Clinical trial NCT04163991
Conditions: Rheumatoid Arthritis
Keywords: Rheumatoid Arthritis RA VIB4920 MEDI4920
Sponsor: Amgen
Start date: 2019-12-09; Completion date: 2021-12-28
Enrollment: 78 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to evaluate the efficacy, safety, and pharmacokinetics (PK) of VIB4920 (formerly MEDI4920) in adult participants with rheumatoid arthritis (RA).

Detailed description:
The overall study period will be approximately 337 days. After a screening period of up to 28 days, the participants will be randomized in a 1:1:1:1:1 ratio to receive intravenous dose of VIB4920 and/or placebo in 5 cohorts. Participants are to be followed on their stable background anti-RA therapy at least through 12 weeks (Day 85), at which time rescue therapy may be instituted. All participants will be followed at least through the primary (interim) analysis (Day 113), and those who have not instituted rescue therapy will be followed through Day 309 to determine the duration of clinical response. The primary analysis will be after all participants have completed Day 113, and the final analysis will be after all participants have completed follow-up.

Study with completed results acquired from Horizon in 2024.

Arms: arm 1: Participants receive intravenous (IV) infusion of VIB4920 1500 mg on Days 1, 15, 29, and 57 arm 2: Participants receive IV infusion of VIB4920 1500 mg on Days 1 and 57, placebo on Days 15 and 29. arm 3: Participants receive IV infusion of VIB4920 3000 mg on Days 1 and 57, placebo on Days 15 and 29. arm 4: Participants receive IV infusion of VIB4920 3000 mg on Day 1 and placebo on Days 15, 29, and 57. arm 5: Participants receive IV infusion of placebo matched to VIB4920 on Days 1, 15, 29, and 57.
Interventions: intervention 1: VIB4920 intervention 2: Placebo
Intervention descriptions: intervention 1: liquid for IV infusion following dilution in normal saline intervention 2: 0.9% saline for IV infusion

Protocol documents:
Prot_000.pdf: 
Module 5.3.5.1 Clinical Study Protocol  
VIB4920 
VIB4920.P2.S3 - VIB4920 in Subjects with Rheumatoid Arthritis 
Version 4.0 
CONFIDENTIAL AND PROPRIETARY 
Page 1 of 74 
 
 
VIELA BIO  
A PHASE 2, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, MECHANISTIC INSIGHT 
AND DOSAGE OPTIMIZATION STUDY OF THE 
EFFICACY AND SAFETY OF VIB4920 IN PATIENTS 
WITH RHEUMATOID ARTHRITIS (RA) 
(SHORT TITLE: MIDORA)  
 
Investigational Product 
VIB4920 
Protocol Number 
VIB4920.P2.S3  
Clinical Trial Registry Identifiers 
NCT04163991, EudraCT 2019-003697-70 
Version Number 
4.0 
Version Date 
02 October 2020 
Amendment 
3 
IND Number 
IND 128905 
Principal Investigator 
 
 
 
 
 
 
Sponsor 
Viela Bio 
 
Responsible Medical Officer: 
 
, 
Viela Bio 
 
 


Module 5.3.5.1 Clinical Study Protocol  
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SUMMARY OF CHANGES TO THE PROTOCOL  
Protocol Amendment 1; 15 October 2019 
Changes to the protocol in Amendment 1 included the following:  
Protocol Section(s) 
Impacted by Change 
Change 
Reason for Change 
Section 6.1, Schedules of 
Study Assessments, Table 2 
Removed RF isotypes from list of screening 
assessments. RF isotypes will be assessed 
during the study, but not at screening. 
To eliminate unnecessary 
laboratory testing and assays. 
Section 6.1, Schedules of 
Study Assessments 
Section 6.4.3.1, 
Autoantibody Panel 
Removed ANA from list of assessments. 
ANA will not be assessed during the study. 
To eliminate unnecessary 
laboratory testing and assays. 
Section 6.1, Schedules of 
Study Assessments 
Section 6.4.3.1, 
Autoantibody Panel 
Section 6.4.3.6, Serum and 
Plasma Biomarkers 
• In Sections 6.1 and 6.4.3.6: Removed 
ACPA from the autoantibody panel 
planned for the study assessments. 
ACPA will still be assessed at screening. 
• In Section 6.4.3.6: “ACPA will be 
assessed with a fit-for-purpose 
quantitative assay (in development).” 
The available clinical assay is not 
appropriately quantitative. An 
alternative quantitative assay is in 
development and will be used to 
assess ACPA in samples collected 
on or after Day 1. 
Section 6.1, Schedules of 
Study Assessments 
Section 6.4.3.3, 
Inflammatory Markers 
Section 8.5.2, Serum 
Chemistry 
Removed IgE from list of plasma 
immunoglobulins that will be assessed. 
To eliminate unnecessary 
laboratory testing and assays. 
Section 6.1, Schedules of 
Study Assessments, Table 3 
Removed “Flow cytometry (T regulatory 
panel” from list of study assessments and 
procedures.  
The T regulatory assessment will 
be performed on the PBMC 
samples. 
ACPA = anti-citrullinated protein antibodies; ANA = antinuclear antibody; IgE = immunoglobulin E; 
PBMC = peripheral blood mononuclear cells; RF = rheumatoid factor. 
 
Protocol Amendment 2; 26 June 2020 
Changes to the protocol in Amendment 2 included the following:  
Protocol Section(s) 
Impacted by Change 
Change 
Reason for Change 
Cover page 
Inserted lead investigator’s name and 
address and clinical trial registry identifiers 
To provide the lead investigator’s 
information and the registry 
information in the protocol 
Synopsis, 
 
 
 
 
  
Section 6.1, Schedules of 
Study Assessments, 
• 
 
 
 
 
  
• 
In Section 6.1, removed Vectra DA 
testing and replaced it with a blood 
sample for other biomarkers.  
To eliminate unnecessary 
laboratory testing  


Module 5.3.5.1 Clinical Study Protocol  
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Section 6.4.3.2, Multi-
biomarker Disease Activity 
Panel (Vectra DA), 
References 
• 
In References, removed the reference 
related to Vectra DA testing      
Section 7.1.1.2 Dose 
Preparation 
In Section 7.1.1.2, added a sentence about 
the required filter 
To ensure that the requirement for 
use of a filter, which is in the 
Pharmacy Manual, is easily noted 
Section 5.2 Exclusion criteria 
(Exclusion 18)  
In Exclusion criterion 18, added text to 
require investigators to  
• 
Consider the risks associated with 
SARS-CoV-2 circulation when 
assessing the suitability of a subject for 
enrollment, including both the subject’s 
epidemiologic risk and health-related 
risks.   
• 
Ensure that the subject has a 
documented negative SARS-CoV-2 
viral test within two weeks prior to 
randomization 
To address risks associated with 
the COVID-19 pandemic, which 
had not begun at the time of study 
start.  
Section 2.1.6, Risk 
Assessment--2.1.6.3 
Infections, and Section 13   
References.  
• 
In Section 2.1.6.3, added potential risks 
of VIB4920 as they relate to COVID-
19 or to COVID-19 vaccine response 
and individual subject risk factors for 
SARS-CoV-2 infection and for severe 
COVID-19 disease  
• 
In Section 13 added relevant references   
To address infection risks 
associated with the COVID-19 
pandemic, which had not begun at 
the time of study start.  
Section 2.2 Study Rationale  
In Section 2.2, added text addressing the 
benefit-risk of conducting this study during 
the potential circulation of SARS-CoV-2 
and steps taken to minimize risk  
To address the benefit-risk of 
conducting the study during the 
potential circulation of SARS-
CoV-2, because of the onset of 
the COVID-19 pandemic. 
Section 6.1 Schedules of 
Study Assessments 
Section 8.5 Clinical 
Laboratory Findings  
8.5.5 Testing for SARS-
CoV-2 
• 
In Section 6.1, Table 2, Screening 
Assessments and Procedures, added a 
requirement for subject to have a 
documented negative SAR-CoV-2 viral 
test within 14 days of randomization. 
• 
In Sections 8.5 and 8.5.5, description of 
testing for SARS-CoV-2 is provided.  
To establish testing for SARS-
CoV-2 prior to Dose 1 as a safety 
measure 
Protocol Amendment 3; 30 Sept 2020 
Changes to the protocol in Amendment 3 included the following:  
Protocol Section(s) 
Impacted by Change 
Change 
Reason for Change 
Section 5.1 Inclusion Criteria 
In Inclusion 6, the circumstance under 
which a subject can be enrolled if 
methotrexate (MTX) intolerant is expanded 
to clarify that this includes if MTX is 
contraindicated 
Clarification in response to 
investigator query 
Section 5.2 Exclusion 
Criteria 
In Exclusion 21, blood tests at screening 
that exclude from enrollment were changed 
A high rate of screen failure 
(>20%) due to abnormal 


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from a prothrombin time (PT) or partial 
thromboplastin time (PTT) > upper limit of 
normal (ULN) to > 1.2 x ULN 
coagulation values (primarily 
PTT values close to ULN) was 
unexpectedly observed. Tubes 
were not expired, and there were 
no instrumentation, maintenance 
or quality control issues in the 
laboratory. Sites were reinstructed 
in sample handling. The 
permissible limit for PT or PTT 
result was increased to eliminate 
unnecessary screen failures 
without affecting subject safety.  
Section 5.2 Exclusion 
Criteria 
At the end of Section 5.2, under Repeat of 
screening laboratory tests, guidance is 
provided to allow for some tests to be 
repeated within the initial screening period 
to assess for eligibility   
The information was provided to 
sites in the administrative 
clarification letter dated 
11Sep2020 and is now added to 
the protocol for clarity 
Section 7.1.1.2 Dose 
preparation 
In Section 7.1.1.2, the timing between vial 
puncture to start of IV bag administration 
may not exceed 4 hours at room 
temperature or 24 hours at 2-8°C 
To clarify the information for 
investigators 
Section 8.4 Adverse events 
of special interest 
In Section 8.4, the process for reporting of 
adverse events of special interest (AESI) 
was clarified 
To ensure that the process of 
reporting of AESIs was clear to 
investigators.  
 


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STATEMENT OF COMPLIANCE  
The study will be conducted in compliance with this clinical study protocol, Good Clinical 
Practices (GCP) as outlined by International Council for Harmonisation E6(R2), and all 
applicable local and national regulatory requirements. Enrollment at any clinical study site may 
not begin prior to that site receiving approval from the ethics committee of record for the 
protocol and all materials provided to potential participants. 
Any amendments to the protocol or changes to the consent document will be approved before 
implementation of that amendment. Reconsent of previously enrolled participants may be 
necessary depending on the nature of the amendment. 
The Principal Investigator will ensure that changes to the study plan as defined by this protocol 
will not be made without prior agreement from the Sponsor and documented approval from the 
ethics committee of record, unless such a change is necessary to eliminate an immediate hazard 
to the study participants. 
All personnel involved in the conduct of this study have completed Human Subjects Protection 
and GCP Training as outlined by their governing institution. 


Module 5.3.5.1 Clinical Study Protocol  
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VIB4920.P2.S3 - VIB4920 in Subjects with Rheumatoid Arthritis 
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TABLE OF CONTENTS 
1 
SYNOPSIS ....................................................................................................................... 14 
2 
INTRODUCTION ........................................................................................................... 17 
2.1 
Background ................................................................................................................... 17 
2.1.1 
Description of VIB4920 ............................................................................................. 17 
2.1.2 
Rheumatoid Arthritis ................................................................................................. 17 
2.1.3 
Evidence for the CD40 Pathway in RA ..................................................................... 18 
2.1.4 
Summary of Nonclinical Experience ......................................................................... 19 
2.1.5 
Summary of Clinical Experience ............................................................................... 19 
2.1.5.1 
Summary of Safety Experience .............................................................................. 20 
2.1.6 
Risk Assessment ........................................................................................................ 21 
2.1.6.1 
Anaphylaxis, Serious Allergic Reactions, and Infusion-related Reactions ............ 21 
2.1.6.2 
Immune Complex Disease ...................................................................................... 21 
2.1.6.3 
Infections................................................................................................................. 21 
2.1.6.4 
Thromboembolism .................................................................................................. 22 
2.1.6.5 
Exposure in Utero ................................................................................................... 23 
2.2 
Study Rationale ............................................................................................................. 23 
2.3 
Study Hypotheses.......................................................................................................... 24 
3 
OBJECTIVES AND ENDPOINTS ................................................................................. 24 
3.1 
Primary Objectives and Endpoints................................................................................ 24 
3.1.1 
Primary Objectives..................................................................................................... 24 
3.1.2 
Primary Endpoints ..................................................................................................... 24 
3.2 
Secondary Objectives and Endpoints............................................................................ 25 
3.2.1 
Secondary Objectives................................................................................................. 25 
3.2.2 
Secondary Endpoints ................................................................................................. 25 
 
 
 
 
 
 
4 
STUDY PLAN ................................................................................................................. 26 
4.1 
Study Design ................................................................................................................. 26 
4.2 
Dose and Treatment Regimen Rationale ...................................................................... 28 
4.3 
Rationale for Study Population ..................................................................................... 28 


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4.4 
Rationale for Primary Endpoint Selection .................................................................... 29 
5 
POPULATION ................................................................................................................ 29 
5.1 
Inclusion Criteria .......................................................................................................... 29 
5.2 
Exclusion Criteria ......................................................................................................... 30 
6 
STUDY CONDUCT ........................................................................................................ 33 
6.1 
Schedules of Study Assessments .................................................................................. 33 
6.2 
Screening Period ........................................................................................................... 39 
6.2.1 
Informed Consent....................................................................................................... 39 
6.2.2 
Demographics and Baseline Characteristics .............................................................. 39 
6.2.3 
Safety Assessments at Screening ............................................................................... 39 
6.3 
Randomization .............................................................................................................. 40 
6.4 
Treatment Period ........................................................................................................... 40 
6.4.1 
Efficacy Assessments................................................................................................. 40 
6.4.1.1 
Composite Disease Scores ...................................................................................... 40 
6.4.1.2 
Assessments for Composite Disease Scores ........................................................... 41 
6.4.1.3 
Time to Start of Rescue Medication ....................................................................... 41 
6.4.1.4 
Patient-reported Outcomes ...................................................................................... 41 
6.4.2 
Safety Assessments .................................................................................................... 42 
6.4.3 
Biomarker Evaluation and Methods .......................................................................... 43 
6.4.3.1 
Autoantibody Panel ................................................................................................. 43 
6.4.3.2 
Inflammatory Markers ............................................................................................ 43 
6.4.3.3 
Flow Cytometry for B-Cell and T-Cell Subsets ..................................................... 43 
6.4.3.4 
Leukocyte Populations and Intracellular Cytokines ............................................... 43 
6.4.3.5 
Serum and Plasma Biomarkers ............................................................................... 43 
6.4.3.6 
RNA Analysis and Optional DNA Analysis ........................................................... 43 
6.4.4 
Immunogenicity Assessments .................................................................................... 44 
6.4.5 
Pharmacokinetic Assessments ................................................................................... 44 
6.4.6 
Pharmacodynamic Assessments ................................................................................ 44 
6.5 
Discontinuation or Withdrawal ..................................................................................... 44 
6.5.1 
Discontinuation of Treatment .................................................................................... 44 
6.5.2 
Withdrawal from Study.............................................................................................. 45 
6.5.3 
Replacement of Subjects ............................................................................................ 45 


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6.5.4 
Subjects Lost to Follow-up ........................................................................................ 45 
6.6 
Study Suspension or Termination ................................................................................. 45 
6.7 
End of Study ................................................................................................................. 46 
7 
STUDY INTERVENTIONS ........................................................................................... 46 
7.1 
Description of Products................................................................................................. 46 
7.1.1 
VIB4920 ..................................................................................................................... 46 
7.1.1.1 
Inspection, Storage, and Handling .......................................................................... 46 
7.1.1.2 
Dose Preparation ..................................................................................................... 47 
7.1.1.3 
Dosing and Administration ..................................................................................... 48 
7.1.1.4 
Investigational Product Accountability ................................................................... 49 
7.1.1.5 
VIB4920 Handling and Disposal ............................................................................ 49 
7.1.2 
Placebo ....................................................................................................................... 50 
7.1.2.1 
Formulation, Storage, Preparation, and Handling .................................................. 50 
7.1.2.2 
Dosing and Administration ..................................................................................... 50 
7.2 
Treatment Assignment and Bias Minimization ............................................................ 50 
7.2.1 
Treatment Allocation ................................................................................................. 50 
7.2.2 
Randomization Strategy and Procedure ..................................................................... 50 
7.2.3 
Extent and Maintenance of Blinding ......................................................................... 50 
7.2.4 
Unblinding Procedures............................................................................................... 50 
7.2.4.1 
Unblinding in the Event of a Medical Emergency.................................................. 50 
7.2.4.2 
Unblinding for the Primary (Interim) Analysis ...................................................... 51 
7.3 
Assessment and Verification of Compliance ................................................................ 51 
7.4 
Concomitant Medications and Treatments ................................................................... 51 
7.4.1 
Prohibited Medications .............................................................................................. 51 
7.4.2 
Rescue Therapy .......................................................................................................... 51 
8 
SAFETY ASSESSMENTS .............................................................................................. 52 
8.1 
Definitions..................................................................................................................... 52 
8.2 
Documenting Adverse Events....................................................................................... 54 
8.3 
Reporting Adverse Events ............................................................................................ 54 
8.4 
Adverse Events of Special Interest ............................................................................... 54 
8.5 
Clinical Laboratory Findings ........................................................................................ 55 
8.5.1 
Hematology ................................................................................................................ 55 


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8.5.2 
Serum Chemistry ....................................................................................................... 55 
8.5.3 
Coagulation Parameters ............................................................................................. 56 
8.5.4 
Urinalysis ................................................................................................................... 56 
8.5.5 
Testing for SARS-CoV-2 ........................................................................................... 56 
8.6 
Vital Signs, Body Weight, and Physical Examinations ................................................ 56 
8.7 
Electrocardiogram ......................................................................................................... 56 
8.8 
Pregnancy ...................................................................................................................... 56 
8.9 
Overdose or Misuse ...................................................................................................... 57 
9 
STATISTICAL CONSIDERATIONS............................................................................. 57 
9.1 
General Considerations ................................................................................................. 57 
9.2 
Statistical Hypotheses ................................................................................................... 57 
9.3 
Determination of Sample Size ...................................................................................... 57 
9.4 
Analysis Sets ................................................................................................................. 57 
9.5 
Methods for Statistical Analyses .................................................................................. 58 
9.5.1 
Analysis of the Primary Efficacy Endpoint ............................................................... 58 
9.5.2 
Analysis of Secondary Efficacy Endpoints................................................................ 58 
9.5.3 
Safety Analysis .......................................................................................................... 59 
9.5.4 
Pharmacokinetics Analysis ........................................................................................ 59 
9.5.5 
Immunogenicity Analysis .......................................................................................... 59 
9.5.6 
Pharmacodynamics and Biomarker Analysis ............................................................ 59 
9.5.7 
Exploratory Analysis ................................................................................................. 59 
10 
ETHICAL CONSIDERATIONS ..................................................................................... 60 
10.1 
Good Clinical Practice .................................................................................................. 60 
10.2 
Ethics Review ............................................................................................................... 60 
10.3 
Informed Consent.......................................................................................................... 60 
10.4 
Data Privacy .................................................................................................................. 61 
10.5 
Disclosure ..................................................................................................................... 61 
10.6 
Biological Specimens and Data .................................................................................... 61 
11 
OVERSIGHT ................................................................................................................... 61 
11.1 
Safety Data Monitoring Board ...................................................................................... 61 
11.2 
Quality Control and Assurance ..................................................................................... 62 
11.3 
Monitoring .................................................................................................................... 62 


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11.4 
Audits ............................................................................................................................ 62 
11.5 
Records ......................................................................................................................... 63 
11.5.1 
Data Capture and Management .................................................................................. 63 
11.5.2 
Source Documentation ............................................................................................... 63 
11.5.3 
Records Retention ...................................................................................................... 63 
12 
PUBLICATION POLICY ............................................................................................... 64 
13 
REFERENCES ................................................................................................................ 64 
14 
APPENDICES ................................................................................................................. 68 
 
LIST OF TABLES 
Table 1 ............ Highly Effective Methods of Contraception for Females of Childbearing Potential
.............................................................................................................................. 30 
Table 2 ............ Screening Assessments and Procedures ............................................................... 34 
Table 3 ............ Schedule of Study Assessments and Procedures ................................................. 36 
Table 4 ............ Summary of Composite Disease Scores and Assessments .................................. 41 
Table 5 ............ Description of Investigational Products ............................................................... 46 
Table 6 ............ Infusion Times ..................................................................................................... 48 
Table 7 ............ Summary of Treatments by Cohort and Dose Day .............................................. 49 
Table 8 ............ Alternate Study Completion Schedules Following Rescue Therapy ................... 52 
Table 9 ............ CTCAE Grading of Infusion-related Reactions ................................................... 55 
 
LIST OF FIGURES 
Figure 1 ........... Study Flow Diagram ............................................................................................ 27 
 
LIST OF APPENDICES 
Appendix 1 ..... Guidance for Anaphylaxis Diagnosis .................................................................. 69 
Appendix 2 ..... Actions Required in Cases of Increases in Liver Biochemistry and Evaluation of 
Hy’s Law .............................................................................................................. 70 
Appendix 3 ..... Investigator’s Agreement ..................................................................................... 73 


Module 5.3.5.1 Clinical Study Protocol  
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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
ACPA 
anti-citrullinated protein antibody(ies) 
ACR 
American College of Rheumatology 
ADA 
anti-drug antibody(ies) 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
anti-HBc 
hepatitis B core antibody 
AST 
aspartate aminotransferase 
bDMARD 
biologic disease-modifying anti-rheumatic drug 
β-hCG 
serum human chorionic gonadotropin  
CD 
cluster of differentiation 
CD40L 
CD40 ligand 
CDAI 
Clinical Disease Activity Index 
CDM 
Clinical Data Management 
cDMARD 
conventional disease-modifying anti-rheumatic drug 
CI 
confidence interval 
CL 
systemic clearance 
CRO 
contract research organization 
CRP 
C-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAS28-CRP  
Disease Activity Score in 28 Joints Using C-reactive Protein 
DMARD 
disease-modifying anti-rheumatic drug 
DMP 
Data Management Plan 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDV 
early discontinuation visit 
EU 
European Union 
EULAR 
European League Against Rheumatism 
FACIT-Fatigue 
Functional Assessment of Chronic Illness Therapy - Fatigue 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HAQ 
Health Assessment Questionnaire 
HBsAg 
hepatitis B surface antigen 
HPF 
high power field 
IB 
Investigator’s Brochure 
ICF 
informed consent form 


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Abbreviation 
Definition 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
IL 
interleukin 
IP 
investigational product 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
IXRS 
interactive voice/web response system 
JAK 
Janus kinase 
KLH 
keyhole limpet hemocyanin 
mAb 
monoclonal antibody(ies) 
MAD 
multiple ascending dose 
MBDA 
multi-biomarker disease activity test 
MDGA 
physician global assessment of disease activity 
MMRM 
mixed-effect model for repeated measures 
MTX 
methotrexate 
NOAEL 
no-observed-adverse-effect level 
PD 
pharmacodynamic(s) 
PGA 
patient global assessment of disease activity 
PK 
pharmacokinetic(s) 
PI 
Principal Investigator 
PRO 
patient-reported outcome 
PTT 
partial thromboplastin time 
RA 
rheumatoid arthritis 
RF 
rheumatoid factor 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAR 
suspected adverse reaction 
SC 
subcutaneous 
sCD40L 
soluble CD40 ligand 
SDAI 
Simplified Disease Activity Index 
SDMC 
Safety Data Monitoring Committee 
SID 
subject identification number 
SJC 
swollen joint count 
t1/2 
terminal elimination half-life 
TB 
tuberculosis 
TBL 
total bilirubin 
TDAR 
T-cell dependent antibody response inhibition 
TEAE 
treatment-emergent adverse event 


Module 5.3.5.1 Clinical Study Protocol  
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Abbreviation 
Definition 
TESAE 
treatment-emergent serious adverse event 
TJC 
tender joint count 
Tn3 
an engineered form of the third fibronectin type III protein domain of human 
Tenascin C 
TNF 
tumor necrosis factor 
ULN 
upper limit of normal 
VAS 
visual analog scale 
w/v 
weight/volume 
WBC 
white blood cell count 


Module 5.3.5.1 Clinical Study Protocol  
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1 
SYNOPSIS  
Title 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Mechanistic Insight and 
Dosage Optimization Study of the Efficacy and Safety of VIB4920 in Patients with 
Rheumatoid Arthritis (RA) (short title: MIDORA) 
Phase 
2 
Study Design 
Randomized, double-blind, placebo-controlled, parallel-cohort study 
Rationale 
The cluster of differentiation 40 (CD40)/CD40 ligand (CD40L) pathway has been 
extensively studied for its role in immunity and autoimmunity, especially its role in 
B and T cell activation and costimulation. Activation of CD40 has been shown to be 
critical for germinal center formation, immunoglobulin class switching, and expression 
of cytokines such as IFNα, tumor necrosis factor α (TNFα), and interleukin-6 (IL-6). It 
is generally accepted that B cells contribute to the pathophysiology of RA. Defective 
central and peripheral B-cell tolerance checkpoints in RA result in accumulation of 
autoreactive B cells. By blocking the CD40/CD40L interaction, VIB4920 may act as an 
immune modulator in RA. Genome-wide association studies have identified a common 
variant in the CD40 locus that increases the risk of RA, and the expression of CD40L 
on CD4+ T helper cells is increased in patients with active RA. These observations 
suggest that inhibition of the CD40L/CD40 pathway may be beneficial in RA. The 
potential for use of VIB4920 in RA was suggested in a phase 1b study, in a population 
similar to that in this current study, in which the 2 highest doses of VIB4920 
demonstrated sustained clinical benefit and an acceptable safety profile. 
Target Population 
Adults with active, moderate-to-severe adult-onset RA (Disease Activity Score in 
28 Joints Using C-reactive Protein [DAS28-CRP] > 3.2, ≥ 4 tender joints, and 
≥ 4 swollen joints) who have: 
• Serum rheumatoid factor (RF) and/or anti-citrullinated protein antibodies (ACPAs) 
• A prior inadequate response to methotrexate, other conventional disease-modifying 
anti-rheumatic drugs, or an anti-TNFα agent  
• No prior treatment with rituximab or B-cell depletive agents 
Number of Subjects 
Approximately 75 subjects will be randomized in a 1:1:1:1:1 ratio among 5 treatment 
groups; approximately 15 subjects to each cohort. 
Length of 
Participation 
Screening period: Up to 28 days 
On-study period: approximately 309 (± 7) days 
Interventions 
Cohort 1: VIB4920 1500 mg on Days 1, 15, 29, and 57 
Cohort 2: VIB4920 1500 mg on Days 1 and 57, placebo on Days 15 and 29 
Cohort 3: VIB4920 3000 mg on Days 1 and 57, placebo on Days 15 and 29 
Cohort 4: VIB4920 3000 mg on Day 1 and placebo on Days 15, 29, and 57 
Cohort 5: Placebo on Days 1, 15, 29, and 57  
Primary Objectives 
and Primary 
Endpoints 
Primary objectives: 
• To evaluate the effect of VIB4920 on disease activity as assessed by a composite 
measure in subjects with adult-onset RA 
• To evaluate the safety and tolerability of VIB4920 in subjects with adult-onset RA 
Primary endpoints: 
• Change in DAS28-CRP from baseline to Day 113 
• The incidence of treatment-emergent adverse events (TEAEs) and 
treatment-emergent serious adverse events and TEAEs of special interest during the 
study 


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Secondary 
Objectives and 
Corresponding 
Endpoints 
Secondary objectives: 
• To characterize the pharmacokinetics (PK) of VIB4920 in subjects with adult-onset 
RA 
• To evaluate the pharmacodynamic effect of VIB4920 in subjects with adult-onset 
RA 
• To evaluate the immunogenicity of VIB4920 in subjects with adult-onset RA 
• To evaluate the effect of VIB4920 on autoantibodies in subjects with adult-onset RA 
• To assess the effect of VIB4920 on clinical remission as assessed by a composite 
measure in subjects with adult-onset RA 
• To evaluate the duration of clinical response to VIB4920 as assessed by time to 
institution of rescue therapy 
Secondary endpoints: 
• The PK profile of VIB4920  
• The time-concentration profile of total soluble CD40L 
• The proportion of subjects with anti-drug antibodies to VIB4920 
• Change in RF and ACPAs from baseline to Day 113  
• The proportion of subjects with clinical remission defined as DAS28-CRP < 2.6 at 
Day 113 
• Time to start of new treatment for RA (rescue medication)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


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Number of Sites 
Approximately 30 sites in 2-4 countries 
Study Duration 
Estimated duration: 19 months 
Data Monitoring 
Committee 
An external, independent Safety Data Monitoring Committee will evaluate safety data 
at regular intervals throughout the study and make recommendations to the Sponsor as 
needed. The Committee will not perform a futility analysis or consider early study 
completion for efficacy. 
 


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2 
INTRODUCTION  
2.1 
Background  
2.1.1 
Description of VIB4920  
VIB4920 (formerly MEDI4920) is a cluster of differentiation 40 ligand (CD40L) antagonist that 
is a non-antibody biologic composed of 2 identical Tn3 modules fused to human serum albumin. 
Each Tn3 is an engineered form of the third fibronectin type III protein domain of human 
Tenascin C. Polyglycine linkers join the 2 Tn3 domains and the second Tn3 domain to the 
human serum albumin protein. Each Tn3 binds specifically to human CD40L and inhibits its 
interaction with human CD40. The CD40/CD40L interaction plays a critical role in T-cell 
dependent immunity, antigen presentation and activation of B cells, which produce 
autoantibodies and inflammatory mediators that contribute to autoimmune disease pathology. By 
blocking the CD40/CD40L interaction, VIB4920 may act as an immune modulator with potential 
therapeutic activity in a range of autoimmune diseases, including rheumatoid arthritis (RA).  
In nonclinical studies, disruption of the CD40/CD40L interaction with antibodies against CD40L 
has been shown to be beneficial in autoimmune disease models (Choi et al, 2018; Kalled et al, 
2001; Croft et al, 2013). In clinical studies of monoclonal antibodies (mAbs) targeting CD40L, 
expected changes in biomarkers were observed, but further development was terminated because 
of thromboembolic events considered to be related to interaction of the Fc region of the 
anti-CD40L mAbs with platelets (Boumpas et al, 2003; Robles-Carrillo et al, 2010; Visvanathan 
et al, 2019). VIB4920 is not an antibody, does not have an Fc receptor, and was not associated 
with platelet aggregation in nonclinical studies or with thrombotic events or coagulation 
abnormalities in phase 1 studies.  
2.1.2 
Rheumatoid Arthritis  
RA is a chronic systemic inflammatory disease that is associated with significant morbidity and 
mortality. The disease is characterized by inflammation of the synovial joints that can result in 
pain, swelling, and joint damage with secondary deformity and progressive disability. 
Worldwide, the prevalence of RA is estimated to be between 0.6-1.1% with variations across 
geographical regions. The incidence is 2-3 times higher in women than in men with a peak age of 
onset between 35-55 years of age (Symmons, 2002). Uncontrolled active RA causes joint 
damage, disability, and decreased quality of life; comorbidities include cardiovascular disease 
and osteoporosis, and reduced life expectancy (Wong et al, 2001). 
Rapidly acting anti-inflammatory medications, including nonsteroidal anti-inflammatory drugs 
and systemic and intraarticular corticosteroids, are often used to treat RA, generally in 
combination with disease-modifying anti-rheumatic drugs (DMARDs). Two main classes of 
DMARDs are available for the treatment of RA: conventional DMARDs (cDMARDs; such as 
methotrexate [MTX], sulfasalazine, leflunomide, and hydroxychloroquine) and biologic 
DMARDs (bDMARDs; such as tumor necrosis factor [TNF]-inhibitors). MTX is the most 
commonly used DMARD for the treatment of moderate and severe RA; however, many patients 
fail to achieve an adequate or sustained response to MTX alone (Smolen et al, 2017). To improve 
efficacy, MTX is being combined with newer biologic agents targeting various components of 
the immune system, including anti-TNFα agents (etanercept, infliximab, adalimumab, 
certolizumab, and golimumab) and agents targeting different compartments of the immune 


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system such as B cells (rituximab), cytotoxic T lymphocyte antigen 4 (abatacept), and 
interleukin-6 (IL-6) receptors (tocilizumab). Newer oral compounds such as inhibitors of Janus 
kinase (JAK; tofacitinib) are also used. Despite the availability and utility of multiple therapeutic 
agents for the treatment of RA, there is a need for new treatments to reduce disease activity, 
because only a minority of patients achieve clinical remission (Smolen et al, 2017; Bykerk and 
Massarotti, 2012). 
2.1.3 
Evidence for the CD40 Pathway in RA  
It is generally accepted that B cells contribute to the pathophysiology of RA (van Baarsen et al, 
2013). Defective central and peripheral B-cell tolerance checkpoints in RA result in 
accumulation of autoreactive B cells (Bugatti et al, 2014), and depletion of CD20-positive 
B cells with rituximab results in clinical improvement in a subset of patients. Approximately 
80% of patients with RA have detectable levels of rheumatoid factors (RFs), which are 
antibodies of any isotype (immunoglobulin [Ig] M, IgG, IgA) against the Fc portion of IgG. The 
majority of patients with RA also have detectable levels of anti-citrullinated protein antibodies 
(ACPAs). Indeed, the presence of RF or ACPA is included in the American College of 
Rheumatology (ACR) 2010 diagnostic criteria for RA (Aletaha et al, 2010). 
The CD40 receptor is a member of the TNF family of receptors expressed on the plasma 
membrane of antigen-stimulated B cells, macrophage, and dendritic cells (Croft et al, 2013). The 
CD40 receptor functions to provide a co-stimulatory signal for B cells that have bound antigen. 
The cognate ligand for CD40 is CD40L (also known as CD154), which is expressed on the 
plasma membrane of T cells and other cell types, including platelets. Cell contact-dependent 
interaction between CD40L and CD40 is critical for the development of a comprehensive 
immune response (Ford et al, 2014).  
The CD40/CD40L pathway has been extensively studied for its role in immunity and 
autoimmunity, especially its role in B cell and T cell activation and B and T cell costimulation 
(Karnell et al, 2018). Specifically, activation of CD40 has been shown to be critical for germinal 
center formation, Ig-class switching, and expression of cytokines such as IFNα, TNFα, and IL-6. 
Genome-wide association studies have identified a common variant in the CD40 locus that 
increases the risk of RA (Scheinman, 2013). The RA risk allele is a gain-of-function allele that 
increases the amount of CD40 on the surface of primary human B-lymphocyte cells and probably 
other cell types (Li et al, 2013). The expression of CD40L on CD4+ T helper cells is also 
increased in patients with active RA compared to those in clinical remission or healthy controls 
(Berner et al, 2000; Zhang et al, 2013). Taken together, these observations suggest that inhibition 
of the CD40L/CD40 pathway may be beneficial in RA. 
In clinical studies of mAbs targeting CD40L, expected changes in biomarkers were observed, but 
further development was terminated because of thromboembolic events considered to be related 
to Fc region of the mAbs (Boumpas et al, 2003; Robles-Carrillo et al, 2010; Visvanathan et al, 
2019). 
Data from a phase 1b study of VIB4920 in patients with RA, in which higher doses of VIB4920 
were shown to have activity against RA, provide additional support for the importance of the 
CD40/CD40L pathway in RA. 


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2.1.4 
Summary of Nonclinical Experience  
In nonclinical pharmacology studies, VIB4920 was shown to bind human CD40L specifically 
and with high affinity. Additionally, VIB4920/soluble CD40 ligand (sCD40L) immune 
complexes were used in human ex vivo platelet aggregation assays in various concentrations 
without inducing platelet aggregation. In single- and repeat-dose pharmacokinetic (PK), 
toxicokinetic, and pharmacodynamic (PD) studies of VIB4920 in cynomolgus monkeys, there 
were no VIB4920-related adverse findings, and the no-observed-adverse-effect levels (NOAELs) 
for repeat-dose studies were the highest doses tested for most of the studies: 150 mg/kg weekly 
intravenous (IV) and subcutaneous (SC) and 300 mg/kg weekly IV for the 5-week studies; 
250 mg/kg weekly SC for the 6-month study. The NOAEL for the single dose study was 
600 mg/kg IV. No NOAEL was established for IV dosing at 150 or 300 mg/kg weekly for 
6 months because of early euthanasia of one animal on Day 92 for a potential systemic infection, 
and an opportunistic fungal infection detected in one animal at scheduled Day 192 necropsy. 
However, the NOAEL for the SC cohort in the 6-month study was 250 mg/kg weekly. There 
were no VIB4920-related effects on female or male reproductive endpoints, but embryo-fetal 
studies have not been conducted. See the Investigator’s Brochure (IB) for details. 
2.1.5 
Summary of Clinical Experience  
A phase 1a, randomized, blinded (Investigator and participants were blinded to treatment 
assignment, and Sponsor was unblinded to treatment assignment), placebo-controlled, first-time-
in-human study (D5100C00001) to evaluate the safety and tolerability of single-ascending IV 
doses of VIB4920 was conducted in healthy volunteers (Karnell et al, 2019). Fifty-six healthy 
adult male subjects were IV administered a single dose of either placebo (N = 12) or VIB4920 
(N = 44) at doses of 3, 10, 30, 100, 300, 1000, or 3000 mg. No deaths, thromboembolic events, 
severe or serious hypersensitivity reactions, severe or serious infections, or infusion-related 
reactions were observed. PK was linear with dose proportional increases in exposure, and the 
increase in total sCD40L after VIB4920 administration was dose-dependent, indicating binding 
of VIB4920 to sCD40L and target engagement. A dose-response model generated for T-cell 
dependent antibody response inhibition (TDAR) (based on antibody responses to keyhole limpet 
hemocyanin [KLH]) showed that the 1000 mg dose achieved ~78% inhibition of TDAR and the 
3000 mg dose ~86% inhibition of TDAR compared with placebo, indicating adequate inhibition 
for the 2 highest doses tested.  
In Study D5100C00001, there was a decrease in anti-drug antibody (ADA) incidence and titers 
observed with increasing doses of VIB4920 (incidence of 90% in subjects at doses ≤ 100 mg and 
29% at doses ≥ 300 mg) consistent with the immunosuppressive mechanism of action of 
VIB4920. There was no association of ADA with any treatment-emergent adverse events 
(TEAEs) reported in this study. The PK and total sCD40L profiles were similar between 
ADA-positive subjects with low titer and ADA-negative subjects; however, subjects with high 
ADA titers (defined as > 480) had reduced VIB4920 and total sCD40L concentrations compared 
to subjects who were negative or had low ADA titers. 
VIB4920 was assessed in a subsequent phase1b, randomized, double-blind, placebo-controlled, 
multiple ascending dose (MAD) study (D5100C00002) to evaluate the safety, tolerability, PK, 
immunogenicity, PD, and clinical response of VIB4920 in 57 subjects with moderate-to-severe 
adult-onset RA as defined by Disease Activity Score in 28 Joints Using C-reactive Protein 


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(DAS28-CRP) > 3.2 at screening and an inadequate response to MTX or other cDMARDs and/or 
a biologic anti-TNFα agent (Karnell et al, 2019). Subjects received VIB4920 (N = 42) at doses of 
75, 500, 1000, or 1500 mg or placebo (N = 15) by IV infusion every other week for a total of 
7 doses over 12 weeks followed by a 12-week follow-up period. The PK profile of VIB4920 
following IV infusions suggested the absence of target-mediated clearance. Following the first 
IV infusion, the mean systemic clearance (CL) ranged from 405-654 mL/day in subjects with 
adult-onset RA. The mean terminal elimination half-life (t1/2, last dose) was 7.8-9.7 days. The 
mean volume of distribution at steady state was 4.10-5.60 L, indicating limited extravascular 
distribution of VIB4920. Repeat administration of VIB4920 led to substantial and prolonged 
elevation of total sCD40L; this PD effect plateaued at doses ≥ 500 mg. ADA developed in 
3/6 subjects in the 75 mg group, 3/10 subjects in the 500 mg group, 1/12 subjects in the 1000 mg 
group, and 0/12 subjects in the 1500 mg group. There was no apparent impact of ADA on PK, 
PD (total sCD40L), or safety. 
VIB4920 significantly reduced disease activity as quantified by DAS28-CRP score at Day 85 in 
the 1000 mg and 1500 mg groups. Reductions in DAS28-CRP score were evident as early as 
Day 15, after a single dose of VIB4920. As compared with placebo, this reduction was both 
clinically and statistically meaningful in the groups receiving the 2 highest doses of VIB4920: 
the adjusted mean (standard error) difference compared to placebo at Week 12 for VIB4920 
1000 mg and 1500 mg groups were -1.2 (0.4) and -1.4 (0.4) with p-values of 0.006 and 0.002, 
respectively. Low disease activity or DAS28-CRP remission (score of ≤ 3.2) was achieved in 
50% of subjects at 1000 mg and 75% at 1500 mg compared to 13.4% in placebo at Day 85. The 
statistically significant response over placebo observed in DAS28-CRP at Day 85 with the 
VIB4920 1000 mg and VIB4920 1500 mg doses was maintained for 3 months after the last dose 
until the end of the study at Day 169. A statistically significant reduction in RF was observed 
over placebo for the 500 mg (34.9%; p = 0.010), 1000 mg (44.6%; p < 0.001), and 1500 mg 
(48.0%; p < 0.001) doses at Day 85. The adjusted mean difference vs placebo in Vectra DA® 
score from baseline to Day 85 was -10.3 (90% confidence interval [CI]: -17.4, -3.3; p = 0.018) 
and -14.4 (90% CI: -21.5, -7.2; p = 0.001) for the 1000 mg and 1500 mg doses, respectively. The 
safety profile of VIB4920 in subjects with adult-onset RA was acceptable for further 
development. 
2.1.5.1 
Summary of Safety Experience  
VIB4920 has been shown to be well-tolerated and to have an acceptable safety profile in both 
animals and humans. Animal toxicology is described in the IB.  
The safety of VIB4920 was evaluated in single-ascending dose (SAD) clinical study in healthy 
volunteers and in a MAD study in subjects with active RA. Overall, VIB4920 was well-tolerated 
with a balanced distribution of TEAEs observed between placebo and the active dose groups in 
both studies. There were no infusion-related reactions, severe infections or deaths (Karnell et al, 
2019). One serious adverse event (SAE) of fractured tibia was reported in the placebo group in 
the SAD study. VIB4920 showed inhibition of the TDAR IgG response after the second 
administration of KLH on Day 15 at higher doses ≥ 300 mg.  
In the MAD study in RA, VIB4920 was generally well-tolerated with a balanced distribution of 
TEAEs between placebo and the 4 active groups. There were few clinically significant laboratory 
abnormalities. One Grade 4 SAE of encephalitis occurred in the 1500 mg cohort that was 


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considered by the Investigator to be unrelated to investigational product (IP). After completion of 
follow-up in the study, the subject had a recurrence of similar symptoms and was diagnosed with 
metastatic melanoma of the brain. 
In both studies, there was a decrease in ADA incidence and titers observed with increasing doses 
of VIB4920, consistent with the immunosuppressive mechanism of action of VIB4920. There 
was no identified association of ADA with any TEAEs reported in either study. 
2.1.6 
Risk Assessment  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
. 
 
  
 
 
 
 
 
  
 
 


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2.1.6.5 
Exposure in Utero  
No embryo-fetal studies have been conducted to date. 
2.2 
Study Rationale  
VIB4920 is being developed for the treatment of B-cell dependent autoimmune disease, 
including RA. Based on the data in support of the role of both B cells and CD40L in the 
pathogenesis of RA, and the medical need for new treatments for RA, the efficacy and safety of 
VIB4920 are being explored in the current study.  
Data from previous studies also provide a rationale for the current study. In the phase 1a SAD 
study (D5100C00001) in healthy volunteers, VIB4920 was shown to have an acceptable safety 
profile for further development and to result in a dose-dependent increase in total sCD40L, 
indicating binding of VIB4920 to sCD40L and target engagement. A phase 1b MAD study 
(D5100C00002) in subjects with adult-onset RA demonstrated an acceptable safety profile in 
subjects and provided preliminary clinical and 
 in support of the potential efficacy 
of VIB4920 for the treatment of RA. 
The current study is designed to further characterize the safety and tolerability of single and 
multiple IV doses of VIB4920 in subjects with adult-onset RA and to obtain an assessment of 
efficacy and effects on biomarkers in these subjects. These data, along with PK and PD data, will 
be useful in the selection of dose and dosing interval for further development.  
After this study was opened to enrollment in December 2019, the onset of the pandemic caused 
by SARS-CoV-2 resulted in temporary closure of the study to enrollment. The decision to re-
open the study was based on an overall assessment of potential benefit-risk for subjects in the 
study during what is likely to be continued circulation of COVID-19. There are no clear data on 
the possible potentiation of COVID-19 risk by active RA on or off treatment (Favalli et al, 2020, 
Gianfrancesco et al, 2020), and there are no data on the effect of VIB4920 on this risk. A 
potential risk of VIB4920 is infection (See Section 2.1.6.3 Infections), based on its mechanism of 
action. The subjects in this study, however, have the health risk of active RA despite treatment 


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and the potential of the benefit, based on data from the Phase 1b study, of improvement in their 
RA in response to treatment with VIB4920. In addition, the standard of care for their treatment is 
likely to include a drug that can increase the risk of infection.  
The following are included in this study to minimize risk to subjects: 
1. Opening a site only after review of local COVID-19 epidemiology, availability of healthcare 
resources, ability to monitor site activities, and the presence of a site plan to minimize patient 
exposure to SARS-CoV-2 during site visits. Each of these factors is likely to differ over time 
in ways that are difficult to predict, so ongoing risk assessment is required. 
2. Assessment of the benefit-risk for each individual subject for determination of suitability for 
enrollment based on known risk factors for COVID-19 severity and possible or known 
exposure to SARS-CoV-2.  
3. Ensuring that the subject has a documented negative SARS-CoV-2 viral test within two 
weeks prior to randomization. 
Considering the measures taken to minimize risk to subjects participating in this study and the 
benefit that may be afforded to study subjects, the benefit-risk assessment supports re-opening 
the study.     
 
2.3 
Study Hypotheses  
1. VIB4920 will reduce disease activity in subjects with adult-onset RA of moderate to high 
systemic activity. 
2. VIB4920 will be well-tolerated and have an acceptable safety profile in subjects with 
adult-onset RA. 
3. The duration of reduction in disease activity and PD parameters observed after dosing 
will inform dose selection for further study. 
3 
OBJECTIVES AND ENDPOINTS  
3.1 
Primary Objectives and Endpoints  
3.1.1 
Primary Objectives  
• To evaluate the effect of VIB4920 on disease activity as assessed by a composite measure 
in subjects with adult-onset RA. 
• To evaluate the safety and tolerability of VIB4920 in subjects with adult-onset RA. 
3.1.2 
Primary Endpoints  
• Change in DAS28-CRP from baseline to Day 113. 
• The incidence of TEAEs and treatment-emergent serious adverse events (TESAEs) and 
treatment-emergent AEs of special interest (AESIs) during the study. AESIs include: 
− Thrombotic and embolic events 
− Anaphylaxis and clinically significant (Grade 3 or higher) hypersensitivity reactions 
(see Appendix 1) 


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− Severe infusion-related reactions (Common Terminology Criteria for Adverse Events 
[CTCAE] Grade 3 or higher) 
− Immune complex disease 
− Severe (Grade 3 or higher) and/or opportunistic infections 
− Hepatic function abnormality meeting the definition of Hy’s Law (see Appendix 2) 
− Malignant neoplasm 
3.2 
Secondary Objectives and Endpoints  
3.2.1 
Secondary Objectives  
• To characterize the PK of VIB4920 in subjects with adult-onset RA 
• To evaluate the PD effect of VIB4920 in subjects with adult-onset RA 
• To evaluate the immunogenicity of VIB4920 in subjects with adult-onset RA 
• To evaluate the effect of VIB4920 on autoantibodies in subjects with adult-onset RA 
• To assess the effect of VIB4920 on clinical remission as assessed by a composite 
measure in subjects with adult-onset RA 
• To evaluate the duration of clinical response to VIB4920 as assessed by time to 
institution of rescue therapy 
3.2.2 
Secondary Endpoints  
• The PK profile of VIB4920 
• The time-concentration profile of total sCD40L 
• The proportion of subjects with ADAs to VIB4920  
• Change in RF and ACPAs from baseline to Day 113 
• The proportion of subjects with clinical remission defined as DAS28-CRP < 2.6 at 
Day 113 
• Time to start of new treatment for RA (rescue medication) 
3.3 
  
3.3.1 
  
 
   
 
 
  
 
 
 
 
 
  
 
 
3.3.2 
  
 
 
 
 
 


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4 
STUDY PLAN  
4.1 
Study Design  
This is a multicenter, randomized, double-blind (Investigator, subject, and Sponsor will be 
blinded to treatment assignment), placebo-controlled, parallel-cohort study to evaluate the safety, 
efficacy, and PK of VIB4920 in adults with active, moderate-to-severe adult-onset RA 
(DAS28-CRP > 3.2; 
 and presence of serum RF and/or ACPA who have 
had an inadequate response to MTX, cDMARD, or an anti-TNFα agent; who are not currently 
receiving an anti-TNFα agent; and who have had no prior treatment with rituximab or B-cell 
depletive agents. The study is planned to be conducted at approximately 30 sites in 2-4 countries. 
After a screening period of up to 28 days, approximately 75 subjects will be randomized in a 
1:1:1:1:1 ratio using an interactive voice/web response system (IXRS) into 5 cohorts:  
Cohort 1: VIB4920 1500 mg on Days 1, 15, 29, and 57 (N = 15) 
Cohort 2: VIB4920 1500 mg on Days 1 and 57, placebo on Days 15 and 29 (N = 15) 
Cohort 3: VIB4920 3000 mg on Days 1 and 57, placebo on Days 15 and 29 (N = 15) 
Cohort 4: VIB4920 3000 mg on Day 1 and placebo on Days 15, 29, and 57 (N = 15) 
Cohort 5: Placebo on Days 1, 15, 29, and 57 (N = 15) 
A study schematic is presented in Figure 1. 
Subjects are to be followed on their stable background anti-RA therapy at least through 12 weeks 
(Day 85), at which time rescue therapy may be instituted. All subjects are followed at least 
through the primary (interim) analysis (Day 113), and those who have not instituted rescue 
therapy will be followed through Day 309 to determine the duration of clinical response.  
The primary analysis will be after all subjects have completed Day 113, and the final analysis 
will be after all subjects have completed follow-up. 


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Figure 1 
Study Flow Diagram  
 
 
N = total number of subjects planned for each cohort. 
 


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4.2 
Dose and Treatment Regimen Rationale  
All subjects in this study receive the background therapy that was established for them by their 
personal physician. Although there is use of a placebo in this study, no subject is untreated, and 
both placebo and VIB4920 are add-on therapies to the subject’s treatment. To accomplish the 
research aims of this study and to permit an assessment of the efficacy of VIB4920 in a 
pre-treated population, subjects are asked, but not required, to delay institution of any new 
treatment for RA for 12 weeks (Day 85), a limited period not expected to result in significant 
harm, to permit this assessment (FDA draft guidance, 2013). 
The safety, tolerability, and PD effects of a single IV dose of up to 3000 mg of VIB4920 in 
healthy volunteers and multiple IV doses of up to 1500 mg in subjects with adult-onset RA have 
been assessed. No dose-limiting toxicities were identified in these human studies, and the 
observed safety profiles were acceptable for continued development. No thrombotic events were 
observed, and no infusion-related reactions were observed. 
In subjects with RA in a MAD study, VIB4920 doses of 1000 mg and 1500 mg every 2 weeks 
for 3 months were efficacious in significantly decreasing disease activity, and this clinical 
efficacy persisted for at least 3 months after the last dose. Low disease activity or clinical 
remission at Day 85 was achieved in 50% and 75% of subjects in the 1000 mg and 1500 mg dose 
groups, respectively, per the DAS28-CRP score.  
Four dosing regimens with varying dosage levels and dosing intervals were selected for the 
evaluation of the efficacy and safety of VIB4920 in adult subjects with RA in this phase 2 study. 
The cohort 1 dosing regimen was selected to be similar to dosing in subjects with RA that was 
observed to be efficacious in the MAD study. 
Cohorts 2 and 3 explore less frequent dosing that, based on the duration of clinical effect 
observed in the MAD study, might improve the patient experience without compromising 
clinical efficacy.  
The cohort 4 dosing schedule was selected to determine the effect of a single induction dose on 
the duration of clinical response. Given the previously observed long duration of activity, a 
strategy of higher induction dose with a longer dosing interval may be effective.  
Data generated on the clinical effect of VIB4920 in these dosing cohorts will aid in the selection 
of dosing strategies for future studies. 
4.3 
Rationale for Study Population  
Subjects will be adults diagnosed with adult-onset RA according to the European League 
Against Rheumatism (EULAR)/ACR 2010 criteria (Aletaha et al, 2010) at least 6 months prior 
to screening. Subjects must, based on moderate-to-severe disease despite DMARD therapy, have 
failed a prior regimen. To avoid confounding interpretation of safety and efficacy data based on 
the use of prior biologics, especially B-cell depletive agents, patients with prior use of these 
drugs, other than prior but not current use of TNF inhibitors, are excluded. Patients must have 
at least 4 tender and 4 swollen joints to permit assessment of joint response during the study.  
This DMARD-experienced population represents one at high medical need, and it is the 
population in which VIB4920 was previously studied and in which the 2 highest doses of 


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VIB4920 demonstrated clinically meaningful, sustained clinical benefit with an acceptable safety 
profile. Use of a similar population will contribute to assessment of dosing strategies and expand 
the understanding of the safety of the combination of VIB4920 with MTX.  
4.4 
Rationale for Primary Endpoint Selection  
The primary efficacy endpoint, the change in DAS28-CRP from baseline to Day 113, is a 
standardized measure that is widely used in clinical trials of RA and in the care of patients with 
RA (Prevoo et al, 1995). 
The primary endpoints for the assessment of safety, which are the incidence of TEAEs, TESAEs, 
and AESIs, are widely used and accepted methods to assess safety in clinical trials. Other 
important safety parameters will be assessed, including vital signs, laboratory parameters, 
electrocardiograms (ECGs), and physical examinations; if clinically important, they will be 
recorded as adverse events (AEs) or SAEs.  
5 
POPULATION  
5.1 
Inclusion Criteria  
To be included in the study, each individual must satisfy all the following criteria: 
1. Male or female adults, ≥ 18 years of age at time of informed consent. 
2. Written informed consent and any locally required authorization (eg, Health Insurance 
Portability and Accountability Act in the United States, European Union [EU] Data 
Privacy Directive in the EU) obtained from the subject prior to performing any 
protocol-related procedures, including screening evaluations. 
3. Diagnosed with RA according to the EULAR/ACR 2010 criteria (Aletaha et al, 2010) 
≥ 6 months prior to screening. 
4. DAS28-CRP > 3.2 at screening with 
 assessed 
for DAS28 present at screening and confirmed present at Visit 2 prior to randomization. 
5. Positive for RF and/or ACPA at screening, in accordance with criteria at the central 
laboratory. 
6. Treated with MTX given orally, SC, or intramuscularly at a dose of 7.5-25.0 mg/week, 
with or without a concomitant cDMARD other than leflunomide, with MTX and the 
cDMARD delivered by the same route for ≥ 12 weeks without change in dose for 
≥ 6 weeks prior to screening, 
OR, if MTX intolerant or if MTX is contraindicated, treated with one or more cDMARD 
for ≥ 12 weeks without change in dose for ≥ 6 weeks prior to screening. (JAK inhibitors 
are not considered cDMARDs).  
7. Willing and able to comply with the protocol, complete study assessments, and complete 
the study period. 
8. Females of childbearing potential who are sexually active with a non-sterilized male 
partner must use a highly effective method of contraception (Table 1) from signing 
informed consent and must agree to continue using such precautions through the end of 
the follow-up of the study; cessation of contraception after this point should be discussed 
with a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal 
method are not acceptable methods of contraception. A recommendation that the female 


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partners (of childbearing potential) of male study participants should use a highly 
effective method of contraception other than a barrier method will be made. 
a. Females of childbearing potential are defined as those who are not surgically sterile 
(ie, surgical sterilization includes bilateral tubal ligation, bilateral oophorectomy, or 
hysterectomy) or those who are not postmenopausal (defined as 12 months with no 
menses without an alternative medical cause and a follicle-stimulating hormone 
within the postmenopausal range as established by the clinical laboratory). 
b. Because some of the background medications used in RA and accepted in the current 
study (eg, MTX or leflunomide) are known to have potential deleterious effects on 
conception, pregnancy, and fetal health, the Investigator must inform the subjects 
about these risks and should manage every case of planned conception or pregnancy 
according to the local medical practice standards. 
9. Non-sterilized male subjects who are sexually active with a female partner of 
childbearing potential must use a condom with spermicide from Day 1 through to the end 
of the study. 
Table 1 
Highly Effective Methods of Contraception for Females of Childbearing 
Potential  
Physical Methods 
Hormonal Methods 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) a 
• Bilateral tubal occlusion 
• Vasectomized partner b 
• Sexual abstinence c 
 
• Combined (estrogen and progestogen-containing 
hormonal contraception) 
• Oral (combined pill) 
• Injectable 
• Transdermal (patch) 
• Progestogen-only hormonal contraception 
associated with inhibition of ovulation d 
• Injectable 
• Implantable 
• Intravaginal 
 
a 
This is also considered to be a hormonal method. 
b 
With appropriate post-vasectomy documentation of surgical success (absence of sperm in ejaculate). 
c 
Sexual abstinence is considered to be a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of the study and if it is the preferred and usual lifestyle of the patient. 
d 
Progestogen-only hormonal contraception, where inhibition of ovulation is not the primary mode of action 
(minipill) is not accepted as a highly effective method. 
5.2 
Exclusion Criteria  
Any of the following excludes an individual from participation in the study: 
1. Prior or current (1) inflammatory joint disease other than RA (eg, gout, reactive arthritis, 
psoriatic arthritis, seronegative spondyloarthropathy, Still’s disease, or Lyme disease); (2) 
other systemic autoimmune disorder (eg, systemic lupus erythematosus, inflammatory 
bowel disease, scleroderma, inflammatory myopathy, mixed connective tissue disease, or 


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other overlapping syndrome) or polymyalgia rheumatica except that patients with RA and 
secondary Sjögren’s syndrome may enroll. 
2. Severe interstitial lung disease. 
3. Prior receipt of any biologic B-cell-depleting therapy (eg, rituximab, ocrelizumab, 
ofatumumab). 
4. Receipt of any anti-TNFα biologic agent < 8 weeks prior to screening (discontinuation 
could have been for any reason: lack of efficacy, safety/tolerability issues, or lack of 
access to drug). 
5. Receipt of any bDMARD with a mechanism of action other than direct TNF blockade, 
including any JAK inhibitor, < 12 weeks or < 5 half-lives of the drug (whichever is 
longer) prior to screening. 
6. Receipt of any experimental therapy < 12 weeks or < 5 half-lives of the drug (whichever 
is longer) prior to screening. 
7. Injectable corticosteroids (including intraarticular) or treatment with > 10 mg/day dose of 
oral prednisolone or equivalent within 4 weeks prior to screening. Concomitant treatment 
with oral corticosteroids ≤ 10 mg/day prednisone or equivalent is permitted provided that 
the dose is stable for ≥ 4 weeks prior to screening and during the screening period and is 
expected to remain stable for the duration of the treatment period. Inhaled or topical 
corticosteroids given for asthma, chronic obstructive pulmonary disease, or 
dermatological conditions are allowed, provided doses are expected to be stable during 
the study. 
8. Previous treatment with anti-CD40L compounds at any time before randomization. 
9. History of confirmed deep venous thrombosis or arterial thromboembolism within 
2 years of enrollment OR history of recurrent deep venous thrombosis or arterial 
thromboembolism OR patients with risk factors for venous thromboembolism or arterial 
thrombosis (eg, immobilization or major surgery within 12 weeks before screening), 
prothrombotic status (including, but not limited to, known congenital or inherited 
deficiency of antithrombin III, protein C, protein S, or confirmed diagnosis of 
catastrophic antiphospholipid syndrome). 
10. Treatment with anticoagulant drugs (clopidogrel, prasugrel, warfarin, low molecular 
weight heparin, others). Low-dose aspirin treatment (up to 325 mg/day) is allowed.  
11. History of solid organ or cell-based transplantation. 
12. Active malignancy or history of malignancy that was active within the last 15 years, 
except as follows: 
a. In situ carcinoma of the cervix following apparently curative therapy > 12 months 
prior to screening; or  
b. Cutaneous basal cell or squamous cell carcinoma following apparently curative 
therapy. 
13. Pregnancy, lactation, or planning to become pregnant during the duration of the study. 
14. Positive test for, or prior treatment for, hepatitis B, hepatitis C, or HIV infection. A 
positive test for hepatitis B is detection of either (1) hepatitis B surface antigen (HBsAg); 
or (2) hepatitis B core antibody (anti-HBc). 
15. Evidence of active tuberculosis (TB) or being at high risk for TB based on: 


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a. History of active TB or untreated/incompletely treated latent TB. Patients with latent 
TB who have documentation of completion of treatment according to local guidelines 
may be enrolled. 
b. History of recent (≤ 12 weeks prior to screening) close contact with someone with 
active TB (close contact is defined as ≥ 4 hours/week OR living in the same 
household OR in a house where a person with active TB is a frequent visitor). 
c. Signs or symptoms that could represent active TB by medical history or physical 
examination. 
d. Positive, indeterminate or invalid interferon-gamma release assay test result at 
screening, unless previously adequately treated for latent TB. Patients with an 
indeterminate test result can repeat the test once, but if the repeat test is also 
indeterminate, the patient is excluded.  
e. Chest radiograph that suggests a possible diagnosis of TB or suggests that a work-up 
for TB should be considered; all patients must have had a chest radiograph with an 
acceptable reading within 6 months prior to screening or at screening. 
16. History of (a) more than one episode of herpes zoster in the 12 months prior to screening 
or (b) any opportunistic infection in the 12 months prior to screening, excluding localized 
mucocutaneous candidiasis. 
17. Known history of severe allergy or reaction to any component of the IP formulation. 
18. Severe cardiovascular, respiratory, endocrine, gastrointestinal, hematological, 
neurological, psychiatric, or systemic disorder or any other condition that, in the opinion 
of the Investigator, would place the patient at unacceptable risk of complications, 
interfere with evaluation of the IP, or confound the interpretation of patient safety or 
study results.   
 
Subjects should be assessed for epidemiologic risk of COVID-19 (recent exposures, high-
risk housing) and for health-related risk of COVID-19 severity based on current 
understanding of risk factors for severe disease when making a decision regarding the 
individual subject’s risk of participation. Subjects who have active COVID-19 infection 
or disease or other significant infection, or, in the judgment of the investigator, who may 
be at unacceptable risk of COVID-19 or its complications should not be randomized. 
 
Ensure that the subject has a documented negative SARS-CoV-2 test within two weeks 
prior to randomization. Subjects with a positive test for SARS-CoV-2 may be rescreened 
at least 2 weeks after a positive test if asymptomatic and at least 3 weeks after 
symptomatic COVID-19 illness.  
 
19. Inflammatory osteoarthritis.  
20. Receipt of live vaccine or live therapeutic infectious agent within the 4 weeks prior to 
screening. 
21. Blood tests at screening that meet any of the following criteria: 
a. Aspartate aminotransferase (AST) > 2 × upper limit of normal (ULN) for the central 
laboratory 
b. Alanine aminotransferase (ALT) > 2 × ULN 


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c. Total bilirubin (TBL) > 2 × ULN unless AST, ALT, and hemoglobin are within 
central laboratory normal range and the patient has a known history of Gilbert 
syndrome  
d. Hemoglobin < 85 g/L 
e. Neutrophils < 1.5 × 109/L 
f. Platelets < 100 × 109/L 
g. Prothrombin time or partial thromboplastin time (PTT) > 1.2 x ULN 
22. History of alcohol or drug abuse that, in the opinion of the Investigator, might affect 
patient safety or compliance with visits, or interfere with safety or other study 
assessments. 
Repeat of screening laboratory tests 
Repeat of study laboratory tests noted below is acceptable in the event that an initial screening 
safety laboratory result is outside of acceptable limits for the study. If the initial value is 
exclusionary, and the investigator considers the value to be a potential outlier not representative 
of the subject’s true state of health, testing may be repeated once, using the central laboratory, at 
the investigator’s discretion, in accordance with the following: 
• This applies to serum hematology, coagulation and chemistry parameters only.  
o It does not apply to hepatitis B, hepatitis C, HIV, RF, ACCP, or CRP tests, which may 
not be repeated (unless for technical reasons there is no study result) 
o Repeat of inconclusive or positive Quantiferon test must be handled as in exclusion 15 
o 
A positive SARS-CoV-2 test must be handled as in exclusion 18.  
 
• 
The subject must be within the initial 28-day screening period. If the 28-day screening period 
has elapsed, the subject must be fully rescreened in accordance with protocol requirements.  
 
• 
The blood test is repeated in the central laboratory. 
 
• 
The blood test is repeated only once. 
 
Rescreening Procedures: Patients may be rescreened once if, in the Investigator’s judgment, the 
reason for ineligibility is likely to have resolved at the time of rescreening. 
6 
STUDY CONDUCT  
Subjects will undergo a screening period of up to 28 days followed by randomization on Day 1. 
Subjects will receive 4 doses of IP (VIB4920 or placebo) on Day 1, Day 15 (± 1 day), Day 29 
(± 3 days), and Day 57 (± 3 days). Thereafter, subjects will be followed for safety and to assess 
duration of efficacy. The expected full duration of each subject’s participation in this study is up 
to 337 days. 
6.1 
Schedules of Study Assessments  
Table 2 summarizes the screening procedures for the study. In some cases, more than one 
screening visit may be required to complete all procedures.  


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Table 2 
Screening Assessments and Procedures  
Study Period 
Screening 
Visit Number 
V1 
Study Day 
Procedure 
Day -28 to 
Day -1 
Written informed consent and IXRS assignment of SID number 
X 
Medical history 
X 
Assessment of prior and concomitant medications 
X 
Vital signs (temperature, pulse, respiration rate, and blood pressure) 
X 
Assessment of AEs/SAEs a 
X 
Height and weight 
X 
Physical examination excluding pelvic and rectal exam   
X 
  
 
Physician Global Assessment of Disease Activity  
X 
12-lead ECG 
X 
Chest radiograph (posterior-anterior and lateral) if reading not available from x-ray within 
6 months prior to screen 
X 
DAS28-CRP for RA b 
X 
Blood collection for: 
• Safety laboratory testing (serum chemistry, hematology, and coagulation) 
• Serum β-hCG pregnancy test (all females) 
• Follicle-stimulating hormone (potentially postmenopausal females) 
• Hepatitis B, hepatitis C, HIV-1, and HIV-2 testing 
• IGRA testing for TB 
• 
 
• 
 
• CRP, RF, and ACPA testing 
X 
Urine collection for urinalysis (dipstick and, for abnormal dipstick, microscopic) 
X 
Ensure that the subject has a documented negative SARS-CoV-2 viral test within two weeks 
prior to randomization 
X 
 
 
 
Verify eligibility criteria based on data from Screening Visit prior to scheduling Visit 2 
X 
ACPA = anti-citrullinated protein antibodies; AE = adverse event; β-hCG = serum human chorionic gonadotropin; 
CRP = C-reactive protein; DAS28-CRP = Disease Activity Score in 28 Joints Using C-reactive Protein; 
ECG = electrocardiogram; IGRA = interferon-gamma release assay; IXRS = interactive voice/web response system; 
; RA = rheumatoid arthritis; RF = rheumatoid factor; SAE = serious adverse event; 
sCD40L = soluble CD40 ligand; SID = subject identification; 
; TB = 
tuberculosis; 
; V1 = visit 1. 
a 
All AEs will be recorded from the date of informed consent through the end of the study. 
b 
DAS28-CRP for RA will be calculated and the result provided to the Investigator as part of the determination of 
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The schedules of study assessments for the treatment period are presented in Table 3. 
Subjects should be asked to complete all PRO assessments prior to other procedures. 
All laboratory sample collections and assessments that are scheduled for a dosing day must be 
performed prior to dosing, except for post-dose PK sampling. Safety laboratory results from the 
day of dosing will not be available prior to dosing because a central laboratory will perform 
those analyses. Any ECG performed on the day of dosing should be examined by the 
Investigator prior to dosing to assess the safety of dosing.  
Whenever vital signs, 12-lead ECGs, and blood draws are scheduled for the same nominal time, 
blood draws should occur after ECGs and vital signs (temperature, pulse, respiratory rate, and 
blood pressure). If these investigations did not occur in this order, at least 15 minutes must elapse 
between blood draw and either ECG or vital signs. 
Abnormal laboratory or ECG results that, in the Investigator’s opinion, represent a clinically 
significant finding or clinically significant change from baseline should be repeated as soon as 
possible, preferably within 48 hours. If urgent results are needed, testing can be sent to a local 
laboratory, but blood for the same tests should be sent to the central laboratory as well. 
The following results from Visit 2 to the end of study will not be made available to the study site 
personnel, subjects, or contract research organization (CRO) and Sponsor personnel directly 
associated with the conduct of the study, except as specified in Sections 7.2.3 and 7.2.4.2, to 
minimize bias and because results of some 
 
 
 


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Table 3 
Schedule of Study Assessments and Procedures  
Visit number 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 or 
EDV 
Study Day  
Procedure  
1 
Dose 1 
15 ± 1d 
Dose 2 
29 ± 3d 
Dose 3 
57 ± 3d 
Dose 4 
85 g 
± 3d 
113 
± 5d 
141 
± 5d 
169 
± 5d  
197 
± 7d 
225 
± 7d 
253 
± 7d 
281 
± 7d 
309 
± 7d 
Assessment of 
AEs/SAEs/AESIs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient global assessment of 
disease activity  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
Vital Signs 
X e 
X e 
X e 
X e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
Full physical examination  
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
Symptom-driven physical 
examination 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physician global assessment 
of disease activity 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DAS28-CRP for RA, 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy test a  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety labs (chemistry, 
hematology, coagulation) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Total sCD40L (plasma) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Autoantibody panel (RF, RF 
isotypes)   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Table 3 
Schedule of Study Assessments and Procedures  
Visit number 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 or 
EDV 
Study Day  
Procedure  
1 
Dose 1 
15 ± 1d 
Dose 2 
29 ± 3d 
Dose 3 
57 ± 3d 
Dose 4 
85 g 
± 3d 
113 
± 5d 
141 
± 5d 
169 
± 5d  
197 
± 7d 
225 
± 7d 
253 
± 7d 
281 
± 7d 
309 
± 7d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRP   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Flow cytometry sample   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK sample b 
X f 
X f 
X f 
X f 
X 
X 
X 
X 
X 
X 
 
 
 
ADA (plasma)  
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PBMC collection c 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
Verify eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization  
X 
 
 
 
 
 
 
 
 
 
 
 
 
IP administration d, e 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
ACPA = antibodies to citrullinated peptides; ADA = anti-drug antibody; AE = adverse event; AESI = adverse event of special interest; 
 
; cDMARD = conventional disease-modifying anti-rheumatic drug; ECG =electrocardiogram; EDV = early discontinuation visit; 
 
; Ig = immunoglobulin; IP = investigational product; 
 
 MTX = methotrexate; PBMC = peripheral blood mononuclear cells; PK = pharmacokinetics; RA = rheumatoid arthritis; RF 
= rheumatoid factor; SAE = serious adverse event; 
 
; V = visit. 
a 
In females of childbearing potential; result must be negative prior to dosing. 
b 
On study days when IP is not administered, only one plasma sample for PK is required to be collected at a consistent time across the different study days.  
c 
Whole blood will be collected on indicated days for processing to PBMCs. 
d 
IP administration should, wherever possible, be at a consistent time of day for each dose. All procedures and blood sampling, except for postdose PK, must 
be performed before IP administration. 


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e 
Vital signs will be obtained prior to the start of each IP infusion, every 30 (± 5) minutes during the infusion, and at the end of the infusion (+ 5 minutes). 
Vital signs also will be checked every hour (± 10 minutes) during the 4-hour observation period after Dose 1 and at the end (+ 10 minutes) of the one-hour 
observation period after Doses 2, 3 and 4. If vital signs are abnormal, they should be repeated.  
f 
Plasma samples for PK of VIB4920 will be collected predose (within 30 minutes prior to start of infusion), and within 10 minutes of the end of infusion. 
g 
After the Day 85 visit, the dose of background cDMARDs and corticosteroids may be adjusted or a new cDMARD may be added (except that MTX and 
leflunomide may not be used concurrently and rituximab may not be added without discontinuation of VIB4920) if it is clinically indicated to improve 
disease management.


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The study assessments are described by study period in the following sections, with reference to 
the study schedules of assessment for details by study visit. 
6.2 
Screening Period  
All screening procedures listed in Table 2 will be performed within 28 days prior to 
randomization. 
6.2.1 
Informed Consent  
Subjects officially enter the screening period following provision of informed consent.  
All candidates for enrollment will sign an informed consent form (ICF) prior to any 
protocol -related procedures, including screening activities. Informed consent must be obtained 
by the Principal Investigator (PI) or a designee, such as an Investigator, with Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC) approved qualifications. See Section 10.3 for 
additional details. 
After signing the ICF, each subject will be assigned a subject identification (SID) number that 
will be used on all subject documentation.  
Numbers will be assigned in ascending sequential order. This number will also correspond to the 
subject number entered on test materials. Rescreened patients will receive a new SID number. 
See Section 5.2 for limitations on rescreening. 
6.2.2 
Demographics and Baseline Characteristics  
Demographic information to be collected includes date of birth, sex, race, and ethnicity. Medical 
history information to be collected includes all ongoing conditions and relevant/significant 
medical history (including all major hospitalizations and surgeries), as determined by the 
Investigator. Prior and concomitant medications will be recorded. A complete physical 
examination (with the exception of rectal and pelvic examinations) will be conducted, including 
vital signs, height, and weight. 
As part of the eligibility evaluation, the DAS28-CRP assessments will be performed at screening 
along with testing for RF and ACPA.  
Subjects will also complete the PGA on an electronic tablet at a screening visit. 
6.2.3 
Safety Assessments at Screening  
Safety-related screening assessments will include AEs, safety laboratory tests (serum chemistry, 
hematology, and urinalysis), coagulation parameters, chest X-ray (unless recent reading available 
[prior 6 months]), ECG, and serum human chorionic gonadotropin (β-hCG) pregnancy test for 
females. For details on safety assessments, see Section 6.4.2 and 8. 
Safety tests only scheduled for screening include: 
• Hepatitis B testing: HbsAg, anti-HBc 
• Hepatitis C antibody 
• HIV testing: HIV-1 antibody, HIV-2 antibody 


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• TB testing (eg, QuantiFERON®-TB Gold Test or other interferon-gamma release assay 
test) as per local standard of care guidelines 
6.3 
Randomization  
 
. The results of laboratory values from Visit 2 will not be available prior 
to randomization, which will be based on values from Visit 1. 
Subjects who continue to meet all eligibility criteria will be randomized. A subject is considered 
randomized into the study when the Investigator notifies the IXRS that the subject meets 
eligibility criteria and the IXRS provides the assignment of treatment group and allocates 
treatment, including IP kit number. A randomized subject is one who has been deemed eligible 
and has been assigned to a treatment group.  
6.4 
Treatment Period  
All assessments that will be conducted in the treatment period are summarized by study visit in 
Table 3. Efficacy assessments are described in Section 6.4.1 and safety assessments are 
described in Section 6.4.2. 
6.4.1 
Efficacy Assessments  
Over the course of the study, Investigator assessments for a given subject should be completed 
by the same Investigator, designated physician, or qualified site personnel whenever possible. 
6.4.1.1 
Composite Disease Scores  
DAS28-CRP: The DAS28-CRP is a composite score that includes the assessment of 
28 specified joints for tenderness and swelling 
 the PGA, and CRP levels (mg/L) 
(Table 4). Calculation of the DAS28-CRP scores will use the equation in Section 9.5.1. The 
established definition of remission by DAS28-CRP score is DAS28-CRP < 2.6 (Anderson et al, 
2012). Low disease activity is defined as DAS28-CRP ≤ 3.2, and an improvement of 
DAS28-CRP score > 0.6 defines a responder (Wells et al, 2009). 
 
 
 
 
 
 
Table 4 summarizes the assessments that comprise each composite score. Details on the 28-joint 
count, MDGA, and PGA are given in Section 6.4.1.2 and details on CRP testing are provided in 
Section 6.4.3.2. 


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Table 4 
Summary of Composite Disease Scores and Assessments  
Assessment 
Composite Disease Scores 
DAS28-CRP 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
CRP (mg/dL) 
X 
 
X 
 CRP = C-reactive protein; DAS28-CRP = Disease Activity Score in 
28 Joints Using C-reactive Protein; 
 
 
 
6.4.1.2 
Assessments for Composite Disease Scores  
 
 
 
 in Table 3. 
 
 
 
 
 
 
 
 
 
 
CRP: See Section 6.4.3.2. 
6.4.1.3 
Time to Start of Rescue Medication  
Investigators will record on the electronic case report form (eCRF) when a subject starts rescue 
medication (see Section 7.4.2). 
6.4.1.4 
  
  
 
 
 
.  
 
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6.4.2 
Safety Assessments  
Safety assessments will be conducted during the active treatment period according to the 
assessments shown in Table 3 and will consist of: 
• Monitoring and recording all AEs (including AESIs) and SAEs (see Section 8.1 through 
8.4 for details) 
• Safety laboratory tests: hematology, serum chemistry, coagulation parameters, and 
urinalysis (see Section 8.5 for details) 
• Concomitant medications (see Section 7.4 for details) 
• Vital signs, physical examination (full or symptom-driven depending on the visit), and 
body weight (see Section 8.6 for details) 
• ECG (see Section 8.7 for details) 
• Urine pregnancy test (for females of childbearing potential) (see Section 8.8 for details) 
For definitions of safety terminology, see Section 8.1. 


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6.4.3 
  
 
 
6.4.3.1 
Autoantibody Panel  
Serum will be collected to assess and quantify RF, RF isotypes (IgA, IgG, and IgM). 
 
  
 
 
  
6.4.3.3 
Flow Cytometry for B-Cell and T-Cell Subsets  
Whole blood samples will be collected for the assessment of changes in the number, activation 
status, and frequency of B- and T-cell subsets. 
6.4.3.4 
Leukocyte Populations and Intracellular Cytokines  
Whole blood samples will be collected for subsequent separation of peripheral blood 
mononuclear cells to assess change in leukocyte populations and intracellular cytokines after 
VIB4920 administration. 
6.4.3.5 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  


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6.4.4 
Immunogenicity Assessments  
Plasma samples for immunogenicity (ADA to VIB4920) will be obtained prior to IP 
administration according to the visits specified in Table 3 and will be assessed using a validated 
immunoassay. 
6.4.5 
Pharmacokinetic Assessments  
Plasma samples to determine the concentration of VIB4920 will be taken according to the visits 
specified in Table 3 and measured using a validated immunoassay. 
6.4.6 
  
 
. 
6.5 
Discontinuation or Withdrawal  
6.5.1 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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The reason(s) for discontinuing IP must be recorded on the appropriate page of the eCRF. 
6.5.2 
Withdrawal from Study  
Subjects who discontinue IP and have not received rescue therapy should remain in the study and 
complete all study visits and assessments with the exception of those directly related to dosing, 
unless they have withdrawn consent for study participation or withdrawn consent for specific 
assessments (if subjects will not agree to return for visits, safety data can be collected by 
telephone call if subjects agree). Subjects who discontinue IP following the initiation of rescue 
therapy will complete the study according to procedures in Section 7.4.2. 
Subjects who choose to discontinue IP or withdraw from the study will be asked for the reason 
for discontinuation or withdrawal, such as an AE, lack of efficacy, or other reason, and the 
reason will be recorded in the eCRF.  
Subjects who wish to withdraw from the study will be invited to return, if willing, for a single 
additional early discontinuation visit (EDV) unless all study procedures to be completed at the 
EDV visit had been completed within the past 30 days.  
6.5.3 
Replacement of Subjects  
Subjects will not be replaced after randomization. 
6.5.4 
Subjects Lost to Follow-up  
For subjects who are lost to follow-up (ie, those subjects whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), the Investigator should 
show due diligence by documenting in the source documents the steps taken to contact the 
subject, eg, dates of telephone calls, registered letters, etc. 
Efforts to ensure complete subject follow-up include proactive site contact of subjects who have 
missed visits (at least 3 documented attempts to reach by telephone and at least 3 documented 
attempts to reach by letter) or through emergency/other contact if subjects have provided such 
contacts. Email can be used for contact and scheduling of visits as long as subjects have given 
permission for email contact.  
6.6 
Study Suspension or Termination  
The Sponsor reserves the right to temporarily suspend or terminate this study at any time. The 
reasons for temporarily suspending or terminating the study may include, but are not limited to, 
the following:  
• The incidence or severity of AEs indicates a potential health hazard to subjects.  
• Subject enrollment is unsatisfactory. 
• Noncompliance that might significantly jeopardize the validity or integrity of the study.  
• Sponsor decision to terminate development. 
If Viela Bio determines that temporary suspension or termination of the study is required, Viela 
Bio will communicate the reasons for taking such action to all participating investigators (or 
head of the medical institution, where applicable). When feasible, Viela Bio will provide 


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advance notice to all participating investigators (or head of the medical institution, where 
applicable) of the impending action. 
If the study is suspended or terminated for safety reasons, Viela Bio will promptly inform all 
investigators, heads of the medical institutions (where applicable), and/or institutions conducting 
the study. Viela Bio or designee will also promptly inform the relevant regulatory authorities of 
the suspension/termination along with the reasons for such action. Where required by applicable 
regulations, the Investigator or head of the medical institution must inform the IRB/IEC 
promptly and provide the reason(s) for the suspension/termination. If the study is suspended for 
safety reasons and it is deemed appropriate by the Sponsor to resume the study, approval from 
the relevant regulatory authorities (and IRBs/IECs, when applicable) will be obtained prior to 
resuming the study. 
6.7 
End of Study  
The study will be completed once the last active subject has completed all assessments listed for 
Visit 14 (Day 309 ± 7 days). If the last active subject has received rescue therapy, the study will 
end when that subject completes participation according to the procedures described in 
Section 7.4.2. 
7 
STUDY INTERVENTIONS  
7.1 
Description of Products  
Table 5 provides a description of IP to be used in the study. Details are presented in the 
following sections. 
Table 5 
Description of Investigational Products  
IPs 
Concentration and Formulation as Supplied 
Manufacturer 
 
) 
 
 
 
 
 
 
Placebo 
0.9% (w/v) saline 
Provided by site 
IP = investigational product; IV = intravenous; w/v = weight/volume. 
7.1.1 
VIB4920  
7.1.1.1 
Inspection, Storage, and Handling  
Each vial selected for dose preparation should be inspected. VIB4920 is supplied as a clear to 
opalescent, colorless to yellow liquid; free from, or practically free from, visible particles. 
VIB4920 is a sterile liquid Drug Product (500 mg VIB4920 per vial, nominal) intended for IV 
infusion following dilution in normal saline. 
If there are any defects noted with VIB4920, the Investigator and site monitor should be notified 
immediately. 
The IP will be appropriately labeled in accordance with national laws and regulations. VIB4920 
is provided with 3 vials per kit. 


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VIB4920 should not be shaken and requires no special biohazard handling. It must be stored at 
2ºC to 8ºC (36ºF to 46ºF) in a refrigerator with adequate temperature monitoring. VIB4920 must 
not be frozen. It should be stored in the original outer package in a location with limited access. 
7.1.1.2 
Dose Preparation  
VIB4920 is supplied as a sterile liquid in a 6R glass vial at a nominal fill volume of 5.0 mL, 
stoppered with 20 mm Teflon-coated elastomeric stopper, and sealed with flip-off cap overseal. 
No incompatibilities between VIB4920 and IV infusion bags made of polyolefin or polyvinyl 
chloride have been observed. 
VIB4920 does not contain preservatives and any unused portions must be discarded. Preparation 
of IP and IV bags is to be performed aseptically.  
The total allowable in-use storage time from the time of the first vial puncture of VIB4920 to 
start of IV bag administration should not exceed 4 hours at room temperature or 24 hours at 2°C 
to 8°C. However, IP (VIB4920 or placebo) must be administered the same day the IP is assigned. 
If there is a delay in the administration of IP such that it will not be administered within the 
specified timeframe, the study monitor must be notified immediately. 
DO NOT FREEZE. If storage time exceeds these limits, a new dose must be prepared from new 
vials. 
The dose preparation steps for 1500 mg are as follows: 
One kit (3 vials) of VIB4920, one 250 mL IV bag containing 0.9% (weight/volume [w/v]) 
saline, and one IV infusion pump are required for administration of each 1500 mg dose of 
VIB4920. 
• 15.0 mL of 0.9% (w/v) saline should be removed from a prefilled 250 mL IV bag. 
• 15.0 mL of VIB4920 will be obtained from three (3) 500 mg vials by withdrawing 
5.0 mL from each vial. Use a new needle for each withdrawal. 
• IP should be added to the saline bag. 
• Gently mix the contents of the IV bag. The saline bag should then be inspected to ensure 
the solution is clear. 
• Prepared bags will be covered with an opaque cover to protect blinding. 
The dose preparation steps for 3000 mg are as follows: 
Two kits (6 vials) of VIB4920, one 250 mL IV bag containing 0.9% (w/v) saline, and one IV 
infusion pump are required for administration of each 3000 mg dose of VIB4920. 
• 30.0 mL of 0.9% (w/v) saline should be removed from a prefilled 250 mL IV bag. 
• 30.0 mL of VIB4920 will be obtained from six (6) 500 mg vials by withdrawing 5.0 mL 
from each vial. Use a new needle for each withdrawal. 
• IP should be added to the saline bag. 
• Gently mix the contents of the IV bag. The saline bag should then be inspected to ensure 
the solution is clear. 
• Prepared bags will be covered with an opaque cover to protect blinding. 
IP must be infused through a low-protein binding 0.2 - 0.22 µm in-line filter. 


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During preparation of the IP for infusion, the capacity of the tubing should be calculated in order 
to adjust the volume of IP solution needed to prime the IV tubing. This step is also necessary 
because the same volume of saline will be needed to flush the IV tubing at the completion of the 
infusion in order to deliver the complete volume of IP solution. Because the IV tubing contains 
IP solution, the saline flush must be infused using the same infusion rate as that used for the IP 
solution in the infusion bag. 
For example, if the IV tubing capacity is 15 mL, the IV tubing should be primed with 15 mL of 
IP solution from the infusion bag before initiating the infusion. Once the infusion bag is empty, 
the IV tubing should be flushed with at least 15 mL of 0.9% (w/v) saline via the infusion pump at 
the same rate as dosing. The start time of the infusion will be the time when infusion of the IP 
solution from the infusion bag (with IV tubing primed with IP solution) is started. The stop time 
of the infusion will be the time when the IV tubing has been flushed with a volume of 0.9% 
(w/v) normal saline equivalent to IV tubing capacity (eg, 15 mL for the example above) to 
administer the residual IP solution. 
7.1.1.3 
Dosing and Administration  
IP administration should, wherever possible, be at a consistent time of day for each dose. Vital 
signs will be obtained prior to the start of each IP infusion, every 30 (± 5) minutes during the 
infusion, and at the end of the infusion (+ 5 minutes). Vital signs also will be checked every hour 
(± 10 minutes) during the 4-hour observation period after Dose 1 and at the end (+ 10 minutes) 
of the one-hour observation period after Doses 2, 3, and 4. If vital signs are abnormal, they 
should be rechecked.  
IP will be infused using an IV infusion pump. An experienced and qualified staff member will 
place the IV access. Infusion times will be as per Table 6. For Doses 1 and 4, IP will be either 
VIB4920 1500 mg, VIB4920 3000 mg, or placebo (Table 7). For Doses 2 and 3, IP will be either 
VIB4920 1500 mg or placebo.  
Table 6 
Infusion Times  
Dose 1, Day 1 
Infusion Time 
(VIB4920 mg/min)a, b 
Dose 2, Day 15 
Infusion Time 
(VIB4920 mg/min) a, c, d 
Dose 3, Day 29 
Infusion Time 
(VIB4920 mg/min)a, d 
Dose 4, Day 57 
Infusion Time 
(VIB4920 mg/min)a, d,  
120 min  
(~13-25 mg/min) 
60 min  
(25 mg/min) 
60 min  
(25 mg/min) 
90 min  
(~17-33 mg/min) 
SDMC = Safety Data Monitoring Committee. 
a 
Or placebo matched to that dose of VIB4920. 
b 
If, after dosing of at least 4 subjects with Dose 1, > 25% of the subjects dosed have a Grade 2 or higher infusion 
reaction, all subsequent doses that could include 3000 mg (ie, Dose 4) will be administered over 
180 minutes(~8-17 mg/min) and Doses 2 and 3 will be administered over 120 minutes (~13 mg/min). 
c 
If > 25% of the subjects dosed have a Grade 2 or higher infusion reaction, Dose 3 will be administered over 
120 minutes and Dose 4 will be administered over 180 minutes. 
d 
For other scenarios, dose reactions will be reviewed by the SDMC or SDMC Chair to recommend dose 
duration. 
 


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Table 7 
Summary of Treatments by Cohort and Dose Day  
Cohort 
Dose 1, Day 1 
Dose 2, Day 15 
Dose 3, Day 29 
Dose 4, Day 57  
Cohort 1 
VIB4920 1500 mg 
VIB4920 1500 mg 
VIB4920 1500 mg 
VIB4920 1500 mg 
Cohort 2 
VIB4920 1500 mg 
Placebo 
Placebo 
VIB4920 1500 mg 
Cohort 3 
VIB4920 3000 mg 
Placebo 
Placebo 
VIB4920 3000 mg 
Cohort 4 
VIB4920 3000 mg 
Placebo 
Placebo 
Placebo 
Cohort 5 
Placebo 
Placebo 
Placebo 
Placebo 
Subjects who have had an infusion-related reaction of Grade 1 or Grade 2 may be premedicated 
prior to subsequent dosing with antihistamines and/or acetaminophen in accordance with doses 
in the package instructions. For details on grading of infusion-related reactions, refer to 
Section 8.4. 
The study SDMC will also monitor infusion-related reactions to suggest appropriate rate of 
infusion and use of pre-medications if infusion-related reactions are observed. 
A physician must be present at the site or immediately available to respond to emergencies 
during administration of IP. Appropriate drugs and medical equipment to treat acute hypotensive, 
bronchoconstrictive, or anaphylactic reactions must be immediately available and study 
personnel must be trained to recognize and treat these reactions. Additionally, appropriate drugs 
and medical equipment to treat infusion-related reactions must be immediately available, and 
study personnel must be trained to recognize and treat infusion-related reactions. Fully functional 
resuscitation facilities should be available. 
To monitor for infusion and/or hypersensitivity reactions, subjects will be closely monitored in a 
clinical study facility with personnel, drugs, and medical equipment nearby for at least 4 hours 
after the end of the infusion for the first dose. Subsequently, subjects must remain in the clinical 
study facility for at least 1 hour after each dose. 
Further information on IP preparation and administration is provided in the IP Manual. 
7.1.1.4 
Investigational Product Accountability  
Study site staff will maintain a record of the IP received, dispensed, administered, and destroyed. 
All records will be maintained with controlled access. An unblinded study monitor will perform 
IP accountability and compliance monitoring during the study. The Investigator will administer 
the IP only to subjects included in this study and according to the procedures established in this 
study protocol. Each administration of study product will be documented and transferred to the 
eCRF. 
7.1.1.5 
VIB4920 Handling and Disposal  
The Investigator or designee must return any unused vials of VIB4920 to Viela Bio or designee 
regardless of whether the study was completed or terminated prematurely. At the time of return, 
the Investigator must verify that unused or partially used IPs have been returned and that no IPs 
remain at the site. As an alternative to returning unused IP at the end of the study, the 
Investigator may destroy unused IP on site with agreement from Viela Bio. 


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7.1.2 
Placebo  
7.1.2.1 
Formulation, Storage, Preparation, and Handling  
Placebo will be 0.9% (w/v) saline provided by the site as 250 mL prefilled IV bags.  
7.1.2.2 
Dosing and Administration  
For each dose of placebo, one 250 mL IV bag containing 0.9% (w/v) saline and one IV infusion 
pump is required for administration. 
7.2 
Treatment Assignment and Bias Minimization  
7.2.1 
Treatment Allocation  
Subjects will be randomized 1:1:1:1:1 by IXRS to Cohorts 1 to 5 using a parallel-cohort design. 
IP (VIB4920 or placebo) must be administered the same day the IP is assigned. If there is a delay 
in the administration of IP such that it will not be administered within the specified timeframe, 
the study monitor must be notified immediately. 
7.2.2 
Randomization Strategy and Procedure  
An IXRS will be used for randomization to a treatment group and assignment of IP kit numbers. 
A subject is considered randomized into the study when the Investigator notifies the IXRS that 
the subject meets eligibility criteria and the IXRS provides the assignment of treatment group. 
Additional details are provided in the IXRS Manual. 
7.2.3 
Extent and Maintenance of Blinding  
This is a double-blind study in which VIB4920 and the saline placebo are not identical in 
appearance. For maintaining the blinding of the subjects, Investigators, site staff, Sponsor, CRO 
and staff, a local unblinded pharmacy staff member will be nominated by each site and will have 
the responsibility of allocating, dispensing, and preparing the IP, and covering the IV bags with 
an opaque bag to maintain the blind.  
In addition, a separate unblinded monitor will be used for the oversight of IP management. If 
treatment allocation for a subject becomes known to the Investigator or other study staff involved 
in the management of study subjects, the Sponsor must be notified immediately. 
7.2.4 
Unblinding Procedures  
7.2.4.1 
Unblinding in the Event of a Medical Emergency  
In the event of a medical emergency, the Investigator may unblind an individual subject’s IP 
allocation. Instructions for unblinding an individual subject’s IP allocation are contained in the 
IXRS manual. In general, unblinding should only occur if management of the medical 
emergency would be different based on the subject having received IP. In the majority of cases, 
the management of a medical emergency would be the same whether or not IP was received by 
the subject. If this was the case, the IP allocation should not be unblinded. 


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7.2.4.2 
Unblinding for the Primary (Interim) Analysis  
The primary efficacy analysis will be conducted after all subjects have completed the Day 113 
visit (Visit 7) or discontinued early from the study. As the primary analysis will be an interim 
analysis, a small prespecified number of Sponsor staff who are not directly involved in the 
conduct of the study will be unblinded for decision-making purposes. Study site personnel, 
subjects, and CRO and Sponsor personnel directly associated with the conduct of the study will 
remain blinded to the treatment assignment for individual subjects and the results of the primary 
(interim) analysis until the completion of the study. 
7.3 
Assessment and Verification of Compliance  
Site staff will administer all IPs IV at the study center. The dose and date of administration of IP 
must be recorded in the subject eCRF. Treatment compliance will be assessed based on this 
information. 
7.4 
Concomitant Medications and Treatments  
Although subjects are asked to remain on their stable background medications until the Day 85 
visit, subjects should receive all medications, including treatments for RA, that are considered by 
their physician to be necessary for their health. 
The Sponsor recommends that Investigators ensure that all patients are up to date with 
required vaccinations prior to entry into the study. 
7.4.1 
Prohibited Medications  
If a subject receives any of the listed prohibited medications after the screening visit and prior to 
Day 85, the Investigator must notify the Sponsor/designee Medical Monitor immediately. These 
changes in medications must be clearly recorded, with the reason for the change, in the eCRF. 
The prohibited medications are: 
• Rescue medication prior to Day 85 (defined in Section 7.4.2) 
• Investigational agents 
• Live vaccines or live therapeutic infectious agents 
• Plasmapheresis or plasma exchange 
7.4.2 
Rescue Therapy  
Rescue therapy is any new or intensified immunosuppressive, conventional, or bDMARD 
treatment for RA, including: 
• Initiation of or increase in dose of any cDMARD 
• Initiation of a bDMARD therapy or JAK inhibitor therapy 
• Increase in baseline corticosteroid dose 
• Intraarticular steroid injection > 40 mg methylprednisolone (or its equivalent) OR more 
than one intraarticular steroid injection of any dose. One intraarticular steroid injection 
≤ 40 mg methylprednisolone in one joint is permitted and not considered rescue therapy. 
If a subject receives rescue therapy prior to the final dose of IP, IP will be discontinued 
(Section 6.5.1).  


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Subjects administered rescue therapy do not need to be followed until Day 309 but can complete 
the study at or after Day 113. Subjects must also complete a 3-month safety follow-up period 
after the final dose of IP and must return for at least one visit after initiating rescue therapy to 
complete remaining assessments (Table 8). 
Table 8 
Alternate Study Completion Schedules Following Rescue Therapy  
Last Dose Prior to Rescue Therapy 
Last Study Visit 
≤ Dose 3 (Day 29 ± 3d) 
Day 113 OR  
+ 1 visit post-initiation of rescue therapy, whichever is later 
≥ Dose 4 (Day 57 ± 3d) 
Day 141 OR  
+ 1 visit post-initiation of rescue therapy, whichever is later  
Note: All actions include the required Day 113 visit, 3 months of follow-up, and one visit post-initiation of rescue 
therapy. 
8 
SAFETY ASSESSMENTS  
An independent SDMC will perform evaluations of safety data at specified regular intervals 
throughout the study and make recommendations to the Sponsor regarding further conduct of the 
study. See Section 11.1 for details on SDMC activities.  
8.1 
Definitions  
• Adverse event – An AE is any untoward medical occurrence associated with the use of 
an intervention in humans whether or not it is considered intervention-related. 
• Serious adverse event – A SAE is considered “serious” if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes:  
− Death 
− A life-threatening AE. (An event is considered “life-threatening” if, in the view of 
either the Investigator or Sponsor, its occurrence places the patient or subject at 
immediate risk of death. It does not include an AE or suspected adverse reaction 
(SAR) that, had it occurred in a more severe form, might have caused death.) 
− Inpatient hospitalization or prolongation of existing hospitalization 
− A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
− A congenital anomaly/birth defect 
− Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
• Causality or relatedness: The Investigator is required to provide an assessment of the 
relationship of AEs and SAEs to the IP. An event will be considered “not related” to use 
of IP if any of the following tests are met: 


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− An unreasonable temporal relationship between administration of the IP and the onset 
of the event (eg, the event occurred either before, or too long after, administration of 
the IP for it to be considered IP-related) 
− A causal relationship between the IP and the event is biologically implausible (eg, 
death as a passenger in an automobile accident) 
− A clearly more likely alternative explanation for the event is present (eg, typical 
adverse reaction to a concomitant drug and/or typical disease-related event) 
Individual AE/SAE reports will be considered “related” to use of the IP if the “not related” 
criteria are not met.  
“Related” implies that the event is considered to be “associated with the use of the drug” 
meaning that there is “a reasonable possibility” that the event may have been caused by the IP 
(ie, there are facts, evidence, or arguments to suggest possible causation). 
• Adverse reaction – An adverse reaction is any AE caused by a drug. 
• Suspected adverse reaction – A SAR is any AE for which there is a reasonable 
possibility that the drug caused the AE. For the purposes of safety reporting to regulatory 
agencies, “reasonable possibility” means there is evidence to suggest a causal relationship 
between the drug and the AE. SAR implies a lesser degree of certainty about causality 
than an adverse reaction. 
• Unexpected – An event is considered unexpected if it is not listed in the IB, is not listed 
at the specificity or severity that has been observed, or, if an IB is not required or 
available, is not consistent with the risk information described in the General 
Investigational Plan or elsewhere. Unexpected also refers to events that are mentioned in 
the IB as occurring with a class of drugs or as anticipated from the pharmacological 
properties of the drug but are not specifically mentioned as occurring with the particular 
IP. 
• Severity or intensity: Severity will be assessed according to the following scale: 
− Grade 1: An event of mild intensity that is usually transient and may require only 
minimal treatment or therapeutic intervention. The event does not generally interfere 
with usual activities of daily living. 
− Grade 2: An event of moderate intensity that is usually alleviated with additional, 
specific therapeutic intervention. The event interferes with usual activities of daily 
living, causing discomfort but poses no significant or permanent risk of harm to the 
subject. 
− Grade 3: A severe event that requires intensive therapeutic intervention. The event 
interrupts usual activities of daily living, or significantly affects the clinical status of 
the subject. 
− Grade 4: An event, and/or its immediate sequelae, that is associated with an imminent 
risk of death or with physical or mental disabilities that affect or limit the ability of 
the subject to perform activities of daily living (eating, ambulation, toileting, etc). 
− Grade 5: Death (loss of life) as a result of an event. 


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8.2 
Documenting Adverse Events  
AEs spontaneously reported by the subject and/or in response to an open question from the study 
personnel or revealed by observation will be recorded during the study at the investigational site. 
For each AE, the Investigator will evaluate and report the onset (date and time), resolution (date 
and time), severity, causality, action taken, serious outcome (if applicable), and whether or not it 
caused the subject to discontinue the study. The AE term should be reported in standard medical 
terminology when possible. 
8.3 
Reporting Adverse Events  
All AEs (related and unrelated) will be recorded from written ICF signature up to the end of the 
study, whether or not they are related to the study. Any SAEs considered related to the IP and 
discovered by the Investigator at any time after the study should be reported.   
All SAEs must be reported within 24 hours by submitting a SAE Report Form by email to: 
 
 
Alternatively, the SAE Report Form can be submitted by fax to: 
 
 
Additional follow-up information, if required or available, should all be reported within one 
business day of receipt, should be completed on a follow-up SAE form, placed with the original 
SAE information and kept with the appropriate section of the eCRF and/or study file. 
The designated Sponsor representative (ICON) will work with the Investigator to ensure that all 
the necessary information is provided within one calendar day of initial receipt for fatal and 
life-threatening events and within 5 calendar days of initial receipt for all other SAEs. 
Viela Bio or designee is responsible for notifying the relevant regulatory authorities of certain 
events. It is the PI’s responsibility to notify the IRB or IEC of all SAEs that occur at his or her 
site. Investigators will also be notified of all unexpected, serious, drug-related events (7/15 Day 
Safety Reports) that occur during the clinical trial. Each site is responsible for notifying its IRB 
or IEC of these additional SAEs. 
8.4 
Adverse Events of Special Interest  
An AESI is an AE of scientific and medical interest specific to understanding of the IP and may 
require close monitoring and collection of additional information by the Investigator. An AESI 
may be serious or nonserious. The rapid reporting of AESIs allows ongoing surveillance of these 
events in order to characterize and understand them in association with the use of this IP. 
The following AESIs will be particularly monitored in this study and should be reported to 
ICON Patient Safety within 24 hours of awareness as in Section 8.3.   
• Thrombotic and embolic events 
• Anaphylaxis and clinically significant (Grade 3 or higher) hypersensitivity reactions (see 
Appendix 1 for guidance on diagnosis of anaphylaxis reactions) 
• Severe infusion-related reactions (CTCAE Grade 3 or higher; Table 9) 


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• Immune complex disease 
• Severe (Grade 3 or higher) and/or opportunistic infections 
• Hepatic function abnormality meeting the definition of Hy’s Law (see Appendix 2) 
• Malignant neoplasm 
Table 9 
CTCAE Grading of Infusion-related Reactions  
Grade 1 
Mild transient reaction; infusion interruption not indicated; intervention not indicated 
Grade 2 
Therapy or infusion interruption indicated but responds promptly to symptomatic treatment (eg, 
antihistamines, NSAIDs, narcotics, IV fluids); prophylactic medications indicated for ≤ 24 hrs 
Grade 3 
Prolonged (eg, not rapidly responsive to symptomatic medication and/or brief interruption of 
infusion); recurrence of symptoms following initial improvement; hospitalization indicated for 
clinical sequelae 
Grade 4 
Life-threatening consequences; urgent intervention indicated 
Grade 5 
Death 
CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous; NSAID = nonsteroidal 
anti-inflammatory drug. 
Note: These CTCAE grades are specific to infusion-related reactions. 
Source: Common Terminology Criteria for Adverse Events v5. 
8.5 
Clinical Laboratory Findings  
Blood, urine and respiratory (swab or saliva) samples will be collected for laboratory safety tests 
as specified in the Schedule of Assessments shown in Table 2 (screening) and Table 3 (treatment 
period). Laboratory testing is described below. For further details regarding laboratory 
assessments, see the Study Laboratory Manual. 
8.5.1 
Hematology  
The hematology panel will include a complete blood count, with white blood cell count (WBC) 
and differential (basophils, eosinophils, lymphocytes, monocytes, and neutrophils), hemoglobin, 
hematocrit, and platelet count. 
8.5.2 
Serum Chemistry  
Serum chemistry assessments will include: 
• Albumin 
• Alkaline phosphatase (ALP) 
• ALT 
• AST 
• Bicarbonate 
• Blood urea nitrogen 
• CRP  
• Calcium 
• Chloride 
• Cholesterol 
• Creatinine 
• HbA1C 
• Immunoglobulins: Total, IgA, IgG, and IgM 
• Magnesium 
• Phosphorus 
• Potassium 
• Sodium 
• TBL (if > 1.5 ULN, indirect and direct 
bilirubin will be measured) 
• Total protein 
• Triglycerides (fasting not required unless 
abnormal at baseline, in which case an 8-hour 
fast is required) 


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• Gamma-glutamyl transferase 
• Glucose (random) 
 
• Uric acid 
Tests for AST, ALT, ALP, and TBL must be conducted concurrently and assessed concurrently. 
8.5.3 
Coagulation Parameters  
Coagulation parameters will include prothrombin time and PTT. 
8.5.4 
Urinalysis  
Urinalysis will evaluate color, appearance, and specific gravity. Dipstick analysis will include 
pH, protein, glucose, blood, ketones, and bilirubin. Samples with abnormal dipstick will have 
microscopy performed. Microscopy will include WBC/HPF (high power field) and red blood cell 
count/HPF. 
8.5.5 
Testing for SARS-CoV-2  
The investigator must ensure that the subject has a documented negative SARS-CoV-2 viral test 
within two weeks prior to randomization. Testing for antibodies to SARS-CoV-2 will not meet 
the testing requirement.  
 
8.6 
Vital Signs, Body Weight, and Physical Examinations  
Vital signs, including systolic and diastolic blood pressure (mmHg), pulse rate (beats/min), 
respiratory rate (breaths/min), body temperature (ºC), and body weight (kg), will be measured 
using clinically acceptable methods and devices as defined in the schedule of assessments in 
Table 2 (screening), Table 3 (treatment period), and the IP Administration Manual.  
Depending on the visit, physical examinations will be either a full examination (with the 
exception of rectal and pelvic examinations) or a symptom-driven examination.  
8.7 
Electrocardiogram  
A 12-lead ECG will be performed according to the schedule of assessments in Table 2 
(screening) and Table 3 (treatment period). All ECG recordings will be made with the subject in 
a supine position, having rested in this position for at least 5 minutes before the start of the ECG. 
Each ECG will include ventricular heart rate and intervals (PR, QRS, QT, QTc). The Investigator 
will be responsible for providing an interpretation of the ECG. Clinically significant 
abnormalities will be recorded as AEs.  
8.8 
Pregnancy  
Serum β-hCG pregnancy test(s) will be completed for all females during the screening period 
and urine pregnancy tests will be completed in females of childbearing potential at all subsequent 
study visits (Table 3). At Visits 2 through 5 (dosing visits), pregnancy testing must be completed 
prior to administration of IP. Urine pregnancy tests will be performed at the site.  


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8.9 
Overdose or Misuse  
Any instance of overdose (suspected or confirmed and irrespective of whether or not it involved 
VIB4920) must be communicated to Viela Bio or a specified designee within 24 hours and be 
fully documented as a SAE. Details of any signs or symptoms and their management should be 
recorded, including details of any antidote(s) administered. 
9 
STATISTICAL CONSIDERATIONS  
9.1 
General Considerations  
Tabular summaries will be presented by treatment group. Categorical data will be summarized 
by the number and percentage of subjects in each category. Continuous variables will be 
summarized by descriptive statistics. Additional details of statistical analyses will be described in 
the statistical analysis plan (SAP). 
9.2 
Statistical Hypotheses  
Four primary hypotheses will be tested (each of the 4 VIB4920 cohorts vs placebo). The null and 
alternative hypothesis for each VIB4920 cohort compared with placebo are listed below. 
Null hypothesis: The mean change from baseline to Day 113 in DAS28-CRP score for the 
VIB4920 group is equal to that for the placebo group. 
Alternative hypothesis: The mean change from baseline to Day 113 in DAS28-CRP score for 
the VIB4920 group is not equal to that for the placebo group. 
9.3 
Determination of Sample Size  
The planned sample size of 75 subjects (15 subjects per treatment group) will provide 
approximately 80% power to detect a difference of 1.2 in mean change from baseline to Day 113 
in DAS28-CRP (assumed standard deviation of 1.25) between the VIB4920 and placebo 
treatment groups at a 2-sided alpha level of 0.10 using a 2-sample t-test. 
9.4 
Analysis Sets  
Full analysis set: The full analysis set includes all subjects randomized and receiving any dose 
of IP in the study. Subjects will be analyzed according to the treatment randomized. The efficacy 
analysis will be based on the full analysis set. 
Safety analysis set: The safety analysis set includes all subjects who received any dose of IP. 
Subjects will be analyzed according to the treatment that they actually received. The safety and 
ADA analysis will be based on the safety analysis set. 
PK analysis set: The PK analysis set includes all subjects who receive IP and have at least one 
quantifiable plasma PK observation post-first dose. Subjects will be analyzed according to the 
treatment that they actually received. The PK analysis will be based on the PK analysis set. 


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9.5 
Methods for Statistical Analyses  
9.5.1 
Analysis of the Primary Efficacy Endpoint  
Primary efficacy analyses: 
The primary efficacy endpoint of change from baseline DAS28-CRP to Day 113 will be 
analyzed using a mixed-effect model for repeated measures (MMRM) approach. 
DAS28-CRP values will be calculated as follows (Wells et al, 2009):  
DAS28-CRP = 0.56 × √ (TJC28) + 0.28 × √ (SJC28) + 0.014 × PGA + 0.36 × ln(CRP + 1) + 
0.96, 
where 
, and PGA is the patient 
global assessment on a scale 0-100 mm. The range of the DAS28-CRP score is 0.96-9.31. 
Handling plan for rescue medication use:  
For subjects who take rescue medications, the data collected after administration of the rescue 
medications will not be included in the primary analysis. This approach attempts to reduce the 
confounding effects of rescue medications. 
Handling plan for treatment discontinuation: 
Subjects who discontinue IP without receiving rescue medications will be asked to come to 
scheduled evaluations until the end of study. The data collected after discontinuation of IP will 
be included in the analysis. 
Handling plan for missing data: 
Missing data will be handled using the MMRM approach. 
Supplementary analysis with a different handling plan for rescue medication use and missing 
data due to dropouts will be detailed in the SAP. 
Multiplicity adjustment: 
The type I error rate will be controlled at 0.1 level (2-sided) for the primary efficacy analysis 
using the following sequential testing strategy. 
1. The primary endpoint will be tested for Cohort 1 (VIB4920 1500 mg on Days 1, 15, 29, 
and 57) compared with placebo 
2. If p-value is ≤ 0.1 in step 1, the primary endpoint will be tested for Cohort 3 (VIB4920 
3000 mg on Days 1 and 57) compared with placebo 
3. If p-value is ≤ 0.1 in both step 1 and step 2, the primary endpoint will be tested for 
Cohort 2 (VIB4920 1500 mg on Days 1 and 57) and Cohort 4 (VIB4920 3000 mg on 
Day 1) compared with placebo using the Hochberg method (Hochberg 1988) 
9.5.2 
Analysis of Secondary Efficacy Endpoints  
The continuous secondary endpoints of change in RF and ACPA from baseline to Day 113 will 
be analyzed using a MMRM approach.  
The binary secondary endpoint of the proportion of subjects with DAS28-CRP < 2.6 at Day 113 
will be analyzed using a logistic regression model. 


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Time to start of new treatment for RA (rescue medication) will be analyzed using the Cox 
proportional hazards model. 
9.5.3 
Safety Analysis  
Safety endpoints will be summarized descriptively. 
The number and percentage of subjects reporting TEAEs will be summarized for each treatment 
group by system organ class and preferred terms, by severity, and by relationship to the IP. The 
number and percentage of subjects reporting SAEs and AESIs will also be summarized.  
AESI identification will be based on MedDRA coding. The search criteria for the AESIs will be 
established prior to database lock for the primary analysis. 
Clinically important abnormalities in vital signs, laboratory parameters, ECGs, and physical 
examinations will be recorded as AEs or SAEs. 
9.5.4 
Pharmacokinetics Analysis  
Plasma VIB4920 concentration data will be tabulated by dose cohort together with descriptive 
statistics. Individual and mean plasma concentration-time profiles of VIB4920 by treatment will 
be generated.  
Noncompartmental analysis will be performed for VIB4920-treated subjects. When possible, the 
following PK parameters will be accessed for VIB4920 plasma concentration: maximum 
observed concentration (Cmax), area under the concentration-time curve (AUC), CL, and t1/2. 
Additional PK parameters may be determined and reported as appropriate. Descriptive statistics 
for PK parameters will be provided. 
The plasma concentration of VIB4920, summary statistics, PK profile, and the additional 
PK-related analyses will be reported in a clinical PK report. 
9.5.5 
Immunogenicity Analysis  
ADA will be summarized using descriptive statistics for each population. Number and 
percentage of subjects who developed positive ADA will be summarized by treatment group. 
The impact of ADA on PK endpoint will be assessed. The potential association of ADA with 
safety and efficacy may be explored if data allow. 
9.5.6 
  
 
 
9.5.7 
  
  


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10 
ETHICAL CONSIDERATIONS  
10.1 
Good Clinical Practice  
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Council for Harmonisation 
(ICH)/Good Clinical Practice (GCP), applicable regulatory requirements, and the Viela Bio 
policy on Ethical Interactions. 
10.2 
Ethics Review  
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC as appropriate. The Investigator must submit 
written approval to Viela Bio or representative before he or she can enroll any patient into the 
study. 
The PI is responsible for informing the IRB or IEC of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB or IEC must approve all advertising 
used to recruit subjects for the study. The protocol must be re-approved by the IRB or IEC upon 
receipt of amendments and annually, as local regulations require. The PI is also responsible to 
adhere to requirements stipulated by the respective IRB/IEC and for providing the IRB/IEC with 
reports of any reportable serious adverse drug reactions from any other study conducted with the 
IP. Viela Bio will provide this information to the PI. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. Copies of all correspondence between the 
Investigator and the IRB/IEC is provided to Viela Bio’s representative. 
10.3 
Informed Consent  
The PI, or an Investigator or other study site designee with IRB/IEC-approved qualifications, 
will ensure that the patient is given full and adequate oral and written information about the 
nature, purpose, possible risk, and benefit of the study. Patients must also be notified that they 
are free to discontinue from the study at any time. The patients will be informed that their study 
record and medical records/documents that pertain directly to the study will be reviewed and 
possibly copied by Viela Bio or its designee, or a governmental agency (such as the Food and 
Drug Administration [FDA]), and that every effort will be made to maintain patient 
confidentiality. The patient should be given the opportunity to ask questions and allowed time to 
consider the information provided. 
The ICF must be witnessed and dated by the PI or his/her designee, and the original retained by 
the Investigator/study site as part of that subject’s record. 
The Investigator must maintain the original, signed ICF. A copy of the signed ICF must be given 
to the patient. 
Patients may be rescreened within 30 days under the current and signed ICF. 
The ICF must be fully approved by an IRB or an IEC prior to its use with study participants. 


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10.4 
Data Privacy  
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written consent 
is obtained from Viela Bio. However, authorized regulatory officials, IRB/IEC personnel, Viela 
Bio and its authorized representatives are allowed full access to the records. 
Identification of subjects and CRFs shall be by initials, screening, and treatment numbers only. If 
required, the subject’s full name may be made known to an authorized regulatory agency or other 
authorized official. 
10.5 
Disclosure  
Viela Bio is responsible for preparing and providing the appropriate regulatory authorities with 
Clinical Study Reports, according to the applicable regulatory requirements. 
10.6 
Biological Specimens and Data  
Study data are protected by the use of a SID number, which is a number specific to the subject. 
The Investigator is in control of the information that is needed to connect a study sample to a 
subject. A subject’s consent to the use of data does not have a specific expiration date, but the 
subject may withdraw consent at any time by notifying the Investigator. If consent is withdrawn, 
any samples collected prior to that time may still be given to and used by the Sponsor, but no 
new data or samples will be collected unless specifically required to monitor the safety of the 
subject. 
Leftover samples stored for future research will be labeled with a sample identification number. 
If the subject withdraws consent for participating in future research, the Sponsor will locate the 
subject’s sample and destroy it. If the subject consents to have his/her samples used for future 
research, this additional research may not start immediately and may start at any time during the 
storage period. The subject’s sample(s) will be stored by the Sponsor with similar samples in a 
secure central laboratory. The subject’s samples will not be kept for more than 25 years after the 
end of the study in which they were collected. If the subject chooses not to allow his/her study 
samples to be used for future research, the samples will be destroyed by the Sponsor once they 
are no longer required for the main study. 
If consent is withdrawn, the Sponsor and the Investigator will ensure that the subject’s sample(s) 
are destroyed unless the identification number has been removed and the subject can no longer 
be linked to any samples. However, if the subject’s sample has already been used for research, 
the Sponsor is not required to destroy the results of this research. In this case only, the remaining 
sample(s) will be destroyed. 
11 
OVERSIGHT  
11.1 
Safety Data Monitoring Board  
The external, independent SDMC is responsible for safeguarding the interests of study 
participants via review of accumulating safety data and for supporting study integrity and 
interpretability based on their review of ongoing study conduct. The SDMC will provide Viela 
Bio with recommendations for actions with respect to study conduct and the management of 


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subjects treated under the study protocol. The SDMC members are independent of Viela Bio and 
any CRO/organization collaborating with Viela Bio on the study.  
The SDMC will not be charged with any formal interim analysis, will not conduct a futility 
analysis, and will not be asked to consider early study completion for efficacy. For additional 
details, refer to the SDMC Charter. 
11.2 
Quality Control and Assurance  
To ensure compliance with GCP and all applicable regulatory requirements, Viela Bio may 
conduct a quality assurance audit. See Section 11.4 for details regarding the audit process. 
11.3 
Monitoring  
Before an investigational site can enter a subject into the study, a representative of Viela Bio or 
of the CRO will visit the investigational study site to: 
• Determine the adequacy of the facilities. 
• Discuss with the investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of Viela Bio or its representatives. This will 
be documented in a Clinical Study Agreement between Viela Bio and the Investigator. 
During the study, a representative from Viela Bio will have regular contact with the 
investigational site for the following: 
• Provide information and support to the investigator(s). 
• Confirm that facilities remain acceptable. 
• Confirm compliance with the principles of GCP and regulatory requirements. 
• Review of written ICFs for subjects screened/enrolled. 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the eCRFs, and that IP accountability checks are being performed. 
• Perform source data verification. This includes a comparison of the data in the CRFs with 
the subject medical records at the hospital or practice, and other records relevant to the 
study for accuracy and completeness. This will require direct access to all original 
medical and other study-related records for each subject (eg, clinic charts). 
• Record and report any protocol deviations not previously sent to Viela Bio. 
• Confirm AEs and SAEs have been properly documented on eCRFs and confirm that any 
SAEs have been forwarded to Viela Bio or representative and those SAEs that met 
criteria for reporting have been forwarded to the IRB/IEC. 
• During scheduled monitoring visits, the Investigator and the investigational site staff 
must be available to meet with the study monitor in order to discuss the progress of the 
study, make necessary corrections to CRF entries, respond to data clarification requests, 
and respond to any other study-related inquiries from the monitor. 
11.4 
Audits  
To ensure compliance with GCP and all applicable regulatory requirements, Viela Bio may 
conduct a quality assurance audit.  


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Authorized representatives of Viela Bio, a regulatory authority, an IEC and/or an IRB may visit 
the site to perform audits or inspections, including source data verification. The purpose of a 
Viela Bio audit or inspection is to systematically and independently examine all study -related 
activities and documents to determine whether these activities were conducted, and data were 
recorded, analyzed, and accurately reported according to the protocol, GCP guidelines of the 
ICH, and any applicable regulatory requirements. 
Initial IRB/IEC approval, and all materials approved by the IRB/IEC for this study, including the 
ICF and recruitment materials, must be maintained by the Investigator and made available for 
inspection. 
In addition to the above, representatives of Viela Bio auditing staff or government inspectors 
may review the conduct/results of the study at the investigational site. The Investigator should 
contact Viela Bio immediately if contacted by a regulatory agency about an inspection. The 
Investigator cooperates with the auditor(s), makes available to the auditor all requested 
documentation, and ensures that issues detected during the course of these audits are 
satisfactorily resolved. The Investigator supplies Viela Bio with copies of all documentation and 
correspondence related to regulatory agency audits as outlined in the Clinical Trial Agreement. If 
the results of the audit result in a Form FDA 483 (or similar document from another regulatory 
agency), the Investigator promptly provides a copy to a Viela Bio representative and a draft 
response to Viela Bio prior to submission to the regulatory agency. 
11.5 
Records  
11.5.1 
Data Capture and Management  
Clinical Data Management (CDM) will be performed according to the Data Management Plan 
(DMP). The DMP will document procedures and roles and responsibilities related to CDM 
activities, including data validation, data transfer and reconciliation, CDM communications, 
medical coding and dictionaries, CDM reports, and data formats. 
A 21 CFR Part 11 compliant electronic data capture system will be used for data collection and 
query handling. The Investigator will ensure that data are recorded on the eCRFs as specified in 
the study protocol and in accordance with the eCRF Completion Guidelines provided. 
The Investigator ensures the accuracy, completeness, and timeliness of the data recorded and of 
the provision of answers to data queries according to the Clinical Study Agreement. The 
Investigator will sign the completed eCRFs electronically. Upon completion of the study, a copy 
of the completed eCRFs will be provided to the study site for archival purposes. 
11.5.2 
Source Documentation  
Viela Bio will be allowed to conduct site visits to the investigation facilities for the purpose of 
monitoring any aspect of the study. The Investigator agrees to allow the monitor to inspect the 
drug storage area, IP stocks, drug accountability records, subject charts, study source documents, 
and other records relative to study conduct. 
11.5.3 
Records Retention  
Investigators must maintain all documentation relating to the study for a period of 2 years after 
the last marketing application approval or, if not approved, 2 years following the discontinuance 


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of the test article for investigation. If it becomes necessary for Viela Bio or the regulatory 
authority to review any documentation relating to the study, the Investigator must permit access 
to such records. 
12 
PUBLICATION POLICY  
The publication policy of Viela Bio is discussed in the Investigator's Clinical Research 
Agreement. 
13 
REFERENCES  
Aletaha D, Nell VP, Stamm T, Uffmann M, Pflugbeil S, Machold K, et al. Acute phase reactants 
add little to composite disease activity indices for rheumatoid arthritis: validation of a clinical 
activity score. Arthritis Res Ther. 2005;7(4):R796-806. 
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. 2010 
Rheumatoid arthritis classification criteria: an American College of Rheumatology/European 
League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569-81. 
Anderson J, Caplan L, Yazdany J, Robbins ML, Neogi T, Michaud K, et al. Rheumatoid arthritis 
disease activity measures: American College of Rheumatology recommendations for use in 
clinical practice. Arthritis Care Res. 2012;64(5):640–7. 
Berner B, Wolf G, Hummel KM, Muller GA, Reuss-Borst MA. Increased expression of CD40 
ligand (CD154) on CD4+ T cells as a marker of disease activity in rheumatoid arthritis. Ann 
Rheum Dis. 2000;59(3):190-5. 
Boumpas DT, Furie R, Manzi S, Illei GG, Wallace DJ, Balow JE, et al. A short course of 
BG9588 (anti-CD40 ligand antibody) improves serologic activity and decreases hematuria in 
patients with proliferative lupus glomerulonephritis. Arthritis Rheum. 2003;48(3):71927. 
Bugatti S, Vitolo B, Caporali R, Montecucco C, Manzo A. B cells in rheumatoid arthritis: from 
pathogenic players to disease biomarkers. Biomed Res Int. 2014;2014:681679. 
Bykerk VP, Massarotti EM. The new ACR/EULAR classification criteria for RA: how are the 
new criteria performing in the clinic? Rheumatology (Oxford). 2012;51 Suppl 6:vi10-5. 
Cella D, Yount S, Sorensen M, Chartash E, Sengupta N, Grober J. Validation of the Functional 
Assessment of Chronic Illness Therapy Fatigue Scale relative to other instrumentation in patients 
with rheumatoid arthritis. J Rheumatol. 2005;32(5):811-9. 
Choi EW, Lee KW, Park H, Kim H, Lee JH, Song JW, et al. Therapeutic effects of anti-CD154 
antibody in cynomolgus monkeys with advanced rheumatoid arthritis. Sci Rep. 2018;8(1):2135. 
Croft M, Benedict CA, Ware CF. Clinical targeting of the TNF and TNFR superfamilies. Nat 
Rev Drug Discov. 2013;12(2):147-68. 
Curtis JR, van der Helm-van Mil AH, Knevel R, Huizinga TW, Haney DJ, Shen Y, et al. 
Validation of a novel multibiomarker test to assess rheumatoid arthritis disease activity. Arthritis 
Care Res. 2012;64(12):1794-803. 


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Davis JC, Totoritis MC, Rosenberg J, Sklenar TA, Wofsy D. Phase I clinical trial of a 
monoclonal antibody against CD40-ligand (IDEC-131) in patients with systemic lupus 
erythematosus. J Rheumatol. 2001;28(1):95-101. 
Dillman RO. Infusion reactions associated with the therapeutic use of monoclonal antibodies in 
the treatment of malignancy. Cancer Metastasis Rev. 1999;18(4):465-71. 
Docherty AB, Harrison EM, Green CA, Hardwick HE, Pius R, Norman L, et al. Features of 
20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation 
Protocol: prospective observational cohort study. BMJ. 2020;369:m1985.  
FACIT.org [website]. Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-
fatigue), a 13-item fatigue scale [link to questionnaire]. Available from: 
https://www.facit.org/FACITOrg/Questionnaires 
Favalli EG, Ingegnoli F, De Lucia O, Cincinelli G, Cimaz R, Caporali R. COVID-19 infection 
and rheumatoid arthritis: Faraway, so close!. Autoimmun Rev. 2020;19(5):102523. 
Felson DT, Smolen JS, Wells G, Zhang B, van Tuyl LH, Funovits J, et al. American College of 
Rheumatology/European League Against Rheumatism provisional definition of remission in 
rheumatoid arthritis for clinical trials. Arthritis Rheum. 2011;63(3):573-86. 
Ford ML, Adams AB, Pearson TC. Targeting co-stimulatory pathways: transplantation and 
autoimmunity. Nat Rev Nephrol. 2014;10(1):14-24. 
Gianfrancesco M, Hyrich KL, Al-Adely S, Carmona L, Danila MI, Gossec L, et al. 
Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: 
data from the COVID-19 Global Rheumatology Alliance physician-reported registry. Ann 
Rheum Dis. 2020;79(7):859-866.   
HAQ [website]. Mapi Research Trust. Health Assessment Questionnaire (HAQ) Basic 
Description. Available from: https://eprovide.mapi-trust.org/instruments/health-assessment-
questionnaire#contact_and_conditions_of_use 
Hirohata S. The role of CD40-CD40 ligand interactions in suppression of human B cell 
responsiveness by CD4+ T cells. Cell Immunol. 1997;182(1):20-8. 
Hochberg Y.  A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 
1988;75(4):800-02. 
Huang W, Sinha J, Newman J, Reddy B, Budhai L, Furie R, et al. The effect of anti-CD40 ligand 
antibody on B cells in human systemic lupus erythematosus. Arthritis Rheum. 
2002;46(6):1554-62. 
Kalled SL, Cutler AH, Ferrant JL. Long-term anti-CD154 dosing in nephritic mice is required to 
maintain survival and inhibit mediators of renal fibrosis. Lupus. 2001;10(1):9-22. 
Karnell JL, Rieder SA, Ettinger R, Kolbeck R. Targeting the CD40-CD40L pathway in 
autoimmune diseases: Humoral immunity and beyond. Adv Drug Deliv Rev. 2019;15(141):92-
103. doi: 10.1016/j.addr.2018.12.005. [Epub 2018 Dec 13 ahead of print] 
Karnell JL, Albulescu M, Drabic S, Wang L, Moate R, Baca M, et al. A CD40L-targeting protein 
reduces autoantibodies and improves disease activity in patients with autoimmunity. Sci Transl 
Med. 2019;11(489). pii: eaar6584. doi: 10.1126/scitranslmed.aar6584. 


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Li G, Diogo D, Wu D, Spoonamore J, Dancik V, Franke L, et al. Human genetics in rheumatoid 
arthritis guides a high throughput drug screen of the CD40 signaling pathway. PLoS Genet. 2013 
May; 9(5): e1003487. 
Lillegraven S, Kvien TK. Measuring disability and quality of life in established rheumatoid 
arthritis. Best Pract Res Clin Rheumatol. 2007;21(5):827-40. 
Orbai AM, Bingham CO. Patient reported outcomes in rheumatoid arthritis clinical trials. Curr 
Rheumatol Rep. 2015;17(4):28. 
Petrilli CM, Jones SA, Yang J, Rajagopalan H, O’Donnell L, Chernyak Y, et al. Factors 
associated with hospital admission and critical illness among 5279 people with coronavirus 
disease 2019 in New York City: prospective cohort study. BMJ. 2020;369:m1966.  
Prevoo ML, van’t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. 
Modified disease activity scores that include twenty-eight-joint counts. Development and 
validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis 
Rheum. 1995;38(1):44-8. 
Robles-Carrillo L, Meyer T, Hatfield M, Desai H, Dávila M, Langer F, et al. Anti-CD40L 
immune complexes potently activate platelets in vitro and cause thrombosis in FCGR2A 
transgenic mice. J Immunol. 2010;185(3):1577-83. 
Rohekar G, Pope J. Test-retest reliability of patient global assessment and physician global 
assessment in rheumatoid arthritis. J Rheumatol. 2009;36(10):2178-82. 
Scheinman R. NF-κB and rheumatoid arthritis: will understanding genetic risk lead to a 
therapeutic reward? For Immunopathol Dis Therap. 2013;4(2):93-110. 
Schuler W, Bigaud M, Brinkmann V, Di Padova F, Geisse S, Gram H, et al. Efficacy and safety 
of ABI793, a novel human anti-human CD154 monoclonal antibody, in cynomolgus monkey 
renal allotransplantation. Transplantation. 2004;77(5):717-26. 
Smolen JS, Landewe R, Bijlsma J, Burmester G, Chatzidionysiou K, Dougados M, et al. EULAR 
recommendations for the management of rheumatoid arthritis with synthetic and biological 
disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76(6):960-77. 
Symmons DP. Epidemiology of rheumatoid arthritis: determinants of onset, persistence and 
outcome. Best Pract Res Clin Rheumatol. 2002;16(5):707-22. 
United States Food and Drug Administration. Guidance for industry. Rheumatoid arthritis: 
developing drug products for treatment [draft guidance 2013]. Available from: 
fda.gov/media/86066/download. Accessed 10Jul2019.  
van Baarsen LG, de Hair MJ, Ramwadhdoebe TH, Zijlstra IJ, Maas M, Gerlag DM, et al. The 
cellular composition of lymph nodes in the earliest phase of inflammatory arthritis. Ann Rheum 
Dis. 2013;72(8):1420-4. 
  
Visvanathan S, Daniluk S, Ptaszyński R, Muller-Ladner U, Ramanujam M, Rosenstock B, et al. 
Effects of BI 655064, an antagonistic anti-CD40 antibody, on clinical and biomarker variables in 
patients with active rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase 
IIa study. Ann Rheum Dis. 2019;78(6):754-60.  


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Wells G, Becker JC, Teng J, Dougados M, Schiff M, Smolen J, et al. Validation of the 28-joint 
Disease Activity Score (DAS28) and European League Against Rheumatism response criteria 
based on C-reactive protein (CRP) against disease progression in patients with rheumatoid 
arthritis, and comparison with the DAS28 based on erythrocyte sedimentation rate. Ann Rheum 
Dis. 2009;68(6):954-60. 
Wong JB, Ramey DR, Singh G. Long-term morbidity, mortality, and economics of rheumatoid 
arthritis. Arthritis Rheum. 2001;44(12):2746-9. 
Zhang B, Wu T, Chen M, Zhou Y, Yi D, Guo R. The CD40/CD40L system: a new therapeutic 
target for disease. Immunol Lett. 2013;153(1-2):58-61. 
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adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 
2020;395(10229):1052-62.   


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14 
APPENDICES  
 


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APPENDIX 1 
GUIDANCE FOR ANAPHYLAXIS DIAGNOSIS  
The National Institute of Allergy and Infectious Disease (NIAID) and Food and Allergy 
Anaphylaxis Network (FAAN) define anaphylaxis as a serious allergic reaction that is rapid in 
onset and may cause death. They recognize 3 categories of anaphylaxis, with criteria designated 
to capture from 80% of cases (category 1) to > 95% of all cases of anaphylaxis (for all 3 
categories). Their clinical criteria for diagnosing anaphylaxis are: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen 
lips-tongue-uvula) 
AND AT LEAST ONE OF THE FOLLOWING 
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow (PEF), hypoxemia) 
b. Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence) 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours): 
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula) 
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia) 
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence) 
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours): 
a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in 
systolic BP 
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline. 
Reference 
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson FN Jr, Bock SA, Branum A, et al. 
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. J Allergy Clin Immunol. 2006;117(2):391-7. 


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APPENDIX 2 
ACTIONS REQUIRED IN CASES OF INCREASES IN LIVER 
BIOCHEMISTRY AND EVALUATION OF HY’S LAW  
Introduction 
This Appendix describes the process to be followed in order to identify and appropriately report 
cases of Hy’s Law. It is not intended to be a comprehensive guide to the management of elevated 
liver biochemistries.  
During the course of the study, the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a subject meets potential 
Hy’s Law (PHL) criteria at any point during the study. 
The Investigator participates, together with Viela Bio clinical project representatives, in review 
and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria are met. 
HL criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than drug-induced liver injury (DILI) caused by the IP.  
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
adverse events (AEs) and serious adverse events (SAEs) according to the outcome of the review 
and assessment in line with standard safety reporting processes. 
Definitions 
Potential Hy’s Law 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3 × upper limit of 
normal (ULN) together with total bilirubin (TBL) ≥ 2 × ULN at any point during the study 
following the start of investigational product (IP) irrespective of an increase in alkaline 
phosphatase (ALP). 
Hy’s Law  
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN, where no other reason, other than the IP, 
can be found to explain the combination of increases; eg, elevated ALP indicating cholestasis, 
viral hepatitis, another drug. 
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the elevations 
in transaminases and TBL must occur. 
Identification of Potential Hy’s Law Cases 
In order to identify cases of PHL, it is important to perform a comprehensive review of 
laboratory data for any subject who meets any of the following identification criteria in isolation 
or in combination: 
• ALT ≥ 3 × ULN 
• AST ≥ 3 × ULN 
• TBL ≥ 2 × ULN 
The Investigator will, without delay, review each new laboratory report and, if the identification 
criteria are met, will: 
• Notify the Sponsor study representative 


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• Determine whether the subject meets PHL criteria by reviewing laboratory reports from 
all previous visits 
• Promptly enter the laboratory data into the laboratory electronic case report form (eCRF). 
Follow-up 
Potential Hy’s Law Criteria Are Not Met 
If the subject does not meet PHL criteria, the Investigator will: 
• Inform the Sponsor representative that the subject has not met PHL criteria 
• Perform follow-up on subsequent laboratory results according to the guidance provided 
in the clinical study protocol. 
Potential Hy’s Law Criteria Are Met 
If the subject does meet PHL criteria, the Investigator will notify the Sponsor study 
representative, who will then inform the central study team. The Medical Monitor contacts the 
Investigator to provide guidance, discuss and agree an approach for the study subject’s follow-up 
and the continuous review of data. Subsequent to this contact, the Investigator will: 
• Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically indicated  
• Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the Study Physician.  
• If, at any time (in consultation with the medical monitor), the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures. 
Review and Assessment of Potential Hy’s Law Cases 
The instructions in this section should be followed for all cases where PHL criteria are met. 
No later than 3 weeks after the biochemistry abnormality was initially detected, the Medical 
Monitor will contact the Investigator in order to review available data and agree on whether there 
is an alternative explanation for meeting PHL criteria other than DILI caused by the IP. The 
Medical Monitor and Safety Physician will also be involved in this review together with other 
subject matter experts as appropriate. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE: 
• If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF 
• If the alternative explanation is an AE/SAE, record the AE/SAE in the eCRF accordingly 
and follow the Sponsor standard processes 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IP: 
• Report an SAE (report term ‘Hy’s Law’) according to Sponsor standard processes  


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− The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply 
− As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned 
If there is an unavoidable delay of over 3 weeks in obtaining the information necessary to assess 
whether or not the case meets the criteria for HL, then it is assumed that there is no alternative 
explanation until such time as an informed decision can be made: 
• Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and causality 
assessment as per above 
• Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met. Update the SAE report according to the outcome of the 
review 
 
Reference 
FDA. Guidance for Industry: Drug-induced liver injury: premarketing clinical evaluation. 2009. 
Available from: 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM174090.pdf 


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APPENDIX 3 
INVESTIGATOR’S AGREEMENT  


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INVESTIGATOR’S AGREEMENT  
I have read the protocol, appendices, and accessory materials related to Study VIB4920.P2.S3 
and agree to the following: 
• To conduct this study as described by the protocol and any accessory materials 
• To protect the rights, safety, and welfare of the participants under my care 
• To provide oversight to all personnel to whom study activities have been delegated 
• To control all investigational products provided by the Sponsor and maintain records of 
the disposition of those products 
• To conduct the study in accordance with all applicable local and national regulations, the 
requirements of the ethics committee of record for my clinical site, and Good Clinical 
Practices as outlined by International Council for Harmonisation E6(R2) 
• To obtain approval for the protocol and all written materials provided to participants prior 
to initiating the study at my site 
• To obtain informed consent – and updated consent in the event of new information or 
amendments – from all participants enrolled at my study site prior to initiating any 
study-specific procedures or administering investigational products to those participants 
• To maintain records of each subject’s participation and all data required by the protocol 
 
Name 
Title 
Institution 
 
 
 
Signature 
Date 
 
 
 


Signature Page for VV-CLIN-001820 v1.0
Signature Page for VV-CLIN-001820 v1.0
Approval
05-Oct-2020 15:23:01 GMT+0000
Approval
evelopment Lead
05-Oct-2020 15:39:14 GMT+0000
Approval
onal Science Representative
05-Oct-2020 17:58:18 GMT+0000
Approval
05-Oct-2020 18:29:08 GMT+0000
Approval
06-Oct-2020 12:16:14 GMT+0000
Approval
06-Oct-2020 17:28:53 GMT+0000


Full Name and Role:   
 
 
 
 
 
Signature & Date: 
 
 
 
 
 
Full Name and Role:   
 
 
 
 
 
Signature & Date: 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
Statistical Analysis Plan 
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VIELA BIO, INC. 
 
STATISTICAL ANALYSIS PLAN 
Investigational Product: 
VIB4920 
Protocol Number: 
VIB4920.P2.S3 
 
A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, MECHANISTIC INSIGHT AND DOSAGE 
OPTIMIZATION STUDY OF THE EFFICACY AND SAFETY 
OF VIB4920 IN PATIENTS WITH RHEUMATOID 
ARTHRITIS (RA) 
(SHORT TITLE: MIDORA)  
 
 
 


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TABLE OF CONTENTS 
1 
INTRODUCTION ......................................................................................................6 
2 
Study Overview ...........................................................................................................6 
2.1 
Study Objectives and Endpoints...........................................................................6 
2.2 
Study Design ...........................................................................................................7 
2.3 
Sample Size .............................................................................................................8 
3 
Statistical Methods ......................................................................................................8 
3.1 
General Considerations .........................................................................................8 
3.1.1 
Definition of Baseline .......................................................................................8 
3.1.2 
Analysis Windows ............................................................................................8 
3.2 
Protocol Deviations ................................................................................................8 
3.3 
Analysis Sets ...........................................................................................................9 
3.3.1 
Full analysis set ................................................................................................9 
3.3.2 
Safety analysis set .............................................................................................9 
3.3.3 
Pharmacokinetics analysis set .........................................................................9 
3.4 
Study Subjects ........................................................................................................9 
3.4.1 
Subject Disposition...........................................................................................9 
3.4.2 
Demographics, Baseline Characteristics, and Medical History .................10 
3.4.3 
Investigational product Exposure ................................................................10 
3.4.4 
Prior and Concomitant Medications ............................................................10 
3.5 
Efficacy Analyses .................................................................................................11 
3.5.1 
Primary Efficacy Endpoint(s) and Analyses ...............................................11 
3.5.1.1 
Primary efficacy endpoint .......................................................................11 
3.5.1.2 
Primary efficacy analysis ........................................................................12 
3.5.1.3 
Handling plan for Intercurrent Events ..................................................12 
3.5.1.4 
Handling plan for missing data ..............................................................12 
3.5.1.5 
Sensitivity analysis of primary efficacy endpoint .................................12 
3.5.1.6 
Subgroup analyses of primary endpoint ................................................13 
3.5.1.7 
Multiplicity adjustment ...........................................................................13 
3.5.2 
Secondary Efficacy Endpoints and Analyses ..............................................13 
3.5.2.1 
Secondary efficacy endpoints ..................................................................13 
3.5.2.2 
Secondary efficacy analysis .....................................................................13 
 
 
 
 
 
 
 
 
 
 
 
 
3.6 
Safety Analysis .....................................................................................................17 
3.6.1 
Adverse Events ...............................................................................................17 
3.6.2 
Clinical Laboratory Evaluation ....................................................................18 
3.6.3 
Other Safety Evaluations ..............................................................................18 
3.6.3.1 
Overdose ...................................................................................................18 
3.6.3.2 
Vital signs ..................................................................................................18 
3.6.3.3 
Electrocardiogram ...................................................................................19 
3.6.3.4 
Weight .......................................................................................................19 
3.7 
Pharmacokinetics .................................................................................................19 
3.8 
Immunogenicity....................................................................................................19 


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3.9 
Pharmacodynamics ..............................................................................................20 
 
 
 
 
 
 
 
 
4 
Planned Analysis .......................................................................................................21 
4.1 
Primary Efficacy Analysis ...................................................................................21 
4.2 
Final Analysis .......................................................................................................21 
5 
References ..................................................................................................................21 
6 
Appendix ....................................................................................................................23 
 
LIST OF TABLES 
Table 1 
Study Objectives and Endpoints.....................................................................6 
Table 2 
Definition of ADA Status ...............................................................................20 
LIST OF FIGURES 
Figure 1 
Study Flow Diagram ..................................................................................7 


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LIST OF ABBREVIATIONS  
Abbreviation or Specialized Term 
Definition 
ACPA 
anti-cyclic citrullinated peptide antibody 
ADA 
anti-drug antibodies 
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under the concentration-time curve 
bDMARD 
biologic disease-modifying anti-rheumatic drug 
CDAI 
Clinical Disease Activity Index  
cDMARD 
conventional disease-modifying anti-rheumatic drug 
CI 
confidence interval 
CL 
systemic clearance 
Cmax 
maximum observed concentration 
CRP 
C-reactive protein 
CTCAE 
common terminology criteria for adverse event 
DAS28-CRP 
Disease Activity Score in 28 Joints Using C-reactive Protein 
ECG 
electrocardiogram 
FACIT-Fatigue 
Functional Assessment of Chronic Illness Therapy - Fatigue 
HAQ 
Health Assessment Questionnaire 
IL-6 
interleukin-6  
IP 
Investigational product 
MDGA 
physician global assessment of disease activity 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed-effect model for repeated measures 
MTX 
methotrexate 
LSMeans 
least square means 
PD 
Pharmacodynamic(s) 
PGA 
patient global assessment of disease activity 
PK 
Pharmacokinetic(s) 
PT 
preferred term 
QTc 
corrected QT interval 
RA 
rheumatoid arthritis 
RF 
rheumatoid factor 
sCD40L 
soluble CD40 ligand 
SDAI 
Simplified Disease Activity Index 
SE 
standard error 
SJC28 
28 swollen joint count  
SOC 
system organ class 


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Abbreviation or Specialized Term 
Definition 
SPP 
statistical programming plan 
t1/2 
terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TEAESI 
treatment-emergent adverse event of special interest 
TESAE 
treatment-emergent serious adverse event 
TJC28 
28 tender joint count  
VAS 
visual analog scale 
WHO 
world health organization 


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1 INTRODUCTION  
This document describes the statistical analysis for protocol VIB4920.P2.S3, a Phase 2 
randomized, double-blind, placebo controlled, parallel-cohort study to evaluate the safety, 
efficacy, and pharmacokinetics (PK) of VIB4920 in adults with moderate-to-severe 
rheumatoid arthritis (RA). 
2 STUDY OVERVIEW  
2.1 
Study Objectives and Endpoints  
The objectives and corresponding endpoints are listed in Table 1 below: 
Table 1 
Study Objectives and Endpoints  
Primary objective 
Endpoints/variables 
• To evaluate the effect of VIB4920 on disease 
activity as assessed by a composite measure in 
subjects with adult-onset RA 
• Change in Disease Activity Score in 28 Joints 
Using C-reactive Protein (DAS28-CRP) from 
baseline to Day 113 
• To evaluate the safety and tolerability of 
VIB4920 in subjects with adult-onset RA 
• Incidence of treatment emergent adverse events 
(TEAEs), treatment emergent serious adverse 
events (TESAEs), and treatment emergent adverse 
events of special interest (TEAESIs) 
Secondary objectives 
Endpoints/variables 
• To characterize the PK of VIB4920 in subjects 
with adult-onset RA 
• PK profile 
• To evaluate the pharmacodynamic (PD) effect of 
VIB4920 in subjects with adult-onset RA 
• Total soluble CD40 ligand (sCD40L) 
• To evaluate the immunogenicity of VIB4920 in 
subjects with adult-onset RA 
• Anti-drug antibodies (ADA) 
• To evaluate the effect of VIB4920 on 
autoantibodies in subjects with adult-onset RA 
• Rheumatoid factor (RF) 
• Anti-cyclic citrullinated peptide antibody (ACPA) 
• To assess the effect of VIB4920 on clinical 
remission as assessed by a composite measure in 
subjects with adult-onset RA 
• DAS28-CRP < 2.6 
• To evaluate the duration of clinical response to 
VIB4920 as assessed by time to institution of 
rescue therapy 
• Time to start of new treatment for RA (rescue 
medication) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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Table 1 
Study Objectives and Endpoints  
•
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
2.2 
Study Design  
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-cohort study to 
evaluate the safety, efficacy, and PK of VIB4920 administered intravenously in adults with 
active, moderate-to-severe adult-onset RA who have had an inadequate response to 
methotrexate, conventional disease-modifying anti-rheumatic drug (cDMARD), or an anti-
TNFα agent.  
After a screening period of up to 28 days, approximately 75 subjects will be randomized in a 
1:1:1:1:1 ratio into 5 cohorts (treatment groups) as shown in Figure 1 below. Subjects are to 
be followed on their stable background anti-RA therapy at least through 12 weeks (Day 85), 
at which time rescue therapy may be instituted. All subjects are followed at least through the 
primary analysis (Day 113), and those who have not instituted rescue therapy will be 
followed through Day 309 to determine the duration of clinical response. 
A study schematic is presented in Figure 1. 
Figure 1 
Study Flow Diagram  
 


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2.3 
Sample Size  
The planned sample size of 75 subjects (15 subjects per treatment group) will provide 
approximately 80% power to detect a difference of 1.2 in mean change from baseline to 
Day 113 in DAS28-CRP (assumed standard deviation of 1.25) between the VIB4920 and 
placebo treatment groups at a 2-sided alpha level of 0.10 using a 2-sample t-test. 
3 STATISTICAL METHODS  
3.1 
General Considerations  
All statistical calculations will be primarily performed using SAS® System Version 9.4 or 
higher. Categorical data will be summarized by the frequency counts and percentage of 
subjects in each category. Continuous variables will be summarized by descriptive statistics, 
including number of observations, mean, standard deviation, median, first quartile, third 
quartile, minimum, and maximum. 
3.1.1 
Definition of Baseline  
Unless otherwise specified, baseline will be defined as the last non-missing valid observation 
prior to the first administration of IP. In cases where baseline measurements are taken on the 
same day as IP and no times are reported, it will be assumed that these measurements are 
taken prior to IP being administered. 
3.1.2 
Analysis Windows  
Analysis visit windows will be used for all visit-based assessments to map longitudinal 
observations to scheduled visits and thereby allow for by-visit analyses, since not all 
assessments are performed on the scheduled day. Unless otherwise specified, all longitudinal 
efficacy, safety, and biomarker data analyses will be based on the analysis visit windows. The 
analysis visit windows will be calculated by bisecting the interval between adjacent 
scheduled visit days except for the first post-treatment visit. The first post-treatment visit will 
start at Day 2. The detailed analysis visit windows will be specified in the statistical 
programming plan (SPP). 
The actual assessment day will be mapped to the windows defined for each scheduled study 
visit with following rules:  
• If more than one assessment falls within a visit window, the closest non-missing 
assessment to the scheduled day will be used in the analysis. 
• If 2 non-missing assessment actual dates are equidistant from the target day, the later 
visit will be used in the analysis. 
• For retest values of laboratory data, the retest value (the last valid observation 
assessed on the same visit day) will be chosen. 
3.2 
Protocol Deviations  
All protocol deviations will be classified as either major protocol deviations or minor 
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deviations, which may significantly impact the completeness, accuracy, and/or reliability of 
the study data or that may significantly affect a subject’s rights, safety, or well-being. All the 
protocol deviations will be listed, and the major protocol deviation will be summarized. Some 
classifications of major protocol deviations are listed below.  
• Did not meet inclusion criteria or met exclusion criteria. 
• Blindness of treatment assignment was broken by site investigator  
• Received prohibited concomitant medication 
• Serious breach of good clinical practice. 
The list may be updated and will be finalized and documented prior to the database lock for 
the primary analysis. 
3.3 
Analysis Sets  
3.3.1 
Full analysis set  
The full analysis set includes all randomized subjects who received any dose of IP. Subjects 
will be analyzed according to the treatment randomized. The efficacy analysis will be based 
on the full analysis set. 
3.3.2 
Safety analysis set  
The safety analysis set includes all subjects who received any dose of IP. Subjects will be 
analyzed according to the treatment that they actually received. The safety and ADA analyses 
will be based on the safety analysis set. 
3.3.3 
Pharmacokinetics analysis set  
The PK analysis set includes all subjects who received IP and have at least one quantifiable 
plasma PK observation post-first dose. Subjects will be analyzed according to the treatment 
that they actually received. PK analyses will be based on the PK analysis set. 
3.4 
Study Subjects  
3.4.1 
Subject Disposition  
A summary of subject disposition will be presented using the categories presented below.  
• Screened 
• Screen failed with reasons 
• Randomized 
• Randomized but not treated 
• Randomized and treated 


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• Completed treatment  
• Discontinued treatment with reasons 
• Completed study 
• Discontinued study with reasons 
A Kaplan-Meier curve of the time to study discontinuation will be provided.  
3.4.2 
Demographics, Baseline Characteristics, and Medical History  
The demographics (age, gender, race, ethnicity, height, weight, and body mass index) will be 
summarized by treatment group and overall for the full analysis set.  
A summary of baseline disease characteristics, by treatment group and overall for the full 
analysis set will include DAS28-CRP, 
, MDGA, PGA, 
CDAI, SDAI, HAQ, CRP, ACPA (positive/negative), RF (positive/negative),  and presence 
of rheumatoid nodules.  
Significant medical history findings will be summarized by Medical Dictionary for 
Regulatory Activities (MedDRA) system organ class (SOC) and preferred term (PT) by 
treatment group and overall for the full analysis set. 
3.4.3 
Investigational product Exposure  
The number of doses received, amount (mg) of the IP received, durations of the IP exposure, 
and total subject years exposure will be summarized by treatment using the safety analysis 
set. 
• Duration of the IP exposure is defined as (last dose date + 28 ‒ first dose date + 1) 
• The amount of IP received: if a subject received partial dose at a dosing visit, then the 
amount of IP at that dosing visit will be estimated based on the actual volume 
administered. 
• Treatment compliance for an individual patient = (Total number of doses received)/ 
(Total number of doses planned per protocol) ×100%.  
Number of subjects with at least one entire dose not administered, infusion interrupted, and 
infusion rate decreased will be summarized using the safety analysis set. 
3.4.4 
Prior and Concomitant Medications  
Number (%) of subjects who receive prior medications and concomitant medications will be 
summarized by world health organization (WHO) Drug dictionary Anatomical Therapeutic 
Chemical (ATC) category and PT based on the safety analysis set. At each level of 
summarization, a subject is counted once if he/she reported one or more medications at that 
level. The prior and concomitant medications are defined as below.  


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• Prior medications are defined as medications with a stop date occurring before the 
first IP administration date. 
• Concomitant medications are defined as medications with a stop date on or after the 
first IP administration date. 
RA medication history will be summarized by medication category (cDMARD, biologic 
DMARD [bDMARD], JAK Inhibitor, etc.). The reasons for treatment discontinuation will 
also be summarized. 
Use of RA-related medications at baseline, defined as all RA-related medications with an 
intake at the date of first dose of IP (ie, start date on or before the date of first dose and end 
date on or after date of first dose or ongoing) will be summarized for the full analysis set. The 
number and percentage of subjects who receive rescue therapy will also be summarized for 
the full analysis set.  
Rescue therapy is any new or intensified immunosuppressive, cDMARD, or bDMARD 
treatment for RA, including: 
• Initiation of or increase in dose of any cDMARD 
• Initiation of bDMARD therapy or Janus kinase inhibitor therapy 
• Increase in baseline corticosteroid dose 
• Intraarticular steroid injection > 40 mg methylprednisolone (or its equivalent) OR 
more than one intraarticular steroid injection of any dose. One intraarticular steroid 
injection ≤ 40 mg methylprednisolone in one joint is permitted and not considered rescue 
therapy 
The missing start/stop date of medications will be imputed as appropriate and the details of 
the imputation will be included in the SPP. 
3.5 
Efficacy Analyses  
3.5.1 
Primary Efficacy Endpoint(s) and Analyses  
3.5.1.1 
Primary efficacy endpoint  
The primary efficacy endpoint is change from baseline DAS28-CRP to Day 113.  
DAS28-CRP: 
DAS28-CRP values will be calculated as follows (Wells et al, 2009):  
DAS28-CRP = 0.56 × √ (TJC28) + 0.28 × √ (SJC28) + 0.014 × PGA (0 - 100 mm visual 
analogue scale [VAS]) + 0.36 × ln(CRP[mg/L] + 1) + 0.96 
Low disease activity is defined as DAS28-CRP ≤ 3.2, and an improvement of DAS28-CRP 
score > 0.6 defines a responder. Remission is defined as DAS28-CRP < 2.6. 


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3.5.1.2 
Primary efficacy analysis  
The primary efficacy endpoint will be analyzed using the mixed-effect model for repeated 
measures (MMRM) approach for the full analysis set. The model will include fixed effects 
for treatment, visit, visit by treatment interaction, and baseline DAS28-CRP score. 
From the model, the estimated treatment effect (ie the difference [VIB4920 – placebo] in 
least square means [LSMeans]) at Day 113 will be obtained, together with a two-sided 90% 
confidence interval (CI), standard error (SE) and p-value. The significance of treatment effect 
will be tested by using a two-sided test at significance level α of 0.1. Additionally, estimates 
of the LSMeans for each treatment group will be obtained, together with the associated SE. 
Longitudinal presentations of results over time based on the same analysis will be created.  
Model assumptions for MMRM will be checked with graphical displays (residual plots and a 
quartile-quartile plot). If the model assumptions are not met, appropriate data transformations 
or the non-parametric approaches will be used. 
3.5.1.3 
Handling plan for Intercurrent Events  
Rescue medication use:  
For subjects who take rescue medications defined in section 3.4.4, the data collected after 
administration of the rescue medications will not be included in the primary analysis. This 
approach attempts to reduce the confounding effects of rescue medications. 
Treatment discontinuation: 
Subjects who discontinue IP without receiving rescue medications will be asked to come to 
scheduled evaluations until the end of study. The data collected after discontinuation of IP 
will be included in the analysis. 
3.5.1.4 
Handling plan for missing data  
Missing data will be handled using the MMRM approach. If any of the DAS28-CRP 
component cannot be evaluated at a visit, that component will be imputed using last 
observation carried forward (LOCF) approach.  
3.5.1.5 
Sensitivity analysis of primary efficacy endpoint  
The sensitivity analysis will be performed for the primary efficacy endpoint using the same 
model as the primary analysis with the following handling plan for the rescue medication use 
and treatment discontinuation. 
• Impute result after rescue medications using the worst score including baseline. For 
subjects who discontinue IP without receiving rescue medications, include data collected 
after discontinuation of study treatment. 
• Include data collected after rescue medications and data collected after 
discontinuation of study treatment. 


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CRP, RF, and ACPA values were provided unblinded by the central laboratory in violation of the 
protocol starting from 20Jan2021. Reports were required to be accessed by site, signed by 
investigator, and filed, and thus the assumption is that a very wide set of people at site, CRO and 
sponsor had access to these potentially unblinding data. The blinding was restored on 27Jan2021. 
After consulting with DSMB statistician, we will perform a sensitivity analysis by removing 
data that might have introduced bias (see Appendix 1). 
3.5.1.6 
Subgroup analyses of primary endpoint  
No subgroup analyses are planned for the primary endpoint due to the small sample size per 
treatment group in the study. 
3.5.1.7 
Multiplicity adjustment  
The type I error rate will be controlled at 0.1 level (2-sided) for the primary efficacy analysis 
using the following sequential testing strategy. 
1. The primary endpoint will be tested for Cohort 1 (VIB4920 1500 mg on Days 1, 15, 
29, and 57) compared with placebo 
2. If p-value is ≤ 0.1 in step 1, the primary endpoint will be tested for Cohort 3 
(VIB4920 3000 mg on Days 1 and 57) compared with placebo 
3. If p-value is ≤ 0.1 in both step 1 and step 2, the primary endpoint will be tested for 
Cohort 2 (VIB4920 1500 mg on Days 1 and 57) and Cohort 4 (VIB4920 3000 mg on 
Day 1) compared with placebo using the Hochberg method (Hochberg, 1988). 
3.5.2 
Secondary Efficacy Endpoints and Analyses  
3.5.2.1 
Secondary efficacy endpoints  
The secondary efficacy endpoints are as follows: 
• The proportion of subjects with clinical remission defined as DAS28-CRP < 2.6 at 
Day 113 
• Time to start of rescue medication  
• Change in RF and ACPAs from baseline to Day 113 
3.5.2.2 
Secondary efficacy analysis  
The proportion of subjects with DAS28-CRP < 2.6 at Day 113 will be analyzed for the full 
analysis set using a logistic regression model, with treatment and baseline DAS28-CRP score 
included in the model. Subjects who receive rescue medications before Day 113 and who 
prematurely discontinue from the study before Day 113 will be considered non-responders. 
Intermittent missing data and missing DAS28-CRP component will be imputed using LOCF 
approach.  
The estimated treatment effect (ie, the odds ratio for VIB4920 versus placebo), corresponding 
90% CI, and 2-sided p-value will be presented.  
Longitudinal presentations of results over time will be created using the full analysis set. 
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rescue. Subjects who prematurely discontinue from the study will be considered non-
responder for the visits after discontinuation. 
Time to start of rescue medication will be analyzed using the Cox proportional hazards model 
with treatment group included in the model. Subjects without rescue will be censored. The 
hazard ratio of VIB4920 versus placebo will be estimated together with its associated 90% 
CI. The Kaplan-Meier curve of the time to rescue will be provided. 
The change in RF and ACPAs from baseline to Day 113 will be analyzed for the full analysis 
set using the MMRM approach, with treatment, visit, visit by treatment interaction, and 
corresponding baseline value. The data collected after discontinuation of IP will be included 
in the analysis. The data collected after administration of the rescue medications will be 
excluded. The sensitivity analysis will be performed with the data collected after 
administration of the rescue medications included. 
The details of these analyses and presentations of results will be the same as those described 
for the primary efficacy endpoint in section 3.5.1.2. 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 


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3.6 
Safety Analysis  
3.6.1 
Adverse Events  
In general, if an AE onset is on or after the first dose of IP administration, the AE will be 
considered as a TEAE. Otherwise, the AE will be considered as a non-treatment emergent 
AE.  
An overall summary table will be showing the number and percentage of subjects with at 
least 1 event in any of the following categories: TEAE, TESAE, TEAE with outcome of 
death, TEAE leading to discontinuation of IP, grade 3 or higher TEAE, serious and/or grade 3 
or higher TEAE, IP related TEAE, IP related TESAE.  
AEs will be coded using the most recent version of MedDRA. All TEAEs will be 
summarized overall and by MedDRA SOC and PT, by severity and by relationship to IP. 
Specific AEs will be counted once for each subject for calculating rates, but all events will be 
presented in subject listings. In addition, if the same AE occurs multiple times within a 
particular subject, the highest severity and level of causality will be reported. 
The TEAEs, TESAEs, TEAEs resulting in death, TEAEs leading to discontinuation of IP, 
Grade 3 or higher TEAEs, IP related TEAEs, and IP related TESAEs will be summarized by 
SOC and PT. TESAEs will be summarized by SAE criteria as well. In addition, a summary of 
TEAEs sorted by frequency will be presented by PT.  
An AESI is one of scientific and medical interest specific to understanding of the IP. AESIs 
for this protocol include: 


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• Thrombotic and embolic events 
• Anaphylaxis and clinically significant (Grade 3 or higher) hypersensitivity reactions 
• Severe Infusion-related reactions (common terminology criteria for adverse event 
(CTCAE) Grade 3 or higher) 
• Immune complex disease 
• Severe (Grade 3 or higher) and/or opportunistic infections 
• Hepatic function abnormality (meeting the definition of Hy’s Law) 
• Malignant neoplasm 
TEAESIs will be summarized by SOC and PT. 
Listings will be provided for all TEAEs and non-treatment emergent AEs. 
3.6.2 
Clinical Laboratory Evaluation  
The hematology, coagulation, serum chemistry, urinalysis, and immunoglobulins parameters, 
as well as changes from baseline, will be summarized with descriptive statistics at each visit. 
Shift from the baseline relative to the normal range will also be summarized. Additionally, 
worst toxicity grade, ≥grade 3 toxicity post-baseline, and shift from baseline to worst toxicity 
grade in hematology, coagulation and serum chemistry parameter will be produced. 
3.6.3 
Other Safety Evaluations  
3.6.3.1 
Overdose  
The incidence of TEAE associated with overdose will be summarized by MedDRA SOC and 
PT if applicable. 
3.6.3.2 
Vital signs  
The observed values along with the changes from baseline will be summarized for systolic 
blood pressure, diastolic blood pressure, body temperature, heart rate, and respiratory. In 
addition, a summary of subjects with clinically significant vital signs values (meeting any of 
following criteria) will be provided. 
• Systolic blood pressure: <90 mmHg, >160 mmHg 
• Diastolic blood pressure: <60 mmHg, >100 mmHg 
• Heart rate: <50 Beats/min, >100 beats/min 
• Respiratory rate: <12 breaths/min, >23 breaths/min 
• Temperature: <36°C, >38°C 


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3.6.3.3 
Electrocardiogram  
The observed values along with the changes from baseline will be summarized for heart rate, 
RR interval, PR Interval, QRS duration, QT interval and the corrected QT interval (QTc) 
using Bazett’s and Fridericia’s corrections. The number (%) of subjects meeting the 
following criteria will be summarized. 
• QTc > 450 msec 
• QTc > 480 msec 
• QTc > 500 msec 
• QTc increases from baseline > 30 msec 
• QTc increases from baseline > 60 msec 
In addition, the overall clinical evaluation of ECG results (normal, abnormal, not clinically 
significant abnormal, clinically significant abnormal) will also be summarized. 
3.6.3.4 
Weight  
The observed values and the changes from baseline in the weight and BMI will be 
summarized. 
3.7 
Pharmacokinetics  
Plasma VIB4920 concentration data will be tabulated by dose cohort together with 
descriptive statistics. Individual and mean plasma concentration-time profiles of VIB4920 by 
treatment will be generated.  
Noncompartmental analysis will be performed for VIB4920-treated subjects. When possible, 
the following PK parameters will be accessed for VIB4920 plasma concentration: maximum 
observed concentration (Cmax), area under the concentration-time curve (AUC), systemic 
clearance (CL), and terminal elimination half-life (t1/2). Additional PK parameters may be 
determined and reported as appropriate. Descriptive statistics for PK parameters will be 
provided. 
The plasma concentration of VIB4920, summary statistics, PK profile, and the additional 
PK-related analyses will be reported in a clinical PK report (an addendum to the clinical 
study report). 
3.8 
Immunogenicity  
The ADA status will be summarized for the safety analysis set by the categories defined in 
Table 2. The ADA incidence rate will also be summarized, where the incidence is the 
proportion of the subjects with ADA positive post-baseline only or boosted their pre-existing 
ADA during the study period. The boosted ADA is defined as ADA level of ≥4× baseline 
level. If data allow, the ADA titer for the ADA positive subjects will be summarized and the 
impact of ADA on efficacy and safety will be evaluated. 


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Table 2 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
3.9 
Pharmacodynamics  
Total sCD40L level, as well as change from baseline, will be summarized with descriptive 
statistics at each visit. 
 
  
 
  
 
 
 
  
 
 
 


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4 PLANNED ANALYSIS  
4.1 
Primary Efficacy Analysis  
The primary efficacy analysis will be conducted after all subjects have completed the Day 
113 visit or discontinued early from the study. As the primary analysis will be an interim 
analysis, a small prespecified number of Sponsor staff who are not directly involved in the 
conduct of the study will be unblinded for decision-making purposes. Study site personnel, 
subjects, and CRO and Sponsor personnel directly associated with the conduct of the study 
will remain blinded to the treatment assignment for individual subjects and the results of the 
primary analysis until the completion of the study. The efficacy and safety data prior to the 
data cut-off for the primary analysis will be analyzed.  
4.2 
Final Analysis  
The final analysis will be conducted after all subjects have completed the study.  
 
5 REFERENCES  
Aletaha et al, 2005 
Aletaha D, Nell VP, Stamm T, Uffmann M, Pflugbeil S, Machold K, et al. Acute phase 
reactants add little to composite disease activity indices for rheumatoid arthritis: validation of 
a clinical activity score. Arthritis Res Ther. 2005; 7(4): R796-806 
Hochberg, 1988 
Hochberg Y.  A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 
1988; 75(4): 800-02. 
Smolen et al, 2003 
Smolen JS, Breedveld FC, Schiff MH, Kalden JR, Emery P, Eberl G, van Riel PL, Tugwell P. 
A simplified disease activity index for rheumatoid arthritis for use in clinical 
practice. Rheumatology (Oxford) 2003; 42: 244–257.  
Wells et al, 2009 
Wells G, Becker JC, Teng J, Dougados M, Schiff M, Smolen J, et al. Validation of the 28-
joint Disease Activity Score (DAS28) and European League Against Rheumatism response 
criteria based on C-reactive protein (CRP) against disease progression in patients with 
rheumatoid arthritis, and comparison with the DAS28 based on erythrocyte sedimentation 
rate. Ann Rheum Dis. 2009; 68(6): 954-60. 






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Figure 1.  Geometric mean percent reduction from baseline in rheumatoid factor (Phase 1b 
study of VIB4920) 
 


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