E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsing ANCAassociated vasculitis (AAV) |
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E.1.1.1 | Medical condition in easily understood language |
Relapsing inflammatory disease affecting small vessels associated with anti-neutrophilic cytoplasmatic antibodies (ANCA) |
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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 |
The principle research objective is to demonstrate the superiority of rituximab against azathioprine in the prevention of disease flare in ANCAassociated vasculitis patients with relapsing disease |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are to demonstrate: 1. Sustained disease remission beyond the 24 month treatment period 2. Long term safety of rituximab administration 3. The optimal remission maintenance therapy in ANCAassociated vasculitis following induction of disease remission with rituximab |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Written informed consent 2.A diagnosis of ANCA Associated Vasculitis (AAV) [granulomatosis with polyangiitis or microscopic polyangiitis],according to the definitions of the Chapel Hill Consensus Conference 3.Current or historical ANCA positivity by ELISA 4.Disease flare relapse defined by one major or three minor disease activity items on the Birmingham Vasculitis Activity Score for Wegener’s (BVAS/WG), in patients that have previously achieved remission following at least 3 months of induction therapy, with a combination of glucocorticoids and an immunosuppressive agent (cyclophosphamide or methotrexate or rituximab) 5.Aged 15 years and over |
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E.4 | Principal exclusion criteria |
1.Age less than 15 years (age less than 18 years at centres that do not treat paediatric patients) 2.Exclusions related to medication: Previous therapy with: a.Any biological B cell depleting agent (such as rituximab or belimumab) within the past 6 months b.Alemtuzumab or antithymocyte globulin within the last 12 months c.IVIg, infliximab, etanercept, adalimumab, abatacept or plasma exchange in past 3 months d.Any investigational agent within 28 days of screening, or 5 half lives of the investigational drug (whichever is longer) 3.Exclusions related to general health: a.Significant or uncontrolled medical disease not related to AAV, which in the investigators opinion would preclude patient participation b.Presence of another multisystem autoimmune disease, including Churg Strauss syndrome, systemic lupus erythematosus, antiGBM disease, or cryoglobulinaemic vasculitis c.Any concomitant condition anticipated to likely require greater than 4 weeks per year of oral or systemic glucocorticoid use and which would preclude compliance with the glucocorticoid protocol (e.g. poorlycontrolled asthma, COPD, psoriasis, or inflammatory bowel disease) d.History of severe allergic or anaphylactic reactions to humanised or murine chimeric monoclonal antibodies e.Known infection with HIV (HIV testing will not be a requirement for trial entry)Íž a past or current history of hepatitis B virus or hepatitis C virus infection. f.Ongoing or recent (last 12 months) evidence of active tuberculosis or known active infection (screening for tuberculosis is part of ‘standard of care’ in patients with established AAV) or evidence of untreated latent tuberculosis. Screening for tuberculosis is as per local practice. g.History of malignancy within the past five years or any evidence of persistent malignancy, except fully excised basal cell or squamous cell carcinomas of the skin, or cervical carcinoma in situ which has been treated or excised in a curative procedure. h.Pregnancy or inadequate contraception |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the time to disease relapse (either minor or major relapse) from randomisation |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Event driven end-point at follow-up visits at 7 different time-points year 1, at 3 time-points year 2 and 3 and finally twice during the fourth year. The trial visits should not be more frequent than routine visits. |
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E.5.2 | Secondary end point(s) |
The secondary endpoints are: 1. Proportion of patients who maintain remission at 24 and 48 months 2. Time to a major or second minor relapse 3. Cumulative accrual of damage as measured by the combined damage assessment score (CDA) 4. Healthrelated quality of life as measured using SF36 5. Cumulative glucocorticoid exposure 6. Severe adverse event rate 7. Infection (treated with either intravenous or oral antibiotics) rate |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Follow-up visits at 7 different time-points year 1, at 3 time-points year 2 and 3 and finally twice during the fourth year. The trial visits should not be more frequent than routine visits |
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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 | Yes |
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 |
Immunogenecity of rituximab (development of anti-bodies against rituximab) |
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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) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
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) | Yes |
E.8.2.2 | Placebo | No |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 35 |
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 |
Australia |
Canada |
Japan |
Mexico |
New Zealand |
United States |
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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 trial will end when the final patient has completed 12 months of follow up (has been in the trial for 36 months in total) |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |