors
University of Leeds (UK)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Able and willing to give written informed consent and comply with the requirements of the study protocol 2. Patients with rheumatoid arthritis for at least 6 months, diagnosed according to the revised 1987 American College of Rheumatology (ACR) criteria for the classification of rheumatoid arthritis 3. Patients who have experienced an inadequate response to previous or current treatment with etanercept, infliximab or adalimumab because of toxicity or inadequate efficiency (etanercept for >3 months at 25 mg twice weekly, at least 4 infusions of infliximab at >=3 mg/kg or adalimumab for >=3 months at 40 mg every other week) or be unsuitable for treatment with anti-TNF therapy because of contra-indication 4. Patients who have been washed out from etanercept, infliximab or adalimumab or ¡Ý4 weeks prior to treatment with rituximab 5. All Disease Modifying Anti-Rheumatic Drugs (DMARDs) other than methotrexate should be withdrawn at least 4 weeks prior to rituximab therapy (see above for anti-TNF therapy) 6. 28-item Disease Activity Score (DAS28) >3.2 7. Age 18-80 years 8. Corticosteroids (<=10 mg/day prednisolone or equivalent) permitted if stable for at least 4 weeks prior to screening and NSAIDs permitted if stable for at least 2 weeks prior to screening. 9. Patients of reproductive potential (males and females) using a reliable means of contraception (e.g., contraceptive pill, IntraUterine Device [IUD], physical barrier) 10. If female and of childbearing potential, a negative urine pregnancy test within two weeks prior to therapy 11. Presence of erosive joint disease of at least 1 joint on x-ray (except if Distal InterPhalangeal [DIP] joint of the hand)
Exclusion criteria
Exclusion criteria: 1. Bone/joint surgery within 8 weeks prior to therapy or joint surgery planned within 24 weeks of therapy 2. Rheumatic autoimmune disease other than RA or significant systemic involvement secondary to RA 3. History of, or current, inflammatory joint disease other than RA or other systemic rheumatic disorder Excluded previous/concomitant medications: 1. Concurrent treatment with any DMARD (apart from methotrexate) or any anti-TNF therapy or other biologic agent 2. Treatment with any investigational agent within 4 weeks of screening or 5 half lives of the investigational drug 3. Previous treatment with any cell depleting therapy therapies including investigational agents (e.g., CAMPATH®, anti-CD4, anti-CD5, anti-CD3, antiCD19) 4. Intra-articular or parenteral steroids within 4 weeks prior to therapy except for joints undergoing arthroscopy and/or Magnetic Resonance Imaging (MRI) where IA steroids are not permitted within 12 weeks prior to therapy 5. Receipt of a live vaccine within 4 weeks prior to randomisation Exclusions for General Safety: 1. History of severe allergic or anaphylactic reactions to humanised or murine monoclonal antibodies (e.g., infliximab or adalimumab) 2. Evidence of significant uncontrolled concomitant diseases such as cardiovascular disease, nervous system, pulmonary, renal, hepatic, endocrine or gastrointestinal disorders 3. Known active bacterial, viral, fungal mycobacterial infection (including tuberculosis, or atypical mycobacterial disease but excluding fungal infection of the nailbeds) or any episode of infection requiring hospitalisation or treatment with intravenous (iv) antibiotics within 4 weeks of therapy or oral antibiotics within 2 weeks of therapy 4. History of, or currently active, primary or secondary immunodeficiency 5. History of solid organ malignancy in the past 5 years (excluding basal cell or squamous cell carcinomas of the skin which have been excised and cured) 6. Pregnant women or breastfeeding mothers 7. History of alcohol, drug or chemical abuse within 6 months prior to screening 8. Neuropathies or neurovasculopathies which might interfere with pain evaluation 9. Intolerance or contraindications to oral (po) or iv steroids Laboratory exclusion criteria (at screening): 1. Serum creatinine >140 mmol/l 2. ASpartate aminoTransferase (AST) or ALanine aminoTransferase (ALT) >2.5 times upper limit of normal 3. Platelet count <100 4. Haemoglobin <8.5 5. Neutrophils <1.5x10.3/µl 6. Positive tests for hepatitis B surface antigen or hepatitis C antibody 7. Levels of IgG and/or IgM below 5.65 and 0.55 mg/mL respectively
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Proportion of patients with B cells receiving three doses of rituximab vs proportion of patients with B cells who receive standard dose (two doses) rituximab who achieve ACR20 response at Week 28. | — |
Secondary
| Measure | Time frame |
|---|---|
| Disease Activity Measures: 1. Proportion of patients with ACR50 response at 6 months 2. Proportion of patients with ACR70 response at 6 months 3. Change in DAS28-ESR from baseline to 6 months 4. EUropean League Against Rheumatism (EULAR) response rates at 6 months 5. Change in ACR core set from baseline to 6 months 6. Change in 36-item Short Form health survey (SF-36) from baseline to 6 months 7. Proportion of patients achieving DAS28-ESR remission at 6 months 8. Proportion of patients achieving DAS28-ESR low disease state at 6 months Disability measures: 1. Change in Health Assessment Questionnaire (HAQ) score from baseline at weeks 12, 28, 40 and 52 Quality of Life: 1. Change in the Rheumatoid Arthritis Quality of Life (RA-QoL) score from baseline at weeks 12, 28, 40 and 52 Radiological: 1. Change in modified Sharp Radiographic Score for X-rays of dominant hand from baseline at 12 months, measuring total score, erosion score and joint space narrowing score 2. Change in ultrasound score for synovitis in dominant hand, assessed on grey scale and power Doppler, from baseline at weeks 28, 40 and 52 3. Change in MRI score (high field and peripheral) for synovitis, bone oedema and erosions in dominant hand from baseline at weeks 12, 28, and 40 Immunological: 1. Proportion of patients with PPC depletion (measured at week 2, 4 and 6) and correlation of this with response and relapse (measured at 6, 9 and 12 months) 2. Change in serological status (rheumatoid factor positivity or not) from baseline at 6 months | — |
Countries
United Kingdom
Outcome results
None listed