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.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Tocilizumab (TCZ) is an anti-IL6 receptor monoclonal antibody. IL6 is a pro-inflammatory cytokine. Dyregulated production of this cytokine is implicated in the pathogenesis of rheumatoid arthritis (RA). It signals via the activation of key proteins - Janus kinases (JAKs) and transcription factors of the STAT family. By disrupting these pathways TCZ may be able to influence key immune cells and their function with minimal to no collateral effect on other systems. Primary Objective: To determine in patients with early, treatment naive RA, how TCZ and Methotrexate (MTX) combination or TCZ monotherapy influences key signalling pathways as well as explore other mechanisms of action including p38δ mitogen activated protein (MAP) kinase, MAP kinase kinase (MKK) 3 and MKK6. There is no information on this. These investigations will elucidate mechanism of action of TCZ/MTX and TCZ monotherapy as well as possibly identify patient subgroups that gain particular benefit from TCZ therapy. |
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E.2.2 | Secondary objectives of the trial |
Effective biologic drugs such as TCZ offer the opportunity of achieving disease control (remission) rapidly. There is also increasing data suggesting these newer complex biologic treatments may be able to reset the disease if used in early, untreated RA with the result that the therapies can be stopped rather than continued longterm. Finally, RA is associated with poor health outcomes and death due to early heart disease (atherosclerosis) it is unclear whether there is evidence of abnormalities in newly diagnosed RA but gaining good control of RA disease is important as this should hopefully reduce this increased risk. TCZ is usually given in combination with methotrexate (MTX; a standard treatment) but may also be given on its own. Secondary Objectives: In patients that receive TCZ either on its own or in combination with methotrexate; 1. Proportion of patients that achieve clinical remission, to answer: how rapidly can clinical remission be achieved? 2. Is there significant re |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Diagnosis of rheumatoid arthritis (2010 ACR/EULAR RA classification criteria) 2.Symptom duration ≤12months 3. No previous disease modifying anti-rheumatic drug (DMARD) therapy 4. Active RA at baseline (defined as: DAS28 ≥ 3.2) 5. Active hand and/or wrist joint evaluable by US and MRI (with no planned surgery during the study period) 6. Patients without any contraindication to MRI |
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E.4 | Principal exclusion criteria |
1.Patients unwilling or unable to receive MTX for the duration of the study. 2.Patients with inflammatory joint disease of different origin, mixed connective tissue disease, Reiter’s syndrome, psoriatic arthritis, systemic lupus erythematosis, or any arthritis with onset prior to 16 years of age. 3.Suspicion of diagnosis of tuberculosis: positive quantiferon +/- abnormal chest x-ray – as per clinician judgement. Prior history of TB with confirmed full chemotherapy +/- latent TB adequately treated may be included as per physician’s discretion. 4.Intramuscular, oral or intra-articular (of non-target joint) corticosteroid within 28 days of the screening visit; intra-articular steroid of the chosen target joint within 12 weeks of screening. 5. Patients with serious infections within 3 month of enrolment (screening) or persistent infections. 6. Patients at significant risk of infection (e.g. leg ulceration, indwelling urinary catheter, septic joint within 1 year (or ever if prosthetic joint still in situ). 7. Known positive serology for hepatitis B or C, or HIV |
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E.5 End points |
E.5.1 | Primary end point(s) |
In patients with early, treatment-naive RA treated with either TCZ/MTX combination or TCZ monotherapy : • This is an exploratory study to evaluate change in expression of JAK 1-3 (as well as STAT and p38 MAPK). |
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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 | No |
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 | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Tocilizumab + Methotrexate combination |
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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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
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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Last visit of the last subject. |
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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 | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |