| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| Rheumatoid arthritis (RA) in adults. RA is a long-term disease that leads to inflammation of the joints and surrounding tissues. It can also affect other organs. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| 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 |
Primary Objective:
To evaluate the safety and tolerability of subcutaneous (SC) tocilizumab (TCZ) monotherapy and/or in combination with MTX or other non-biologic DMARDs comprising AEs, physical examination, vital signs, and clinical laboratory assessments, including immunogenicity, in patients with active rheumatoid arthritis (RA) in a 24 week study. |
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| E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
To assess the efficacy of SC TCZ monotherapy and/or in combination with MTX or other non-biologic DMARDs over time using endpoints such as DAS28 ESR, ACR response scores, EULAR response criteria, SDAI or CDAI, TJC/SJC, PROs at Week 24, including onset of action at Week 2.
To evaluate the reasons for and time to corticosteroid and NSAID dose reductions and/or discontinuations from week 16 onward in a 24-week study.
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Exploratory Objectives:
To evaluate prevalence and extent of RA medication intolerance, utilizing an intolerance specific questionnaire derived from the Methotrexate Intolerance Severity Score (MISS), in a 24-week study. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must meet the following criteria for study entry:
1. Able and willing to give written informed consent and comply with the requirements of the study protocol.
2. Patients at least 18 years of age.
3. Patients with a diagnosis of active RA according to the revised (1987) ACR criteria or EULAR/ACR (2010) criteria.
4. Oral corticosteroids (≤10 mg/day prednisone or equivalent) and NSAIDs (up to the maximum recommended dose) are permitted if on a stable dose regimen for ≥4 weeks prior to Baseline.
5. Permitted non-biologic DMARDs are allowed if at a stable dose for at least 4 weeks prior to Baseline.
6. Receiving treatment on an outpatient basis, not including TCZ.
7. Females of childbearing potential and males with female partners of childbearing potential may participate in this study only if using a reliable means of contraception (e.g., physical barrier [patient or partner], contraceptive pill or patch, spermicide and barrier, or intrauterine device) during the study and for at least 3 months following the last dose of TCZ.
8. If female of childbearing potential, the patient must have a negative pregnancy test at the Screening and Baseline visits.
9. Patients that are conventional DMARD inadequate responders (IR), or are biological DMARD-IR with a maximum of an inadequate response to not more than one biological DMARD.
10. Have moderate to severe RA (DAS28 ≥ 3.2, ≥ 1 swollen joint). |
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| E.4 | Principal exclusion criteria |
A patient will be excluded if the answer to any of the following statements is “yes”:
General:
1. Major surgery (including joint surgery) within 8 weeks prior to Screening or planned major surgery within 6 months following baseline.
2. Rheumatic autoimmune disease other than RA, including systemic lupus erythematosis, mixed connective tissue disorder, scleroderma, polymyositis, or significant systemic involvement secondary to RA (e.g., vasculitis, pulmonary fibrosis or Felty’s syndrome). Secondary Sjögren’s syndrome with RA is permitted.
3. Functional Class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis.
4. Diagnosis of juvenile idiopathic arthritis or juvenile RA and/or RA before the age of 16.
5. Prior history of or current inflammatory joint disease other than RA (e.g., gout, Lyme disease, seronegative spondyloarthropathy including reactive arthritis, psoriatic arthritis, and arthropathy of inflammatory bowel disease).
6. Patients with lack of peripheral venous access.
Excluded Previous or Concomitant Therapy:
7. Exposure to TCZ (either intravenous [IV] or SC) at any time prior to Baseline.
8. Treatment with any investigational agent within 4 weeks (or five half-lives of the investigational drug, whichever is longer) of Screening.
9. Previous treatment with any cell-depleting therapies, including investigational agents or approved therapies, some examples are CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti CD19, and anti-CD20.
10. Treatment with IV gamma globulin, plasmapheresis within 6 months of Baseline.
11. Treatment with more than one biologic DMARD
12. Intraarticular or parenteral corticosteroids within 4 weeks prior to Baseline.
13. Immunization with a live/attenuated vaccine within 4 weeks prior to Baseline.
14. Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation.
Exclusions for General Safety:
15. History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies.
16. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus), or gastrointestinal (GI) disease.
17. History of diverticulitis, diverticulosis requiring antibiotic treatment, or chronic ulcerative lower GI disease such as Crohn’s disease, ulcerative colitis, or other symptomatic lower GI conditions that might predispose to perforation.
18. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial, or other infections (including but not limited to tuberculosis [TB] and atypical mycobacterial disease, hepatitis B and C, and herpes zoster, but excluding fungal infections of nail beds).
19. Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of Screening or oral antibiotics within 2 weeks of Screening.
20. Active TB requiring treatment within the previous 3 years. Patients should be screened for latent TB and, if positive, treated following local practice guidelines prior to initiating TCZ. Patients treated for TB with no recurrence in 3 years are permitted.
21. Current liver disease as determined by the Investigator.
22. Positive hepatitis B surface antigen or hepatitis C antibody.
23. Primary or secondary immunodeficiency (history of or currently active).
24. Evidence of active malignant disease, malignancies diagnosed within the previous 10 years (including hematological malignancies and solid tumors, except basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that has been excised and cured), or breast cancer diagnosed within the previous 20 years.
25. Pregnant women or nursing (breast feeding) mothers.
26. Patients with reproductive potential not willing to use an effective method of contraception.
27. History of alcohol, drug, or chemical abuse within 1 year prior to Screening.
28. Neuropathies or other conditions that might interfere with pain evaluation.
Laboratory Exclusion Criteria (at Screening):
29. Serum creatinine >1.4 mg/dL (124 μmol/L) in female patients and >1.6 mg/dL (141 μmol/L) in male patients.
30. Alanine aminotransferase or aspartate aminotransferase >1.5 times upper limit of normal (ULN).
31. Total bilirubin >ULN.
32. Platelet count <100 x 109/L (100,000/mm3).
33. Hemoglobin <85 g/L (8.5 g/dL; 5.3 mmol/L).
34. White blood cells <3.0 x 109/L (3000/mm3).
35. Absolute neutrophil count <2.0 x 109/L (2000/mm3).
36. Absolute lymphocyte count <0.5 x 109/L (500/mm3). |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety Outcome Measures:
1. Incidence and severity of AEs, serious adverse events, and AEs of special interest over time up to Week 24.
2. Rates of AEs leading to dose modification or study withdrawal up to Week 24.
3. Assessment of physical examination and vital signs up to Week 24.
4. Incidence of clinically significant laboratory abnormalities following TCZ SC administration up to Week 24.
5. Assessment of immunogenicity following SC TCZ administration up to Week 24 and 8 weeks after last dose.
6. Rates of AEs leading to dose modification of concomitant RA medication(s) (NSAIDs, DMARDs and glucocorticoids) up to Week 24.
Efficacy Outcome Measures:
1. Change in DAS28-ESR up to Week 24.
2. ACR response scores up to Week 24.
3. EULAR response criteria up to Week 24.
4. Change in SDAI or CDAI up to Week 24.
5. Change in total TJC and total SJC over time.
6. Proportion of patients and reasons for corticosteroid and/or NSAID dose reductions and/or discontinuation over time.
Immunogenicity Outcome Measures:
Immunogenicity samples will be collected from all patients at Baseline, every 12 weeks during the study, at study completion or early withdrawal visit and at follow-up visit 8 weeks after the last dose.
Anti-TCZ antibodies, TCZ levels, and soluble IL-6 receptors are to be measured during the study. In addition, for any patients withdrawn due to hypersensitivity reaction (serious or non serious), these will be collected at the time of the event and at least 6 weeks after the last dose.
On dosing days, samples must be taken prior to dosing (trough drug levels). Samples taken on non-dosing days may be taken at any convenient time.
Patient-Reported Outcome Measures:
1.1. Patient Global Assessment of disease activity visual analogue scale (VAS) up to Week 24.
2. Patient Pain VAS up to Week 24.
3. Health Assessment Questionnaire-Disability Index up to Week 24.
4. Patient compliance (patient diary cards and return records) up to Week 24.
5. Patient Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) up to Week 24.
6. Patient reported assessment of RA medication intolerance utilizing an intolerance specific questionnaire derived from the Methotrexate Intolerance Severity Score up to Week 24, if applicable.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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 | No |
| 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) | 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 20 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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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| The end of the study will occur when the last patient last visit (LPLV) occurs. The LPLV is either the date of the last patient visit of the last patient to complete the study or the date at which the last data point from the last patient, which is required for the statistical analysis, is received, whichever is the later date. |
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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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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