Clinical trial NCT00987389
Conditions: Granulomatosis With Polyangiitis (Wegener's) (GPA) Microscopic Polyangiitis (MPA)
Keywords: Vasculitis Granulomatosis with Polyangiitis Microscopic Polyangiitis Wegener's ANCA-Associated Vasculitis GPA MPA Treatment Plasma exchange Glucocorticoids ANCA-Positive
Sponsor: University of Pennsylvania
Start date: 2010-05-01; Completion date: 2017-08-01
Enrollment: 704 participants; Allocation: RANDOMIZED; Intervention model: FACTORIAL

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.

Arms: arm 1: Participants in this arm undergo plasma exchange and take a standard glucocorticoid dose. arm 2: Participants in this arm do not undergo plasma exchange and take a standard glucocorticoid dose. arm 3: Participants in this arm undergo plasma exchange and take a reduced glucocorticoid dose. arm 4: Participants in this arm do not undergo plasma exchange and take a reduced glucocorticoid dose.
Interventions: intervention 1: Plasma Exchange intervention 2: No Plasma Exchange intervention 3: Glucocorticoids [Standard Dose] intervention 4: Glucocorticoids [Reduced Dose]
Intervention descriptions: intervention 1: 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. intervention 2: No plasma exchange. intervention 3: 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. intervention 4: 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.

Protocol documents:
Prot_SAP_000.pdf: 
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Plasma exchange and glucocorticoid dosing in anti-neutrophil 
cytoplasm antibody associated vasculitis: a randomized controlled 
trial. PEXIVAS 
Short title: PEXIVAS 
 
Protocol Version: 3.1   
 
EUDRACT number: 2009-013220-24 
ISRCTN number: ISRCTN07757494 
Clinicaltrials.gov registration number: NCT00987389 
 
Trial Sponsor: Cambridge University Hospitals NHS Foundation Trust, UK 
 
Data Management and Analysis Centre: Birmingham Clinical Trials Unit (BCTU), UK 
 
 
PEXIVAS is a joint venture of the European Vasculitis Study Group (EUVAS) and the 
Vasculitis Clinical Research Consortium (VCRC). 
 
 
Funding:  
National Institutes of Health Research (UK): Number, HTA 08/56/04 
Food and Drug Administration/National Institutes of Health (USA): FDA R01 FD003516 and 
the National Institutes of Health (USA) - National Institute of Arthritis and Musculoskeletal and 
Skin Diseases: U54 AR0573319  
National Health and Medical Research Council (Australia): 626939 
Canadian Institutes of Health Research (Canada): 211079  
 
 
 
 
 
 
 
 
  
 
 
 
 


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PEXIVAS Trial Management Group 
 
Chief Investigators 
 
 
 
 
 
Clinical Trials 
Dr. David Jayne 
 
 
 
 
             Professor Keith Wheatley 
Cambridge University Hospitals NHS Foundation Trust              CRUK Clinical Trials Unit 
dj106@cam.ac.uk 
 
 
 
 
 
Tel: 0121 415 9119 
 
Professor Peter Merkel                                                                    k.wheatley@bham.ac.uk 
University of Pennsylvania 
pmerkel@upenn.edu 
 
 
 
 
Dr. Michael Walsh 
 
 
 
 
 
Statistics 
McMaster University Health Science Centre 
 
 
Ms. Natalie Ives 
lastwalsh1975@gmail.com 
 
 
                          University of Birmingham  
 
 
                                                                              Clinical Trials Unit (BCTU) 
 
 
                                                                   
 
Tel: 0121 415 9113 
                                                                         
 
 
n.j.ives@bham.ac.uk 
 
PEXIVAS Study Offices 
For general queries about the study and for information on site set-up: 
Europe 
United States of 
America 
Canada 
Australasia 
Biljana Brezina & Elizabeth 
Broadhurst 
Vasculitis Research Office, Box 246 
Addenbrooke’s Hospital 
Hills Road 
Cambridge 
CB2 0QQ 
United Kingdom 
 
Tel: +44(0) 1223 256731 
Fax: +44 (0) 1223586767 
Email:  
add-tr.pexivastrial@nhs.net 
Carol A. McAlear 
Vasculitis Center,  
University of 
Pennsylvania 
 
Tel: +00 781 3214567 
Email: 
cmcalear@upenn.edu 
 
Dr. Michael Walsh 
Dept of Clinical 
Epidemiology & 
Biostatistics & Medicine 
Room 2C9, 1200 West St 
Main 
McMaster University 
Health Science Centre, 
Hamilton 
Ontario, L8N 3Z5 
Canada 
 
Tel: + 1 905 522 1155  
ext 35016  
Fax: 905.521.6153 
Email: 
lastwalsh1975@gmail.com 
 
Dr. Chen Au Peh  
Australasian Kidney Trials Network 
University of Queensland 
Level 1, Building 33 
Princess Alexandra Hospital 
Ipswich Rd, Woolloongabba 
QLD 4102, Australia  
 
Telephone: +61 732402625 
E-mail:  
chen.peh@adelaide.edu.au 
For queries about collection of data and data analysis: 
Birmingham Clinical Trials Unit (BCTU), School of Health & Population Sciences, College of Medical & 
Dental Sciences, Public Health Building,, University of Birmingham, Edgbaston, Birmingham B15 2TT, 
United Kingdom 
Tel: 0121 415 9100 (answering machine outside office hours); Fax: 0121 415 9135 
 
Renal Trial Coordinator 
Mrs Elizabeth Brettell +44 (0) 121 415 9130 e.a.brettell@bham.ac.uk 
 
 
Statistician 
Ms. Natalie Ives 
+44 (0) 121 415 9113 n.j.ives@bham.ac.uk 
 
Randomisation 
Internet: https://www.trials.bham.ac.uk/PEXIVAS 
Telephone: 0800 953 0274 (toll free in UK, available 9am to 5pm UK time) 
Or +44 (0)121 415 9137 (from outside the UK, available 9am to 5pm UK time) 


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1 
Protocol Synopsis 
 
Title 
Plasma exchange and glucocorticoid dosing in anti-neutrophil cytoplasm 
antibody associated vasculitis: a randomized controlled trial. PEXIVAS 
Short Title 
PEXIVAS 
Clinical Phase 
III 
Principal 
Investigators 
David Jayne 
Peter A. Merkel 
Michael Walsh 
Trial Sponsor 
Cambridge University Hospitals NHS Foundation Trust 
 
Sample Size 
700 participants 
Accrual Period 
78  months 
Study Duration 
90  months 
Study Design 
Multi-centre, international, open label, factorial design, randomized control 
trial in severe ANCA-associated vasculitis (AAV). Seven  hundred 
participants will be randomized, 1:1, to receive adjunctive plasma exchange 
(PLEX) in addition to standard immunosuppressive therapy and 
glucocorticoids (GC) or standard immunosuppressive therapy and GC 
without PLEX. The same 700 patients will be randomized, 1:1, to receive 
reduced-dose GC taper or standard-dose GC taper. There will be a minimum 
duration of follow-up of 1 year. 
Primary Study 
Objectives 
1. To determine the efficacy of PLEX in addition to 
immunosuppressive therapy and GC in reducing death and end-stage 
renal disease (ESRD) 
2. To determine the non-inferiority of a reduced-dose GC regimen in 
reducing death and ESRD 
Primary Outcome 
Measures 
 
Composite of i) all-cause mortality or ii) End-stage renal disease 
Secondary 
Objectives 
For both of i) PLEX in addition to immunosuppressive therapy and GC 
compared to immunosuppressive therapy and GC alone; and ii) reduced-
dose GC compared to standard-dose GC: 
1. To determine the effect on disease activity 
2. To determine the effect on mortality 
3. To determine the effect on ESRD 
4. To determine safety 
5. To determine effects on health related quality of life  
 


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Secondary 
Outcome 
Measures 
1. Sustained Remission  
2. All-cause mortality 
3. ESRD 
4. Serious Adverse Events 
5. Serious infections 
6. Medical Outcomes Survey Short Form – 36 (SF-36) 
7. EuroQoL EQ5D Index Score 
 
 
Exploratory 
Objectives 
For each of i) PLEX in addition to immunosuppressive therapy and GC 
compared to immunosuppressive therapy and GC alone; and ii) reduced-
dose of GC compared to standard-dose GC: 
1. To determine the cost-effectiveness 
2. To determine the effects on measures of disease-related damage 
3. To determine the effects on long-term renal function 
Exploratory 
Outcome 
Measures 
1. Incremental cost-effectiveness ratio 
2. Combined Damage Assessment Index (CDA) 
3. Estimated glomerular filtration rate (eGFR) 
 
Inclusion Criteria 
1. New or previous relapsing clinical diagnosis of granulomatosis with 
polyangiitis (Wegener’s) or microscopic polyangiitis consistent with 
the Chapel-Hill consensus definitions  
AND 
2. Positive test, at any point in the subjects’s disease course, by ELISA, 
for proteinase 3-ANCA or myeloperoxidase-ANCA  
AND 
3. Severe vasculitis defined by at least one of the following: 
a. Renal involvement with both:  
i. Renal biopsy demonstrating focal necrotizing 
glomerulonephritis or active urine sediment 
characterized by glomerular haematuria or red cell 
casts and proteinuria  
AND 
ii. eGFR <50 ml/min/1.73 m2. Patients known to have a 
stable eGFR <50 ml/min/1.73 m2 for greater than 
three months prior to enrollment are NOT eligible. 
b. Pulmonary hemorrhage due to active vasculitis defined by: 
i. A compatible chest x-ray or CT scan (diffuse 
pulmonary infiltrates)  
AND 
ii. The absence of an alternative explanation for all 
pulmonary infiltrates (e.g. volume overload or 
pulmonary infection)  
AND 
iii. At least one of the following: 


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1. Evidence of alveolar hemorrhage on 
bronchoscopic examination or increasingly 
bloody returns with bronchoalveolar lavage 
2. Observed hemoptysis 
3. Unexplained anemia (<10 g/dL) or 
documented drop in hemoglobin (>1 g/dL) 
from less than 10g/dl 
4. Increased diffusing capacity of carbon dioxide 
4. Provision of informed consent by patient or a surrogate decision 
maker. In some participating countries permission has also been 
granted to use deferred consent for enrolling a patient until a legal 
representative becomes available to consent on their behalf. Please 
check your national regulations for further guidance. 
 
Exclusion Criteria 
1. A diagnosis of vasculitis other than granulomatosis with polyangiitis 
(Wegener’s) or microscopic polyangiitis 
2. A positive serum test for anti-glomerular basement membrane 
antibody test or renal biopsy demonstrating linear glomerular 
immunoglobulin deposition 
3. Receipt of dialysis for >21 days immediately prior to randomization 
or prior renal transplant 
4. Age <15 years (age <18 years at centres that do not treat pediatric 
patients) 
5. Pregnant at time of study entry 
6. 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 
7. A comorbidity or condition that, in the opinion of the investigator, 
precludes the use of cyclophosphamide/rituximab, glucocorticoids, 
or plasma exchange or absolutely mandates the use of plasma 
exchange  
8. Plasma exchange in 3 months prior to randomization 
 
Treatment 
Description 
Plasma Exchange:  
 Seven (7) plasma exchanges of 60 mL/kg, will be performed within 
14 days after randomization.  
 Plasma exchange may be provided by centrifugation or filter 
separation according to local practice and availability.  
 Anticoagulation may be provided by heparinization or citrate 
according to local practice.  
 Replacement fluid will consist of human serum albumin (3-5% 
depending on local availability). Albumin may be combined with 
crystalloid (e.g. saline).  
 Patients with active bleeding may receive supplemental plasma to 
replace clotting factors according to local practice. 


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Immunosuppressive and glucocorticoid therapy will be determined by the 
protocol for the first 12 months after trial entry 
 
Glucocorticoids:  
 All patients will receive between 1 and 3 g of IV 
methylprednisolone over 1 to 3 days, then daily oral GC.  
 Oral GC may consist of prednisone or prednisolone and 
administered through a weight-based protocol.  
 All participants will receive either 50, 60 or 75 mg/day (based on 
weight) of oral GC for 7 days 
o Participants in the standard-dose group will continue at 50, 
60 or 75 mg/day for 7 additional days and taper to between 
12.5 and 20 mg/day at 3 months and 5 mg/day at 6 months.  
o Participants in the reduced-dose group will continue at 25, 30 
or 40 mg/day for 7 days and taper to between 6 and 10 
mg/day by 3 months and 5 mg/day by 6 months. 
 All patients will receive 5 mg/day from 6 months to 12 months after 
randomization. 
 
Immunosuppressive Remission-Induction Therapy:  
To consist of either cyclophosphamide or rituximab, per preference of site 
investigators/patients. 
 
Cyclophosphamide:  
 Participants may be treated with either intravenous (15mg/kg/pulse) 
or oral (2mg/kg/day) CYC according to local preferences.  
 CYC doses will be reduced for advanced age, poor baseline renal 
function, or cytopenias.  
 
Rituximab: 
 Participants who are prescribed rituximab will receive 4 intravenous 
doses of 375 mg/m² according to the following schedule: 
o Dose 1 within first 14 days of participation 
o Subsequent doses: should follow the prior dose by 7 days but 
this may range between 5 and 14 days due to practical 
considerations for arranging rituximab infusions locally. 
o All doses should be given within 42 days of enrollment in the 
study. 
o Note: Rituximab will not be given within the 48 hours prior to 
receiving a PLEX treatment. 
 
Immunosuppressive Remission-Maintenance Therapy:  
 
Azathioprine: 
 Participants receiving cyclophosphamide will be transitioned to 


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azathioprine as maintenance immunosuppression no earlier than 3 
months and no later than 6 months after starting CYC provided a 
remission is induced. 
 Azathioprine (2 mg/kg/day) will begin immediately after the last 
dose of oral CYC or 7 days after the last dose of IV CYC with dose 
reduction for advanced age, cytopenias, or based on TPMT 
genetic/activity testing (if performed).  
 Patients intolerant of azathioprine may use an alternative 
immunosuppressive agent at the discretion of the local investigator. 
 
Prophylactic Therapies:  
Infection prophylaxis such as with low-dose sulfamethoxazole-trimethoprim 
(i.e. one single strength tablet [480 mg total] daily or one double strength 
tablet [960 mg total] thrice weekly) and osteoporosis prophylaxis. The use 
of prophylactic therapies will be left to local practice and the discretion of 
local investigators. 
Other Therapies:  
Treatments for AAV not included in the study protocol will not be allowed 
as adjunctive therapies (e.g. intravenous immunoglobulin, anti-TNF alpha 
therapy, high-dose sulfamethoxazole-trimethoprim or other 
immunomodulatory treatments).  
 
Sample Size 
700 patients.  
 
Primary Analyses 
 The primary analysis will be of time to the composite endpoint of 
all-cause mortality or end-stage renal disease using log-rank test and 
Cox proportional hazards models, with survival curves generated 
using the Kaplan-Meier method.  
 
Secondary 
Analyses 
1. Sustained remission will be analyzed by comparing the difference in 
proportions (and associated 95% confidence intervals) of patients 
that achieve a sustained remission in each treatment group.  
2. Death and ESRD will be analyzed separately in an identical manner 
to the composite primary endpoint. 
3. Safety analyses will be performed by assessing the 95% confidence 
interval of the rate difference of serious adverse events between 
treatment groups.  
4. The rate of serious infections will be assessing the 95% confidence 
interval of the rate difference between the treatment groups both for 
the first year and at trial end..  
5. Health-related quality of life using the SF-36 Physical Composite, 
Mental Composite and EQ-5D Index Score will be assessed by 
constructing repeated measures models. 
Safety and 
Monitoring 
Adverse events will be assessed at each study visit. 
Important expected adverse events will be actively surveyed (i.e. must 
be assessed to complete the case report form). 


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An independent Data Monitoring Committee (DMC)/Data Safety 
Monitoring Board (DSMB) will review adverse event data annually or 
more frequently if requested by the DMC/DSMB. 
 
 
2 
Glossary of Terms 
 
 
Common Closing Date 
12  months after the last patient is enrolled 
 
End Stage Renal Disease 
The requirement of a renal replacement therapy (hemodialysis or 
peritoneal dialysis) for at least 12 consecutive weeks or the receipt 
of a renal transplantation. 
First Relapse 
The first major or minor relapse. 
 
Major Relapse 
New or recurrent disease activity that occurs after remission has 
been initially induced and affects a major item of the BVAS/WG 
(gangrene, scleritis, retinal exudates/haemorrhage, sensorineural 
deafness, mesenteric ischemia, pulmonary haemorrhage, respiratory 
failure, red blood cell urinary casts, rise in creatinine >30% or fall in 
creatinine clearance >25%, meningitis, spinal cord lesion, stroke, 
cranial nerve palsy, sensory peripheral neuropathy, mononeuritis 
multiplex, or other manifestation deemed major by the investigator). 
 
Minor Relapse 
New or recurrent disease activity that occurs after remission has 
been initially induced but does not constitute a major relapse/does 
not affect a major item of the BVAS/WG. 
 
Remission 
The absence of disease activity (BVAS/WG= 0) 
 
Resistant Disease 
Active AAV that does not improve or worsens despite commencing 
the allocated induction of remission therapy. 
 
Sustained remission 
Remission that is obtained within 6 months of randomization and 
lasts without a first relapse until at least 12 months after 
randomization. 
 
