E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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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 |
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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 safety and tolerability of tocilizumab (TCZ) monotherapy or in combination with non-biologic disease-modifying antirheumatic drugs (DMARDs) in patients with moderate to severe active RA
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E.2.2 | Secondary objectives of the trial |
• To assess the efficacy of TCZ monotherapy or in combination with non-biologic DMARDs
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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. Diagnosis of active RA of ≥ 6 months duration and moderate to severe disease activity defined as DAS28 > 3.2 at screening 4. Receiving treatment on an outpatient basis 5. Patients on ≥ 1 non-biologic DMARDs and/or anti-TNF therapy (see section 6.1) at a stable dose for a period ≥ 8 weeks at any time prior to treatment (baseline) 6. Patients with inadequate clinical response to a stable dose of non-biologic DMARD or anti-TNF therapy 7. If patients are receiving an oral corticosteroid, the dose must have been stable for at least 25 out of 28 days prior to treatment (baseline) 8. Able and willing to give written informed consent and comply with the requirements of the study protocol
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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 enrollment 2. Rheumatic autoimmune disease other than RA, Sjögren’s Syndrome with RA is permitted 3. Functional class IV as defined by the ACR Classification of Functional Status 4. Prior history of or current inflammatory joint disease other than RA Drug-specific 5. Treatment with any investigational agent or with anakinera, calcineurin inhibitors, mycophenolate, mofetil or mycophenolic acid within 4 weeks (or 5 half-lives of investigational agent, whichever is longer) before screening 6. Previous treatment with any cell-depleting therapies 7. Previous treatment with abatacept 8. Treatment with leuflunomide in combination with MTX. 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 12. Previous treatment with TCZ (exception may be granted for single-dose exposure on a case by case basis) 13. Any previous treatment with alkylating agents
Laboratory analyses (at screening) 14. Serum creatinine > 124 μmol/L (1.4 mg/dL) in female patients and > 141 μmol/L (1.6 mg/dL) in male patients 15. ALT (SGPT) or AST (SGOT) > 1.5 ULN (If initial sample yields ALT [SGPT] or AST [SGOT] > 1.5 ULN, a second sample may be taken and tested during the screening period) 16. Platelet count < 100 x 10(9)/L (100,000/mm3) 17. Hemoglobin < 85 g/L (8.5 g/dL; 5.3 mmol/L) 18. WBC count < 1.0 x 10(9)/L (3000/mm3), ANC < 0.5 x 10(9)/L (500/mm3) 19. ANC < 1 x 10(9)/L (1000/mm3) 20. Positive hepatitis B surface antigen (HBsAg) or hepatitis C antibody 21. Total bilirubin > ULN (If initial sample yields bilirubin > ULN, a second sample may be taken and tested during the screening period) 22. Triglycerides > 10 mmol/L (> 900 mg/dL) at screening (non-fasted)
General medical 23. Pregnant women or nursing (breastfeeding) mothers 24. Females of child-bearing potential who are not using a reliable means of contraception, e.g. physical barrier (patient and partner), contraceptive pill or patch, spermicide and barrier, or IUD 25. History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies 26. CXR evidence of any clinically significant abnormality 27. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus) or GI disease 28. In patients with a history of diverticulitis or diverticulosis requiring antibiotic treatment, the treating physician needs to consider the benefit-risk ratio 29. A history of chronic ulcerative lower GI disease such as Crohn’s disease, ulcerative colitis or other symptomatic lower GI conditions that might predispose to perforations 30. Uncontrolled disease states where flares are commonly treated with oral or parenteral corticosteroids 31. Current liver disease as determined by principal investigator. Patients with prior history of ALT (SGPT) elevation are not excluded 32. 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 CXR 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 4 weeks of screening, or oral antibiotics within 2 weeks prior to screening (does not apply to treatment of latent TB). 33. History of or currently active primary or secondary immunodeficiency 34. Evidence of active malignant disease, malignancies diagnosed within the previous 10 years (including hematological 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 35. Active tuberculosis (TB) requiring treatment within the previous 3 years. 36. 36. Patients should be screened for latent TB, prior to biologics use, as per local guidelines or good clinical practice in your country. Patients with latent tuberculosis should be treated with standard antimycobacterial therapy (at least 4 weeks) before initiating TCZ and have a negative CXR for active TB at screening. 37. HIV positive patient 38. History of alcohol, drug or chemical abuse within the 6 months prior to screening 39. Neuropathies or other painful conditions that might interfere with pain evaluation 40. Patients with lack of peripheral venous access 41. Body weight of > 150 kg
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E.5 End points |
E.5.1 | Primary end point(s) |
• Incidence of adverse events and serious adverse events during 24 weeks of TCZ monotherapy or combined treatment with TCZ and one or more of the background non-biologic disease modifying anti-rheumatic drugs (DMARDs) approved for rheumatoid arthritis (RA) in patients with moderate to severe active RA |
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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 | No |
E.6.7 | Pharmacodynamic | No |
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 | 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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 15 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 240 |
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 | 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
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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 | 6 |