Abatacept for the Treatment of Relapsing, Non-Severe, Granulomatosis With Polyangiitis (Wegener's)
Abatacept for the Treatment of Relapsing, Non-Severe, Granulomatosis With Polyangiitis (Wegener's)
Multi-center, randomized, double-blind, placebo-controlled trial to evaluate the efficacy of
 abatacept to achieve sustained glucocorticoid-free remission in patients with relapsing
 non-severe granulomatosis with polyangiitis (Wegener's) (GPA) . Participants will be
 randomized 1:1 to receive either abatacept 125 mg or placebo administered by subcutaneous
 injection once a week. Participants will continue on study treatment for a minimum of 12
 months unless they experience a disease relapse or disease flare.

 Participants who experience a non-severe disease relapse, non-severe disease worsening, or
 who have not achieved remission by month 6 will have the option of entering an open-label
 trial period whereby they would receive open-label abatacept.
Multi-center, randomized, double-blind, placebo-controlled trial to evaluate the efficacy of
 abatacept to achieve sustained glucocorticoid-free remission in patients with relapsing
 non-severe GPA. Patients who enter the trial will be maintained on a stable dose of their
 maintenance immunosuppressive agent which may include methotrexate (MTX), azathioprine (AZA),
 or mycophenolate (MA) and will undergo a blinded randomization to receive abatacept or
 placebo. Patients will additionally receive prednisone 30 mg daily that will then be tapered
 to zero using a standardized tapering schedule.

 If an enrolled patient experiences a non-severe relapse or non-severe disease worsening
 though common closing, or if they have not achieved remission by month 6, they will have the
 option of entering an open-label trial period whereby they would receive abatacept in
 conjunction with their maintenance immunosuppressive and a standardized glucocorticoid taper.
 Patients with a severe disease relapse or severe disease worsening will have met criteria for
 early termination criteria and be removed from active study treatment. Patients will remain
 on study until reaching criteria for early termination or until common closing, 12 months
 after randomization of the final patient. After common closing or early termination, patients
 will be treated with best medical judgment and will undergo a post-treatment safety visit 3
 months after coming off of study treatment.
Inclusion Criteria:

 1. Patients must be considered as being best characterized as GPA and not microscopic
 polyangiitis (MPA) or eosinophilic granulomatosis with polyangiitis (EGPA) and must
 have met at least 2 of the 5 modified ACR classification criteria for GPA. These do
 not need to be present at the time of study entry. The modified ACR criteria are:

 1. Nasal or oral inflammation, defined as the development of painful or painless
 oral ulcers or purulent or bloody nasal discharge

 2. Abnormal chest radiograph, defined as the presence of nodules, fixed infiltrates,
 or cavities

 3. Active urinary sediment, defined as microscopic hematuria (>5 red blood cells per
 high power field) or red blood cell casts

 4. Granulomatous inflammation on biopsy, defined as histologic changes showing
 granulomatous inflammation within the wall of an artery or in the perivascular or
 extravascular area (artery or arteriole)

 5. Positive anti-neutrophil cytoplasmic antibody (ANCA) test specific for
 proteinase-3 or myeloperoxidase measured by enzyme-linked immunoassay

 2. Relapse of GPA within the 28 days prior to screening where the active disease features
 meet the following definition of non-severe disease:

 1. No disease manifestations that would be scored as a major element in the BVAS/WG

 2. Absence of any disease feature that poses an immediate threat to either a
 critical individual organ or the patient's life

 3. Age 15 and older

 4. Willing and able to comply with treatment and follow-up procedures

 5. Both women and men must be willing to use an effective means of birth control while
 receiving treatment through this study. Women should continue the use of an effective
 means of birth control for a minimum of 14 weeks after the last dose of study drug.
 Effective contraception methods include abstinence, oral contraceptives (birth control
 pills), IUD, diaphragm, Norplant, approved hormone injections, condoms, or medical
 sterilization. If applicable, participating sites will defer to their local
 authorities if they require stricter guidelines on the types of allowable
 contraception methods.

 6. Willing and able to provide written informed consent (and written assent of minor
 participants if applicable.)

 Exclusion Criteria:

 1. Presence of involvement that does not meet the criteria for non-severe disease

 2. Treatment with CYC within 3 months prior to screening

 3. Treatment with methylprednisolone 1000 mg within 28 days prior to enrollment

 4. Treatment with prednisone or prednisolone> 30 mg/day for > 28 days immediately prior
 to study entry

 5. Initiation or dose increase of the maintenance immunosuppressive agent (MTX, AZA, MA)
 within 3 months prior to screening

 6. Evidence of active infection (includes chronic infection)

 7. Patients who are pregnant or who are nursing

 8. Known infection with human immunodeficiency virus (HIV), hepatitis C, or a positive
 hepatitis B surface antigen

 9. Inability to comply with study guidelines

 10. Cytopenia: platelet count < 100,000/mm3, white blood cell count (WBC) < 3,000/mm3 (3 x
 109/L), absolute neutrophil count < 1500/mm3, hemoglobin (Hgb) < 8.5 g/dL

 11. Chronic renal insufficiency defined by a creatinine clearance of less than or equal to
 20 ml/min

 12. AST or ALT > 3 times above the upper limit of the normal laboratory range

 13. Known current use of illegal drugs

 14. Other uncontrolled disease (co-morbidity) that could prevent a patient from fulfilling
 the study requirements or that would substantially increase the risk of study
 procedures

 15. 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

 16. Receipt of an investigational agent or device within 30 days prior to enrollment or 5
 half lives of the investigational drug (whichever is longer)

 17. A live vaccination fewer than 3 months before enrollment

 18. Current clinical, radiographic, or laboratory evidence of active tuberculosis

 19. A history of active tuberculosis within the past 3 years even if treated

 20. A history of active tuberculosis greater than 3 years ago unless there is
 documentation of prior anti-tuberculosis treatment of appropriate duration and type

 21. Latent tuberculosis unless there is documentation of prior anti-tuberculosis treatment
 of appropriate duration and type

 22. Latent tuberculosis currently being treated with isoniazid (INH) or other therapy for
 latent tuberculosis given according to local health authority guidelines (e.g., Center
 for Disease Control (CDC)) who have received such therapy for 4 weeks or less prior to
 randomization (Day 1). Subjects with a positive tuberculosis screening test indicative
 of latent tuberculosis will be eligible for the study if they have no evidence of
 current tuberculosis on chest xray at screening and they are actively being treated
 for tuberculosis with INH or other therapy for latent tuberculosis given according to
 local health authority guidelines (e.g., CDC) that has been given for at least 4 weeks
 prior to randomization (Day 1). These subjects must complete treatment according to
 local health authority guidelines.

 23. History of herpes zoster that resolved less than 2 months prior to enrollment

 24. Treatment with rituximab or any other biologic B cell depleting agent within the past
 6 months

 25. Treatment with alemtuzumab or anti-thymocyte globulin within the last 12 months

 26. Treatment with intravenous immunoglobulin given at an immunomodulatory dosage or
 plasma exchange within the past 3 months. Patients can be enrolled if they are
 otherwise eligible and receiving immunoglobulin replacement for hypogammaglobulinemia.

 27. Treatment with infliximab, etanercept, adalimumab, tocilizumab, or any other biologic
 agent within the past 3 months or 5 half lives of the agent (whichever is longer)