Rituximab for the Treatment of Wegener's Granulomatosis and Microscopic Polyangiitis
Rituximab for the Treatment of Wegener's Granulomatosis and Microscopic Polyangiitis
Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis is the most common type of
 small blood vessel inflammation in adults. ANCA-associated vasculitis includes Wegener's
 granulomatosis (WG) and microscopic polyangiitis (MPA). Rituximab is a man-made antibody used
 to treat certain types of cancer. The purpose of this study is to determine the effectiveness
 of rituximab in treating patients with WG and MPA.

 Study hypothesis: Rituximab is not inferior to conventional therapy in its ability to induce
 disease remission by Month 6.
Current conventional therapies for ANCA-associated vasculitis (AAV) are associated with high
 incidences of treatment failure, disease relapse, substantial toxicity, and patient morbidity
 and mortality. Rituximab is a monoclonal antibody used to treat non-Hodgkin's lymphoma. This
 study will evaluate the efficacy of rituximab with glucocorticoids in inducing disease
 remission in patients with severe forms of AAV (WG and MPA).

 The study consists of two phases: a 6-month remission induction phase, followed by a 12-month
 remission maintenance phase. All participants will receive at least 1 g of pulse intravenous
 methylprednisolone or a dose-equivalent of another glucocorticoid preparation. Depending on
 the participant's condition, he or she may receive up to 3 days of intravenous
 methylprednisolone for a total of 3 g of methylprednisolone (or a dose-equivalent). During
 the remission induction phase, all participants will receive oral prednisone daily (1
 mg/kg/day, not to exceed 80 mg/day). Prednisone tapering will be completed by the Month 6
 study visit.

 Next, participants will be randomly assigned to one of two arms. Arm 1 participants will
 receive rituximab (375 mg/m^2) infusions once weekly for 4 weeks and cyclophosphamide (CYC)
 placebo daily for 3 to 6 months. Arm 2 participants will receive rituximab placebo infusions
 once weekly for 4 weeks and CYC daily for 3 to 6 months. During the remission maintenance
 phase, participants in Arm 1 will discontinue CYC placebo and start oral azathioprine (AZA)
 placebo daily until Month 18. Participants in Arm 2 will discontinue CYC and start AZA daily
 until Month 18. Participants who fail treatment before Month 6 will be crossed over to the
 other treatment arm unless there are specific contraindications. Participants in either group
 who reach clinical remission before they complete 6 months of therapy may switch from
 CYC/placebo to AZA/placebo if directed by their physicians.

 All participants will be followed for at least 18 months. Initially, study visits are weekly,
 progressing to monthly and then quarterly visits as the study proceeds. Blood collection will
 occur at each study visit.
Inclusion Criteria:

 -  Weight of at least 88 pounds(40 kilograms)

 -  Diagnosis of Wegener's granulomatosis or microscopic polyangiitis according to the
 definitions of the Chapel Hill Consensus Conference

 -  Newly diagnosed patient of Wegener's granulomatosis or microscopic polyangiitis OR
 must be experiencing a disease flare characterized by: (a) active disease with a
 Birmingham Vasculitis Activity Score for Wegener's granulomatosis (BVAS/WG) of 3 or
 greater that would normally require treatment with CYC; OR (b) disease severe enough
 to require treatment with CYC; OR (c) must be positive for either PR3-ANCA (ANCA
 directed against proteinase 3) or MPO-ANCA (ANCA directed against myeloperoxidase)at
 the screening

 -  Willing to use acceptable forms of contraception for the duration of the study and for
 up to 1 year after stopping study medications

 -  Willing to report pregnancies (female participants or male participants' partners)
 occurring at any time during the study and for up to 1 year after stopping study
 medications

 -  Parent or guardian willing to provide informed consent, if applicable

 Exclusion Criteria:

 -  Diagnosis of Churg-Strauss Syndrome according to the definitions of the Chapel Hill
 Consensus Conference

 -  Have limited disease that would not normally be treated with CYC

 -  Requires mechanical ventilation because of alveolar hemorrhage

 -  History of severe allergic reactions to human or chimeric monoclonal antibodies

 -  Active systemic infection

 -  Have a deep-space infection, such as osteomyelitis, septic arthritis, or pneumonia
 complicated by pleural cavity or lung abscess, within 6 months prior to study entry

 -  History of or current hepatitis B or C infection

 -  HIV (human immunodeficiency virus) infected

 -  Acute or chronic liver disease that, in the opinion of the investigator, may interfere
 with the study

 -  History of or active cancer diagnosed within the last 5 years. Individuals with
 squamous cell or basal cell carcinomas of the skin and individuals with cervical
 carcinoma in situ who have received curative surgical treatment may be eligible for
 this study.

 -  History of anti-glomerular basement membrane (anti-GBM) disease

 -  Other uncontrolled disease, including drug and alcohol abuse, that may interfere with
 the study

 -  Pregnancy or breastfeeding