Clinical trial NCT01934504: Defining Immune Tolerance in ANCA-associated Vasculitis (AAV)
Official title: Defining Immune Tolerance in ANCA-associated Vasculitis (AAV)
Study type: OBSERVATIONAL
Overall status: TERMINATED
Conditions: ANCA-Associated Vasculitis
Keywords: clinical tolerance
biomarker(s) identification
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Immune Tolerance Network (ITN)
First posted: 2013-09-04
Enrollment: 33
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Non-tolerant: Patients who have persistently active disease. Tolerant: Those patients who have become ANCA negative, having been ANCA positive at the time of their acute presentation but have been in prolonged disease- free remission off all immunotherapy for at least two years. Healthy controls: Individuals with similar age distribution to participants in the Non-tolerant and Tolerant cohorts.

Brief summary: 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: 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markers that define immunological tolerance so that immunotherapy medicines may be correctly changed and safely withdrawn in some people.

Eligibility criteria: 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.

Primary outcomes:
measure: Tolerance Biomarker Identification
timeFrame: Difference from baseline to week 26
Secondary outcomes:
measure: Tolerance Signature Stability
timeFrame: Baseline to Week 26
measure: Tolerance Signature Versus Clinical Status
timeFrame: Baseline to Week 26
measure: Immunosuppression Associated Signature
timeFrame: Baseline to 8 Weeks Post-Immunosuppression Withdrawal
Other outcomes:
Locations:
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
state: England
city: London
country: United Kingdom
facility: University College London, Centre for Nephrology
state: England
city: London
country: United Kingdom
facility: Hammersmith Hospital
state: England
Study officials:
affiliation: University College London, Centre for Nephrology
name: Alan Salama, MD
role: STUDY_CHAIR
References: