A Randomized, Double-blind, Placebo-controlled, Parallel-group Study of the Safety, Tolerability, Pharmacokinetics, and Therapeutic Efficacy of SAR441344 in Adult Patients With Primary Sjögren's Syndrome (pSjS)
Phase: PHASE2
Conditions: Sjögren's Syndrome, Sjogren's Syndrome
Sponsor: Sanofi

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disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
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Based on Template: Sanofi OneDocument Version 2.0, dated 14-OCT-2019 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 03 
Protocol title: 
A randomized, double-blind, placebo-controlled, 
parallel-group study of the safety, tolerability, 
pharmacokinetics, and therapeutic efficacy of SAR441344 in 
adult patients with primary Sjögren’s syndrome (pSjS) 
Protocol number: 
ACT16618 
Amendment 
number: 
03 
Compound number 
(INN/Trademark): 
SAR441344 
Study phase: 
Phase 2 
Short title: 
Safety, tolerability, pharmacokinetics, and therapeutic 
efficacy of SAR441344 in primary Sjögren’s syndrome (pSjS) 
phaethuSA 
Sponsor name: 
Global Sponsor: Sanofi-Aventis Recherche & Développement 
Local US Sponsor: Sanofi US. Services Inc  
Legal registered 
address: 
Sanofi-Aventis Recherche & Développement 
1 avenue Pierre Brossolette 
91380 Chilly-Mazarin 
France 
Sanofi US. Services Inc 
55 Corporate Drive 
Bridgewater, NJ 08807 
USA 
Monitoring Team’s 
Representative 
Name and Contact 
Information 
Regulatory agency identifier number(s): 
IND: 
147616 
EudraCT: 
2020-000511-77 
NCT: 
NCT04572841 
WHO: 
U1111-1244-2266 
EUDAMED 
Not applicable 
Other: 
Not applicable 
Date: 
05-Apr-2022
Total number of pages: 
107 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 03 
All 
[05 April 2022], version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 02  
All 
[28 July 2021], version 1 (electronic 2.0) 
Amended Clinical Trial Protocol 01  
All 
[27 August 2020], version 1 (electronic 1.0) 
Original Protocol 
 
[29 May 2020], version 1 (electronic 1.0) 
Amended protocol 03 (05 April 2022) 
This amended protocol (Amendment 03) 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 main purpose of the amendment is to adapt inclusion/exclusion criteria I06, E17, E18, and 
E22 to better account for the required characteristics of Sjögren`s syndrome (ESSDAI >5 and 
baseline treatment) to facilitate recruitment, without compromising safety requirements. In 
addition, the discontinuation due to Coronavirus Disease 2019 (COVID19) was adjusted. Further 
Section 9.5 (Interim analysis) was revised with an option of additional analysis. Finally, 
discrepancies are also being addressed in this amendment, as well as minor corrections and 
clarifications.  
Protocol amendment summary of changes table 
Section # 
and Name 
Description of Change 
Brief Rationale 
Cover page 
NCT04572841 added. 
Update. 
1.1. Synopsis 
“Approximately A maximum of 88 participants 
will be randomized to study intervention such that 
approximately 80 participants complete the study 
and be evaluable for the analysis of the primary 
endpoint.” 
Adaption given the current drop-out rate is above the 
initial estimated 10%. 
1.3. Schedule of 
activities 
Adaption of footnote f: “[…]. If the suspicion of a 
SARS-CoV-2 infection is confirmed in the case of 
biologically proven COVID-19 infection, the 
Investigator may permanently discontinue the 
IMP for the participant treatment should be 
As different variants of COVID-19 emerge and 
worldwide vaccination continues, the need for 
permanent discontinuation of IMP due to COVID-19 
infection is less certain and can be assessed on a case-
by-case basis. 
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Section # 
and Name 
Description of Change 
Brief Rationale 
stopped (Section 7.1.1). If according to the 
Investigator a permanent IMP discontinuation 
is not necessary or in the best interest of the 
participant, the Investigator can consider a 
temporary discontinuation until the 
participant’s COVID-19 PCR is negative 
(Section 7.1.2 ).” 
2.3.1.1.2 Risk 
mitigation  
“In the case of biologically proven COVID-19 
infection, the Investigator may permanently 
discontinue the IMP for the participant, who 
will be asked to continue attending the 
protocol scheduled visits until the EOS. If 
according to the Investigator a permanent IMP 
discontinuation is not necessary or in the best 
interest of the participant, the Investigator can 
consider a temporary discontinuation if the 
patient does not have severe or critical 
COVID-19 infection as defined per WHO 
guidelines (25). The participant must 
temporarily discontinue IMP until the 
participant’s COVID-19 PCR is negative. A 
discontinuation of more than 30 days will be 
considered as permanent discontinuation. All 
COVID-19 infections will be reviewed by the 
DMC as AESI.”  
As different variants of COVID-19 emerge and 
worldwide vaccination continues, the need for 
permanent discontinuation of IMP due to COVID-19 
infection can be assessed on a case-by-case basis. 
 
Taking into account this risk, the potential risk of 
an increased infectious risk due to lymphopenia, 
and potential relevance in SARS-CoV-2 infections 
(34), patients with a significant severe 
lymphopenia will be excluded from this study (see 
exclusion criterion E 22 in Section 5.2). 
Clarification with regards to exclusion criterion E22, to 
better account for characteristics of Sjogren’syndrome. 
5.1 Inclusion 
criteria 
Adaption of Inclusion criterion I06: Rheumatoid 
factor positive and/or IgG > upper limit of normal 
(ULN) at Screening. IgG > lower limit of normal 
at Screening. 
To better account for the characteristics of Sjögren`s 
syndrome. 
5.2 Exclusion 
criteria 
Adaption of E17: “High dose of 
hydroxychloroquine or chloroquine 
 or methotrexate 
 or a change in 
hydroxychloroquine, or chloroquine or 
methotrexate dose within 12 weeks prior to Day 
1/Randomization or expected changes during the 
course of the study.” 
Adaption of E18: “[…] Previous treatment with 
azathioprine and other thiopurines, methotrexate, 
mycophenolate mofetil, sulfasalazine, or 
cyclosporine A within 3 months.” 
To better adapt to common baseline treatments for 
Sjögren`s syndrome.  
5.2 Exclusion 
criteria 
Adaption of E22:  
- 
Lymphocytes 
/mm3 
/mm3 
Patients with active pSjS have lymphopenia due to 
SjS activity with no increased risk of infection. 
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Section # 
and Name 
Description of Change 
Brief Rationale 
5.4 Screen 
failures  
Sentence was added: 
“If a participant was re-screened once under 
the amended protocol 1 or 2 due to I06 or E22 
(Lymphocytes 
/mm3), participant might 
be re-screened a second time, at the 
Investigator`s discretion.” 
Clarification given the protocol amendment. 
5.4 Screen 
failures 
Footnote “b” was added to Table 3; I05: “Re-
testing or re-Screening is allowed once, if 
results in the central laboratory for anti-
Ro/SSA are equivocal and no other reasons 
apply that prohibit re-screening.” 
Clarification. 
6.3 Measures to 
minimize bias: 
Randomization 
and blinding. 
 “The preliminary PK and Biomarker data, if 
needed and available during the course of the 
study, will refer to mean data with descriptive 
statistics and individual data, without revealing 
any individual randomization numbers or 
participant numbers.” 
Clarification.  
6.5.1 Prohibited 
concomitant 
medication 
• High dose of hydroxychloroquine or chloroquine 
, or a change in 
hydroxychloroquine or chloroquine dose within 
12 weeks prior to Day 1/Randomization, or 
expected changes during the course of the study. 
•High dose of methotrexate 
, or a change in methotrexate 
dose within 12 weeks prior to Day 1/ 
Randomization, or expected changes during 
the course of the study. 
• Previous treatment with azathioprine or other 
thiopurines, methotrexate, mycophenolate mofetil, 
sulfasalazine, or cyclosporine A within 3 months 
prior to Screening and during the course of the 
study. 
To better adapt to common baseline treatments for 
Sjögren`s syndrome. 
6.5.2 Key 
authorized 
medications 
• Low dose hydroxychloroquine or chloroquine 
treatment
 and a stable dose 
within 12 weeks prior to Day1/ Randomization. No 
change in dose is permitted during the study 
unless for the management of an AE. Dose and 
any change will be recorded on the participant e 
CRF. Hydroxychloroquine or chloroquine cannot be 
started during the course of the study. 
•Methotrexate up to
 or 
equivalent and a stable dose within 12 weeks 
prior to Day 1/ Randomization. No change in 
dose is permitted during the study unless for 
the management of an AE. Dose and any 
change will be recorded on the participant 
eCRF. Methotrexate cannot be started during 
the study. Concomitant therapy with folic acid 
is permitted. 
To better adapt to common baseline treatments for 
Sjögren`s syndrome and clarification. 
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Section # 
and Name 
Description of Change 
Brief Rationale 
7.1.1. Definitive 
discontinuation  
• Diagnosed and biologically proven SARS CoV 2 
infection. 
In the case of biologically proven COVID-19 
infection, the Investigator may permanently 
discontinue the IMP for the participant, who 
will be asked to continue attending the 
protocol scheduled visits until EOS. If 
according to the Investigator a permanent IMP 
discontinuation is not necessary or in the best 
interest of the participant, the Investigator can 
consider a temporary discontinuation per 
Section 7.1.2. The participant cannot restart 
IMP until the participant’s COVID-19 PCR is 
negative. All COVID-19 infections will be 
reviewed by the DMC as AESI. 
As different variants of COVID-19 emerge and 
worldwide vaccination continues, the need for 
permanent discontinuation of IMP due to COVID-19 
infection can be assessed on a case-by-case basis. 
7.1.2 Temporary 
discontinuation 
[…]. If the COVID 19 diagnosis is confirmed, the 
IMP should be discontinued definitely (Section 
7.1.1). 
In the case of biologically proven COVID-19 
infection, if according to the Investigator a 
permanently IMP discontinuation is not 
necessary or in the best interest of the 
participant and the participant does not have 
severe or critical COVID-19 as defined by 
WHO guidelines (25), the participant can 
temporarily discontinue IMP until the 
participant’s COVID-19 PCR is negative. 
As different variants of COVID-19 emerge and 
worldwide vaccination continues, the need for 
permanent discontinuation of IMP due to COVID-19 
infection is less certain and can be assessed on a case-
by-case basis. 
8 Study 
assessments and 
procedures 
[…] Repeat or unscheduled samples may be 
taken for safety reasons or for technical issues 
with the samples, this could be done locally if 
approved by the Sponsor. 
Clarification. 
9.2 Sample size 
determination 
Approximately Up to 88 participants are 
expected to be randomly assigned to the IMP, 
expecting a total of 80 evaluable participants with 
approximately 40 evaluable participants per 
group. 
Adaption given the current drop-out rate is above the 
initial estimated 10%. 
9.3 Populations 
for analyses 
In Table 5, row pharmacokinetic: 
All randomized and treated participants (safety 
population) with adequate PK results without 
any important deviation related to IMP 
administration, for whom the PK data are 
considered interpretable. Participants having 
received only placebo will not be part of the PK 
population. Participants will be analyzed 
according to the intervention they received. 
In Table 5, row pharmacodynamic: 
All randomized and treated participants (safety 
population) with at least one post-baseline PD 
data. no important deviations impacting PD 
Clarification. 
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Section # 
and Name 
Description of Change 
Brief Rationale 
measurements, for whom the PD data are 
considered sufficient and interpretable. 
Participants will be analyzed according to the 
intervention they received. 
9.5. Interim 
analysis 
Beside those described interim analyses, 
additional analyses for internal decision 
making might be conducted. For those 
analyses, if decided to do so, a Statistician, 
Programmer, and Clinical Study Director will 
work independently to the study team to 
ensure maintenance of blinding. 
Adding the option of an additional analysis if needed for 
internal decision making throughout the study. 
pSjS: primary Sjögren`s syndrome, SoA: Schedule of Assessments. 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 03 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 7 
LIST OF TABLES ......................................................................................................................................... 12 
LIST OF FIGURES ........................................................................................................................................ 12 
1 
PROTOCOL SUMMARY ............................................................................................................... 13 
1.1 
SYNOPSIS ..................................................................................................................................... 13 
1.2 
SCHEMA ........................................................................................................................................ 18 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 19 
2 
INTRODUCTION ............................................................................................................................ 23 
2.1 
STUDY RATIONALE...................................................................................................................... 23 
2.2 
BACKGROUND ............................................................................................................................. 24 
2.2.1 
Primary Sjögren’s syndrome .......................................................................................................... 24 
2.2.2 
SAR441344 .................................................................................................................................... 24 
2.2.2.1 
Preclinical data ............................................................................................................................... 25 
2.2.2.2 
Clinical data .................................................................................................................................... 26 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 27 
2.3.1 
Risk assessment ............................................................................................................................ 27 
2.3.1.1 
Risk assessment and mitigation in the context of SARS-CoV-2 ................................................... 29 
2.3.2 
Benefit assessment ........................................................................................................................ 32 
2.3.3 
Overall benefit: risk conclusion ...................................................................................................... 32 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 33 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 35 
4 
STUDY DESIGN ............................................................................................................................ 36 
4.1 
OVERALL DESIGN ........................................................................................................................ 36 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 36 
4.2.1 
Participant input into design ........................................................................................................... 37 
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4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 37 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 38 
5 
STUDY POPULATION .................................................................................................................. 39 
5.1 
INCLUSION CRITERIA .................................................................................................................. 39 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 41 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 44 
5.3.1 
Meals and dietary restrictions ........................................................................................................ 44 
5.3.2 
Caffeine, alcohol, and tobacco ....................................................................................................... 44 
5.3.3 
Activity ............................................................................................................................................ 44 
5.4 
SCREEN FAILURES...................................................................................................................... 44 
6 
STUDY INTERVENTION ............................................................................................................... 46 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 46 
6.1.1 
Investigational medicinal product(s) ............................................................................................... 46 
6.1.1.1 
SAR441344 .................................................................................................................................... 47 
6.1.1.2 
Placebo .......................................................................................................................................... 47 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 47 
6.2.1 
Intravenous preparation and handlings.......................................................................................... 48 
6.2.2 
Subcutaneous preparation and handlings ..................................................................................... 48 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 48 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 50 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 50 
6.5.1 
Prohibited concomitant medication ................................................................................................ 51 
6.5.2 
Key authorized concomitant medications ...................................................................................... 51 
6.6 
DOSE MODIFICATION .................................................................................................................. 52 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 52 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 53 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 53 
7.1.1 
Definitive discontinuation ............................................................................................................... 53 
7.1.1.1 
Handling of participants after definitive intervention discontinuation ............................................. 54 
7.1.2 
Temporary discontinuation ............................................................................................................. 54 
7.1.2.1 
Rechallenge ................................................................................................................................... 55 
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7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 55 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 56 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 57 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 57 
8.1.1 
European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index .................. 57 
8.1.2 
European League Against Rheumatism Sjögren’s Syndrome Patient Reported Index ................ 58 
8.1.3 
Multidimensional Fatigue Inventory ............................................................................................... 58 
 ....................................................................... 58 
 ........................................................................................................................ 58 
 ..................................... 59 
................................................................................................................................ 59 
 .......................................................................................................... 59 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 60 
................................................................................................................... 60 
8.2.2 
Vital signs ....................................................................................................................................... 60 
8.2.3 
Electrocardiograms ........................................................................................................................ 60 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 60 
8.2.5 
Local tolerability ............................................................................................................................. 61 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 61 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 62 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 62 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 62 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 62 
8.3.5 
Pregnancy ...................................................................................................................................... 63 
8.3.6 
Adverse event of special interest ................................................................................................... 63 
8.3.7 
Guidelines for reporting product complaints .................................................................................. 65 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 65 
8.5 
PHARMACOKINETICS .................................................................................................................. 65 
8.6 
PHARMACODYNAMICS ............................................................................................................... 66 
8.7 
GENETICS ..................................................................................................................................... 67 
 .................................................................................................................... 67 
 ............................................................................................................................. 67 
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 ............................................................................................................................... 68 
8.9 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 69 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 70 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 70 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 70 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 70 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 71 
9.4.1 
General considerations .................................................................................................................. 71 
9.4.2 
Primary endpoint(s) ........................................................................................................................ 71 
9.4.2.1 
Additional analyses of the primary endpoint .................................................................................. 71 
9.4.3 
Key secondary endpoint(s) ............................................................................................................ 72 
9.4.3.1 
Additional analyses of the key secondary endpoints ..................................................................... 72 
 ..................................................................................................... 72 
9.4.5 
Analysis of safety data ................................................................................................................... 73 
9.4.5.1 
Adverse events .............................................................................................................................. 73 
9.4.5.2 
Local tolerability ............................................................................................................................. 74 
9.4.5.3 
Immunogenicity .............................................................................................................................. 74 
9.4.5.4 
Extent of study treatment exposure and compliance ..................................................................... 75 
9.4.5.5 
Laboratory data .............................................................................................................................. 75 
9.4.5.6 
Vital signs ....................................................................................................................................... 75 
9.4.5.7 
Electrocardiogram .......................................................................................................................... 75 
9.4.6 
Analysis of pharmacokinetic data .................................................................................................. 75 
9.4.6.1 
Pharmacokinetic parameters ......................................................................................................... 75 
9.4.6.2 
Pharmacokinetic/Pharmacodynamic analysis ............................................................................... 75 
9.4.7 
Other analyses ............................................................................................................................... 75 
9.4.7.1 
Biomarkers ..................................................................................................................................... 75 
9.5 
INTERIM ANALYSES .................................................................................................................... 76 
9.6 
DATA MONITORING COMMITTEE (DMC) ................................................................................... 76 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 77 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 77 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 77 
10.1.2 
Financial disclosure........................................................................................................................ 78 
10.1.3 
Informed consent process .............................................................................................................. 78 
10.1.4 
Data protection ............................................................................................................................... 79 
10.1.5 
Committees structure ..................................................................................................................... 80 
10.1.6 
Dissemination of clinical study data ............................................................................................... 80 
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10.1.7 
Data quality assurance .................................................................................................................. 80 
10.1.8 
Source documents ......................................................................................................................... 81 
10.1.9 
Study and site start and closure ..................................................................................................... 81 
10.1.10 Publication policy ........................................................................................................................... 82 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 82 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 84 
10.3.1 
Definition of AE .............................................................................................................................. 84 
10.3.2 
Definition of SAE ............................................................................................................................ 86 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................... 87 
10.3.4 
Reporting of SAEs.......................................................................................................................... 88 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION .............................................................................................................................. 89 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 92 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 93 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 98 
10.8 
APPENDIX 8: ABBREVIATIONS ................................................................................................... 98 
10.9 
APPENDIX 9: PROTOCOL AMENDMENT HISTORY ................................................................ 100 
11 
REFERENCES ............................................................................................................................. 104 
 
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LIST OF TABLES  
Table 1 - Risk assessment ............................................................................................................................ 28 
Table 2 - Objectives and endpoints ............................................................................................................... 33 
 ................................................................................................................ 45 
Table 4 - Overview of study interventions administered ............................................................................... 46 
Table 5 - Populations for analyses ................................................................................................................ 70 
Table 6 - Primary endpoint analysis .............................................................................................................. 71 
Table 7 - Key secondary endpoints analyses ............................................................................................... 72 
Table 8 - Safety analyses .............................................................................................................................. 74 
Table 9 - Protocol-required laboratory assessments .................................................................................... 83 
 
LIST OF FIGURES  
Figure 1 - Study schema ............................................................................................................................... 18 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: A randomized, double-blind, placebo-controlled, parallel-group study of the 
safety, tolerability, pharmacokinetics, and therapeutic efficacy of SAR441344 in 
adult patients with primary Sjögren’s syndrome (pSjS) 
Short title: 
Safety, tolerability, pharmacokinetics, and therapeutic efficacy of SAR441344 in 
primary Sjögren’s syndrome (pSjS) 
Rationale: 
Cluster of differentiation 40 (CD40)/cluster of differentiation 40 ligand (CD40L) interaction is 
required for B-cell activation/maturation, dendritic cell maturation, and T-cell dependent antibody 
response (TDAR). Given its stimulatory role, deregulated expression of CD40L can be associated 
with abnormal inflammatory and autoimmune responses. Given these findings, the disruption of 
the CD40/CD40L pathway in autoimmune diseases (particularly those where pathogenic B-cell 
responses are a hallmark of the disease), would be predicted to impact both cellular and humoral 
responses, with therapeutic benefit. 
Sjögren’s syndrome (SjS) is a chronic complex autoimmune disease primarily characterized by 
inflammation and progressive destruction of the exocrine glands (ie, autoimmune epithelitis). 
Though the pathophysiology of SjS is still not fully understood, it is documented that 
CD40/CD40L interaction and B-cell pathology play a role. As expected, higher soluble CD40L 
levels can be found in patients with SjS. Indeed, an antibody against CD40 (iscalimab) recently 
showed promising results on clinical outcome markers in a primary SjS (pSjS) proof of concept 
study, further indicating that inhibition of the CD40/CD40L could be beneficial in pSjS. 
SAR441344 is an antagonist monoclonal antibody (mAb) which binds to CD40L, blocking the 
interaction with CD40 expressed on the surface of antigen presenting cells. This study will 
evaluate the therapeutic efficacy of SAR441344 in adult patients with pSjS, as well as safety, 
tolerability, pharmacokinetics (PK), and pharmacodynamics (PD). 
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Objectives and endpoints 
 
Objectives 
Endpoints 
Primary 
• 
To evaluate the therapeutic efficacy of one dose level 
of SAR441344 versus placebo over 12 weeks in adult 
patients with primary Sjögren’s syndrome (pSjS), 
assessed by the change of the European League 
Against Rheumatism (EULAR) Sjögren’s Syndrome 
Disease Activity Index (ESSDAI).  
• 
Change in ESSDAI from Baseline to Week 12. 
Secondary 
• 
To evaluate the therapeutic efficacy of one dose level 
of SAR441344 versus placebo over 12 weeks in adult 
patients with pSjS, assessed by the EULAR Sjögren’s 
Syndrome Patient Reported Index (ESSPRI).  
• 
Change in ESSPRI from Baseline to Week 12. 
• 
To evaluate the therapeutic efficacy on fatigue of 
one dose level of SAR441344 versus placebo over 
12 weeks in adult patients with pSjS, assessed by the 
Multidimensional Fatigue Inventory (MFI).  
• 
Change in MFI general fatigue subscale and other 
subscales from Baseline to Week 12. 
• 
To evaluate the pharmacokinetic (PK) exposure of 
one dose level of SAR441344 over 12 weeks in adult 
patients with pSjS. 
• 
Descriptive statistics of SAR441344 concentrations, 
including mean, median, and standard deviation. 
• 
Pharmacokinetic parameters for SAR441344 will be 
reported (maximum concentration [Cmax], time to 
Cmax [tmax], area under the curve over the dosing 
interval [AUC0-tau], and terminal half-life [t1/2z]). 
• 
To evaluate the safety and tolerability of one dose 
level of SAR441344 versus placebo in adult patients 
with pSjS as determined by adverse events (AEs). 
• 
Incidence of treatment-emergent AEs (TEAEs), 
serious AEs (SAEs), and AEs of special interest 
(AESIs) from Baseline to Week 24 (End of Study 
[EoS]). 
• 
Incidence of study investigational medicinal product 
discontinuation and withdrawals due to TEAEs from 
Baseline to Week 24 (EoS).  
• 
To evaluate the local tolerability of one dose level of 
SAR441344 versus placebo over 12 weeks in adult 
patients with pSjS. 
• 
Change in participant reported local tolerability 
scale. 
• 
Incidence of AEs related to local tolerability findings. 
• 
To evaluate the safety and tolerability of one dose 
level of SAR441344 versus placebo over 12 weeks in 
adult patients with pSjS determined by 
electrocardiogram, vital signs, and laboratory 
evaluations. 
• 
Participants with medically significant changes in 
vital signs, electrocardiogram, and/or laboratory 
evaluations.  
• 
To measure the immunogenicity of one dose level of 
SAR441344 versus placebo over 12 weeks in adult 
patients with pSjS. 
• 
Antidrug antibodies at Baseline, Week 4, Week 8, 
Week 12, and Week 24.  
 
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Objectives 
Endpoints 
l
i
Overall design: 
ACT16618 is a multicenter, randomized, double-blind, placebo-controlled, parallel group proof of 
concept Phase 2 study to assess the safety, tolerability, PK, and therapeutic efficacy of 
SAR441344 in pSjS. Participants included are diagnosed with pSjS, with systemic disease 
(European League Against Rheumatism [EULAR] Sjögren’s Syndrome Disease Activity Index 
[ESSDAI] score ≥5) and significant biological activity. Participants will be randomized at 
Baseline (Day 1) to SAR441344 or placebo in a 1:1 ratio and will receive a single intravenous 
(IV) loading dose on Day 1, followed by 5 subcutaneous (SC) doses administered once every 
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2 weeks (q2w). The Screening period has a maximum duration of 30 days, followed by a 
treatment period for 12 weeks. The follow-up period has a 12-week duration. Randomization will 
be stratified by EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) ≥5 versus <5.  
This study will be reviewed by an independent Data Monitoring Committee (DMC). 
Disclosure Statement: This is a parallel-group treatment study with 2 groups that is blinded for 
the participant and Investigator. 
Number of participants: 
Approximately 88 participants will be randomized to study intervention such that approximately 
80 participants complete the study and be evaluable for the analysis of the primary endpoint.  
Intervention groups and duration: 
Participants will receive SAR441344, with a single IV loading dose of 
 mg or matching 
placebo on Day 1, followed by 5 doses of 
 mg SC q2w or matching placebo. Screening will 
last up to 30 days, followed by a 12-week treatment period (with the last investigational medicinal 
product [IMP] administration scheduled at Week 10), and a 12-week follow-up period, leading to 
a drug-free surveillance period of approximately 4 half-lives.  
Study intervention(s) 
Investigational medicinal product(s) 
• Formulation: SAR441344, a humanized anti-CD40L mAb, will be supplied in single use 
vials containing 
 mg SAR441344 (
 mg/mL; extractable volume:  mL). Placebo 
will be prepared using the same formulation as SAR441344 without the active protein and 
supplied in single use vials (extractable volume:  mL). 
• Route(s) of administration: IV and SC. 
Dose regimen: One IV loading dose of 
 mg or matching placebo (infusion duration: 1 hour) 
followed by 5 administrations of 
 mg or matching placebo SC q2w. 
Statistical considerations: 
• Sample size considerations: 
- 
The sample size was derived with respect to the primary endpoint (mean change from 
Baseline to Week 12 in the ESSDAI score) by applying the Quantitative Decision 
Making approach. 
• Main analysis populations: 
- 
Efficacy population: all randomly assigned participants who did actually receive at 
least 1 complete dose of IMP with at least 1 post-IMP administration measurement, 
with available Baseline assessment of the ESSDAI.  
Participants will be analyzed according to the intervention they actually received. 
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- 
Safety population: all randomized participants exposed to the IMP (regardless of the 
amount of treatment administered) are included in the safety population. Participants 
will be analyzed according to the intervention they actually received. 
- 
Pharmacokinetic population: all participants without any important deviation related 
to IMP administration, for whom the PK data are considered interpretable. Participants 
having received only placebo will not be part of the PK population. 
• Analysis of primary endpoint:  
- 
The difference to placebo of mean change from Baseline to Week 12 in ESSDAI score 
will be derived using a linear mixed model with repeated measurements over time 
within participant, including the fixed effects for participant-specific baseline 
ESSDAI, visit, treatment group, and visit-by-treatment group interaction, jointly with 
90% confidence interval. 
• Analysis of key secondary endpoints: 
- 
The difference to placebo of mean change from Baseline to Week 12 in ESSPRI will 
be derived using a linear mixed model with repeated measurements over time within 
participant, including the fixed effects for participant-specific baseline ESSPRI, visit, 
treatment group, and visit-by-treatment group interaction, jointly with 90% confidence 
interval. 
- 
The difference to placebo of mean change from Baseline to Week 12 in 
Multidimensional Fatigue Inventory (MFI) general fatigue subscale and other 
subscales will be derived using a linear mixed model with repeated measurements over 
time within participant, including the fixed effects for participant-specific baseline, 
visit, treatment group, and visit-by-treatment group interaction, jointly with 
90% confidence intervals. 
• Analysis of safety endpoints: 
- 
Incidence of treatment-emergent adverse events (TEAEs), serious adverse events 
(SAEs), and adverse events of special interest (AESIs) from Baseline to Week 24 (End 
of Study [EoS]) will be presented. 
- 
Incidence of TEAEs leading to definitive treatment discontinuation will be presented.  
- 
Descriptive statistics of laboratory variables, electrocardiograms (ECGs), and vital 
signs will be presented.  
Data Monitoring Committee: Yes 
 
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1.2 
SCHEMA  
Figure 1 - Study schema  
 
D: Day, IV: intravenous, LD: loading dose, PCB: placebo, q2w: once every 2 weeks, R: randomization, SAR: SAR441344, SC: subcutaneous, V: Visit, W: Week.  
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
Phase 
Screening 
Treatment Period 
Follow-up Period 
Day/Week 
D-30 to D-1 
D1 
(BL) 
W02 
W04 
W06 
W08 
W10 
W12 
(EoTa) 
W16c 
W20c 
W24 
(EoSb,c) 
Visit window  
 
 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±4 d 
±4 d 
±4 d 
Visits 
V00 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
V10 
Informed consent form 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Participant demography 
X 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medicationsd 
< 
- 
- 
- 
- 
- 
- 
- 
- 
- 
> 
Inclusion 
 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Phone call before visite 
 
X 
 
 
 
 
 
X 
 
 
 
Phone call to evaluate potential SARS-CoV-2 infectionf 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study treatment administration 
 
 
 
 
 
 
 
 
 
 
 
SAR441344 administration or placebog 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Safety  
 
 
 
 
 
 
 
 
 
 
 
Physical examinationsh 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
Body temperature 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
Vital signs 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
ECG 
X 
X 
 
X 
 
 
 
X 
 
 
X 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
FSHi 
X 
 
 
 
 
 
 
 
 
 
 
β-HCG blood testj 
X 
 
 
 
 
 
 
 
 
 
 
Tuberculosis screeningk 
X 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
Coagulation 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
Clinical chemistryl 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
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Phase 
Screening 
Treatment Period 
Follow-up Period 
Day/Week 
D-30 to D-1 
D1 
(BL) 
W02 
W04 
W06 
W08 
W10 
W12 
(EoTa) 
W16c 
W20c 
W24 
(EoSb,c) 
Visit window  
 
 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±4 d 
±4 d 
±4 d 
Visits 
V00 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
V10 
Urinalysism 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
Urine pregnancy test, WOCBP onlyn 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Local tolerabilityo 
 
 
X 
X 
X 
X 
X 
 
 
 
 
Antidrug antibodies 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Adverse event collection 
< 
- 
- 
- 
- 
- 
- 
- 
- 
- 
> 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
Plasma sample collection (SAR441344)  
 
Xp 
X  
X 
X 
X 
X 
X 
X 
 
X 
Efficacy 
 
 
 
 
 
 
 
 
 
 
 
ESSDAIq 
Xr 
X 
 
X 
 
X 
 
X 
 
 
X 
ESSPRIs 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Multidimensional Fatigue Inventory (MFI) 
 
X 
 
 
 
 
 
X 
 
 
X 
 
Xu 
 
 
 
 
 
Pharmacodynamics 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
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Phase 
Screening 
Treatment Period 
Follow-up Period 
Day/Week 
D-30 to D-1 
D1 
(BL) 
W02 
W04 
W06 
W08 
W10 
W12 
(EoTa) 
W16c 
W20c 
W24 
(EoSb,c) 
Visit window  
 
 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±2 d 
±4 d 
±4 d 
±4 d 
Visits 
V00 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
V10 
Biomarker 
 
 
 
 
 
 
 
 
 
 
 
Anti-Ro/SSA antibodies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: assessments during the treatment period will be performed prior to IMP dosing, unless otherwise specified. 
a If the participant discontinues the study before Week 12, the EoT visit should be performed, if possible. If the participant discontinues the IMP before Week 12, the EoT visit and the complete follow-up period 
should be performed. 
b If the participant discontinues the study in the follow-up period, the EoS visit should be performed, if possible. 
c In exceptional cases, under regional or national emergencies (eg, natural disaster, epidemic diseases, terrorist attack) due to which a visit at the clinical study site is no longer possible or safe, one or more 
follow-up visits can be performed remotely (eg, via telephone call). This should be done according to local regulations and approved by the Sponsor. At least one follow-up visit should be performed on site 
(EoS visit), even if the visit window needs to be extended (to a maximum of 8 weeks). 
d Stable background therapy with hydroxychloroquine or chloroquine, low doses of oral corticosteroids, topical therapy and pharmacological stimulants (glands), and NSAIDs are allowed; see Section 6.5 for detailed 
information. Participants need to be informed about restrictions on concomitant medication including nonprescription drugs as described in Section 6.5 at Screening and throughout the study. 
e 
 (Section 6.5.2). 
 
f 
Participants will be contacted before each visit (latest on the day before the visit) by the Investigator or designee, to evaluate for signs and symptoms of a potential SARS-CoV-2 infection. In case of suspicion of 
such infection, the participant will be asked to not come to the study site and will be referred to a testing facility or her/his primary care physician according to local regulations. If the suspicion of a SARS-CoV-2 
infection is excluded and there is no other reason to pause treatment due to the Investigator judgment, the treatment can continue. In the case of biologically proven COVID-19 infection, the Investigator may 
permanently discontinue the IMP for the participant (Section 7.1.1). If according to the Investigator a permanent IMP discontinuation is not necessary or in the best interest of the participant, the Investigator can 
consider a temporary discontinuation until the participant’s COVID-19 PCR is negative (Section 7.1.2). 
g On D1: SAR441344 
 mg IV administration or placebo (infusion duration: 
). On W02, W04, W06, W08, and W10: 
 mg SC administration of SAR441344 or placebo. See Section 6.1 for details. 
h In visits where physical examinations are not scheduled, physical examinations can still be performed if participants present with any symptoms. 
i 
Should be performed more than once, but only on postmenopausal women, where amenorrhea is present for less than 12 months (see Appendix 4 [Section 10.4]).  
j 
 To be done for all female participants. 
k QuantiFERON® tuberculosis Gold test and medical history. 
l 
Fasting is preferred. Fasting/non-fasting status will be recorded at the time of blood collection for serum glucose assessment. 
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m Urine dipstick analysis performed locally at the site. If positive for a pathological finding and rated clinically significant by the Investigator, the urine sample will be sent to the central laboratory for a quantitative 
analysis. 
n If the urine pregnancy test is positive, a blood pregnancy test needs to be analyzed by the central laboratory. 
o Will be assessed by a local tolerability questionnaire as described in Section 8.2.5. 
p On D1, 
q Will be rated according to Seror et al (2010 and 2015]) as described in Section 8.1.1. The ESSDAI should be rated by the same Investigator per participant throughout the study, if possible.  
r 
Study inclusion will be based on the ESSDAI score during Screening (see Section 5.1 inclusion criterion I 04 and Section 8.1.1). 
s Will be rated according to Seror et al (2011 and 2015) as described in Section 8.1.2. 
t 
Topical medication, pharmacological stimulants, and NSAIDs need to be paused at least 12 hours prior to these assessments. 
u This test can be performed during the Screening period or at Baseline. The same result will be used for inclusion and Baseline. 
v See Section 8.1.4. 
w See Section 8.1.5. 
x 
 
y Optional. 
 BL: Baseline, BUN: blood urea nitrogen,
, D: Day, 
, ECG: electrocardiogram, EoT: End of Treatment, EoS: End of 
Study, EQ-5D-5L: EuroQoL questionnaire with 5 dimensions and 5 levels per dimension, ESSDAI: EULAR Sjögren’s Syndrome Disease Activity Index, ESSPRI: EULAR Sjögren’s Syndrome Patient Reported Index, 
EULAR: European League Against Rheumatism, FSH: follicle-stimulating hormone, HCG: human chorionic gonadotropin, Ig: immunoglobulin, IMP: investigational medicinal product, IV: intravenous, 
A, NSAID: non-steroidal anti-inflammatory drug, 
, PK: pharmacokinetic(s), RF: rheumatoid factor, 
 
SARS-CoV-2: severe acute respiratory syndrome coronavirus-2; SC: subcutaneous, V: Visit, W: Week, WOCBP: women of childbearing potential.  
 
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2 
INTRODUCTION  
SAR441344 is a novel, potent CD40L inhibiting mAb that is being developed to treat several 
autoimmune diseases. The disruption of the CD40/CD40L pathway in autoimmune diseases, 
particularly those where pathogenic B-cell responses are a key hallmark of disease, would be 
predicted to impact both cellular and humoral responses and have therapeutic benefit, including 
SjS. 
2.1 
STUDY RATIONALE  
The purpose of this proof of concept study is to obtain data on safety, tolerability, PK, and 
therapeutic efficacy for one dose level of SAR441344 in adult patients with pSjS. 
SAR441344 is an antagonist mAb which binds to human CD40L. Binding of SAR441344 blocks 
interaction with CD40 expressed on the surface of antigen-presenting cells, such as B-cells, thus, 
disrupting the CD40/CD40L signaling pathway. Dysregulation of cellular and humoral immune 
responses has been clearly demonstrated as a key factor in many autoimmune disorders (1). 
CD40L is, therefore, identified as a target for treating a number of autoimmune diseases, 
including pSjS.  
Although the pathophysiology of pSjS is not fully understood, it is documented that CD40/CD40L 
interaction and B-cell pathology play a major role (2). B-cell hyperactivity includes the 
production of autoantibodies like anti-Ro/SSA, anti-La/SSB, or rheumatoid factor (RF), as well as 
hypergammaglobulinemia and increased levels of free light chains. Autoimmune epithelitis, 
presented in exocrine glands (namely salivary and lacrimal glands) as part of pSjS, presents 
ectopic lymphoid structures (germinal-like centers) in histology. It is known that glandular 
epithelial cells show increased expression of CD40 (2, 3). Sjögren’s syndrome patients show 
elevated soluble CD40L levels (4) and a recently published proof of concept study evaluating an 
anti-CD40 antibody (iscalimab) indicated signs of efficacy after a 12-week treatment period. Data 
suggest that the CD40/CD40L interaction plays a relevant role in pSjS pathomechanism and may 
have potential for disease modification (5).  
In non-obese diabetic NOD/ShiLtJ mice (model of SjS), use of an anti-CD40L antibody after 
development of a SjS-like disease was able to inhibit ectopic lymphoid structure formation and 
autoantibody production (6). Considering these findings, targeting pSjS with SAR441344 can be 
justified. For this reason, the primary objective of this study is to evaluate the therapeutic efficacy 
of SAR441344 in adult patients with pSjS measured by the EULAR ESSDAI. Other objectives 
will include further assessment of efficacy by the EULAR ESSPRI, MFI, and gland function test. 
In addition, this study will assess the PK, PD, and safety, including antidrug antibodies, of 
SAR441344 in comparison with placebo. 
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2.2 
BACKGROUND  
2.2.1 Primary Sjögren’s syndrome  
Sjögren’s syndrome is a chronic complex autoimmune disease primarily characterized by 
inflammation and progressive destruction of the exocrine glands (ie, autoimmune epithelitis). The 
main glands affected include the lacrimal and salivary glands, leading to dryness of mouth and 
eyes. The disease is often accompanied by severe pain and fatigue. These key manifestations are 
common in all phenotypes of the disease and are measured by the ESSPRI (7). However, a subset 
of patients (approximately 30%) develop, with variable severity, extra-glandular manifestations, 
including vasculitis, interstitial lung disease, kidney involvement, arthralgia, and central nervous 
system (CNS)/peripheral nervous system (PNS) involvement (3). These manifestations are 
measured by the ESSDAI (7, 8).  
Thus, the spectrum of SjS can vary from a benign slowly progressive exocrinopathy to a 
heterogeneous potentially life-threatening systemic disorder, also characterized by an increased 
risk of non-Hodgkin’s lymphoma (approximately 5% of the patients), based on the increased 
B-cell activity found in the disease. Primary SjS is the second prevalent systemic autoimmune 
disorder after rheumatoid arthritis and is predominant in women in a 9:1 ratio (female:male) 
(3, 9).  
Apart from topical treatments for salivary and lacrimal glands, no treatment is approved for pSjS, 
revealing a significant unmet medical need. 
2.2.2 SAR441344  
SAR441344 is derived from the humanized mAb IDEC-131, with 2 major modifications: 
1) affinity maturation of the variable region, and 2) mutations in the Fc region to inhibit binding to 
the FcγRIIa receptor. Similar to the first-generation IDEC-131, SAR441344 binds to CD40L and 
prevents binding to and signaling via CD40. Additional information on SAR441344 may be found 
in the Investigator’s Brochure (IB). CD40L is a member of the tumor necrosis factor alpha 
superfamily. It is transiently expressed on the surface of cells and platelets as a homotrimer and 
may be released in a biologically active form into circulation (10). CD40L is expressed on a 
variety of cell types including T helper (Th) cells, platelets, endothelial cells, smooth muscle cells, 
macrophages, and antigen presenting cells. 
Through its interactions with CD40, CD40L is best known for its role as an immunologic second 
signal expressed on Th cells and is required for B-cell activation/maturation and dendritic cell 
maturation (11). CD40L loss of function is associated with the development of 
hyper-immunoglobulin (Ig) M syndrome and is characterized by inhibition of B-cell maturation, 
loss of germinal center formation, absence of isotype switching, affinity maturation, somatic 
hypermutation, and inability to form long lived plasma cells and memory B-cells (12). In addition 
to its role in B-cell maturation, CD40L is thought to enhance macrophage effector function and 
aid in the development of CD8+ memory T-cells. Disruption of the CD40/CD40L pathway in 
autoimmune diseases, particularly those where pathogenic B-cell responses are a key hallmark of 
disease, would be predicted to impact both cellular and humoral responses and have therapeutic 
benefit.  
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Consistent with CD40L’s role as a necessary second signal for B-cell maturation, 
isotype-switched Ig production, somatic hypermutation, germinal center formation, formation of 
long-lived plasma, and memory cells, anti-CD40L antibody therapies are known to be potent 
inhibitors of TDAR. While TDAR is often used to evaluate immunosuppression or 
immunomodulation, TDAR inhibition with anti-CD40L represents a downstream PD effect of 
anti-CD40L therapy. To evaluate the IMP effect on TDAR, keyhole limpet hemocyanin (KLH) 
immunization was used to characterize TDAR by inhibition of anti-KLH IgG production in the 
first in human (FIH) studies (see Section 2.2.2.2). 
Given the critical role of CD40L in the adaptive immune response, anti-CD40L therapies have 
been developed for the treatment of diseases such as immune thrombocytopenia purpura, multiple 
sclerosis, and systemic lupus erythematosus with some early signs of efficacy. Unfortunately, 
first-generation anti-CD40L therapies were associated with increased thromboembolic events in 
human studies and ultimately resulted in the discontinuation of their development (The term 
thromboembolic event or thromboembolism is used in this document to denote any arterial or 
venous thrombotic or embolic events). Elevated thromboembolic risk seen with first-generation 
anti-CD40L mAb therapies resulted from platelet activation triggered by FcγRIIa activation by 
higher order immune complexes containing both the anti-CD40L mAb and CD40L (membrane or 
soluble) which is expressed by platelets (13, 14). 
Understanding Fc-mediated thromboembolic risk resulted in the engineering of second-generation 
anti-CD40L therapies that either did not contain an Fc or contained a modified Fc with low 
FcγRIIa binding, with the goal of eliminating thromboembolic risk. SAR441344 has a modified 
Fc region. There are at least 3 second-generation anti-CD40L mAb in clinical studies treating 
patients: dapirolizumab, VIB4920 (MEDI4920), and BMS-986004 (15, 16, 17). Based on trial 
disclosures in clinicaltrials.gov, over 400 participants have been dosed with a second-generation 
anti-CD40L therapy, and to the Sponsor’s knowledge, no thromboembolic events have been 
observed in the published data as of the date of the protocol. In the first in human study with 
SAR441344 (
 and 
, see Section 2.2.2.2), no thromboembolic event has 
occurred to the date of the protocol after treatment with SAR441344. 
2.2.2.1 Preclinical data  
The potential for SAR441344 to induce thromboembolic events was evaluated using an in vitro 
platelet activation assay and platelet rich plasma from healthy subjects, multiple sclerosis and 
systemic lupus erythematosus patients. The in vitro platelet activation assays demonstrated that 
SAR441344 in combination with recombinant human soluble CD40L (rhsCD40L) does not 
increase platelet activation as measured by CD62P expression as compared with first-generation 
anti-CD40L antibodies combined with rhsCD40L. SAR441344 effects on platelets were similar to 
that of the IgG1 negative control. Details on the extensive preclinical evaluation on the 
thromboembolic risk are described in the IB.  
In summary, SAR441344 nonclinical data demonstrated that thromboembolism is not an 
identified hazard of the SAR441344 toxicology profile. The SAR441344 toxicology profile is 
consistent with its pharmacology and includes decreased cellularity in germinal centers, moderate 
decrease in B-cells and decreased TDAR to KLH antigen. Effects on immune system and 
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potential opportunistic infections are expected hazards of SAR441344. These effects on the 
immune system are monitorable and expected to resolve after antibody discontinuation. Antidrug 
antibody (ADA) formation was observed at lower doses in SAR441344 toxicology studies, but the 
mechanism of action of SAR441344 is expected to reduce the impact of ADA formation at higher 
doses. The 6-month Good Laboratory Practice (GLP) toxicity study no observed adverse effect 
level (NOAEL) was 
 mg/kg/week IV, with a Day 169 area under the curve (AUC) from 
hour 0 to 168 hours (AUC0 - 168) of 
 µg × h/mL in cynomolgus monkeys. The maximum 
concentration (Cmax) achieved was 
 µg/mL. For details on the non-GLP and GLP toxicity 
studies performed within the preclinical assessment of SAR441344, please refer to the IB. 
Details, 
including further nonclinical PD and PK studies, are described in the IB. 
2.2.2.2 Clinical data  
 
 is a completed Phase 1, double-blind, randomized, parallel design, placebo-controlled 
single ascending dose study to evaluate the safety, tolerability, PK, and PD of IV doses of 
SAR441344 in healthy adult subjects. Five sequential ascending single doses of matching 
SAR441344 (
 mg) or matching placebo were diluted to a final 
volume of approximately 100 mL in 0.9% normal saline and administered on Day 1 by IV 
infusion over approximately 1 hour. All participants were immunized with a 
(Day ). A total of 40 healthy adult subjects, including 22 (55.0%) males and 18 (45.0%) females 
were treated. Each cohort had 8 subjects, 6 receiving SAR441344 and 2 receiving placebo.  
Overall, a single IV dose of SAR441344 between
 to 
 mg administered in healthy male 
and female adult subjects was safe and well tolerated. There were no serious or severe TEAEs. No 
trends in vital signs, ECGs, or laboratory values were identified, including assays meant to 
identify potential increased thromboembolic or infectious risks. 
The time to Cmax (tmax) for SAR441344 was observed between 1 hour (end of infusion) to 2 hours 
postdose. SAR441344 exposure increased with no deviation from dose proportionality from 
 to 
 mg. The mean terminal half-lives (t1/2z) ranged from 
 days over the dose 
range. 
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 is a completed Phase 1, double-blind, randomized, placebo-controlled multiple 
ascending dose study investigating 5 dose levels of SAR441344 (
and 
 mg) or placebo controls. Each cohort received 3 repeated 
administrations of SAR441344 2 weeks apart (Days 
 and 
). Each of the 5 dose 
cohorts were planned to contain 2 subjects who would receive placebo and 8 subjects who would 
receive SAR441344, and all subjects were to receive 
 on Day  and Day 
. 
Overall, 5 dose levels of SAR441344 between 
 mg administered SC as 3 doses q2w 
in healthy male and female adult subjects appeared safe and well tolerated. There were no serious 
or severe TEAEs. Three subjects discontinued treatment secondary to adverse events (AEs) of 
elevated transaminases (leading to an AESI, judged to be unrelated to the study drug treatment by 
the Investigator), a presyncope in the setting of hypotension (classified as unrelated to study 
drug), and pityriasis rosea (placebo group). No concerning trends in vital signs, ECGs or 
laboratory values were identified, including assays meant to identify a potential for increased risk 
for thromboembolism or infection. The tmax for SAR441344 was observed between
 days 
postdose after Day  dosing and between
 days after Day 
 dosing. 
SAR441344 exposure increased with no deviation from 
dose proportionality from
 mg. The mean t1/2z ranged from
 days over the dose 
range. The 
 induced a strong TDAR 
 in 
placebo subjects. SAR441344 treatment caused a dose-dependent inhibition of the TDAR, with 
partial inhibition in the 
 mg and 
 mg cohorts (
 respectively), and 
 in the 
 mg, 
 mg, and 
 mg dose cohorts. The extent of 
inhibition at steady state would be anticipated to be more extensive than the values observed in 
the 
study after 3 administrations. 
2.3 
BENEFIT/RISK ASSESSMENT  
2.3.1 Risk assessment  
Based on the review of the cumulative data for SAR441344, there are no important identified 
risks for SAR441344. 
Important potential risks include: 
• Thromboembolic events. 
• Infections, including opportunistic infections. 
• Immunogenicity/hypersensitivity. 
• Injection site reactions/local tolerability at injection site. 
Details of the risks together with a summary of the cumulative nonclinical and clinical safety data 
are provided in Table 1 below. 
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Table 1 - Risk assessment  
Potential risk of clinical 
significance 
Summary of data/rationale for 
risk 
Mitigation strategy 
Thromboembolic events 
The first-generation anti-CD40L therapies 
were associated with an increased risk of 
thromboembolic events. 
The SAR441344 nonclinical package did 
not identify thromboembolism as a hazard. 
No events have been publicly reported with 
other second-generation anti-CD40L 
therapies in clinical studies. 
Platelet count and D-dimer were monitored 
throughout the FIH Study 
and while transient abnormal 
values were occasionally noted, there were 
no clinically significant sustained changes 
from baseline.  
Risk assessment:  
• 
Regular monitoring of platelet counts and 
AEs which may suggest possible 
thromboembolic events. 
• 
Confirmed thromboembolic event to be 
reported as AESI. 
Risk Minimization: 
• 
Removal or modification of the Fc region 
is believed to have addressed the 
thromboembolic risk as indicated by 
second-generation therapies showing no 
elevated risk in nonclinical models or 
clinical studies (see Section 2.2). 
• 
Exclusion of participants with any history 
of thromboembolic events, as well as 
myocardial infarction, stroke, 
antiphospholipid syndrome, and/or 
participants requiring antithrombotic 
treatment. 
Infection including opportunistic 
infections 
SAR441344 inhibits CD40/CD40L 
interactions which plays a key role in the 
adaptive immune response, particularly 
humoral immunity. 
Based on the findings of the 13-week GLP 
toxicology study and knowledge of the 
CD40L loss of function phenotype in 
humans, inhibition of CD40L may increase 
the risk of upper and lower respiratory 
infections and gastrointestinal infections as 
well as opportunistic infections.  
In the 13-week GLP toxicology study, a 
moderate decrease in B-cells was noted, 
without a significant decrease in cell 
numbers and recovered after a 10-week 
recovery period. In the 6-month GLP 
toxicology study without a recovery period 
dose-independent slight to moderate 
decreases in absolute counts of 
B-lymphocytes were observed with 
statistical significance for all SAR441344 
treated groups. Treatment with anti-CD40L 
therapies is associated with modest 
reductions in IgG in clinical studies. Both 
were not detected in the FIH study so far. 
Risk assessment and mitigation strategy for 
SARS-CoV-2 is detailed in Section 2.3.1.1.  
Risk assessment: 
• 
AE reporting. Severe infections, including 
opportunistic infections, are considered 
AESI. 
• 
Baseline detection and exclusion of TB, 
HIV, hepatitis tests, to be repeated in 
case of suspicion. 
Risk minimization: 
• 
Exclusion of participants with active or 
latent tuberculosis with TB test, HIV 
infection, chronic viral hepatitis or other 
known opportunistic infection, history of 
severe parasitic infections, as well as 
active infections or chronic ongoing 
infections of any course.  
• 
No live vaccines/live components; vaccine 
policy. 
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Potential risk of clinical 
significance 
Summary of data/rationale for 
risk 
Mitigation strategy 
Immunogenicity/hypersensitivity 
Due to its mechanism of action, 
SAR441344 may reduce the risk of ADA 
formation in humans. Nevertheless, ADA 
may result in alterations in SAR441344 
exposure and in extreme cases could result 
in a Type III hypersensitivity reaction. In 
total, only 4 subjects developed ADA 
Risk assessment:  
• 
ADA detection during the study through 
4 half-lives.  
• 
Hypersensitivity reactions will be 
systematically monitored (eg, chills, rash, 
urticaria, hypotension).  
• 
Anaphylactic reaction/acute allergic as 
well as infusion related reaction to be 
reported as an AESI. 
Risk minimization: 
• 
IV administration of 1 hour minimum with 
a monitoring period of 3 hours at the 
study site afterwards. 
• 
Symptomatic treatment of any 
immunogenicity related AEs. 
• 
ADA will be checked if there is a safety 
concern. 
Injection site reaction/local 
tolerability at injection site 
IV administration in study 
 has 
been well tolerated up to
 mg IV, there 
was 1 subject reported to experience an 
infusion site reaction. Subcutaneous 
administration in 
 up to 
 mL 
was overall well tolerated, with 
3 SAR441344-treated subjects showing 
mild injection site reactions. 
Risk assessment: 
• 
Thorough medical examination of the 
injection sites and implementation of 
assessment scale. 
• 
Severe injection and infusion site reaction 
will be reported as AESI. 
Risk minimization:  
• 
Loading dose will be administered IV to 
avoid large volume SC injection. 
• 
Monitoring of the injection site after IMP 
injection. 
Study intervention: 
SAR441344 
Loading dose 
 mg IV or matching placebo Day 1  
5 doses of 
 mg SC or matching placebo q2w 
ADA: antidrug antibody, AE: adverse event, AESI adverse event of special interest, CD40: cluster of differentiation 40, CD40L: cluster of 
differentiation 40 ligand, EOS: end of study, FIH: first in human, GLP: Good Laboratory Practice, HIV: human immunodeficiency virus, 
Ig: immunoglobulin, IMP: investigational medicinal product, IV: intravenous, q2w: once every 2 weeks, SARS-CoV-2: severe acute respiratory 
syndrome coronavirus-2; SC: subcutaneous, TB: tuberculosis. 
2.3.1.1 Risk assessment and mitigation in the context of SARS-CoV-2  
2.3.1.1.1 Risk assessment  
A potential risk for infections is already described for SAR441344. Severe acute respiratory 
syndrome coronavirus-2 (SARS-CoV-2) infection is a pandemic, with uncertainties regarding the 
epidemiology, clinical course and immunity remaining. The relevance of immunosuppression for 
the entire course of the disease is currently unclear but could a present a potential risk. 
Assessment of the infectious risk of other anti-CD40L or CD40L compounds, which were or are 
in clinical development, is limited to information from early clinical trials with small sample sizes 
before the coronavirus infectious disease due to SARS-CoV-2 (COVID-19) pandemic. Overall, 
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these data showed only a slight increase of upper respiratory tract infections but did not reveal 
significant increased infection rates.  
Although CD40L/CD40 interaction is important for B-cell differentiation, there is, based on 
preclinical and clinical data from the FIH study, currently no evidence that SAR441344 is B-cell 
depleting: a slight decrease of B-cells was noted in the 13-week GLP toxicology study, which was 
reversible in the recovery period. The same was seen in 6-month GLP study, which was run 
without a recovery period (GLP studies described in Section 2.2.2.1). Throughout the FIH, no 
decrease in B-cells was recorded. Therefore, the comparison with B-cell depleting drugs, such as 
rituximab and ocrelizumab, in terms of infectious risk is limited. However, it is important to note 
that although viral infections and infections of the respiratory tract are noted as very common 
during treatment with these compounds, severe infections remain limited.  
Although the role of CD40L in immune response in general is well established, there are no 
detailed data available on the specific role of CD40L in the course of a SARS-CoV-2 
infection/COVID-19. Currently, there is no evidence that CD40L is relevant for the viral infection 
with SARS-CoV-2. There is evidence that the development of viral clearance and a potential 
protective immunity follow the generation of an adaptive immune response, including the 
production of neutralizing antibodies, in which the CD40/CD40L interaction plays a key role 
(18, 19, 20, 21, 22, 23). Therefore, blocking CD40L may prevent antibody formation and immune 
response in case of an acute SARS-CoV-2 infection and may prevent long-term immunity. 
Taking into account the potential risk of increased infection rates based on the mode of action of 
SAR441344 and knowledge of similar and related compounds, and the potential role of CD40L 
for adaptive immune response to a SARS-CoV-2 infection, an increased risk for study participants 
in the situation of the COVID-19 pandemic may be assumed, hence appropriate risk mitigation is 
implemented. 
2.3.1.1.2 Risk mitigation  
One potential risk of SAR441344 is increased rate of infections. In times of an ongoing pandemic, 
this risk is additionally increased. Therefore risk mitigation actions have been established to 
address the risk of infection for participants included in this clinical trial. 
To stop spreading the SARS-CoV-2 distribution and to reduce the risk of infection, clear 
protective measures are described by global health agencies such as the World Health 
Organization (24), but also on national/local level. Study sites should ensure that before the study 
start and throughout the study local guidance is applied to the conduct of the study on the site 
level. 
Stopping rules were implemented to provide guidance for Investigators: 
• In case of suspicion of COVID-19 (eg, fever, cough, shortness of breath in a context of 
possible infected contact), temporary discontinuation of the IMP will be considered by the 
Investigator in accordance with Section 7.1.2, considering the following to evaluate 
individual benefit-risk of continuation or stop of IMP: the probability of COVID-19 
disease, possibility of rapid diagnosis, severity of symptoms, and risk factors. 
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• In the case of biologically proven COVID-19 infection, the Investigator may permanently 
discontinue the IMP for the participant, who will be asked to continue attending the 
protocol scheduled visits until the EOS. If according to the Investigator a permanent IMP 
discontinuation is not necessary or in the best interest of the participant, the Investigator 
can consider a temporary discontinuation if the patient does not have severe or critical 
COVID-19 infection as defined per WHO guidelines (25). The participant must 
temporarily discontinue IMP until the participant’s COVID-19 PCR is negative. A 
discontinuation of more than 30 days will be considered as permanent discontinuation. All 
COVID-19 infections will be reviewed by the DMC as AESI. 
• In case of investigational site closure or complete regional or national lock-down due to a 
local epidemic or international pandemic, the study may be suspended completely or on 
selected sites or regions by the Sponsor. Every effort will be kept to continue the 
follow-up of already recruited patients as close to the Schedule of Activities (SoA) as 
possible (Section 10.1.9).  
Temporary treatment discontinuations and adaptions of the follow-up period may be considered in 
exceptional cases as described in Section 7.1.2. 
Participants will be contacted before each visit by an Investigator or designee, to evaluate for 
signs and symptoms of a potential SARS-CoV-2 infection. In case of suspicion of such infection, 
the participant will be asked to not come to the study site and will be referred to a testing facility 
or her/his primary care physician according to local regulations. If the suspicion of a 
SARS-CoV-2 infection is excluded and there is no other reason to pause treatment due to the 
Investigator judgment, the treatment can continue. If the suspicion of a SARS-CoV-2 infection is 
confirmed, treatment should be paused.  
Severe illness can occur in otherwise healthy individuals of any age, but it predominantly occurs 
in adults with underlying medical comorbidities including: chronic lung disease, cardiovascular 
disease, diabetes mellitus, hypertension, obesity, and cancer (26, 27, 28, 29, 30, 31, 32). High risk 
populations for COVID-19 are excluded due to the general selection of study participants for this 
proof-of-concept study, according to the inclusion/exclusion criteria I 08, E 04, E 05, E 09, and E 
13 (Section 5.1 and Section 5.2). This also includes significantly immunocompromised 
participants, already excluded by E 06, E 07, E 09, and E 18 (Section 5.2). 
In addition to this, patients who live in long-term care facilities and nursing homes will be 
excluded from study participation as they have a high risk of SARS-CoV-2 infections (33). 
According to exclusion criteria E 06 and E 09 (Section 5.2), it is expected, that participants with 
acute infection or having a high risk for an asymptomatic SARS-CoV-2 infection (eg, living with 
a person that is currently infected) are not included in the study.  
Taking into account this risk, the potential risk of an increased infectious risk due to lymphopenia, 
and potential relevance in SARS-CoV-2 infections (34), patients with a severe lymphopenia will 
be excluded from this study (see exclusion criterion E 22 in Section 5.2). There is even more 
evidence on the role of neutropenia and infectious risk within pSjS in a longitudinal follow-up of 
a cohort of 300 pSjS patients over 18 years: 30% showed idiopathic neutropenia and those 
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patients had a higher incidence of hospital admission caused by infection (35). Therefore, patients 
with a neutropenia will be excluded from study participation (see exclusion criterion E 22 in 
Section 5.2).  
An extensive risk assessment on the COVID-19 pandemic has been performed. This led to a risk 
mitigation plan including stopping rules, which take into account the current knowledge and also 
potential uncertainties, including plans for lock-down situations. A participant selection that 
considers the risk population of COVID-19 is in place for the study. This should address and 
reduce the risk for participants included in this study. 
2.3.2 Benefit assessment  
Primary SjS comes with a high unmet medical need, as there is no approved drug for systemic 
treatment. This applies in particular to patients feasible for inclusion in this study (ie, ESSDAI ≥5, 
which implies a systemic manifestation of SjS and is associated with significant impact on 
wellbeing and quality of life).  
Pharmacodynamic data from the 
 study provide a proof-of-mechanism showing a 
significant suppression of TDAR to KLH measured by levels of 
 after the 
administration of 
 in healthy subjects treated with SAR441344 or placebo, which 
supports the potential of clinical efficacy. Transferability of successful TDAR suppression into clinical 
efficacy was seen with other second-generation CD40L compounds (eg, MEDI/VIB4920 [17]). 
2.3.3 Overall benefit: risk conclusion  
SAR441344 was investigated in two Phase 1 first in human studies, 
 (single ascending 
dose) and 
 (multiple ascending dose), to assess the safety, tolerability, PK, and PD of 
IV and SC doses. In combination with PK, safety, and tolerability data, PD data also aided in the 
selection of a safe and efficacious dose for this Phase 2 study.  
No safety or tolerability concerns have been identified in the Phase 1 first in human studies. In 
addition, results indicate that SAR441344 treatment with 
 mg (3 doses of 
 mg SC, each 
2 weeks apart) leads 
 in healthy subjects, which supports the 
potential for clinical efficacy. 
As there is no approved medication for systemic treatment of pSjS, the disease comes with a high 
unmet medical need. A treatment with SAR441344 and therefore interruption of the 
CD40/CD40L interaction provides a clear rationale based on what is known on the 
pathophysiology of pSjS (Section 2.2.1). An antibody against CD40 (iscalimab) recently showed 
promising results on clinical outcome markers in a 12-week pSjS proof of concept study, 
indicating that inhibition of the CD40/CD40L could be beneficial in pSjS (5).  
To date, there is no identified risk and the important potential risks associated with SAR441344 
are well defined, and appropriate risk mitigation strategies, including those for COVID-19, are in 
place. Therefore, the overall benefit-risk balance is favorable for further clinical development of 
SAR441344 in pSjS. 
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3 
OBJECTIVES AND ENDPOINTS  
Table 2 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
To evaluate the therapeutic efficacy of one dose level 
of SAR441344 versus placebo over 12 weeks in adult 
patients with primary Sjögren’s syndrome (pSjS), 
assessed by the change of the European League 
Against Rheumatism (EULAR) Sjögren’s Syndrome 
Disease Activity Index (ESSDAI). 
• 
Change in ESSDAI from Baseline to Week 12. 
Secondary 
• 
To evaluate the therapeutic efficacy of one dose level 
of SAR441344 versus placebo over 12 weeks in adult 
patients with pSjS, assessed by the EULAR Sjögren’s 
Syndrome Patient Reported Index (ESSPRI).  
• 
Change in ESSPRI from Baseline to Week 12. 
• 
To evaluate the therapeutic efficacy on fatigue of 
one dose level of SAR441344 versus placebo over 
12 weeks in adult patients with pSjS, assessed by the 
Multidimensional Fatigue Inventory (MFI).  
• 
Change in MFI general fatigue subscale and other 
subscales from Baseline to Week 12. 
• 
To evaluate the pharmacokinetic (PK) exposure of 
one dose level of SAR441344 over 12 weeks in adult 
patients with pSjS. 
• 
Descriptive statistics of SAR441344 concentrations, 
including mean, median, and standard deviation. 
• 
Pharmacokinetic parameters for SAR441344 will be 
reported (maximum concentration [Cmax], time to 
Cmax [tmax], area under the curve over the dosing 
interval [AUC0-tau], and terminal half-life [t1/2z]). 
• 
To evaluate the safety and tolerability of one dose 
level of SAR441344 versus placebo in adult patients 
with pSjS as determined by adverse events (AEs). 
• 
Incidence of treatment-emergent AEs (TEAEs), 
serious AEs (SAEs), and AEs of special interest 
(AESIs) from Baseline to Week 24 (End of Study 
[EoS]). 
• 
Incidence of study investigational medicinal product 
discontinuation and withdrawals due to TEAEs from 
Baseline to Week 24 (EoS). 
• 
To evaluate the local tolerability of one dose level of 
SAR441344 versus placebo over 12 weeks in adult 
patients with pSjS. 
• 
Change in participant reported local tolerability scale. 
• 
Incidence of AEs related to local tolerability findings. 
• 
To evaluate the safety and tolerability of one dose 
level of SAR441344 versus placebo over 12 weeks in 
adult patients with pSjS determined by 
electrocardiogram, vital signs, and laboratory 
evaluations. 
• 
Participants with medically significant changes in vital 
signs, electrocardiogram, and/or laboratory 
evaluations.  
• 
To measure the immunogenicity of one dose level of 
SAR441344 versus placebo over 12 weeks in adult 
patients with pSjS. 
• 
Antidrug antibodies at Baseline, Week 4, Week 8, 
Week 12, and Week 24.  
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Objectives 
Endpoints 
l
. 
i
 
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3.1 
APPROPRIATENESS OF MEASUREMENTS  
The ESSDAI, used for the primary endpoint, is a validated and established outcome measurement 
for therapeutic efficacy in SjS, evaluating disease activity mainly on extra-glandular 
manifestations (7, 36). It is used in clinical trials as a standard outcome measurement for efficacy, 
especially in similar trials using a 12-week treatment period (eg, iscalimab [5]). The ESSPRI, 
used as a key secondary endpoint for the measurement of therapeutic efficacy, is used as a 
validated and established efficacy marker in clinical trials, as well (7, 37). Another key secondary 
endpoint is the change in MFI rating as fatigue is one of the key symptoms of SjS, impacting the 
quality of life of patients significantly (38).  
In terms of safety, the TEAEs, SAEs, AESIs, ECG, vital signs, and laboratory analyses will be 
recorded, and local tolerability will be examined. SAR441344 will be administered SC after an 
initial IV loading dose. Measurement of local tolerability will be done with a verbal descriptor 
scale (VDS) and Investigator rating, described in Section 8.2.5. Antidrug antibodies will be 
measured as well, although the mechanism of action of SAR441344 (prevention of CD40/CD40L 
interaction) is expected to decrease the risk of ADA formation (see Section 2.2.2).  
 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
ACT16618 is a multicenter, randomized, double-blind, placebo-controlled, parallel group proof of 
concept Phase 2 study to assess the safety, tolerability, PK, and therapeutic efficacy of 
SAR441344 in pSjS. Participants included are diagnosed with pSjS according to the American 
College of Rheumatology/EULAR 2016 criteria with systemic disease (ESSDAI score ≥5) and 
significant biological activity. Participants will be randomized at Baseline (Day 1) to SAR441344 
or placebo in a 1:1 ratio and will receive a single IV loading dose on Day 1, followed by 5 SC 
doses administered q2w. Randomization will be stratified by Baseline ESSPRI score ≥5 
versus <5. 
The safety data of this study will be reviewed by an independent DMC. 
The total duration of the study will be 24 weeks (28 weeks including maximum screening 
duration) for each participant: 
• Screening up to 30 days (Day -30 to Day -1). 
• Treatment period of 12 weeks (Day 1 to Week 12). 
• Follow-up period of 12 weeks (Week 12 to Week 24). 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
Participant population will be selected based on ESSDAI, as well as elevated markers of chronic 
B-cell activation, ensuring that participants will have a systemic manifestation of the disease. A 
stratification based on ESSPRI (score ≥5 versus <5) ensures that participants are impacted in 
different degrees on the key features of the disease along all phenotypes: fatigue, dryness, and 
pain as along with high biological activity. This will target a population with high medical need 
and better likelihood of clinical efficacy in a 12-week study. 
The study is placebo-controlled as there is no approved systemic treatment for pSjS that could be 
used as an active comparator. Background therapy with low doses of steroids and/or 
hydroxychloroquine or chloroquine will be allowed (Section 6.5.2). 
The primary objective is to compare the efficacy of SAR441344 with placebo measured by 
ESSDAI scoring, which is the activity index to measure the involvement of different organs in 
pSjS. Other measurements for therapeutic efficacy include ESSPRI and MFI, which will evaluate 
key features of the disease: dryness, pain, and fatigue. 
Treatment duration will be 12 weeks, which should be sufficient to see a significant improvement 
in clinical efficacy and reach the proof-of-concept for SAR441344, based on the selection of 
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participants, and due to what is known from other companies working on the CD40/CD40L 
interaction in pSjS (eg, iscalimab, an anti-CD40 antibody [5, 39]). 
A Screening period is planned for up to 30 days, to ensure that all laboratory and score results are 
evaluated for Baseline. The follow-up period will have a duration of 12 weeks (up to Week 24), to 
ensure an approximate 4-half-life period surveillance after the last drug administration (on 
Week 10). 
One optional sub-study is planned: 
(Section 1.3). 
These samples will be used for research purposes related to inflammation and immunity in the 
context of CD40L-targeted treatment. In addition, research may be performed to help understand 
disease subtypes and drug response, to develop and validate bioassay methods, or to identify new 
drug targets or biomarkers. 
4.2.1 Participant input into design  
Participants were involved in the design of the study as a patient panel review of the abbreviated 
protocol has taken place. There was general agreement with the study design. Feedback of the 
patient panel was taken into account for the design of the visits, learning about the burden of 
certain assessments, and concomitant therapy. 
4.3 
JUSTIFICATION FOR DOSE  
A loading dose of 
 mg IV or matching placebo is planned on Day 1. Afterwards, IMP 
administration will be continued with 
 mg SC or matching placebo q2w for 5 doses. The 
last IMP administration will take place on Week 10.  
SAR441344 was safe and well tolerated at single IV doses up to 
 mg and at multiple doses 
SC (3 × q2w) up to 
 mg in healthy subjects. Of note, a maximal tolerated dose has not been 
reached in either of these clinical studies (see Section 2.2.2.2). 
In the multiple ascending dose study in healthy subjects 
, SAR441344 inhibited 
KLH-TDAR in a dose dependent manner after SC 3 × q2w and the sequential administration of 
 (Day  and Day 
). A dose of 
 mg SC 3 × q2w in healthy subjects 
Hence, high probability of clinical efficacy for this dose is expected. During 
the 
 study, no ADAs were detected in the dose level of 
 mg SC 3 × q2w. A dose of 
 mg q2w SC will be given with a
 mL syringe injection throughout this study.  
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The rationale of choosing a loading dose is that steady state is predicted to be reached only after 
12 weeks of q2w dosing. An IV loading dose of double the SC maintenance dose on Day 1 would 
assure that plasma concentration close to steady state would be reached after the second 
administration. 
Finally, predicted exposure for a 
 mg dose administered q2w for 12 weeks (predicted AUC 
over the dosing interval [AUC0-tau]: 
 µg × h/mL) gives an acceptable safety margin of 
. 
The predicted Cmax after the IV loading dose 
 mg is 
 µg/mL, which is 
than 
the Cmax at NOAEL (for the definition of NOAEL, see Section 2.2.2.1). 
4.4 
END OF STUDY DEFINITION  
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the last visit (EoS visit). 
The end of the study is defined as the date of the last visit of the last participant in the study, 
globally. 
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5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and randomization 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: 
Age 
I 01. Participant must be 18 to 80 years of age inclusive, at the time of signing the informed 
consent. 
Type of participant and disease characteristics 
I 02. Diagnosis of pSjS according to the American College of Rheumatology/EULAR 2016 
criteria (40) with a score of ≥4 at Screening. For the following criteria, historical data can 
be used: 
- 
Labial salivary gland with lymphocytic sialadenitis and focus sore of ≥1 foci/4 mm2, 
- 
Ocular staining score ≥5 (or van Bijsterveld score ≥4) in at least 1 eye, 
- 
Schirmer test ≤5 mm/5 minutes in at least 1 eye, 
- 
Unstimulated whole saliva flow rate ≤0.1 mL/min. 
I 03. Disease duration since first diagnosis of pSjS ≤ 15 years based on medical history. 
I 04. Participants with moderate to severe disease activity set with ESSDAI total score ≥5, based 
on the following domains at Screening: glandular, articular, muscular, hematological, 
biological, and constitutional, lymphadenopathy. 
I 05. Seropositive for anti-Ro/SSA antibodies.  
I 06. IgG > lower limit of normal at Screening. 
I 07. Stimulated salivary flow rate of ≥0.1 mL/min at Screening or Baseline. 
Weight  
I 08. Body weight within 45 to 120 kg (inclusive) and body mass index within the range of 
18.0 to 35.0 kg/m2 (inclusive) at Screening. 
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Sex 
I 09. Male or female. 
Contraceptive use by men or women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. 
a) Male participants must follow the guidance for contraceptive use: 
- 
Male participants, whose partners are of childbearing potential (including lactating 
women), must accept to use, during sexual intercourse, a double contraception method 
according to the following algorithm: eg, condom plus intra-uterine device from the 
inclusion until completion of EoS visit (see contraceptive guidance in Appendix 4 
[Section 10.4]). Condom with spermicide may be used as a valid double contraception 
method for this study. 
- 
Male participants, whose partners are pregnant, must use, during sexual intercourse, a 
condom from inclusion until completion of the EoS visit (see contraceptive guidance 
in Appendix 4 [Section 10.4]). 
- 
Male participants have agreed not to donate sperm from inclusion in the study up to 
6 months after the last dose. (see contraceptive guidance in Appendix 4 
[Section 10.4]). 
b) A female participant is eligible to participate if she is not pregnant or breast-feeding, 
and follows the following guidance for contraceptive use: 
- 
Female participant must use a double contraception method including one highly 
effective method of birth control (as defined in Appendix 4 [Section 10.4]), except if 
she has undergone sterilization at least 6 months earlier or is postmenopausal. 
Menopause is defined as being amenorrheic for at least 12 months or, in the absence of 
12 months of amenorrhea, a plasma follicle-stimulating hormone (FSH) level >ULN as 
defined by central laboratory readout (more than 1 measurement, see contraceptive 
guidance in Appendix 4 [Section 10.4]). Contraception as described is required from 
signing of the informed consent until completion of the EoS visit. Use of hormonal 
contraception is permitted in this study. 
Informed Consent 
I 10. Having signed a written informed consent prior to any procedure related to the study. 
I 11. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1) 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. In countries where legal age of majority is above 
18 years, a specific ICF must also be signed by the participant’s legally authorized 
representative. 
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5.2 
EXCLUSION CRITERIA  
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Any autoimmune disease (except pSjS and Hashimoto thyroiditis) with or without 
secondary SjS. 
E 02. History, clinical evidence, suspicion or significant risk for thromboembolic events, as well 
as myocardial infarction, stroke, and/or antiphospholipid syndrome and any participants 
requiring antithrombotic treatment. 
E 03. Active life-threatening or organ-threatening complications of SjS disease at the time of 
Screening based on treating physician evaluation including but not restricted to:  
- 
Vasculitis with renal, digestive, cardiac, pulmonary, or CNS involvement 
characterized as severe, 
- 
Active CNS or PNS involvement requiring high dose steroids, 
- 
Severe renal involvement defined by objective measures, 
- 
Lymphoma. 
E 04. Cardiac heart failure stage III or IV according to the New York Heart Association. 
E 05. Severe pulmonary impairment documented by an abnormal pulmonary function test: 
diffusing capacity for carbon monoxide (DLCO) <40% of predicted or forced vital capacity 
(FCV) <60% of predicted within the last 6 months before Screening. 
E 06. Serious systemic viral, bacterial or fungal infection (eg, pneumonia, pyelonephritis), 
infection requiring hospitalization or IV antibiotics or significant chronic viral (including 
history of recurrent or active herpes zoster), bacterial, or fungal infection (eg, 
osteomyelitis) 30 days before and during Screening. 
E 07. Participants with a history of invasive opportunistic infections, such as, but not limited to 
histoplasmosis, listeriosis, coccidioidomycosis, candidiasis, pneumocystis jirovecii, and 
aspergillosis, regardless of resolution. 
E 08. Evidence of active or latent tuberculosis (TB) as documented by medical history (eg, chest 
X-rays) and examination, and TB testing: A positive or 2 indeterminate 
QuantiFERON®-TB Gold tests at Screening (regardless of prior treatment status). 
E 09. Evidence of any clinically significant, severe or unstable, acute or chronically progressive, 
uncontrolled infection or medical condition (eg, cerebral, cardiac, pulmonary, renal, 
hepatic, gastrointestinal, neurologic, or any known immune deficiency) or previous, active 
or pending surgical disorder, or any condition that may affect participant safety in the 
judgment of the Investigator (including vaccinations which are not updated based on local 
regulation).  
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E 10. History or presence of diseases which exclude diagnosis of SjS as per the American 
College of Rheumatology/EULAR 2016 criteria (40) including, but not limited to, 
sarcoidosis, amyloidosis, graft-versus-host disease, IgG4-related disease, and history of 
head and neck radiation treatment.  
E 11. History of a systemic hypersensitivity reaction or significant allergies, other than localized 
injection site reaction, to any humanized mAb. 
E 12. Clinically significant multiple or severe drug allergies, intolerance to topical 
corticosteroids, or severe post-treatment hypersensitivity reactions (including, but not 
limited to, erythema multiforme major, linear IgA dermatosis, toxic epidermal necrolysis, 
and exfoliative dermatitis). 
E 13. Any prior history of malignancy or active malignancy, including lymphoproliferative 
diseases and lymphoma (except successfully treated carcinoma in situ of the cervix, 
nonmetastatic squamous cell or basal cell carcinoma of the skin) within 5 years prior to 
Baseline. 
E 14.  Substance abuse (including cannabis) and/or alcohol abuse, current or in the last year. 
Prior/concomitant therapy 
E 15. Unstable dose of nonsteroidal anti-inflammatory drugs (NSAIDs) and/or unstable use of 
topical and/or pharmacological stimulant treatment for salivary and lacrimal glands 
4 weeks before Screening. 
E 16. High-dose steroids (>10 mg/day prednisone equivalent), or a change in steroid dose within 
4 weeks prior to Day 1/Randomization or expected changes during the course of the study. 
E 17. High dose of hydroxychloroquine or chloroquine 
, or methotrexate 
 or change in hydroxychloroquine, chloroquine, or 
methotrexate dose within 12 weeks prior to Day 1/Randomization or expected changes 
during the course of the study. 
E 18. Participants treated with the following medications/procedures prior to Screening within 
the given timeframe: 
- 
Previous treatment with azathioprine and other thiopurines, mycophenolate mofetil, 
sulfasalazine, or cyclosporine A within 3 months. 
- 
Previous treatment with cyclophosphamide, leflunomide, or belimumab within 
6 months. 
- 
Previous treatment with rituximab within 12 months. 
- 
Previous bone marrow transplantation, total lymphoid irradiation or ablative ultra 
high-dose cyclophosphamide or IV Ig. 
- 
Previous treatment with any other biologic drug within 5 times the half-life of the 
drug. 
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E 19. Received administration of any live (attenuated) vaccine within 3 months prior to 
Day 1/Randomization (eg, varicella zoster vaccine, oral polio, rabies). 
Prior/concurrent clinical study experience 
E 20. Treatment with any investigational drug within 1 month of Screening and/or within 
5 half-lives or longer if required by local regulations (whichever is longer). 
Diagnostic assessments 
E 21. Clinically significant abnormal ECG or vital signs at Screening that may affect the conduct 
of the study in the judgment of the Investigator. 
 
E 23. Positive human immunodeficiency virus (HIV) serology (anti-HIV1 and anti-HIV2 
antibodies) or a known history of HIV infection, active or in remission. 
E 24. Positive result on any of the following tests: hepatitis B surface antigen (HBsAg), 
anti-hepatitis B core antibodies (anti-HBc Ab), anti-hepatitis C virus antibodies 
(HCV-Ab). 
E 25. If female, pregnant (defined as positive β-human chorionic gonadotropin [HCG] blood 
test) and/or breastfeeding. 
Other exclusions 
E 26. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized. 
E 27. Participant not suitable for participation, whatever the reason, as judged by the 
Investigator, including medical or clinical conditions, or participants potentially at risk of 
noncompliance to study procedures. 
E 28. Participants are employees of the clinical study site or other individuals directly involved 
in the conduct of the study, or immediate family members of such individuals (in 
conjunction with Section 1.61 of the International Council for Harmonisation-Good 
Clinical Practice Ordinance E6). 
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E 29. Individuals residing in long-term care facilities or nursing homes. 
E 30. Hypersensitivity to any of the IMPs, including any constituent thereof, or drug or other 
allergy that, in the opinion of the Investigator, contraindicates participation in the study.  
5.3 
LIFESTYLE CONSIDERATIONS  
5.3.1 Meals and dietary restrictions  
No specific dietary restrictions are applicable throughout the study. Fasting is preferred in those 
visits where clinical chemistry (laboratory) will be assessed, as per the SoA (Section 1.3). Fasting 
is defined as no food/no drinks beside water without any supplements for at least 10 hours. This 
includes concomitant medication, which should be taken on site after blood drawn, to keep fasting 
conditions. Fasting/non-fasting status will be recorded at the time of blood collection.  
5.3.2 Caffeine, alcohol, and tobacco  
During the study, it is recommended that participants should try to abstain from drinking alcohol 
and using tobacco products as much as possible. No recommendations or restrictions apply 
regarding caffeine.  
5.3.3 Activity  
No restriction is required.  
5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to the IMP. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure reasons, 
eligibility criteria, and any SAEs. 
Individuals who are defined as screen failures as described above may be rescreened once, based 
on the inclusion or exclusion criteria leading to screen failure as described in Table 3. If other 
reasons prevent randomization of the participant in time (after a maximum of 30 days), which are 
not covered by inclusion and exclusion criteria, rescreening can be performed once, at the 
Investigator’s discretion. If a participant was re-screened once 
(Lymphocytes 
/mm3), participant might be re-screened a second time, 
at the Investigator’s discretion. 
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Table 3 - 
  
 
There is no requirement for a waiting period between the screen failure date and the rescreen date. 
Rescreened participants should be assigned with a new participant number. Participants who are 
rescreened must sign a new informed consent and all Visit 0 procedures must be repeated. 
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6 
STUDY INTERVENTION  
Study intervention is defined as any investigational intervention(s) or placebo intended to be 
administered to a study participant according to the study protocol. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
A complete description of the IMP and its proper handling will be provided in the pharmacy 
manual available to the clinical site. 
6.1.1 Investigational medicinal product(s)  
The IMPs are SAR441344 and matching placebo and will be supplied in vials of  mL containing 
SAR441344 (
 mg/  mL) or matching placebo. Table 4 provides a summary of the 
characteristics of each IMP. 
For each participant, the appropriate number of vials will be provided according to the dispensing 
scheme indicated in the SoA (see Section 1.3). 
Home administration will not be considered in this clinical trial, particularly as this is a first in 
patient study. Under no circumstances will the Investigator supply the IMP to a third party, allow 
the IMP to be used other than as directed by this clinical study protocol, or dispose of IMP in any 
other manner. 
Table 4 - Overview of study interventions administered  
ARM name 
SAR441344 Active 
Placebo 
Intervention name 
SAR441344  
Placebo 
Type  
Drug 
Drug 
Dose formulation 
SAR441344 will be supplied as a 
 mg/  mL 
vial  
Placebo will be supplied in vials (identical to 
SAR441344 in appearance)  
Unit dose strength(s) 
SAR441344 
 mg/  mL 
Placebo
mL  
Dosage level(s) 
One IV loading dose of SAR441344 
 mg 
(infusion duration: 1 hour) at Day 1 followed by 
administration of SAR441344 
 mg SC q2w  
One IV loading dose of placebo  mL (infusion 
duration: 1 hour) at Day 1 followed by 
administration of placebo  mL SC q2w  
Route of 
administration 
IV loading dose at Day 1 
SC at Weeks 2, 4, 6, 8, and 10 
IV loading dose at Day 1 
SC at Weeks 2, 4, 6, 8, and 10  
Use 
Experimental active  
Experimental placebo  
IMP and NIMP 
IMP  
IMP  
Packaging and labeling 
Study Intervention will be provided in vials in 
the treatment box (ie,  vials per treatment 
box). Each vial and box will be labeled as 
required per country requirement  
Study Intervention will be provided in vials in 
the treatment box (ie,  vials per treatment 
box). Each vial and box will be labeled as 
required per country requirement 
Current/Former 
name(s) or alias(es) 
Not applicable 
Not applicable 
IMP: investigational medicinal product, IV: intravenous, q2w: every 2 weeks, SC: subcutaneous. 
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6.1.1.1 SAR441344  
SAR441344 is a humanized mouse monoclonal IgG1 antagonist antibody against CD40L, with a 
modification to the Fc region to prevent binding to FcγRIIa and associated platelet activation. 
The drug product is a sterile, clear to opalescent solution practically free of particles. It is 
packaged in an ISO 2R USP/Ph. Eur. Type I borosilicate glass vial, stoppered with a 13 mm 
USP/Ph. Eur. elastomeric stopper and sealed with an aluminum seal. Each SAR441344 product 
single use vial contains a nominal volume of  mL of 
 mg/mL SAR441344 solution. 
An overfill volume of 
 mL is included to allow for withdrawal of  mL of solution (
 mg 
SAR441344). The composition of SAR441344 drug product solution includes SAR441344, 
L-histidine HCl, L-Histidine, L-arginine HCl, sucrose, polysorbate-80, and water for injection. 
The pH of the formulated solution is
 
6.1.1.2 Placebo  
Each matching placebo is packaged as described for SAR441344 and is of the same composition 
as the active drug without the monoclonal antibody as described in Section 6.1.1.1. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
A complete description of the IMP preparation for IV and SC administration will be provided in 
the pharmacy manual available to the clinical site. 
The product must be stored at 2°C to 8°C (36°F to 46°F) and protected from light prior to 
preparation with limited shaking (no vortex). The IMP should not be frozen. Light exposure is 
permitted during preparation and administration. Sites are requested to maintain a temperature log 
to ensure storage temperature remains within acceptable limits. 
The Investigator or designee must confirm that appropriate temperature conditions have been 
maintained during transit for all IMP received and any discrepancies are reported and resolved 
before its use. 
Only participants randomized in the study may receive the IMP and only the Investigator or 
authorized site staff may supply or administer the IMP. The IMP must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IMP accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). 
Handling of used vials is described in the pharmacy manual. 
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Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor. 
Some deficiencies may be recorded through a complaint procedure (see Section 8.3.7).  
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party, allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
6.2.1 Intravenous preparation and handlings  
The IMP will be administered by IV infusion over a minimum of 60 minutes. The IMP will be 
diluted in 0.9% saline. A complete and detailed description can be found in the pharmacy manual.  
6.2.2 Subcutaneous preparation and handlings  
The IMP should be prepared in an appropriate syringe (details are provided in the pharmacy 
manual). Each SC dose will require  injections with  mL IMP per injection. All IMP SC 
injections should be administered in the abdomen. It is recommended that SC injection sites are 
alternated between the 4 quadrants of the abdomen with the injection sites at least 2 cm from the 
umbilicus. 
A complete and detailed description can be found in the pharmacy manual. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
A randomized treatment kit number list will be generated centrally by Sanofi for the IMPs. The 
IMPs (SAR441344 or matching placebo) will be packaged in accordance with the list. The Sanofi 
Clinical Supply Chain team will provide the randomized treatment kit number list to the 
centralized treatment allocation system (interactive response technology [IRT]). This centralized 
treatment allocation system will generate the participant randomization list according to which it 
will allocate the IMP to the participants. The Investigator or designee will obtain the treatment kit 
number at randomization (Day 1, Baseline) and subsequent scheduled dosing visits via an IRT 
that will be available 24 hours/day. Although the kit number will vary for the individual 
participant, the treatment group assignment and randomization will not change throughout the 
study. 
Randomization will take place on Baseline/Day 1. Randomization will be stratified by ESSPRI <5 
or ESSPRI ≥5 at Baseline. For the process of randomization at Baseline/Day 1, the ESSPRI 
collected at Baseline/Day 1 and the ESSDAI collected at Screening (based on the 7 domains listed 
in inclusion criterion I 04 [Section 5.1]) will be entered in the IRT before randomization takes 
place. 
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A participant who has been allocated to a randomized study intervention will be considered a 
randomized participant, regardless whether the treatment kit was used or not (ie, participant 
registered by the IRT). A participant cannot be randomized more than once in the study. 
SAR441344 and placebo will be provided in identically matched  mL vials. To protect the blind, 
each treatment kit of  mL (SAR441344/placebo) vials will be prepared so that the treatments 
(SAR441344 and its matching placebo) are identical and indistinguishable and will be labeled 
with a treatment kit number. 
Unblinding 
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
Investigator has the sole responsibility for determining if the unblinding of a participant’s 
intervention assignment is warranted (eg, in case of an AE, the code must only be broken in 
circumstances when the knowledge of the IMP is required for treating the participant). Participant 
safety must always be the first consideration when making such a decision. If the Investigator 
decides that the unblinding is warranted, he/she may, at his/her discretion, contact Sponsor to 
discuss the situation prior to unblinding a participant’s intervention assignment, unless this could 
delay emergency treatment of the participant. Code breaking can be performed at any time by 
using the proper module of the IRT. If a participant’s intervention assignment is unblinded, the 
Sponsor must be notified within 24 hours after breaking the blind. The date, time of the day, and 
reason that the blind was broken must be recorded in the source documentation and electronic 
case report form (e-CRF), as applicable. If the code is broken by the Investigator, the participant 
must be withdrawn from the study treatment. 
Methods of blinding 
• This is a double-blind study. 
• There is a slight color difference between SAR441344 and matching placebo, but the 
difference is not visually apparent, so SAR441344 and placebo cannot be distinguished by 
the site staff and participant. 
• The Bioanalyst and the Pharmacokineticist responsible for the sample analysis and PK 
evaluation will be unblinded. However, they will agree not to disclose the randomization 
schedule or the individual unblinded analytical results before the official opening of the 
randomization schedule. The preliminary PK and biomarker data, if needed and available 
during the course of the study, will refer to mean data with descriptive statistics and 
individual data, without revealing any individual randomization numbers or participant 
numbers. 
• In case of an interim analysis, a Statistician, Programmer, and the Clinical Study Director 
will be unblinded for the analyses and work independently to the study team to ensure 
maintenance of the blind. They will keep the randomization schedule in a locked area, 
which is not accessible to the Sponsor’s clinical team and will not disclose the 
randomization or the individual unblinded data before the official opening of the 
randomization (see Section 9.5). 
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• The DMC will have access to unblinded data if deemed necessary by the DMC. No 
unblinding information will be shared by the DMC with the study team. Details about the 
distribution of unblinding data to the DMC while protecting the blind are described in the 
DMC charter and Appendix 1 (Section 10.1.5). 
• For the ESSDAI (outcome measurement, not for inclusion), an evaluation of the single 
domains will be performed by the Investigator and recorded in the e-CRF. The total score 
will not be displayed by the e-CRF to the Investigator, site staff, or the study team. 
• Laboratory assessments listed as PD markers and biomarkers in the SoA (see Section 1.3) 
will be blinded from Baseline/Day 1 throughout the study, except for those which are 
needed for screening and primary endpoint rating, ie,
 
(see Table 9). In case of a safety concern, unblinding can be performed by the Investigator 
and/or Sponsor for the PD marker.  
6.4 
STUDY INTERVENTION COMPLIANCE  
As participants are dosed at the site, they will receive the IMP directly from the Investigator or 
designee. The date and time of each dose administered in the clinic will be recorded in the source 
documents and recorded in the e-CRF. The dose of IMP and study participant identification will 
be confirmed at the time of dosing by a member of the study site staff other than the person 
administering the IMP. Details on administration of the IMP and recording of the IMP 
administration can be found in the pharmacy manual.  
6.5 
CONCOMITANT THERAPY  
Any medication (including over-the-counter or prescription medicines, vitamins, and/or herbal 
supplements) that the participant is receiving at the time of randomization or receives during the 
study must be recorded along with: 
• Reason for use. 
• Dates of administration including start and end dates. 
• Dosage information including dose and frequency. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Participants must abstain from taking nonprescription drugs (including vitamins and dietary or 
herbal supplements, if not stated otherwise below) within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of IMP until 
completion of the EoS visit, unless, in the opinion of the Investigator and Sponsor, the medication 
will not interfere with the study. 
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6.5.1 Prohibited concomitant medication  
• High-dose steroids 
, or a change in steroid dose within 
4 weeks prior to Day 1/Randomization, or changes during the course of the study. 
• High dose of hydroxychloroquine or chloroquine
, or a change in 
hydroxychloroquine or chloroquine dose within 12 weeks prior to Day 1/Randomization, 
or expected changes during the course of the study. 
• High dose of methotrexate 
, or change in methotrexate 
dose within 12 weeks prior to Day 1/Randomization, or expected changes during the 
course of the study. 
• Pharmacological stimulant treatment for lacrimal and salivary gland function with 
 and during the course of the study. 
• Ocular dryness treatment with 
 and during the course of 
the study. 
• Previous treatment with azathioprine or other thiopurines, mycophenolate mofetil, 
sulfasalazine, or cyclosporine A 
 and during the course 
of the study. 
• Previous treatment with cyclophosphamide, leflunomide, or belimumab 
and during the course of the study. 
• Previous treatment with rituximab within 
and during the 
course of the study. 
• Previous treatment with bone marrow transplantation, total lymphoid irradiation or 
ablative ultrahigh-dose cyclophosphamide or IV Ig, and during the course of the study. 
• Previous treatment with any other biologic drug 
and during the course of the study. 
• Received administration of any
and during the course 
of the study. 
• Products
 
6.5.2 Key authorized concomitant medications  
• Oral corticosteroids 
No change in dose is permitted during the study 
unless for the management of an AE. The dose and any change will be recorded on the 
participant e-CRF. Oral corticosteroids cannot be started during the course of the study. 
• Low dose hydroxychloroquine or chloroquine treatment 
 No change in dose is permitted during the 
study unless for the management of an AE. Dose and any change will be recorded on the 
participant e-CRF. Hydroxychloroquine or chloroquine cannot be started during the course 
of the study. 
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• Methotrexate up to
. No change in dose is permitted during the study unless for the 
management of an AE. Dose and any change will be recorded on the participant e-CRF. 
Methotrexate cannot be started during the study. Concomitant therapy with folic acid is 
permitted. 
• Nonsteroidal anti-inflammatory drugs are allowed, if a stable compound with a stable dose 
(on-demand medication is permitted if the dose is stable) is used 
 No change in dose is permitted during the study unless for the 
management of an AE. Dose and any change will be recorded on the participant e-CRF. 
Nonsteroidal anti-inflammatory drugs cannot be started during the course of the study. 
Medication has to be paused at least 12 hours before glandular function tests.  
• Topical medication (eg, artificial tears) for treatment of dryness of mouth and eyes is 
allowed, if a stable compound 
and if the medication is not listed in Section 6.5.1. No change in 
dose is permitted during the study. Dose and any change will be recorded on the 
participant e-CRF. Topical medication cannot be started during the course of the study. 
Medication has to be paused at least 12 hours before glandular function tests. 
. No change in dose is permitted during the study. The dose and any 
dose changes will be recorded on the participant e-CRF. Pharmacological stimulants 
cannot be started during the course of the study. This medication has to be paused at least 
12 hours before glandular function tests. 
 
• Other concomitant medication may be considered on a case-by-case basis by the 
Investigator in consultation with the Medical Monitor. 
6.6 
DOSE MODIFICATION  
No dose modifications are planned for this study. For the justification of dose, see Section 4.3. 
Details on temporary and definitive IMP discontinuation on an individual level is described in 
Section 7. 
6.7 
INTERVENTION AFTER THE END OF THE STUDY  
No intervention is planned following the end of the study. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
The IMP should be continued whenever possible and considered safe. In case the IMP is stopped, 
it should be determined whether it is temporary. Definitive IMP discontinuation should be 
considered as the last resort. Any IMP discontinuation should be fully documented in the e-CRF. 
In any case, the participant should remain in the study as long as possible. 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  
7.1.1 Definitive discontinuation  
In certain instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) the IMP. See Section 7.1.1.1 for how to proceed in case of definite 
discontinuation and the SoA (Section 1.3) for data to be collected at the time of discontinuation of 
IMP and follow-up and for any further evaluations that need to be completed. 
Participants may decide to definitively withdraw from treatment with the IMP at any time and for 
any reason. This decision may also rest with the Investigator or Sponsor. All efforts should be 
made to document the reason(s) for IMP discontinuation in the e-CRF. 
In case of the following events, a definitive discontinuation of the IMP is mandatory. This list is 
not intended to be exhaustive: 
• At the request of the participant: ie, withdrawal of consent for the study. 
• Pregnancy of a female participant. 
• Thromboembolic events including, but not limited to, deep vein thrombosis, pulmonary 
embolism, myocardial infarction, and stroke. 
• Occurrence of any malignancy. 
• Severe hypersensitivity or anaphylactic reaction. 
• Severe injection site reaction. 
• Any AE, per Investigator judgment, that may jeopardize the safety of the participant.  
• Any code breaking performed by the Investigator.  
• At the specific request of the Sponsor.  
Discontinuation of the IMP for laboratory abnormalities should be considered by the Investigator 
when a participant meets one of the conditions outlined in Appendix 6 (Section 10.6) or if the 
Investigator believes that it is in the best interest of the participant.  
In the case of biologically proven COVID-19 infection, the Investigator may permanently 
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discontinue the IMP for the participant, who will be asked to continue attending the protocol 
scheduled visits until EOS. If according to the Investigator a permanent IMP discontinuation is 
not necessary or in the best interest of the participant, the Investigator can consider a temporary 
discontinuation per Section 7.1.2. 
The participant cannot restart IMP until the participant’s COVID-19 PCR is negative. All 
COVID-19 infections will be reviewed by the DMC as AESI. 
Any abnormal laboratory value or ECG parameter will be immediately rechecked for 
confirmation before making a decision regarding possible definitive IMP discontinuation for the 
concerned participant. All efforts should be made to reassess, in a clinically relevant timeframe 
(using either a local or central laboratory), the clinical significance of laboratory abnormalities 
and corrective actions before making a decision of definitive discontinuation of the IMP for the 
concerned participant. 
7.1.1.1 Handling of participants after definitive intervention discontinuation  
Participants will be followed-up according to the study procedures specified in this protocol up to 
the scheduled date of study completion (EoS visit), or up to recovery or stabilization of any AE to 
be followed-up as specified in this protocol, whichever comes last. 
If possible, and after the definitive discontinuation of the IMP, participants will be assessed using 
the procedure normally planned for the End of Treatment (EoT) visit, including a PK and ADA 
sample. Afterwards, the complete follow-up period should be performed, if possible.  
All cases of definitive intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the e-CRF when considered as confirmed. 
7.1.2 Temporary discontinuation  
Temporary IMP discontinuation may be considered by the Investigator because of suspected 
AE(s). For all temporary IMP discontinuations, duration should be recorded by the Investigator in 
the appropriate pages of the e-CRF. Planned visits should take place as scheduled, if possible, 
during this period of discontinuation. Temporary IMP discontinuation can appear only once per 
subject/treatment period. 
Temporary IMP discontinuation may also apply in exceptional cases, under regional or national 
emergencies (eg, natural disaster, epidemic diseases, terrorist attack) due to which a visit at the 
clinical study site is no longer feasible. In the case of an exceptional temporary treatment 
discontinuation, the discontinuation should be approved by the Sponsor. The Sponsor should also 
be notified to determine if treatment should be resumed. If deemed safe, the treatment can be 
resumed at the next scheduled visit. During the discontinuation period, remote checks 
(eg, telephone calls) will take the place of on-site visits per the SoA. 
• If the above emergency scenario occurs during the follow-up period, one or more 
follow-up visits can be performed remotely (eg, via telephone call), but at least one 
follow-up visit should be performed on site (EoS visit), even if the visit window needs to 
be extended (to a maximum of 8 weeks). Remote follow-up should be done according to 
local regulations and approved by the Sponsor. 
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• If the above emergency scenario leads to site closure or complete regional or national 
lock-down, the study may be suspended for the affected sites (Section 10.1.9). 
In case of suspicion of COVID-19 (eg, fever, cough, shortness of breath in a context of possible 
infected contact), temporary discontinuation of IMP will be considered. The following should be 
considered to evaluate individual benefit-risk for resuming or stopping of IMP: the probability of 
COVID 19 disease, possibility of rapid diagnosis, severity of symptoms, and risk factors. 
In the case of biologically proven COVID-19 infection, if according to the Investigator a 
permanent IMP discontinuation is not necessary or in the best interest of the participant and the 
participant does not have severe or critical COVID-19 as defined by WHO guidelines (25), the 
participant can temporarily discontinue IMP until the participant’s COVID-19 PCR is negative. 
A discontinuation of IMP greater than 30 days +2 days (according to the visit window) will be 
considered definitive and relevant e-CRF sections should be populated.  
7.1.2.1 Rechallenge  
Reinitiation of treatment with the IMP will be considered with close and appropriate clinical 
and/or laboratory monitoring after the Investigator has determined, according to his/her best 
medical judgment, that the causality of the event was unlikely related to the IMP(s) and if the 
selection criteria for the study are still met (see Section 5.1 and Section 5.2). 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
A participant may withdraw from the study at any time at his/her own request or may withdraw at 
any time at the discretion of the Investigator for safety, behavioral, compliance, or administrative 
reasons. In these situations, if possible, the EoT visit (including a PK and ADA sample collection) 
should be performed if discontinuation is during the treatment period, or the EoS should be 
performed if discontinuation is during the follow-up period, as shown in the SoA 
(see Section 1.3). 
If participants no longer wish to receive the IMP, they will be encouraged to remain in the study. 
The EoT visit should be performed and the Investigator should discuss with the participants to 
attend the follow-up period visits.  
Participants who withdraw from the IMP should be explicitly asked about the contribution of 
possible AEs to their decision, and any AE information elicited must be documented. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
e-CRF and in the participant’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented. 
In addition, a participant may withdraw his/her consent to stop participating in the study. If the 
participant withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. If a participant withdraws 
from the study, he/she may request destruction of any samples taken and not tested (eg, archival 
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samples for future use), and the Investigator must document this in the site study records. The site 
should document any case of withdrawal of consent. 
Participants who have withdrawn from the study cannot be randomized more than once in the 
study. Their participant and randomization numbers must not be reused. 
7.3 
LOST TO FOLLOW UP  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should 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 (where possible, several 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. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1). 
The Statistical Analysis Plan (SAP) will specify how these patients lost to follow-up for their 
primary endpoints will be considered. 
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8 
STUDY ASSESSMENTS AND PROCEDURES  
• Study procedures and their timing are summarized in the SoA (see Section 1.3). Protocol 
waivers or exemptions are not allowed. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All Screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.  
• Procedures conducted as part of the participant’s routine clinical management (eg, FSH) 
and obtained before signing of the ICF may be utilized for screening purposes provided 
the procedures met the protocol-specified criteria and were performed within the time 
frame defined in the SoA and/or in inclusion or exclusion criteria (see Section 1.3 and 
Section 5). 
• The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, will not exceed 500 mL 
(the exact assessment specific volumes are described in the laboratory manual). Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the 
samples, this could be done locally if approved by the Sponsor. 
• Participants will be contacted before each visit (latest on the day before the visit) by the 
Investigator or designee, to evaluate for signs and symptoms of a potential SARS-CoV-2 
infection. In case of suspicion of such infection, the participant will be asked to not come 
to the study site and will be referred to a testing facility or her/his primary care physician 
according to local regulations. If the suspicion of a SARS-CoV-2 infection is excluded and 
there is no other reason to pause treatment due to the Investigator judgment, the treatment 
can continue. If the suspicion of a SARS-CoV-2 infection is confirmed, treatment should 
be stopped (Section 7.1.1). 
8.1 
EFFICACY ASSESSMENTS  
8.1.1 European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index  
The ESSDAI is a validated and established outcome measurement for therapeutic efficacy in SjS, 
evaluating disease activity mainly on extra-glandular manifestations. This score consists of 
12 organ-specific domains (constitutional, lymphadenopathy, glandular, articular, cutaneous, 
pulmonary, renal, muscular, PNS, CNS, hematological, and biological), which are scored based 
on organ-specific items in 3 to 4 different severity grades. This score is summed up over all 
12 domains in a weighted way to summarize into a total score (7, 36). The maximum theoretical 
range is 0 to 123. Within this study all domains will be measured, and the primary objective is 
based on the total score. Inclusion (ESSDAI ≥5) will be based on the following 7 domains: 
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glandular, articular, muscular, hematological, biological, constitutional, and lymphadenopathy. 
During the study, ESSDAI should be rated by the same Investigator or designee for one 
participant, if possible (8). 
8.1.2 European League Against Rheumatism Sjögren’s Syndrome Patient Reported Index  
The ESSPRI is a validated and established outcome measurement, reported by patients, which 
rates the key disease manifestations fatigue, dryness, and pain based on a numeric scale ranging 
from 0 to 10, where 0 is defined as no symptoms and 10 as maximum imaginable complaints. The 
total score is the mean score of the 3 scales (7, 37).  
8.1.3 Multidimensional Fatigue Inventory  
The MFI is a validated, 20-item self-report instrument to evaluate fatigue by investigating the 
following components: general fatigue, physical fatigue, mental fatigue, reduced motivation, and 
reduced activity. Using a scale from 1 (“yes, this is true”) to 5 (“no, this is not true”), patients 
indicate how the listed statements apply to their current fatigue situation. Each of the 5 scales is to 
be considered independently. Scores can range from the minimum of 4 to the maximum of 20. 
A total score ranged from 20 to 100 will also be derived. A higher score is related with a higher 
degree of fatigue (38). 
 
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8.2 
SAFETY ASSESSMENTS  
Planned time points for all safety assessments are provided in the SoA. 
  
