| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To confirm the efficacy and safety of rituximab in patients with resistant RA
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| E.2.2 | Secondary objectives of the trial |
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
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal 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 All DMARDs other than methotrexate should be withdrawn at least 4 weeks prior to rituximab therapy (see above for anti-TNF therapy)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)
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| E.4 | Principal 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
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| E.5 End points |
| E.5.1 | 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 depletion in peripheral blood
b) Proportion of patients achieving B cell depletion in synovium ( defined as grades 0 and 1 on a standardised immunohistochemistry scale of 0-3) at week 26
c) Proportion of patients who relapse with B cell depletion in peripheral blood but not in synovium
Relapse is defined as having shown at least an ACR 20 response by week 24 and then subsequent deterioration with an increase in DAS 28 of at least 1.2
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The initial phase of the study is 26 weeks (with treatment given at the beginning and end of the first 2 weeks). After this patients will be followed every 3 months for a total study duration of 24 months with one further safety assessment at 36 months.
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
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