Rituximab Vasculitis Maintenance Study
Condition: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Microscopic Polyangiitis; Wegener Granulomatosis
MeSH terms: Granulomatosis with Polyangiitis; Microscopic Polyangiitis; Vasculitis; Systemic Vasculitis; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Intervention: Rituximab; Azathioprine
Intervention description: 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.; 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 The dose should then by reduced by 50% and azathioprine completely withdrawn at month 27.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%.
Intervention MeSH terms: Rituximab; Azathioprine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 188.0
Sex: All
Minimum age: 15 Years
Healthy volunteers: No
Keywords: vasculitis; ANCA vasculitis; microscopic polyangiitis; granulomatosis; Wegener's; AAV; vasculitides

Summary:

      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.
    

Eligibility criteria:

        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