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

NCT ID: NCT00987389

Last Updated: 2020-05-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 704 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-05-31
• Study Completion Date: 2017-08-31

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.

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.

Conditions

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Plasma Exchange with Standard Glucocorticoids

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

Group Type: EXPERIMENTAL

Plasma Exchange

Intervention Type: PROCEDURE

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.

Glucocorticoids [Standard Dose]

Intervention Type: DRUG

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.

No Plasma Exchange with Standard Glucocorticoids

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

Group Type: ACTIVE_COMPARATOR

No Plasma Exchange

Intervention Type: OTHER

No plasma exchange.

Glucocorticoids [Standard Dose]

Intervention Type: DRUG

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.

Plasma Exchange with Reduced-Dose Glucocorticoids

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

Group Type: EXPERIMENTAL

Plasma Exchange

Intervention Type: PROCEDURE

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.

Glucocorticoids [Reduced Dose]

Intervention Type: DRUG

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.

No Plasma Exchange with Reduced-Dose Glucocorticoids

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

Group Type: ACTIVE_COMPARATOR

No Plasma Exchange

Intervention Type: OTHER

No plasma exchange.

Glucocorticoids [Reduced Dose]

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: PROCEDURE

No Plasma Exchange

No plasma exchange.

Intervention Type: OTHER

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.

Intervention Type: 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.

Intervention Type: DRUG

Eligibility 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 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

• Minimum Eligible Age: 15 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Cambridge University Hospitals NHS Foundation Trust

