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 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.

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 > 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 < or = to 20 ml/min

12. Known current use of illegal drugs

13. 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

14. 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

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

16. A live vaccination fewer than 3 months before enrollment

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

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

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

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

21. 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.

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

23. Treatment with rituximab or any other biologic B cell depleting agent within the past
6 months or past treatment with rituximab or any other biologic B cell depleting agent
where the B lymphocyte count remains < 60 cells/uL

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

25. Treatment with intravenous immunoglobulin or plasma exchange within the past 3 months

26. 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)