| 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 |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10039073 |
| E.1.2 | Term | Rheumatoid arthritis |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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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 compare the impact on disease activity of continued vs. tapered prednisone in RA patients with stable low disease activity (LDA [Disease Activity Score in 28 joints (DAS28) erythrocyte sedimentation rate (ESR) score <= 3.2]) or remission (DAS28 ESR score <= 2.6). |
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| E.2.2 | Secondary objectives of the trial |
-To compare the proportion of patients who continue vs. taper prednisone with LDA or remission at Week 24, who haven’t suffered a disease flare and showed no confirmed adrenal insufficiency requiring replacement therapy
-To compare between patients who continue vs. taper prednisone:(1)changes in CDAI and SDAI (2)the proportion of patients with >=1 flare; time to first flare; number of flares; >=1 administration of flare rescue medication; time to first administration, and number of administrations of flare rescue medication(3)cumulative prednisone exposure(4)the proportion of patients who maintain LDA or remission and who maintain the baseline disease activity level(5)proportion of patients who permanently discontinue study treatment due to insufficient flare control,(6)changes in the ACR core set, (7)identify predictors of successful prednisone dose-tapering(8)changes in patient-reported outcomes
-To evaluate the safety and tolerability of TCZ and proposed prednisone-tapering scheme |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Age >= 18 years
- RA of >= 6 months duration diagnosed according to American College of Rheumatology (ACR)/European League against Rheumatology (EULAR) criteria
Track TCZ-experienced patients:
- Have received tocilizumab (TCZ) either subcutaneous (SC, 162 milligrams [mg] once a week [QW]) or intravenous (IV, 8 mg/kilogram [kg] every 4 weeks [Q4W]) for the treatment of RA for at least 24 weeks prior to randomization
- Have received 5- 15 mg/day of glucocorticoids (GCs) [prednisone or equivalent] for the treatment of RA for at least 20 weeks prior to screening
- Currently receiving 5 mg/day of prednisone
- Have attained and maintained LDA (DAS28 ESR score <=3.2) or remission (DAS28 ESR score <=2.6) for at least 4 weeks prior to randomization
Track TCZ-naïve patients:
- Have active RA (defined as DAS28 ESR score >3.2)
- Are considered by the investigator as inadequate responders to conventional synthetic disease-modifying antirheumatic drug (csDMARDs) or biologic disease-modifying antirheumatic drug (bDMARDs)
- Are receiving 5-15 mg/day prednisone (or equivalent) for the treatment of RA
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| E.4 | Principal exclusion criteria |
- Major surgery (including joint surgery) within 8 weeks prior to screening, or planned major surgery during the study and up to 6 months after randomization
- Pregnant women or nursing (breastfeeding) mothers
- Body weight of >=150 kg
- RA of functional class IV, as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis
- Rheumatic autoimmune disease other than RA, including systemic lupus erythematosus, mixed connective tissue disease, scleroderma, polymyositis, or significant systemic involvement secondary to RA (e.g., vasculitis, pulmonary fibrosis, or Felty syndrome). Secondary Sjögren syndrome with RA may be allowed per the discretion of the investigator
- Diagnosed with juvenile idiopathic arthritis or juvenile RA and/or RA before the age of 16 years
- Prior or current inflammatory joint disease other than RA (e.g., gout, Lyme disease, sero-negative spondyloarthropathy, including reactive arthritis, psoriatic arthritis, arthropathy of inflammatory bowel disease), or prior or current joint infections
- Previous history of primary or secondary adrenal insufficiency
- Intraarticular (IA) or parenteral GCs for the treatment of RA within 4 weeks prior to screening
- Previous treatment with GCs for conditions other than RA, at any dose and in any formulation used continuously for > 1 week, during the last 1 year prior to screening. Topical GC creams or ointments for the treatment of skin conditions (e.g. eczema) are allowed
- Immunization with a live/attenuated vaccine within 30 days prior to screening
- Any previous treatment with alkylating agents such as chlorambucil or with total lymphoid irradiation
- Inadequate hematological, renal and liver functions
- History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies
- Evidence of current serious uncontrolled cardiovascular (including uncontrolled hyperlipidemia), nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus) or gastrointestinal (GI) disease
- Current liver disease as determined by the investigator
- History of diverticulitis, peptic ulcer disease, 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 perforations
- Known active current or history of recurrent bacterial, viral, fungal, mycobacterial, or other opportunistic infections (including, but not limited to, tuberculosis [TB] and atypical mycobacterial disease, hepatitis B and C, Epstein-Barr virus, cytomegalovirus and herpes zoster, but excluding fungal infections of nail beds)
- Neuropathies or other conditions that might interfere with pain evaluation unless related to primary disease under investigation
- 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
- Active TB requiring treatment within the previous 3 years (patients previously treated for TB with no recurrence within 3 years are permitted). All TCZ-naïve patients must be screened for latent TB and if positive, should be treated following local practice guidelines prior to initiating TCZ
- History of or currently active, primary or secondary immunodeficiency
- Evidence of active malignant disease, malignancies diagnosed within the previous 10 years (including haematological malignancies and solid tumours, except basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that was excised and cured), or breast cancer diagnosed within the previous 20 years
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change in DAS28 ESR between randomization and Week 24 post-randomization |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Randomization and Week 24 |
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| E.5.2 | Secondary end point(s) |
1 The proportion of patients with LDA (DAS28 ESR score <= 3.2) or remission (DAS28 ESR score <= 2.6) at Week 24 post-randomization, who have not suffered a disease flare and who showed no confirmed adrenal insufficiency that required replacement therapy
2 Change in clinical disease activity index (CDAI)/ simplified disease activity index (SDAI) between randomization and Week 24 post-randomization
3 The proportion or patients with >=1 flare, the time to first flare and the number of flares
4 The proportion of patients with >=1 administration of flare rescue medication, the time to first administration, and the number of administrations of flare rescue medication
5 Cumulative prednisone exposure (dose) between randomization and Week 24 post-randomization
6 The proportion of patients who maintain LDA (DAS28 ESR score <=3.2) or remission (DAS28 ESR score <=2.6) and the proportion of patients who maintain the baseline disease activity level at Week 24 post-randomization
7 The proportion of patients who permanently discontinue study treatment due to insufficient flare control
8 Changes in the ACR core set from randomization to post-randomization Week 24, including: swollen and tender joint counts; patient’s assessment of pain and global status; physician’s assessment of global status; Health assessment questionnaire–Disability index (HAQ-DI); and acute phase reactants (high sensitivity C-reactive protein [hsCRP] and ESR)
9 Incidence of adverse events (AEs) including non-serious and serious AEs, and AEs of special interest
10 Changes in vital signs, physical findings, and clinical laboratory results during and following TCZ administration
11 Assessment of immunogenicity (anti-TCZ antibodies)
12 Proportion of patients with confirmed adrenal insufficiency that required replacement therapy
13 Rheumatoid arthritis impact of disease (RAID) score
14 Work productivity and activity impairment questionnaire: Specific health problem (WPAI:SHP)
15 Health assessment questionnaire–Disability index (HAQ-DI) score
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 24
2: From Randomization up to Week 24
3-4: Up to Week 24
5: From Randomization up to Week 24
6: Week 24
7: Up to Week 24
8: From Randomization up to Week 24
9-10: Up to Week 28
11: Up to Week 24 (performed on event driven basis)
12: Up to Week 24
13-14: Enrolment (Track TCZ-naïve patients only), randomization and Week 24
15: Randomization and 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 | Yes |
| 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 | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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 | 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 | No |
| 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 |
| Egypt |
| France |
| Germany |
| Italy |
| Lebanon |
| Russian Federation |
| Serbia |
| Slovenia |
| Switzerland |
| Tunisia |
| Turkey |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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. This is expected to occur 28 weeks after the last patient has been randomized into the 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 | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 20 |
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