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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00987389
Recruitment Status : Completed
First Posted : September 30, 2009
Results First Posted : May 26, 2020
Last Update Posted : May 26, 2020
Sponsor:
Collaborators:
Cambridge University Hospitals NHS Foundation Trust
University of Birmingham
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Information provided by (Responsible Party):
Peter Merkel, University of Pennsylvania

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 Other: No Plasma Exchange Drug: Glucocorticoids [Standard Dose] Drug: Glucocorticoids [Reduced Dose] 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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Layout table for study information
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

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Steroids Vasculitis

Arms and Interventions
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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.
 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.
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.


Outcome Measures
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Primary Outcome Measures :
  1. Composite of i) All-cause Mortality or ii) End-stage Renal Disease [ Time Frame: Time frame varied by subject: minimum of 1 year - maximum of 7 years ]
    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.


Secondary Outcome Measures :
  1. Number of Participants With Sustained Remission [ Time Frame: Time frame varied by subject: minimum of 1 year - maximum of 7 years ]
    Remission that occurs before 6 months, and lasts without a first relapse until at least 12 months after randomization

  2. Rate of Serious Infection Events [ Time Frame: Time frame varied by subject: minimum of 1 year - maximum of 7 years ]
    Serious infections defined as an infectious syndrome that requires intravenous antibiotics or hospitalization for treatment.

  3. Health-related Quality of Life Using the SF-36 Physical Composite [ Time Frame: 12 months ]
    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.

  4. Health-related Quality of Life Using the SF-36 Mental Composite [ Time Frame: 12 months ]
    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.

  5. Health-related Quality of Life Using the EQ-5D Index Descriptive System [ Time Frame: 12 months ]
    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.


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   15 Years and older   (Child, Adult, Older Adult)
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 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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00987389


Locations
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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
Layout table for investigator information
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
  Study Documents (Full-Text)

Documents provided by Peter Merkel, University of Pennsylvania:
Study Protocol and Statistical Analysis Plan  [PDF] November 19, 2015

More Information
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Additional Information:

Publications of Results:

Other Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Layout table for additonal information
Responsible Party: Peter Merkel, Professor, University of Pennsylvania
ClinicalTrials.gov Identifier: NCT00987389    
Obsolete Identifiers: NCT03919825
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    Key Record Dates
Results First Posted: May 26, 2020
Last Update Posted: May 26, 2020
Last Verified: May 2020
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:
Layout table for MeSH terms
Granulomatosis with Polyangiitis
Microscopic Polyangiitis
Vasculitis
Systemic Vasculitis
Vascular Diseases
Cardiovascular Diseases
Lung Diseases, Interstitial
Lung Diseases
Respiratory Tract Diseases
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Skin Diseases, Vascular
Skin Diseases
 Autoimmune Diseases
Immune System Diseases
Cerebral Small Vessel Diseases
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs