PEXIVAS

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

Research summary

Granulomatosis with polyangiitis (Wegener’s) (GPA) 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). The prevalence of AAV is estimated at 14 - 30 patients per 100 000 in England (1). Left untreated, AAV has a universally poor prognosis with mortality approaching 100% within 5 years (2). The introduction of treatment regimens based on cyclophosphamide (CYC) and glucocorticoids (GC) have transformed AAV from a rapidly fatal disease to one of chronic morbidity and reduced survival often preceded by end-stage renal disease (ESRD).

Plasma exchange (PLEX), 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. GC are a standard of care in the treatment of AAV. High doses of GC early in disease although undeniably 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 GC dosing.

There is a need for therapies with reduced toxicity while improving disease control. Defining the role of therapies that are already in use but that are invasive, expensive, but unproven is a priority in AAV research. PEXIVAS is a randomized controlled trial to test two interventions in a two-by-two factorial design (standard care and PLEX compared to standard care alone and a standard-dose GC compared to a low dose GC regimen) to address these issues. This trial will randomize patients with AAV in a two-by-two factorial design. Randomization to each intervention will be in a one-to-one ratio stratified by the other intervention. Patients will be randomized to receive either adjunctive PLEX or no PLEX and randomized to receive either a standard GC dose or a low GC dose. All patients will receive standard immunosuppressive induction therapy. The primary outcome of the trial will be the composite endpoint of all-cause mortality or end-stage renal disease.

clinicaltrials.gov

Main inclusion criteria

  • Patients must meet all of the following criteria:

  • New or previous relapsing clinical diagnosis of granulomatosis with polyangiitis (Wegener’s), or microscopic polyangiitis consistent with the Chapel-Hill consensus definitions (see 7.13.5) AND
  • Positive test, at any point in the subjects’ disease course, by ELISA, for proteinase 3-ANCA or myeloperoxidase-ANCA AND
  • Severe vasculitis defined by at least one of the following manifestations:
    • Renal involvement characterized by both of the following:
      • Evidence of glomerulonephritis by either of the following:
        • Renal biopsy demonstrating focal necrotizing glomerulonephritis or
        • Active urine sediment characterized by glomerular haematuria/cellular casts and proteinuria
      • An estimated glomerular filtration (eGFR) rate of <50 ml/min/1.73 m2. Patients known to have a stable eGFR <50 ml/min/1.73 m2 for greater than three months prior to enrollment are NOT eligible.
    • Pulmonary hemorrhage due to active vasculitis defined by the following:
      • A compatible chest x-ray or CT scan (diffuse pulmonary infiltrates)
      • AND
      • The absence of an alternative explanation for all pulmonary infiltrates (i.e. volume overload or pulmonary infection)
      • AND
      • 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) from less than 10g/dl
        • An increased diffusing capacity of carbon dioxide
  • Provision of informed consent by patient or a surrogate decision-maker. In some participating countries, permission has also been granted to use deferred consent for enrolling a patient until a legal representative becomes available to consent on their behalf. Please check your national regulations for further guidance.

Main exclusion criteria

Patients must have none of the following:

  • A diagnosis of vasculitis other than granulomatosis with polyangiitis (Wegener’s) or microscopic polyangiitis
  • A positive serum test for anti-glomerular basement membrane or a renal biopsy demonstrating linear glomerular immunoglobulin deposition
  • Receipt of dialysis for greater than 21 days immediately prior to randomization or prior renal transplant
  • Age <15 years. In centres that do not routinely treat patients <18 years or if no local investigator routinely treats patients <18 years, enrollment may be restricted to patients 18 years or older*
  • Pregnant 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 treatment with >1 dose of rituximab within the last 28 days
  • A comorbidity or condition that, in the opinion of the investigator, precludes the use of cyclophosphamide/rituximab, glucocorticoids, or plasma exchange or absolutely mandates the use of plasma exchange
  • Plasma exchange in 3 months prior to randomization

* Patients < 18 years of age will be excluded in Germany

Chief investigator

Prof Peter Merkel

Contact details

Senior Clinical Trials Coordinator: Dr Maria King

Telephone: 01223 596441 | Email: [email protected]