A Phase 2, International, Multicenter, Randomized, Double-blind, Placebo-controlled, Dose-ranging Study of Efficacy and Safety of SAR441566 in Adults With Moderate to Severe Plaque Psoriasis
Phase: PHASE2
Conditions: Psoriasis
Sponsor: Sanofi

 
 
 
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According to Template: Sanofi OneDocument Version 9, dated 08-FEB-2023 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 04 
Protocol title: 
A Phase 2, International, Multicenter, Randomized, Double-
blind, Placebo-controlled, Dose-ranging study of Efficacy 
and Safety of SAR441566 in Adults with Moderate to Severe 
Plaque Psoriasis 
Protocol number: 
DRI17849 
Amendment number: 
04 
Compound number 
(INN/Trademark): 
SAR441566 
Not applicable/Not applicable 
Brief title: 
A study to evaluate efficacy and safety of SAR441566 in 
adults with plaque psoriasis  
Study name: 
SPECIFI-PSO 
Study phase: 
Phase 2 
Sponsor name: 
Sanofi-Aventis Recherche & Développement 
Legal registered address:  
82 Avenue Raspail 
94250 Gentilly 
France 
Monitoring team’s 
representative name and 
contact information 
  
 
Regulatory agency identifier number(s): 
IND: 
166996 
NCT: 
NCT06073119 
WHO: 
U1111-1290-5787 
EUDAMED: 
Not applicable yet 
EU trial number: 
2023-503911-14 
  
  
 
 
Date: 
25-Apr-2024 
Total number of pages: 
127 
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Page 2 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
 
Document 
Country/countries impacted 
by amendment 
Date, version 
Amended Clinical Trial protocol 04 
All 
25-Apr-2024, version 1 (electronic 4.0) 
Amended Clinical Trial protocol 03 
Czech Republic 
04-Dec-2023, version 1 (electronic 3.0) 
Amended Clinical Trial protocol 02 
EU 
22-Nov-2023, version 1 (electronic 2.0) 
Amended Clinical Trial protocol 01 
Japan 
19-Oct-2023, version 1 (electronic 1.0) 
Original Protocol 
Not applicable 
08-Jun-2023, version 1 (electronic 2.0) 
Amended protocol 04 (25 April 2024) 
This amended protocol (amendment 04) is considered to be substantial based on the criteria set 
forth in Article 2(2)(13) of the Regulation of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
This amendment is implemented to unify at a global level (where possible) local country 
amendments made at the request of Health Authorities and to add further clarifications to the 
protocol. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Legal registered address 
The legal registered address of Sanofi-Aventis 
Recherche & Développement has been changed 
to 82 Avenue Raspail, 94250 Gentilly, France. 
From February 1st, 2024, headquarter office 
location for the Sponsor “Sanofi-Aventis 
Recherche & Développement” has moved 
from Chilly-Mazarin to Gentilly, France. 
1.1 Synopsis 
3 Objectives, Endpoints 
and Estimands 
PASI secondary endpoint clarified as "percent 
change from baseline" and not "change from 
baseline" as previously described. 
The intended wording was "percent change", 
the word "percent" was omitted in error. 
 
sPGA secondary timepoint clarified as Week 12 
and not “from baseline to Week 12”. 
sPGA is not a response/change assessment, 
therefore analysis only required at Week 12 
and not in comparison to baseline. 
 
sPGA exploratory timepoint clarified at Week 4 
and 8 and not “from baseline to Week 4 and 8. 
sPGA is not a response/change assessment, 
therefore analysis only required at Week 4 
and 8 and not in comparison to baseline. 
1.3 Schedule of activities 
(SoA) – footnote a 
7.1 IMP Discontinuation 
Clarified the assessments required when 
patients prematurely discontinue treatment. 
Further distinguished between patients who 
The requirement for patients to undergo all 
assessments once withdrawn from treatment 
is deemed not necessary especially with 
regards to assessments directly linked with 
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Section # and Name 
Description of Change 
Brief Rationale 
7.1.1 Permanent 
discontinuation 
withdraw from IMP and those who withdraw from 
the study ie, consent withdrawal.  
the administration of IMP such as PK, bloods 
etc. 
3 Objectives, Endpoints 
and Estimands – Table 2 
9.2.2.2 Main analytical 
approach 
The word "prohibited medication" has been 
replaced by "concomitant medication which could 
have an impact on the efficacy of the IMP " to 
include all possible prohibited, permitted, and 
rescue medications. 
Clarification. 
5.2 Exclusion Criteria 
 
5.2 Exclusion Criteria 
6.9.2 Prohibited 
concomitant medication 
E18: Clarified that the use of 1,25-dihydroxy 
vitamin D3 and analogues is prohibited only 
when administered at high doses with the intent 
to treat psoriasis. Oral intake for the treatment of 
other indications is not restricted.  
Restrictions around the intake of Vitamin D 
was too broad. 
 
j
5.5 Re-testing Laboratory 
Inclusion/Exclusion criteria 
Clarified that only those assessments that did not 
meet eligibility criteria at the initial assessment, 
or were performed earlier than 28 days before 
randomization (outside screening timelines), 
must be repeated at re-screening. Removed the 
restriction of laboratory assessments that can be 
repeated ie, those that are not of explicit 
exclusionary laboratory testing. 
Repeating all screening assessments would 
be an inconvenience for patients and site 
staff and there is no clinical justification to 
support this.  
 
Removed repeated text that required 
consultation with the medical monitor. 
Repetition. 
6.5 Study IMP compliance 
Clarified in the first paragraph that “When 
participants are dosed at the site, the 
Investigator or the designee will provide IMP to 
the participant from a new IMP kit, and not from 
a previous IMP kit”. 
Clarification. 
 
Clarified that participants would be determined 
compliant if they received 80% or more of their 
scheduled IMP during the treatment period. 
Guidance provided to investigators on 
compliance estimations in line with Sanofi 
procedures. 
6.9.3 Permitted 
concomitant therapy 
Clarification of the text for better linguistic 
understanding. 
Clarification of the text. 
7.1.1 Permanent 
discontinuation 
Provided recommended wash out period for 
SAR441566 before starting another treatment.  
Additional guidance given to investigators in 
case they want to start another treatment in 
patients who discontinue SAR441566. 
7.1.3 
 
Clarified that the 
 will 
be used for the assessment of 
l. This is in line with other sections of 
the protocol.  
Aligning text throughout the protocol.  
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Section # and Name 
Description of Change 
Brief Rationale 
7.1.4 Temporary 
discontinuation 
Clarified that temporary IMP discontinuations 
correspond to ≥2 consecutive IMP doses not 
being administered. 
Provide clear guidance to investigators. 
8 Study Assessments and 
Procedures 
Corrected previous wording that allowed the use 
of local laboratory results to determine eligibility 
as long as these fell within protocol required 
timelines. Eligibility should be determined based 
on central laboratory results with specific 
exceptions for TB and pregnancy testing. 
Incorrect process included in error. 
8.4.8 Adverse events of 
special interest 
Removed AESI relating to drug abuse with IMP. 
This was in error copied from the protocol 
template and not applicable to this study and 
IMP. 
Included in error. 
8.8 Biomarkers 
This section of the study protocol stated in error 
that the proteomics blood sample was an 
optional sample. This was not in line with other 
sections of the protocol and ICF, which stated 
that the proteomics sample is mandatory. 
Protocol wording inconsistency. 
9.3 Interim Analysis 
 
EoS is the last visit for these patients. 
10.3.2 Definition of an 
SAE 
Typographical error, for clarification the word 
“intervention” was added to the following 
sentence: “Medical or scientific judgment should 
be exercised by the Investigator 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”. 
Definition error. 
i
10.13.3 Amended protocol 
03 (04 December 2023) 
This section has been added to the protocol 
amendment history. 
Keeping track of previous amendments. 
Throughout 
Minor editorial, typographical error corrections 
and document formatting revisions. 
Minor, therefore, have not been summarized. 
 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 04 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 5 
LIST OF TABLES ......................................................................................................................................... 11 
LIST OF FIGURES ........................................................................................................................................ 11 
LIST OF ABBREVIATIONS .......................................................................................................................... 12 
1 
PROTOCOL SUMMARY ............................................................................................................... 15 
1.1 
SYNOPSIS ..................................................................................................................................... 15 
1.2 
SCHEMA ........................................................................................................................................ 20 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 21 
2 
INTRODUCTION ............................................................................................................................ 26 
2.1 
STUDY RATIONALE...................................................................................................................... 26 
2.2 
BACKGROUND ............................................................................................................................. 26 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 27 
2.3.1 
Risk assessment ............................................................................................................................ 28 
2.3.2 
Benefit assessment ........................................................................................................................ 28 
2.3.3 
Overall benefit/risk conclusion ....................................................................................................... 28 
3 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS ......................................................................... 30 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 32 
3.1.1 
Measurements of disease severity and extension by the clinician ................................................ 32 
3.1.1.1 
Psoriasis Area and Severity Index (PASI) ..................................................................................... 32 
3.1.1.2 
static Psoriasis Global Assessment (sPGA) .................................................................................. 33 
3.1.1.3 
Body Surface Area (BSA) .............................................................................................................. 33 
 
3.1.2 
Appropriateness of patient reported outcome measures ............................................................... 33 
3.1.2.5 
Dermatology Life Quality Index (DLQI) .......................................................................................... 34 
 
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4 
STUDY DESIGN ............................................................................................................................ 35 
4.1 
OVERALL DESIGN ........................................................................................................................ 35 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 35 
4.2.1 
Patient input into design ................................................................................................................. 35 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 35 
4.4 
END-OF-STUDY DEFINITION ...................................................................................................... 37 
5 
STUDY POPULATION .................................................................................................................. 38 
5.1 
INCLUSION CRITERIA .................................................................................................................. 38 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 39 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 44 
5.3.1 
Meals and dietary restrictions ........................................................................................................ 44 
5.3.2 
Fasting, caffeine, alcohol, and tobacco ......................................................................................... 45 
5.3.3 
Activity ............................................................................................................................................ 45 
5.4 
SCREEN FAILURES...................................................................................................................... 45 
5.5 
RE-TESTING: LABORATORY INCLUSION/EXCLUSION CRITERIA .......................................... 46 
5.6 
CRITERIA FOR TEMPORARILY DELAYING 
ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY IMP .................................... 46 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 47 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 47 
6.1.1 
Devices .......................................................................................................................................... 48 
6.2 
PREPARATION, HANDLING, STORAGE, AND ACCOUNTABILITY ........................................... 48 
6.3 
ASSIGNMENT TO STUDY TREATMENT ..................................................................................... 49 
6.4 
BLINDING ...................................................................................................................................... 49 
6.5 
STUDY IMP COMPLIANCE ........................................................................................................... 50 
6.6 
DOSE MODIFICATION .................................................................................................................. 51 
6.7 
CONTINUED ACCESS TO IMP AFTER THE END OF THE STUDY ........................................... 51 
6.8 
TREATMENT OF OVERDOSE ...................................................................................................... 51 
6.9 
PRIOR AND CONCOMITANT THERAPY ..................................................................................... 52 
6.9.1 
Prior Therapy ................................................................................................................................. 52 
6.9.2 
Prohibited concomitant therapy ..................................................................................................... 52 
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6.9.3 
Permitted concomitant therapy ...................................................................................................... 54 
6.9.4 
Rescue medicine ............................................................................................................................ 55 
7 
DISCONTINUATION OF STUDY IMP AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 56 
7.1 
DISCONTINUATION OF STUDY IMP  .......................................................................................... 56 
7.1.1 
Permanent discontinuation ............................................................................................................ 56 
 
7.1.4 
Temporary discontinuation ............................................................................................................. 58 
7.1.5 
Rechallenge ................................................................................................................................... 58 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 58 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 59 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 60 
8.1 
ADMINISTRATIVE AND GENERAL/BASELINE PROCEDURES ................................................. 60 
8.2 
EFFICACY ASSESSMENTS  ........................................................................................................ 61 
8.2.1 
Psoriasis area and severity index (PASI) ...................................................................................... 61 
8.2.2 
static Psoriasis Global Assessment (sPGA) .................................................................................. 62 
8.2.3 
Body surface Area (BSA) ............................................................................................................... 63 
8.2.8 
Dermatology Life Quality Index (DLQI) .......................................................................................... 65 
8.3 
SAFETY ASSESSMENTS  ............................................................................................................ 66 
8.3.1 
Physical examinations ................................................................................................................... 66 
8.3.2 
Vital signs ....................................................................................................................................... 67 
8.3.3 
Electrocardiograms ........................................................................................................................ 67 
8.3.4 
Clinical safety laboratory tests ....................................................................................................... 68 
8.3.5 
Tuberculosis assessment and QuantiFERON® ............................................................................ 68 
8.3.6 
Pregnancy testing .......................................................................................................................... 69 
8.4 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 69 
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8.4.1 
Time period and frequency for collecting AE and SAE information ............................................... 70 
8.4.2 
Method of detecting AEs and SAEs ............................................................................................... 70 
8.4.3 
Follow-up of AEs and SAEs ........................................................................................................... 70 
8.4.4 
Regulatory reporting requirements for SAEs ................................................................................. 70 
8.4.5 
Pregnancy ...................................................................................................................................... 71 
8.4.6 
Cardiovascular and death events .................................................................................................. 71 
8.4.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 71 
8.4.8 
Adverse events of special interest ................................................................................................. 72 
8.4.9 
Medication errors or misuses of medicinal product ....................................................................... 72 
8.4.10 
Guidelines for reporting product complaints .................................................................................. 73 
8.4.11 
Medical device deficiencies ........................................................................................................... 73 
8.5 
PHARMACOKINETICS .................................................................................................................. 73 
8.6 
PHARMACODYNAMICS ............................................................................................................... 74 
8.8 
BIOMARKERS ............................................................................................................................... 74 
8.9 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 75 
8.10 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS ................................................................................................................................. 75 
8.11 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 75 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 77 
9.1 
POPULATIONS FOR ANALYSES ................................................................................................. 77 
9.2 
STATISTICAL ANALYSES ............................................................................................................ 78 
9.2.1 
General considerations .................................................................................................................. 78 
9.2.2 
Primary endpoint analyses ............................................................................................................. 78 
9.2.2.1 
Definition of endpoint ..................................................................................................................... 78 
9.2.2.2 
Main analytical approach ............................................................................................................... 78 
9.2.2.3 
Sensitivity/Supplementary analysis ................................................................................................ 79 
9.2.3 
Secondary endpoints analyses ...................................................................................................... 79 
9.2.4 
Exploratory/Tertiary endpoint(s) analyses ..................................................................................... 79 
9.2.5 
Multiplicity adjustment .................................................................................................................... 80 
9.2.6 
Safety analyses .............................................................................................................................. 80 
9.2.6.1 
Adverse events .............................................................................................................................. 80 
9.2.6.2 
Laboratory variables, vital signs, and electrocardiograms (ECGs) ................................................ 81 
9.2.7 
Other analyses ............................................................................................................................... 81 
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9.3 
INTERIM ANALYSES  ................................................................................................................... 82 
9.4 
SAMPLE SIZE DETERMINATION ................................................................................................. 82 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 83 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 83 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 83 
10.1.2 
Financial disclosure........................................................................................................................ 85 
10.1.3 
Informed consent process .............................................................................................................. 85 
10.1.4 
Data protection ............................................................................................................................... 86 
10.1.5 
Committees structure ..................................................................................................................... 88 
10.1.5.1 Data Monitoring Committee ........................................................................................................... 88 
10.1.6 
Dissemination of clinical study data and results ............................................................................ 89 
10.1.7 
Data quality assurance .................................................................................................................. 89 
10.1.8 
Source documents ......................................................................................................................... 90 
10.1.9 
Study and site start and closure ..................................................................................................... 90 
10.1.10 Publication policy ........................................................................................................................... 91 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 92 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ......................................................................... 93 
10.3.1 
Definition of AE .............................................................................................................................. 93 
10.3.2 
Definition of SAE ............................................................................................................................ 95 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................... 96 
10.3.4 
Reporting of SAEs.......................................................................................................................... 98 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................... 99 
10.4.1 
Definitions ...................................................................................................................................... 99 
10.4.2 
Contraception guidance ................................................................................................................. 99 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS AND STUDY IMP RESTART/RECHALLENGE GUIDELINES ........................ 102 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC/REGION REQUIREMENTS ............................................. 108 
10.7.1 
China ............................................................................................................................................ 108 
10.7.2 
Germany ...................................................................................................................................... 108 
10.7.3 
Japan ........................................................................................................................................... 108 
10.7.4 
Czech Republic ............................................................................................................................ 108 
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10.8 
APPENDIX 8: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................. 109 
10.9 
APPENDIX 9: COLLECTION, STORAGE AND FUTURE USE OF DATA AND HUMAN 
BIOLOGICAL SAMPLES ............................................................................................................. 109 
10.9.1 
Compliance with Member State applicable rules for the collection, storage, and future use 
of human biological samples (Article 7.1h) .................................................................................. 109 
10.9.2 
Compliance with Member State applicable rules for the collection, storage, and future use 
of (personal) data (article 7 (1 d) of EU Regulation 536/2014) .................................................... 109 
10.10.1 Dermatology Life Quality Index (DLQI) ........................................................................................ 110 
10.13 
APPENDIX 13: PROTOCOL AMENDMENT HISTORY .............................................................. 122 
10.13.1 Amended protocol 03 (04 December 2023) ................................................................................. 122 
10.13.2 Amended protocol 02 (22 November 2023) ................................................................................. 122 
10.13.3 Amended protocol 01 (19 October 2023) .................................................................................... 124 
11 
REFERENCES ............................................................................................................................. 126 
 
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LIST OF TABLES  
Table 1 - Objectives and endpoints ............................................................................................................... 30 
Table 2 - Summary of primary estimands for main endpoints ....................................................................... 32 
Table 3 - Study intervention administered ..................................................................................................... 47 
Table 4 - Study arms ..................................................................................................................................... 48 
.................................................................................... 53 
Table 6 - Populations for analyses ................................................................................................................ 77 
Table 7 - Protocol-required laboratory tests .................................................................................................. 92 
 
LIST OF FIGURES  
Figure 1 - Graphical study design. ................................................................................................................ 20 
 
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LIST OF ABBREVIATIONS  
 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
AST: 
aspartate aminotransferase 
AUC: 
area under the curve 
AxMP: 
auxiliary medicinal product 
BCG: 
Bacillus-Calmette-Guérin 
BID: 
bis in die - twice a day 
BMI: 
body mass index 
BSA: 
body surface area 
BUN: 
blood urea nitrogen 
CASP8: 
caspase-8 
CBC: 
complete blood count 
CIOMS: 
Council for International Organizations of Medical Sciences 
Cmax: 
maximum plasma concentration 
CNIL: 
Commission Nationale de l’Informatique et des Libertés 
CPK: 
creatine phosphokinase 
CRP: 
C-reactive protein 
CSICF: 
core study informed consent form 
CYP: 
cytochrome P450 
D1: 
first day of IMP intake, baseline, randomization 
DDI: 
drug-drug interaction 
DLQI: 
dermatology life quality index 
DNA: 
deoxyribonucleic acid 
DTP: 
direct to participant 
ECG: 
electrocardiogram 
eCRF: 
electronic case report form 
EFPIA: 
European Federation of Pharmaceutical Industries and Associations 
EoS: 
end of study 
EoT: 
end of treatment 
ETIP: 
experienced targeted immunotherapy population 
EU: 
European Union 
EUDAMED: 
European database for Medical Devices 
FDA: 
Food and Drug Administration 
FSH: 
follicle stimulating hormone 
GCP: 
Good clinical practice 
GDPR: 
general data protection regulation 
HBcAb: 
hepatitis B core antibody 
HBsAb: 
hepatitis B surface antibody 
HBsAg: 
hepatitis B surface antigen 
HBV: 
hepatitis B virus 
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hCG: 
human chorionic gonadotropin 
HCV: 
hepatitis C virus 
HDL: 
high-density lipoprotein 
HIV: 
human immunodeficiency virus 
hsCRP: 
high-sensitivity C-reactive protein 
IB: 
investigator's brochure 
ICF: 
informed consent form 
ICH: 
International council for harmonization of technical requirements for 
pharmaceuticals for human use 
IDMC: 
Independent data monitoring committee 
IEC: 
Independent Ethics Committee 
IgM: 
immunoglobulin 
IGRA: 
interferon gamma release assay 
IL: 
interleukin 
IM: 
intramuscular 
IMP: 
investigational medicinal product 
IND: 
investigational new drug 
IRB: 
institutional review board 
ITT: 
intent-to-treat 
IUD: 
intrauterine device 
IUS: 
intrauterine hormone-releasing system 
IWRS: 
interactive web response system 
LDL: 
low-density lipoprotein 
LTBI: 
latent tuberculosis infection 
MAD: 
multiple ascending dose 
MCH: 
mean corpuscular hemoglobin 
MCP-mod: 
multiple comparison procedures modelling 
MCV: 
mean corpuscular volume 
mTNFα: 
membrane bound tumor necrosis factor alpha 
MTX: 
methotrexate 
NCT: 
national center for tumor 
NEMO: 
nuclear factor kappa B essential modulator 
NF-κB: 
nuclear factor kappa B 
NMPA: 
National Medical Products Administration 
NRS: 
numeric rating scale 
NTIP: 
naïve targeted immunotherapy population 
PASI: 
psoriasis area and severity index 
PCR: 
polymerase chain reaction 
PCSA: 
potentially clinically significant abnormalities 
PD: 
pharmacodynamics 
 
P-gp: 
P-glycoprotein 
PK: 
pharmacokinetic 
PMDA: 
Pharmaceuticals and Medical Devices Agency 
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POM: 
proof of mechanism 
PRO: 
patient reported outcome 
 
QD: 
quaque die - once a day 
QTLs: 
quality tolerance limits 
RBC: 
red blood cell 
RIPK-1: 
receptor-interacting protein kinase 1 
RNA: 
ribonucleic acid 
SAD: 
single ascending dose 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
sPGA: 
static psoriasis global assessment 
sTNFα: 
soluble tumor necrosis factor alpha 
SUSAR: 
suspected unexpected serious adverse reaction 
t1/2z: 
terminal elimination half-life 
TB: 
tuberculosis 
TE: 
treatment-emergent 
TEAE: 
treatment-emergent adverse event 
TNF: 
tumor necrosis factor 
TNFR1: 
tumor necrosis factor receptor 1 
TNFR2: 
tumor necrosis factor receptor 2 
TNFα: 
tumor necrosis factor alpha 
Tregs: 
regulatory T-cells 
ULN: 
upper limit of normal 
WBC: 
white blood cell 
WHO: 
World health organisation 
Wnumber: 
week followed by the week number from baseline 
WOCBP: 
woman of child-bearing potential 
WONCBP: 
woman of non-child-bearing potential 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: 
 
A Phase 2, International, Multicenter, Randomized, Double-blind, Placebo-controlled, 
Dose-ranging study of Efficacy and Safety of SAR441566 in Adults with Moderate to Severe 
Plaque Psoriasis 
Brief title: 
A study to evaluate efficacy and safety of SAR441566 in adults with plaque psoriasis  
Regulatory agency identifier number(s): 
IND: 
166996 
NCT: 
NCT06073119 
WHO: 
U1111-1290-5787 
EUDAMED: 
Not applicable yet 
EU trial number: 
2023-503911-14 
Rationale: 
Tumor necrosis factor alpha (TNFα) is a cytokine with pleiotropic effects on both pathologic and 
homeostatic processes. In psoriasis, TNFα plays a key role in driving inflammation. 
Consequently, the inhibition of TNFα signaling is a frequently used therapy option in the 
management of psoriasis. 
SAR441566 is a small molecule inhibitor of tumor necrosis factor receptor 1 (TNFR1) signaling, 
by changing the configuration of the soluble TNF alpha (sTNFα) trimer and preventing its 
interaction with TNFR1. SAR441566 binds to the center of sTNFα resulting in an allosteric 
stabilization of a naturally occurring asymmetric form of the sTNFα, which would otherwise be 
transient (1, 2). Using analytical size exclusion, O’Connell et al. (1) demonstrated that this 
asymmetric trimer has an impaired capacity to engage with TNFR1. The authors further 
demonstrated that stabilizing the asymmetric sTNFα trimer, impairs TNFR1 signaling in vitro. In 
contrast to biologic TNF inhibitors, this small molecule appears to preserve signaling through 
TNFR2. TNFR2 signaling contributes to Treg expansion and function; and is crucial for host 
defense against a variety of pathogens. Thus, maintenance of TNFR2 function can potentially 
result in lower infection risks and enhanced immune homeostasis by preserving Treg cells’ 
functionality. 
The doses to be tested in this study were selected according to the assessments of preliminary 
safety, pharmacokinetic and pharmacodynamics of SAR441566 in former single ascending dose 
(SAD, TDU16919) and multiple ascending dose (MAD, TDR16920) studies, and proof of 
mechanism phase 1 study (PDY16918) in mild to moderate Psoriasis participants. In these 
first-in-human studies, SAR441566 demonstrated favorable safety, pharmacokinetic and 
pharmacodynamic characteristics, which supports the advancement of SAR441566 into clinical 
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studies in participants with moderate to severe psoriasis. The aim of this Phase 2 trial is to 
evaluate the efficacy, suitable dose, and safety of SAR441566 in treating plaque psoriasis. 
Two populations of participants are eligible for this study: 
1. Naïve targeted Immunotherapy population (NTIP): Participants naïve to biologics and 
small molecules to treat psoriasis. This population is the primary population for efficacy 
analysis, to demonstrate the superiority of SAR441566 compared to placebo in the NTIP. 
2. Experienced targeted Immunotherapy population (ETIP): Participants who previously 
received targeted immunotherapy for psoriasis. The ETIP is for exploratory purposes only, 
to assess efficacy of SAR441566 compared to placebo in the ETIP. 
Objectives and endpoints: 
 
  
Objectives 
Endpoints 
Primary 
 
• 
To demonstrate the superiority of SAR441566 over 
placebo in participants with moderate to severe 
plaque psoriasis, in the NTIP. 
• 
Proportion of participants with a 75% or greater 
PASI score (Psoriasis Area and Severity Index 
score) improvement (reduction) from baseline 
(PASI75) at Week 12. 
Secondary 
 
• 
To evaluate the efficacy of SAR441566 in plaque 
psoriasis as compared to placebo in the NTIP. 
• 
PASI percent change from baseline to Week 12. 
• 
Proportion of participants with static Psoriasis 
Global Assessment (sPGA) score 0 (complete 
clearance) or 1 (minimal disease) at Week 12. 
• 
To evaluate the safety of SAR441566. 
• 
Incidence of TEAE, SAEs, and AEs of AESIs. 
• 
Incidence of study IMP permanent discontinuations 
and study withdrawals due to TEAEs. 
• 
Participants with medically significant changes in 
vital signs, ECG, and/or laboratory evaluations. 
• 
To assess pharmacokinetics of SAR441566 in 
participants with moderate to severe plaque 
psoriasis. 
• 
Plasma pre-dose and post-dose concentrations of 
SAR441566. 
 
 
 
 
 
For China, see Section 10.7.1 details. 
Overall design synopsis: 
Phase 2, international, multicenter, randomized, double-blind, placebo-controlled, parallel group, 
dose-ranging study of efficacy and safety of SAR441566 in adult participants with moderate to 
severe plaque psoriasis. 
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Summary: 
This is a parallel group, Phase 2, randomized, double-blind, placebo controlled, dose-ranging, 
international, multicenter, 12-week study. It is designed to assess the therapeutic dose, efficacy, 
and safety of treatment with SAR441566 in male and female adults with moderate to severe 
plaque psoriasis. 
Study details include: 
• Screening period (4 weeks and not less than 11 days before Day 1). 
• Treatment period (12 weeks ±3 days). 
• Post-treatment period (safety follow-up) (4 weeks ±3 days). 
• The total number of study visits will be 7. 
Participants who satisfy the inclusion and exclusion criteria will be randomized to either 
SAR441566 or matching placebo, administered orally for 12 weeks. 
Visits during the 12-week treatment period will occur at Week 0 (baseline/randomization), 2, 4, 8, 
and 12 weeks. Followed by a 4-week post-treatment period. 
Number of participants: 
Approximately 207 adult participants who meet the inclusion/exclusion criteria will be 
randomized to either SAR441566 or matching placebo in two different strata, ie, NTIP and ETIP. 
• NTIP: Approximately 144 participants will be randomized to either SAR441566 or 
matching placebo (120 in the five SAR441566 groups and 24 in the placebo group) in this 
stratum. This population is the primary population for efficacy analysis. 
• ETIP: Approximately 63 participants will be randomized to either SAR441566 or 
matching placebo (54 in the three SAR441566 groups and 9 in the placebo group) in this 
stratum. This population is for exploratory purposes only. 
Study arms and duration: 
In the NTIP, there are 6 arms in this stratum with parallel groups of 200 mg BID (n=24), 100 mg 
BID (n=24), 200 mg QD (n=24), 100 mg QD (n=24), 50 mg QD (n=24), or placebo (n=24), at a 
randomization ratio of 1:1:1:1:1:1. Duration of IMP treatment is 12 weeks. (See Figure 1 for 
schema). 
In the ETIP, there are 4 arms in this stratum with parallel groups of 200 mg BID (n=18), 200 mg 
QD (n=18), 100 mg QD (n=18) or placebo (n=9), at a randomization ratio of 2:2:2:1. Duration of 
IMP treatment is 12 weeks. (See Figure 1 for schema). 
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Study interventions 
Investigational medicinal product (IMP) 
SAR441566 
• Formulation: Tablets, 
. 
• Route of administration: oral. 
Matching placebo 
• Formulation: Tablets (indistinguishable from SAR441566 tablets and contain the same 
inactive ingredients as 
, but do not 
contain SAR441566). 
• Route of administration: oral. 
SAR441566 and Placebo dose regimen: 
 
SAR441566 or placebo can be given with or without food. 
Post-trial access to study medication: No post-trial access is planned for this study. 
Study duration 
• Screening period (up to 4 weeks and no less than 11 days). 
• Treatment period (12 weeks ±3 days). 
• Post-treatment period (safety follow-up) (4 weeks ±3 days). 
Statistical considerations: 
• Primary endpoint: 
- 
The proportion of participants with PASI75 response at Week 12 in the NTIP. 
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The primary endpoint analysis will be the comparison between SAR441566 treatment groups and 
placebo in the proportion of participants with PASI75 response at Week 12, using a 
Cochran-Mantel-Haenszel test, in the NTIP. To control the overall Type I error of 0.05, 
multiplicity adjustment will be made among SAR441566 three doses (200 mg BID, 100 mg BID, 
200 mg QD) comparing to placebo. 
• Main secondary endpoints: 
- 
Percent change from baseline in PASI score at Week 12 in the NTIP. 
- 
Proportion of participants with sPGA score of 0 or 1 at Week 12 in the NTIP. 
Categorical secondary endpoint will be analyzed using a Cochran-Mantel-Haenszel test in NTIP. 
Continuous secondary endpoint will be analyzed by fitting an Analysis of Covariance model with 
the baseline covariates in NTIP. No multiplicity adjustment for the secondary efficacy endpoints 
will be made. 
Data Monitoring committee: Yes 
An Independent Data Monitoring Committee (IDMC) has been appointed for this study. The 
IDMC is a group of independent scientists and physicians who are appointed to monitor the safety 
throughout the study and the scientific integrity of the study IMP. During the double-blind 
treatment period, the unblinded safety data will be reviewed by the IDMC. The IDMC will 
provide recommendations to the Sponsor regarding the study conduct to ensure the protection and 
the safety of the participants. The composition of the committee is dependent upon the scientific 
skills and knowledge required for monitoring the study. The IDMC specific roles and interaction 
with the Sponsor will be described in the IDMC charter. 
 
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1.2 
SCHEMA  
Figure 1 - Graphical study design.  
 
 
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1.3 
 SCHEDULE OF ACTIVITIES (SoA)  
 
Procedurea 
Screening period 
(up to 4 weeks and 
not less than 
11 days before 
Day 1)b 
Treatment period 
(12 weeks)c  
Post-treatment 
period (4 weeks 
after last dose IMP) 
Baseline/ 
randomization 
 
 
 
End of 
Treatment (EoT) 
End of Study (EoS) 
VISIT 
1 
2 
3 
4 
5 
6 
7 
DAY 
-28 to -11 
1 
15(±3) 
29(±3) 
57(±3) 
85(±3) 
113(±3) 
WEEK 
-4 to -1.5 
0 
2 
4 
8 
12 
16 
Participant Eligibility 
Informed consent 
X 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
Xd 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Height and weight measurements 
X 
 
 
 
 
 
 
Complete physical examinatione 
X 
 
 
 
 
 
 
Medical historyf 
X 
 
 
 
 
 
 
Psoriasis historyg 
X 
 
 
 
 
 
 
Current medical conditions 
X 
 
 
 
 
 
 
Highly sensitive pregnancy test (urine or serum) as per local regulations 
(WOCBP only) 
X 
 
 
 
 
 
 
FSH (only when applicable to confirm post-menopausal status) 
X 
 
 
 
 
 
 
Tuberculosis assessment and QuantiFERON®h 
X 
 
 
 
 
 
 
HIV, Hepatitis B and C screeningi 
X 
 
 
 
 
 
 
Vital Signsj 
X 
X 
X 
X 
X 
X 
X 
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Procedurea 
Screening period 
(up to 4 weeks and 
not less than 
11 days before 
Day 1)b 
Treatment period 
(12 weeks)c  
Post-treatment 
period (4 weeks 
after last dose IMP) 
Baseline/ 
randomization 
 
 
End of 
Treatment (EoT) 
End of Study (EoS) 
VISIT 
1 
2 
3 
4 
5 
6 
7 
DAY 
-28 to -11 
1 
15(±3) 
29(±3) 
57(±3) 
85(±3) 
113(±3) 
WEEK 
-4 to -1.5 
0 
2 
4 
8 
12 
16 
Treatmentk 
Targeted physical examinatione 
 
X 
X 
X 
X 
X 
 
Randomization  
 
X 
 
 
 
 
 
Contact Interactive Web Response Systems (IWRS) 
X 
X 
X 
X 
X 
X 
X 
IMP intakec 
 
X 
X 
X 
X 
X 
 
IMP dispensed for home administrationl 
 
X 
X 
X 
X 
 
 
IMP compliance checkm 
 
 
X 
X 
X 
X 
 
Medication Intake Questionnaire (paper)n 
 
===================================→ 
 
Clinical Assessmentso 
Psoriasis Area and Severity Index (PASI) 
X 
X 
 
X 
X 
X 
 
static Psoriasis Global Assessment (sPGA) 
X 
X 
 
X 
X 
X 
 
 
Body Surface Area (BSA) assessmentp 
X 
X 
 
X 
X 
X 
 
 
Patient Reported Outcome Measures (Questionnaires)q 
DLQI questionnaire 
 
X 
 
 
 
X 
 
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Procedurea 
Screening period 
(up to 4 weeks and 
not less than 
11 days before 
Day 1)b 
Treatment period 
(12 weeks)c  
Post-treatment 
period (4 weeks 
after last dose IMP) 
Baseline/ 
randomization 
 
 
End of 
Treatment (EoT) 
End of Study (EoS) 
VISIT 
1 
2 
3 
4 
5 
6 
7 
DAY 
-28 to -11 
1 
15(±3) 
29(±3) 
57(±3) 
85(±3) 
113(±3) 
WEEK 
-4 to -1.5 
0 
2 
4 
8 
12 
16 
Screening & Diagnostic tests  
Urine pregnancy test (WOCBP only)t 
 
X 
 
X 
X 
X 
X 
12-lead Triplicate ECGu 
X 
X 
X 
X 
X 
X 
X 
Laboratory tests (include hematology- CBC with differential and liver 
chemistries- complete metabolic panel)v 
X 
X 
X 
X 
X 
X 
X 
Fasting lipids panelw 
 
X 
 
X 
 
X 
 
Pharmacodynamics 
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Procedurea 
Screening period 
(up to 4 weeks and 
not less than 
11 days before 
Day 1)b 
Treatment period 
(12 weeks)c  
Post-treatment 
period (4 weeks 
after last dose IMP) 
Baseline/ 
randomization 
 
