Defining Immune Tolerance in ANCA-associated Vasculitis (AAV)

Study Overview
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Brief Summary
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The goal of the study is to find biological markers (certain proteins or cellular markers found in a blood test) that will inform doctors which patients diagnosed with ANCA-associated vasculitis (AAV) are most likely to be able to stop their medications suppressing their immune systems and remain in remission.

Detailed Description
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Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are small vessel vasculitides that typically follow a chronic course and are associated with serious illness and death.Three clinical conditions are recognized: microscopic polyangiitis (MPA); granulomatosis with polyangiitis (Wegener's, GPA); and eosinophilic granulomatosis with polyangiitis (EPA, formerly Churg Strauss Syndrome). Though these conditions have different clinical features, they can have overlapping immunological characteristics. The precise cause of AAV is not understood, but there are clear genetic associations which, in the context of predisposing environmental factors, such as infections, may lead to development of disease. There are no diagnostic criteria for AAV, but there are validated classification criteria and disease definitions. There is a need to find biological markers that define immunological tolerance so that immunotherapy medicines may be correctly changed and safely withdrawn in some people.

Official Title
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Defining Immune Tolerance in ANCA-associated Vasculitis (AAV)

Conditions
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ANCA-Associated Vasculitis

Intervention / Treatment
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* Procedure: Venipuncture for blood sample collection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Tolerant AAV participants: Age 18 years or older Diagnosis of granulomatosis with polyangiitis (Wegener's, GPA) or microscopic polyangiitis (MPA) according to the definitions of the Chapel Hill Consensus Conference (CHCC) History of being myeloperoxidase (MPO)-ANCA positive during a disease flare In clinical remission with Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) = 0 and off all immunosuppression for ≥ 2 years Negative MPO-ANCA and proteinase 3 (PR3)-ANCA by ELISA at screening For women of child-bearing potential, a negative urine or serum pregnancy test at the time of screening Ability to sign and understand informed consent Willingness to comply with study procedures. Non-Tolerant AAV participants: Age 18 years or older Diagnosis of granulomatosis with polyangiitis (Wegener's), GPA or microscopic polyangiitis (MPA) according to the definitions of the CHCC History of being MPO-ANCA positive during a disease flare Within the past 5 years, must have had a disease exacerbation, defined as an increase in the BVAS/WG score and re-institution of immunosuppressive therapy after therapy had been reduced or completely discontinued In clinical remission with BVAS/WG = 0 and on minimal maintenance therapy for ≥3 months prior to the screening visit. Minimal maintenance therapy is defined as: Low-dose glucocorticoids (≤10 mg of prednisone or prednisolone daily) and/or: Azathioprine ≤ 150mg daily or Mycophenolate mofetil (MMF) ≤ 1 gram daily or mycophenolate sodium ≤ 720 mg daily. Positive MPO-ANCA by ELISA on at least 2 occasions within the last 52 weeks, the most recent result being within 8 weeks of visit -1 For women of child-bearing potential, a negative urine or serum pregnancy test at the time of screening Ability to sign and understand informed consent Willingness to comply with study procedures. Healthy Controls: Healthy participant age ≥18 years For women of child-bearing potential, a negative urine or serum pregnancy test at the time of screening Ability to sign and understand informed consent Willingness to comply with study procedures. Exclusion Criteria: Tolerant AAV Participants: Use of systemic intravenous (IV) or oral glucocorticoids for ˃ 1 month for any non-vasculitis indication within 8 weeks of the screening visit Any prior treatment with rituximab Presence of known chronic viral infections or autoimmune diseases History of malignancy, excluding non-melanomatous skin cancers or cervical cancer carcinoma in situ within 5 years of the screening visit. Non-Tolerant AAV participants: Use of IV pulse glucocorticoids (methylprednisolone or other) or cyclophosphamide within the year prior to the screening visit Use of IV or oral glucocorticoids for > 1 month for any non- vasculitis indication within 8 weeks of screening visit Any prior treatment with rituximab Maintenance therapy with methotrexate within 3 months of the screening visit Presence of known chronic viral infections or other autoimmune diseases History of malignancy, excluding non-melanoma skin cancers or cervical cancer carcinoma in situ within 5 years of the screening visit. Healthy Controls: Use of IV or oral glucocorticoids for > 1 month for any non-vasculitis indication within 8 weeks of the screening visit Presence of known chronic viral infections or other autoimmune diseases History of malignancy, excluding non-melanoma skin cancers or cervical cancer carcinoma in situ within 5 years of the screening visit. AAV Participants Discontinuing Immunosuppression: Any prior treatment with rituximab Maintenance therapy with methotrexate within 3 months of the screening visit Presence of known chronic viral infections or other autoimmune diseases History of malignancy, excluding non-melanoma skin cancers or cervical cancer carcinoma in situ, within 5 years of the screening visit.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Tolerant AAV<br>Tolerant participants with AAV | Procedure: Venipuncture for blood sample collection<br>* Analysis samples from the blood sample collection at specific time points.<br>* Other names: Peripheral venous blood draw;|
| Non-Tolerant AAV<br>Non-Tolerant participants with ANCA-associated vasculitis (AAV) | Procedure: Venipuncture for blood sample collection<br>* Analysis samples from the blood sample collection at specific time points.<br>* Other names: Peripheral venous blood draw;|
| Healthy Controls<br>Healthy participants that fulfill eligibility criteria -similar in age to Tolerant and Non-Tolerant AAV participants. | Procedure: Venipuncture for blood sample collection<br>* Analysis samples from the blood sample collection at specific time points.<br>* Other names: Peripheral venous blood draw;|
| AAV Discontinuing Immunosuppression<br>Participants have been in clinical remission and on minimal maintenance therapy for at least 2 years prior to screening. Their primary physicians have planned to discontinue immunosuppression medication in the next year after screening. | Procedure: Venipuncture for blood sample collection<br>* Analysis samples from the blood sample collection at specific time points.<br>* Other names: Peripheral venous blood draw;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerance Biomarker Identification | Identification of biomarkers associated with clinical tolerance in patients with ANCA-associated vasculitis by comparative immunophenotyping of individual leukocyte subsets from tolerant and non-tolerant patients with AAV. Due to early study termination, data was not available to evaluate this endpoint. | Difference from baseline to week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerance Signature Stability | Measurement of the stability of a tolerance immune signature in patients with AAV over time. Due to early study termination, data was not available to evaluate this endpoint. | Baseline to Week 26 | 
| Tolerance Signature Versus Clinical Status | Correlation of possible changes in the tolerance signature with changes in clinical status. Due to early study termination, data was not available to evaluate this endpoint. | Baseline to Week 26 | 
| Immunosuppression Associated Signature | Definition of an immune signature associated with maintenance immunosuppression. Due to early study termination, data was not available to evaluate this endpoint. | Baseline to 8 Weeks Post-Immunosuppression Withdrawal | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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clinical tolerance, biomarker(s) identification