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

Plasma Exchange and Glucocorticoid Dosing in the Treatment of Anti-neutrophil Cytoplasm Antibody Associated Vasculitis: an International Randomized Controlled Trial

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.

Study Overview

• Status: Completed
• Conditions: Microscopic Polyangiitis (MPA); Granulomatosis With Polyangiitis (Wegener's) (GPA)
• Intervention / Treatment: Procedure: Plasma Exchange; Drug: Glucocorticoids [Standard Dose]; Other: No Plasma Exchange; Drug: Glucocorticoids [Reduced Dose]

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 Type: Interventional
• Enrollment (Actual): 704
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Southport, Australia
    • Gold Coast Hospital
  • Australian Capital Territory
    • Garran, Australian Capital Territory, Australia
      • Canberra Hospital
  • New South Wales
    • Concord, New South Wales, Australia
      • Concord Repatriation General Hospital
    • New Lambton Heights, New South Wales, Australia
      • John Hunter Hospital,
    • Randwick, New South Wales, Australia
      • Prince of Wales Hospital
    • St. Leonards, New South Wales, Australia
      • Royal North Shore Hospital
  • Queensland
    • Herston, Queensland, Australia
      • Royal Brisbane and Women'S Hospital
    • Nambour, Queensland, Australia
      • Nambour Hospital
    • Woolloongabba, Queensland, Australia
      • Princess Alexandra Hospital
  • South Australia
    • Adelaide, South Australia, Australia
      • Royal Adelaide Hospital
    • Adelaide, South Australia, Australia
      • Flinders Medical Centre,
  • Tasmania
    • Hobart, Tasmania, Australia
      • Royal Hobart Hospital
  • Victoria
    • Clayton, Victoria, Australia
      • Monash Medical Centre
    • Fitzroy, Victoria, Australia
      • St Vincent's Hospital
    • Geelong, Victoria, Australia
      • The Geelong Hospital
    • Heidelberg, Victoria, Australia
      • Austin Hospital
    • Parkville, Victoria, Australia
      • The Royal Melbourne Hospital
  • Western Australia
    • Fremantle,, Western Australia, Australia
      • Fremantle Hospital,
• Belgium
  • Leuven, Belgium
    • University Hospitals Leuven
• Canada
  • Alberta
    • Calgary, Alberta, Canada
      • University of Calgary
    • Edmonton, Alberta, Canada
      • University of Alberta
  • British Columbia
    • Vancouver, British Columbia, Canada
      • St Paul's Hospital
  • Ontario
    • Hamilton, Ontario, Canada
      • St Joseph's Hospital
    • London, Ontario, Canada
      • London Health Sciences Centre
    • Ottawa, Ontario, Canada
      • The Ottawa Hospital
    • Toronto, Ontario, Canada
      • Mount Sinai Hospital
    • Toronto, Ontario, Canada
      • St Michael's Hospital
  • Quebec
    • Montreal, Quebec, Canada, H2X 3J4
      • Hôpital Saint-Luc
• Czechia
  • Prague, Czechia
    • General Faculty Hospital
• Denmark
  • Aarhus, Denmark
    • Aarhus University Hospital
  • Copenhagen, Denmark
    • Rigshospitalet
  • Copenhagen, Denmark
    • Herlev Hospital
  • Holstebro, Denmark
    • Holstebro Hospital and University of Aarhus
• France
  • Boulogne-sur-Mer, France
    • Centre Hospitalier de Boulogne
  • Brest, France
    • Chu Brest
  • Brest, France
    • CHRU Brest Hopital La Cavale Blanche
  • Caen, France
    • CHU Caen - Nephrology Department
  • Clermont Ferrand, France
    • CHU Clermont-Ferrand
  • Colmar, France
    • Colmar Hospital - Nephrology
  • D'Angers, France
    • CHU d'Angers
  • Grenoble, France
    • Centre Hospitalier Universitaire de Grenoble
  • Metz, France
    • Hopital Site Sainte Blandine
  • Mulhouse, France
    • Centre Hospitalier de Mulhouse
  • Paris, France
    • Hôpital COCHIN
  • Paris, France
    • Hopital Europeen Georges-Pompidou
  • Paris, France
    • Hopital Bichat Claude Bernard
  • Pringy, France
    • Centre Hospitalier de la Région d'Annecy
  • Toulouse, France
    • CHU De Toulouse-Hotel Dieu Saint Jacques
  • Tours, France
    • CHU Hôpital Bretonneau
  • Valenciennes, France
    • Centre Hospitalier de Valenciennes
• Greece
  • Thessaloniki, Greece
    • Hippokration Hospital
• Italy
  • Brescia, Italy
    • University of Brescia
  • Parma, Italy
    • Azienda Ospedaliero Universitaria di Parma
• Japan
  • Kyoto, Japan, 606-8507
    • Kyoto University Hospital
  • Miyazaki, Japan
    • University of Miyazaki Hospital
  • Osaka, Japan
    • Kitano Hospital
  • Tokyo, Japan
    • Teikyo University Hospital
  • Tokyo, Japan
    • Tokyo Metropolitan Geriatric Hospital
  • Ibaraki
    • Tsukuba, Ibaraki, Japan, 305-8572
      • University of Tsukuba
• Mexico
  • Mexico City, Mexico
    • Instituto Nacional de Enfermedades Respiratorias
• New Zealand
  • Dunedin, New Zealand
    • Dunedin Hospital
  • Hamilton, New Zealand, 3204
    • Waikato Hospital
  • Auckland
    • Takapuna, Auckland, New Zealand
      • North Shore Hospital
• Norway
  • Tromsø, Norway
    • University Hospital North Norway HF
  • Trondheim, Norway
    • St Olavs Hospital, Trondheim University Hospital
• Sweden
  • Linkoping, Sweden
    • Linköping University Hospital
  • Malmo, Sweden
    • Skåne University Hospital
  • Stockholm, Sweden
    • Karolinska Institute
• United Kingdom
