Principal Investigator: Curry Koening
Keywords: Rheumatology Department: Rheumatology
IRB Number: 00078403
Specialty: Rheumatology
Sub Specialties: Vasculitis
Recruitment Status: Recruiting

Contact Information

Jessica Gonzalez
jessica.gonzalez@hsc.utah.edu
801-585-0797

Brief Summary

This multicenter, randomized, placebo-controlled phase III trial will seek to determine the efficacy of
abatacept to reduce the treatment failure rate through 12 months. This trial will enroll 150 patients
with relapsing, non-severe GPA within the 28 days prior to screening. At enrollment, patients will be
randomized to receive either abatacept 125 mg given subcutaneously every week or placebo. All
patients will receive prednisone 30 mg daily which will be tapered according to a standardized
schedule. Patients who are receiving a maintenance immunosuppressive agent consisting of
methotrexate (MTX), azathioprine (AZA), or mycophenolate (MA) at the time of enrollment will
remain on these medications without dosage increase or reduction. Safety and efficacy data will be
collected at month 1, 3 and every 3 months thereafter. Patients who experience a non-severe relapse
or non-severe disease worsening prior to common closing, or who have not achieved remission by
month 6 will be eligible to go on to an open-label extension period whereby they will receive
abatacept. Common closing will occur 12 months after randomization of the last patient.
This trial will be conducted by the Vasculitis Clinical Research Consortium (VCRC) and the
European Vasculitis Society (EUVAS) with support by Bristol-Myers Squibb.

3. Study Endpoints

a. Primary outcome

  •  The primary study endpoint will be the ability of abatacept to reduce the treatment failure rate through 12 months

b. Secondary outcomes

The secondary study endpoints will include:

  • Duration of glucocorticoid-free periods
  • Duration of remission with abatacept versus placebo
  • Severity of relapses in those treated with abatacept versus placebo
  • Health-related quality of life in those treated with abatacept versus placebo
  • Prevention of disease- or treatment-related damage with abatacept versus placebo
  • Safety of abatacept in GPA

Detailed Description

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

c. Identification of Patients
i. Inclusion Criteria
Patients must meet all of the following criteria to be eligible for enrollment:
1. Patients 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:
a. Nasal or oral inflammation, defined as the development of painful or painless oral
ulcers or purulent or bloody nasal discharge
b. Abnormal chest radiograph, defined as the presence of nodules, fixed infiltrates, or
cavities
c. Active urinary sediment, defined as microscopic hematuria (> 5 red blood cells per
high power field) or red blood cell casts
d. 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)
e. 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:
a. No disease manifestations that would be scored as a major element in the BVAS/WG
(49)
b. Absence of any disease feature that poses an immediate threat to either a critical
individual organ or the patient’s life
3. Age of 15 years or 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 the 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 with the written assent of those < 18
years of age.

Exclusion Criteria

ii. 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 infants
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. 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) 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 x-ray 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., Center for
Disease Control) 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 deleting 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)