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

Phase 3

Completed

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

• Registration Number: NCT00987389
• Lead Sponsor: University of Pennsylvania

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.

Study Timeline

• Study First Submitted: 2009-09-23
• Study First Submitted QC: 2009-09-28
• Study First Posted: 2009-09-30
• Study Start: 2010-05
• Primary Completion: 2017-08
• Study Completion: 2017-08
• Results First Submitted: 2018-10-31
• Status Verified: 2020-05
• Results First Submitted QC: 2020-05-19
• Last Update Submitted: 2020-05-19
• Results First Posted: 2020-05-26
• Last Update Posted: 2020-05-26

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 704

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
Plasma Exchange with Standard Glucocorticoids	Plasma Exchange	Participants in this arm undergo plasma exchange and take a standard glucocorticoid dose.
Plasma Exchange with Standard Glucocorticoids	Glucocorticoids [Standard Dose]	Participants in this arm undergo plasma exchange and take a standard glucocorticoid dose.
Plasma Exchange with Reduced-Dose Glucocorticoids	Glucocorticoids [Reduced Dose]	Participants in this arm undergo plasma exchange and take a reduced glucocorticoid dose.
No Plasma Exchange with Standard Glucocorticoids	No Plasma Exchange	Participants in this arm do not undergo plasma exchange and take a standard glucocorticoid dose.
No Plasma Exchange with Standard Glucocorticoids	Glucocorticoids [Standard Dose]	Participants in this arm do not undergo plasma exchange and take a standard glucocorticoid dose.
Plasma Exchange with Reduced-Dose Glucocorticoids	Plasma Exchange	Participants in this arm undergo plasma exchange and take a reduced glucocorticoid dose.
No Plasma Exchange with Reduced-Dose Glucocorticoids	No Plasma Exchange	Participants in this arm do not undergo plasma exchange and take a reduced glucocorticoid dose.
No Plasma Exchange with Reduced-Dose Glucocorticoids	Glucocorticoids [Reduced Dose]	Participants in this arm do not undergo plasma exchange and take a reduced glucocorticoid dose.

Primary Outcome Measures

Name	Time	Method
Composite of i) All-cause Mortality or ii) End-stage Renal Disease	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

Name	Time	Method
Number of Participants With Sustained Remission	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
Health-related Quality of Life Using the SF-36 Physical Composite	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.
Health-related Quality of Life Using the SF-36 Mental Composite	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.
Rate of Serious Infection Events	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.
Health-related Quality of Life Using the EQ-5D Index Descriptive System	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.

Trial Locations

Locations (98)

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; 🇺🇸 Saint 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

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