 
Height and weight 
• Height (in cm) will be measured only at Screening. 
• Weight (in kg) should be taken with the participant wearing light clothing, no shoes. The 
same scale should be used throughout the study. 
• Body mass index will be calculated automatically at each visit weight is measured as per 
the SoA (Section 1.3). 
8.2.2 Vital signs  
• Vital signs will be measured in a sitting position after 5 minutes of rest and will include 
tympanic temperature, systolic and diastolic blood pressure, and pulse. 
• Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available. 
8.2.3 Electrocardiograms  
• A single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3). 
• Electrocardiogram parameters will be based upon the automatic reading of the device. 
These ECG parameters and morphology need to be reviewed by the Investigator. If the 
device does not provide automatic reading, then the ECG parameters will need to be 
determined and interpreted by the Investigator. 
• At the post-randomization visits, ECGs will be performed prior to IMP administration. All 
ECGs will be performed with the participant in a reclined position. Electrocardiogram 
parameters include: heart rate, QRS duration, PR, QT, and QTc interval. 
8.2.4 Clinical safety laboratory assessments  
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency (see Section 1.3). 
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• The Investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study in the AE section of the e-CRF. 
The laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the Investigator to be more severe than expected for the 
participant’s condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 14 weeks after the last dose of IMP should be repeated 
until the values return to normal or baseline or are no longer considered clinically 
significant by the Investigator or Medical Monitor. 
- 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, and the Sponsor 
notified. 
- 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), 
must be conducted in accordance with the laboratory manual and the SoA 
(see Section 1.3). 
• If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the Investigator (eg, SAE, AE, or dose modification), then the 
results must be recorded in the e-CRF. 
8.2.5 Local tolerability  
The evaluation of SC injection site reactions following IMP injection will be performed by the 
Investigator or designees. 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
Adverse events will be reported by the participant or, when appropriate, by a caregiver, surrogate, 
or the participant’s legally authorized representative (see Appendix 1 [Section 10.1]).  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the IMP or study procedures, or that caused the 
participant to discontinue the study.  
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8.3.1 Time period and frequency for collecting AE and SAE information  
All SAEs will be collected from the signing of the ICF until the EoS visit at the time points 
specified in the SoA (see Section 1.3). 
All AEs will be collected from the signing of the ICF at the time points specified in the SoA 
(Section 1.3). 
All SAEs and AESIs (defined in Section 8.3.6) will be recorded and reported to the Sponsor or 
designee immediately and under no circumstance should 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 it being available. 
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the IMP or study participation, the Investigator must promptly notify the Sponsor. 
8.3.2 Method of detecting AEs and SAEs  
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3 Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. At the prespecified study end date, all SAEs and AESIs 
will be followed until resolution, stabilization, the event is otherwise explained, or the participant 
is lost to follow-up. Further information on follow-up procedures is provided in Appendix 3 
(Section 10.3). 
8.3.4 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention 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 a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IECs), and Investigators. 
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• Adverse events that are considered expected will be specified in the reference safety 
information (see IB).  
• Suspected unexpected serious adverse reactions (SUSARs) are reported to regulatory 
authorities, Investigators, and IRBs/IECs as follows: 
- 
For SUSARs that are life-threatening or result in death, reporting is no later than 
7 days after first knowledge by the Sponsor, with all relevant follow-up 
information subsequently reported within an additional 8 days. 
- 
For SUSARs, other than those that are life-threatening or result in death, reporting 
is no later than 15 days after first knowledge by the Sponsor. 
• An Investigator who receives an Investigator safety report describing a SAE, SUSAR, or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
will review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. It is the responsibility of the Sponsor to assess whether an 
event meets the criteria for a SUSAR, and therefore, is expedited to regulatory authorities. 
8.3.5 Pregnancy  
• Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of IMP and until the EoS visit.  
• If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4). 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6 Adverse event of special interest  
Adverse event of special interest 
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
Investigator to the Sponsor is required. Such events may require further investigation in order to 
characterize and understand them. Adverse events of special interest may be added, modified, or 
removed during a study by protocol amendment. 
All reported AESIs will be reviewed by an independent DMC.  
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For AESIs, the Sponsor is to be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Appendix 3 (Section 10.3), even if a seriousness criterion is 
not met, using the corresponding pages of the case report form (to be sent) or screens in the 
e-CRF: 
• Pregnancy of a female participant entered in a study as well as pregnancy occurring in a 
female partner of a male participant entered in a study with IMP:  
- 
Pregnancy occurring in a female participant entered in the clinical study or in a female 
partner of a male participant entered in the clinical study. It will be qualified as an 
SAE only if it fulfills one of the seriousness criteria (see Appendix 3 [Section 10.3]). 
- 
In the event of pregnancy in a female participant, IMP should be discontinued.  
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined (see Appendix 4 
[Section 10.4]). 
• Symptomatic overdose (serious or nonserious) with IMP: 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator and any qualified designees and defined as: 
- 
Intravenous doses: increase of at least 30% of the dose to be administered or the 
dose is administered in less than 30 minutes. 
- 
Subcutaneous doses: At least twice the intended dose within the planned intervals 
(2 weeks ±2 days).  
Of note, asymptomatic overdose has to be reported as a standard AE.  
• If increase in ALT >3 × ULN, see the “Increase in ALT” flow chart in Appendix 6 
(Section 10.6). 
- 
However, if the increase in ALT is ≥2 × the baseline value (with baseline ALT ≥ULN) 
but ≤3 × ULN, then ALT should be retested within 72 hours of initial sample to 
determine if the retest value meets the AESI criterion of ALT >3 × ULN. If so, 
proceed as above and follow the guidelines of Appendix 6 (Section 10.6). If not, 
monitoring of the laboratory findings will be up to the medical judgment of the 
Investigator.  
Other project specific AESI(s) 
- 
Confirmed diagnosis of an arterial and/or venous thrombotic or embolic event. All 
signs and symptoms, clinical or biological, suggestive of a thromboembolic event 
should be investigated immediately. Only confirmed thromboembolic events should be 
reported as an AESI. 
- 
Confirmed diagnosis of lymphoma, due to the risk of lymphoma in SjS patients. All 
signs and symptoms, clinical or biological, suggestive of a lymphoma should be 
investigated. Only confirmed lymphoma should be reported as an AESI. 
- 
Anaphylaxis.  
- 
Severe infusion related reactions. 
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- 
Severe IMP injection or infusion site reaction.  
- 
Severe infections including opportunistic infections. 
- 
Tuberculosis or initiation of medications for suspected tuberculosis. 
- 
Diagnosed and biologically proven SARS-CoV-2 infection. 
8.3.7 Guidelines for reporting product complaints  
Any defect in the IMP must be reported as soon as possible by the Investigator to the monitoring 
team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
8.4 
TREATMENT OF OVERDOSE  
The Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the Investigator/treating physician should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities, at least for 
28 days. 
3. Obtain a plasma sample for PK analysis if requested by the Medical Monitor (determined 
on a case-by-case basis). 
4. Document appropriately in the e-CRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.5 
PHARMACOKINETICS  
SAR441344 concentrations at selected time points will be reported using descriptive statistics. 
Additional PK parameters such as Cmax, tmax, t1/2z, and AUC0-tau will be estimated using a 
population PK approach. These parameters will be presented in a separate standalone report. 
• Blood samples will be collected for measurement of plasma concentrations of SAR441344 
as specified in the SoA (see Section 1.3). Detailed procedures of sample preparation, 
storage, and shipment will be described in the specific laboratory manual.  
• A maximum of 5 samples may be collected at additional time points during the study if 
warranted and agreed upon between the Investigator and the Sponsor. The timing of 
sampling may be altered during the course of the study based on newly available data 
(eg, to obtain data closer to the time of peak plasma concentrations) to ensure appropriate 
monitoring. 
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• Instructions for the collection and handling of biological samples will be provided by the 
Sponsor. The actual date and time (24-hour clock time) of each sample will be recorded. 
• Samples will be used to evaluate the PK of SAR441344. Each plasma sample will be 
divided into 2 aliquots (1 each for PK and a backup). Samples collected for analysis of 
SAR441344 plasma concentration may also be used to evaluate safety or efficacy aspects 
related to concerns arising during or after the study. 
• Genetic analyses will not be performed on these plasma samples unless consent for this 
was signed by the participant. Participant confidentiality will be maintained.  
• At visits during which plasma samples for the determination of multiple aspects of the 
IMP will be taken, one sample of sufficient volume can be used. 
Drug concentration information that would unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. 
8.6 
PHARMACODYNAMICS  
Several biomarkers related to the mechanism of action of SAR441344 and pathophysiology of SjS 
will be used to assess PD effects of SAR441344. The following PD parameters (which are well 
known markers to investigate PD effects in clinical studies for pSjS) will be assessed: 
 
All other biomarkers will be described in Section 8.8. 
• A positive treatment effect of SAR441344 should result 
 as 
indicated by:  
- 
Decrease in
 pointing to a polyclonal B-cell 
activation within pSjS, if treatment results in a decrease, a PD effect could be 
demonstrated.
 levels are part of the ESSDAI score. 
- 
Decrease in 
 as an autoantibody is a B-cell activation marker and known to be 
increased in pSjS, a PD effect could be shown by a reduction of 
 level. 
- 
Decrease in 
: both factors are associated 
with increased disease activity in pSjS and a PD effect could be demonstrated by a 
reduction in
 
• The evidence of 
 is characterized by poor prognosis and more severe 
organ manifestation in pSjS. A PD effect could be shown by an elevation of
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8.7 
GENETICS  
  
  
 (Section 1.3), 
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 as indicated in Section 8.7. 
- 
Serum samples will be tested for 
 Details on the rationale can be found in 
Section 8.6. 
- 
Serum samples will be tested for anti-Ro/SSA antibodies (only at Screening) to ensure 
presence of disease activity at inclusion. 
- 
Leftover samples will be stored and used for future analysis as described below, if 
consented. 
-
- 
Tested in plasma samples, 
- 
Exploratory PD marker to evaluate 
 activity in response to 
SAR441344, 
- 
 protein levels in plasma are expected to show a decrease with 
SAR441344 treatment, indicative of reduced
 
-
- 
Tested in plasma samples,  
- 
Exploratory PD marker to evaluate 
 in response to SAR441344. 
- 
- 
Tested in whole blood, 
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- 
Exploratory PD marker to evaluate effects on 
 in 
response to SAR441344, 
- 
levels in plasma are expected to show a decrease in 
this marker with SAR441344 treatment, indicative for an effect on the 
 
(see SoA [Section 1.3]) 
(see Section 8.7.2), 
 
A summary of sample volumes and timing of collection for the above biomarker assessment is 
presented in the laboratory manual. 
8.9 
IMMUNOGENICITY ASSESSMENTS  
Antidrug antibodies to SAR441344 will be evaluated in serum samples collected from all 
participants according to the SoA (see Section 1.3). Additionally, serum samples should also be 
collected at the final visits from participants who discontinued the IMP or were withdrawn from 
the study. These samples will be tested by the Sponsor or Sponsor’s designee. 
Serum samples will be screened for antibodies binding to SAR441344 and the titer of confirmed 
positive samples will be reported. Other analyses may be performed to verify the stability of 
antibodies to SAR441344 and/or further characterize the immunogenicity of SAR441344. 
The detection and characterization of antibodies to SAR441344 will be performed using a 
validated assay method by or under the supervision of the Sponsor. Plasma samples will be 
collected for detection of antibodies to SAR441344 for evaluation of SAR441344 serum 
concentration to enable interpretation of the antibody data. Samples may be stored for a maximum 
of 5 years (or according to local regulations) following the last participant’s last visit for the study 
at a facility selected by the Sponsor to enable further analysis of immune responses to 
SAR441344. 
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9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES  
No formal statistical hypothesis testing will be performed. 
9.2 
SAMPLE SIZE DETERMINATION  
The sample size was derived with respect to the primary endpoint (mean change from Baseline to 
Week 12 in the ESSDAI score) for applying the Quantitative Decision Making approach as 
described by Quan et al (45). Assuming a variability of 
 and an effect size of
, as derived 
based on (39), a sample size of 80 evaluable participants results in an overall probability
.  
Approximately 88 participants are expected to be randomly assigned to the IMP, expecting a total 
of 80 evaluable participants with approximately 40 evaluable participants per group. 
9.3 
POPULATIONS FOR ANALYSES  
The following populations are defined (Table 5): 
Table 5 - Populations for analyses  
Population 
Description 
Screened 
All participants who sign the ICF. 
Randomized 
All participants from screened population who have been allocated to a randomized intervention (by IRT) 
regardless of whether the intervention was received or not. Participants treated with the study intervention 
without being randomized or before the randomization will not be considered as randomized. 
Efficacy 
All randomly assigned participants who did actually receive at least 1 complete dose of IMP with at least 
1 post-IMP administration measurement, with available Baseline assessment of the ESSDAI.  
Participants will be analyzed according to the intervention they actually received. 
Safety 
All randomized participants exposed to the IMP (regardless of the amount of treatment administered) are 
included in the safety population. Participants will be analyzed according to the intervention they actually 
received. 
Pharmacokinetic 
All randomized and treated participants (safety population) with adequate PK results. Participants having 
received only placebo will not be part of the PK population. Participants will be analyzed according to the 
intervention they received. 
Pharmacodynamic 
All randomized and treated participants (safety population) with at least one post-baseline PD data. 
Participants will be analyzed according to the intervention they received. 
PK/PD population 
All participants being included in both the PK and the PD populations will be included in the PK/PD 
population. However, participants being included in the PD population and having received only placebo 
will be part of the PK/PD population. 
ADA 
All randomized participants treated with SAR441344 with at least one post-baseline ADA result (positive, 
negative or inconclusive). 
ADA: Anti-drug antibodies, ICF: informed consent form, IMP: investigational medicinal product, PD: pharmacodynamic, PK: pharmacokinetic. 
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Note: “Screened” means a participant's, or their legally acceptable representative’s, agreement to 
participate in a clinical study following completion of the informed consent process.  
9.4 
STATISTICAL ANALYSES  
A SAP will be finalized prior to database lock and it will include a more technical and detailed 
description of the statistical analyses described in this section. This section is a summary of the 
planned statistical analyses of the most important endpoints including primary and key secondary 
endpoints. 
9.4.1 General considerations  
The treatment difference in primary endpoint will be assessed based on the Quantitative Decision 
Making methodology. Specific decision criteria to be used will be documented separately before 
database lock. 
Descriptive analyses will include summarization of quantitative variables (using n, mean, standard 
deviation, inter-quartile range, median, minimum, and maximum) and qualitative data (by 
reporting absolute and relative frequencies).  
9.4.2 Primary endpoint(s)  
For the primary analysis, a linear mixed model with repeated measurements will be fitted to 
estimate the difference in mean change in ESSDAI from Baseline to Week 12. The model 
includes fixed effects for participant-specific baseline ESSDAI, visit, treatment group, and 
visit-by-treatment group interaction. Repeated measurements for each visit are taken within 
subject (Table 6). Point estimate and 90% confidence interval for the difference of means between 
the 2 groups (SAR443144 versus placebo) will be derived from the linear model framework. 
Table 6 - Primary endpoint analysis  
Primary Endpoint 
Statistical Analysis Methods 
Change in ESSDAI from Baseline 
to Week 12. 
The difference to placebo of mean change from Baseline to Week 12 in ESSDAI score will 
be derived using a linear mixed model with repeated measurements over time within 
participant, including fixed effects for participant-specific baseline ESSDAI, visit, treatment 
group, and visit-by-treatment group interaction, jointly with 90% confidence interval.  
ESSDAI: European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index. 
9.4.2.1 Additional analyses of the primary endpoint  
For sensitivity analysis of the primary endpoint, a linear mixed model with repeated 
measurements will be fitted to estimate the mean change in ESSDAI over time, including fixed 
factors for participant-specific baseline ESSDAI, visit, stratum, treatment group, visit-by-stratum 
interaction, visit-by-treatment group interaction, stratum-by-treatment group interaction, and 
visit-by-stratum-by-treatment group interaction. Repeated measurements for each visit are taken 
within subject. 
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The model-based estimate of the difference between treatments of the change in ESSDAI from 
Baseline to Week 12 will be provided, jointly with a 90% confidence interval. 
Observed mean and mean change from Baseline in single domains of ESSDAI will be 
summarized descriptively by visit. 
Descriptive statistics of the observed change from Baseline to Week 12 in ESSDAI will be 
provided overall and by ESSPRI at Baseline (ESSPRI <5 or ESSPRI ≥5). 
9.4.3 Key secondary endpoint(s)  
The main analysis provided for the primary endpoint of change from Baseline to Week 12 will be 
repeated for the key secondary endpoints (ESSPRI, MFI general fatigue subscale and other 
subscales; Table 7).  
Table 7 - Key secondary endpoints analyses  
Secondary Endpoint 
Statistical Analysis Methods 
Change in ESSPRI from Baseline 
to Week 12. 
 
The difference to placebo of mean change from Baseline to Week 12 in ESSPRI will be 
derived using a linear mixed model with repeated measurements over time within 
participant, including fixed effects for participant-specific baseline ESSPRI, visit, treatment 
group, and visit-by-treatment group interaction, jointly with 90% confidence interval.  
Change in MFI general fatigue 
subscale and other subscales from 
Baseline to Week 12. 
The difference to placebo of mean change from Baseline to Week 12 in MFI general fatigue 
subscale and other subscales (physical fatigue, mental fatigue, reduced motivation, and 
reduced activity) will be derived using a linear mixed model with repeated measurements 
over time within participant, including fixed effects for participant-specific baseline, visit, 
treatment group, and visit-by-treatment group interaction, jointly with 90% confidence 
intervals.  
ESSPRI: European League Against Rheumatism Sjögren’s Syndrome Patient Reported Index, MFI: Multidimensional Fatigue Inventory. 
9.4.3.1 Additional analyses of the key secondary endpoints  
A linear mixed effects model similar to the model applied to the primary endpoint will be fit to the 
key secondary endpoints (ESSPRI, MFI general fatigue subscale).  
Descriptive statistics of the observed mean and mean change from Baseline by visit in single 
domains and overall score will be provided for the key secondary endpoints (ESSPRI, MFI 
general fatigue subscale and other subscales).  
  
Details on the analysis of tertiary endpoints will be provided in the SAP. 
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9.4.5 Analysis of safety data  
The safety evaluation will be based upon the review of the individual values (clinically significant 
abnormalities), descriptive statistics (summary tables, figures) and, if needed, on statistical 
analysis (appropriate estimations, confidence intervals). No statistical significance tests will be 
performed on safety data. 
Potentially clinically significant abnormality (PCSA) values are defined as abnormal values 
considered medically important by the Sponsor, according to predefined criteria/thresholds based 
on literature reviews and defined by the Sponsor for clinical laboratory tests, vital signs, and ECG 
parameters. 
All the safety analyses will be performed using the safety population.  
For all safety data variables, the following observation periods are defined and used for classification 
of AEs, determination of on-treatment PCSA values, and the last on-treatment value for laboratory and 
vital sign parameters:  
• The pre-treatment period is defined as the time between informed consent signature and 
the first IMP administration. 
• The TEAE period is defined as the time from the first IMP administration up to the EoS 
visit (EoS included). It may be split further into the following periods:  
- 
On-treatment period, defined as the time from the first IMP administration up to EoT 
visit +7 days (last day included), 
- 
Residual treatment period, defined as the time from EoT visit + 8 days up to the EoS 
visit (EoS included).  
• The post-treatment period is defined as the time starting after the TEAE period. 
9.4.5.1 Adverse events  
9.4.5.1.1 Definitions  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA; 
version in use by the Sponsor at the time of database lock). Clinical judgment should be used to 
determine the severity of AEs as described in Section 10.3.3. 
Adverse events will be classified into predefined standard categories according to chronological 
criteria: 
• Pre-treatment AEs: AEs that occurred, worsened, or became serious during the 
pre-treatment period. 
• Treatment-emergent AEs: AEs that occurred, worsened, or became serious during the 
TEAE period. 
• Post-treatment: AEs that occurred, worsened, or became serious during the post-treatment 
period. 
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Treatment-emergent AEs will be assigned to the treatment received as per safety population.  
If the onset date (or time) of an AE (occurrence, worsening, or becoming serious) is incomplete or 
missing, the AE will be considered as a TEAE unless a partial date (or time) shows it as a pre- or 
post-treatment event. 
All AEs reported in the study will be listed, sorted by participant, onset date, and time. 
Table 8 - Safety analyses  
Safety measures 
Statistical analysis methods 
Adverse events  
• 
AEs  
• 
TEAEs  
• 
SAEs  
• 
AEs leading to IMP or study discontinuation  
• 
AEs leading to death  
• 
AESIs  
• 
PCSAs 
 
