Abatacept for the Treatment of Relapsing, Non-Severe, Granulomatosis With Polyangiitis (Wegener's)

NCT ID: NCT02108860

Last Updated: 2024-07-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 65 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-04-25
• Study Completion Date: 2023-12-20

Brief Summary

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.

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.

Conditions

Granulomatosis With Polyangiitis (Wegener's); Granulomatosis With Polyangiitis; Wegener's Granulomatosis; ANCA-Associated Vasculitis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Blinded abatacept

Participants will receive blinded abatacept 125 mg administered by subcutaneous injection once a week for at least 12 months. Subjects may be removed from treatment earlier due to a disease relapse, disease worsening, or if they have not achieved remission by treatment month 6.

Group Type: EXPERIMENTAL

Abatacept

Intervention Type: DRUG

Those randomized to abatacept will receive abatacept 125 mg administered by subcutaneous injection once a week Participants randomized to either the abatacept or the placebo arm 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. .

blinded placebo

Participants will receive blinded placebo. Placebo will be administered by subcutaneous injection once a week for at least 12 months. Subjects may be removed from treatment earlier due to a disease relapse, disease worsening, or if they have not achieved remission by treatment month 6.

Group Type: PLACEBO_COMPARATOR

placebo

Intervention Type: DRUG

Those randomized to placebo will receive a sterile placebo solution administered by subcutaneous injection once a week.

Interventions

Abatacept

Those randomized to abatacept will receive abatacept 125 mg administered by subcutaneous injection once a week Participants randomized to either the abatacept or the placebo arm 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. .

Intervention Type: DRUG

placebo

Those randomized to placebo will receive a sterile placebo solution administered by subcutaneous injection once a week.

Intervention Type: DRUG

Other Intervention Names

CTLA4-Ig; Orencia

Eligibility Criteria

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)

• Minimum Eligible Age: 15 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

The Cleveland Clinic

OTHER

Sponsor Role: collaborator

Bristol-Myers Squibb

INDUSTRY

Sponsor Role: collaborator

University of Pennsylvania

OTHER

Sponsor Role: collaborator

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

NIH

Sponsor Role: collaborator

University of South Florida

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Carol A Langford, MD, MHS

Role: PRINCIPAL_INVESTIGATOR

The Cleveland Clinic

Jeffrey P Krischer, PhD

Role: PRINCIPAL_INVESTIGATOR

University of South Florida

Peter A Merkel, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

University of Pennsylvania

Locations

Cedars Sinai Medical Center, Los Angeles

Los Angeles, California, United States

University of South Florida Rheumatology

Tampa, Florida, United States

University of Kansas Medical Center

Kansas City, Kansas, United States

University of Michigan

Ann Arbor, Michigan, United States

Mayo Clinic Rochester

Rochester, Minnesota, United States

Hospital for Special Surgery

New York, New York, United States

Cleveland Clinic

Cleveland, Ohio, United States

Oregon Health & Science University

Portland, Oregon, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

Vanderbilt University

Nashville, Tennessee, United States

University of Calgary

Calgary, Alberta, Canada

University of British Columbia, St. Paul's Rheumatology Clinic

Vancouver, British Columbia, Canada

St. Joseph's Hospital, Hamilton

Hamilton, Ontario, Canada

Mount Sinai Hospital, Toronto

Toronto, Ontario, Canada

Medius Kliniken

Kirchheim unter Teck, , Germany

St. Vincent's University Hospital

Dublin, , Ireland

University of Aberdeen

Aberdeen, , United Kingdom

University of Cambridge- Addenbrookes Hospital

Cambridge, , United Kingdom

Nottingham University Hospitals

Nottingham, , United Kingdom

Royal Berkshire Hospital

Reading, , United Kingdom

Countries

United States; Canada; Germany; Ireland; United Kingdom

References

Hung W, Cusnir I, Habib S, Smylie M, Solez K, Yacyshyn E. Immune checkpoint inhibitor-induced granulomatosis with polyangiitis. Rheumatology (Oxford). 2021 Jun 18;60(6):e190-e191. doi: 10.1093/rheumatology/keaa818. No abstract available.

Reference Type: DERIVED

PMID: 33367837 (View on PubMed)

Other Identifiers

2013-005535-24

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

U54AR057319

Identifier Type: NIH

Identifier Source: secondary_id

View Link

ABROGATE 5527

Identifier Type: -

Identifier Source: org_study_id