Please select the eligibility criteria that correspond to the clinical trial below.
Title: Plasma Exchange and Glucocorticoid Dosing in the Treatment of Anti-neutrophil Cytoplasm Antibody Associated Vasculitis: an International Randomized Controlled Trial
Brief Summary: The purpose of this study is to determine whether plasma exchange as well as immunosuppressive therapy are effective in reducing death and end-stage renal disease (ESRD). The trial will also study whether a reduced cumulative dosing regimen of glucocorticoids is as effective as a standard disease regimen.

The FDA-OOPD is one of the funding sources for this study.


Options:
A: Key Inclusion Criteria:

* Clinical diagnosis Wegener's granulomatosis or microscopic polyangiitis by Chapel Hill criteria.
* Disease flare in the past 26 weeks requiring treatment with high dose corticosteroids and 1 of the following medications: rituximab, oral cyclophosphamide OR IV cyclophosphamide.
* Tested positive for anti-proteinase 3 (anti-PR3) or anti-myeloperoxidase (anti-MPO) antibodies at any time prior to enrollment.
* Achieve remission no more than 26 weeks after first dose of induction treatment. Remission is defined as a Birmingham Vasculitis Activity (BVAS) score of 0 and receiving less than 10 mg/day of oral prednisone (or equivalent) on 2 consecutive visits 21 to 35 days apart.
* Maintenance therapy on this study must start no more than 2 weeks after confirmation of remission.

Key Exclusion Criteria:

* Pregnant or nursing.
* Receipt of a B cell targeted therapy (other than rituximab) at anytime
* Receipt of an investigational biological agent within the past 60 days.
* Required management of acute or chronic infections within the past 60 days.
* Current drug or alcohol abuse or dependence.
* Current or past positive test for human immunodeficiency virus (HIV), hepatitis B, or hepatitis C.
* History of severe allergic reaction to contrast agents or biological medicines.
B: 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
C: Inclusion Criteria:

• New or previous clinical diagnosis of granulomatosis with polyangiitis or microscopic polyangiitis consistent with the Chapel-Hill consensus definitions

AND

• Positive test for proteinase 3-ANCA or myeloperoxidase-ANCA

AND

* Severe vasculitis defined by at least one of the following:

  1. Renal involvement characterized by both of the following:

     * Renal biopsy demonstrating focal necrotizing glomerulonephritis or active urine sediment characterized by glomerular haematuria or red cell casts and proteinuria

     AND
     * eGFR \<50 ml/min/1.73 m2
  2. Pulmonary hemorrhage due to active vasculitis defined by:

     * A compatible chest x-ray or CT scan (diffuse pulmonary infiltrates)

     AND
     * The absence of an alternative explanation for all pulmonary infiltrates (e.g. volume overload or pulmonary infection)

     AND
  3. At least one of the following:

     * Evidence of alveolar hemorrhage on bronchoscopic examination or increasingly bloody returns with bronchoalveolar lavage
     * Observed hemoptysis
     * Unexplained anemia (\<10 g/dL) or documented drop in hemoglobin \>1 g/dL)
     * Increased diffusing capacity of carbon dioxide
* Provision of informed consent by patient or a surrogate decision maker

Exclusion Criteria:

* A diagnosis of vasculitis other than granulomatosis with polyangiitis or microscopic polyangiitis
* Positive serum anti-glomerular basement membrane antibody test or renal biopsy demonstrating linear glomerular immunoglobulin deposition
* Receipt of dialysis for \>21 days immediately prior to randomization or prior renal transplant
* Age \<15 years
* Pregnancy at time of study entry
* Treatment with \>1 IV dose of cyclophosphamide and/or \>14 days of oral cyclophosphamide and/or \>14 days of prednisone/prednisolone (\>30 mg/day) and/or \>1 dose of rituximab within the 28 days immediately prior to randomization
* A comorbidity that, in the opinion of the investigator, precludes the use of cyclophosphamide, glucocorticoids, or plasma exchange or absolutely mandates the use of plasma exchange
* Plasma exchange in 3 months prior to randomization
D: 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

Answer: C