Rituximab Vasculitis Maintenance Study

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