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 effect of TCZ in combination with MTX versus TCZ alone (i.e. receiving placebo matching MTX) on DAS28 remission at week 24 in MTX inadequate responders with moderate to severe active RA. |
|
E.2.2 | Secondary objectives of the trial |
To compare the effect of TCZ plus MTX versus TCZ plus PBO on progression of structural damage at week 52 in MTX inadequate responders with moderate to severe active RA who may receive a DMARD in addition to TCZ and MTX/PBO after week 24.
To compare the safety of TCZ plus MTX versus TCZ plus PBO with regard to AEs and laboratory assessments in MTX inadequate responders with moderate to severe active RA who may receive a DMARD in addition to TCZ and MTX/PBO after week 24.
To assess clinical and radiographic efficacy over 2 years (including earlier time points) of treatment with TCZ plus MTX versus TCZ plus PBO as assessed by measures including clinical disease activity, x-rays and quality of life and functional scales.
To assess the course of disease activity as well as treatment efficacy and safety in patients for the duration of 52 weeks after discontinuation of TCZ because of remission. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or non-pregnant, non-nursing female 2. ≥ 18 years of age 3. Body weight ≤ 150 kg 4. Patients currently experiencing active moderate to severe RA (DAS28 > 4.4) according to the revised 1987 ACR criteria for the diagnosis of RA at baseline. At screening the DAS28 must be equal or greater than 4.0 (DAS28 ≥4.0). 5. Patients currently receiving MTX (oral or parenteral) for at least 12 weeks and who have received MTX at a stable dose of at least 15 mg/week for at least 6 weeks prior to treatment (day 1), with the following exception: 10 mg instead of 15 mg is acceptable in patients with a body weight < 50 kg, low grade toxicity to MTX (such as nausea), or calculated glomerular filtration rate (or creatinine clearance) < 60 mL/min. Patients with a history of parenteral (subcutaneous or intramuscular) MTX prior to baseline are eligible. However, prior to treatment (day 1) these patients must have been on a stable dose of oral MTX of at least 15 mg/week for at least 6 weeks. 6. If patients are receiving an oral corticosteroid, the dose must have been ≤ 10 mg/day prednisone (or equivalent) and stable for at least 25 out of 28 days prior to treatment (day 1) 7. Patients receiving treatment on an outpatient basis 8. Patients able and willing to give written informed consent and comply with the requirements of the study protocol
|
|
E.4 | Principal exclusion criteria |
Disease 1. Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomization 2. Rheumatic autoimmune disease other than RA, including systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), scleroderma, polymyositis, or significant systemic involvement secondary to RA (e.g. vasculitis, pulmonary fibrosis or Felty’s syndrome). Patient with interstitial pulmonary fibrosis and still able to tolerate MTX therapy are permitted. Sjögren’s Syndrome with RA is permitted 3. Functional class IV as defined by the ACR Classification of Functional Status in RA (largely or wholly incapacitated with patient bedridden or confined to wheel chair, permitting little or no self-care) 4. Prior history of or current inflammatory joint disease other than RA (e.g. gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease) Drug-specific 5. Treatment with any investigational agent within 4 weeks (or 5 half-lives of investigational agent, whichever is longer) before screening 6. Previous treatment with TCZ 7. Previous treatment with any biologic drug that is used in the treatment of RA 8. Any previous treatment with alkylating agents, such as cyclophosphamide or chlorambucil, or with total lymphoid irradiation 9. Treatment with IV gamma globulin, plasmapheresis or Prosorba® column within 6 months before baseline 10. Intraarticular or parenteral corticosteroids within 6 weeks prior to baseline 11. Immunization with a live/attenuated vaccine within 4 weeks prior to baseline Laboratory analyses (at screening) 12. Serum creatinine > 142 μmol/L (1.6 mg/dL) in female patients and > 168 μmol/L (1.9 mg/dL) in male patients and no active renal disease 13. ALT (SGPT) or AST (SGOT) > 1.5 x ULN 14. Platelet count < 100 x 10e9/L (100,000/mm3) 15. Hemoglobin < 85 g/L (8.5 g/dL; 5.3 mmol/L) 16. WBC count < 1.0 x 10e9/L (1000/mm3), absolute neutrophil count < 1.0 x 10e9/L (1000/mm3). Patients enrolled prior to amendment based on a lower ANC threshold may continue to stay in the study, if deemed appropriate by the investigator. 17. Absolute lymphocyte count < 0.5 x 109/L (500/mm3) 18. Positive hepatitis B surface antigen or hepatitis C antibody 19. Total bilirubin > ULN 20. Triglycerides > 10 mmol/L (> 900 mg/dL) at screening (non-fasted or fasting) |
|
E.5 End points |
E.5.1 | Primary end point(s) |
• DAS28 remission rate (RR) at week 24. DAS28 remission is defined as DAS28 < 2.6. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
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 |
Qualitiy of Life and Disability Assessments |
|
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 | Yes |
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 | Yes |
E.8.1.7.1 | Other trial design description |
this study is placebo controlled for MTX and open label for TCZ |
|
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.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 72 |
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
|
The end of the trial is defined as the date of the last visit of the last participating patient in this study (LPLV; week 104 or later, if the last patient has discontinued TCZ for remission and is being followed beyond week 100). |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
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 | 4 |