Rheumatoid Arthritis
Conditions
Interventions
Trade Name: Mabthera
Product Name: Mabthera
Product Code: N/A
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed
Sponsors
University of Leeds
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 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 25mg twice weekly, at least 4 infusions of infliximab at = 3 mg/kg or adalimumab for =3 months at 40mg 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 for=4 weeks prior to treatment with rituximab 5. Patients must have received methotrexate at a dose of 10-25mg/week (po or parenteral) at a stable dose for 4 weeks prior to screening 6. All DMARDs other than methotrexate should be withdrawn at least 4 weeks prior to rituximab therapy (see above for anti-TNF therapy) 7. DAS28 >5.1 8. Age 18-80 years 9. Corticosteroids (=10mg/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. 10. Patients of reproductive potential (males and females) using a reliable means of contraception (eg contraceptive pill, IUD, physical barrier) 11. Must be willing to receive oral folate 12. If female and of childbearing potential, a negative urine pregnancy test within two weeks prior to therapy 13. Presence of erosive joint disease of at least 1 joint on x-ray ( except if DIP joint of the hand) Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range
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 3.2.4 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 (eg 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 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 (?ever) 3.2.5 Exclusions for General Safety: 1. History of severe allergic or anaphylactic reactions to humanised or murine monoclonal antibodies (eg 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 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 po or iv steroids 3.2.6 Laboratory Exclusion Criteria (at screening): 1. Serum creatinine >140mmol/l 2. AST or 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 0.55mg/mL respectively
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To confirm the efficacy and safety of rituximab in patients with resistant RA ; Secondary Objective: To explore the effects of rituximab on underlying structural joint disease, the synovium and B cell profiles in the peripheral circulation To explore why relapse occurs after rituximab therapy ; Primary end point(s): Proportion of patients achieving ACR50 response at Week 24. Secondary outcomes: These will be measured at weeks 12, 24, 36, 48, unless otherwise stated below. 1. Disease Activity Response: a) Proportions of patients with ACR 20,ACR50 and ACR70 b) Change in Disease Activity Score (DAS 28) from baseline c) Proportion of patients who are categorical DAS 28 responders(EULAR response) d) Change in swollen and tender joint counts from baseline e) Change in CRP and ESR f) Proportion of patients becoming seronegative for Rheumatoid Factor 2. Disability outcomes: a) change in HAQ from baseline b) change in patient’s global assessment (VAS) c) change in physician’s global assessment (VAS) 3. Quality of Life a) RA QoL change from baseline b) Pain Score (VAS) change from baseline 4. Radiographic outcomes: a) X ray change in modified Sharp scores, erosion score (measured as grade 0-3.5 in 0.5 increments) and joint space narrowing score (measured as grade 0 – 4 with 0.5 increments) b) Ultrasound: changes in synovitis on grey scale and power doppler scores (measured 0-3) c) MRI: change in bone erosion (0-10) and bone oedema (0-3) as measured by EULAR-OMERACT scales 5. B cell activity: a) Proportion of patients achieving full B cell | — |
Countries
United Kingdom
Outcome results
None listed