Biologics in Refractory Vasculitis (BIOVAS): A Pragmatic, Randomised, Double-blind, Placebo-controlled, Modified-crossover Trial of Biologic Therapy for Refractory Primary Non-ANCA Associated Vasculitis in Adults and Children
Phase: PHASE2
Conditions: Giant Cell Arteritis, Takayasu Arteritis, Cogan Syndrome, Relapsing Polychondritis, Cryoglobulinemic Vasculitis, IgA Vasculitis, Polyarteritis Nodosa, Cutaneous Polyarteritis Nodosa, Primary Angiitis of Central Nervous System
Sponsor: Cambridge University Hospitals NHS Foundation Trust

1 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
 
 
 Clinical Trial Protocol 
 
 
Trial Title: 
Biologics in refractory vasculitis (BIOVAS): A pragmatic, randomised, double-
blind, placebo-controlled, modified-crossover trial of biologic therapy for 
refractory primary non-ANCA associated vasculitis in adults and children 
 
Protocol Number: 
BIOVAS 
 
EudraCT Number: 
2019-003964-30 
 
Investigational Products: 
Infliximab, rituximab and tocilizumab 
 
 
Protocol Version:  
4.0 
 
 
 
Chief Investigator: 
Professor David Jayne 
CI Address: 
Vasculitis Research Office, Box 246, Addenbrooke’s Hospital, Hills Road, 
Cambridge, CB2 0QQ, United Kingdom 
Telephone: 
01223 748062 
 
Trial Sponsor: 
Cambridge University Hospitals NHS Foundation Trust and University of 
Cambridge  
 
SAE Reporting: 
Dr David Jayne, BIOVAS Chief Investigator, or 
Maria King, BIOVAS Trial Coordinator 
Vasculitis & Lupus Research Group 
Box 157, Department of Medicine 
Addenbrooke’s Hospital  
Hills Road 
Cambridge, CB2 0QQ,  
 
 
United Kingdom 
Telephone: 01223 768317 
Email: add-tr.biovas@nhs.net 

2 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
 
 
1. Protocol Signatures: 
I give my approval for the attached protocol entitled “Biologics in refractory vasculitis (BIOVAS): A 
pragmatic, randomised, double-blind, placebo-controlled, modified-crossover trial of biologic therapy for 
refractory primary non-ANCA associated vasculitis in adults and children” Version 4.0 dated 17th 
November 2021 
Chief Investigator 
 
Name:  David Jayne 
 
 
Signature: 
 
 
Date: 12/01/2022 
 
Site Signatures 
 
I have read the attached protocol entitled “Biologics in refractory vasculitis (BIOVAS): A pragmatic, 
randomised, double-blind, placebo-controlled, modified-crossover trial of biologic therapy for refractory 
primary non-ANCA associated vasculitis in adults and children” Version 4.0, dated 17th November 2021,  
and agree to abide by all provisions set forth therein. 
 
I agree to comply with the conditions and principles of Good Clinical Practice as outlined in the European 
Clinical Trials Directives 2001/20/EC and 2005/28/EC, the Medicines for Human Use (Clinical Trials) 
Regulations 2004 (SI 2004/1031) and any subsequent amendments of the clinical trial regulations, the 
Sponsor’s SOPs, and other regulatory requirements as amended. 
 
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 
 
Principal Investigator 
 
Name:  David Jayne 
 
Signature: 
 
 
Date: 19/04/2022 
 
 
 
 

3 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
 
2. Trial Management Committee(s) and Protocol Contributors 
 
David Jayne 
Chief Investigator, Cambridge 
Pani Gopaluni  
TMG member, Cambridge 
Hiba Mohamed 
Trial Physician, Cambridge 
Maria King 
Trial Coordinator, Cambridge 
Lynne Whitehead  
Trial Pharmacist, Cambridge 
 
 
Neil Basu 
Collaborator, Glasgow 
Paul Brogan 
Collaborator, London 
David D’Cruz 
Collaborator, London 
Despina Eleftheriou 
Collaborator, London 
Bridget Griffiths 
Collaborator, Newcastle 
Peter Lanyon 
 
Collaborator, Nottingham 
Raashid Luqmani 
Collaborator, Oxford 
Justin Mason 
Collaborator, London 
John Mills 
Patient Representative, Derby 
Ann Morgan 
Collaborator, Leeds 
Joanna Robson 
Collaborator Bristol 
 
 
Theophile Bigirumurame 
Statistician, Newcastle 
Thomas Jaki 
Statistician, Lancaster 
James Wason 
Statistician, Newcastle 
 
 
Gurdeep Sagoo 
Health Economist, Leeds 
 
 
Richard Watts 
DMC Chair, Norwich 
Jane Holmes 
DMC Member, Oxford 
MIchael Ehrenstein 
DMC Member, London 
 
 
Hector Chinnoy 
TSC Chair, Manchester 
David Carruthers 
TSC Member, Birmingham 
Lesley Noblett 
TSC Member, Cambridge 
Christian Pagnoux 
TSC Member, Toronto 

4 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
Table of Contents 
 
Clinical Trial Protocol .........................................................................................................................1 
1. 
Protocol Signatures: ...................................................................................................................2 
Site Signatures .......................................................................................................................................... 2 
2. 
Trial Management Committee(s) and Protocol Contributors........................................................3 
3. 
Abbreviations ............................................................................................................................8 
4. 
Trial Synopsis ........................................................................................................................... 11 
5. 
Trial Flow Chart ........................................................................................................................ 18 
6. 
Introduction ............................................................................................................................ 19 
6.1. 
Background ................................................................................................................................ 19 
6.2. 
Clinical Data ............................................................................................................................... 20 
6.2.1. 
Efficacy .............................................................................................................................. 20 
6.2.2. 
  Safety and tolerability ..................................................................................................... 21 
6.2.3. 
Pharmacokinetics & pharmacodynamics .......................................................................... 21 
7. 
Rationale for Trial .................................................................................................................... 21 
8. 
Trial Design .............................................................................................................................. 22 
8.1. 
Statement of Design .................................................................................................................. 22 
8.2. 
Number of Centres .................................................................................................................... 22 
8.3. 
Number of Participants ............................................................................................................. 22 
8.4. 
Participants Trial Duration ......................................................................................................... 23 
8.5. 
Trial Objectives .......................................................................................................................... 23 
8.5.1. 
Primary objective .............................................................................................................. 23 
8.5.2. 
 Secondary objectives ....................................................................................................... 23 
8.6. 
Trial Outcome Measures ........................................................................................................... 23 
9. 
Selection and withdrawal of participants .................................................................................. 25 
9.1. 
Inclusion Criteria ........................................................................................................................ 25 
9.2. 
Exclusion Criteria ....................................................................................................................... 25 
9.3. 
      Treatment Assignment and Randomisation Number .......................................................... 26 
9.4. 
Method of Blinding .................................................................................................................... 26 
9.5. 
 Participant Withdrawal Criteria ................................................................................................ 28 
9.5.1. 
Withdrawal from protocol treatment............................................................................... 28 
9.5.2. 
Withdrawal of consent ..................................................................................................... 29 
10. 
 Trial Treatments .................................................................................................................. 29 
10.1. 
Treatment Summary .................................................................................................................. 29 
10.1.1. 
Infliximab .......................................................................................................................... 30 
10.1.1.1. 
Legal Status .............................................................................................................. 30 
10.1.1.2. 
Supply ....................................................................................................................... 30 
10.1.1.3. 
Packing and Labelling ............................................................................................... 30 
10.1.1.4. 
Storage Conditions ................................................................................................... 30 
10.1.1.5. 
Maximum duration of treatment of a participant ................................................... 30 
10.1.1.6. 
Dose .......................................................................................................................... 30 
10.1.1.7. 
Administration.......................................................................................................... 31 
10.1.1.8. 
Known drug reactions .............................................................................................. 31 
10.1.1.9. 
Dose modifications ................................................................................................... 31 
10.1.1.10. 
Procedures for monitoring treatment compliance .................................................. 31 
10.1.1.11. 
Placebo for infliximab............................................................................................... 31 
10.1.2. 
Rituximab .......................................................................................................................... 31 
10.1.2.1. 
Legal status ............................................................................................................... 31 
10.1.2.2. 
Supply ....................................................................................................................... 31 
10.1.2.3. 
Packing and Labelling ............................................................................................... 31 
10.1.2.4. 
Storage conditions ................................................................................................... 31 

5 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
10.1.2.5. 
Maximum duration of treatment of a participant ................................................... 31 
10.1.2.6. 
Dose .......................................................................................................................... 32 
10.1.2.7. 
Administration.......................................................................................................... 32 
10.1.2.8. 
Known drug reactions .............................................................................................. 32 
10.1.2.9. 
Dose modifications ................................................................................................... 32 
10.1.2.10. 
Procedures for monitoring treatment compliance .................................................. 32 
10.1.2.11. 
Placebo/Active comparator products ...................................................................... 32 
10.1.3. 
Tocilizumab ....................................................................................................................... 32 
10.1.3.1. 
Legal status ............................................................................................................... 32 
10.1.3.2. 
Supply ....................................................................................................................... 32 
10.1.3.3. 
Packing and Labelling ............................................................................................... 33 
10.1.3.4. 
Storage conditions ................................................................................................... 33 
10.1.3.5. 
Maximum duration of treatment of a participant ................................................... 33 
10.1.3.6. 
Dose .......................................................................................................................... 33 
10.1.3.7. 
Administration.......................................................................................................... 33 
10.1.3.8. 
Known drug reactions .............................................................................................. 33 
10.1.3.9. 
Dose modifications ................................................................................................... 33 
10.1.3.10. 
Procedures for monitoring treatment compliance .................................................. 34 
10.1.3.11. 
Placebo for tocilizumab ............................................................................................ 34 
10.2 
Non Investigational Medicinal Products .................................................................................... 34 
10.2.1 
Glucocorticoids ................................................................................................................. 34 
10.3 
Treatment of relapse ................................................................................................................. 35 
10.3.1 
Minor Relapse ................................................................................................................... 35 
10.3.2 
Major Relapse ................................................................................................................... 35 
10.4 
Concomitant Therapy ................................................................................................................ 35 
10.5 
Emergency unblinding ............................................................................................................... 35 
10.6 
Accountability and dispensing ................................................................................................... 36 
10.6.1 
Drug accountability ........................................................................................................... 36 
10.6.2 
Returns and destruction ................................................................................................... 36 
11 
Procedures and assessments .................................................................................................... 36 
11.1 
Participant identification ........................................................................................................... 36 
11.2 
Consent ...................................................................................................................................... 37 
11.3 
Screening evaluation ................................................................................................................. 37 
11.3.1 
Screening Assessments ..................................................................................................... 37 
11.3.2 
Participant Registration/Randomisation .......................................................................... 38 
11.4 
Treatment Period ...................................................................................................................... 38 
11.4.1 
Clinic Visits ........................................................................................................................ 38 
11.4.3 
IMP Visits .......................................................................................................................... 39 
11.4.4. 
Safety monitoring visits .................................................................................................... 40 
11.5 
Trial assessments ....................................................................................................................... 40 
11.5.1 
Timing of assessments ...................................................................................................... 40 
11.6 
Trial clinic visit Schedule of Events (SoE) ................................................................................... 41 
11.7 
IMP Schedule of Events (SoE) .................................................................................................... 42 
11.8 
End of Trial Participation ........................................................................................................... 43 
11.9 
Trial restrictions ......................................................................................................................... 43 
12 
Assessment of Safety ............................................................................................................... 43 
12.1 
Definitions ................................................................................................................................. 43 
12.1.1 
Adverse event (AE) ............................................................................................................ 43 
12.1.2 
Adverse reaction to an investigational medicinal product (AR) ....................................... 44 
12.1.3 
Unexpected adverse reaction ........................................................................................... 44 
12.1.4 
Serious adverse event or serious adverse reaction (SAE / SAR) ....................................... 44 
12.1.5 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ............................................. 44 

6 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
12.1.6 
Reference Safety Information (RSI) .................................................................................. 44 
12.2 
Expected Adverse Reactions/Serious Adverse Reactions (AR /SARs) ....................................... 45 
12.3 
Expected Adverse Events/Serious Adverse Events (AE/SAE) .................................................... 45 
12.4 
Pregnancy Reporting ................................................................................................................. 45 
12.5 
Evaluation of adverse events..................................................................................................... 45 
12.5.1 
Assessment of seriousness ............................................................................................... 45 
12.5.2 
Assessment of causality .................................................................................................... 46 
12.5.3 
Clinical assessment of severity ......................................................................................... 46 
12.5.4 
Recording of adverse events ............................................................................................. 46 
12.6 
Reporting serious adverse events ............................................................................................. 46 
12.7 
Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) .............................. 47 
12.7.1 
Who should report and whom to report to? .................................................................... 47 
12.7.2 
When to report? ............................................................................................................... 47 
12.7.2.1 
Fatal or life-threatening SUSARs .................................................................................. 47 
12.7.2.2 
Non-fatal and non-life-threatening SUSARs ................................................................. 47 
12.7.3 
How to report?.................................................................................................................. 47 
12.7.3.1 
Minimum criteria for initial expedited reporting of SUSARs ........................................ 47 
12.7.3.2 
Follow-up reports of SUSARs ........................................................................................ 48 
12.7.3.3 
Format of the SUSARs reports ...................................................................................... 48 
13 
Toxicity – Emergency Procedures ............................................................................................. 48 
14 
Evaluation of Results (Definitions and response/evaluation of outcome measures) ................... 48 
14.1 
Response criteria ....................................................................................................................... 48 
14.1.1 
Time to treatment failure ................................................................................................. 48 
Storage and Analysis of Samples ...................................................................................................... 49 
15 
Statistics .................................................................................................................................. 49 
15.1 
Statistical methods .................................................................................................................... 49 
15.2 
Interim analyses......................................................................................................................... 50 
15.3 
Number of Participants to be enrolled ...................................................................................... 50 
15.3.1 
Sample size determination ............................................................................................... 50 
15.4 
Criteria for the premature termination of the trial ................................................................... 52 
15.5 
Procedure to account for missing or spurious data .................................................................. 53 
15.6 
Economic evaluation ................................................................................................................. 53 
15.6.1 
Data Collection .................................................................................................................. 53 
15.6.2 
Within trial cost effectiveness analysis ............................................................................. 53 
15.6.3 
Modelling long-term cost effectiveness ........................................................................... 54 
15.7 
Definition of the end of the trial................................................................................................ 54 
16 
Data handling and record keeping ............................................................................................ 55 
16.1 
CRF ............................................................................................................................................. 55 
16.2 
Source Data ............................................................................................................................... 55 
16.3 
Data Protection & Participant Confidentiality ........................................................................... 55 
17 
Data Monitoring Committee/Trial Steering Committee ............................................................. 55 
17.1 
Independent Data Monitoring Committee................................................................................ 56 
17.2 
Trial Steering Committee (TSC) ................................................................................................. 56 
17.3 
Trial Management Group (TMG) ............................................................................................... 56 
18 
Ethical & Regulatory considerations ......................................................................................... 56 
18.1 
Ethical committee review .......................................................................................................... 56 
18.2 
Regulatory Compliance .............................................................................................................. 56 
18.3 
Protocol Amendments ............................................................................................................... 56 
18.4 
Peer Review ............................................................................................................................... 57 
18.5 
Declaration of Helsinki and Good Clinical Practice .................................................................... 57 
18.6 
GCP Training .............................................................................................................................. 57 
19 
Sponsorship, Financial and Insurance ....................................................................................... 57 

7 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
20 
Monitoring, Audit & Inspection ................................................................................................ 57 
21 
Protocol Compliance and Breaches of GCP ................................................................................ 58 
22 
Publications policy ................................................................................................................... 58 
23 
References ............................................................................................................................... 58 
24 
Appendices .............................................................................................................................. 60 
24.1 
Appendix 1 - Trial Management / Responsibilities .................................................................... 60 
24.1.1 
Participant registration/ Randomisation procedure ........................................................ 60 
24.1.2 
CRF Completion & Data management .............................................................................. 60 
24.1.3 
Preparation & submission of amendments ...................................................................... 60 
24.1.4 
Preparation and submission of Annual Safety Report/Annual Progress Reports ............ 60 
24.1.5 
Data protection/ confidentiality ....................................................................................... 60 
24.1.6 
Trial documentation & archiving ...................................................................................... 60 
24.2 
Appendix 2 – Authorisation of Participating Sites ..................................................................... 61 
24.2.1 
Required Documentation ................................................................................................. 61 
24.2.2 
Procedure for initiating/opening a new site ..................................................................... 61 
24.2.3 
Principal Investigator Responsibilities .............................................................................. 61 
24.3 
Appendix 3 - Safety Reporting Flow Chart................................................................................. 62 
24.4 
Appendix 4 – NAAV Classification Criteria ................................................................................. 63 
24.5 
Appendix 5: Steroid weaning templates ................................................................................... 66 
 

8 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
3. Abbreviations 
Ab 
Antibody 
ACR 
American College of Rheumatology 
 
ADR 
Adverse Drug Reaction 
AE/AR 
Adverse event/Adverse Reaction 
AESIs 
Adverse Events of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCA 
Antineutrophil cytoplasmic antibody 
BVAS 
Birmingham Vasculitis Activity Score 
BVAS-BIOVAS 
Birmingham Vasculitis Activity Score modified for BIOVAS 
CCTU 
Cambridge Clinical Trials Unit 
CA 
Competent Authority 
CHCC 2012 
Chapel Hill Consensus Conference 2012 
CHF 
Congestive Heart Failure 
CHU-9D 
Child Health Utility 9D Index 
CNS 
Central Nervous System 
CPAN 
Cutaneous polyarteritis nodosa 
CRF 
Case Report Form 
CRP 
C-reactive Protein 
CSS 
Churg-Strauss syndrome 
CTA 
Clinical Trial Authorisation 
CTIMP 
Clinical Trial of Investigational Medicinal Product 
 
CYP 
Cytochrome P450 
DADA2 
Deficiency of adenosine deaminase type 2 
DMC 
Data Monitoring Committee 
DSUR 
Development Safety Update Report 
eCRF 
Electronic Case Report Form 
EMA 
European Medicines Agency 
EoT 
End of Trial 
EQ-5D-5L 
EuroQol five-dimension scale 
ESR 
Erythrocyte Sedimentation Rate 
EULAR 
European League Against Rheumatism 
EUVAS 
European Vasculitis Study Group 
FBC 
Full Blood Count 
FDA 
Food and Drug Administration 
GCA 
Giant Cell Arteritis 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation  
GIACTA 
An Efficacy and Safety Study of Tocilizumab (RoActemra/Actemra) in 
Participants with Giant Cell Arteritis 
GP 
General Practitioner 
HACA 
Human anti-mouse antibody  
HAMA 
Human anti-chimeric antibody 
HB 
Hepatitis B 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
HRA 
Health Research Authority 
HSTCL 
Hepatosplenic T-Cell Lymphoma 

9 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
HTA 
Health Technology Assessment 
ICER 
Incremental cost effectiveness ratio  
ICF 
Informed Consent Form 
IgA 
Immunoglobulin A 
IgAV 
IgA vasculitis 
IgG 
Immunoglobulin G 
IL-1 
Interleukin 1 
IL-6 
Interleukin 6 
IL6-R 
Interleukin 6-receptor 
IMP 
Investigational Medicinal Product 
INF 
Infliximab 
INF-PBO 
Infliximab placebo 
ISF 
Investigator Site File 
ITAS 
Indian Takayasu’s Arteritis Activity Score 
IUD 
Intrauterine Device 
IV 
Intravenous 
JIA 
Juvenile Idiopathic Arthritis 
LFT 
Liver Function Tests 
LVV 
Large Vessel Vasculitis 
MHRA 
Medicines and Healthcare products Regulatory Agency  
MPA 
Microscopic Polyangiitis 
MPO 
Myeloperoxidase  
MRA 
Magnetic Resonance Angiography 
MTX 
Methotrexate 
NAAV 
Non-ANCA associated vasculitis 
NHS 
National Health Service 
NICE 
The National institute for Health and Care Excellence 
NIH 
National Institutes of Health 
NIHR 
National Institute for Health Research 
NIMP 
Non Investigational Medicinal Product 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
PACNS 
Primary angiitis of the central nervous system 
PAN 
Polyarteritis Nodosa 
PBO 
Placebo 
PET 
Positron Emission Tomography 
PGA 
Physician’s Global Assessment 
PI 
Principal Investigator 
PIS 
Participant Information Sheet  
PMR 
Polymyalgia rheumatica 
PR3 
Proteinase 3 
PRES 
Posterior reversible encephalopathy syndrome  
PRINTO 
The Paediatric Rheumatology International Trials Organisation 
PSV 
Primary Systemic Vasculitis 
PVAS 
Paediatric Vasculitis Activity Score 
PVDI 
Paediatric Vasculitis Damage Index 
QALYs 
Quality-adjusted life year  
QoL 
Quality of Life 
R&D 
Research and Development 
RA 
Regulatory Agency 
REC 
Research Ethics Committee 
RP 
Relapsing Polychondritis 

10 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
RPDAI 
Relapsing Polychondritis Disease Activity Index 
RSI 
Reference Safety Information 
RTX 
Rituximab 
RTX-PBO 
Rituximab placebo 
SAE/SAR 
Serious Adverse Event/Serious Adverse Reaction 
SAP 
Statistical Analysis Plan 
SmPC 
Summary of Product Characteristics 
SoE 
Schedule of Events 
SUSAR 
Suspected unexpected serious adverse reaction 
TA 
Takayasu’s Arteritis 
TARGET  
Treatment according to Response in Giant Cell Arteritis 
TB 
Tuberculosis 
TCZ 
Tocilizumab 
TCZ-PBO 
Tocilizumab placebo 
TMF 
Trials Master Folder 
TMG 
Trial Management Group 
TNF 
Tumour Necrosis Factor 
TSC 
Trial Steering Committee 
TTF 
Time to Treatment Failure 
UKGCA 
UK Giant Cell Arteritis 
VDI 
Vasculitis Damage Index 
WG 
Wegener's Granulomatosis 
 
 
 

11 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
4. Trial Synopsis 
 
Title of clinical trial 
Biologics in refractory vasculitis (BIOVAS): A pragmatic, randomised, 
double-blind, placebo-controlled, modified-crossover trial of biologic 
therapy for refractory primary non-ANCA associated vasculitis in adults 
and children 
Sponsor name 
Cambridge University Hospitals NHS Foundation Trust and the 
University of Cambridge 
EudraCT  number  
2019-003964-30 
 
Purpose of the clinical 
trial 
To establish the evidence for clinical and cost effectiveness of three 
biologics in comparison to placebo in the treatment of refractory 
primary non-ANCA Associated Vasculitis (NAAV) 
Trial Design  
A pragmatic, randomised, double-blind, placebo-controlled, modified-
crossover phase 2B trial of biologic therapy for refractory primary 
NAAV in adults and children 
Medical condition or 
disease under 
investigation 
The 8 NAAV diseases listed below will be included in the trial. These will 
be grouped together and henceforth referred to as primary group. 
1. Giant cell arteritis (GCA) 
2. Takayasu’s arteritis (TA) 
3. Polyarteritis nodosa (PAN) or cutaneous polyarteritis (CPAN) 
unrelated to hepatitis B  
4. Relapsing polychondritis (RP) 
5. IgA vasculitis (IgAV) 
6. Cogan’s syndrome 
7. Non-infective cryoglobulinaemia 
8. Primary angiitis of central nervous system (PACNS) 
 
* All analyses (other than secondary Bayesian analysis) will be conducted on the 
primary group. For Bayesian analyses the primary group will be divided into 2 sub-
groups: Group 1 (GCA and TA) and Group 2 (PAN, CPAN, RP, IgAV, Cogan’s syndrome, 
non-infective cryoglobulinaemia, PACNS). 
Primary objective 
To determine the clinical efficacy of each of the 3 IMPs in comparison 
to placebo in the treatment of refractory NAAV as 1 disease group 
(primary group) 
Secondary objectives 
1. To assess the clinical efficacy of each of the three IMPs 
compared to placebo using Bayesian hierarchical analyses for 
2 groups: Group 1 (GCA & TA) and Group 2 (PAN, CPAN, RP, IgAV, 
Cogan’s syndrome, non-infective cryoglobulinaemia, PACNS)  
2. To assess the clinical efficacy of each of the 3 IMPs compared 
to placebo for each of the 8 NAAV diseases  
3. To assess the safety of each of the 3 IMPs compared to placebo   
4. To assess the safety and risks associated with sequential use of 
different IMPs 
5. To assess the cost-effectiveness of each of the 3 IMPs 
compared to placebo  
6. To compare the clinical and cost-effectiveness of each IMP 
compared to other IMPs in the primary group  
 
Trial Outcome 
Measures 
Primary outcome measures:  
Primary outcome is time to treatment failure (TTF). 

12 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
      
TTF for each IMP is the time from the start of IMP treatment, to 
treatment failure (see definitions below) or the end of trial 
participation (censored).  
 
Primary treatment failure is progressive disease (defined by 
appearance of ≥1 new/worse severe or ≥3 new/worse non-severe 
items) on Birmingham vasculitis activity score (BVAS) v3 modified for 
BIOVAS (BVAS v3-BIOVAS) or paediatric vasculitis activity score (PVAS) 
within 120 days from the time of IMP commencement; or failure to 
achieve clinical response (see definitions below) by 120 days from the 
time of IMP commencement. In such cases, TTF will be recorded as 
zero.  
 
Secondary treatment failure is defined as having achieved response  
(definition below) by 120 days from the time of IMP commencement, 
and subsequently relapse after 120 days from IMP commencement.       
      
If an adverse reaction to an IMP precludes the participant from 
receiving further doses of the trial drug, this will also be considered  
treatment failure. 
 
The primary outcome for each active IMP is pooled across all 
participants in the primary group and compared against placebo. 
 
Response is defined by: 
 
Absence 
of 
new/worse 
BVAS 
v3-BIOVAS 
(adults)/PVAS(children) items assessed at each 120 day 
evaluation time point after commencing IMP AND 
 
Prednisolone  ≤10mg/day or   ≤0.2mg/kg for children 
(whichever is lower) unless baseline dose is   <10mg/day for 
adults or  <0.2mg/kg for children (whichever is lower) in which 
case it should not be more than the baseline dose*  
*where baseline dose is the dose of oral prednisolone (mg/day), or 
equivalent oral steroid, averaged over the 7 days prior to the start 
of each new IMP. 
 
      
 
Relapse is defined by either: 
 
Appearance of ≥ 1 severe (new/worse) or ≥ 3 non-severe 
(new/worse) BVAS v3-BIOVAS/PVAS items from the time of 
BVAS response (as defined above) assessed at the 120 day 
evaluation time points# OR  
 
The need to increase the dose of prednisolone to > 
20mg/day to treat vasculitis OR 
 
The need to increase the dose of an immunomodulator or 
immune-suppressive therapy in order to treat vasculitis 
 

13 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
# Non-severe items can be upgraded by the investigator to severe based 
on their potential clinical impact, e.g. headache in GCA, thus could 
meet failure criteria if only one or two items are present.       
       
For an increase in 1 or 2 non-severe new/worse BVAS-BIOVAS/PVAS 
items which does not meet the relapse definition, the current IMP is 
continued and the participant may be treated, at the physician’s 
discretion, with a prednisolone dose increase to no more than 
20mg/day (or 0.3mg/kg but no more than 20mg/day in children) which 
will be reduced to the previous dose within next 6 weeks. 
 
Secondary outcome measures:  
1. Bayesian hierarchical analysis to assess treatment effects of 
each of the IMPs compared to placebo and each IMP against 
other IMPs in 2 NAAV sub-groups: large vessel vasculitis 
(GCA/TA) and all other NAAV subgroups enrolled in the trial. 
2. Proportion of participants achieving response at the 120 day 
evaluation time point after the start of each IMP. 
3. Proportion of participants achieving response at every 120 day 
evaluation time point defined by a BVAS v3-BIOVAS/ PVAS of ≤ 
1 non-severe (no new/worse) item, prednisolone dose ≤ 50% 
of the dose at the start of the IMP treatment and ≤ 10mg/day 
(0.2 mg/kg/day for children, whichever is lower) and an ESR < 
30mm/hr or CRP <10 mg/L   
4. Increase in disease related damage measured by VDI/PVDI 
from start to end of an IMP  treatment   
5. Physician’s global assessment (PGA) (Likert scale 0-10) at every 
120 day evaluation time point from the time of IMP 
commencement 
6. Serious adverse events/adverse events of special interests 
(SAEs/AESIs) 
7. EQ-5D-5L or Child Health Utility (CHU9D) assessments at every 
120 day evaluation time point  
8. NHS resource use and out of pocket costs and lost productivity 
Randomisation: 
After obtaining consent and establishing eligibility, participants are 
randomised      to a fixed sequence of 4 trial IMPs. Each sequence will 
consist of 3 active IMP treatments and a placebo. The order of the IMPs 
in each sequence will be randomly allocated (e.g. RTX-INF-TCZ-PBO or 
INF-PBO-RTX-TCZ) from a list of 24 permutations. Further, the placebo 
in each sequence will be randomly allocated to mirror the drug 
administration schedule of 1 of the active IMPs in order to maintain the 
blind. Of the 72 different permutations possible, the 36 sequences that 
lead to unblinding will be excluded. Participants with a pre-trial history 
of failure/contraindication to 1 biologic IMP will have that failed IMP 
removed from their allocated sequence and will be randomised to a 
reduced number of  IMPs. Participants that have previously failed two 
or more active trial IMPs will not be eligible to enter the trial. 
Modified crossover 
design 
Participants responding to an IMP by the next evaluation will continue 
the same IMP until relapse or to the end of trial participation. At non-
response (primary failure) or relapse (secondary failure), participants 
will progress to the next IMP in the sequence only at defined time 

14 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
points of 120, 240, 360, 480 and 600 days  from the time of first IMP 
commencement.  
In the exceptional circumstance of an IMP not being available due to a 
general hospital stock issue, moving to the next intervention 
(IMP/placebo) in the randomised sequence is allowed after discussion 
with the CI. 
Double blind 
Participants and investigators are blinded to active-vs-placebo IMP 
treatment allocation in each block of randomised sequence. The 
central coordinator and local trial pharmacy will be unblinded to 
facilitate logistics of drug preparation, administration and to minimise 
participant risk. 
Sample Size 
A total of 140 participants (adults and children) with refractory NAAV 
will be randomised to this trial. 
Summary of eligibility 
criteria 
 
Inclusion Criteria: 
1. Aged at least 5 years  
2. Have given, or their parent/ legal guardian aged ≥ 16 years old 
has given, written informed consent 
3. Diagnosis of NAAV (Appendix 4) 
4. Refractory disease defined by:  
a) Active disease, BVASv3-BIOVAS/ PVAS with ≥ 1 severe 
(new/worse) or ≥ 3 non-severe (new/worse) items 
despite 12 weeks of conventional therapy prior to 
screening visit  OR 
b) Inability to reduce prednisolone below 15mg/day or 
(0.2mg/kg/day in case of children) without relapse in 
the 12 weeks prior to screening visit 
      
Exclusion Criteria: 
1. Previous treatment failure/contraindication to ≥ 2 active trial 
IMPs 
2. Increase 
in 
the 
dose 
or 
frequency 
of 
background 
immunosuppressive (e.g. methotrexate) or anti-cytokine 
therapy within 30 days of  screening visit 
3. Use of intravenous immunoglobulins within 30 days (unless 
required 
clinically 
for 
immunodeficiency), 
or 
cyclophosphamide or lymphocyte depleting biologic (e.g. 
rituximab) within 6 months of  initiating trial treatment 
4. Concomitant use of any biologic and/or anti-TNF agent other 
than the trial IMPs during the trial period 
5. Have an active systemic bacterial, viral or fungal infection, or 
tuberculosis 
6. Hepatitis B (HB) core antibody (Ab) or HB surface antigen 
positive or hepatitis C antibody positive or human 
immunodeficiency virus (HIV) antibody test positive  
7. History of malignancy within five years prior to screening visit 
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 

15 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
8. Pregnant or breastfeeding, or inability/unwillingness to use a 
highly effective method of contraceptive if a woman of 
childbearing potential (WOCBP;see section 11.9) 
9. Severe disease, which in the opinion of the physician prevents 
randomisation to placebo 
10. Recent or upcoming major surgery within 45 days of screening 
visit 
11. Leukocyte count  < 3.5 x 109 cells/l, platelet count  < 100 x 109 
cells/l, neutrophil count of < 2 x 109 cells/l      
12. ALT or AST > 3 times the upper limit of normal 
13. Symptomatic congestive heart failure (NYHA class III/IV) 
requiring prescription medication within 90 days of  screening 
visit      
14. Demyelinating disorders 
15. History or presence of any medical condition or disease which, 
in the opinion of the Investigator, may place the participant at 
unacceptable risk because of trial participation      
16. Administration of live or live attenuated vaccines within 45 
days of screening 
17. Have received an investigational medicinal product (IMP) 
within 5 half-lives or 30 days prior to screening  
18. Diagnosis of adenosine deaminase type 2 (DADA2) 
19. Hypersensitivity to the active IMP substance or to any of the 
formulation excipients 
 
Investigational 
medicinal products  
being studied 
1. Infliximab (INF) – anti-tumour necrosis factor (TNF) agent 
2. Rituximab (RTX) – B cell depleting agent 
3. Tocilizumab (TCZ) – anti-interleukin 6-receptor (IL6-R) agent 
Each IMP will be individually compared to placebo (PBO).  
Investigational 
medicinal product and 
dosage 
All IMPs will be administered intravenously. Bio-similar agents are 
permitted.      
1. Infliximab 5mg/kg on days 1, 15(+/- 3d), 43 (+/-3d), 70 (+/-3d) 
then every 56 days (+/-14d) thereafter. 
2. Rituximab 1g on IMP Days 1, 15 (+/-3d), 180 (+/-14d), 360 (+/-
14d) and 540 (+/-14d). (Children, 750mg/m2/dose, maximum 1 
g per dose). 
3. Tocilizumab 8mg/kg (maximum 800mg) every 30 days (+/- 7d); 
10 mg/kg (maximum 800 mg) for children < 30 kg.  
In the case of a known contraindication to/failure of a trial IMP, that 
particular drug will not be included in the sequence generation at the 
time of randomisation. 
 
Comparator product  
One of the agents in the sequence will be a placebo (Sodium Chloride 
0.9%), the dosing schedule of which will be randomly allocated to match 
one of the other active IMP in the sequence in order to maintain the 
blind. A minimum washout period of 30 days is mandatory between two 
interventions. 
NIMPs  
Steroids. Prednisolone dose before entry or during relapse waiting for 

16 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
the next IMP initiation is unrestricted. Once on an IMP treatment, 
physicians are recommended to reduce the steroid dose as per best 
medical practice. Recommended dose weaning templates provided in 
appendix 5.  
Route(s) of 
administration  
Infliximab, rituximab, tocilizumab and matched placebo will be 
administered intravenously 
Maximum duration of 
treatment of a 
participant  
Screening period: up to 28 days 
Treatment period: 720 days 
 
Procedures: 
Screening & enrolment 
IMP will be administered within 28 days of the start of the screening 
period once eligibility has been confirmed and randomisation 
performed. 
1. Clinical evaluation of participants by trial investigators to 
ensure the participants meet all of the inclusion criteria and 
none of the exclusion criteria 
2. Screening laboratory  
3. Serum pregnancy test  
Procedures:  
Baseline 
 
Baseline procedures can be conducted during the screening period 
once eligibility confirmed, or on the day of first IMP administration.  
1. Clinical assessment of disease activity  
2. BVAS-BIOVAS or PVAS (and Indian Takayasu Clinical Activity 
Score (ITAS)/ Relapsing polychondritis disease activity index 
(RPDAI) where applicable) 
3. Damage assessment (VDI or PVDI) 
4. PGA 
5. EQ-5D-5L/ Child Health Utility (CHU9D) 
6. Health resource use 
7. Concomitant medications 
8. Baseline blood tests  
9. Steroid review  
Procedures: 
Treatment period 
 
Each participant is assessed every 120 days +/-14 days (Days 120, 240, 
360, 480, 600 and 720) to establish response to therapy. Additional 
unscheduled visits may also occur to capture relapse data. The 
following procedures will take place at each visit during the course of 
treatment phase 
1. Clinical assessment of disease activity 
2. BVAS-BIOVAS/PVAS (and ITAS or RPDAI where applicable) 
3. Damage assessment VDI/PVDI 
4. PGA 
5. EQ-5D/ CHU9D 
6. Health resource use 
7. Concomitant medications 
8. Blood tests  
9. Patient steroid diary review 
10. Safety review 
11. Urine pregnancy test (as part of monthly safety monitoring) IMPs 
are administered as detailed above. 
as above Procedures:  
End of trial 
The trial will end when the last participant has completed their day 
720 trial clinic visit.  
Procedures for safety 
monitoring during trial 
Monthly safety assessments (AE/SAE review, routine clinical bloods 
review, urine pregnancy testing for WOCBP). 

17 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
Furthermore, a Data Monitoring Committee (DMC) will provide 
independent oversight of this trial. 
Criteria for withdrawal 
of participants   
Participants will be withdrawn from the trial and no further follow-up 
procedures carried out if a participant withdraws consent. 
 
Participants will be withdrawn from trial treatment (but follow-up 
encouraged) for any of the following reasons: 
1. Participant withdrawal of consent      
2. Physician decision to withdraw participant from trial either due 
to uncontrolled disease or drug related toxicity 
3. Pregnancy during the trial period 
4. Life threatening infections 
5. Lack or loss of response to all of the IMPs within 720 days 
6. If an unblinded event occurs 
 

18 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
5. Trial Flow Chart 
 
 
Consented (n=140)
Randomisation to a sequence of 4 trial IMPs* and 
initiate the first IMP
Remission
Relapse
Trial 
duration
2 Years
Trial visits 
every 
120 days
+ IMP 
administrations
Trial end
Outcomes
Primary:
•
Time to 
treatment  
failure
Secondary:
•
Disease activity 
scores
•
Health 
economic 
assessments
•
Damage 
assessments
•
SAEs/AESIs
* IMPs (infliximab, tocilizumab, rituximab or placebo) are represented as ABCD in the flow diagram 
Next drug in the sequence
TRIAL FLOW DIAGRAM
A
B
C
D

Primary treatment 
failure OR 
Progressive disease
 

19 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
 
6. Introduction 
6.1. Background 
The primary systemic vasculitides are rare autoimmune disorders characterised by inflammation and 
necrosis of blood vessels leading to tissue infarction, organ failure and death. They are classified by the 
predominant size of blood vessel involved into large, medium and small vessel vasculitis and include a 
number of different syndromes in each group (Jennette et al. 2012). Vasculitis syndromes other than Anti-
neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) have been grouped under the term 
non-ANCA associated vasculitis (NAAV), shown in Table 1 are the diseases being studied in this trial. These 
diseases will be collectively referred to as the primary group. 
 
Table 1 NAAV diseases under investigation in this trial 
Classification* 
Disease 
Large vessel vasculitis 
Giant cell arteritis 
Takayasu’s arteritis 
Medium vessel vasculitis 
Polyarteritis nodosa 
Cutaneous polyarteritis nodosa 
Small vessel vasculitis 
Cryoglobulinaemic vasculitis 
IgA Vasculitis 
Other vasculitis 
Cogan’s syndrome 
Primary angiitis of the central nervous system 
Relapsing polychondritis 
*Adapted from the Chapel Hill Consensus Conference 2012 
 
ANCA associated vasculitis has well evidenced therapy and rituximab, a monoclonal antibody directed 
against B cells was licensed by the US Food and Drug Administration (FDA) and European Medicines 
Agency (EMA) in 2011 and 2013 respectively, and National Institute of Clinical Excellence (NICE) approved 
in 2013 (Stone et al. 2010; Jones et al. 2010). NAAV, with a combined incidence of ~20/million/year (Table 
2) are less well studied and have no licensed therapies except for glucocorticoids, and more recently, 
Tocillizumab for GCA, as described below. Currently, treatment strategies in NAAV mirror ANCA 
associated vasculitis treatments due to similarities in disease pathogenesis and manifestations (Mukhtyar 
et al. 2009; Mukhtyar et al. 2009a). 
 
     Table 2 Incidence and prevalence of NAAV 
Disease 
Incidence 
Prevalence 
Giant cell arteritis 
63/million 
900/million 
Takayasu's arteritis 
1-2/million 
4.7/million 
Polyarteritis nodosa (Hepatitis 
negative) 
4-10/million 
30/million 
Relapsing polychondritis 
0.7/million 
10/million  
IgA Vasculitis in children 
60-200/million 
(children) 
33/million (children) 
IgA Vasculitis in adults 
13/million 
25/million 
Cryoglobulinaemia 
1-2/million 
10/million 
Cogan’s syndrome 
1-2/million 
10/million 
Primary CNS vasculitis 
2.4/million 
24/million 
      
Clinical presentations, treatment responses and the disease course of NAAV are heterogeneous, but there 
are major overlaps in pathogenesis and treatment. Current therapies are only partially effective and 

20 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
commonly result in side effects. Over one third of patients pursue a course marked by repeated disease 
flares and/or progressive disease with high risks of vital organ damage, high cumulative exposure to 
glucocorticoids and immunosuppressive agents with attendant chronic morbidity and mortality. There is 
a three-fold increase in direct medical costs for refractory vasculitis when compared to patients in 
remission (Trieste et al. 2012). Based on 2014 US health costs, refractory vasculitis at 
$88,000/year/patient cost more than double the health costs of non-refractory disease at 
$30,000/year/patient. In marked contrast to ANCA associated vasculitis, patients with NAAV lack 
standardised treatment pathways and there is wide variance in practice and outcomes. The introduction 
of evidence-based therapies will help to harmonise therapy, improve patient quality of life and long-term 
outcomes, and reduce current levels of drug-associated toxicity. It has the potential also to reduce the 
societal and economic burden of vasculitis.       
      
Biological therapy plays a major role in the treatment of single organ autoimmune diseases, e.g. asthma, 
rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. For multi-system autoimmunity, 
belimumab has been licensed and NICE approved for systemic lupus erythematosus, rituximab for ANCA-
associated vasculitis and tocilizumab has been licensed and NICE approved for short-term use in refractory 
giant cell arteritis (Jones et al. 2010; Villiger et al. 2016; Stone et al. 2017). There is considerable trial and 
observational data supporting a useful role for the three biologics in this trial in vasculitis. Refractory 
patients have the greatest need for better treatment with potentially preventable morbidity and 
mortality. Advances in trial design in ANCA associated vasculitis have been translated to giant cell arteritis 
but have not been exploited in the other syndromes where the low incidence has been a major barrier to 
research. The lack of evidence in children is more acute as they are often excluded from trials, but there 
is also clinical experience with the biologics in this trial iin children where tocilizumab and infliximab are 
licensed for other indications (Akamine & Punaro 2019) in the EU and rituximab is currently licenced for 
AAV by the FDA. Although tocilizumab has been approved for giant cell arteritis, some patients are not 
responsive and alternative biologics may be cheaper and as effective. 
 
6.2. Clinical Data 
6.2.1. Efficacy 
      
Biologics targeting pathogenic pathways, such as tumour necrosis factor-inhibitors, anti-interleukin 6-
receptor (anti-IL6r) or anti-B cells have been used to treat refractory NAAV. Robust evidence in the form 
of randomised controlled trial evidence in the treatment of NAAV mainly comes from studies in GCA and 
a few small clinical trials in TA. Such evidence is lacking for other forms of NAAV. 
      
Two randomised controlled trials have shown efficacy of tocilizumab, an anti-IL6 receptor, for remission 
induction in giant cell arteritis (Villiger et al. 2016; Stone et al. 2017). In An efficacy and safety trial of 
Tocilizumab in participants with GCA (GIACTA) trial (Stone et al. 2017), tocilizumab combined with a 26-
week prednisolone taper was shown to be superior to either a 26-week or 52-week prednisolone taper in 
maintaining sustained remission at 52 weeks (56% vs. 14%, p<0.001). However, this trial does not inform 
the management of participants that do not achieve remission with tocilizumab (44% of the participants 
in the GIACTA trial). A recent review by NICE highlights that more evidence is needed in this field not only 
for tocilizumab but also for other alternatives (NICE 2018). A comparative data between biologics, both 
for efficacy and safety is of particular importance, and is unlikely to be produced by the pharmaceutical 
industry, yet is essential for optimal patient care and personalisation of treatment.      
      
A trial of infliximab (TNF inhibitor) failed to show efficacy in a small and underpowered giant cell arteritis 
trial (Hoffmann et al. 2007). In this trial 44 adult participants with a new diagnosis of GCA were recruited 
in a 2:1 ratio to either infliximab or placebo. Primary endpoint of being in remission at 24 weeks was 
similar in both groups (43% vs. 50%, p=NS). This trial suffers from some methodological issues which 

21 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
include an assumption of large effect size of 50%, small sample size and early termination. Observational 
data over almost two decades have supported use of TNF inhibitor in giant cell arteritis, Takayasu’s 
arteritis and polyarteritis nodosa (Ferfar et al. 2016). There is preliminary clinical and experimental 
evidence in GCA that tocilizumab failures may respond to infliximab and vice versa (Muratore et al. 2017; 
Hernandez-Rodriguez et al. 2003; Visvanathan et al. 2011; Deng et al. 2010; Espígol-Frigolé et al. 2013; 
Weyand & Goronzy 2013). We believe that the clinical equipoise remains despite the recent tocilizumab 
approval and clinical trial evidence against TNF inhibitors.  
      
The proven efficacy of rituximab in ANCA associated vasculitis; pathological similarities between ANCA 
associated vasculitis and NAAV, as well as experience in NAAV (Nakagomi et al. 2018), support further trial 
of rituximab. We have conducted a systematic literature review (unpublished) that identified 389 cases 
of NAAV successfully treated with these agents) in line with a meta-analysis of giant cell arteritis 
/Takayasu’s arteritis (Osman et al. 2014). Experience with rituximab in ANCA associated vasculitis (Stone 
et al. 2010; Jones et al. 2010) has demonstrated improved disease control and reduced costs in refractory 
subgroups that parallel better disease control, reduced exposure to glucocorticoids and 
immunosuppression and lower co-morbidity risks. We have reported secondary failure of biologics in a 
related secondary vasculitis, Behcet’s syndrome (Furuta et al. 2012). 
      
6.2.2.     Safety and tolerability 
 
All of the IMPs  being studied in this trial are licensed therapies for other auto-immune conditions : 
rituximab is licensed for AAV (FDA and EMA approved in adults and children)), tocilizumab licensed for 
GCA (FDA and EMA), infliximab licensed for rheumatoid arthritis (FDA and EMA). Tocilizumab is 
approved for use in paediatric patients with Juvenile idiopathic arthritis (JIA) with well-established safety 
profiles and tolerability, and recommended as a second line treatment in rare refractory paediatric 
vasculitides (deGraeff et al, 2019). Rituximab is used in routine practice for ANCA associated vasculitis, 
and in non-ANCA associated vasculitis of the young.  Furthermore, the European SHARE guidance 
describes recommended use of all three biologics in paediatric populations (deGraeff et al. 2019). The 
centres that are participating in this trial are well versed with safety and tolerability issues associated 
with each of the IMPs.      
 
6.2.3. Pharmacokinetics & pharmacodynamics 
 
These are well established and are reflected in the summary of product characteristics (SmPCs) of each 
IMP.        
 
7. Rationale for Trial 
Glucocorticoids remain the standard therapy for remission induction in NAAV and are used with or 
without immunosuppressive agents depending on the syndrome and severity. Glucocorticoids at high 
doses control systemic inflammation and reduce acute injury but may not induce long-term treatment 
free remission and carry a heavy burden of almost universal toxicity (Nesher et al. 1994). Vasculitides are 
characterised by frequent relapses, which further contribute to disease-related damage and drug-related 
toxicity.      
 
Steroid use is associated with the risk of diabetes, hypertension, thrombosis, gastro-intestinal 
haemorrhage, psychosis, insomnia, skin fragility, changed appearance, alopecia, osteoporosis, infections 
and obesity. The elderly are particularly vulnerable to an increased risk of fragility fractures and cataracts 
that have major impacts on their mobility and quality of life. Analyses of European Vasculitis Study group 
(EUVAS) clinical trials have shown that the majority of deaths within the first 12 months are treatment-

22 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
related adverse events, such as infections (48%) (Flossmann et al. 2011). In a French study of AAV 
participants around 90% of serious infections occurred in relation to glucocorticoids and reduced doses 
or alternate day dosing regimens were associated with reduced infections (Charlier et al. 2009). Thus, 
there is a clear and important need to reduce the use of glucocorticoids in NAAV.      
 
One third of NAAV patients have refractory disease, either failing to achieve remission or relapsing despite 
relapse prevention strategies. This subgroup experiences the poorest outcomes, the highest drug related 
toxicity and is most demanding on health resources and is the focus of BIOVAS. Our proposed testing of 
biologics in BIOVAS concords with the current treatment pathway (see Fig.1) based on European League 
Against Rheumatism (EULAR) consensus statements supported by low grade evidence, expert opinion and 
a few small trials (Mukhtyar 2009)           
 
The pathology of vasculitis is characterised by pro-inflammatory cytokines (IL-1, IL-6 and TNF) and 
infiltration of vessels by neutrophils and lymphocytes. This results in fibrinoid necrosis of the vessel wall 
and thrombotic occlusion or aneurysmal dilatation or intimal proliferation and stenosis of the vessel 
lumen. A complex genetic predisposition has been identified for giant cell arteritis and Takayasu’s arteritis.      
 
Biologics targeting pathogenic pathways, such as tumour necrosis factor-inhibitors, anti-IL6r or anti-B cells 
have been used to treat refractory NAAV. Evidence in support of the agents chosen for this trial has been 
discussed in section 6.2.1.      
 
 
      
 
8. Trial Design 
8.1. Statement of Design 
A multi-centre, pragmatic, randomised double blind, placebo-controlled, modified-crossover phase 2B 
trial of infliximab, rituximab and tocilizumab for refractory NAAV in adults and children. 
8.2. Number of Centres 
This multicentre trial will include approximately 17 UK centres.  
8.3. Number of Participants 
140 eligible participants with refractory NAAV will be enrolled in this trial. 
Figure 1 Current treatment pathway in NAAV 

23 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
8.4. Participants Trial Duration 
The trial comprises a screening period of up to 28 days and a 720 day (+/- 14 days) treatment period. 
During trial participation, each participant will be required to attend 8 trial related trial clinic visits. 
Attendance for IMP infusions will vary for each participant dependent on their treatment allocation at any 
particular time. Each participant will receive a minimum of 5 and a maximum of 24 IMP infusions 
throughout the 720 day trial treatment period unless withdrawn from the trial. In the exceptional event 
of a supply issue of hospital stocks of any of the IMPs, patients may be switched to the next IMP in 
sequence.  This should occur even if a patient is allocated the placebo equivalent of the active IMP whose 
supply is affected: they would still be switched to the next treatment in their randomised sequence. 
Switching in this exceptional circumstance would not affect the overall trial duration for that patient. 
 
There will be some overlap between IMP administration and trial clinic visits which will mean a minimum 
of 11 visits and a maximum of 25 visits in total including the screening visit. Trial clinic visits will happen 
at baseline and every 120 days +/- 14 days following successful screening. For convenience +/- 14 days 
will not be mentioned when referring to trial visits from hereon. 
8.5. Trial Objectives 
BIOVAS will test the hypothesis that biologics are superior to placebo in the control of refractory NAAV. 
Each of the three trial biologics (infliximab, rituximab and tocilizumab) will be compared to placebo in a 
sequential modified crossover, placebo-controlled design.  
 
All analyses (other than secondary Bayesian analysis) will be conducted on primary group. For Bayesian 
analysis the primary group will be sub-divided into 2 sub-groups: Group 1 (GCA and TA) and Group 2 (PAN, 
CPAN, RP, IgAV, Cogan’s syndrome, non-infective cryoglobulinaemia, PACNS). 
8.5.1. Primary objective 
To establish evidence for clinical effectiveness of three different biologics: infliximab, rituximab and 
tocilizumab in comparison to placebo in the treatment of refractory NAAV as one disease group (primary 
group).      
8.5.2.     Secondary objectives 
To establish safety, clinical and cost-effectiveness of each of the biologic agents compared to placebo; and 
to establish the clinical and cost-effectiveness of each biologic agent compared to the other biologic 
agents studied in the trial.  
1. To assess the clinical efficacy of each of the three IMPs compared to placebo using Bayesian 
hierarchical analyses for 2 groups: Group 1 (GCA & TA) and Group 2 (PAN, CPAN, RP, IgAV, Cogan’s 
syndrome, non-infective cryoglobulinaemia, PACNS)  
2. To assess the clinical efficacy of each of the 3 IMPs compared to placebo for each of the 8 NAAV 
diseases  
3. To assess the safety of each of the three IMPs compared to placebo           
4. To assess the safety and risks associated with sequential use of different IMPs 
5. To assess the cost-effectiveness of each of the three active IMPs compared to placebo  
6. To compare the clinical and cost-effectiveness of each IMP compared to other IMPs in the primary 
group  
8.6. Trial Outcome Measures 
          Primary outcome measures:  
Primary outcome is time to treatment failure (TTF). 
      

24 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
TTF for each IMP is the time from the start of IMP treatment, to treatment failure (see definitions below) 
or the end of trial participation (censored).  
 
Primary treatment failure is progressive disease (defined by appearance of ≥1 new/worse severe or ≥3 
new/worse non-severe items) on Birmingham vasculitis activity score (BVAS) v3 modified for BIOVAS trial 
(BVASv3-BIOVAS) or paediatric vasculitis activity score (PVAS) within 120 days from the time of IMP 
commencement; or failure to achieve clinical response (see definitions below) by 120 days from the time 
of IMP commencement. In such cases, TTF will be recorded as zero.  
 
Secondary treatment failure is subsequent relapse (see definitions below) after 120 days of IMP 
commencement in patients who have achieved response by 120 days from the time of IMP 
commencement,       
      
If an adverse reaction to an IMP precludes the participant from receiving further doses of the trial drug, it 
will also be considered a treatment failure. 
 
The primary outcome for each active IMP is pooled across all participants in the primary group and 
compared against placebo. 
 
Response is defined by: 
 
Absence of new/worse BVAS V3-BIOVAS(adults)/PVAS (children) items assessed at each 120 
evaluation time point after commencing IMP AND 
 
Prednisolone ≤10mg/day or ≤0.2mg/kg for children (whichever is lower), unless the baseline dose 
is ≤10mg/day or ≤0.2mg/kg for children (whichever is lower), in which case it should not be more 
than the baseline dose* 
*baseline dose is the dose of oral prednisolone, mg/day, or equivalent oral steroid, averaged over the 7 
days prior to the start of each new IMP. 
 
 
      
     Relapse is defined by either: 
 
Appearance of ≥ 1 severe (new/worse) or ≥ 3 non-severe (new/worse) BVAS v3-
BIOVAS/PVAS items from the time of BVAS response (as defined above) assessed at the 120 
day  evaluation time points# OR  
 
The need to increase the dose of prednisolone to > 20mg/day to treat vasculitis OR 
 
The need to increase the dose  of an immunomodulator or immune-suppressive therapy in 
order to treat vasculitis 
 
# Non-severe items can be upgraded by the investigator to severe based on their potential clinical 
impact, e.g. headache in GCA, thus could meet failure criteria if only one or two items are present.       
       
For an increase in one or two non-severe new/worse BVAS v3-BIOVAS/PVAS items which does not meet 
the relapse definition, the current IMP is continued and the participant may be treated, at the 
physician’s discretion, with a prednisolone dose increase to no more than 20mg/day (or 0.3mg/kg but 
no more than 20mg/day in children) which will be reduced to the previous dose within next 6 weeks. 
 
Secondary outcome measures:       
1. Bayesian hierarchical analysis to assess treatment effects of each of the IMPs compared to 
placebo and each IMP against  other IMPs  in 2 NAAV sub-groups: large vessel vasculitis 
(GCA/TA) and all other NAAV subgroups enrolled in the trial 
2. Proportion of participants achieving response at 120 days evaluation after the start of each IMP. 

25 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
3. Proportion of participants achieving response at every 120 day evaluation time point defined by 
a BVAS v3-BIOVAS/ PVAS of ≤ one non-severe (no new/worse) item, prednisolone dose ≤ 50% of 
the dose at the start of the IMP treatment and ≤ 10mg/day (0.2 mg/kg/day for children, 
whichever is lower) and an ESR < 30mm/hr or CRP <10 mg/L   
4. Increase in disease related damage measured by VDI/PVDI from start to end of an IMP  
treatment   
5. Physician’s global assessment (PGA) (Likert scale 0-10)  at every 120 day evaluation time point 
from the time of IMP commencement 
6. Serious adverse events/adverse events of special interests (SAEs/AESIs) 
7. EQ-5D-5L or Child Health Utility (CHU9D) assessments at every 120 day evaluation time point   
8. NHS resource use and out of pocket costs and lost productivity 
9. Selection and withdrawal of participants  
9.1. Inclusion Criteria 
To be included in the trial the participant must:      
1. Aged at least 5 years  
2. Have given, or their parent/legal guardian aged ≥ 16 years old has given, written informed 
consent 
3. Diagnosis of NAAV (Appendix 4) 
4. Refractory disease defined by:  
 
Active disease, BVAS v3-BIOVAS/ PVAS with ≥ 1 severe (new/worse) or ≥ 3 non-severe 
(new/worse) items despite 12 weeks of conventional therapy OR      
 
Inability to reduce prednisolone below 15mg/day or (0.3mg/kg/day in case of 
children) without relapse in the 12 weeks prior to screening visit 
9.2. Exclusion Criteria 
Participants are excluded from the trial if any of the following criteria apply: 
1. Previous treatment failure/contraindication to ≥ 2 active trial IMPs 
2. Increase in the dose or frequency of background immunosuppressive (e.g. methotrexate) or 
anti-cytokine therapy within 30 days prior to screening visit 
3. Use of plasma exchange or intravenous immunoglobulins (unless required clinically for 
immunodeficiency) within the 30 days, or cyclophosphamide or lymphocyte depleting 
biologic (e.g. rituximab) within 6 months of  initiating trial treatment 
4. Concomitant use of any biologic and/or anti-TNF agent other than the trial IMPs for the 
duration of the trial.       
5. Have an active systemic bacterial, viral or fungal infection, or active/latent tuberculosis 
assessed/documented as per local clinical practice; this includes COVID19 testing if warranted 
and as per local routine practice. 
6. Hepatitis B (HB) core antibody (Ab) or HB surface antigen positive or hepatitis C antibody 
positive or human immunodeficiency virus (HIV) antibody test positive       
7. History of malignancy within five years prior to screening visit 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 
8. Pregnant or breastfeeding, or inability/unwillingness to use a highly effective method of 
contraceptive if a woman of childbearing potential (WOCBP; Section 11.9)  
9. Severe disease, which in the opinion of the physician prevents randomisation to placebo      
10. Recent or upcoming major surgery within 45 days of screening visit      

26 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
11. Leukocyte count < 3.5 x 109 cells/l, platelet count < 100 x 109 cells/l, neutrophil count of < 2 x 
109 cells/l      
12. ALT or AST > 3 times the upper limit of normal      
13. Symptomatic congestive heart failure (NYHA class III/IV) requiring prescription medication 
within 90 days of screening visit       
14. Demyelinating disorders      
15. History or presence of any medical condition or disease which, in the opinion of the 
Investigator, may place the participant at unacceptable risk because of trial participation 
16. Administration of live or live attenuated vaccines within 45 days of screening 
17. Have received an investigational medicinal product (IMP) within 5 half-lives or 30 days prior 
to screening 
18. Diagnosis of adenosine deaminase type 2 (DADA2) 
19. Hypersensitivity to the active IMP substance or to any of the formulation excipients (unless 
IMP excluded for a particular patient pre-randomisation) 
 
9.3.            Treatment Assignment and Randomisation Number 
 
Following informed consent all participants entering screening will be assigned a unique Trial ID number. 
All eligible participants will be assigned to trial treatment in accordance with the randomisation schedule 
and randomisation must occur before any investigational product is administered.  
      
Once eligibility has been confirmed, participants will be randomised to a fixed sequence of four different 
IMPs, each sequence will contain three active IMPs and a placebo. The order of the treatments in each 
sequence is randomly allocated (e.g. RTX-INF-TCZ-PBO or INF-PBO-RTX-TCZ). Furthermore, the placebo in 
each sequence is chosen randomly to mirror one of the active IMPs. In the case of a known 
failure/contraindication to a trial IMP, that particular drug will not be included in the sequence generation 
at the time of randomisation. This was deemed necessary to maximise the data obtained from a limited 
number of eligible participants in this rare disease setting.   
      
Access to the web-based randomisation system (Sealed Envelope) will be via individual user accounts 
provided to the principal investigator (PI) and suitably trained and delegated members of the research 
team at each site as appropriate. Once randomisation occurs, immediate allocation of IMP sequence will 
be performed. A blinded confirmatory email containing a blinded code e.g. CZ7 will be sent to the local 
clinical team and to the Trial Coordinator.  
 
 
9.4. Method of Blinding 
 
 
This is a double-blinded trial.  The double-blinded period will be the time from start of first IMP in the 
randomised sequence up to failure on all IMPs (maximum duration 24 months). During this period, neither 
participants nor local trial team will know whether the participant is on active or placebo IMP. When a 
participant is on a placebo IMP, they will receive saline with infusion characteristics (duration of 
administration, frequency and pre-medications) to match one of the active IMPs. There is a small risk of 
unbinding as tocilizumab can lower ESR and CRP. However this risk is small as any treatment that can 
induce a response can also lower ESR and CRP.  
 

27 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
 When participants are randomised to a sequence, the central coordinator and local pharmacy teams will 
be unblinded to the sequence allocation.  This is for practical and safety purposes:  the unblinded central 
coordinator will notify the investigator or delegated member of the trial team which treatment protocol 
to prescribe, to ensure that the participant is booked for the relevant treatment visits for a particular 
intervention. Local unblinded pharmacy (and any other authorised site personnel as appropriate) will be 
able to verify whether they are preparing active or placebo for that particular in IMP the sequence.   
 
For example:  if a participant is allocated to the following sequence:  RTX-INF-TCZ-RTX-Placebo, the 
unblinded coordinator would notify investigator that the prescription to prepare for the first IMP in the 
sequence for this randomised participant would be RTX OR RTX-Placebo.  The IMP would be labelled as 
such (RTX/RTX-Placebo) in order to maintain the blind during this intervention phase of the randomised 
sequence. 
 
 
Given that there are three active IMPs plus placebo, 24 permutations are possible. At each placebo 
position three possibilities (RTX or INF or TCZ placebo) exist, hence there are 72 possible sequences in 
total. With this design there are 36 sequences where the IMPs can be un-blinded by an educated guess 
and such sequences are excluded from sequence generation (shown in red in Figure 2). From the design 
of the trial, it could be inferred that two agents other than the placebo and its matched IMP are active 
agents. If the placebo and its matched IMP were to be in the first three places of the sequence then it 
would be easy to guess the IMPs that follow are active agents thus leading to unblinding. Such sequences 
will be removed.       
 
At or prior to each trial clinic visit, investigators will make a decision to either carry on with the same IMP 
or switch to the next IMP in the participants’ randomised sequence.  Central coordinator must be notified 
of a planned IMP switch, so that they can then provide site delegated members with the next IMP/placebo 
in the participants’ randomised sequence to ensure the correct treatment protocol is prescribed (for 
example, if a patient with the randomised sequence RTX-INF-TCZ-RTX-Placebo fails first intervention in 
the sequence, they would be switched to the next, which is INF.  The investigator or delegated member 
of trial team will be notified that the next in sequence is INF OR INF placebo, to ensure the correct IMP 
protocol is prescribed, whilst maintaining the blind for this intervention period.  
 
In the exceptional event of a supply issue of hospital stocks of any of the IMPs at any point in the study, 
patients may be switched to the next IMP in sequence, and the reason (I.e. Supply issue) documented.  In 
order to maintain the blind, even if a patient was on the placebo equivalent of the active IMP whose 
supply is affected, they would still be switched to the next treatment in their randomised sequence, and 
this would not affect the overall trial duration for that patient.  If the active IMP with the supply issue is 
the one with a placebo match allocated, and the supply issue for the active IMP is subsequently resolved 
by the time the matched allocation is due (whether for active or placebo), this may go ahead. 
 
Further instructions on randomisation and IMP switching can be found in the Trial Procedures Manual. 
 
 

28 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
        Figure 2 Randomisation permutations and placebo matched possibilities 
 
9.5.      Participant Withdrawal Criteria 
 
Participants may withdraw from the trial treatment or from the trial completely, at any time at their 
request, or they may be withdrawn at any time at the discretion of the investigator.   
9.5.1. Withdrawal from protocol treatment 
Participants may be withdrawn from trial treatment for any of the following reasons: 
1. Participant withdrawal of consent      
2. Physician decision to withdraw participant from trial either due to uncontrolled 
disease or drug related toxicity 
3. Pregnancy during the trial period 
4. Life threatening infections 
5. Lack or loss of response to all of the IMPs within 720 days 
6. If an unblinded event occurs 
 
Participants who discontinue trial treatment will be encouraged to continue to participate in trial visits in 
accordance with the schedule of events (SoE). With ongoing consent, the trial participants should remain 
in the trial and data will continue to be collected.  
 
A participant’s trial visit non-compliance will not automatically lead to withdrawal from the trial. The 
participant will be encouraged to attend a clinic visit at their earliest convenience in case of a missed trial 

29 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
clinic visit. If the investigator decides to continue the same IMP then the participant can continue to 
receive the same IMP.  
 
Withdrawal is anticipated to be a rare occurrence. 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 withdraw the patient from the trial 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. 
 
9.5.2. Withdrawal of consent  
If the participant explicitly states they no longer wish to contribute further data to the trial, the 
investigator should inform the BIOVAS co-ordinating centre in writing and the withdrawal of consent 
should be documented by the in the participant’s medical records and in the electronic Case Report 
Form (eCRF). No further trial procedures will be undertaken and the only data that will be collected 
following withdrawal will be resolution/stability of adverse reactions. However, data and samples 
collected up to the time of consent withdrawal will be included in the data reported for the trial. 
These participants’ subsequent management will follow standard of care. 
 
 
 
10.     Trial Treatments 
10.1. 
Treatment Summary  
For the purpose of this trial, infliximab, rituximab, tocilizumab and placebo to match (Sodium Chloride 
0.9%) are all considered Investigational Medicinal Products (IMP) conducted with a Clinical Trial 
Authorisation. The use of bio-similar agents are permitted as per local policy (with the brand in use and 
batch number being recorded, in such a manner that unblinding does not occur). Also allowed is any bio-
similar non-UK stock which has received interim MHRA approval for clinical use, for example, interim non-
UK supply of Tocilizumab.  
In the case of a known failure/contraindication to one of the trial IMPs, that particular drug will not be 
included in the sequence generation at the time of randomisation.  
 
In the exceptional event of a supply issue of hospital stocks of any of the IMPs at any point in the study, 
patients may be switched to the next IMP in sequence, and the reason (I.e. Supply issue) documented.  In 
order to maintain the blind, even if a patient was on the placebo equivalent of the active IMP whose 
supply is affected, they would still be switched to the next treatment in their randomised sequence, and 
this would not affect the overall trial duration for that patient.  If the active IMP with the supply issue is 
the one with a placebo match allocated, and the supply issue for the active IMP is subsequently resolved 
by the time the matched allocation is due (whether for active or placebo), this may go ahead. 
 
Since immunosuppressive therapy can impair response to vaccines, please ensure that  there is at least 4 
weeks between last vaccine dose andinitiating trial IMP.  Investigators should follow the most up-to-date 
JCVI advice regarding further vaccine doses in immunosuppressed patients, paying close attention to any 
further guidelines and recommendations relating to time windows between vaccine and rituximab dosing 
for trial participants if they are due to receive rituximab as their randomised IMP. 
 
A minimum washout period of 30 days is mandatory between any 2 IMPs. This interval reflects current 
clinical practise and our understanding of the mode of action of biologics. It is assumed that the biologic 

30 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
‘switch off’ after withdrawal in non-responding patients will not influence propensity to respond to the 
next IMP. The biologic half-life of TNF inhibitor and anti-IL6r is 10 days, and 22 days for rituximab. As drug 
switching occurs due to progressive disease or a relapse, it will be assumed that the previous IMP was 
ineffective, and the benefit seen from the subsequent IMP (which is assessed 120 days after starting the 
IMP) is not associated with exposure to the first drug or due to a synergistic effect. However, rituximab 
has a prolonged effect on B cell counts; while experience in AAV suggests a delayed therapeutic response 
after four months is unlikely, the possibility of a synergy between prior B cell depletion and anti-cytokine 
agent remains. Sensitivity analyses will be performed on the primary end-point to investigate this 
possibility. We will also be employing analytical washouts (5) to counteract the effect of the preceding 
drug on patient-reported outcomes. 
 
For further information on treatments, the pharmacy manual and Trial Procedures Manual should be 
consulted. 
 
10.1.1. Infliximab 
A human/mouse chimeric TNF Inhibitor monoclonal antibody. 
10.1.1.1. 
Legal Status 
Infliximab IV is licensed in the UK, US, Canada and Australia. It is used to treat the following indications: 
rheumatoid arthritis, adult Crohn’s disease, paediatric Crohn’s disease, ulcerative colitis, paediatric 
ulcerative colitis, ankylosing spondylitis, psoriatic arthritis and psoriasis. The Single Hub and Access point 
for paediatric Rheumatology in Europe (SHARE) Initiative recommends infliximab as a second-line 
therapy in rare refractory vasculitides in children (deGraeff et al. 2019). 
10.1.1.2. 
Supply 
Infliximab IV is available commercially and will be supplied from local hospital stock for the duration of 
the trial. There is no requirement to ring-fence. For detailed instructions on how to prepare and handle 
infliximab, please refer to the most recent version of the SmPC for the brand of drug used at the 
participating site. 
 
10.1.1.3. 
Packing and Labelling 
 The IMP will have a blinded label at the point of treatment.  
10.1.1.4. 
Storage Conditions 
Infliximab should be kept in a secure place under appropriate storage conditions as stated in the current 
version of the SmPC of the brand being used within the trial. 
10.1.1.5. 
Maximum duration of treatment of a participant 
The maximum dose received will be 15 infusions of Infliximab over the 2 year trial period.  
10.1.1.6. 
Dose 
Participants will receive infliximab IV 5mg/kg at days 1, 15(+/-3d), 43 (+/-3d), 70, (+/- 3d) followed by 
dosing every 56 days (or 8 weeks, +/-14d).  Doses will be on days 1,15,43,70, 126, 182, 238, 294, 350, 
406, 462, 518, 574, 630, 686, or until treatment failure. 
Dose calculations for adult participants will be based on actual body weight as measured during the 
Screening period (if first IMP in sequence) or preceding trial assessment visit. Dose calculations for 
paediatric patients will be based on body weight as measured during the screening visit (if first IMP in 
sequence) or in the preceding trial assessment visit. 

31 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
10.1.1.7. 
Administration 
Infliximab should be administered IV as per local practice including any pre-medication protocols.  
10.1.1.8. 
Known drug reactions 
Known Infliximab reactions are summarised in section 4.8 of Remsima SmPC approved by the MHRA for 
use in this trial. Concomitant use of anakinra, etanercept or abatacept with Infliximab is not 
recommended. Investigators should refer to the SmPC to review any other prohibited concomitant 
therapy use with infliximab.   
10.1.1.9. 
Dose modifications  
No dose modifications will be made.  
10.1.1.10. Procedures for monitoring treatment compliance  
Infliximab will be administered IV to participants. Administration of the blinded IMP will be documented 
in the source documents i.e. participant hospital records and CRFs. 
10.1.1.11. Placebo for infliximab   
Infliximab-placebo will consist of a matched volume of Sodium Chloride 0.9% and be administered IV to 
participants according to the infliximab schedule of events. 
 
10.1.2. Rituximab 
Rituximab is a human/mouse chimeric anti-CD20 monoclonal antibody. 
10.1.2.1. 
Legal status 
Rituximab IV is approved for the treatment of adult participants with AAV in the United States, Canada, 
Switzerland, Australia, Japan and the European Union. Rituximab IV is approved by the FDA for the 
treatment of ANCA associated vasculitis in children over the age of 2 years. Furthermore, the Single Hub 
and Access point for paediatric Rheumatology in Europe (SHARE) Initiative recommends rituximab as a 
second-line therapy in rare refractory vasculitides in children (deGraeff et al. 2019). For further 
information, please refer to the SmPC for rituximab for the brand used.   
10.1.2.2. 
Supply  
Rituximab IV is available commercially and will be supplied from local hospital stock for the duration of 
the trial with no requirement to ring-fence. For detailed instructions on how to prepare and handle 
Rituximab, please refer to the most recent version of the SmPC for the brand of drug used at the 
participating site. 
10.1.2.3. 
Packing and Labelling 
The IMP will have a blinded label at the point of treatment.   
10.1.2.4. 
Storage conditions 
Rituximab should be kept in a secure place under appropriate storage conditions as stated in the 
current version of the SmPC of the brand being used within the trial. 
10.1.2.5. 
Maximum duration of treatment of a participant 
The maximum dose received will be 5 x 1g over the 2 year trial period. 

32 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
10.1.2.6. 
Dose 
Adult participants will receive rituximab IV 1000mg in an appropriate volume of 0.9% sodium chloride 
solution on Days 1 , 15 (+/-3d), then 180 (+/-14d), 360 (+/-14d) and 540 (+/- 14 d) (i.e. first 2 doses 14 
days apart followed by infusions every 180 days). 
Children will receive 750mg/m2/dose (maximum 1g per dose) at the same time intervals, with BSA to be 
calculated using body weight measured at screening visit (if first IMP in sequence) or preceding trial 
assessment visit, as per the modified Boyd formula provided in the children’s British National formulary 
(https://bnfc.nice.org.uk/guidance/body-surface-area-in-children-image.html) (Sharkey et al, 2001). 
 Children who reach 16 years old will be dosed as per the adult regimen. 
10.1.2.7. 
Administration 
Before each infusion all participants should receive premedication including antipyretic (e.g. 
paracetamol) and antihistamine (e.g. chlorphenamine) and 100mg IV methyl-prednisolone as per local 
practice. Rituximab should be administered IV as per local practice. 
10.1.2.8. 
Known drug reactions 
Known Rituximab reactions are summarised in section 4.8 of Mabthera SmPC approved by the MHRA 
for use in this trial.  Currently there are limited data on possible drug interactions with rituximab.  
10.1.2.9. 
Dose modifications 
No dose modifications will be made.  
10.1.2.10. Procedures for monitoring treatment compliance 
Rituximab will be administered IV to participants, following administration of the pre-medication 
regimen. Administration of the pre-medication regimen and the blinded IMP will be documented in 
the source documents i.e. participant hospital records and CRFs. 
10.1.2.11. Placebo/Active comparator products 
Rituximab-placebo will consist of a matched volume of Sodium Chloride 0.9% and be administered IV to 
participants according to the rituximab schedule of events.  
10.1.3. Tocilizumab 
 
Tocilizumab is an anti-IL6 receptor humanised monoclonal antibody. 
10.1.3.1. 
Legal status 
Tocilizumab is licenced to treat adults with Giant Cell Arteritis. Whilst the solution for subcutaneous 
administration and not the solution for infusion is indicated for GCA, this trial will use the solution for 
infusion due to easier preparation of a comparable placebo and for consistent mode of 
administration across all three IMPs.  The Single Hub and Access point for paediatric Rheumatology 
in Europe (SHARE) Initiative recommends tocilizumab as a second-line therapy in rare refractory 
vasculitides in children (deGraeff et al. 2019). 
10.1.3.2. 
Supply 
Tocilizumab IV is available commercially and will be supplied from local hospital stock (including non-
UK MHRA-approved interim supplied stock) for the duration of the trial. There is no requirement to 

33 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
ring-fence. For detailed instructions on how to prepare and handle tocilizumab, please refer to the 
most recent version of the SmPC for the brand of drug used at the participating site. 
10.1.3.3. 
Packing and Labelling 
The IMP will have a blinded label at the point of treatment.   
10.1.3.4. 
Storage conditions 
Tocilizumab should be kept in a secure location under appropriate storage conditions as stated in the 
current version of the SmPC of the brand being used within the trial. 
10.1.3.5. 
Maximum duration of treatment of a participant 
The maximum dose received will be 24 x 800mg every 30 days over the 2 year trial period. 
10.1.3.6. 
Dose 
Participants will receive tocilizumab IV 8mg/kg (maximum 800mg) on Days 1, 30, 60, 90, 120, 150, 180, 
210, 240, 270, 300, 330, 360, 390, 420, 450, 480, 510, 540, 570, 600, 630, 660 and 690 (i.e. every 30 
days, +/-7d) of IMP schedule or until treatment failure.  Dosing is based on weight measured at most 
recent trial visit prior to start of IMP. 
Children <30kg will receive tocilizumab IV 10mg/kg (maximum 800mg) on Days 1, 30, 60, 90, 120, 150, 
180, 210, 240, 270, 300, 330, 360, 390, 420, 450, 480, 510, 540, 570, 600, 630, 660 and 690 (i.e. every 
30 days, +/- 7d) of IMP schedule or until treatment failure.  Children >30kg would receive the adult 
dosing regimen. 
10.1.3.7. 
Administration 
Tocilizumab will be administered IV as per local practice. 
10.1.3.8. 
Known drug reactions 
Known Tocilizumab reactions are summarised in section 4.8 of RoActemra SmPC approved by the 
MHRA for use in this trial. Investigators should refer to the SmPC for details on permitted/prohibited 
concomitant medication use with Tocilizumab, and ensure patients are monitored appropriately 
during treatment. 
10.1.3.9. 
 Dose modifications 
Dose modifications are as per section 4.2 of RoActemra SmPC. 
Dose adjustments due to laboratory abnormalities.  
• Liver enzyme abnormalities 
Laboratory Value 
Action 
> 1 to 3 x Upper 
Limit of Normal 
(ULN) 
Modify the dose of the concomitant MTX if appropriate 
For persistent increases in this range, reduce Tocilizumab dose to 4 mg/kg or 
interrupt Tocilizumab until alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) have normalised 
Restart with 4 mg/kg or 8 mg/kg, as clinically appropriate 
> 3 to 5 x ULN 
Interrupt Tocilizumab dosing until < 3 x ULN and follow recommendations 
above for > 1 to 3 x ULN 

34 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
(confirmed by 
repeat testing). 
For persistent increases > 3 x ULN, discontinue Tocilizumab 
> 5 x ULN 
Discontinue Tocilizumab 
 
• Low absolute neutrophil count (ANC) 
 
In patients not previously treated with Tocilizumab, initiation is not recommended in patients with an 
absolute neutrophil count (ANC) below 2 x 109/l.  Investigators should discuss this with the CI prior to 
treatment start. 
 
Laboratory Value 
(cells x 109/ l ) 
Action 
ANC > 1  
Maintain dose 
ANC 0.5 to 1 
Interrupt Tocilizumab dosing 
When ANC increases > 1 x 109/ l resume Tocilizumab at 4 mg/kg and increase 
to 8 mg/kg as clinically appropriate 
ANC < 0.5 
Discontinue Tocilizumab 
 
• Low platelet count 
 
Laboratory Value 
(cells x 103/ μL) 
Action 
 
50 to 100 
Interrupt Tocilizumab dosing 
When platelet count > 100 x 103/ μ resume Tocilizumab at 4 mg/kg and 
increase to 8 mg/kg as clinically appropriate 
< 50 
Discontinue Tocilizumab 
10.1.3.10. Procedures for monitoring treatment compliance 
The blinded IMP will be administered IV to participants and will be documented in the source documents 
i.e. participant hospital records and CRFs. 
10.1.3.11. Placebo for tocilizumab 
Tocilizumab-placebo will consist of a matched volume of Sodium Chloride 0.9% and be administered IV 
to participants according to the tocilizumab, schedule of events.  
 
10.2 Non Investigational Medicinal Products 
10.2.1 Glucocorticoids 
For the purpose of this trial, glucocorticoids will be considered a Non Investigational Medicinal Product 
(NIMP). Prednisolone or an equivalently dosed steroid (e.g. hydrocortisone) may be used.  
 
Steroid dosing is not protocolised, however recommended steroid weaning templates have been provided 
in the appendix (See appendix 5). 
 
Steroid dose prior to trial entry and during treatment of a relapse, prior to next IMP initiation, is 
unrestricted.  
 

35 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
Once an IMP has been initiated, physicians are recommended to reduce the steroid dose as per best 
medical practice. 
 
Steroid doses will be captured using a participant steroid diary. 
 
See section 10.3 for details of Steroid dosing during treatment of a relapse.  
10.3 Treatment of relapse 
10.3.1 Minor Relapse 
A minor relapse is defined as the appearance of one or two non-severe BVAS items. A minor relapse does 
not require a change in IMP. The participant may be treated, at the physician’s discretion, with a transient 
steroid increase to no more than 20mg/day reduced to previous dose within 6 weeks.   
 
10.3.2 Major Relapse 
A relapse prompting change to next IMP is defined by worsening of BVAS v3-BIOVAS/PVAS by either: 
1. 
≥ 1 severe (new/worse) items OR  
2. 
≥ 3 non-severe (new/worse)* items OR  
3. 
The need to increase the dose of prednisolone to ˃ 20mg/day (or ≥0.25mg/kg/day for 
children) to treat vasculitis OR  
4. 
An increase in the dose of immunomodulator or immune-suppressive therapy 
* Non-severe items can be upgraded by the investigator to severe based on their potential clinical impact, e.g. 
headache in GCA, thus could meet failure criteria if only one or two items are present.  
 
Participants experiencing a major relapse of vasculitis will have achieved their primary endpoint for that 
IMP. In this situation, the current IMP should be halted and the participant may be treated with steroids 
at a dose and regimen as per local Investigator decision until the next IMP is initiated. Investigators must 
inform central coordination team of IMP discontinuation and decision to move to the next IMP in 
sequence as soon as the decision is made. The next IMP will only be administered at the subsequent pre-
specified scheduled trial clinic visit (i.e. only on Days 120, 240, 360, 480 and 600 (+/- 14 days)).  
 
10.4 Concomitant Therapy 
Steroids will be tapered (Section 10.2.1) and stable adjunctive immunosuppressive therapy (such as 
methotrexate/azathioprine/mycophenolate/leflunomide) will be given as per local Investigator decision. 
Adjunctive immunosuppressive therapy may be initiated and the dose increased once the primary end-
point (treatment failure) is reached. However no dose modification or commencement of adjunctive 
immunosuppressive therapy is allowed within the 30 days prior to initiation of the next IMP.  Prophylaxis 
against infections and bone protection will be given as per local practice.  Investigators should note any 
prohibited/permitted conmeds as specified in each IMP SmPC at the time the patient is receiving that 
particular IMP or IMP-placebo 
10.5 Emergency unblinding 
In the event of a valid medical or safety reason (e.g. in the case of an SAR where it is necessary for the 
investigator or treating health care professional to know which treatment the participant is receiving 
before the participant can be treated), the responsibility to break the treatment code resides solely with 
the treating clinician (i.e. investigator or sub-investigator). Investigators should note that the occurrence 
of an SAE should not routinely precipitate the immediate unblinding. 
 
The online Sealed Envelope randomisation system will be used for emergency unblinding.  Appropriately 
trained and delegated site staff will be given the necessary access rights and permissions to access this 

36 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
facility.  The name, contact details of the unblinder and reason for unblinding will be recorded within the 
Sealed Envelope system.  
 
The unblinder will not be shown the treatment allocation sequence on-screen.  Instead, the allocation 
will be sent to  the unblinder by email  and should be printed and retained confidentially within the 
Investigator Site File. An email stating that an unblinding has taken place will be automatically sent to 
the coordination team for oversight purposes. It is the responsibility of the treating physician to 
promptly document and explain the necessity for unblinding to the CI and the Sponsor.  The IMPs in use 
are licenced biologic drugs and the trial physicians will have knowledge of their effects and risks, and the 
trial teams will know which IMP treatment protocol a participant is on at any one time; therefore in the 
event of the online unblinding system being unavailable, or in an emergency setting, it should be 
assumed that a participant is on active IMP and treated accordingly and IMP stopped.  The central trial 
coordinator should be notified immediately by email that unblinding is needed and the system is 
unavailable, and that IMP has been stopped.  Unblinding should occur as soon as the online system is 
reavailable. If an unblinding event occurs the participant will be withdrawn from the trial.  Further 
details are provided in the trial procedures manual. 
10.6 Accountability and dispensing  
10.6.1 Drug accountability  
Accountability records will be maintained by the site pharmacy, detailing which treatment was 
dispensed at each treatment visit, including batch number.  Refer to pharmacy manual for further 
details. 
10.6.2 Returns and destruction   
Sites must maintain a full accountability record for the IMPs which may include receipt, storage, 
dispensing, administration, return of unused IMP and destruction of returned/unused trial medication. 
Template accountability forms will be supplied to sites. However, sites are permitted to use their own 
drug accountability records as long as these are available to the Sponsor. Refer to pharmacy manual for 
further details. 
 
11 Procedures and assessments 
All procedures and assessments will be conducted in the hospital setting by suitably trained medical 
professionals. Procedures and assessments are summarised in both the Clinic Visit SoE (Section 11.6) 
and IMP SoE (Section11.7). 
 
11.1 Participant identification  
 
  
Participants will be identified by the trial team during their attendance to outpatient clinics or during the 
course of an inpatient admission. Participants and/or their guardians (for paediatric participants) will be 
approached by the investigator or researchers who are part of the clinical care team. However, if the trial 
team are not involved in the participant’s clinical care, verbal consent from the participant and/or their 
guardian (for paediatric participants) will be sought by the clinical care team to allow them to be 
approached by the trial team. Once contact has been made with the participant and/or their guardians, 
the trial team will outline and explain the aims of the trial. A copy of the Participant Information Sheet 
will be provided to interested participants and/or their guardians, who will then be given the opportunity 
to consider the information with relatives and then to discuss the trial with trial staff and have any queries 
answered before consenting to participate in the trial. 

37 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
11.2 Consent  
The Informed Consent Form and Assent form will be approved by the REC and must be in compliance with 
GCP, local regulatory requirements and legal requirements.  The investigator or designee must ensure 
that each trial participant, or his/her legally acceptable representative where appropriate, 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 participant or legal guardians 
of participants under the age of 16 before any trial-specific activity is performed. Written informed assent 
will also be sought from participants aged 5-15 years old. Any paediatric participant that turns 16 during 
the trial will be re-consented using the adult PIS and ICF.  
 
The informed consent and assent form used for this trial and any change made during the course of this 
trial, must be prospectively approved by the REC.  The investigator will retain the original of each 
participant signed informed consent form. 
 
Should a participant require a verbal translation of the trial documentation by a locally approved 
interpreter/translator, it is the responsibility of the individual investigator to use locally approved 
translators.   
 
Any new information which becomes available, which might affect the participant’s and/or their 
guardians’ willingness to continue participating in the trial will be communicated to the participant and/or 
their guardians as soon as possible. This information will be provided verbally over the telephone and/or 
at their next visit. 
 
Participants will be encouraged to enrol in the UK and Ireland Vasculitis Rare Disease Group (UKIVAS) 
registry at the time of enrolment in to the BIOVAS trial if not already registered. The UKIVAS registry is 
collaboration between patients, clinicians and scientists to create the first comprehensive database of 
vasculitis patients in the UK and Ireland. By collecting longitudinal data, the UKIVAS aims to provide an 
evidence base to enhance diagnosis and treatment of patients with vasculitis. Furthermore, participants 
are provided with the option to consent to having their data collected for registration into Public Health 
Englands’ National Congenital Abnormality and Rare Disease Registration Service (NCARDRS), which forms 
part of the UK Rare Diseases Strategy.  Participating sites are requested to collect data such as NHS 
number/full name/Date of Birth/Diagnosis and Date of Diagnosis for those patients who have provided 
optional consent, which is sent every 6 months via secure (i.e. nhs.net to nhs.net) email to the NCARDRS.   
 
11.3 Screening evaluation 
11.3.1 Screening Assessments 
Trial specific assessments will only be conducted after participants have given written informed consent. 
After consent has been obtained, participants will be reviewed to ensure they meet all of the inclusion 
criteria and none of the exclusion criteria of the trial. 
 
Consented participants will enter a screening period of up to 28 days. During the screening period the 
following procedures and assessments will be performed: 
● Demographics: date of birth, sex, race 
● Medical history/investigations/medication will be assessed in relation to eligibility 
● Physical exam 
● Vital signs 
● Tuberculosis (latent/active) screening as per local Investigator’s clinical practice  
● Urine dipstick test as per local investigator’s clinical practice 
● The following laboratory tests: 

38 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
o Biochemistry: CRP, LFT, U&E, Lipid profile  
o Haematology: FBC, ESR 
o Immunology: Immunoglobulins 
o Virology: HIV, HBV, HCV (as per local practice). COVID19 test is recommended if this is 
part of local practice. 
o Serum pregnancy test for WOCBP only 
● Birmingham Vasculitis Activity Score v3 modified for BIOVAS(BVASv3-BIOVAS)/Paediatric 
Vasculitis Activity Score (PVAS) and physicians global assessment (PGA). 
● Indian Takayasu’s Arteritis Activity Score (ITAS) (TA participants only) 
● Relapsing polychondritis disease activity index (RPDAI) (RP participants only) 
● Participants will start recording their daily steroid use from date of informed consent. 
 
11.3.2 Participant Registration/Randomisation 
Once a participant has been confirmed eligible for the trial, the participant may be randomised and a 
unique trial ID will be allocated.  
 
Randomisation can occur at any point during the screening period after all eligibility criteria have been 
met.   Please ensure that there is at least 4 weeks between COVID-19 vaccine dose and baseline (D1) visit 
and receiving first dose of IMP. 
Details on randomisation using Sealed Envelope are provided in the Randomisation Manual. 
  
11.4 Treatment Period 
11.4.1 Clinic Visits 
The treatment period comprises Trial Clinic Visits 2 to 8 (Days 1, 120, 240, 360, 480, 600 and 720). All clinic 
visits will occur within a +/- 14 day window of the scheduled visit, unless under exceptional circumstances 
and first discussed with the central BIOVAS coordinator. The following procedures will be performed: 
 
Physical examination  
 
Vital signs 
 
Urine dipstick test as per local investigator’s clinical practice 
 
Standard of care bloods: CRP, LFT, FBC, ESR, U&E, immunoglobulins, lipid profile 
 
Birmingham Vasculitis Activity Score (BVAS) v3 modified for BIOVAS (BVAS v3-BIOVAS)/ 
Paediatric Vasculitis Activity Score (PVAS) 
 
Physician global assessment (PGA) 
 
Indian Takayasu Clinical Activity Score (ITAS) for TA participants only 
 
Relapsing polychondritis disease activity index (RPDAI) for RP participants only 
 
Vasculitis Damage Index (VDI)/ Paediatric Vasculitis Damage Index (PVDI) 
 
EuroQol (EQ-5D-5L)/Child Health Utility Index 9D (CHU-9D) 
 
Health resource use (NHS resource use/out of pocket costs/lost productivity) 
 
Review of participant steroid diary 
 
Serious Adverse Event (SAE)/ Adverse Event of Special Interest (AESI) review 
 
Concomitant medications review 
 
Administration of allocated IMP treatment if applicable 
If a participant is assessed to be experiencing a relapse, the current IMP may be halted and the participant 
switched to the next IMP in their allocated sequence. The participant IMP record CRF should be updated 
and the central coordination office in Cambridge and local pharmacy teams informed as soon as possible 
if there is a change in IMP. Day 1 of the next IMP in the sequence will only be administered at the 
subsequent pre-specified scheduled trial clinic visit (i.e. only on Days 120, 240, 360, 480 and 600 (+/- 14 
days). 

39 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
 
In the exceptional event of an IMP hospital stock/supply issue of an IMP at the time of a patient either 
starting IMP1, during the trial, or switching to next in sequence, the IMP in question (or its placebo 
equivalent) can be skipped to the following IMP in sequence, and the reason for additional switching 
documented. It is recommended to discuss with the CI any potential hospital IMP stock supply issues as 
they arise.  If the active IMP with the supply issue is the one with a placebo match allocated, and the 
supply issue for the active IMP is subsequently resolved by the time the matched allocation is due 
(whether for active or placebo), this may go ahead. 
 
An example of this is a Tocilizumab hospital stock shortage due to increased demand as a COVID treatment 
globally. In such a circumstance, if a patient was randomised to a sequence where IMP1 was either 
Tocilizumab or Tocilizumab placebo, and there was a hospital shortage of this, the patient can immediately 
be switched to the next IMP in sequence.  If the IMP shortage was encountered during the trial or at the 
time of a planned IMP switch due to relapse the patient can switch IMP at the next scheduled visit, due 
to supply issue, and treated with steroid accordingly until next scheduled visit.  If the active IMP with the 
supply issue is the one with a placebo match allocated, and the supply issue for the active IMP is 
subsequently resolved by the time the matched allocation is due (whether for active or placebo), this may 
go ahead. 
 
Urinary pregnancy testing will be performed monthly from day 1 through to 1 month after the last dose 
of IMP in the trial.  Patients can perform these tests at home if they do not have a treatment or trial visit 
scheduled at the time the monthly test is due to be performed; see section 11.4.4. 
 
A telephone call to the participant 2 weeks prior to their scheduled four monthly trial clinic visits is 
recommended to be made by the local trial team to try and gauge the disease activity. This may aid the 
logistics of drug administration, assist pharmacy and ward teams in case of a potential switch in IMP. 
 
 
11.4.2 Unscheduled Visit 
An unscheduled visit will be arranged for participants experiencing a relapse. The following assessments 
and procedures should be performed: 
 
Physical examination  
 
Vital signs 
 
Urine dipstick test as per local investigator’s clinical practice. 
 
Standard of care bloods: CRP, LFT, FBC, ESR, U&E, immunoglobulins. 
 
Birmingham Vasculitis Activity Score (BVAS)v3-BIOVAS/ Paediatric Vasculitis Activity Score 
(PVAS) 
 
Physician global assessment (PGA) 
 
Indian Takayasu Clinical Activity Score (ITAS) for TA participants only 
 
Relapsing polychondritis disease activity index (RPDAI) for RP participants only 
 
Vasculitis Damage Index (VDI)/ Paediatric Vasculitis Damage Index (PVDI) 
 
EuroQol (EQ-5D-5L)/Child Health Utility Index 9D (CHU-9D) 
 
Health resource use (NHS resource use/out of pocket costs/lost productivity) 
 
Serious Adverse Event (SAE) review 
 
Concomitant medications review 
11.4.3 IMP Visits 
IMP administration will follow the scheduled visits listed in the IMP SoE (Section 11.7). The initiation of 
IMP administration will begin at IMP Day 1, which occurs at pre-specified scheduled trial clinic visit (i.e. 
only on Days 120, 240, 360, 480 and 600 (+/- 14 days)).  Where an IMP visit coincides with a monthly 
pregnancy test, this can be performed in clinic on the same day as the treatment visit, as well as 

40 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
conducting AE/SAE review with the patient.  Most recent clinical blood tests (within 30 days of treatment 
visit) should also be reviewed prior to administering IMP.   
 
11.4.4. Safety monitoring visits 
 
Additionally, safety reviews will be conducted monthly, either remotely by telephone with the patient, or 
in person if coinciding with a treatment visit.  Safety monitoring will include: AESI/SAE review, routine 
clinical blood review (for patients on Tocilizumab/Tocilizumab dosing schedule, routine blood 
FBC/WBC/ESR/CRP/LFT and lipid results available within past 30 days; for Infliximab/infliximab placebo 
and rituximab/rituximab placebo schedules, review of FBC/WBC and LFT at a minimum; results available 
within past 30 days), review of urine pregnancy test result (for WOCBP participants). 
 
11.5 Trial assessments 
Procedures and assessments at the scheduled visits are listed in the Clinic Visit SoE (Section 11.6) whilst 
IMP infusion activity is listed in a separate IMP SoE (Section 11.7)  
 
For the purposes of this trial, a month will be deemed to have 30 days and a year 360 days. The total 
duration of the trial will be 720 days (2 years). 
11.5.1 Timing of assessments 
Participants will be seen every 120 days (+/-14days) for clinic visits. Upon randomisation, participants will 
be allocated a sequence of 4 IMP treatments. The first allocated IMP will be given on Day 1 of the 
treatment period and the participant will continue to follow the first IMP treatment dosing schedule as in 
the first IMP SoE (Section 11.7) until the investigator deems the participant to have met the treatment 
failure criteria as previously defined.  
 
If the treatment failure criteria have been met, the second IMP in the randomisation sequence will then 
be initiated at the next scheduled clinic visit (i.e. Days 120, 240, 360, 480 or 600). The first dose of the 
second IMP will be given beginning at Day 1/Visit 1 of the second IMP SoE (Section 11.7) and continue 
following the second IMP SoE schedule until treatment failure.  
 
Upon treatment failure of the second IMP, the third IMP will then be initiated at the next scheduled clinic 
visit (i.e. Days 240, 360, 480 or 600).  The first dose of the third IMP will be given beginning at Day 1/Visit 
1 of the third IMP SoE (Section 11.7) and continue following the third IMP SoE schedule until treatment 
failure. 
Upon treatment failure of the third IMP, the fourth IMP in the randomisation sequence will then be 
initiated at the next scheduled clinic visit (i.e. Days 360, 480 or 600). The first dose of the fourth IMP will 
be given beginning at Day 1/Visit 1 of the fourth IMP SoE (Section 11.7) and continue following the fourth 
IMP SoE schedule. 
 
The clinic visit schedule (Section 11.6) will remain as per the schedule assigned at randomisation and will 
not be affected by change in IMP.  
 
Additional unscheduled visits will also occur to capture relapse data.  
 

41 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
11.6 Trial clinic visit Schedule of Events (SoE) 
 
 
 
 
SCR
1
2
3
4
5
6
7
8
Day
 -14 to -
1
1
15
30
60
90
120
135
150
180
210
225
240
270
300
315
330
360
390
405
420
450
480
495
510
540
570
585
600
630
660
675
690
720
Month
1
2
3
4
4.5
5
6
7
7.5
8
9
10
10.5
11
12
13
13.5
14
15
16
16.5
17
18
19
19.5
20
21
22
22.5
23
24
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Virology screeningf
Serum pregnancy test 
(WOCBP only)h
RPDAI (RP patients only)
ITAS (TA patients only)
PGA
Resource use 
questionnaire
Dispense / review patient  
steroid diary
Concomitant medications 
review
AESI/SAE review
Unscheduled V
 Treatment Period
Study 
Timepointa
EQ5D-L/CHU-9D
VDI/PVDI
BVAS/PVAS
 Clinic Visit Number 
Informed Consent
Demographics, Medical 
History, Prior Medications
Physical Examinationc
Vital Signsd
Routine blood testse
Routine Immunoglobulins 
blood test
Randomisationb
Tuberculosis screeningg

42 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
11.7 IMP Schedule of Events (SoE) 
Treatment Period (as per patient schedule) 
 
 
a. 
Trial clinic visits must occur within a +/- 14 day window of the scheduled trial clinic visit. 
b. 
Randomisation must occur after all screening procedures have been performed and the participant has been confirmed eligible to enter the trial. 
c. 
Physical examination  
d. 
Vital signs will include body weight (kg), heart rate, body temperature and blood pressure. 
e. 
Standard of care bloods will include: CRP, LFT, FBC, U&E, lipid profile and ESR. 
f. 
Virology screening bloods will include: HIV, HBV and HCV as per local practice. 
g. 
Tuberculosis screening as per local practice. 
h. 
Serum pregnancy test at screen only.  Urine pregnancy tests monthly thereafter as part of monthly safety review. 
i. 
,  Infliximab up to D70 and Rituximab D15 visits should occur within a +/-3d window, with subsequent doses occurring within a +/-14d window.  All Tocilizumab visits should occur within a +/-7d window 
j. 
Infliximab infusions will be administered at days 1, 15 (+/-3d), 42 (+/-3d) and 70 (+/-3d), then every 56 days (+/-14d) thereafter (ie days 126, 182, 238, 294, 350, 406, 462, 518, 630 and 686. 
k. 
Rituximab infusions will be administered on IMP Days 1   and 15 (+/-3d),, Days 180 (+/-14d),, 360 (+/-14d),  and 540 (+/-14d), 
l. 
Tocilizumab infusions will be administered every 30 days (+/-7 d), on IMP Days 1, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360, 390, 420, 450, 480, 510, 540, 570, 600, 630, 660 and 690.
1
15 30 43 60
70 90 120 126 150 180 182 210 238 240 270 294 300 330 350 360 390 406 420 450 462 480 510 518 540 570 574 600 630 660 686 690 720
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
14
15
16
17
18
19
20
21
22
23
24
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1
2
3
4
5
X
X
X
X
X
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
INFLIXIMAB/ INFLIXIMAB-
PLACEBO infusion (Days 
1,15,43,70, then every 56 days)
IMP Visit Number for rituximab
RITUXIMAB/ RITUXIMAB-
PLACEBO infusion (Day 1 and 
15, followed by every 180 days)
IMP Visit Number for 
Tocilizumab
TOCILIZUMAB/ TOCILIZUMAB-
PLACEBO infusion (every 30 
days)
IMP 
Timepoin
From start of IMP
Day
Month
IMP Visit Number for Infliximab
Safety monitoring-ALL IMPs
includes: monthly urine 
pregnancy test & review, 
AE/SAE review, clinlab results 
review

43 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
11.8 End of Trial Participation 
Participants are considered to have completed the trial once they have completed 2 years of treatment 
phase i.e. completed their Day 720 trial clinic visit. 
If a participant is withdrawn from trial treatment early, they will still be encouraged to attend the 
remaining clinic visits and undergo the trial assessments as detailed in the schedule of events.  
11.9 Trial restrictions 
Participants should not receive live or live attenuated vaccines within 45 days of screening or throughout 
the trial, or within 12 months of the last dose of Rituximab. 
A serum pregnancy test will be performed on women of childbearing potential (WOCBP) during the 
screening period.  At the time of an investigator-initiated switch to next IMP in the randomised sequence, 
a urine pregnancy test is required, as per standard clinical practice for initiation of a biologic.  
Furthermore, for safety monitoring purposes, monthly urine pregnancy tests will be carried out.  These 
can be performed by the patient at home if the monthly tests do not match the patient’s randomised IMP 
dosing schedule. 
A women is considered of childbearing potential if she is fertile, following menarche, and until becoming 
post-menopausal* unless is permanently sterile**. 
 
*Post-menopausal is defined as: No menses for 12 or more months without an alternative medical 
cause.  FSH laboratory value can be used to confirm post-menopausal status in women not using 
hormonal contraception or homone replacement therapy. 
**Permanently sterile is defined as: hysterectomy, bilateral salpingectomy, bilateral oophorectomy. 
 
Women of childbearing potential are required to use a highly effective method of contraception for the 
duration of the trial and for 12 months after the completion of the trial/last treatment.  This includes: 
● Combined hormonal contraception (pill, contraceptive injection or implant) 
● Progesterone only hormonal contraception (pill, contraceptive injection or implant) 
● Intrauterine device (IUD) 
● Intrauterine hormone releasing system (IUS) 
● Bilateral tube occlusion 
● Vasectomised partner 
● True abstinence (where this is in accordance with the particpants preferred and usual lifestyle) 
 
 
12 Assessment of Safety  
12.1 
Definitions 
12.1.1 Adverse event (AE) 
Any untoward medical occurrence in a participant or clinical trial participant 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. 
Due to the underlying clinical conditions of the trial populations, it is not practicable to record all 
adverse events in this trial.  Therefore, only adverse events of special interest (AESIs) as described in 
section 12.3 will be reported from the point of informed consent until the end of participation in the 

44 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
trial for each participant. 
 
12.1.2 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 argument to 
suggest a causal relationship. 
12.1.3 Unexpected adverse reaction  
An adverse reaction, the nature, or severity of which is not consistent with the applicable reference 
safety information (RSI) (Section 12.1.6). 
 
When the outcome of the adverse reaction is not consistent with the applicable RSI 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 participant /event outcome or action criteria. 
12.1.4 Serious adverse event or serious adverse reaction (SAE / SAR) 
Any untoward medical occurrence that at any dose: 
- 
results in death 
- 
is life-threatening 
- 
requires hospitalisation or prolongation of existing in participants´ hospitalisation 
- 
results in persistent or significant disability or incapacity 
- 
is a congenital anomaly or birth defect. 
- 
is an important medical event - Some medical events may jeopardise the participant or may 
require an IMP to prevent one of the above characteristics/ consequences. Such events 
(hereinafter referred to as ‘important medical events’) should also be considered as ‘serious’ 
 
Life-threatening in the definition of a serious adverse event or serious adverse reaction refers to an 
event in which the participant 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. 
 
When reporting a SAE, causality and expectedness should be assessed for each IMP. 
12.1.5 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. 
 
Any potential SUSARs will be assessed by an unblinded central safety officer.  
12.1.6 Reference Safety Information (RSI) 
A list of medical events that defines which reactions are expected for the IMP within a given trial and 
thus determining which Serious Adverse Reactions (SARs) require expedited reporting.  
The RSI is contained in a clearly identified section of the Summary of Product Characteristics (SmPC). 
 
For this trial the Reference Safety Information is:  
Section 4.8 of the following SmPCs approved by the MHRA for use in this trial: 

45 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
● Mabthera (rituximab) 100 mg concentrate for solution for infusion, Roche Products Limited 
Table 4 dated 27/02/2020 
● RoActemra (tocilizumab) 20mg/ml concentrate for solution for infusion, Roche Products 
Limited  Table 1 dated 17/10/2019  
● Remsima (infliximab) 100mg powder for concentrate for solution for infusion, Napp 
Pharmaceuticals Limited, Table 1 dated 12/12/2019  
 
12.2 
Expected Adverse Reactions/Serious Adverse Reactions (AR /SARs) 
All expected Adverse Reactions are listed in the latest MHRA approved version of the RSI as specified in 
section 12.1.6.  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 
12.6. 
12.3 
Expected Adverse Events/Serious Adverse Events (AE/SAE) 
 
Any pre-planned or elective surgery that necessitates hospital admission will not be considered a SAE and 
does not need expedited reporting, however details will be collected in the CRF. 
 
All serious adverse events should be reported according to guidance in section 12.6. 
 
In addition to all SAEs, all infections requiring antimicrobial, antiviral or antifungal treatment are being 
collected as adverse events of special interest (AESIs) as part of the BIOVAS trial. 
 
Each Principal Investigator must report all AESIs to the CI using the CRF in a timely manner. If the AESI is 
deemed to be serious, then the reporting procedure for an SAE should be followed as detailed in section 
12.6.  
 
12.4 
Pregnancy Reporting 
All pregnancies within the trial should be reported to the Chief Investigator and the Sponsor using the 
relevant Pregnancy Reporting Form within 24 hours of notification. 
Details of all pregnancies in female participants will be collected after the start of trial treatment and until 
12 months after the last dose of IMP. 
Pregnancy is not considered an SAE unless a negative or consequential outcome (e.g., spontaneous 
abortion, foetal death, stillbirth, congenital anomalies, and ectopic pregnancy) is recorded for the mother 
or child/foetus.   
Any SAE occurring in association with a pregnancy, brought to the investigator’s attention after the 
participant has completed the trial and considered by the investigator as possibly related to the trial 
treatment, should be reported to Sponsor within 24 hours. 
12.5 
Evaluation of adverse events  
The Sponsor expects that reportable adverse events (i.e. AESI, SAEs, Pregnancies) are recorded from the 
point of Informed Consent regardless of whether a participant has yet received a medicinal product. 
Individual adverse events should be evaluated by the investigator.  This includes the evaluation of its 
seriousness, and any relationship between the investigational medicinal product(s) and/or concomitant 
therapy and the adverse event (causality).   
12.5.1 Assessment of seriousness  
 

46 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
Seriousness is assessed against the criteria in section 12.1.4.This defines whether the event is an adverse 
event, serious adverse event or a serious adverse reaction 
12.5.2 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 or recording in the appropriate section of the CRF. 
12.5.3 Clinical assessment of severity 
 
Mild: 
The participant is aware of the event or symptom, but the event or symptom is easily 
tolerated 
Moderate: The participant experiences sufficient discomfort to interfere with or reduce his or her 
usual level of activity 
Severe: 
Significant impairment of functioning; the participant is unable to carry out usual activities 
and / or the participant’s life is at risk from the event. 
 
12.5.4 Recording of adverse events 
 Adverse events of special interest (AESI) should be recorded on the AESI reporting form as described in 
section 12.3. Serious Adverse Events and Serious Adverse Reactions should be reported to the sponsor 
as detailed in section 12.6 
12.6 
Reporting serious adverse events 
Each Principal Investigator must report all serious adverse events to the Chief Investigator using the trial 
specific SAE form within 24 hours of their awareness of the event.   
 
The Chief Investigator is responsible for ensuring the assessment of all SAEs for expectedness and 
relatedness is completed and the onward notification of all SAEs to the Sponsor immediately but not more 
than 24 hours of first notification.  The Sponsor has to keep detailed records of all SAEs reported to them 
by the trial team.  
 
The Chief Investigator is also responsible for prompt reporting of all serious adverse event findings to the 
competent authority (e.g. MHRA) of each concerned Member State if they could: 

47 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
● adversely affect the health of participants   
● impact on the conduct of the trial  
● alter the risk to benefit ratio of the trial 
● alter the competent authority’s authorisation to continue the trial in accordance with Directive 
2001/20/EC 
 
The completed SAE form should be emailed.  Details of where to report the SAE’s can be found on the 
BIOVAS SAE form and the front cover of the protocol.   
12.7 
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 12.1.6 for the Reference Safety Information to be used 
in this trial. 
12.7.1 Who should report and whom to report to? 
The Sponsor delegates the responsibility of notification of SUSARs to the Chief Investigator. The Chief 
Investigator must report all the relevant safety information previously described, to the:  
● Sponsor  
● competent authorities in the concerned member states (e.g. MHRA) 
● Ethics Committee in the concerned member states 
 
The Chief Investigator shall inform all investigators concerned of relevant information about SUSARs that 
could adversely affect the safety of participants. 
12.7.2 When to report? 
12.7.2.1 Fatal or life-threatening SUSARs 
The CI must inform the Sponsor of any fatal SUSAR immediately but not more than 24 hours of first 
notification. The MHRA and Ethics Committee must 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 all parties within an additional 8 calendar days. 
12.7.2.2 Non-fatal and non-life-threatening SUSARs 
All other SUSARs and safety issues must be reported to the Sponsor immediately but not more than 24 
hours of first notification. The MHRA and Ethics Committee should be notified 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. 
12.7.3 How to report? 
12.7.3.1 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 participant (e.g. trial participant code number) 

48 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
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) 
12.7.3.2 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. 
12.7.3.3 Format of the SUSARs reports 
Electronic reporting is the expected method for expedited reporting of SUSARs to the competent 
authority. The format and content as defined by the competent authority should be adhered to. 
.  
 
Pregnancy is not considered an AE unless a negative or consequential outcome is recorded for the mother 
or child/foetus.  If the outcome meets the serious criteria, this would be considered an SAE. 
13 Toxicity – Emergency Procedures 
For this trial, any dose of infliximab in excess of 5mg/kg (adults and children); tocilizumab in excess of 
800mg (adults and children); rituximab in excess of 1000 mg IV within a 24 hour period (children: 
maximum 1000mg/dose)will be considered an overdose. There is no specific recommended treatment for 
overdose of infliximab, tocilizumab or rituximab.  
 
In the event of an infliximab, rituximab or tocilizumab overdose, the investigator should: 
 
- 
Contact the Trial Physician immediately. 
- 
Closely monitor the participant for AE/SAE and laboratory abnormalities. 
- 
Document the quantity of the excess dose as well as the duration of the overdosing in the CRF. 
 
Decisions regarding dose interruptions will be made by the investigator in consultation with the Trial 
Physician based on the clinical evaluation of the participant. 
 
14 Evaluation of Results (Definitions and response/evaluation of outcome 
measures) 
Timings and details of efficacy assessments are shown in the Clinic Visit SoE (section 11.6).  
Trial objectives are shown in section 8.5. 
14.1 
Response criteria 
14.1.1 Time to treatment failure 
Primary treatment failure is defined as progressive disease (worsening of Birmingham vasculitis activity 
score v3.0 modified for BIOVAS (BVAS v3-BIOVAS) or paediatric vasculitis activity score (PVAS) compared 

49 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
to baseline) within 120 days or failure to achieve response (see definition below) by 120 days. In such 
cases, TTF will be zero. 
 
Secondary treatment failure is defined as having achieved response (definition below) by 120 days from 
the time of IMP commencement, and subsequently relapse after 120 days from IMP commencement.       
 
Response is defined by: 
 
Absence of new/worse BVAS v3-BIOVAS (adults) / PVAS (children) items assessed at the 120 
days evaluation time point after commencing IMP AND 
 
Prednisolone  ≤ 10mg/day or ≤ 0.2 mg/kg for children (whichever is lower), unless the baseline 
dose is ≤ 10mg/day or ≤ 0.2 mg/kg children (whichever is lower) in which case it should not 
be more than the baseline dose* 
* Baseline dose is the dose of oral prednisolone, mg/day, or equivalent steroid, averaged over the 7 days 
prior to the start of each new IMP.      
      
Relapse is defined by either: 
1. Appearance of ≥ 1 severe (new/worse) or ≥ 3 non-severe (new/worse) BVAS v3-
BIOVAS/PVAS items from the time of BVAS   response  (as defined above) assessed at 
120 day evaluation time points # OR  
2. The need to increase the dose of prednisolone to > 20mg/day to treat vasculitis OR 
3. The need to increase the dose of an immunomodulator or immune-suppressive therapy 
in order to treat vasculitis. 
# Non-severe items can be upgraded by the investigator to severe based on their potential clinical impact, 
e.g. headache in GCA, thus could meet failure criteria if only one or two items are present.       
       
For an increase in one or two non-severe new/worse BVAS/PVAS items, which does not meet the relapse 
definition, the current IMP is continued and the participant may be treated, at the physician’s discretion, 
with a prednisolone increase to no more than 20mg/day (or 0.3mg/kg but no more than 20mg/day in 
children) which will be reduced to the previous dose within 6 weeks.      
 
A minor relapse is defined as an increase in one or two non-severe BVAS items. A minor relapse does not 
require a change in IMP. The participant may be treated, at the physician’s discretion, with a transient 
steroid increase of no more than 20mg/day reduced to previous dose within 6 weeks.    
 
Storage and Analysis of Samples  
No samples will be stored as part of the BIOVAS trial. All specimens will be analysed at each participating 
site via standard of care processes. 
15 Statistics 
15.1 
Statistical methods  
 
Data analysis: 
 
A full Statistical Analysis Plan (SAP) will be developed and finalised prior to the final database lock.  
 

50 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
For the primary analysis, we will include all participants who were entered and randomised. For the TTF 
outcome we will use a mixed-effects Cox regression model (as implemented by the ‘coxme’ package in R). 
The unit of analysis will be each allocation to a treatment (so that a participant may contribute up to four 
data points). Fixed effects are treatment assignment; a normally distributed random effect for each 
individual is included. Ties in the outcome are handled using the method of Efron. The effect of each 
experimental treatment vs. placebo will be estimated from this model, with Wald tests performed. 
 
If a participant drops out of the trial during a treatment period, then their TTF will be censored at the time 
of dropout. The only exception to this will be if a participant drops out before the first remission 
assessment is done (so that it is not clear whether they went into remission or not) – in that case, their 
outcome will be imputed with a multiple imputation procedure. We expect dropout to be low, so it is 
possible there will be no such issues with the analysis. 
 
As a secondary analysis, we will repeat the above for each of the eight disease subgroups. As an 
exploratory analysis we will also use a Bayesian hierarchical model that will allow information to be 
borrowed between the different disease subgroups if there is evidence the effect size is similar (37). A full 
analysis plan will be developed with sensitivity analyses proposed to ensure results are robust. 
 
Secondary outcomes will be analysed in the pooled set of all participants, in a similar way to the primary 
outcome, but with a suitable regression model used for the type of data. Time-to-event outcomes will be 
analysed in the same way as the primary outcome; binary outcomes will use a mixed-effects logistic 
regression model. 
 
15.2 
Interim analyses 
No interim analyses are planned with regards to the primary endpoint, but the Trial Management Group 
and Trial Steering Committee will 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. 
 
15.3 
Number of Participants to be enrolled 
15.3.1 Sample size determination 
There are three primary hypotheses of the trial – superiority of: 
1. infliximab vs. placebo, 
2. rituximab vs. placebo and 
3. tocilizumab vs. placebo 
They will be evaluated on the time to treatment failure (TTF) outcome. The primary analysis is in the entire 
group of participants. Secondary analyses involve testing for a difference in individual diseases either 
using frequentist or Bayesian hierarchical methods depending on the sample size. Where some clinical 
experience exists we will elicit priors for Bayesian analyses before the start of the trial (36). We present 
here the power for the main (pooled) analysis and for various samples sizes. 
 
Because the diseases are rare, we cannot necessarily choose the sample size based on a specified effect 
size. Instead we investigate the power of the design given a realistic number of participants that could be 
recruited over the course of the trial. Since the trial design is novel, there are no sample size formulae 
available. Instead we use simulations to explore the power of the trial design. For the power calculation 
we make these assumptions: 1) Each participant is followed up until they relapse on all four treatments, 

51 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
or two years from the initial randomisation has passed; 2) the final test statistics for the three comparisons 
(infliximab vs. placebo, rituximab vs. placebo, tocilizumab vs. placebo) are each tested at a nominal two-
sided 5% type I error rate. Due to sample size constraints, we do not make a formal adjustment for 
multiple testing. Instead we note that since we would only take forward treatments that are significantly 
better than placebo, the trial design has a maximum chance of incorrectly recommending an ineffective 
treatment of 7.5% (each hypothesis is 2.5% one-sided). Due to the correlation between tests, the actual 
maximum chance is likely to be closer to 5%. 
 
Simulations were performed in R with 5000 replicates per scenario. The TTF variable is simulated using an 
exponentially distributed random variable. If the simulated variable is less than four months, then the 
participant is classified as never having gone into remission, with their TTF included as zero. If the 
simulated variable is greater than four months, then the TTF is included as the simulated value. To allow 
for correlation of the TTF outcomes for a particular participant, we use a random frailty term for each 
participant. In the simulations this is uniformly distributed between 0.5 and 2. The parameter of the 
exponential distribution used for a participant’s TTF outcome will then be the overall hazard parameter 
for the treatment allocated multiplied by the frailty of the participant. In more mathematical language, 
let λj be the overall hazard parameter for arm j and θk be the frailty term for participant k; then if 
participant k is allocated arm j the hazard parameter for the TTF will be λjθk. The analysis used in the 
simulations is a mixed-effects Cox regression model (as implemented by the ‘coxme’ package in R). 
Treatment assignment is included as a fixed effect and a random effect for each individual is included. 
Ties in the outcome are handled using the method of Efron. 
 
We explored the power of the trial for pooled sample and different sample sizes. This involved specifying 
the TTF parameters for the four arms and exploring in what proportion of simulation replicates was each 
IMP (infliximab, rituximab & tocilizumab) significantly superior to placebo. We first considered the 
situation where two experimental treatments had the same effect as placebo (mean TTF of 0.3 years), 
and the other one varied in effect. The power of the trial to find the latter was significantly better than 
placebo is shown in Figure 3a (shown below). The power of the trial is 90% for the sample size of 140 
when the mean TTF is 6 months. 
 
We also examined the power to conclude significance of the second experimental treatment, for different 
effect sizes, when the first experimental treatment had a mean TTF of 0.6 years. The power is shown in 
Figure 3b (shown below). The power for lower sample sizes is notably lower in this case. However, the 
trial would still have high power for realistic treatment effects in the pooled analysis and larger disease 
subgroups. The lower power is because when one experimental treatment has a positive effect it will 
result in fewer participants being allocated to the other one (as they stay longer on the effective 
treatment). Again, the type I error rate is properly controlled. 
 

52 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
 
 
 
 
 
We finally looked at the power of the trial design to find significant treatment effects of infliximab, 
rituximab & tocilizumab when they had mean TTF of 8 months. Table 5 shows the probability of a 
participant not going into remission, the mean time in remission (conditional on going into remission) and 
the power for testing infliximab vs. placebo and tocilizumab vs. placebo in the different subgroups and 
the overall sample. There will be a cap on recruitment, a maximum of 50 participants in each disease 
group, in order to prevent the ‘easy to recruit group’, for e.g. giant cell arteritis, dominating the total 
sample.  
 
Table 1 Probability of a participant achieving and mean time in remission 
 
 
Placebo 
Infliximab 
Rituximab 
Tocilizumab 
Probability of 
not going into 
remission 
67% 
39.3% 
39.3% 
39.3% 
Mean time in 
remission 
3.6 months 
8 months 
8 months 
8 months 
Power: n=20 
N/A 
47.9% 
49.0% 
47.5% 
Power: n=40 
N/A 
77.3% 
77.6% 
77.8% 
Power: n=140 
N/A 
>99.9% 
>99.9% 
>99.9% 
 
15.4 
Criteria for the premature termination of the trial 
.   The trial may be terminated prematurely in the event of: 
 
1) a significant safety signal indicating harm of one of the treatment regimens as determined by the 
DSMB in conjunction with the TSC and sponsor, or 
2)    the funder (NIHR) terminating support for the trial. 
Figure 3 Simulations used to explore the power of the trial to conclude significance of experimental treatments 
as their mean time to remission varies. 3a Experimental treatments 1, 2 and placebo have their mean time to 
remission set to 0.3 years. 3b Experimental treatment 1 has mean time to remission set to 0.6 years; placebo 
set to 0.6 years. 

53 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
15.5 
Procedure to account for missing or spurious data 
For the primary outcome, if a participant drops out of the trial during a treatment period, then their TTF 
will be censored at the time of dropout. The only exception to this will be if a participant drops out 
before the first remission assessment is done (so that it is not clear whether they went into remission or 
not) – in that case, their outcome will be imputed with a multiple imputation procedure.  
 
Secondary endpoints will be analysed with mixed-effects models which account for missing data under a 
Missing At Random (MAR) assumption. 
15.6 
Economic evaluation 
15.6.1 Data Collection 
Quality of life (QoL) and cost effectiveness will be assessed in all randomised participants via the 
following validated research questionnaires: 
 
EQ-5D-5L (EuroQol) or Child Health Utility Index 9D (CHU-9D) 
 
 
QoL and health economic questionnaire packs will be administered to trial participants at the following 
time points, regardless of whether the participant is receiving treatment or not: 
 
Day 1 post randomisation  
 
120 days post randomisation (+/- 14 days)  
 
240 days post randomisation (+/- 14 days)  
 
360 days post randomisation (+/- 14 days)  
 
480 days post randomisation (+/- 14 days)  
 
600 days post randomisation (+/- 14 days)  
 
720 days post randomisation (+/- 14 days)  
 
Any unscheduled visits  
Research staff will provide the participant with the questionnaires in clinic where the participants 
and/or participant’s guardians will be asked to complete the questionnaires. If possible, all 
questionnaires should be completed prior to the participant’s clinical consultation as this aids objectivity 
and compliance.  
 
The baseline questionnaires must be completed after consent has been obtainedand prior to first dose 
of IMP.  The health resource use questionnaires should be completed prior to clinical assessment.   
15.6.2 Within trial cost effectiveness analysis 
The within trial economic evaluation will estimate the incremental cost effectiveness ratio (ICER) for each 
of treatment permutations compared to placebo over a period of 24 months from the perspective of the 
NHS and social care sector. A secondary analysis will be undertaken from the societal perspective. The 
analyses will use trial data collected to 24 months follow up. 
 
The primary outcome measure of the trial is TTF. The trial economic evaluation will, for consistency, use 
the same primary outcome measure. However, economic evaluations are designed to inform resource 
allocation decisions, so evaluations will also be produced using overall survival and quality adjusted life 
years (QALYs) outcome measures. The estimation of QALYs requires the production of utility weights for 
each health state observed in the trial population. We will use the EQ-5D-5L (EuroQol) or Child Health 
Utility 9D (CHU-9D) instruments for this purpose. 
 

54 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
Measurement of resource use: NHS resource use associated with each treatment modality will be 
collected. Data will also be collected on hospital admissions, extra outpatient visits, and use of supportive 
drugs to contribute to a health economics analysis of additional health costs related to treatment and the 
trial. Data collection will be through trial CRFs (investigations, drugs, referrals for other services), 
participant completed health economic questionnaires (the resource use questionnaire; contact with 
participant, community and social care services plus additional costs mentioned below) and use of 
hospital episode statistics (HES). Participant out of pocket expenditure will include travel costs to attend 
clinics and other miscellaneous expenditure. Lost productivity will be estimated based on employment 
status of the participant/and/or guardians (for paediatric participants). We will also measure and value 
the time contribution of carers (applicable to adult and paediatric participants). These data will be 
extracted from participant completed health economic questionnaires. Costs and outcomes will be 
discounted at 3.5% in line with current recommendations. 
 
Incremental cost effectiveness ratios will be presented. Analyses will combine crossover data to predict 
the expected cost-effectiveness of each treatment alone. Parameter uncertainty will be quantified using 
non-parametric bootstrapping techniques. Outputs will be presented as ICERs, cost effectiveness 
acceptability curves and expected net benefit. The permutation with the highest expected net benefit 
(mathematically identical to identifying the most cost-effective option with an incremental cost-
effectiveness ratio below the threshold using the NICE threshold of £20,000 per QALY) will be highlighted 
as the preferred treatment choice. Given the number of permutations there will be very small numbers 
of participants under each permutation and so the impact of missing data will be examined using 
imputation methods. Sensitivity analyses will explore the impact of key cost drivers and factors that might 
affect the outcomes measured on decision uncertainty. 
 
15.6.3 Modelling long-term cost effectiveness 
A long-term cost effectiveness analysis is required to capture the full impact of any therapy where it is 
possible that there is a difference in morbidity or mortality between IMPs. The exact structure of the cost 
effectiveness model will be established in discussions with the clinicians on the trial team and after 
analysis of any adverse event data observed in the trial. It is likely that the model will be a Markov or semi-
Markov state model. As far as possible the initial transition rates for the model will be estimated from the 
trial data – this will include data up to 24 months. For all model parameters for which data could not be 
collected within the trial e.g. longer term outcomes, recommended best practice will be followed in 
identifying and synthesising evidence in the published literature. 
 
The long term modelling will adopt strategies for addressing issues of perspective and discounting as the 
within trial analysis. The incremental cost effectiveness ratios and expected net benefit will be estimated. 
To address uncertainty, probabilistic sensitivity analyses will be undertaken using Monte Carlo simulation 
techniques.  
15.7 
Definition of the end of the trial  
The competent authority and Ethics Committee must be notified of the end of a clinical trial within 90 
days of its completion. The end of the trial will be the date of the last participant’s Day 720 Clinical Trial 
Visit.  
 

55 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
16 Data handling and record keeping 
16.1 
CRF 
All data will be recorded on electronic CRF (eCRF), which will be identified by trial ID. Full date of birth is 
also required for the purposes of randomisation.  In the event of technical difficulty or unavailability of 
eCRF, paper CRF will be used as back up and the data will be entered into the database at a later date. All 
trial data in the CRF/eCRF 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/eCRF will be accessible to trial coordinators, data managers, the investigators, Clinical 
Trial Monitors, Auditors and Inspectors as required. 
 
Copies of the hand-written CRF pages (if used) should be returned by email or post to the trial coordinating 
centre at Cambridge within 2 weeks of the evaluations. The investigator at each participating site will 
retain the original of each completed CRF in the relevant sections of their Investigator Site File. The 
investigators must ensure that the CRFs and other trial related documentation sent to the trial 
coordination centre does not contain any patient identifiable information. 
All hand-written 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. 
 
The participant steroid diary should be copied at each trial visit, and used to calculate average steroid use 
since last visit, which will be recorded in the CRF/eCRF. 
 
 
16.2 
Source Data 
To enable peer review, monitoring, audit and/or inspection the investigator must agree to keep records 
of all participating participants (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 participant medical records, signed consent forms, physician assessment forms 
including BVAS, ITAS, RPDAI and participant questionnaires and diary, laboratory results, prescriptions. 
Data reported on the eCRF that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained.  
16.3 
Data Protection & Participant Confidentiality 
All investigators and trial site staff involved in this trial must comply with the requirements of the Data 
Protection ACT 2018 and Trust Policy with regards to the collection, storage, processing, transfer and 
disclosure of personal information and will uphold the Act’s core principles.  
 
Participants will be assigned a unique identifier by the trial team upon enrolment to the trial.  
 
17 Data Monitoring Committee/Trial Steering Committee 
 

56 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
17.1 
Independent Data Monitoring Committee 
A Data Monitoring Committee will provide oversight of this trial. In line with NIHR guidelines the 
composition of the IDMC will be reviewed by the NIHR Programme Director and will include independent 
members only. The BIOVAS IDMC will consist of, at a minimum, two independent clinicians with 
experience in vasculitis trials and a statistician.  
 
A comprehensive charter for this trial will be drafted and implemented prior to the start of the trial. It is 
anticipated that the IDMC will receive summary safety reports and meet approximately 6 monthly to 
discuss the trial progress and review safety data. Ad hoc meetings of the IDMC can also be requested as 
needed to review reported safety events. 
 
17.2 
Trial Steering Committee (TSC) 
The role of the TSC is to provide overall supervision of the trial. The TSC will monitor the progress of the 
trial and maximise the chances of completing the trial within the agreed time scale and budget.  In line 
with NIHR guidelines the composition of the TSC will be reviewed by the NIHR Programme Director and 
will include a minimum of 75% independent members. The BIOVAS TSC will include an independent UK 
based Chair, independent clinician(s) and an individual able to represent a patient and/or wider public 
perspective. In addition, they will receive a summary of all SAEs to ensure that there are no major safety 
concerns. The TSC will meet regularly via teleconference. 
17.3 
Trial Management Group (TMG) 
The members of the TMG will meet via teleconference on a regular basis and are responsible for the 
design, conduct and overall management of the trial.  
 
18 Ethical & Regulatory considerations 
18.1 
Ethical committee review 
Before the start of the trial or implementation of any amendment we will obtain approval of the trial 
protocol, protocol amendments, informed consent forms and other relevant documents e.g., 
advertisements and GP information letters from the REC.  All correspondence with the REC will be retained 
in the Trial Master File/Investigator Site File. 
 
Annual reports will be submitted to the REC in accordance with national requirements.  It is the Chief 
Investigator’s responsibility to produce the annual reports as required. 
 
18.2 
Regulatory Compliance  
The trial will not commence until a Clinical Trial Authorisation (CTA) is obtained from the MHRA. The 
protocol and trial conduct will comply with the Medicines for Human Use (Clinical Trials) Regulations 2004 
and any relevant amendments. 
 
Development Safety Update Reports (DSURs) will be submitted to the MHRA in accordance with national 
requirements. It is the Chief Investigators responsibility to produce the annual reports as required. 
18.3 
Protocol Amendments 
Protocol amendments must be reviewed and agreement received from the Sponsor for all proposed 
amendments prior to submission to the HRA, REC and/or MHRA. 

57 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
 
The only circumstance in which an amendment may be initiated prior to HRA, REC and/or MHRA approval 
is where the change is necessary to eliminate apparent, immediate risks to the participants (Urgent Safety 
Measures).  In this case, accrual of new participants will be halted until the HRA, REC and/or MHRA 
approval has been obtained.   
 
18.4 
Peer Review 
The trial protocol has been designed by the Trial Management Committee, which includes representatives 
from Cambridge University and Cambridge University Hospitals NHS Foundation Trust. The trial design has 
been reviewed by external reviewers and by the funding panel as part of the application process for a HTA 
grant from NIHR. 
18.5 
Declaration of Helsinki and Good Clinical Practice 
The trial will be performed in accordance with the spirit and the letter of the declaration of Helsinki, the 
conditions and principles of Good Clinical Practice, the protocol and applicable local regulatory 
requirements and laws. 
18.6 
GCP Training 
All trial staff must hold evidence of appropriate GCP training or undergo GCP training prior to undertaking 
any responsibilities on this trial.  This training should be updated every 2 years or in accordance with your 
Trust’s policy.  
 
19 Sponsorship, Financial and Insurance  
The trial is sponsored by Cambridge University Hospitals NHS Foundation Trust and University of 
Cambridge.  The trial is funded by the National Institute for Health Research (NIHR) HTA programme 
(award 17/83/01). The views expressed are those of the authors and not necessarily those of the NIHR of 
Department of Health 
 
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 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.  
 
The University of Cambridge will arrange insurance for negligent harm caused as a result of protocol 
design and for non-negligent harm arising through participation in the clinical trial. 
 
20 Monitoring, Audit & Inspection 
The investigator must make all trial documentation and related records available should an MHRA 
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 participant data must be 
handled and treated confidentially. 
 
The Sponsor’s monitoring frequency will be determined by an initial risk assessment performed prior to 
the start of the trial. A detailed monitoring plan will be generated detailing the frequency and scope of 

58 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
the monitoring for the trial.  Throughout the course of the trial, the risk assessment will be reviewed and 
the monitoring frequency adjusted as necessary. 
 
Remote monitoring will be conducted for all participating sites. The scope and frequency of the 
monitoring will be determined by the risk assessment and detailed in the Monitoring Plan for the trial. 
21 Protocol Compliance and Breaches of GCP 
Prospective, planned deviations or waivers to the protocol are not allowed under the UK regulations on 
Clinical Trials and must not be used.  
 
Protocol deviations, non-compliances, or breaches are departures from the approved protocol. They can 
happen at any time, but are not planned. They must be adequately documented on the relevant forms 
and reported to the Chief Investigator and Sponsor immediately.   
 
Deviations from the protocol which are found to occur constantly again and again will not be accepted 
and will require immediate action and could potentially be classified as a serious breach.  
 
Any potential/suspected serious breaches of GCP must be reported immediately to the Sponsor without 
any delay. 
22 Publications policy 
Ownership of the data arising from this trial resides with the trial team.  On completion of the trial the 
data will be analysed and tabulated and a Final Trial Report prepared. 
 
The aim of this trial is to establish the clinical and cost-effectiveness of biologics in refractory NAAV. The 
data will also help to establish the much needed evidence in the treatment of these conditions. Evidence 
generated from this trial will inform NHS policy development, enhance service provision and optimise 
resource usage. We also anticipate added value through the collaborative nature of this trial in 
harmonizing treatment pathways and improving outcomes for NAAV across the UK. The direct comparison 
of targeted biologics has the potential to offer new insights into the relevant contribution of different 
pathogenetic pathways, although BIOVAS does not aim to be a mechanistic trial and will not collect 
biologic samples. Parallel mechanistic studies by BIOVAS participants, such as the TARGET Partnership and 
UKGCA Consortium will leverage further value from the trial. There is a paucity of detailed phenotype; 
outcome and health utilisation data on NAAV necessary for the appropriate refinement of clinical services, 
BIOVAS will contribute valuable data in this regard. A parallel biomarker trial will be developed through 
participating Biomedical Research Centres to optimize the value and opportunity of the clinical cohort and 
outcome data. 
 
A trial website will contain fields accessible to the general public and health care professionals as well as 
trial specific functionality. It will also update the wider community on trial progress. 
 
The output from this trial will be presented at national and international specialist conferences, published 
in peer reviewed international journals. Participants will be made aware of the trial results through our 
PPI group, in the clinics, by letters to the participants, by advertising in participant magazines, newsletters 
and participant attended workshops and conferences.  
23 References 
 
Akamine, K. & Punaro, M., 2019. Biologics for childhood systemic vasculitis. Pediatric nephrology (Berlin, 

59 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
Germany), 34(11), pp.2295–2309. 
Charlier, C. et al., 2009. Risk factors for major infections in Wegener granulomatosis: analysis of 113 patients. Annals 
of the rheumatic diseases, 68(5), pp.658–63. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18504289 
[Accessed November 24, 2016]. 
deGraeff, N. et al., 2019.  European consensus-based recommendations for the diagnosis and treatment of rare 
paediatric vasculitides-the SHARE inititative.  Rheumatology 58 pp.656-671 
Deng, J. et al., 2010. Th17 and Th1 T-Cell Responses in Giant Cell Arteritis. Circulation, 121(7), pp.906–915. Available 
at: http://www.ncbi.nlm.nih.gov/pubmed/20142449 [Accessed February 21, 2017]. 
Espígol-Frigolé, G. et al., 2013. Increased IL-17A expression in temporal artery lesions is a predictor of sustained 
response to glucocorticoid treatment in patients with giant-cell arteritis. Annals of the rheumatic diseases, 
72(9), 
pp.1481–7. 
Available 
at: 
http://ard.bmj.com/lookup/doi/10.1136/annrheumdis-2012-201836 
[Accessed February 21, 2017]. 
Ferfar, Y. et al., 2016. Biotherapies in large vessel vasculitis. Autoimmunity Reviews, 15(6), pp.544–551. 
Flossmann, O. et al., 2011. Long-term patient survival in ANCA-associated vasculitis. Annals of the rheumatic 
diseases, 70(3), pp.488–494. 
Furuta, S. et al., 2012. Switching of anti-TNF-α agents in Behçet’s disease. Clinical and experimental rheumatology, 
30(3 Suppl 72), pp.S62-8. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23010387 [Accessed August 27, 
2015]. 
Hernandez-Rodriguez, J. et al., 2003. Tissue production of pro-inflammatory cytokines (IL-1 , TNF  and IL-6) correlates 
with the intensity of the systemic inflammatory response and with corticosteroid requirements in giant-cell 
arteritis. Rheumatology, 43(3), pp.294–301. Available at: https://academic.oup.com/rheumatology/article-
lookup/doi/10.1093/rheumatology/keh058 [Accessed February 20, 2017]. 
Hoffmann, G.S. et al., 2007. Infliximab for Maintenance of Glucocorticosteroid-Induced Remission of Giant Cell 
Arteritis. Annals of internal medicine, (146), pp.621–630. 
Jennette, J.C. et al., 2012. 2012 Revised International Chapel Hill Consensus Conference Nomenclature of 
Vasculitides. 
In 
Revmatologiia 
(Bulgaria). 
pp. 
5–15. 
Available 
at: 
http://www.ncbi.nlm.nih.gov/pubmed/23045170 [Accessed July 10, 2014]. 
Jones, R.B. et al., 2010. Rituximab versus Cyclophosphamide in ANCA-Associated Renal Vasculitis. The New England 
journal of medicine, 363(3), pp.211–20. 
Mukhtyar, C., Guillevin, L., Cid, M.C., Dasgupta, B., de Groot, K., Gross, W., Hauser, T., Hellmich, B., Jayne, D., 
Kallenberg, C.G.M., Merkel, P. a, et al., 2009. EULAR recommendations for the management of large vessel 
vasculitis. Annals of the rheumatic diseases, 68, pp.318–323. 
Mukhtyar, C., Guillevin, L., Cid, M.C., Dasgupta, B., de Groot, K., Gross, W., Hauser, T., Hellmich, B., Jayne, D., 
Kallenberg, C.G.M., Merkel, P.A., et al., 2009. EULAR recommendations for the management of primary small 
and medium vessel vasculitis. Annals of the Rheumatic Diseases, 68(3), pp.310–317. Available at: 
http://ard.bmj.com/cgi/doi/10.1136/ard.2008.088096. 
Muratore, F., Pipitone, N. & Salvarani, C., 2017. Standard and biological treatment in large vessel vasculitis: 
guidelines and current approaches. Expert review of clinical immunology, pp.1–16. Available at: 
https://www.tandfonline.com/doi/full/10.1080/1744666X.2017.1285699 [Accessed February 20, 2017]. 
Nakagomi, D. et al., 2018. Comment on: Rituximab therapy for Takayasu arteritis: a seven patients experience and a 
review of the literature. Rheumatology. Available at: http://www.ncbi.nlm.nih.gov/pubmed/29385531 
[Accessed March 29, 2018]. 
Nesher, G., Sonnenblick, M. & Friedlander, Y., 1994. Analysis of steroid related complications and mortality in 
temporal arteritis: a  15-year survey of 43 patients. The Journal of rheumatology, 21(7), pp.1283–1286. 
NICE, 
2018. 
Tocilizumab 
for 
treating 
giant 
cell 
arteritis. 
NICE 
guideline, 
(April). 
Available 
at: 
nice.org.uk/guidance/ta518. 
Osman, M. et al., 2014. The Role of Biological Agents in the Management of Large Vessel Vasculitis (LVV): A 
Systematic 
Review 
and 
Meta-Analysis. 
PloS 
one, 
9(12), 
p.e115026. 
Available 
at: 
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4269410&tool=pmcentrez&rendertype=abstrac
t [Accessed March 18, 2015]. 
Sharkey I et al  2001.  Body surface area estimation in children using weight alone: application in paediatric oncology.  
British Journal of Cancer 85(1):23-28. 
Stone, J.H. et al., 2010. Rituximab versus Cyclophosphamide in ANCA-Associated Vasculitis. The New England journal 
of medicine, 363, pp.221–32. Available at: http://www.nejm.org/doi/full/10.1056/NEJMoa0909905#t=article 
[Accessed March 20, 2015]. 
Stone, J.H. et al., 2017. Trial of Tocilizumab in Giant-Cell Arteritis. The New England journal of medicine, 377(4), 

60 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
pp.317–328. 
Trieste, L. et al., 2012. Systemic vasculitis: How little we know about their societal and economic burden. Clinical and 
Experimental Rheumatology, 30(4 SUPPL.73), pp.6–8. 
Villiger, P.M. et al., 2016. Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, 
randomised, double-blind, placebo-controlled trial. The Lancet, 6736(16), pp.1–7. Available at: 
http://linkinghub.elsevier.com/retrieve/pii/S0140673616005602. 
Visvanathan, S. et al., 2011. Tissue and serum markers of inflammation during the follow-up of patients with giant-
cell arteritis--a prospective longitudinal study. Rheumatology (Oxford, England), 50(11), pp.2061–70. Available 
at: http://www.ncbi.nlm.nih.gov/pubmed/21873264 [Accessed February 15, 2017]. 
Weyand, C.M. & Goronzy, J.J., 2013. Immune mechanisms in medium and large-vessel vasculitis. Nature reviews. 
Rheumatology, 
9(12), 
pp.731–40. 
Available 
at: 
http://www.nature.com/doifinder/10.1038/nrrheum.2013.161 [Accessed February 21, 2017]. 
 
 
 
24 Appendices 
24.1 
Appendix 1 - Trial Management / Responsibilities 
24.1.1 Participant registration/ Randomisation procedure 
See section 9.3 of the Trial Protocol. 
24.1.2 CRF Completion & Data management 
The sponsor or designee is responsible for the data management of this trial including quality checking 
of the data.  
 
Data entered into the eCRF by authorised site personnel should be accurate, complete, and verifiable 
from source documents and completed in a timely manner. 
 
24.1.3 Preparation & submission of amendments 
The Sponsor has delegated responsibility for preparing and submitting amendments to the trial team. 
24.1.4 Preparation and submission of Annual Safety Report/Annual Progress Reports 
The Sponsor has delegated responsibility for preparing and submitting amendments to the trial team. 
24.1.5 Data protection/ confidentiality 
24.1.6 Trial documentation & archiving 
Each participating site is responsible for archiving their own trial data including source data, the 
Investigator Site File (ISF) for the appropriate time period as determined by the regulations governing 
clinical trials in place at the time of archival. The archiving facility may be at the participating site or 
at another appropriate location off-site as per local policy. The trial team will advise when the site 
may commence archiving. The site will need to provide the name and address of the archival facility 
to the Trial team. In case of audit or inspection following archival, the participating site will be 
expected to retrieve the relevant documentation within a reasonable timeframe. 

61 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
24.2 
Appendix 2 – Authorisation of Participating Sites 
24.2.1 Required Documentation 
Prior to initiating a participating site, the following documentation is required; 
● PI and other key trial team staff CV (signed and dated) and GCP certificate 
● Authority approval (HRA, REC, MHRA)  
● Local R & D capability and capacity approval 
● Participating Site Agreement  executed, including pharmacy participating  site agreement 
● Participant Information Sheets and consent forms on local headed paper 
● Protocol signed and dated by PI  
● Delegation of Authority Log 
● Confirmation of randomisation system training 
24.2.2 Procedure for initiating/opening a new site 
When all the regulatory paperwork is in place, prior to site opening, an initiation teleconference will take 
place. This will be led by the trial physician or clinical trial coordinator with as many of the local team 
present as is practicable. This initiation meeting constitutes training for the trial and it is therefore 
imperative that all members of the trial team who will be involved in the trial are represented at the 
meeting.  A log of attendees will be completed during the meeting.  The presentation slides will be 
provided to the site in advance of the meeting. A trial initiation form will be completed for each site 
initiation meeting. Copies of all initiation documentation must be retained in the Investigator Site File 
(ISF) and TMF. 
 
The sponsor’s regulatory green light procedure will be followed.  Following the green light, the site will 
be opened for recruitment and the randomisation system opened to that site. 
 
24.2.3 Principal Investigator Responsibilities 
The PI has overall responsibility for the conduct of the trial at the participating site. 
 
In particular, the PI has responsibilities which include (but are not limited to): 
● Ensuring the appropriate approvals are sought and obtained 
● Continuing oversight of the trial 
● Ensuring the trial is conducted according to the currently approved protocol 
● Ensuring consent is received in accordance with the protocol and national requirements 
● Ensuring that the ISF is accurately maintained 
● Delegation  of  activities  to  appropriately  trained  staff  (this  must  be documented on the 
Delegation of Authority Log) 
● Providing protocol or specialised training to new members of the trial team and ensuring that if 
tasks are delegated, the member of staff is appropriately trained and qualified 
● Appropriate attendance at the initiation meeting 
● Dissemination of important safety or trial-related information to all stakeholders at the 
participating site 
● Safety reporting within the timelines and assessment of causality and expectedness of all SAEs 
 
 
 

62 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
24.3 
Appendix 3 - Safety Reporting Flow Chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event (AE) 
No 
 
 
 
 
 
No – 
unrelated or 
unlikely 
 
 
 
 
 
 
 
Yes -
Expected 
 
Yes 
 
 
 
 
 
Yes - Definitely, Probably or 
Possibly  
 
 
 
 
 
 
No - Unexpected 
Is there a causal relationship to the IMP? 
Serious Adverse Event 
 
Record on the trial SAE form. 
Notify the trial coordinator 
immediately (within 24 hrs of 
becoming aware of the event) 
Was the event serious? 
Was the event specified in the 
protocol as an AESI? 
 
If Yes, record on the trial AESI 
form and send to the trial 
coordinator within 14 days 
 
If no, record AE in medical notes. 
Was the SAE one of the recognised undesirable effects of 
the IMP? 
Serious Adverse Reaction 
 
Record on the trial SAE form. 
Notify the trial coordinator 
immediately (within 24 hrs of 
becoming aware of the event) 
SUSAR 
 
Record on the trial SAE form. 
Notify the trial coordinator 
immediately (within 24 hrs of 
becoming aware of the event) 

63 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
24.4 
Appendix 4 – NAAV Classification Criteria 
 
GCA: 
1. AGE > 50 years (mandatory) AND  
2. Elevated inflammatory markers (mandatory) AND 
3. Either Imaging (CT/PET/MRA/US) or biopsy (showing current disease activity) OR  
4. Unequivocal cranial symptoms of GCA or PMR symptoms with historical evidence from either 
imaging/biopsy confirming a diagnosis of GCA. 
 
 
Takayasu’s Arteritis: consistent with ACR criteria with mandatory imaging  
 
Takayasu’s arteritis 1990 ACR  
 
1. Age at disease onset < 50 years  
Development of symptoms or findings related to Takayasu arteritis at age <50 years  
2. Claudication of extremities  
Development and worsening of fatigue and discomfort in muscles of 1 or more 
extremity while in use, especially the upper extremities  
3. Decreased brachial artery pulse  
Decreased pulsation of 1 or both brachial arteries  
4. BP difference >10 mm Hg  
Difference of >10 mm Hg in systolic blood pressure between arms  
5. Bruit over subclavian arteries or aorta  
Bruit audible on auscultation over 1 or both subclavian arteries or abdominal aorta  
6. Arteriogram abnormality  
Arteriographic narrowing or occlusion of the entire aorta, its primary branches, or 
large arteries in the proximal upper or lower extremities, not due to arteriosclerosis, 
fibromuscular dysplasia, or similar causes; changes usually focal or segmental  
* For purposes of classification, a participant shall be said to have Takayasu arteritis if at least 3 of these 
6 criteria are present. The presence of any 3 or more criteria yields a sensitivity of 90.5% and a specificity 
of 97.8%. BP = blood pressure (systolic; difference between arms).  
 
Paediatric diagnosis of Takayasu’s Arteritis: consistent with EULAR/PRINTO/PRES 2008 classification 
criteria. 
 
c-TA EULAR/PRINTO/PRES Ankara 2008 classification definition 
 
Angiographic abnormalities of the aorta or its main branches and pulmonary arteries showing 
aneurysm/dilation (mandatory criterion) plus one of the five following criteria: 
1. Pulse deficit or claudication 
2. Four limbs BP discrepancy 
3. Bruits 
4. Hypertension 
5. Acute phase response (ESR >20; or CRP > reference range for laboratory) 
 
PAN: consistent with EMA criteria (angiographic and/or biopsy evidence of disease) and exclusion of other 
vasculitides (Figure 1). 

64 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
 
 
Figure 1: EMA algorithm for diagnosis of PAN 
 
Paediatric diagnosis of PAN: consistent with EULAR/PRINTO/PRES classification criteria. 
 
c-PAN EULAR/PRINTO/PRES Ankara 2008 classification criteria  
 
Histopathology or angiographic abnormalities (mandatory) plus one of the five following criteria: 
1. Skin involvement 
2. Myalgia/muscle tenderness 
3. Hypertension 
4. Peripheral neuropathy 
5. Renal involvement 
 
Relapsing polychondritis: consistent with McAdam’s criteria – meet at least 3 of 6 McAdam’s criteria 
and/or 1 of 6 with histological confirmation 
 

65 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
McAdam’s relapsing polychondritis criteria 
Histopathology plus one of six of the following criteria OR three of six of the following criteria: 
1. Recurrent chondritis of both auricles 
2. Nonerosive inflammatory polyarthritis 
3. Chondritis of nasal cartilages 
4. Inflammation of ocular structures 
Conjunctivitis/keratitis/scleritis/uveitis 
5. Chondritis of respiratory tract 
Laryngeal/tracheal cartilages 
6. Cochlear and/or vestibular damage 
Neurosensory hearing loss/tinnitus/vertigo 
 
IgA vasculitis: Diagnosis based on typical clinical features and biopsy. Consistent with the following Chapel 
Hill Consensus Conference 2012 (CHCC2012): 
 
Vasculitis, with IgA1‐dominant immune deposits, affecting small vessels (predominantly capillaries, 
venules, or arterioles). Often involves skin and gastrointestinal tract, and frequently causes arthritis. 
Glomerulonephritis indistinguishable from IgA nephropathy may occur. 
 
Paediatrics diagnosis of IgA vasculitis: consistent with the following EULAR/PRINTO/PRES criteria. 
 
HSP EULAR/PRINTO/PRES Ankara 2008 classification criteria 
Purpura or petechiae (mandatory) with lower limb predominance and at least one of the following 
criteria: 
1. Abdominal pain 
2. Histopathology 
3. Arthritis or arthralgia 
4. Renal involvement 
Cogan’s syndrome: Consistent with the following Chapel Hill Consensus Conference 2012 (CHCC2012) 
definition and exclusion of mimics:  
 
Cogan’s syndrome characterized by ocular inflammatory lesions, including interstitial keratitis, uveitis, and 
episcleritis, and inner ear disease, including sensorineural hearing loss and vestibular dysfunction. 
Vasculitic manifestations may include arteritis (affecting small, medium, or large arteries), aortitis, aortic 
aneurysms, and aortic and mitral valvulitis. 
 
Non-infective cryoglobulinaemia: Consistent with the following Chapel Hill Consensus Conference 2012 
(CHCC2012) definition and exclusion of infective cause: 
 
Vasculitis with cryoglobulin immune deposits affecting small vessels (predominantly capillaries, venules, 
or arterioles) and associated with serum cryoglobulins. Skin, glomeruli, and peripheral nerves are often 
involved. 
 
CNS vasculitis: Clinical diagnosis, imaging or biopsy and exclusion of mimics – 
infection/drugs/malignancy. Peer review process for confirmation of diagnosis.  
 
 
 

66 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
 
 
 
 
24.5 
Appendix 5: Steroid weaning templates 
 

67 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769 
 

68 
 
BIOVAS                                                                   Version Number:  4. 0                                  Version Date:  17th November 2021 
EudraCT 2019-003964-30 
 
IRAS: 269769