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

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified April 2014 by University of South Florida
Sponsor:
Collaborators:
The Cleveland Clinic
Bristol-Myers Squibb
University of Pennsylvania
Information provided by (Responsible Party):
University of South Florida
ClinicalTrials.gov Identifier:
NCT02108860
First received: March 27, 2014
Last updated: April 4, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention Phase
Granulomatosis With Polyangiitis (Wegener's)
Granulomatosis With Polyangiitis
Wegener's Granulomatosis
ANCA-Associated Vasculitis
Drug: Abatacept
Drug: placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Abatacept (CTLA4-Ig) for the Treatment of Relapsing, Non-Severe, Granulomatosis With Polyangiitis (Wegener's) (ABROGATE)

Resource links provided by NLM:


Further study details as provided by University of South Florida:

Primary Outcome Measures:
  • Treatment failure after 12 months of study treatment [ Time Frame: 12 months ] [ Designated as safety issue: No ]

    Treatment failure will be defined as relapse, disease worsening, or failure to achieve a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) = 0 or 1 by 6 months.

    Relapse will be defined as any of the following after remission: an increase in BVAS/WG, development of a new BVAS/WG item, or symptoms/signs of GPA that cannot be attributed to any cause other than GPA and that requires institution or dosage increase of prednisone.

    Disease worsening will be defined as any of the following prior to remission: an increase in BVAS/WG, development of a new BVAS/WG item, or symptoms/signs of GPA that cannot be attributed to any cause other than GPA and that requires institution or dosage increase of prednisone.



Secondary Outcome Measures:
  • Duration of glucocorticoid-free periods [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    Effect of abatacept on increasing duration of glucocorticoid-free periods for participants. Patients will be treated with abatacept for a minium of 12 months unless they reach study criteria for early termination or until common closing. Common closing will be 12 months after randomization of the final patient.

  • Duration of remission with abatacept versus placebo [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    Duration of GPA disease remission on participants on abatacept versus placebo. Patients will be treated with abatacept for a minium of 12 months unless they reach study criteria for early termination or until common closing. Common closing will be 12 months after randomization of the final patient.

  • Severity of relapses in those treated with abatacept versus placebo [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    Severity of GPA disease relapses in those treated with abatacept versus placebo. Patients will be treated with abatacept for a minium of 12 months unless they reach study criteria for early termination or until common closing. Common closing will be 12 months after randomization of the final patient.

  • Health-related quality of life in those treated with abatacept versus placebo [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    Health-related quality of life in those treated with abatacept versus placebo as assessed using the SF-36 and PROMIS questionnaires. Patients will be treated with abatacept for a minium of 12 months unless they reach study criteria for early termination or until common closing. Common closing will be 12 months after randomization of the final patient.

  • Number and severity of adverse events [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
    Safety of abatacept in patients with GPA as assessed by reported adverse events. Patients will be treated with abatacept for a minium of 12 months unless they reach study criteria for early termination or until common closing. Common closing will be 12 months after randomization of the final patient.


Estimated Enrollment: 150
Study Start Date: April 2014
Estimated Study Completion Date: September 2018
Estimated Primary Completion Date: August 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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.
Drug: 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. .
Other Names:
  • Abatacept
  • CTLA4-Ig
  • Orencia
Placebo Comparator: 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.
Drug: placebo
Those randomized to placebo will receive a sterile placebo solution administered by subcutaneous injection once a week.
Other Name: placebo

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.

  Eligibility

Ages Eligible for Study:   15 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  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:

    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, 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. 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:

  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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02108860

Contacts
Contact: Cristina Burroughs 813-396-9237 cristina.burroughs@epi.usf.edu
Contact: Renee Leduc 813-396-9308 renee.leduc@epi.usf.edu

Locations
United States, Ohio
Cleveland Clinic Not yet recruiting
Cleveland, Ohio, United States, 44195
Contact: Carol A Langford, MD, MHS    216-445-6056    langfoc@ccf.org   
Principal Investigator: Carol A Langford, MD, MHS         
Sponsors and Collaborators
University of South Florida
The Cleveland Clinic
Bristol-Myers Squibb
University of Pennsylvania
Investigators
Principal Investigator: Carol A Langford, MD, MHS The Cleveland Clinic
Principal Investigator: Jeffrey P Krischer, PhD University of South Florida
Principal Investigator: Peter A Merkel, MD, MPH University of Pennsylvania
  More Information

Additional Information:
No publications provided

Responsible Party: University of South Florida
ClinicalTrials.gov Identifier: NCT02108860     History of Changes
Other Study ID Numbers: ABROGATE 5527, 2013-005535-24, 5527
Study First Received: March 27, 2014
Last Updated: April 4, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board
United States: Data and Safety Monitoring Board

Keywords provided by University of South Florida:
Granulomatosis with polyangiitis (Wegener's)
Granulomatosis with polyangiitis
Wegener's granulomatosis
Wegener granulomatosis
GPA
Anti Neutrophil Cytoplasmic Antibody Associated Vasculitis
ANCA Associated Vasculitis
AAV
Vasculitis
Systemic vasculitis
Systemic inflammatory disease
Lung Diseases
Respiratory Tract Diseases
Vascular Diseases
Abatacept
CTLA4-Ig
Immunosuppressive agent
Prednisone
Glucocorticoids
Glucocorticoid
Corticosteroid
Corticosteroids
Treatment
Pharmacologic Actions
Therapeutic Uses
Anti Inflammatory Agents

Additional relevant MeSH terms:
Wegener Granulomatosis
Vasculitis
Systemic Vasculitis
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Vascular Diseases
Cardiovascular Diseases
Lung Diseases, Interstitial
Lung Diseases
Respiratory Tract Diseases
Autoimmune Diseases
Immune System Diseases
Anti-Inflammatory Agents
Glucocorticoids
Immunosuppressive Agents
Abatacept
Antibodies, Antineutrophil Cytoplasmic
Therapeutic Uses
Pharmacologic Actions
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Immunologic Factors
Antirheumatic Agents

ClinicalTrials.gov processed this record on July 31, 2014