Please select the eligibility criteria that correspond to the clinical trial below.
Title: Mycophenolate Mofetil Versus Azathioprine for Maintenance Therapy in ANCA Associated Systemic Vasculitis
Brief Summary: The aim of IMPROVE is to define the optimal maintenance therapy for ANCA-associated vasculitides (AASV) by comparing the AZA (standard regimen) with MMF in terms of efficacy, i.e. in preventing relapses.

HYPOTHESIS :

MMF might be more effective than azathioprine as maintenance drug in AASV patients, reducing by 50% relapse rate, with a same frequency of adverse effects


Options:
A: 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
B: Inclusion Criteria:

Inclusion (requires all):

* New diagnosis of AASV (WG or MPA) (within the previous six months)
* Active disease (defined by at least one major or three minor BVAS 2003 items, see appendix 1)
* ANCA positivity (c-ANCA and PR3-ANCA or p-ANCA and MPO-ANCA) or histology confirming active vasculitis from any organ (see appendix )
* Written informed consent

Exclusion Criteria:

* Previous treatment with:

  * MMF: more than two weeks ever.
  * Cyclophosphamide: more than two weeks daily oral or more than 1 pulse of IV CYC (15mg/kg)
  * Rituximab or high dose intravenous immunoglobulin within the last twelve months
* Active infection (including hepatitis B, C, HIV and tuberculosis).
* Known hypersensitivity to MMF, AZA or CYC.
* Cancer or an individual history of cancer (other than resected basal cell skin carcinoma).
* Females who are pregnant, breast feeding, or at risk of pregnancy and not using a medically acceptable form of contraception.
* Any condition judged by the investigator that would cause the study to be detrimental to the patient.
* Any other multi-system autoimmune disease including Churg Strauss angiitis, SLE, anti GBM disease and cryoglobulinaemia.
C: Inclusion Criteria:

* Newly diagnosed patients with WG, MPA or renal-limited vasculitis.
* ANCA positivity. ANCA positivity requires PR3-ANCA or a typical cANCA pattern by indirect immunofluorescence (IIF), preferably confirmed by anti-PR3 ELISA. MPO-ANCA determined by ELISA requires demonstration of pANCA, and pANCA by IIF requires confirmation by anti-MPO ELISA. Optionally, central review of ANCA serology can be performed.
* Age 18 to 75 years

Exclusion Criteria:

* Any cytotoxic drug within previous year, unless started within one months of entry and according to the protocol design
* Co-existence of another systemic autoimmune disease, e.g. SLE
* Hepatitis B or Hepatitis C infection
* HIV positivity
* Failure to achieve remission after 6 months of CYC therapy
* Failure to control progressive disease with induction protocol
* Malignancy (usually exclude unless agreed with trial co-ordinator)
* Pregnancy or inadequate contraception
* Age below 18 and above 75 years\*
* Endstage renal failure unless active extrarenal disease requires treatment (temporal dependency of hemodialysis is not an exclusion criterion)
* Inability for informed consent

  * After discussion with the trial administrator, patients less than 18 years may be incorporated on separate application according to the appropriate local ethic committee.
D: Inclusion Criteria:

* Newly diagnosed WG, MPA, PAN without HBV infection, or CSS
* Patients can be still be enrolled within 1 month after starting corticosteroids if prescribed according to protocol.
* within or after the 65th of anniversary
* Age ≥ 65 years

Exclusion Criteria:

* Any cytotoxic drug within previous year
* Co-existence of another systemic autoimmune disease, e.g., SLE, RA
* Virus-associated vasculitides
* HIV positivity
* Malignancy (usually excluded unless approved by the trial coordinator)
* Age \< 65 years
* Inability to give informed consent

Answer: C