| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Active rheumatoid arthritis |
|
| 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 the efficacy and safety at week 24 of rituximab 500 mg i.v. x2 and rituximab 1000 mg i.v. x2 when used in combination with MTX compared to continued MTX monotherapy in patients with active rheumatoid arthritis that currently have an inadequate clinical response to MTX.
2. To investigate by a population analysis approach the pharmacokinetics (PK) of rituximab in the target RA patient population and the influence of covariates on the PK parameters.
3. To explore the long-term efficacy and safety of further courses of rituximab.
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|
| E.2.2 | Secondary objectives of the trial | |
| E.2.3 | Trial contains a sub-study | No |
| 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 active 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 are to receive, or who are currently 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. Age 18-80 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.
|
|
| 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., systemic lupus erythematosus, inflammatory bowel disease, scleroderma, inflammatory myopathy, mixed connective tissue disease or other overlap syndrome).
4. Diagnosis of juvenile idiopathic arthritis (JIA), also known as 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 24 weeks of randomization.
6. Lack of peripheral venous access.
7. Pregnancy or breast feeding.
8. Significant cardiac or pulmonary disease (including obstructive pulmonary disease).
9. Evidence of significant uncontrolled concomitant disease such as, but not limited to, 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 completion of oral anti-infectives within 2 weeks prior to baseline.
12. History of deep space/tissue infection (e.g. fasciitis, abscess, osteomyelitis) within 52 weeks prior to baseline.
13. History of serious recurrent or chronic infection (for screening for a chest infection a chest radiograph will be performed at screening if not performed within 12 weeks prior to 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 swelling (e.g. Parkinsons 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. Previous treatment with any approved or investigational biologic agent for RA.
19. Previous treatment with an anti-alpha 4 integrin antibody or co-stimulation modulator.
20. Concurrent treatment with any biologic agent or DMARD other than MTX. Treatment 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).
21. 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, anti-BLys/ BAFF, and anti-CD20).
22. Treatment with any investigational agent within 28 days of baseline or 5 half-lives of the investigational drug (which ever is the longer).
23. Receipt of any vaccine within 28 days prior to baseline.
24. Intra-articular or parenteral glucocorticoids within 4 weeks prior to baseline.
25. Intolerance or contraindications to i.v. glucocorticoids.
26. Positive serum human chorionic gonadotropin (hCG) measured prior to the first rituximab/placebo infusion.
27. Positive tests for hepatitis B surface antigen (HBsAg) or hepatitis C serology.
28. Hemoglobin < 8.0 g/dL.
29. Concentrations of serum IgG and/or IgM below 5.0 and 0.40 mg/mL.
30. Absolute neutrophil count (ANC) < 1.5 x 10(3)/µL.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the proportion of patients with an ACR20 response at week 24. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| 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) | 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 31 |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| Each patient is eligible to receive further courses of rituximab for up to a total treatment period of 240 weeks (approximately 5 years) from their initial treatment or until 31 December 2010, whichever is sooner. The end of treatment is therefore defined as the 240 week time point or 31 December 2010, following which there will be an additional period of at least a year of safety follow-up (SFU). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| 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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