Conditions: Granulomatosis With Polyangiitis (GPA) Microscopic Polyangiitis (MPA)
Keywords: Granulomatosis with Polyangiitis (GPA) Microscopic Polyangiitis (MPA) IFX-1 ANCA AAV
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 20
Healthy volunteers: no

Brief summary:
The purpose of this study is to investigate the safety and tolerability of two dose regimens of IFX-1 as add-on to standard of care (SOC) in subjects with GPA and MPA compared with placebo.

Detailed description:
Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are related systemic v anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), a potentially life-threatening disease.

GPA is a necrotizing vasculitis predominantly involving small- to medium-sized vessels (e.g., capillaries, venules, arterioles, arteries, and veins). MPA is a necrotizing vasculitis that primarily affects capillaries, venules, or arterioles, most commonly manifesting as necrotizing glomerulonephritis and/or pulmonary capillaritis. MPA.

Primed neutrophils are activated by ANCA and generate C5a that engages C5a receptors on neutrophils. Therefore, patients with ANCA-related disease have elevated plasma and urine levels of C5a in active disease and not in remission.

IFX-1 is a monoclonal antibody specifically binding to the soluble human complement split product C5a and the resulting nearly complete blockade of C5a-induced biological effects may be effective in the treatment of subjects with AAV.

Arms:
arm 1: Will receive IFX-1 low dose regimen diluted in sodium chloride solution arm 2: Will receive IFX-1 high dose regimen diluted in sodium chloride solution arm 3: Will receive placebo

Interventions: intervention 1: IFX-1 low dose intervention 2: IFX-1 high dose intervention 3: Placebo
Intervention descriptions: intervention 1: Single IV infusions of IFX-1 intervention 2: Single IV infusions of IFX-1 intervention 3: Placebo

Protocol document:
Prot_SAP_000.pdf: 
 
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CLINICAL STUDY PROTOCOL 4.0 
AMENDMENT 3.0 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED,  
MULTICENTER, PARALLEL-GROUP PHASE II STUDY TO INVESTIGATE THE  
SAFETY AND EFFICACY OF TWO DIFFERENT DOSE REGIMENS OF IFX-1 AS ADD-ON  
TO STANDARD OF CARE IN SUBJECTS WITH GRANULOMATOSIS WITH POLYANGIITIS 
(GPA) AND MICROSCOPIC POLYANGIITIS (MPA) 
 
 
Study Number: IFX-1-P2.6 
Study Product: IFX-1 
IND Number: 137457 
Sponsor: 
 
InflaRx GmbH 
Winzerlaer Strasse 2 
07745 Jena 
Germany  
Sponsor’s Responsible Medical Officer: 
, MD 
 
InflaRx GmbH 
Coordinating Investigator: 
, MD, MPH 
Version and Date of Protocol: Version 4.0 
Final, 25 March 2019 
Amendment:  Version 3.0 


 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................................. 9 
DEFINITION OF TERMS .................................................................................................................... 11 
STUDY SYNOPSIS ............................................................................................................................ 14 
SPONSOR SIGNATURE PAGE ........................................................................................................ 21 
COORDINATING INVESTIGATOR SIGNATURE PAGE .................................................................. 22 
INVESTIGATOR SIGNATURE PAGE(S) .......................................................................................... 24 
1 
SCHEDULE OF ASSESSMENTS ...................................................................................... 25 
2 
INTRODUCTION ................................................................................................................. 30 
2.1 
BACKGROUND INFORMATION ON THE INDICATION ................................................... 30 
2.2 
BACKGROUND INFORMATION ON IFX-1 ........................................................................ 31 
2.3 
RATIONALE FOR THE STUDY .......................................................................................... 32 
2.3.1 
Study Population ................................................................................................................. 32 
2.3.2 
Dosing Regimen .................................................................................................................. 32 
2.3.3 
Study Design ....................................................................................................................... 33 
2.3.4 
Expected Benefits ............................................................................................................... 33 
2.4 
RISK-BENEFIT ASSESSMENT .......................................................................................... 34 
2.4.1 
Potential Risks .................................................................................................................... 34 
2.4.2 
Risk Associated with Lack of Efficacy ................................................................................. 34 
2.4.3 
Conclusion .......................................................................................................................... 34 
3 
OBJECTIVES ..................................................................................................................... 36 
3.1 
PRIMARY OBJECTIVE ....................................................................................................... 36 
3.2 
SECONDARY OBJECTIVES .............................................................................................. 36 
4 
STUDY DESIGN ................................................................................................................. 37 
4.1 
OVERALL STUDY DESIGN AND PLAN ............................................................................ 37 
4.2 
NUMBER OF SUBJECTS AND STUDY SITES ................................................................. 37 
4.3 
STUDY DURATION ............................................................................................................ 37 


 
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4.4 
INDEPENDENT DATA MONITORING COMMITTEE ........................................................ 38 
4.5 
PREMATURE TERMINATION OF THE STUDY ................................................................ 38 
5 
STUDY POPULATION ....................................................................................................... 40 
5.1 
SCREEN FAILURES ........................................................................................................... 40 
5.2 
INCLUSION CRITERIA ....................................................................................................... 40 
5.3 
EXCLUSION CRITERIA...................................................................................................... 41 
5.4 
DISCONTINUATION OF INDIVIDUAL SUBJECT PARTICIPATION ................................. 43 
5.4.1 
Lack of Efficacy ................................................................................................................... 43 
5.4.2 
Withdrawal of Informed Consent ......................................................................................... 43 
5.4.3 
Discontinuation of the Investigational Medicinal Product .................................................... 44 
5.4.4 
Lost to Follow-up ................................................................................................................. 44 
6 
STUDY TREATMENTS ...................................................................................................... 45 
6.1 
DETAILS OF THE INVESTIGATIONAL MEDICINAL PRODUCT ...................................... 45 
6.1.1 
Description of the Investigational Medicinal Product .......................................................... 45 
6.1.2 
Packaging and Labeling ...................................................................................................... 45 
6.1.3 
Shipment ............................................................................................................................. 46 
6.1.4 
Storage ................................................................................................................................ 46 
6.1.5 
Drug Accountability ............................................................................................................. 47 
6.1.6 
Reconstitution of IFX-1........................................................................................................ 47 
6.1.7 
Administration ..................................................................................................................... 47 
6.2 
DETAILS OF THE STANDARD OF CARE ......................................................................... 48 
6.2.1 
Rituximab ............................................................................................................................ 49 
6.2.2 
Cyclophosphamide .............................................................................................................. 50 
6.2.3 
Glucocorticoids .................................................................................................................... 51 
6.2.4 
Azathioprine ........................................................................................................................ 52 
6.2.5 
Methotrexate ....................................................................................................................... 53 
6.2.6 
Mycophenolate Mofetil and Mycophenolate Sodium .......................................................... 55 
6.3 
RANDOMIZATION AND BLINDING ................................................................................... 57 
6.4 
PROCEDURES IN CASE OF SPECIFIC SIDE EFFECTS ................................................. 58 
6.4.1 
Specific Side Effects of IFX-1 ............................................................................................. 58 
6.4.2 
Overdose of IFX-1 ............................................................................................................... 59 
7 
PRIOR AND CONCOMITANT THERAPY .......................................................................... 60 


 
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7.1 
RECOMMENDED CONCOMITANT THERAPY ................................................................. 60 
7.2 
PERMITTED GLUCOCORTICOID THERAPY ................................................................... 60 
7.3 
RESCUE THERAPY ........................................................................................................... 61 
7.4 
PROHIBITED THERAPY .................................................................................................... 62 
8 
STUDY PROCEDURES AND VISIT SCHEDULE .............................................................. 63 
8.1 
SCREENING ....................................................................................................................... 63 
8.2 
TREATMENT PERIOD ....................................................................................................... 63 
8.3 
FOLLOW-UP PERIOD ........................................................................................................ 64 
8.4 
SAFETY FOLLOW-UP VISIT .............................................................................................. 64 
8.5 
UNSCHEDULED VISIT ....................................................................................................... 64 
9 
STUDY VARIABLES AND ASSESSMENT METHODS .................................................... 65 
9.1 
STUDY SUBJECTS ............................................................................................................ 65 
9.1.1 
Demographics and Baseline Characteristics ...................................................................... 65 
9.1.2 
AAV Medical History ........................................................................................................... 65 
9.1.3 
General Medical History ...................................................................................................... 65 
9.1.4 
Prior and Concomitant Therapy .......................................................................................... 66 
9.2 
EFFICACY .......................................................................................................................... 66 
9.2.1 
Efficacy Variables ................................................................................................................ 66 
9.2.2 
Methods of Assessing Efficacy Variables ........................................................................... 66 
9.2.2.1 
Birmingham Vasculitis Activity Score Version 3.0 .............................................................. 66 
9.2.2.2 
Vasculitis Damage Index..................................................................................................... 67 
9.2.2.3 
Physician Global Assessment ............................................................................................. 67 
9.2.2.4 
Renal Variables ................................................................................................................... 68 
9.2.2.5 
36-Item Short Form Survey Version 2 ................................................................................ 68 
9.2.2.6 
Anti-neutrophil Cytoplasmic Antibody Status ...................................................................... 69 
9.3 
SAFETY .............................................................................................................................. 69 
9.3.1 
Safety Variables .................................................................................................................. 69 
9.3.2 
Methods of Assessing Safety Variables .............................................................................. 70 
9.3.2.1 
Adverse Events ................................................................................................................... 70 
9.3.2.2 
Glucocorticoid Toxicity Index .............................................................................................. 70 
9.3.2.3 
Physical Examinations ........................................................................................................ 70 
9.3.2.4 
Vital Signs ........................................................................................................................... 70 
9.3.2.5 
Electrocardiogram ............................................................................................................... 71 
9.3.2.6 
Safety Laboratory ................................................................................................................ 71 


 
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9.3.2.7 
Renal Variables ................................................................................................................... 72 
9.3.2.8 
Pregnancy ........................................................................................................................... 72 
9.3.2.9 
Serology .............................................................................................................................. 72 
9.3.2.10 Anti-Glomerular Basement Membrane Disease Assessment ............................................. 73 
9.3.2.11 Anti-Drug Antibodies ........................................................................................................... 73 
9.4 
PHARMACOKINETICS, PHARMACODYNMICS, AND BIOMARKERS ............................ 73 
9.4.1 
Variables ............................................................................................................................. 73 
9.4.2 
Methods of Assessing Variables ......................................................................................... 74 
9.4.2.1 
Pharmacokinetics ................................................................................................................ 74 
9.4.2.2 
Pharmacodynamics ............................................................................................................. 74 
9.4.2.3 
Biomarkers .......................................................................................................................... 74 
10 
ADVERSE EVENT REPORTING ....................................................................................... 76 
10.1 
ADVERSE EVENTS ............................................................................................................ 76 
10.1.1 
Definition ............................................................................................................................. 76 
10.1.2 
Documentation and Reporting ............................................................................................ 77 
10.2 
SERIOUS ADVERSE EVENTS .......................................................................................... 80 
10.2.1 
Definition ............................................................................................................................. 80 
10.2.2 
Documentation and Reporting ............................................................................................ 81 
10.3 
ADVERSE EVENTS OF SPECIAL INTEREST .................................................................. 82 
10.4 
SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS ................................... 82 
10.4.1 
Definition ............................................................................................................................. 82 
10.4.2 
Documentation and Reporting ............................................................................................ 82 
10.5 
PREGNANCY ..................................................................................................................... 82 
10.6 
THERAPEUTIC PROCEDURES ........................................................................................ 83 
11 
STATISTICS ....................................................................................................................... 84 
11.1 
GENERAL CONSIDERATIONS ......................................................................................... 84 
11.2 
DETERMINATION OF SAMPLE SIZE ................................................................................ 84 
11.3 
ANALYSIS SETS ................................................................................................................ 84 
11.4 
ENDPOINTS ....................................................................................................................... 85 
11.4.1 
Safety .................................................................................................................................. 85 
11.4.1.1 Primary ................................................................................................................................ 85 
11.4.1.2 Secondary ........................................................................................................................... 85 
......................................................................................................................... 85 
11.4.2 
Efficacy ................................................................................................................................ 86 


 
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11.4.3 
Quality of Life ...................................................................................................................... 87 
11.4.4 
Pharmacokinetics ................................................................................................................ 87 
11.4.5 
Pharmacodynamics ............................................................................................................. 87 
11.4.6 
Biomarkers .......................................................................................................................... 87 
11.5 
ANALYSES OF ENDPOINTS ............................................................................................. 88 
11.5.1 
Safety .................................................................................................................................. 88 
11.5.2 
Efficacy ................................................................................................................................ 88 
11.5.3 
Quality of Life ...................................................................................................................... 89 
11.5.4 
Pharmacokinetics ................................................................................................................ 89 
11.5.5 
Pharmacodynamics ............................................................................................................. 89 
11.5.6 
Biomarkers .......................................................................................................................... 89 
11.6 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ................................................ 89 
11.7 
PRIOR AND CONCOMITANT THERAPY .......................................................................... 90 
11.8 
SUBJECT DISPOSITION.................................................................................................... 90 
11.9 
TREATMENT EXPOSURE ................................................................................................. 90 
11.10 
HANDLING OF MISSING DATA ......................................................................................... 90 
11.11 
INTERIM ANALYSIS ........................................................................................................... 90 
12 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS ................................................... 91 
12.1 
GOOD CLINICAL PRACTICE ............................................................................................. 91 
12.2 
ETHICS COMMITTEE AND RESPONSIBLE REGULATORY AUTHORITY ..................... 91 
12.3 
SUBJECTS INFORMATION AND INFORMED CONSENT ............................................... 91 
12.4 
PROTOCOL AMENDMENTS ............................................................................................. 92 
13 
DOCUMENTATION ............................................................................................................ 93 
13.1 
ELECTRONIC CASE REPORT FORMS ............................................................................ 93 
13.2 
ARCHIVING ........................................................................................................................ 94 
14 
SUPERVISION OF THE CLINICAL STUDY ...................................................................... 95 
14.1 
ACCESS TO SOURCE DATA ............................................................................................ 95 
14.2 
MONITORING ..................................................................................................................... 95 
14.3 
INDEPENDENT DATA MONITORING COMMITTEE ........................................................ 96 


 
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14.4 
AUDITS ............................................................................................................................... 96 
14.5 
INSPECTIONS .................................................................................................................... 96 
15 
DATA PROTECTION AND CONFIDENTIALITY ............................................................... 98 
15.1 
DECLARATION REGARDING DATA PROTECTION ........................................................ 98 
15.2 
DECLARATION REGARDING THE ANONYMIZED TRANSFER OF PERSONAL DATA 98 
16 
ADMINISTRATIVE AGREEMENTS ................................................................................... 99 
16.1 
ADHERENCE TO THE PROTOCOL/PROTOCOL DEVIATIONS ...................................... 99 
16.2 
FINANCING AND INSURANCE ......................................................................................... 99 
16.3 
NOTIFICATION OF THE LOCAL AUTHORITIES .............................................................. 99 
16.4 
PUBLICATION POLICY AND REGISTRATION ................................................................. 99 
16.4.1 
Publication Policy ................................................................................................................ 99 
16.4.2 
Registration ....................................................................................................................... 100 
17 
REFERENCES .................................................................................................................. 101 
18 
APPENDICES ................................................................................................................... 105 
18.1 
CHAPEL HILL CONSENSUS CONFERENCE ................................................................. 105 
18.2 
MAJOR SIDE EFFECTS ASSOCIATED WITH GLUCOCORTICOID THERAPY ............ 107 
18.3 
BIRMINGHAM VASCULITIS ACTIVITY SCORE VERSION 3.0 ...................................... 108 
18.4 
GLOSSARY AND SCORING FOR BVAS VERSION 3.0 ................................................. 109 
18.5 
OTHER MULTISYSTEM AUTOIMMUNE DISEASES ...................................................... 113 
18.6 
VASCULITIS DAMAGE INDEX ........................................................................................ 114 
18.7 
PHYSICIAN GLOBAL ASSESSMENT .............................................................................. 115 
18.8 
36-ITEM SHORT FORM SURVEY ................................................................................... 116 
18.9 
GLUCOCORTICOID TOXICITY INDEX ........................................................................... 122 
 


 
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LIST OF TABLES  
Table 1 
Dosing Schedule for IFX-1 and Placebo ....................................................................... 48 
Table 2 
Summary of Clinical Data on Rituximab for Use in GPA/MPA ...................................... 49 
Table 3 
Pulse Regimen of Cyclophosphamide .......................................................................... 50 
Table 4 
Summary of Clinical Data on Cyclophosphamide ......................................................... 51 
Table 5 
Standardized Dosing Schedule for Glucocorticoid Tapering ......................................... 52 
Table 6 
Summary of Clinical Data on Azathioprine .................................................................... 53 
Table 7 
Summary of Clinical Data on Methotrexate ................................................................... 54 
Table 8 
Summary of Clinical Data on Mycophenolate Mofetil and Mycophenolate Sodium ...... 56 
Table 9 
Renal Variables ............................................................................................................. 68 
Table 10 
Pharmacodynamic Variables ....................................................................................... 74 
Table 11 
Biomarker Variables .................................................................................................... 74 
 


 
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LIST OF ABBREVIATIONS 
AAV 
ANCA-associated vasculitis 
ADA 
anti-drug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
ANCA 
anti-neutrophil cytoplasmic antibody 
anti-HBc 
hepatitis B core antigen 
AZA 
azathioprine 
BVAS 
Birmingham Vasculitis Activity Score 
CH50 
50% hemolytic complement 
CHCC 
Chapel Hill Consensus Conference 
CMO 
Contract Manufacturing Organization 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CYC 
cyclophosphamide 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
ELISA 
enzyme-linked immunosorbent assay test 
FAS 
Full analysis set 
FSH 
follicle-stimulating hormone 
GBM 
glomerular basement membrane 
GC 
glucocorticoid 
GCP 
Good Clinical Practice 
GPA 
granulomatosis with polyangiitis 
GTI 
Glucocorticoid Toxicity Index 
 
 
 
 
HIV 
human immunodeficiency virus 
HS 
hidradenitis suppurativa 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 


 
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IDMC 
Independent Data Monitoring Committee 
Ig 
immunoglobulin 
IMP 
investigational medicinal product 
IWRS 
Interactive Web Response System 
MAC 
membrane attack complex 
MCP 
monocyte chemoattractant protein 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMF 
mycophenolate mofetil 
MPA 
microscopic polyangiitis 
MPO 
myeloperoxidase 
MPS 
mycophenolate sodium 
MTX 
methotrexate 
NaCl 
sodium chloride 
PD 
pharmacodynamic(s) 
PGA 
Physician Global Assessment 
PK 
pharmacokinetic(s) 
PR3 
proteinase 3 
PRO 
patient-reported outcome 
RTX 
rituximab 
SAE 
serious adverse event 
SAF 
Safety analysis set 
SF-36 
36-item Short Form survey 
SOC 
standard of care 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
UACR 
urinary albumin:creatinine ratio 
ULN 
upper limit of normal 
VDI 
Vasculitis Damage Index 
 


 
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DEFINITION OF TERMS 
Baseline 
A value or quantity that serves as a reference for 
comparisons over time. 
Central laboratory 
A laboratory where all subject-derived samples 
(e.g., serum, plasma) are centrally analyzed and if 
necessary, distributed for analysis to specialized 
laboratories. 
Compliance 
Adherence to all the study-related requirements, 
Good Clinical Practice requirements, and the 
applicable regulatory requirements. 
Clinical remission 
BVAS = 0 
Clinical response 
Reduction in BVAS of ≥50% from Baseline and 
no worsening in any body system. 
Consent 
The act of obtaining informed consent for 
participation in a clinical study from subjects 
deemed eligible or potentially eligible to 
participate in the clinical study. Subjects entered 
into a study are those who sign the informed 
consent form directly or through their legally 
acceptable representatives. 
Electronic case report form 
An electronic form for recording subjects’ data 
during the study, as required by the protocol. 
End of Study  
Overall study completion: the day of the last visit 
of the last subject in the study. 
Individual subject: the time point after which no 
further study-related procedures are performed. 
Endpoint 
Key measurement or observation used to measure 
the effect of experimental variables in a study. 
Enrollment 
The time point at which a subject formally starts 
to participate in the study by signing an informed 
consent form.  
Follow-up Period 
After IMP administration in Week 16 to 
Week 24, during which no IFX-1 or placebo is 
given.  


 
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Investigational medicinal product 
A pharmaceutical form of an active substance or 
placebo being tested or used as a reference in the 
current study, including products already with a 
marketing authorization but used or assembled 
(formulated or packaged) in a way different from 
the authorized form. 
Limited disease flare (minor 
relapse) 
Any new occurrence or worsening of one or more 
of the minor BVAS items listed in Appendix 18.4 
after clinical remission (BVAS = 0). 
Remission Induction Phase 
The time from the start of remission induction 
therapy until clinical remission (BVAS = 0), 
during which RTX or CYC plus GCs are given as 
standard of care.  
Remission Maintenance Phase 
The time from clinical remission until Week 24, 
during which subjects are allowed to change 
standard of care.  
Safety follow-up visit 
To be performed for any subject who 
discontinues from the study during the Treatment 
Period (i.e., until Week 16) at 1 month (±3 days) 
after the last IMP administration. 
Screening 
The predetermined series of procedures with 
which each investigator selects an appropriate 
and representative sample of subjects for 
randomization into the study. 
Severe disease flare (major 
relapse) 
BVAS >3 or experiencing one of the major 
BVAS items listed in Appendix 18.4 that requires 
treatment with other than permitted AAV therapy 
after clinical remission (BVAS = 0). 
Standard of care 
RTX or CYC administration plus standard dose 
glucocorticoids (GCs) in the Remission Induction 
Phase. 
RTX, CYC, AZA, MTX, MMF, or MPS plus 
standard dose GCs (if tapering is still ongoing) in 
the Remission Maintenance Phase. 


