ACQUIVAS

Acquired Immunodeficiency in ANCA Associated Vasculitis

Research summary

Antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) has been transformed from a largely fatal condition to a chronic relapsing disorder following the introduction of cyclophosphamide and glucocorticoids 40 years ago. Despite refinement in the dosing regimens of these agents, and the introduction of novel agents such as rituximab, a B cell depleting therapy, the natural history of AAV is characterised by frequent relapses, necessitating repeated periods of intensified immunosuppression, and its consequent toxicity.

The ACQUIVAS trial, in addition to offering a therapeutic intervention, which aims to maximise responses to pneumococcal vaccination, also aims to understand the processes that lead to immune dysregulation in patients with AVV. The impact of sub-clinical Cytomegalovirus (CMV) reactivation and T cell exhaustion on pneumococcal vaccine responses will be addressed as exploratory endpoints in this trial. In addition, genetic factors which influence B cell function and the development of hypogammaglobuliaemia and may therefore influence vaccine response will be studied.

All-cause mortality and rates of infection remain increased in patients with AAV compared to the general population. The cumulative adverse effects of disease activity and treatments now dominate patient outcomes. These include an increased propensity for infection and acquired humoral immune deficiency as long term consequences of immunosuppression.

Vaccination against pneumococcus is recommended as a strategy to reduce infection risk in individuals with AAV. However, the effect of rituximab and B cell depletion on vaccine responses in patients with AAV is yet to be explored, and the available data from other autoimmune diseases in very limited. Poor response to vaccination has been identified as an important predictor of all-cause death in patients with AAV. Therefore, optimisation of current vaccine strategies in autoimmune disease such as AAV is vital.

This is a phase IIb, open-label trial to evaluate the responses of patients with ANCA associated vasculitis (AAV) to pneumococcal vaccination. It has been designed primarily to assess the immunogenicity of pneumococcal vaccines in patients with AAV treated with rituximab compared to disease controls, but also to provide mechanistic information on vaccine response by comparing AAV patients and healthy controls.

www.clinicaltrials.gov

Main inclusion criteria

  1. To be included in the trial all participants must:

    1. Have given written informed consent to participate

    2. Be aged 40 years and over

  2. For patients in Group 1 only (rituximab treated):

    1. Have a diagnosis of AAV [granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) or eosinophilic granulomatosis with polyangiitis (eGPA)]

    2. Have current or historical PR3/MPO ANCA positivity by ELISA or histological confirmation of AAV

    3. Have received ≥ 2g rituximab

    4. Have received their last dose of rituximab at least 12 months prior to enrolment

    5. Be in stable remission with a prednisolone dose of ≤ 5mg/day

  3. For patients in Group 1 only (rituximab treated):

    1. Have a diagnosis of AAV [granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) or eosinophilic granulomatosis with polyangiitis (eGPA)]

    2. Have current or historical PR3/MPO ANCA positivity by ELISA or histological confirmation of AAV

    3. Have received ≥ 2g rituximab

    4. Have received their last dose of rituximab at least 12 months prior to enrolment

    5. Be in stable remission with a prednisolone dose of ≤ 5mg/day

  4. For patients in Group 2 only (disease controls who have never received rituximab):

    1. Have a diagnosis of AAV (GPA, MPA or eGPA)

    2. Have current or historical PR3/MPO ANCA positivity by ELISA or histological confirmation of AAV

    3. Have received cyclophosphamide (oral or IV) as initial induction therapy

    4. Be on stable immunosuppression for the 6 months preceding screening including prednisolone ≤ 5mg/day AND either azathioprine, methotrexate or mycophenolate mofetil (at stable or tapering dose)

  5. For healthy controls:

    1. Healthy individuals aged 40 years and over

Main exclusion criteria

  1. The presence of any of the following will preclude participant inclusion:

    1. Age < 40 years

    2. History of severe allergic or anaphylactic reactions to pneumococcal vaccinations

    3. Females who are pregnant, plan to become pregnant, or breast feeding

    4. Medical, psychiatric, cognitive or other conditions that, in the investigator's opinion, compromise the patient's ability to understand the patient information, give informed consent, comply with the trial protocol, or to complete the study.

    5. 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.

    6. Replacement immunoglobulin (IVIg) administered intravenously or subcutaneously in the 12 weeks prior to screening visit.

  2. For patients in Groups 1 and 2 only (AAV patients):

    1. Presence of another multisystem autoimmune rheumatic disease

    2. The prior receipt of more than 36g of cumulative cyclophosphamide ever (either IV or oral)

  3. For patients in group 1 only (rituximab group):

    1. The receipt of any immune suppressing agent (azathioprine, methotrexate or mycophenolate mofetil) after rituximab

    2. The prior receipt of more than 36g of cumulative cyclophosphamide ever (either IV or oral)

  4. For patients in Group 2 only (disease controls):

    1. A relapse of AAV within the 6 months prior to screening which has necessitated an increase in prednisolone or azathioprine, methotrexate or MMF dose.

    2. Previous rituximab therapy at any time

  5. For healthy controls:

    1. Any history of any autoimmune condition

    2. Any history of use of immune suppressing medication, including > 4 weeks of oral glucocorticoids, within the 5 years prior to screening.

Chief investigator

Dr Rona Smith

Contact details

Senior Clinical Trials Coordinator: Kim Mynard

Telephone: 01223 768317 | Email: [email protected]