Granulomatosis With Polyangiitis (Wegener's) (GPA), Microscopic Polyangiitis (MPA)
Conditions
Keywords
Vasculitis, Granulomatosis with Polyangiitis, Microscopic Polyangiitis, Wegener's, ANCA-Associated Vasculitis, GPA, MPA, Treatment, Plasma exchange, Glucocorticoids, ANCA-Positive
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.
Interventions
PROCEDUREPlasma 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.
OTHERNo Plasma Exchange
No plasma exchange.
DRUGGlucocorticoids [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.
DRUGGlucocorticoids [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.
Sponsors
Cambridge University Hospitals NHS Foundation Trust
University of Birmingham
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
15 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 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. |
| 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. |
Countries
Australia, Belgium, Canada, Czechia, Denmark, France, Greece, Italy, Japan, Mexico, New Zealand, Norway, Sweden, United Kingdom, United States
Participant flow
Pre-assignment details
704 subjects were enrolled into the study and randomized to either plasma exchange or no plasma exchange, and randomized to receive either standard dose GC or reduced dose GC.
Participants by arm
| Arm | Count |
|---|---|
| Plasma Exchange 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. | 352 |
| No Plasma Exchange Participants in this arm do not undergo plasma exchange. | 352 |
| Total | 704 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Ineligible | 0 | 3 | 0 | 0 |
| Overall Study | Lost to Follow-up | 4 | 1 | 3 | 1 |
| Overall Study | Multiple different reasons | 1 | 0 | 3 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 3 | 2 | 1 |
| Overall Study | Withdrawn from Treatment | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Plasma Exchange | Total | No Plasma Exchange |
|---|---|---|---|
| Age, Continuous | 62.8 years STANDARD_DEVIATION 14.4 | 63.2 years STANDARD_DEVIATION 14 | 63.5 years STANDARD_DEVIATION 13.7 |
| ANCA Binding Specificity: MPO | 209 Participants | 418 Participants | 209 Participants |
| ANCA Binding Specificity: PR3 | 143 Participants | 286 Participants | 143 Participants |
| Race/Ethnicity, Customized Arab | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black African | 4 Participants | 6 Participants | 2 Participants |
| Race/Ethnicity, Customized Chinese | 1 Participants | 6 Participants | 5 Participants |
| Race/Ethnicity, Customized Coloured African | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized European | 281 Participants | 558 Participants | 277 Participants |
| Race/Ethnicity, Customized Japanese | 6 Participants | 12 Participants | 6 Participants |
| Race/Ethnicity, Customized Latin America | 5 Participants | 10 Participants | 5 Participants |
| Race/Ethnicity, Customized Missing | 3 Participants | 4 Participants | 1 Participants |
| Race/Ethnicity, Customized Native N/S American or Aborigine | 16 Participants | 23 Participants | 7 Participants |
| Race/Ethnicity, Customized Other | 24 Participants | 52 Participants | 28 Participants |
| Race/Ethnicity, Customized Other Asian | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Other Black | 5 Participants | 7 Participants | 2 Participants |
| Race/Ethnicity, Customized South Asian | 7 Participants | 22 Participants | 15 Participants |
| Region of Enrollment Australia | 44 Participants | 94 Participants | 50 Participants |
| Region of Enrollment Belgium | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment Canada | 97 Participants | 191 Participants | 94 Participants |
| Region of Enrollment Czechia | 7 Participants | 10 Participants | 3 Participants |
| Region of Enrollment Denmark | 25 Participants | 57 Participants | 32 Participants |
| Region of Enrollment France | 21 Participants | 52 Participants | 31 Participants |
| Region of Enrollment Italy | 18 Participants | 26 Participants | 8 Participants |
| Region of Enrollment Japan | 6 Participants | 12 Participants | 6 Participants |
| Region of Enrollment Mexico | 4 Participants | 7 Participants | 3 Participants |
| Region of Enrollment New Zealand | 6 Participants | 10 Participants | 4 Participants |
| Region of Enrollment Norway | 0 Participants | 8 Participants | 8 Participants |
| Region of Enrollment Poland | 5 Participants | 7 Participants | 2 Participants |
| Region of Enrollment Spain | 1 Participants | 2 Participants | 1 Participants |
| Region of Enrollment Sweden | 5 Participants | 9 Participants | 4 Participants |
| Region of Enrollment United Kingdom | 88 Participants | 179 Participants | 91 Participants |
| Region of Enrollment United States | 24 Participants | 39 Participants | 15 Participants |
| Severity of Renal Disease at Presentation: Creatinine <500umol/min | 251 Participants | 499 Participants | 248 Participants |
| Severity of Renal Disease at Presentation: Requiring Dialysis or Creatinine >=500umol/min | 101 Participants | 205 Participants | 104 Participants |
| Sex: Female, Male Female | 149 Participants | 307 Participants | 158 Participants |
| Sex: Female, Male Male | 203 Participants | 397 Participants | 194 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 46 / 352 | 53 / 352 |
| other Total, other adverse events | 0 / 352 | 0 / 352 |
| serious Total, serious adverse events | 225 / 352 | 224 / 352 |
Outcome results
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: Time frame varied by subject: minimum of 1 year - maximum of 7 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Plasma Exchange | Composite of i) All-cause Mortality or ii) End-stage Renal Disease | 100 Participants |
| No Plasma Exchange | Composite of i) All-cause Mortality or ii) End-stage Renal Disease | 109 Participants |
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.
Time frame: 12 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Plasma Exchange | Health-related Quality of Life Using the EQ-5D Index Descriptive System | 0.79 score on a scale |
| No Plasma Exchange | Health-related Quality of Life Using the EQ-5D Index Descriptive System | 0.77 score on a scale |
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.
Time frame: 12 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Plasma Exchange | Health-related Quality of Life Using the SF-36 Mental Composite | 51.94 score on a scale |
| No Plasma Exchange | Health-related Quality of Life Using the SF-36 Mental Composite | 51.40 score on a scale |
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.
Time frame: 12 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Plasma Exchange | Health-related Quality of Life Using the SF-36 Physical Composite | 39.04 units on a scale |
| No Plasma Exchange | Health-related Quality of Life Using the SF-36 Physical Composite | 37.96 units on a scale |
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: Time frame varied by subject: minimum of 1 year - maximum of 7 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Plasma Exchange | Number of Participants With Sustained Remission | 200 Participants |
| No Plasma Exchange | Number of Participants With Sustained Remission | 197 Participants |
Secondary
Rate of Serious Infection Events
Serious infections defined as an infectious syndrome that requires intravenous antibiotics or hospitalization for treatment.
Time frame: Time frame varied by subject: minimum of 1 year - maximum of 7 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Plasma Exchange | Rate of Serious Infection Events | 145 events |
| No Plasma Exchange | Rate of Serious Infection Events | 132 events |