OTHER

Sponsor Role: collaborator

University of Birmingham

OTHER

Sponsor Role: collaborator

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

NIH

Sponsor Role: collaborator

University of Pennsylvania

OTHER

Sponsor Role: lead

Responsible Party

Peter Merkel

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

David Jayne, MD

Role: PRINCIPAL_INVESTIGATOR

Cambridge University Hospitals NHS Foundation Trust

Peter Merkel, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

University of Pennsylvania

Michael Walsh, MD

Role: PRINCIPAL_INVESTIGATOR

McMaster University

Locations

Cedars-Sinai Medical Center

Los Angeles, California, United States

Boston University School of Medicine

Boston, Massachusetts, United States

Mayo Clinic

Rochester, Minnesota, United States

Washington University School of Medicine

St Louis, Missouri, United States

University of North Carolina

Chapel Hill, North Carolina, United States

Cleveland Clinic

Cleveland, Ohio, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

University of Pittsburgh

Pittsburgh, Pennsylvania, United States

University of Virginia

Charlottesville, Virginia, United States

Canberra Hospital

Garran, Australian Capital Territory, Australia

Concord Repatriation General Hospital

Concord, New South Wales, Australia

John Hunter Hospital,

New Lambton Heights, New South Wales, Australia

Prince of Wales Hospital

Randwick, New South Wales, Australia

Royal North Shore Hospital

St Leonards, New South Wales, Australia

Royal Brisbane and Women's Hospital

Herston, Queensland, Australia

Nambour Hospital

Nambour, Queensland, Australia

Princess Alexandra Hospital

Woolloongabba, Queensland, Australia

Flinders Medical Centre,

Adelaide, South Australia, Australia

Royal Adelaide Hospital

Adelaide, South Australia, Australia

Royal Hobart Hospital

Hobart, Tasmania, Australia

Monash Medical Centre

Clayton, Victoria, Australia

St Vincent's Hospital

Fitzroy, Victoria, Australia

The Geelong Hospital

Geelong, Victoria, Australia

Austin Hospital

Heidelberg, Victoria, Australia

The Royal Melbourne Hospital

Parkville, Victoria, Australia

Fremantle Hospital,

Fremantle, Western Australia, Australia

Gold Coast Hospital

Southport, , Australia

University Hospitals Leuven

Leuven, , Belgium

University of Calgary

Calgary, Alberta, Canada

University of Alberta

Edmonton, Alberta, Canada

St Paul's Hospital

Vancouver, British Columbia, Canada

St Joseph's Hospital

Hamilton, Ontario, Canada

London Health Sciences Centre

London, Ontario, Canada

The Ottawa Hospital

Ottawa, Ontario, Canada

Mount Sinai Hospital

Toronto, Ontario, Canada

St Michael's Hospital

Toronto, Ontario, Canada

Hopital Saint-Luc

Montreal, Quebec, Canada

General Faculty Hospital

Prague, , Czechia

Aarhus University Hospital

Aarhus, , Denmark

Herlev Hospital

Copenhagen, , Denmark

Rigshospitalet

Copenhagen, , Denmark

Holstebro Hospital and University of Aarhus

Holstebro, , Denmark

Centre Hospitalier de Boulogne

Boulogne-sur-Mer, , France

CHRU Brest Hopital La Cavale Blanche

Brest, , France

CHU Brest

Brest, , France

CHU Caen - Nephrology Department

Caen, , France

CHU Clermont-Ferrand

Clermont-Ferrand, , France

Colmar Hospital - Nephrology

Colmar, , France

CHU D'Angers

D'Angers, , France

Centre Hospitalier Universitaire de Grenoble

Grenoble, , France

Hopital Site Sainte Blandine

Metz, , France

Centre Hospitalier de Mulhouse

Mulhouse, , France

Hopital Bichat Claude Bernard

Paris, , France

Hopital Cochin

Paris, , France

Hopital Europeen Georges-Pompidou

Paris, , France

Centre Hospitalier de la Region d'Annecy

Pringy, , France

CHU De Toulouse-Hotel Dieu Saint Jacques

Toulouse, , France

CHU Hopital Bretonneau

Tours, , France

Centre Hospitalier de Valenciennes

Valenciennes, , France

Hippokration Hospital

Thessaloniki, , Greece

University of Brescia

Brescia, , Italy

Azienda Ospedaliero Universitaria di Parma

Parma, , Italy

University of Tsukuba

Tsukuba, Ibaraki, Japan

Kyoto University Hospital

Kyoto, , Japan

University of Miyazaki Hospital

Miyazaki, , Japan

Kitano Hospital

Osaka, , Japan

Teikyo University Hospital

Tokyo, , Japan

Tokyo Metropolitan Geriatric Hospital

Tokyo, , Japan

Instituto Nacional de Enfermedades Respiratorias

Mexico City, , Mexico

North Shore Hospital

Takapuna, Auckland, New Zealand

Dunedin Hospital

Dunedin, , New Zealand

Waikato Hospital

Hamilton, , New Zealand

University Hospital North Norway HF

Tromsø, , Norway

St Olavs Hospital, Trondheim University Hospital

Trondheim, , Norway

Linkoping University Hospital

Linköping, , Sweden

Skane University Hospital

Malmo, , Sweden

Karolinska Institute

Stockholm, , Sweden

Western Infirmary

Glasgow, Scotland, United Kingdom

Aberdeen Royal Infirmary

Aberdeen, , United Kingdom

Queen Elizabeth Hospital

Birmingham, , United Kingdom

Brighton and Sussex University Hospitals

Brighton, , United Kingdom

Addenbrooke's Hospital

Cambridge, , United Kingdom

Kent and Canterbury Hospital

Canterbury, , United Kingdom

University Hospitals Coventry and Warwickshire NHS Trust

Coventry, , United Kingdom

Royal Infirmary of Edinburgh

Edinburgh, , United Kingdom

Royal Devon & Exeter Hospital (Wonford)

Exeter, , United Kingdom

St James's University Hospital

Leeds, , United Kingdom

Royal Liverpool University Hospital

Liverpool, , United Kingdom

Royal Free Hospital

London, , United Kingdom

The Royal London Hospital

London, , United Kingdom

St. George's Hospital

London, , United Kingdom

Hammersmith Hospital

London, , United Kingdom

Manchester Royal Infirmary

Manchester, , United Kingdom

Freeman Hospital

Newcastle, , United Kingdom

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences

Oxford, , United Kingdom

Churchill Hospital

Oxford, , United Kingdom

Royal Preston Hospital

Preston, , United Kingdom

Royal Berkshire Hospital, Reading

Reading, , United Kingdom

Countries

United States; Australia; Belgium; Canada; Czechia; Denmark; France; Greece; Italy; Japan; Mexico; New Zealand; Norway; Sweden; United Kingdom

References

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.

Reference Type: BACKGROUND

PMID: 23497590 (View on PubMed)

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.

Reference Type: RESULT

PMID: 32053298 (View on PubMed)

Fussner LA, Flores-Suarez LF, Cartin-Ceba R, Specks U, Cox PG, Jayne DRW, Merkel PA, Walsh M; PEXIVAS Investigators. Alveolar Hemorrhage in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Results of an International Randomized Controlled Trial (PEXIVAS). Am J Respir Crit Care Med. 2024 May 1;209(9):1141-1151. doi: 10.1164/rccm.202308-1426OC.

Reference Type: DERIVED

PMID: 38346237 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 36155131 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Related Links

http://www.rarediseasesnetwork.org/vcrc

Related Info

http://www.vasculitis.org/

Related Info

Other Identifiers

R01FD00351604

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

2009-013220-24

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

PEXIVAS

Identifier Type: -

Identifier Source: org_study_id

NCT03919825

Identifier Type: -

Identifier Source: nct_alias