Treatment-emergent adverse event incidence tables will be 
presented by system organ class, high-level group term, 
high-level term, and preferred term for each treatment group 
and overall, showing the number (n) and percentage (%) of 
participants experiencing a TEAE.  
Multiple occurrences of the same event in the same participant 
will be counted only once in the tables. The denominator for 
computation of percentages will be the safety population within 
each treatment group. In addition, TEAEs will be described 
according to maximum intensity and relation to the IMP.  
Adverse events that occur outside the treatment emergent 
period will be listed separately. 
Proportion of patients with at least 1 TEAE, treatment emergent 
SAE, TEAE leading to death, and TEAE leading to definitive 
treatment discontinuation will be tabulated by treatment group 
and overall.  
The incidence of PCSAs occurring during the TEAE period will 
be summarized by treatment group overall and by baseline 
status. 
AE: adverse event, AESI: adverse event of special interest, IMP: investigational medicinal product, PCSA: potentially clinically significant 
abnormality, SAE: serious adverse event, TEAE: treatment-emergent adverse event. 
9.4.5.2 Local tolerability  
The number (%) of participants with injection site reactions will be summarized overall and by 
maximum severity by treatment group. Observed mean and mean change from Baseline in VDS 
will be summarized descriptively by visit. The incidence of AEs related to local tolerability 
findings will be summarized over time.  
9.4.5.3 Immunogenicity  
Antidrug antibodies to SAR441344 will be summarized by visit. 
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9.4.5.4 Extent of study treatment exposure and compliance  
A summary table presenting the exposure of treatment (ie, the number of days or weeks of 
administration) will be provided by treatment group for the safety population. 
9.4.5.5 Laboratory data  
Descriptive statistics of laboratory variables (laboratory values and changes from baseline), will 
be provided for each scheduled visit where laboratory data will be collected as per the SoA 
(Section 1.3; Baseline and post-Baseline time points). Descriptive statistics of changes from 
Baseline to last on-treatment value and from Baseline to worst on-treatment value will be 
presented for selected parameters by treatment group.  
9.4.5.6 Vital signs  
Descriptive statistics of all vital signs variables (values and changes from Baseline) will be 
calculated for each scheduled visit (baseline and post-baseline time points). Descriptive statistics 
of changes from Baseline to last on-treatment value and from Baseline to worst on-treatment 
value will be presented for selected parameters by treatment group. 
9.4.5.7 Electrocardiogram  
Descriptive statistics (including number, mean, median, standard deviation, minimum, and 
maximum) of all ECG variables (values and changes from Baseline), will be calculated for each 
visit (Baseline and post- Baseline time points), last and worst on-treatment value, and presented 
by treatment group. Only data measured before or on the day of the last IMP administration will 
be included in this analysis.  
9.4.6 Analysis of pharmacokinetic data  
9.4.6.1 Pharmacokinetic parameters  
The analysis of PK parameters will be described and reported separately. 
9.4.6.2 Pharmacokinetic/Pharmacodynamic analysis  
The analysis of PK/PD relationship will be described and reported separately. 
9.4.7 Other analyses  
9.4.7.1 Biomarkers  
Biomarker analyses will be described and reported separately. 
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9.5 
INTERIM ANALYSES  
An interim analysis for decision making may be implemented once approximately 50% of the 
planned participants have completed the study up to EoT (Week 12). The outcome may lead to 
early termination, continuation without any changes, or continuation with changes. 
A protocol amendment/amended protocol will be submitted for approval before any substantial 
changes to the study conduct are implemented.  
For this interim analysis, a Statistician, Programmer, and Clinical Study Director will work 
independently to the study team to ensure maintenance of blinding. 
A separate SAP for this interim analysis, if performed, will describe the corresponding analyses to 
be performed at interim and in greater detail. 
Once all participants have completed their EoT (Week 12) visit, selected sponsor personnel 
including study statistician and study programmer may be unblinded to generate initial reports 
(early analysis) based on the final SAP for internal decision making. Details of the personnel to be 
unblinded will be documented separately. 
Beside those described interim analyses, additional analyses for internal decision making might be 
conducted. For those analyses, if decided to do so, a Statistician, Programmer, and Clinical Study 
Director will work independently to the study team to ensure maintenance of blinding. 
9.6 
DATA MONITORING COMMITTEE (DMC)  
For details on the DMC, refer to Appendix 1 (Section 10.1.5). 
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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 in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and the applicable amendments and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines, 
- 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines, 
- 
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation - GDPR). 
• 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 implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
• The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC.  
- 
Determining whether an incidental finding should be returned to a participant and, if it 
meets the appropriate criteria, to ensure the finding is returned (an incidental finding is 
a previously undiagnosed medical condition that is discovered unintentionally and is 
unrelated to the aims of the study for which the tests are being performed). The 
following should be considered when determining the return of an incidental finding: 
- 
The return of such information to the study participant (and/or his/her designated 
healthcare professional, if so designated by the participant) is consistent with all 
applicable national, state, or regional laws and regulations in the country where the 
study is being conducted, and 
- 
The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical validity.  
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- 
The participant in a clinical study has the right to opt out of being notified by the 
Investigator of such incidental findings. In the event that the participant has opted 
out of being notified and the finding has consequences for other individuals, eg, the 
finding relates to a communicable disease, Investigators should seek independent 
ethical advice before determining next steps. 
- 
In case the participant has decided to opt out, the Investigator must record in the 
site medical files that she/he does not want to know about such findings. 
- 
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 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations. 
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical trial participants or on the scientific value of the trial) prior to their implementation. 
10.1.2 Financial disclosure  
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3 Informed consent process  
For the ICF and the optional future use of sample ICF, the following applies: 
• The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study, in language and terms they are able to understand.  
• Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center.  
• The medical record must include a statement that written informed consent was obtained 
before the participant was screened in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
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• Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study.  
• A copy of the signed and dated ICF(s) must be provided to the participant or the 
participant’s legally authorized representative.  
Participants who are rescreened are required to sign a new ICF. 
The optional future use of the sample ICF will address the use of remaining mandatory samples 
and the use of the archival samples for optional exploratory research (see Section 1.3, Section 8.7, 
and Section 8.8). The Investigator or authorized designee will explain to each participant the 
objectives of the exploratory research. Participants will be told that they are free to refuse to 
participate and may withdraw their consent at any time and for any reason during the storage 
period.  
10.1.4 Data protection  
All personal data collected related to participants, Investigators, or any person involved in the 
study, which may be included in the Sponsor’s databases, shall be treated in compliance with all 
applicable laws and regulations including the GDPR.  
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
Participant race and ethnicity will be collected in this study because these data are required by 
regulatory agencies (eg, on African-American population for the FDA) and due to several 
differences noted in SjS patients of different ethnicities eg, in genome-wide analysis of genetic 
polymorphisms showing different results in different ethnicities (2). 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred to the Sponsor. 
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant as described in the informed consent.  
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent 
access to this data by any unauthorized third party. 
• Participant data are intended to be used for the whole drug development program from 
collection to reimbursement. 
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10.1.5 Committees structure  
Data Monitoring Committee 
The DMC will be charged with monitoring the safety of participants in this study. It will also be 
responsible for providing recommendations for protecting the safety and ensuring the welfare of 
these participants to the Sponsor during the study. The DMC is justified by the early stage of 
development of SAR441344 in patients with pSjS. This committee is comprised of 
externally-based individuals with expertise in the diseases under study or clinical research and 
biostatistics.  
The DMC responsibilities and the data review processes are fully described in the DMC charter. 
In the above capacities, the DMC is advisory to the Sponsor. The Sponsor is responsible for 
promptly reviewing and for taking into account in a timely manner the recommendations of the 
DMC in terms of study continuation with or without alterations or of potential study termination. 
10.1.6 Dissemination of clinical study data  
Sanofi shares information about clinical trials and results on publically accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations. These 
websites include clinicaltrials.gov, EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance and intellectual property. 
For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials. Details on data sharing criteria and process for 
requesting access can be found at this web address: clinicalstudydatarequest.com.  
10.1.7 Data quality assurance  
• All participant data relating to the study will be recorded on printed or e-CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the case report form (CRF).  
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
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• Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in separate study documents. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations). 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF 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. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.  
10.1.8 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 reported on the CRF or entered in the e-CRF 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, depending on the study. Also, current medical records must be available. 
• Definition of what constitutes source data can be found in the study reference manual.  
10.1.9 Study and site start and closure  
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 open and will be the study start date. 
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. 
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• Note: in case of investigational site closure or complete regional or national lock-down 
due to a local epidemic or international pandemic, the study may be suspended regionally 
or nationally at the affected sites. Every effort will be kept to continue the follow-up of 
already recruited patients as close to the SoA as possible. 
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 study termination by the Sponsor, as well as reasons for the early closure of a study 
site by the Sponsor or Investigator may include but are not limited to: 
• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio, 
- 
Discontinuation of further study intervention 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 no 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 Contract Research 
Organization(s) 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. 
10.1.10 
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 in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
• The tests detailed in Table 9 will be performed by the central laboratory.  
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• Local laboratory results are only required in the event that the central laboratory results are 
not available in time for either IMP administration and/or response evaluation. If a local 
sample is required, it is important that the sample for central analysis is obtained at the 
same time. Additionally, if the local laboratory results are used to make either an IMP 
decision or response evaluation, the results must be entered into the e-CRF. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations Pregnancy testing: For Screening, a 
HCG test (blood) will be obtained from all female participants, which must be deemed 
negative (see Section 5) During the study, β-HCG testing will be performed for women of 
childbearing potential (WOCBP), if the urine test is positive, a blood test will be sent to 
the central laboratory. 
Table 9 - Protocol-required laboratory assessments  
Laboratory assessments 
Parameters 
Hematology 
• 
Platelet count 
• 
Red blood cell (RBC) count 
• 
Hemoglobin 
• 
Hematocrit 
• 
RBC indices: mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), 
% reticulocytes 
• 
White blood cell (WBC) count with differential: neutrophils, lymphocytes, monocytes, 
eosinophils, basophils 
Coagulation 
• 
International normalized ratio (INR), activated partial thromboplastin time (aPTT) 
Clinical chemistrya 
• 
Blood urea nitrogen (BUN), creatinine (including glomerular filtration rate calculation, 
according to the Cockcroft-Gault formula) 
• 
Serum glucoseb  
• 
Serum electrolytes: potassium, sodium, calcium 
• 
Liver function tests: aspartate aminotransferase (AST)/serum glutamic-oxaloacetic 
transaminase (SGOT), alanine aminotransferase (ALT)/serum glutamic-pyruvic 
transaminase (SGPT), alkaline phosphatase, total and direct bilirubin 
• 
Creatine phosphokinase 
• 
Total protein 
Routine urinalysis 
• 
pH, specific gravity, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase (performed by dipstick locally at the site), quantitative measurement 
for glucose, protein, erythrocytes, and leucocytes count will be required in the event that 
the urine sample test is positive for any of the above parameters by urine dipstick and 
rated clinically significant by the Investigator (sample will be sent to central laboratory)  
• 
Microscopic examination (if blood or protein is abnormal) 
• 
β-human chorionic gonadotropin (HCG) for women of childbearing potential (performed 
locally at the site)c 
Test only performed at Screening  • 
Follicle-stimulating hormone (as needed in postmenopausal women) 
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Laboratory assessments 
Parameters 
• 
Highly sensitive serum β-HCG pregnancy test  
• 
Serology: human immunodeficiency virus antibody 1/2, hepatitis B surface antigen 
(HBsAg), hepatitis B core antibody, (HBc Ab), and hepatitis C antibody (HCV-Ab) 
• 
QuantiFERON® tuberculosis-Gold test 
• 
Anti-Ro/SSA 
PD/Genetics/Biomarker 
• 
Performed in the central laboratory:
, rheumatoid 
factore, 
d, 
i
 
• 
Performed by the Sponsord: deoxyribonucleic acid, ribonucleic acid samples, 
 
• 
All study-required laboratory assessments will be performed by a central laboratory if not 
listed otherwise in this table 
NOTES: 
a Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or monitoring event are given 
in Appendix 6 (Section 10.6). 
b Fasting glucose is preferred. Fasting/non-fasting status will be recorded at the time of blood collection for glucose assessment. 
c Local urine testing will be standard for the protocol unless serum testing is required by local regulation or Institutional Review 
Board/Independent Ethics Committee. 
d The Investigator and study site will be blinded for these parameters. Unblinding is appropriate in case of a safety issue. 
e Rheumatoid factor will be unblinded at Screening, but blinded from Visit 1 on throughout the study. 
Investigators must document their review of each laboratory safety report. 
Laboratory/analyte results that could unblind the study will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded. Therefore, the Investigator and the 
study site will be blinded for
, 
 (
 is unblinded at Screening), 
 as well as all analysis performed by the Sponsor as indicated in Table 9. 
Unblinding is appropriate in case of a safety issue and deemed necessary in the discretion of the 
Investigator. 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
10.3.1 Definition of AE  
AE definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
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Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, electrocardiogram, radiological scans, vital signs 
measurements), including those that worsen from Baseline, considered clinically 
significant in the medical and scientific judgment of the Investigator (ie, not related to 
progression of underlying disease) eg,  
- 
Symptomatic and/or,  
- 
Requiring either corrective treatment or consultation, and/or  
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI. 
• Exacerbation of a chronic or intermittent preexisting condition including either an increase 
in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE.  
Events NOT meeting the AE definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
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10.3.2 Definition of SAE  
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death 
b) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
Baseline is not considered an AE. 
d) Results in persistent disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 
f) Other situations: 
- 
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the participant or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These events should usually be 
considered serious. 
- 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
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10.3.3 Recording and follow-up of AE and/or SAE  
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information in the e-CRF. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AESI/AE/SAE e-CRF page. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission to 
Sponsor. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories: 
• Mild: an event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
• Moderate: an event that causes sufficient discomfort and interferes with normal everyday 
activities. 
• Severe: an event that prevents normal everyday activities. An AE that is assessed as severe 
should not be confused with a SAE. Severe is a category utilized for rating the intensity of 
an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
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• The Investigator will also consult the Investigator’s Brochure and/or Product Information, 
for marketed products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the Investigator always make an assessment of causality for every event before 
the initial transmission of the SAE data to the Sponsor. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathology examinations, or 
consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor with a copy of any post-mortem findings 
including histopathology. 
• New or updated information will be recorded in the originally completed e-CRF. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
10.3.4 Reporting of SAEs  
SAE reporting to the Sponsor via an electronic data collection tool 
• The primary mechanism for reporting an SAE to the Sponsor will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) in order to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, then the site can report this information on a paper SAE form (see next section) or 
to the Medical Monitor by telephone. 
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• Contacts for SAE reporting can be found in the Investigator site file. 
SAE reporting to the Sponsor via paper CRF 
• Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the Medical Monitor. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames. 
• Contacts for SAE reporting can be found in the Investigator site file. 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION  
DEFINITIONS: 
Woman of childbearing potential 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy, 
- 
Documented bilateral salpingectomy, 
- 
Documented bilateral oophorectomy, 
For individuals with permanent infertility due to an alternate medical cause other than 
the above (eg, Mullerian agenesis, androgen insensitivity), Investigator discretion 
should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
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- 
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
confirmation with more than one FSH measurement (>ULN as defined by central 
laboratory readout) is required. 
- 
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study randomization. 
CONTRACEPTION GUIDANCE: 
 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency  
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS)c 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual 
partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used. Spermatogenesis cycle is approximately 90 days.) 
Highly Effective Methodsb That Are User Dependent  
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulationc 
- 
oral 
- 
intravaginal 
- 
transdermal 
- 
injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
- 
oral 
- 
injectable 
• 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the 
participant.) 
a Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for those 
participating in clinical studies. 
b Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when used consistently 
and correctly. 
c If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited 
to those which inhibit ovulation as the primary mode of action. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal [coitus interruptus]), spermicides only, and 
lactational amenorrhea method (LAM) are not acceptable methods of contraception for this study. Male condom and female condom 
should not be used together (due to risk of failure with friction). 
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COLLECTION OF PREGNANCY INFORMATION:  
Male participants with partners who become pregnant  
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive the investigational medicinal product. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure.  
Female participants who become pregnant  
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the Sponsor within 24 hours of learning 
of a participant’s pregnancy.  
• The participant will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the participant and the neonate, and the 
information will be forwarded to the Sponsor. Generally, follow-up will not be required 
for longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of 
pregnancy will be reported, regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure. 
• Any pregnancy complication or elective termination of a pregnancy for medical reasons 
will be reported as an AE or SAE.  
• A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring at 
>22 weeks gestational age) is always considered to be an SAE and will be reported as 
such.  
• Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in  
Section 8.3.4. While the Investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting.  
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 
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10.5 
APPENDIX 5: GENETICS  
 
 
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10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-
UP ASSESSMENTS  
 
Neutropenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting AEs in Appendix 3 (Section 10.3) is met. 
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Thrombocytopenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting AEs in Appendix 3 (Section 10.3) is met. 
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*If unable to retest in 72 hours, use original lab results to decide on further reporting/monitoring/discontinuation.  
Note: 
“Baseline” refers to ALT sampled at baseline visit; or if baseline value unavailable, to the latest ALT sampled before the baseline visit. The 
algorithm does not apply to the instances of increase in ALT during screening. 
See Appendix 3 (Section 10.3) for guidance on safety reporting. 
Normalization is defined as ≤ULN or baseline value, if baseline value is >ULN. 
 
ALT > 3 ULN
Monitor LFTs every 72 hours
ALT ≤ 5 ULN
ALT > 3 ULN &
Total Bilirubin > 2 ULN 
Permanent Discontinuation of IMP
ALT > 5 ULN 
In ANY CASE, FOLLOW the instructions listed in the box below: 
1.
INFORM the Site Monitor who will forward the information to the Study Manager
2.
INVESTIGATE specifically for malaise with or without loss of consciousness, dizziness, and/or 
hypotension and/or episode of arrhythmia in the previous 72 hours; rule out muscular injury
3.
PERFORM the following tests:
- LFTs: AST, ALT, alkaline phosphatase, total and conjugated bilirubin and prothrombin time / INR
- CPK, serum creatinine, complete blood count
- Anti-HAV IgM, anti-HBc IgM, (HBV-DNA if clinically indicated), anti-HCV and HCV RNA, anti-
CMV IgM and anti-HEV IgM antibodies
- Depending on the clinical context, check for recent infection with EBV, herpes viruses, and toxoplasma
- Hepatobiliary ultrasonography (or other imaging investigations if needed)
4.
CONSIDER Auto-antibodies: antinuclear, anti-DNA, anti-smooth muscle, anti-LKM
5.
CONSIDER consulting with hepatologist
6.
CONSIDER patient hospitalisation if INR>2 (or PT<50%) and/or central nervous system disburbances 
suggesting hepatic encephalopathy
7.
MONITOR LFTs after discontinuation of IMP:
- As closely as possible (or every 48 hours) until stabilization, then every 2 weeks until return to 
normal/baseline or clinical resolution.
8.
FREEZE serum sample (5ml x 2)
9.
In case of SUSPICION of GILBERT Syndrome, a DNA diagnostic test should be done
COMPLETE the specific CRF forms 
for „ALT Increase” and inform the 
Monitoring Team within 24 hours
Confirm ALT > 3 ULN
Retest within 72 hours of initial sample*
IMP administration can be continued as 
long as – under close monitoring –
conditions for permanent 
discontinuation or temporary 
interruption per protocol are not met
INCREASE IN ALT
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Increase in serum creatinine is to be recorded as an AE only if at least 1 of the criteria listed in the 
general guidelines for reporting AEs in Appendix 3 (Section 10.3) is met. 
 
Increase in creatine phosphokinase (CPK) is to be recorded as an AE only if at least 1 of the 
criteria in the general guidelines for reporting AEs in Appendix 3 (Section 10.3) is met. 
 
