| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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 compare the effects of the combination of Etanercept (ETN) and Methotrexate (MTX) to methotrexate alone on radiographic change and clinical disease activity in subjects with active early rheumatoid arthritis over 12 months |
|
| E.2.2 | Secondary objectives of the trial |
Secondary:
1. To evaluate the safety of each treatment group over 24 months
2. To compare the effects of the combination of ETN and MTX to MTX alone on radiographic change and clinical disease activity over 12 months in Period 2 in subjects who first received 12 months of MTX alone
3. To compare the effects of the combination of ETN and MTX to ETN alone on radiographic change and clinical disease activity over 12 months in Period 2 in subjects who first received 12 months of the combination of ETN and MTX
4. To compare the effects of the combination of ETN and MTX for 24 months to MTX alone for 12 months followed by the combination of ETN and MTX on radiographic change and clinical disease activity over 24 months
5. To compare the effects of the combination of ETN and MTX to MTX alone on radiographic change and clinical disease activity over 24 months |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Is age 18 years or older
2. Satisfies the 1987 ACR Revised Criteria for Rheumatoid Arthritis (see Attachment 1)
3. Has disease duration of ≥ 3 months and =< 2 years
4. Has active disease at the time of randomization as indicated by a DAS28 ≥ 3.2 (see Attachment 2) and at least one of the following two criteria: Westergren erythrocyte sedimentation rate (ESR) ≥28 mm/hour or C-reactive protein (CRP) levels ≥20 mg/L
5. Demonstrates functional status of Class I, II, or III as defined by ACR revised criteria (see Attachment 3)
6. Demonstrates a negative serum pregnancy test at screening if female of childbearing potential. A woman of childbearing potential is defined as one who is biologically capable of becoming pregnant. This includes women who are using contraceptives or whose sexual partners are either sterile or using contraceptives. Sexually active women participating in the study must use a medically acceptable form of contraception. Medically acceptable forms of contraception for women include oral contraception, injectable or implantable methods, intrauterine devices, or properly used barrier contraception
7. Agrees to use a medically accepted form of contraception during the study if sexually active male. Medically acceptable forms of contraception for males are a properly used barrier contraceptive or sterilization.
8. Is capable of understanding and signing an informed consent form
9. Is able and willing to self-inject study drug or have a designee who can do so
10. Is able and willing to take oral medication
11. Is able to store injectable test article at 2° C to 8° C
12. Demonstrates a negative tuberculosis screening test, only if required by local country guidelines |
|
| E.4 | Principal exclusion criteria |
1. Received any previous treatment with MTX
2. Received any previous treatment with ETN or other tumour necrosis factor (TNF) antagonist (e.g., a TNF monoclonal antibody or a soluble TNF receptor)
3. Received any of the following within 4 weeks of baseline visit: leflunomide, hydroxychloroquine, chloroquine, cyclosporine, sulphasalazine, auranofin, intramuscular gold, azathioprine, minocycline, D-penicillamine, or interleukin-1 receptor antagonist (IL-1ra).
4. Received cyclophosphamide within 6 months of screening visit
5. Received any investigational drug within 3 months of screening visit
6. Received anti-CD4, diphtheria interleukin-2 fusion protein, anti interleukin-6 (anti-IL-6), rituxamab or other immunosuppressive biologic during the last 6 months before screening, and treatment with such agents more than 6 months before screening if there are persistent signs of immunosuppression (with a subsequent abnormal absolute T-cell count) at screening visit
7. Received any live (attenuated) vaccines within 4 weeks of screening visit
8. Received intra-articular corticosteroid injection within 4 weeks of screening visit
9. Received bolus intramuscular/intravenous treatment with corticosteroids (> 20 mg prednisone or equivalent) within 4 weeks of screening visit
10. Concomitant use of more than one nonsteroidal anti-inflammatory drug (NSAID)
11. Uses a dose of NSAID greater than the maximum recommended dose in the product information at the screening visit
12. Is taking > 10 mg/day of prednisone or equivalent
13. Has significant concurrent medical diseases including cancer or a history of cancer (other than resected cutaneous basal and squamous cell carcinoma, and in situ cervical cancer) within 5 years of entering the screening period, uncompensated congestive heart failure, myocardial infarction within 12 months, unstable angina pectoris, uncontrolled hypertension, severe pulmonary disease, or history of human immunodeficiency virus (HIV) infection, immunodeficiency syndromes, primary Sjögren’s syndrome, psoriasis, connective tissue diseases other than RA (e.g., psoriatic arthritis, systemic lupus erythematosus), or central nervous system (CNS) demyelinating events suggestive of multiple sclerosis
14. Has a history of anti-cardiolipin antibodies associated with a thrombotic event or recurrent fetal loss
15. Has a history of confirmed blood dyscrasias
16. Has a significant active infection or any underlying diseases that could predispose subjects to infections (e.g., a history of recurring infections, nonhealing leg ulcers, advanced or poorly controlled diabetes)
17. Demonstrates liver function abnormality (serum glutamic-oxaloacetic transaminase [SGOT]/aspartate aminotransferase [AST], serum glutamic-pyruvic transaminase [SGPT]/alanine aminotransferase [ALT] > 2x upper limit of normal [ULN]
18. Has a history of known liver cirrhosis, fibrosis, or fatty liver
19. Has a history of any viral hepatitis within 1 year of screening
20. Has renal disease (creatinine level > 175 mmol/L)
21. Has leukopenia (white blood cells < 3500 x 106/L)
22. Has thrombocytopenia (platelets < 125 x 109/L)
23. Has a hemoglobin level of < 85 g/L
24. Has any condition judged by the physician to cause this study to be detrimental to the subject
25. Has a history of drug abuse or psychiatric disease that would interfere with the ability to comply with the study protocol
26. Has a history of alcohol abuse or excessive alcohol beverage consumption
27. Is pregnant or breast-feeding
28. Is scheduled for elective major surgery within the first year of study participation |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The radiographic and clinical efficacy endpoints will be co primary
The primary radiographic efficacy endpoint is the change in modified TSS from baseline to Month 12.
The primary clinical efficacy endpoint is the proportion of subjects achieving remission (i.e., DAS28 value of <2.6 at 12 months). |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| 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 | 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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 | No |
| 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 |
|
| 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
|
| The end of the trial is the last follow-up visit for safety of the last patient randomized. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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