| 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 |
1. To determine if a second course with an increased dose of rituximab is associated with improved responses compared to re-treatment with the same dose.
2. To determine if there is a difference in response rates if a total annual dose of 2g rituximab is given as either a single course (2 × 1000 mg) or as divided courses (two courses each of 2 × 500 mg, given 24 weeks apart).*(not in the UK)
3. To investigate the pharmacokinetics of rituximab associated with 2 courses of treatment. |
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| E.2.2 | Secondary objectives of the trial | |
| 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. Receiving treatment FOR RA on an outpatient basis.
4. Swollen joint count (SJC) ≥ 8 (66 joint count), and tender joint count (TJC) ≥ 8 (68 joint count) at screening and baseline.
5. At screening, either CRP ≥ 0.6 mg/dL (6 mg/L) OR ESR ≥ 28 mm/h.
6. Minimum age 18 years.
7. Glucocorticoids ≤ 10 mg/day prednisolone or equivalent permitted if stable for at least 4 weeks prior to baseline.
8. Use of NSAIDs is permitted if stable for at least 2 weeks prior to baseline.
9. For patients of reproductive potential (males and females), use of a reliable means of contraception (e.g. hormonal contraceptive, patch, intrauterine device, physical barrier) throughout study participation.
10. Must have an inadequate response to MTX and have been receiving and tolerating this at a dose of 10-25 mg/wk (p.o. or parenteral) for at least 12 weeks, with the last 4 weeks prior to baseline at a stable dose.
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| E.4 | Principal exclusion criteria |
1. Rheumatic autoimmune disease other than RA, or significant systemic involvement secondary to RA (including but not limited to vasculitis, pulmonary fibrosis or Felty’s syndrome). Secondary Sjogren’s syndrome or secondary limited cutaneous vasculitis with RA is permitted.
2. Functional class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis.
3. History of, or current, inflammatory joint disease other than RA (e.g., gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease) or other systemic autoimmune disorder (e.g., SLE, inflammatory bowel disease, scleroderma, inflammatory myopathy, mixed connective tissue disease or other overlap syndrome).
4. Diagnosis of juvenile idiopathic arthritis (JIA) or juvenile rheumatoid arthritis (JRA) and/or RA before age 16.
5. Any surgical procedure, including bone/joint surgery/Synovectomy (including joint fusion or replacement) within 12 weeks prior to baseline or planned within 48 weeks of randomization.
6. Lack of peripheral venous access.
7. Pregnancy or lactation.
8. Significant cardiac or pulmonary disease (including obstructive pulmonary disease).
9. Evidence of significant uncontrolled concomitant disease such as nervous system, renal, hepatic, endocrine or gastrointestinal disorders which, in the investigator’s opinion, would preclude patient participation.
10. Primary or secondary immunodeficiency (history of, or currently active), including known history of HIV infection.
11. Known active infection of any kind (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with i.v. anti-infectives within 4 weeks of baseline or oral anti-infectives within 2 weeks prior to baseline.
12. History of deep space/tissue infection (e.g. fasciitis, abscess, osteomyelitis) within 52 weeks of baseline.
13. History of serious recurrent or chronic infection (to check for chest infection a chest x-ray will be performed at screening if not performed within 12 weeks of screening).
14. History of cancer, including solid tumors, hematologic malignancies and carcinoma in situ (except basal cell and squamous cell carcinoma of the skin that have been excised and cured).
15. Any neurological (congenital or acquired), vascular or systemic disorder which could affect any of the efficacy assessments, in particular, joint pain and swellin (e.g. Parkinson’s disease, cerebral palsy, diabetic neuropathy).
16. Currently active alcohol or drug abuse or history of alcohol or drug abuse within 24 weeks prior to baseline.
17. History of a severe allergic or anaphylactic reaction to a biologic agent or known hypersensitivity to any component of rituximab or to murine proteins.
18. Concurrent treatment with any biologic agent or DMARD other than MTX. Treatment with all DMARDS (including etanercept) must be discontinued 14 days prior to baseline, except for the following: azathioprine ≥ 28 days; leflunomide for ≥ 8 weeks (or ≥ 14 days after 11 days of standard cholestyramine or activated charcoal washout); infliximab ≥ 8 weeks; adalimumab ≥ 8 weeks. In the event that abatacept becomes an approved treatment for RA during the course of this study, this must also be discontinued for ≥ 8 weeks prior to baseline.
19. Previous treatment with > 1 biological agent approved for use in RA.
20. Previous treatment with any cell depleting therapies, including investigational agents (e.g. CAMPATH, anti- CD4, anti-CD5, anti-CD3, anti-CD19, anti-CD11a, anti-CD22, BLys/ BAFF, and anti-CD20).
21. Previous treatment with any investigational agent within 28 days of baseline or 5 half-lives of the investigational drug (whichever is the longer).
22. Receipt of ANY vaccine within 28 days prior to baseline (it is recommended that a patient’s vaccination record and the need for immunization prior to receiving rituximab/placebo should be carefully investigated).
23. Intra-articular or parenteral glucocorticoids within 4 weeks prior to baseline.
24. Intolerance or contra-indications to i.v. glucocorticoids.
25. Positive serum hCG measured at screening or a positive pregnancy test prior to the first rituximab infusion.
26. Positive tests for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb) or hepatitis C serology.
27. Haemoglobin < 8.0 g/dL.
28. Levels of IgG and/or IgM below 5.0 and 0.40 mg/mL, respectively.
29. Absolute neutrophil count < 1.5 × 103/µL.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of patients with an ACR20 response at Week 48. In addition, responders and non-responders will also be analyzed. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Information not present in EudraCT |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Different dose and regimen of rituximab |
|
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 61 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| 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
|
Patients will receive study medication for a total of 240 weeks or until rituximab is commercially available for rheumatoid arthritis (whichever is the later). The end of treatment is therefore defined as the 240 time point, or Dec 2010 following which there will be an additional period of at least a year of safety follow-up.
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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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
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