| 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 assess the efficacy of treatment with MRA versus placebo, in combination with stable, ongoing therapy, with regard to signs and symptoms, in patients with moderate to severe active RA and inadequate response to current DMARD treatment.
2. To assess the safety of MRA versus placebo in combination with stable, ongoing therapy, with regard to adverse events and laboratory assessments in patients with moderate to severe active RA and inadequate response to current DMARD treatment.
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| E.2.2 | Secondary objectives of the trial |
| To explore the pharmacokinetics, immunogenicity and pharmacodynamic parameters of MRA in this patient population. |
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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 of ³ 6 months duration diagnosed according to the revised 1987 American College of Rheumatology (ACR; formerly American Rheumatism Association) criteria (Appendix 2).
3. Receiving treatment on an outpatient basis.
4. Prior to randomization, will have discontinued etanercept for ³ 2 weeks, infliximab or adalimumab for ³ 8 weeks (see exclusion # 5), anakinra for ³ 1 week.
5. Have received permitted DMARDs, each at a stable dose, for at least 8 weeks prior to baseline.
6. Swollen joint count (SJC) ³ 6 (66 joint count) and tender joint count (TJC) ³ 8 (68 joint count) at screening and baseline.
7. At screening either CRP ³ 1 mg/dL (10 mg/L) or ESR ³ 28 mm/hr
8. Age ³ 18 years
9. Oral corticosteroids (£ 10 mg/day prednisone or equivalent) and NSAIDs (up to the maximum recommended dose) are permitted if the dose has been stable for at least 6 weeks prior to baseline.
10. Females of child-bearing potential and males with female partners of child-bearing potential may participate in this trial only if using a reliable means of contraception (e.g. physical barrier (patient and partner), contraceptive pill or patch, spermicide and barrier, or IUD).
11. If female and of childbearing potential, the patient must have a negative urine pregnancy test within three weeks prior to baseline.
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| E.4 | Principal exclusion criteria |
General:
1. Major surgery (including joint surgery) within eight weeks prior to screening or planned surgery within six months following randomization.
2. Rheumatic autoimmune disease other than RA, including SLE, MCTD, scleroderma, polymyositis, or significant systemic involvement secondary to RA (e.g., vasculitis, pulmonary fibrosis or Felty’s syndrome). Sjögren’s Syndrome with RA is allowable.
3. Functional class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis.
4. Prior history of or current inflammatory joint disease other than RA (e.g., gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease).
Excluded Previous or Concomitant Therapy:
5. Unsuccessful treatment with an anti-TNF agent (i.e. significant safety issues or lack of efficacy; Patients who terminated previous anti-TNF treatment due to cost or discomfort with the subcutaneous injections, may participate in this study.) (See Inclusion #4 for anti-TNF agent washouts.)
6. Treatment with any investigational agent within four weeks (or five half-lives, whichever is longer) of screening.
7. Previous treatment with any cell depleting therapies, including investigational agents (e.g. CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19 and anti-CD20).
8. Treatment with intravenous gamma globulin, plasmapheresis or Prosorba ä column within six months of baseline.
9. Intra-articular or parenteral corticosteroids within six weeks prior to baseline.
10. Immunization with a live/attenuated vaccine within four weeks prior to baseline.
11. Previous treatment with MRA (an exception to this criterion may be granted for single dose exposure upon application to the sponsor on a case by case basis).
12. Any previous treatment with alkylating agents such as cyclophosphamide or chlorambucil, or with total lymphoid irradiation.
Exclusions for General Safety
13. History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies.
14. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (incl. obstructive pulmonary disease), renal, hepatic, endocrine (incl. uncontrolled diabetes mellitus) or gastrointestinal disease.
15. Uncontrolled disease states, such as asthma, psoriasis or inflammatory bowel disease where flares are commonly treated with oral or parenteral corticosteroids.
16. Current liver disease as determined by principal investigator. (Patients with prior history of ALT elevation will not be excluded.)
17. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections (including but not limited to tuberculosis and atypical mycobacterial disease, granulomatous disease on chest X-ray, Hepatitis B and C, and herpes zoster, but excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with IV antibiotics within four weeks of screening or oral antibiotics within two weeks prior to screening.
18. Primary or secondary immunodeficiency (history of or currently active).
19. History of malignancy, including solid tumors and hematologic malignancies (except basal cell carcinoma of the skin that has been excised and cured).
20. Pregnant women or nursing (breast feeding) mothers.
21. History of alcohol, drug or chemical abuse within the six months prior to screening.
22. Neuropathies or other painful conditions that might interfere with pain evaluation.
23. Patients with lack of peripheral venous access
24. Body weight of > 150 kg
Laboratory Exclusion criteria (at screening)
25. Serum creatinine > 1.4 mg/dL in female patients and > 1.6 mg/dL in male patients
26. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 times upper limit of normal (ULN). (If initial sample yields ALT or AST > 1.5 times the ULN, a second sample may be taken and tested during the screening period.)
27. Platelet count < 100,000/mm3
28. Hemoglobin < 8.5 g/dL
29. White Blood Cells < 3000/mm3
30. Absolute Neutrophil Count < 2000/mm3
31. Absolute Lymphocyte Count < 500/mm3
32. Positive Hepatitis BsAg, or Hepatitis C antibody
33. Total Bilirubin > ULN. (If initial sample yields Bilirubin > ULN, a second sample may be taken and tested during the screening period.)
34. Triglycerides > 10 mmol/L (> 900 mg/dL) at screening (non-fasted)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary:The primary endpoint is the proportion of patients with an ACR20 response at week 24 |
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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 | No |
| 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 | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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) | 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) | 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.8.6 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
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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