  • Aberdeen, United Kingdom, AB25 2
    • Aberdeen Royal Infirmary
  • Birmingham, United Kingdom, B15 2TQ
    • Queen Elizabeth Hospital
  • Brighton, United Kingdom, BN2 5BE
    • Brighton and Sussex University Hospitals
  • Cambridge, United Kingdom, CB22QQ
    • Addenbrooke's Hospital
  • Canterbury, United Kingdom
    • Kent and Canterbury Hospital
  • Coventry, United Kingdom, CV2 2DX
    • University Hospitals Coventry and Warwickshire NHS Trust
  • Edinburgh, United Kingdom, EH16 4SA
    • Royal Infirmary of Edinburgh
  • Exeter, United Kingdom
    • Royal Devon & Exeter Hospital (Wonford)
  • Leeds, United Kingdom
    • St James's University Hospital
  • Liverpool, United Kingdom, L7 8XP
    • Royal Liverpool University Hospital
  • London, United Kingdom, NW3 2QG
    • Royal Free Hospital
  • London, United Kingdom, W12 0HS
    • Hammersmith Hospital
  • London, United Kingdom, SW17 0QT
    • St. George's Hospital
  • London, United Kingdom, SE1 2PR
    • The Royal London Hospital
  • Manchester, United Kingdom
    • Manchester Royal Infirmary
  • Newcastle, United Kingdom
    • Freeman Hospital
  • Oxford, United Kingdom, OX3 7LJ
    • Churchill Hospital
  • Oxford, United Kingdom, OX3 7LD
    • Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences
  • Preston, United Kingdom, PR2 9HT
    • Royal Preston Hospital
  • Reading, United Kingdom, RG1 5AQ
    • Royal Berkshire Hospital, Reading
  • Scotland
    • Glasgow, Scotland, United Kingdom
      • Western Infirmary
• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston University School of Medicine
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States
      • Washington University School of Medicine
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh
  • Virginia
    • Charlottesville, Virginia, United States, 22904
      • University of Virginia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Plasma Exchange with Standard Glucocorticoids; Participants in this arm undergo plasma exchange and take a standard glucocorticoid dose.	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 [Standard Dose]; 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 a standard regimen.
Active Comparator: No Plasma Exchange with Standard Glucocorticoids; Participants in this arm do not undergo plasma exchange and take a standard glucocorticoid dose.	Drug: Glucocorticoids [Standard Dose]; 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 a standard regimen.; Other: No Plasma Exchange; No plasma exchange.
Experimental: Plasma Exchange with Reduced-Dose Glucocorticoids; Participants in this arm undergo plasma exchange and take a reduced glucocorticoid dose.	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 [Reduced Dose]; 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 a reduced regimen.
Active Comparator: No Plasma Exchange with Reduced-Dose Glucocorticoids; Participants in this arm do not undergo plasma exchange and take a reduced glucocorticoid dose.	Other: No Plasma Exchange; No plasma exchange.; Drug: Glucocorticoids [Reduced Dose]; 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 a reduced regimen.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of i) All-cause Mortality or ii) End-stage Renal Disease	The primary outcome was a composite of death from any cause or end-stage renal disease (ESRD), defined as ≥12 continuous weeks of renal replacement therapy.	Time frame varied by subject: minimum of 1 year - maximum of 7 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Sustained Remission	Remission that occurs before 6 months, and lasts without a first relapse until at least 12 months after randomization	Time frame varied by subject: minimum of 1 year - maximum of 7 years
Rate of Serious Infection Events	Serious infections defined as an infectious syndrome that requires intravenous antibiotics or hospitalization for treatment.	Time frame varied by subject: minimum of 1 year - maximum of 7 years
Health-related Quality of Life Using the SF-36 Physical Composite	Quality of life was measured using the 36-item Short Form (SF-36) physical composite scores. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.	12 months
Health-related Quality of Life Using the SF-36 Mental Composite	Quality of life was measured using the 36-item Short Form (SF-36) mental composite scores. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.	12 months
Health-related Quality of Life Using the EQ-5D Index Descriptive System	EuroQoL-5 Dimensions consist of 2 elements: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D descriptive system comprised of following 5 dimensions: 1.Mobility, 2.Self-Care, 3.Usual Activities, 4.Pain/Discomfort and 5.Anxiety/Depression. Each of these 5 dimensions has 5 levels: 1: no problems; 2: slight problems; 3: moderate problems; 4: severe problems; 5: Unable to do. The digits for each of 5 dimensions were combined in a 5-digit number describing the participant's health state: e.g. state 11111 indicates no problem on any of the 5 dimensions. Health state index scores generally range from less than 0 (where 0 is a health state equivalent to death; negative values are valued as worse than death) to 1 (perfect health), with higher scores indicating higher health utility.	12 months