 
 
 
 
 
 


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3 
Abbreviations 
 
 
AAV 
ANCA-associated vasculitis 
ANCA 
Anti-neutrophil cytoplasm antibody 
AZA 
Azathioprine 
BCTU 
BVAS/WG 
Birmingham Clinical Trials Unit 
Birmingham Vasculitis Activity Score/Wegener’s Granulomatosis 
version 
CDA 
Combined Damage Assessment Index 
CYC 
Cyclophosphamide 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
eGFR 
Estimated glomerular filtration rate 
EQ5D 
EuroQoL 5D Quality of Life Questionnaire 
ESRD 
End-stage renal disease 
FDA 
Food and Drug Administration 
GC 
Glucocorticoids 
GPA 
Granulomatosis with Polyangiitis (Wegener’s) 
MDRD 
Modification of Diet in Renal Disease 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MPA 
Microscopic Polyangiitis 
NIAMS 
National Institute of Arthritis and Musculoskeletal and Skin Diseases 
NIH 
National Institutes of Health 
NIHR 
National Institutes for Health Research 
PLEX 
Plasma Exchange 
TMC 
Trial Management Committee 
TPMT 
Thiopurine Methyltransferase 
TSC 
Trial Steering Committee 
SAE 
Serious Adverse Event 
SF-36 
Medical Outcomes Survey Short Form 36 Questionnaire 
SUSAR 
Suspected unexpected Serious Adverse Reaction 
 
 
 
 
 
 
 
 
 
 


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4 
Table of Contents 
1 
Protocol Synopsis............................................................................................................. 3 
2 
Glossary of Terms ............................................................................................................ 8 
3 
Abbreviations ................................................................................................................... 9 
4 
Table of Contents ........................................................................................................... 10 
5 
Background and Rationale ............................................................................................. 13 
5.1 
Target Population ........................................................................................................... 13 
5.2 
Plasma Exchange for Treatment of ANCA-Associated Vasculitis ................................ 15 
5.3 
The treatment of ANCA-Associated Vasculitis with Glucocorticoids .......................... 17 
6 
Trial Objectives .............................................................................................................. 17 
6.1 
Primary Objectives ......................................................................................................... 17 
6.2 
Secondary Objectives ..................................................................................................... 17 
6.3 
Exploratory Objectives ................................................................................................... 18 
7 
Trial Design ................................................................................................................... 18 
7.1 
Overview ........................................................................................................................ 18 
7.2 
Number of Centres ......................................................................................................... 19 
7.3 
Number of Participants................................................................................................... 19 
7.4 
Methods to Protect Against Bias .................................................................................... 19 
7.5 
Study Duration ............................................................................................................... 20 
7.6 
Trial Endpoints ............................................................................................................... 20 
7.6.1 
Primary Endpoint .................................................................................................... 20 
7.6.2 
Secondary Endpoints .............................................................................................. 20 
7.6.3 
Tertiary Endpoints .................................................................................................. 20 
7.7 
Treatments ...................................................................................................................... 21 
7.7.1 
Adjunctive Plasma Exchange Induction Therapy ................................................... 21 
7.7.2 
Glucocorticoids Therapy ......................................................................................... 21 
7.7.3 
Cyclophosphamide Remission-Induction Immunosuppressive Therapy................ 23 
7.7.4 
Rituximab Remission-Induction Therapy ............................................................... 25 
7.7.5 
Remission-Maintenance Immunosuppressive Therapy .......................................... 26 
7.8 
Guidelines for the Treatment of Resistant Disease ........................................................ 26 
7.9 
Guidelines for the Treatment of Major Relapses ........................................................... 27 
7.10 Guidelines for the Treatment of Minor Relapses ........................................................... 27 
7.11 Prophylactic Therapies ................................................................................................... 27 
7.12 Criteria for Discontinuation ........................................................................................... 28 
7.12.1 
Individual Subject ................................................................................................... 28 


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7.12.2 
Trial ......................................................................................................................... 28 
7.13 Patient Selection ............................................................................................................. 28 
7.13.1 
Inclusion Criteria .................................................................................................... 28 
7.13.2 
Exclusion Criteria ................................................................................................... 29 
7.13.3 
Randomization ........................................................................................................ 29 
7.13.4 
Subject Withdrawal Criteria ................................................................................... 30 
7.13.5 
Disease definitions .................................................................................................. 30 
7.14 Screening Evaluation and Informed Consent ................................................................. 32 
7.15 Baseline Data.................................................................................................................. 32 
7.16 Randomization ............................................................................................................... 32 
7.17 Induction of Remission .................................................................................................. 33 
7.18 Maintenance of Remission ............................................................................................. 33 
7.19 Termination of Study ..................................................................................................... 33 
8 
Assessment of Safety ..................................................................................................... 33 
8.1 
Definitions ...................................................................................................................... 33 
8.1.1 
Adverse event.......................................................................................................... 33 
8.1.2 
Adverse reaction of an investigational medicinal product (AR) ............................ 33 
8.1.3 
Unexpected adverse reaction .................................................................................. 34 
8.1.4 
Serious adverse event or serious adverse reaction .................................................. 34 
8.2 
Expected adverse drug reactions .................................................................................... 34 
8.3 
Recording and evaluation of adverse events .................................................................. 35 
    8.4      Recording and evaluation of serious adverse events                                                     35 
8.4.1          Assesment of seriousness 
8.4.2 
Assessment of causality .......................................................................................... 36 
8.5 
Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) ................ 36 
8.5.1 
Who should report and whom to report to? ............................................................ 36 
8.5.2 
When to report?....................................................................................................... 36 
8.5.3 
How to report? ........................................................................................................ 37 
8.6 
Reporting adverse events ............................................................................................... 37 
8.7 
Known Potential Risks ................................................................................................... 37 
8.7.1 
Plasma Exchange .................................................................................................... 37 
8.7.2 
Glucocorticoids ....................................................................................................... 38 
8.7.3 
Cyclophosphamide .................................................................................................. 40 
8.7.4 
Azathioprine ............................................................................................................ 41 
9 
Study Risk Assessment .................................................................................................. 43 


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9.1 
Risks to the Subjects ...................................................................................................... 43 
9.2 
Adequacy of Protection Against Risks........................................................................... 44 
9.3 
Potential Benefits of the Proposed Research to the Subject and Others ........................ 44 
9.4 
Importance of the Knowledge to be Gained................................................................... 45 
10 
Study Monitoring ........................................................................................................... 45 
11 
Data and Safety Monitoring Plan ................................................................................... 45 
12 
Statistical Considerations ............................................................................................... 46 
12.1 Sample Size Estimation .................................................................................................. 46 
12.2 Planned Analyses ........................................................................................................... 46 
12.2.1 
Interim Analyses ..................................................................................................... 46 
12.2.2 
Primary Endpoint Analyses .................................................................................... 46 
12.2.3 
Secondary Endpoint Analyses ................................................................................ 47 
12.2.4 
Tertiary Endpoint Analyses .................................................................................... 48 
13 
Biomedical Substudies ................................................................................................... 48 
14 
Ethical Considerations ................................................................................................... 49 
14.1 Evaluation of Risks to Patients ...................................................................................... 49 
14.2 Protection Against Risks ................................................................................................ 49 
14.3 Potential Benefits to Participants ................................................................................... 50 
14.4 Trial Ethical Approval .................................................................................................... 50 
14.5 GCP Statement ............................................................................................................... 50 
15 
Trial Organization .......................................................................................................... 50 
15.1 Principal Investigators .................................................................................................... 50 
15.2 Data Management and Analysis Centre ......................................................................... 50 
15.3 Trial Communications .................................................................................................... 51 
15.4 Trial Publication Policy .................................................................................................. 51 
16 
Funding .......................................................................................................................... 51 
17 
Reference List ................................................................................................................ 52 
18 
Appendices ..................................................................................................................... 54 
18.1 Birmingham Vasculitis Activity Score for WG Vasculitis (BVAS/WG) ...................... 54 
18.2 CDA - Combined Damage Assessment Index ............................................................... 63 
18.3 SF-36 .............................................................................................................................. 65 
18.4 EQ5D .............................................................................................................................. 68 
18.5 Modification of Diet in Renal Disease (MDRD) Estimated Glomerular Filtration Rate 
Calculation ..................................................................................................................... 71 
 


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5 
Background and Rationale 
 
Granulomatosis with polyangiitis (Wegener’s) (GPA) 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). The prevalence of AAV is estimated at 14 - 30 patients per 100 000 in England (1). Left 
untreated, AAV has a universally poor prognosis with mortality approaching 100% within 5 
years (2). The introduction of treatment regimens based on cyclophosphamide (CYC) and 
glucocorticoids (GC) have transformed AAV from a rapidly fatal disease to one of chronic 
morbidity and reduced survival often preceded by end-stage renal disease (ESRD).  
Plasma exchange (PLEX), 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. GC 
are a standard of care in the treatment of AAV. High doses of GC early in disease although 
undeniably 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 GC dosing. 
There is a need for therapies with reduced toxicity while improving disease control. Defining the 
role of therapies that are already in use but that are invasive, expensive, but unproven is a 
priority in AAV research. PEXIVAS is a randomized controlled trial to test two interventions in 
a two-by-two factorial design (standard care and PLEX compared to standard care alone and a 
standard-dose GC compared to a low dose GC regimen) to address these issues. 
5.1 
Target Population 
 
Current standard treatment regimens still have poor outcomes. Unselected cohorts now 
demonstrate 5 year renal survival (defined as the composite of ESRD or death) of 60 to 70% 
(3;4). In patients with vital organ threatening disease (e.g. kidneys or lungs), renal survival is 
worse. Long-term follow-up data from three recently completed RCTs by the European 
Vasculitis Study Group (EUVAS) with 285 patients with an estimated glomerular filtration rate 
(eGFR) of less than 50 ml/min/1.73 m2 demonstrated 5 year ESRD-free survival was only 54% 
and the median time to renal failure or death was 6 years despite the exclusion of patients with 
lung hemorrhage (Figure 1). In the subgroup of patients with a creatinine of less than 500, a 
group traditionally thought to have a favorable prognosis, 33% died or developed ESRD by 5 
years (Figure 2). Additionally, patients with lung hemorrhage, who were excluded from these 
studies, have a mortality of up to 50% in the first year. 


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0.00
0.25
0.50
0.75
1.00
0
2
4
6
8
Time (years)
 
Figure 1 Differences in long-term renal survival (end-stage renal disease or death) on the basis of 
estimated glomerular filtration (eGFR) for patients with ANCA-associated vasculitis enrolled in three 
randomized trials. Blue line represents patients with an eGFR of ≤ 50 ml/min/1.73 m2; red line represents 
patients with an eGFR of >50 ml/min/1.73 m2. 
 
0.00
0.25
0.50
0.75
1.00
0
2
4
6
8
Time (years)
 
Figure 2 Differences in long-term renal survival (end-stage renal disease or death) on the basis of 
estimated glomerular filtration (eGFR) for patients with ANCA-associated vasculitis enrolled in two 
randomized trials with baseline creatinines < 500 µmol/L. Blue line represents patients with an eGFR of ≤ 
50 ml/min/1.73 m2; red line represents patients with an eGFR of >50 ml/min/1.73 m2. 
 


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Poor outcomes in AAV are attributed both to ineffective therapies and complications of standard 
treatments, CYC and GC. Approximately 20% of patients either do not have adequate disease 
control or are intolerant of their induction of remission treatment (5-7). An additional 50% of 
patients will have relapsing AAV over the subsequent five years. Inadequate disease control is 
associated with increased immunosuppressive medication and thus increased risk for treatment 
related toxicity and progressive organ scarring and death. Additionally, between 25 and 50% of 
patients with severe AAV experience a severe infection within the first 12 months of treatment 
and the most frequently cited causes of death are infection or uncontrolled vasculitis (8;9). 
Treatment regimens that minimize toxicity and infections while providing adequate disease 
control are therefore needed. 
5.2 
Plasma Exchange for Treatment of ANCA-Associated Vasculitis  
PLEX removes potentially pathogenic antibodies as well as mediators of coagulation and 
inflammation from the circulation and has been advocated as a method of rapidly controlling 
AAV. Early studies of PLEX in rapidly progressive glomerulonephritis due predominantly to 
AAV have had mixed results (10-12). These studies had heterogeneous treatment regimens, 
small sample sizes, and short follow-up periods.  
MEPEX examined the effect of PLEX on renal recovery for patients with renal failure due to 
AAV (8). This trial compared PLEX to IV methylprednisolone as an addition to standard therapy 
in 137 incident patients with severe AAV manifested by a creatinine >500 µmol/L or dialysis 
dependency at presentation and demonstrated an absolute reduction in the development of ESRD 
by 24% (95% CI 6.5 – 41%) after 12 months for patients treated with PLEX. There was no 
demonstrable difference in mortality at 12 months between those treated with PLEX compared to 
IV methylprednisolone (mortality of 25% in both groups). Long-term results from MEPEX, 
however, did not demonstrate a statistically significant difference between the treatment groups 
in terms of ESRD or death (p=0.57) (Figure 3).  
The role of PLEX in patients with less severe renal dysfunction at the time of presentation is 
even less clear. Exploratory work from Jayne et al found patients with a renal biopsy 
demonstrating active lesions were the most likely to have a benefit from PLEX. In patients who 
do not have advanced, chronic renal injuries, the rapid disease control afforded by PLEX may 
prevent renal (or other vital organ) scarring and thus the cascade of glomerulosclerosis and 
hyperfiltration that perpetuates renal injury.  
PLEX is also widely used for patients with lung hemorrhage due to AAV. This practice comes 
from cohort data in AAV and experience with anti-glomerular basement membrane disease but 
has never been rigorously tested and in contemporary cohort data appears effective only in 
selected subgroups of patients with lung hemorrhage (13). However, PLEX has the potential to 
exacerbate haemorrhage through removal of clotting factors and increase the risk of infection 
through antibody removal. Its use in this indication demands critical appraisal.  


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0.00
0.25
0.50
0.75
1.00
0
2
4
6
8
Time (years)
MeP
PLEX
 
Figure 3 Results of long-term follow-up of the MEPEX study. Renal survival is defined as the composite 
of end-stage renal disease or all-cause mortality. 
  
A systematic review of PLEX in AAV identified nine randomized studies. The study populations 
were skewed towards severe renal dysfunction and often included diseases other than AAV. A 
meta-analysis of the nine trials that reported death and ESRD outcomes showed a benefit at 
reducing dialysis dependency (relative risk [RR] 0.64; 95% confidence interval [CI] 0.47 to 0.88) 
but no benefit at reducing mortality (RR 1.01; 95% CI 0.71 to 1.43). When considering the 
composite endpoint of death or dialysis the relative risk was 0.81 (95% CI 0.66 to 1.00) (Figure 
4). 
 


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Figure 4 Meta-analysis 9 studies including 387 patients examining the effect of adjunctive plasma 
exchange on the endpoint of end-stage renal disease or death in patients with rapidly progressive 
glomerulonephritis. 
5.3 
The treatment of ANCA-Associated Vasculitis with Glucocorticoids 
High dose oral GC are the standard of care for the treatment of AAV on the basis of cohort data 
prior to the widespread use of cytotoxic medications and strategies for earlier diagnosis with 
ANCA testing. There is a complex relationship between GC dose and its effects on the immune 
system as an immunosuppressive versus an anti-inflammatory (14). There is also an increasing 
trend to reduce GC doses to mitigate their toxicity while maintaining efficacy, a trend supported 
by laboratory evidence of a ceiling effect of GC dosing with respect to anti-inflammatory 
properties (15). When combined with cytotoxic medications, high dose GC may significantly 
increase treatment related toxicity while adding little to therapeutic efficacy.  
Infections in AAV are most common in the first two months of treatment when GC doses are 
highest. Although this relationship is confounded by disease activity and co-treatment with CYC, 
it is important to note that infection rates fall in parallel with decreasing GC dose despite the 
maintenance of constant immunosuppression. Dose dependent increases in infections are also 
observed in rheumatoid arthritis and lupus nephritis (16;17). Furthermore, high cumulative doses 
of GC are associated with osteoporosis, infections, cardiovascular disease and gastrointestinal 
bleeding (18). Despite the association between higher GC doses and adverse events and despite 
their widespread use, there is a paucity of literature to guide the optimal exploitation of GC in 
AAV.  
6 
Trial Objectives 
6.1 
Primary Objectives 
1. To determine the efficacy of PLEX in addition to immunosuppressive therapy and 
glucocorticoids with respect to death and end-stage renal disease (ESRD) 
2. To determine whether a reduced-dose glucocorticoids regimen is non-inferior to a 
standard-dose regimen with respect to death and ESRD 
6.2 
Secondary Objectives 
Secondary objective are limited to those of direct relevance to the assessment of the efficacy and 
safety of the investigational treatments. 
For both of PLEX in addition to immunosuppressive therapy and glucocorticoids compared to 
immunosuppressive therapy and glucocorticoids alone and for a reduced-dose of glucocorticoids 
compared to a standard-dose of glucocorticoids: 
1. To determine the effect on disease activity 
2. To determine the effect on death 
3. To determine the effect on ESRD 
4. To determine safety 
5. To determine effects on serious infections 
6. To determine effects on health related quality of life 


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6.3 
Exploratory Objectives 
For each of PLEX in addition to immunosuppressive therapy and glucocorticoids compared to 
immunosuppressive therapy and glucocorticoids alone and for a reduced-dose of glucocorticoids 
compared to a standard-dose of glucocorticoids: 
1. To determine the cost effectiveness 
2. To determine the effects on measures of disease related damage 
3. To determine the effects on long term renal function 
7  Trial Design 
7.1 
Overview 
 
This trial will randomize patients with AAV in a two-by-two factorial design. Randomization to 
each intervention will be in a one-to-one ratio stratified by the other intervention. Patients will be 
randomized to receive either adjunctive PLEX or no PLEX and randomized to receive either a 
standard GC dose or a low GC dose. All patients will receive standard immunosuppressive 
induction therapy. The primary outcome of the trial will be the composite endpoint of all-cause 
mortality or end-stage renal disease.  


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7.2 
Number of Centres 
PEXIVAS will occur in multiple centres internationally including Europe, North America and 
Australia/New Zealand. Over 90 centres are planned to recruit patients. 
7.3 
Number of Participants 
This study will aim to recruit 700 patients with AAV over six and half years (6.5) years.  
7.4 
Methods to Protect Against Bias 
Participants will be allocated to the interventions in a one-to-one ratio by a central randomization 
facility utilizing a computerized minimization algorithm. The algorithm will not be made 
available to investigators. 350 patients will receive PLEX and be compared to 350 patients that 
do not. 350 patients will receive reduced-dose GC and be compared to 350 patients that receive 
standard-dose GC. Allocation will follow a minimisation scheme (see 7.13.3) based on the 
following prognostic factors in AAV: severity of renal disease at presentation (requiring dialysis 
or creatinine ≥ 500 µmol/L vs. <500 µmol/L), age (<60, ≥ 60 years old), ANCA subtype (PR3-
ANCA vs. MPO-ANCA), severity of lung hemorrhage (no hemorrhage, lung hemorrhage with 
an oxygen saturation of ≤85% on room air or ventilated, or lung hemorrhage with an oxygen 
saturation of >85% on room air), and planned induction immunosuppressive therapy to be used 
(oral CYC vs. intravenous CYC vs. rituximab). 
PLEX is an invasive procedure requiring the placement of a large central venous catheter and the 
use of a large, complex device with additional monitoring and nursing care. As such, it is not 
feasible to blind either patients or treating physicians to this treatment allocation. There is the 
potential for treating physicians to alter their treatment on the basis of knowing whether the 
patient will receive PLEX. This will partially be controlled by randomly determining their GC 
regimen. Although CYC dosing will be protocol driven, the route of administration will not. The 
 
Severe AAV 
Standard Therapy with 
Cyclophosphamide or 
Rituximab
Adjunctive Plasma 
Exchange 
Standard-Dose 
Glucocorticoids 
Reduced-Dose 
Glucocorticoids 
No 
Plasma Exchange 
Standard-Dose 
Glucocorticoids 
Reduced Dose 
Glucocorticoids 
Figure 5 General schema of randomization. 


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route of CYC administration, determined before randomization, will therefore be used as a 
stratification variable thus removing some potential for confounding (see 7.13.3 below).  
7.5 
Study Duration 
Each patient will be followed until study close with a minimum duration of follow-up of 1 year. 
Patient recruitment is anticipated to require 6.5 years. Therefore, the maximum duration of 
follow-up is 7.5 years. Patients will be followed more frequently when they begin the trial when 
the interventions are most intense and treatment is designed to induce remission of disease 
(Induction of Remission Period) and follow-up will be less intense after this period (Maintenance 
of Remission Period). The patient follow-up schedule is provided below (Table 4). 
7.6 
Trial Endpoints 
7.6.1 Primary Endpoint 
The primary endpoint for this trial is a composite of all-cause mortality or end-stage renal 
disease. End-stage renal disease is defined as the requirement of a renal replacement therapy 
(hemodialysis or peritoneal dialysis) for at least 12 consecutive weeks or the receipt of a renal 
transplantation. Endpoints will be ascertained at study assessments. In the event a patient does 
not attend an assessment, investigators will attempt to contact any or all of the following: (in 
order) the patient, the patient’s family physician/general practitioner, the patient’s next of kin, 
and the patient’s listed contacts in order to ascertain their endpoint status. In countries with vital 
status registries, we will use the registry to ascertain missing patient’s endpoint status. 
7.6.2 Secondary Endpoints 
The secondary objectives will be assessed using the following outcome measures: 
 
Sustained remission (remission that occurs before 6 months after randomization and lasts 
without a first relapse until at least 12 months after randomization) 
 
All-cause mortality 
 
End stage renal disease (ESRD) as described above  
 
Serious adverse events defined as any medical occurrence that results in permanent 
disability, hospitalization or the prolongation of a hospitalization, is life threatening or 
results in death (Section 8.1.4). 
 
Serious infections defined as an infectious syndrome that requires intravenous antibiotics 
or hospitalization for treatment. 
 
Medical Outcomes Survey Short Form 36 (SF-36) Physical Composite Score and Mental 
Composite Score. 
 
EuroQoL EQ5D Index score. 
7.6.3 Tertiary Endpoints 
The tertiary objectives will be assessed using the following outcome measures: 
 Estimated glomerular filtration rate (Modification of Diet in Renal Disease four variable 
formula) 
 Combined Damage Index 
 Cost-Effectiveness Ratios 


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7.7 
Treatments 
7.7.1 Adjunctive Plasma Exchange Induction Therapy 
PLEX therapy will only be prescribed in addition to standard induction therapy.  PLEX will 
consist of 7 exchanges within 14 days of randomization, of at least 60 ml/kg (based on actual 
body weight) per session using albumin (3% to 5% depending on local availability, with or 
without crystalloid) as a replacement solution. The minimum replacement solution volume is 
3000 mL. Intravenous immunoglobulin should not be used after PLEX. 
The following parameters may be determined according to local practice: 1) PLEX may be 
performed by centrifugation or filter separation technique, double filtration apheresis (DFA) is 
not permitted 2) Anticoagulation may be provided by citrate or by heparin but it is suggested that 
in patients with active bleeding regional citrate anticoagulation be utilized, 3) PLEX may be 
performed via a central venous catheter if patient is deemed unsuitable for peripheral venous 
access, the latter is strongly recommended, and 4) monitoring of coagulation parameters or 
immunoglobulin levels, and 5) PLEX dose may be reduced for PLEX related complications 
according to local best medical practice and indication and dose alteration noted for future 
analysis. 
7.7.1.1 Patients with Bleeding Risks 
Renal biopsy the day of PLEX should be avoided, to minimize the risk of bleeding from 
dilutional coagulopathy. 
 
Local practice should be followed for patients with active bleeding including patients with 
known pulmonary hemorrhage or a bleeding episode from any source within the 24 hours prior 
to PLEX treatment. This may include fresh frozen plasma at the end of the exchange. This 
information will be recorded in the case report form. 
7.7.1.2 Additional Plasma Exchange Treatments 
Patients will not receive additional PLEX treatments for ongoing signs or symptoms of AAV 
(unless they imminently threaten vital organ function – see Major Relapses section 7.9), 
serological markers of disease (e.g. elevated ANCA titres), elevated markers of inflammation, or 
histologic evidence of disease activity. Any PLEX treatments considered outside of the treatment 
protocol should be discussed with the trial medical monitor and the details must be recorded in 
the patient’s trial case report form. 
7.7.2 Glucocorticoids Therapy 
 
7.7.2.1 Patients Who Have Not Received Any Glucocorticoid Therapy Prior To 
Randomization 
GC therapy shall commence with intravenous (IV) methylprednisolone irrespective of the GC 
group the patient is allocated to. IV methylprednisolone shall be given as three daily pulse doses 
(minimum 1g maximum 3g, total dose). Each pulse dose may be between 0.5 g and 1 g at the 
local investigators discretion. The day following the last IV methylprednisolone dose, patients 
will commence the randomized oral GC regimen (see 7.7.2.5 below). 
 


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7.7.2.2. Patients Who Have Received <3 g IV Methylprednisolone Within 14 days Prior To 
Randomization 
IV methylprednisolone administered within 14 days prior to randomization will contribute to the 
maximum allowable dose of 3g. If  <3 g of IV methylprednisolone were given within 14 days 
prior to randomization, participants may receive additional IV methylprednisolone over 3 days 
after randomization to reach a minimum of 1 g and a maximum of 3 g (including all IV 
methylprednisolone given within 14 days prior to randomization). The day following the last IV 
methylprednisolone dose, patients will commence the randomized oral GC regimen (see 7.7.2.5 
below). 
 
7.7.2.3. Patients Who Have Received Oral GC But No IV Methylprednisolone Within 14 
Days Prior to Randomization 
Oral GC given prior to randomization do not impact on the protocol GC regimen in terms of 
either IV methylprednisolone or oral GC. These patients should be treated as if they had not 
received any GC prior to randomization (see 7.7.2.1 above). 
 
7.7.2.4 Patients Who Have Received ≥3 g Of IV Methylprednisolone Within 14 Days Prior 
to Randomization 
Patients that have received ≥3 g IV methylprednisolone within 14 days prior to randomization 
should begin the oral GC regimen according to their randomized group within 24 hours of 
randomization (see 7.7.2.5 below) 
7.7.2.5. Randomized Oral GC Therapy 
Oral GC therapy shall commence according to previously received IV methylprednisolone as 
detailed in sections 7.7.2.1 through 7.7.2.4 above.  Oral GC therapy will consist of non-enteric 
coated prednisone or prednisolone at equivalent mg to mg doses. Dosing will depend on patient 
weight with three possible weight categories. All oral GC will be given as a single daily dose. 
Patients intolerant of oral medications or for whom oral medications are contraindicated may be 
given an equivalent daily IV dose.  Pre-printed prescriptions for oral GC therapy will be 
provided for each patient in the trial after randomization to ensure adherence to the allocated GC 
regimen. The standard-dose regimen and reduced-dose regimen are summarized in Table 1. The 
reduced-dose regimen will expose patients to approximately 50% of the standard oral dose over 
the first 3 months and 53% over the first 6 months of treatment. Oral GC therapy will continue at 
a dose of 5 mg/day until at least week 52 of the study after which GC therapy will revert to local 
practice. Alternate day dosing regimens (i.e. those that use two different doses on alternate days) 
may be used to achieve the appropriate average daily dose required by the protocol but 
differences in alternative day doses may not be >5 mg. For example, a dose of 12.5 mg/day may 
be achieved by alternating daily doses of 15 mg/day and 10 mg/day. 


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Table 1 Dosing for oral Glucocorticoids in the standard and reduced-dose limbs from trial 
start 
Week 
Standard 
Reduced-dose 
 
<50 
kg 
50-75 kg 
>75 kg 
<50 
kg 
50-75 kg 
>75 kg 
 
pulse 
pulse 
pulse 
Pulse 
pulse 
pulse 
1 
50 
60 
75 
50 
60 
75 
2 
50 
60 
75 
25 
30 
40 
3-4 
40 
50 
60 
20 
25 
30 
5-6 
30 
40 
50 
15 
20 
25 
7-8 
25 
30 
40 
12.5 
15 
20 
9-10 
20 
25 
30 
10 
12.5 
15 
11-12 
15 
20 
25 
7.5 
10 
12.5 
13-14 
12.5 
15 
20 
6 
7.5 
10 
15-16 
10 
10 
15 
5 
5 
7.5 
17-18 
10 
10 
15 
5 
5 
7.5 
19-20 
7.5 
7.5 
10 
5 
5 
5 
21-22 
7.5 
7.5 
7.5 
5 
5 
5 
23-52 
5 
5 
5 
5 
5 
5 
>52 
Investigators’ Local Practice 
Investigators’ Local Practice 
 
7.7.3 Cyclophosphamide Remission-Induction Immunosuppressive Therapy 
Standard induction therapy with CYC will be prescribed for at least 13 weeks and no more than 
26 weeks. As the experience of using either oral or intra-venous routes of administration varies 
between centres and there is no apparent difference in efficacy or safety, the study protocol will 
allow the use of either oral or IV CYC. The CYC regimens will be identical for all treatment 
groups.  
A starting dose of 15 mg/kg/pulse will be used for pulse CYC (maximum 1.2 g/dose) or 2 
mg/kg/day for oral CYC (maximum 200 mg/day) with reductions made for age and renal 
function in each group according to previous trials conducted in Europe. Oral CYC will be 
administered daily with the recommendation for morning administration of full dose, if tolerated. 
Pulse CYC will be administered IV at a frequency of every two weeks for the first 3 doses then 
every three weeks thereafter (Table 2). Modifications to dose and frequency will be made in the 
case of leucopenia.  
For patients undergoing PLEX, PLEX will not occur for at least 24 hours following an IV dose 
of CYC.   


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Table 2. Pulse intravenous cyclophosphamide schedule. Doses may be modified for age and renal function. After 
week 13, patients in remission may be transitioned to remission-maintenance therapy. 
 
Time (weeks) 
Pulse number 
Dose 
0 
1 
15 mg/kg 
2 
2 
15 mg/kg 
4 
3 
15 mg/kg 
7 
4 
15 mg/kg 
10 
5 
15 mg/kg 
13 
6 
15 mg/kg 
16 
7 
15 mg/kg 
19 
8 
15 mg/kg 
22 
9 
15 mg/kg 
25 
10 
15 mg/kg 
 
For patients receiving PLEX and daily CYC (oral or IV), on days when PLEX is performed, 
CYC will be given following PLEX. PLEX will not be performed for at least 12 hours following 
a dose of oral CYC. 
Full (complete) blood counts will be performed according to local protocol but the following 
minimum is recommended: patients receiving oral CYC should have their blood count monitored 
weekly for the first four weeks and weekly for four weeks after any dose adjustment and every 
other week thereafter. Patients receiving pulse CYC should have their blood count monitored 10 
to 14 days after each dose and within 1 day prior to each dose.  
Concomitant use of mesna is optional and left to the discretion of the investigator and local 
practice. 
7.7.3.1 Dosage Modifications 
7.7.3.1.1 Renal Function and Age 
Starting doses of CYC should be adjusted for advanced age or reduced renal function. Renal 
function may change over the course of the trial and medication dosages may be adjusted to 
reflect these changes (Table 3.) 
7.7.3.1.2 Leucopenia 
 
Oral cyclophosphamide 
Oral CYC should be held if the total WBC count is <4x109/L. Oral CYC may be restarted at a 
dose at 25 mg/day less than previous once the WBC count is >4x109 on two consecutive tests or 
>5x109 on at least 1 test. After an episode of leucopenia, WBC counts should be monitored at 
least weekly for at least four weeks. 


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In the case of severe (WBC < 1x109/L) or prolonged (< 4x109/L for >2 weeks) leucopenia, oral 
CYC should be restarted at a dose at least 50 mg/day lower than the previous dose once the 
weekly WBC count permits. In cases of severe leucopenia, consideration should also be given to 
granulocyte-colony stimulating factor (G-CSF), fungal prophylaxis, and other precautions for 
patients with severe leucopenia. 
Patients with a declining WBC count but no overt leucopenia (i.e. WBC count <6x109 and at 
least 2x109/L lower than previous) should have their WBC count rechecked within 1 week and 
have their oral CYC reduced by at least 25 mg/day if the WBC count continues to fall. 
Pulse cyclophosphamide  
The WBC count should be determined within 1 day prior to an IV pulse CYC. If the WBC count 
is <4x109/L, the CYC dose should be postponed until the WBC count is >4x109/L and the dose 
should be reduced to 75% of the planned dose (planned dose x 0.75). 
The WBC count nadir should also be determined 10 to 14 days after the pulse dose is given. If 
the nadir is <3x109/L, the next pulse should be reduced even if the next pre-dose WBC count is 
>4x109/L. For a nadir <2x109/L, the next dose should be 60% of the previous dose (previous 
dose x 0.6). For a nadir of 2-3x109/L, the next dose should be 80% of the previous dose 
(previous dose x 0.8). 
7.7.3.1.3 Other Dose Modifications 
Similar dose reductions to those made for leucopenia may be made for thrombocytopenia and 
anemia at the investigator’s discretion. Dose alterations should also be made in the event of 
infectious complications.  
Table 3. Oral and intravenous cyclophosphamide dose adjustments (mg/kg) for age and renal 
impairment. NOTE: dose reductions for renal impairment should reflect renal function at the 
time the dose is given rather than baseline renal function. 
 
Oral Cyclophosphamide 
IV Cyclophosphamide 
 
eGFR (ml/min/1.73 m2) 
eGFR (ml/min/1.73 m2) 
Age 
>30 
≤30 
>30 
≤30 
<60 
2 
1.5 
15 
12.5 
60-70 
1.5 
1.25 
12.5 
10 
>70 
1.25 
1 
10 
7.5 
 
7.7.4 Rituximab Remission-Induction Therapy 
Rituximab may be prescribed to patients as induction remission therapy. Rituximab will be 
prescribed as 4 intravenous doses of 375 mg/m² according to the following schedule: 
 
1. Dose 1 within first 14 days of participation  
2. Subsequent doses should occur 7 days after the previous dose. Doses may, however, 
occur 5 to 14 days to accommodate practical considerations of administering rituximab 
and to accommodate plasma exchange. All doses must be given within 42 days of the 


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first dose. PLEX should not be given within the first 48 hours after administering 
rituximab. 
 
Prophylaxis against infusion reactions must be given as 100 mg of intravenous hydrocortisone or 
equivalent with or without an anti-histamine agent immediately preceding the first rituximab 
infusion, and local guidelines should be followed before subsequent infusions of rituximab. 
 
The use of rituximab will not be allowed in Germany for this trial. 
 
7.7.5 Remission-Maintenance Immunosuppressive Therapy 
Patients who have completed at least 13 weeks of CYC treatment and achieved a clinical 
remission of disease will be converted to maintenance therapy. A clinical remission is defined as 
the absence of disease activity that causes symptoms or signs of active vasculitis and has a 
BVAS/WG of 0. Symptoms or signs of disease that are due to the effects of scarring or damage 
caused by vasculitis or are a side-effect of therapy are not considered active disease (e.g. isolated 
persistent proteinuria or some cases of isolated microscopic hematuria or healing lung 
cavitations). Patients will remain on CYC therapy for no longer than 26 weeks.  
Azathioprine 
Maintenance therapy consists of azathioprine at a target dose of 2 mg/kg/day (rounded to the 
nearest 25 mg/day) and will begin immediately after the last dose of oral CYC or 7 days after the 
last dose of IV CYC. Patients intolerant of azathioprine will be permitted to be maintained on 
either a lower dose or on an alternative agent such as methotrexate or mycophenolate mofetil at 
their physician’s discretion. TPMT activity or polymorphism assessments may be performed 
according to local availability and practice. Bone marrow and hepatotoxicity should be assessed 
according to local practice but as a minimum we suggest checking full blood counts and 
aminotransferases every two weeks for the first month of azathioprine therapy and then every 
two months for the first year of therapy and every three months thereafter. 
7.7.5.1 Azathioprine Dosage Modifications 
The starting dose of azathioprine may be reduced to 1.5 mg/kg/day in patients >60 years old and 
to 1 mg/kg/day in patients >75 years old. 
 
Patients with a WBC count <4x109/L should have their azathioprine temporarily held and have 
their WBC count checked weekly. Once the WBC count is >4x109/L, azathioprine should be 
restarted at a dose of at least 25 mg/day less than the previous dose with continued weekly 
monitoring for at least one month.  
 
Patients with a declining WBC count but no overt leucopenia (i.e. WBC count <6x109 and at 
least 2x109/L lower than previous) should have their WBC count rechecked within 1 week and 
have their oral azathioprine reduced by at least 25 mg/day if the WBC count continues to fall. 
7.8 
Guidelines for the Treatment of Resistant Disease 
Resistant disease is active AAV that does not improve or worsens despite administration of the 
allocated induction of remission therapy.  
For failure to improve or worsening of nephritis, lung hemorrhage, or other major organ 
threatening disease (neurological, gastrointestinal, cardiac, eye) within the first two weeks from 


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entry, we recommend a repeated course of IV methyl prednisolone (1-3g total dose) or high dose 
oral prednisone/prednisolone (1 mg/kg for 1 week) according to local practice. Oral 
prednisone/prednisolone dosing should return to the allocated tapering regimen at that regimen’s 
starting dose (i.e. restart tapering regimen). Consideration of other therapies must be discussed 
with the medical monitor. 
7.9 
Guidelines for the Treatment of Major Relapses 
A major relapse is new or worsened disease activity that occurs after remission has been initially 
induced and affects a major item of the BVAS/WG. New or worsening disease activity which 
occurs while the patient is on ≥20 mg/day of prednisone is considered resistant disease (Section 
7.8).  
For patients who received cyclophosphamide at the start of the study, major relapses may be 
treated with the reintroduction of cyclophosphamide (if it occurs during the maintenance of 
remission phase), an increase in the dose of cyclophosphamide if tolerated, rituximab, additional 
doses of IV methylprednisolone (up to 3 g), an increase in oral prednisone/ prednisolone to the 
same doses used during the initial induction of remission. 
For patients who received rituximab at the start of the study, major relapses may be treated with 
the reintroduction of rituximab, introduction of cyclophosphamide, additional doses of IV 
methylprednisolone (up to 3 g), an increase in oral prednisone/ prednisolone to the same doses 
used during the initial induction of remission. 
The use of plasma exchange to treat a major relapse must be discussed with the medical monitor. 
7.10 Guidelines for the Treatment of Minor Relapses 
A minor relapse is new or worsening disease activity that occurs after remission has been 
initially induced that does NOT affect a major item of the BVAS/WG. New or worsening disease 
activity which occurs while the patient is on ≥20 mg/day of prednisone is considered resistant 
disease.  
 
