E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adult Rheumatoid Arthritis |
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E.1.1.1 | Medical condition in easily understood language |
Adult Rheumatoid Arthritis |
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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 | 14.1 |
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 |
In a multicentre, randomized, two-armed, parallel group, double-blind design in patients with early rheumatoid arthritis to investigate whether it is possible by adding tocilizumab to achieve:
1. Inflammatory control as assessed by number of patients who achieve remission (DAS28<2.6) after 12 months of and
2. Sustained remission (DAS28 < 2.6 for 6 consecutive months) after 12 months of treatment and
3. Radiological control assessed by number of patients without radiological progression of the hands/wrists and upper feet from baseline to 12 months of treatment (Increase in total Sharp score (TSS), joint spacing narrowing (JSN) or joint erosions (JE) > 0.5 units)
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E.2.2 | Secondary objectives of the trial |
• Changes in DAS28 assessment
• Proportion of patients with DAS28 remission
• Changes in ACR-N assessment
• Proportion of patients with ACR/EULAR BOOLEAN-based remission
• Proportion of patients with ACR50/70/90 response
• Changes in HAQ assessment
• Proportion of patients with a HAQ score of 0,5 or less
• Changes in Total Sharp Score (TSS) assessment
• Changes in Joint Spacing Narrowing (JSN) assessment
• Changes in Joint Erosions (JE) assessment
• Changes in DXR as assessed by X-ray of the hands
• Changes in DEXA of the lumbar spine and hip joints
• Frequency and change in RAMRIS (MR score: synovitis, erosion, oedema, composite score)
• Number of patients receiving intra-articular glucocorticosteroid injections between visit 1 – 3, 4 – 6, 7 – 16
• Cumulated dose of intra-articular glucocorticosteroid administered between visit 1 – 3, 4 – 6, 7 – 16
• Frequency and severity of adverse events including serious adverse events
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Patients (>/= 18 years) with rheumatoid arthritis according to the ACR/EULAR (2010) classification criteria (1) who have been diagnosed </= 6 months
• DAS28 score at baseline >/= 2.6
• Number of swollen joints >/= 1
• Receiving treatment on an outpatient basis
• Negative pregnancy test (serum HCG) for women of childbearing potential prior to trial start. Fertile women included in the trial should use contraception during the entire trial period (i.e. one of the following methods: Oral contraception, intrauterine device (IUD), depot injection of progesterone, subdermal implantation, contraceptive vaginal ring, transdermal depot plaster). In addition, contraception should be used for a period of 150 days after any discontinuation of trial medicine.
• Ability and willingness to give written informed consent and to meet the requirements of the trial protocol.
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E.4 | Principal exclusion criteria |
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 rheumatoid arthritis
3. Functional class IV as defined by the ACR Classification of Functional
Status in Rheumatoid Arthritis
4. Prior history of or current inflammatory joint disease other than RA
5. Treatment with any investigational agent within 4 weeks (or 5 half-lives
of investigational agent, whichever is longer) of screening
6. Previous treatment with any TNF-α inhibitor, tocilizumab, rituximab and abatacept
7. Pregnant women or nursing (breastfeeding) mothers
8. History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies incl. tocilizumab. Hypersensitivity to the active substance or to latex or any other excipients
9. Previous treatment with any cell-depleting therapy
10. Primary or secondary immunodeficiency (history of or currently active)
11. Known active current or history of recurrent infection (including TB)
12. Body weight of > 150 kg
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E.5 End points |
E.5.1 | Primary end point(s) |
• Proportion of patients achieving a DAS28 remission (< 2.6) at month 16
• Proportion of patients obtaining sustained remission (DAS28 < 2.6 for 6 consecutive months) at month 16
• Proportion of patients without radiological progression of the hands/wrists and upper feet from start of treatment to months 16 of treatment (increase in total Sharp score (TSS), joint spacing narrowing (JSN), or joint erosions (JE) > 0.5 units).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Evaluation will be after 12 months of treatment with tocilizumab, which is month 16 in the study. |
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E.5.2 | Secondary end point(s) |
• Changes in DAS28 assessment
• Proportion of patients with DAS28 remission
• Changes in ACR-N assessment
• Proportion of patients with ACR/EULAR BOOLEAN-based remission
• Proportion of patients with ACR50/70/90 response
• Changes in HAQ assessment
• Proportion of patients with a HAQ score of 0,5 or less
• Changes in Total Sharp Score (TSS) assessment
• Changes in Joint Spacing Narrowing (JSN) assessment
• Changes in Joint Erosions (JE) assessment
• Changes in DXR as assessed by X-ray of the hands
• Changes in DEXA of the lumbar spine and hip joints
• Frequency and change in RAMRIS (MR score: synovitis, erosion, oedema, composite score)
• Number of patients receiving intra-articular glucocorticosteroid injections between visit 1 – 3, 4 – 6, 7 – 16
• Cumulated dose of intra-articular glucocorticosteroid administered between visit 1 – 3, 4 – 6, 7 – 16
• Frequency and severity of adverse events including serious adverse events
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints will be evaluated at month 4, 7, 10, 13 and 16 depending on endpoint. |
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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 | 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 | 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 | 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 occurs (LPLV). The LPLV is either the date of the 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 statistical analysis (i.e., key safety and efficacy results for decision making), 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 | 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 |