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Collaborators: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); Cambridge University Hospitals NHS Foundation Trust; University of Birmingham
• Investigators: Principal Investigator: Peter Merkel, MD, MPH, University of Pennsylvania; Principal Investigator: David Jayne, MD, Cambridge University Hospitals NHS Foundation Trust; Principal Investigator: Michael Walsh, MD, McMaster University

Publications and helpful links

General 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.
• Walsh M, Merkel PA, Peh CA, Szpirt WM, Puechal X, Fujimoto S, Hawley CM, Khalidi N, Flossmann O, Wald R, Girard LP, Levin A, Gregorini G, Harper L, Clark WF, Pagnoux C, Specks U, Smyth L, Tesar V, Ito-Ihara T, de Zoysa JR, Szczeklik W, Flores-Suarez LF, Carette S, Guillevin L, Pusey CD, Casian AL, Brezina B, Mazzetti A, McAlear CA, Broadhurst E, Reidlinger D, Mehta S, Ives N, Jayne DRW; PEXIVAS Investigators. Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis. N Engl J Med. 2020 Feb 13;382(7):622-631. doi: 10.1056/NEJMoa1803537.
• Jayne D, Walsh M, Merkel PA, Peh CA, Szpirt W, Puechal X, Fujimoto S, Hawley C, Khalidi N, Jones R, Flossmann O, Wald R, Girard L, Levin A, Gregorini G, Harper L, Clark W, Pagnoux C, Specks U, Smyth L, Ito-Ihara T, de Zoysa J, Brezina B, Mazzetti A, McAlear CA, Reidlinger D, Mehta S, Ives N, Brettell EA, Jarrett H, Wheatley K, Broadhurst E, Casian A, Pusey CD. Plasma exchange and glucocorticoids to delay death or end-stage renal disease in anti-neutrophil cytoplasm antibody-associated vasculitis: PEXIVAS non-inferiority factorial RCT. Health Technol Assess. 2022 Sep;26(38):1-60. doi: 10.3310/PNXB5040.

Helpful Links

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Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2010
• Primary Completion (Actual): August 1, 2017
• Study Completion (Actual): August 1, 2017

Study Registration Dates

• First Submitted: September 23, 2009
• First Submitted That Met QC Criteria: September 28, 2009
• First Posted (Estimate): September 30, 2009

Study Record Updates

• Last Update Posted (Actual): May 26, 2020
• Last Update Submitted That Met QC Criteria: May 19, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: Treatment; Glucocorticoids; Vasculitis; Granulomatosis with Polyangiitis; Wegener's; MPA; GPA; Plasma exchange; ANCA-Associated Vasculitis; Microscopic Polyangiitis; ANCA-Positive
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Respiratory Tract Diseases; Immune System Diseases; Autoimmune Diseases; Lung Diseases; Lung Diseases, Interstitial; Cerebral Small Vessel Diseases; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Vasculitis; Granulomatosis with Polyangiitis; Microscopic Polyangiitis; Systemic Vasculitis; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Glucocorticoids
• Other Study ID Numbers: PEXIVAS; R01FD00351604 (Other Grant/Funding Number: Food and Drug Administration (FDA)); 2009-013220-24 (EudraCT Number)