A Phase 2, Randomized, Placebo-controlled, Parallel-group, Double-blinded, proof-of Concept Study to Evaluate the Safety and Efficacy of Intravenous Efgartigimod in Adult Participants With Primary Sjögren's Syndrome
Phase: PHASE2
Conditions: Primary Sjögren's Syndrome
Sponsor: argenx

Clinical Study Protocol ARGX-113-2106 v2.0 
 
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CLINICAL STUDY PROTOCOL 
 
 
 
Protocol Title: 
A Phase 2, Randomized, Placebo-Controlled, Parallel-Group, 
Double-Blinded, Proof-of-Concept Study to Evaluate the Safety and 
Efficacy of Intravenous Efgartigimod in Adult Participants With 
Primary Sjögren’s Syndrome  
Protocol Number: 
ARGX-113-2106 
Version Number: 
2.0 (Amendment 1) 
Compound: 
Efgartigimod (ARGX-113) 
Study Phase: 
2 
Sponsor Name: 
argenx BV 
Legal Registered  
Address: 
Industriepark Zwijnaarde 7 
9052 Zwijnaarde (Ghent) 
Belgium 
Phone: +32 9 310 34 00  
Fax: +32 9 310 34 99 
Regulatory Agency 
Identifier Number(s): 
EUDRACT: 2021-005911-30 
Approval Date: 
05 Dec 2022 
 
 
System Version: 1.0, Status: Approved, Document ID: VV-TMF-90329

Clinical Study Protocol ARGX-113-2106 v2.0 
 
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Sponsor’s Medical 
Contact: 
 
, MD  
Global Clinical Trial Physician 
argenx BV  
33 Arch St  
Boston, MA  
United States 
Email:
 
Contract Research 
Organization: 
IQVIA 
 
24-Hour Urgent 
Medical Helpline:  
IQVIA’s Medical Emergency Contact Center can be accessed 24/7 by 
calling the relevant telephone number(s) 
IQVIA 24/7 Medical Emergency Contact Center (MECC): 
EU: +33 1 86 99 00 19 
Serious Adverse 
Event Reporting: 
Email: safety@argenx.com 
Fax: +1 833 874 7325  
The information contained in this medium is the property of argenx BV and/or its subsidiaries 
(jointly “argenx”) and is confidential and proprietary. Without prior authorization from argenx, 
information contained herein may not be used, reproduced, divulged, published, or otherwise 
disclosed to anyone. 
 
System Version: 1.0, Status: Approved, Document ID: VV-TMF-90329

Clinical Study Protocol ARGX-113-2106 v2.0 
 
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SIGNATURE OF SPONSOR 
 
Protocol Title: 
A Phase 2, Randomized, Placebo-Controlled, Parallel-Group 
Double-Blinded, Proof-of-Concept Study to Evaluate the Safety and 
Efficacy of Intravenous Efgartigimod in Adult Participants With 
Primary Sjögren’s Syndrome  
 
Protocol Number: 
ARGX-113-2106 
Sponsor Signatory: 
 
 
See appended signature page  
 
, MD, PhD 
Chief Medical Officer 
 
Date  
 
 
 
System Version: 1.0, Status: Approved, Document ID: VV-TMF-90329

Clinical Study Protocol ARGX-113-2106 v2.0 
 
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SIGNATURE OF THE INVESTIGATOR 
Investigator’s Acknowledgment 
I have read the protocol for study ARGX-113-2106. 
Title: A Phase 2, Randomized, Placebo-Controlled, Parallel-Group, Double-Blinded, 
Proof-of-Concept Study to Evaluate the Safety and Efficacy of Intravenous Efgartigimod in 
Adult Participants With Primary Sjögren’s Syndrome  
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor’s representative.  
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a participant in order to obtain their consent to participate.  
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use guidelines on Good Clinical Practice and with the applicable 
regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study, I will communicate my intention 
immediately in writing to the sponsor. 
 
SUMMARY OF CHANGES 
Protocol Amendment Summary of Changes Table 
Global protocol document history 
Date 
Investigator Name 
Institution 
Address 
(please hand print or type) 
 
 
 
 
Signature 
 
 
 
Date 
 
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Clinical Study Protocol ARGX-113-2106 v2.0 
 
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v2.0 amendment 1 
05 Dec 2022 
Original Protocol v1.0 
18 Aug 2022 
Amendment 1 (05 Dec 2022) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
The primary rationale for this amendment is to permit the use of historic biopsy where taken 
within 12 months of enrollment to prevent participants from needing to undergo unnecessary 
procedures, and to update the permitted/excluded concomitant medications to allow participants 
to receive required therapy. Other clarifications and corrections have been made and are 
summarized below. 
The major changes from protocol version 1.0 to protocol version 2.0 are summarized in the 
following table. Minor editorial changes, including the correction of typographical errors and 
formatting inconsistencies, are not summarized in the table. Refer to the List of Abbreviations 
for any undefined abbreviations. 
Section # and Name 
Description of Change 
Brief Rationale 
Cover page 
Sponsor’s Medical Contact details 
updated from 
, MD to 
, MD. 
To reflect change in personnel for this 
study role. 
Section 1.1, Synopsis 
Changed text stating 60-day follow-up 
period to 56-day (±3 days) follow-up 
period. 
Minor error in original protocol wording 
required update. 
Section 1.3, Schedule 
of Activities 
Removed PK sampling requirement from 
Safety Follow-up Visit. 
Not required as part of safety analyses. 
No IMP is expected to be detectable in the 
blood at the point of Safety Follow-Up 
Visit. 
Removed parotid biopsy sampling at 
IMP discontinuation visit. 
Included in error in original protocol; 
parotid biopsy sampling to occur at week 
24 or at the EDV, whichever is earlier.  
Clarified that participants at sites 
performing parotid biopsy may be 
enrolled based on a historical biopsy 
from within 12 months prior to 
screening, where participant has not 
received immunomodulatory treatment 
for pSS from 6 months prior to biopsy 
through to screening. 
To prevent participants from needing to 
undergo unnecessary procedures. 
Added footnote for parotid biopsy EDV 
sampling timepoint stating that this 
should only occur when this visit occurs 
after week 16. 
Changes in biopsy results are not expected 
to be visible prior to week 16. 
Section 1.1, Synopsis 
Minor updates made to description of 
pSS. 
Wording updates made for accuracy and 
clarity. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 2.2, 
Background 
Section 4.2, Scientific 
Rationale for Study 
Design 
Addition of statement: “The totality of 
data from all endpoints used in the study 
will be utilized to determine treatment 
response in this population.” 
Added to clarify why various secondary 
endpoints were used for pSS. 
Section 5.1, Inclusion 
Criteria 
Updated inclusion criterion 4 to state “at 
screening”. 
 
All criteria based on status at screening 
instead of based on historical findings. 
Section 5.2, Exclusion 
Criteria 
 
Updated exclusion criterion 15 from 
“IVIg, SCIg, or PLEX < 12 weeks before 
screening” to “IVIg, SCIg, or PLEX ≤ 12 
weeks before screening”. 
Changed to ≤ 12 weeks for consistency 
with other exclusion criteria.  
Clarified that exclusion criteria 18 
requires anticholinergic agents to be at a 
stable dose 4 weeks prior to screening or 
during screening. 
Requirement to be at a stable dose 4 weeks 
prior to screening was not included in 
original protocol in error. 
Modified exclusion criteria around prior 
and concomitant medications. 
Prior and concomitant medications 
permitted during study have been modified 
to ensure participants have access to 
required therapies during study; prior and 
concomitant medication exclusion criteria 
have been updated to align with this. 
Section 6.5, Study 
Compliance 
Addition of requirement “Documentation 
will include both start and end time of 
infusion.” 
Sentence added to ensure start and end 
times are captured. 
Section 6.6, Dose 
Modification 
Replacement of text “weight has changed 
by more than ±10% during the insert 
time frame” with “weight has changed 
(increased or decreased) by more than 
10% from baseline”. 
Minor error in original protocol wording 
required update. 
Section 6.8, Treatment 
of Overdose 
Modified text on treatment of overdose 
to remove requirement to immediately 
report and to clarify that overdose must 
be recorded in the eCRF. 
Previous text was not clear regarding 
where the overdose should be captured or 
who it was to be reported to. 
Section 6.9, Prior and 
Concomitant Therapy 
Medication requirements added for the 
period prior to study treatment, and the 
follow-up period after study treatment. 
Detail on prior therapies and therapies 
during follow-up period previously not 
detailed in this section. 
Addition of requirement: “Any treatment 
used for pSS in the last 6 months prior to 
screening should also be recorded.” 
Added to allow verification via eCRF that 
the patient has not taken any prohibited 
medications in the 6 months prior to 
screening 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 7.1.1, 
Permanent 
Discontinuation  
Added in IMP discontinuation visit for 
participants who permanently 
discontinue IMP. 
Clarified that if the discontinued 
participant is unable or unwilling to 
attend further study visits, the study site 
will perform an EDV and the SFV. 
IMP discontinuation visit previously not 
included in this section, in error. Updated 
to correct this and improve readability. 
Section 7.1.1, 
Permanent 
Discontinuation  
Section 8.5, 
Pharmacokinetics 
Added that blood samples for 
participants remaining in the study 
following IMP discontinuation will be 
collected for PK analyses as per the SoA 
for up to 3 weeks post IMP 
discontinuation. 
IMP is expected to still be detectable in 
blood following permanent 
discontinuation. 
Section 1.3, Schedule 
of Activities 
Section 8.2.3, ESSDAI 
Added information on ESSDAI-related 
laboratory tests (gammaglobulins, 
cryoglobulins, C3, Cs4 and CH50). 
Tests included in original protocol, but not 
detailed that this was part of the ESSDAI 
efficacy assessments. 
Section 8.2, Efficacy 
Assessments 
Section 8.2.7.2, 
Salivary Flow Rate 
Replaced “study manual” with 
“Investigator Site File”. 
Study does not include use of a formal 
study manual; information will instead be 
included in Investigator Site File. 
Section 8.2.7.1, SGUS 
Added names of the 4 major salivary 
glands (left and right parotid and 
submandibular glands). 
Added to clarify the glands used in 
calculation of the overall ultrasound score. 
Section 8.3.2, Vital 
Signs 
Changed “oral temperature” to “body 
temperature”. 
Updated as non-oral methods of body 
temperature measurement are also 
considered acceptable. 
 
Section 8.5, 
Pharmacokinetics 
Updated to state that on visits without 
IMP administration, a single blood 
sample will be collected as described in 
the SoA. 
Clarified for consistency with SoA. 
Added that “Samples collected after the 
end of infusion should be collected in the 
opposite arm from the arm used for IMP 
infusion.” 
Clarification of required process. 
Section 1.3, Schedule 
of Activities 
Section 8.5, 
Pharmacokinetics 
Section 8.6, 
Pharmacodynamics 
Section 8.8, 
 
Section 8.9 
Immunogenicity 
Assessments 
Updated blood sampling requirements to 
state that on visits without IMP 
administration, samples may be collected 
at any time during the visit. 
No restrictions are considered required 
around blood sample timings on these 
visits. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 9.3.2, Primary 
Endpoint Analysis 
Text amended to focus on effect 
estimates. 
Removed p-value from CRESS 
responder analysis text. 
Sample size calculations were based upon 
the confidence interval for the proportion 
of CRESS responders in the efgartigimod 
treatment group. 
 
Section 1.1, Synopsis 
Section 9.5, Sample 
Size Determination 
Text updated from “approximately 
30 participants will be enrolled” to state 
that participants will be randomized to 
achieve approximately 15 randomized 
participants with an IgG value at 
screening > 16.0 g/L and 15 participants 
without > 16.0 g/L.  
Over 30 participants may be required to be 
enrolled to achieve approximately 
15 randomized participants in each IgG 
subgroup. Approximately 
% of 
participants are expected to have IgG 
> 16.0 g/L. 
 
 
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Clinical Study Protocol ARGX-113-2106 v2.0 
 
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TABLE OF CONTENTS 
SIGNATURE OF SPONSOR ..........................................................................................................3 
SIGNATURE OF THE INVESTIGATOR ......................................................................................4 
LIST OF ABBREVIATIONS ........................................................................................................14 
1. 
PROTOCOL SUMMARY ..........................................................................................17 
1.1. 
Synopsis ......................................................................................................................17 
1.2. 
Schema ........................................................................................................................21 
1.3. 
Schedule of Activities .................................................................................................22 
2. 
INTRODUCTION ......................................................................................................27 
2.1. 
Study Rationale ...........................................................................................................27 
2.2. 
Background .................................................................................................................27 
2.3. 
Benefit/Risk Assessment ............................................................................................27 
2.3.1. 
Risk Assessment .........................................................................................................27 
2.3.2. 
Benefit Assessment .....................................................................................................28 
2.3.3. 
Overall Benefit-Risk Conclusion ................................................................................28 
3. 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS ..................................................29 
4. 
STUDY DESIGN .......................................................................................................32 
4.1. 
Overall Design ............................................................................................................32 
4.2. 
Scientific Rationale for Study Design ........................................................................32 
4.3. 
Justification for Dose ..................................................................................................33 
4.4. 
End-of-Study Definition .............................................................................................33 
5. 
STUDY POPULATION .............................................................................................35 
5.1. 
Inclusion Criteria ........................................................................................................35 
5.2. 
Exclusion Criteria .......................................................................................................35 
5.3. 
Lifestyle Considerations .............................................................................................37 
5.3.1. 
Meals and Dietary Restrictions ...................................................................................37 
5.3.2. 
Caffeine, Alcohol, and Tobacco .................................................................................37 
5.3.3. 
Activity .......................................................................................................................37 
5.4. 
Screen Failures ............................................................................................................37 
5.5. 
Criteria for Temporarily Delaying Enrollment ...........................................................38 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ........................39 
6.1. 
Study Intervention(s) Administered ...........................................................................39 
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6.2. 
Preparation, Handling, Storage, and Accountability ..................................................40 
6.3. 
Assignment to Study Intervention ..............................................................................40 
6.4. 
Blinding ......................................................................................................................40 
6.5. 
Study Compliance .......................................................................................................40 
6.6. 
Dose Modification ......................................................................................................41 
6.7. 
Continued Access to IMP After the End of the Study ................................................41 
6.8. 
Treatment of Overdose ...............................................................................................41 
6.9. 
Prior and Concomitant Therapy ..................................................................................41 
7. 
DISCONTINUATION OF IMP AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................46 
7.1. 
Discontinuation of IMP ..............................................................................................46 
7.1.1. 
Permanent Discontinuation .........................................................................................46 
7.1.2. 
Temporary Discontinuation ........................................................................................46 
7.2. 
Participant Discontinuation/Withdrawal From the Study ...........................................47 
7.3. 
Lost to Follow-up .......................................................................................................47 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................48 
8.1. 
Administrative Procedures ..........................................................................................48 
8.1.1. 
Use and Storage of Biological Samples ......................................................................48 
8.2. 
Efficacy Assessments .................................................................................................48 
8.2.1. 
CRESS ........................................................................................................................48 
8.2.2. 
Parotid Gland Histology .............................................................................................49 
8.2.3. 
ESSDAI ......................................................................................................................50 
8.2.4. 
ClinESSDAI ...............................................................................................................50 
8.2.5. 
STAR ..........................................................................................................................51 
8.2.6. 
Patient-Reported Outcomes ........................................................................................52 
8.2.6.1. 
ESSPRI .......................................................................................................................52 
8.2.6.2. 
52 
8.2.6.3. 
52 
8.2.6.4. 
53 
8.2.6.5. 
53 
8.2.6.6. 
53 
8.2.7. 
Additional Efficacy Measures ....................................................................................54 
8.2.7.1. 
SGUS ..........................................................................................................................54 
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8.2.7.2. 
Salivary Flow Rate .....................................................................................................54 
8.2.7.3. 
Schirmer’s Test ...........................................................................................................54 
8.2.7.4. 
OSS .............................................................................................................................54 
8.3. 
Safety Assessments .....................................................................................................54 
8.3.1. 
Physical Examinations ................................................................................................55 
8.3.2. 
Vital Signs ..................................................................................................................55 
8.3.3. 
Electrocardiograms .....................................................................................................55 
8.3.4. 
Protocol-Required Laboratory Tests...........................................................................55 
8.3.5. 
Pregnancy Testing ......................................................................................................55 
8.4. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting .....................55 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................56 
8.4.2. 
Method of Detecting AEs and SAEs ..........................................................................56 
8.4.3. 
Follow-up of AEs and SAEs .......................................................................................56 
8.4.4. 
Regulatory Reporting Requirements for SAEs ...........................................................56 
8.4.5. 
Pregnancy ...................................................................................................................57 
8.4.6. 
Adverse Events of Special Interest .............................................................................57 
8.5. 
Pharmacokinetics ........................................................................................................58 
8.6. 
Pharmacodynamics .....................................................................................................58 
8.7. 
Genetics ......................................................................................................................58 
8.8. 
.58 
8.9. 
Immunogenicity Assessments ....................................................................................59 
8.10. 
Health Economics or Medical Resource Utilization and Health Economics .............59 
9. 
STATISTICAL CONSIDERATIONS .......................................................................60 
9.1. 
Statistical Hypothesis ..................................................................................................60 
9.2. 
Analysis Sets ...............................................................................................................60 
9.3. 
Statistical Analyses .....................................................................................................60 
9.3.1. 
General Considerations ...............................................................................................60 
9.3.2. 
Primary Endpoint Analysis .........................................................................................61 
9.3.3. 
Secondary Endpoint Analyses ....................................................................................61 
9.3.4. 
Exploratory Endpoint Analyses ..................................................................................61 
9.3.5. 
Safety Analyses ..........................................................................................................61 
9.3.6. 
Other Analyses ............................................................................................................62 
9.4. 
Interim Analysis ..........................................................................................................62 
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9.5. 
Sample Size Determination ........................................................................................62 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................63 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................63 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................63 
10.1.2. 
Financial Disclosure ...................................................................................................63 
10.1.3. 
Informed Consent Process ..........................................................................................64 
10.1.4. 
Recruitment Strategy ..................................................................................................64 
10.1.5. 
Data Protection ...........................................................................................................64 
10.1.6. 
Committees Structure .................................................................................................64 
10.1.7. 
Dissemination of Clinical Study Data ........................................................................65 
10.1.8. 
Data Quality Assurance ..............................................................................................65 
10.1.9. 
Source Documents ......................................................................................................65 
10.1.10. 
Study and Site Start and Closure ................................................................................66 
10.1.11. 
Publication Policy .......................................................................................................67 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................68 
10.2.1. 
Other Screening Tests .................................................................................................69 
10.2.1.1. 
SARS-CoV-2 ..............................................................................................................69 
10.2.1.2. 
Hepatitis B Virus ........................................................................................................69 
10.2.1.3. 
Hepatitis C Virus ........................................................................................................69 
10.2.1.4. 
Human Immunodeficiency Virus ...............................................................................69 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................71 
10.3.1. 
Definition of AE .........................................................................................................71 
10.3.2. 
Definition of SAE .......................................................................................................72 
10.3.3. 
Recording and Follow-up of AE and/or SAE .............................................................73 
10.3.4. 
Reporting of SAEs and AESIs ....................................................................................74 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ......................................................76 
10.4.1. 
Women of Childbearing Potential Definition .............................................................76 
10.4.2. 
Contraception Guidance .............................................................................................76 
10.4.2.1. 
Female Contraception for WOCBP ............................................................................76 
10.4.2.2. 
Male Contraception ....................................................................................................76 
10.5. 
Appendix 5: Operational Considerations for COVID-19 Risk Mitigation .................77 
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10.6. 
Appendix 6: Home Study Visits .................................................................................77 
10.7. 
Appendix 7: Efficacy Endpoint Data ..........................................................................78 
10.7.1. 
ESSDAI ......................................................................................................................78 
10.8. 
Appendix 8: ACR-EULAR Classification Criteria ....................................................82 
11. 
REFERENCES ...........................................................................................................84 
 
LIST OF TABLES 
Table 1: 
Study ARGX-113-2106 Objectives and Endpoints ....................................................29 
Table 2: 
Study Intervention(s) Administered ...........................................................................39 
Table 3: 
Study Arm(s) ..............................................................................................................39 
Table 4: 
Prior and Concomitant Therapy ..................................................................................43 
Table 5: 
Comparison of Domain Weights of Original ESSDAI and clinESSDAI ...................51 
Table 6: 
Protocol-Required Safety Laboratory Tests ...............................................................68 
Table 7: 
Interpretation of Hepatitis B Serological Test Results ...............................................69 
Table 8: 
Interpretation of the Hepatitis C Antibody Test .........................................................69 
Table 9: 
Interpretation of HIV Test Results .............................................................................70 
Table 10: ESSDAI: Domain and Item Definitions and Weights ................................................78 
Table 11: ACR-EULAR Classification Criteria for Primary Sjögren’s Syndrome ....................83 
 
LIST OF FIGURES 
Figure 1: 
ARGX-113-2106 Study Overview .............................................................................21 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Expansion 
21 CFR 
Title 21 of the Code of Federal Regulations 
AChR-Ab 
anti-acetylcholine receptor antibody 
ACR 
American College of Rheumatology 
ADA 
antidrug antibody(ies) 
ADL 
activities of daily living 
AE 
adverse event 
AESI 
adverse event of special interest 
 
 
C3 
complement component 3 
C4 
complement component 4 
CIDP 
chronic inflammatory demyelinating polyneuropathy 
clinESSDAI 
clinical EULAR Sjögren’s syndrome disease activity index 
CRESS 
Composite of Relevant Endpoints for Sjögren’s Syndrome 
CRO 
contract research organization 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMARD 
disease-modifying antirheumatic drug 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EDV 
early discontinuation visit 
efgartigimod IV 
efgartigimod formulation for intravenous administration 
eGFR 
estimated glomerular filtration rate 
ESSDAI 
EULAR Sjögren’s syndrome disease activity index 
ESSPRI 
EULAR Sjögren’s Syndrome Patient Reported Index 
EULAR 
European Alliance of Associations for Rheumatology 
FcRn 
neonatal crystallizable fragment receptor 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
gMG 
generalized myasthenia gravis 
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Abbreviation 
Expansion 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
independent ethics committee 
 
 
 
 
IgG 
immunoglobulin G 
 
 
IMP 
investigational medicinal product 
IRB 
institutional review board 
IRT 
interactive response technology 
ITP 
immune thrombocytopenia 
IV 
intravenous 
IVIg 
intravenous immunoglobulin 
JAK 
Janus kinase 
MedDRA 
Medical Dictionary for Regulatory Activities  
 
 
NCI 
National Cancer Institute 
NSAID 
non-steroidal anti-inflammatory drug 
OLE 
open-label extension 
OSS 
ocular staining score 
 
 
 
 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic(s) 
 
  
PK 
pharmacokinetic(s) 
PLEX 
plasma exchange 
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Abbreviation 
Expansion 
PMDA 
Pharmaceuticals and Medical Devices Agency 
pSS 
primary Sjögren’s syndrome 
PT 
preferred term 
 
 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCIg 
subcutaneous immunoglobulin 
 
 
SFV 
safety follow-up visit 
SGUS 
salivary gland ultrasonography 
SoA 
schedule of activities 
SOC 
system organ class 
SS-A 
Sjögren’s syndrome–related antigen A 
SS-B 
Sjögren’s syndrome–related antigen B 
STAR 
Sjögren’s Tool for Assessing Response 
SUSAR 
suspected unexpected serious adverse reaction 
SWSF 
stimulated whole salivary flow  
TEAE 
treatment-emergent adverse event 
UWSF 
unstimulated whole salivary flow 
 
  
WOCBP 
women of childbearing potential 
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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title:  
A phase 2, randomized, placebo-controlled, parallel-group, double-blinded, proof-of-concept 
study to evaluate the safety and efficacy of intravenous efgartigimod in adult participants with 
primary Sjögren’s syndrome 
Rationale:  
pSS is a chronic, progressive autoimmune disease of unknown etiology, typically characterized 
by an autoimmune exocrinopathy. Currently, no immunomodulatory treatment is available for 
pSS. The purpose of this study is to evaluate the effect of efgartigimod, a human FcRn antagonist 
that can rapidly reduce IgG levels, including pathogenic antibodies. Efgartigimod has the 
potential to successfully treat pSS and improve disease manifestations by the reduction of IgG 
autoantibodies. 
Objectives, Endpoints, and Estimands:  
Objectives 
Endpoints 
Primary 
• To evaluate the effect of 
efgartigimod IV compared to 
placebo on CRESS 
• Proportion of CRESS responders on ≥ 3 of 5 items at week 24 
(refer to Section 8.2.1). The 5 items are:  
− Systemic disease activity: clinESSDAI 
− Patient-reported symptoms: ESSPRI  
− Tear gland function: Schirmer’s test and OSS 
− Salivary gland function: UWSF rate and SGUS 
− Serology (serum IgG and/or RF) 
Secondary 
• To evaluate the effect of 
efgartigimod IV compared to 
placebo on the histology of 
the parotid gland (selected 
sites only) 
• Change in the relative counts of lymphocytic infiltrate (stained for 
CD45) at week 24 
• Change in B/B+T cell ratio at week 24 
• To evaluate the safety of 
efgartigimod IV compared to 
placebo in participants with 
pSS 
• Incidence and severity of TEAEs, AESIs, and SAEs by SOC and PT  
• Changes in vital sign measurements, ECG results, and clinical 
laboratory safety evaluations  
• To evaluate the effect of 
efgartigimod IV compared to 
placebo on clinical efficacy 
parameters  
• Proportion of participants with minimal clinically important 
improvement in ESSDAI: improvement of ≥ 3 points in ESSDAI 
score at week 24 
• Proportion of participants with low disease activity: ESSDAI score 
of < 5 at week 24 
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Objectives 
Endpoints 
• Proportion of participants with minimal clinically important 
improvement in clinESSDAI: improvement of ≥ 3 points in 
clinESSDAI score at week 24 
• Proportion of participants with low disease activity: clinESSDAI 
score of < 5 at week 24 
• Proportion of participants with minimal clinically important 
improvement in ESSPRI: decrease of 1 point or ≥ 15% at week 24 
• Change in ESSDAI score at week 24 
• Change in clinESSDAI score at week 24 
• Change in ESSPRI score at week 24 
• To evaluate the effect of 
efgartigimod IV compared to 
placebo on STAR 
• Proportion of participants with STAR score of ≥ 5 at week 24 
• To evaluate the PK of 
efgartigimod IV 
• Efgartigimod serum concentration-time profile  
• To evaluate the PD of 
efgartigimod IV 
 
• Values, changes from baseline, and percent reduction from baseline 
in total IgG levels in serum 
• Values, changes from baseline, and percent reduction from baseline 
in autoantibodies in serum:  
− Anti-Ro/SS-A  
− Anti-La/SS-B 
• To evaluate the 
immunogenicity of 
efgartigimod IV 
• Incidence and prevalence of ADA against efgartigimod in serum 
Exploratory 
• 
 
 
 
 
• 
 
 
• 
 
• 
 
 
 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
 
 
 
• 
 
• 
 
 
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Objectives 
Endpoints 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
 
 
 
 
  
• 
 
  
 
• 
 
 
 
  
• 
 
 
• 
 
• 
 
  
• 
 
 
• 
 
 
 
• 
 
 
 
• 
 
 
•
 
 
• 
 
 
 
• 
 
Note: Estimands are not defined for this phase 2 study. 
Overall Design Synopsis: 
This is a randomized, placebo-controlled, parallel-group, double-blinded, multicenter, proof-of-
concept phase 2 study in pSS. Participants will be randomized to receive efgartigimod or placebo 
for 24 weeks. At the end of the randomized treatment period, eligible participants may roll over 
to an OLE study or remain in this study through the end of the 56-day (± 3 days) follow-up 
period.  
Brief Summary: 
The purpose of this study is to assess the efficacy and safety of FcRn blocking therapy with 
efgartigimod in participants with pSS. Efgartigimod has the potential to successfully treat pSS 
and improve disease manifestations by the reduction of IgG autoantibodies in pSS. After a 
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4-week screening period, participants will receive IMP weekly for 24 weeks, followed by entry 
into an OLE study or a 56-day (± 3 days) follow-up period.  
Health Measurement/Outcome: The purpose of this study is to assess the efficacy and safety of 
FcRn blocking therapy with efgartigimod in participants with pSS.  
Study Intervention and Intervention Form: The study intervention will be efgartigimod IV 
10 mg/kg or placebo IV. 
Condition/Disease: pSS 
Study Duration:  
• Approximately 36 weeks for participants not enrolling in the OLE study 
• Approximately 28 weeks for participants enrolling in the OLE study 
Treatment Duration: 24 weeks 
Visit Frequency: weekly (site and home) 
Number of Participants: 
Participants will be randomized in a 2:1 ratio (efgartigimod:placebo) to achieve approximately 
15 randomized participants with an IgG value at screening > 16.0 g/L and 15 randomized 
participants without an IgG value at screening > 16.0 g/L. 
Eligibility of participants will be assessed during a 4-week screening period. After the screening 
period, eligible participants will be randomized in a 2:1 ratio between efgartigimod and placebo 
arms, respectively. 
Note: Enrolled means the participant or their legally acceptable representative agrees to 
participate in the clinical study after completing the informed consent process.  
Study Arms and Duration: 
For participants not enrolling in the OLE study, the study duration is approximately 36 weeks, 
spanning the following study periods: 
• Screening: ≤ 4 weeks  
• Treatment: 24 weeks  
• Follow-up: 56 days 
For participants rolling over to the OLE study, the study duration is approximately 28 weeks, 
spanning the following study periods: 
• Screening: ≤ 4 weeks  
• Treatment: 24 weeks  
All participants will receive efgartigimod IV 10 mg/kg or placebo once weekly for 24 weeks 
during the treatment period. 
Data Monitoring/Other Committee: No 
 
 
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1.2. 
Schema 
Figure 1: 
ARGX-113-2106 Study Overview 
 
ACR=American College of Rheumatology; D=day; ESSDAI=EULAR Sjögren’s syndrome disease activity index; 
EULAR=European Alliance of Associations for Rheumatology; IV=intravenous; n=number of participants; 
OLE=open-label extension; pSS=Sjögren’s syndrome; SS-A=anti-Sjögren’s syndrome–related antigen A; 
SWSF=stimulated whole salivary flow (rate); UWSF=unstimulated whole salivary flow (rate); W=week 
 
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1.3. 
Schedule of Activities 
Study week 
SCR 
Study week 
SFVa 
(56 d 
after 
final 
dose) 
Applicable 
protocol 
section(s) 
−28 
to −2 
BL 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 IMP 
d/c 
visitb 
EDVc 
(≤ 7 d 
after 
final 
dose) 
±Days 
±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 
+2 
±3 
Visitsd,e  
1 
2 
3 
4 
5 
6 
7 
8 
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 NA 
NA 
NA 
Informed 
consent 
X 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.1.3 
Inclusion and 
exclusion 
criteria  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 
Medical/ 
surgical historyf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.3 
Demographyg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examinationh 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.3.1 
Brief physical 
examination 
(symptom 
driven)i 
 
 
X X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
8.3.1 
Vital signsj 
X 
X X X X X X X X X X X X X X X X X X X X X X X X X 
X 
X 
X 
8.3.2 
ECG 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
8.3.3 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3 
Glandular function 
UWSF/SWSF 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
8.2.7.2 
Schirmer’s test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
8.2.7.3 
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Study week 
SCR 
Study week 
SFVa 
(56 d 
after 
final 
dose) 
Applicable 
protocol 
section(s) 
−28 
to −2 
BL 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 IMP 
d/c 
visitb 
EDVc 
(≤ 7 d 
after 
final 
dose) 
±Days 
±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 
+2 
±3 
Visitsd,e  
1 
2 
3 
4 
5 
6 
7 
8 
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 NA 
NA 
NA 
OSS 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
8.2.7.4 
SGUS 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
8.2.7.1  
Histology 
Parotid biopsy 
(selected sites 
only)k 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Xl 
 
8.2.2 
Safety laboratory assessments (Table 6) 
Clinical 
laboratory tests 
(hematology and 
chemistry) 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
8.3.4 
Serology 
HIV/hepatitis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.3.4 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
8.3 
Pregnancy 
testingm 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
8.3.5 
PCR COVID-19 
testn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.2.1.1 
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Study week 
SCR 
Study week 
SFVa 
(56 d 
after 
final 
dose) 
Applicable 
protocol 
section(s) 
−28 
to −2 
BL 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 IMP 
d/c 
visitb 
EDVc 
(≤ 7 d 
after 
final 
dose) 
±Days 
±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 
+2 
±3 
Visitsd,e  
1 
2 
3 
4 
5 
6 
7 
8 
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 NA 
NA 
NA 
Blood samples 
 
 
8.8 
PKr  
 
X X X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
 
8.5 
Total IgGo 
X 
X X X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
8.6 
 
8.8 
Anti-Ro/SS-A, 
anti-La/SS-B 
autoanti- 
bodieso  
X 
X X X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
5.1, 8.6 
Immuno- 
genicityo  
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
8.9 
 
 
  
8.8 
Systemic disease activity 
ESSDAIt  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
8.2.3 
clinESSDAI 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
8.2.4 
Patient-reported outcome questionnairesv  
ESSPRI  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
8.2.6.1 
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Study week 
SCR 
Study week 
SFVa 
(56 d 
after 
final 
dose) 
Applicable 
protocol 
section(s) 
−28 
to −2 
BL 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 IMP 
d/c 
visitb 
EDVc 
(≤ 7 d 
after 
final 
dose) 
±Days 
±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 ±1 
+2 
±3 
Visitsd,e  
1 
2 
3 
4 
5 
6 
7 
8 
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 NA 
NA 
NA 
 
8.2.6.2 
 
8.2.6.3 
  
8.2.6.4 
 
8.2.6.6 
 
8.2.6.5 
IMP 
administrationv  
 
X X X X X X X X X X X X X X X X X X X X X X X X 
 
 
 
 
6 
Concomitant 
therapiesw 
 
Continuous monitoring 
6.9 
AEsw 
 
Continuous monitoring 
8.4 
BL=baseline; C3=Complement component 3; C4=Complement component 4; CH50=Total hemolytic complement; clinESSDAI=clinical ESSDAI; D=day; 
d/c=discontinuation; ECG=electrocardiogram; EDV=early discontinuation visit; ESSDAI=EULAR Sjögren’s syndrome disease activity index; ESSPRI=EULAR 
Sjögren’s Syndrome Patient Reported Index; EULAR=European Alliance of Associations for Rheumatology; ICF=informed consent form; IgG=immunoglobulin 
G; IMP=investigational medicinal product; IV=intravenous; 
; NA=not applicable; OSS=ocular staining score; 
; PCR=polymerase chain reaction; PD=pharmacodynamics; 
; PK=pharmacokinetics; 
; SCR=screening; SFV=safety follow-up visit; 
; SGUS=salivary gland ultrasonography; SS-
A=Sjögren’s syndrome–related antigen A; SS-B=Sjögren’s syndrome–related antigen B; SWSF=stimulated whole salivary flow; UWSF=unstimulated whole 
salivary flow; W=week 
a For participants who discontinue IMP but remain in the study attending on-site visits, safety follow-up assessments will occur on the previously scheduled visit 
closest to 56 days (±3 days) from the final IMP dose. 
b The IMP discontinuation visit will be performed at the next scheduled visit after permanent IMP discontinuation and applies for participants who discontinue 
IMP but remain in the study. Participants who permanently discontinue IMP will perform the IMP discontinuation visit and then be asked to proceed with their 
regularly scheduled visits (Section 7.1.1).  
c The EDV applies for participants who discontinue the study. 
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d Visits 4, 6-8, 10-12, 14-16, 18-20, and 22-24 may be performed in the participant’s home by a home nurse. 
e Safety, efficacy, and predose sampling activities will be performed before administering IMP. 
f Medical/surgical history includes all significant findings, surgeries, and preexisting conditions (including allergies, if any) present at screening including start 
and end date, if known. 
g Demographic characteristics comprise age, birth year, sex, race, and ethnicity (per local regulations). Race and ethnicity data will be source verified only if 
permitted by local laws. 
h Physical examination will include height and weight. Height will be measured at the baseline visit only.  
i The brief physical examination is symptom driven and will be performed as necessary to assess the ESSDAI. It will also include weight.  
j Vital signs (Section 8.3.2) will all be measured before collecting any blood sample or administering IMP infusions. 
k 
 
. Participants at sites performing parotid biopsy may be enrolled based on a historical 
biopsy obtained in the 12 months prior to baseline visit. Historical biopsy may only be used for participant enrollment when participant has not received 
immunomodulatory treatment for pSS (such as steroids, immunosuppressants, antimalarials, or biologics) from 6 months prior to biopsy through to screening. 
l Participant should have a biopsy at EDV only when this visit occurs after week 16.  
m Pregnancy testing will use a highly sensitive serum test at screening, and a urine test at all subsequent visits before IMP administration. Local regulations will 
be followed if they require more stringent or frequent testing.  
n COVID-19 testing will occur within 72 hours of baseline. Participants will be tested for SARS-CoV-2 if they are symptomatic or if applicable law requires 
testing. COVID-19 testing may be performed at a central or local laboratory.  
o On IMP administration visits, blood samples must be collected predose (preferably within 2 hours before the infusion). On other visits, the blood sample may 
be collected any time during the visit. 
p Blood samples will be collected for 
 
 
q 
 
r On IMP administration visits, blood samples for PK analyses will be collected predose (preferably within 2 hours before IMP administration) and postdose 
(within 30 minutes after the end of infusion). On other visits, a single blood sample may be collected any time during the visit. Blood samples for participants 
remaining in the study following IMP discontinuation will be collected for PK analysis for up to 3 weeks post IMP discontinuation. 
s 
 
t ESSDAI-related laboratory tests include gammaglobulins, cryoglobulins, C3, C4 and CH50. The biological domain will be blinded postbaseline and sites will 
score only the clinical domains of the ESSDAI.  
u Patient-reported outcome questionnaires will be administered before any other study visit procedure where safe, and before discussions with staff about 
disease/treatment. 
v The IMP will be administered as an approximately 1-hour IV infusion. Participants will be monitored for safety for ≥ 30 minutes after the end of IMP 
administration. 
w AEs and use of concomitant therapies will be continuously monitored from the time the ICF is signed until the last study-related activity. 
 
 
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2. 
INTRODUCTION 
The purpose of this study is to assess the efficacy and safety of human FcRn blocking therapy 
with efgartigimod compared to placebo, in participants with pSS.  
2.1. 
Study Rationale 
For many decades, the clinical needs for pSS have been left unresolved because of the rareness 
of the disease and the complexity of the underlying pathogenic mechanisms. It has become clear 
that B-cell activation and development of autoantibodies play an important role in pSS.  
Efgartigimod is a first-in-class antibody fragment that binds to the FcRn. This binding prevents 
FcRn from recycling IgG and leads to a reduction in circulating disease-causing autoantibodies. 
Efgartigimod is being clinically developed in autoimmune diseases mediated by pathogenic IgG 
autoantibodies after approval by the United States FDA and Japan’s PMDA for use in adult 
patients with AChR-Ab seropositive gMG.  
Efgartigimod may be a viable treatment option for individuals diagnosed with pSS because it has 
been shown to reduce IgG levels, including IgG autoantibodies, that may underlie some of the 
autoimmune disease manifestations in these participants. Therefore, the reduction of 
autoantibodies may successfully reduce disease activity and symptoms in pSS participants.  
2.2. 
Background 
pSS is a chronic, progressive autoimmune disease of unknown etiology, typically characterized 
by an autoimmune exocrinopathy. Along with symptoms of excessive dryness, manifestations 
include profound fatigue, chronic pain, extraglandular organ system involvement, and increased 
risk of lymphomas. A hallmark of pSS is B-cell hyperactivity, causing a vicious cycle of immune 
activation through cytokine production, antigen presentation, and autoantibody secretion, 
potentially causing tissue damage. Currently, no immunomodulatory treatment is available for 
pSS.  
This study aims to evaluate the effect of efgartigimod, an FcRn antagonist that can rapidly 
reduce IgG, including pathogenic antibodies. Efgartigimod has the potential to successfully treat 
pSS and improve disease manifestations by the reduction of IgG autoantibodies in pSS. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of efgartigimod is 
provided in the current IB.  
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of efgartigimod is provided in the current IB. 
2.3.1. 
Risk Assessment 
Overall, available data confirm that efgartigimod IV has been well tolerated across studies in 
different indications and has an acceptable safety profile.  
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Potential clinically 
significant risk  
Summary of data/ 
rationale for risk 
Mitigation strategy 
Serious infection  
Efgartigimod reduces IgG levels, 
potentially hindering immune 
response and increasing the 
infection risk. 
Exclude participants with clinically 
significant uncontrolled infections 
(Section 5.2). 
Monitor for infections, considered an 
adverse event of special interest (AESI; 
Section 8.4.6), and temporarily interrupt 
IMP dosing as specified in Section 7.1. 
Infusion-related 
reactions (IRR) 
All therapeutic proteins have the 
potential to elicit immune 
responses, potentially resulting in 
hypersensitivity or allergic 
reactions such as rash, urticaria, 
angioedema, serum sickness, and 
anaphylactoid or anaphylactic 
reactions. 
As with any IV infusion, the potential 
exists for IRR, which may occur during or 
within 48 hours after infusion.  
Pretreatment to prevent an IRR is not 
required. IMP will be administered by a 
healthcare professional.  
2.3.2. 
Benefit Assessment 
Efgartigimod has been investigated in nonclinical studies, phase 1 clinical pharmacology studies 
in healthy participants, and phase 2/3 clinical studies in participants with IgG-driven 
autoimmune diseases, including gMG, primary ITP, CIDP, and pemphigus.  
In clinical studies, efgartigimod effectively reduces IgG antibody levels, including pathogenic 
autoantibodies. The efficacy of efgartigimod to improve clinical outcomes in gMG and reduce 
pathogenic autoantibodies was confirmed in a pivotal phase 3 study in participants with gMG 
(ARGX-113-1704). Clinical benefit was also observed in phase 2 studies in primary ITP 
(ARGX-113-1603) and pemphigus (ARGX-113-1701), in which pathogenic autoantibodies 
underlie the disease pathology (refer to current efgartigimod IB). Available clinical data support 
the clinical benefit of efgartigimod for reducing pathogenic IgG autoantibodies, which may 
mitigate autoimmune dysfunction and improve symptoms, as well as the ability to function, in 
participants with pSS. 
2.3.3. 
Overall Benefit-Risk Conclusion 
The potential risks associated with efgartigimod are justified by the anticipated benefits afforded 
to participants with pSS in this study and considering the measures implemented to minimize 
risks. The favorable balance between risks and anticipated efficacy/benefit supports the use of 
efgartigimod in the clinical development for pSS. 
More detailed information about the known and expected benefits and risks of efgartigimod and 
reasonably expected AEs can be found in the current IB. 
 
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3. 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS 
Table 1: 
Study ARGX-113-2106 Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• To evaluate the effect of 
efgartigimod IV compared to 
placebo on CRESS 
• Proportion of CRESS responders on ≥ 3 of 5 items at week 24 (refer 
to Section 8.2.1). The 5 items are:  
− Systemic disease activity: clinESSDAI 
− Patient-reported symptoms: ESSPRI  
− Tear gland function: Schirmer’s test and OSS 
− Salivary gland function: UWSF rate and SGUS 
− Serology (serum IgG and/or RF) 
Secondary 
• To evaluate the effect of 
efgartigimod IV compared to 
placebo on the histology of 
the parotid gland (selected 
sites only) 
• Change in the relative counts of lymphocytic infiltrate (stained for 
CD45) at week 24 
• Change in B/B+T cell ratio at week 24 
• To evaluate the safety of 
efgartigimod IV compared to 
placebo in participants with 
pSS 
• Incidence and severity of TEAEs, AESIs, and SAEs by SOC and PT  
• Changes in vital sign measurements, ECG results, and clinical 
laboratory safety evaluations  
• To evaluate the effect of 
efgartigimod IV compared to 
placebo on clinical efficacy 
parameters  
• Proportion of participants with minimal clinically important 
improvement in ESSDAI: improvement of ≥ 3 points in ESSDAI 
score at week 24 
• Proportion of participants with low disease activity: ESSDAI score of 
< 5 at week 24 
• Proportion of participants with minimal clinically important 
improvement in clinESSDAI: improvement of ≥ 3 points in 
clinESSDAI score at week 24 
• Proportion of participants with low disease activity: clinESSDAI 
score of < 5 at week 24 
• Proportion of participants with minimal clinically important 
improvement in ESSPRI: decrease of 1 point or ≥ 15% at week 24 
• Change in ESSDAI score at week 24 
• Change in clinESSDAI score at week 24 
• Change in ESSPRI score at week 24 
• To evaluate the effect of 
efgartigimod IV compared to 
placebo on STAR 
• Proportion of participants with STAR score of ≥ 5 at week 24 
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Objectives 
Endpoints 
• To evaluate the PK of 
efgartigimod IV 
• Efgartigimod serum concentration-time profile  
• To evaluate the PD of 
efgartigimod IV 
• Values, changes from baseline, and percent reduction from baseline 
in total IgG levels in serum 
• Values, changes from baseline, and percent reduction from baseline 
in autoantibodies in serum:  
− Anti-Ro/ SS-A  
− Anti-La/ SS-B 
• To evaluate the 
immunogenicity of 
efgartigimod IV 
• Incidence and prevalence of ADA against efgartigimod in serum 
Exploratory 
• 
 
 
 
 
• 
 
 
• 
 
• 
 
 
 
 
• 
 
• 
 
• 
 
• 
 
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• 
 
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• 
 
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Objectives 
Endpoints 
• 
 
 
 
  
• 
 
 
• 
 
• 
 
  
• 
 
 
• 
 
 
 
• 
 
 
 
• 
 
 
• 
 
 
• 
 
 
 
• 
 
Note: Estimands are not defined for this phase 2 study. 
ADA=antidrug antibody; AESI=adverse event of special interest; 
;
 
 clinESSDAI=clinical EULAR Sjögren’s syndrome disease activity 
index; CRESS=Composite of Relevant Endpoints for Sjögren’s Syndrome; ECG=electrocardiogram; 
ESSDAI=EULAR Sjögren’s syndrome disease activity index; ESSPRI=EULAR Sjögren’s Syndrome Patient 
Reported Index;
 IgG=immunoglobulin G; 
 
; IV=intravenous; 
; OSS=ocular staining score; 
; PD=pharmacodynamic(s); PK=pharmacokinetic(s); pSS=primary 
Sjögren’s syndrome; PT=preferred term; SAE=serious adverse event; SGUS=salivary gland ultrasonography; 
SOC=system organ class; SS-A=Sjögren’s syndrome-related antigen A; SS-B=Sjögren’s syndrome–related antigen 
B; STAR=Sjögren’s Tool for Assessing Response; SWSF=stimulated whole salivary flow; 
TEAE=treatment-emergent adverse event; UWSF=unstimulated whole salivary flow; 
 
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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a randomized, double-blinded, placebo-controlled, phase 2, multicenter study. 
For participants not enrolling in the OLE study, the study duration is approximately 36 weeks, 
spanning the following study periods: 
• Screening: ≤ 4 weeks  
• Treatment: 24 weeks  
• Follow-up: 56 days 
For participants enrolling in the OLE study, the study duration is approximately 28 weeks, 
spanning the following study periods: 
• Screening: ≤ 4 weeks  
• Treatment: 24 weeks  
The study population includes adult participants with pSS, per ACR/EULAR 2016 classification 
criteria, with at least a moderate level of systemic disease activity (ESSDAI ≥ 5). 
Participants will be randomized to receive efgartigimod IV 10 mg/kg or placebo in a 2:1 ratio, 
respectively.  
All participants will receive efgartigimod IV 10 mg/kg or placebo once weekly for 24 weeks 
during the treatment period. 
IMP will be administered as an approximately 1-hour IV infusion by site staff or a home nurse. 
The final dose will be administered at week 23. 
At week 24, eligible participants may roll over to the single-arm OLE study. 
4.2. 
Scientific Rationale for Study Design 
pSS is characterized by mononuclear inflammatory infiltrates and IgG plasma cells in salivary 
and lacrimal glands that lead to irreversible destruction of the glandular tissue and is 
accompanied by a sensation of dryness of mouth and eyes. B cells play a central role in the 
immunopathogenesis and exhibit signs of hyperactivity.1 In addition, autoantibodies can create 
immune complexes that maintain and amplify the production of IFN alpha. This combination 
results in a cycle of immune activation that leads to tissue damage. Currently, no 
immunomodulatory treatment is available for pSS. In this study, we aim to evaluate the effect of 
efgartigimod, an FcRn antagonist that can rapidly reduce IgG, including pathogenic antibodies. 
Efgartigimod has the potential to successfully treat pSS and improve disease manifestations by 
the reduction of IgG autoantibodies and immune complexes in pSS. 
This study aims to investigate the efficacy and safety of efgartigimod compared to placebo in 
participants with pSS. The study design is randomized, double-blinded, and placebo-controlled 
to evaluate the effect of efgartigimod administered as an IV infusion compared to placebo. The 
study consists of a treatment period when all participants will receive weekly IV infusions for 
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24 weeks. The comparison to placebo is justified because there are no standardized approved 
therapies for pSS. 
The primary endpoint is the effect of efgartigimod IV compared to placebo on CRESS 
(Section 8.2.1). The CRESS composite measures systemic disease activity, patient-reported 
symptoms, tear gland function, salivary gland function, and serology, developed to assess 
treatment efficacy in participants with pSS. CRESS has been selected as the primary efficacy 
endpoint because a composite is presumed to be more appropriate in demonstrating drug efficacy 
compared to an endpoint that reports on a single aspect of this heterogeneous disease.2 In 
randomized controlled studies that previously showed negative primary endpoint results using 
ESSDAI, post hoc analysis of the study data using CRESS resulted in higher response rates in 
participants treated with efgartigimod, compared to those given placebo. Use of CRESS also 
resulted in decreased placebo response rates compared with the use of the ESSDAI minimal 
clinically important improvement, which is essential to demonstrating treatment efficacy.2 
The secondary endpoints complement the primary endpoint and provide additional information 
on efficacy (ESSDAI, clinESSDAI, ESSPRI, STAR [Section 8.2]), histology, safety, PK, PD, 
and immunogenicity. The totality of data from all endpoints used in the study will be utilized to 
determine treatment response in this population.  
4.3. 
Justification for Dose 
Weekly doses of efgartigimod IV 10 mg/kg will be administered to attain a maximal total IgG 
reduction (PD effect), thereby ensuring maximal clinical response on the efficacy outcomes. 
Because the hypothesis for treating pSS with efgartigimod is to reduce the pathogenic 
autoreactive IgG, the selected dose and frequency target a nearly maximal PD effect (ie, 
reduction of pathogenic IgGs). Considering the chronic nature of pSS, the dosing regimen of 
weekly IV administration reflects the need for chronic treatment to maintain pathogenic IgG 
autoantibody suppression and symptom reduction. 
The cumulative data from a phase 1 study in healthy adult participants; phase 2 studies in 
participants with gMG, ITP, and pemphigus; phase 3 studies in participants with gMG and ITP; 
and PK/PD modeling results showed that weekly infusions of efgartigimod IV 10 mg/kg 
demonstrated an approximately 70% reduction in IgG, including pathogenic autoantibodies. 
Maximal IgG reduction was associated with clinical efficacy observed in gMG, ITP, and 
pemphigus studies. Furthermore, this dose has been safe and well tolerated in all study 
populations and has demonstrated similar PK and PD profiles across indications. Accordingly, 
the 10 mg/kg weekly IV dose regimen was selected for this study. 
4.4. 
End-of-Study Definition 
The end-of-study is defined as the date of the last participant’s last visit.  
A participant will have completed the study if the treatment period (or follow-up period, if 
applicable) has been completed.  
• Participants rolling over to the OLE study will have completed this study at week 24 
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• Participants not rolling over to the OLE study will have completed this study after the 
SFV or EDV. If a participant continued in the study after discontinuing IMP, this will 
be week 24 or at the SFV (if permanent IMP discontinuation is < 56 days from week 24).  
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5. 
STUDY POPULATION 
Prospective approvals of protocol deviations to enrollment criteria, also known as protocol 
waivers or exemptions, are not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Is at least the legal age of consent for clinical trials when signing the informed consent 
form 
2. Is capable of providing signed informed consent, as described in Section 10.1.3, and 
complying with protocol requirements 
3. Agrees to use contraceptive measures consistent with local regulations and the following: 
a. Male participants: refer to Section 10.4.2.2 
b. WOCBP (defined in Section 10.4.1) must have a negative serum pregnancy test at 
screening and a negative urine pregnancy test at baseline before receiving IMP. 
Contraceptive requirements are provided in Section 10.4. 
4. Meets the following criteria at screening: 
a. ACR/EULAR 2016 pSS who met criteria ≤ 7 years before screening 
b. ESSDAI ≥ 5 
c. Anti-Ro/SS-A positive 
d. Residual salivary flow (UWSF rate > 0 and/or SWSF rate > 0.10) 
5.2. 
Exclusion Criteria  
Participants will be excluded from the study if any of the following criteria apply: 
1. Known autoimmune disease or any medical condition that, in the investigator’s 
judgment, would interfere with an accurate assessment of clinical symptoms of pSS or 
puts the participant at undue risk 
2. History of malignancy unless considered cured by adequate treatment with no evidence 
of recurrence for ≥ 3 years before the first administration of IMP. Adequately treated 
participants with the following cancers may be included at any time: 
a. Basal cell or squamous cell skin cancer 
b. Carcinoma in situ of the cervix 
c. Carcinoma in situ of the breast 
d. Incidental histological finding of prostate cancer (TNM stage T1a or T1b) 
3. Clinically significant uncontrolled active acute or chronic bacterial, viral, or fungal 
infection 
4. Positive serum test at screening for an active infection with any of the following: 
a. HBV that is indicative of an acute or chronic infection, unless associated with a 
negative HBsAg or negative HBV DNA test 
b. HCV based on HCV antibody assay unless a negative RNA test is available 
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c. HIV based on test results of a CD4 count of < 200 cells/mm3 that are associated with 
an AIDS-defining condition 
d. HIV based on test results of a CD4 count of 200 cells/mm3 not adequately treated 
with antiviral therapy 
5. Clinically significant disease, recent major surgery (within 3 months of screening), or 
intention to have surgery during the study; or any other medical condition that, in the 
investigator’s opinion, would confound the results of the study or put the participant at 
undue risk 
6. Current participation in another interventional clinical study 
7. Known hypersensitivity to IMP or 1 of its excipients 
8. History (within 12 months of screening) of current alcohol, drug, or medication abuse as 
assessed by the investigator 
9. Pregnant or lactating state or intention to become pregnant during the study 
10. Previously participation in an efgartigimod clinical study and treatment with ≥ 1 dose of 
IMP 
11. Total IgG of < 4 g/L at screening  
12. Secondary Sjögren’s syndrome overlap syndromes where another confirmed autoimmune 
rheumatic or systemic inflammatory condition (eg, rheumatoid arthritis, systemic lupus 
erythematosus, scleroderma, inflammatory bowel disease) is the primary diagnosis 
13. Positive SARS-CoV-2 PCR test at screening 
14. Any severe systemic pSS manifestation that may put the participant at undue risk based 
on the investigator’s opinion 
Note: Medications cited in exclusion criteria 15-22 are also prohibited during the screening 
period. 
15. IVIg, SCIg, or PLEX ≤ 12 weeks before screening  
16. Live or live-attenuated vaccine ≤ 4 weeks before screening  
17. Pilocarpine and/or any other pharmacological stimulant for salivary and lacrimal glands 
that is not at a stable dose in the 4 weeks prior to screening or is started≤ 4 weeks from 
screening 
18. Anticholinergic agents which are not at a stable dose  weeks prior to screening or during 
screening 
19.  Corticosteroids: 
a. Intramuscular or IV corticosteroids ≤ weeks from screening 
b. Oral corticosteroids if above 10 mg, or if not at a stable dose ≤ weeks from 
screening 
c. 
 ≤  weeks from screening 
d. Use of 
 is prohibited 
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20. DMARDs: 
a. Cyclophosphamide ≤ 24 weeks from screening  
b. 
 ≤  weeks from screening. 
c. Antimalarials and conventional DMARDs: 
 
 are 
allowed only if started > 
 weeks before screening and at a stable dose ≥  weeks 
from screening. Combination therapies are not allowed. 
d. Biologic DMARDs: ≤ 
 weeks from screening. Rituximab and other CD20 depleting 
monoclonal antibodies are not allowed ≤ 
 weeks from screening. 
21. IMP in another clinical study: 
a. Prohibited ≤ 12 weeks or 5 half-lives (whichever is longer), or for CD20 depleting 
monoclonal antibodies, ≤ 24 weeks or 5 half-lives (whichever is longer)  
b. Nonbiologic IMP: Prohibited ≤ 12 weeks or 5 half-lives (whichever is longer) 
c. Biologic IMP: Prohibited ≤ 24 weeks or 5 half-lives (whichever is longer) before 
screening 
22. Chinese traditional medicine with known immunomodulatory action 
23. Pharmacological topical ophthalmic agents (eg, non-steroidal anti-inflammatory drugs 
[NSAIDs], 
) 
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
No restrictions apply. 
5.3.2. 
Caffeine, Alcohol, and Tobacco 
No restrictions apply except for those described in the exclusion criteria (Section 5.2, exclusion 
criterion 8). 
5.3.3. 
Activity 
No restrictions apply. 
5.4. 
Screen Failures 
A screen failure occurs when a participant consenting to participate in the clinical study is not 
assigned to IMP. A minimal set of screen failure information (demography, screen failure details, 
eligibility criteria, SAE reports) is required to ensure transparent reporting of screen failure 
participants and respond to regulatory authority queries.  
• Retesting: Participants with exclusionary clinical laboratory results, ECGs, vital sign 
measurements, etc that are inconsistent with their medical history or clinical 
evaluation can be retested within the remaining screening period to confirm the test 
value(s).  
• Rescreening: Participants who do not initially meet this study’s eligibility criteria 
may be rescreened once. For example, if the participant does not meet eligibility 
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criteria because of an acute illness ongoing during screening (considering the illness 
itself does not violate inclusion/exclusion criteria), they may be rescreened once the 
illness is resolved or the medical issue stabilized. Rescreened participants will be 
reconsented and assigned a new participant number for each rescreening event. 
5.5. 
Criteria for Temporarily Delaying Enrollment 
Not applicable.  
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6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
All IMP is manufactured according to Good Manufacturing Practice regulations.  
6.1. 
Study Intervention(s) Administered 
Table 2: 
Study Intervention(s) Administered 
Intervention label 
Efgartigimod IV 
Placebo 
Intervention name 
Efgartigimod IV concentrate for 
solution  
Placebo solution for IV infusion 
Intervention description 
Sterile, colorless, clear concentrate 
solution for efgartigimod 20 
mg/mL infusion 
Sterile, colorless, clear concentrate 
solution for infusion, with the same 
excipients, but without the active 
ingredient (efgartigimod) 
Type  
Biologic 
Placebo 
Dose formulation 
Infusion 
Infusion 
Unit dose strength(s) 
20 mg/mL 
Not applicable 
Dosage level(s) 
10 mg/kg once weekly for 
24 weeks 
Placebo once weekly for 24 weeks 
Route of administration 
IV infusion 
IV infusion 
Use 
Experimental 
Placebo comparator 
IMP and NIMP/AxMP 
IMP 
IMP 
Sourcing 
Centrally by the sponsor 
Centrally by the sponsor 
Packaging and labeling 
IMP will be provided in glass vials. 
Each vial will be labeled per 
country requirements. 
IMP will be provided in glass vials. 
Each vial will be labeled per 
country requirements. 
Former name 
ARGX-113 
Not applicable 
AxMP=auxiliary medicinal product; IMP=investigational medicinal product; IV=intravenous; 
NIMP=noninvestigational medicinal product 
 
Table 3: 
Study Arm(s) 
Arm title 
IMP 
Placebo 
Arm type 
Experimental 
Placebo 
Arm description 
Efgartigimod IV 10 mg/kg 
once weekly for 24 weeks 
Placebo IV once weekly for 
24 weeks 
Associated intervention labels 
Efgartigimod IV 
Placebo 
IMP=investigational medicinal product; IV=intravenous 
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6.2. 
Preparation, Handling, Storage, and Accountability 
The IMP will be supplied to the investigational site by the sponsor’s designated IMP supply 
vendor.  
The pharmacy manual provides detailed instructions on the preparation, handling, storage, 
accountability, and disposition of unused IMP. 
The investigator or designee is responsible for the correct and safe storage of the IMP. All IMP 
must be stored in a secure, environmentally controlled, and monitored (manual or automated) 
area following the labeled storage conditions, with access limited to the investigator and 
authorized site staff.  
The investigator or designee must confirm that appropriate temperature conditions have been 
maintained for all IMP received during transit. Any discrepancies are reported and resolved 
before using the IMP. 
Only participants enrolled in the study may receive IMP, and only authorized site staff or 
designee may supply IMP.  
Appropriate dilutions in a 0.9% saline solution in an infusion bag will be prepared before 
administration with an IV pump. 
IMP must be stored refrigerated (2 °C to 8 °C) and protected from direct sunlight in secondary 
packaging. It should not be shaken or exposed to freezing temperatures. 
Participants will be monitored for safety for ≥ 30 minutes after the end of IMP administration. 
6.3. 
Assignment to Study Intervention 
All participants will be randomized to IMP using IRT in a 2:1 ratio of efgartigimod or placebo, 
respectively.  
Upon confirmation of eligibility at baseline, the participant will be randomized through IRT and 
stratified by IgG value at screening (> 16.0 g/L or ≤ 16 g/L). 
6.4. 
Blinding 
This is a double-blinded study. The IRT will be programmed with blind-breaking instructions. In 
case of an emergency, the investigator is solely responsible for determining if unblinding of the 
IMP assignment is necessary. Participant safety must always be the first consideration in making 
such a determination. If the investigator decides that unblinding is warranted, the investigator 
may contact the sponsor to discuss the situation before unblinding a participant’s IMP unless this 
could delay emergency treatment for the participant. If a participant’s intervention assignment is 
unblinded, the sponsor must be notified within 24 hours of this occurrence. The date and reason 
for the unblinding must be recorded in the source documents. 
6.5. 
Study Compliance 
Participants will receive IMP under medical supervision at the site. The date and time of each 
dose administered will be recorded in the source documents. Documentation will include both 
start and end time of infusion. 
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At home visits (Section 1.3), IMP will be administered by a health care professional (nurse). The 
date and time of each dose administered will be recorded in the source documents. 
Deviation(s) from the prescribed dosage regimen will be recorded.  
Any participant who misses a scheduled dose (±2 days) will wait to receive the next scheduled 
dose (refer to Section 1.3). 
6.6. 
Dose Modification 
The maximum total efgartigimod dose per efgartigimod infusion is 1200 mg for participants 
weighing ≥ 120 kg. The IMP weight-based dose will be recalculated if a participant’s weight has 
changed (increased or decreased) by more than 10% from baseline. 
6.7. 
Continued Access to IMP After the End of the Study 
At the end of the study, argenx will comply with all local laws and regulations to ensure 
participants have continued access to IMP considered medically essential. 
At week 24 (visit 25) eligible participants will have the option to enroll in the OLE study, where 
all participants will be treated with efgartigimod IV.  
Participants will be ineligible for OLE study enrollment if either of the following criteria apply: 
• Permanently discontinued from IMP (regardless of whether the participant completed 
the study) 
• Discontinued from the study 
Participants who complete the week 24 (visit 25) visit while temporarily interrupted from IMP 
(refer to Section 7.1.1) may enroll in the OLE study at the discretion of the investigator. These 
participants will enter the OLE study but will not be dosed with efgartigimod IV until they meet 
the relevant conditions specified by the protocol for the OLE study. 
6.8. 
Treatment of Overdose 
Any dose of efgartigimod > 10% of the intended weekly amount will be considered an overdose. 
The sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator or treating physician should: 
• Evaluate the participant to determine, in consultation with the medical monitor, if 
possible, whether IMP should be interrupted. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities (as 
medically appropriate and at least until the next scheduled follow-up). 
•  Record the overdose, the quantity of the excess dose, and the duration of the 
overdose in the eCRF. 
6.9. 
Prior and Concomitant Therapy 
Participants should stay on a stable regimen of medications throughout the study. Any 
medication or vaccine (including over-the-counter or prescription medicines, recreational drugs, 
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vitamins, and/or herbal supplements [including Chinese traditional medicine]) or other specific 
categories of interest that the participant is receiving at the time of screening, or receives during 
the study must be recorded. Any treatment used for pSS in the 6 months prior to screening 
should also be recorded. 
Recording should include the following information: 
• Reason for use 
• Dates of administration, including start and end dates 
• Dosage information (ie, dose and frequency) 
The following medications or treatments are not permitted during the periods listed in Table 4. 
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Table 4: 
Prior and Concomitant Therapy 
Medication 
Prior to study treatment period 
Period participant is receiving IMP 
(Section 5.2) 
Follow-up period 
Live or live-attenuated 
vaccines 
Prohibited ≤ 4 weeks before screening 
Prohibited 
Permitted from 28 
days after the last 
IMP dose 
SCIg 
Prohibited ≤ 12 weeks before screening 
Prohibited 
Permitted 
IVIg 
Prohibited ≤ 12 weeks before screening 
Prohibited 
Permitted 
Corticosteroid steroids: 
Intra-muscular or intravenous 
corticosteroids 
Prohibited ≤ 4 weeks before screening 
Prohibited 
Permitted 
Oral corticosteroids 
Permitted at stable dose up to 10 mg at 
least 4 weeks before screening 
Dose up to 10 mg  
Permitted 
Inhaled corticosteroids 
Permitted 
Permitted 
Permitted 
Intra-articular steroids 
Prohibited ≤ 4 weeks before screening 
Prohibited 
Permitted 
Topical steroids 
Topical (non-ophthalmic) steroids are 
permitted  
Topical ophthalmic steroids are 
prohibited. 
Topical (non-ophthalmic) steroids are 
permitted  
Topical ophthalmic steroids are 
prohibited. 
Permitted 
DMARDs 
Conventional DMARDS / 
antimalarials 
 
 
 
 
 
 
 
Permitted 
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Medication 
Prior to study treatment period 
Period participant is receiving IMP 
(Section 5.2) 
Follow-up period 
Cyclophosphamide 
Prohibited ≤ 24 weeks from screening  
Prohibited 
Permitted 
Biologic DMARDS 
Prohibited ≤ 12 weeks of screening  
Rituximab and other CD20 depleting 
mAbs: prohibited ≤ 24 weeks of 
screening  
Prohibited 
Permitted 
Targeted synthetic DMARDs: 
  
Prohibited ≤ weeks from screening 
Prohibited 
Permitted 
IMPs: 
IMP in another clinical study 
Prohibited ≤ 12 weeks or 5 half-lives 
(whichever is longer)  
CD20 depleting mAbs: prohibited 
≤ 24 weeks or 5 half-lives (whichever is 
longer)  
Prohibited 
Permitted 
Nonbiologic IMP in another 
clinical study 
Prohibited ≤ 12 weeks or 5 half-lives 
(whichever is longer) 
Prohibited 
Permitted 
Biologic IMP in another 
clinical study 
Prohibited ≤ 24 weeks or 5 half-lives 
(whichever is longer) before screening 
Prohibited 
Permitted 
Other: 
Chinese traditional medicine 
with known 
immunomodulatory action 
Prohibited 
Prohibited 
Permitted 
Anticholinergic agents  
Permitted at stable dose 4 weeks prior to 
screening or during screening 
Permitted at stable dose 
Permitted 
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Medication 
Prior to study treatment period 
Period participant is receiving IMP 
(Section 5.2) 
Follow-up period 
Topical symptomatic 
medications for pSS  
Permitted 
Baseline, week 16, week 24, and 
EDV/IMP discontinuation visits, 
participants will be required to withhold 
ophthalmic lubricants, ophthalmic 
lubricating ointments, hydroxyl cellulose 
ophthalmic inserts, and saliva substitutes 
before efficacy assessments are 
completed. 
Permitted 
Pharmacological topical 
ophthalmic agents (eg, 
NSAIDs, cyclosporine)  
Prohibited 
Prohibited 
Permitted 
Pilocarpine and/or any other 
pharmacological stimulant for 
salivary and lacrimal glands  
Permitted at stable dose in the  weeks 
prior to screening 
Permitted at stable dose 
 
 
Permitted 
; DMARD=disease-modifying antirheumatic drug; EDV= early discontinuation visit; 
 
IMP=investigational medicinal product; IVIg= intravenous immunoglobulin; 
; 
 NSAID=non-steroidal anti-inflammatory drug; pSS=primary Sjögren’s syndrome; SCIg=subcutaneous immunoglobulin 
 
