| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10039073 |
| E.1.2 | Term | Rheumatoid arthritis |
|
| 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 investigate the safety, tolerability and efficacy of rituximab in combination with tocilizumab in patients with active RA despite a stable dose of methotrexate. |
|
| E.2.2 | Secondary objectives of the trial |
To investigate the pharmacokinetics of rituximab and tocilizumab when given in combination to rheumatoid arthritis patients.
To explore the effect of the combination of rituxmab and tocilizumab upon exploratory pharmacodynamic endpoints in rheumatoid arthritis. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Roche Sample Respository Research Project in association with WX21956 |
|
| E.3 | Principal inclusion criteria |
1. Able and willing to give written informed consent and comply with the requirements of the study protocol
2. Age 18 - 65 years
3. Rheumatoid arthritis diagnosed according to the American Rheumatism Association 1987 revised criteria for the classification of RA
4. Functional Status I-III according to the 1991 ACR revised criteria for the classification of global functional status in RA
5. Swollen joint count (SJC) ≥ 4 (28 joint count) and tender joint count (TJC) ≥ 4 (28 joint count) at screening and baseline
6. DAS28-ESR > 3.2 at screening
7. CRP ≥ 0.6 mg/dL using a high-sensitivity assay and/or ESR ≥ 30 mm/h at screening
8. RF positive and/or anti-CCP positive
9. Must have an inadequate response to MTX and have been receiving and tolerating this at a dose of 7.5 - 25 mg weekly (p.o. or parenterally) for at least 12 weeks, with the last 4 weeks prior to screening at a stable dose
10. Patients may have failed (through lack of efficacy or tolerability) up to 1 approved anti-TNF agent (infliximab, etanercept or adalimumab), and up to 6 non-biologic disease-modifying antirheumatic drugs (DMARDs), including MTX. The following non-biologic DMARDS are considered as a single agent for this count:
- All forms of gold
- Leflunomide
- Chloroquine and hydroxychloroquine
- Dapsone or azathioprine
- Sulfasalazine and mesalazine
- Cyclosporine A
11. All DMARDs other than methotrexate must be withdrawn at least 4 weeks prior to randomization except as follows: 2 weeks for etanercept, 8 weeks for infliximab, and 12 weeks for leflunomide (8 weeks if cholestyramine or activated charcoal is used to accelerate leflunomide withdrawal)
12. Oral corticosteroids (≤ 10 mg/day prednisolone or equivalent) and NSAIDs (up to the maximum recommended dose, including COX-2 inhibitors) are permitted if the dose has been stable for at least 4 weeks prior to baseline. No patient may be using more than one NSAID simultaneously (with the exception of low-dose aspirin for cardioprotection)
13. Patients must be willing to receive oral folic acid at a stable dose of at least 5 mg/week
14. Current treatment for RA on an outpatient basis
15. Female patients of child bearing potential may participate in this study if using reliable means of contraception for the duration of the study, and for up to 3 months after their last dose of tocilizumab, and up to 1 year after their last dose of rituximab, or until their peripheral CD20+ B cells have repleted
16. Female patients of childbearing age must have a negative serum pregnancy test at screening
17. Male patients with female partners of child bearing potential may participate in this study only if the patient or the partner are using reliable means of contraception for the duration of the study, and for up to 3 months after their last dose of tocilizumab, and up to 1 year after their last dose of rituximab, or until their peripheral CD20+ B cells have repleted.
