Plasma Exchange and Glucocorticoids for Treatment of Anti-Neutrophil Cytoplasm Antibody (ANCA) - Associated Vasculitis (PEXIVAS)

University of Pennsylvania

Status and phase: Completed; Phase 3

Conditions: Granulomatosis With Polyangiitis (Wegener's) (GPA); Microscopic Polyangiitis (MPA)

Treatments: Drug: Glucocorticoids [Reduced Dose]; Other: No Plasma Exchange; Drug: Glucocorticoids [Standard Dose]; Procedure: Plasma Exchange

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT00987389

R01FD00351604 (Other Grant/Funding Number)

2009-013220-24 (EudraCT Number)

PEXIVAS

Details and patient eligibility

About

The purpose of this study is to determine whether plasma exchange as well as immunosuppressive therapy are effective in reducing death and end-stage renal disease (ESRD). The trial will also study whether a reduced cumulative dosing regimen of glucocorticoids is as effective as a standard disease regimen.

The FDA-OOPD is one of the funding sources for this study.

Full description

Granulomatosis with polyangiitis (Wegener's) (WG) and microscopic polyangiitis (MPA) are syndromes of primary systemic vasculitis associated with anti-neutrophil cytoplasm antibodies (ANCA). Together, these syndromes are grouped as ANCA-associated systemic vasculitis (AAV).

Plasma exchange, a method of rapidly removing potentially pathogenic ANCA and other mediators of inflammation and coagulation, has shown promise as an adjunctive therapy in AAV to improve early disease control and improve rates of renal recovery in severe disease. Glucocorticoids (steroids) are a standard of care in the treatment of AAV. High doses of glucocorticoids early in disease, although reduce disease activity due to their anti-inflammatory and immunosuppressive properties, also increase the risk of infection, particularly in the elderly and in the presence of uremia. There is no randomized trial data to guide glucocorticoids dosing.

Patients with severe new or relapsing AAV and pulmonary hemorrhage and/or renal disease will be eligible for this trial.

Subjects participating in this study will be randomized to receive one of the following groups;

1. Plasma exchange - 7 exchanges and, either standard or low-dose glucocorticoids or
2. No plasma exchange and, either standard or low-dose glucocorticoids

All studies will receive standard remission-induction therapy with either cyclophosphamide or rituximab.

Enrollment: 704 patients

Sex: All

Ages: 15+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• New or previous clinical diagnosis of granulomatosis with polyangiitis or microscopic polyangiitis consistent with the Chapel-Hill consensus definitions

AND

• Positive test for proteinase 3-ANCA or myeloperoxidase-ANCA

AND

• Severe vasculitis defined by at least one of the following:

  1. Renal involvement characterized by both of the following:

     • Renal biopsy demonstrating focal necrotizing glomerulonephritis or active urine sediment characterized by glomerular haematuria or red cell casts and proteinuria

     AND

     • eGFR <50 ml/min/1.73 m2

  2. Pulmonary hemorrhage due to active vasculitis defined by:

     • A compatible chest x-ray or CT scan (diffuse pulmonary infiltrates)

     AND

     • The absence of an alternative explanation for all pulmonary infiltrates (e.g. volume overload or pulmonary infection)

     AND

  3. At least one of the following:

     • Evidence of alveolar hemorrhage on bronchoscopic examination or increasingly bloody returns with bronchoalveolar lavage
     • Observed hemoptysis
     • Unexplained anemia (<10 g/dL) or documented drop in hemoglobin >1 g/dL)
     • Increased diffusing capacity of carbon dioxide

• Provision of informed consent by patient or a surrogate decision maker

Exclusion criteria

• A diagnosis of vasculitis other than granulomatosis with polyangiitis or microscopic polyangiitis
• Positive serum anti-glomerular basement membrane antibody test or renal biopsy demonstrating linear glomerular immunoglobulin deposition
• Receipt of dialysis for >21 days immediately prior to randomization or prior renal transplant
• Age <15 years
• Pregnancy at time of study entry
• Treatment with >1 IV dose of cyclophosphamide and/or >14 days of oral cyclophosphamide and/or >14 days of prednisone/prednisolone (>30 mg/day) and/or >1 dose of rituximab within the 28 days immediately prior to randomization
• A comorbidity that, in the opinion of the investigator, precludes the use of cyclophosphamide, glucocorticoids, or plasma exchange or absolutely mandates the use of plasma exchange
• Plasma exchange in 3 months prior to randomization

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: None (Open label)

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704 participants in 4 patient groups

Plasma Exchange with Standard Glucocorticoids

Experimental group

Description:

Participants in this arm undergo plasma exchange and take a standard glucocorticoid dose.

Treatment:

Procedure: Plasma Exchange

Drug: Glucocorticoids [Standard Dose]

No Plasma Exchange with Standard Glucocorticoids

Active Comparator group

Description:

Participants in this arm do not undergo plasma exchange and take a standard glucocorticoid dose.

Treatment:

Other: No Plasma Exchange

Drug: Glucocorticoids [Standard Dose]

Plasma Exchange with Reduced-Dose Glucocorticoids

Experimental group

Description:

Participants in this arm undergo plasma exchange and take a reduced glucocorticoid dose.

Treatment:

Procedure: Plasma Exchange

Drug: Glucocorticoids [Reduced Dose]

No Plasma Exchange with Reduced-Dose Glucocorticoids

Active Comparator group

Description:

Participants in this arm do not undergo plasma exchange and take a reduced glucocorticoid dose.

Treatment:

Other: No Plasma Exchange

Drug: Glucocorticoids [Reduced Dose]