Clinical trial NCT00987389: Plasma Exchange and Glucocorticoids for Treatment of Anti-Neutrophil Cytoplasm Antibody (ANCA) - Associated Vasculitis
Official title: Plasma Exchange and Glucocorticoid Dosing in the Treatment of Anti-neutrophil Cytoplasm Antibody Associated Vasculitis: an International Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Granulomatosis With Polyangiitis (Wegener's) (GPA)
Microscopic Polyangiitis (MPA)
Keywords: Vasculitis
Granulomatosis with Polyangiitis
Microscopic Polyangiitis
Wegener's
ANCA-Associated Vasculitis
GPA
MPA
Treatment
Plasma exchange
Glucocorticoids
ANCA-Positive
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
Collaborators: name: Cambridge University Hospitals NHS Foundation Trust
name: University of Birmingham
name: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
First posted: 2009-09-30
Enrollment: 704
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Composite of i) All-cause Mortality or ii) End-stage Renal Disease
timeFrame: Time frame varied by subject: minimum of 1 year - maximum of 7 years
Secondary outcomes:
measure: Number of Participants With Sustained Remission
timeFrame: Time frame varied by subject: minimum of 1 year - maximum of 7 years
measure: Rate of Serious Infection Events
timeFrame: Time frame varied by subject: minimum of 1 year - maximum of 7 years
measure: Health-related Quality of Life Using the SF-36 Physical Composite
timeFrame: 12 months
measure: Health-related Quality of Life Using the SF-36 Mental Composite
timeFrame: 12 months
measure: Health-related Quality of Life Using the EQ-5D Index Descriptive System
timeFrame: 12 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Boston
country: United States
facility: Boston University School of Medicine
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Garran
country: Australia
facility: Canberra Hospital
state: Australian Capital Territory
city: Concord
country: Australia
facility: Concord Repatriation General Hospital
state: New South Wales
city: New Lambton Heights
country: Australia
facility: John Hunter Hospital,
state: New South Wales
city: Randwick
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: St. Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Nambour
country: Australia
facility: Nambour Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Flinders Medical Centre,
state: South Australia
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Fitzroy
country: Australia
facility: St Vincent's Hospital
state: Victoria
city: Geelong
country: Australia
facility: The Geelong Hospital
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Hospital
state: Victoria
city: Parkville
country: Australia
facility: The Royal Melbourne Hospital
state: Victoria
city: Fremantle,
country: Australia
facility: Fremantle Hospital,
state: Western Australia
city: Southport
country: Australia
facility: Gold Coast Hospital
city: Leuven
country: Belgium
facility: University Hospitals Leuven
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Vancouver
country: Canada
facility: St Paul's Hospital
state: British Columbia
city: Hamilton
country: Canada
facility: St Joseph's Hospital
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Toronto
country: Canada
facility: St Michael's Hospital
state: Ontario
city: Montreal
country: Canada
facility: Hopital Saint-Luc
state: Quebec
city: Prague
country: Czechia
facility: General Faculty Hospital
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Copenhagen
country: Denmark
facility: Herlev Hospital
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Holstebro
country: Denmark
facility: Holstebro Hospital and University of Aarhus
city: Boulogne-sur-Mer
country: France
facility: Centre Hospitalier de Boulogne
city: Brest
country: France
facility: CHRU Brest Hopital La Cavale Blanche
city: Brest
country: France
facility: CHU Brest
city: Caen
country: France
facility: CHU Caen - Nephrology Department
city: Clermont Ferrand
country: France
facility: CHU Clermont-Ferrand
city: Colmar
country: France
facility: Colmar Hospital - Nephrology
city: D'Angers
country: France
facility: CHU D'Angers
city: Grenoble
country: France
facility: Centre Hospitalier Universitaire de Grenoble
city: Metz
country: France
facility: Hopital Site Sainte Blandine
city: Mulhouse
country: France
facility: Centre Hospitalier de Mulhouse
city: Paris
country: France
facility: Hopital Bichat Claude Bernard
city: Paris
country: France
facility: Hopital Cochin
city: Paris
country: France
facility: Hopital Europeen Georges-Pompidou
city: Pringy
country: France
facility: Centre Hospitalier de la Region d'Annecy
city: Toulouse
country: France
facility: CHU De Toulouse-Hotel Dieu Saint Jacques
city: Tours
country: France
facility: CHU Hopital Bretonneau
city: Valenciennes
country: France
facility: Centre Hospitalier de Valenciennes
city: Thessaloniki
country: Greece
facility: Hippokration Hospital
city: Brescia
country: Italy
facility: University of Brescia
city: Parma
country: Italy
facility: Azienda Ospedaliero Universitaria di Parma
city: Tsukuba
country: Japan
facility: University of Tsukuba
state: Ibaraki
city: Kyoto
country: Japan
facility: Kyoto University Hospital
city: Miyazaki
country: Japan
facility: University of Miyazaki Hospital
city: Osaka
country: Japan
facility: Kitano Hospital
city: Tokyo
country: Japan
facility: Teikyo University Hospital
city: Tokyo
country: Japan
facility: Tokyo Metropolitan Geriatric Hospital
city: Mexico City
country: Mexico
facility: Instituto Nacional de Enfermedades Respiratorias
city: Takapuna
country: New Zealand
facility: North Shore Hospital
state: Auckland
city: Dunedin
country: New Zealand
facility: Dunedin Hospital
city: Hamilton
country: New Zealand
facility: Waikato Hospital
city: Tromsø
country: Norway
facility: University Hospital North Norway HF
city: Trondheim
country: Norway
facility: St Olavs Hospital, Trondheim University Hospital
city: Linkoping
country: Sweden
facility: Linkoping University Hospital
city: Malmo
country: Sweden
facility: Skane University Hospital
city: Stockholm
country: Sweden
facility: Karolinska Institute
city: Glasgow
country: United Kingdom
facility: Western Infirmary
state: Scotland
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
city: Brighton
country: United Kingdom
facility: Brighton and Sussex University Hospitals
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: Canterbury
country: United Kingdom
facility: Kent and Canterbury Hospital
city: Coventry
country: United Kingdom
facility: University Hospitals Coventry and Warwickshire NHS Trust
city: Edinburgh
country: United Kingdom
facility: Royal Infirmary of Edinburgh
city: Exeter
country: United Kingdom
facility: Royal Devon & Exeter Hospital (Wonford)
city: Leeds
country: United Kingdom
facility: St James's University Hospital
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital
city: London
country: United Kingdom
facility: Royal Free Hospital
city: London
country: United Kingdom
facility: The Royal London Hospital
city: London
country: United Kingdom
facility: St. George's Hospital
city: London
country: United Kingdom
facility: Hammersmith Hospital
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
city: Newcastle
country: United Kingdom
facility: Freeman Hospital
city: Oxford
country: United Kingdom
facility: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences
city: Oxford
country: United Kingdom
facility: Churchill Hospital
city: Preston
country: United Kingdom
facility: Royal Preston Hospital
city: Reading
country: United Kingdom
facility: Royal Berkshire Hospital, Reading
Study officials:
affiliation: Cambridge University Hospitals NHS Foundation Trust
name: David Jayne, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pennsylvania
name: Peter Merkel, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: McMaster University
name: Michael Walsh, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.