Clinical trial NCT01697267
Conditions: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis Microscopic Polyangiitis Wegener Granulomatosis
Keywords: vasculitis ANCA vasculitis microscopic polyangiitis granulomatosis Wegener's AAV vasculitides
Sponsor: Cambridge University Hospitals NHS Foundation Trust
Start date: 2013-04-01; Completion date: 2019-11-21
Enrollment: 188 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Rituximab is now established as an effective drug for anti-neutrophil cytoplasmic antibody (ANCA) vasculitis following major European and US trials reported in 2010. After a time, its effect wears off and the disease can return. This occurs in at least half of patients within 2 years of receiving Rituximab. A preliminary study in Cambridge has suggested that repeating rituximab every six months stops the disease returning and is safe.

The RITAZAREM trial will find out whether repeating rituximab stops vasculitis returning and whether it works better than the older treatments, azathioprine or methotrexate. It will also tell us how long patients remain well after the repeated rituximab treatments are stopped, and if repeated rituximab is safe. We should also learn useful information about the effects of rituximab on quality of life and economic measures. The trial results will help decide the best treatment for future patients who have their vasculitis initially treated with rituximab.

RITAZAREM aims to recruit patients with established ANCA vasculitis whose disease has come back 'relapsing vasculitis'. All patients will be treated with rituximab and steroids and we anticipate that most will respond well. If their disease is under reasonable control after four months, further treatment with either rituximab (a single dose ever four months for two years) or azathioprine tablets will be chosen randomly. The patients in the rituximab and azathioprine groups will then be compared. Patients will be in the trial for four years.

The study has been designed by members of the European Vasculitis Study group (EUVAS) and the Vasculitis Clinical Research Consortium (VCRC). It will include 190 participants from 30 hospitals in Europe, the USA, Australia and Mexico.

RITAZAREM is being funded by Arthritis Research UK, the U.S. National Institutes of Health and by Roche/Genentech.

Detailed description:
Patients will be recruited at the time of relapse. All will receive rituximab 375 mg/m2/week x 4 and glucocorticoids.

Those patients that achieve disease control (BVAS/WG ≤ 1 and daily prednisone dose ≤ 10 mg) by month 4 will be randomised to the rituximab or control remission maintenance groups.

Treatment is protocolised for the entire duration of the study, until the common close date, when the final patient recruited has completed 36 months within the study or until the patient has completed 48 months on study whichever the sooner. Patients in the rituximab arm will receive treatment until month 20, and those in the azathioprine arm until month 27.

Arms: arm 1: Rituximab maintenance: 1g at 4, 8, 12, 16 \& 20 months with standardised steroid taper arm 2: Azathioprine Maintenance: 2mg/kg/day with standardised steroid taper, from month 4 (randomisation) (200 mg maximum daily dose). Azathioprine withdrawn at month 27.
Interventions: intervention 1: Rituximab intervention 2: Azathioprine
Intervention descriptions: intervention 1: Rituximab IV infusion 1000 mg x 1 dose at months 4, 8, 12, 16 and 20 and glucocorticoids. Four - six hour infusion. Treatment with rituximab will cease at month 20. intervention 2: Oral dosage form. Target dose is 2mg/kg; maximum daily dose is 200mg. This should be continued until month 24. The dose should then by reduced by 50% and azathioprine completely withdrawn at month 27.

The dose should be rounded down to the nearest 25mg. The dose may vary on alternate days e.g. 100mg one day, 150mg the next for patients on an overall dose of 125mg daily.

If patients are aged over 60 years, reduce the dose by 25%. If patients are aged over 75 years, reduce the dose by 50%.

Protocol documents:
Prot_000.pdf: 
EudraCT number: 2012-001102-14 
 
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RITAZAREM     
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          Date: 12th July 2019 
Clinical Trial Protocol 
 
 
Trial Title: 
An international, open label, randomised controlled trial 
comparing rituximab with azathioprine as maintenance therapy 
in relapsing ANCA-associated vasculitis 
Protocol Number: 
RITAZAREM 
 
EudraCT Number:         2012-001102-14  
Japanese Reference 
 Number: 
UMIN000012409 
ClinicalTrials.gov:          NCT01697267 
Website:  
http://RareDiseasesNetwork.org/VCRC/RITAZAREM 
 
Investigational Product: Rituximab 
Protocol Version:           5.1 12th July 2019 
 
 
Chief Investigators:      Prof David Jayne 
 
Prof Peter A. Merkel 
CI Address:                  Box 157, Dept. Medicine 
Division of Rheumatology      
Addenbrooke’s Hospital 
University of Pennsylvania 
Hills Road 
 
 
3400 Spruce St,  
 
 
 
 
 
 
White Building, 5th Floor  
Cambridge, CB2 0QQ  
Philadelphia, PA 19104  
United Kingdom 
United States of America 
Telephone: 
00 44 1223 586796 
 
00 1 215 614 4401 
Email: 
dj106@cam.ac.uk 
 
pmerkel@upenn.edu 
Trial Sponsor: 
Cambridge University Hospitals NHS Foundation Trust (Rest of 
World) 
North American  
Sponsor: 
University of Pennsylvania (US and Canada) 
Japan Sponsor: 
Okayama University (Japan) 
Ireland Sponsor: 
University College Cork 


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Funding: 
Arthritis Research UK, U.S. National Institutes of Health, 
Japanese Ministry of Health, Labour and Welfare and 
Roche/Genentech 
 
RITAZAREM is a joint venture of the European Vasculitis Study 
Group (EUVAS) and the Vasculitis Clinical Research Consortium 
(VCRC). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


EudraCT number: 2012-001102-14 
 
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RITAZAREM     
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SAE Reporting: 
Dr Rona Smith, RITAZAREM trial physician, or 
Kim Mynard, RITAZAREM UK Trial Coordinator 
Vasculitis Research Office, Box 118 
Addenbrooke’s Hospital  
Hills Road 
Cambridge, CB2 0QQ,  
United Kingdom. 
Telephone: 00 44 1223 349350 
Email: RITAZAREM@medschl.cam.ac.uk 
 
 
Carol McAlear, RITAZAREM US Trial Coordinator 
University of Pennsylvania 
White Building, 5th Floor 
3400 Spruce Street 
Philadelphia, PA  19104 
 
Telephone: 00 1 781 321 4567 
 
Fax: 00 1 215-614-4402 
 
Email: cmcalear@pennmedicine.upenn.edu 
 
 
 
 
 


EudraCT number: 2012-001102-14 
 
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1 
Protocol Signatures: 
I give my approval for the attached protocol entitled “An international, open label, 
randomised controlled trial comparing rituximab with azathioprine as maintenance 
therapy in relapsing ANCA-associated vasculitis” Version 5.1 dated 12th July 2019. 
 
Chief Investigators 
 
Name: 
Prof David Jayne 
Prof Peter A. Merkel 
 
Signatures: ___________________ 
_______________________      
 
Date: 
___________________ 
___________________ 
 
 
 
Site Signatures 
 
I have read the attached protocol entitled “An international, open label, randomised 
controlled trial comparing rituximab with azathioprine as maintenance therapy in 
relapsing ANCA-associated vasculitis” Version 5.1, dated 12th July 2019 agree to abide 
by all provisions set forth therein. 
 
I agree to comply with the International Conference on Harmonisation Tripartite 
Guideline on Good Clinical Practice CPMP/ICH/135/95; the Declaration of Helsinki and 
all applicable regulatory requirements and laws (The European Clinical Trials Directives 
2001/20/EC and 2005/28/EC in Europe, The National Research Act 1974 in the United 
States and the Therapeutic Goods Regulations 1990 in Australia). 
 
Japanese investigators agree to comply with the International Conference on 
Harmonisation Tripartite Guideline on Good Clinical Practice, the Declaration of Helsinki, 
and the Ethics Guideline for Clinical Studies promulgated on 2008 by Ministerial 
Notification No. 415 of Ministry of Health, Labour Welfare of Japan.  
 
 
I agree to ensure that the confidential information contained in this document will not 
be used for any other purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the Sponsor 
 
Site Principal Investigator 
 
Name:  
________________________________________ 
 
Signature: 
________________________________________ 
 
Date: 
____________________________ 
 


EudraCT number: 2012-001102-14 
 
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2 
Trial Management Committee and Protocol Contributors 
 
Prof David Jayne (Chair/Principal and Chief investigator) 
Prof Peter A. Merkel (Principal and Chief Investigator) 
 
Dr Rona Smith (Trial Physician) 
 
Dr Ulrich Specks 
 
Dr Rachel Jones 
 
Dr Simon Bond (Statistician) 
 
Kim Mynard (Trial Co-ordinator) 
 
Carol McAlear (Trial Co-ordinator) 
 
 
 
 
Trial Steering Committee 
 
Professor Jane Armitage (Independent Chair) 
 
Dr Simon Bowman (Independent Expert Member) 
 
Dr Frances Hall (Independent Expert Member) 
 
All members of the TMC (as above) are also member of TSC 


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3 
Table of Contents 
 
1 
Protocol Signatures: ................................................................................. 4 
2 
Trial Management Committee and Protocol Contributors .......................... 5 
3 
Table of Contents ..................................................................................... 6 
4 
Abbreviations and Definitions ................................................................... 8 
5 
Trial Synopsis ........................................................................................... 9 
6 
Trial Flow Chart .......................................................................................14 
7 
Introduction ............................................................................................15 
7.1 
Background ......................................................................................... 15 
7.2 
Data from Non-Clinical Studies .............................................................. 15 
7.3 
Clinical Data ........................................................................................ 16 
8 
Rationale for Trial ...................................................................................17 
9 
Trial Design .............................................................................................17 
9.1 
Statement of Design ............................................................................. 17 
9.2 
Number of Centres ............................................................................... 17 
9.3 
Number of Subjects .............................................................................. 18 
9.4 
Trial Duration ...................................................................................... 18 
9.5 
Trial Objectives.................................................................................... 18 
9.6 
Trial Endpoints .................................................................................... 18 
10 
Selection and Withdrawal of Subjects and Randomisation ....................19 
10.1 
Inclusion Criteria ................................................................................. 19 
10.2 
Exclusion Criteria ................................................................................. 19 
10.3 
Enrolment and Assignment and Trial Number ........................................... 20 
10.4 
Randomisation .................................................................................... 21 
10.5 
Method of Blinding ............................................................................... 21 
10.6 
Subject Withdrawal Criteria ................................................................... 21 
11 
Trial Treatments ..................................................................................22 
11.1 
Rituximab ........................................................................................... 22 
11.2 
Azathioprine ........................................................................................ 25 
11.3 
Methotrexate ....................................................................................... 26 
11.4 
Mycophenolate Mofetil .......................................................................... 27 
11.5 
Concomitant Therapy ........................................................................... 28 
11.6 
Treatment of relapse ............................................................................ 30 
12 
Procedure and Assessments .................................................................30 
12.1 
Screening Evaluation ............................................................................ 30 
12.2 
Baseline Data ...................................................................................... 30 
12.3 
Trial Assessments ................................................................................ 30 
12.4 
Long-Term Follow-up Assessments ......................................................... 31 
12.5 
Trial Restrictions .................................................................................. 31 
13 
Assessment of Safety ...........................................................................31 
13.1 
Definitions .......................................................................................... 31 
13.2 
Expected Adverse Reactions/Serious Adverse Reactions (AR /SARs)…………….33 
13.3 
Expected Adverse Events/Serious Adverse Events (AE/SAE) ....................... 35 
13.4 
Recording and Evaluation of Adverse Events .......................................... 366 
13.5 
Reporting Serious Adverse Events .......................................................... 37 
13.6 
Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) .... 37 
13.7 
Pregnancy Reporting ............................................................................ 39 
14 
Toxicity – Emergency Procedures .........................................................39 
15 
Evaluation of Results ............................................................................39 
15.1 
Response Criteria ................................................................................. 39 
16 
Statistics ..............................................................................................40 
16.1 
Statistical Methods ............................................................................... 40 


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16.2 
Interim Analyses .................................................................................. 40 
16.3 
Number of Subjects to be Enrolled ......................................................... 40 
16.4 
Criteria for the Termination of the Trial ................................................... 41 
16.5 
Procedure to Account for Missing or Spurious Data ................................... 41 
16.6 
Definition of the End of the Trial ............................................................. 41 
17 
Data Handling and Record Keeping ......................................................41 
17.1 
CRF ................................................................................................... 41 
17.2 
Source Data ........................................................................................ 41 
17.3 
Data Protection .................................................................................. 422 
18 
RITAZAREM Committees ......................................................................42 
19 
Ethical & Regulatory Considerations .....................................................42 
19.1 
Consent .............................................................................................. 42 
19.2 
Ethical Committee Review ..................................................................... 42 
19.3 
Regulatory Compliance ......................................................................... 43 
19.4 
Trial Documentation Amendments .......................................................... 43 
19.5 
Peer Review ........................................................................................ 43 
19.6 
Declaration of Helsinki and ICH Good Clinical Practice ............................... 43 
19.7 
GCP Training ....................................................................................... 43 
20 
Sponsorship, Financial and Insurance ..................................................43 
21 
Monitoring, Audit & Inspection .............................................................44 
22 
Protocol Compliance and Breaches of GCP ............................................44 
23 
Publications Policy ...............................................................................44 
24 
Publications .........................................................................................44 
25.1 
Appendix 1: Schedule of events ........................................................46 
 


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4 
Abbreviations and Definitions 
Abbreviations 
AAV 
ANCA-associated vasculitis 
ANCA 
Anti-neutrophil cytoplasmic antibody 
BVAS/WG 
Birmingham Vasculitis Activity Score for Wegener’s 
CA 
Competent Authority 
CCTU 
Cambridge Clinical Trials Unit 
CDA 
Combined Damage Assessment Index  
CMV 
Cytomegalovirus 
COPD 
Chronic obstructive pulmonary disease 
CRF 
Case Report Form 
CRO 
Clinical Research Organisation 
DNA 
Deoxyribonucleic acid 
DSMB 
Data Safety and Monitoring Committee 
EC 
Ethics Committee (encompassing Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)) 
EQ5D 
EuroQol 5D Quality of Life Questionnaire 
FDA 
The Food and Drug Administration 
GC 
Glucocorticoids 
GP 
General Practitioner 
GPA 
Granulomatosis with polyangiitis (Wegener’s)  
HACA 
Human Antichimeric antibodies 
IB 
Investigator’s Brochure 
ICH-GCP 
International Conference on Harmonisation – Good Clinical Practice 
IEC 
Independent Ethics Committee 
IRB 
Independent Review Board 
IV 
Intravenous 
MHRA 
Medicines and Healthcare products Regulatory Agency  
MMF 
Mycophenolate Mofetil 
MPA 
Microscopic Polyangiitis  
mRNA 
Messenger RNA 
NHS 
National Health Service 
PROMIS 
Patient Reported Outcomes Measurement Information System 
NIH 
National Institutes of Health 
R&D 
Research and Development 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SF-36 
Short Form (36) Health Survey 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TMC 
Trial Management Committee 
TPMT 
Thiopurine methyltransferase  
VCRC 
Vasculitis Clinical Research Consortium 
 
Definitions 
Relapse (flare) 
The occurrence of any new BVAS/WG item. 
Major Relapse 
The development of a new or recurrent major disease 
activity item using the BVAS/WG assessment tool 
Minor Relapse 
Any increase in disease activity that does not meet the 
definition of Major Relapse 
Remission 
BVAS/WG≤1 (one minor persistent BVAS/WG item) and 
GC dose ≤10mg/day 
Complete Remission 
BVAS/WG = 0 independent of GC 
Sustained Remission 
Remission lasting more than 6 months without a relapse 


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5 
Trial Synopsis 
 
Title  
An international, open label, randomised, 
controlled trial comparing rituximab with 
azathioprine as maintenance therapy in 
relapsing ANCA-associated vasculitis (AAV) 
Sponsor name 
 
North American Sponsor 
Japan Sponsor 
Ireland Sponsor 
Cambridge University Hospitals NHS 
Foundation Trust 
University of Pennsylvania 
Okayama University 
University College Cork 
Disease Under Investigation 
ANCA-associated vasculitis (AAV) 
Purpose of Clinical Trial 
To demonstrate the superiority of rituximab 
against azathioprine in the prevention of 
disease relapse in AAV patients with relapsing 
disease 
Clinical Phase 
III (3) 
Trial Design  
Multi-centre, international, open-label, 
randomised controlled trial in relapsing AAV.  
At least 160 participants will be randomised 
1:1 to receive fixed-interval repeat rituximab 
dosing or azathioprine maintenance therapy 
The trial has 3 phases and will last for 48 
months: 
Induction – 0-4 months 
Maintenance – 4-24 months 
Long-term follow-up –patients will have a 
minimum of 12, and maximum of 
24 months follow-up 
 
Primary objective 
To assess the efficacy of rituximab compared 
to azathioprine in the prevention of disease 
relapse in AAV patients with relapsing disease 
Secondary objectives 
To demonstrate: 
1. Sustained disease remission beyond 
the 24 month treatment period 
2. Long term safety of rituximab 
administration 
3. The optimal remission maintenance 
therapy in AAV following induction of 
disease remission with rituximab 
Trial Endpoints 
Primary: 
Time to disease relapse (either minor or 
major relapse) from randomisation. 
 
Secondary: 
1. Proportion of patients who maintain 
remission at 24 and 48 months 
2. Time to a major or second minor 
relapse 
3. Cumulative accrual of damage as 
measured by the combined damage 
assessment score (CDA) 


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4. Health-related quality of life as 
measured using SF-36  
5. Cumulative glucocorticoid exposure 
6. Severe adverse event rate  
7. Infection (treated with either 
intravenous or oral antibiotics) rate 
 
Exploratory: 
1. Health economic assessment based on 
EQ5D 
2. Health-related quality of life and 
patient-reported domains as measured 
using PROMIS 
3. Serum rituximab levels, and 
correlation with circulating B cell 
counts including key subsets and 
immunoglobulin levels 
4. Changes in ANCA titres (both anti-MPO 
and anti-PR3 subsets) in relation to 
treatment, response, and relapse. 
5. HACA rate and levels 
6. Serum will be stored for future 
biomarker studies 
7. mRNA will stored for disease and 
inflammatory gene activation studies 
8. DNA will be stored for future genetic 
studies 
 
Sample Size 
Enrolment will be ongoing until at least 160 
patients are randomised. It is anticipated this 
will require 190 patients to be recruited.  
Summary of Eligibility Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Key Exclusion Criteria 
Subjects must meet all of the following 
criteria to be eligible for enrolment: 
1. Written informed consent (15 years 
and above) 
2. A diagnosis of AAV (granulomatosis 
with polyangiitis (Wegener's) or 
microscopic polyangiitis), according to 
the definitions of the Chapel Hill 
Consensus Conference 
3. Current or historical PR3/MPO ANCA 
positivity by ELISA  
4. Disease relapse defined by one major 
or three minor disease activity items 
on the Birmingham Vasculitis Activity 
Score for Wegener’s (BVAS/WG), in 
patients that have previously achieved 
remission following induction therapy 
 
 
1. Age < 15 years (age < 18 years at 
centres that do not treat paediatric 
patients) 
2. Previous therapy with any biological B cell 


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depleting agent (such as rituximab or 
belimumab) within the past 6 months 
 
Randomisation 
Patients will be stratified at the time of 
randomisation (month 4) according to: 
1. ANCA type (anti-PR3 or anti-MPO) 
2. Relapse severity (severe or non-
severe) 
3. Selected prednisone induction regimen 
(1A or 1B) 
Investigational Medicinal 
Product and Dosage 
Rituximab 
 
Induction Regimen 
Patients will be recruited at the time of 
relapse.  All will receive rituximab 
375 mg/m2/week x 4 doses and 
glucocorticoids. 
 
Patients that achieve disease control 
(BVAS/WG ≤ 1 and daily prednisone dose ≤ 
10mg) by month 4 will be randomised to the 
rituximab or control remission maintenance 
groups. 
 
Rituximab maintenance group 
Rituximab 1000 mg at months 4, 8, 12, 16 
and 20 and glucocorticoids. 
 
Active Comparator Products 
Azathioprine 
 
Induction Regimen 
Patients will be recruited at the time of 
relapse. All will receive rituximab 
375 mg/m2/week x 4 and glucocorticoids. 
 
Those patients that achieve disease control 
(BVAS/WG ≤ 1 and daily prednisone dose 
≤ 10 mg) by month 4 will be randomised to 
the rituximab or control remission 
maintenance groups. 
 
Control maintenance group 
Azathioprine 2 mg/kg/day from month 4 to 
24. Dose reductions for intolerance, abnormal 
liver function tests, cytopenias, or based on 
abnormal TPMT genotype/activity testing (if 
performed) will be made.  Methotrexate 
25 mg/week, for patients with GFR > 
50 ml/min and intolerant of azathioprine even 
at a reduced dose of 1 mg/kg/day, or 
mycophenolate mofetil 2 g/day, for patients 
intolerant of azathioprine and with GFR < 
50 ml/min, and glucocorticoids.  Intolerance 
is defined as the occurrence of an adverse 


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effect (see section 11.2.i) NOT lack of 
efficacy.  At month 24, the azathioprine, 
methotrexate, mycophenolate mofetil dose 
will be reduced by 50% and stopped at 
month 27 (dose = 0 mg/day at month 27).  
Route of Administration 
Rituximab will be administered intravenously. 
Azathioprine and mycophenolate mofetil will 
be administered orally.  
Methotrexate can be given orally, 
subcutaneously, or intramuscularly. 
 
Concomitant Therapy 
Glucocorticoids at induction 
 
For all glucocorticoid dosing, prednisone may 
be substituted for prednisolone. 
 
The investigator may choose one of two 
permitted GC regimens:  
 
Oral prednisone (prednisolone will be 
allowed), commencing at 1.0mg/kg/day 
(maximum 60 mg/day),  
or 0.5mg/kg/day (maximum 30 mg/day), 
both reducing to 10mg/day by month 3 (See 
schedule 1, pg. 26).   
 
Maximum daily dose of GC is 60 mg 
prednisone in week 0.  Round down to the 
nearest 5 mg above 20 mg.  Round down to 
the nearest 2.5 mg below 20 mg.  GC to be 
administered in a single daily dose. 
 
Intravenous (IV) GCs are not mandated by 
the protocol.  At the investigator’s discretion, 
patients may receive up to a maximum 
cumulative dose of 3000mg IV 
methylprednisolone, between 14 days prior to 
enrolment and 7 days after enrolment. 
 
Glucocorticoids in Maintenance Phase: 
 
A GC dose of prednisolone 10 mg/day or less 
is a requirement for randomisation.  GC 
reduces to 5 mg/day by month 6, according 
to schedule 2 (pg. 26).  At month 16, GC 
dose is reduced to 2.5mg/day and at month 
20 GC are completely withdrawn.  
Maximum Treatment Duration 
Treatment is protocolised for the entire 
duration of the study, until the common close 
date, when the final patient recruited has 
completed 36 months within the study or 
until the patient has completed 48 months on 
study whichever the sooner.  Patients in the 
rituximab arm will receive treatment until 


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month 20, and those in the azathioprine arm 
until month 27. 
Summary of Study Procedures
 
 Screening:  
 
Procedures to establish inclusion/exclusion 
criteria. 
 
Baseline: 
Baseline data will include: 
1. Date of birth, sex, limited medical 
history 
2. Medications, including prior AAV 
treatments 
3. Height/weight 
4. Urinary HCG in women of child bearing 
potential at screening or on Day 1 of 
rituximab treatment 
5. Disease activity assessment 
(BVAS/WG) 
6. Disease related damage assessment 
(CDA) 
7. Patient self-reported SF-36 
questionnaire, EQ5D questionnaire and 
PROMIS questionnaires. 
 
Treatment period: 
Evaluations will be performed at months 0, 
1.5, 3, 4, 8, 12, 16, 20, 24, 27, 30, 36, and 
every 6 months until the last patient has 
completed 36 months in the study.  
The maximum duration in the study is 48 
months. Assessments will also be performed 
at the time of relapse or study termination 
/withdrawal. 
 
End of Trial: 
The trial will end when the last patient has 
completed 36 months in the trial (from 
enrolment).  
Safety and Monitoring 
The NIH-sponsored VCRC Data and Safety 
Monitoring Board will provide independent 
oversight of this trial. 


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6 
Trial Flow Chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Induction therapy with 
rituximab (4 x 375mg/m2) 
and GC  
Screening and Enrolment 
Randomisation
1g at 4, 8, 12, 16 & 20 months 
Standardised GC taper 
Rituximab Maintenance 
 
2mg/kg/day 
Standardised GC taper 
Azathioprine Maintenance 
 
No therapy 
Follow-up to between 36 months 
(min) and 48 months (max) 
Azathioprine withdrawal month 27 
Follow-up to between 36 months 
(min) and 48 months (max) 
4 month induction 
phase 
20 month remission phase 
12-24 month follow-up phase 
At 4 months for patients 
demonstrating disease 
control (BVAS/WG ≤ 1 and 
GC dose ≤ 10mg per day) 
Follow-Up Phase 
Follow-Up Phase 


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7 
Introduction 
7.1 Background 
ANCA-associated vasculitis (AAV): Disease overview and current treatment 
 
Granulomatosis with polyangiitis (GPA) (formally Wegener’s granulomatosis (WG)) and 
microscopic polyangiitis (MPA) are primary systemic vasculitides, predominantly 
involving microscopic blood vessels with no or scanty immune deposits. Their 
association with circulating auto-antibodies to neutrophils (ANCA) has led to these 
conditions being grouped together as ANCA-associated vasculitis (AAV) (1, 2). The 
cause of AAV is unknown. AAV has an annual incidence of 20 per million and an 
approximate prevalence of 200/million (3). It is a multi-system autoimmune disease 
that causes tissue damage especially to the respiratory tract and kidneys, and causes 
early mortality, organ failure including end stage renal disease, and chronic morbidity.   
Prior to the availability of effective treatment, AAV was almost universally fatal, with a 
93% mortality within 2 years due to pulmonary and renal failure (4). The introduction 
of what is now termed conventional immunosuppressive treatment transformed 
survival. Administration of cytotoxic immunosuppression (cyclophosphamide or 
methotrexate) and corticosteroids for at least one year induces remission in 
approximately 80% of patients. However, there are a significant proportion of patients 
that inadequately respond to traditional therapy. Also, relapsing disease is common 
with over 50% of patients experiencing a relapse within 5 years (5, 6, 7, 8). Relapse is 
associated with increased exposure to immunosuppressive medications and 
corticosteroids and at least 25% suffer severe early or late toxicity from these agents 
(9). The majority of relapses in the NORAM trial were minor, but were associated with a 
higher cumulative cyclophosphamide and glucocorticoid exposure (10). As treatment 
exposure is the greatest modifiable cause of damage, then prevention of relapses, 
minor as well as major is highly desirable. There is a major unmet need for safer 
therapy that leads to sustained treatment free remission in patients with relapsing 
disease, which will reduce drug toxicity that results from cumulative exposure to 
cyclophosphamide and glucocorticoids. 
 
Rituximab 
 
Rituximab is an IgG1 kappa, chimeric murine/human monoclonal antibody directed 
against the B-cell surface molecule CD20, resulting in B cell depletion. CD20 is thought 
to regulate an early step in the activation process for cell cycle initiation and 
differentiation. CD20 is not found on pro- or pre-B cells or mature plasma cells (the 
source of 95% of circulating IgG), so rituximab eliminates peripheral B cells without 
preventing regeneration of B cells from precursors and does not directly affect 
immunoglobulin levels. The cytotoxic effect is achieved by antibody-dependent cell-
mediated cytotoxicity (ADCC), complement-mediated cell lysis and apoptosis (11). 
Rituximab was licensed for the treatment of non-Hodgkin’s lymphoma in 1997 and for 
rheumatoid arthritis in 2006. Rituximab was licensed for AAV by the US FDA in 2011. In 
these conditions, rituximab was well tolerated with a favourable safety profile. 
 
 
7.2 Data from Non-Clinical Studies 
In vivo preclinical studies have shown that rituximab depletes >95% B cells from the 
peripheral blood cynomolgus monkeys. This depletion occurs presumably through 
complement and cell-mediated processes. The B-cell compartments within lymphatic 
tissue, including spleen, mandibular lymph node, and/or sub-mucosal lymphoid 
nodules, were also depleted within a short period of treatment, but to a lesser extent. 
Consistent with rituximab binding only to CD20+ B cells, T cell numbers were 
unaffected after treatment with rituximab.  


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7.3 Clinical Data 
 
7.3.1 Efficacy 
 
Rationale for the use of rituximab in AAV 
 
B cells play a key role in the pathogenesis of AAV.  Not only are they the precursors of 
ANCA secreting plasma cells, but they also act as antigen presenting cells for 
autoreactive T cells, providing co-stimulatory support and initiating T cell activation, as 
well as producing pro-inflammatory cytokines, such as IL-6 and TNFα. Specifically 
depleting B cells with targeted biological agents, such as rituximab, is therefore a 
promising approach to the treatment of AAV 
 
Rationale for clinical trial design and dosage 
 
Rituximab in AAV: Remission induction therapy 
 
Randomised controlled trial data on the efficacy of rituximab in AAV is available from 
the RITUXVAS (n=44) (12) and RAVE (n=197) (13) studies. Both compared a rituximab 
based regimen to a cyclophosphamide based regimen as induction therapy for AAV. The 
RITUXVAS trial included newly diagnosed renal AAV. RAVE included patients with new 
and relapsing AAV. Neither trial identified differences in remission or severe adverse 
event rates between groups. However, the RAVE study included patients with an 
existing diagnosis of AAV, experiencing disease relapse, as well as those with a new 
diagnosis. It was in this subgroup of 101 patients that rituximab demonstrated 
superiority to cyclophosphamide in a prespecified exploratory analysis, with 62.2% 
patients in the rituximab group entering complete remission, when compared with 42% 
in the cyclophosphamide group (13).   
 
Rituximab in AAV: Remission maintenance therapy 
 
Results from uncontrolled studies consistently suggest that after a single course of 
rituximab AAV remissions occur and are sustained without the need for maintenance 
immunosuppression. However the majority of relapsing AAV patients treated with 
rituximab will relapse, with a mean time to relapse of one year (14). ANCA and B cell 
levels however lack the sensitivity to predict relapses and guide the timing of re-
treatment.    
 
Pilot data on the efficacy of rituximab as a maintenance agent is available from a cohort 
of 84 patients followed up at Addenbrooke’s hospital between 2002 and 2010. Between 
2002 and 2006, 34 patients received non protocolised treatment with rituximab which 
involved either, 2x1g doses, or 4x375mg/m2 doses at the outset, and only further 
treatment with rituximab if a clinical relapse occurred. From 2006-2011, 50 patients 
received a protocolised course of rituximab therapy comprising of 2x1g or 4x375mg/m2 
doses initially, followed by 1g every 6 months for 2 years. Relapse free survival in the 
protocolised group was considerably higher than that in the non-protocolised group 
(Figure 1) (15).Six monthly re-treatment with rituximab resulted in prolonged B cell 
depletion, without a significant fall in immunoglobulin levels or an increased risk of 
severe adverse events or serious infections. 
 
 
 
 


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8 
Rationale for Trial 
 
Rituximab is an established induction agent in AAV, especially for those with relapsing 
disease. Its role as a maintenance agent is less clear. 50% will pursue a chronic 
relapsing course with 77% relapsing a second time within 2 years of a single course of 
rituximab. Therefore the major unmet need is prevention of future relapse in relapsing 
patients. Pilot data suggests that 6 monthly rituximab over 2 years is effective, safe, 
and leads to sustained treatment free remission. This is the platform for definitive study 
in a controlled trial which, if positive, will re-define remission therapy for AAV. Relapses 
however did still occur, the vast majority (90%) within the 2 months preceding 
subsequent rituximab doses, and so a 4 monthly repeat dosing strategy has been 
adopted for the study. 
 
The study aims to improve outcomes for AAV patients by comparing a rituximab 
regimen to the current standard of care – azathioprine or methotrexate and 
glucocorticoids. In addition to answering the primary question of which is the superior 
therapy for preventing relapse in AAV, a number of key secondary questions will be 
addressed: 
 
Does sustained rituximab therapy have long-term benefit beyond the treatment 
period? 
 
Is sustained rituximab safe? 
 
What is the optimal remission therapy after rituximab induction?  
 
9 
Trial Design 
 
9.1 Statement of Design 
RITAZAREM is a multi-centre, international, open label, randomised controlled trial in 
relapsing AAV. Patients will be randomised, 1:1, to receive fixed interval repeat 
rituximab dosing or azathioprine maintenance therapy. 
 
9.2 Number of Centres 
RITAZAREM is a joint venture of the European Vasculitis Study Group (EUVAS) and the 
Vasculitis Clinical Research Consortium (VCRC). 
 
RITAZAREM will occur in multiple centres internationally including Europe, North 
America and Australia/New Zealand and Japan. Plans are for approximately 50-60 
centres to recruit patients. 
 
Relapse Free Survival
0
10
20
30
0
20
40
60
80
100
Protocol
Non-protocol
Months
Relapse free survival
Figure 1. 
At 24 months, 24% (12/50)  
of protocolised patients have 
relapsed, compared to 71% 
(24/34) non-protocolised 
patients 


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9.3 Number of Subjects 
Enrolment will be ongoing until at least 160 patients are randomised. It is anticipated 
this will require 190 patients to be recruited. Any patients in the induction phase when 
enrolment is halted will continue to follow the protocol and be randomised if the 
relevant criteria are met. 
 
9.4 Trial Duration 
The trial has 3 phases and will last for 48 months: 
 
Induction – 0-4 months 
Maintenance – 4-24 months 
Long-term follow-up –patients will have a minimum of 12, and maximum of 24 
months follow-up 
 
9.5 Trial Objectives 
 
9.5.1 Primary objective 
To assess the efficacy of rituximab compared to azathioprine in the 
prevention of disease relapse in AAV patients with relapsing disease  
9.5.2 Secondary objectives 
To demonstrate 
1. Sustained disease remission beyond the 24 month treatment period 
2. Long term safety of rituximab administration 
3. The optimal remission maintenance therapy in AAV following induction of 
disease remission with rituximab 
 
9.6 Trial Endpoints  
 
9.6.1 Primary endpoint 
The primary endpoint is the time to disease relapse (either minor or major 
relapse) from randomisation. Any patients who have not relapsed at study close 
will be censored. Further details of how relapse/censoring dates will be defined 
are given below. 
A blinded Independent Adjudication Committee will be convened to look at all endpoint 
data. 
 
 
Situation 
Date of Relapse or Censoring  
Outcome 
No baseline assessments 
Randomization  
Censored 
Relapse documented between 
scheduled visits 
Unscheduled visit date 
Relapsed 
Drop-out with no relapse 
Date of last assessment with no 
documented relapse  
Censored 
Treatment discontinuation for 
undocumented relapse 
Date of last assessment with no 
documented relapse  
Censored 
Treatment discontinuation for 
toxicity or other reason, or 
protocol deviation 
The patient will be followed up as 
per protocol and date of relapse 
or censoring observed accordingly 
Relapsed/censored 
Death due to relapse 
Date of Death 
Relapsed 
Death due to other causes 
Date of Death  
Censored 
Death or progression after 
 More than one missed visit 
Date of last assessment with no 
documented relapse  
Censored 


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9.6.2 Secondary endpoints 
1. Proportion of patients who maintain remission at 24 and 48 months 
2. Time to a major or second minor relapse 
3. Cumulative accrual of damage as measured by the combined damage assessment 
score (CDA) 
4. Health-related quality of life as measured using SF-36  
5. Cumulative GC exposure 
6. Severe adverse event rate  
7. Infection (treated with intravenous or oral antibiotics) rates 
 
9.6.3 Exploratory endpoints 
1. Health economic assessment based on EQ5D 
2. EQ5D is a standardised instrument for use as a measure of health  
outcome, 
providing a simple descriptive profile and a single index value for health status.  It 
is designed to be completed by patients. 
3. Health-related quality of life and patient-reported outcomes as measured using the 
Patient-Reported Outcomes Measurement Information System assessment 
(PROMIS).  PROMIS is a set of validated health-related quality of life assessment 
questionnaires covering domains that include fatigue, physical function, pain, and 
global health.  
4. Serum rituximab levels and correlation with circulating B cell counts including key 
subsets and immunoglobulin levels  
5. Changes in ANCA titres (both anti-MPO and anti-PR3 subsets) in relation to 
treatment, response, and relapse 
6. HACA rate and level 
7. Serum will be stored for future biomarker studies  
8. mRNA will be stored for disease and inflammatory gene activation 
9. DNA will be stored for various studies 
 
10 Selection and Withdrawal of Subjects and Randomisation 
 
10.1 Inclusion Criteria 
To be included in the trial the patient must have: 
 
1. Provided written informed consent (15 years and above) 
2. A diagnosis of AAV [granulomatosis with polyangiitis or microscopic polyangiitis], 
according to the definitions of the Chapel Hill Consensus Conference 
3. Current or historical PR3/MPO ANCA positivity by ELISA  
4. Disease relapse defined by one major or three minor disease activity items on 
the Birmingham Vasculitis Activity Score for Wegener’s (BVAS/WG), in patients 
that have previously achieved remission following at least 3 months of induction 
therapy, with a combination of glucocorticoids and an immunosuppressive agent 
(cyclophosphamide or methotrexate or rituximab or mycophenolate mofetil) 
 
 
All patients will receive induction therapy with rituximab. Only those entering 
remission by 4 months will be randomised 1:1 to the rituximab or control groups 
 
10.2 Exclusion Criteria 
The presence of any of the following will preclude patient inclusion:  
 
1. Age < 15 years (age < 18 years at centres that do not treat paediatric patients) 
2. Exclusions related to medication: 
Previous therapy with: 


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a. Any biological B cell depleting agent (such as rituximab or belimumab) within 
the past 6 months 
b. Alemtuzumab or anti-thymocyte globulin (ATG) within the last 12 months 
c. IVIg, infliximab, etanercept, adalimumab, abatacept or plasma exchange in 
past 3 months 
d. Any investigational agent within 28 days of screening, or 5 half lives of the 
investigational drug (whichever is longer) 
 
3. Exclusions related to general health: 
a. Significant or uncontrolled medical disease not related to AAV, which in the 
investigators opinion would preclude patient participation 
b. Presence of another multisystem autoimmune disease, including Churg Strauss 
syndrome, systemic lupus erythematosus, anti-GBM disease, or 
cryoglobulinaemic vasculitis,  
c. Any concomitant condition anticipated to likely require greater than 4 weeks 
per year of oral or systemic glucocorticoid use and which would preclude 
compliance with the glucocorticoid protocol (e.g. poorly-controlled asthma, 
COPD, psoriasis, or inflammatory bowel disease). 
d. History of severe allergic or anaphylactic reactions to humanised or murine 
chimeric monoclonal antibodies 
e. Known infection with HIV (HIV testing will not be a requirement for trial entry); 
a past or current history of hepatitis B virus or hepatitis C virus infection. 
f. Ongoing or recent (last 12 months) evidence of active tuberculosis or known 
active infection (screening for tuberculosis is part of ‘standard of care’ in 
patients with established AAV) or evidence of untreated latent tuberculosis.  
Screening for tuberculosis is as per local practice. 
g. History of malignancy within the past five years or any evidence of persistent 
malignancy, except fully excised basal cell or squamous cell carcinomas of the 
skin, or cervical carcinoma in situ which has been treated or excised in a 
curative procedure. 
h. Pregnancy or inadequate contraception in women of childbearing potential 
i. Breast feeding or lactating 
j. Medical, psychiatric, cognitive or other conditions that, in the investigator's 
opinion, compromise the patient's ability to understand the patient information, 
to give informed consent, to comply with the trial protocol, or to complete the 
study. 
 
4. Exclusion criteria related to laboratory parameters: 
a. Bone marrow suppression as evidenced by a total white count < 4 x109/l, 
haemoglobin < 7 gm/dl or platelet count < 100,000/μl 
b. Aspartate aminotransferase or alanine aminotransferase or amylase > 2.5 
times the upper limit of normal, unless attributed to vasculitis 
 
10.3 Enrolment and Assignment and Trial Number 
The patient will be allocated a unique trial identification number to be used on all trial 
related material for the patient upon enrolment. Patients will be enrolled by logging into 
an internet based website (TENALEA) provided by the Cambridge Clinical Trials Unit. 
After logging in, the investigator will confirm eligibility criteria, ANCA subtype, relapse 
severity and the prednisolone induction regimen followed (1A or 1B).  Investigators are 
required to enter the height and weight of the patient.  Body surface area and the dose 
for each of the 4 rituximab induction infusions (375mg/m2) will be automatically 
calculated within TENALEA using the Dubois and Dubois formula (17).  A target date for 
randomisation four months in the future will be generated.  This information should be 
recorded on the enrolment CRF page. 


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10.4 Randomisation 
 
At the time of enrolment, a target date for randomisation (4 months from enrolment) 
will be generated.  Randomization will be performed by the local investigator for those 
patients in remission (BVAS/WG ≤ 1 and daily prednisone dose ≤ 10mg) by 
month 4.  
 
Patients can be randomised from 14 days before, to 14 days after, month 4.  If patients 
attend their month 3 visit and are in remission, then they can be randomised up to 14 
days before month 4, to enable time to organise rituximab infusion or azathioprine 
supply according to treatment allocation.  Those not in remission at month 3 are 
reassessed at month 4 and if they enter remission must be randomised and commence 
allocated therapy within the next 14 days.  Those not in remission at month 4 are not 
randomised, even if they had been considered in remission at the month 3 visit, and 
are treated at the investigator’s discretion.  Follow-up data will continue to be collected 
unless consent is withdrawn.   
 
The randomization algorithm will then assign the patient to either the rituximab 
maintenance therapy or the control arm, where patients receive azathioprine, unless 
there is a contraindication when mycophenolate mofetil or methotrexate are 
alternatives (see section 11.1.4). Maintenance therapy with rituximab or 
azathioprine must not be administered prior to the month 4 visit.  Notification of 
the treatment allocation will be forwarded to the central study co-ordinator, local 
investigator and local pharmacy by electronic mail (email) upon randomization. In the 
event that access to the internet is unavailable, the investigator may call the central 
study coordinator, based at Addenbrooke’s Hospital, Cambridge, UK who will access the 
randomization program and inform the investigator of the treatment allocation and 
ensure randomization information reaches the appropriate study personnel. 
 
Patients will be stratified at the time of randomisation according to: 
1. ANCA type (anti-PR3 or anti-MPO) 
2. Relapse severity (severe or non-severe) 
3. Selected prednisone induction regimen (1A or 1B) 
 
10.5 Method of Blinding 
This will be an open label study. 
 
A non-blinded, open label study has been chosen for reasons of simplicity and 
practicality in view of RITAZAREM being an international multi-centre trial. Previous 
EUVAS studies with similar end-points have also been unblinded yet have led to robust 
and reproducible conclusions. 
 
10.6 Subject Withdrawal Criteria 
Patients will be withdrawn from the trial immediately if they choose to withdraw their 
consent to participate. Otherwise subjects will be followed until the end of the trial or 
until death. In the event that consent to participate is withdrawn, it will be requested of 
patients that the study team continue to 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. Subjects will not be randomized if they do not achieve 
disease control (BVAS/WG ≤ 1 and daily prednisone dose ≤ 10mg) by month 4 and will 


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be treated at the discretion of the local investigators, although they will continue to be 
followed and data collected for safety purposes. 
 
Withdrawal is anticipated to be a rare occurrence. Local investigators may stop 
the randomised treatment for appropriate medical reasons, be that individual adverse 
events or new information gained about a treatment. Pregnant patients will be treated 
with best medical practice, and continue in long term follow up. Non-compliant patients 
will be helped to return to protocol compliance, and continue in long term follow up.  
Any decision to stop the randomised treatment MUST be discussed with the chief 
investigator in order not to adversely affect the conduct of the trial. Patients will 
continue to be followed up, and data collected and documented as set out in the 
protocol, unless they withdraw their consent for this. 
 
 
11 Trial Treatments 
 
Rituximab, azathioprine, methotrexate and mycophenolate mofetil are all considered 
IMPs for the purposes of this study.  Glucocorticoids are a non-IMP. 
11.1 Rituximab 
Rationale for rituximab dosing 
Induction Phase: 
375mg/m2/week x 4 doses, was the dose used in both the randomised controlled 
rituximab induction trials in vasculitis (RITUXVAS and RAVE) and will be the induction 
dose used in RITAZAREM.   
 
Maintenance Phase: 
Neither RITUXVAS nor RAVE addressed the question of repeat dosing with rituximab as 
a maintenance strategy. The two largest data sets presently available utilising repeat 
rituximab as a maintenance strategy, employed doses of 1000mg x 2 every 6 months 
(Mayo Clinic) (total 8000mg in 24 months) or 1000mg every 6 months (Cambridge, 
UK) (total 4000mg in 24 months). The selected dose for RITAZAREM, 1000mg every 4 
months (5000mg in total), falls between these two regimens. In addition, 9 out of 10 
relapses seen in the Cambridge cohort occurred in the 2 months prior to a scheduled 
rituximab dose, yet responded to further rituximab.  Reducing the interval between 
rituximab doses to 4 months has the potential to further reduce relapse rates. 
 
B cell depletion is a pharmacodynamic surrogate for rituximab efficacy. Because B cell 
return typically commences after four months, by reducing the dosing interval to four 
months the study aims to maintain 100% B cell depletion for the 24 month treatment 
phase. 
 
No data exists for a total rituximab dose below 1000mg in vasculitis. Adopting a 
375mg/m2 dose every 4 months as a maintenance strategy would result in a median 
dose of 700mg. The MAINRITSAN study is employing a 500mg dose every 6 months. 
This is likely to result in under dosing, because 20% of patients relapsed using 1000mg 
every 6 months in the Cambridge cohort. In addition, more frequent maintenance 
dosing is inconvenient for patients and more expensive.  
 
11.1.1 Dosage schedules 
 
Induction Regimen 
Patients will be recruited at the time of relapse. All will receive rituximab 
375 mg/m2/week x 4 doses and glucocorticoids.  The first dose of rituximab 


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should be given within 14 days of enrolment into the trial. All induction doses 
of rituximab should be completed by week 6.  
 
Patients that achieve disease control (BVAS/WG ≤ 1 and daily prednisone dose 
≤ 10mg) by month 4 will be randomised to the rituximab or control remission 
maintenance groups.  
 
First infusion: The recommended initial infusion rate for rituximab 
(MabThera/Rituxan) is 50 mg/h; subsequently, the rate can be escalated in 50 
mg/h increments every 30 minutes to a maximum of 400 mg/h. 
 
Subsequent infusions: Subsequent infusions of rituximab (MabThera/Rituxan) 
can be started at a rate of 100 mg/h and increased by 100 mg/h increments 
every 30 minutes to a maximum of 400 mg/h. 
 
Pre-medication with 100 mg IV methylprednisolone will be administered prior 
the first infusion to minimise infusion reactions. Sites will follow local pre-
medication practice for infusions 2, 3, and 4. 100 mg IV methylprednisolone 
will be administered prior to each maintenance dose. 
 
Infusions of rituximab in the maintenance phase should be given within 2 
weeks of the randomisation at month 4 (if randomisation allocation is to the 
rituximab arm). Further infusions at month 8 onwards must be given within 
+/- 2 weeks of the assessment date. 
 
Rituximab maintenance group 
Rituximab 1000 mg x 1 dose at months 4, 8, 12, 16 and 20 and glucocorticoids. 
Dose of rituximab for maintenance therapy must not be administered 
prior to the month 4 visit.   
 
11.1.2 Route of Administration 
Rituximab will be administered intravenously. 
 
11.1.3 Maximum dosage allowed 
The induction dose will vary depending on the body surface area of the patient.  
The maximum dose administered during the maintenance phase will be 5g. 
 
11.1.4 Maximum duration of treatment of a subject 
Treatment with rituximab will cease at month 20. Patients will continue to be 
followed until month 36 at a minimum. 
 
11.1.5 Known Drug Reactions & Interaction with Other Therapies 
Infusion reactions (within 24 hours of the infusion) occur in up to 50% of 
patients receiving rituximab. Pre-medication with 100 mg IV 
methylprednisolone will be administered prior the first infusion to minimise the 
effect of such reactions. Administration of 100 mg IV methylprednisolone for 
induction infusions 2, 3, and 4 is at the local investigator’s discretion. 100 mg 
IV methylprednisolone will be administered prior to each maintenance dose. 
Symptoms include – fever, rigors, urticaria/rash, pruritis, flushing, angiodema, 
nausea, vomiting, fatigue, headache, rhinitis, throat irritation, bronchospasm 
and hypotension. Following treatment, sepsis, leucopaenia and neutropaenia 
can occur. In patients with autoimmune diseases, severe skin reactions such as 
Toxic Epidermal Necrolysis (TEN) and Stevens- Johnson Syndrome (SJS) with 


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fatal outcome have been reported very rarely with Rituximab in the post-
marketing setting. For autoimmune and oncology indications, in case of the 
occurrence of severe skin reactions, Rituximab treatment should be 
discontinued. The decision to re-administer Rituximab must be carefully 
assessed based on the individual patient`s benefit–risk profile. The cases of 
TEN and SJS have been reported with either first time use or with later 
infusions. Some of the cases occurred on the day of dosing or within a few days 
of dosing. In other cases, the event occurred weeks or up to four months after 
the dose. 
 
Please always refer to the Investigator Brochure for expected adverse events 
associated with rituximab administration. 
 
11.1.6 Dosage Modifications 
Rituximab will be administered at a dose of 375mg/m2 x 4, at weekly intervals 
during the induction phase of the trial. Patients achieving remission and 
randomised to the rituximab remission maintenance group will receive rituximab 
1000mg, at months 4, 8, 12, 16 and 20. The dose of rituximab does not need to 
be adjusted for renal function.  
 
If the IgG level falls below 3g/l, it should be repeated in the month prior to the 
next scheduled dose of rituximab and the dose not administered if the IgG level 
remains <3g/l. If the IgG level has risen and is ≥3g/l, then rituximab should be 
administered as per protocol.  For those with an IgG level remaining < 3g/l, the 
IgG level is checked again within the month prior to the next scheduled dose of 
rituximab and this dose only given if the level has risen to ≥3g/l. IgM and IgA 
levels are ignored for the purpose of rituximab dosing. Dosing of azathioprine 
(methotrexate and mycophenolate mofetil) should continue according to protocol 
regardless of IgG level. 
 
11.1.7 Legal Status of the Drug 
Rituximab (Mabthera) has marketing authorisation numbers EU/1/98/067/001 
and EU/1/98/067/002, which were granted in the EU to Roche Registration 
Limited.  Rituximab has a license for use in stage III-IV follicular lymphoma 
(Non-Hodgkins lymphoma) and in chronic lymphocytic leukaemia in both 
untreated and relapsing/refractory patients. It has a license for use in severe 
active rheumatoid arthritis, in combination with methotrexate, when patients 
have had an inadequate response or demonstrated intolerance to other disease 
modifying agents, including one or more anti-TNF agents.   
 
In the United States rituximab is licensed for use in lymphoma, rheumatoid 
arthritis, and induction therapy for AAV (with regimen of 375mg/m2 x 4 doses). 
 
Rituximab is also approved for use in Canada, Switzerland, Australia, Japan and 
the European Union for GPA and MPA (AAV). 
 
For further information, please refer to the Investigator Brochure (IB). 


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11.1.8 Drug Storage and Supply 
Rituximab must be stored as directed by the relevant IB, and the container 
should be kept in the outer carton to protect from light.  Rituximab (MabThera) 
will be supplied directly by Roche to non-US sites, and rituximab (Rituxan) to all 
US sites by Genentech. Trial-specific prescriptions will be used for the entirety of 
the trial.  
 
 
11.2 Azathioprine 
Azathioprine is converted in the liver to 6-mercaptopurine, which impairs purine 
synthesis, incorporation of purines into DNA and DNA polymerase repair activity. 
Lymphocyte function is reduced, B cells more than T cells, as well as the cellular 
component of the inflammatory response. Azathioprine is well absorbed orally, and its 
elimination requires hepatic metabolism by xanthine oxidase. Therefore an important 
interaction is with allopurinol, a xanthine oxidase inhibitor. 
 
Patients randomised to the control arm will receive oral azathioprine, to be taken daily. 
The maximum daily dose allowed is 200mg. The maximum treatment period is 27 
months, with tapering at month 24 as described below.  
 
i. Adverse Effects 
Major adverse effects include nausea and vomiting, dose-dependent 
myelosuppression and reversible, cholestatic hepatotoxicity. An increased 
incidence of malignancy particularly skin cancers and lymphoma has been 
seen after prolonged administration in transplant recipients. There could 
potentially be an increased susceptibility for developing macrophage activation 
syndrome (MAS) with the use of azathioprine in patients with autoimmune 
conditions.  Physicians should be attentive to symptoms of infection such as 
EBV and cytomegalovirus (CMV), as these are known triggers for MAS.  Please 
always refer to the Summary of Product Characteristics (SmPC) or package 
insert or monograph for expected adverse events associated with 
azathioprine. 
 
 
ii. Administration 
The target dose is 2mg/kg. The maximum daily dose is 200mg. 
This should be continued until month 24. The dose should then by reduced by 
50% and azathioprine completely withdrawn at month 27. 
The dose should be rounded down to the nearest 25mg. The dose may vary 
on alternate days e.g. 100mg one day, 150mg the next for patients on an 
overall dose of 125mg daily. 
 
Dose of azathioprine for maintenance therapy must not be administered 
prior to the month 4 visit.   
 
 
iii. Monitoring 
Full blood count (FBC/CBC) and ALT or AST (for hepatotoxicity), should be 
measured routinely for patients taking azathioprine, more frequently in the 
initial period following initiation 
 
iv. Leucopenia related to azathioprine 


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Stop oral azathioprine if the white cell count (WBC) < 4 x 109/l 
Restart with a dose reduced by 25% when WBC > 4 x 109/l. Monitor weekly 
for four weeks. If leucopenia is severe (WBC < 1 x 109/l or < 4 x 109/l for 
more than 2 weeks), restart azathioprine at 50mg per day, when WBC > 4 x 
109/l.  Increase weekly to target dose as WBC allows. 
Temporary prophylaxis to prevent PJP (PCP) and fungal infection are 
recommended until WCC > 4 x 109/l. G-CSF may be considered. 
For a falling WBC, (<6 x 109/l and a fall of > 2 x 109/l over the previous 
count), then reduce dose by 25%. 
 
v. Azathioprine intolerance 
Dose reductions for intolerance, abnormal liver function, cytopenias, or based 
on TPMT genotype/activity testing (if performed) will be made. Patients 
homozygous for abnormal TPMT genotype/profoundly reduced enzyme activity 
will not receive azathioprine. Methotrexate 25 mg/week will be substituted, for 
patients with GFR > 50 ml/min and intolerant of azathioprine even at a 
reduced dose of 1 mg/kg/day, Mycophenolate mofetil 2 g/day will be 
substituted, for patients intolerant of azathioprine and with GFR < 50 ml/min, 
and glucocorticoids.  Intolerance is defined as the occurrence of an adverse 
event (see section 11.2.i) NOT lack of efficacy.  
 
11.3  Methotrexate 
Methotrexate is a folic acid antagonist. Its cytotoxic effect is mediated by binding of 
dihydrofolic acid reductase, which inhibits the reduction of folic acid to tetrahydrofolate, 
which is essential for the synthesis of purine and pyramidine. Methotrexate easily 
penetrates the tissues after oral administration, with the highest concentrations being 
seen in the liver and kidneys. Most methotrexate is excreted unchanged through the 
urine within 24 hours. Renal disease causes accumulation of methotrexate, and in rare 
cases methotrexate can form complexes in the kidneys leading to renal damage.   
 
Methotrexate is to be given, in a weekly dose. The maximum dose allowed is 
25mg/week. The maximum treatment period is 27 months. 
 
 
i. Adverse Effects 
Adverse events include myelosuppression occurring day 7-14 after a single 
dose, infections due to immunosuppression, stomatitis, gastrointestinal 
disturbance (nausea, vomiting, diarrhoea), alopecia, hypersensitivity reactions 
and central nervous systemic disturbance (headaches, drowsiness and blurred 
vision).  Rare, but serious side effects include pulmonary fibrosis and a 
reversible hepatotoxicity manifest by increased transaminases. Patients should 
only drink minimal amounts of alcohol, and methotrexate should be avoided if 
there is pre-existing liver disease. 
Methotrexate is teratogenic, and therefore adequate contraceptive methods 
must be employed whilst on the drug and for 6 months after stopping it.  
Concomitant administration of folate antagonists, such as co-trimoxazole and 
trimethoprim should be avoided, as acute megaloblastic pancytopaenia has 
been reported. As it is renally excreted methotrexate should be avoided in 
patients with moderate to severe renal impairment.  Please always refer to the 
Summary of Product Characteristics (SmPC) or package insert or monograph 
for expected adverse events associated with methotrexate. 
 
ii. Administration 


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Patients commencing methotrexate after induction of remission should start at 
a dose of 10mg per week. This should increase by 2.5mg weekly to a target 
dose of 25mg weekly. This should be continued until month 24. The dose 
should then by reduced by 50% and methotrexate completely withdrawn at 
month 27.  Folic acid, 5mg weekly, should also be commenced. 
Methotrexate is given orally, although parenteral, intramuscular, or 
subcutaneous administration can be used if oral medication is not tolerated. 
In the case of gastrointestinal disturbance, methotrexate can be given in 2 
divided doses on the same day. Metoclopramide can also be administered.   
 
iii. Monitoring 
Full blood count (FBC) and liver function tests (LFTs) should be measured 
routinely for patients taking methotrexate, more frequently in the initial period 
following initiation. 
 
Methotrexate dosage should be monitored per local practice if concomitant 
treatment with aspirin or non-steroidal anti-inflammatory drugs (NSAIDs, such 
as ibuprofen, indomethacin, naproxen, and many others) is commenced, as 
concomitant use of methotrexate and NSAIDs has been associated with fatal 
methotrexate toxicity. 
Methotrexate should be stopped if transaminases rise > 3 fold of the normal 
range, or WBC < 3 x 109/l or platelet count < 100,000/μl.  Methotrexate can 
be re-started at a reduced dose of 50%, if the abnormal parameter 
normalises. 
 
11.4 Mycophenolate Mofetil 
MMF is a prodrug that is hydrolysed to form mycophenolic acid. Mycophenolic acid 
reversibly inhibits inosin-monophosphate-dehydrogenase (IMDH), a key enzyme of de 
novo purine synthesis. Lymphocytes are key effector cells in AAV, whose proliferation 
and function relies almost exclusively on de novo purine synthesis whereas most other 
cells use the salvage pathway. 
 
MMF is to be taken orally, twice daily. The maximum dose allowed is 3g/day. The 
maximum treatment period is 27 months. Mycophenolic acid is an acceptable 
alternative to MMF. 
 
i. Adverse Effects 
Adverse effects of mycophenolate mofetil include gastro-intestinal (GI) 
disturbance leucopenia and infection including cytomegalovirus (CMV). In a 
systematic review of transplant patients, leucopenia and CMV were 
significantly more common only at the very highest MMF dose (3g), compared 
with azathioprine. The frequency of malignancy in a three year transplant 
study where MMF was combined with other immunosuppressive drugs showed 
no difference compared to azathioprine. GI adverse effects may be related to 
accumulation of the metabolite, mycophenolic acid glucoronide, which 
accumulates in renal failure. Dose reduction in those with a creatinine 
clearance of less than 25 ml/min may be required. Hypogammaglobulinaemia 
and bronchiectasis in association with recurrent infections has been reported 
in patients receiving mycophenolate mofetil particularly in combination with 
other immunosuppressants.  Mycophenolate mofetil is a powerful human 
teratogen, with an increased risk of spontaneous abortions and congenital 
malformations in case of exposure during pregnancy.  Please always refer to 
the Summary of Product Characteristics (SmPC) or package insert or 


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monograph for expected adverse events associated with mycophenolate 
mofetil. 
 
ii. Administration 
Mycophenolate mofetil will be administered orally. The drug will be started at 
1g per day and dose increased to the target dose of 2g per day if tolerated.  
The dose can be increased to 3g daily for those with a sub optimal response. 
This should be continued until month 24. The dose should then by reduced by 
50% and mycophenolate mofetil completely withdrawn at month 27. 
  
 
iii. Monitoring 
The total white cell count (WBC) should be measured routinely for patients 
taking MMF, more frequently in the initial period following initiation. Stop if 
WBC < 4 x 109/l. Restart with MMF dose reduced by at least 500mg when 
WBC > 4 x 109/l. Monitor weekly for one month.  If severe (WBC < 1 x 109/l 
or prolonged (WBC < 4 x 109/l for > 2 weeks), MMF should be withdrawn. 
 
 
11.5 Concomitant Therapy  
 
11.5.1  Glucocorticoids 
Glucocorticoids at Induction: 
For all glucocorticoid dosing, prednisone may be substituted for prednisolone. The 
investigator may choose one of two permitted glucocorticoid regimens to allow for 
variabilities in disease severity and glucocorticoid prescribing.   
 
Oral prednisone (prednisolone will be allowed), commencing at 1.0mg/kg/day 
(maximum of 60 mg/day), or 0.5mg/kg/day (maximum of 30 mg/day), both reducing 
to 10mg/day by month 3.  It is advised to start at 1.0mg/kg/day (maximum 60 
mg/day) initially for those with life or organ threatening manifestations, such as severe 
nephritis or pulmonary haemorrhage and 0.5mg/kg/day (maximum 30 mg/day) for 
those with less severe disease.  However, this is left to physician discretion, although 
the initial dose MUST be specified on the randomisation form, as it will be a 
stratification criterion.  The chosen prednisolone regimen must be commenced by the 
time of the first rituximab (induction) infusion.  Regardless of the dose chosen the 
tapering must adhere to schedule 1 below. 
 
Schedule 1: 
 
Induction Schedule A 
(1 mg/kg group) 
Induction Schedule B 
(0.5 mg/kg group) 
Week 
 
<60kg 
 
≥60kg 
 
<60kg 
 
 
≥60kg 
 
0 
50 
 
60 
25 
 
30 
2 
35 
 
45 
20 
 
25 
4 
25 
 
35 
17.5 
 
20 
6 
20 
 
25 
15 
 
17.5 
8 
15 
 
17.5 
12.5 
 
15 
10 
12.5 
12.5 
12 
10 
10 
 
The maximum daily dose of prednisolone is 60 mg in week 0 in Schedule A. The 
maximum daily dose of prednisolone is 30 mg in week 0 in Schedule B. 


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The dose should be rounded down to the nearest 5 mg above 20 mg and to the nearest 
2.5 mg below 20 mg. Prednisolone is to be administered in a single daily dose. 
 
Intravenous (IV) GC are not mandated by the protocol. But, at the investigator’s 
discretion, patients may receive up to a maximum cumulative dose of 3000mg IV 
methylprednisolone, between 14 days prior to enrolment and 7 days after enrolment. 
 
Glucocorticoids in Maintenance: 
A GC dose of 10 mg/day or less is a requirement for randomisation. GC reduces to 
5 mg/day by month 6, according to schedule 2, and continues at 5 mg daily until month 
16. GC dose is then reduced to 2.5mg/day and completely withdrawn at month 20. 
 
 
 
Schedule 2: 
 
Week 
Maintenance Schedule 
Daily prednisone dose 
(mg) 
12 
10 
14 
10 
16 
(randomisation) 
10 
18 
7.5 
20 
7.5 
22 
5 
24 
5 
 
 
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 7.5 mg/day may be achieved by alternating daily doses of 10 mg/day and 5 
mg/day. 
 
Adverse effects 
The following are expected adverse effects if GC therapy: sepsis, hypertension, fluid 
retention, hyperglycaemia and diabetes mellitus, peptic ulceration, osteoporosis, 
avascular necrosis, cushingoid appearance, striae, alopecia and hirsutism. 
 
11.5.2 Prophylactic therapies 
 
 
Prophylaxis for infection, such as with low-dose sulfamethoxazole-trimethoprim 
and prophylaxis for osteoporosis with calcium and vitamin D supplementation are 
strongly recommended and treatment with bisphosphonates to be considered but 
implementation is left to local practice. 
 
11.5.3 Plasma exchange 
 
Plasma exchange can be administered during the induction period following local 
practice at the discretion of the investigator. Rituximab will not be administered 
within the 48 hours prior to receiving a plasma exchange treatment. 
 


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11.6  Treatment of relapse 
Patients experiencing their first minor relapse after randomisation and before month 24 
of the treatment phase will remain on the randomised treatment (rituximab or 
azathioprine) and will have their oral prednisolone/prednisone increased to 20mg/day 
for one week decreasing in 2.5mg increments each week to reach 5mg/day after six 
weeks. The second minor relapse or first major relapse, occurring before month 24 of 
the treatment phase will result in the patient being withdrawn from protocolised 
treatment and returned to treatment according to local best practice.  Any relapse 
occurring after the 24 month treatment phase will be treated according to local best 
medical practice. 
 
12 Procedure and Assessments 
 
12.1 Screening Evaluation 
Patients must review and sign the ICF prior to undergoing any study-related 
assessment. Patients will be evaluated by their local trial investigators to ensure they 
meet all the inclusion criteria and none of the exclusion criteria as stated in sections 
10.1 and 10.2 of this protocol. The screening visit requires confirmation of the diagnosis 
of AAV (ANCA positivity, current or historical and pertinent histology results) and 
documentation of organ manifestations of active AAV. They will then undergo a baseline 
assessment.  Therapy with IV methylprednisolone may begin during screening. 
 
12.2 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: 
a) Height and weight 
b) Sex 
c) Age and date of birth 
d) Any significant past medical history 
e) Concomitant medications, including previous treatment for AAV and prior 
cyclophosphamide exposure 
f) Full blood count (including platelets and differential white cell count) 
g) Biochemical series (including renal function and immunoglobulin levels) 
h) Pregnancy test in females of child bearing potential 
i) Viral screen for: 
 
 Hepatitis B. Please ensure hepatitis B surface antigen (HbSAg) and anti-
hepatitis B core antibody (anti-HBc) are checked 
 
Hepatitis C (if performed) 
j) Disease activity assessment (BVAS/WG) (including urine sample) 
k) Damage related assessment (CDA) 
l) Patient self-reported SF-36 questionnaire, EQ5D questionnaire and PROMIS 
questionnaires.   
 
12.3 Trial Assessments 
12.3.1 Timing of assessments 
Evaluations will be performed at months 0, 1.5, 3, 4, 8, 12, 16, 20, 24, 27, 
30, 36, and every 6 months until the last patient has completed 12 months of 
follow up (36 months from study entry)  
Only those patients that achieve disease control (BVAS/WG ≤ 1 and daily 
prednisone dose ≤ 10mg) by month 4 will be randomised to the rituximab or 
control remission maintenance groups. Patients who are not randomised will 


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continue to be followed up as per protocolised assessment until the common 
study closure date. 
 
12.3.2 Assessment data 
The following assessments will be performed at the above time points (except 
CDA and SF-36/EQ5D): 
a. 
Disease activity assessment (BVAS/WG) (including urine sample) 
b. Damage related assessment (CDA) – completed at months 0, 4, 12, 24, 
36 and 48. 
c. Quality of life evaluations – Short form 36 (SF-36) questionnaire and 
EQ5D questionnaire at months 0, 4, 12, 24, 36, 42 and 48 months.  
PROMIS questionnaires at every assessment up to and including 48 
months. 
d. Blood tests including a full blood count and immunoglobulin levels (refer 
to schedule of assessment, Appendix 1, for collection of biomarker 
samples for DNA, RNA and serum). 
e. Treatment exposure to prednisolone, rituximab and azathioprine 
f. Adverse event review and concomitant medication review 
The above assessments will also be performed at the time of relapse or study 
termination/withdrawal. 
 
12.4 Long-Term Follow-up Assessments 
All patients will be followed until the last patient to be recruited has completed 36 
months from study entry. With a two year recruitment period the median duration of 
follow-up will be 48 months from entry (range 36-48 months). 
 
12.5 Trial Restrictions 
There are no specific restrictions to daily activities for participants of the study. Both 
male and female subjects should take adequate contraceptive precautions for the 
duration of the interventional phase of the trial (initial 24 months). In addition, 
contraception should be continued for 12 months after the last dose of rituximab 
(Investigators in republic of Ireland ONLY, please see Ireland specific appendix, for 
additional details regarding contraception). No live vaccines should be given to enrolled 
patients during the first 27 months of the trial.  
13 Assessment of Safety  
 
13.1 Definitions 
 
13.1.1 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 
unfavourable 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. 
 
13.1.2 Adverse reaction to an investigational medicinal product (AR) 
All untoward and unintended responses to an investigational medicinal product 
related to any 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 


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argument to suggest a causal relationship. 
 
13.1.3 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. 
 
13.1.4 Serious adverse event (SAE) or serious adverse reaction 
Any untoward medical occurrence or effect that: 
 
Results in death 
 
Is life-threatening 
 
Requires hospitalization or prolongs an existing hospitalization 
 
Results in persistent or significant disability or incapacity 
 
Is a congenital anomaly or birth defect 
 Other important medical events that may not be immediately life-
threatening or results in death or hospitalisation but may jeopardise the 
patient of may require intervention to prevent one of the other outcomes 
listed in the definition above should also be considered ‘serious’ 
 
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. 
 
Important medical events should be reported on the serious adverse event (SAE) 
form under the ‘other’ category. 
 
13.1.5 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A serious adverse reaction, the nature and severity of which is not consistent 
with the information set out in the Reference Safety Information 
13.1.6 Reference Safety Information (RSI) 
The information used for assessing whether an adverse reaction is expected.  
RSI for rituximab is the Investigator’s Brochure (IB) (Section 6 – Guidance for 
the Investigator).   
UK sites, will use Rituximab IB version 16.  Any subsequent versions will be 
reviewed by the trial physician.  Provided there is no significant change to the 
safety information, which would necessitate a protocol amendment, 
subsequent versions will not be circulated to investigators and Version 16 of 
the IB will continue to be used as the RSI for the duration of the study.  If 
there is a significant change in safety information, the protocol will be amended 
and the Rituximab IB version number updated. 
 
For non UK sites, updated IBs will be circulated to country leads, and they 
would continue to follow current regulatory practices in their country, with 
regards to submission to ethics and regulatory bodies.  It will be clearly 


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documented in site TMFs what practice should be followed, and what version of 
the Rituximab IB is being used as RSI. 
For the comparator drugs - azathioprine, methotrexate and mycophenolate 
mofetil the RSI will be: 
 
UK & Europe: 
  • 
Methotrexate (Concordia International) SmPC section 4.8, dated 
31/08/2018 
• 
Mycophenolate Mofetil (Accord Heathcare Ltd) SmPC section 4.8, dated 
06/10/2016 
• 
Azathioprine (Aspen) SmPC section 4.8, dated 06/04/2017 
USA – Package Insert 
Canada - Monograph 
Japan – Package Insert 
New Zealand – Data Sheet (equivalent of SmPC/Package Insert) 
Australia – Product Information (equivalent of SmPC/Package Insert) 
All the drugs which we use in the RITAZAREM trial are prescribed for clinical 
use as approved drugs. 
The Package Insert, Monograph, Product Information, Data Sheet and SmPC 
are very close. 
 
13.2 Expected Adverse Reactions/Serious Adverse Reactions (AR /SARs) 
 
All expected Adverse Reactions are listed in the latest version of the reference 
safety information as specified in section 13.1.6.  This must be used when 
making a determination as to the expectedness of the adverse reaction.  If the 
adverse reaction meets the criteria for seriousness, this must be reported as per 
section 13.4.5. 
 
Rituximab 
 
Infusion reactions (within 24 hours of the infusion) may occur in up to 50% of 
patients receiving rituximab. Pre-medication with 100 mg IV methylprednisolone 
will be administered prior the first infusion to minimise the effect of such 
reactions. Sites will follow local pre-medication practice for infusions 2, 3, and 4. 
100 mg IV methylprednisolone will be administered prior to each maintenance 
dose. Symptoms include – fever, chills, rigors, urticaria/rash, pruritis, flushing, 
angioedema, nausea, vomiting, fatigue, headache, rhinitis, throat irritation, 
bronchospasm and hypotension. However, lower rates were observed in the two 
randomised controlled induction trials.  In the RITUXVAS study, 2/33 patients 
experienced an infusion reaction and in RAVE, only 1/99 experienced an infusion 
reaction severe enough to prevent administration of further infusions of 
rituximab. 
 
Infusion reactions – fever, chills, rash, pruritis, flushing, throat irritation, 
angioedema, nausea and vomiting, fatigue, headache, hypotension and 
bronchospasm. 
Mild infusion reactions are common, and can be treated by stopping the infusion, 
and restarting at a lower rate, together with antihistamine, antiemetic and 
paracetamol. 
Severe infusion reactions have occurred but are rare. Hydrocortisone and 
adrenaline should be available for administration if needed (as per hospital 
protocol). Following a moderate or severe infusion reaction, patients should be 


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admitted to hospital for observation. 
 
Following treatment, bone marrow suppression including leucopaenia and 
neutropaenia can occur.  Following rituximab treatment, severe skin reactions 
such as TEN (Toxic epidermal necrolysis) and SJS (Stevens Johnson Syndrome) 
have been reported very rarely (see section 11.1.5).  Infusion reactions, skin 
reactions, leucopaenia and neutropaenia do not require reporting, unless they 
meet the criteria for a serious adverse event (SAE) – see section 13.1.4 for 
definition of SAE. 
 
Infections can also occur, including very rarely, reactivation of hepatitis B, and 
progressive multifocal leucoencephalopathy caused by reactivation of the JC 
virus.  All infections are being collected as adverse events of interest. See 
section 13.4.   
 
If discontinuation of rituximab is being considered for any reason, then the TMC 
must be consulted. 
 
Azathioprine 
 
The following expected adverse drug reactions may occur in patients taking 
azathioprine: hematotoxicity, hepatotoxicity, pancreatitis and gastrointestinal 
disturbances. Hypersensitivity reactions may also occur (including malaise, 
dizziness, vomiting, diarrhoea, fever, rigors, myalgia, arthralgia, rash, 
hypotension and interstitial nephritis) and there is increased susceptibility to 
infections. Macrophage activation syndrome (MAS) has also been reported in 
patients with autoimmune diseases taking azathioprine. 
 
Mycophenolate Mofetil 
 
Patients receiving immunosuppressive regimens involving combinations of 
medicinal products, including Mycophenolate Mofetil, are at increased risk of 
developing lymphomas and other malignancies, particularly of the skin. Patients 
receiving Mycophenolate Mofetil should be instructed to report immediately any 
evidence of infection, unexpected bruising, bleeding or any other manifestation 
of bone marrow depression. Patients treated with immunosuppressants, 
including Mycophenolate Mofetil, are at increased risk for opportunistic infections 
(bacterial, fungal, viral and protozoal), fatal infections and sepsis. Other 
suspected adverse drug reactions include gastrointestinal disturbance (nausea, 
constipation, flatulence, anorexia, weight loss, vomiting, abdominal pain, gastro-
intestinal inflammation, ulceration, and bleeding, hepatitis, jaundice, 
pancreatitis), hypogammaglobulinaemia, bronchiectasis and blood disorders 
(including leucopenia, anaemia, thrombocytopenia, pancytopenia, and red cell 
aplasia). Mycophenolate mofetil is a powerful human teratogen, with an 
increased risk of spontaneous abortions and congenital malformations in case of 
exposure during pregnancy. 
 
Methotrexate 
 
Acute or chronic interstitial pneumonitis, often associated with blood 
eosinophilia, may occur and deaths have been reported. Symptoms typically 
include dyspnoea, cough (especially a dry non-productive cough) and fever for 
which patients should be monitored at each follow-up visit. Patients should be 
informed of the risk of pneumonitis and advised to contact their doctor 


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immediately should they develop persistent cough or dyspnoea. Methotrexate 
may be hepatotoxic, particularly at high dosage or with prolonged therapy. Liver 
atrophy, necrosis, cirrhosis, fatty changes, and periportal fibrosis have been 
reported. Bone marrow suppression (avoid concomitant use with another anti-
folate drug (e.g. trimethoprim)) and gastrointestinal disturbance (nausea and 
abdominal discomfort) may also be seen as adverse drug reactions with 
methotrexate therapy. 
 
Please also see Summary of Product Characteristics (SmPC) or Package Insert or 
Monograph for expected adverse events for azathioprine, methotrexate, mycophenolate 
and glucocorticoids. Please see Investigator Brochure (IB) for expected adverse events 
for rituximab. 
 
13.3 Expected Adverse Events/Serious Adverse Events (AE/SAE) 
 
All serious adverse events, including serious adverse drug reactions (see section 
13.2) should be reported according to guidance in section 13.5.   
 
In addition to all SAEs, the following selected adverse events (AEs) are being 
collected as part of the RITAZAREM trial. 
 
1. Infections (all episodes requiring treatment with intravenous (IV) or oral 
antibiotics or infections that are commonly understood to be 
opportunistic) 
2. Occurrence of hypogammaglobulinaemia (IgG <5g/l) 
3. An adverse event that results in a change in dose of trial IMPs (rituximab, 
azathioprine, methotrexate or mycophenolate mofetil (MMF)) 
4. An adverse event that results in the addition of a relevant concomitant 
medication (see section 13.3.1 for list) 
5. An adverse event manifested by the occurrence of a relevant laboratory 
abnormality (see section 13.3.2 for list) 
6. New malignancies 
 
 
13.3.1  Relevant concomitant medications 
1. Any anticoagulant, including warfarin, or newer equivalent agents, aspirin, 
clopidogrel, dipyridamole etc.  This will identify any patient who has had a 
venous thromboembolic event or cardiovascular event – both important co-
morbidities in the AAV population. 
2. IVIg – indicative of hypogammaglobulinaemia or recurrent infections 
3. Any antibiotic, antiviral or antifungal agent – a corresponding infection form 
should have been completed, so this will act as an important cross check 
 
13.3.2  Relevant laboratory abnormalities 
1. Haemoglobin < 100g/l 
2. White cell count < 3.0 x 109/l 
3. Platelet count < 75 x 109/l 
4. Creatinine > 30% rise from baseline AND > 120µmol/l 
5. ALT or AST > 3 times upper limit of normal 
 
Non-serious expected or unexpected adverse events, except those listed in section 
13.3, will not be collected or reported as part of this trial.   


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13.4 Recording and Evaluation of Adverse Events 
 
The Sponsor expects that all SAEs and selected adverse events highlighted in section 
13.3 are recorded from the point of informed consent regardless of whether a patient 
has yet received a medicinal product.  Individual serious adverse events should be 
evaluated by the investigator, including evaluation of its seriousness, causality and any 
relationship between the investigational medicinal product(s). The indication for any 
new concomitant medication, and cause of laboratory abnormality will be captured on 
the AE CRF page. 
 
13.4.1 Assessment of seriousness  
Seriousness is assessed against the criteria in section 13.1.4. This defines 
whether the event is an adverse event, serious adverse event or a serious 
adverse reaction. 
 
13.4.2 Assessment of causality 
Definitely: A causal relationship is clinically/biologically certain. This is 
therefore an Adverse Reaction 
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. This is therefore an 
Adverse Reaction. 
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. This is 
therefore an Adverse Reaction. 
Unlikely: 
A causal relation is improbable and another documented cause of 
the AE is most plausible. This is therefore an Adverse Event. 
Unrelated: A causal relationship can be definitely excluded and another 
documented cause of the AE is most plausible. This is therefore 
an Adverse Event. 
 
 
Unlikely and Unrelated causalities are considered NOT to be trial drug related 
Definitely, Probable and Possible causalities are considered to be trial drug 
related 
 
A pre-existing condition must not be recorded as an AE or reported as an SAE 
unless the condition worsens during the trial and meets the criteria for reporting 
as a SAE or selected adverse event (see section 13.3.) 
 
Investigators will be prompted on the follow up form completed at each visit to 
complete an infection form or new malignancy form if either of these events 
have occurred since the last trial visit.  Details regarding the changes in dose of 
IMPs (rituximab, azathioprine, methotrexate and mycophenolate mofetil) 
including new dose, date of change and reason for change will be captured on 
the follow up form. 
 
The occurrence of hypogammaglobulinaemia (IgG < 5g/l) is flagged when data is 
entered into the trial database, and is reported to the DSMB on a 6 monthly 
basis. 
 


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The occurrence of a relevant laboratory abnormality or the addition of a new 
concomitant medication will be flagged as data is entered into the trial database.  An 
adverse event form will be generated, and the relevant abnormality and data identified 
pre-filled on the form.  Forms will then be sent to investigators for completion.  
Completed adverse event forms must be submitted to the CCTU within 2 weeks. 
 
 
 
13.5 Reporting Serious Adverse Events 
 
Each Principal Investigator needs to record all serious adverse events and report 
these to the Chief Investigators.  The Chief Investigators have delegated 
responsible for assessing all SAEs, to the trial physician, (currently) Dr Rona 
Smith, for expectedness and notification of all SAEs to the Sponsor immediately, 
but not more than 24 hours after first notification.  Individual SAEs will be 
assessed by the trial physician, and if advice is needed, this will be sought from 
one of the CIs, blinding them to treatment allocation.  The Sponsor has to keep 
detailed records of all SAEs reported to them by the trial team.  
 
All Serious Adverse Events must be reported to the central trials co-ordinator or 
trial physician in Cambridge, currently Kim Mynard or Dr Rona Smith, within 24 
hours of the investigator becoming aware of the event, via email 
(RITAZAREM@medschl.cam.ac.uk) . Cumulative safety reports will be generated 
and sent monthly to the sponsor, the TMC and the DSMB and every three 
months to all Principal Investigators.  All single SAE case reports will also be sent 
to the DSMB in real-time. 
 
The Chief Investigator is also responsible for prompt reporting of all serious 
adverse events to the 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 
authorization to continue the trial in accordance with Directive 2001/20/EC. The 
Chief Investigator may delegate the responsibility for reporting serious adverse 
events to the competent authority of any member state outside the UK to the 
lead investigator for that member state.  
 
An adverse event or reaction that meets serious criteria irrespective of 
consistency (expected or unexpected) with the applicable product information 
(e.g. investigators brochure for unapproved investigational product or summary 
of product characteristics) must be reported to the sponsor unless explicitly 
listed within the protocol that REPORTING is not necessary.  
 
 
 
13.6 Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) 
 
All suspected adverse reactions related to an investigational medicinal product 
(the tested IMP and comparators) which occur in the concerned trial, and that 
are both unexpected and serious (SUSARs) are subject to expedited reporting. 
Please see section 13.1.6 for the Reference Safety Information to be used in this 
trial. 
 
13.6.1 Who should report and whom to report to? 
The Sponsor delegates the responsibility of notification of the occurrence of 


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SUSARs to the Competent Authority (CA), Ethics Committee (EC)/IRB and any 
other investigators to the Chief Investigators.  The Chief Investigators should 
report all the relevant safety information previously described, to the Sponsor.  
The Chief Investigators have delegated the responsibility for reporting to the 
member state Competent Authority and local EC/IRB to the lead investigator of 
each member state. 
The Chief Investigators shall inform all investigators concerned of relevant 
information about SUSARs that could adversely affect the safety of subjects.  
Information about SUSARs will be sent to the DSMB within 24 hours of receipt 
by the Chief Investigators. 
 
13.6.2 When and what events to report? 
 
13.6.2.1 Fatal or life-threatening SUSARs 
The CA, Research Ethics Committee and Sponsor should be notified as 
soon as possible but no later than 7 calendar days after the trial team 
and 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 CA, 
Ethics Committee and Sponsor within an additional 8 calendar days. 
 
In addition to the timelines above, investigators should be aware of, and 
comply with, the reporting timelines in their respective countries.  
 
13.6.2.2 Non fatal and non life-threatening SUSARs 
All other SUSARs and safety issues must be reported to the competent 
authority and Ethics Committee in the concerned member state as soon 
as possible but no later than 15 calendar days after first knowledge of 
the minimum criteria for expedited reporting. Further relevant follow-up 
information should be given as soon as possible. 
 
 
13.6.3 How to report? 
 
13.6.3.1 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. trial 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: 
 
- A unique clinical trial identification (EudraCT number or in 
case of non-European Community trials the sponsor's trial 
protocol code number) 
 - A unique case identification (i.e. sponsor's case identification 
number). 
 


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13.6.3.2 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. Further 
available relevant information should be reported as follow-up reports. 
 
In certain cases, it may be appropriate to conduct follow-up of the long-
term outcome of a particular reaction. 
 
13.6.3.3 Format of the SUSARs reports 
 
Electronic reporting, when available, is the expected method for expedited 
reporting of SUSARs to the CA. The format and content as defined by the 
CA should be adhered to. 
 
13.7 Pregnancy Reporting 
 
All pregnancies within the trial (either the trial participant or the participant’s partner) 
should be reported to the Chief Investigator and the Sponsor using the relevant 
Pregnancy Reporting Form within 24 hours of notification. 
Pregnancy is not considered an AE unless a negative or consequential outcome is 
recorded for the mother or child/foetus.  If the outcome meets serious criteria, this 
would be considered an SAE. 
 
14 
Toxicity – Emergency Procedures 
 
In the event of toxicity reactions, standard medical practices will be employed, 
including emergency care and hospitalization if needed.  All medications in this study 
are licensed for use in medicine and their uses are familiar to the physicians and staff 
at all participating centres.   
 
15 
Evaluation of Results  
 
The primary endpoint is the time to relapse (including both major and minor – see 
definitions in section 15.1) from randomisation. This will be reported when all subjects 
have completed the 24 month treatment phase of the study.  
  
15.1 Response Criteria 
15.1.1 Remission 
For the purpose of this study, and progression to randomisation for allocation 
to one of the two arms of the maintenance phase of the study, remission 
equates to achievement of disease control (defined as a BVAS/WG ≤ 1 and 
daily prednisone dose ≤ 10mg) by month 4. 
 
15.1.2 Major relapse 
Major relapse is defined as the development of a new or recurrent major 
disease activity item using the BVAS/WG that in the opinion of the 
investigator requires treatment with > prednisone 20mg/day for any period 
of time and/or increase in dose of immunosuppressive medication and/or 
addition or substitution of another immunosuppressive medication. 
 
Subjects experiencing a major relapse will have met the end point of the 
trial.  Further treatment decisions are made by the investigator and are not 
determined by the protocol.  All patients will continue to be followed for 
safety purposes. 


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15.1.3 Minor relapse 
Minor Relapse = "Any increase in disease activity that does not meet the 
definition of Major Relapse." 
 
Although subjects experiencing a minor relapse will have met the trial end-
point they will remain in the trial on the following protocol (Relapse 
Schedule): minor relapses will be treated with an increase in prednisone to 
20 mg/day for 7 days, reducing by 2.5 mg every week back to 5 mg/day .   
Treatment of a minor relapse will be allowed only once during the trial period.  
At the time of a second minor relapse, further treatment decisions are made 
by local investigators and are not determined by the protocol. All patients will 
continue to be followed for safety purposes. 
 
16 
Statistics 
 
16.1 Statistical Methods  
The study will have a 24 month recruitment period. The minimum follow-up period will 
be 24 months of treatment plus 12 months post-treatment, totalling 36 months. The 
maximum follow-up period will be 24 months of treatment plus 24 months post-
treatment, totalling 48 months.  
 
The primary intention to treat analysis will be based on a Cox proportional hazard 
model. There will be a closed testing procedure, first the null hypothesis will be for a 
hazard ratio of 1 at all time points. If this is rejected at a 5% level then two further 
sub-hypotheses will be examined using time-varying covariates: 
1. A hazard ratio of 1 up to 24 months post-randomisation (i.e. during treatment). 
2. A hazard ratio of 1 after 24 months post-randomisation (i.e. post-treatment). 
 
A detailed statistical analysis plan will be produced before the final data base lock and 
this plan will include sub-group analyses and handling of missing or spurious data. 
 
16.2 Interim Analyses 
No interim analyses are planned, but an independent Data Monitoring Committee (Data 
and Safety Monitoring Board) will be convened to review efficacy and safety data, and 
will advise on the need for any additional analyses or alterations to the conduct or even 
continuation of the trial if there are major safety concerns.  
 
16.3 Number of Subjects to be Enrolled 
Enrolment will be ongoing until at least 160 patients are randomised. It is anticipated 
190 patients will be required to be recruited to meet the goal of 160 patients 
randomized. Any patients in the induction phase when enrolment is halted will continue 
to follow the protocol and be randomised if the relevant criteria are met. 
 
A power of 90% is achieved under the alternative hypothesis of a hazard ratio of 0.42 
at the 5% significance level with 58 observed relapses. Randomising 160 patients will 
achieve this over the course of the study assuming a drop-out rate up to 5% at 2 years 
and a relapse-free rate of 75% and 50% at 4 years in the experimental and control 
arms respectively.  
 
Based on data from the Cambridge cohort study, the overall hazard ratio is estimated 
(95% confidence interval) as 0.230 (0.116, 0.458) based on 37 observed relapses. For 
the early period the hazard ratio estimate is 0.210 (0.098, 0.449) based on 30 
observed relapses. For the late period the hazard ratio estimate is 0.323 (0.061, 1.729) 


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based on seven observed relapses. Hence the sample size/power calculations are robust 
as they are based on a hazard ratio of 0.42 under the alternative hypothesis; the value 
of 0.42 is at the upper end of the confidence intervals for the overall and early period 
hazard ratios from the pilot data. The projected drop-out rate is based on the recently 
published EUVAS IMPROVE trial (16). It justifies the assumption of a rate below 5% in 
the second year. 
 
16.4 Criteria for the Termination of the Trial 
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. Safety data will be reviewed by the DMC/DSMB on 
an annual basis. The trial is planned to close 36 months after the final patient is 
enrolled (common closing date). 
 
16.5 Procedure to Account for Missing or Spurious Data 
A detailed statistical analysis plan will be produced before the final data base lock and 
this plan will include sub-group analyses.  The only aspect of missing data that will 
affect the primary analysis is the handling of patients who drop out before the 
scheduled study close; the process for handling such events is given in the definition of 
the primary endpoint in section 9.6.1. 
 
16.6 Definition of the End of the Trial  
The trial will end when the final patient has completed 12 months of follow up (has 
been in the trial for 36 months in total). 
 
17 
Data Handling and Record Keeping 
 
17.1 CRF 
All data will be transferred into a Case Report Form (CRF) which will be anonymised.  
All trial data in the CRF must be extracted from and be consistent with the relevant 
source documents. The CRFs must be completed, dated and signed by the investigator 
or designee in a timely manner. It remains the responsibility of the investigator for the 
timing, completeness, legibility and accuracy of the CRF pages. The CRF will be 
accessible to trial coordinators, data managers and the investigators as required. 
 
All CRF pages must be clear, legible and completed in black ink. Any errors should be 
crossed with a single stroke so that the original entry can still be seen. Corrections 
should be inserted and the change dated and initialled by the investigator or designee. 
If it is not clear why the change has been made, an explanation should be written next 
to the change. Typing correction fluid must not be used. Changes must not be made to 
the CRF pages once the original has been returned to the trial coordination centre. 
 
Completed CRF pages should be returned to the trial coordinating centre within 2 weeks 
of the evaluations.  
 
17.2 Source Data 
To enable monitoring, audit and/or inspection the investigator must agree to keep 
records of all participating patients (sufficient information to link records e.g., CRFs, 
hospital records and samples), all original signed informed consent forms and copies of 
the CRF pages. Data sources will include patient medical records and on-line test 
results, patient questionnaires (SF-36, EQ5D, PROMIS) and flowsheets of blood results. 
 


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17.3 Data Protection 
All investigators and trial site staff involved in this trial must comply with the 
requirements of the EU General Data Protection Regulation and Data Protection Act 
2018 or applicable local laws for sites outside the UK and Trust/Institution Policy with 
regards to the collection, storage, processing and disclosure of personal information 
and will uphold the Act’s core principles. 
 
18 
RITAZAREM Committees 
 
The NIH-sponsored VCRC Data and Safety Monitoring Committee will provide oversight 
of this study. This is a standing DSMB that provides such oversight for existing VCRC 
studies of vasculitis, including randomised controlled interventional studies. A 
comprehensive charter for this study will be drafted and implemented prior to the start 
of the study. It is anticipated that the DSMB will meet at least 6 monthly to discuss the 
study progress and more frequently, if needed.   
 
The role of the Trial Steering Committee (TSC) (page 5) is to provide overall 
supervision of the study on behalf of Arthritis Research UK.  The TSC will monitor the 
progress of the study and maximise the chances of completing the study within the 
agreed time scale and budget.  The TSC will meet regularly via teleconference. 
 
The Trial Management Committee (TMC) (page 5) is responsible for the design, conduct 
and overall management of the study.  The members meet via regular teleconferences. 
 
19 
Ethical & Regulatory Considerations 
 
19.1 Consent 
The Informed Consent form must be approved by the EC and must be in compliance 
with ICH GCP, local regulatory requirements and legal requirements. The investigator 
must ensure that each trial participant is fully informed about the nature and objectives 
of the trial and possible risks associated with their participation. 
 
The investigator or designee will obtain written informed consent from each patient 
before any trial-specific activity is performed. The informed consent form used for this 
trial and any change made during the course of this trial, must be prospectively 
approved by the EC. The investigator will retain the original of each patients signed 
informed consent form in the Investigator Site File (ISF). 
 
Should a patient require a translation of the trial documentation by a locally approved 
interpreter/translator, it is the responsibility of the individual investigator to use locally 
approved translators.   
 
All trial documentation in a different language (other than English), including the 
translation and back translation of documents must be reviewed and approved by the 
Sponsor prior to use. All sections of the approved documents must appear in the 
translation. The translated version must be appropriately dated and include version 
control. 
 
19.2 Ethical Committee Review 
Ethical committee approval will be obtained before the start of the trial or 
implementation of any amendment, or use of any participant Information sheet, 
informed consent form and other relevant documents e.g., advertisements and GP 
information letters if applicable from the EC. All correspondence with the EC will be 
retained in the Trial Master File/Investigator Site File. 


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Annual reports will be submitted to the EC in accordance with national requirements. It 
is the Chief Investigators responsibility to produce the annual reports as required. 
 
19.3 Regulatory Compliance  
The trial will not commence until a Clinical Trial Authorisation (CTA) is obtained from 
the relevant Competent Authority for example the MHRA or FDA. The protocol and trial 
conduct in the UK will comply with the Medicines for Human Use (Clinical Trials) 
Regulations 2004 and any relevant amendments. For sites outside the UK, the trial will 
be conducted in accordance with the applicable local regulatory requirements and laws.   
 
Annual Safety Reports will be submitted to the relevant Competent Authority in 
accordance with national requirements. It is the Chief Investigators responsibility to 
produce the annual reports as required. 
 
19.4 Trial Documentation Amendments 
Trial documentation amendments including protocol amendments must be reviewed 
and agreement received from the Sponsor for all proposed amendments prior to 
submission to the EC and/or relevant Competent Authority.  
 
The only circumstance in which an amendment may be initiated prior to EC and/or 
relevant Competent Authority approval is where the change is necessary to eliminate 
apparent, immediate risks to the patients (Urgent Safety Measures). In the case, 
accrual of new patients will be halted until the EC and/or relevant Competent Authority 
approval has been obtained. 
 
19.5 Peer Review 
The trial protocol has been designed by the Trial Management Committee. The protocol 
has been reviewed by representatives of Roche/Genentech. Input from members of the 
VCRC and EUVAS has been sought and incorporated. The DSMB also reviewed the 
protocol prior to finalisation. 
 
19.6 Declaration of Helsinki and ICH Good Clinical Practice 
The trial will be performed in accordance with the spirit and the letter of the declaration 
of Helsinki, the ICH Good Clinical Practice Guidelines (CPMP/ICH/135/95), the protocol 
and applicable local regulatory requirements and laws. 
 
19.7 GCP Training 
All trial staff must hold evidence of appropriate GCP training (or local equivalent) or 
undergo GCP training (or local equivalent) prior to undertaking any responsibilities on 
this trial. This training should be updated every 2 years or in accordance with your 
Trust/Institution’s policy.  
 
20 
Sponsorship, Financial and Insurance  
 
The trial will be sponsored by Cambridge University Hospitals NHS Foundation Trust 
except in the US and Canada, where it will be sponsored by the University of 
Pennsylvania (North American Sponsor), Japan (Okayama University) and Ireland 
(University College Cork).   
 
Funding sources for this trial include: Arthritis Research UK, U.S. National Institutes of 
Health, and Roche/Genentech, Japanese Ministry of Health, Labour and Welfare. 
 


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Cambridge University Hospitals NHS Foundation Trust, as a member of the NHS Clinical 
Negligence Scheme for Trusts, will accept full financial liability for harm caused to 
participants in the clinical trial caused through the clinical negligence of its employees 
and honorary contract holders. There are no specific arrangements for compensation 
should a participant be harmed through participation in the trial, but no-one has acted 
negligently.   
 
21 
Monitoring, Audit & Inspection 
 
The investigator must make all trial documentation and related records available should 
a CA Inspection occur. Should a monitoring visit or audit be requested, the investigator 
must make the trial documentation and source data available to the Sponsor’s 
representative. All patient data must be handled and treated confidentially. 
 
On-site monitoring for targeted SDV has been outsourced by the Sponsor. The Sponsor 
retains oversight of all trial activities via monitoring meetings with the CRO. Central 
monitoring and statistical analysis will be undertaken by the trial team at 
Addenbrooke’s Hospital throughout the trial.  
 
22 
Protocol Compliance and Breaches of GCP 
 
The investigator must not implement any deviation from the protocol without formal 
written agreement from the Sponsor and Chief Investigator. If this necessitates a 
subsequent protocol amendment, or halt to the trial this should be submitted to the EC, 
CA & Trust/Institution for review and approval if appropriate.  
 
Potential/suspected serious breach of GCP must be reported immediately to the 
Sponsor. 
 
23 
Publications Policy  
 
Ownership of the data arising from this trial resides with the Sponsor. On completion of 
the trial the data will be analysed and tabulated and a Clinical Study Report prepared 
by the Trial Management Committee. All investigators participating in the study will be 
credited. Anonymous Trial data will be shared with Roche/Genentech at three time 
points: when all patients have completed the induction phase; when all patients have 
completed the maintenance phase and on completion of the study. All publications need 
to be reviewed by the Sponsor before being submitted. The Sponsor will provide Roche 
with details of any publications or presentations for review 45 days in advance of 
submission, and 15 days in the case of abstracts.  
 
 
24 
Publications  
 
1. Watts RA, Suppiah R, Merkel PA, Luqmani R. Systemic vasculitis--is it time to 
reclassify? Rheumatology (Oxford). 2011 Apr;50(4):643-5.  
2. Falk RJ, Jennette JC. ANCA disease: where is this field heading? J Am Soc Nephrol. 
2010 May;21(5):745-52. Epub 2010 Apr 15.  
3. Watts RA, Scott DG. Epidemiology of the vasculitides. Curr Opin Rheumatol 
2003;15:11-16.  
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  


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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, Harper L, Jayne DR, Flores Suarez LF, Gregorini G, Gross WL, Luqmani 
R, Pusey CD, Rasmussen N, Sinico RA, Tesar V, Vanhille P, Westman K, Savage CO; 
EUVAS (European Vasculitis Study Group). Pulse versus daily oral cyclophosphamide 
for induction of remission in antineutrophil cytoplasmic antibody-associated 
vasculitis: a randomized trial. Ann Intern Med. 2009 May 19;150(10):670-80.  
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. Etanercept plus standard therapy for Wegener's granulomatosis. N Engl J Med 2005 
Jan 27;352(4):351-61.  
9. Seo P, Min YI, Holbrook JT, Hoffman GS, Merkel PA, Spiera R, Davis JC, Ytterberg 
SR, St Clair EW, McCune WJ, Specks U, Allen NB, Luqmani RA, Stone JH; WGET 
Research Group. Damage caused by Wegener's granulomatosis and its treatment: 
prospective data from the Wegener's Granulomatosis Etanercept Trial (WGET). 
Arthritis Rheum. 2005 Jul;52(7):2168-78.  
 
10. Faurschou M, Westman K, Rasmussen N, de Groot K, Flossmann O, Höglund P, 
Jayne DR. Brief Report: long-term outcome of a randomized clinical trial comparing 
methotrexate to cyclophosphamide for remission induction in early systemic 
antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2012 
Oct;64(10):3472-7 
11. Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE et al. Depletion of B cells in 
vivo by a chimeric mouse human monoclonal antibody to CD20. Blood. 1994; 
83(2):435-445.  
12. Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, Savage CO, 
Segelmark M, Tesar V, van Paassen P, Walsh D, Walsh M, Westman K, Jayne DR; 
European Vasculitis Study Group. Rituximab versus cyclophosphamide in ANCA-
associated renal vasculitis. N Engl J Med. 2010 Jul 15;363(3):211-20.  
13. Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg CG, St 
Clair EW, Turkiewicz A, Tchao NK, Webber L, Ding L, Sejismundo LP, Mieras K, 
Weitzenkamp D, Ikle D, Seyfert-Margolis V, Mueller M, Brunetta P, Allen NB, 
Fervenza FC, Geetha D, Keogh KA, Kissin EY, Monach PA, Peikert T, Stegeman C, 
Ytterberg SR, Specks U; RAVE-ITN Research Group. Rituximab versus 
cyclophosphamide for ANCA-associated vasculitis.  N Engl J Med. 2010 Jul 
15;363(3):221-32.  
14. Jones RB, Ferraro AJ, Chaudhry AN, Brogan P, Salama AD, Smith KG, Savage CO, 
Jayne DR. A multicenter survey of rituximab therapy for refractory antineutrophil 
cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2009 Jul;60(7):2156-
68. 
15. Smith RM, Jones RB, Guerry MJ, Laurino S, Catapano F, Chaudhry A, Smith KG, 
Jayne DR. Rituximab for remission maintenance in relapsing antineutrophil 
cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2012 Nov;64(11):3760-
9. 
16. Hiemstra TF, Walsh M, Mahr A, Savage CO, de Groot K, Harper L, Hauser T, 
Neumann I, Tesar V, Wissing KM, Pagnoux C, Schmitt W, Jayne DR. Mycophenolate 
mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic 
antibody-associated vasculitis: a randomized controlled trial. JAMA. 2010 Dec;304 
(21):2381-8.  
17. Du Bois D, Du Bois EF. A formula to estimate the approximate surface area if height 
and weight be known. Internal Medicine. 1916 Jun;17(6):863-71.


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25.  
Appendices: 25.1 Appendix 1: Schedule of events 
Study Date 
M=Month 
R = Randomisation 
*Screen 
**M0 
M1.5 
M3 
M4 (R) 
M8 
M12 
M16 
M20 
M24 
M27 
M30 
M36 
M42 
M48 
Data Forms 
 
 
 
Eligibility Review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinary HCG∞  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Follow up  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comorbidities 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BVAS/WG 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CDA 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
SF-36, EQ5D 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
PROMIS questionnaires 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical Labs ◊ 
 
 
FBC/CBC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ESR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry (electrolytes, creatinine, LFTs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CRP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ANCA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lymphocyte markers 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunoglobulins 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hepatitis B≠  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Specimens● 
 
 
Serum 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DNA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
RNA 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
**There are also visits at weeks 1, 2, 3 and 4 for rituximab infusions, during which the Treatment Form is completed by the PI.    
*Please note, the screening visit and month 0 visit must take place within 2 weeks of each other.                                               ∞ In women of child bearing potential     
◊Laboratory test results are permitted to be within ± 2 weeks of the date of the study evaluation.                                              ≠Hepatitis B screening by HBsAg and anti-HBcore Ab 
•Please remember to take all biomarker samples prior to rituximab infusion.                                                                              ±Withdrawn subjects will continue to follow the visit schedule 
The M48 assessments will be performed at the time of relapse or study termination/withdrawal 

SAP_001.pdf: 
Statistical Analysis Plan 
RITAZAREM 
Maintenance Phase 
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CCTU/TPL007V3 Approved:24/01/2018  
Statistical Analysis Plan 
TRIAL FULL TITLE 
An international, open label, randomised controlled trial 
comparing rituximab with azathioprine as maintenance 
therapy in relapsing ANCA-associated vasculitis 
EUDRACT NUMBER 
2012-001102-14 
SAP VERSION 
Maintenance Phase SAP v2.0 
ISRCTN NUMBER 
 
SAP VERSION DATE 
25th January 2021 
TRIAL STATISTICIAN 
Dr Simon Bond 
TRIAL CHIEF 
INVESTIGATORS 
Dr David Jayne and Dr Peter Merkel 
SAP AUTHOR 
Marianna Nodale 
1 SAP Signatures 
I give my approval for the attached SAP entitled RITAZAREM – Maintenance Phase 
SAP v2.0 dated 25th January 2021. 
Chief Investigators 
Name:  
Dr David Jayne 
 
 
Dr Peter Merkel 
 
Signature: 
                                                                             
 
 
Date: 10 FEB 2021                                               14 FEB 2021                               
Statistician 
 
 
 
 
 
Author 
Name:  
Dr Simon Bond 
 
 
Marianna Nodale 
 
Signature: 
                                                                                                         
 


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RITAZAREM 
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Date:  
                                                                                                         
 


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2 Table of Contents 
1 
SAP Signatures .................................................................................................. 1 
2 
Table of Contents ............................................................................................. 3 
3 
Abbreviations and Definitions ........................................................................... 6 
3.1 
Abbreviations ............................................................................................. 6 
3.2 
Definitions ................................................................................................. 7 
4 
Introduction ...................................................................................................... 7 
4.1 
Preface ....................................................................................................... 7 
4.2 
Purpose of the analysis ............................................................................... 8 
5 
Study Objectives and Endpoints ........................................................................ 9 
5.1 
Study Objectives ......................................................................................... 9 
5.1.1 
Primary objective ................................................................................. 9 
5.1.2 
Secondary objectives ............................................................................ 9 
5.2 
Endpoints ................................................................................................... 9 
5.2.1 
Primary endpoint .................................................................................. 9 
5.2.2 
Secondary endpoints .......................................................................... 10 
5.2.3 
Exploratory endpoints ........................................................................ 11 
6 
Study Methods ................................................................................................ 11 
6.1 
General Study Design and Plan ................................................................. 11 
6.2 
Inclusion-Exclusion Criteria and General Study Population ....................... 12 
6.2.1 
Inclusion Criteria ................................................................................ 12 
6.2.2 
Exclusion Criteria ............................................................................... 13 
6.3 
Randomisation and Blinding ..................................................................... 14 
6.4 
Study Schedule ......................................................................................... 14 
7 
Sample Size .................................................................................................... 18 
8 
General Considerations ................................................................................... 18 
8.1 
Timing of Analyses ................................................................................... 18 


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8.2 
Analysis Populations ................................................................................. 19 
8.2.1 
Safety Population ............................................................................... 19 
8.2.2 
Full Analysis Population (randomised patients) ................................... 19 
8.2.3 
Per Protocol Populations (maintenance and follow-up) ....................... 19 
8.4 
Covariates and Subgroups ........................................................................ 21 
8.5 
Missing Data ............................................................................................ 21 
8.6 
Interim Analyses and Data Monitoring ...................................................... 21 
8.8 
Multi-centre Studies ................................................................................. 22 
8.9 
Multiple Testing ....................................................................................... 22 
9 
Summary of Study Data ................................................................................... 22 
9.1 
Subject Disposition ................................................................................... 23 
9.1.1 
Visit dates .......................................................................................... 23 
9.1.2 
Subject disposition ............................................................................. 24 
9.1.3 
CONSORT diagram ............................................................................. 26 
9.2 
Derived variables ...................................................................................... 27 
9.3 
Protocol Deviations .................................................................................. 35 
9.4 
Demographic and Baseline Variables ........................................................ 35 
9.4.1 
Demographics .................................................................................... 35 
9.4.2 
Enrolment characteristics ................................................................... 35 
9.4.3 
Stratification variables ........................................................................ 35 
9.5 
Concurrent Illnesses and Medical Conditions ............................................ 36 
9.5.1 
Baseline Medical History ..................................................................... 36 
9.6 
Prior and Concurrent Medications ............................................................. 37 
9.6.1 
Prior treatment ................................................................................... 37 
9.6.2 
Concomitant Medication..................................................................... 38 
9.7 
Disease activity assessment (BVAS/WG) .................................................... 38 
9.8 
Disease related assessment (CDA) ............................................................ 39 
9.9 
Treatment Compliance ............................................................................. 43 


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9.10 Treatment Exposure ................................................................................. 43 
9.10.1 
Rituximab treatment ....................................................................... 43 
9.10.2 
Glucocorticoid treatment ................................................................. 44 
10 
Efficacy Analyses ......................................................................................... 47 
10.1 Primary efficacy analysis ........................................................................... 47 
10.2 Secondary outcomes ................................................................................ 48 
10.3 Censoring ................................................................................................ 49 
11 
Safety Analyses ............................................................................................ 52 
11.1 Serious Adverse Events ............................................................................. 52 
11.2 Adverse Events ......................................................................................... 53 
11.3 Hypogammaglobulinemia ......................................................................... 54 
11.4 Deaths ..................................................................................................... 54 
11.5 Pregnancies .............................................................................................. 55 
11.6 Clinical Laboratory Evaluations ................................................................. 55 
12 
Quality of Life Analysis ................................................................................ 58 
12.1 EQ5D ........................................................................................................ 58 
12.2 SF-36 questionnaire ................................................................................. 59 
12.3 PROMIS ..................................................................................................... 60 
13 
Figures ........................................................................................................ 61 
14 
Reporting Conventions ................................................................................ 63 
15 
Technical Details ......................................................................................... 63 
15.1 Data anomalies and corrections ................................................................ 64 
16 
References ................................................................................................... 64 
17 
Listing of Tables, Listings and Figures ......................................................... 66 
 
 


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3 Abbreviations and Definitions 
3.1 Abbreviations 
AAV 
ANCA-associated vasculitis 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCA 
Auto-antibodies to neutrophils 
anti-MPO  
Myeloperoxidase antibodies 
anti-PR3  
Proteinase 3 antibodies 
AST 
Aspartate aminotransferase 
ATG 
Anti-thymocyte globulin 
AUC 
Area under the curve 
BVAS/WG  
Birmingham vasculitis activity score for Wegener’s  
CA 
Competent authority 
CCTU 
Cambridge clinical trial unit 
CD19 
B-lymphocyte antigen CD19 
CDA 
Combined damage assessment index 
CF 
Conversion factor 
CI 
Confidence interval 
CONSORT 
Consolidated Standards of Reporting Trials 
COPD 
Chronic obstructive pulmonary disease 
CRF 
Case report form 
CRP 
C-reactive protein 
CVD 
Cerebro-vascular disease 
CYC 
Cyclophosphamides 
DSMB 
Data safety monitoring board 
ELISA 
Enzyme-linked immunosorbent assay 
ENT 
Ear, nose, throat 
EQ5D 
A standardised instrument for use as a measure of health outcome 
ESR 
Erythrocyte sedimentation rate 
EUDRACT 
European Clinical Trials Database 
EUVAS 
European Vasculitis Study Group 
FBC/CBC 
Full/Complete blood count 
GC 
Glucocorticoids 
GFR 
Glomerular filtration rate 
GEE 
Generalised estimating equation 
GPA 
Granulomatosis with polyangiitis 
HCG 
Human chorionic gonadotrophin 


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IgG, IgA, IgM 
Immunoglobulin G, A, M 
IHD 
Ischemic heart disease 
IMP 
Investigational medical product 
IV 
Intravenous 
IVIG 
Intravenous immunoglobulin 
MedDRA 
Medical dictionary for regulatory activities 
MPA 
Microscopic polyangiitis  
PI 
Principal investigator 
PROMIS 
Patient-reported outcomes measurement information system 
PT 
Preferred term 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAR 
Serious adverse reaction 
SF-36 
Short form (36) health survey 
SOC 
System organ class  
SUSAR 
Suspected unexpected serious adverse reaction 
VCRC 
Vasculitis Clinical Research Consortium 
WBC 
White blood cell count 
WG 
Wegener’s granulomatosis 
3.2 Definitions 
Relapse (flare)  
The occurrence of any new BVAS/WG item.  
Major Relapse  
The development of a new or recurrent major disease activity item 
using the BVAS/WG assessment tool  
Minor Relapse  
Any increase in disease activity that does not meet the definition of 
Major Relapse  
Remission  
BVAS/WG≤1 (one minor persistent BVAS/WG item) and GC dose 
≤10mg/day 
Complete Remission  BVAS/WG = 0 independent of GC  
Sustained Remission  Remission lasting more than 6 months without a relapse  
4 Introduction 
4.1 Preface 
Granulomatosis with polyangiitis (GPA) (formally Wegener’s granulomatosis (WG)) 
and microscopic polyangiitis (MPA) are primary systemic vasculitides, predominantly 
involving microscopic blood vessels with no or scanty immune deposits. Their 


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association with circulating auto-antibodies to neutrophils (ANCA) has led to these 
conditions being grouped together as ANCA-associated vasculitis (AAV) (1, 2). The 
cause of AAV is unknown. AAV has an annual incidence of 20 per million and an 
approximate prevalence of 200/million (3). It is a multi-system autoimmune 
disease that causes tissue damage especially to the respiratory tract and kidneys, 
and causes early mortality, organ failure including end stage renal disease, and 
chronic morbidity.  
Prior to the availability of effective treatment, AAV was almost universally fatal, with 
a 93% mortality within 2 years due to pulmonary and renal failure (4). The 
introduction of what is now termed conventional immunosuppressive treatment 
transformed survival. Administration of cytotoxic immunosuppression 
(cyclophosphamide or methotrexate) and corticosteroids for at least one year 
induces remission in approximately 80% of patients. However, there are a 
significant proportion of patients that inadequately respond to traditional therapy. 
Also, relapsing disease is common with over 50% of patients experiencing a relapse 
within 5 years (5, 6, 7, 8). Relapse is associated with increased exposure to 
immunosuppressive medications and corticosteroids and at least 25% suffer severe 
early or late toxicity from these agents (9). The majority of relapses in the NORAM 
trial were minor, but were associated with a higher cumulative cyclophosphamide 
and glucocorticoid exposure (10). As treatment exposure is the greatest modifiable 
cause of damage, then prevention of relapses, minor as well as major is highly 
desirable. There is a major unmet need for safer therapy that leads to sustained 
treatment free remission in patients with relapsing disease, which will reduce drug 
toxicity that results from cumulative exposure to cyclophosphamide and 
glucocorticoids. 
4.2 Purpose of the analysis 
This analysis will report on the maintenance phase of the trial (from randomisation 
to month 48 of follow-up). It will address the efficacy of rituximab compared to 
azathioprine in the prevention of disease relapse in patients with ANCA-associated 
vasculitis with relapsing disease. 
 
 


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5 Study Objectives and Endpoints 
5.1 Study Objectives 
(ICH E3; 8) 
5.1.1 Primary objective 
To assess the efficacy of rituximab compared to azathioprine in the prevention of 
disease relapse in AAV patients with relapsing disease.  
5.1.2 Secondary objectives 
To demonstrate: 
1. Sustained disease remission beyond the 24 month treatment period. 
2. Long term safety of rituximab administration. 
3. The optimal remission maintenance therapy in AAV following induction of 
disease remission with rituximab. 
5.2 Endpoints 
(ICH E9; 2.2.2) 
The final analysis will assess primary, secondary, and exploratory endpoints, which 
are described below for completeness. All endpoints to be assessed in the 
maintenance phase are described in sections 9 to 12.  
5.2.1 Primary endpoint 
The primary endpoint is the time to disease relapse (either minor or major relapse) 
from randomisation. Any patients who have not relapsed at study close will be 
censored. Further details of how relapse/censoring dates will be defined are given 
below (Table 1). 
In the efficacy analysis, the date of the month 4 visit will be used as time-zero (i.e. 
randomisation). According to the protocol, patients might be randomised in 
advance of the month 4 visit (provided they achieved disease remission by the 
month 3 visit), however maintenance therapy (with either treatment) was not 
allowed to be administered before the month 4 visit1. 
                                           
1 For a more in-depth description of randomisation procedures and trial’s timelines, 
including definitions of the induction and maintenance phase, see Induction Phase SAP, 
section 9.1.1, and refer to the protocol, section 10.4. 


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Treatment duration is taken to be strictly 20 months post-randomisation, i.e. date 
of the month 4 visit + 20 months, and not the actual time of the month 24 visit 
when the last visit was administered. This affords a common timeline for all 
patients, irrespective of time slippages in the schedule of visits. 
In the analysis, the censoring rules detailed in Table 1 will be implemented. 
Censoring time will be taken from the last assessment with no documented relapse 
(scheduled visit), the date of death (unscheduled visit) or the common close date. 
The time of relapse will be taken from the relapse form (unscheduled visit). Further 
particulars are detailed in section 10.3. 
Table 1: Censoring rules 
Situation 
Date of Relapse or Censoring 
Outcome 
No baseline assessments 
Randomization 
Censored 
Relapse documented 
between scheduled visits 
Unscheduled visit date 
Relapsed 
Drop-out with no relapse 
Date of last assessment with no 
documented relapse 
Censored 
Treatment discontinuation 
for undocumented relapse 
Date of last assessment with no 
documented relapse 
Censored 
Treatment discontinuation 
for toxicity or other reason, 
or protocol deviation 
The patient will be followed up 
as per protocol and date of 
relapse or censoring observed 
accordingly 
Relapsed/censored 
Death due to relapse 
Date of Death 
Relapsed 
Death due to other causes 
Date of Death 
Censored 
Death or progression after  
more than one missed visit 
Date of last assessment with no 
documented relapse 
Censored 
 
5.2.2 Secondary endpoints 
1. Proportion of patients who maintain remission at 24 and 48 months2. 
2. Time to a major or second minor relapse. 
3. Cumulative accrual of damage as measured by the combined damage 
assessment score (CDA). 
4. Health-related quality of life as measured using SF-36. 
5. Cumulative GC exposure. 
6. Severe adverse event rate. 
7. Infection (treated with intravenous or oral antibiotics) rates. 
                                           
2 Time measured from enrolment. 


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5.2.3 Exploratory endpoints 
1. Health economic assessment based on EQ5D. EQ5D is a standardised 
instrument for use as a measure of health outcome, providing a simple 
descriptive profile and a single index value for health status. It is designed to 
be completed by patients. 
2. Health-related quality of life and patient-reported outcomes as measured 
using the Patient-Reported Outcomes Measurement Information System 
assessment (PROMIS). PROMIS is a set of validated health-related quality of 
life assessment questionnaires covering domains that include fatigue, 
physical function, pain, and global health. 
The analysis of the following exploratory endpoints is not planned in this 
Statistical Analysis Plan; these endpoints may be explored in future analyses: 
3. Serum rituximab levels and correlation with circulating B cell counts 
including key subsets and immunoglobulin levels. 
4. Changes in ANCA titres (both anti-MPO and anti-PR3 subsets) in relation to 
treatment, response, and relapse. 
5. HACA rate and level. 
6. Serum will be stored for future biomarker studies. 
7. mRNA will be stored for disease and inflammatory gene activation. 
8. DNA will be stored for various studies. 
6 Study Methods 
6.1 General Study Design and Plan 
(ICH E3; 9) 
This is an international, multi-centre, open label, two-arm parallel study in patients 
with vasculitis. Following an induction phase where patients receive rituximab only, 
patients who have achieved remission in the induction phase will be randomised, 
1:1, to receive fixed interval repeat rituximab dosing or azathioprine maintenance 
therapy. Those not in remission after the induction phase will not be randomised. The 
group receiving azathioprine will act as the control group. 
Patients will be randomised using stratified block randomisation. Patients will be 
stratified at the time of randomisation according to: 
1. ANCA type (anti-PR3 or anti-MPO). 
2. Relapse severity (severe or non-severe). 


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3. Selected prednisone induction regimen (1A or 1B). 
 
 
Figure 1: Study design flowchart 
6.2 Inclusion-Exclusion Criteria and General Study Population 
(ICH E3; 9.3. ICH E9; 2.2.1) 
6.2.1 Inclusion Criteria 
To be included in the trial the patients must have: 
1. Provided written informed consent (15 years and above). 
2. A diagnosis of AAV [granulomatosis with polyangiitis or microscopic 
polyangiitis], according to the definitions of the Chapel Hill Consensus 
Conference. 
3. Current or historical PR3/MPO ANCA positivity by ELISA. 
4. Disease relapse defined by one major or three minor disease activity items 
on the Birmingham Vasculitis Activity Score for Wegener’s (BVAS/WG), in 
patients that have previously achieved remission following at least 3 months 
of induction therapy, with a combination of glucocorticoids and an 


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immunosuppressive agent (cyclophosphamide or methotrexate or rituximab 
or mycophenolate mofetil). 
 
6.2.2 Exclusion Criteria 
The presence of any of the following will preclude patient inclusion: 
1. Age < 15 years (age < 18 years at centres that do not treat paediatric 
patients). 
2. Exclusions related to medication: 
Previous therapy with: 
a. Any biological B cell depleting agent (such as rituximab or belimumab) 
within the past 6 months. 
b. Alemtuzumab or anti-thymocyte globulin (ATG) within the last 12 
months. 
c. IVIg, infliximab, etanercept, adalimumab, abatacept or plasma 
exchange in past 3 months. 
d. Any investigational agent within 28 days of screening, or 5 half-lives 
of the investigational drug (whichever is longer). 
3. Exclusions related to general health: 
a. Significant or uncontrolled medical disease not related to AAV, which 
in the investigators opinion would preclude patient participation. 
b. Presence of another multisystem autoimmune disease, including 
Churg Strauss syndrome, systemic lupus erythematosus, anti-GBM 
disease, or cryoglobulinaemic vasculitis. 
c. Any concomitant condition anticipated to likely require greater than 4 
weeks per year of oral or systemic glucocorticoid use and which would 
preclude compliance with the glucocorticoid protocol (e.g. poorly-
controlled asthma, COPD, psoriasis, or inflammatory bowel disease). 
d. History of severe allergic or anaphylactic reactions to humanised or 
murine chimeric monoclonal antibodies. 
e. Known infection with HIV (HIV testing will not be a requirement for 
trial entry); a past or current history of hepatitis B virus or hepatitis C 
virus infection. 
f. Ongoing or recent (last 12 months) evidence of active tuberculosis or 
known active infection (screening for tuberculosis is part of ‘standard 
of care’ in patients with established AAV) or evidence of untreated 
latent tuberculosis. Screening for tuberculosis is as per local practice. 
g. History of malignancy within the past five years or any evidence of 
persistent malignancy, except fully excised basal cell or squamous cell 


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carcinomas of the skin, or cervical carcinoma in situ which has been 
treated or excised in a curative procedure. 
h. Pregnancy or inadequate contraception in women of childbearing 
potential. 
i. Breast feeding or lactating. 
j. Medical, psychiatric, cognitive or other conditions that, in the 
investigator's opinion, compromise the patient's ability to understand 
the patient information, to give informed consent, to comply with the 
trial protocol, or to complete the study. 
4. Exclusion criteria related to laboratory parameters: 
a. Bone marrow suppression as evidenced by a total white count < 4 
x109/l, haemoglobin < 7 gm/dl or platelet count < 100,000/μl. 
b. Aspartate aminotransferase or alanine aminotransferase or amylase > 
2.5 times the upper limit of normal, unless attributed to vasculitis. 
6.3 Randomisation and Blinding 
(ICH E3; 9.4.3, 9.4.6. ICH E9; 2.3.1, 2.3.2) 
This is an open-label (unblinded) study. Patients who achieved disease control by 
month 4 (BVAS/WG ≤ 1 and daily prednisone dose ≤ 10mg) will be randomised 1:1 to 
receive either rituximab or azathioprine. A blocked randomisation will be 
performed, using a block size of 6. Patients will be stratified at the time of 
randomisation according to: 
1. ANCA type (anti-PR3 or anti-MPO). 
2. Relapse severity (severe or non-severe). 
3. Selected prednisone induction regimen (1A or 1B). 
 
Randomisation will be performed using a web-based system (TENALEA). This will be 
accessed by the principal investigator (PI) and suitably trained site staff though a 
secure, person specific log-in. 
6.4 Study Schedule 
(ICH E3; 9.5.1. ICH E9; 2.2.2) 
Table 2 illustrate the schedule of events for the entire trial. The induction phase of 
the trial comprises the first 4 months from enrolment. At month 4 patients who 
have achieved remission are randomised to either maintenance therapy with 
rituximab or azathioprine. The maintenance phase of the trial, comprising 20 


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months of treatment and a 12-24 months follow up phase, commences at month 4 
from enrolment. 
Completed Case Report Forms (CRFs) are expected to be returned to the trial 
coordinating centre within 2 weeks of evaluation and the Data Manager routinely 
queries sites for missing/delayed forms. 
Important notes regarding the schedule of events: 
• 
The Screening and Month 0 visits must take place within 2 weeks of each 
other. 
• 
The Treatment Form at Month 0 visit is completed by the PI at weeks 1, 2, 3 
and 4 for rituximab infusion. 
• 
Laboratory tests results are permitted to be within ± 2 weeks of the date of 
the study evaluation. 
• 
Unscheduled assessments are performed at the time of relapse or study 
termination/withdrawal. Unscheduled assessment are retained for safety 
reviewing and not incorporated in the summary statistics of the scheduled 
visits. 
• 
Biomarker research samples are taken prior to rituximab infusion. 


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Table 2: Time and events schedule 
 
Screening 
Month 
0 
Month 
1.5 
Month 
3 
Month 
4 (R) 
Month 
8 
Month 
12 
Month 
16 
Month 
20 
Month 
24 
Month 
27 
Month 
30 
Month 
36 
Month 
42 
Month 
48 
Unscheduled 
Visit 
Forms 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrolment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinary HCG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Comorbidities 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medication 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
Follow Up 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
BVAS/WG 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CDA 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
SF-36, EQ5D 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
PROMIS 
questionnaires 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event 
review 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 


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Screening 
Month 
0 
Month 
1.5 
Month 
3 
Month 
4 (R) 
Month 
8 
Month 
12 
Month 
16 
Month 
20 
Month 
24 
Month 
27 
Month 
30 
Month 
36 
Month 
42 
Month 
48 
Unscheduled 
Visit 
Clinical Labs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FBC/CBC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ESR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry 
(electrolytes, 
creatinine, LFTs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CRP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ANCA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lymphocyte 
markers 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunoglobulins 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hepatitis B 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research samples 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DNA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RNA 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 


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7 Sample Size 
(ICH E3; 9.7.2. ICH E9; 3.5) 
Enrolment will be ongoing until 160 patients are randomised. It is anticipated 190 
patients will be required to be recruited to meet the goal of 160 patients 
randomized. Any patients in the induction phase when enrolment is halted will 
continue to follow the protocol and be randomised if the relevant criteria are met. 
A power of 90% is achieved under the alternative hypothesis of a hazard ratio of 
0.42 at the 5% significance level with 58 observed relapses. Randomising 160 
patients will achieve this over the course of the study assuming a drop-out rate up 
to 5% at 2 years and a relapse-free rate of 75% and 50% at 4 years in the 
experimental and control arms respectively. 
Based on data from the Cambridge cohort study, the overall hazard ratio is 
estimated (95% confidence interval) as 0.230 (0.116, 0.458) based on 37 observed 
relapses. For the early period the hazard ratio estimate is 0.210 (0.098, 0.449) 
based on 30 observed relapses. For the late period the hazard ratio estimate is 
0.323 (0.061, 1.729) based on seven observed relapses. Hence the sample 
size/power calculations are robust as they are based on a hazard ratio of 0.42 
under the alternative hypothesis; the value of 0.42 is at the upper end of the 
confidence intervals for the overall and early period hazard ratios from the pilot 
data. The projected drop-out rate is based on the recently published EUVAS 
IMPROVE trial (16). It justifies the assumption of a rate below 5% in the second year. 
8 General Considerations 
8.1 Timing of Analyses 
The trial is planned to close 36 months after the final patient is enrolled. All those 
eligible who have been randomised and entered into the maintenance phase of the 
trial will be followed until the last patient to be enrolled has completed 36 months 
from study entry. The maintenance phase analysis will be performed after the last 
enrolled patient (excluding drop-outs) has reached Month 36 visit, this is the 
common close of the trial. 


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The statistical analysis plan (SAP) will be approved according to the requirements of 
CCTU/SOP023 before database lock. Permission to lock the database will be 
requested from the chief investigator (CI) using CCTU/FRM094, and the data 
programmers will deposit the data in a folder to which the trial statistician is given 
restricted access (following CCTU/SOP057). 
An independent adjudication committee (blinded to treatment) will review all 
relapses prior to analysis and any changes deemed necessary will be recorded and 
included into MACRO database3. Data queries will be referred to the data 
management team for resolution (using CCTU/TPL064). 
8.2 Analysis Populations 
(ICH E3; 9.7.1, 11.4.2.5. ICH E9; 5.2) 
Prior to database lock, each patient will be included or excluded from each analysis 
population defined below. The trial management team will agree on inclusion to 
each population prior to the analysis. 
8.2.1 Safety Population 
The safety population comprises all consented subjects enrolled in the trial, 
regardless of whether they achieved remission and were randomised at month 4. 
The treatment group will be analysed as randomised (rituximab or azathioprine), 
patients who were enrolled but not randomised will be classified as belonging to 
the induction group (induction). 
8.2.2 Full Analysis Population (randomised patients) 
The full analysis population is defined as all participants who achieved remission in 
the induction phase of the trial and were randomised to the maintenance phase, 
regardless of whether they actually received any maintenance treatment. The 
treatment group will be analysed as randomised (rituximab or azathioprine). 
8.2.3 Per Protocol Populations (maintenance and follow-up) 
The per-protocol populations includes all randomised patients who have not 
deviated from protocolised treatment either during the maintenance phase of the 
trial (from randomisation to month 24) or follow-up (from randomisation to end of 
                                           
3 Details of data utilised in the formal relapse adjudication process can be found in a 
separate document [reference]. 


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trial). Thus two per-protocol populations will be defined: maintenance compliant 
and follow-up compliant. It is assumed that maintenance compliance is necessary 
for follow-up compliance, and the two per-protocol populations will be defined 
using this inclusive criterion. Patients who withdraw from trial or from protocolised 
treatment will be assessed for compliance up to the point of their withdrawal. 
Compliance to the protocol of all trial treatments (rituximab, azathioprine, 
methotrexate, and mycophenolate Mofetil) will be considered, according to the 
randomised treatment allocation (rituximab or azathioprine schedules). Compliance 
to prednisolone schedule is not considered. In the case of treatment of relapse, 
what treatments are in accordance with the protocol are detailed in Section 11.6 of 
the protocol: 
Patients experiencing their first minor relapse after randomisation and before 
month 24 of the treatment phase will remain on the randomised treatment 
(rituximab or azathioprine) and will have their oral prednisolone/prednisone 
increased to 20mg/day for one week decreasing in 2.5mg increments each 
week to reach 5mg/day after six weeks. The second minor relapse or first 
major relapse, occurring before month 24 of the treatment phase will result 
in the patient being withdrawn from protocolised treatment and returned to 
treatment according to local best practice. Any relapse occurring after the 24 
month treatment phase will be treated according to local best medical 
practice. 
Due to the complexity of the data involved, each patient course of treatments will 
be assessed individually and an independent adjudication committee (blinded to 
subject ID) will determine each patient’s inclusion/exclusion in the per protocol 
population base on data taken from the Treatment Form, Follow-Up Form and 
Relapse Form. It is expected that these data be reviewed concurrently with the 
formal adjudication of relapses and incorporated into the trial’s database prior to 
hard lock4. 
 
 
                                           
4 Details of data used to assess inclusion in the per-protocol populations can be found in 
document “Medication Compliance v 1.0” and a separate report will be produced by the 
independent adjudication committee detailing each patient’s assessment and outcome. 


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8.4 Covariates and Subgroups 
(ICH E3; 9.7.1, 11.4.2.1. ICH E9; 5.7) 
In all formal hypothesis testing, the models will be adjusted for the following 
covariates: 
1. ANCA type (anti-PR3 or anti-MPO) 
2. Relapse severity (severe or non-severe) 
3. Selected prednisone induction regimen (1A or 1B) 
the same stratifying variables used for randomisation. 
8.5 Missing Data 
(ICH E3; 9.7.1, 11.4.2.2. ICH E9; 5.3. EMA Guideline on Missing Data in 
Confirmatory Clinical Trials) 
The sample size of non-missing values will be reported for summary tables. It is 
expected that the incidence of missing data will be low. Missing data will be 
assumed to be missing at random. In practice, missing values will be ignored for 
calculation of summary statistics. The number of non-missing values will be 
reported and used instead of the population or subgroup size as a denominator as 
needed. The overall size of the population, including missing values will be 
reported within the title of the table or figure to convey the amount of missing data. 
Due to logistic reasons, the PROMIS questionnaire was not administered to the full 
study population. The number of sites and patients not taking part will be noted.  
8.6 Interim Analyses and Data Monitoring 
(ICH E3; 9.7.1, 11.4.2.3. ICH E9; 4.1, FDA Feb 2010 “Guidance for Industry Adaptive 
Design Clinical Trials for Drugs and Biologics”) 
No interim analyses are planned. 
An independent Data Monitoring Committee (Data and Safety Monitoring Board, 
DSMB) will be convened to review efficacy and safety data on a quarterly basis, and 
will advise on the need for any additional analyses or alterations to the conduct or 
even continuation of the trial if there are major safety concerns. 
 
 


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8.8 Multi-centre Studies 
(ICH E3; 9.7.1, 11.4.2.4. ICH E9; 3.2) 
RITAZAREM is a joint venture of the European Vasculitis Study Group (EUVAS) and 
the Vasculitis Clinical Research Consortium (VCRC). RITAZAREM will occur in 
multiple centres internationally including Europe, North America and Australia/New 
Zealand. Plans are for approximately 50-60 centres to recruit patients. 
Data is recorded in a single MACRO database across all study centres. Study centre 
will form part of the information recorded, so that it can be identified during the 
statistical analysis. Recruitment and patient’s retention rate will be reported by site 
and grouped by country. 
8.9 Multiple Testing 
(ICH E3; 9.7.1, 11.4.2.5. ICH E9; 2.2.5) 
For the primary outcome of the trial, the primary intention to treat analysis will be 
based on a Cox proportional hazard model. There will be a closed testing 
procedure, first the null hypothesis will be for a hazard ratio of 1 at all time points. 
If this is rejected at a 5% level then two further sub-hypotheses will be examined 
using time-varying covariates: 
1. A hazard ratio of 1 up to 24 months post-randomisation (i.e. during treatment). 
2. A hazard ratio of 1 after 24 months post-randomisation (i.e. post-treatment). 
9 Summary of Study Data 
All continuous variables will be summarised using the following descriptive 
statistics: n (non-missing sample size), mean, standard deviation, median, 
maximum and minimum. The frequency and percentages (based on the non-
missing sample size) of observed levels will be reported for all categorical 
measures. Summary tables will be structured with a column for each treatment arm 
(“Azathioprine”, “Rituximab”,), as well as a total column. Additionally some summary 
tables (e.g. baseline demographic) will also be presented split by induction regimen 
(“1A”, “1B”).  All tables will be annotated with the total population size relevant to 
that table/treatment, including any missing observations. In general, where 
appropriate, data will be listed sorted by site, subject and visit. 


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Only deviations from the general overview will be noted in the subsequent sub-
sections within section 9. 
9.1 Subject Disposition 
9.1.1 Visit dates 
The three phases of the trial are defined as follows: 
1. Induction phase: enrolment to Month 4 (inclusive) 
2. Maintenance phase: Month 4 to Month 24 (inclusive) 
3. Follow-up phase: Month 24 (exclusive) to Month 36/42/48 (common close) 
A target randomisation date (RandomDate) four months in the future was generated 
at enrolment to help local sites organise rituximab or azathioprine supply for the 
maintenance phase. Patients could be randomised from 14 days before to 14 days 
after Month 4 visit. If patients attended their Month 3 visit and were in remission, 
then they could be randomised up to 14 days before Month 4. Those not in 
remission at Month 3 were reassessed at Month 4 and, if they entered remission, 
were then randomised and commenced allocated therapy within the next 14 days. 
Those not in remission at Month 4 were not randomised (even if they had been 
considered in remission at Month 3 visit) and treated at the investigator’s 
discretion, follow-up data continued to be collected unless consent was withdrawn. 
Maintenance therapy (with either treatment) was not administered before the Month 
4 visit. Consequently, the month 4 visit will be considered as both the end of the 
Induction Phase of the trial and the beginning of the Maintenance Phase of the trial. 
It will be used as time zero for the primary endpoint of the Maintenance Phase (time 
to disease relapse from randomisation). 
When calculating time elapsed in days, months or years (e.g. when calculating time 
from randomisation), full dates (yyyy-mm-dd) appropriately formatted, will be 
converted to the number of days since 1970-01-01, with negative values for earlier 
dates, following the default representation of dates in the R language5. A full year is 
taken to be 365.25 days long, a standardisation that approximates for the 
                                           
5 https://stat.ethz.ch/R-manual/R-devel/library/base/html/Dates.html 


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occurrence of leap years. A month is taken to be 1/12th of a full year. First day of 
the month/year will be used for fuzzy dates. 
9.1.2 Subject disposition 
Patient disposition will be determined using information collected in the following 
CRF forms: 
• 
Withdrawal Form (v2) 
• 
Withdrawal from Trial Form (v3) 
• 
Withdrawal from Protocolised Treatment Form (v3) 
• 
Death Form  
• 
End of Trial Form.  
The Withdrawal Form v2 in version 2.0 of the CRF was superseded by two new 
forms (Withdrawal from Protocolised Treatment v3 and Withdrawal from Trial Form 
v3 ) in version 3.0 of the CRF, approved 16 Dec 2015. This allowed a clearer 
distinction between those patients discontinuing protocolised treatment, who 
remain under long term follow up, and those withdrawing from the trial completely, 
who have no further data collected. 
Table 3 lists the criteria used to reconcile the two types of withdrawal forms, based 
on the reason of discontinuation given in v2 of the form. V3 criteria will be used in 
the report. 
When either “Investigator decision” or “Other” was selected in the v2 form, sites 
were asked to confirm whether the patient was withdrawn from study or from 
protocolised treatment by adding the text “STUDY” or “PROTOCOL” respectively in 
the relevant “Please Specify” text box. 
When “Participant decision” was selected, sites were asked to confirm that this 
indeed meant the patient withdrew consent to further participation in the study, or 
otherwise to reclassify the withdrawal reason as “Other” and add “PROTOCOL” in the 
relevant text box. 


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Table 3: Withdrawal forms harmony 
V2 
V3 
Withdrawal 
Withdrawal from 
Study 
Withdrawal from 
Protocolised Treatment 
WDReason 
Text box 
WDRea1 
WDPRO2 
1-Not in Remission 
at Month 4 
 
 
1-Not in Remission at 
Month 4 
2-Participant 
decision 
 
2-Withdrawal of 
consent 
 
3-Investigator 
decision 
“STUDY” 
3-Other 
 
“PROTOCOL” 
 
3-Investigator decision 
4-Relapse 
 
 
2-Relapse 
5-Death 
 
1-Death 
 
6-Other 
“STUDY” 
3-Other 
 
“PROTOCOL” 
 
4-Other 
Data management will check each form to ensured consistency and completeness 
across all the forms.


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9.1.3 CONSORT diagram 
A CONSORT diagram (Figure 2) will be presented to show patient disposition within 
the study. 
Figure 2: Example CONSORT diagram for the trial
 
 
 
1 Patients not eligible for randomisation remain under long-term follow up, unless they withdraw consent. 
2 The full analysis population includes all randomised patients, including those subsequently withdrawn. 
 


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9.2 Derived variables 
The following derived variables will be calculated from source variables recoded in 
MACRO: 
1. Baseline Medical History 
• 
Prior disease duration (years) - calculated from the date of diagnosis to 
the date of screening. First day of the month/year will be used for fuzzy 
dates. Date difference in years will be rounded to 1 decimal figure. 
• 
Historical ANCA positivity (Positive both/anti-PR3/anti-MPO, Negative, 
Missing) – a categorical variable, calculated from variables in the 
Enrolment Form recording historical positivity to anti-PR3 and anti-MPO 
ANCA. Calculated according to the following rules (if only one value is 
confirmed and the other is missing, the missing one is assumed to be 
negative): 
Table 4: Historical ANCA positivity 
Anti-MPO 
  
  
Positive 
Negative 
Anti-PR3 
Positive 
Positive for 
Positive for 
  
both anti-PR3 
& anti-MPO 
anti-PR3 
Negative 
Positive for 
Negative 
  
anti-MPO 
 
 
• 
Total number of Body Systems affected (integer) – a count of the number 
of organ manifestations reported in the Baseline Medical History Form 
(max count = 11). The variable will be reported both as categorical and 
continuous. 
2. Prior treatment 
• 
Cyclophosphamide (Yes/No) – categorical variable determining whether 
subjects have ever received any cyclophosphamide treatment, either IV or 
oral. Calculated from oral and IV cyclophosphamide variables; patients 
can receive either treatment or both. In incomplete cases the subject will 
be regarded as not having received the treatment specified. 
• 
Cumulative cyclophosphamide dose (g) - continuous variable, sum of the 
Oral and IV cyclophosphamide doses (g); patients can receive either 


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treatment or both. In incomplete cases the subject will be regarded as not 
having received the treatment specified (i.e. dose = 0 g). 
• 
Rituximab or cyclophosphamide (Yes/No) – categorical variable 
determining whether subjects have ever received any rituximab or 
cyclophosphamide treatment, either IV or oral. Calculated rituximab and 
cyclophosphamide variables; patients can receive either treatment or 
both. In incomplete cases the subject will be regarded as not having 
received the treatment specified. 
• 
Number of prior immunosuppressants (excluding glucocorticoids) 
(integer) - a count of the number of prior immunosuppressants 
(excluding glucocorticoids) received by each subject. The following 
treatments are included: cyclophosphamide (Oral or IV), rituximab, 
azathioprine, methotrexate, mycophenolate mefotil, IVIG, anti-TNFs, and 
other immunosuppression listed in the Baseline Medical History Form. In 
incomplete cases the subject will be regarded as not having received the 
treatment specified. The variable will be reported both as categorical and 
continuous. 
3. Disease Activity (BVAS/WG) 
• 
BVAS/WG status (categorical) – Disease status is determined from section 
12 of the BVAS/WG form. At any given visit each patient is assigned a 
current disease status: "Severe flare/new disease", "Limited flare/new 
disease", "Persistent disease", "Remission". If multiple statuses are 
selected on the form a hierarchical classification is employed: "Remission" 
excludes all others, "Severe flare/new" trumps "Limited flare/new" and 
"Persistent" is trumped by all others. The data manager is responsible for 
the consistency of the data & raises queries accordingly (in particular it is 
expected that “Remission” be mutually exclusive of all other selections). 
4. Disease related assessment (CDA) 
• 
Total CDA score (integer) - Accrual of damage as measured by the 
combined damage assessment (CDA) score. Each persistent or new 
occurrence of damage is recorded as “Yes” and given a score of 1. The 
cumulative accrual of damage is obtained by summing across the 


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different types of damage to get an overall score (max score = 64)6. The 
variable will be reported both as categorical and continuous. 
• 
Change in total CDA score between month 4 and month 12 (integer) – 
difference in Total CDA score between month 4 (randomisation) and 
month 12, calculated for complete-case records only. The variable will be 
reported both as categorical and continuous. 
• 
Change in total CDA score between month 4 and month 24 (integer) – 
difference in Total CDA score between month 4 (randomisation) and 
month 24, calculated for complete-case records only. The variable will be 
reported both as categorical and continuous. 
• 
Change in total CDA score between month 4 and month 36 (integer) – 
difference in Total CDA score between month 4 (randomisation) and 
month 36, calculated for complete-case records only. The variable will be 
reported both as categorical and continuous. 
• 
Change in total CDA score between month 4 and month 48 (integer) – 
difference in Total CDA score between month 4 (randomisation) and 
month 48, calculated for complete-case records only. The variable will be 
reported both as categorical and continuous. 
• 
Change in total CDA score between month 24 and month 36 (integer) – 
difference in Total CDA score between month 24 (end of maintenance 
treatment) and month 36, calculated for complete-case records only. The 
variable will be reported both as categorical and continuous. 
• 
Change in total CDA score between month 24 and month 48 (integer) – 
difference in Total CDA score between month 24 (end of maintenance 
treatment) and month 48, calculated for complete-case records only. The 
variable will be reported both as categorical and continuous. 
5. Treatment Exposure (Treatment Form)  
                                           
6 A different scoring system from the one used in the Induction phase report is employed. 
This new scoring system is based on COMBIVAS’s VDI (Vasculitis Damage Index) form. The 
new scoring system has a maximum score of 64, compared to the Induction phase report 
one that had a maximum score of 110. For comparison new CDA scores for the Induction 
phase months (visits Month 0 and Month 4) will be included in this report. Further details on 
how the CDA score is computed can be found in section 9.8. 


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• 
Total maintenance rituximab dose (mg) – cumulative rituximab dose 
across the maintenance phase of treatment only7, from the Treatment 
Form of months 4, 8, 12, 16 and 20. Missing data (due to early 
withdrawal or any other reason –e.g. missing form) will be ignored (i.e. 
it’s assumed no treatment was given, 0 mg).  
• 
Overall full rituximab treatment - maintenance (Yes/No) – categorical 
variable, determining whether the subject has received all five full 
rituximab infusions as per protocol. Subjects are assumed to have 
followed protocol unless deviations were explicitly recorded in the 
Treatment form (i.e. “Treat6” = 1), any recorded deviation is considered 
an overall non-compliance, while missing forms are ignored. 
• 
Number of full rituximab infusions administered (integer) – calculated 
across the maintenance phase of treatment, from the Treatment form of 
month 4,8,12,16 and 20. Counts explicitly the number of months when 
rituximab treatment was administered according to protocol. Thus “3 
doses” would mean that 3 infusions administered were  given as per 
protocol. Missing forms (NA) are ignored. 
• 
Total maintenance IV methylpredniso(lo)ne dose (mg) – cumulative IV 
methylpredniso(lo)ne dose across the maintenance phase of treatment 
only8, from the Treatment form. Missing data (due to early withdrawal or 
any other reason –e.g. missing form) will be ignored (i.e. it’s assumed no 
treatment was give, 0 mg). 
6. Treatment exposure (Follow Up Form) 
• 
Average predniso(lo)ne dose (mg/day) – average predniso(lo)ne dose, 
from randomisation to the end of trial, using the most recent daily dose 
as recorded in the Follow Up form at month 4, 8, 12, 16, 20, 24, 27, 30, 
36, 42, and 48. If predniso(lo)ne treatment was explicitly recorded as not 
given in the Follow Up Form (i.e. FUp1a1= “No”) then a dose = 0 mg/day 
will be implied, while missing data (due to early withdrawal or any other 
reason –e.g. missing form) will be ignored.  
                                           
7 A separate variable in the Follow Up form reports cumulative rituximab dose at 24 months, 
which includes doses administered during the induction phase. 
8 A separate variable in the Follow Up form reports cumulative IV methylpredniso(lo)ne dose 
at 24 months, which includes doses administered during the induction phase 


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• 
Average predniso(lo)ne dose (mg/day) in the maintenance phase – as 
above but calculated using the most recent daily dose as recorded in the 
Follow Up form at month 4, 8, 12, 16, 20, and 24 only. 
• 
AUC of predniso(lo)ne dose (mg) – Area under the curve of predniso(lo)ne 
dose, calculated using the most recent daily dose as recorded in the 
Follow Up form at month 4, 8, 12, 16, 20, 24, 27, 30, 36, 42, and 48 
employing a vertical step function and assuming a month to be 30 days. 
Missing data will be assumed to have a value of 0 mg/day. 
• 
AUC of predniso(lo)ne dose (mg) in the maintenance phase – as above but 
calculated using the most recent daily dose as recorded in the Follow Up 
form at month 4, 8, 12, 16, 20, and 24 only. 
• 
Average azathioprine dose (mg/day) - average azathioprine dose, from 
randomisation to the end of trial, using the most recent daily dose as 
recorded in the Follow Up form at month 4, 8, 12, 16, 20, 24, 27, 30, 36, 
42, and 48. Missing data (due to early withdrawal or any other reason –
e.g. missing form) will be ignored. 
• 
Average azathioprine dose (mg/day) in the maintenance phase – as above 
but calculated using the most recent daily dose as recorded in the Follow 
Up form at month 4, 8, 12, 16, 20, and 24 only. 
• 
Average methotrexate dose (mg/week) - average methotrexate dose, 
from randomisation to the end of trial, using the most recent daily dose 
as recorded in the Follow Up form at month 4, 8, 12, 16, 20, 24, 27, 30, 
36, 42, and 48. Missing data (due to early withdrawal or any other reason 
–e.g. missing form) will be ignored. 
• 
Average methotrexate dose (mg/week) in the maintenance phase – as 
above but calculated using the most recent daily dose as recorded in the 
Follow Up form at month 4, 8, 12, 16, 20, and 24 only. 
• 
Average mycophenolate mofetil dose (mg/week) - average 
mycophenolate mofetil dose, from randomisation to the end of trial, 
using the most recent daily dose as recorded in the Follow Up form at 
month 4, 8, 12, 16, 20, 24, 27, 30, 36, 42, and 48. Missing data (due to 
early withdrawal or any other reason –e.g. missing form) will be ignored. 
• 
Average mycophenolate mofetil dose (mg/week) in the maintenance 
phase – as above but calculated using the most recent daily dose as 
recorded in the Follow Up form at month 4, 8, 12, 16, 20, and 24 only. 


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• 
Number of oral immunosuppressants (azathioprine, methotrexate and 
mycophenolate mofetil) (integer) – counts the number of treatments of 
oral immunosuppressants (either azathioprine, methotrexate and 
mycophenolate mofetil) administered per patient at each visit, during the 
maintenance phase and overall (from randomisation to the end of trial). 
Missing data will be ignored. 
7. Clinical Laboratory Evaluations 
• 
ANCA status (Positive Both/anti-PR3/anti-MPO, Negative, Unknown) – a 
categorical variable, calculated from variables in the Clinical Laboratory 
Test Form recording ANCA positivity (anti-PR3 and anti-MPO) at each 
visit. Calculated according to the following rules: 
Table 5: ANCA Status 
Anti-MPO 
  
  
Positive 
Negative 
Not measured 
Anti-PR3 
Positive 
Positive 
Positive 
Positive 
  
PR3 & MPO 
PR3 
PR3 
Negative 
Positive 
Negative 
Unknown 
  
MPO 
 
 
Not measured Positive 
Unknown 
Unknown 
  
MPO 
 
 


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Table 6: Details of formulas for derived variables 
Variable name 
Label 
Type 
Original variables 
(MACRO ShortCode) 
Formula 
MHDuration 
Prior disease 
duration 
Real 
MHDat1, Visit1 
Date difference 
(years) 
HisANCA 
Historical ANCA 
positivity 
Category 
MHEli1, MHEli2 
See Table 4 for 
details 
BLM_Score 
BLM_Score_cat 
Total number of 
Body Systems 
affected 
Integer/ 
Category 
BLM_* variables 
Sum 
MHCycl 
Total 
cyclophosphamide 
Category 
MHTre3, MHTre4 
if either = 1  
then => 1 (Yes)              
else => 0 (No) 
MHCyclDose 
Cumulative 
cyclophosphamide 
dose 
Real 
MHCyc1, MHIVC1 
Sum 
MHRitCyc 
Previous treatment 
with rituximab or 
cyclophosmaphide 
(either IV or oral) 
Category 
MHTre5, MHCycl 
if either = 1  
then => 1 (Yes)              
else => 0 (No) 
MHImmN 
MHImmN_cat 
Number of prior 
immunosuppressants 
Integer/ 
Category 
CumCyclo, MHTre5, 
MHTre6, MHTre7, 
MHTre8, MHTre11, 
MHTre12, MHImS1, 
MHImS2, MHImS3, 
MHImS4, MHImS5, 
MHImS6 
Sum 
BVASStatus 
Disease status 
Category 
BVAS12a, 
BVAS12b, 
BVAS12c, 
BVAS12d 
Hierarchical order, 
categories evaluated 
in order, from the 
most specific to the 
most general: 
1. Remission 
2. Severe flare 
3. Limited flare 
4. Persistent 
CDAScore 
CDAScore_cat 
CDAScore_grp 
Total CDA score 
Integer/ 
Category 
selected variables of  
CDA Form  
(see section 9.8) 
Sum 
CDADiff 
CDADiff_cat 
Change in total CDA 
score between 
month 4 and month 
12, month 24, month 
36 & month 48. 
Change in total CDA 
score between 
Integer/ 
Category 
CDAScore 
Difference 


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month 24 and month 
36 & month 48 
TreatRituxSum 
Total rituximab dose 
(mg) 
Real 
TreatTotalRitux 
Sum 
TreatRituxPrtcol 
Overall full rituximab 
treatment 
Category 
TreatAdmnProtcol 
Yes if 
sum(TreatAdminProt
ocol=”Yes”)=5 
TreatRituxMonths 
Number of full 
rituximab infusions 
Integer/ 
Category 
TreatAdmnProtcol 
count(TreatAdminPr
otocol=”Yes”) 
TreatMPredDose 
Total IV 
methylpredniso(lo)ne 
dose (mg) 
Real 
TreatMPredDose 
Sum 
PredMean 
PredMean24 
Average 
predniso(lo)ne dose 
(mg/day) - (Overall 
/Maintenance) 
Real 
FUp1aPredDose 
Average 
If FUp1a1 then 
Fu1aPredDose=0 
PredAUC 
PredAUC24 
AUC of 
predniso(lo)ne dose 
(mg) - (Overall 
/Maintenance) 
Real 
FUp1aPredDose 
Vertical step 
function, assumes 
month=30days 
AZAMean 
AZAMean24 
Average azathioprine 
dose (mg/day) - 
(Overall 
/Maintenance) 
Real 
FUp1cAzathiDose 
Average 
MTXMean 
MTXMean24 
Average 
methotrexate dose 
(mg/week) - (Overall 
/Maintenance) 
Real 
FUp1dMTXDose 
Average 
MMFMean 
MMFMean24 
Average 
mycophenolate 
mofetil dose dose 
(mg/week) - (Overall 
/Maintenance) 
Real 
FUp1eMMFDose 
Average 
N.Month 
N.overall 
N.maint 
Number of oral 
immunosuppressants 
integer 
Azathioprn follwup 
FUp1dMTX 
FUp1eMMF 
group by subject & 
month 
 
ANCA 
ANCA Status 
Category 
CLAnt5 & CLAnt7 
CLAnt9 & CLAnt11 
CLAnt13 & CLAnt15 
CLAnt1_2 & 
CLAnt3_2 
See Table 5 for 
details 
 
 
 


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9.3 Protocol Deviations 
Protocol deviations in the administration of treatments (rituximab and GCs) are 
detailed in section 9.9.  
9.4  Demographic and Baseline Variables 
Demographic details and subject characteristics, as specified in the Enrolment and 
Baseline Medical History Forms (Demography section), will be recorded at the 
screening visit and entered in the MACRO database. 
The following demographic and baseline variables will be summarised in 
accordance with section 9 using the full analysis population. Frequency tables will 
be presented by treatment allocation (“Azathioprine”, “Rituximab”) and further sub-
divided by induction regimen at enrolment (“1A”, “1B”). 
9.4.1 Demographics 
• 
Age (years), coarsening into ranges: 
− 
Under 18 
− 
18–64 
− 
65-85 
− 
Above 85 
• 
Sex (M/F) 
• 
Race (White/Black/Asian/Hispanic/Other) 
• 
Weight (kg), converting from imperial units if necessary (1 lb = 2.205 Kg) 
and rounding to 1 decimal figure 
• 
Height (cm), converting from imperial units if necessary (1 inch = 2.54 cm) 
and rounding to 1 decimal figure 
9.4.2 Enrolment characteristics 
• 
Body Surface Area9 (m2, 2 decimal figures) 
• 
Predniso(lo)ne induction regimen (1A/1B) 
• 
ANCA type (anti-PR3/anti-MPO) 
• 
Relapse type (Severe/Non severe) 
• 
Induction dose of Rituximab (mg/infusion) 
9.4.3 Stratification variables 
                                           
9 Calculated using the Du Bois formula (14) 


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The Enrolment Form records the stratification variables at baseline (Month 0): 
prednisolone induction regimen, ANCA type, and relapse severity. The following 
frequency tables will be summarised in accordance with section 9: 
• 
Relapse severity (Severe/Non-severe) stratified by prednisolone regimen 
(1A/1B). 
• 
ANCA type (anti-PR3/anti-MPO) stratified by prednisolone regimen (1A/1B). 
• 
Relapse severity (Severe/Non-severe) stratified by ANCA type (anti-PR3/anti-
MPO). 
Corresponding mosaic plots will also be produced. 
9.5 Concurrent Illnesses and Medical Conditions 
Any relevant medical history, as specified in the Baseline Medical History Form, will 
be recorded at the screening visit and entered in the MACRO database. 
The following baseline medical history variables will be summarised in accordance 
with section 9 using the full analysis population. Frequency tables will be presented 
by treatment allocation (“Azathioprine”, “Rituximab”) and further sub-divided by 
induction regimen at enrolment (“1A”, “1B”). 
9.5.1 Baseline Medical History 
• 
Prior disease duration (years) – derived variable, details in section 9.2 
• 
Historical ANCA positivity – derived variable, details in section 9.2 
• 
Historical organ involvement, broken down by Body System and abnormality 
type, (counts): 
− 
Constitutional Symptoms 
− 
Joints 
− 
Skin 
− 
Mucous membranes/Eyes 
− 
Ear/Nose/Throat 
− 
Heart 
− 
Gastrointestinal tract 
− 
Lungs 
− 
Kidneys 
− 
Nervous system 
− 
Other 


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− 
Total number of Body Systems affected – derived variable, details in 
section 9.2 
• 
Co-morbidities (counts): 
− 
Hypertension 
− 
Ischemic Heart Disease (IHD) 
− 
Chronic Lung Disease (COPD) 
− 
Cerebrovascular Disease (CVD) 
− 
Cancer 
− 
Venus Thromboembolism 
− 
Diabetes Mellitus 
9.6 Prior and Concurrent Medications 
Previous medication history to treat vasculitis as specified in the Baseline Medical 
History Form (Medication History section) will be recorded at the screening visit and 
entered in the MACRO database. 
The following baseline medical history variables will be summarised in accordance 
with section 9 using the full analysis population. Frequency tables will be presented 
by treatment allocation (“Azathioprine”, “Rituximab”) and further sub-divided by 
induction regimen at enrolment (“1A”, “1B”). 
9.6.1 Prior treatment 
Number of patients who have ever received the following as a treatment for 
vasculitis: 
• 
Methylprednisolone 
• 
Prediso(lo)ne 
• 
Oral Cyclophosphamide  
• 
IV Cyclophosphamide 
• 
Cyclophosphamide (CYC) – derived variable, details in section 9.2 
• 
Rituximab 
• 
Azathioprine 
• 
Methotrexate 
• 
Mycophenolate Mofetil 
• 
Sulfamethoxazole/Trimethoprim 
• 
Plasma Exchange 


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• 
IVIG 
• 
Anti-TNFs 
• 
Other immunosuppression 
Doses for the following treatments: 
• 
Rituximab (mg) 
• 
Oral Cyclophosphamide (g) 
• 
IV Cyclophosphamide (g) 
• 
Cumulative cyclophosphamide dose (g) – derived variable, details in section 
9.2 
Total counts of the following treatments: 
• 
Number of prior immunosuppressants (excluding glucocorticoids) – derived 
variable, details in section 9.2 
9.6.2 Concomitant Medication 
Any relevant concomitant medication prescribed during the trial will be recorded in 
the Concomitant Medication Form at Screening, months 0 to 48 and Unscheduled 
visit if applicable10. The data will be entered in the MACRO database and retained 
for safety monitoring. Data will be reported as table listings per patient, per study 
visit. The following information, when available, will be reported: 
• 
Medication name (generic names only) 
• 
Category (Anticoagulant/Antiplatelet, IVIg, Antimicrobial, Other) 
• 
Dose (units) 
• 
Frequency (one daily, twice daily, three times daily, four times a day, 
alternate days, weekly, other, as required) 
• 
Comments 
9.7 Disease activity assessment (BVAS/WG) 
The Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis (BVAS/WG) 
will be used to record disease activity (1).  
                                           
10 Concomitant medication from Screening to Month 4 visit were recorded in the Induction 
Phase analysis and report. 


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The BVAS/WG Form, automatically scored by MACRO11, will be reported at Month 4, 
8, 12, 16, 20, 24, 27, 30, 36, 42 and 48, using the full analysis population. The 
following variables will be summarised in accordance with section 9. 
• 
The total count of Body Organ System involvement: 
1. General 
2. Cutaneous 
3. Mucous membranes/eyes 
4. Ear, nose & throat (ENT) 
5. Cardiovascular 
6. Gastrointestinal 
7. Pulmonary 
8. Renal 
9. Nervous system 
10. Other (all item’s descriptions will be listed, by subject ID and visit) 
• 
Total number of items: 
1. Major New/Worse 
2. Minor New/Worse 
3. Major persistent 
4. Minor persistent 
• 
Total major items – calculated by MACRO 
• 
Total minor items - calculated by MACRO 
• 
Total BVAS/WG score - calculated by MACRO 
• 
Current disease status – derived variable, details in section 9.2: 
1. Severe flare/new disease 
2. Limited flare/new disease 
3. Persistent disease 
4. Remission 
• 
Physician’s global assessment (PGA) 
9.8 Disease related assessment (CDA) 
The Combined Damage Assessment (CDA) Index will be used to record organ 
damage that has occurred in patients since the onset of vasculitis. Accrual of 
                                           
11 https://onlinelibrary.wiley.com/doi/epdf/10.1002/1529-
0131%28200104%2944%3A4%3C912%3A%3AAID-ANR148%3E3.0.CO%3B2-5 


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damage as measured by the CDA score. Each persistent or new occurrence of 
damage is recorded as “Yes” and given a score of 1. The cumulative accrual of 
damage is obtained by summing across the different types of damage to get an 
overall score. CDA should never decrease, and items that are recorded at one visit 
should always be recorded at subsequent visits. 
The CDA Form will be scored by cumulative sum of each of the Body Organ Systems 
detailed below, assigning a value of 1 for each item ticked as present (“Yes” 
checkbox ticked). Only the listed items contribute to the specified Body Organ 
System, non-listed items will be ignored. The “No” checkboxes will also be ignored: 
items are assumed to be not present unless the “Yes” checkbox has been explicitly 
ticked. 
The CDA Form will be reported at Month 4, 12, 24, 36, 42 and 48 visits, using the 
full analysis population. The following CDA variables will be summarised in 
accordance with section 9. 
• Damage to each Body Organ System, reported as a categorical variable 
(yes/no) surmising whether any listed sub-item is reported (i.e. “No” means a 
score of zero): 
a. 
Musculoskeletal, max score = 5 
1 - Significant muscle atrophy or weakness (any item) 
2 - Deforming/erosive arthritis 
3 - Osteoporosis/vertebral collapse 
4 - Avascular necrosis 
5 - Osteomyelitis 
b. 
Skin/Membranes, max score = 3 
1 - Alopecia 
2 - Cutaneous ulcers 
3 - Mouth ulcers 
c. 
Ocular, max score = 7 
1 - Cataract 
2 - Retinal changes or Retinal artery occlusion or Retinal vein occlusion 
3 - Optical nerve atrophy 
4 - Low vision or Diplopia 
5 - Blindness in one eye (left or right) 
6 - Blindness in second eye (both) 
7 - Orbital wall destruction 


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d. 
ENT, max score = 6 
1 - Sensorineural hearing loss or Conductive hearing loss (Ear section) 
2 - Chronic rhinitis/crusting (Nose section) 
3 - Nasal bridge collapse/saddle nose or Nasal septal perforation (Nose 
section) 
4 - Chronic sinusitis (Sinuses section) 
5 - Subglottic stenosis (no surgery) (Subglottic stenosis section) 
6 - Subglottic stenosis (surgery) (Subglottic stenosis section) 
e. 
Pulmonary, max score = 7 
1 - Pulmonary hypertension 
2 - Pulmonary fibrosis 
3 - Pulmonary infarction 
4 - Pleural fibrosis 
5 - Chronic asthma 
6 - Chronic breathlessness 
7 - Irreversible loss of lung function 
f. 
Cardiac, max score = 7 
1 - Angina or Percutaneous coronary intervention 
2 - Myocardial infarction 
3 - Coronary artery bypass graft 
4 - Cardiomyopathy (NYHA Class I/II or NYHA class III/IV) 
5 - Valvular Disease 
6 - Pericarditis or Pericardectomy 
7 - Hypertension (any item) 
g. 
Vascular Disease, max score = 8 
1 - Absent pulses in 1 limb  
2 - 2nd episode of absent pulses in 1 limb 
3 - Major vessel stenosis 
4 - Claudication > 3 months 
5 - Minor tissue loss 
6 - Major tissue loss 
7 - Subsequent major tissue loss 
8 - Deep venous thrombosis or Complicated venous thrombosis 
h. 
Gastrointestinal, max score = 4 
1 - Gut infarction/resection 
2 - Mesenteric insufficiency/pancreatitis 
3 - Esophageal stricture/surgery 
4 - Chronic peritonitis 
i. 
Renal, max score = 3 
1 - Estimated/measured GFR<50% 


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2 - Proteinuria (any item) 
3 - End-stage renal disease or Dialysis 
j. 
Neuropsychiatric, max score = 8 
1 - Cognitive impairment (Psychiatric section) 
2 - Major psychosis (Psychiatric section) 
3 - Seizures (Neurological section) 
4 - Cerebrovascular accident (Neurological section) 
5 - 2nd cerebrovascular accident (Neurological section) 
6 - Cranial nerve lesion (Neurological section) 
7 - Sensory polyneuropathy (any item) or Motor Neuropathy (Neurological 
section) 
8 - Transverse myelitis (Neurological section) 
k. 
Other, max score = 6 
1 - Gonadal failure (Premature ovarian failure or Azoospermia) 
2 - Marrow failure (Refractory cytopenia or Myelodysplastic syndrome) 
3 - Diabetes mellitus 
4 - Chemical cystitis (any item) (Other section) 
5 - Malignancy (Bladder cancer or Cervical cancer or Hemotopoetic 
malignancy or Solid tumour malignancy) 
6 - Other (Other section) 
• Total CDA score, max = 6412 – derived variable, details in section 9.2. The 
variable will be reported both as continuous and categorical, coarsening into 
ranges: 
− 
less than 5 
− 
5-10 
− 
11-15 
− 
16-20 
− 
greater than 20 
• Change in total CDA score between month 4 and month 12 – derived 
variable, details in section 9.2 
• Change in total CDA score between month 4 and month 24 – derived 
variable, details in section 9.2 
• Change in total CDA score between month 4 and month 36 – derived 
variable, details in section 9.2 
                                           
12 A different scoring system from the one used for the Induction Phase report is employed 
here to calculate an overall CDA score. The new scoring system is based on COMBIVAS VDI 
(Vasculitis Damage Index) form. A comparison between the old and new system for the 
Induction Phase will be presented. 


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• Change in total CDA score between month 4 and month 48 – derived 
variable, details in section 9.2 
• Change in total CDA score between month 24 and month 36 – derived 
variable, details in section 9.2 
• Change in total CDA score between month 24 and month 48 – derived 
variable, details in section 9.2 
9.9 Treatment Compliance 
Compliance to treatment during the maintenance phase of the trial was assessed 
based on information collected in the Treatment and Follow Up forms. A 
comprehensive overview of the process involved is described in a separate 
document13. All randomised patients (full analysis population) were assessed by an 
independent committee for compliance to allocated treatment during the active 
maintenance phase (from randomisation to month 24) and during follow-up (from 
month 24 to end of trial). Outcomes were recorded into a spreadsheet sent to data 
management to be added to the main MACRO data download.  
The following variables found in the spreadsheet will be summarised in accordance 
with section 9: 
• Maintenance compliance (Yes/No) & reasons for non-compliance 
• Follow-up compliance (Yes/No) & reasons for non-compliance 
9.10 Treatment Exposure 
In the maintenance phase, all patients allocated to rituximab treatment received 
rituximab 1000 mg x 1 dose at months 4, 8, 12, 16 and 20 and glucocorticoids. 
Patients randomised to the control arm will receive oral azathioprine, to be taken 
daily, with a target dose of 2mg/kg. The maximum daily dose allowed is 200mg. 
The maximum treatment period is 27 months, with tapering after month 2414. In 
the event of azathioprine intolerance (see section 11.2.i of the protocol), 
methotrexate 25 mg/week will be substituted for patients with GRF > 50 ml/min, 
and mycophenolate Mofetil will be substituted for patients with GRF < 50 ml/min.  
9.10.1 Rituximab treatment 
                                           
13 See Medication Compliance.docx 
14 See section 11.2 of the protocol for further details of azathioprine administration. 


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The Treatment form records details of rituximab treatment, at months 4, 8, 12, 16 
and 20, as recorded by the PI. The form will be reported at each time point using 
the full analysis population. The following variables will be summarised in 
accordance with section 9: 
• Rituximab dose (mg) 
• Rituximab  administered according to protocol (Yes/No) 
• Reasons for non-compliance, counts: 
a) Rituximab not administered as IgG < 3g/L 
b) Incomplete 
c) Interrupted 
d) Other 
Reasons given for incomplete/interrupted/other treatment non-compliance will be 
listed per patient, per visit. 
In addition, total cumulative rituximab dose after 24 months as recorded in the 
Follow Up form as well as the following derived variable (details in section 9.2) will 
be calculated across the maintenance therapy period15 and summarised in 
accordance with section 9: 
• 
Cumulative rituximab dose (mg) up to 24 months16 
• Total rituximab dose in maintenance phase (mg) – derived variable, details in 
section 9.2 
• Overall full rituximab treatment (Yes/No) – derived variable, details in section 
9.2 
• Number of full rituximab infusions – derived variable, details in section 9.2 
9.10.2 Glucocorticoid treatment 
Concomitant glucocorticoid (GC) treatment in the maintenance phase was permitted 
as follows. A GC dose of 10 mg/day or less is a requirement for randomisation. GC 
reduces to 5 mg/day by month 6, according to schedule 2 (Table 7), and continues 
at 5 mg daily until month 16. GC dose is then reduced to 2.5mg/day and 
completely withdrawn at month 20. 
                                           
15 From randomisation to month 24 from enrolment inclusive. 
16 As recorded in the Follow Up form at month 24, it includes induction phase doses. 


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Table 7: CG Schedule 2 
 
Maintenance 
Schedule 
Daily Prednisolone 
dose (mg) 
Week  
 
12 
10 
14 
10 
16 
(randomisation) 
10 
18 
7.5 
20 
7.5 
22 
5 
24 
5 
 
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 greater than 5 mg. For 
example, a dose of 7.5 mg/day may be achieved by alternating daily doses of 10 
mg/day and 5 mg/day. 
For all patients follow-up daily dose of prednisolone was recorded at each visit in 
the maintenance phase (months 4, 8, 12, 16, 20, 24, 27, 30, 36, 42 and 48) in the 
Follow-Up Form. Section 1 and 2 of the form will be reported at each time point 
using the full analysis population. The following variables will be summarised in 
accordance with section 9: 
• Number of patients receiving the following treatment since the last 
evaluation: 
a) Predniso(lo)ne 
b) Rituximab17 
c) Azathioprine  
d) Methotrexate 
e) Mycophenolate Mofetil 
f) Pneumocystis prophylaxis 
i) Co-trimoxazole 
                                           
17 Rituximab treatments as recorded in the Follow-Up Form. Includes rituximab received as part of 
protocol and outside of protocol. 


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ii) Dapsone 
iii) Other 
g) Aspirin 
h) Warfarin 
• Doses of the following treatments at each visit: 
a) Predniso(lo)ne (mg/day) 
b) Azathioprine (mg/day) 
c) Methotrexate (mg/week) 
d) Mycophenolate Mofetil (g/day) 
• In addition, the following derived variables (details in section 9.2) will be 
calculated across the maintenance phase (from month 4 to month 24) and 
overall (from randomisation to the end of the trial): 
a) Average predniso(lo)ne dose (mg/day) 
b) AUC of predniso(lo)ne dose (mg/day) 
c) Azathioprine (mg/day) 
d) Methotrexate (mg/week) 
e) Mycophenolate Mofetil (g/day) 
IV methylpredniso(lo)ne treatment, as recorded in the Treatment Form, will be 
reported at each time point using the full analysis population. The following 
variables will be summarised in accordance with section 9: 
• IV methylpredniso(lo)ne treatment (Yes/No) 
• Dose (mg) 
• Cumulative IV methylpredniso(lo)ne dose (mg) up to 24 months 
• Total IV methylpredniso(lo)ne dose in maintenance phase (mg) – derived 
variable, details in section 9.2 
 
Reasons given for significant deviations from the GC protocol (defined as a +/- 25% 
of the protocol specified dose, for period greater than 2 weeks) will be listed per 
patient, per visit in the appendix. Additionally a frequency table of the number of 
predniso(lo)ne deviations per patient per visit will be provided. 
A count of the number of patients whose dose of azathioprine, methotrexate, or 
mycophenolate was changed will be reported per visit, and overall. Details (date of 
dose change, clinical side effects/intolerances, laboratory abnormalities, other 


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reasons) as recorded in Section 2 of the form will be listed per patient per visit in 
the appendix. 
10 Efficacy Analyses 
Efficacy analyses will be performed on the full analysis population. Additionally the 
primary efficacy analysis will be presented for the two per-protocol populations 
(maintenance and follow-up compliant populations).  
10.1 Primary efficacy analysis 
The primary efficacy outcome measure of the trial is relapse-free survival, where a 
relapse is either major or minor (see definitions above). The primary analysis will be 
a Cox regression model adjusted for the stratification factors (ANCA type, relapse 
severity and prednisone induction regimen) for the difference in the distribution of 
relapse-free survival between the rituximab arm and the azathioprine (control) arm 
(two-sided at α-level of 5%). Assuming a proportional hazard holds, the hazard 
ratio together with the 95% confidence interval will be estimated using a Cox 
regression model adjusted for the stratification factors. 
There will be a closed testing procedure, first the null hypothesis will be teste for a 
hazard ratio of 1 at all time points. If this is rejected at a 5% level then two further 
sub-hypothesis will be examined using time-varying covariates: 
1. A hazard ratio of 1 up to 20 months post-randomisation (i.e. during 
treatment). 
2. A hazard ratio of 1 after 20 months post-randomisation (i.e. post-
treatment). 
Kaplan-Meier estimates for relapse-free survival at 24 and 48 months18 and median 
relapse-free survival with the corresponding 95% confidence intervals by treatment 
allocation will be presented.  
Additional analyses will consider in turn the interaction of treatment with each of 
the three stratification variables, i.e. ANCA type, relapse severity and induction 
regimen. Frequency tables and Kaplan-Meier plots, as well hazard ratios and 95% 
                                           
18 Time measured from enrolment, in reality this corresponds to 20 months and 44 months 
post-randomisation. 


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confidence intervals of a Cox proportional hazard model including interactions will 
be presented. These results are to be taken as exploratory only, as these analyses 
were not planned in the protocol, are likely under-powered and are not adjusted for 
multiple comparisons.  
The following tables and figures will be reported, taking into account events 
occurring after randomisation (i.e. excluding the induction phase): 
• No. of relapses: 
a) by type (major or minor) 
b) by phase (during treatment or post-treatment) 
c) per participant 
• No. of participants with a relapse (major or minor)19 by type at: 
a) All time points 
b) During treatment (up to month 20 post-randomisation) 
c) Post-treatment (after 20 months post-randomisation) 
• Kaplan-Meier curve with at risk population, from randomisation 
i) Overall curve 
ii) Stratified by ANCA type, relapse severity and induction regimen 
• Median relapse-free survival (95% confidence interval) 
• 24-month and 48-month20 relapse-free survival rate 
• Hazard ratios21 at: 
a) All time points 
b) During treatment (up to month 20 post-randomisation) 
c) Post-treatment (after 20 months post-randomisation). 
10.2 Secondary outcomes 
These analyses will mirror those described for the primary endpoint above with the 
secondary outcomes as the end points of the analyses. These are only intended to 
be exploratory given the power of the study: 
1. Time to a major or second minor relapse. 
                                           
19 Primary endpoint. 
20 Time measured from enrolment, in reality this corresponds to 20 months and 44 months 
post-randomisation. 
21 Close testing procedure will be implemented. 


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2. Time to a major relapse22. 
10.3 Censoring 
Any patients who have not relapsed at study close will be censored. Further details 
of how relapse/censoring dates will be defined are given below: 
Situation 
Date of Relapse or Censoring 
Outcome 
No baseline assessments 
Randomization 
Censored 
Relapse documented 
between scheduled visits 
Unscheduled visit date 
Relapsed 
Drop-out with no relapse 
Date of last assessment with no 
documented relapse 
Censored 
Treatment discontinuation 
for undocumented relapse 
Date of last assessment with no 
documented relapse 
Censored 
Treatment discontinuation 
for toxicity or other reason, 
or protocol deviation 
The patient will be followed up 
as per protocol and date of 
relapse or censoring observed 
accordingly 
Relapsed/censored 
Death due to relapse 
Date of Death 
Relapsed 
Death due to other causes 
Date of Death 
Censored 
Death or progression after  
more than one missed visit 
Date of last assessment with no 
documented relapse 
Censored 
 
In the efficacy analysis, the date of the month 4 visit will be used as time-zero (i.e. 
randomisation). According to the protocol patients might be randomised in advance 
of the month 4 visit (provided they achieved disease remission by the month 3 
visit), however maintenance therapy (with either treatment) was not allowed to be 
administered before the month 4 visit23. 
Treatment duration is taken to be strictly 20 months post-randomisation, i.e. date 
of the month 4 visit + 20 months, and not the actual time of the month 24 visit 
when the last visit was administered. This affords a common timeline for all 
patients, irrespective of time slippages in scheduled visits. 
In the analysis, in accordance with the protocol, the censoring time will be taken to 
be: 
1. If no baseline assessment: time of randomisation, 
2. Otherwise, the latest date between:  
                                           
22 This endpoint was not originally included in the protocol (v4.0). 
23 For a more in-depth description of randomisation procedures and trial’s timelines, 
including definitions of the Induction and Maintenance Phase, see Induction Phase SAP, 
section 9.1.1, and refer to the protocol, section 10.4. 


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a. the last completed scheduled visit (or the last completed scheduled 
visit before more than two missed visits) 
b. death due to other causes (unscheduled visit) 
c. the common close date (for those patients whose end of trial visit, 
either month 42 or month 48, would have occurred after the common 
close)24. 
The time of relapse will be taken from the relapse form (unscheduled visit). 
Patients will be considered to have had an event (e.g. first relapse) if the event 
occurred, either: 
1. prior to the censoring date  
2. within 12 months (& 14 days, allowing for a 2 weeks slippage) of the 
censoring date. 
This is on account of the last censoring rule in the table above: in the case of death 
or progression after more than one missed visit, the patient is to be censored at the 
date of the last assessment with no documented relapse.  
Looking at the schedule of visits in the trial, 12 months is the longest span of time 
for 3 consecutive visits (month 30, month 36, month 42) thus any event occurring 
after 12 months of the censoring date will have occurred after more than a missed 
visit and should be disregarded (the patient is censored instead at the last 
scheduled visit before the missed visits).  
This is the case with patient AS3-001, who had a relapse after more than one 
missed visit. The relapse occurred 408 days after month 27 visit, the patient having 
missed month 30 and month 36 visits. The event was therefore disregarded and the 
patient censored at month 27. See below an illustration of the patient visits 
scheduled (black dots: attended visits; green line: censoring date; red line: relapse; 
dashed line: end of trial date; dotted lines: randomisation and common close 
date)25.  
                                           
24 It was agreed with sites that patients who had not completed their month 42 or month 48 
visit by the time of the common close would be followed up until the common close date. 
25 A copy of similar illustration is retained for each patient for further inspection. 


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The shortest time span for 3 consecutive visits (month 24, month 27, month 30) is 
6 months, thus any event occurring within 6 months has occurred with no more 
than one missed visit and should be retained (patient relapsed). 
Thus in the case of patient N15-001, who had a relapse after 108 days of month 16 
visit and subsequently missed both visits month 20 and month 24, the relapse 
occurred within the 12 months of the censoring date and indeed was found not to 
have occurred after more than one missed visit. Consequently the event was 
retained and the patient was counted as “relapsed” on this date. 
 
Events happening between 6 and 12 months of the censoring date require further 
investigation. Depending on the last visit before any missing gaps, these events 
could fall after either one or two missed visits (e.g. an event 200 days after month 
30 would happen after one missed visits, while an event 200 days after month 24 


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would happen after two missed visits). Thus the 12 months threshold is not strong 
enough to determine the outcome. The analysis code explicitly checks for such 
instanced, which must then be adjudicated independently. None were found.  
Likewise, by inspection, all deaths were by other causes and occurred before more 
than one missed visit, and thus no special considerations are needed (all patients 
who died where censored at the time of death). 
An independent adjudication committee (blinded to treatment) will review all 
relapses and deaths. This will ensure that “deaths due to relapse” are recorded in 
the trial database as a relapse (i.e. there exists a corresponding relapse form). The 
censoring date of “deaths due to other causes” will also be verified in cases with 
more than one missed visit. 
11 Safety Analyses 
11.1 Serious Adverse Events 
All serious adverse events (SAE), including serious adverse drug reactions will be 
reported according to guidance in sections 13.4 and 13.5 of the protocol. 
All Serious Adverse Events must be reported to the central trials co-ordinator or 
trial physician in Cambridge within 24 hours of the investigator becoming aware of 
the event and will be entered in a separate database. Individual SAEs will be 
assessed by the trial physician, and if advice is needed, this will be sought from one 
of the CIs, blinding them to treatment allocation. Monthly SAE listings, blinded to 
treatment allocation, will be reviewed by both CIs however. The Sponsor has to keep 
detailed records of all SAEs reported to them by the trial team. 
Frequency tables for all SAEs will be reported using the safety population and 
stratified by both treatment arm and induction regimen as well as their interaction. 
Separate tables will report: 
• 
SAEs where date of onset occurred after randomisation26   
• 
SAEs occurring during treatment (up to 20 months after randomisation) 
                                           
26 SAEs occurring during the induction period (prior to randomisation) were reported 
separately, see Induction Phase SAP and report. 


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• 
SAEs occurring after treatment ended (from 20 months after randomisation 
onwards) 
Additionally, counts of subjects and events stratified by relatedness 
(Unrelated/Related) will be reported, grouped by System Organ Class, High Level 
Group Term and Preferred Term based on the MedDRA code. 
11.2 Adverse Events 
In addition to all SAEs, the following selected adverse events (AEs) are being 
collected as part of the RITAZAREM trial: 
1. Infections (all episodes requiring treatment with intravenous (IV) or oral 
antibiotics or infections that are commonly understood to be opportunistic)  
2. Occurrence of hypogammaglobulinemia (IgG <5g/l)  
3. Occurrence of hypogammaglobulinemia (IgG <3g/l)  
4. An adverse event that results in a change in dose of trial IMPs (rituximab, 
azathioprine, methotrexate or mycophenolate mofetil (MMF))  
5. An adverse event that results in the addition of a relevant concomitant 
medication (see section 13.3.1 for list)  
6. An adverse event manifested by the occurrence of a relevant laboratory 
abnormality (see section 13.3.2 for list)  
7. New malignancies 
Infections are recorded using the Infection Form and entered in the MACRO 
database. Frequency tables for serious and non-serious infections with date of 
onset occurring in the maintenance phase will be reported using the safety 
population and stratified by induction regime. The number of patients with newly 
occurring IgG < 5g/L and newly occurring IgG < 3g/L will be reported. Additionally, 
counts of subjects and events for non-serious infections will be reported, grouped 
by High Level Group Term and Preferred Term based on the MedDRA code. 
Individual listings of infections are reported to the DSMB and reviewed quarterly. 
New malignancies are recorded using the New Malignancy Form and entered in the 
MACRO database. All instances of new malignancies detected during the 
maintenance phase will be reported as individual listings sorted per patient by site. 
The following detail will be reported: 


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• 
Treatment arm 
• 
Malignancy Detection date  
• 
Malignancy Diagnosis date  
• 
Malignancy Site 
 
• 
Malignancy Type 
 
• 
Malignancy Reoccurrence 
• 
Malignancy Treatment (Surgery, Radiotherapy, Chemotherapy, Other) 
 
• 
Malignancy Associated with SAE (Yes/No) 
• 
Malignancy Comments 
11.3 Hypogammaglobulinemia  
Hypogammaglobulinemia is defined as a value of IgG < 5 g/L measured at any 
stage of the trial (including visits occurring during the induction period). Frequency 
tables for hypogammaglobulinemia will be reported using the full analysis 
population and stratified by treatment arm and: 
a) Induction regimen (1A/1B) 
b) ANCA type (anti-PR3/anti-MPO) 
c) Relapse type (Severe/Non severe) 
d) Previous treatment with rituximab (Yes/No) 
e) Previous treatment with cyclophosphamide (Yes/No) 
f) Previous treatment with rituximab or cyclophosphamide (Yes/No) 
g) Baseline (Screening/Month 0) IgG (g/L). 
A logistic regression analysis will be carried out to predict 
hypogammaglobulinemia, using the above as predictor variables. Individual 
univariate models and a multivariate model will be considered. Outcomes (Estimate, 
95% CI and P-value) will be surmised in tabular form. 
These analysis are to be considered exploratory only, as they were not specified in 
the protocol and the data is observational. 
11.4 Deaths 
All deaths within the trial (whether considered a SAE or not) will be reported to the 
Chief Investigator and the Sponsor using the relevant Death Form. Deaths occurring 
in the maintenance phase will be documented and reported separately to SAEs. 
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the full analysis population. Additionally the following causes of death will be 
summarised: 
All causes of death that apply: 
• 
Infection 
• 
Active vasculitis 
• 
Pulmonary embolus 
• 
Withdrawal of renal replacement therapy 
• 
Acute myocardial infarction 
• 
Sudden death (cause unknown) 
• 
Cerebrovascular disease 
• 
Cancer 
• 
Unknown 
• 
Other 
Missing data will be treated as cause of death not applicable. 
11.5 Pregnancies 
Pregnancy or inadequate contraception in women of childbearing potential forms 
one of the exclusion criteria for the study. A pregnancy test was performed at 
baseline for all women of childbearing potential to assess eligibility. Data was 
retained for safety and will not be reported. 
All pregnancies within the trial (either the trial participant or the participant’s 
partner) will be reported to the Chief Investigator and the Sponsor using the 
relevant Pregnancy Reporting Form within 24 hours of notification. Pregnancy is not 
considered an adverse event (AE) unless a negative or consequential outcome is 
recorded for the mother or child/foetus. If the outcome meets serious criteria, this 
would be considered an SAE. Data from the Pregnancy Reporting Form of all 
pregnancies occurring in the maintenance phase will be reported as listings sorted 
by site. 
11.6 Clinical Laboratory Evaluations 
Clinical laboratory tests will be performed at baseline (either at Screening or Month 
0, taking the latest value if assessment were performed at both visits), and at each 
visit in the maintenance phase (months 4, 8, 12, 16, 20, 24, 27, 30, 36, 42 and 48). 
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in the MACRO database. Data management will ensure that any missing values are 
due to the test not being performed (“Not measured” thick-box). 
The following variables will be summarised in accordance with section 9 using the 
full analysis population. Missing values will be assumed to be “not measured” 
without cross-referencing the relevant tick-box.  
• 
Clinical Labs 
− 
Haemoglobin (g/dL) 
− 
Platelets (cells x 109/L) 
− 
WBC (cells x 109/L) 
− 
ESR (mm/h) 
− 
Creatinine (µmol/L) 
− 
CRP (mg/L) 
− 
ALT (U/L) 
− 
AST (U/L) 
• 
ANCA 
− 
Anti-PR3 (positive/negative) 
− 
Anti-MPO (positive/negative) 
− 
ANCA status – derived variable, details in section 1.1 
• 
Lymphocyte markers 
− 
CD19 (cells x 109/L and %) 
• 
Immunoglobulins 
− 
IgG (g/L)  
− 
IgM (g/L) 
− 
IgA (g/L) 
Table 8 lists the preferred unit for reporting and the multiplicative conversion factor 
(CF)27 employed for those clinical labs collected in the CRF using different 
measurement units.  
 
 
                                           
27 Conversion factors taken from http://www.scymed.com/en/smnxfd/smnxfdac.htm 


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Table 8: Conversion factors 
Variable 
Original unit 
CF 
Reporting 
unit 
Haemoglobin 
g/L 
0.1 
g/dL 
Haemoglobin 
mmol/L 
1.611344 
g/dL 
WBC 
cells x 103/mm3 
1 
cells x 109/L 
Creatinine 
g/dL 
88.42 x 103 
µmol/L 
Creatinine 
mg/dL 
88.42 
µmol/L 
CRP 
mg/dL 
10 
mg/L 
CD19 
cells x 103/mm3 
1 
cells x 109/L 
CD19 
cells/µL 
0.001 
cells x 109/L 
IgG 
mg/dL 
0.01 
g/L 
IgM 
mg/dL 
0.01 
g/L 
IgA 
mg/dL 
0.01 
g/L 
 
Laboratory values outside the ranges detailed in Table 8 will be considered un-
physiological, and will be considered outliers and excluded from the analysis. All 
such values will be listed in a separate table (grouped by item, subject, and visit) 
and queried by the data manager. 
Table 9: Physiological ranges for laboratory tests 
Variable 
Minimum 
Maximum 
Reporting unit 
Haemoglobin 
5 
20 
g/dL 
Platelets 
5 
900 
cells x 109/L 
WBC 
1 
40 
cells x 109/L 
ESR 
0 
200 
mm/h 
Creatinine 
30 
1500 
µmol/L 
CRP 
0 
600 
mg/L 
ALT 
0 
1000 
U/L 
AST 
0 
1000 
U/L 
CD19 
0 
5 
cells x 109/L 
CD19 
0 
100 
% 
IgG 
0 
25 
g/L 
IgM 
0 
8 
g/L 
IgA 
0 
8 
g/L 
 


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Values reported with a < or > sign will not be included in the analysis, except for 
measurements reported within the lower bounds specified in Table 10: these will be 
censored to “0” and included in the analysis accordingly. Excluded values will be 
listed in a separate table (grouped by item, subject, and visit). A table will report the 
number of censored values, grouped by item, subject, and visit. 
Table 10: Lower bounds of clinical labs measurements 
Variable 
Sign 
Value 
Unit 
CRP 
< 
5  
mg/L 
CD19 
< 
1  
% 
CD19 
< 
0.02  
cells x 109/L 
IgM 
< 
0.3  
g/L 
IgA 
< 
0.3 
g/L 
12 Quality of Life Analysis 
Health-related quality of life and patient-reported outcomes will be assessed using 
questionnaires. Exploratory analyses of Quality of Life data outcomes as planned in 
the protocol are to be carried out by the Cambridge team. Details are outside the 
scope of this SAP. 
12.1 EQ5D  
EQ5D is a standardised instrument for use as a measure of health outcome, 
providing a simple descriptive profile and a single index value for health status. 
The answers to each question will be reported at Month 4, 12, 24, 36, 42 and 48 
visit, using the full analysis population. EQ5Q profiles will be summarised into a 
utility score for each patient using the EQ-5D-3L Index Calculator28. Index scores 
are based on general population valuation surveys that use the TTO or VAS method 
for the UK (12). The following variables will be summarised in accordance with 
section 9: 
1. Mobility 
2. Self-Care 
3. Usual Activities 
                                           
28 https://www.economicsnetwork.ac.uk/health/EQ_5D_index_calculator.xls  


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4. Pain/Discomfort 
5. Anxiety/Depression  
6. Overall index score (TTO and VAS method) 
12.2 SF-36 questionnaire 
The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and 
easily administered quality-of-life measures. 
The answers to each question will be reported at Month 4, 12, 24, 36, 42 and 48 
visit, using the full analysis population. The SF-36 questionnaire will be scored 
according to the scoring method of the RAND 36-Item Health Survey 1.029 . All 36 
individual items of the questionnaire, as well as the total score of the following 
domains, will be will be summarised in accordance with section 9: 
1. Physical Functioning (PF) 
2. Bodily pain (BP) 
3. Role limitations due to physical health (RP) 
4. Role limitations due to emotional problems (RE) 
5. Energy/fatigue (EV) 
6. Emotional well-being (MH) 
7. Social functioning (SF) 
8. General health (GH) 
9. Change in Health (CH) 
Additionally, two distinct, higher order summary scores will be derived from the 
above domains:  
1. Physical Component Summary (PCS) 
2. Mental Component Summary (MCS) 
calculated using the subscale scoring coefficients (Table 11) and reference 
populations mean and standard deviation (PCS: 82.261 and 20.867; MCS: 63.7796 
and 19.582) employed in PEXIVAS study30. 
 
 
                                           
29 https://www.rand.org/health/surveys_tools/mos/36-item-short-form/scoring.html  
30 The scoring procedure is explained in detail in [13, 14]. 


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Table 11: factor score coefficients for PCS and MCS (14) 
Subscale 
PCS 
coefficients 
MCS 
coefficients 
Physical Functioning (PF) 
0.418 
-0.213 
Role limitations due to physical health (RP) 
0.334 
-0.087 
Bodily pain (BP) 
0.366 
-0.125 
General health (GH) 
0.222 
0.036 
Energy/fatigue (EV) 
-0.017 
0.286 
Social functioning (SF) 
-0.083 
0.201 
Role limitations due to emotional problems (RE) 
-0.179 
0.394 
Emotional well-being (MH) 
-0.200 
0.444 
Formulas to calculate the PCS and MCS scores: 
• 
For the PCS: 
AGPHYSCO=(PF*0.456)+(RP*0.362)+(BP*0.367)+(GH*0.199)+(EV*-
0.050)+(SF*-0.028)+(RE*-0.110)+(MH*-0.256) 
PCS = ((AGPHYSCO-82.261)/20.867)*10)+50 
• 
For the MSC: : AGMENTCO=(PF*-0.227)+(RP*-0.102)+(BP*-
0.130)+(GH*0.036)+(EV*0.278)+(SF*0.272)+(RE*0.329)+(MH*0.460)  
and then PCS = ((AGMENTCO -63.7796)/19.582)*10)+50 
12.3 PROMIS 
The Patient-Reported Outcomes Measurement Information System assessment 
(PROMIS) is a set of validated health-related quality of life assessments 
questionnaires covering the domains that include fatigue, physical function, pain 
and global health.  
The PROMIS questionnaire will be reported for all visits (Month 4, 8, 12, 16, 20, 24, 
27, 30, 36, 42 and 48) using the ITT population. The number of sites and 
individuals where the PROMIS questionnaire was not administered will be noted. 
Individual items as well as the following totals, will be will be summarised in 
accordance with section 9: 


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1. Fatigue 
2. Pain 
3. Physical Ability 
4. Patient’s Global Assessment 
13 Figures 
Figure 1: CONSORT diagram.  
Figure 2: Tree map of recruitment, by site and country. 
Figure 3-5: Mosaic plots of relapse type by induction regimen, ANCA type by 
induction regimen and relapse type by ANCA type. 
Figure 6: Histograms of medical history at baseline. 
Figure 7: Bar chart of Organ Systems involvement at baseline. 
Figure 8: Bar chart of disease status by treatment arm. 
Figure 9: Histograms of BVAS/WG scores by treatment arm. 
Figure 10: Histogram of CDA score at month 0 and month 4 by induction regimen 
(Induction phase)31. 
Figure 11: Bar chart of CDA Score (grouped) at month 0 and month 4 (Induction 
phase). 
Figure 12: Change in CDA Score (from baseline to month 4) (Induction phase). 
Figure 13: Histogram of CDA score by treatment arm (Maintenance phase). 
Figure 14: Bar chart of CDA score (grouped) by treatment arm (Maintenance phase). 
Figure 15: Boxplot of CDA score by treatment arm (Maintenance phase). 
Figure 16: Change in CDA Score (from month 4 to month 12) (Maintenance phase). 
Figure 17: Change in CDA Score (from month 4 to month 24) (Maintenance phase). 
Figure 18: Mosaic plot of treatment compliance (maintenance and follow up). 
Figure 19: Bar chart of treatment compliance in maintenance phase by site. 
Figure 20: Bar chart of treatment compliance in follow up phase by site. 
Figure 21: Kaplan-Meier plot of relapse-free survival by treatment arm – Primary 
endpoint. 
                                           
31 Figure 8, 9 and 10 are similar to those found in the Induction phase report but obtained 
using a different scoring system for the CDA form. The figures are offered here as a 
comparison of the two scoring systems. The maintenance phase figures use the new scoring 
system exclusively. 


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Figure 22: Kaplan-Meier plot of relapse-free survival by treatment arm and 
induction regimen – Primary endpoint. 
Figure 23: Kaplan-Meier plot of relapse-free survival by treatment arm and ANCA 
status – Primary endpoint. 
Figure 24: Kaplan-Meier plot of relapse-free survival by treatment arm and relapse 
type – Primary endpoint 
Figure 25: Forest plot of cox proportional hazards model – Primary endpoint. 
Figure 26: Kaplan-Meier plot of relapse-free survival by treatment arm – Secondary 
endpoint. 
Figure 27: Forest plot of cox proportional hazards model – Secondary endpoint. 
Figure 28: Kaplan-Meier plot of relapse-free survival by treatment arm – Tertiary 
endpoint. 
Figure 29: Forest plot of cox proportional hazards model – Tertiary endpoint. 
Figure 30: Serious Adverse Events, forest plot of frequency and relative risk by 
treatment arm. 
Figure 31: Non-serious infections, forest plot of frequency and relative risk by 
treatment arm. 
Figure 32: Kaplan-Meier plot of SAE-free survival by treatment arm. 
Figure 33-45: Boxplots by treatment arm of continuous clinical lab tests: 
  Haemoglobin, Platelets, WBC, ESR, Creatinine, CRP, ALT, AST, CD19, 
  CD19 (%), IgG, IgM, and IgA. 
Figure 46-48: Stacked bar charts by treatment arm of discrete clinical lab tests: 
 
 
  Anti-PR3, Anti-MPO, and ANCA status. 
Figure 49: Alluvial plot of ANCA status by treatment arm, showing change from 
month 4 to month 24 and to month 36. 
Figure 50: Bar charts of EQ-5D-5L questionnaire item's responses. 
Figure 51: Boxplot of EQ-5D-5L index totals (VAS Health state, OTT utility score, 
and VAS utility score) by treatment arm. 
Figure 52-54: Bar charts of PROMIS questionnaire item's responses (fatigue, pain, 
physical ability). 
Figure 55: Bar chart of PROMIS questionnaire sub-totals by treatment arm. 
Figure 56: Boxplots of PROMIS questionnaire sub-totals by treatment arm. 
Figure 57: Boxplot of PROMIS questionnaire total score by treatment arm. 
Figure 58-63: Bar charts of SF-36 questionnaire item's responses. 
Figure 64: Boxplot of SF-36 questionnaire sub-totals by treatment arm. 


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Figure 65: Boxplot of SF-36 questionnaire PCS and MCS components by treatment 
arm. 
14 Reporting Conventions 
The following conventions will be adhered to in this report: 
• 
P-values ≥0.001 will be reported to 3 decimal places; p-values less than 0.001 
will be reported as “<0.001”.  
• 
The mean, standard deviation, and any other statistics other than quantiles, will 
be reported to one decimal place greater than the original data. Quantiles, such 
as median, or minimum and maximum will use the same number of decimal 
places as the original data.  
• 
Estimated parameters, not on the same scale as raw observations (e.g. 
regression coefficients) will be reported to 3 significant figures.  
For manuscripts that use the values produced in this report, conventions detailed in 
[15] will be implemented.  
15 Technical Details 
Protocol version 4.0 (20th June 2017) was used to develop this document. No changes 
were made to the protocol during the development of this SAP.  
The software package R version 3.6.1 (2019-07-05) will be used on a Windows 
computer and copies of the code employed will be stored. Medical Dictionary for 
Regulatory Activities MedDRA 20.0 (March 2017) is used to classify SAE/AEs. 
Each report and individual table or graph will be annotated with: 
• 
Date and time stamp 
• 
Name of the code file that produced the analysis 
• 
Author 
• 
Population used 
The individual code files will have comments that convey: 
• 
Author 
• 
Date and time of writing 


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• 
Description of any revisions 
• 
Description of the inputs and outputs 
• 
Reference to any parent code file that runs the code 
The population to be used in a table or figure will be explicitly set at the start of a 
block of code that computed the output by looking up the population from the 
table of tables.  
A reviewing statistician will have an overview of the entire analyses and will 
explicitly check the code producing the efficacy analysis as well as any other pieces 
of code as desired. 
15.1 Data anomalies and corrections 
Data found in MACRO database with subject ID “CN2-004” has been excluded from 
the analysis completely. This ID was used in error for a patient later enrolled under 
ID “CN2-005”. 
For patient “US7-003” any scheduled visit information collected after the patient’s 
withdrawal from trial was removed in the analysis. The issue arose because the 
withdrawal form was handed in late by the site and the data manager, unaware, 
continued to enter data collected past this point into MACRO. This data was later 
removed from MACRO, however the empty forms and the dates of the visits 
persisted creating some confusion over the patient’s disposition. 
Two serious adverse events found in the SAE database with subject ID pre-fixed 
with “NR” have been excluded from the analysis completely. Patient ID “NR-N01-
001” denotes a patient who was enrolled in the trial but died before being 
consented, subject ID “N01-001” was later reused for a different patient. Patient ID 
“NR-NZ-001” was used for a patient who was enrolled, consented but was found to 
be ineligible, therefore removed from the trial and the database. The ID was not 
reused, as the site did not recruit further. 
16 References 
1. Watts RA, Suppiah R, Merkel PA, Luqmani R. Systemic vasculitis--is it time to 
reclassify? Rheumatology (Oxford). 2011 Apr;50(4):643-5.  
2. Falk RJ, Jennette JC. ANCA disease: where is this field heading? J Am Soc 
Nephrol. 2010 May;21(5):745-52. Epub 2010 Apr 15.  


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3. Watts RA, Scott DG. Epidemiology of the vasculitides. Curr Opin Rheumatol 
2003;15:11-16.  
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, Harper L, Jayne DR, Flores Suarez LF, Gregorini G, Gross WL, 
Luqmani R, Pusey CD, Rasmussen N, Sinico RA, Tesar V, Vanhille P, Westman K, 
Savage CO; EUVAS (European Vasculitis Study Group). Pulse versus daily oral 
cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-
associated vasculitis: a randomized trial. Ann Intern Med. 2009 May 
19;150(10):670-80.  
7. DeGroot K, Rasmussen N, Bacon PA, Tervaert JW, Feighery C, Gregorini G, et al. 
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Statistical Analysis Plan 
RITAZAREM 
Maintenance Phase 
SAP version v2.0: RITAZAREM 
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17 Listing of Tables, Listings and Figures 
 
A listing of tables and figures included in the report can be found in the following 
document: 
 
meta_table.csv (Command Line)