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

Study Overview
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Brief Summary
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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
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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; Plasma exchange - 7 exchanges and, either standard or low-dose glucocorticoids or No plasma exchange and, either standard or low-dose glucocorticoids All studies will receive standard remission-induction therapy with either cyclophosphamide or rituximab.

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

Conditions
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Granulomatosis With Polyangiitis (Wegener's) (GPA), Microscopic Polyangiitis (MPA)

Intervention / Treatment
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* Procedure: Plasma Exchange
* Other: No Plasma Exchange
* Drug: Glucocorticoids [Standard Dose]
* Drug: Glucocorticoids [Reduced Dose]


Participation Criteria
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Eligibility Criteria
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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: 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 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 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

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Plasma Exchange with Standard Glucocorticoids<br>Participants in this arm undergo plasma exchange and take a standard glucocorticoid dose. | Procedure: Plasma Exchange<br>* 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.<br>Drug: Glucocorticoids [Standard Dose]<br>* 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.<br>|
| Active Comparator: No Plasma Exchange with Standard Glucocorticoids<br>Participants in this arm do not undergo plasma exchange and take a standard glucocorticoid dose. | Other: No Plasma Exchange<br>* No plasma exchange.<br>Drug: Glucocorticoids [Standard Dose]<br>* 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.<br>|
| Experimental: Plasma Exchange with Reduced-Dose Glucocorticoids<br>Participants in this arm undergo plasma exchange and take a reduced glucocorticoid dose. | Procedure: Plasma Exchange<br>* 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.<br>Drug: Glucocorticoids [Reduced Dose]<br>* 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.<br>|
| Active Comparator: No Plasma Exchange with Reduced-Dose Glucocorticoids<br>Participants in this arm do not undergo plasma exchange and take a reduced glucocorticoid dose. | Other: No Plasma Exchange<br>* No plasma exchange.<br>Drug: Glucocorticoids [Reduced Dose]<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vasculitis, Granulomatosis with Polyangiitis, Microscopic Polyangiitis, Wegener's, ANCA-Associated Vasculitis, GPA, MPA, Treatment, Plasma exchange, Glucocorticoids, ANCA-Positive