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

Microscopic Polyangiitis (MPA) Clinical Trial

— PEXIVAS  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00987389
• Other study ID #: PEXIVAS
• Secondary ID: R01FD00351604200
• Status: Completed
• Phase: Phase 3
• Start date: May 2010
• Est. completion date: August 2017

Study information

• Verified date: May 2020
• Source: University of Pennsylvania
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Other known NCT identifiers

• NCT03919825

Recruitment information / eligibility

• Status: Completed
• Enrollment: 704
• Est. completion date: August 2017
• Est. primary completion date: August 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 15 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Granulomatosis with Polyangiitis
• Granulomatosis With Polyangiitis (Wegener's) (GPA)
• Microscopic Polyangiitis
• Microscopic Polyangiitis (MPA)
• Systemic Vasculitis
• Vasculitis

Intervention

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.

Other:
• No Plasma Exchange
No plasma exchange.

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.
• 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.

Locations

Country	Name	City	State
Australia	Flinders Medical Centre,	Adelaide	South Australia
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Monash Medical Centre	Clayton	Victoria
Australia	Concord Repatriation General Hospital	Concord	New South Wales
Australia	St Vincent's Hospital	Fitzroy	Victoria
Australia	Fremantle Hospital,	Fremantle,	Western Australia
Australia	Canberra Hospital	Garran	Australian Capital Territory
Australia	The Geelong Hospital	Geelong	Victoria
Australia	Austin Hospital	Heidelberg	Victoria
Australia	Royal Brisbane and Women's Hospital	Herston	Queensland
Australia	Royal Hobart Hospital	Hobart	Tasmania
Australia	Nambour Hospital	Nambour	Queensland
Australia	John Hunter Hospital,	New Lambton Heights	New South Wales
Australia	The Royal Melbourne Hospital	Parkville	Victoria
Australia	Prince of Wales Hospital	Randwick	New South Wales
Australia	Gold Coast Hospital	Southport
Australia	Royal North Shore Hospital	St. Leonards	New South Wales
Australia	Princess Alexandra Hospital	Woolloongabba	Queensland
Belgium	University Hospitals Leuven	Leuven
Canada	University of Calgary	Calgary	Alberta
Canada	University of Alberta	Edmonton	Alberta
Canada	St Joseph's Hospital	Hamilton	Ontario
Canada	London Health Sciences Centre	London	Ontario
Canada	Hopital Saint-Luc	Montreal	Quebec
Canada	The Ottawa Hospital	Ottawa	Ontario
Canada	Mount Sinai Hospital	Toronto	Ontario
Canada	St Michael's Hospital	Toronto	Ontario
Canada	St Paul's Hospital	Vancouver	British Columbia
Czechia	General Faculty Hospital	Prague
Denmark	Aarhus University Hospital	Aarhus
Denmark	Herlev Hospital	Copenhagen
Denmark	Rigshospitalet	Copenhagen
Denmark	Holstebro Hospital and University of Aarhus	Holstebro
France	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
Greece	Hippokration Hospital	Thessaloniki
Italy	University of Brescia	Brescia
Italy	Azienda Ospedaliero Universitaria di Parma	Parma
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	University of Tsukuba	Tsukuba	Ibaraki
Mexico	Instituto Nacional de Enfermedades Respiratorias	Mexico City
New Zealand	Dunedin Hospital	Dunedin
New Zealand	Waikato Hospital	Hamilton
New Zealand	North Shore Hospital	Takapuna	Auckland
Norway	University Hospital North Norway HF	Tromsø
Norway	St Olavs Hospital, Trondheim University Hospital	Trondheim
Sweden	Linkoping University Hospital	Linkoping
Sweden	Skane University Hospital	Malmo
Sweden	Karolinska Institute	Stockholm
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	Western Infirmary	Glasgow	Scotland
United Kingdom	St James's University Hospital	Leeds
United Kingdom	Royal Liverpool University Hospital	Liverpool
United Kingdom	Hammersmith Hospital	London
United Kingdom	Royal Free Hospital	London
United Kingdom	St. George's Hospital	London
United Kingdom	The Royal London Hospital	London
United Kingdom	Manchester Royal Infirmary	Manchester
United Kingdom	Freeman Hospital	Newcastle
United Kingdom	Churchill Hospital	Oxford
United Kingdom	Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences	Oxford
United Kingdom	Royal Preston Hospital	Preston
United Kingdom	Royal Berkshire Hospital, Reading	Reading
United States	Boston University School of Medicine	Boston	Massachusetts
United States	University of North Carolina	Chapel Hill	North Carolina
United States	University of Virginia	Charlottesville	Virginia
United States	Cleveland Clinic	Cleveland	Ohio
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	Mayo Clinic	Rochester	Minnesota
United States	Washington University School of Medicine	Saint Louis	Missouri

Sponsors (4)

Lead Sponsor	Collaborator
University of Pennsylvania	Cambridge University Hospitals NHS Foundation Trust, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), University of Birmingham

Countries where clinical trial is conducted

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

References & Publications (2)

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. — View Citation

Walsh M, Merkel PA, Peh CA, Szpirt WM, Puéchal 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-Suárez LF, Ca — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

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