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

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Granulomatosis With Polyangiitis (Wegener's) (GPA); Microscopic Polyangiitis (MPA)	Procedure: Plasma Exchange; Drug: Glucocorticoids	Phase 3

Detailed 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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	704 participants
Allocation:	Randomized
Intervention Model:	Factorial Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Plasma Exchange and Glucocorticoid Dosing in the Treatment of Anti-neutrophil Cytoplasm Antibody Associated Vasculitis: an International Randomized Controlled Trial
Actual Study Start Date :	May 2010
Actual Primary Completion Date :	August 2017
Actual Study Completion Date :	August 2017

Arms and Interventions

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Arm	Intervention/treatment
No Plasma Exchange; Participants in this arm do not undergo plasma exchange	Drug: Glucocorticoids; During the study, a standard glucocorticoids dose regimen will be compared to a reduced glucocorticoids dose regimen. All subjects' patients will receive the same glucocorticoids dose for the first two weeks then the dose will decrease following either a standard regimen or a reduced regimen.
Experimental: Plasma Exchange	Procedure: Plasma Exchange; Plasma exchange is a procedure whereby blood is taken from the body and separated by a machine into blood cells and plasma, which is the liquid part of blood. The plasma is discarded and the blood cells are returned to the body with a plasma substitute. Drug: Glucocorticoids; During the study, a standard glucocorticoids dose regimen will be compared to a reduced glucocorticoids dose regimen. All subjects' patients will receive the same glucocorticoids dose for the first two weeks then the dose will decrease following either a standard regimen or a reduced regimen.

Outcome Measures

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Primary Outcome Measures :

1. Composite of i) all-cause mortality or ii) End-stage renal disease [ Time Frame: 2 years after the final subject is enrolled ]

Secondary Outcome Measures :

1. Sustained remission [ Time Frame: 2 years after the final subject is enrolled ]
   Remission that occurs before 6 months, and lasts without a first relapse until at least 12 months after randomization
2. Rate of serious infections [ Time Frame: 12 months after first subject enrolled and at study end ]
3. Health-related quality of life using the SF-36 Physical Composite, Mental Composite and EQ-5D Index Score [ Time Frame: 12 months after study enrollment is completed ]

Eligibility Criteria

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Ages Eligible for Study:	15 Years and older (Child, Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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 with both:

     • 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 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
• Inability or unwillingness to comply with birth control/abstinence
• 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

Contacts and Locations

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  Show 98 Study Locations

Sponsors and Collaborators

University of Pennsylvania

Cambridge University Hospitals NHS Foundation Trust

University of Birmingham

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Investigators

Principal Investigator:	David Jayne, MD	Cambridge University Hospitals NHS Foundation Trust
Principal Investigator:	Peter Merkel, MD, MPH	University of Pennsylvania
Principal Investigator:	Michael Walsh, MD	McMaster University

More Information

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Additional Information:

Related Info 

Related Info 

Publications:

Walsh M, Merkel PA, Peh CA, Szpirt W, Guillevin L, Pusey CD, De Zoysa J, Ives N, Clark WF, Quillen K, Winters JL, Wheatley K, Jayne D; PEXIVAS Investigators. Plasma exchange and glucocorticoid dosing in the treatment of anti-neutrophil cytoplasm antibody associated vasculitis (PEXIVAS): protocol for a randomized controlled trial. Trials. 2013 Mar 14;14:73. doi: 10.1186/1745-6215-14-73.

Responsible Party:	Peter Merkel, Professor, University of Pennsylvania
ClinicalTrials.gov Identifier:	NCT00987389 History of Changes
Other Study ID Numbers:	PEXIVAS; R01FD00351604 ( Other Grant/Funding Number: Food and Drug Administration (FDA) ); 2009-013220-24 ( EudraCT Number )
First Posted:	September 30, 2009
Last Update Posted:	March 16, 2018
Last Verified:	March 2018

Keywords provided by Peter Merkel, University of Pennsylvania:

Vasculitis; Granulomatosis with Polyangiitis; Microscopic Polyangiitis; Wegener's; ANCA-Associated Vasculitis; GPA	MPA; Treatment; Plasma exchange; Glucocorticoids; ANCA-Positive

Additional relevant MeSH terms:

Vasculitis; Systemic Vasculitis; Granulomatosis with Polyangiitis; Microscopic Polyangiitis; Vascular Diseases; Cardiovascular Diseases; Lung Diseases, Interstitial; Lung Diseases; Respiratory Tract Diseases; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoimmune Diseases; Immune System Diseases	Cerebral Small Vessel Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Antibodies; Glucocorticoids; Immunologic Factors; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists