Rituximab Vasculitis Maintenance Study
Rituximab Vasculitis Maintenance Study
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.
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.
Inclusion Criteria:

 1. A diagnosis of AAV [granulomatosis with polyangiitis or microscopic polyangiitis],
 according to the definitions of the Chapel Hill Consensus Conference

 2. Current or historical PR3/MPO ANCA positivity by ELISA

 3. 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)

 4. Written informed consent

 Exclusion Criteria:

 1. Age < 15 years (age < 18 years at centres that do not treat paediatric patients)

 2. Exclusions related to medication:

 Previous therapy with:

 1. Any biological B cell depleting agent (such as rituximab or belimumab) within the
 past 6 months

 2. Alemtuzumab or anti-thymocyte globulin (ATG) within the last 12 months

 3. IVIg, infliximab, etanercept, adalimumab, abatacept or plasma exchange in past 3
 months

 4. 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:

 1. Significant or uncontrolled medical disease not related to AAV, which in the
 investigators opinion would preclude patient participation

 2. Presence of another multisystem autoimmune disease, including Churg Strauss
 syndrome, systemic lupus erythematosus, anti-GBM disease, or cryoglobulinaemic
 vasculitis,

 3. 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).

 4. History of severe allergic or anaphylactic reactions to humanised or murine
 chimeric monoclonal antibodies

 5. 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.

 6. 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.

 7. 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.

 8. Pregnancy or inadequate contraception in pre-menopausal women

 9. Breast feeding or lactating

 4. Exclusion criteria related to laboratory parameters:

 1. Bone marrow suppression as evidenced by a total white count < 4 x109/l,
 haemoglobin < 7 gm/dl or platelet count < 100,000/μl

 2. Aspartate aminotransferase or alanine aminotransferase or amylase > 2.5 times the
 upper limit of normal, unless attributed to vasculitis