ANCA-Associated Vasculitis
Conditions
Keywords
clinical tolerance, biomarker(s) identification
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markers that define immunological tolerance so that immunotherapy medicines may be correctly changed and safely withdrawn in some people.
Interventions
PROCEDUREVenipuncture for blood sample collection
Analysis samples from the blood sample collection at specific time points.
Sponsors
Immune Tolerance Network (ITN)
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tolerance Biomarker Identification | Difference from baseline to week 26 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tolerance Signature Stability | Baseline to Week 26 | 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. |
| Tolerance Signature Versus Clinical Status | Baseline to Week 26 | 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. |
| Immunosuppression Associated Signature | Baseline to 8 Weeks Post-Immunosuppression Withdrawal | Definition of an immune signature associated with maintenance immunosuppression. Due to early study termination, data was not available to evaluate this endpoint. |
Countries
United Kingdom
Participant flow
Recruitment details
Participants diagnosed with granulomatosis with polyangiitis (Wegener's, GPA) or microscopic polyangiitis, and a history positive for the presence of MPO-ANCA+ during disease flares were recruited for 3 cohorts; healthy participants were recruited for 1 cohort. Participants were recruited from 3 sites in Great Britain from Dec 2013 to Feb 2015.
Participants by arm
| Arm | Count |
|---|---|
| Tolerant AAV Subjects in the Tolerant ANCA-associated vasculitis (AAV) cohort have been in clinical remission with Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) scores of zero and have been off all immunosuppression medications for at least 2 years prior to screening. Subjects have blood samples and other assessments collected for analysis at Week 0 and Week 26. | 6 |
| Non-Tolerant AAV Subjects in the Non-Tolerant ANCA-associated vasculitis (AAV) cohort have had a disease exacerbation and re-institution of immunosuppressive therapy in the past 5 years. Subjects have also been in clinical remission with Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) scores of zero and on minimal maintenance therapy for at least 3 months prior to screening. Subjects have blood samples and other assessments collected for analysis at Week 0 and Week 26. | 3 |
| Healthy Controls Healthy participants without autoimmune disease. Subjects have blood samples and other assessments collected for analysis at Week 0 and Week 26. | 16 |
| AAV Discontinuing Immunosuppression Subjects in the ANCA-associated vasculitis (AAV) Discontinuing Immunosuppression group have been in clinical remission with Birmingham Vasculitis Activity Score for Wegener's Granulomatosis BVAS/WG) scores of zero and on minimal maintenance therapy for at least 2 years prior to screening. The subjects' primary physicians have planned to discontinue immunosuppression medication in the next year after screening. Subjects have blood samples and other assessments collected for analysis at Week 0 and at 8 weeks after discontinuation of immunosuppression medication. | 8 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Protocol Deviation | 0 | 0 | 0 | 2 |
| Overall Study | Study Terminated by Sponsor | 1 | 0 | 5 | 5 |
Baseline characteristics
| Characteristic | Healthy Controls | Tolerant AAV | Non-Tolerant AAV | AAV Discontinuing Immunosuppression | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 12 Participants | 5 Participants | 1 Participants | 5 Participants | 23 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 1 Participants | 2 Participants | 3 Participants | 10 Participants |
| Age, Continuous | 69.4 years STANDARD_DEVIATION 7.1 | 73.7 years STANDARD_DEVIATION 13.5 | 58.3 years STANDARD_DEVIATION 7.6 | 64.8 years STANDARD_DEVIATION 7.5 | 68.1 years STANDARD_DEVIATION 9.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 6 Participants | 3 Participants | 8 Participants | 33 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 5 Participants | 3 Participants | 6 Participants | 29 Participants |
| Region of Enrollment United Kingdom | 16 participants | 6 participants | 3 participants | 8 participants | 33 participants |
| Sex: Female, Male Female | 9 Participants | 2 Participants | 2 Participants | 5 Participants | 18 Participants |
| Sex: Female, Male Male | 7 Participants | 4 Participants | 1 Participants | 3 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 6 | 0 / 3 | 0 / 16 | 0 / 8 |
| serious Total, serious adverse events | 0 / 6 | 0 / 3 | 0 / 16 | 0 / 8 |
Outcome results
Primary
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.
Time frame: Difference from baseline to week 26
Population: No analyses were performed due to slow enrollment and early study closure.
Secondary
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.
Time frame: Baseline to 8 Weeks Post-Immunosuppression Withdrawal
Population: No analyses were performed due to slow enrollment and early study closure.
Secondary
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.
Time frame: Baseline to Week 26
Population: No analyses were performed due to slow enrollment and early study closure.
Secondary
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.
Time frame: Baseline to Week 26
Population: No analyses were performed due to slow enrollment and early study closure.