Please select the eligibility criteria that correspond to the clinical trial below.
Title: An International, Open Label, Randomised Controlled Trial Comparing Rituximab With Azathioprine as Maintenance Therapy in Relapsing ANCA-associated Vasculitis
Brief 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.


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:

* Patients aged over 18 years-old with newly diagnosed systemic Wegener's granulomatosis,
* microscopic polyangitis with at least one factor of poor prognosis according to the five factors score (proteinuria \> 1 g/day, renal insufficiency defined as a serum creatininemia \> 140 µmol/L, specific cardiomyopathy, gastrointestinal tract and/or CNS involvement).

Exclusion Criteria:

* MPA patients with no poor prognosis factor;
* localized WG;
* relapse of previously known WG or MPA;
* treatment with corticosteroids for more than 1 month prior to diagnosis and start of immunosuppressant;
* co-existence of another multi-system autoimmune disease;
* malignancy (unless considered in complete remission and with no therapy for at least 3 years);
* contra-indication to corticosteroids or study immunosuppressants; pregnancy or no use of contraception in non-menopaused women;
* infection with human immunodeficiency virus; mental or physical disturbances not permitting to give consent.
C: Inclusion Criteria:

* Diagnosis of Wegener's granulomatosis or microscopic polyangiitis, using criteria adapted by EUVAS from the disease definitions of the Chapel Hill consensus conference
* Biopsy proven, pauci-immune, necrotising and/or crescentic glomerulonephritis, in the absence of other defined glomerulopathy
* Severe renal impairment defined by: (i) oliguria (\<400ml/24hr), or (ii) intention to commence dialysis within 48 hours of admission, and (iii) creatinine \>500umol/l (5.8mg/dl).

Exclusion Criteria:

* Age under 18 or over 80 years
* Inadequate contraception in women of child-bearing age
* Pregnancy
* Previous malignancy
* Hepatitis B antigenaemia, anti-hepatitis C virus or anti-human immunodeficiency virus antibody
* Diagnosis of Churg-Strauss syndrome, Henoch-Schönlein purpura, rheumatoid vasculitis, mixed essential cryoglobulinaemia or systemic lupus erythematosus
* Circulating anti-GBM antibodies or linear IgG staining of the GBM on renal biopsy
* Life-threatening non-renal manifestations of vasculitis, including alveolar hemorrhage requiring mechanical ventilation within 24 hours of admission
* On dialysis for \> two weeks prior to entry
* Creatinine \> 200umol/l (2.3mg/dl) one year or more before entry
* A second clearly defined cause of renal failure
* Previous episode of biopsy-proven necrotising and/or crescentic glomerulonephritis
* \> two weeks treatment with cyclophosphamide or azathioprine
* \> 500mg IV methyl prednisolone
* Plasma exchange within the preceding year
* \> three months treatment with oral prednisolone
* Allergy to study medications.
D: Inclusion Criteria:

* Diagnosis of clinically active SNV
* Life-expectancy \> 1 year
* Written informed consent

Exclusion Criteria:

* Creatinine clearance \< 10 ml/min/1.73 mq
* Aminotransferase levels more than twice the upper limit of the normal range
* HBsAg positivity
* anti-HCV Ig and HCV-RNA positivity
* HIV positivity
* Active malignancies
* Coexistence of connective tissue disease
* Prednisolone, cyclophosphamide or methotrexate hypersensitivity
* Pregnancy

Answer: A