Minor Relapses may be treated with up to 20 mg/day of prednisone or prednisolone for a 
maximum of 14 days. Following this, if disease activity is controlled, patients will resume their 
GC regimen starting at the next dose below 20 mg/day. If disease activity is not controlled within 
14 days, patients will be regarded as having a major relapse.   
7.11 Prophylactic Therapies 
Consideration should be given to therapies to prevent the complications of treating AAV. This 
includes, but is not limited to, the use of prophylaxis against glucocorticoid induced 
osteoporosis, prophylaxis of Pneumocystis jiroveci (formerly P. carinii) pneumonia infections 
for at least 6 months. Appropriate prophylactic therapy includes sulfamethoxazole-trimethoprim 
as a single strength tablet daily (i.e. 480 mg daily) or a double strength tablet every other day 
thrice weekly (i.e. 960 mg Monday, Wednesday, and Friday). The use of prophylactic therapies 
will be left to local practice and the discretion of local investigators. Care should also be taken by 
the investigators to ensure the non-immunologic sequelae of AAV are also treated (e.g. 
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7.12 Criteria for Discontinuation 
7.12.1 Individual Subject 
Patients will be withdrawn if they withdraw consent. All other patients will be followed until 
trial termination or death. 
7.12.2 Trial 
Either factor of the trial may be discontinued in the event of clear evidence of harm or benefit for 
one treatment regimen on the recommendation of the DMC/DSMB and in conjunction with the 
Trial Management Committee. The Haybittle-Peto approach will be used whereby all interim 
analyses use a difference of 3 standard errors (approximately p=0.002) as a stopping guideline 
(19;20). Efficacy and safety data will be reviewed by the DMC/DSMB on an annual basis. The 
trial is planned to stop 12 months after the last patient is enrolled (common closing date). 
7.13 Patient Selection 
7.13.1 Inclusion Criteria 
Patients must meet all of the following criteria: 
1. New or previous relapsing clinical diagnosis of granulomatosis with polyangiitis 
(Wegener’s), or microscopic polyangiitis consistent with the Chapel-Hill consensus 
definitions (see 7.13.5) AND 
2. Positive test, at any point in the subjects’s disease course, by ELISA, for proteinase 3-
ANCA or myeloperoxidase-ANCA AND 
3. Severe vasculitis defined by at least one of the following manifestations: 
a. Renal involvement characterized by both of the following: 
i. Evidence of glomerulonephritis by either of the following: 
1. Renal biopsy demonstrating focal necrotizing glomerulonephritis 
or  
2. Active urine sediment characterized by glomerular 
haematuria/cellular casts and proteinuria  
AND 
ii. An estimated glomerular filtration (eGFR) rate of <50 ml/min/1.73 m2. 
Patients known to have a stable eGFR <50 ml/min/1.73 m2 for greater than 
three months prior to enrollment are NOT eligible. 
b. Pulmonary hemorrhage due to active vasculitis defined by the following: 
i. A compatible chest x-ray or CT scan (diffuse pulmonary infiltrates)  
AND 
ii. The absence of an alternative explanation for all pulmonary infiltrates (i.e. 
volume overload or pulmonary infection)  
AND 
iii. At least one of the following: 
1. Evidence of alveolar hemorrhage on bronchoscopic examination or 
increasingly bloody returns with bronchoalveolar lavage 
2. Observed hemoptysis 
3. Unexplained anemia (<10 g/dL) or documented drop in 
hemoglobin (>1 g/dL) from less than 10g/dl 
4. An increased diffusing capacity of carbon dioxide 


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4. Provision of informed consent by patient or a surrogate decision maker. In some 
participating countries permission has also been granted to use deferred consent for 
enrolling a patient until a legal representative becomes available to consent on their 
behalf. Please check your national regulations for further guidance. 
 
7.13.2 Exclusion Criteria 
Patients must have none of the following: 
1. A diagnosis of vasculitis other than granulomatosis with polyangiitis (Wegener’s) or 
microscopic polyangiitis 
2. A positive serum test for anti-glomerular basement membrane or a renal biopsy 
demonstrating linear glomerular immunoglobulin deposition 
3. Receipt of dialysis for greater than 21 days immediately prior to randomization or prior 
renal transplant 
4. Age <15 years. In centres that do not routinely treat patients <18 years or if no local 
investigator routinely treats patients <18 years, enrollment may be restricted to patients 
18 years or older* 
5. Pregnant at time of study entry 
6. 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 
treatment with >1 dose of rituximab within the last 28 days 
7. A comorbidity or condition that, in the opinion of the investigator, precludes the use of 
cyclophosphamide/rituximab, glucocorticoids, or plasma exchange or absolutely 
mandates the use of plasma exchange 
8. Plasma exchange in 3 months prior to randomization 
 
* Patients < 18 years of age will be excluded in Germany 
7.13.3 Randomization 
Allocation will occur according to a minimization scheme. Minimization allows the allocation of 
treatments to be balanced for known prognostic risk factors and is particularly useful in small 
trials (<1000 participants) in diseases with many prognostic risk factors (>3).  
The prognostic factors that will serve as minimization strata in PEXIVAS are:  
 severity of renal disease at presentation (requiring dialysis or creatinine ≥ 500 µmol/L 
(5.6 mg/dL) vs. <500 µmol/L) 
 age (<60, ≥ 60 years old) 
 ANCA binding specificity (PR3 vs. MPO) 
 severity of lung hemorrhage (no hemorrhage, hemorrhage with blood oxygen saturation 
>85% on room air, or hemorrhage with blood oxygen saturation ≤ 85% on room air or 
ventilated) 
 induction immunosuppression therapy to be used (IV CYC vs. oral CYC vs. rituximab).  
 
Participants will be minimized in a one-to-one ratio to each intervention or control group by a 
central facility utilizing a computerized randomization algorithm. Randomization will be 
performed using an internet/world wide web based secure program from the Birmingham 
Clinical Trials Unit. This program will provide the investigator with the patient’s unique trial 
identification number and the allocated interventions. The randomization program will also 


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inform the responsible PLEX centre, the study pharmacy and the trial coordinator of the patient’s 
identification number and treatment allocation by email. The minimization sequence will not be 
shared with any investigator. 
7.13.4 Subject Withdrawal Criteria 
Subjects will be withdrawn from the trial at any time that they withdraw consent to participate. 
Patients will otherwise be followed to either the trial end or until death. In the event that consent 
to participate is withdrawn, we will request that we be allowed to collect vital status information 
from the patient and/or their family physician or general practitioner. Subjects who are 
withdrawn will not be replaced. 
7.13.5 Disease definitions 
Granulomatosis with polyangiitis (Wegener’s) is characterised by granulomatous inflammation 
of the respiratory tract, together with necrotizing vasculitis affecting small to medium-sized 
vessels (21). A C-ANCA pattern by IIF with ANCA specific for antibodies to PR3, is found in 
over 90% of untreated patients, a minority have MPO-ANCA. Diagnosis requires the presence of 
chronic inflammation, with a history of at least four weeks affecting the upper and/or lower 
respiratory tract and not attributable to another cause. The diagnosis may be supported by 
characteristic histology, such as a focal, necrotizing, pauci-immune glomerulonephritis; or non-
renal biopsies with an inflammatory exudate dominated by polymorphonuclear leucocytes with 
at least one of (1) necrotizing vasculitis affecting small to medium-sized vessels; (2) epithelioid 
granulomata; or (3) giant cells; and the exclusion of other causes.  
 
Microscopic polyangiitis is characterised by a chronic inflammatory process with non-
granulomatous vasculitis of small vessels (i.e. capillaries, venules, arterioles or small arteries) 
(22). In contrast to granulomatosis with polyangiitis (Wegener’s), granulomatous vasculitis of 
the respiratory tract and/or lung nodules/cavities are absent. Renal involvement is usual and is 
reflected by a focal, necrotizing, pauci-immune glomerulonephritis. Arteritis of medium-sized 
vessels may also occur. Microscopic polyangiitis is associated with MPO-ANCA or PR3-ANCA; 
minorities are ANCA negative or recognise other ANCA autoantigens. Diagnosis of microscopic 
polyangiitis requires the exclusion of secondary causes of vasculitis, including drugs, infections 
and malignancy, and vasculitis mimics, such as, anti-phospholipid syndrome and atheroembolic 
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8.   Study Procedures and Assessments 
Table 4 Summary of PEXIVAS trial assessments and data collected at each assessment.  
*Only performed on women who have child-bearing potential 
** Sites may opt out of this during informed consent 
§ Separate consent for use of renal pathology specimen for research; only applies to patients who have undergone renal biopsy as part of clinical care 
 
Induction of Remission 
Maintenance of Remission 
 
 
Study Visits 
 
Screen 
 
Baseline 
 
 
WK 
2 
WK 
4 
WK 
8 
WK 
12 
 
WK 
26 
WK 
39 
WK 
52 
Every 26 WKs 
until Study 
Termination 
Relapse Visit  
or  
Termination Visit 
Study Drug 
 
 
 
 
 
 
 
 
 
 
 
 
 
Glucocorticoid Dose 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
PLEX Type/Details 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Data Forms 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Data 
X 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Weight 
 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Medications 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
BVAS/WG 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
CDA 
 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
SF-36 and EQ5D 
 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
Adverse Event Report 
 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Clinical Labs 
 
 
 
 
 
 
 
 
 
 
 
 
 
ANCA 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
Anti-GBM 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Creatinine 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Pregnancy Test* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Research Specimens 
 
 
 
 
 
 
 
 
 
 
 
 
 
DNA** 
 
X 
 
 
 
 
 
 
 
 
 
 
 
RNA 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Serum 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
Plasma 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
Renal pathology§ 
 
X 
 
 
 
 
 
 
 
 
 
 
 


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7.14 Screening Evaluation and Informed Consent 
Potential participants will undergo a screening evaluation by a study physician or qualified study 
nurse to determine if the patient meets all of the inclusion criteria and none of the exclusion 
criteria. The screening visit requires documentation of ANCA results, organ manifestations of 
active AAV, serum creatinine/eGFR result, assessment of treatment with cyclophosphamide and 
glucocorticoids in the last 14 days, assessment of use of dialysis within the last 21 days, a 
pregnancy test where applicable, documentation of pulmonary hemorrhage if applicable, anti-
glomerular basement membrane antibody result, and available pertinent histology results. 
 
Informed consent will be sought from all potentially eligible patients. Detailed study information 
will be reviewed with eligible patients or the family or legal guardians of eligible patients that 
are unable to understand the consent process due to medical or mental illness. After disclosure of 
the study details and potential risks and benefits of participating in the study, patients will be 
given adequate time to consider consenting to participate. Patients that participate will undergo a 
baseline visit as soon as possible and will then be randomized. 
Therapy with IV methylprednisolone and/or cyclophosphamide may begin during screening. 
7.15 Baseline Data 
Baseline data will include basic demographic information, laboratory data, and clinical data and 
will be collected prior to receiving study therapy. This information will include: 
 Date of birth, sex, limited medical history 
 Medications 
 Height/Weight 
 Disease activity assessment (BVAS/WG) 
 Disease related damage assessment (CDA) 
 Serum creatinine/dialysis status 
 Patient self-reported Short Form 36 questionnaire and EQ-5D questionnaire 
 Biological specimens for biobank 
7.16 Randomization 
Before randomization, the investigator or treating physician must decide on induction treatment 
(i.e., IV cyclophosphamide, oral cyclophosphamide, or rituximab). Randomization may be 
performed by the local investigator or other qualified local research staff. Patients will be 
randomized by logging in to an internet based website provided by the Birmingham Clinical 
Trials Unit (https://www.trials.bham.ac.uk/PEXIVAS). After logging in the investigator will 
confirm the eligibility criteria and specify the intended route of cyclophosphamide. The 
randomization algorithm will then assign the patient to either PLEX or no PLEX and to either 
reduced-dose glucocorticoids or usual dose glucocorticoids and will assign the patient a unique 
trial identification number to be used on all trial related material for the patient. Notification of 
the treatment allocation and trial identification number will be forwarded to the trial coordinator, 
the local investigator and local plasma exchange provider, and the local pharmacy via electronic 
mail (email) upon randomization. In the event access to the internet is unavailable, the 
investigator may call the Birmingham Clinical Trials Unit (BCTU), Tel: 0800 953 0274 (toll free 
in UK, available 9am to 5pm UK time), or +44 (0)121 415 9137 (from outside the UK, available 
9am to 5pm UK time) who will access the paper randomization system and inform the 


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investigator of the treatment allocation and ensure randomization information reaches the 
appropriate study personnel. 
7.17 Induction of Remission 
During remission induction  (up to 6 months) patients will be seen at weeks 2, 4, 8, 12. During 
these study visits, basic clinical and laboratory data will be collected and will include: 
 Medications (including glucocorticoid dose) 
 Disease activity assessment (BVAS/WG) and CDA (week 12) 
 Serum creatinine 
 Adverse Events 
 Patient self-reported Short Form 36 questionnaire and EQ-5D questionnaire (week 12) 
7.18 Maintenance of Remission 
During the maintenance of remission phase patients will be seen at 26, 39, 52 weeks and then 
every 26 weeks. During these study visits, basic clinical and laboratory data will be collected and 
will include: 
 Medications 
 Disease activity assessment (BVAS/WG, and CDA) 
 Serum creatinine 
 Patient self-reported Short Form 36 questionnaire and EQ-5D questionnaire (each visit 
except week 39) 
 Adverse events 
7.19 Termination of Study 
Follow-up for all patients will end on the common Termination of Study date. If a patient has not 
been reviewed in the last 3 months, they be seen for a final study visit. At the termination of 
study visit, basic clinical and laboratory data will be collected and will include: 
 Medications 
 Disease activity assessment (BVAS/WG and CDA) 
 Serum creatinine 
 Patient self-reported Short Form 36 questionnaire and EQ-5D questionnaire 
 Adverse events 
8 
Assessment of Safety 
8.1 
Definitions 
8.1.1 Adverse event 
Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment. 
An adverse event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an investigational 
medicinal product, whether or not considered related to the investigational medicinal product 
8.1.2 Adverse reaction of an investigational medicinal product (AR) 
All untoward and unintended responses to an investigational medicinal product related to any 


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dose administered. All adverse events judged by either the reporting investigator or the sponsor 
as having a reasonable causal relationship to a medicinal product qualify as adverse reactions. 
The expression “reasonable causal relationship” means to convey in general that there is 
evidence or argument to suggest a causal relationship 
8.1.3 Unexpected adverse reaction 
An adverse reaction, the nature, or severity of which is not consistent with the applicable product 
information (e.g. investigator's brochure for an unapproved investigational product or summary 
of product characteristics (SmPC) for an authorised product). 
 
When the outcome of the adverse reaction is not consistent with the applicable product 
information this adverse reaction should be considered as unexpected. 
 
The term “severe” is often used to describe the intensity (severity) of a specific event. This is not 
the same as “serious,” which is based on patient/event outcome or action criteria. 
8.1.4 Serious adverse event or serious adverse reaction 
Any untoward medical occurrence or effect that: 
- 
results in death, 
- 
is life-threatening 
- 
requires hospitalisation or prolongation of existing inpatients hospitalisation, 
- 
results in persistent or significant disability or incapacity, 
- 
is a congenital anomaly or birth defect. 
 
Life-threatening in the definition of a serious adverse event or serious adverse reaction refers to 
an event in which the subject was at risk of death at the time of event; it does not refer to an 
event which hypothetically might have caused death if it were more severe. 
8.2 
Expected adverse drug reactions 
Plasma exchange is associated with the following adverse reactions, in 5-10% of procedures 
(details in section (8.6)): 
 
 Respiratory: dyspnea 
 Cardiac: arrhythmias, hypotension 
 Metabolic: hypocalcemia, metabolic alkalosis 
 Hematologic: coagulation abnormalities, bleeding 
 Infection: bacterial infections, catheter related blood stream infections, transmission of 
viral infections via blood products 
 Dermatologic: urticaria 
 Neurologic: paresthesia 
 
Plasma exchange is also associated with the following Serious Adverse Events, in 0.5% of 
procedures: 
 Respiratory: acute respiratory distress syndrome, non-cardiogenic pulmonary edema 
(TRALI or transfusion-related acute lung injury), pneumothorax, hemothorax 
 Cardiac: arrhythmias, hypotension, arterial dissection, air embolism 
 Hematological: bleeding, bleeding diathesis, venous thrombosis 


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 Infection: blood stream infections, sepsis 
 
Prednisone and prednisolone are associated with the following adverse drug reactions (details in 
section 8.6):  
 
 >10%: 
  Central nervous system: Insomnia, nervousness 
  Gastrointestinal: Increased appetite, indigestion 
 1% to 10%: 
  Central nervous system: Dizziness or lightheadedness, headache 
  Dermatologic: Hirsutism, hypopigmentation 
  Endocrine & metabolic: Diabetes mellitus, glucose intolerance, hyperglycemia 
  Neuromuscular & skeletal: Arthralgia 
  Ocular: Cataracts, glaucoma 
  Respiratory: Epistaxis 
  Miscellaneous: Diaphoresis 
 <1% (Limited to important): Cushing's syndrome, edema, fractures, hallucinations, 
hypertension, muscle-wasting, osteoporosis, pancreatitis, pituitary-adrenal axis 
suppression, seizures 
Prednisone and Prednisolone are also associated with the following Serious Adverse Events: 
 Musculoskeletal: insufficiency fractures, avascular osteonecrosis 
 Cardiovascular: premature atherosclerosis, myocardial infarction 
 Gastrointestinal: ulceration and bleeding 
 Central nervous system: psychosis 
 Endocrine: hyperosmolar non-ketotic state, Addisonian crisis 
 Miscellaneous: Bacterial infections, fungal infections, viral infections, ocular herpes 
zoster 
 
8.3 
Recording and evaluation of adverse events 
Non-serious expected or unexpected adverse events, with the exception of infections, will not be 
collected or reported as part of this trial.   
Infections are defined as episodes, which require treatment with intravenous (IV) or oral 
antibiotics or hospitalization, or infections that are commonly understood to be opportunistic. 
8.4 
Recording and evaluation of serious adverse events 
Individual serious adverse events need to be recorded by the investigator and reported to the 
Cambridge central study coordinator for evaluation immediately, and within 24 hours of the 
investigator becoming aware of the event. This includes the evaluation of its seriousness and the 
causality between the investigational medicinal product(s) and/or concomitant therapy and the 
adverse event. 
 
The sponsor has to keep detailed records of all SAEs reported to him by the investigator(s´) and 
to perform an evaluation with respect to seriousness, causality and expectedness. 


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8.4.1 Assessment of seriousness 
Mild: 
The subject is aware of the event or symptom, but the event or symptom is easily 
tolerated 
Moderate: The subject experiences sufficient discomfort to interfere with or reduce his or her 
usual level of activity 
Severe: 
Significant impairment of functioning; the subject is unable to carry out usual 
activities and / or the subject’s life is at risk from the event. 
8.4.2 Assessment of causality 
Probable: A causal relationship is clinically / biologically highly plausible and there is a 
plausible time sequence between onset of the AE and administration of the 
investigational medicinal product and there is a reasonable response on 
withdrawal. 
Possible: A causal relationship is clinically / biologically plausible and there is a plausible 
time sequence between onset of the AE and administration of the investigational 
medicinal product. 
Unlikely: A causal relation is improbable and another documented cause of the AE is most 
plausible. 
Unrelated: A causal relationship can be definitely excluded and another documented cause of 
the AE is most plausible. 
8.5 
Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) 
All suspected adverse reactions related to an investigational medicinal product (the tested 
investigations medical products and comparators) which occur in the concerned trial, and that are 
both unexpected and serious (SUSARs) are subject to expedited reporting.  
8.5.1 Who should report and whom to report to? 
The chief investigator and central study coordinator (not the sponsor) should report all the 
relevant safety information previously described to the concerned competent authorities and to 
the Ethics Committee concerned. The chief investigator and central study coordinator (not the 
sponsor) shall inform all investigators concerned of relevant information about SUSARs that 
could adversely affect the safety of subjects. 
8.5.2 When to report? 
8.5.2.1 Fatal or life-threatening SUSARs 
The MHRA and the Research Ethics Committee should be notified within 24 hours of 
knowledge of the event but no later than 7 calendar days after the sponsor has first knowledge of 
the minimum criteria for expedited reporting. 
In each case relevant follow-up information should be sought and a report completed as soon as 
possible. It should be communicated to the MHRA and the Ethics Committee within an 
additional eight calendar days. 
8.5.2.2 Non fatal and non life-threatening SUSARs 
All other SUSARs and safety issues must be reported to the competent authority and the Ethics 
Committee in the concerned Member States as soon as possible but no later than 15 calendar 
days after the sponsor has first knowledge of the minimum criteria for expedited reporting. 
Further relevant follow-up information should be given as soon as possible. 


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8.5.3 How to report? 
8.5.3.1 Minimum criteria for initial expedited reporting of SUSARs 
Information on the final description and evaluation of an adverse reaction report may not be 
available within the required time frames for reporting. For regulatory purposes, initial expedited 
reports should be submitted within the time limits as soon as the minimum following criteria are 
met: 
a) a suspected investigational medicinal product, 
b) an identifiable subject (e.g. study subject code number), 
c) an adverse event assessed as serious and unexpected, and for which there is a reasonable 
suspected causal relationship, 
d) an identifiable reporting source, and, when available and applicable: 
- an unique clinical trial identification (EudraCT number or in case of non-European 
Community trials the sponsor's trial protocol code number) 
- an unique case identification (i.e. sponsor's case identification number). 
8.5.3.2 Follow-up reports of SUSARs 
In case of incomplete information at the time of initial reporting, all the appropriate information 
for an adequate analysis of causality should be actively sought from the reporter or other 
available sources. The sponsor should report further relevant information after receipt as follow-
up reports. 
In certain cases, it may be appropriate to conduct follow-up of the long-term outcome of a 
particular reaction. 
8.5.3.3 Format of the SUSARs reports 
Electronic reporting should be the expected method for expedited reporting of SUSARs to the 
MHRA. In that case, the format and content as defined by the Guidance 1 should be adhered to. 
The CIOMS-I form is a widely accepted standard for expedited adverse reactions reporting. 
However, no matter what the form or format used, it is important that the basic information/data 
elements described in annex 3 of the EU directive, when available, be included in any expedited 
report (some items may not be relevant, depending on the circumstances). 
8.6 
Reporting adverse events 
The sponsor is responsible for the prompt notification to all concerned investigator(s), the 
Research Ethics Committee and competent authority (e.g. MHRA) of each concerned Member 
State of findings that could adversely affect the health of subjects, impact on the conduct of the 
trial or alter the competent authority’s authorisation to continue the trial in accordance with 
Directive 2001/20/EC. 
8.7 
Known Potential Risks 
8.7.1 Plasma Exchange 
 
Mortality: PLEX has a reported fatality rate of 1 death per 20,000 exchanges (Canadian 
Apheresis Group, unpublished data). The dominant causes are respiratory or cardiac 
complications, often attributable to underlying diagnoses such as TTP. Respiratory complications 
include acute respiratory distress syndrome, and noncardiacogenic pulmonary edema (TRALI), 


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while cardiac complications include arrhythmias and hypotension. Both respiratory and cardiac 
complications are more common with plasma replacement than albumin replacement fluids. 
 
Coagulation Abnormalities: PLEX with albumin as a replacement fluid decreases clotting 
factors. Prothrombin time may increase 30% and partial thromboplastin time may double. These 
changes tend to normalize within 4 hours after PLEX but may become more long lasting with 
repeated PLEX procedures over a short period. The bleeding risk from the depletion of 
coagulation factors may be increased by the use of systemic anticoagulation (e.g. heparin). 
 
Infection Risks: PLEX reduces immunoglobulin levels and may therefore increase the risk of 
infection. This risk is increased by the placement of central venous catheters and concomitant 
renal failure. Viral transmission from plasma products may also occur. The risks are largely 
dependent on the local plasma donor population and screening procedures used. 
 
Metabolic:  PLEX procedures utilizing citrate anticoagulation may induce severe hypocalcemia 
due to the binding of free calcium by citrate. PLEX with citrate anticoagulation may also induce 
metabolic alkalosis when there is concurrent renal impairment, especially if plasma is the sole 
replacement fluid. 
 
Drug Removal: Highly protein bound drugs are significantly removed during PLEX. Drugs such 
as prednisone and prednisolone are largely unaffected but cyclophosphamide (10-60% protein 
bound) and azathioprine (30% protein bound) may be removed by PLEX. The administration of 
drugs particularly antibiotics and cyclophosphamide after a PLEX treatment may minimize this 
removal. 
 
Complications of Central Line Placement:  CVC placement may be complicated by discomfort, 
bleeding, perforation or dissection of an arterial vessel, air embolism, pneumothorax, 
hemothorax, local infection, or a blood stream infection, or thrombosis.  
 
Hypotension: PLEX may result in a reduction in blood pressure due to a diminished intravascular 
volume. This risk may be slightly higher in machines utilizing discontinuous blood flow 
technology. Vasovagal reactions, hypocalcemia, and ACE inhibitors may also contribute to 
hypotension.  
 
Dyspnea: PLEX procedures, particularly in patients with renal disease, may be complicated by 
dyspnea due to volume overload. Dyspnea may also occur from allergic bronchospasm or non-
cardiogenic pulmonary edema (TRALI) in patients that receive fresh frozen plasma as 
replacement fluid, or from complement activation in machines that utilize bio-incompatible 
membranes.  
8.7.2 Glucocorticoids 
From post-marketing experience, the following side-effect incidences are commonly quoted. The 
occurrence of drug reactions is generally dose dependent. Table 5 lists additional major reactions 
to prednisolone. 
 


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 
>10% of patients experience: 
  Central nervous system: Insomnia, nervousness 
  Gastrointestinal: Increased appetite, indigestion 
 
 
1% to 10% of patients experience: 
  Central nervous system: Dizziness or lightheadedness, headache 
  Dermatologic: Hirsutism, hypopigmentation 
  Endocrine & metabolic: Diabetes mellitus, glucose intolerance, hyperglycemia 
  Neuromuscular & skeletal: Arthralgia 
  Ocular: Cataracts, glaucoma 
  Respiratory: Epistaxis 
  Miscellaneous: Diaphoresis 
 
<1% of patients experience (Limited to important): Cushing's syndrome, edema, fractures, 
hallucinations, hypertension, muscle-wasting, osteoporosis, pancreatitis, pituitary-adrenal axis 
suppression, seizures 
 
Table 5 Commonly recognized adverse reactions to oral glucocorticoids. 
Dermatologic and soft tissue 
Renal 
Skin thinning and purpura 
Hypokalemia 
Cushingoid appearance 
Fluid volume shifts 
Alopecia 
Genitourinary and reproductive 
Acne 
Amenorrhea/infertility 
Hirsutism 
Intrauterine growth retardation 
Striae 
Bone 
Hypertrichosis 
Osteoporosis 
Eye 
Avascular necrosis 
Posterior subcapsular cataract 
Muscle 
Elevated intraocular 
pressure/glaucoma 
Myopathy 
Exophthalmos 
Neuropsychiatric 
Cardiovascular 
Euphoria 
Hypertension 
Dysphoria/depression 
Perturbations of serum lipoproteins 
Insomnia/akathisia 
Premature atherosclerotic disease 
Psychosis 
Arrhythmias with pulse infusions 
Pseudo tumor cerebri 
Gastrointestinal 
Endocrine 


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Gastritis 
Diabetes mellitus 
Peptic ulcer disease 
Hypothalamic-pituitary-adrenal insufficiency 
Pancreatitis 
Infectious disease 
Steatohepatitis 
Heightened risk of typical infections 
Visceral perforation 
Opportunistic infections 
 
Herpes zoster 
 
8.7.3 Cyclophosphamide 
 
Serious side effects include infertility, carcinogenesis, mutagenesis and an increased risk of 
bacterial, viral and fungal infections. 
 
Digestive System: Nausea and vomiting commonly occur with Cyclophosphamide therapy. 
Anorexia and, less frequently, abdominal discomfort or pain and diarrhea may occur. There are 
isolated reports of hemorrhagic colitis, oral mucosal ulceration and jaundice occurring during 
therapy. These adverse drug effects generally remit when cyclophosphamide treatment is 
stopped. 
 
Skin and Its Structures: Alopecia occurs commonly in patients treated with Cyclophosphamide. 
The hair can be expected to grow back after treatment with the drug or even during continued 
drug treatment, though it may be different in texture or color. Skin rash occurs occasionally in 
patients receiving the drug. Pigmentation of the skin and changes in nails can occur. Very rare 
reports of Stevens-Johnson syndrome and toxic epidermal necrolysis have been received during 
postmarketing surveillance; due to the nature of spontaneous adverse event reporting, a definitive 
causal relationship to Cyclophosphamide has not been established. 
 
Hematopoietic System: Leukopenia occurs in patients treated with Cyclophosphamide, is related 
to the dose of drug, and can be used as a dosage guide. Leukopenia of less than 2000 cells/mm3 
develops commonly in patients treated with an initial loading dose of the drug, and less 
frequently in patients maintained on smaller doses. The degree of neutropenia is particularly 
important because it correlates with a reduction in resistance to infections. Fever without 
documented infection has been reported in neutropenic patients. Thrombocytopenia or anemia 
develop occasionally in patients treated with Cyclophosphamide. These hematologic effects 
usually can be reversed by reducing the drug dose or by interrupting treatment. Recovery from 
leukopenia usually begins in 7 to 10 days after cessation of therapy. 
 
Urinary System: Cystitis and urinary bladder fibrosis. Hemorrhagic ureteritis and renal tubular 
necrosis have been reported to occur in patients treated with Cyclophosphamide. Such lesions 
usually resolve following cessation of therapy. 
Infections: Patients have a reduced resistance to all infections. 


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Respiratory System: interstitial pneumonitis has been reported as part of the postmarketing 
experience. Interstitial pulmonary fibrosis has been reported in patients receiving high doses of 
Cyclophosphamide over a prolonged period. 
 
Other: Anaphylactic reactions have been reported; death has also been reported in association 
with this event. Possible cross-sensitivity with other alkylating agents has been reported. SIADH 
(syndrome of inappropriate ADH secretion) has been reported with the use of 
Cyclophosphamide. Malaise and asthenia have been reported as part of the postmarketing 
experience. 
8.7.4 Azathioprine 
The principal and potentially serious toxic effects of azathioprine are hematologic and 
gastrointestinal. The risks of secondary infection and neoplasia are also significant. The 
frequency and severity of adverse reactions depend on the dose and duration of azathioprine as 
well as on the patient's underlying disease or concomitant therapies. The incidence of 
hematologic toxicities and neoplasia encountered in groups of renal homograft recipients is 
significantly higher than that in studies employing azathioprine for rheumatoid arthritis. The 
relative incidences in clinical studies are summarized below and in Table 6: 
 
Table 6 Adverse side effects associated with azathioprine in patients treated to prevent rejection 
of a renal transplant or treated for rheumatoid arthritis. 
Toxicity 
Renal Transplant 
Rheumatoid Arthritis 
Leucopenia (any degree) 
>50% 
28% 
<2.5x109 cells/L 
16% 
5.3% 
Infections 
20% 
<1% 
Neoplasia/Lymphoma 
0.5% 
Unknown 
Other Adverse Events 
2.8% 
 
 
Hematologic: Leukopenia and/or thrombocytopenia are dose-dependent and may occur late in 
the course of therapy with azathioprine. Dose reduction or temporary withdrawal may result in 
reversal of these toxicities. Infection may occur as a secondary manifestation of bone marrow 
suppression or leucopenia, but the incidence of infection in renal transplantation is 30 to 60 times 
that in rheumatoid arthritis. Macrocytic anemia and/or bleeding have been reported. 
 
Thiopurine S-methyl transferase (TPMT) genotyping or phenotyping can help identify patients 
with low or absent TPMT activity (homozygous for non-functional alleles) who are at increased 
risk for severe, life-threatening myelosuppression from azathioprine. Death associated with 
pancytopenia has been reported in patients with absent TPMT activity receiving azathioprine. 
Gastrointestinal: Nausea and vomiting may occur within the first few months of therapy with 
azathioprine, and occurred in approximately 12% of 676 rheumatoid arthritis patients. The 
frequency of gastric disturbance often can be reduced by administration of the drug in divided 
doses and/or after meals. However, in some patients, nausea and vomiting may be severe and 
may be accompanied by symptoms such as diarrhea, fever, malaise, and myalgias. Vomiting 
with abdominal pain may occur rarely with a hypersensitivity pancreatitis. Hepatotoxicity 
manifest by elevation of serum alkaline phosphatase, bilirubin, and/or serum transaminases is 
known to occur following azathioprine use, primarily in allograft recipients. Hepatotoxicity has 


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been uncommon (less than 1%) in rheumatoid arthritis patients. Hepatotoxicity following 
transplantation most often occurs within 6 months of transplantation and is generally reversible 
after interruption of azathioprine. A rare, but life-threatening hepatic veno-occlusive disease 
associated with chronic administration of azathioprine has been described in transplant patients 
and in one patient receiving azathioprine for panuveitis. Periodic measurement of serum 
transaminases, alkaline phosphatase, and bilirubin is indicated for early detection of 
hepatotoxicity. If hepatic veno-occlusive disease is clinically suspected, azathioprine should be 
permanently withdrawn. 
 
Others: Additional side effects of low frequency have been reported. These include skin rashes, 
alopecia, fever, arthralgias, diarrhea, steatorrhea, negative nitrogen balance, reversible interstitial 
pneumonitis and hepatosplenic T-cell lymphoma. 
 
Serious Side Effects: 
Severe leucopenia, thrombocytopenia, macrocytic anemia, and/or pancytopenia may occur in 
patients being treated with IMURAN. Severe bone marrow suppression may also occur. Patients 
with intermediate TPMT activity may be at an increased risk of myelotoxicity if receiving 
conventional doses of azathioprine. Patients with low or absent TPMT activity are at an 
increased risk of developing severe, life-threatening myelotoxicity if receiving conventional 
doses of azathioprine. TPMT genotyping or phenotyping can help identify patients who are at an 
increased risk for developing azathioprine toxicity. Hematologic toxicities are dose-related and 
may be more severe in renal transplant patients whose homograft is undergoing rejection. Bone 
marrow and hepatotoxicity should be assessed according to local practice but as a minimum we 
suggest checking full blood counts and aminotransferases every two weeks for the first month of 
azathioprine therapy and then every two months for the first year of therapy and every three 
months thereafter. Delayed hematologic suppression may occur. Prompt reduction in dosage or 
temporary withdrawal of the drug may be necessary if there is a rapid fall in or persistently low 
leukocyte count, or other evidence of bone marrow depression. Leucopenia does not correlate 
with therapeutic effect; therefore the dose should not be increased intentionally to lower the 
white blood cell count. 
 
Serious infections are a constant hazard for patients receiving chronic immunosuppression, 
especially for homograft recipients. Fungal, viral, bacterial, and protozoal infections may be fatal 
and should be treated vigorously. Reduction of azathioprine dosage and/or use of other drugs 
should be considered. 
 
Azathioprine is mutagenic in animals and humans, carcinogenic in animals, and may increase the 
patient's risk of neoplasia. Renal transplant patients are known to have an increased risk of 
malignancy, predominantly skin cancer and reticulum cell or lymphomatous tumors. The risk of 
post-transplant lymphomas may be increased in patients who receive aggressive treatment with 
immunosuppressive drugs. The degree of immunosuppression is determined, not only by the 
immunosuppressive regimen, but also by a number of other patient factors. The number of 
immunosuppressive agents may not necessarily increase the risk of post-transplant lymphomas. 
However, transplant patients who receive multiple immunosuppressive agents may be at risk for 
over-immunosuppression; therefore, immunosuppressive drug therapy should be maintained at 
the lowest effective levels. Information is available on the spontaneous neoplasia risk in 


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rheumatoid arthritis, and on neoplasia following immunosuppressive therapy of other 
autoimmune diseases. It has not been possible to define the precise risk of neoplasia due to 
azathioprine. The data suggest the risk may be elevated in patients with rheumatoid arthritis, 
though lower than for renal transplant patients. However, acute myelogenous leukemia as well as 
solid tumors have been reported in patients with rheumatoid arthritis who have received 
azathioprine.  
 
Azathioprine has been reported to cause temporary depression in spermatogenesis and reduction 
in sperm viability and sperm count in mice at doses 10 times the human therapeutic dose; a 
reduced percentage of fertile matings occurred when animals received 5 mg/kg.11 
9 
Study Risk Assessment 
Data from this trial will be handled by the Birmingham Clinical Trials Unit (BCTU), a full time 
research facility dedicated to, and with substantial experience in, the design and conduct of 
randomized clinical trials. The BCTU is an experienced clinical trials unit that has participated in 
numerous large, multinational studies in the areas of hematology, oncology and renal medicine. 
The BCTU recognizes the responsibilities of a data management centre with respect to the 
ethical practice of research and the adequate protection of human subjects. All BCTU staff 
members are trained and certified in Good Clinical Practice standards. Additionally, all staff and 
investigators in this study who contact patients or their data or have the potential to handle 
patient data are required to complete and provide documentation of Good Clinical Practice 
certification. 
 
9.1 
Risks to the Subjects 
 
a. Human Subjects Involvement and Characteristics: 
The proposed research project will involve 700 adult patients with systemic vasculitis of all 
health statuses. Inclusion criteria includes having a diagnosis of ANCA-associated vasculitis 
(AAV, granulomatosis with polyangiitis, microscopic polyangiitis) with at least one severe 
manifestation that is either nephritis or lung hemorrhage. Patients with anti-glomerular basement 
membrane disease, other forms of vasculitis, or who are pregnant will be excluded. A patient 
who subsequently becomes pregnant during the trial does not have to be excluded provided that 
she remains consented for the trial and that all teratogenic medications are switched to safer 
alternatives, as per clinical practice. Two interventions are planned in this study in addition to 
standard care; with 50% of patients exposed to each intervention: 1) adjuvant plasma exchange; 
and 2) low-dose oral glucocorticoids. 
 
b. Sources of Materials: 
Medical records will be reviewed for all subjects. Routine physical examinations will be 
performed. The extent of data collection are contained in the protocol. One hundred and twenty 
millilitres in total of extra blood will be taken for research purposes at the same time as routine 
blood tests during the first year of the study. .These biomarker samples will be sent on a regular 
basis to the international coordinating PEXIVAS centre at Cambridge. Only local investigators 
will have access to any identifiable information on study subjects. 
 


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c. Potential Risks: 
The hazards of this trial to patient safety are low-moderate given the experience of the 
investigators with the proposed interventions. These hazards for plasma exchange include the 
risk of adverse events related to central line placement (some patients may be able to have this 
procedure performed using peripheral intravenous access), the risks of infectious diseases due to 
receipt of a blood product, the risk of hypomagnesemia or hypocalcemia with citrate anti-
coagulation, and the risk of a coagulopathy/bleeding diathesis (Section 8.2 and 8.6.1). Of note, 
the serious adverse event rate in a previous trial of plasma exchange in severe AAV was not 
greater than in the group not receiving plasma exchange.  
 
For the reduced-dose GC regimen, these hazards include the theoretical risk of precipitating a 
flare of AAV or delay in the time to remission of their AAV.  
 
In addition, all subjects will experience the potential inconvenience of study appointments. Lost 
school or work time for both patients and their family members is unavoidable in performing this 
study. However, every effort will be made to perform study visits in an efficient manner and to 
have them coincide with appointments that would be made with standard care to minimize the 
excess burden of the study. The medical interviews are not anticipated to be psychologically 
harmful or stressful.  
9.2 
 Adequacy of Protection Against Risks 
 
a. Recruitment and Informed Consent: 
Recruitment will occur through the investigators’ clinical practices and from referring 
physicians. The Ethics Committee/Institutional Review Board of each participating center will 
approve this protocol as well as the consent forms to be used prior to study start or enrollment. 
Details of the goals of the research and the risk and benefits of the protocol will be reviewed with 
each potential study subject. Recruitment will occur by physicians, study nurses, and research 
coordinators. 
 
Patients who decline to participate in any or all parts of the study will still have available the 
opportunity of evaluation by a vasculitis expert if they or their physician feels this is appropriate. 
 
Strict patient confidentiality will be observed throughout all aspects of the study. While medical 
records will be reviewed by members of the research team, no individually identifiable patient 
data will be distributed to non-research or care-giving team members. BUT the onsite monitor 
could have access to identifiable patient info during inspections. 
 
In the event of adverse effects from the study, the full resources of the hospital will be available 
to intervene as medically necessary.  Licensed physicians expert in the care of patients with 
vasculitis are available at all times at each study site. 
 
9.3 
Potential Benefits of the Proposed Research to the Subject and Others 
As described above, the potential risks to the study subjects in participating in this study are low-
moderate. Participants in this study are unlikely to gain direct benefit from participation. If the 
study leads to higher quality care or therapeutic trials for vasculitis then study patients could 


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theoretically benefit in the future. All subjects will potentially have the satisfaction of helping to 
contribute to medical knowledge of vasculitis. Further understanding of both the clinical and 
molecular aspects of vasculitis is of great medical importance and because progress in 
understanding these diseases is expected from this study it is felt that the potential benefits of this 
research outweigh the risks of participation. 
9.4 
Importance of the Knowledge to be Gained 
Knowledge to be gained from this study will be highly important. The optimization of treatment 
strategies for patients with severe AAV has the potential to dramatically and directly affect 
clinical practice and patient outcomes. This is underscored by the current widely varied practice 
patterns regarding use of plasma exchange technology and the consistently poor outcomes of the 
AAV patient population. Furthermore, the relative rarity of patients with AAV has traditionally 
made it difficult to collect high quality data on interventions that affect hard, clinical endpoints. 
This trial would also allow a unique perspective on the pathogenesis of AAV given the novel 
mechanism of action of the plasma exchange therapy.  
10 Study Monitoring 
 
PEXIVAS will employ central statistical monitoring of data. This monitoring process will be 
applied by the Birmingham Clinical Trials Unit. Trial sites identified by the central statistical 
monitoring process as having outlying data or that have extensive quality control issues will 
undergo on-site monitoring. Additional sites will undergo random on-site monitoring on a 
periodic basis. 
11 Data and Safety Monitoring Plan 
An independent Data Monitoring Committee/Data and Safety Monitoring Board (DMC/DSMB) 
will be established for this trial and will include at least one member from each of the following 
designations: a statistician, an expert in vasculitis and an expert in trial methodology. The 
DMC/DSMB will meet annually to review all collected data and may meet more frequently if 
required after analysis of the available data. The DMC/DSMB will advise the Trial Management 
Committee and the independent Trial Steering Committee on the safety of continuing this 
clinical trial. A report from each meeting of the DMC/DSMB will be forwarded to each 
Institutional Review Board at each participating center.  
 
All unexpected serious adverse events will be reported to the Trial Management Committee and 
the trial Sponsors (the Cambridge University Hospitals NHS Foundation Trust) by facsimile 
within 24 hours of knowledge of their occurrence by local investigators. The receipt of all 
serious adverse events must be acknowledged by the Sponsor and the Sponsor must forward 
notification of all serious events to the responsible authorities of participating countries within 7 
days of the initial notification. All other serious adverse events must be reported to the Sponsor 
and the Trial Management Committee within 14 days of knowledge of their occurrence by the 
local investigator. The Sponsor will process, record and report these serious adverse events and a 
report will be forwarded to the responsible regulatory agency of each participating country and 
the local institutional review boards of each participating center in the United States annually. A 
listing of all suspected serious adverse reactions will also be made available globally as per 


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European law. All data regarding the occurrence of serious adverse events will be made available 
to the DMC/DSMB for review. 
12 Statistical Considerations 
12.1 Sample Size Estimation 
The sample size for this trial is event driven in order to detect a hazard ratio of 0.64 (PLEX 
versus no PLEX) with 80% power and a two sided alpha of 0.05. Protocol versions 1.0 and 2.0 
estimated a required sample size of 500 predicting 164 events over the study period equivalent to 
a 12% absolute risk reduction of the primary endpoint at five years - 44% in the control group vs. 
32% in PLEX group (overall 38%). This sample size estimate assumed a five year median time 
to ESRD or death on the basis of previous extended follow-up studies in randomized trials of 
AAV of a similar severity to those targeted in this study (Figure 1). Review of PEXIVAS event 
rates in 2014 indicates a two year event rate of 24% and predicted overall five year event rate of 
30-35%. Improvements in death and ESRD have been recently reported in registry studies. In 
order to obtain the required number of events the sample size needs to be increased to 675-725 
patients allowing a 10% loss to follow-up in or cross over between treatment groups. The trial 
now plans to enroll 700 patients over a six and a half year period with a minimum of one year of 
follow-up and therefore a maximum follow-up of seven and a half years in order to observe at 
least 160 events. These calculations assume no significant interaction between the two treatment 
factors. Although this absolute risk appears larger than is often clinically significant, the 
expensive and invasive nature of the primary intervention, PLEX warrants a relatively large 
effect size. Additionally, this effect size is close to the estimated effect of PLEX in the meta-
analysis of prior studies (80% power to detect a relative risk reduction of 27% with our sample 
size compared to a relative risk reduction of 20% in the meta-analysis). 
While this effect size appears reasonable to detect for PLEX, it is unlikely a reduction in GC will 
result in a 12% absolute risk reduction of death or dialysis. However, we expect approximately 
25% of patients to experience a severe infection based on prior studies. A sample size of over 
700 patients will allow 80% power to detect at least a 10% absolute risk reduction in severe 
infections (relative risk reduction of severe infection by 40%), a finding of clinical significance. 
In terms of the non-inferiority hypothesis, a sample size of 700 patients would allow >80% 
power to ensure that the reduced-dose GC regimen results in an increase in ESRD or death by no 
more than 11% (one-sided alpha of 0.05). 
12.2 Planned Analyses 
12.2.1 Interim Analyses 
Interim analyses of efficacy and safety are planned annually.  The Haybittle-Peto approach will 
be used whereby all interim analyses use a difference of 3 standard errors (approximately 
p=0.002) as a stopping guideline. Safety data will be reviewed by the DMC/DSMB on an annual 
basis or more frequently if required by the DMC/DSMB or Trial Management Committee. 
12.2.2 Primary Endpoint Analyses 
The final analysis of all trial data will occur one years after the final patient is enrolled. 
The primary analysis for this study will be a comparison between groups of time-to the 
development of ESRD or death by any cause. The primary comparison groups will be composed 
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a reduced-dose GC regimen to those treated with a standard-dose (comparison 2). A test for 
interaction between treatments will be performed but will be interpreted cautiously. It is 
anticipated that the randomization/minimization strategy will be successful and the primary 
analysis can be conducted with a simple log-rank test. Kaplan-Meier survival curves will be 
constructed for visual analysis of time-to-event comparisons. In the event that important co-
variables are unbalanced between groups, a Cox proportional hazards or an extended Cox model 
to account for any differences. The primary analysis will be based on the intention to treat 
principle, with all patients analysed in the arms to which they were allocated irrespective of 
compliance with the allocated treatment. For all tests, 95% confidence intervals will be 
constructed where appropriate and a p-value of <0.05 will be considered significant. No 
corrections for multiple tests will be made. 
 
There is a risk of cross-over of patients randomized to not receive PLEX to the PLEX arm, 
although this practice will be discouraged and any such decision on protocol-defined parameters. 
The primary intention to treat analysis will deal with this cross-over in a conservative manner 
(bias to the null). To explore the potential that this cross-over may reduce the true magnitude of 
effect of PLEX, secondary analyses will be performed. Secondary analyses will therefore also 
include a per protocol analysis where patients are classified with respect to the intervention they 
ultimately received rather than the intervention they were randomized to. For the purpose of this 
analysis, patients will be regarded as having received PLEX if they received at least one 
complete exchange. Patients will be regarded as receiving the standard-dose of GC if they 
receive at least 70% of the cumulative dose of the standard regimen in the first 6 months of 
therapy. Patients will be regarded as receiving the reduced-dose of GC if they receive no more 
than 130% of the cumulative doses of the reduced-dose regimen in the first 6 months of therapy. 
Secondary analyses will not, irrespective of their differences from primary analyses, supplant the 
planned primary analyses. 
12.2.3 Secondary Endpoint Analyses 
12.2.3.1 Sustained Remission 
Disease activity will be analyzed in terms of sustained remissions. Patients will have obtained a 
sustained remission if they achieve a BVAS/WG of zero (complete remission) within 26 weeks 
of randomization and maintain a BVAS/WG of zero from complete remission until at least 52 
weeks after randomization. The proportion of patients that achieve a sustained remission will be 
calculated and an absolute risk difference and relative risk with the associated 95% confidence 
interval will be calculated.  
12.2.3.2 Death and ESRD 
Death and ESRD will be analyzed as separate endpoints in a manner identical to primary 
composite endpoint. 
12.2.3.3 Quality of Life Measures 
Quality of life data will be analyzed using mixed effect repeated measures with the interventions 
specified as independent variables.  
12.2.3.4 Serious Adverse Events 
The proportion of patients that experience at least one serious adverse event will be analyzed as a 
categorical variable by intervention utilizing a Fisher’s exact test. If appropriate, a more complex 


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model of serious adverse event occurrences will be constructed utilizing adverse events as count 
variables.  
An analysis of major subgroups of adverse events will be performed separately but in an 
identical manner as the overall adverse events analyses (e.g. infections, malignancy, 
cardiovascular complications). 
12.2.4 Tertiary Endpoint Analyses 
12.2.4.1 Renal Function 
Renal function will be compared between groups using serial estimated glomerular filtration 
rates as the outcome in longitudinal panel data analysis with the intervention as an independent 
variable. Patients who reach ESRD will be considered to have an estimated glomerular filtration 
rate of zero.  
12.2.4.2 Economic Analyses 
An economic evaluation will be conducted in order to estimate whether it is cost-effective to 
provide PLEX, in addition to standard care, for severe AAV. Additionally, the cost-effectiveness 
of low dose GC, compared to high dose GC, will also be estimated. 
The health care costs for each patient will be estimated by monitoring the resource use for each 
patient and assigning appropriate unit costs to these resource items. This will enable the total 
treatment cost to be identified for each patient, along with the mean cost of each of the treatment 
regimes. 
The main measures of effectiveness within the economic analysis will be the level of mortality 
and ESRD, along with the EQ-5D. This will enable the overall treatment effect to be estimated 
for each patient as well as the mean level of effectiveness for each treatment regime. Cost 
effectiveness will be determined by estimation of incremental cost-effectiveness ratios and cost 
effectiveness acceptability curves. 
    
12.2.4.3 Planned Subgroup Analyses 
Several a priori subgroup analyses are planned with respect to both primary and secondary 
outcomes. The subgroups will be each strata included for minimization. Subgroup analyses will 
employ a test of interaction to explore whether there is evidence that the treatment effect differs 
across subgroups.  
13 Biomedical Substudies 
Biomedical substudies are anticipated for the PEXIVAS Trial. Study sites will not all participate 
in all substudies. The organization of Biomedical Substudies will be coordinated by the 
Biomedical Substudy Committee. Consent for the procurement of biological specimens for use 
by an international team will be obtained during the consent procedure for the trial. Sites may opt 
out of participating in biomedical substudies but still participate in the clinical trial. Biological 
specimens considered may include DNA, RNA, plasma, and renal biopsy specimens. 


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14 Ethical Considerations 
14.1 Evaluation of Risks to Patients 
Medical records will be reviewed for all subjects and routine physical examinations will be 
performed. No specimens will be collected that are not considered the current standard of care. 
Specimens will be handled locally unless otherwise indicated. Only local investigators will have 
access to any identifiable information on study subjects. 
The hazards of this trial to patient safety are low-moderate given the experience of the 
investigators with the proposed interventions. These hazards for plasma exchange include the 
risk of adverse events related to central line placement (some patients may be able to have this 
procedure performed using peripheral intravenous access), the risks of infectious diseases due to 
receipt of a blood product, the risk of hypomagnesemia or hypocalcemia with citrate anti-
coagulation, and the risk of a coagulopathy/bleeding diathesis (See Section 8 above for details). 
Of note, the serious adverse event rate in a previous trial of plasma exchange in severe AAV was 
not greater than in the group not receiving plasma exchange. 
For the reduced-dose GC regimen, these hazards include the theoretical risk of precipitating a 
flare of AAV or delay in the time to remission of their AAV. In the event of excess disease 
activity, the trial protocol allows for additional glucocorticoid treatment in order to regain control 
of the patient’s disease.  
In addition, all subjects will experience the potential inconvenience of study appointments. Lost 
school or work time for both patients and their family members is unavoidable in performing this 
study. However, every effort will be made to perform study visits in an efficient manner and to 
have them coincide with appointments that would be made with standard care to minimize the 
excess burden of the study. The medical interviews are not anticipated to be psychologically 
harmful or stressful.  
14.2 Protection Against Risks 
Recruitment will occur through the investigators’ clinical practices and from referring 
physicians. The Institutional Review Board of each participating center will provide ethical 
review and approval for this protocol as well as the consent forms to be used prior to study start 
or enrollment. Details of the goals of the research and the risk and benefits of the protocol will be 
reviewed with each potential study subject. Recruitment will occur by physicians, study nurses, 
and research coordinators. 
Patients who decline to participate in any or all parts of the study will still have available the 
opportunity of evaluation by a vasculitis expert if they or their physician feels this is appropriate. 
Strict patient confidentiality will be observed throughout all aspects of the study. While medical 
records will be reviewed by members of the research team, no individually identifiable patient 
data will be distributed to non-research or care-giving team members. 
In the event of adverse effects from the study, the full resources of the hospital will be available 
to intervene as medically necessary.  Licensed physicians expert in the care of patients with 
vasculitis are available at all times at each study site. 


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14.3 Potential Benefits to Participants 
As described above, the potential risks to the study subjects in participating in this study are low-
moderate. Participants in this study are unlikely to gain direct benefit from participation. If the 
study leads to higher quality care or therapeutic trials for vasculitis then study patients could 
theoretically benefit in the future. All subjects will potentially have the satisfaction of helping to 
contribute to medical knowledge of vasculitis. Further understanding of both the clinical and 
molecular aspects of vasculitis is of great medical importance and because progress in 
understanding these diseases is expected from this study it is felt that the potential benefits of this 
research outweigh the risks of participation. 
14.4 Trial Ethical Approval 
Each national coordinator or local coordinator will apply for national or regional ethics approval 
as well as regulatory approval (e.g. MHRA, Health Canada etc). 
International sponsorship will be provided by the Cambridge University Hospitals NHS 
Foundation Trust upon signing of the site agreement with each trial site. Site agreements will be 
contingent upon the provision of evidence that study personnel have completed Good Clinical 
Practice training. 
14.5 GCP Statement  
This clinical trial will be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and all 
applicable regulatory requirements. 
15 Trial Organization 
15.1 Principal Investigators 
David Jayne 
Peter Merkel 
Michael Walsh 
15.2 Data Management and Analysis Centre 
Birmingham Clinical Trials Unit 
School of Health & Population Sciences 
College of Medical & Dental Sciences 
Public Health Building 
Edgbaston 
Birmingham 
B15 2TT 
Telephone 0121 415 9131 
Fax 0121 415 9135 
Email: PEXIVAS-trial@contacts.bham.ac.uk 
  
  
 
 


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15.3 Trial Communications 
Trial communication will be provided in the form of twice yearly electronic newsletters, annual 
investigator’s meetings, site monitoring visits, and electronic mail (emerging issues). 
 
A medical monitor will be available on-call for the trial at all times to advice investigators on 
issues surrounding the interface between clinical practice and trial protocol. Contact information 
for the medical monitor is available on the investigator’s area of the trial website (website 
address) or from the Trial Coordination Centre. 
 
15.4 Trial Publication Policy 
The Writing Committee will approve all publications using PEXIVAS data and the authorship. 
The Writing Committee will be composed of the PI’s, BCTU statistical and data analysis staff, 
and investigators with expertise in clinical and basic science related to AAV. 
 
16 Funding 
This trial is currently funded by the Medical Research Council of the United Kingdom, the 
National Institutes of Health Research (UK), the United States Food and Drug Administration 
Office for Orphan Product Development, the US National Institutes of Health (National Institute 
of Arthritis and Musculoskeletal and Skin Diseases), the Canadian Institutes of Health Research, 
and the National Health and Medical Research Council (Australia). 
 


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17 Reference List 
 
 
(1)  Watts RA, Scott DG. Epidemiology of the vasculitides. Semin Respir Crit Care Med 
2004 Oct;25(5):455-64. 
 
(2)  Frohnert PF, Sheps SG. Long-term follow-up study of periarteritis nodosa. Am J Med 
1967;43:8-11. 
 
(3)  Koldingsnes W, Nossent H. Epidemiology of Wegener's granulomatosis in northern 
Norway. Arthritis Rheum 2000 Nov;43(11):2481-7. 
 
(4)  Booth AD, Almond MK, Burns A, Ellis P, Gaskin G, Neild GH, et al. Outcome of 
ANCA-associated renal vasculitis: a 5-year retrospective study. Am J Kidney Dis 2003 
Apr;41(4):776-84. 
 
(5)  Jayne D, Rasmussen N, Andrassy K, Bacon P, Tervaert JW, Dadoniene J, et al. A 
randomized trial of maintenance therapy for vasculitis associated with antineutrophil 
cytoplasmic autoantibodies. N Engl J Med 2003 Jul 3;349(1):36-44. 
 
(6)  De Groot K, Jayne D, Tesar V, Savage C. Randomised controlled trial of daily oral 
versus pulse cyclophosphamide for induction of remission in ANCA-associated systemic 
vasculitis. Kidney & Blood Pressure Research 2005;28:195. 
 
(7)  DeGroot K, Rasmussen N, Bacon PA, Tervaert JW, Feighery C, Gregorini G, et al. 
Randomized trial of cyclophosphamide versus methotrexate for induction of remission in 
early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis & 
Rheumatism 2005 Aug;52(8):2461-9. 
 
(8)  Jayne D, Gaskin G, Rasmussen N, Abramowicz D, Ferrario F, Guillevin L, et al. 
Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive 
therapy for severe renal vasculitis. J Am Soc Nephrol 2007;18:2180-8. 
 
(9)  Etanercept plus standard therapy for Wegener's granulomatosis. N Engl J Med 2005 Jan 
27;352(4):351-61. 
 (10)  Pusey CD, Rees AJ, Evans DJ, Peters DK, Lockwood CM. Plasma exchange in focal 
necrotizing glomerulonephritis without anti-GBM antibodies. Kidney international 1991;. 
40(4). 
 (11)  Cole E, Cattran D, Magil A, Greenwood C, Churchill D, Sutton D, et al. A prospective 
randomized trial of plasma exchange as additive therapy in idiopathic crescentic 
glomerulonephritis. The Canadian Apheresis Study Group. Am J Kidney Dis 1992 
Sep;20(3):261-9. 
 (12)  Glockner WM, Sieberth HG, Wichmann HE, Backes E, Bambauer R, Boesken WH, et al. 
Plasma exchange and immunosuppression in rapidly progressive glomerulonephritis: a 
controlled, multi-center study. Clin Nephrol 1988 Jan;29(1):1-8. 


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 (13)  Yamagata K, Hirayama K, Mase K, Yamaguchi N, Kobayashi M, Takahashi H, et al. 
Apheresis for MPO-ANCA-associated RPGN-indications and efficacy: lessons learned 
from Japan nationwide survey of RPGN. J Clin Apher 2005 Dec;20(4):244-51. 
 (14)  Rota S, Rambaldi A, Gaspari F, Noris M, Daina E, Benigni A, et al. Methylprednisolone 
dosage effects on peripheral lymphocyte subpopulations and eicosanoid synthesis. 
Kidney Int 1992 Oct;42(4):981-90. 
 (15)  Irakam A, Miskolci V, Vancurova I, Davidson D. Dose-related inhibition of 
proinflammatory cytokine release from neutrophils of the newborn by dexamethasone, 
betamethasone, and hydrocortisone. Biol Neonate 2002 Aug;82(2):89-95. 
 (16)  Wolfe F, Caplan L, Michaud K. Treatment for rheumatoid arthritis and the risk of 
hospitalization for pneumonia: associations with prednisone, disease-modifying 
antirheumatic drugs, and anti-tumor necrosis factor therapy. Arthritis Rheum 2006 
Feb;54(2):628-34. 
 (17)  Illei GG, Yarboro CH, Kuroiwa T, Schlimgen R, Austin HA, Tisdale JF, et al. Long-term 
effects of combination treatment with fludarabine and low-dose pulse cyclophosphamide 
in patients with lupus nephritis. Rheumatology (Oxford) 2007 Jun;46(6):952-6. 
 (18)  Saag KG, Koehnke R, Caldwell JR, Brasington R, Burmeister LF, Zimmerman B, et al. 
Low dose long-term corticosteroid therapy in rheumatoid arthritis: an analysis of serious 
adverse events. Am J Med 1994 Feb;96(2):115-23. 
 (19)  Haybittle JL. Repeated assessments of results in clinical trials of cancer treatments. 
British Journal of Radiology 1971;44:793-7. 
 (20)  Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al. Design and 
analysis of randomised clinical trials requiring prolonged observation of each patient. I. 
Introduction 
and design. British Journal of Cancer 1976;34:585-612. 
 (21)  Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, et al. Nomenclature of 
systemic vasculitides. Proposal of an international consensus conference. Arthritis 
Rheum 1994 Feb;37(2):187-92. 
 (22)  Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, et al. Nomenclature of 
systemic vasculitides. Proposal of an international consensus conference. Arthritis 
Rheum 1994 Feb;37(2):187-92. 
 
 
 
 
 
 


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18 Appendices 
18.1 Birmingham Vasculitis Activity Score for WG Vasculitis (BVAS/WG) 
Instructions:  
Mark only if abnormality is ascribable to the presence of active ANCA-Associated Vasculitis. Mark "Persistent" or "New/Worse" depending upon if the 
abnormality is persistent disease activity since the last assessment and not worse within the previous 28 days or if the abnormality is newly present or worse 
within the previous 28 days correspondingly. If no items are present in any section, tick "none". Major items are in bold and marked with *. All WG-related 
clinical features need to be documented on this form if they are related to active diseases. Use "OTHER" category as needed. 
                                                            Persistent    New/Worse    None 
                                             Persistent    New/Worse    None 
1.  GENERAL                                                                             (  ) 
8. RENAL                                                                
                            (  )    
a.  arthralgia/arthritis                                                    
a. hematuria (no RBC casts)                          
                 
b.  fever (> 38 degrees C)  
                 
     (> 1 + or > 10 RBC/hpf) 
2.  CUTANEOUS                                       
                                 (  ) 
b. *RBC casts and / or  
      glomerulonephritis                                          
                 
a. purpura                                                                     
c.  *rise in creatinine > 30% or fall                    
                 
b. skin ulcer                                                                  
       in creatinine clearance > 25%          
c. *gangrene 
                 
Note: If both hematuria and RBC casts are present, score only 
the RBC casts (the major item). 
3.  MUCOUS MEMBRANES/EYES                                        (  )      
a. mouth ulcers                                                             
9. NERVOUS SYSTEM                                                                         (  )      
b. conjunctivitis/episcleritis                                         
a. *meningitis                                               
                 
c. retro-orbital mass/proptosis                                      
b. *cord lesion                                              
                 
d. uveitis                                                                       
c. *stroke                                                      
                 
e. *scleritis                                                                   
d. *cranial nerve palsy                                
                 
f. *retinal exudates/haemorrhage 
                 
e. *sensory peripheral neuropathy            
                 
4.  EAR, NOSE & THROAT                                                     (  ) 
f. *motor mononeuritis multiplex      
                 
a.  bloody nasal discharge /                         
     nasal crusting / ulcer                                               
 
10. OTHER (describe all items and * items deemed major)           (  ) 
b. sinus involvement                                                    
c. swollen salivary gland                                              
Major 
 
 
d. subglottic inflammation                                           
 
_______________________ 
                 
e. conductive deafness                                                 
f. *sensorineural deafness       
                 
 
_______________________ 
                 
5.  CARDIOVASCULAR                                                          (  )      
a. pericarditis   
                 
 
_______________________ 
                 
6. GASTROINTESTINAL                                                        (  ) 
a. *mesenteric ischemia    
                 
 
_______________________ 
                 
7. PULMONARY                                                                       (  ) 
a. pleurisy                                                                     
11. TOTAL NUMBER OF ITEMS:                                                        (  )     
b. nodules or cavities                                                    
a.                        b.                        c.                       d. 
c. other infiltrate secondary to WG                              
___ ___              ___ ___              ___ ___             ___ ___ 
d. endobronchial involvement                                      
Major                 Minor                  Major                Minor                                    
e. *alveolar hemorrhage                                            
New / Worse      New / Worse       Persistent          Persistent 
f. *respiratory failure      
                 
 
DETERMINING DISEASE STATUS: 
12. CURRENT DISEASE STATUS     (check only one) 
Severe Disease / Flare: > 1 new/worse Major item 
 
Limited Disease / Flare: > new/worse Minor item 
Severe Disease/Flare      
 
Persistent Disease: Continued (but not new/worse) activity 
Limited Disease/Flare    
 
Remission: No active disease, including either new /worse or 
Persistent Disease          
 
persistent items 
Remission 
 
 
 
Remission 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Maximum activity 
 
 
 
 
 
 
 
 
 
 
 


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Birmingham Vasculitis Activity Score Modified for Wegener’s Granulomatosis (BVAS/WG) 
 
An Introduction and Glossary of Terms 
 
Purpose of assessment 
 
BVAS/WG is designed to document clinical features that are directly due to active WG or 
MPA (AAV).  In addition, the instrument separates the features that represent new or worse 
disease activity from those that represent persistent activity.  In scoring BVAS for WG, it is very 
important not to confuse activity with damage.  Damage, defined as the presence of non-healing 
scars, and is a concept distinct from current disease activity.  Damage will be scored separately in 
PEXIVAS using another index, the Combined Damage Assessment (CDA), which is not the 
subject of this exercise. 
 
Recording disease activity 
 
The list of items in BVAS/WG includes clinical symptoms and signs, as well as information 
obtained from additional tests (e.g., chest x-rays) or subspecialty consultations.  When using the 
BVAS/ WG evaluation form, one scores only these items attributable to currently active WG (after 
the exclusion of obvious causes such as infection, hypertension, and treatment toxicity).  BVAS 
scores may vary rapidly, and reflect the need for therapy.  
 
New Patients  
 
If the patient is being evaluated for the first time and has not been treated, all of the abnormalities 
noted should be recorded as NEW/WORSE () regardless of their duration.  After going through 
the entire items list, also remember to consider adding any other significant items to the “Other” 
section, if relevant.  A list of “Other” items that might be included in these sections is displayed at 
the end of the glossary.  If a section has no items present, check the “none” box. 
 
Follow-up Patients  
 
If the patient is being evaluated in follow-up, there may be some abnormalities that are NEW or 
WORSE () within the previous 28 days.  Other abnormalities may have been present on the 
previous assessment and are neither new nor worse, but rather still present (PERSISTENT ).  By 
making this distinction, one differentiates new, acute disease activity from persistent disease 
activity.  It is important to remember that persistent activity is activity, not damage.  Thus, 
persistent purpura should be scored as activity.  In contrast, weakness from mononeuritis multiplex 
of 4 months duration is damage, and should not be scored in BVAS.  Sometimes (admittedly), it is 
difficult to be certain whether a symptom or sign is due to persistent activity or to damage.  As in 
caring for real patients, in evaluating such cases one relies on clinical judgement to make this 
distinction. 
 
Checking the boxes 
 


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Check one of the boxes for each item ( or ) only if the abnormality is ascribed to the 
presence of active WG.  If no abnormalities ascribable to WG are present in a given organ 
system, check the “none” box.  In this way, we can be certain that you did not overlook an 
organ system on the scoring  
 
sheet.  Sometimes you will have patients in whom abnormalities are present that are not due to 
AAV (e.g., hematuria due to urinary infection or cyclophosphamide toxicity).  In these cases, 
you should NOT record them in the BVAS/WG list, even though they are present, because they 
cannot be ascribed to active AAV.  In some patients, abnormalities that were due to previous 
episodes of WG may still be evident, even though the disease is entirely inactive (e.g., stroke).  
These features should also NOT be recorded on BVAS/WG, since they represent non-healing 
scars (damage). 
 
 Check this box only if the abnormality is NEW/WORSE within the previous 28 days 
(unless this is the first presentation of untreated disease). 
 Check this box only if the abnormality is PERSISTENT since the last assessment and not  
worse within the previous 28 days. 
( ) Check this space if there is not a single major or minor item that is new/worse within a 
particular organ system. 
 
Necessity for “Judgement Calls” 
 
As in clinical practice, one must sometimes make “judgement calls” in scoring BVAS/WG.  
For example, persistent sinus symptoms are often notoriously difficult to classify with certainty 
as either active disease or permanent damage.  Similarly, small amounts of hematuria (usually 
with RBC casts) may persist for months in patients whose disease is otherwise quiescent.  In 
both such cases, the physician is unlikely to intensify treatment in the absence of other 
indications of active disease.  For this reason, these findings (and analogous findings in other 
organ systems) should not be scored in BVAS/WG.  If subsequent events cause you to re-
consider your judgement call, you may go back and change your initial decision regarding a 
particular finding. 
 
You will note that for some features (e.g., sensorineural deafness, most of the neurological 
items) there is no persistent box.  This reflects the fact that if these features are present, they are 
new/worse by definition.  If the feature is still present at subsequent assessments — as 
mononeuritis multiplex is likely to be — the feature is (by definition) damage, and should not 
be scored. 
 
Recording Major and Minor Items 
 
Individual items are defined as Major by the presence of an asterisk (*).  All other items are 
defined as Minor.  If you list additional items in the “Other” section, you should indicate whether 
the item is “Major” or “Minor”.  In general, a Major item is one whose presence would have 
traditionally prompted the use of cyclophosphamide.  Minor items are those more likely to be 
treated with methotrexate or an increase in prednisone. 
 


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If you decide that a particular abnormality is due to the presence of active WG, you must 
distinguish problems that are new/worse from those problems that are persistent.  For each item 
where there is an abnormality, you need to check either the NEW/WORSE box or the 
PERSISTENT box, but not both. 
 
 
 
 
Summing Up BVAS/WG 
 
Now add up all of the Major (*) items marked in the New/Worse column, and enter the sum in the 
appropriate box on the right side of the page.  Repeat this for the Minor items in the 
NEW/WORSE column, and then do the same for the Major and Minor items in the Persistent 
column. 
 
Defining disease status 
 
Severe disease/flare: If any Major item is recorded, the patient has a “Severe Flare”.   
Limited disease/flare: If any Minor item is recorded, the patient has a “Limited Flare”. 
Persistent Disease: Persistent disease indicates the presence of 1 or more persistent items 
attributed to active disease. 
Remission: Remission indicates no active disease (i.e., no new/worse and no persistent items 
present). 
 
Physician’s Global Assessment 
 
Finally, use the 10 point likert scale to record your assessment of the overall disease activity in this 
case.  Remember that you should not be influenced by the presence of any accumulated damage, 
complication of treatment, social/emotional problems, or other issues not related to active 
vasculitis. 
 
 
BVAS/WG 
 
GLOSSARY OF TERMS 
 
GENERAL RULE: Disease features are scored only when they are attributable to active 
WG/MPA, after exclusion of other obvious causes (e.g., infection, hypertension, toxicity of 
treatment, etc.).  THIS IS THE MOST IMPORTANT ASPECT OF SCORING TO 
REMEMBER! 
 
If the patient is presenting for the first time and has not been treated, then all items due to WG that 
is currently active are defined as NEW/WORSE, regardless of how long the patient has had them.    
 
If an item is new or represents a deterioration of status occurring in the previous 28 days, it is 
scored in the NEW/WORSE box.   


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If the feature was present at the previous evaluation and is not new or worse but still represents 
ongoing disease activity, record it as PERSISTENT. 
 
Check box ( or ) only if the abnormality is ascribable to the presence of active WG. 
 
 Check this circle only if the abnormality is NEW/WORSE within the previous 28 days. 
 Check this box only if the abnormality is PERSISTENT since the last assessment and not  
worse within the previous 28 days.  
 
For some features, further information (e.g., a chest radiograph or subspecialty consult) may be 
required to determine if an abnormality is new or worse. 
 
Glossary definitions used in BVAS/WG  
 
Remember that for most patients, you will be able to complete the BVAS evaluation form on the 
same day you evaluate the patient.  However, on other occasions, you may require further 
information before entering some items.  For example, if the patient has new onset of stridor, you 
would usually ask an ENT colleague to investigate this further to determine whether or not it is 
due to active WG.  We suggest that you leave such items blank temporarily, but complete them 
once the information is available.  
 
1.  General 
Arthralgia: 
Joint pain without obvious swelling. 
Arthritis: 
Joint inflammation. 
Fever: 
Documented temperature elevation.  The value refers to oral temperatures 
(38.0ºC).   
 
 
2.  Cutaneous 
Purpura: 
Petechiae (small red spots), palpable purpura, or ecchymoses (large plaques) 
in skin or oozing (in the absence of trauma) in the mucous membranes. 
Ulcer: 
Open sore in a skin surface. 
*Gangrene: 
Extensive tissue necrosis (e.g., digit).  Gangrene refers not to superficial 
infarction (e.g., a nailbed infarct), but rather to severe ischemia affecting the 
viability of a substantial portion of tissue, such as an entire fingertip. 
* If new/worse, this denotes a major item for assessment of flares. 
 
