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

April 13, 2016 updated by: National Institute of Allergy and Infectious Diseases (NIAID)
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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

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markers that define immunological tolerance so that immunotherapy medicines may be correctly changed and safely withdrawn in some people.

Study Type

Observational

Enrollment (Actual)

33

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
    • England
      • Cambridge, England, United Kingdom, CB2 0QQ
        • Addenbrooke's Hospital
      • London, England, United Kingdom, NW32PF
        • University College London, Centre for Nephrology
      • London, England, United Kingdom, W12 0HS
        • Hammersmith Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

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.

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Tolerant AAV
Tolerant participants with AAV
Procedure: Venipuncture for blood sample collection
Analysis samples from the blood sample collection at specific time points.
Other Names:
  • Peripheral venous blood draw
Non-Tolerant AAV
Non-Tolerant participants with ANCA-associated vasculitis (AAV)
Procedure: Venipuncture for blood sample collection
Analysis samples from the blood sample collection at specific time points.
Other Names:
  • Peripheral venous blood draw
Healthy Controls
Healthy participants that fulfill eligibility criteria -similar in age to Tolerant and Non-Tolerant AAV participants.
Procedure: Venipuncture for blood sample collection
Analysis samples from the blood sample collection at specific time points.
Other Names:
  • Peripheral venous blood draw
AAV Discontinuing Immunosuppression
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
Analysis samples from the blood sample collection at specific time points.
Other Names:
  • Peripheral venous blood draw

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Tolerance Biomarker Identification
Time Frame: 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.
Difference from baseline to week 26

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Tolerance Signature Stability
Time Frame: 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.
Baseline to Week 26
Tolerance Signature Versus Clinical Status
Time Frame: 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.
Baseline to Week 26
Immunosuppression Associated Signature
Time Frame: 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.
Baseline to 8 Weeks Post-Immunosuppression Withdrawal

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

Collaborators

Immune Tolerance Network (ITN)

Investigators

  • Study Chair: Alan Salama, MD, University College London, Centre for Nephrology

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 1, 2013

Primary Completion (Actual)

February 1, 2015

Study Completion (Actual)

February 1, 2015

Study Registration Dates

First Submitted

August 29, 2013

First Submitted That Met QC Criteria

August 29, 2013

First Posted (Estimate)

September 4, 2013

Study Record Updates

Last Update Posted (Estimate)

May 20, 2016

Last Update Submitted That Met QC Criteria

April 13, 2016

Last Verified

April 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DAIT ITN051AI
  • AVATARS (Other Identifier: Mayo Clinic in Arizona)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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