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10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS  
Not applicable.  
10.8 
APPENDIX 8: ABBREVIATIONS  
 
ADA: 
antidrug antibody 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
anti-HBc Ab: 
anti-hepatitis B core antibodies 
AST: 
aspartate aminotransferase 
AUC: 
area under the curve 
AUC0-tau: 
area under the curve over the dosing interval 
CD40: 
cluster of differentiation 40 
CD40L: 
cluster of differentiation 40 ligand 
CFR: 
Code of Federal Regulations 
CIOMS: 
Council for International Organizations of Medical Sciences 
Cmax: 
maximum concentration 
CNS: 
central nervous system 
CONSORT: 
Consolidated Standards of Reporting Trials 
COVID-19: 
coronavirus infectious disease due to SARS-CoV-2 
CPK: 
creatine phophokinase 
CRF: 
case report form 
CSR: 
clinical study report 
DMC: 
Data Monitoring Committee 
 
ECG: 
electrocardiogram 
e-CRF: 
electronic case report form 
EoS: 
End of Study 
EoT: 
End of Treatment 
EQ-5D-5L: 
EuroQoL questionnaire with 5 dimensions and 5 levels per dimension 
ESSDAI: 
EULAR Sjögren’s Syndrome Disease Activity Index 
ESSPRI: 
EULAR Sjögren’s Syndrome Patient Reported Index 
EULAR: 
European League Against Rheumatism 
FIH: 
first in human 
FSH: 
follicle-stimulating hormone 
GCP: 
Good Clinical Practice 
GDPR: 
General Data Protection Regulation 
GLP: 
Good Laboratory Practice 
HBsAg: 
hepatitis B surface antigen 
HCG: 
human chorionic gonadotropin 
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HCV-Ab: 
hepatitis C antibody 
HIPAA: 
Health Insurance Portability and Accountability ACt 
HIV: 
human immunodeficiency virus 
HRT: 
hormonal replacement therapy 
IB: 
Investigator’s Brochure 
ICF: 
informed consent form 
ICH: 
International Council for Harmonisation 
IEC: 
Independent Ethics Committee 
Ig: 
immunoglobulin 
IMP: 
investigational medicinal product 
IRB: 
Institutional Review Board 
IRT: 
interactive response technology 
IV: 
intravenous(ly) 
KLH: 
keyhole limpet hemocyanin 
mAb: 
monoclonal antibody 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MFI: 
Multidimensional Fatigue Inventory 
 
NOAEL: 
no observed adverse effect level 
NSAID: 
nonsteroidal anti-inflammatory drug 
PBMC: 
peripheral blood mononuclear cell(s) 
PCSA: 
Potentially clinically significant abnormality 
PD: 
pharmacodynamic(s) 
PK: 
pharmacokinetic(s) 
PNS: 
peripheral nervous system 
pSjS: 
primary Sjögren’s syndrome 
q2w: 
once every 2 weeks 
RF: 
rheumatoid factor 
rhsCD40L: 
recombinant human soluble cluster of differentiation 40 
SAE: 
serious adverse event 
SAP: 
Statistical Analysis Plan 
SARS-CoV-2: 
severe acute respiratory syndrome coronavirus-2 
SC: 
subcutaneous(ly) 
SjS: 
Sjögren’s syndrome 
SoA: 
Schedule of Activities 
SUSAR: 
suspected unexpected serious adverse reaction 
t1/2z: 
terminal half-life 
TDAR: 
T-cell dependent antibody response 
TEAE: 
treatment-emergent adverse event 
Th: 
T helper 
tmax: 
time to maximum concentration 
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ULN: 
upper limit of normal 
VAS: 
visual analogue scale 
VDS: 
verbal descriptor scale 
WOCBP: 
women of childbearing potential 
 
10.9 
APPENDIX 9: PROTOCOL AMENDMENT HISTORY  
Amended protocol 01 (27 August 2020) 
This amended protocol (Amendment 01) 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 purpose of the amendment is to have minor adjustments in the exclusion criteria E01, E11, 
E14, and E30 to address comments raised by the EU participating National Competent Authorities 
during review of the clinical trial application, via the Voluntary Harmonisation Procedure. It was 
clarified that participants with any autoimmune disease (except primary Sjögren’s syndrome and 
Hashimoto thyroiditis) are excluded from the study (E01), that participants with an addiction 
history within the last year are excluded from the study (E14). In addition, it was specified, that 
participants with a history of hypersensitivity against humanized monoclonal antibodies are 
excluded from the study (E11), as well as participants with known hypersensitivity to any 
constituent of the IMP (E30). Finally, clarification of minor discrepancies are also being 
addressed in this amendment, as well as minor editorial and document formatting revisions. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
Activities 
Multidimensional Fatigue Inventory (MFI) at 
Screening deleted. 
Correction of the timepoint. Assessment was not 
planned at screening (typing error) and would add 
additional burden to participants, as assessment is 
not necessary at this timepoint. 
5.2 Exclusion 
criteria  
 E 01. Any autoimmune disease (except pSjS and 
Hashimoto thyroiditis) with or without secondary SjS. 
Clarification that participants with any autoimmune 
disease (except primary Sjögren`s syndrome [pSjS] 
and Hashimoto thyroiditis) are excluded from this 
study.  
 5.2 Exclusion 
criteria 
E11. History of a systemic hypersensitivity reaction or 
significant allergies, other than localized injection site 
reaction, to any biologic molecule humanized 
monoclonal antibody. 
Clarification that participants with a history of a 
systemic hypersensitivity reaction or significant 
allergies against humanized mAb are excluded from 
the study to increase subject safety. 
5.2 Exclusion 
criteria 
E14. Current Substance abuse (including cannabis) 
and/or alcohol abuse, current or in the last year.  
Adapted that participants with a 1-year addiction 
history are excluded as well.  
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Section # and 
Name 
Description of Change 
Brief Rationale 
5.2 Exclusion 
criteria 
E 30. Sensitivity Hypersensitivity to any of the IMPs, 
including or components any constituent thereof, 
or drug or other allergy that, in the opinion of the 
Investigator, contraindicates participation in the study 
Adaption for clarification. 
7.1.2 Temporary 
discontinuation. 
For all temporary IMP discontinuations, duration 
should be recorded by the Investigator in the 
appropriate pages of the e-CRF. Planned visits 
should take place as scheduled, if possible, during 
this period of discontinuation. Temporary IMP 
discontinuation can appear only once per 
subject/treatment period. [….]. A discontinuation of 
IMP greater than 30 days + 2 days (according to 
the visit window) will be considered definitive and 
relevant eCRF sections should be populated. 
Specification is added for clarification and according 
to the visit window.  
9.2 Sample size 
determination 
Assuming a variability of
 and an effect size of
, 
as derived based on (38), a sample size of 80 
evaluable participants results in an overall probability 
. 
Reference is added for clarification. 
10.4 Appendix 4 
However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH 
measurement (>ULN as defined by central laboratory 
readout 40 IU/L or mIU/mL) is required. 
Discrepancy with Inclusion criteria I09 was 
corrected. 
pSjS: primary Sjögren`s syndrome, IMP: investigational medicinal product, e-CRF: electronic case report form, FSH: follicle-stimulating 
hormone, mAb: monoclonal antibody, ULN: upper limit of normal. 
Amended protocol 02 (28 July 2021) 
This amended protocol (amendment 02) 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 main purpose of the amendment is to have an adjustment in the inclusion criterion I03 and to 
allow re-screening for I06 to better reflect the participant population to aid recruitment without 
compromising on safety requirements. In addition, Section 9.5 (Interim analysis) was extended 
with an early analysis after all participants have completed their End of Treatment/ Week 12 visit, 
to allow for internal decision making. Further Section 6.2 was adapted to allow destruction of 
vials according to local regulations and a reference to the pharmacy manual was added. Finally, 
clarification of discrepancies are also being addressed in this amendment, as well as minor 
editorial and document formatting revisions. 
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Protocol amendment summary of changes table 
Section # 
and Name 
Description of Change 
Brief Rationale 
2.2.2.2 Clinical 
data 
 
 is a completed a Phase 1, double-
blind, randomized, parallel design, placebo-
controlled single ascending dose study […]. 
Correction of a typing error.  
2.2.2.2 Clinical 
data 
 
 is a concluded completed Phase 1, 
double-blind, randomized, placebo-controlled 
multiple ascending dose study [….]. 
Adapted: 
is completed.  
 2.3.3. Overall 
benefit: risk 
conclusion 
No safety or tolerability concerns have been 
identified in the ongoing Phase 1 first in human 
studies. 
 Adapted: Phase first-in human studies are completed. 
5.1 Inclusion 
criteria 
I 03. Disease duration since first diagnosis of 
pSjS ≤ 7 15 years based on medical history. 
 
Adjustment to more accurately reflect the pSjS 
population. 
5.4 Screen 
Failures 
Table 3 
I06 is added to Inclusion criteria leading to screen 
failure, which are permitted for rescreening. With 
the following footnote:” Re-Screening of I06 is 
permitted if in the investigator`s discretion 
due to disease activity a change of these 
parameters could be expected.” 
Adjustment to more accurately reflect the pSjS 
population. 
6.2 Preparation/ 
handling/ 
storage/ 
accountability 
The used vials will be kept by the Pharmacist in a 
secure location up to the full documented 
reconciliations performed with the Sponsor at the 
end of the study. The Pharmacist should wait for 
the written approval form from the Sponsor before 
proceeding with their destruction. Any annotation 
on the vials should be considered as source 
documents until the time of vial destruction. 
Handling of used vials is described in the 
pharmacy manual. 
Adaption to allow destruction of vials according local 
regulations. Reference to the pharmacy manual added. 
6.3 Measures to 
minimize bias: 
Randomization 
and blinding 
If the Investigator decides that the unblinding is 
warranted, he/she may, at his/her discretion, 
contact Sponsor to discuss the situation the 
Investigator should make every effort to contact 
the Sponsor prior to unblinding a participant’s 
intervention assignment, unless this could delay 
emergency treatment of the participant. 
Adapted due to adapted Sponsor wording.  
7.1.2 Temporary 
discontinuation 
A discontinuation of IMP greater than 30 days + 
2 days (according to the visit window) will be 
considered definitive and relevant e-CRF sections 
should be populated. 
Correction of a typing error. 
8.5 
Pharmacokinetics 
Blood samples of approximately 2 mL will be 
collected for measurement of plasma 
concentrations of SAR441344 as specified in the 
SoA. 
For clarification. Details will be in the laboratory manual. 
A maximum amount of blood collection will not exceed 
500 mL over the duration of the study (see Section 8). 
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Section # 
and Name 
Description of Change 
Brief Rationale 
8.7.1 
Deoxyribonucleic 
acid 
A 3 mL whole blood sample for DNA isolation will 
be collected from participants who have 
consented to participate in the genetic analysis 
component of the study at Baseline 
For clarification. Details will be in the laboratory manual. 
A maximum amount of blood collection will not exceed 
500 mL over the duration of the study (see Section 8). 
8.7.2 Ribonucleic 
acid 
At the study visits specified in the SoA 
(Section 1.3), a 2.5 mL RNA blood samples will 
be collected and stored from consenting 
participants. 
For clarification. Details will be in the laboratory manual. 
A maximum amount of blood collection will not exceed 
500 mL over the duration of the study (see Section 8). 
8.9 
Immunogenicity 
assessments 
Antidrug antibodies to SAR441344 will be 
evaluated in serum samples (3.5 mL per sample) 
collected from all participants according to the 
SoA. 
For clarification. Details will be in the laboratory manual. 
A maximum amount of blood collection will not exceed 
500 mL over the duration of the study (see Section 8). 
9.3 Populations 
for analyses 
Table◦5 - Populations for analyses: 
Enrolled: All participants who sign the ICF. 
Screened: All participants who sign the ICF. 
Randomized: All enrolled participants who are 
randomly assigned to the IMP. All participants 
from screened population who have been 
allocated to a randomized intervention (by 
IRT) regardless of whether the intervention 
was received or not. Participants treated with 
the study intervention without being 
randomized or before the randomization will 
not be considered as randomized. 
ADA: All randomized participants treated with 
SAR441344 with at least one post-baseline 
ADA result (positive, negative or 
inconclusive). 
Adaptation to follow current standards in population 
definition and adding a missing population (ADA) 
needed for analysis. 
9.5. Interim 
Analyses 
In all scenarios mentioned above For this 
interim analysis, a Statistician, Programmer, and 
Clinical Study Director will work independently to 
the study team to ensure maintenance of 
blinding. 
The A separate SAP for this interim analysis, if 
performed, will describe the corresponding 
analyses to be performed at interim in greater 
detail, if it is to be performed. 
For clarification.  
9.5 Interim 
Analyses 
Once all participants have completed their 
EoT (Week 12) visit, selected sponsor 
personnel including study statistician and 
study programmer may be unblinded to 
generate initial reports (early analysis) based 
on the final SAP for internal decision making. 
Details of the personnel to be unblinded will 
be documented separately. 
Adaption to allow for internal decision making while 
keeping the blind once all subjects have completed their 
EoT visit. 
ADA: Anti-drug antibodies, EoT: End of treatment, pSjS: primary Sjögren`s syndrome, SAP: statistical analysis plan, SoA: Schedule of 
Assessments. 
 
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11 
REFERENCES  
1. Rose N, Mackay I. Autoimmune Disease: The Consequence of Disturbed Homeostasis. In: 
Rose N, Mackay I, editors. The Autoimmune Diseases. 5th ed. Amsterdam: Academic Press; 
2014. p. 3-7. 
2. Nocturne G, Mariette X. B cells in the pathogenesis of primary Sjögren syndrome. Nat Rev 
Rheumatol 2018;14(3):133-45. 
3. Brito-Zerón P, Baldini C, Bootsma H, Bowman SJ, Jonsson R, Mariette X, et al. Sjögren 
syndrome. Nat Rev Dis Primers. 2016;2:16047. 
4. Goules A, Tzioufas AG, Manousakis MN, Kirou KA, Crow MK, Routsias JG, et al. Elevated 
levels of soluble CD40 ligand (sCD40L) in serum of patients with systemic autoimmune 
diseases; J Autoimmun. 2006;26(3):165-71. 
5. Fisher BA, Szanto A, Ng WF, Bombardieri M, Posch MG, Papas AS, et al. Assessment of the 
anti-CD40 antibody iscalimab in patients with primary Sjögren's syndrome: a multicenter, 
randomised, double-blind, placebo-controlled, proof-of-concept study. Lancet Rheumatol 
2020;2(3):e142-52. 
6. Wieczorek G, Bigaud M, Pfister S, Ceci M, McMichael K, Afatsawo C, et al. Blockade of 
CD40–CD154 pathway interactions suppresses ectopic lymphoid structures and inhibits 
pathology in the NOD/ShiLtJ mouse model of Sjögren’s syndrome. Ann Rheum Dis. 
2019;78(7):974-8. 
7. Seror R, Theander E, Brun JG, Ramos-Casals M, Valim V, Dörner T, et al. Validation of 
EULAR primary Sjögren’s syndrome disease activity (ESSDAI) and patient indexes 
(ESSPRI). Ann Rheum Dis. 2015;74(5):859-66. 
8. Seror R, Bowman SJ, Brito-Zeron P, Theander E, Bootsma H, Tzioufas A, et al. EULAR 
Sjögren’s syndrome disease activity index (ESSDAI): a user guide. RMD Open. 
2015;1(1):e000022. 
9. Mariette X, Criswell LA .Primary Sjögren’s Syndrome. N Engl J Med. 2018;378:931-9. 
10. Yacoub D, Benslimane N, Al-Zoobi L, Hassan G, Nadiri A, Mourad W. CD154 is released 
from T-cells a disintegrin and metalloproteinase domain containing protein 10 (ADAM10) and 
ADAM17 in a CD40 Protein-dependent manner. J Biol Chem. 2013;288(50):36083-93. 
11. Schonbeck U, Libby P. The CD40/CD154 receptor/ligand dyad. Cell Mol Life Sci. 
2001;58(1):4-43. 
12. Hirbod-Mobarakeh A, Aghamohammadi A, Rezaei N. Immunoglobulin class switch 
recombination deficiency type 1 or CD40 ligand deficiency: from bedside to bench and back 
again. Expert Rev Clin Immunol. 2014;10(1):91-105. 
VV-CLIN-0588009 4.0

Amended Clinical Trial Protocol 03  
05-Apr-2022 
SAR441344-ACT16618 
Version number: 1 
 
 
Property of the Sanofi group - strictly confidential 
Page 105 
13. Langer F, Ingersoll SB, Amirkhosravi A, Meyer T, Siddiqui FA, Ahmad S, et al. The role of 
CD40 in CD40L- and antibody-mediated platelet activation. Thromb Haemost. 
2005;93(6):1137-46. 
14. Robles-Carrillo L, Meyer T, Hatfield M, Desai H, Dávila M, Langer F, et al. Anti-CD40L 
immune complexes potently activate platelets in vitro and cause thrombosis in FCGR2A 
transgenic mice. J Immunol. 2010;185(3):1577-83. 
15. Furie R, Bruce I, Dörner T, Leon M, Leszczyński P, Urowitz M, et al. Efficacy and Safety of 
Dapirolizumab Pegol in Patients with Moderately to Severely Active Systemic Lupus 
Erythematosus: A Randomized, Placebo-Controlled Study [abstract]. Arthritis Rheumatol. 
2019;71 (suppl 10). 
16. Tocoian A, Buchan P, Kirby H, Soranson J, Zamacona M, Walley R, et al. First-in-human trial 
of the safety, pharmacokinetics and immunogenicity of a PEGylated anti-CD40L antibody 
fragment (CDP7657) in healthy individuals and patients with systemic lupus erythematosis 
Lupus. 2015;24(10):1045-56. 
17. Karnell JL, Albulescu M, Drabic S, Wang L, Moate R, Baca M, et al. CD40L-targeting 
protein reduces autoantibodies and improves disease activity in patients with autoimmunity. 
Sci Transl Med. 2019;11(489):eaar6584. 
18. Callaway E. The race for coronavirus vaccines: a graphical guide. Nature. 
2020;580(7805):576-7. 
19. Thevarajan I, Nguyen THO, Koutsakos M, Druce J, Caly L, van de Sandt CE, et al. Breadth of 
concomitant immune responses prior to patient recovery: a case report of non-severe COVID-
19. Nat Med. 2020;26(4):453-5. 
20. Gao Q, Bao L, Mao H, Wang L, Xu K, Yang M, et al. Rapid development of an inactivated 
vaccine for SARS-CoV-2.bioRxiv. 2020. Preprint article, not peer-reviewed. 
21. Zhou P, Yang X, Wang X, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated 
with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270-3. 
22. Ni L, Ye F, Cheng M-L, Feng Y, Deng Y-Q, Zhao H, et al. Detection of SARS-CoV-2-
specific humoral and cellular immunity in COVID-19 convalescent individuals. Immunity. 
2020;S1074-7613(20):30181-3. 
23. Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al. Treatment of 5 critically ill patients with 
COVID-19 with convalescent plasma. JAMA. 2020;323(16):1582-9. 
24. World Health Organization. Coronavirus disease (COVID-19) advice for the public [Internet]. 
2020 [updated 2020 Apr 29; cited 2020 May 05]. Available from: 
URL:https://www.who.int/emergencies/diseases/novel-coronavirus-2019/advice-for-public 
VV-CLIN-0588009 4.0

Amended Clinical Trial Protocol 03  
05-Apr-2022 
SAR441344-ACT16618 
Version number: 1 
 
 
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Page 106 
25. World Health Organization. Clinical Spectrum of SARS-CoV-2 Infection [Online]. [Last 
updated 2021 October 19; cited 2022 February 18]. Available from: 
URL:https://www.covid19treatmentguidelines.nih.gov/overview/clinical-spectrum/ 
26. Mehra MR, Desai SS, Kuy SR, Henry TD, Patel AN. Cardiovascular disease, drug therapy, 
and mortality in Covid-19. N Engl J Med. Epub 2020 May 1. 
27. Gandhi RT, Lynch JB, del Rio C. Mild or moderate Covid-19. N Engl J Med. Epub 2020 Apr 
24. 
28. Dai M, Liu D, Liu M, Zhou F, Li G, Chen Z, et al. Patients with cancer appear more 
vulnerable to SARS-COV-2: a multi-center study during the COVID-19 outbreak. Cancer 
Discov. 2020.  
29. Lighter J, Phillips M, Hochman S, Sterling S, Johnson D, Francois F et al. Obesity in patients 
younger than 60 years is a risk factor for Covid-19 hospital admission. 2020;ciaa415.  
30. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality 
of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 
2020;395(10229):1054-62. 
31. Guan Wj, Zheng-yi N, Hu Y, Liang WH, Chun-quan O, Jian-Xing H, et al. Clinical 
characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708-20. 
32. Centers for Disease Control and Prevention. COVID-19 Response Team; Preliminary 
Estimates of the Prevalence of Selected Underlying Health Conditions Among Patients with 
Coronavirus Disease 2019-United States, February 12-March 28 2020. MMWR Morb Mortal 
Wkly Rep. 2020;69(13):382-6. 
33. Arons MM, Hatfield KM, Reddy SC, Kimball A, James A Jacobs JR, et al. Presymptomatic 
SARS-CoV-2 infections and transmission in a skilled nursing facility.N Engl J Med. 
2020;382(22):2081-90. 
34. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized 
patients with 2019 novel coronavirus-infected pneumonia in wuhan, China. JAMA. 
2020;323(11):1061-9. 
35. Brito-Zerón P, Soria N, Muñoz S, Bové A, Akasbi M, Belenguer R, et al. Prevalence and 
clinical relevance of autoimmune neutropenia in patients with primary Sjögren's syndrome. 
Semin Arthritis Rheum. 2009;38(5):389-95. 
36. Seror R, Ravaud P, Bowman SJ, Baron G, Tzioufas A, Theander E, et al. EULAR Sjögren's 
syndrome disease activity index: development of a consensus systemic disease activity index 
for primary Sjögren's syndrome. Ann Rheum Dis. 2010;69(6):1103-9. 
37. Seror R, Ravaud P, Mariette X, Bootsma H, Theander E, Hansen A, et al. EULAR Sjogren’s 
Syndrome Patient Reported Index (ESSPRI): development of a consensus patient index for 
primary Sjogren’s syndrome. Ann Rheum Dis. 2011;70:968-72. 
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05-Apr-2022 
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Version number: 1 
 
 
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Page 107 
38. Smets EM, Garssen B, Bonke B, De Haes JC. The Multidimensional Fatigue Inventory (MFI) 
psychometric qualities of an instrument to assess fatigue. J Psychosom Res. 1995;39(3):315-
25. 
39. Fisher B, Zeher M, Ng WF, Bombardieri M, Posch M, Papas AS, et al. The Novel Anti-CD40 
Monoclonal Antibody CFZ533 Shows Beneficial Effects in Patients with Primary Sjögren’s 
Syndrome: A Phase IIa Double-Blind, Placebo-Controlled Randomized Trial [abstract]. 
Arthritis Rheumatol. 2017;69(suppl 10). 
40. Shiboski CH, Shiboski SC, Seror R, Criswell LA, Labetoulle M, Lietman TM, et al. 2016 
American College of Rheumatology/European League Against Rheumatism Classification 
Criteria for Primary Sjögren's Syndrome: A Consensus and Data-Driven Methodology 
Involving Three International Patient Cohorts. Arthritis Rheumatol. 2017;69(1):35-45. 
41. Guy W. ECDEU Assessment Manual for Psychopharmacology. Rockville (MD): National 
Institute of Mental Health; 1976. 
42. Szende A, Oppe M, Devlin N, editors. EQ-5D value sets: inventory, comparative review and 
user guide. Springer Netherlands; 2007. 91 p. 
43. Shaw JW, Johnson JA, Coons SJ. US valuation of the EQ-5D health states: development and 
testing of the D1 valuation model. Med Care. 2005;43(3):203-20. 
44. Rischmueller M, Tieu J, Lester S. Primary Sjögren's Syndrome. Best Pract Res Clin 
Rheumatol. 2016;30(1):189-220. 
45. Quan H, Chen X, Lan Y, L Xiaodong, Kubiak R, Bonnet N, et al. Applications of Bayesian 
Analysis to Proof-Of-Concept Trial Planning and Decision Making. Pharm Stat. 2020;1-14.  
 
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