Rituximab Vasculitis Maintenance Study

Study Overview
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Brief Summary
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Rituximab is now established as an effective drug for anti-neutrophil cytoplasmic antibody (ANCA) vasculitis following major European and US trials reported in 2010. After a time, its effect wears off and the disease can return. This occurs in at least half of patients within 2 years of receiving Rituximab. A preliminary study in Cambridge has suggested that repeating rituximab every six months stops the disease returning and is safe. The RITAZAREM trial will find out whether repeating rituximab stops vasculitis returning and whether it works better than the older treatments, azathioprine or methotrexate. It will also tell us how long patients remain well after the repeated rituximab treatments are stopped, and if repeated rituximab is safe. We should also learn useful information about the effects of rituximab on quality of life and economic measures. The trial results will help decide the best treatment for future patients who have their vasculitis initially treated with rituximab. RITAZAREM aims to recruit patients with established ANCA vasculitis whose disease has come back 'relapsing vasculitis'. All patients will be treated with rituximab and steroids and we anticipate that most will respond well. If their disease is under reasonable control after four months, further treatment with either rituximab (a single dose ever four months for two years) or azathioprine tablets will be chosen randomly. The patients in the rituximab and azathioprine groups will then be compared. Patients will be in the trial for four years. The study has been designed by members of the European Vasculitis Study group (EUVAS) and the Vasculitis Clinical Research Consortium (VCRC). It will include 190 participants from 30 hospitals in Europe, the USA, Australia and Mexico. RITAZAREM is being funded by Arthritis Research UK, the U.S. National Institutes of Health and by Roche/Genentech.

Detailed Description
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Patients will be recruited at the time of relapse. All will receive rituximab 375 mg/m2/week x 4 and glucocorticoids. Those patients that achieve disease control (BVAS/WG ≤ 1 and daily prednisone dose ≤ 10 mg) by month 4 will be randomised to the rituximab or control remission maintenance groups. Treatment is protocolised for the entire duration of the study, until the common close date, when the final patient recruited has completed 36 months within the study or until the patient has completed 48 months on study whichever the sooner. Patients in the rituximab arm will receive treatment until month 20, and those in the azathioprine arm until month 27.

Official Title
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An International, Open Label, Randomised Controlled Trial Comparing Rituximab With Azathioprine as Maintenance Therapy in Relapsing ANCA-associated Vasculitis

Conditions
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Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Microscopic Polyangiitis, Wegener Granulomatosis

Intervention / Treatment
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* Biological: Rituximab
* Drug: Azathioprine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A diagnosis of AAV [granulomatosis with polyangiitis or microscopic polyangiitis], according to the definitions of the Chapel Hill Consensus Conference Current or historical PR3/MPO ANCA positivity by ELISA Disease relapse defined by one major or three minor disease activity items on the Birmingham Vasculitis Activity Score for Wegeners (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 or mycophenolate mofetil) Written informed consent Exclusion Criteria: Age < 15 years (age < 18 years at centres that do not treat paediatric patients) Exclusions related to medication: Previous therapy with: Any biological B cell depleting agent (such as rituximab or belimumab) within the past 6 months Alemtuzumab or anti-thymocyte globulin (ATG) within the last 12 months IVIg, infliximab, etanercept, adalimumab, abatacept or plasma exchange in past 3 months Any investigational agent within 28 days of screening, or 5 half lives of the investigational drug (whichever is longer) Exclusions related to general health: Significant or uncontrolled medical disease not related to AAV, which in the investigators opinion would preclude patient participation Presence of another multisystem autoimmune disease, including Churg Strauss syndrome, systemic lupus erythematosus, anti-GBM disease, or cryoglobulinaemic vasculitis, 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. poorly-controlled asthma, COPD, psoriasis, or inflammatory bowel disease). History of severe allergic or anaphylactic reactions to humanised or murine chimeric monoclonal antibodies Known infection with HIV (HIV testing will not be a requirement for trial entry); a past or current history of hepatitis B virus or hepatitis C virus infection. 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. 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. Pregnancy or inadequate contraception in pre-menopausal women Breast feeding or lactating Exclusion criteria related to laboratory parameters: Bone marrow suppression as evidenced by a total white count < 4 x109/l, haemoglobin < 7 gm/dl or platelet count < 100,000/μl Aspartate aminotransferase or alanine aminotransferase or amylase > 2.5 times the upper limit of normal, unless attributed to vasculitis

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab Maintenance<br>Rituximab maintenance: 1g at 4, 8, 12, 16 & 20 months with standardised steroid taper | Biological: Rituximab<br>* Rituximab IV infusion 1000 mg x 1 dose at months 4, 8, 12, 16 and 20 and glucocorticoids. Four - six hour infusion. Treatment with rituximab will cease at month 20.<br>* Other names: MabThera;|
| Active Comparator: Azathioprine Maintenance<br>Azathioprine Maintenance: 2mg/kg/day with standardised steroid taper, from month 4 (randomisation) (200 mg maximum daily dose). Azathioprine withdrawn at month 27. | Drug: Azathioprine<br>* Oral dosage form. Target dose is 2mg/kg; maximum daily dose is 200mg. This should be continued until month 24. The dose should then by reduced by 50% and azathioprine completely withdrawn at month 27. The dose should be rounded down to the nearest 25mg. The dose may vary on alternate days e.g. 100mg one day, 150mg the next for patients on an overall dose of 125mg daily. If patients are aged over 60 years, reduce the dose by 25%. If patients are aged over 75 years, reduce the dose by 50%.<br>* Other names: Imuran;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse-free Survival | The primary efficacy outcome measure of the trial is relapse-free survival, where a relapse is either major or minor. The primary analysis will be a Cox regression model adjusted for the stratification factors (ANCA type, relapse severity and prednisone induction regimen) for the difference in the distribution of relapse-free survival between the rituximab arm and the azathioprine (control) arm (two-sided at α-level of 5%). | Any patients who have not relapsed at up to a maximum of 4 years will be censored. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants in Remission at 24 and 48 Months | Proportion of patients who maintain remission at 24 and 48 months | 24 and 48 months | 
| Combined Damage Assessment Score (Disease Related Damage Assessment) | Cumulative accrual of damage as measured by the combined damage assessment score (CDA). Each persistent or new occurrence of damage is given a score of 1. The cumulative accrual of damage is obtained by summing across the different types of damage to get an overall score (max score = 64). | data in Rows represent the change from randomization (month 4) to months 12, 24, 36, and 48. | 
| Cumulative GC Exposure | Cumulative glucocorticoid (GC) exposure during the trial. The trial had a common close out date when the final patient reached month 36 in the trial. Patients were followed until month 48 or the common close out date, whichever happened sooner. Therefore, follow up varied between 36 and 48 months. Cumulative glucocorticoid exposure is presented as a dose in mg for during the treatment period (up to month 24) and across the whole trial (until month 48 or common close out when the final patient reached month 36). | Up to 48 months | 
| Severe Adverse Event Rate | Severe adverse event (SAE) rate | Up to 48 months | 
| Infection Rates | Infection (treated with intravenous or oral antibiotics) rates | Up to 4 years | 
| Health-related Quality of Life Using the SF-36 Physical Composite | The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life. | 4 months | 
| Health-related Quality of Life Using the SF-36 Mental Composite | The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life. | 4 months | 
| Health-related Quality of Life Using the SF-36 Physical Composite | The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life. | 12 months | 
| Health-related Quality of Life Using the SF-36 Mental Composite | The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life. | 12 months | 
| Health-related Quality of Life Using the SF-36 Physical Composite | The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life. | 24 months | 
| Health-related Quality of Life Using the SF-36 Mental Composite | The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life. | 24 months | 
| Health-related Quality of Life Using the SF-36 Physical Composite | The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life. | 36 months | 
| Health-related Quality of Life Using the SF-36 Mental Composite | The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life. | 36 months | 
| Health-related Quality of Life Using the SF-36 Physical Composite | The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life. | 48 months | 
| Health-related Quality of Life Using the SF-36 Mental Composite | The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life. | 48 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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vasculitis, ANCA vasculitis, microscopic polyangiitis, granulomatosis, Wegener's, AAV, vasculitides