 
3.  Mucous Membranes and Eyes 


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Mouth ulcers: 
Ulcers localized in the mouth.  Exclude other causes, such as drugs, 
Crohn's disease, pemphigus, etc. 
Conjunctivitis: 
Inflammation of the conjunctivae (exclude infectious causes). 
Episcleritis: 
Inflammation of the superficial sclera. 
Retro-orbital mass/ 
Proptosis: 
Protrusion of the eye caused by an inflammatory mass behind the 
globe.  This may be associated with diplopia due to infiltration of 
extra-ocular muscles. 
Uveitis: 
Inflammation of the uveal tract (iris, ciliary body, choroid) confirmed 
by ophthalmologist. 
*Scleritis 
Inflammation of the deep sclera (specialist opinion usually required). 
*Retinal exudates: 
Any area of soft retinal exudates (exclude hard exudates) seen on 
ophthalmoscopic examination. 
*Retinal 
haemorrhages: 
Any area of retinal hemorrhage seen on ophthalmoscopic examination. 
* If new/worse, this denotes a major item for assessment of flares. 
 
 
4. ENT 
 
Bloody nasal 
discharge: 
Blood stained secretions from the nose, irrespective of severity or 
frequency, occurring since the last visit. 
Nasal crusting: 
Discharge of large serous or serosanguinous crusts. 
Nasal ulceration: 
Nasal mucosal lesions (not due to trauma). 
Sinus involvement: 
Tenderness or pain over paranasal sinuses or X-ray evidence of 
sinusitis.  If nasal bridge collapse is observed, this may be recorded 
separately (in the section for “Other” items). 
Swollen salivary 
glands 
Tender swelling of one or more major salivary glands not due to an 
infection, stone, or other non-WG cause.  
Subglottic 
inflammation: 
Inspiratory stridor with significant narrowing of subglottic space 
confirmed by further examination (usually by an ENT specialist). 
Conductive 
deafness: 
Any hearing loss due to middle ear involvement, preferably confirmed 
by audiometry. 
*Sensorineural 
deafness: 
Deafness caused by damage to the auditory nerve or cochlea. 
* If new/worse, this denotes a major item for assessment of flares. 
 
 
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Pericarditis: 
Pericardial pain and/or friction rub on clinical assessment. 
 
 
6.  Abdominal 
 
Mesenteric 
ischemia: 
Defined as severe abdominal pain, bloody diarrhea, gut perforation/ 
infarction due to WG. 
* If new/worse, this denotes a major item for assessment of flares. 
 
7.  
Chest/Pulmonary 
 
Pleurisy: 
Pleural pain and/or friction rub on clinical assessment or new onset of 
radiologically confirmed pleural effusion.  Other causes (e.g., 
infection, cancer) should be excluded. 
Nodules or cavities: New lesions, detected by CXR. 
*Tracheobronchial 
involvement: 
Pseudotumour or ulceration of tracheobronchial tree.  Requires 
bronchoscopy to exclude tumor or infection. 
*Alveolar 
haemorrhage: 
Major pulmonary bleeding, with shifting pulmonary infiltrates.  Other 
causes of bleeding should be excluded. 
*Respiratory 
failure: 
Dyspnea requiring artificial ventilation. 
* If new/worse, this denotes a major item for assessment of flares. 
 
 
8.  Renal 
 
*Hematuria: (no 
RBC casts) 
1+ on urinalysis; 10 rbc/hpf.  Infection should be excluded.   
The hematuria must be considered due to active renal vasculitis, not 
just prior damage.  
*RBC casts and/or 
Glomerulonephriti
s 
The appearance of RBC casts in the urinary sediment and/or evidence 
of active glomerulonephritis on biopsy.  RBCs are essentially the 
“surrogate” for glomerulonephritis. 
Rise in creatinine > 
30% or creatinine 
clearance fall > 
25%: 
Deterioration in renal function that is attributable to active WG and 
meets these criteria. 
* If new/worse, this denotes a major item for assessment of flares. 
 
 
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*Meningitis: 
Severe headache +/- neck stiffness, ascribed to inflammatory 
meningitis after the exclusion of infection, bleeding, and other causes. 
*Stroke: 
Cerebrovascular accident resulting in focal neurological signs such as 
paresis, weakness, etc. 
*Cord lesion: 
Transverse myelitis with extremity weakness or sensory loss. 
*Cranial nerve 
palsy: 
Isolated acute cranial nerve palsy (excluding sensorineural hearing 
loss, which is listed in ENT). 
*Sensory 
Peripheral 
neuropathy: 
Neuropathy resulting in glove and/or stocking distribution of sensory 
loss.  Other causes should be excluded (e.g., idiopathic, metabolic, 
vitamin deficiencies, infectious, toxic, hereditary). 
*Motor 
mononeuritis 
multiplex: 
Neuritis of named peripheral nerve, only scored if motor involvement.  
On EMG/NCV evaluation, multiple nerve dysfunction may be 
documented, but clinical involvement of only one named nerve is 
required to score this item.  Other causes should be excluded (diabetes, 
sarcoidosis, carcinoma, amyloidosis). 
* If new/worse, this denotes a major item for assessment of flares. 
 
 
10. Other: 
 
Significant features attributable to active WG not listed above.  Please 
provide full details and designate item as Major or Minor items.  
Potential “Other” items are listed below. 
If defined as new/worse, this may denote a major or minor item for assessment of flares. 
 
 
Examples of Potential “Other” items: 
 Weight loss (>2 kg over 28 day period) 
 Seizures 
 Genitourinary involvement 
 Cardiac valvular lesions 
 Cutaneous infarctions (splinter hemorrhages, digital infarcts) 
 Pulmonary infiltrates (not due to alveolar hemorrhage, cavity) 
 New loss of pulses / threatened loss of limb 
 Angina (ischemic cardiac pain secondary to WG) 
 Cardiomyopathy 
 Pancreatitis 
 Aural D/C 


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 Many others…. 


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18.2 CDA - Combined Damage Assessment Index  
 
Musculoskeletal                        None: ∆ 
 Ear                                               None: ∆ 
Osteoporosis/vertebral collapse 
Sensorineural hearing loss  
L    R    B 
 Bone fracture: 
Conductive hearing loss           
L    R    B 
  Due to renal dystrophy 
Tympanic membrane            
L    R    B 
perforation or scarring 
   Due to osteoporosis 
 
   Due to both 
Tinnitus                                      
L    R    B 
 Muscle atrophy due to glucocorticoids: 
Eustachian tube dysfunction  
L    R    B 
   Normal strength, atrophy on exam 
Auricular cartilage deformity  
L    R    B 
   Weak on examination, normal ADLs 
Cholesteatoma                         
L    R    B 
   Weak and has difficulty with ADLs 
 Nose                                              
None: ∆ 
Avascular necrosis 
Chronic rhinitis/crusting 
Deforming/erosive arthritis 
Nasolacrimal duct obstruction 
Osteomyelitis 
Nasal bridge collapse/saddle nose 
 Skin/Membranes               
None: ∆ 
 Nasal septal perforation 
Alopecia 
 Anosmia 
Mouth ulcers 
 Ageusia 
Cutaneous scarring 
 Sinuses                                       
None: ∆ 
Cutaneous ulcers 
 Chronic sinusitis 
Striae 
 Neo-ossification of sinuses 
Gangrene with permanent tissue loss 
 Subglottic stenosis                 
None: ∆ 
Easy bruising 
  No intervention required 
 Ocular                                    
None: ∆ 
  Intervention required 
Proptosis               
 L    R    B 
 Pulmonary                              
 None: ∆ 
Pseudotumor                   
 L    R    B 
 Irreversible loss of lung function 
Scleral thinning              
L    R    B 
 Fixed large airway obstruction 
Scleral perforation           
L    R    B 
 Pulmonary hypertension 
Optic nerve edema          
L    R    B 
 Pulmonary fibrosis 
Optic nerve atrophy         
L    R    B 
 Pulmonary embolism 
Retinal changes                
L    R    B 
 Pulmonary infarction 
Retinal artery occlusion   
L    R    B 
 Vena caval filter 
Retinal vein occlusion      
L    R    B 
 Continuous oxygen dependency 
Low vision                        
L    R    B 
 Chronic asthma 
Diplopia                             L    R    B 
 Pleural fibrosis 
Blindness                           L    R    B 
 Chronic breathlessness 
Cataracts                            L    R    B 
 FEV1   _____ ______  .  ______ 
Glaucoma                           L    R    B 
 FVC     _____ ______   .  ______ 
Orbital wall destruction    
L    R    B 
 RVSP  _____ ______ 
Instructions:  This is for recording organ damage that has occurred in patients since the onset of vasculitis.  Co-morbidity that exists before the onset of 
vasculitis must not be scored.  A new patient should have a CDA of zero unless he has had vasculitis for at least 6 months, and the damage has developed or 
become worse since the onset of vasculitis.  A finding must be present for 6 months to be scored.  Damage is irreversible, and only rarely should a scored item 
not be carried forward.Where applicable, please include the primary data values, in addition to marking the relevant box 


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Physician Global Assessment: mark line to indicate the total burden of damage in this patient: 
NONE    0  - 1  -  2  -  3  -  4  -  5  -  6  -  7  -  8  -  9  -  10    MAXIMUM 
 Cardiac                          
None: ∆ 
 Neurologic                         
None: ∆ 
 Hypertension:  BP  ______ / _______ 
Seizures 
 Pre-HTN: SBP 130-139 or DBP 80-89 
Transverse myelitis 
  Stage I: SBP 140-149 or DBP 90-99 
 Sensory polyneuropathy: 
  Stage II: SBP >149 or DBP >99 
  Mild 
 Angina 
  Moderate 
 Myocardial infarction 
  Severe 
 Percutaneous coronary intervention 
Motor neuropathy (mononeuritis) 
 Coronary artery bypass graft 
Neuropathic pain 
 LV dysfunction:  EF:  ___ ____ % 
Cerebrovascular accident 
   NYHA Class I/II 
2nd Cerebrovascular accident 
   NYHA Class III/IV 
Cranial nerve lesion, specify: 
 Third degree AV block 
 Psychiatric                           
None: ∆ 
 Valvular disease: 
Cognitive impairment 
   Specify: 
Anxiety disorder due to vasculitis 
 Pericarditis or pericardectomy 
Mood disorder due to vasculitis 
 Vascular Disease              
None: ∆ 
Major psychosis 
 Absent pulses in 1 limb 
 Endocrine                      
None: ∆ 
 2nd episode of absent pulses in 1 limb 
Diabetes insipidus 
 Major vessel stenosis 
Premature ovarian failure 
 Claudication > 3 months 
Azoospermia 
 Minor tissue loss 
Impaired fasting glucose 
 Major tissue loss 
Diabetes mellitus 
 Subsequent major tissue loss 
 Hematology/Oncology  
None: ∆ 
 Deep venous thrombosis 
Bladder cancer 
 Complicated venous thrombosis 
Cervical cancer 
 Carotid artery disease 
Hematopoetic malignancy 
 Renal artery stenosis 
Solid tumor malignancy 
 Arterial thrombosis/occlusion 
   Specify: 
   Specify:  
Refractory cytopenia 
 Gastrointestinal                 
None: ∆ 
Myelodysplastic syndrome 
 Gut infarction/resection 
 Other                               
None: ∆ 
 Hepatic fibrosis 
Weight gain > 10 lbs/4.4 kg 
 Mesenteric insufficiency/pancreatitis 
Fibromyalgia 
 Esophageal stricture/surgery 
 Drug-induced cystitis: 
 Chronic peritonitis 
 with microscopic hematuria 
 Renal                                      
None: ∆ 
 with gross hematuria 
 Estimated/measured GFR<50% 
 requiring transfusion 
 Chronic kidney disease 
 requiring cystectomy 
 End-stage renal disease 
Damage requiring surgical intervention 
 Dialysis 
  Specify: 
 Renal transplant 
Medications to manage side effects 
of immunosuppressive agents 
 Proteinuria: 
 
   < 3g/24h 
  Specify: 
   >3g/24h 
Hypogammaglobulinemia 


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18.3 SF-36  (example) 
 
HEALTH STATUS – SF 36 V2 (as reported by participant)        Page 1 of 3 
 
This survey asks for your views about your health.  This information will help keep track of how you feel 
and how well you are able to do your usual activities.  Thank you for completing this survey! 
Your Health and Well Being 
  
1.  In general, would you say your health is: 
 
 
 
Excellent 
 Very Good 
       Good 
 
Fair 
 
Poor 
 
 
2.  Compared to in year ago, how would you rate your health in general now? 
 
            Much better 
Somewhat better    About the         Somewhat           Much worse 
           now than one     now than one      same as one    worse now than    now than one 
              year ago 
       year ago           year ago         one year ago           year ago 
 
 
 
3.  The following questions are about activities you might do during a typical day.  Does your health 
now limit you in these activities?  If so, how much? 
 
Yes, 
 
Yes, 
 
   No, 
                                                                         limited a lot       limited a little     not limited at all 
a) Vigorous Activities, such as 
   running, lifting heavy objects, 
   participating in strenuous sports. 
 
b) Moderate activities, such as moving 
    a table, pushing a vacuum cleaner, 
    bowling, or playing golf. 
 
c) Lifting or carrying groceries 
 
d) Climbing several flights of stairs 
 
e) Climbing one flight of stairs 
  
f) Bending, kneeling, or stopping 
 
g) Walking more than a mile 
 
h) Walking several hundred yards 
 
i) Walking one hundred yards  
  
j) Bathing or dressing yourself 


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HEALTH STATUS – SF 36 V2  
 
 
 
 
Page 2 of 3 
 
4.  During the past 4 weeks, how much of the time have you had any of the following problems with 
your work or other regular daily activities as a result of your physical health? 
 
                                                                    
All 
      Most          Some 
     A little 
  None 
                                                                       
of the          of the         of the          of the            of the 
                                                                  
time            time            time            time              time 
a) Cut down on the amount of time 
     you spent on work or other activities 
 
b)  Accomplished less than you would like 
 
c) Were limited in the kind of work or other  
      activities 
 
d) Had difficulty performing the work or  
    other activities (ie, it took extra effort) 
 
5. During the past 4 weeks, how much of the time have you had any of the following problems with 
your work or other regular daily activities as a result of any emotional problems (such as feeling 
depressed or anxious)? 
 
 
 
 
 
 
  All 
     Most            Some 
     A little 
None 
                                                                        
of the         of the           of the          of the          of the 
                                                                  
time           time              time            time             time 
a) Cut down on the amount of time you 
    spent on work or other activities. 
 
b) Accomplished less than you would like 
 
c) Did work or other activities less 
    carefully than usual 
 
6.  During the past 4 week, to what extent has your physical health or emotional problems interfered 
with your normal social activities with family, friends, neighbors or groups? 
      
 Not at all 
 
Slightly 
 
Moderately 
 
Quite a bit 
    Extremely 
 
 
7.  How much bodily pain have you had during the past 4 weeks? 
 
  None  
       Very Mild  
Mild 
 
 Moderate 
     Severe  
     Very Severe 
 
 
8.  During the past 4 weeks, how much did pain interfere with your normal work (including both 
work outside the home and housework)?  
    
Not at all 
 
Slightly 
 
Moderately 
 
Quite a bit 
    Extremely 
 
 
 


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HEALTH STATUS – SF 36 V2  
 
 
 
 
Page 3 of 3 
 
9.  These questions are about how your feel and how things have been with you during the past 4 
weeks. For each question please give the one answer that comes closest to the way you have been 
feeling.  How much of the time during the past 4 weeks… 
 
 
 
 
 
 
 
 
 
 
 
All 
       Most         Some 
     A little 
None 
                                                                        
of the           of the        of the          of the           of the 
                                                                  
time             time           time            time             time 
a) Did you feel full of life? 
 
b) Have you been very nervous 
 
c) Have you felt so down in the dumps 
That nothing could cheer you up? 
  
d) Have you felt calm and peaceful? 
 
e) Did you have a lot of energy? 
 
f) Have you felt downhearted and  
Depressed? 
 
g) Did you feel worn out? 
 
h) Have you been happy? 
 
i) Did you feel tired? 
 
10.  During the past 4 week, how much of the time has your physical health or emotional problems 
interfered with your social activities (like visiting friends, relatives, etc.)? 
 
All of the time         Most of the time         Some of the time          A little of the time         None of the time 
 
 
 
11.  How TRUE or FALSE is each of the following statements for you? 
 
                                                             Definitely         Mostly         Don’t       Mostly      Definitely 
 
 
 
 
            true                 true             know       false            false 
 
a)  I seem to get sick a little easier 
     than other people 
 
b)  I am healthy as anybody I know 
 
c)  I expect my health to get worse 
 
d)  My health is excellent 
 


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18.4 EQ5D 
 
 
 
 
 
 
 
 
 
 
 
EQ-5D HEALTH QUESTIONNAIRE 
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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By placing a check-mark in one box in each group below, please indicate which 
statements best describe your own state of health today.  
  
  
Mobility  
 
 
  
  
 
 
 
Self-Care  
  
 
  
  
 
 
 
Usual Activities (e.g. work, study, housework, family or leisure activities)  
 
 
  
  
 
Pain/Discomfort  
   
  
 
 
Anxiety/Depression  
 
I am not anxious or depressed  
I am moderately anxious or depressed  
I am extremely anxious or depressed  
 
 
 
 
 
 
I have no problems in walking about  
  
I have some problems in walking about    
I am confined to bed  
  
I have no problems with self-care  
  
I have some problems with washing or dressing myself  
I am unable to wash or dress myself  
  
I have no problems with performing my usual activities  
  
I have no problems with self-care  
  
I have some problems with washing or dressing myself  
I am unable to wash or dress myself  
  
I have no problems with performing my usual activities  
  
I have no problems with self-care  
  
I have some problems with washing or dressing myself  
I am unable to wash or dress myself  
  
I have no problems with performing my usual activities  
  


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To help people say how good or bad their state of health is, we  
have drawn a scale (rather like a thermometer) on which the 
best state you can imagine is marked 100 and the worst state 
you can imagine is marked 0.  
  
We would like you to indicate on this scale how good or bad 
your  
own health is today, in your opinion. Please do this by drawing a  
line from the box below to whichever point on the scale indicates  
how good or bad your state of health is today.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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18.5 Modification of Diet in Renal Disease (MDRD) Estimated Glomerular Filtration Rate 
Calculation 
 
The four variable MDRD equation is: 
 
GFR = 186 x Scr -1.154 x age -0.203 x 1.210 if black x 0.742 if female 
 
Note 1: serum creatinine (Scr) is given in mg/dl (divide by 88.4 to convert to µmol/L) and age is 
given in years. 
 
Note 2: Use multiplier of 175 instead of 186 if sCr was IDMS-standardized. IDMS = isotope 
dilution mass spectrometry. 
 
A free on-line calculator (available for serum creatinine in mg/dL or µmol/L) is available at:  
 
http://www.hdcn.com/calcf/gfr.htm