| 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 assess the efficacy of MRA alone versus MTX alone with regard to reduction in signs and symptoms in patients with active rheumatoid arthritis (RA).
• To assess the safety of MRA alone versus MTX alone with regard to adverse events and laboratory assessments in patients with active RA.
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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 greater than or equal to 3 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 greater than or equal to 2 weeks, infliximab or adalimumab for greater than or equal to 8 weeks (see exclusion # 5), anakinra for greater than or equal to 1 week, leflunomide for > 12 weeks (or greater than or equal to 4 weeks after 11 days of standard cholestyramine washout).
5. All DMARDs withdrawn prior to baseline.
6. Swollen joint count (SJC) greater than or equal to 6 (66 joint count) and tender joint count (TJC) greater than or equal to 8 (68 joint count) at screening and baseline.
7. At screening either CRP greater than or equal to 1 mg/dL (10 mg/L) or ESR less than or equal to 28 mm/hr
8. Age greater than or equal to 18 years
9. Oral corticosteroids (less than or equal to 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.
12. Must be willing to receive oral folate.
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| E.4 | Principal exclusion criteria |
1. Major surgery (including joint surgery) within eight weeks prior to screening or planned major 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 (Appendix 3)
4. Prior history of or current inflammatory joint disease other than RA (e.g., gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease).
1. Treatment with MTX within 6 months prior to randomization.
2. Discontinued previous MTX treatment as a result of clinically important toxic effects or lack of response as determined by the investigator.
3. 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.)
4. Treatment with any investigational agent within four weeks (or five half-lives of the investigational agent, whichever is longer) of screening.
5. Previous treatment with any cell depleting therapies, including investigational agents (e.g. CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19 and anti-CD20).
6. Treatment with intravenous gamma globulin, plasmapheresis or Prosorba column within six months of baseline.
7. Intra-articular or parenteral corticosteroids within six weeks prior to baseline.
8. Immunization with a live/attenuated vaccine within four weeks prior to baseline.
9. 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).
10. Any previous treatment with alkylating agents such as cyclophosphamide or chlorambucil, or with total lymphoid irradiation.
1. History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies.
2. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (incl. obstructive pulmonary disease), renal, hepatic, endocrine (incl. uncontrolled diabetes mellitus) or gastrointestinal disease.
3. Uncontrolled disease states, such as asthma, psoriasis or inflammatory bowel disease where flares are commonly treated with oral or parenteral corticosteroids.
4. Current liver disease as determined by principal investigator. (Patients with prior history of ALT elevation will not be excluded.)
5. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections (including but not limited to tuberculosis and atypical mycobacterial disease, clinically significant abnormalities on chest X-ray as determined by the investigator, 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.
6. Primary or secondary immunodeficiency (history of or currently active).
7. Evidence of active malignant disease, malignancies diagnosed within the previous 10 years (including hematologic malignancies and solid tumors, except basal cell carcinoma of the skin that has been excised and cured), or breast cancer diagnosed within the previous 20 years.
8. Pregnant women or nursing (breast feeding) mothers.
9. History of alcohol, drug or chemical abuse within the six months prior to screening.
10. Neuropathies or other painful conditions that might interfere with pain evaluation.
11. Patients with lack of peripheral venous access
12. Body weight of > 150 kg
1. Serum creatinine > 124 micromoles per litre (1.4 mg/dL) in female patients and > 141 micromoles per litre (1.6 mg/dL) in male patients
2. 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.)
3. Platelet count < 100 x 10 to the power of nine per litre (100,000/cubic mm)
4. Hemoglobin < 85 g/L (8.5 g/dL; 5.3 mmol/L)
5. White Blood Cells < 3 x 10 to the power of nine per litre (3000/ cubic mm)
6. Absolute Neutrophil Count < 2 x 10 to the power of nine per litre (2000/ cubic mm)
7. Absolute Lymphocyte Count < 0.5 x 10 to the power of nine per litre (500/ cubic mm)
8. Positive Hepatitis BsAg, or Hepatitis C antibody
9. Total Bilirubin > ULN. (If initial sample yields Bilirubin > ULN, a second sample may be taken and tested during the screening period.)
10. 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) | Yes |
| 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
| 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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In the main study, patients not entering the transition phase or the proposed open label extention study will have follow up visits at weeks 4, 8 and 12 after the last infusion.
Patients with a defined level of improvement may remain on blinded treatment (transition phase) for upto 128 weeks following the start of the main study. |
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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 | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
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