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7. 
DISCONTINUATION OF IMP AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
Discontinuation of specific sites or the entire study are described in Appendix 1 (Section 10.1). 
7.1. 
Discontinuation of IMP 
7.1.1. 
Permanent Discontinuation 
Permanent discontinuation of IMP occurs when the participant stops receiving the IMP before 
the end of the study, does not resume receiving IMP, and does not withdraw informed consent. 
The investigator will document the primary reason for early discontinuation of IMP. Participants 
who permanently discontinue IMP will complete the IMP discontinuation visit and will be 
encouraged to remain in the study and attend any previously scheduled visits. Blood samples for 
participants remaining in the study following IMP discontinuation will be collected for PK 
analyses as per the SoA (Section 1.3) for up to 3 weeks post IMP discontinuation.  
If the participant is unable or unwilling to attend study visits for any reason, the study site will 
perform an EDV and the SFV. The study sites will attempt to perform the EDV within the 7 (+2) 
days after the participant’s final IMP administration. The SFV will occur 56 ±3 days after the 
participant’s final IMP administration. 
Additionally, the following circumstances will result in the permanent discontinuation of IMP: 
• The participant becomes pregnant or intends to become pregnant (refer to 
Section 8.3.5). 
• The investigator considers discontinuing IMP is in the participant’s best interest (the 
sponsor will be informed).  
• The participant develops an SAE or AE that contraindicates further administration of 
IMP in the investigator’s opinion or an AE of CTCAE severity grade 4 that is 
considered related to IMP by the sponsor.  
• The participant receives a prohibited medication or substance (refer to Section 6.9). 
Participants permanently discontinuing IMP will be ineligible for roll over to the OLE study.  
7.1.2. 
Temporary Discontinuation 
Temporary discontinuation occurs when the participant discontinues receiving IMP before the 
end of the study but may resume once the cause for the discontinuation has been resolved.  
Reasons requiring temporary interruption may include an AE that meets the following criteria: 
• Any SAE considered related to IMP by the sponsor 
• Clinically significant active infection considered related to the IMP by the sponsor 
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7.2. 
Participant Discontinuation/Withdrawal From the Study 
Withdrawal from the study is defined as the permanent cessation of further participation in any 
study assessment before its planned completion. 
The reason for permanent withdrawal from the study will be recorded. 
The following circumstances will result in the permanent discontinuation and withdrawal from 
the study: 
• The participant withdraws consent 
• At the request of the sponsor  
If the participant also withdraws consent to disclose future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. Participants 
withdrawing from the study may request the destruction of collected, untested samples. 
Participants withdrawn from the study will be ineligible to roll over into the OLE study.  
7.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if repeatedly failing to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be completed if a participant fails to complete a required study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible, counsel the participant on the importance of maintaining the 
assigned visit schedule, and ascertain whether the participant wishes to continue in 
the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (when possible, 3 telephone 
calls, and if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record. 
− Participants who continue to be unreachable will be considered to have withdrawn 
from the study.  
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8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol waivers or 
exemptions are not allowed. 
Adherence to the study design requirements, including those specified in the SoA, is required for 
study conduct. 
All screening evaluations must be completed and reviewed to confirm that participants meet all 
eligibility criteria before randomization. The investigator will maintain a screening log to record 
details of all participants screened and confirm eligibility or record reasons for screening failure, 
as applicable. 
Operational considerations because of the COVID-19 pandemic are provided in Section 10.5. 
8.1. 
Administrative Procedures 
All significant findings, surgeries, and preexisting conditions (including allergies, if any) present 
at screening will be reported. Complete information will be collected on medical and surgical 
history, and concomitant medical conditions, specifying those ongoing at screening. 
8.1.1. 
Use and Storage of Biological Samples 
Biological samples collected at the screening visit may be used to validate methods to measure 
efgartigimod, antibodies, and biomarkers. Participants must consent to their samples being used 
in this manner before such measurements are made. 
After the protocol-defined laboratory analyses have been completed, any remaining samples may 
be stored for ≤ 15 years after the end-of-study, in the laboratory or long-term storage designated 
by the sponsor or research partners worldwide. These samples may be used for future additional 
medical, academic, or scientific research to address any scientific questions related to 
efgartigimod, FcRn biology, or pSS unless prohibited by local regulations or the participant.  
As stated in Section 7.2, participants withdrawing from the study may request the destruction of 
collected, untested samples. 
8.2. 
Efficacy Assessments 
Time points for all efficacy assessments are provided in the SoA (Section 1.3). 
Patient-reported outcome questionnaires are recommended to be administered before any other 
study assessment and may be completed ≤ 1 day before the visit. It is preferrable that the same 
physician assesses the clinical efficacy parameters at all visits. 
Instructions on administering these assessments are provided in the Investigator Site File. 
8.2.1. 
CRESS 
The primary efficacy endpoint is the proportion of responders on ≥ 3 of 5 items at week 24 using 
CRESS. CRESS has been developed to assess treatment efficacy in participants with pSS. 
CRESS consists of the following items, with definitions of treatment response and lower disease 
activity2: 
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• Systemic disease activity: as measured with clinESSDAI (Section 8.2.4)  
− Response is defined as a score of < 5 points. 
• Patient-reported symptoms: as measured with ESSPRI (Section 8.2.6.1)  
− Response is defined as a decrease of ≥ 1 point or ≥ 15% from baseline. 
• Tear gland function: as measured with Schirmer’s test (Section 8.2.7.3) and OSS 
(Section 8.2.7.4)  
− If Schirmer’s test is ≤ 5 mm at baseline (abnormal), a response is defined as an 
increase of at least 5 mm from baseline. OR 
− If OSS is ≥ 3 points at baseline (abnormal), a response is defined as a decrease of 
at least 2 points from baseline. OR 
− If both OSS and Schirmer’s scores are normal at baseline, a response is defined as 
no change that results in an abnormal OSS or Schirmer’s score.  
• Salivary gland function: as measured with UWSF (Section 8.2.7.1) and SGUS  
− UWSF: at least 25% increase in score, or if score is 0 mL/min at baseline, any 
increase from baseline OR 
− SGUS: at least 25% decrease in total Hocevar score3 from baseline 
• Serology: as measured with serum IgG and RF 
− RF: Decrease of at least 25% from baseline OR 
− IgG: Reduction of at least 10% from baseline 
8.2.2. 
Parotid Gland Histology 
A secondary efficacy measure is the relative amount of lymphocytic infiltrate that can be 
assessed with CD45 immunohistochemical staining of the parotid gland. Increased lymphocytic 
infiltrate positive for CD45 has been observed in parotid gland biopsies of participants with 
pSS.4 Additionally, the ratio of B/B+T cells will be assessed as a secondary outcome measure. 
: 
• 
 
 
 
 
• 
 
• 
 
 
 
 
• 
 
− 
 
 
 
 
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8.2.3. 
ESSDAI 
The ESSDAI was designed to measure disease activity in patients with pSS.5 The ESSDAI 
consists of 12 domains, 11 related to organ involvement (cutaneous, pulmonary, renal, articular, 
muscular, peripheral nervous system, central nervous system, hematological, glandular, 
constitutional, and lymphadenopathic) and 1 biological domain reflecting B-cell activity 
(Section 10.7.1). The activity levels of each domain (range: 0-3 points) are multiplied by their 
respective weights (range: 1-6 points) to obtain the total score. 
ESSDAI-related laboratory tests include the following: 
• Gammaglobulins 
• Cryoglobulins 
• C3, C4 and CH50 
The gammaglobulin and cryoglobulin results will be blinded post-baseline. 
8.2.4. 
ClinESSDAI 
ClinESSDAI derives from the ESSDAI and its score provides an accurate evaluation of disease 
activity independent of B-cell biomarkers.6 The clinical domains in clinESSDAI have different 
weights than in ESSDAI (Table 5). 
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Table 5: 
Comparison of Domain Weights of Original ESSDAI and clinESSDAI 
Domain (activity level) 
ESSDAI 
clinESSDAI 
Constitutional (0-2) 
3 
4 
Lymphadenopathy (0-3) 
4 
4 
Glandular (0-2) 
2 
2 
Articular (0-3) 
2 
3 
Cutaneous (0-3) 
3 
3 
Pulmonary (0-3) 
5 
6 
Renal (0-3) 
5 
6 
Muscular (0-3) 
6 
7 
Peripheral nervous system (0-3) 
5 
5 
Central nervous system (0-3) 
5 
5 
Hematological (0-3) 
2 
2 
Biological (0-2) 
1 
NA 
Score total 
0-123 
0-135 
Source: Seror et al, 20166  
clinESSDAI=clinical EULAR Sjögren’s syndrome disease activity index; ESSDAI=EULAR Sjögren’s syndrome 
disease activity index; EULAR= European Alliance of Associations for Rheumatology; NA=not applicable 
8.2.5. 
STAR 
STAR has been developed to assess the efficacy of treatments for pSS.7 A secondary efficacy 
endpoint for this study will be the proportion of responders (STAR score of ≥ 5) at week 24. 
This composite measure contains 5 domains:  
• Systemic activity: 3 points 
− clinESSDAI decrease of ≥ 3 points (Section 8.2.4) 
• Patient-reported outcome: 3 points 
− ESSPRI decrease of at least 1 point or ≥ 15% (Section 8.2.6.1)  
− Symptoms of dryness, pain, and fatigue rated on 3 numeric rating scales  
• Lacrimal gland function (assessed by Schirmer’s test or OSS): 1 point 
− Schirmer’s test (Section 8.2.7.3)  
▪ If abnormal score at baseline: increase of ≥ 5 mm from baseline  
▪ If normal score at baseline: no change to abnormal  
− OSS (Section 8.2.7.4)  
▪ If abnormal score at baseline: decrease of ≥ 2 points from baseline  
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8.2.6.4. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.6.5. 
 
 
 
 
  
 
 
 
8.2.6.6. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.2.7. 
Additional Efficacy Measures 
8.2.7.1. 
SGUS 
The SGUS grading system of Hocevar et al13 rates 5 parameters: parenchymal echogenicity, 
homogeneity, presence of hypoechogenic areas, hypoechogenic reflections, and the clearness of 
salivary gland borders. The overall ultrasound score will be calculated by summation of the 
grades for the 5 subscores for all 4 major salivary glands (left and right parotid and 
submandibular glands). The overall ultrasound score can range from 0 to 48. 
8.2.7.2. 
Salivary Flow Rate 
SWSF and UWSF rates will be assessed in this study. Details of the collection will be further 
specified in the Investigator Site File.  
8.2.7.3. 
Schirmer’s Test 
Schirmer’s test is an assessment of tear gland function in which a strip of filter paper is applied 
under the eyelid to measure the quantity of tear production. A result of ≤ 5 mm indicates 
abnormal tear gland function.14  
8.2.7.4. 
OSS 
OSS will be used in this study to assess tear gland function in participants with pSS. OSS uses 
lissamine green dye to grade the conjunctiva, and fluorescent dye to grade the cornea. A score of 
≥ 3 points indicates abnormal tear gland function.15 
8.3. 
Safety Assessments 
Time points for all safety assessments are provided in the SoA (Section 1.3). Safety measures 
will be assessed before IMP infusion unless otherwise stated. 
At screening, clinically significant abnormalities in any safety assessment will be reported as 
medical history. New abnormal or worsened preexisting conditions observed after screening that 
the investigator considers clinically significant will be reported as an AE. 
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8.3.1. 
Physical Examinations 
A complete physical examination will include, at a minimum, assessments of the 
musculoskeletal, gastrointestinal, pulmonary, cardiovascular, respiratory, and neurological 
systems, and general appearance, skin, and lymph nodes. Additionally, physical examinations 
will be performed to assess ESSDAI, as appropriate. Height and weight will also be measured 
without shoes, attired in light clothing, and recorded using validated instruments. 
Brief physical examination will include weight; assessments of gastrointestinal, pulmonary, 
cardiovascular, and respiratory systems; and general appearance. Additionally, physical 
examinations will be performed to assess ESSDAI, as appropriate. 
8.3.2. 
Vital Signs 
Body temperature, pulse rate, respiratory rate, and blood pressure will be recorded before blood 
collection for laboratory tests. 
Blood pressure and pulse will be assessed with the participant rested and seated.  
8.3.3. 
Electrocardiograms 
Single 12-lead ECGs will be obtained using an ECG machine.  
8.3.4. 
Protocol-Required Laboratory Tests 
Blood and urine samples will be analyzed at a central laboratory for serum chemistry and 
hematology, urinalysis, serology (eg, viral marker testing), and specialty laboratory parameters. 
Refer to Appendix 2 (Section 10.2) for the list of protocol-required laboratory tests to be 
performed and the SoA (Section 1.3) for the timing. 
The investigator must review the laboratory results, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory results must 
be retained with source documents.  
Abnormal laboratory findings associated with the underlying disease are not considered 
clinically significant unless judged by the investigator to be more severe than expected for the 
participant’s condition. 
8.3.5. 
Pregnancy Testing 
WOCBP will be tested for pregnancy by serum at screening. Urine tests for pregnancy will occur 
at the time points specified in the SoA (Section 1.3). 
Pregnancy testing in WOCBP will be conducted at the end of relevant systemic exposure (ie, at 
the SFV). 
Additional pregnancy testing may be performed as necessary by the investigator or required by 
local regulations, to establish the absence of pregnancy at any time during the study. 
8.4. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting 
The definitions of AEs and SAEs are provided in Appendix 3 (Section 10.3). 
AEs will be reported by the participant (or, if appropriate, by the caregiver or surrogate). 
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The investigator and qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and monitoring all reported events, 
including those reported by the participant. 
The method of recording, evaluating, and assessing the causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3 
(Section 10.3). 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs will be collected from the signing of the ICF until the SFV, as specified in the SoA 
(Section 1.3). 
All SAEs and AESIs will be recorded and reported to the sponsor or designee immediately, and 
under no circumstance will this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). The 
investigator will submit any updated SAE data to the sponsor within 24 hours of being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after the conclusion 
of the study participation. However, if the investigator learns of any SAE, including death, at any 
time after a participant has been discharged from the study, and they consider the event to be 
reasonably related to IMP or study participation, the investigator must promptly notify the 
sponsor. 
8.4.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and SAEs. Open-ended and 
nonleading verbal questioning of the participant is preferred to inquire about AE occurrences. 
8.4.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator must proactively follow each participant at 
subsequent visits/contacts. All SAEs and AESIs defined in Section 8.4.6 will be followed until 
resolution, stabilization, the event is otherwise explained, or the participant is lost to follow-up 
(defined in Section 7.3). Further information on follow-up procedures is provided in 
Section 10.3. 
8.4.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of IMP 
under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of IMP under clinical investigation. The sponsor will 
comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRBs/IECs, and investigators. 
An investigator who receives a safety report describing an SAE or other specific safety 
information (eg, summary or listing of SAEs) from the sponsor will review and file it with the IB 
and notify the IRB/IEC, if appropriate, according to local requirements. 
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The sponsor or designee will be responsible for reporting SUSARs to the relevant regulatory 
authorities and IEC/IRB, as per applicable regulatory requirements. The sponsor or designee will 
also be responsible for forwarding SUSAR reports to all study investigators, who will be 
required to report these SUSARs to their respective IECs/IRBs per local regulatory requirements.  
8.4.5. 
Pregnancy 
If pregnancy is reported, the investigator will record the pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the pregnancy in the 
female participant or the female partner of the male participant. Contact details are provided in 
Serious Adverse Event Reporting. 
The participant and pregnant female partner, if consented (Section 10.1.3), will be followed to 
determine the outcome of the pregnancy. The investigator will collect follow-up information on 
the participant/pregnant female partner and the neonate and forward it to the sponsor. 
While pregnancy itself is not considered an AE or SAE, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be reported as an AE or SAE. Abnormal 
pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital anomalies, 
ectopic pregnancy) are considered SAEs and will be reported accordingly. 
Any poststudy pregnancy-related SAE considered reasonably related by the investigator to IMP 
will be reported to the sponsor as described in Section 8.4.4. 
Any female participant who becomes pregnant during the study will discontinue IMP. 
8.4.6. 
Adverse Events of Special Interest 
An AESI is an event of scientific and medical concern specific to the sponsor’s product or 
program. An AESI can be serious or nonserious, related or unrelated to the IMP or study 
procedures. These events will be reported according to the timeframe specified in Section 8.4.1 
and Section 10.3.4.  
Efgartigimod treatment leads to reduced IgG levels. As low IgG levels are associated with 
increased infection risks, events in the MedDRA SOC Infections and Infestations are considered 
AESIs in this study. These events will be reported according to the timeframe specified in 
Section 8.4.1 and Section 10.3.4, with the following information provided: 
• Causal pathogen 
• Location of infection 
• Relationship to an underlying medical condition, medical history, and concomitant 
medications 
• Reoccurrence of a previous infection 
• Any confirmatory procedure, culture, or urgent medical intervention 
Participants for whom an AESI has been reported may be temporarily interrupted from IMP 
treatment, as specified in Section 7.1.1. 
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8.5. 
Pharmacokinetics 
On IMP administration visits, blood samples for PK analyses will be collected predose 
(preferably within 2 hours before IMP administration) and postdose (within 30 minutes after the 
end of infusion) as described in the SoA (Section 1.3). Date and time of sample collection will be 
recorded in the participant’s eCRF. On other visits, a single blood sample may be collected any 
time during the visit as described in the SoA. Samples collected after the end of infusion should 
be collected in the opposite arm from the arm used for IMP infusion. 
Blood samples for participants remaining in the study following IMP discontinuation will be 
collected as per the SoA for up to 3 weeks post IMP discontinuation. Efgartigimod serum 
concentrations will be determined using a validated method. 
8.6. 
Pharmacodynamics 
Baseline and postbaseline PD blood samples will be collected at time points specified in the SoA 
(Section 1.3). On IMP administration visits, PD blood samples will be collected predose, 
preferably within 2 hours before IMP administration. Date and time of sample collection will be 
recorded in the participant’s eCRF. On other visits, blood samples may be collected any time 
during the visit as specified in the SoA (Section 1.3). Total IgG levels will be determined using a 
validated method. 
IgG will be assessed at screening as part of the eligibility criteria (Section 5.1) and secondary 
efficacy measures. Total IgG concentrations will be quantified at a central laboratory, and 
postbaseline results will not be reported to investigative sites or other study personnel to 
maintain study blind.  
Participants will also be tested for anti-Ro/SS-A and anti-La/SS-B autoantibodies at the time 
points specified in the SoA (Section 1.3), as a part of inclusion criteria requirements 
(Section 5.1) and secondary efficacy measures. Postbaseline results will be blinded.  
8.7. 
Genetics 
Genetics are not evaluated in this study. 
8.8. 
 
 
  
• 
 
 
 
 
 
 
 
 
 
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• 
 
 
 
 
 
 
 
8.9. 
Immunogenicity Assessments 
Blood samples will be collected at the time points indicated in the SoA (Section 1.3) to evaluate 
serum levels of antidrug antibodies (ADAs) against efgartigimod.  
On IMP administration visits, the blood samples will be collected predose, preferably within 
2 hours before IMP administration. Date and time of sample collection will be recorded in the 
participant’s eCRF. On other visits, blood samples may be collected any time during the visit as 
specified in the SoA (Section 1.3). Samples will be analyzed by the designated laboratory in a 
tiered approach using validated immunogenicity assays.16  
Immunogenicity blood samples that are collected at the screening visit will be used for 
methodology validation and/or for future research purposes (Section 8.1.1).  
8.10. 
Health Economics or Medical Resource Utilization and Health 
Economics 
Health economics and/or medical resource utilizations are not evaluated in this study. 
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9. 
STATISTICAL CONSIDERATIONS 
A SAP will be finalized before database lock and include a more technical and detailed 
description of the statistical analyses to be completed. Any change to the data analysis methods 
described below will be described in the SAP. Any subsequent changes to the planned analysis 
methodology, and their justifications, will be described in the CSR. Additional exploratory 
analyses of the data will be conducted as appropriate and will be reported separately. 
The statistical analyses will be performed by the sponsor’s designated CRO using statistical 
analysis systems (SAS Institute, Cary, NC, US) version 9.4 or higher, and the software package 
R, if applicable. The standard operating procedures and work instructions of the sponsor’s 
designated CRO will be used as the default methodology if not otherwise specified. 
9.1. 
Statistical Hypothesis 
The primary objective is to provide initial evidence of efficacy in this indication across a number 
of clinical endpoints. Accordingly, the focus of this study is on effect estimation with no formal 
statistical hypothesis. 
9.2. 
Analysis Sets 
The following analysis sets are defined: 
Analysis set 
Description 
Full analysis set 
All randomized participants who receive IMP. Participants will be 
assigned in the efficacy analyses according to the IMP they received. 
Safety analysis set 
All participants exposed to IMP. Participants will be assigned in the 
efficacy analyses according to the IMP they received. 
The full analysis set will be used to analyze endpoints related to the efficacy objectives, and the 
safety analysis set will be used to analyze the endpoints and assessments related to safety.  
9.3. 
Statistical Analyses 
9.3.1. 
General Considerations 
In general, data collected will be listed together with appropriate derived variables. Descriptive 
statistical methods will be used to analyze safety and efficacy data. Where appropriate, this may 
include summaries and graphical displays by time point. 
Summaries will be provided by treatment assignment and overall. Summaries will include the 
number of observations (n), mean, SE, 95% CI, median, quartiles, minimum, and maximum for 
continuous measures and categorical measures sample size, frequencies, and percentages. 
P-values for comparing treatment groups may be provided, but these should be interpreted as 
supportive summary statistics. 
The baseline value will be the last assessment before the first IMP administration. 
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All study visits will be recalculated based on actual dates. The rules for calculating the analysis 
visits will be documented in the SAP. Rules for imputing partial dates or missing dates will be 
provided in the SAP. 
9.3.2. 
Primary Endpoint Analysis 
The primary endpoint is response on ≥ 3 of 5 items of CRESS at week 24. The 5 items are 
systemic disease activity (clinESSDAI), patient-reported symptoms (ESSPRI), tear gland 
function (Schirmer’s test, OSS), salivary gland function (UWSF, SGUS), and serology (serum 
IgG and RF). 
A 95% Wilson Score CI for the proportion of CRESS responders will be presented for both 
treatment groups. This will be provided for all full analysis set participants and by IgG stratum at 
screening (> 16.0 g/L or ≤ 16 g/L) for the efgartigimod treatment group. 
Additionally, the CRESS response will be analyzed between efgartigimod and placebo using the 
full analysis set by means of a Cochran-Mantel-Haenszel test, stratified by IgG value at 
screening (> 16.0 g/L or ≤ 16 g/L). The common odds ratio will be provided, along with the 95% 
CI. 
In the event of missing values for the primary endpoint, only those participants who have a 
week 24 value will be included in the primary analysis. A sensitivity analysis, treating those 
participants with missing week 24 data as nonresponders, will be included. 
9.3.3. 
Secondary Endpoint Analyses 
The proportion of responders at week 24 in the clinESSDAI and ESSPRI components of the 
CRESS will be analyzed using the same approach as the overall CRESS response. The ESSDAI 
and STAR responder endpoints will be analyzed similarly. 
Descriptive summaries by time point of the CRESS components, the ESSDAI and STAR scores, 
their changes, and percent changes from baseline will be provided, as appropriate. Estimates of 
the differences in response between treatment groups will be provided based on an analysis of 
covariance (ANCOVA), or suitable alternative, approach.  
The histological parameters, relative counts of lymphocytic infiltrate (stained for CD45), and 
B/B+T cell ratio will be summarized descriptively as raw counts and their changes from 
baseline.  
Full details of the secondary analyses will be included in the SAP. 
9.3.4. 
Exploratory Endpoint Analyses 
Summary statistics will be provided for the continuous exploratory endpoints, with frequency 
tables generated for all categorical endpoints. Full details of the analyses will be included in the 
SAP. 
9.3.5. 
Safety Analyses 
Exposure to IMP will be summarized by treatment group, using the safety analysis set. 
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AEs will be classified using the latest version of the MedDRA classification system. Any AEs 
with missing severity or relationship to IMP will be classified as severe and treatment related, 
respectively. 
Incidence and maximal severity of TEAEs, AESIs, and SAEs will be summarized descriptively. 
Multiple occurrences of a single PT in a participant will be counted only once at the maximum 
grade. Summaries by IMP relatedness will also be provided. Any AEs leading to death or IMP 
discontinuation will also be summarized. 
Laboratory parameters, vital signs, and ECG data will also be analyzed descriptively. 
Full details of the safety summaries will be provided in the appropriate SAP. 
9.3.6. 
Other Analyses 
Additional analyses of the week 16 efficacy results may be provided. 
PK, PD, immunogenicity, and biomarker results will be analyzed descriptively. 
Population PK/PD analysis may be performed based on the PK and PD data and reported 
separately. 
9.4. 
Interim Analysis 
An unblinded interim analysis may be conducted midcourse at the sponsor/designee’s discretion. 
Results will be made available to senior sponsor/designee staff only while maintaining the blind 
for the sites and sponsor clinical team members. 
9.5. 
Sample Size Determination 
Participants will be randomized in a 2:1 ratio (efgartigimod:placebo) to achieve approximately 
15 randomized participants with an IgG value at screening > 16.0 g/L and 15 participants without 
an IgG value at screening > 16.0 g/L. 
Assuming 50% of the 20 randomized efgartigimod participants are CRESS responders, the 95% 
1-sided confidence limit lower bound for the proportion of responders is approximately 33% 
(Wilson score interval). Placebo response rates ranging from 24% to 32% have been reported.2 
Therefore the target sample size should provide sufficient precision of the efgartigimod treatment 
effect at week 24 for planning future studies. 
 
 
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted according to the protocol and the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences international ethical guidelines 
• Applicable ICH GCP guidelines 
• Applicable laws and regulations 
The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, advertisements) 
must be submitted to an IRB/IEC by the investigator and reviewed and approved by the IRB/IEC 
before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementing changes 
made to the study design, except for changes necessary to eliminate an immediate hazard to 
study participants.  
Protocols and any substantial amendments to the protocol will require health authority approval 
before initiation except for changes necessary to eliminate an immediate hazard to study 
participants. 
The investigator is responsible for providing the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently according to the requirements, policies, and procedures established 
by the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies, and all other applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit a complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the study and for 1 year 
after completion of the study. 
The following information will be collected: any significant payments from the sponsor such as a 
grant to fund ongoing research, compensation in the form of equipment, retainer for ongoing 
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consultation or honoraria, proprietary interest in IMP, significant equity interest in the sponsor as 
defined in 21 CFR 54 2(b) (1998). 
10.1.3. 
Informed Consent Process 
The investigator or representative will explain the nature of the study, including risks and 
benefits to the potential participant, and answer all questions before the participant completes the 
informed consent process by signing the ICF. 
Potential participants must be informed that their participation is voluntary. A statement of 
informed consent must be signed that meets the requirements of the IRB/IEC or study center, 
ICH guidelines, 21 CFR 50, local regulations, and, where applicable, privacy and data protection 
requirements. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study if the changes to the ICF affect participant participation. 
A copy of the ICF(s) must be provided to the participant (or their legally authorized 
representative). 
Participants who are rescreened are required to sign a new ICF (Section 5.4).  
10.1.4. 
Recruitment Strategy 
Not applicable. 
10.1.5. 
Data Protection 
The sponsor will assign participants a unique identifier. Any participant records or datasets 
transferred to the sponsor will contain the identifier only; participant names or any information 
that would make the participant identifiable will not be transferred. 
The participant must be informed that the sponsor, sponsor representatives, competent 
authorities, etc may review source data containing identifiers and will use their personal 
study-related data per local data protection law. The level of disclosure must also be explained to 
the participant who will be required to give consent for their data to be used as described in the 
ICF.  
The contract between sponsor and study sites specifies responsibilities of the parties related to 
data protection, including handling of data security breaches and respective communication and 
cooperation of the parties. 
Information technology systems used to collect, process, and store study-related data are secured 
by technical and organizational security measures designed to protect such data against 
accidental or unlawful loss, alteration, or unauthorized disclosure or access. 
10.1.6. 
Committees Structure 
Not applicable. 
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10.1.7. 
Dissemination of Clinical Study Data 
The sponsor will register and disclose the results of clinical studies as required by law. 
10.1.8. 
Data Quality Assurance 
The sponsor or designee is responsible for the data management of this study, including quality 
checking of the data. 
All participant data relating to the study will be recorded on the eCRFs unless transmitted to the 
sponsor (or its designee) electronically (eg, laboratory data) or paper SAE forms. The 
investigator is responsible for verifying data entries are complete, accurate, and verifiable by 
electronically signing the eCRF. 
Guidance on completing eCRFs is provided on the eCRF completion document. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and direct access to source data documents. 
Study processes, study sites (including but not limited to site visits, central laboratories, 
vendors), the study database, and study documentation may be subject to quality assurance audits 
during the study by the sponsor or sponsor’s designee on behalf of the sponsor. In addition, 
inspections may be conducted by foreign or domestic regulatory bodies at their discretion. Such 
audits/inspections can occur during or after the completion of the study. 
Records and documents, including signed ICFs, on the conduct of this study must be retained by 
the investigator for 25 years after study completion unless local regulations or institutional 
policies require a more extended retention period. Without the sponsor’s written approval, no 
records will be destroyed during the retention period. No records may be transferred to another 
location or party without written notification to the sponsor. 
Monitoring details describing strategy and activities are described in a monitoring plan.  
• Study monitors will perform ongoing source data verification to confirm that data 
entered on the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted following the currently approved 
protocol and any other study agreements, ICH GCP, and all applicable regulatory 
requirements. 
10.1.9. 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data entered on the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records. Also, current medical records must be 
available. 
The definition of what constitutes source data and its origin can be found in the monitoring plan. 
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The investigator must maintain accurate documentation (source data) that supports the 
information entered on the eCRF. 
The sponsor or designee will perform monitoring to confirm that data entered on the eCRF by 
authorized site personnel are accurate, complete, and verifiable from source documents; that the 
safety and rights of participants are being protected; and that the study is being conducted in 
accordance with the currently approved protocol and any other study agreements, ICH GCP, and 
all applicable regulatory requirements. 
10.1.10. 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site activated and will be the study start date. 
Study/Site Termination 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed. 
The investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• For study termination: 
− Discontinuation of further compound development 
• For site termination: 
− Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 
− Inadequate or lack of recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
− Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any CROs used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the participant and should assure appropriate participant 
therapy and/or follow-up. 
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10.1.11. 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and consistent with International Committee 
of Medical Journal Editors authorship requirements. 
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10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests listed in Table 6 will be performed as described in the laboratory manual. 
Protocol-specific requirements for the inclusion and exclusion of participants are detailed 
in Section 5.1 and Section 5.2, respectively. 
Additional tests may be performed during the study as determined necessary by the investigator 
or required by local regulations. 
Investigators must document their review of each laboratory test result. 
Table 6: 
Protocol-Required Safety Laboratory Tests  
Laboratory test 
Parameters 
Hematology 
RBC count 
platelet count 
hemoglobin 
hematocrit 
RBC indices: 
MCV 
MCH 
WBC count with differential: 
neutrophils 
eosinophils 
lymphocytes 
basophils 
monocytes 
Serum chemistry 
ALT 
AST 
albumina 
BUN  
bilirubin (total and 
direct)  
creatinine 
GFR 
glucose 
potassium 
sodium 
calcium 
chloride 
bicarbonate 
total proteina 
creatine kinase 
HbA1C 
HDL 
LDL 
triglycerides  
C-reactive protein 
Routine urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase 
• Microscopic examination (if blood or protein is abnormal) 
• Urine protein quantitative analysis (if protein is abnormal) 
Pregnancy testing 
Highly sensitive serum hCG pregnancy serum test at screening and urine test 
at other time points (as needed for WOCBP potential, defined in Section 10.4.1)  
Other tests 
• SARS-CoV-2 nasopharyngeal swab test (PCR) (if applicable) 
• HBV, HCV, HIV (refer to exclusion criterion 4 and Sections 10.2.1.2, 
10.2.1.3, and 10.2.1.4, respectively) 
• Menopausal test (FSH) if applicable (to confirm non-WOCBP status)  
• IgGa (to verify exclusion criterion 11) 
a This result will be blinded postbaseline.  
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; 
FSH=follicle-stimulating hormone; GFR=glomerular filtration rate; HbA1C=glycated hemoglobin; HBV=hepatitis 
B virus; hCG=human chorionic gonadotropin; HCV=hepatitis C virus; HDL=high-density lipoprotein; 
IgG=immunoglobulin G; LDL=low-density lipoprotein; MCH=mean corpuscular hemoglobin; MCV=mean 
corpuscular volume; PCR=polymerase chain reaction; RBC=red blood cell; WBC=white blood cell; 
WOCBP=women of childbearing potential  
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10.2.1. 
Other Screening Tests 
10.2.1.1. SARS-CoV-2 
Participants will be tested for SARS-CoV-2 if they are symptomatic or if applicable law requires 
testing; if applicable, a negative PCR test (central or local laboratory) is required within 72 hours 
before enrollment and should occur regardless of a participant’s vaccination status. 
10.2.1.2. Hepatitis B Virus 
Active acute or chronic HBV is exclusionary. Participants with an active acute or chronic HBV 
at screening will be excluded from the study. 
The serologic marker combinations shown in Table 7 will be used to identify an active HBV 
infection.17  
Table 7: 
Interpretation of Hepatitis B Serological Test Results 
Test result 
Interpretation 
HBsAg 
Anti-HBc 
Anti-HBs 
Positive 
Positive 
Negative 
An active HBV infection is exclusionary 
Negative 
Positive 
Negative 
A low-level chronic HBV infection with impaired liver 
function is exclusionarya 
anti-HBc=total hepatitis B core antibody; anti-HBs=hepatitis B surface antibody; HBsAg=hepatitis B surface 
antigen; HBV=hepatitis B virus 
a This decision will be made by a medical doctor with sufficient experience in hepatology or infectious disease. 
Additional tests (eg, HBV viral load) could be required to determine the participant’s status. 
10.2.1.3. Hepatitis C Virus 
An active acute or chronic HCV infection is exclusionary. The HCV antibody serologic test will 
identify an active infection as indicated in Table 8.  
Table 8: 
Interpretation of the Hepatitis C Antibody Test 
HCV Ab test result 
Interpretation 
Positive 
An active acute or chronic HCV infection is exclusionary unless an RNA test 
indicates HCV negative 
Ab=antibody; HCV=hepatitis C virus 
10.2.1.4. Human Immunodeficiency Virus 
HIV-positive is permissible if all of the following conditions are met: 
• CD4 ≥ 200 cells/mm3 (Table 9, Section 5.2 exclusion criterion 4.d) 
• Viral load is < 200 copies/mm3 or undetectable (Table 9, Section 5.2 exclusion 
criterion 4.c) 
• Participant is receiving stable antiretroviral therapy for at least 3 months (minimally) 
before screening 
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• AIDS-defining condition is absent 
AIDS-defining conditions include the following: 
• Cytomegalovirus retinitis with loss of vision 
• Pneumocystis jiroveci pneumonia 
• Chronic intestinal cryptosporidiosis 
• Mycobacterium tuberculosis (pulmonary or extrapulmonary) 
• HIV-related encephalopathy 
• Invasive cervical cancer 
Table 9: 
Interpretation of HIV Test Results 
HIV test result 
Clinical condition/CD4 count/ 
viral load 
Interpretation 
Positive 
AIDS-defining condition is 
present or CD4 < 200 cells/mm3 
Test results and clinical conditions or CD4 
count confirm the AIDS diagnosis, which is 
exclusionary 
Positive 
Viral load > 200 copies /mm3 
despite participant receiving 
antiretroviral therapy 
Participant is ineligible because the 
antiretroviral therapy is not adequate 
Positive 
Viral load< 200 copies/mm3 but 
the participant is not receiving 
antiretroviral therapy 
Participant is ineligible because not 
receiving antiretroviral therapy 
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• 
An alert email for the SAE and AESI reports on the eCRF will automatically be sent by 
email to the sponsor or designee’s safety mailbox via the EDC system.  
• 
The paper SAE report form should be faxed or emailed to the sponsor’s designee (refer to 
the Serious Adverse Event Reporting details on page 2 of this protocol). 
 
 
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10.4. 
Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. 
Women of Childbearing Potential Definition 
A female is considered a WOCBP unless she is either:  
a. Postmenopausal: A postmenopausal state is defined by continuous amenorrhea for at 
least 1 year without an alternative medical cause with an FSH measurement of 
> 40 IU/L. If a postmenopausal woman is using hormonal therapy, such as hormone 
replacement therapy or hormonal contraceptives, FSH levels might be suppressed and 
therefore an FSH test to confirm a postmenopausal state is not considered valid. In 
this case the postmenopausal state will need to be assessed by the investigator. 
b. Surgically sterilized: Women who have had a documented permanent sterilization 
procedure (eg, hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) 
10.4.2. 
Contraception Guidance 
10.4.2.1. Female Contraception for WOCBP 
WOCBP must use one of the following contraception methods from signing the ICF until the last 
dose of IMP. 
The following Clinical Trials Facilitation and Coordination Group18 acceptable methods are 
permitted for efgartigimod studies: 
• Progestogen-only oral hormonal contraception in which inhibition of ovulation is not 
the primary mode of action 
− Oral 
− Injectable 
− Implantable 
• Male or female condom with or without spermicide 
• Cap, diaphragm, or sponge with spermicide 
10.4.2.2. Male Contraception 
All nonsterilized male participants must use this method from signing of the ICF until the date of 
the last dose of IMP. 
An acceptable method of contraception is a condom with either cap, diaphragm, or sponge with 
spermicide (efgartigimod studies only). 
Males cannot donate sperm while receiving IMP. 
 
 
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10.5. 
Appendix 5: Operational Considerations for COVID-19 Risk 
Mitigation 
Participants will be tested for SARS-CoV-2 if they are symptomatic or if applicable law requires 
testing; if applicable, a negative PCR test (central or local laboratory) is required within 72 hours 
before enrollment and should occur regardless of a participant’s vaccination status. 
During the study, the sites will implement all recommendations issued by the local government 
regarding the spread of COVID-19, including specific guidelines related to clinical research 
performed in clinical research centers. 
This appendix is intended for use only if unforeseen changes in the COVID-19 pandemic lead to 
new restrictions at the site or new risks for participants or site staff from attending visits at the 
site.  
Additional testing for COVID-19 beyond what is listed in the SoA (Section 1.3) is not required 
during the study unless required by local authorities. However, it is recommended that 
participants who develop COVID-19 symptoms while receiving IMP be tested, with results 
reported for the study. 
Critical Parameters to Be Collected During the Study 
All assessments should be performed as indicated in the SoA (Section 1.3). If assessments cannot 
be performed because of the COVID-19 pandemic, the following information must be collected 
from the first visit through end-of-study:  
• All AE and concomitant medication reporting 
• IMP administration 
• Questionnaires 
• Protocol-required laboratory assessments 
10.6. 
Appendix 6: Home Study Visits 
A home nurse may travel to the participant’s home to conduct study visits and perform activities 
in the SoA (Section 1.3), or the participant may attend an alternative location, as determined by 
the site investigator. For each home visit, the investigator or designee will confer with the 
participant via an audio or video interview to elicit answers regarding AEs and concomitant 
medications and the participant’s general well-being. The investigator or designee will also 
ensure the participant has completed all required efficacy assessments that can be performed at 
home (eg, questionnaires). Any scheduled assessments will be conducted before the home nurse 
administers IMP.  
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10.7. 
Appendix 7: Efficacy Endpoint Data 
10.7.1. 
ESSDAI 
Table 10: 
ESSDAI: Domain and Item Definitions and Weights 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 10: 
ESSDAI: Domain and Item Definitions and Weights (Continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 10: 
ESSDAI: Domain and Item Definitions and Weights (Continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 10: 
ESSDAI: Domain and Item Definitions and Weights (Continued) 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Seror et a, 2011l8 
 
 
 
 
 
 
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10.8. 
Appendix 8: ACR-EULAR Classification Criteria 
The ACR-EULAR classification of pSS applies to any individual who meets the following 
inclusion and exclusion criteria and has a score of ≥ 4 when summing the weights from the items 
presented in Table 11. 
Inclusion Criteria 
Inclusion criteria apply to any patient with ≥ 1 symptom of ocular or oral dryness, defined as a 
positive response to ≥ 1 of the following questions:  
1. Have you had daily, persistent, troublesome dry eyes for more than 3 months?  
2. Do you have a recurrent sensation of sand or gravel in the eyes?  
3. Do you use tear substitutes more than 3 times a day?  
4. Have you had a daily feeling of dry mouth for more than 3 months?  
5. Do you frequently drink liquids to aid in swallowing dry food? 
OR suspicion of pSS from the ESSDAI questionnaire (with ≥ 1 positive domain item) 
Exclusion Criteria 
Prior diagnosis of any of the following conditions would exclude diagnosis of pSS and 
participation in pSS studies or therapeutic studies because of overlapping clinical features or 
interference with criteria tests:  
• AIDS  
• Active hepatitis C infection (with positive PCR)  
• Sarcoidosis  
• Amyloidosis  
• Graft-versus-host disease  
• History of head and neck radiation treatment  
• IgG4-related disease  
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Table 11: 
ACR-EULAR Classification Criteria for Primary Sjögren’s Syndrome 
Item 
Weight/Score 
Labial salivary gland with focal lymphocytic sialadenitis and focus score of ≥ 1a 
3 
Anti-Ro/SS-A positive 
3 
OSS of ≥ 519 (or van Bijsterfeld score of ≥ 420) on at least 1 eye 
1 
Schirmer’s test of ≤ 5 mm/5 minutes on at least 1 eyeb 
1 
UWSF rate of ≤ 0.1 mL/min21,b 
1 
Source: Shiboski et al22 
ACR=American College of Rheumatology; EULAR=European Alliance of Associations for Rheumatology; 
OSS=ocular staining score; SS-A=Sjögren’s syndrome–related antigen A; UWSF= unstimulated whole salivary 
flow 
a A pathologist with expertise in the diagnosis of focal lymphocytic sialadenitis and focus score count (based on 
number of foci per 4 mm2) should perform the histopathologic examination following a protocol by Daniels et al.23 
b Patients who are normally taking anticholinergic drugs should be evaluated for objective signs of salivary 
hypofunction and ocular dryness after a sufficient interval off these medications so that these components can be a 
valid measure of oral and ocular dryness. 
 
 
 
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11. 
REFERENCES 
1. Kroese FGM, Abdulahad WH, Haacke E, Bos NA, Vissink A, Bootsma H. B-cell 
hyperactivity in primary Sjögren’s syndrome. Expert Rev Clin Immunol. 
2014;10(4):483-99. 
2. Arends S, de Wolff L, van Nimwegen JF, et al. Composite of Relevant Endpoints for 
Sjögren’s Syndrome (CRESS): development and validation of a novel outcome measure. 
Lancet Rheumatol. 2021;3(8):E553-E562. 
3. Yalcinkaya Y, Mumcu G, Özdemir FT, et al. Are salivary gland ultrasonography scores 
associated with salivary flow rates and oral health-related quality of life in Sjögren 
syndrome? J Rheumatol. 2020;47(12):1774-1779.  
4. Delli K, Haacke EA, Kroese FGM, et al. Towards personalised treatment in primary 
Sjögren’s syndrome: baseline parotid histopathology predicts responsiveness to rituximab 
treatment. Ann Rheum Dis. 2016;75(11):1933-1938. 
5. Seror R, Bowman SJ, Brito-Zeron P, et al. EULAR Sjögren’s syndrome disease activity 
index (ESSDAI): a user guide. RMD Open. 2015;1(1):e000022. 
6. Seror R, Meiners P, Baron G, et al. Development of the ClinESSDAI: a clinical score 
without biological domain. A tool for biological studies. Ann Rheum Dis. 
2016;75(11):1945-1950. 
7. Seror R, Baron G, Camus M, et al; NECESSITY WP5 - STAR development working 
group. Development and preliminary validation of the Sjögren’s Tool for Assessing 
Response (STAR): a consensual composite score for assessing treatment effect in 
primary Sjögren’s syndrome. Ann Rheum Dis. 2022;81(7):979-989. 
8. Seror R, Ravaud P, Mariette X, et al. EULAR Sjögren’s Syndrome Patient Reported 
Index (ESSPRI): development of a consensus patient index for primary Sjögren’s 
syndrome. Ann Rheum Dis. 2011;70(6):968-972. 
9. 
 
 
  
10. 
 
 
 
11. 
 
 
 
12. 
 
 
 
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13. Hocevar A, Ambrozic A, Rozman B, Kveder T, Tomsic M. Ultrasonographic changes of 
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System Version: 1.0, Status: Approved, Document ID: VV-TMF-90329

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System Version: 1.0, Status: Approved, Document ID: VV-TMF-90329