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Study Description

Granulomatosis with polyangiitis (Wegener’s) (GPA) is a systemic inflammatory disease that is characterized by necrotizing, granulomatous inflammation and vasculitis of the small to medium-sized vessels. Despite the availability of medications that can induce remission, disease relapses occur in up to 75% of patients with GPA. The majority of these relapses are not severe, but can nevertheless result in incremental significant morbidity, from both GPA and the use of immunosuppressive treatment required to manage such relapses.   Abatacept (CTLA4-Ig) is comprised of the ligand-binding domain of CTLA4 plus human immunoglobulin. Through this construct abatacept carries the potential to modulate the costimulatory signal required for T cell activation. Based on laboratory data supporting a potential role for activated CD4 T cells in the pathogenesis of GPA, an open-label study was conducted to examine the role of abatacept in non-severe relapsing GPA. In 20 GPA patients treated with abatacept, 90% improved, 80% achieved remission, and 70% reached common closing. Eleven out of 15 patients were able to discontinue prednisone.

This 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. The primary objective of this trial is to determine the efficacy of abatacept to reduce the treatment failure rate. The secondary objectives are to determine the duration of glucocorticoid-free periods, 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, and safety of abatacept in GPA. This trial will be conducted by the Vasculitis Clinical Research Consortium (VCRC) and the European Vasculitis Society (EUVAS) with support by Bristol-Myers Squibb.

ELIGIBILITY CRITERIA:

Ages Eligible for Study:           15 Years and older   (Child, Adult, Older Adult)

Sexes Eligible for Study:          All

Accepts Healthy Volunteers:  No

Inclusion Criteria:

• 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

• 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

• Age 15 and older
• Willing and able to comply with treatment and follow-up procedures
• 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.
• Willing and able to provide written informed consent (and written assent of minor participants if applicable.)

Exclusion Criteria:

• Presence of involvement that does not meet the criteria for non-severe disease
• Treatment with CYC within 3 months prior to screening
• Treatment with methylprednisolone 1000 mg within 28 days prior to enrollment
• Treatment with prednisone > 30 mg/day for > 28 days immediately prior to study entry
• Initiation or dose increase of the maintenance immunosuppressive agent (MTX, AZA, MA) within 3 months prior to screening
• Evidence of active infection (includes chronic infection)
• Patients who are pregnant or who are nursing
• Known infection with human immunodeficiency virus (HIV), hepatitis C, or a positive hepatitis B surface antigen
• Inability to comply with study guidelines
• 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
• Chronic renal insufficiency defined by a creatinine clearance of < or = to 20 ml/min
• Known current use of illegal drugs
• 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
• 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
• Receipt of an investigational agent or device within 30 days prior to enrollment or 5 half lives of the investigational drug (whichever is longer)
• A live vaccination fewer than 3 months before enrollment
• Current clinical, radiographic, or laboratory evidence of active tuberculosis
• A history of active tuberculosis within the past 3 years even if treated
• A history of active tuberculosis greater than 3 years ago unless there is documentation of prior anti-tuberculosis treatment of appropriate duration and type
• Latent tuberculosis unless there is documentation of prior anti-tuberculosis treatment of appropriate duration and type
• 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.
• History of herpes zoster that resolved less than 2 months prior to enrollment
• 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
• Treatment with alemtuzumab or anti-thymocyte globulin within the last 12 months
• Treatment with intravenous immunoglobulin or plasma exchange within the past 3 months
• 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)

Study Design:

Allocation: Randomized

Intervention Model: Parallel Assignment

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose: Treatment

Study Location(s):

Cedars Sinai Medical Center, Los Angeles, Los Angeles, California, United States, 90048

University of California, San Francisco, San Francisco, California, United States, 94143

University of South Florida Rheumatology, Tampa, Florida, United States, 33612

University of Kansas Medical Center, Kansas City, Kansas, United States, 66160

Boston University School of Medicine, Boston, Massachusetts, United States, 02118

University of Michigan, Ann Arbor, Michigan, United States, 48109

Mayo Clinic Rochester, Rochester, Minnesota, United States, 55902

Hospital for Special Surgery, New York, New York, United States, 10021

Cleveland Clinic, Cleveland, Ohio, United States, 44195

Oregon Health & Science University, Portland, Oregon, United States, 97239

University of Pennsylvania, Philadelphia, Pennsylvania, United States, 19104

University of Pittsburgh, Pittsburgh, Pennsylvania, United States, 15261

Vanderbilt University, Nashville, Tennessee, United States, 37240

University of Utah, Salt Lake City, Utah, United States, 84132

University of Calgary, Calgary, Alberta, Canada, T3M 1M4

Alberta Health Services- Edmonton, Edmonton, Alberta, Canada, T6G 2C8

University of British Columbia, St. Paul's Rheumatology Clinic, Vancouver, British Columbia, Canada, V6Z 1Y6

St. Joseph's Hospital, Hamilton, Ontario, Canada

The Ottawa Hospital, Ottawa, Ontario, Canada, k1H 8L6

Mount Sinai Hospital, Toronto, Toronto, Ontario, Canada, M5T 3L9

St. Vincent's University Hospital, Dublin, Ireland

University of Aberdeen, Aberdeen, United Kingdom, AB25 2ZD

University of Cambridge- Addenbrookes Hospital, Cambridge, United Kingdom

Study Website:

https://clinicaltrials.gov/ct2/show/NCT02108860?term=NCT02108860&rank=1