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 adults with WG and MPA.

Study hypothesis: Rituximab is not inferior to conventional therapy in its ability to induce disease remission by Month 6.

Condition	Treatment or Intervention	Phase
Vasculitis Wegener's Granulomatosis	Drug: Rituximab  Drug: Cyclophosphamide  Drug: Azathioprine  Drug: Methylprednisolone (or other glucocorticoid)  Drug: Prednisone	Phase II Phase III

Further Study Details: 

Primary Outcomes: Ability of rituximab to induce complete remission during the first 6 months after randomization
Secondary Outcomes: Rate of selected adverse events experienced by participants receiving rituximab versus those receiving conventional therapy
Expected Total Enrollment:  200

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 adults 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 IV 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 IV 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/m2) 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 the remission induction phase 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.

Ages Eligible for Study:  15 Years and above,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria:

• Weight of at least 88 lbs (40 kg)
• Diagnosis of Wegener's granulomatosis (WG) or microscopic polyangiitis (MPA) according to the definitions of the Chapel Hill Consensus Conference
• Newly diagnosed patient of WG or MPA 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 or MPO-ANCA 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 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

Alabama
      University of Alabama, Birmingham,  Alabama,  35294,  United States; Recruiting
California
      University of California San Francisco, San Francisco,  California,  94143,  United States; Not yet recruiting
Maryland
      Johns Hopkins University, Baltimore,  Maryland,  21224,  United States; Recruiting
Massachusetts
      Boston University, Boston,  Massachusetts,  02118,  United States; Recruiting
Minnesota
      Mayo Clinic Foundation, Rochester,  Minnesota,  55905,  United States; Recruiting
New York
      Hospital for Special Surgery, New York,  New York,  10128,  United States; Not yet recruiting
North Carolina
      Duke University, Durham,  North Carolina,  27710,  United States; Recruiting
Ohio
      The Cleveland Clinic, Cleveland,  Ohio,  44195,  United States; Recruiting
Netherlands
      University Hospital Groningen, Groningen,  9713 GZ,  Netherlands; Not yet recruiting

Study chairs or principal investigators

John H. Stone, MD, MPH,  Principal Investigator,  Johns Hopkins University   

Study ID Numbers:  ITN021AI
Record last reviewed:  March 2005
Last Updated:  March 15, 2005
Record first received:  February 24, 2005
ClinicalTrials.gov Identifier:  NCT00104299
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2005-04-08