|
|
| E.4 | Principal exclusion criteria |
1. Functional Status IV - 1991 ACR criteria
2. Rheumatic AI disease other than RA (e.g SLE, Mixed Connective Tissue Disease, scleroderma/variants, polymyositis) or significant systemic involvement secondary to RA (e.g. vasculitis, pulmonary fibrosis, Felty’s syndrome); Secondary Sjögren’s and limited cutaneous vasculitis or nodulosis with RA allowed
3. History of/current inflammatory joint disease other than RA (e.g: gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease, pseudogout, arthropathy of inflammatory bowel disease)
4. Diagnosis of JIA/JRA and/or RA before age 16
5. Significant +/or uncontrolled concomitant disease e.g cardiovascular disease, nervous system, pulmonary, renal, hepatic, endocrine or GI disorders (including previous complicated diverticulitis) which, in Investigator’s opinion, would preclude participation or impact benefit-risk
6. Any condition or general state of health which, in Investigator’s opinion, would preclude participation
7. Significant cardiac disease (NYHA Class III/IV), known severe COPD (FEV1 < 50% predicted or Functional dyspnea ≥ Grade 3 on MRC Scale) or other significant pulmonary disease
8. Uncontrolled disease (e.g asthma, psoriasis or inflammatory bowel disease) where flares commonly treated with oral or injectable steroids
9. Known active infection of any kind (excluding fungal infections of nail bed), or major episode of infection requiring hospitalization/treatment with i.v. anti-infectives within 4 weeks of baseline or completion of oral anti-infectives within 2 weeks of baseline
10. History of deep space/tissue infection within 52 weeks of baseline
11. Any surgical procedure, including bone/joint surgery/ synovectomy within 8 weeks of baseline or planned during the study
12. History of serious recurrent or chronic infection
13. Active tuberculosis requiring treatment within 2 years of screening
14. Positive TB test result at screening, unless treated with anti-TB therapy for at least 4 weeks prior to receiving study medication and chest radiograph negative for active TB
15. Primary or secondary immunodeficiency (history of, or currently active), including known history of HIV infection
16. History of malignancy, including solid tumors, hematologic malignancies and carcinoma in situ (except basal cell and squamous cell carcinoma of the skin, and melanoma in situ, or cervical carcinoma in situ with no stromal invasion, that have been completely excised and are considered cured)
17. Any neurological, vascular or systemic disorder which could affect efficacy assessments, in particular, joint pain and swelling (e.g. Parkinsons, cerebral palsy, diabetic neuropathy)
18. Current evidence for alcohol, drug or chemical abuse, or recent history of such abuse within 24 weeks of screening
19. Lack of peripheral venous access
20. Pregnancy or breast feeding
21. Body weight > 150 kg or BMI > 35
22. Previous treatment with any biological agent for RA other than infliximab, etanercept or adalimumab
23. Previous treatment with tocilizumab or rituximab
24. Previous/concurrent treatment with anti-alpha 4 integrin inhibitors (e.g. natalizumab)
25. Previous/concurrent 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, anti-CD20)
26. Treatment with intravenous gamma globulin, plasmapheresis or Prosorba® column within 6 months of baseline
27. Any previous treatment with alkylating agents e.g. cyclophosphamide or chlorambucil, or with total lymphoid irradiation
28. Treatment with any investigational agent within 28 days of screening or 5 half-lives of investigational drug (whichever is longer)
29. Previous/current significant safety issues experienced with another biological agent
30. History of severe allergic or anaphylactic reaction to any biologic agent or known hypersensitivity to any component of tocilizumab or rituximab
31. Receipt of any vaccine within 28 days of baseline
32. Intra-articular or parenteral glucocorticoids within 4 weeks of baseline
33. Intolerance or contraindications to i.v. glucocorticoids
34. Positive tests for hepatitis B surface antigen, Hepatitis B core antibody or hepatitis C serology
35. Absolute neutrophil count < 2.0 × 103/μL, white blood cells < 2.5 × 103/μL, platelet count < 100,000/μL
36. Hemoglobin < 8.0 g/dL
37. Serum IgG and/or IgM below 5.0 mg/mL and 0.40 mg/mL, respectively
38. Serum creatinine > 2.0 mg/dL (200 μmol/L)
39. ALT or AST > 1.5 times upper limit of normal.
40. Total bilirubin > 1.5 times upper limit of normal
41. Triglycerides > 400 mg/dL (non-fasted) or > 250 mg/dL (fasted) at screening
42. Positive serum human chorionic gonadotropin measured prior to the first rituximab/placebo infusion
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of patients with a low DAS (DAS </= 3.2) at week 16 using DAS-ESR. |
|
| 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 | No |
| 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 | 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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) | No |
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 28 |
| 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
|
| Last Patient Last Visit (see protocol section 3.1.6) |
|
| 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 | 3 |
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