 
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Study start 
The time point at which the first subject gives 
written informed consent; equivalent to first 
subject’s first visit at the first study site which 
has enrolled a subject into the study. 
Treatment Period 
Week 0 to Week 16, during which IFX-1 or 
placebo is given as add-on to standard of care. 
 


 
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STUDY SYNOPSIS 
Title of Study:  
A randomized, double-blind, placebo-controlled, multicenter, parallel-group Phase II 
study to investigate the safety and efficacy of two different dose regimens of IFX-1 as 
add-on to standard of care in subjects with granulomatosis with polyangiitis (GPA) and 
microscopic polyangiitis (MPA) 
Protocol / Study Number: IFX-1-P2.6 
Type of Study: 
Safety study 
Indication:  
GPA and MPA indicated for therapy with 
cyclophosphamide (CYC) or rituximab 
(RTX) and standard dose glucocorticoid 
(GC) therapy 
Sponsor: InflaRx GmbH 
Coordinating Investigator: 
, MD, MPH 
Study Site(s): 
Approximately 38 sites in the United States of America and Canada 
Phase of Development: II 
Objectives: 
Primary Objective: 
The primary objective is to investigate the safety and tolerability of two dose regimens 
of IFX-1 as add-on to standard of care (SOC) in subjects with GPA and MPA 
compared with placebo 
Secondary Objectives: 
• 
To investigate the clinical response of two dose regimens of IFX-1 in subjects with 
GPA and MPA compared with placebo. 
• 
To generate data for pharmacokinetic (PK) and pharmacodynamic (PD) modeling 
for two dose regimens of IFX-1. 


 
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Methodology:  
This is a prospective, randomized, double-blind, placebo-controlled, parallel-group 
(three treatment groups), multicenter, Phase II study. For each subject, the study will 
comprise a Screening Period (up to 2 weeks), a Treatment Period (Week 0 to 
Week 16), and a Follow-up Period (after investigational medicinal product [IMP] 
administration in Week 16 to Week 24).  
All subjects will receive the IMP, i.e., IFX-1 (400 mg or 800 mg) or placebo from 
Week 0 to Week 16 (i.e., during the Treatment Period). All subjects will receive SOC 
during the Treatment and Follow-up Periods. From Week 0 up to clinical remission 
(Remission Induction Phase). Only the following SOC will be allowed during this 
phase: 
• 
RTX or CYC 
• 
Standard dose of GCs 
Following clinical remission and up to Week 24, subjects are allowed to switch to 
other SOC (azathioprine [AZA]/methotrexate [MTX]/mycophenolate mofetil 
[MMF]/mycophenolate sodium [MPS] plus GCs), to use throughout the remainder of 
the study, or to stay on RTX or CYC (Remission Maintenance Phase). 
A PK substudy will be conducted in 15 subjects who provide additional consent for 
participation in this substudy. Blood samples for the PK substudy will be collected at 
Weeks 1, 4, and 16. 
Number of Subjects: 
A total of 36 subjects are planned to be randomized in the study in a 1:1:1 ratio to three 
treatment groups (Groups A, B, and C). Approximately 24 subjects in the active 
treatment groups and 12 subjects in the placebo group are considered to be sufficient, 
based on medical evaluation, to investigate the safety and tolerability of IFX-1 as add-
on to SOC in subjects with GPA and MPA. 


 
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Study Population: 
Subjects must meet all of the following inclusion criteria at Screening to be 
randomized into the study: 
1. Male or female, ≥18 years of age. 
2. Written informed consent obtained from subject. 
3. Diagnosis of GPA or MPA according to the definitions of the Chapel Hill 
Consensus Conference. 
4. Have at least one “major” item, or at least three other (minor) items, or at least two 
renal items on the Birmingham Vasculitis Activity Score (BVAS) Version 3.0. 
5. New or relapsed GPA or MPA that require treatment with CYC or RTX plus GCs. 
6. Estimated glomerular filtration rate (eGFR) ≥20 mL/min/1.73 m2. 
7. History of positive antigen-specific anti-neutrophil cytoplasmic antibody (ANCA) 
test through a documented positive ELISA test for either anti-proteinase 3 (anti-
PR3) or anti-myeloperoxidase (anti-MPO) antibodies. For newly diagnosed 
subjects a recent positive ELISA testing for either anti-PR3 or anti-MPO is 
mandatory for inclusion. 


 
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Subjects who fulfill any of the following exclusion criteria at Screening are not eligible 
to participate in the study: 
1. Any other multisystem autoimmune disease as listed in Appendix 18.5. 
2. Requires mechanical ventilation because of alveolar hemorrhage at screening. 
3. Have required management of infections, as follows: 
 
a. Chronic infection requiring suppressive anti-infective therapy (such as 
 
latent tuberculosis, pneumocystis, aspergillosis, cytomegalovirus, herpes 
 
simplex virus, herpes zoster or atypical mycobacteria) 
 
b. Use of intravenous antibacterials, antivirals, anti-fungals, or anti-parasitic 
 
agents. 
4. Known or suspected active drug and/or alcohol abuse. 
5. Human immunodeficiency virus, hepatitis B, or hepatitis C viral screening test 
showing evidence of active or chronic viral infection at Screening or a documented 
history of the human immunodeficiency virus, hepatitis B, or hepatitis C. 
6. One of the following abnormal laboratory findings at Screening: 
− White blood cells <3500/mm3 
− Platelet count <120,000/mm3 
− Total bilirubin >3 times the upper limit of normal (ULN) 
− Alanine aminotransferase or aspartate aminotransferase >5 x ULN 
7. Acute or chronic liver disease. 
8. Known hypersensitivity to inactive ingredients of the GC capsules. 
9. History of or active malignancy, lymphoproliferative or myeloproliferative 
disorder. Individuals with squamous cell or basal cell carcinomas of the skin and 
individuals with cervical carcinoma in situ who have received curative surgical 
treatment may be eligible for this study. 
10. History of anti-glomerular basement membrane disease. 
11. Received CYC or RTX within 12 weeks before Screening; if on azathioprine 
(AZA), methotrexate (MTX), mycophenolate mofetil (MMF), or mycophenolate 
sodium (MPS) at the time of Screening, these drugs must be withdrawn prior to 
receiving CYC or RTX. 
12. Received more than 3 g cumulative intravenous GCs within 4 weeks before 
Screening. 
13. Received an oral daily dose of a GC of more than 10 mg prednisone equivalent for 
more than 6 weeks continuously prior to Screening. 
14. Received a CD20 inhibitor, anti-tumor necrosis factor treatment, abatacept, 
alemtuzumab, any other experimental or biological therapy, intravenous 


 
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immunoglobulin or plasma exchange, antithymocyte globulin, or required dialysis 
within 12 weeks before Screening. 
15. Received a live vaccination within 4 weeks before Screening or planned between 
Screening and Week 24. 
16. Subjects with a history of tuberculosis. 
17. Pregnant or lactating. 
18. Clinically significant abnormal electrocardiogram during Screening, e.g., QTcF 
>450 ms. 
19. Female subjects of childbearing potential unwilling or unable to use a highly 
effective method of contraception (pearl index <1%) such as complete sexual 
abstinence, combined oral contraceptive, vaginal hormone ring, transdermal 
contraceptive patch, contraceptive implant, or depot contraceptive injection in 
combination with a second method of contraception such as condom, cervical cap, 
or diaphragm with spermicide during the study and for at least 4 weeks after last 
administration of IFX-1 (timeframes for SOC have to be considered as described in 
the respective Prescribing Information).  
Male subjects with female partners of childbearing potential unwilling to use 
contraception (condoms) during treatment and for at least 4 months after last 
administration of treatment. 
20. Evidence or suspicion that the subject might not comply with the requirements of 
the study protocol. 
21. Any other factor which, in the investigator’s opinion, is likely to compromise the 
subject’s ability to participate in the study. 
22. The subject is an employee or direct relative of an employee at the study site or 
sponsor. 
23. The subject is imprisoned or lawfully kept in an institution. 
24. The subject has participated in an investigational clinical study during the 12 weeks 
(or five times the half-life of the previous IMP, whichever is longer) before 
Screening, or plans to participate in another investigational clinical study during 
their participation in this study. 
Test Product, Dose, and Mode of Administration:  
Subjects in Group A will receive 400 mg IFX-1 (low dose) and subjects in Group B 
will receive 800 mg IFX-1 (high dose). IFX-1 will be provided in 10 mL vials 
containing 100 mg IFX-1 and will be infused after dilution in sodium chloride (NaCl) 
over a period of approximately 30 to 60 minutes via an intravenous line. 
Reference Therapy, Dose, and Mode of Administration: 
Subjects in Group C will receive placebo. The placebo will be provided in 10 mL vials 
containing NaCl, sodium phosphate, and Polysorbate 80. The placebo vials and content 
will have the same appearance as the IFX-1 vials and additives and will be 
administered in the same manner as IFX-1. 


 
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Study Duration: 
The study duration for an individual subject will be up to 26 weeks: a 2-week 
Screening Period, a 16-week Treatment Period, and an 8-week Follow-up Period. 
Criteria for Evaluation 
Primary Endpoint: 
• 
Number and percentage of subjects who experience at least one treatment-emergent 
adverse event (TEAE) per treatment group 
Secondary Endpoints: 
• 
IMP-related serious adverse events (SAEs) 
• 
IMP-related TEAEs 
• 
Adverse events of special interest 
• 
Proportion of subjects achieving clinical response (defined as a reduction in BVAS 
of ≥50% and no worsening in any body system) at Week 16 
• 
Proportion of subjects with clinical remission (BVAS = 0) at Week 16 
• 
IFX-1 concentration pre- and postdose at each IMP administration visit (during the 
Treatment Period at Weeks 0 to 16) until Week 20 
• 
IFX-1 concentration 
 in the PK substudy 
• 
Absolute and relative change from baseline, if applicable, in C5a, 50% hemolytic 
complement (CH50), C-reactive protein (CRP), and IFX-1 blocking activity at each 
measured time point 


 
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Statistical Methods: 
The safety of the subjects will be monitored by an unblinded Independent Data 
Monitoring Committee. 
In general, data will be analyzed by treatment group and will be differentiated further 
(e.g., by visit). 
. 
For the analysis of the primary safety endpoint, the number and percentage of subjects 
who experienced at least one TEAE will be presented. Additionally, the number of 
TEAEs will be analyzed by Medical Dictionary for Regulatory Activities System 
Organ Class and Preferred Term. All subsets of TEAEs (e.g., related TEAEs) will be 
analyzed in the same way as the primary endpoint. 
Continuous safety and efficacy parameters will be analyzed by descriptive statistics for 
absolute values and changes from baseline (absolute and relative) by time point and 
treatment group, as applicable. Categorical safety and efficacy parameters will be 
summarized by absolute and relative frequencies by time point and treatment group.  
The number and percentage of subjects presenting ADA and ANCA antibodies will be 
displayed by time point and treatment group. Actual sampling times and IFX-1 plasma 
concentrations will be tabulated. Results from the PK substudy will be analyzed using 
a PK model and will be reported separately. For the analysis of PD, plasma 
concentrations of C5a, and IFX-1 blocking activity will be analyzed by each time point 
specified in the Schedule of Assessments and also as change from Baseline, if 
applicable. All biomarkers will be analyzed descriptively by time point and treatment 
group. 


 
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SPONSOR SIGNATURE PAGE 
 
Protocol / Study Number: IFX-1-P2.6 
Confirmation of the Final Protocol Amendment 3.0, dated 25 March 2019 
I hereby certify that this is the final version of the protocol amendment: 
 
Study Title: A randomized, double-blind, placebo-controlled, multicenter, 
parallel-group Phase II study to investigate the safety and efficacy of two 
different dose regimens of IFX-1 as add-on to standard of care in subjects 
with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis 
(MPA) 
________________________________________________________________________ 
 
 
 
Sponsor’s Responsible Medical Officer: 
 
 
________________________ 
_________________________________________ 
Date 
 
 
 
 
, MD 
 
 
 
Tel: 
 
 


 
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COORDINATING INVESTIGATOR SIGNATURE PAGE 
 
Protocol / Study Number: IFX-1-P2.6 
Confirmation of the Final Protocol Amendment 3.0, dated 25 March 2019 
 
Study Title: A randomized, double-blind, placebo-controlled, multicenter, 
parallel-group Phase II study to investigate the safety and efficacy of two 
different dose regimens of IFX-1 as add-on to standard of care in subjects 
with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis 
(MPA) 
________________________________________________________________________ 
 
Herewith I declare that I have read and understood the present protocol and agree to 
honor each part of it. By signing this study protocol, I agree to conduct the clinical study, 
following approval by an Ethics Committee, in accordance with the study protocol, the 
current International Council for Harmonisation (ICH) Guideline for Good Clinical 
Practice (GCP), and applicable regulatory requirements. I will ensure that all the subjects 
enrolled in the study by my site will be treated, observed, and documented in accordance 
with this protocol. I will ensure that all persons assisting with the study under my 
supervision are adequately informed about the protocol, the investigational product, and 
their duties. 
 
Coordinating Investigator:  
 
________________________ 
_________________________________________ 
Date 
, MD, MPH  
 
 


 
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INVESTIGATOR SIGNATURE PAGE(S) 
Confirmation of the Final Protocol Amendment 3.0, dated 25 March 2019 
Protocol / Study Number: IFX-1-P2.6 
Study Title: A randomized, double-blind, placebo-controlled, multicenter, 
parallel-group Phase II study to investigate the safety and efficacy of two 
different dose regimens of IFX-1 as add-on to standard of care in subjects 
with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis 
(MPA) 
________________________________________________________________________ 
Herewith I declare that I have read and understood the present protocol and agree to 
honor each part of it. By signing this study protocol, I agree to conduct the clinical study, 
following approval by an Ethics Committee, in accordance with the study protocol, the 
current International Council for Harmonisation (ICH) Guideline for Good Clinical 
Practice (GCP), and applicable regulatory requirements. I will ensure that all the subjects 
enrolled in the study by my site will be treated, observed, and documented in accordance 
with this protocol. I will ensure that all persons assisting with the study under my 
supervision are adequately informed about the protocol, the investigational product, and 
their duties.   
___________________________________________________________________ 
A separate signature page should be created for each principal investigator.  
Names and affiliations to be filled out by the investigator. 
 
Principal Investigator: 
 
Name and affiliation 
_________________________________________ 
 
_________________________________________ 
 
________________________ 
_________________________________________ 
Date 
<Insert name> 
 


 
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1 
SCHEDULE OF ASSESSMENTS 
The Schedule of Assessments is applicable to all subjects. 
 
Screening 
Randomization a 
Treatment Period 
Follow-Up 
Period 
SFU 
USVn 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14/ 
EOS b 
Week 
W -2 to -1 
W0 
W1 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W16 
W20 
W24 
Day 
-14 to -1 
1 
4 
8 
15 
29 
43 
57 
71 
85 
99 
113 
141 
169 
Accepted Time 
Window (in days) 
 
 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±3 
±3 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test c 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
Demographics and 
baseline characteristics d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
36-item Short Form 
survey e 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
BVAS 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
VDI 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
PGA 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 


 
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Screening 
Randomization a 
Treatment Period 
Follow-Up 
Period 
SFU 
USVn 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14/ 
EOS b 
Week 
W -2 to -1 
W0 
W1 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W16 
W20 
W24 
Day 
-14 to -1 
1 
4 
8 
15 
29 
43 
57 
71 
85 
99 
113 
141 
169 
Accepted Time 
Window (in days) 
 
 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±3 
±3 
GTI 
 
 
X f 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
Vital signs g 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
IMP administration: 
IFX-1 or placebo 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Standard of care h 
 
 
X 
Safety laboratory 
measurements * 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Serology: HIV/hepatitis 
B/hepatitis C virus 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ANCA testing 
X 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Anti-GBM 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum sample total 
protein 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Urinalysis i 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
PK: IFX-1 level 
 
 
X 
X 
X k 
X 
X k 
X 
X 
X 
X 
X 
X k 
X 
X 
X 
 


 
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ANCA = anti-neutrophil cytoplasmic antibody; BVAS = Birmingham Vasculitis Activity Score; CH50 = 50% hemolytic complement; CRP = C-reactive protein; 
 EOS = End of Study; GBM = glomerular basement membrane; GTI = glucocorticoid toxicity index; HIV = human 
immunodeficiency virus; IMP = investigational medicinal product; MCP = monocyte chemoattractant protein; PD = pharmacodynamics; PGA = Physician 
Global Assessment; SFU = Safety Follow-Up Visit; SOC = standard of care; VDI = Vasculitis Damage Index 
 
Screening 
Randomization a 
Treatment Period 
Follow-Up 
Period 
SFU 
USVn 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14/ 
EOS b 
Week 
W -2 to -1 
W0 
W1 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W16 
W20 
W24 
Day 
-14 to -1 
1 
4 
8 
15 
29 
43 
57 
71 
85 
99 
113 
141 
169 
Accepted Time 
Window (in days) 
 
 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±3 
±3 
PD: C5a 
  
 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
Biomarker: CH50 
(serum) 
 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
Biomarker: CRP (serum)  
 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
PD: IFX-1 blocking 
activity 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
Anti-drug antibodies 
(serum)  
 
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 
 
Adverse events 
X 
 
X 
X 
Concomitant therapy 
X m 
 
X 
X 


 
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a 
Randomization can be performed at any time between completion of the screening assessments and the first IMP administration on Day 1. 
b 
These assessments should be performed at: 
• 
Week 24 for subjects who complete the study. 
• 
The time when a subject’s participation in the study is discontinued if the subject is prematurely discontinued from the study. 
• 
Safety follow-up visit: 1 month (±3 days) after the last IMP administration for any subject who discontinues from the study until Week 16 (i.e., 
during the Treatment Period). 
c 
Only in women of childbearing potential. To be performed in serum at Screening and Week 24 and in urine (using a dipstick) at the other indicated 
visits. For any subjects who discontinue participation until Week 16, a serum pregnancy test should be performed both at the time of discontinuation and 
at the safety follow-up visit. 
d 
Demographics and baseline characteristics include age, gender, race and ethnicity, height, and smoking status. 
e 
The questionnaire should be completed at the study site before any other assessments are performed. 
f 
Only baseline laboratory parameters and symptoms of the specific list of GTI will be assessed. 
g 
Vital signs include: systolic and diastolic blood pressure, pulse rate (counted for at least 30 seconds after 5 minutes in a sitting position), respiratory rate, 
and body temperature. 
h 
All subjects will use SOC during the Treatment and Follow-up Periods. From Week 0 up to clinical remission (Remission Induction Phase), only 
rituximab or cyclophosphamide plus GCs will be allowed. Following clinical remission and up to Week 24, subjects are allowed to switch to other SOC 
(azathioprine/methotrexate/ mycophenolate mofetil/mycophenolate sodium plus GCs), to use throughout the remainder of the study, or to stay on RTX 
or CYC (Remission Maintenance Phase). 
i 
Urinalysis includes creatinine, total protein, albumin, and MCP-1; all to be analyzed at a central laboratory. 
All derived ratios and the estimated glomerular filtration rate will be calculated at the time points 
when the respective single serum or urinary parameters are planned to be assessed. 
m 
Prior therapy will be recorded at Screening. 
n 
In case of major or minor relapse.  
* 
Additional safety laboratory parameters according to the respective United States Prescribing Information are recommended as follows: 
Cyclophosphamide: blood sampling, including complete blood count and serum creatinine, to be obtained before each CYC IV administration and for 
oral administration at least every 2 weeks.  
Methotrexate: complete blood count with differential and platelet counts, hepatic enzymes, renal function tests to be obtained before starting treatment 
with methotrexate. 
AZA, MMF, MPS: For patients that are newly treated: complete blood counts weekly during the first month, twice monthly for the second and third 
months of treatment, then monthly. 


 
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2 
INTRODUCTION 
2.1 
BACKGROUND INFORMATION ON THE INDICATION 
Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are related 
systemic vasculitides that, along with eosinophilic granulomatosis with polyangiitis 
(Churg-Strauss), are grouped under the term anti-neutrophil cytoplasmic antibody 
(ANCA)-associated vasculitis (AAV). Both GPA and MPA are associated with ANCA, 
have many identical clinical manifestations, have many similar histologic features, and 
have similar outcomes. GPA and MPA predominantly affects small vessels and are 
associated with myeloperoxidase-ANCA (MPO-ANCA) or proteinase 3 (PR3-ANCA). 
Although neither sensitive nor specific, common complaints and signs of GPA and MPA 
include fatigue, fever, weight loss, arthralgia, rhinosinusitis, cough, and dyspnea, urinary 
abnormalities (an active urine sediment) with or without renal insufficiency, purpura, and 
neurologic dysfunction. These forms of vasculitis can present and progress slowly over 
months or explosively over days. If untreated, GPA and MPA progresses from a limited 
disease process (e.g., inflammation centered on the upper respiratory tract or lung) to a 
generalized phase, characterized by multiple complications of small-vessel vasculitis 
(i.e., leukocytoclastic vasculitis of the skin, mononeuritis multiplex, alveolar hemorrhage, 
rapidly progressive glomerulonephritis, and mesenteric vasculitis) [Rheinhold-Keller 
2004].  
GPA and MPA most commonly occur in older adults, although these diseases have been 
reported at all ages [Jennette 1997, Seo 2004]. Men and women are equally affected, and 
the diseases are far more common among white individuals than those of other 
races/ethnicity [Falk 1990].  
The incidence of these conditions in the United States of America is approximately 6,000 
new cases per year, and the estimated prevalence is 25,000 to 30,000 cases [Watts 2015]. 
The overall incidence rates of AAV in Europe are reported to be in the range of 13 to 
approximately 20 per million [Watts 2015]. The prevalence of AAV is estimated to be 46 
to 184 per million [Ormerod 2008, Reinhold-Keller 2000]. The prevalence of AAV has 
generally increased over the last 20 years, and this could reflect improved patient survival 
and case identification, e.g., by using multiple retrieval sources [Watts 2015]. 
The Standard of Care as recommended in the guideline for AAV [Yates 2016] usually 
consists of rituximab (RTX) or cyclophosphamide (CYC) administration for remission-
induction, with glucocorticoid (GC) tapering followed by azathioprine (AZA), 
methotrexate (MTX), mycophenolate mofetil (MMF), or mycophenolate sodium (MPS) 
for remission-maintenance. Alternatively, a second cycle of RTX can be given. 
Although treatment failures and disease relapses decreased due to the improvement of 
remission-induction regimens during recent years, patients with MPA and GPA treated 
with conventional regimens have a 9-fold increased mortality risk in the first year 


 
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attributed to infection, cardiovascular disease, malignancies, vasculitis activity, and renal 
disease [Luqmani 2011 a, Flossmann 2011]. It is proven that current therapies contribute 
to more than half of this increased risk rather than the underlying disease itself [Little 
2010]. Most of the side effects are attributed to the high-dose of GCs, which are still part 
of Standard of Care for MPA and GPA. GCs have long-term side effects such as 
osteoporosis, Cushing’s syndrome, increased infection risk and risk of diabetes mellitus 
[Goupil 2013, Moghadam-Kia 2010, Charlier 2009, McGregor 2012], and progressive 
organ damage [Robson 2015]. Therefore, the replacement of GCs by IFX-1 may improve 
the short- and long-term safety of treatment of MPA and GPA for the induction of 
remission. 
2.2 
BACKGROUND INFORMATION ON IFX-1 
IFX-1 is a monoclonal antibody which specifically binds to the soluble human 
complement split product C5a. Nonclinical studies have demonstrated that IFX-1 binds to 
its target rapidly and is capable of a nearly complete blockade of C5a-induced biological 
effects while not affecting cleavage of C5 and formation of the complement membrane 
attack complex (MAC).  
Various nonclinical studies have been conducted to assess pharmacological and 
toxicological aspects of IFX-1, none of which revealed any obvious toxicological or 
safety concerns for IFX-1. IFX-1 was well tolerated and did not show any toxicity with 
any of the doses tested.  
IFX-1 is an investigational medicinal product (IMP) and is not approved in any country 
worldwide. To date, IFX-1 has been investigated in one Phase I study in healthy subjects 
and in three Phase II studies: in subjects with early septic organ dysfunction, in subjects 
undergoing complex cardiac surgery, and in subjects with moderate to severe hidradenitis 
suppurativa (HS). 
 Based on the study data available, IFX-1 was safe and well 
tolerated when administered to healthy subjects and patients. 
In addition to GPA and MPA, IFX-1 is also in clinical development for moderate to 
severe HS. 
 


 
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2.3 
RATIONALE FOR THE STUDY 
AAV is a group of potentially life-threatening autoimmune diseases. Experimental data 
from animal models and in vitro experiments demonstrate that primed neutrophils are 
activated by ANCA and generate C5a that engages C5a receptors on neutrophils. As 
expected, patients with ANCA-related disease have elevated plasma and urine levels of 
C5a in active disease and not in remission [Chen 2017].  
Given the mode of action of IFX-1 as a monoclonal antibody specifically binding to the 
soluble human complement split product C5a and the resulting nearly complete blockade 
of C5a-induced biological effects, it may be effective in the treatment of subjects with 
AAV.  
IFX-1 was safe and well tolerated in other life-threatening indications like sepsis and 
cardiac surgery, and long-term data are available from a clinical study in HS. However, 
safety data of IFX-1 in combination with standard of care (SOC) for GPA and MPA are 
not yet available. 
The aim of this study is to evaluate the safety of two dose regimens of IFX-1 as add-on 
SOC for GPA and MPA. Furthermore, the study will collect data on efficacy and 
patient-reported outcomes (PROs) of two different dose regimens of IFX-1 in comparison 
with placebo that could be positively affected by a C5a blocking therapy. 
2.3.1 Study Population 
Patients with newly diagnosed or relapsed GPA or MPA that require treatment with 
rituximab (RTX) or cyclophosphamide (CYC) plus standard dose glucocorticoids (GCs) 
will be randomized in this study. Patients with life-threatening symptoms will not be 
randomized because IFX-1 has not yet been investigated in this indication. 
The exclusion criteria (Section 4.2) will ensure that the study population is as 
homogenous as possible.  
2.3.2 Dosing Regimen 
The aim of treatment with IFX-1 is to achieve almost complete blockade of the overall 
available C5a (existing and newly produced) in human whole blood during the entire 
treatment period.  
 According to available data and derived estimates, dosing with 


 
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800 mg every 2 weeks will result in mean IFX-1 trough levels in the range of 10 to 
20 µg/mL, which, based on available data, should result in a complete blocking of C5a 
over the entire treatment period. 
Based on the assumption that the trough level for 800 mg dosing is 4 to 20 µg/mL, the 
trough level for 400 mg should be in the range of 1 to 5 µg/mL two weeks after dosing. 
According to the available data, this level of drug should be able to keep C5a level under 
the normal control levels by the end of the treatment period. 
The toxicological profile of IFX-1 is considered adequate to support dose levels of 
800 mg IFX-1 for a time period of 16 weeks. There were no relevant findings in the 
toxicology studies, which would preclude the continued clinical development of IFX-1. 
2.3.3 Study Design 
This will be the first study conducted in patients with GPA and MPA and the 
double-blind, placebo-controlled design is deemed appropriate for the primary objective 
of this study (i.e., to monitor the safety of patients with GPA and MPA when IFX-1 is 
administered at two different doses in combination with SOC). 
A control group will be used to evaluate the safety and efficacy of the two IFX-1 doses 
compared with placebo. The use of placebo as the control is justified as subjects will 
continue to receive SOC throughout the study in the active groups and the placebo group. 
Both the subjects and the study site personnel (including the investigator) will be blinded 
to minimize any bias. The half-life of IFX-1 is expected to be 3 to 4 days in GPA and 
MPA patients and in order to achieve steady-state faster, all subjects will receive four 
administrations of the IMP during the first 2 weeks (on Days 1, 4, 8, and 15). Thereafter, 
subjects will receive the IMP once every 2 weeks, the planned regimen of IFX-1 to be 
used for the treatment of GPA and MPA. 
The study will be conducted in compliance with this study protocol, the International 
Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human 
Use (ICH) guidelines for Good Clinical Practice (GCP), and the applicable regulatory 
requirements. 
2.3.4 Expected Benefits 
The subjects who will be treated with IFX-1 or placebo in this study will benefit from an 
improvement in GPA and MPA-related symptoms since all subjects will receive SOC for 
GPA and MPA and therefore all subjects will receive the best possible treatment for their 
disease. As two-thirds of the subjects will additionally receive IFX-1, they may 
experience a faster response to treatment.  


 
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2.4 
RISK-BENEFIT ASSESSMENT 
Considerations on risk-benefit-related aspects are derived from nonclinical data and 
clinical Phase I data in healthy subjects, as well as from clinical data from three other 
Phase II studies conducted in subjects with early, newly developing abdominal or 
pulmonary derived septic organ dysfunction, in subjects undergoing complex cardiac 
surgery, and in subjects with HS. In addition, the mode of action of IFX-1 is clearly 
supported in subjects with GPA and MPA [Van Timmerman 2012].  
2.4.1 Potential Risks 
No subject with GPA or MPA has been treated with IFX-1 to date, but IFX-1 was 
generally well tolerated in other studies and no new risks are anticipated. Subsequently, 
no subject with GPA or MPA has been treated with IFX-1 in combination with SOC, 
therefore the drug-drug interactions, safety, tolerability, and efficacy of IFX-1 have not 
yet been investigated. 
Potential and theoretical risks associated with administration of IFX-1 may include 
infections, meningitis/meningococcal septicemia, and anaphylactic reactions/acute 
allergic hypersensitivity (Section 6.4.1). 
The major side effects associated with the use of GCs are listed in Appendix 18.2. 
2.4.2 Risk Associated with Lack of Efficacy 
RTX or CYC and standardized GC tapering will be administered as the SOC until clinical 
remission (i.e., during the Remission Induction Phase) and can be given after clinical 
remission at the discretion of the investigator. Due to the treatment response rate of up to 
90% of this established remission induction therapy, the risk of lack of efficacy is 
deemed to be very low in this study. In accordance with the current guidelines for AAV, 
subjects can further receive AZA, MTX, MMF, or MPS after clinical remission as 
deemed appropriately by the investigator [Yates 2016]. In case of any relapses, 
immediate treatment, as described in Section 7.3, is foreseen to avoid harm to the 
subjects. 
With the administration of IFX-1 or placebo, no deterioration in health status is expected 
with respect to GPA and MPA 
. 
In addition, an unblinded Independent Data Monitoring Committee (IDMC) will monitor 
the safety of the subjects and the study can be terminated by the IDMC. The same applies 
to the Investigator or the subject, who can prematurely discontinue the study. 
2.4.3 Conclusion 
GPA and MPA are the two major forms of systemic vasculitis associated with ANCA 
[Hoffman 1998]. The incidence of these conditions in the United States is approximately 


 
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6,000 new cases per year, and the estimated prevalence is 25,000 to 30,000 [Watts 2015]. 
In a 20-year United States population-based study, the annual incidence of AAV was 3.3 
per 100,000. The incidence rate of GPA was 1.3 and of MPA was 1.6. The overall 
prevalence of AAV was 42.1 per 100,000 [Berti 2017]. If untreated, AAV progresses 
from limited disease processes (e.g., inflammation centered on the upper respiratory tract 
or lung) to a generalized phase, characterized by multiple complications of small-vessel 
vasculitis (i.e., leukocytoclastic vasculitis of the skin, mononeuritis multiplex, alveolar 
hemorrhage, rapidly progressive glomerulonephritis, and mesenteric vasculitis) 
[Reinhold-Keller 2000]. The outcome of untreated severe disease is death. 
Although treatment failures and disease relapses decreased due to improvement of 
remission induction regimens during the last years, patients with MPA and GPA treated 
with conventional regimens have a nine-fold increased mortality risk in the first year 
attributed to infection, cardiovascular disease, malignancies, vasculitis activity, and renal 
disease [Flossmann 2011, Luqmani 2011]. It is proven that current therapies contribute 
more than half of this increased risk rather than the underlying disease itself [Little 2010]. 
Most of the side effects are contributed to the high dose of GCs which are still part of 
SOC for MPA and GPA. GCs have long-term side effects such as osteoporosis, 
Cushing’s syndrome, increased infection risk and risk of diabetes [Moghadam-Kia 2010, 
Charlier 2009, McGregor 2012, Goupil 2013] and progressive organ damage 
[Robson 2015]. 
It was demonstrated that C5a and C5b receptors are involved in the pathogenesis of AAV 
and C5a levels are increased in patients with AAV [Chen 2017, Furuta 2013, Halbwachs 
2012, Kettritz 2014]. Since IFX-1 is a monoclonal antibody, which specifically binds to 
the soluble human complement split product C5a, it is capable of a nearly complete 
blockade of C5a-induced biological effects while not affecting cleavage of C5 and 
formation of the complement MAC. Therefore, IFX-1 could be effective in the treatment 
of subjects with AAV and will be administered as add-on to SOC for AAV to improve 
the time to clinical remission. 
In case of a lack of efficacy, subjects can receive other immunosuppressive therapy at the 
discretion of the investigator, or in case of a relapse after IMP treatment, subjects can 
receive adequate rescue medication as described in Section 7.3. Risk-limiting procedures 
are anticipated and therefore the hypothesized benefit of treatment with IFX-1 outweighs 
the potential risks for subjects participating in this study. 


 
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3 
OBJECTIVES 
3.1 
PRIMARY OBJECTIVE 
The primary objective of the study is to investigate the safety and tolerability of two dose 
regimens of IFX-1 as add-on to SOC in subjects with GPA and MPA compared with 
placebo. 
3.2 
SECONDARY OBJECTIVES 
The secondary objectives of the study are: 
• 
To investigate the clinical response of two dose regimens of IFX-1 in subjects with 
GPA and MPA compared with placebo. 
• 
To generate data for pharmacokinetic (PK) and pharmacodynamic (PD) modeling for 
two dose regimens of IFX-1. 
All study endpoints are listed in Section 11.4. 


 
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4 
STUDY DESIGN 
4.1 
OVERALL STUDY DESIGN AND PLAN 
This is a prospective, randomized, double-blind, placebo-controlled, parallel-group, 
multicenter, Phase II study. For each subject, the study will comprise a Screening Period 
(up to 2 weeks), a Treatment Period (Week 0 up to Week 16), and a Follow-up Period 
(after the IMP administration in Week 16 to Week 24). All subjects will receive the IMP, 
i.e., IFX-1 or placebo, from Week 0 to Week 16 and SOC throughout the whole study.  
A total of 36 subjects are planned to be randomized to one of three treatment groups in a 
1:1:1 ratio: 
• 
Group A: 400 mg IFX-1 plus SOC 
• 
Group B: 800 mg IFX-1 plus SOC 
• 
Group C: placebo plus SOC 
The IMP dosing schedule is presented in Table 1. 
During the entire study, subjects will receive SOC at the discretion of the investigator as 
described in Section 6.2. The remission induction therapy used during the Remission 
Induction Phase normally comprise RTX or CYC and a standard dose of GCs. At the 
discretion of the investigator, subjects are allowed to switch to other SOC 
(AZA/MTX/MMF/MPS plus a standard dose of GCs) after clinical remission or to stay 
on RTX or CYC during the Remission Maintenance Phase. RTX or CYC plus 
intravenous GCs use can be started immediately after all screening assessments are 
performed, independent from the planned date of randomization. The recommended dose 
regimens for the SOC are described in Sections 6.2.1 to 6.2.6. 
A PK substudy will be conducted in 15 subjects who provide additional consent for 
participation in this substudy. Subjects will be sequentially included for participation in 
the PK substudy, regardless of their assigned dose group if consent for participation is 
given. 
4.2 
NUMBER OF SUBJECTS AND STUDY SITES 
This multicenter study is planned to be conducted at approximately 38 sites in the United 
States of America and Canada. 
A total of 36 subjects (12 subjects per treatment group) will be randomized. 
4.3 
STUDY DURATION 
The study start is defined as the date of the first screening visit of the first subject who 
signs informed consent, and the end of the study is defined as the date of the last visit of 
the last subject, as recorded in the electronic case report form (eCRF). 


 
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The study duration for an individual subject will be up to 26 weeks and will include the 
following study periods: 
• 
Screening: up to 14 days before randomization (Week -2 to Week -1 [Day -14 to 
Day -1]). 
• 
Treatment Period: starts in Week 0 (Day 1) and ends in Week 16 (Day 113). 
• 
Follow-up Period: starts after administration of IMP in Week 16 (Day 113) and ends 
in Week 24 (Day 169). 
IFX-1 or placebo will be administered during the total Treatment Period for a total of 
11 infusions. 
4.4 
INDEPENDENT DATA MONITORING COMMITTEE 
The safety of the subjects will be monitored by an unblinded IDMC. The IDMC will 
review the safety data of subjects who have completed the IMP administration in 
Week 16 and after subjects complete the Follow-up Period. The time points for the 
IDMC reviews will be defined in the IDMC charter. Safety analyses will be provided by 
an unblinded statistician. 
4.5 
PREMATURE TERMINATION OF THE STUDY 
The study may be discontinued by the sponsor at any site in case any of the following 
criteria are met: 
• 
The study protocol is not adequately adhered to (protocol deviations) despite training 
of the study site personnel. 
• 
The data quality is deficient. 
• 
The recruitment is inadequate. 
• 
The IDMC recommends stopping the study for safety reasons. 
Additionally, the entire study can be discontinued at all sites by the sponsor at any time 
for any reason (e.g., medical or ethical).  
The investigator(s) will be notified in writing, outlining the reasons for discontinuation, 
and the investigator(s) must promptly inform all participating subjects. Detailed 
instructions on further assessments will be provided. 
All study materials, except documents needed for archiving requirements, will be 
returned to the sponsor, including all records regarding the IMP. The clinical monitor will 
ensure that any outstanding data clarification issues and queries are resolved and that all 
study records at the study site are complete. 


 
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In accordance with applicable regulatory requirements, the sponsor will promptly inform 
the competent regulatory authorities of the discontinuation and its reason(s), and the 
investigator or sponsor will promptly inform the Ethics Committee. 
The approval of the study can be rescinded, or the study can be discontinued by a 
competent authority or a responsible Ethics Committee. 


 
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5 
STUDY POPULATION 
5.1 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the study but are 
not subsequently randomized to a treatment group. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demographics, screen failure details, eligibility criteria, and any non-treatment-emergent 
serious adverse event (SAE). 
Rescreening of subjects who do not meet the criteria for participation in this study is not 
allowed. 
5.2 
INCLUSION CRITERIA 
Subjects must meet all of the following criteria at Screening to be randomized into the 
study: 
Inclusion Criteria 
Rationale 
1. Male or female, ≥18 years of age. 
Safety concern 
2. Written informed consent obtained from subject. 
Administrative 
3. Diagnosis of GPA or MPA according to the definitions of the 
Chapel Hill Consensus Conference (CHCC). 
Effectiveness 
4. Have at least one “major” item, or at least three (minor) other 
items, or at least two renal items on the Birmingham Vasculitis 
Activity Score (BVAS) Version 3.0. 
Effectiveness 
5. New or relapsed GPA or MPA that require treatment with CYC or 
RTX plus GCs. 
Effectiveness 
6. Estimated glomerular filtration rate (eGFR) ≥20 mL/min/1.73 m2. 
Effectiveness 
7. History of positive antigen-specific anti-neutrophil cytoplasmic 
antibody (ANCA) test through a documented positive ELISA test 
for either anti-proteinase 3 (anti-PR3) or anti-myeloperoxidase 
(anti-MPO) antibodies. For newly diagnosed subjects a recent 
positive ELISA testing for either anti-PR3 or anti-MPO is 
mandatory for inclusion. 
Effectiveness 


 
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5.3 
EXCLUSION CRITERIA 
Subjects who fulfill any of the following criteria at Screening are not eligible to 
participate in the study: 
Exclusion Criteria 
Rationale 
1. Any other multisystem autoimmune disease as listed in 
Appendix 18.4. 
Safety concern 
2. Requires mechanical ventilation because of alveolar hemorrhage at 
Screening. 
Safety concern 
3. Have required management of infections, as follows: 
 
a. Chronic infection requiring suppressive anti-infective therapy 
(such as latent tuberculosis, pneumocystis, aspergillosis, 
cytomegalovirus, herpes simplex virus, herpes zoster and atypical 
mycobacteria) 
b. Use of intravenous antibacterials, antivirals, anti-fungals, or 
anti-parasitic agents. 
Safety concern 
4. Known or suspected active drug and/or alcohol abuse. 
Safety concern 
5. Human immunodeficiency virus (HIV), hepatitis B, or hepatitis C 
viral screening test showing evidence of active or chronic viral 
infection at Screening or a documented history of HIV, hepatitis B, 
or hepatitis C. 
Safety concern 
6. One of the following abnormal laboratory findings at Screening: 
− 
White blood cells <3500/mm3 
− 
Platelet count <120,000/mm3 
− 
Total bilirubin >3 times the upper limit of normal (ULN) 
− 
Alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) >5 x ULN 
Safety concern 
7. Acute or chronic liver disease. 
Safety concern 
8. Known hypersensitivity to inactive ingredients of the GC capsules. 
Effectiveness 
9. History of or active malignancy, lymphoproliferative or 
myeloproliferative disorder. Individuals with squamous cell or 
basal cell carcinomas of the skin and individuals with cervical 
carcinoma in situ who have received curative surgical treatment 
may be eligible for this study. 
Safety concern 
10. History of anti-glomerular basement membrane (GBM) disease. 
Safety concern 


 
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Exclusion Criteria 
Rationale 
11. Received CYC or RTX within 12 weeks before screening; if on 
AZA, MMF, MPS, or MTX at the time of Screening, these drugs 
must be withdrawn prior to receiving CYC or RTX. 
Safety concern 
12. Received more than 3 g cumulative dose of intravenous GCs 
within 4 weeks before screening. 
Effectiveness 
13. Received an oral daily dose of a GC of more than 10 mg 
prednisone-equivalent for more than 6 weeks continuously prior to 
screening. 
Safety concern 
14. Received CD20 inhibitor, anti-tumor necrosis factor treatment, 
abatacept, alemtuzumab, any other experimental or biological 
therapy, intravenous immunoglobulin or plasma exchange, 
antithymocyte globulin, or required dialysis within 12 weeks 
before Screening. 
Safety concern 
15. Received a live vaccination within 4 weeks before Screening or 
planned between Screening and Week 24. 
Safety concern 
16. Subjects with a history of tuberculosis. 
Safety concern 
17. Pregnant or lactating. 
Safety concern 
18. Clinically significant abnormal electrocardiogram (ECG) during 
Screening, e.g., QTcF >450 ms. 
Safety concern 
19. Female subjects of childbearing potential unwilling or unable to 
use a highly effective method of contraception (pearl index <1%) 
such as complete sexual abstinence, combined oral contraceptive, 
vaginal hormone ring, transdermal contraceptive patch, 
contraceptive implant, or depot contraceptive injection in 
combination with a second method of contraception such as 
condom, cervical cap, or diaphragm with spermicide during the 
study and for at least 4 weeks after last administration of IFX-1 
(timeframes for SOC have to be considered as described in the 
respective Prescribing Information).  
Male subjects with female partners of childbearing potential 
unwilling to use contraception (condoms) during treatment and for 
at least 4 months after last administration of treatment. 
Safety concern 
20. Evidence or suspicion that the subject might not comply with the 
requirements of the study protocol. 
Safety concern 
21. Any other factor which, in the investigator’s opinion, is likely to 
compromise the subject’s ability to participate in the study. 
Safety concern 
22. The subject is an employee or direct relative of an employee at the 
study site or sponsor. 
Administrative 


 
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Exclusion Criteria 
Rationale 
23. The subject is imprisoned or lawfully kept in an institution. 
Administrative 
24. The subject has participated in an investigational clinical study 
during the 12 weeks (or five times the half-life of the previous 
IMP, whichever is longer) before Screening, or plans to participate 
in another investigational clinical study during their participation 
in this study. 
Administrative 
5.4 
DISCONTINUATION OF INDIVIDUAL SUBJECT PARTICIPATION 
Each early discontinuation of individual subject participation, irrespective of the reason 
for discontinuation, must be documented by the investigator. If possible, the date, 
circumstances, and reason for discontinuation should be documented.  
The investigator will attempt to complete all procedures usually required at the end of the 
study (i.e., Week 24) at the time when the subject’s participation in the study is 
discontinued. Subjects who discontinue up to Week 16 will have a safety follow-up visit 
at 1 month (±3 days) after the last IMP administration. 
5.4.1 Lack of Efficacy 
In case of lack of efficacy, i.e., no improvement or deterioration in the BVAS since 
Screening, the investigator or subject can decide whether to discontinue from study 
participation.  
5.4.2 Withdrawal of Informed Consent 
Subjects may discontinue their participation in the study by withdrawing their consent at 
any time without giving reasons. Nevertheless, they should be asked about the reason(s) 
for discontinuation after being informed that they do not need to do so. Information as to 
when they withdrew consent must be documented. 
Subjects are to be informed that when consent is withdrawn, the stored and captured data 
as well as blood samples taken until the time of termination may be used further to: 
• 
Assess effects of the IMP being tested. 
• 
Guarantee that the subject’s personal interests are not adversely affected. 
• 
Comply with the requirement to provide complete documentation when seeking 
marketing authorization. 


 
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5.4.3 Discontinuation of the Investigational Medicinal Product 
Subjects must be discontinued from treatment with the IMP under any of the following 
circumstances: 
• 
Unacceptable toxicity or TEAE, as determined by the investigator. 
• 
Subjects unblinded for IMP administration due to safety concerns or emergency 
treatments. 
• 
Non-compliance with study procedures or with IMP administration.  
• 
Anaphylactic or other serious allergic reaction. 
• 
Serious infection, including meningitis or sepsis. 
• 
If, in the investigator’s or sponsor’s opinion, continued administration of IMP could 
be detrimental to the subject’s well-being.  
• 
In case of major relapse. 
• 
Use of prohibited treatment that in the investigator’s or sponsor’s opinion necessitates 
the subject being removed. 
• 
Biopsy confirmation of any malignancy. 
• 
Pregnancy. 
5.4.4 Lost to Follow-up 
Lost to follow-up is defined as an unsuccessful attempt at contacting a subject.  
At least three phone calls at three different times on consecutive days and a further phone 
call a week later should be performed. In case all calls are unsuccessful in contacting the 
subject, a certified letter will be issued to the subject. If the calls and the letter remain 
unanswered after approximately 1 month, the subject is to be declared as lost to 
follow-up. All the attempts at contacting the subject should be documented in the 
subject’s records. 
The date of being lost to follow-up is defined as the last date with any assessment of the 
subject. 


 
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6 
STUDY TREATMENTS 
6.1 
DETAILS OF THE INVESTIGATIONAL MEDICINAL PRODUCT 
6.1.1 Description of the Investigational Medicinal Product 
Both IFX-1 and placebo are considered IMP. 
IFX-1 is a monoclonal anti-human C5a immunoglobulin as active pharmaceutical 
ingredient, which is formulated in a phosphate buffered saline and Polysorbate 80. IFX-1 
will be supplied in 10 mL glass vials at a concentration of 10 mg/mL (i.e., 100 mg per 
vial) for intravenous administration and will have the following composition: 
Ingredient 
Strength 
IFX-1 
10 mg/mL 
Sodium chloride 
150 mM 
Sodium phosphate 
10 mM 
Polysorbate 80 
0.05% 
Placebo will be supplied in 10 mL glass vials for intravenous administration and will 
have the following composition: 
Ingredient 
Strength 
Sodium chloride 
150 mM 
Sodium phosphate 
10 mM 
Polysorbate 80 
0.05% 
The placebo vials and content will have the same appearance as the IFX-1 vials. 
6.1.2 Packaging and Labeling 
The IMP will be packaged in cardboard boxes and labeled in accordance with all legal 
requirements. Each cardboard box will contain four vials of IFX-1 or placebo. 
The cardboard boxes will be labeled with a unique number (“medcode”). The glass vials 
containing the IMP will be labeled with the same medcode as the cardboard boxes in 
which they are packed. Each cardboard box and each vial will be labeled with a 
multilingual booklet label or a specific single panel label. The labels are part of the 
Clinical Trial Application documentation. 


 
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6.1.3 Shipment 
The IMP will be supplied to study sites by a Contract Manufacturing Organization 
(CMO) on behalf of the sponsor; the CMO will provide the initial and all subsequent 
supplies.  
IMP availability on site will be triggered by an Interactive Web Response System 
(IWRS) ensuring continuous treatment of study subjects (for details refer to the IWRS 
Project Scope and Management document).  
The IMP must be shipped at a temperature of 2°C to 8°C (35.6°F to 46.4°F) and should 
not be frozen. Each shipment will be controlled by a temperature logger, of which a 
read-out must be obtained by the site personnel upon receipt of the shipment.  
Furthermore, the site personnel will check the IMP shipments for any loss, damage, or 
tampering and confirm receipt to the CMO. Records of the receipt of the IMP will be 
maintained by the site. 
Any technical complaints arising from defects in the quality of the IMP, or defects in the 
packaging or labeling of the IMP must be reported to the CMO immediately, and the 
affected IMP must not be used. 
If the shipping temperature is within the specified range, as confirmed by the temperature 
logger read-out and the receipt documentation, the CMO will release the IMP for use at 
the site via immediate notification from the IWRS. In the case of any deviation in the 
shipping temperatures, the notification for IMP release or rejection will be sent within a 
maximum of 24 hours. 
The site personnel will be responsible for adequate handling and accountability of the 
IMP at the study site. Further details on adequate handling of the IMP will be provided in 
the Pharmacy Manual. 
6.1.4 Storage 
The IMP must be stored at 2°C to 8°C (35.6°F to 46.4°F) and should not be frozen. All 
IMP supplies must be stored separately from normal hospital inventories in a locked 
facility with access limited to authorized personnel. All storage facilities must be 
temperature controlled. 
An established and validated local temperature management system with temperature 
logs should be used to record the storage temperature. If this is not possible, the study site 
will be provided with a temperature record form by the Contract Research Organization 
(CRO) and the site personnel will maintain temperature records for the entire duration of 
the study. At a minimum, the daily (working day) minimum and maximum temperatures 
must be documented. 


 
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Any deviation from the specified temperature range must be documented and reported to 
the CMO. Further information will be provided in the Pharmacy Manual. 
6.1.5 Drug Accountability 
During the study, all vials of IMP will be reconciled against the current inventory and the 
dispensing records as a component of the monitoring visits. Data on the administration of 
the IMP kept at the site will be monitored throughout the study by the study monitor. 
Used vials can be destroyed at the site according to institutional policy and in compliance 
with the current applicable regulatory requirements after drug accountability has been 
assessed by the study monitor. If an institutional policy prevents used vials from being 
retained for monitors’ review (e.g. institution must destroy used vials immediately), the 
institution must have an adequate drug accountability process and documentation for 
study monitors’ review. The destruction of any unused vials of the IMP at the study site 
must be documented in a form provided by the CRO. 
After completion of the study, copies of all IMP accountability records will be provided 
to the CRO. Further details on the monitoring procedures will be provided in a 
Monitoring Manual. 
6.1.6 Reconstitution of IFX-1 
The IMP will be reconstituted for infusion in a blinded manner at the study site or at the 
study site’s pharmacy. The reconstituted IMP should be used within 4 hours after dilution 
when stored at room temperature. Otherwise, the reconstituted IMP has to be stored at 
2°C to 8°C (35.6°F to 46.4°F) and used within 24 hours. Details on reconstituting the 
IMP will be provided in the Pharmacy Manual. 
6.1.7 Administration 
The IMP will be administered according to the dosing schedule in Table 1. Subjects will 
receive four administrations during the first 2 weeks and once every 2 weeks thereafter 
until Week 16. 


 
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Table 1 
Dosing Schedule for IFX-1 and Placebo 
 
IFX-1 dose (in mg) 
Visit 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
Week 
W0 
W0 
W1 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W16 
Day 
1 
4 
8 
15 
29 
43 
57 
71 
85 
99 
113 
Group A  
(400 mg IFX-
1) 
400 
400 
400 
400 
400 
400 
400 
400 
400 
400 
400 
Group B 
(800 mg IFX-
1) 
800 
800 
800 
800 
800 
800 
800 
800 
800 
800 
800 
Group C 
(placebo) 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
The IMP will be administered by the responsible personnel at the site as follows:  
• 
The reconstituted IMP will be infused over a period of 30 to 60 minutes 
(±10 minutes) and as described in the Pharmacy Manual. 
• 
At the end of the infusion, the intravenous line will briefly be flushed with 
approximately 10 mL of sterile sodium chloride (NaCl) to ensure that any IMP 
remaining in the line is administered. 
Subjects should remain at the study site for at least 30 minutes after the end of the IMP 
administration; appropriate treatment for potential infusion-related reactions must be 
available during this time.  
Each administration of IMP will be recorded in detail in the source data for the subject 
and eCRF.  
If the scheduled infusion cannot be administered at the scheduled time (also considering 
an acceptable time window of ±1 day during the Treatment Period), the medical monitor 
should be informed. It will be decided on a case-by-case basis whether the IMP may be 
administered at a later time point or whether it should be omitted. 
Further details of the IMP administration will be outlined in the Pharmacy Manual. 
6.2 
DETAILS OF THE STANDARD OF CARE 
The immunosuppressive therapies taken or administered during the study (RTX, CYC, 
AZA, MTX, MMF, MPS, and GCs) are all considered SOC and will not be provided by 
the sponsor. The investigator should follow standard safety laboratory procedures 
according to the current United States Product Information. 


 
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All subjects will receive RTX or CYC plus GCs from Week 0 up to clinical remission 
(Remission Induction Phase). Following clinical remission and up to Week 24, subjects 
are allowed to switch to other SOC (AZA, MTX, MMF, or MPS plus GCs), to use 
throughout the remainder of the study, or to stay on RTX or CYC (Remission 
Maintenance Phase). 
Administration of RTX or CYC plus intravenous GCs can be started immediately after all 
screening assessments are performed, independent from the planned date of 
randomization.  
During the Screening period subjects can take up to 60 mg/day oral prednisolone (or 
equivalent). From Day 1 oral GCs must be used according to the standardized tapering 
schedule presented in Table 5. 
6.2.1 Rituximab 
RTX can be administered during the entire study. For further details on GC 
administration see Section 6.2.3. 
RTX is a genetically engineered chimeric murine/human monoclonal immunoglobulin 
(Ig)G1 kappa antibody directed against the CD20 antigen. Further details on RTX used 
for the treatment of GPA and MPA are summarized in Table 2.  
Table 2 
Summary of Clinical Data on Rituximab for Use in GPA/MPA 
Indication 
Treatment of GPA and MPA in adult patients in combination with GCs. 
Other indications: 
• 
Treatment of non-Hodgkin’s lymphoma. 
• 
Treatment of chronic lymphocytic leukemia. 
• 
Treatment of rheumatoid arthritis. 
Contraindications 
None 
Warnings and 
precautions 
• 
Risk of severe, including fatal, infusion-related reactions typically 
during the first infusion of RTX with time to onset of 30 to 120 minutes. 
Premedication may reduce the incidence and/or the severity of infusion 
reactions. 
• 
Risk of severe, including fatal, mucocutaneous reactions with variable 
time of onset. 
• 
Risk of hepatitis B reactivation among subjects positive for hepatitis B 
surface antigen or hepatitis B core antibody.  
• 
Risk of cardiovascular adverse reactions. RTX infusions should be 
discontinued in patients with serious or life-threatening cardiac 
arrhythmias.  
• 
The use of live vaccines should be avoided. 
• 
RTX can cause neonatal harm and use in pregnancy should be avoided.  


 
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Dosage and 
administration 
A dose of 375 mg/m2 in combination with GCs (once per day) once weekly 
for 4 weeks as an intravenous infusion (independent of IFX-1).  
The use of RTX and/or intravenous GCs may only be started after all 
screening assessments have been completed. Same day infusions of 
intravenous GCs and RTX are permitted. 
GC = glucocorticoid; GPA = granulomatosis with polyangiitis; MPA = microscopic polyangiitis; 
RTX = rituximab 
Source: Prescribing Information for rituximab.  
6.2.2 Cyclophosphamide 
CYC can be administered during the entire study. If used during the first 12 weeks of the 
Treatment Period, it can be administered according to the pulse regimen in Table 3. If 
CYC and IFX-1 or placebo are administered on the same day, the IMP should be 
administered before the CYC treatment. 
Table 3 
Pulse Regimen of Cyclophosphamide 
Time a 
Pulse Number b 
Dosage and Route c 
Week 0 
1 
15 mg/kg intravenously 
Week 2 
2 
15 mg/kg intravenously 
Week 4 
3 
15 mg/kg intravenously 
Week 7 
4 
15 mg/kg intravenously 
Week 10 
5 
15 mg/kg intravenously 
a 
The first three pulses can be given at intervals of 2 weeks and can be given intravenously. 
b 
This regimen implies clinical remission within 3 months. 
c 
Cyclosphosphamide dose reduction indicated for subjects with creatinine values of 300 to 
500 µmol/L. 
CYC as alkylating drug is used off-label for treating patients with AAV. A summary of 
relevant details from the United States Prescribing Information on CYC is provided in 
Table 4. 


 
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Table 4 
Summary of Clinical Data on Cyclophosphamide 
Indication(s) 
• 
Treatment of malignant lymphomas. 
• 
Treatment of minimal change nephrotic syndrome in pediatric 
patients not responding or not tolerating adrenocorticosteroid 
therapy. 
Contraindications 
• 
Hypersensitivity to CYC. 
• 
Urinary outflow obstruction.  
Warnings and 
precautions 
• 
Risk of myelosuppression, bone marrow failure, and severe 
immunosuppression. CYC should not be given to subjects with 
neutrophils ≤1,500/mm3 and platelets <50,000/mm3. 
• 
Latent infections can be reactivated. CYC treatment may not be 
indicated, or should be interrupted, or the dose reduced, in subjects 
who have or who develop a serious infection. 
• 
Urinary tract obstructions should be corrected before starting CYC 
therapy or, if not possible, patients excluded from therapy, because 
of the risk of hemorrhagic cystitis, pyelitis, ureteritis, hematuria, 
and urotoxicity.  
• 
CYC should be administered with caution in patients with risk 
factors for cardiotoxicity or pre-existing cardiac disease.  
• 
Risk of pulmonary toxicity leading to respiratory failure as well as 
late onset pneumonitis.  
• 
CYC is genotoxic and carries a risk of secondary malignancies.  
• 
Risk of veno-occlusive liver disease.  
• 
CYC interferes with oogenesis and spermatogenesis and may 
irreversibly impair male and female reproductive function and 
fertility.  
• 
May interfere with normal wound healing. 
• 
CYC can cause fetal harm and should be avoided during 
pregnancy.  
• 
Risk of hyponatremia associated with increased total body weight, 
acute water intoxication, and a syndrome resembling the syndrome 
of inappropriate secretion of antidiuretic hormone.  
Dosage and 
administration 
See Table 3 for the pulse regimen administered during the study.  
CYC = cyclophosphamide 
Source: Prescribing Information for cyclophosphamide. 
6.2.3 Glucocorticoids 
GCs are a class of corticosteroids and are used as anti-inflammatory agents with a wide 
range of indications. In patients with AAV, GCs are used off-label. GCs have to be 


 
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administered according to the tapering schedule presented in Table 5. For major side 
effects associated with oral GC therapy see Appendix 18.2. 
Table 5 
Standardized Dosing Schedule for Glucocorticoid Tapering 
Time 
Dose in mg 
(daily dose per week) 
Week 0 
60 
Week 1 
50 
Week 2 
40 
Week 3 
40 
Weeks 4, 5 
30 
Weeks 6, 7 
30 
Weeks 8, 9, 10, 11 
25 
Weeks 12, 13 
20 
Weeks 14, 15 
15 
Weeks 16, 17, 18, 19 
10 
Weeks 20, 21, 22, 23 
5 
Weeks 24 
0 
6.2.4 Azathioprine 
Subjects may be switched from RTX or CYC plus GCs to AZA at the investigator’s 
discretion only during the Remission Maintenance Phase.  
AZA is an immunosuppressive purine antimetabolite and is used off-label for treating 
patients with AAV. A summary of relevant details from the United States Prescribing 
Information on AZA is provided in Table 6. 


 
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Table 6 
Summary of Clinical Data on Azathioprine 
Indications 
• 
Add-on therapy for the prevention of rejection in renal 
homotransplantations. 
• 
Treatment of active rheumatoid arthritis.  
Contraindications 
• 
Hypersensitivity to AZA. 
• 
Rheumatoid arthritis previously treated with alkylating agents. 
Warnings and 
precautions 
• 
Risk of lymphomas and other malignancies, particularly of the skin. 
Exposure to sunlight and ultraviolet light should be limited. 
• 
Risk of severe leukopenia, thrombocytopenia, anemias including 
macrocytic anemia, and/or pancytopenia. Severe bone marrow 
suppression may occur. Hematologic toxicities are dose-related and 
delayed hematologic suppression may occur. Patients with low to 
intermediate or absent thiopurine S-methyl transferase activity may 
be at increased risk of myelotoxicity. Genotyping or phenotyping for 
thiopurine S-methyl transferase activity is advisable.  
• 
Risk of developing serious infections. 
• 
AZA impaired male fertility in animals. No data are available in 
humans.  
• 
Risk of developing symptoms of gastrointestinal toxicity during the 
first several weeks of treatment.  
• 
AZA can cause fetal harm and should be avoided during pregnancy.  
Dosage and 
administration 
AZA can be administered at a dose of 2 mg/kg/day up to a maximum 
dose of 200 mg. If the subject is older than 60 years, the dose can be 
reduced by 25% and in subjects older than 70 years, a reduction of 50% 
is recommended. 
AZA = azathioprine 
Source: Prescribing Information for azathioprine.  
6.2.5 Methotrexate 
Subjects may be switched from RTX or CYC plus GCs to MTX at the investigator’s 
discretion only during the Remission Maintenance Phase. 
MTX is an antimetabolite that inhibits dihydrofolic acid reductase and is used off-label 
for treating patients with AAV. A summary of relevant details from the United States 
Prescribing Information on MTX is provided in Table 7. 


 
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Table 7 
Summary of Clinical Data on Methotrexate 
Indications 
• 
Treatment of neoplastic diseases either alone or in combination with 
other anticancer agents. 
• 
Symptomatic control of severe, recalcitrant, disabling psoriasis 
confirmed by biopsy and/or dermatologic consultation and that is not 
adequately responsive to other forms of therapy. 
• 
Management of rheumatoid arthritis including polyarticular-course 
juvenile rheumatoid arthritis if patients are insufficiently responding 
or are intolerant to first-line therapy.  
Contraindications 
• 
Pregnancy (can cause fetal deaths or teratogenic effects) and lactation 
(excreted in human milk). 
• 
Alcoholism, alcoholic liver disease or other chronic liver disease. 
• 
Overt or laboratory evidence of immunodeficiency syndrome. 
• 
Pre-existing blood dyscrasias. 
• 
Hypersensitivity to MTX. 
Warnings and 
precautions 
• 
Potential for serious toxicity at any time of the therapy.  
• 
Due to diminished hepatic and renal function as well as decreased 
folate stores in older patients, relatively low doses should be 
considered.  
• 
Patients should be monitored closely for bone marrow, liver, lung, and 
kidney toxicities.  
• 
Diarrhea and ulcerative stomatitis require interruption of therapy. 
• 
Risk of developing malignant lymphomas in patients with low-dose 
MTX, which may regress following withdrawal of MTX.  
• 
Risk of severe, occasionally fatal, skin reactions within days of MTX 
treatment. Recovery of non-fatal reactions upon discontinuation of 
therapy. 
• 
Risk of opportunistic infections, especially Pneumocystis carinii 
pneumonia.  
• 
Increase risk of soft tissue necrosis and osteonecrosis when given 
concomitantly with radiotherapy.  
Dosage and 
administration 
MTX can be administered as tablets or subcutaneous injection up to a 
maximum dose of 25 mg/week, if the estimated glomerular filtration rate 
is ≤50 mL/min. Oral doses at 20 mg per week or higher can be 
administered as a split dose over 24 hours to ensure absorption. 
MTX = methotrexate 
Source: Prescribing Information for methotrexate tablets and injection.  


 
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6.2.6 Mycophenolate Mofetil and Mycophenolate Sodium 
Subjects may be switched from RTX or CYC plus GCs to MMF or MPS at the 
investigator’s discretion only during the Remission Maintenance Phase.  
MMF and MPS are uncompetitive and reversible inhibitors of inosine monophosphate 
dehydrogenase and are used off-label for treating patients with AAV. A summary of 
relevant details from the United States Prescribing Information on MMF and MPS is 
provided in Table 8. 


 
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Table 8 
Summary of Clinical Data on Mycophenolate Mofetil and 
Mycophenolate Sodium 
 
MMF 
MPS 
Indication(s) 
• 
Prophylaxis of organ rejection in 
patients receiving allogeneic renal, 
cardiac or hepatic transplants. 
• 
Prophylaxis of organ rejection in 
adult patients receiving a kidney 
transplant. 
• 
Prophylaxis of organ rejection in 
children ≥5 years of age who are 
at least 6 months post kidney 
transplant.  
Contraindications 
• 
Hypersensitivity to MMF, 
mycophenolic acid or any other 
component of the drug. 
• 
Hypersensitivity to MPS, 
mycophenolic acid, MMF, or any 
other component of the drug. 
Warnings and 
precautions 
• 
Risk of increased susceptibility to bacterial, viral, fungal, and protozoal as 
well as new or reactivated viral including opportunistic infections. These 
infections may become serious.  
• 
Risk of lymphoma and other malignancies, especially on the skin. Exposure 
to sunlight and ultraviolet light should be limited.  
• 
Use during pregnancy is associated with increased risk of pregnancy loss 
and congenital malformations.  
• 
Risk of progressive multifocal leukoencephalopathy in patients with 
immunosuppressant therapy and impairment of immune function.  
• 
Risk of neutropenia (absolute neutrophil count<1.3 x 103/µL). 
• 
Risk of pure red cell aplasia when used in combination with other 
immunosuppressive agents.  
• 
MMF or MPS should be administered with caution in patients with active 
serious digestive system disease.  
• 
MMF or MPS should be avoided in patients with rare hereditary deficiency 
in hypoxanthine-guanine phosphoribosyl-transferase.  
• 
Contains a source of phenylalanine and should be used with caution in 
patients with phenylketonuria.  
• 
Live vaccine use should be avoided.  
Dosage and 
administration 
MMF can be taken orally, twice daily as 
tablets. Reduction in subjects with a 
creatinine clearance of less than 
25 mL/min may be required. The drug 
intake will be started at 1 g per day and 
the dose increased to the target dose of 
2 g per day, if tolerated. The dose can be 
increased to 3 g daily for those with a 
suboptimal response. 
The recommended daily dose of 
MPS is 1440 mg (8 tablets of 180 mg 
each) to be taken as two separate 
doses of 720 mg each. The dose can 
be increased to 2160 mg/day. 
MMF = mycophenolate mofetil; MPS = mycophenolate sodium 


 
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Source: Prescribing Information for mycophenolate mofetil.  
6.3 
RANDOMIZATION AND BLINDING 
Subjects will be assigned to one of the three treatment groups by means of a computer 
generated randomization list implemented into the IWRS. At each study site, each new 
subject who qualifies for randomization into the study according to the inclusion and 
exclusion criteria will be assigned a number in ascending order, beginning with the 
lowest number available at the study site. This procedure must be adhered to throughout 
the study. Interaction with the automated system will be provided via web access to the 
IWRS. 
The blind will be maintained throughout the Treatment and Follow-up Periods as 
applicable for all IMP administered or provided to the subjects. The label, weight, 
appearance, and handling of the IMP will not compromise the blind. 
If required, the investigator will be provided with technical options and password 
information to selectively break the randomization code for an individual subject via web 
access.  
Safety data for the IDMC analyses will be handled and analyzed by an independent 
unblinded statistician. 
Emergency Identification of Investigational Medicinal Product 
The IWRS will be programmed with instructions for breaking the blind. Any premature 
breaking of the blind should be confined to emergency cases in which knowledge of the 
IMP received is necessary, e.g., to be able to provide appropriate emergency medical 
treatment. Whenever possible, the investigator should contact the medical monitor of the 
responsible CRO before breaking the blind, unless this would delay the emergency 
treatment. Subject safety must always be the primary consideration when determining 
whether to break the blind. 
If a subject’s treatment assignment is unblinded, the medical monitor will receive an alert 
from the IWRS. The investigator must inform the medical monitor within 24 hours of 
breaking the blind and the subject will be discontinued from further participation in the 
study. The date and reason why the blind was broken must be provided by the 
investigator and recorded in the source documentation for the subject and in the eCRF, as 
applicable. 


 
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6.4 
PROCEDURES IN CASE OF SPECIFIC SIDE EFFECTS 
6.4.1 Specific Side Effects of IFX-1 
  
If a side effect occurs or is suspected after administration of IMP, subjects must be 
closely monitored, and as applicable the side effect must be reported as an adverse event 
(AE) (Section 10). Any treatment deemed medically appropriate should be initiated. 
In case of the following specific types of side effects, the procedures reported below must 
be applied.  
Infections: because IFX-1 blocks C5a, there is a theoretical risk of an increased rate of 
infections. Therefore, the investigator (and other health care professionals who take care 
of the subjects) should be closely monitored for signs and symptoms of infections in 
general. In case a subject develops a clinical picture that is difficult to distinguish from 
invasive infection, routine blood cultures and early start of antibiotic treatment are 
recommended. In subjects with bacterial infection, depending on the severity of the 
infection, it is important that concomitant antibiotic therapy be administered during 
treatment with IFX-1 to ensure appropriate control of the source of the infection. The 
investigator should pay close attention to the choice of an appropriate broad spectrum 
antibiotic treatment according to applicable guidelines. The IMP can be interrupted or 
discontinued at the investigator’s discretion. Any invasive infection must be reported as 
an adverse event of special interest (AESI) (Section 10.3).  
Meningitis/Meningococcal Sepsis: in case of signs of meningitis at any time during the 
study, the subject must be closely monitored and the guidelines for treatment of 
meningitis should be followed [Tunkel 2017, Van de Beek 2016]. This includes lumbar 
puncture, blood culture testing, immediate start of treatment with dexamethasone and 
intravenous antibiotics (combination therapy with ampicillin and third generation 
cephalosporin), and a search for the focus of the infection (e.g., computed tomography or 
magnetic resonance tomography). The IMP should be interrupted immediately in case of 
signs and symptoms of meningitis and discontinued if meningitis is confirmed. 
Infusion-Related Reactions/Anaphylactic Reactions and Acute Systemic Allergic 
Hypersensitivity: in case of any severe, acute systemic hypersensitivity reaction during 
or shortly after infusion of IFX-1, the infusion should be stopped immediately and the 
subject discontinued from further dosing. In such cases, subjects should be closely 
monitored for any changes in blood pressure, heart rate, metabolic conditions, or organ 
function, and appropriate measures should be taken to stabilize all vital signs. Fluid 
resuscitation may be needed, as well as vasopressor therapy or other measures to treat 
changes in blood pressure, vital signs, or metabolic conditions in general. In cases of 
emergency with immediate life-threatening potential such as cardiac arrest or similar life-
threatening changes, appropriate cardiopulmonary resuscitation should be started 


 
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immediately according to applicable guidelines, or as established at the study sites 
through existing standard operating procedures or other algorithms for cardiopulmonary 
resuscitation according to current recommended resuscitation guidelines. 
For any potential infusion-related event, the investigator should check for a potentially 
developing or existing anaphylactic reaction. In case an anaphylactic reaction is 
anticipated, appropriate immediate actions should be taken according to the severity or 
stage of the detected anaphylactic reaction as recommended by existing guidelines for the 
treatment of anaphylactic reactions or, if established at the study sites, according to 
available standard operating procedures or other algorithms. 
For further details regarding the definition and management of anaphylaxis, please refer 
to the Second symposium on the definition and management of anaphylaxis: Summary 
report—Second National Institute of Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network symposium (Hugh et al., 2006)  
If the investigator abstains from further dosing the subject can be maintained in the study 
and can continue with study procedures as scheduled. 
In case of an emergency or other situation in which it is medically imperative for the 
investigator to identify the IMP that a subject has received or is receiving, the procedure 
for emergency identification of IMP must be followed. 
6.4.2 Overdose of IFX-1 
The consequences of an overdose with IFX-1 are not known. 
If overdosing of the IMP occurs or is suspected, subjects must be closely monitored for 
any symptoms. In case of any symptoms, treatment as deemed medically appropriate by 
the investigator should be initiated. Overdoses accompanied by adverse outcomes must 
be recorded as treatment-emergent adverse events (TEAEs). 


 
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7 
PRIOR AND CONCOMITANT THERAPY 
Any medication (including, but not limited to, over-the-counter or prescription medicines 
such as aspirin, antacids, vitamins, mineral supplements, and/or herbal supplements), 
vaccine or procedure (e.g., mechanical ventilation) that the subject received during the 
3 months before or at Screening (prior therapy) or receives during the study (concomitant 
therapy) must be recorded in the source documentation and in the eCRF, with details on 
the reason for use, date(s) of administration (with start and end dates), and dosing 
information, including dose, route, and frequency of administration. 
Any AAV therapy that the subjects received 1 year prior to study enrolment will be 
documented in the source and in the eCRF by verbatim name with start and end dates. 
7.1 
RECOMMENDED CONCOMITANT THERAPY 
Osteoporosis prophylaxis 
Treatment measures to prevent osteoporosis are to be administered at the discretion of the 
investigator. 
Pneumocystis Carinii Pneumonia (PCP) Prophylaxis 
It is recommended to prescribe treatment medication to prevent PCP. The treatment 
measures prescribed are at the discretion of the investigator, and can be applied as per 
local practice. For details refer to the current Product Information also, if applicable. 
Permitted concomitant therapy are described in Sections 7.2 and 7.3; prohibited 
concomitant therapies are listed in Section 7.4. 
7.2 
PERMITTED GLUCOCORTICOID THERAPY 
Inhaled and topical GCs can be used for subjects diagnosed with diseases other than 
AAV (for example: eczema, asthma, chronic obstructive pulmonary disease, eosinophilic 
esophagitis), or for subjects with large airway involvement of GPA as documented by 
bronchoscopy. Local injections of GCs into subglottic GPA lesions can be given. All use 
of topical or inhaled GCs must be documented accurately in the source documentation 
and in the concomitant medication section of the eCRF. 
Subjects on an oral GC dose of more than 10 mg/day prednisone-equivalent for more 
than 6 weeks continuously before Screening or who have received more than 3 g 
cumulative dose of intravenous GCs within 4 weeks before Screening will not be 
randomized in this study. 
Intravenous GCs may only be started after all screening assessments have been 
completed. Same day infusions of intravenous GCs as pre-medication prior to each 
infusion of RTX are permitted.  


 
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During the Screening period subjects can take up to 60 mg/day oral prednisolone (or 
equivalent). From Day 1 oral GCs must be used according to the standardized tapering 
schedule presented in Table 5.  
If subjects are on oral GC treatment at a dose of 10 mg/day or less during the Screening 
period, this dose has to be stopped before Day 1. From Day 1, oral GCs must be used 
according to the standardized tapering schedule presented in Table 5.   
7.3 
RESCUE THERAPY 
Rescue therapy will not be provided by the sponsor. The administration or receipt of 
rescue therapy does not necessarily discontinue the subject from IMP administration and 
study participation.  
Severe Disease Flare (Major Relapse): 
A severe disease flare is defined as having a BVAS >3 or experiencing one of the major 
BVAS items listed in Appendix 18.4 that requires treatment with other than permitted 
AAV therapy following clinical remission (BVAS = 0) in this study. Depending on the 
severity of a subject’s presenting symptoms, as well as the clinical picture, the 
investigator will be allowed to prescribe a maximum of 1 g of methylprednisolone per 
day for up to 3 days. In addition, up to 1 mg/kg oral prednisolone (or equivalent) may be 
prescribed with a subsequent tapering schedule per the investigator´s discretion. 
A subject experiencing a major relapse should discontinue study drug but stay in the 
study, receive treatment with standard of care, at the discretion of the investigator, and 
will continue with study procedures as scheduled. 
 
If a subject with a major relapse was discontinued from the study by Week 16, a safety 
follow-up visit must be performed 1 month (± 3 days) after discontinuation. 
Limited Disease Flare (Minor Relapse): 
A limited disease flare is defined as any minor item defined for the BVAS (see 
Appendix 18.4) after clinical remission (BVAS = 0) in this study. At the discretion of the 
investigator, subjects experiencing a limited disease flare can receive, together with the 
standardized GC dosing schedule, up to 20 mg/day of GCs (prednisone-equivalent) that 
should be tapered down to the standardized tapering dose over 14 days. 
A subject experiencing a minor relapse will stay in the study and will continue with study 
procedures as scheduled.  
If a subject with a minor relapse was discontinued from the study by Week 16, a safety 
follow-up visit must be performed 1 month (± 3 days) after discontinuation. 


 
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7.4 
PROHIBITED THERAPY 
The following therapies are prohibited for all subjects during the study: 
• 
Tumor necrosis factor inhibitor treatment (e.g., etanercept) 
• 
Anti-CD20 therapies other than RTX 
• 
Abatacept 
• 
Alemtuzumab 
• 
Any other experimental or biologic therapies 
• 
Intravenous, intramuscular, or sub-cutaneous immunoglobulin 
• 
Plasma exchange 
• 
Antithymocyte globulin 
• 
Live vaccines 
• 
Renal dialysis 
• 
Any other oral or iv. GCs (except for those used as rescue therapy as described in 
Section 7.3) 
If administration of any prohibited concomitant therapy becomes necessary during the 
study for medical reasons, the subject is to be discontinued from further IMP 
administration. (S)he can be maintained in the study and continue with study procedures 
as scheduled. 
The investigator should contact the medical advisor of the sponsor’s designed CRO or the 
sponsor if there are any questions regarding prior or concomitant therapy. 


 
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8 
STUDY PROCEDURES AND VISIT SCHEDULE 
The assessments to be performed at each visit are presented in the Schedule of 
Assessments. The visit schedule is applicable to all subjects in Groups A, B, and C. The 
assessments will be performed according to the methods described in Section 11. 
8.1 
SCREENING  
Screening is the predetermined series of procedures with which each investigator selects 
an appropriate and representative sample of subjects for randomization into the study.  
The screening procedures will be conducted between Day -14 and Day -1 before 
randomization.  
The investigator may pre-screen subjects for study inclusion and exclusion criteria 
without first obtaining written informed consent for participation in the current study on 
the basis of one or both of the following situations: 
• 
Pre-existing data (e.g., for study inclusion and exclusion criteria, as available in 
medical records held by the investigator). 
• 
Initial contact (e.g., routine visit, phone call) where only routine and/or non-
study-specific questions are allowed. 
After subjects have provided written informed consent, potentially eligible subjects will 
be assessed to determine if all inclusion criteria and no exclusion criteria are met. All 
subjects must provide written informed consent before any study-specific assessments or 
procedures are performed. If the subject fulfills all of the inclusion criteria, does not meet 
any of the exclusion criteria, and written informed consent is available, the subject will be 
randomized.  
All randomized subjects will be issued a subject card with relevant contact details, 
including emergency contact details. Subjects will be instructed on the completion of the 
PROs by the investigator at Screening. 
If the subject meets an exclusion criterion or another reason for non-inclusion in the study 
is given after obtaining informed consent, the subject will not be randomized and will be 
deemed a screen failure. 
8.2 
TREATMENT PERIOD 
The Treatment Period will comprise Visits 2 to 12 (Weeks 0 to 16). All visits will have 
an accepted time window of ±1 day.  
At each visit, the planned assessments will be performed predose, unless otherwise 
specified in the Schedule of Assessments. 


 
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If any subject is discontinued during the Treatment Period (i.e., until Week 16), the 
assessments planned for Week 24 should be performed as soon as possible and again at 
the safety follow-up visit (Section 8.4). 
Only RTX or CYC plus GCs may be used as SOC during the Remission Induction Phase 
(i.e., until clinical remission). Subjects are allowed to switch to AZA, MTX, MMF, or 
MPS plus GCs after clinical remission, at the discretion of the investigator.  
8.3 
FOLLOW-UP PERIOD 
The Follow-up Period will comprise Visits 13 to 14 (from after the IMP administration at 
Week 16 to Week 24). All visits will have an accepted time window of ±3 days. 
If any subject is discontinued after Week 16 but before Week 24, the assessments 
planned for Week 24 should be performed as soon as possible.  
RTX, CYC, AZA, MTX, MMF, or MPS plus GCs can be used as SOC during this 
period. 
8.4 
SAFETY FOLLOW-UP VISIT 
This visit will only be performed for any subjects who discontinue the study during the 
Treatment Period (i.e., until Week 16). The visit will occur at 1 month (±3 days) after the 
last IMP administration and the same assessments as for Week 24 will be performed. 
8.5 
UNSCHEDULED VISIT 
Unscheduled visits to the study site will be for subjects with major or minor relapses. The 
assessments specified in the Schedule of Assessments should be performed.  


 
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9 
STUDY VARIABLES AND ASSESSMENT METHODS 
9.1 
STUDY SUBJECTS 
9.1.1 Demographics and Baseline Characteristics 
The following demographic data and baseline characteristics will be documented at 
Screening: 
• 
Age 
• 
Gender 
• 
Race and ethnicity 
• 
Body weight 
• 
Height  
• 
Smoking status 
9.1.2 AAV Medical History 
Widely accepted diagnostic criteria, as opposed to classification criteria or definitions, 
have not yet been developed for GPA and MPA. In 1994, the CHCC developed 
definitions for these vasculitides and some of their mimickers with a revision issued in 
2013 [Jennette 2013]. These definitions, along with the American College of 
Rheumatology Criteria for the classification of vasculitides are useful in formulating the 
diagnostic criteria that will be applied to determine a subject’s eligibility for this study 
(see Appendix 18.1) [Fries 1990]. 
The AAV medical history will be documented in terms of: 
• 
Positive antigen-specific ANCA titer prior to screening (including the type and last 
date of positive ANCA lab test result) as evidenced by a positive ELISA test for 
antibodies to proteinase 3 or antibodies to myeloperoxidase 
• 
Number of major relapses since diagnosis 
• 
Date of most recent major relapse 
• 
Date of AAV diagnosis 
• 
Family history of AAV (first degree family pedigree) 
9.1.3 General Medical History 
A complete medical history for the 12 months prior to screening will be obtained from 
each subject at screening.  


 
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9.1.4 Prior and Concomitant Therapy 
All prior and concomitant therapy will be documented, as described in Section 7. 
9.2 
EFFICACY  
9.2.1 Efficacy Variables 
Efficacy will be assessed on the basis of the following variables: 
• 
BVAS 
• 
Vasculitis Damage Index (VDI) 
• 
Physician Global Assessment (PGA) 
• 
Renal variables 
• 
PRO: 36-item Short Form survey (SF-36) 
• 
 
9.2.2 Methods of Assessing Efficacy Variables 
All assessments will be performed at the time points specified in the Schedule of 
Assessments. 
9.2.2.1 Birmingham Vasculitis Activity Score Version 3.0 
The BVAS Version 3.0 is a validated instrument for the assessment of disease activity 
and response to treatment in AAV [Mukhtyar 2009].  
The BVAS Version 3.0 form is a list of 56 items with a numerical weight attached to 
each item, and each organ system has a ceiling score. The form is divided into nine 
organ-based systems (i.e., general symptoms such as arthralgia, arthritis, and fever, plus 
involvement of eight major organ systems), with each section including symptoms/signs 
that are typical of that particular organ involvement in systemic vasculitis 
(Appendix 18.3). Each organ system has a ceiling score. These scores reflect the 
proportional importance of each manifestation and each organ system. Completion of the 
form provides a numerical score by using the Glossary and Scoring Rules for the BVAS 
(Appendix 18.4). Scoring ranges are higher when any of the features are new or worse. 
Creatinine levels can be scored at a subject’s first assessment only. Higher scores indicate 
more severe disease. A decrease of >16 units is clinically meaningful. 
In order to standardize the BVAS assessment in this study, all attempts should be made 
that the same investigator scores the subject at all visits, and all investigators performing 
the BVAS assessment have to participate in a dedicated training (either face-to-face or 
web-based) and receive a certification prior to screening any subject. This certified 


 
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training is required in order to use the forms properly. Training and/or training material 
as well as certification will be provided.  
9.2.2.2 Vasculitis Damage Index 
The VDI will be used to assess damage induced by GPA or MPA and by the treatment 
applied during this study. The VDI is a validated assessment tool divided into 11 organ 
systems. The scoring sheet is divided into 10 systems plus an 11th section for other items, 
mainly related to the effects of drugs. The VDI is used to record any condition that has 
occurred and lasted for at least 3 months since the start of vasculitis and refers to chronic 
damage whether or not it is related to vasculitis. It consists of 64 items selected by expert 
consensus as representative of the forms of damage developed by subjects with systemic 
vasculitis [Exley 1997]. Completion of the form provides a numerical score by 
summation of each damage (Appendix 18.6). Each item scores 1 point.  
Three scores will be calculated for each subject: 
• 
Total VDI score: 
the total number of items will be counted leading to a 
minimum score of 0 and a maximum score of 64 
• 
System score: 
the extent of disease defined by the number of separate 
systems with at least 1 item score 
• 
Critical damage score: 
the number of items of damage consistent with organ 
failure (as defined in the glossary) 
In order to standardize the VDI assessment in this study, all attempts should be made that 
the same investigator scores the subject at all visits, all investigators performing the VDI 
scoring should conduct a dedicated training (either face-to-face or web-based) and 
receive a certification prior to screening any subject. This certified training is required in 
order to use the forms properly. Training and/or training material as well as certification 
will be provided. 
9.2.2.3 Physician Global Assessment 
The PGA scale is an 11-point scale derived from the BVAS for GPA to record the 
assessment of the overall disease activity of GPA or MPA (not including longstanding 
damage) within the previous 28 days [Stone 2001]. The rating ranges from 0 (remission) 
to 10 (maximum activity) (Appendix 18.7). 
All attempts should be made to ensure that the same investigator scores the subject at all 
visits and when completing this assessment, the investigator should not be influenced by 
the presence of any accumulated damage, complication of treatment, social/emotional 
problems, or other issues not related to active GPA or MPA. 


 
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9.2.2.4 Renal Variables 
Renal variables will be analyzed for both safety and efficacy and will be used to adapt the 
different therapies during the course of the study. 
The renal variables to be analyzed in this study are listed in Table 9. 
Table 9 
Renal Variables 
Variable 
Urine 
Serum 
Calculation 
Laboratory 
Creatinine 
X 
X 
 
Central 
Total protein 
X 
X 
 
Central 
Microalbumin 
X 
 
 
Central 
MCP-1 
X 
 
 
Central 
Urinary MCP-1:creatinine ratio 
 
 
X 
 
UACR 
 
 
X 
 
eGFR 
 
 
X 
 
eGFR = estimated glomerular filtration rate; MCP = monocyte chemoattractant protein; UACR = urinary 
albumin:creatinine ratio 
All derived ratios and the eGFR will be calculated at the time points when the respective 
single serum or urinary parameters are planned to be assessed. 
. Instructions regarding the collection, processing, and shipping of samples for analysis of 
laboratory parameters (i.e., urinary and serum creatinine, 
 and 
urinary monocyte chemoattractant protein [MCP-1]) will be available in the Laboratory 
Manual provided by the responsible lab.  
The eGFR will be calculated by the central laboratory according to the Modified Diet in 
Renal Disease equation: 
eGFR = 175 x (serum creatinine, mg/dL)-1.154 x (age, years)-0.203 x (0.742 if 
female) x (1.212 if black) [Levey 1999].  
9.2.2.5 36-Item Short Form Survey Version 2 
The SF-36 version 2 is a subject-reported generic measurement of health status that has 
proven useful in studies of both general and specific populations, comparing the relative 
burden of diseases and the health benefits produced by different treatments [Ware 1998]. 
Inclusion of the SF-36 has become standard practice for almost all clinical studies and 
observational studies for most rheumatic diseases, including vasculitis [Merkel 2011].  


 
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The SF-36 consists of 36 questions from the following eight domains: vitality, physical 
functioning, bodily pain, general health perceptions, physical role functioning, emotional 
role functioning, social role functioning, and mental health (Appendix 18.8).  
Each domain is directly transformed into a scale from 0 to 100 on the assumption that 
each question carries equal weight. A lower score indicates a poorer health status; a 
higher score indicates a better health status (i.e., a score of zero is equal to maximum 
disability and a score of 100 is equal to no disability). The eight domains are summarized 
to form two distinct higher-ordered clusters (physical health and mental health). 
A paper version of the questionnaire will be provided and thoroughly explained to the 
subjects during their visits to the study site. To avoid bias in the subject’s response, the 
subject has to complete the questionnaire at the study site before the study site personnel 
performs any other assessments. 
The study site personnel will be responsible to enter the data from the completed SF-36 
questionnaire into the eCRF in a timely manner; the original paper questionnaires will 
then be filed in the study records. 
9.2.2.6 Anti-neutrophil Cytoplasmic Antibody Status 
At screening, history of positive antigen-specific ANCA test as evidenced by a positive 
ELISA test of either anti-proteinase 3 (anti-PR3) or anti-myeloperoxidase (anti-MPO) 
antibodies is required to enroll a subject into the study.  
The ANCA testing performed by the central laboratory during the study will comprise 
testing for PR3-ANCA and MPO-ANCA. Further details are provided in the Laboratory 
Manual. 
9.3 
SAFETY 
9.3.1 Safety Variables 
Safety will be assessed on the basis of the following variables: 
• 
AEs 
• 
Glucocorticoid toxicity index (GTI) 
• 
Physical examination 
• 
Vital signs 
• 
ECG 
• 
Laboratory safety parameters 
• 
Renal variables 
• 
Pregnancy test 


 
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• 
Serology: HIV, hepatitis B, and hepatitis C status at Screening 
• 
Anti-GBM status at Screening 
• 
Anti-drug antibody (ADA) status 
9.3.2 Methods of Assessing Safety Variables 
All assessments will be performed at the time points specified in the Schedule of 
Assessments. 
9.3.2.1 Adverse Events 
The incidence, severity, and causality of AEs will be assessed at every visit from 
signature of the informed consent form at Screening to the subject’s last evaluation 
according to the procedures described in Section 10. 
9.3.2.2 Glucocorticoid Toxicity Index 
The GTI has two components: the composite GTI and a specific list. In a first evaluation, 
excellent reliability and validity was shown [Miloslavsky 2016]. The composite GTI 
serves as the primary instrument and is intended to capture common toxicities that are 
sensitive to differing cumulative GC doses over the period of a typical clinical study. 
Nine domains and 31 items are in the composite GTI and 11 items and 23 items are 
included in the specific list. When a specific list item will occur, the most severe 
corresponding item in the composite GTI should also be scored (see Appendix 18.9). The 
composite GTI should be scored on at least twice in this study in a 3-month interval, 
since it measures changes in GC toxicity. The bone domain is excluded since the study is 
shorter than 1 year in duration. Therefore, the total score can range from -35 to 400. 
Higher scores indicate greater GC toxicity, negative scores demonstrate improvement in 
GC toxicity. Further information will be provided in a specific manual. The laboratory 
assessments required for this index are part of the safety laboratory variables. As the GTI 
measures the changes in GC toxicities, only assessment of the specific list items are 
necessary on Day 1. 
9.3.2.3 Physical Examinations 
Physical examination findings that are related to the medical history will be recorded in 
the source documentation and in the eCRF. 
Any abnormality noted after starting treatment with IMP (Day 1) will be evaluated by the 
investigator for whether it constitutes an AE. 
9.3.2.4 Vital Signs 
Vital sign determinations of systolic and diastolic blood pressure, pulse rate (counted for 
at least 30 seconds after 5 minutes in a sitting position), respiratory rate, and body 


 
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temperature will be obtained at each visit. Blood pressure and pulse rate should be 
measured before blood samples are taken.  
9.3.2.5 Electrocardiogram 
If there are any clinically significant findings in the resting 12-lead ECG performed at 
Screening, the investigator must contact the medical monitor at the sponsor-designated 
CRO before randomizing the subject into the study. 
An appropriately certified physician will interpret, sign, and date each ECG. Any 
clinically significant findings will be recorded in the source documentation and in the 
eCRF. Each signed, original ECG will be reviewed by the clinical monitor for correctness 
(date, time, and clinically relevant findings, if applicable) and stored with the source 
documentation at the study site. 
9.3.2.6 Safety Laboratory 
Blood samples for safety laboratory analysis should be obtained after the subjects have 
provided responses to questionnaires and after vital signs assessments have been 
performed, but before administration of IMP.  
Analyses will be conducted by a certified central laboratory.  
Instructions regarding the collection, processing, and shipping of samples for analysis of 
laboratory safety parameters will be available in the Laboratory Manual provided by the 
responsible lab. Instructions for urine pregnancy testing are also provided in the 
Laboratory Manual. 
The following parameters will be assessed using standard validated methods:  
Clinical chemistry: 
serum creatinine, urea, alanine aminotransferase, aspartate 
aminotransferase, gamma-glutamyltransferase, total bilirubin, 
lactate dehydrogenase, alkaline phosphatase, sodium, potassium, 
calcium, total protein and albumin 
Hematology:  
red blood cells (erythrocytes), platelets, hemoglobin, white blood 
cells (including differential blood count), and complete blood 
count 
Coagulation:   
partial thromboplastin time and international normalized rate 
For GTI: 
 
glycosylated hemoglobin and low density lipoprotein 
All abnormal laboratory values will require a comment in the eCRF according to the 
following classification: 
• 
Not clinically significant 


 
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• 
Clinically significant  
• 
Error (e.g., laboratory error, improper sample preparation, hemolysis, or delayed 
transit to laboratory) 
At Screening, any laboratory value that deviates from the reference range and is 
considered by the investigator to be clinically significant, or considered as a result of a 
disease noted in the medical history, must be documented on the medical history page of 
the eCRF. Any deviation from the reference range considered by the investigator as 
clinically significant at any later visit must be documented in the eCRF as an AE if not 
previously documented as an ongoing medical condition or as an ongoing AE. Follow-up 
laboratory investigations due to an AE will be performed at a local laboratory at the 
discretion of the investigator.  
Detailed instructions regarding the collection, processing, etc., of samples will be 
provided in the Laboratory Manual provided by the responsible lab. 
9.3.2.7 Renal Variables 
Renal variables will be measured as described in Section 9.2.2.4. 
9.3.2.8 Pregnancy 
Pregnancy testing will be conducted in all women of childbearing potential. A woman is 
considered to be of childbearing potential (i.e., fertile, following menarche and until 
becoming postmenopausal, unless permanently sterile). Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy. However, in the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient. 
The pregnancy test is to be performed in serum at Screening and Week 24/time of 
discontinuation (and safety follow-up for subjects who discontinue until Week 16) and in 
urine (using a dipstick) at the other visits indicated in the Schedule of Assessments.  
If any pregnancy test is positive, the subject will not be eligible for participation, 
randomization, or continuation in the study.  
Lactating women will not be eligible for participation or continuation in the study. 
9.3.2.9 Serology 
The following serology tests will be performed: HIV test and hepatitis B and C tests. 
Analyses for HIV-1 or HIV-2 antibodies will be conducted by the central laboratory. 


 
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Subjects will not be eligible for participation in the study if they test positive for HIV 
infection.  
Analyses for the presence of hepatitis B infection will be conducted by a central 
laboratory using a hepatitis B DNA polymerase chain reaction test and a hepatitis B 
surface antigen test concurrently. If the result meets or exceeds detection sensitivity, the 
subjects will be excluded from participation in the study. 
Analyses for the presence of anti-hepatitis C antibodies in serum will be conducted by a 
central laboratory via chemiluminescence.  
Detailed instructions regarding the collection, processing, etc., of samples will be 
provided in the Laboratory Manual provided by the responsible lab. 
9.3.2.10 Anti-Glomerular Basement Membrane Disease Assessment 
Subjects with a history of anti-glomerular basement membrane (anti-GBM) disease are 
not eligible for study participation. Blood samples taken at Screening will additionally be 
measured for anti-GBM using an immunoassay to assess the anti-GBM status.  
Detailed instructions regarding the collection, processing, etc., of samples will be 
provided in the Laboratory Manual provided by the responsible CRO. 
9.3.2.11 Anti-Drug Antibodies 
Retention samples will also be collected for possible future analysis. 
ADAs will be measured in serum samples at a specialized laboratory using a validated 
homogeneous electrochemiluminescence-based bridging assay for initial detection as 
well as an additional confirmatory assay in case of positive findings detected in the initial 
test. Samples that are confirmed as ADA-positive will be quasi-quantified by titration.  
Detailed instructions regarding the collection, processing, etc., of samples will be 
included in the Laboratory Manual provided by the responsible lab. 
9.4 
PHARMACOKINETICS, PHARMACODYNMICS, AND BIOMARKERS 
9.4.1 Variables 
PK will be assessed by measuring the IFX-1 concentration in plasma. 
PD will be assessed by measuring: C5a, and IFX-1 blocking activity. 
Biomarkers will be assessed by measuring: 50% hemolytic complement (CH50), 
C-reactive protein (CRP),
.  


 
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9.4.2 Methods of Assessing Variables 
All assessments will be performed at the time points specified in the Schedule of 
Assessments. 
9.4.2.1 Pharmacokinetics 
 
Serial PK blood samples will only be collected from 15 subjects, who provide additional 
consent to participate in the PK substudy. 
 
9.4.2.2 Pharmacodynamics 
Instructions regarding the collection, processing, and shipping of samples to the central 
laboratory will be available in the Laboratory Manual provided by the responsible lab. 
Table 10 
Pharmacodynamic Variables 
Variable 
 
Laboratory 
C5a 
 
Specialized 
IFX-1 blocking activity 
 
Specialized 
 
9.4.2.3 Biomarkers 
Instructions regarding the collection, processing, and shipping of samples to the central 
laboratory will be available in the Laboratory Manual provided by the responsible lab. 
Table 11 
Biomarker Variables 
Variable 
Matrix 
Laboratory 
CH50 
Serum 
Central 
 
 
 
CRP 
Serum 
Central 
 
 
 
CH50 = 50% hemolytic complement; CRP = C-reactive protein; 
 


 
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10 
ADVERSE EVENT REPORTING 
10.1 ADVERSE EVENTS 
10.1.1 Definition 
An AE is any untoward medical occurrence in a subject administered an IMP; an AE 
does not necessarily have to have a causal relationship with the treatment. 
AEs encompass any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease that arises or worsens after the inclusion of the subject into 
the study. 
“Lack of efficacy” and “Failure of the expected pharmacological action” per se will not 
be reported as an AE or SAE. However, the signs and symptoms and/or sequelae 
resulting from lack of efficacy will be reported if they fulfill the definition of an AE. 
AEs may include: 
• 
The significant worsening of the disease or symptoms of the disease under 
investigation following administration of an IMP. 
• 
Illnesses that coincide with an onset after administration of an IMP. 
• 
Exacerbation (i.e., increase in frequency or severity) of a pre-existing condition. 
Chronic illnesses present prior to study entry, other than the indication being 
investigated, should be recorded in the medical history page of the eCRF and only be 
reported as AEs if there is an increase in the frequency or severity of the condition 
during the study. 
• 
For laboratory safety parameters, any absolute values outside of the reference range 
or changes after initial administration of the IMP that are considered by the 
investigator as clinically significant must be recorded in the eCRF as AEs if not 
previously documented as ongoing medical conditions or as ongoing AEs. Examples 
of laboratory abnormalities that should be considered as AEs include those that result 
in discontinuation of treatment with the IMP, withholding treatment with the IMP 
pending some investigational outcome, reduction of IMP dose, or additional 
concomitant therapy. 
• 
Laboratory abnormalities do not need to be listed as separate AEs if they are 
considered to be part of a clinical syndrome that is being reported as an AE. 
Laboratory findings do not need to be reported as AEs in the following cases: 
• 
Abnormal laboratory parameters caused by mechanical or physical influences on the 
blood sample (e.g., hemolysis) and flagged as such by the laboratory in the laboratory 
report. 
• 
Abnormal parameters that are obviously biologically implausible (e.g., values that are 
incompatible with life). 


 
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• 
An abnormal laboratory value that cannot be confirmed after repeated analysis, 
preferably in the same laboratory (i.e., the previous result could be marked as not 
valid and should not necessarily be reported as an AE). 
In addition, at the investigator’s discretion, any changes or trends over time in laboratory 
parameters can be recorded in the eCRF as AEs, if such changes or trends are considered 
to be clinically relevant, even if the absolute values are within the reference range. 
AEs do not include: 
• 
Medical or surgical procedures; the condition that leads to the procedure is an AE. 
• 
Untoward medical findings that occur before initial administration of the IMP if they 
occur in the scope of investigations that are performed for assessing inclusion and 
exclusion criteria (e.g., results of laboratory tests conducted at Screening). 
• 
Situations where an untoward medical occurrence has not occurred, e.g., planned 
hospitalization due to a pre-existing condition that has not worsened, hospitalization 
that occurs for a procedure not associated with an AE (e.g., elective surgery or social 
admission), or hospitalization for a diagnostic procedure that takes less than 24 hours. 
• 
Overdose of an IMP or any concomitant therapy that does not result in any adverse 
signs or symptoms. Details of the dosing (volume, location of infusion, and infusion 
rate) of the IMP will be recorded in the eCRF. 
• 
Anticipated day-to day fluctuations of pre-existing disease(s) or condition(s) present 
at the start of the study that do not worsen. 
• 
The disease/disorder being studied or expected progression, sign, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition. 
At each visit to the study site, the investigator will determine whether any AEs have 
occurred. If known, the medical diagnosis of an AE should be recorded according to the 
listing of individual signs and symptoms. 
10.1.2 Documentation and Reporting 
The observation period for AEs will start with confirmation of signed written informed 
consent at Screening (i.e., at Day -14 to Day -1) and ends at Week 24. 
All AEs reported from the time the subject gives written informed consent to participate 
in the study until 12 weeks after the last administration of IMP will be recorded, 
irrespective of whether they were solicited or reported spontaneously by the subject. AE 
information will be collected and recorded in the eCRF. For subjects who discontinue 
until Week 16, a safety follow-up visit will be performed 1 month (±3 days) after the 
early discontinuation.  


 
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Any AEs judged by the investigator to be at least possibly related to treatment with the 
IMP should be reported to the sponsor regardless of the length of time that has passed 
since the subject has completed the study. 
Every attempt should be made to describe AEs in terms of a diagnosis. If appropriate, 
component symptoms should be listed in addition to the diagnosis. If only nonspecific 
signs or symptoms are present, then these should be recorded as separate diagnoses in the 
eCRF. 
All subjects who experience AEs, irrespective of whether they are considered by the 
investigator to be at least possibly related to treatment with the IMP, must be monitored 
to determine the outcome. The clinical course of each AE will be followed up according 
to accepted standards of medical practice, even after the subject has completed 
participation in the study, until a satisfactory explanation is found or the investigator 
considers it medically justifiable to terminate the follow-up. Should the AE result in 
death, a full pathologist’s report should be provided, if possible. 
AEs will be classified according to their severity, causal relationship to the IMPs, and 
seriousness. 
If the severity of a recurrent AE changes from mild to moderate, from moderate to 
severe, or from mild to severe, this AEs recurrence should be reported as a new AE.  
If the AE is serious or of special interest, as defined in Sections 10.2.1 and 10.3, the 
investigator or other authorized medical personnel at the study site must be notified and 
complete the paper “SAE form” at the time the SAE is detected. SAE reporting should 
occur within 24 hours (Section 10.2.2).  
Severity of Adverse Events 
The severity of AEs will be assessed according to the following criteria: 
Mild  
• 
Transient or mild discomfort 
• 
No limitation in activity 
• 
No medical intervention or therapy required 
Moderate  
• 
Marked limitation in activity 
• 
Some assistance usually required 
• 
Medical intervention or therapy required  
• 
Hospitalization possible 


 
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Severe  
• 
Extreme limitation in activity 
• 
Significant assistance required 
• 
Significant medical intervention or therapy required 
• 
Hospitalization or hospice care probable  
Causal Relationship of Adverse Events 
The investigator must assess whether or not the AE is causally related to administration 
of the IMP. Even if the investigator considers that there is no causal relationship to the 
IMP, the AE must still be reported.  
The causal relationship of AEs to administration of the IMP will be assessed according to 
the following criteria: 
Not related 
• 
Event or laboratory test abnormality with a time to 
administration of the IMP that makes a relationship impossible 
• 
Is most likely explained by concurrent disease or other drugs or 
chemicals (either pathophysiologically or clinically) 
• 
Has occurred before administration of the IMP in comparable 
severity and/or frequency 
Unlikely related 
• 
Event or laboratory test abnormality with a time to 
administration of the IMP that makes a relationship improbable 
(but not impossible) 
• 
Disease or other drugs provide plausible explanations 
Possibly related 
• 
Event or laboratory test abnormality with reasonable time 
relationship to administration of the IMP  
• 
Could also be explained by disease or other drugs 
• 
Information on IMP withdrawal may be lacking or unclear 
Probably related 
• 
Event or laboratory test abnormality with reasonable time 
relationship to administration of the IMP  
• 
Unlikely to be attributed to disease or other drugs 
• 
Response to withdrawal clinically reasonable 
• 
Rechallenge not required 


 
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Certainly related 
• 
Event or laboratory test abnormality with plausible time 
relationship to administration of the IMP  
• 
Cannot be explained by disease or other drugs 
• 
Response to withdrawal plausible (pharmacologically or 
pathologically) 
• 
Event definitive pharmacologically or phenomenologically 
(i.e., an objective and specific medical disorder or a recognized 
pharmacological phenomenon) 
• 
Rechallenge satisfactory, if necessary 
All AEs classified as “possibly”, “probably”, or “certainly” related will be considered as 
“at least possibly related to the IMP”. All AEs classified as “not related” or “unlikely 
related” will be considered as “not related” to the IMP. 
The degree of certainty with which an AE is attributed to administration of the IMP or an 
alternative cause (e.g., natural history of the underlying disease, concomitant therapy, 
AxMP etc) must be determined on the basis of how well the AE can be understood in 
terms of: 
• 
Known pharmacology of the IMP 
• 
Clinically and/or pathophysiologically plausible context 
• 
Reaction of a similar nature previously observed with similar products, or reported in 
the literature for similar products as being product-related (e.g., headache, facial 
flushing, pallor) 
• 
Plausibility supported by the temporal relationship (e.g., the event being related by 
time to administration or termination of treatment with the IMP, drug withdrawal, or 
reproduced on rechallenge) 
10.2 SERIOUS ADVERSE EVENTS 
10.2.1 Definition 
An AE is defined as serious (i.e., as an SAE) according to the ICH E2A guideline if any 
of the following criteria are fulfilled: 
• 
Results in death 
• 
Is life-threatening 
NOTE: the term “life-threatening” in the definition of “serious” refers to an event in 
which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death had it been more severe. 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 


 
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• 
Is a congenital anomaly/birth defect 
• 
Is an important medical event that may not be immediately life-threatening or result 
in death or hospitalization, but may jeopardize the subject or may require intervention 
to prevent one of the other outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should also usually be considered serious. 
The following hospitalizations are not considered to be serious AEs because there is no 
“adverse event” (i.e., there is no untoward medical occurrence) associated with the 
hospitalization: 
• 
Hospitalization for respite care 
• 
Hospitalization planned prior to informed consent (where the condition requiring the 
hospitalization has not changed after administration of IMP) 
10.2.2 Documentation and Reporting 
The observation period for SAEs starts with confirmation of signed written informed 
consent at Screening (i.e., at Day -14 to Day -1) and ends at Week 24. 
Any SAE judged by the investigator to be at least possibly related to treatment with the 
IMP should be reported to the sponsor regardless of the length of time that has passed 
since study completion. 
SAEs have to be documented on “SAE forms” and the investigator must report them 
immediately to the CRO, or no later than 24 hours after becoming aware of the SAE. If 
more information about the SAE becomes available later, this must also be reported 
immediately or no later than 24 hours after becoming aware of the SAE. 
In case of a subject’s death, the investigator will provide the applicable Ethics 
Committee(s) and the applicable responsible authorities with any further information 
requested. 
In all reports, personal data are to be anonymized by using the subject identification 
number. It must be possible to relate the initial and all follow-up reports to each other by 
means of the subject identification number, or name and address, or the like. 
The investigator must report all SAEs to the following contact details: 
Fax: 
 


 
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10.3 ADVERSE EVENTS OF SPECIAL INTEREST 
An AESI is an AE of scientific and medical concern specific to the sponsor’s product or 
program, for which ongoing monitoring and rapid communication by the investigator to 
the sponsor could be appropriate. Such an event might require further investigation in 
order to characterize and understand it. 
For this study, the following AEs are defined as AESIs: 
• 
Infusion-related reactions/anaphylactic reactions and Aacute systemic 
hypersensitivity reaction during or shortly after IFX-1 infusion. 
• 
Meningitis 
• 
Meningococcal septicemia 
• 
Invasive infection 
 
10.4 SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS 
10.4.1 Definition 
Suspected unexpected serious adverse reactions (SUSARs) are side effects whose nature 
or severity is inconsistent with the information available about the product in the 
Investigator’s Brochure. 
10.4.2 Documentation and Reporting 
The sponsor will submit all available information on a SUSAR immediately to the 
applicable Ethics Committee, the applicable regulatory authority, and the investigators in 
this study, at the latest within 15 calendar days after the event becomes known. 
For every SUSAR that results in death or a life-threatening condition, the responsible 
Ethics Committee, the applicable regulatory authority, and the investigators in this study 
must be informed by the sponsor within 7 calendar days after the event becomes known. 
Additional information has to be given within 8 further calendar days. 
10.5 PREGNANCY 
Pregnancy, by definition, is not considered as an AE unless it results in a complication 
(such as a maternal complication during pregnancy) that meets the definition of an AE, 
results in spontaneous abortion or stillbirth, or is associated with a congenital anomaly or 
birth defect in the fetus. Any such complication must then be reported accordingly as an 
SAE. 


 
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A female subject who becomes pregnant while participating in the study, or up to and 
including 28 days after the last dose of IMP, must notify the investigator immediately and 
must discontinue treatment with the IMP. The subject may continue other study 
procedures at the discretion of the investigator.  
The sponsor and the designee of the sponsor must be notified within 5 days of the 
investigator becoming aware of the pregnancy, using the following contact details:  
Fax: 
 
Whenever possible, a pregnancy in subjects exposed to IMP should be followed to term 
so as to assess any potential occurrence of congenital anomalies or birth defects. Any 
follow-up information, including premature termination and the status of the mother and 
child after delivery, should be reported by the investigator. 
In certain situations, it may be necessary to monitor the development of the child for an 
appropriate period after birth. If this is the case, details should be included in this section.  
Severe side effects and complications during a pregnancy as well as congenital birth 
defects are SAEs per definition and, therefore, have to be reported additionally as SAEs 
according to the reporting procedures described above. 
10.6 THERAPEUTIC PROCEDURES 
If a subject requires treatment as a result of an AE/SAE, the treatment must meet the 
recognized standards of medical care in order to restore the subject’s health. Appropriate 
resuscitation devices and medication must be available in order to treat the subject as 
quickly as possible in the event of an emergency. 
The actions taken to treat the AE/SAE must be documented by the investigator either in 
the appropriate eCRF and/or using additional documents. 


 
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11 
STATISTICS 
11.1 GENERAL CONSIDERATIONS 
A detailed statistical analysis plan will be developed and finalized before the final 
unblinding of the study database.  
The statistical analysis plan will include the exact definition of endpoints and variables to 
be analyzed, extensive details on the statistical analysis methods to be used together with 
the structure of tables and figures to be included as end-of-text tables and figures as well 
as appended listings for the clinical study report. 
All endpoints and variables will be adequately evaluated. Individual data will be listed. 
Data will be summarized using suitable descriptive statistics. Data will be analyzed by 
treatment group and treatment period and might be further differentiated (e.g., by visit or 
by study site). 
11.2 DETERMINATION OF SAMPLE SIZE 
No formal sample size calculation was performed for this study. A total of 36 subjects 
will be randomized in a ratio of 1:1:1 in the two active treatment groups and the placebo 
group. 
 
11.3 ANALYSIS SETS 
Safety analysis set (SAF): the SAF will consist of all subjects who will receive at least 
one administration of the IMP (one infusion of IFX-1 or placebo). 
Full analysis set (FAS): the FAS will consist of all subjects who will receive at least one 
administration of the IMP (one infusion of IFX-1 or placebo). 
Safety analyses will be based on the SAF. Efficacy analyses will be provided for the 
FAS. 
More detailed specifications of the analysis sets and analyses will be provided in the 
statistical analysis plan. 


 
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11.4 ENDPOINTS 
11.4.1 Safety 
11.4.1.1 Primary 
The primary safety endpoint is: 
• 
Number and percentage of subjects who experience at least one TEAE per treatment 
group. 
11.4.1.2 Secondary 
The secondary safety endpoints are: 
• 
IMP-related SAEs 
• 
IMP-related TEAEs 
• 
AESIs 
For these secondary endpoints, the number of subjects and events by the Medical 
Dictionary for Regulatory Activities (MedDRA) System Organ Class and Preferred Term 
will be evaluated as well as the percentage of subjects who experience at least one AE in 
the respective category. 


 
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• 
11.4.2 Efficacy 
The secondary efficacy endpoints are: 
• 
Proportion of subjects achieving clinical response (defined as a reduction in BVAS of 
≥50% and no worsening in any body system) at Week 16. Subjects who receive 
rescue medication for major relapse before Week 16 will be considered as not having 
achieved clinical response at each time point later than the first administration of 
rescue therapy. 
• 
Proportion of subjects with clinical remission (BVAS = 0) at Week 16 


 
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• 
11.4.3 Quality of Life 
The SF-36v2 will be analyzed by time point and changes from baseline will be 
determined per overall score, the physical component score (PCS), the mental component 
score (MCS), and per domain.  
11.4.4 Pharmacokinetics 
The secondary PK endpoints are: 
• 
The exposure to IFX-1 in all subjects will be measured as the plasma concentration of 
IFX-1 determined on Day 1 and at all subsequent scheduled visits to the study site 
through Week 24, before administration of IMP, and in Weeks 1 (Day 4), 4, and 16 
after administration of IMP using a separate infusion line. Actual PK sampling times 
will be determined and the plasma concentration of IFX-1 will be assessed by time 
point. 
• 
 
11.4.5 Pharmacodynamics 
The PD of IFX-1 are primarily measured by plasma concentration of C5a and in addition 
by the IFX-1 blocking activity in plasma sample, which are determined at pre-specified 
times after administration of IFX-1. Plasma concentrations of C5a and IFX-1 blocking 
activities will be summarized by time point and as absolute and relative change from 
Day 1. 
  
11.4.6 Biomarkers 
Serum concentrations of CRP, CH50 
 will be summarized by time point and as absolute and relative change from Day 1.  


 
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11.5 ANALYSES OF ENDPOINTS 
11.5.1 Safety 
For all safety endpoints that represent a subset of all observed AEs (e.g., TEAEs, SAEs, 
AESIs) the number of events and the number and percentage of subjects who had at least 
one AE in the respective subset will be displayed overall and by MedDRA System Organ 
Class and Preferred Term stratified by treatment group as well as pooled for the IFX-1 
treatment groups. 
For the primary endpoint, the number and percentage of subjects with TEAEs will be 
further grouped by severity and causal relationship. Where AEs are grouped by severity 
or relationship, the maximum severity/relationship per subject and class of AE will be 
considered. If the number of subjects discontinuing treatment or the study prematurely is 
substantial, further analyses taking into account the time of AE onset and cumulative 
dose may be considered. 
Continuous safety parameters, e.g., safety laboratory parameters or GTI, will be analyzed 
by time point and treatment group using descriptive statistics (i.e., number of 
observations, mean, standard deviation, minimum, median, maximum, lower quartile, and 
upper quartile) for absolute values and absolute and relative changes from baseline, if 
applicable. Categorical safety parameters, such as the number of patients with proteinuria 
and/or hematuria, will be summarized by absolute and relative frequencies by time point 
and treatment group.  
Shifts in safety laboratory parameters from normal at baseline to outside the normal 
ranges will be displayed additionally at each measured time point stratified by treatment 
group. 
The number and percentage of subjects with anti-drug antibodies predose will be 
displayed at each measured time point by treatment group and pooled for the IFX-1 
treatment groups. 
11.5.2 Efficacy 
Subjects who receive rescue medication for major relapse will be considered as not 
having achieved clinical remission at each time point later than the first administration of 
rescue medication. 
Continuous efficacy parameters (e.g., BVAS) will be analyzed by descriptive statistics 
(i.e., number of observations, mean, standard deviation, minimum, median, maximum, 
lower quartile, and upper quartile) for absolute values and changes from baseline 
(absolute and relative) by time point and treatment group. Additionally, the IFX-1 
treatment groups will be pooled for the summary statistics. 
Categorical efficacy parameters, such as the number of patients achieving clinical 
response, will be summarized by absolute and relative frequencies by time point and 


 
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treatment group. Additionally, absolute and relative frequencies will be displayed with 
the IFX-1 treatment groups pooled. The difference in the proportion of subjects with 
clinical response between the IFX-1 treatment groups (individually and pooled) as 
compared with the placebo group will be displayed along with its exact 90% confidence 
interval calculated according to the Agresti-Min method [Agresti 2001].  
11.5.3 Quality of Life 
Absolute values and changes from baseline in the overall SF-36 and per domain at 
Weeks 16 and 24 will be analyzed by descriptive statistics (i.e., number of observations, 
mean, standard deviation, minimum, median, maximum, lower quartile, upper quartile) 
for absolute values and changes from baseline (absolute and relative) by time point and 
treatment group and pooled for the IFX-1 treatment groups. 
11.5.4 Pharmacokinetics 
Actual sampling times and IFX-1 plasma concentrations will be tabulated by subject. 
11.5.5 Pharmacodynamics 
PD endpoints will be analyzed by time point and also as absolute and relative change 
from baseline, if applicable, at each time point using descriptive statistics (i.e., number of 
observations, mean, standard deviation, minimum, median, maximum, lower quartile, 
upper quartile, and geometric mean) for each treatment group and pooled for the IFX-1 
treatment groups 
11.5.6 Biomarkers 
Biomarkers will be analyzed by time point and also as absolute and relative change from 
baseline at each time point using descriptive statistics (e.g., number of observations, 
mean, standard deviation, minimum, median, maximum, lower quartile, upper quartile, 
and geometric mean) for each treatment group and pooled for the IFX-1 treatment 
groups. 
11.6 DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Baseline characteristics and demographic information (including medical history and 
surgeries) will be summarized by treatment group and overall. If applicable, the baseline 
measurement will be defined as the latest measurement obtained prior to the first 
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11.7 PRIOR AND CONCOMITANT THERAPY 
Prior and concomitant therapies will be summarized by absolute and relative frequencies 
by treatment group and overall. Therapies will be defined as concomitant if the start or 
end date is later than the date of first IMP administration, or if no end date is available 
(ongoing therapy).  
In case of incomplete start and/or end dates, a therapy is considered as concomitant if it is 
possible that the therapy was administered after first dose of IMP (e.g., if only end year 
and month are provided and are equal to the month and year of the first IMP 
administration). 
11.8 SUBJECT DISPOSITION 
The disposition of subjects who were enrolled (i.e., signed the written informed consent 
form) in the study as well as reasons for discontinuation from study and treatment will be 
summarized for each group. 
11.9 TREATMENT EXPOSURE 
The administration of IMP will be summarized by time point and treatment group and 
will include the number and percentage of subjects completing each treatment visit and 
the mean dose per infusion at each visit. The actual received cumulative dose in mg and 
the dose relative to the planned cumulative dose will be calculated per subject and will be 
summarized for each treatment group. 
11.10 HANDLING OF MISSING DATA 
The missing value imputation will be defined in the Statistical Analysis Plan. 
11.11 INTERIM ANALYSIS 
No formal interim analysis will be performed. 
An unblinded IDMC will review the safety data, as described in Section 14.3. 


 
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12 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS 
12.1 GOOD CLINICAL PRACTICE 
All persons participating in the conduct of the study (e.g., sponsor, investigators) commit 
themselves to observe the Declaration of Helsinki (64th WMA General Assembly, 
Fortaleza, Brazil, October 2013) as well as all pertinent national laws and the ICH 
guidelines for GCP (June 2017) and CPMP/ICH/135/95 (September 1997). 
12.2 ETHICS COMMITTEE AND RESPONSIBLE REGULATORY 
AUTHORITY 
The protocol and other associated documents will be submitted to the applicable Ethics 
Committee for approval. The study documents will be submitted to the applicable 
regulatory authority. 
The study can only start after obtaining a positive evaluation by the applicable Ethics 
Committee and approval from the applicable regulatory authority. The written approval 
of the applicable Ethics Committee and the applicable responsible regulatory authority 
must be filed in the trial master file. Additionally, each study site must receive a copy of 
these documents to be filed in the investigator site file. 
12.3 SUBJECTS INFORMATION AND INFORMED CONSENT 
The investigator must explain to each potential study subject the nature of the study, the 
objectives, the procedures involved, the expected duration, the potential risks and benefits 
involved, and any discomfort it may entail. The potential subjects must be informed that 
participation in the study is voluntary, that they may withdraw their consent to participate 
at any time, and that withdrawal of consent will not affect the subsequent medical 
treatment of the study subject or the relationship to the treating physician. 
The informed consent must be given by means of standard written statements, written in 
non-technical language. The subjects should read the informed consent form and consider 
their decision before signing and dating the document. A copy of the signed document 
must be given to the subject. No subject can be involved in the study if he/she is related 
to the investigator, any member of the team at the study site, or the sponsor. 
The informed consent of the subject must also refer specifically to the assessment and 
processing of data on the subject’s health. The subject is to be informed explicitly about 
the purpose and extent of the assessment and the use of their personal data, especially the 
health-related data. Informed consent for the storage of samples for possible future 
biomarkers testing and the PK substudy will also be given. 


 
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12.4 PROTOCOL AMENDMENTS 
If modifications are made to the protocol, after it has been positively appraised by the 
Ethics Committee and approved by the responsible regulatory authority, these 
modifications must be reappraised and approved by the Ethics Committee and the 
responsible regulatory authority if the changes: 
• 
Are such that they may affect the subjects’ safety 
• 
Are fundamental to the therapeutic procedures 
• 
Result in further data collection that necessitates changes to the subject information 
and/or informed consent form 
• 
Affect the interpretation of the scientific documents upon which the study is based or 
the significance of the results of the study 
• 
Significantly affect the leadership or conduct of the study 
• 
Concern the quality or the innocuousness of the investigational drug 
Protocol amendments need the authorization of the sponsor, the coordinating investigator, 
and the responsible biostatistician, if applicable. All protocol amendments will be: 
• 
Submitted to the Ethics Committee and, where applicable, to the responsible 
regulatory authority 
• 
Provided in written form to the responsible parties 
• 
Filed in the trial master file 


 
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13 
DOCUMENTATION 
13.1 ELECTRONIC CASE REPORT FORMS 
All data assessments required by this clinical study protocol will be collected in an eCRF 
and entered into a database validated by the CRO for eCRFs. 
The sponsor or its designee will supply the study site with eCRFs. The sponsor or its 
designee will make arrangements to train appropriate study site personnel in the use of 
the eCRF. 
These eCRFs are used to transmit information collected on the performance of this study 
to the sponsor and regulatory authorities. The eCRFs must be completed in English.  
Data will be entered directly into the eCRF by the investigator or study site personnel via 
a single data entry process. Study site personnel will be granted access to the eCRF 
system through a personal user identification and password assigned by the system 
administrator. In the eCRF, subjects will be identified by their subject numbers. The 
eCRF is to be dated and signed electronically by the investigator or a qualified person 
who has been delegated by the investigator to do so on his/her behalf, as documented on 
a signature delegation log filed in the investigator site file. Data entered in the eCRF will 
be stored in a centralized database on a remote server. 
After completion of the entry process, computer logic checks will be run to identify 
items, such as inconsistent dates, missing data, and questionable values. Queries may be 
issued by designees of the sponsor and will be answered by the site.  
Corrections to the eCRF database are recorded in an audit trail that captures a complete 
record of all information. The new information, identification of the person making the 
correction, the date the correction was made, and the reason for change are captured in a 
new record.  
The principal investigator must review the eCRFs for completeness and accuracy and 
must sign and date the appropriate eCRFs as indicated. Furthermore, the principal 
investigator must retain full responsibility for the accuracy and authenticity of all data 
entered into the eCRFs. 
The eCRFs will be reviewed for completeness and acceptability at the study site during 
periodic visits by the clinical monitor. The sponsor and/or its designee will be permitted 
to review the subject’s medical and hospital records pertinent to the study to ensure 
accuracy of the eCRFs. The completed eCRFs are the sole property of the sponsor and 
should not be made available in any form to third parties, except for authorized 
representatives of appropriate governmental health or regulatory authorities, without 
written permission of the sponsor. 
Further information on handling of the eCRF data (e.g., data entry, clarification, and 
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13.2 ARCHIVING 
Because the study is being conducted to obtain marketing authorization, the requirements 
of ICH Guideline E6 section 5.5.11 and 5.5.12 shall be taken into account. 
The investigator is responsible for archiving the investigator site file, the subject’s 
records, and the source data according to applicable regulatory requirements. These 
documents have to be archived for at least 10 years, but should be retained for longer if 
required by regulatory stipulations or by agreement with the sponsor. 
If the investigator can no longer maintain the archive of study records (e.g., due to 
retirement or relocation), the sponsor must be informed in writing about any change in 
responsibility for record retention, including the name of the new responsible party, 
contact information, and location of the study records. Records must not be destroyed 
without prior written consent from the sponsor. 


 
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14 
SUPERVISION OF THE CLINICAL STUDY 
14.1 ACCESS TO SOURCE DATA 
According to ICH guidelines for GCP and the applicable laws, the investigator must 
permit all authorized third parties access to the study site and the medical records of the 
study subjects (source data). These include the clinical monitors, auditors, and other 
authorized employees of the sponsor as well as members of the local or federal 
authorities. All these persons are bound to strict confidentiality. 
14.2 MONITORING 
Monitoring of the study sites will be performed by a CRO designated by the sponsor and 
will be based on the CRO’s monitoring standard operating procedures (SOPs) as well as 
the study-specific Monitoring Manual.  
The clinical monitor, as a representative of the sponsor, has the obligation to follow the 
study closely. The monitor will visit the study site at periodic intervals and, in addition, 
the monitor will be adequately trained and maintain contact with the study site via 
telephone calls as well as in written form, as appropriate. The monitor will be adequately 
trained and maintain a working knowledge of the study through observation, review of 
study records and source documentation, and discussion of the conduct of the study with 
the investigator and study site personnel. Source data review and verification of the most 
important parameters will be performed for all subjects as described in the Monitoring 
Manual. The investigator and institutions involved in the study will permit study-related 
monitoring and provide direct access to all study records and facilities. Adequate time 
and space for monitoring visits should be made by the investigator or other investigator 
site staff. 
The monitor will report via the project manager of the sponsor-designated CRO to the 
sponsor who carefully monitors all aspects of the study for compliance with applicable 
government regulations, with respect to current ICH guidelines for GCP and current 
SOPs. 
Auditors representing the sponsor may also similarly evaluate the study and its monitors. 
For these purposes, the investigator will need to have eCRFs and source documents 
available on request. 
In addition, the study may be evaluated by representatives of the national regulatory 
authorities, who will also be allowed access to study documents. The investigators should 
promptly notify the appointed CRO/Monitor of any audits that will be scheduled with any 
regulatory authority. 
The clinical monitor will discuss the conduct and progress of the study with the 
investigator and other site staff. The investigator must cooperate with the clinical monitor 
to ensure that corrective and preventative action is taken to resolve any problems noted in 


 
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the course of the monitoring, and that the preventative measures are put into place to 
prevent recurrence of issues. 
As part of the responsibilities assumed by participating in the study, the investigator 
agrees to maintain adequate case histories for the subjects treated under this protocol. The 
investigator agrees to maintain accurate source documentation and eCRFs as part of the 
case histories. 
Study records are comprised of source documents, eCRFs, and all other administrative 
documents (e.g., correspondence, clinical study materials, supply shipping manifests, or 
monitoring logs). An investigator site file will be provided with instructions for the 
maintenance of study records. 
14.3 INDEPENDENT DATA MONITORING COMMITTEE 
An unblinded IDMC will be established to allow regular monitoring of the study data to 
detect and report early evidence of unanticipated harm to subjects.  
The safety of the subjects will be monitored by an unblinded IDMC. The IDMC will 
review the safety data of subjects who have completed the IMP administration in 
Week 16 and after subjects complete the Follow-up Period. The time points for the 
IDMC reviews will be defined in the IDMC charter. Safety analyses will be provided by 
an unblinded statistician. 
The reviews will focus on the evaluation of the safety data, including but not limited to 
TEAEs, drug exposure, laboratory test results, and vital signs measurements, based on the 
analysis performed by an unblinded statistician. Further details of the data and outputs to 
be provided to the IDMC will be described in the IDMC charter. Further details on the 
IDMC membership, the responsibilities of the IDMC, the purpose and timing of the 
reviews, and the procedures for ensuring confidentiality and proper communication will 
also be provided in the IDMC charter. The charter will also outline the required content 
of the written report to be provided by the IDMC after each safety review, including their 
recommendations for the future conduct of the study. 
14.4 AUDITS 
In order to guarantee that the conduct of the study is in accordance with ICH guidelines 
for GCP and the national laws, audits may be performed at the study sites to be carried 
out by an independent auditor. In addition, for-cause audits may be scheduled. 
The investigator agrees to give the auditor access to all relevant documents for review. 
14.5 INSPECTIONS 
According to the corresponding ICH guidelines for GCP, inspections of the study sites 
may be performed by the local or regulatory authorities at any time during or after 


 
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completion of the study. The investigator will contact the sponsor or designated CRO 
immediately upon knowledge of a planned inspection. 
The investigator agrees to give the inspectors access to all relevant documents for review. 


 
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15 
DATA PROTECTION AND CONFIDENTIALITY 
Within this study, personal data from the study subjects and data regarding the treatment 
and the course of subject’s welfare will be collected. 
The data will be stored and processed in anonymized form (i.e., without reference to the 
subject’s name) with the aid of a unique subject identification number. 
Data will be managed by a sponsor-designated CRO (data entry, data cleaning, and data 
exports). The safety concept ensures among other things that data access is limited to 
authorized persons, that measures are taken to prevent loss of data, and that the applicable 
laws pertaining to data protection are observed. The data are protected from third party 
access and only members of the study team are permitted access. These members are 
bound to strict confidentiality. 
Personal data will be stored in an anonymous manner after reaching finishing completion 
status of all concomitant scientific projects for at least 15 years, if no other or new 
regulatory requirements come into effect warranting different time periods for archiving. 
15.1 DECLARATION REGARDING DATA PROTECTION 
During data entry, processing, and analysis by a sponsor-designated CRO, all 
requirements of the data protection act will be taken into account. Access to data is 
strictly limited to authorized persons. Data are protected against unauthorized access 
according to current federal legislation and regulations. 
15.2 DECLARATION REGARDING THE ANONYMIZED TRANSFER OF 
PERSONAL DATA 
During data entry, processing, and analysis by a sponsor-designated CRO, all 
requirements of the data protection act will be taken into account. Access to data is 
strictly limited to authorized persons. Data are protected against unauthorized access 
according to current federal legislation and regulations. 


 
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16 
ADMINISTRATIVE AGREEMENTS 
16.1 ADHERENCE TO THE PROTOCOL/PROTOCOL DEVIATIONS 
The clinical study described here will be conducted and analyzed in accordance with 
local laws and ICH guidelines for GCP. 
After a subject has been enrolled, it is the investigator’s responsibility to avoid protocol 
deviations in order to obtain unbiased data for the analysis of the study. 
All protocol deviations will be documented and discussed with the responsible 
biostatistician before closing the database and carrying out the statistical analyses. 
16.2 FINANCING AND INSURANCE 
The study is financed by the sponsor. 
The subjects are covered by an applicable insurance policy for participation in a clinical 
study. One copy of the insurance policy and the insurance conditions will be handed out 
to the subject and one will be filed in the investigator site file. 
16.3 NOTIFICATION OF THE LOCAL AUTHORITIES 
The sponsor, their contractors, and all investigators and their deputies are responsible for 
notifying the local regulatory authority of their participation in the study prior to 
enrollment of the first subject in the study. Responsibility for notification to the local 
authorities has been delegated to a sponsor-designated CRO. 
This extends also to amendments, discontinuation of study arms or of the entire study, 
and the regular conclusion of the study. 
16.4 PUBLICATION POLICY AND REGISTRATION 
16.4.1 Publication Policy 
The rights and obligations of investigators and the sponsor concerning any formal 
presentation or publication of data collected as a direct or indirect result of this study will 
be addressed specifically in the Clinical Study Agreement for the study.  
The first publication must be based upon all data obtained from all analyses, as stipulated 
in the study protocol. 
The sponsor must receive a copy of any intended communications in advance of the 
proposed submission date. This is to allow the sponsor time to review the communication 
for accuracy (thus avoiding potential discrepancies with submissions to regulatory 
authorities), to verify that confidential and/or proprietary information is not inadvertently 


 
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divulged, to provide any relevant supplementary information, and to allow establishment 
of co-authorship (as appropriate). The authorship of communications arising from pooled 
data will include investigators from study sites that contributed data as well as relevant 
personnel from the sponsor. Ownership of all data will remain with the sponsor. 
Furthermore, the publication policy will follow the recommendations of Good Scientific 
Practice of the Deutsche Forschungsgemeinschaft (www.dfg.de) and will meet the 
criteria of the International Committee of Medical Journal Editors 
(http://www.icmje.org). 
16.4.2 Registration 
The sponsor will provide the relevant study protocol information in a public database 
(e.g., ClinicalTrials.gov, https://clinicaltrials.gov/) before or at commencement of the 
study. The sponsor may also provide study information for inclusion in national registries 
according to local regulatory requirements.  
If a potential subject contacts the sponsor regarding participation in the study, the 
investigator agrees that the sponsor may forward the study site and contact details to the 
subject. Based on the inclusion and exclusion criteria for the study, the investigator will 
assess the suitability of the subject for randomization into the study. 
Results of this study will be disclosed according to the relevant regulatory requirements. 
All publications in peer-reviewed medical journals resulting from this study will be listed 
in the original study protocol registration record (e.g., on ClinicalTrials.gov). 


 
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17 
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Agresti A and Min Y. On small-sample confidence intervals for parameters in discrete 
distributions. Biometrics. 2001;57:963-971. 
Berti A, Cornec D, Crowson C, Specks U, Matteson E. The epidemiology of 
antineutrophil cytoplasmic autoantibody-associated vasculitis in Olmsted county, 
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Bossuyt X, Tervaert J, Arimura Y, Blockmans D, Flores-Suarez L, Guillevin L, et al. 
Revised 2017 international consensus on testing of ANCAs in granulomatosis with 
polyangiitis and microscopic polyanhiitis. Nat Rev Rheum. 2017;13:683 692. 
Charlier C, Henegar C, Launay O, Pagnoux C, Berezne A, Bienvenu B, et al. Risk factors 
for major infections in Wegener granulomatosis: analysis of 113 patients. Ann Rhem Dis. 
2009;68:658-663. 
Chen M, Jayne D, Zhao M. Complement in ANCA-associated vasculitis: mechanisms 
and implications for management. Nat Rev Nephrol. 2017;13(6):359-367. 
Exley A, Bacon P, Luqmani R. Development and initial validation of the Vasculitis 
Damage Index for the standardized clinical assessment of damage in the systemic 
vasculitides. Arthritis Rheum. 1997;40(2):371-380. 
Falk R, Hogan S, Carey T, Jennette JC. Clinical course of anti-neutrophil cytoplasmic 
autoantibody-associated glomerulonephritis and systemic vasculitis. The Glomerular 
Disease Collaborative Network. Ann Intern Med. 1990;113:656. 
Flossmann O, Berden A, de Groot K, Hagen C, Harper L, Heijl C, et al. European 
Vasculitis Study Group. Long-term patient survival in ANCA-associated vasculitis. Ann 
Rheum Dis. 2011;70(3):488-494.  
Fries J, Hunder G, Bloch D, Michel B, Arend W, Calabrese L, et al. The American 
College of Rheumatology 1990 criteria for the classification of vasculitis. Arthritis 
Rheum. 1990;33(8):1135-1136. 
Furuta S, Jayne D: Antineutrophil cytoplasm antibody-associated vasculitis: Recent 
developments. Kidney Int. 2013;84:244-249. 
Goupil R, Brachemi S, Nadeau-Fredette A, et al. Lymphopenia and treatment-related 
infectious complications in ANCA-associated vasculitis. Clin J Am Soc Nephrol. 
2013;8:416-423. 
Guillevin L, Durand-Gasselin B, Cevallos R, Gayraud M, Lhote F, Callard P, et al. 
Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients. Arthritis 
Rheum. 1999;42(3):421-430. 


 
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Halbwachs L, Lesavre P: Endothelium-neutrophil interactions in ANCA- associated 
diseases. J Am Soc Nephrol. 2012;23:1449-1461. 
Hoffman G. Classification of the systemic vasculitides: antineutrophil cytoplasmic 
antibodies, consensus and controversy. Clin Exp Rheumatol. 1998;16(2):111-5. 
Jennette J, Falk R. Small-vessel vasculitis. N Engl J Med. 1997;337:1512. 
Jennette J, Falk R, Bacon P. 2012 revised International Chapel Hill Consensus 
Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1-11. 
Kettritz R: With complements from ANCA mice. J Am Soc Nephrol. 2014;25:207-209. 
Levey A, Bosch J, Lewis J, Greene T, Rogers N, Roth D. A more accurate method to 
estimate glomerular filtration rate from serum creatinine: a new prediction equation. 
Modification of Diet in Renal Disease Study Group. Annals of Internal Medicine. 
1999;130(6):461-470. 
Little M, Nightingale P, Verburgh C, et al. European Vasculitis Study (EUVAS) Group: 
Early mortality in systemic vasculitis: Relative contribution of adverse events and active 
vasculitis. Ann Rheum Dis. 2010;69:1036-1043. 
Luqmani R, Bacon P, Moots R, Janssen B, Pall A, Emery P, et al. Birmingham Vasculitis 
Activity Score (BVAS) in systemic necrotizing vasculitis. QJM. 1994;87:671-678. 
Luqmani RA, Suppiah R, Grayson PC, et al. Nomenclature and classification of vasculitis 
- update on the ACR/EULAR diagnosis and classification of vasculitis study (DCVAS). 
Clin Exp Immunol. 2011;164 Suppl 1:11-13. 
McGregor J, Hogan S, Hu Y, Jennette C, Falk R, Nachman P. Glucocorticoids and 
relapse and infection rates in anti-neutrophil cytoplasmic antibody disease. Clin J Am 
Soc Nephrol. 2012;7(2):240-247. 
Merkel P, Aydin S, Boers M, et al. The OMERACT Core Set of Outcome Measures for 
Use in Clinical Trials of ANCA-associated Vasculitis. Journal Rheum. 
2011;38(7):1480-1486. 
Miloslavsky E, Naden R, Bijlsma J, et al. Development of a Glucocorticoid Toxicity 
Index (GTI) using multicriteria decision analysis. Ann Rheum Dis. 2016;76(3):543-546. 
Moghadam-Kia S, Werth V. Prevention and treatment of systemic glucocorticoid side 
effects. Int J of Dematol. 2010;49:239-248. 
Mukhtyar C, Lee R, Brown D, Carruthers D, Dasgupta B, Dubey S, et al. Modification 
and validation of the Birmingham Vasculitis Activity Score (Version 3.0). Ann Rheum 
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Ormerod A, Cook M. Epidemiology of primary systemic vasculitis in the Australian 
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2008;38(11):816-823. 
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pdf [Accessed 06 April 2018] 
Prescribing Information for Methotrexate, tablets. 01/2016. 
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[Accessed 06 April 2018] 
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https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050722s021,050723s019,05
0758s019,050759s024lbl.pdf [Accessed 08 Mar 2018] 
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Rheum. 2000;43(5):1021-1032. 
Robson J, Doll H, Suppiah R, et al. Glucocorticoid treatment and damage in the 
anti-neutrophil cytoplasm antibody-associated vasculitides: Long-term data from the 
European Vasculitis Study Group trials. Rheumatology (Oxford). 2015;54:471-481. 
Seo P, Stone J. The antineutrophil cytoplasmic antibody-associated vasculitides. Am J 
Med. 2004;117:39. 
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Network for the Study of the Systemic Vasculitides (INSSYS). A disease-specific 
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Van de Beek D, Cabellos C, Dzupova O et al. ESCMID guideline: diagnosis and 
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management of ANCA-associated vasculitis. Ann Rheum Dis. 2016;75(9):1583-94. 


 
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18 
APPENDICES 
18.1 CHAPEL HILL CONSENSUS CONFERENCE 
DIAGNOSTIC CRITERIA 
Widely accepted diagnostic criteria, as opposed to classification criteria or definitions, 
have not yet been developed for Wegener’s granulomatosis (GPA) and microscopic 
polyangiitis (MPA). In 1994, the CHCC developed definitions for these vasculitides and 
some of their mimickers [Jennette 1997]. These definitions, along with the American 
College of Rheumatology Criteria for the classification of vasculitides, are useful in 
formulating the diagnostic criteria that will be applied to determine a participant’s 
eligibility for this clinical study [Fries 1990].  
Chapel Hill Consensus Conference Definitions for Microscopic Polyangiitis 
• 
Necrotizing vasculitis with few or no immune deposits affects small vessels (i.e., 
capillaries, venules, or arterioles). 
• 
Necrotizing arteritis involving small and medium-sized arteries may be present. 
• 
Necrotizing glomerulonephritis is very common. 
• 
Pulmonary capillaritis often occurs. 
ACR Criteria for the Classification of Wegener’s Granulomatosis 
Among a group of patients with various forms of systemic vasculitis, the presence of at 
least two of these four criteria is associated with a sensitivity of 88.2% and a specificity 
of 92.0% for WG. 
• 
Nasal or oral inflammation: painful or painless oral ulcers or purulent or bloody nasal 
discharge 
• 
Abnormal chest radiograph: nodules, fixed infiltrates, or cavities 
• 
Urinary sediment: microhematuria or red cell casts 
• 
Granulomatous inflammation on biopsy: granulomatous inflammation within the wall 
of an artery or in the perivascular area 
ACR Criteria for the Classification of Churg-Strauss Syndrome 
Although we wish to exclude Churg-Strauss syndrome (CSS) from this study, we will use 
the following ACR criteria for the classification of this disorder: 
Among a group of patients with various forms of systemic vasculitis, the presence of at 
least four of these six criteria is associated with a sensitivity of 85.0% and a specificity of 
99.7% for CSS. 
• 
Asthma: wheezing or high-pitched rales 


 
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• 
Eosinophilia: >10% of white blood cell differential 
• 
Mononeuropathy or polyneuropathy: mononeuropathy, multiple mononeuropathies, 
or polyneuropathy attributable to vasculitis 
• 
Pulmonary infiltrates, nonfixed: migratory or transitory pulmonary infiltrates 
• 
Paranasal sinus abnormality: acute or chronic paranasal sinus pain, tenderness, or 
radiographic opacification 
• 
Extravascular eosinophils: biopsy, including artery, arteriole, or venule showing 
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18.2 MAJOR SIDE EFFECTS ASSOCIATED WITH GLUCOCORTICOID 
THERAPY 
Body System/ 
Adverse Event 
Dermatologic and soft tissue 
Skin thinning and purpura 
Cushingoid appearance 
Alopecia 
Acne 
Hirsutism 
Striae 
Hypertrichosis 
Eye 
Posterior subcapsular cataract 
Elevated intraocular pressure/glaucoma 
Exophthalmos 
Cardiovascular 
Arrhythmias (with intravenous pulse therapy) 
Hypertension 
Perturbations of serum lipoproteins 
Premature atherosclerotic disease 
Gastrointestinal 
Gastritis 
Peptic ulcer disease 
Pancreatitis 
Steatohepatitis 
Visceral perforation 
Renal 
Hypokalemia 
Fluid volume shifts 
Genitourinary and reproductive 
Amenorrhea/infertility 
Intrauterine growth retardation 
Bone 
Osteoporosis 
Avascular necrosis 
Muscle 
Myopathy 
 
Neuropsychiatric 
Euphoria 
Dysphoria/depression 
Insomnia/akathisia 
Mania/psychosis 
Pseudotumor cerebri 
Endocrine 
Diabetes mellitus 
Hypothalamic-pituitary-adrenal insufficiency 
Infectious disease 
Increased risk for typical infections 
Opportunistic infections 
Herpes zoster 


 
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18.3 BIRMINGHAM VASCULITIS ACTIVITY SCORE VERSION 3.0 
 


 
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18.4 GLOSSARY AND SCORING FOR BVAS VERSION 3.0 
 


 
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18.5 OTHER MULTISYSTEM AUTOIMMUNE DISEASES 
Prohibited Diseases 
Permitted Diseases 
Eosinophilic granulomatosis with 
polyangiitis (Churg-Strauss) according to 
the definitions of the CHCC 
Rheumatoid arthritis without systemic 
and non-articular manifestations (1) 
Systemic lupus erythematosus 
Ankylosing spondylitis without systemic 
and non-articular manifestations (2) 
IgA vasculitis (Henoch-Schönlein) 
Autoimmune thyroiditis (Hashimoto) 
Rheumatoid vasculitis 
Diabetes mellitus type 1 
Sjögren’s syndrome 
 
Cryoglobulinemic vasculitis 
 
Autoimmune hemolytic anemia 
 
Mixed connective tissue disease 
 
Autoimmune lymphoproliferative 
syndrome 
 
If any other multisystem autoimmune disease is not listed, please contact the responsible 
medical monitor for further decisions. 
(1) Including, but not limited to: gastrointestinal, pulmonary, cardiac, renal, neurological, 
skin and ocular manifestations due to RA. 
(2) Spine and joints may be affected. 


 
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18.6 VASCULITIS DAMAGE INDEX 
 


 
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18.7 PHYSICIAN GLOBAL ASSESSMENT 
The Physician Global Assessment scale is an 11-point scale to record the assessment of 
the overall disease activity of the subject. The investigator should not be influenced by 
the presence of any accumulated damage, complication of treatment, social/emotional 
problems, or other issues not related to GPA or MPA. 
Mark to indicate the amount of GPA or MPA disease activity (not including longstanding 
damage) within the previous 28 days: 
 
 


 
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18.8 36-ITEM SHORT FORM SURVEY 
 
 


 
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18.9 GLUCOCORTICOID TOXICITY INDEX 
 
 


 
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35-400