 
End of 
Treatment (EoT) 
End of Study (EoS) 
VISIT 
1 
2 
3 
4 
5 
6 
7 
DAY 
-28 to -11 
1 
15(±3) 
29(±3) 
57(±3) 
85(±3) 
113(±3) 
WEEK 
-4 to -1.5 
0 
2 
4 
8 
12 
16 
Pharmacokinetic (PK) Assessments 
SAR441566 PK 
 
Xy 
Xz 
Xaa 
Xz 
Xaa 
 
Safety 
AE, SAE, TEAE and AESI review 
================================================================================→ 
Concomitant medication review 
================================================================================→ 
a Participants who discontinue IMP treatment prior to completing the 12-week treatment period should be assessed as per the EoT visit at the earliest opportunity and no later than 7 days from the last dose of IMP. 
After the EoT visit: (a) Participants who accept to stay on study without IMP intake: all remaining visits described in the SoA should be performed until the EoS, but only clinical assessments, AE and concomitant 
medication review and patient reported outcomes should be carried out at the study visits. (b) Participants who withdraw consent from the study: should have an EoS visit 4 weeks after their last dose of IMP. 
b The screening period may be extended to 6 weeks (+/- 3 days) if participants are awaiting consultation with a specialist to rule out or treat active TB infection, or approval from Sponsor, according to E 30. 
c The morning IMP at visit days should be taken on site. 
d Prior to randomization. 
e The complete physical examination will consist of evaluation of the following systems: general, head, eyes, ears, nose, throat, neck, cardiovascular, lungs, abdominal, extremities, neurologic, psychiatric, skin, and 
musculoskeletal. The targeted physical exam will consist of evaluation of the following systems: general, eyes, throat, cardiovascular, lungs, abdominal, extremities, and skin, musculoskeletal. Complete and 
targeted physical examinations may be performed by a Doctor of Medicine, Doctor of Osteopathy, Physician’s Assistant, or a Nurse Practitioner. A targeted physical examination may note any changes in the 
participant’s condition since the last assessment and does not preclude examination of any of the body systems as clinically indicated. 
f 
Including but not limited to personal or family history of long QT syndrome, vaccination history, alcohol, nicotine, and current and past 2 years history of drug usage. 
g Include date of psoriasis’s symptoms onset, date of psoriasis diagnosis, history of prior therapies used to treat psoriasis (medication generic name, doses, clinical efficacy response [responder or no-responder], 
reason for discontinuation [side effects, lack of clinical efficacy, medication interaction with other concomitant therapy, remission/lack of symptoms, and other], and length of the therapy), current treatments, and 
history of psoriasis in the family. 
h For TB assessment refer to exclusion criteria E 30. 
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i 
HIV, Hepatitis B and C screening: HIV-1 and HIV-2 antibodies, Hepatitis B surface antigen (HBsAg), IgM Hepatitis B core antibody (HBcAb), total HBcAb, total Hepatitis C antibodies (HCVAb). In case of results 
showing HBcAb positivity, HBV-DNA testing must be performed and confirmed negative prior to randomization. In case of HCVAb positivity, HCV-RNA testing must be performed and confirmed negative before 
randomization. For Japan, HBsAb needs to be tested in addition to HBsAg and (IgM or total) HBcAb - see Section 10.7.3. 
j 
Vital signs include body temperature (°C), heart rate (beats per minute), and systolic and diastolic blood pressure (mm Hg). 
k When several assessments take place at the same visit, the following order is recommended: Patient Reported Outcome Measures (Questionnaires), Triplicate ECG (after 10min of rest), Blood sampling, Urine 
test (when applicable), IMP administration, Vital signs, Physical examination, Clinical assessments, IMP compliance check, verification of the Medication Intake Questionnaire (paper), Prior and concomitant 
medications, AE reporting, IMP dispensed for home administration. And during Post-IMP PK blood sampling visits, conclude with Triplicate ECG (after 10min of rest and within 15min prior to PK blood sampling), 
followed by PK blood sampling. 
l 
Dispensed with Medication Intake Questionnaire (paper). 
m Compliance will be assessed by the investigator by direct questioning, verifying the Medication Intake Questionnaire (paper), and counting returned tablets in each pack during the site visits and documented in the 
source documents and relevant form. Deviations from the prescribed dosage regimen must be recorded. 
n Questionnaire provided to the trial participant on D1 and at each visit, then returned by the participant at each visit and checked by the investigator to verify the IMP intake and potential adverse events. 
o Clinical assessments should be completed by the same physician for a given participant, if possible, to secure longitudinal comparison and avoid any bias. 
p BSA will be extracted from PASI assessment (Section 8.2.3). 
i
 
s Refer to Section 5.3.2 for further details. 
t 
Refer to Section 8.3.6 – Pregnancy testing for instruction on timepoints. 
i
v Hematology: RBC, RBC indices, hemoglobin, hematocrit, thrombocyte count (platelets), leukocyte count (white blood cell count) with differential in absolute counts (including neutrophils, eosinophils, basophils, 
lymphocytes (including CD4 count), monocytes). 
Clinical chemistry: Sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine, creatinine clearance, CPK, calcium, phosphate, total protein, albumin, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin, conjugated bilirubin, unconjugated bilirubin, glucose (non-fasting). 
w Fasting total cholesterol, fasting triglycerides, HDL, and LDL. Participant must be fasting for 8 hours prior to laboratory testing (may consume water). A light meal will be provided by the site after the laboratory 
tests, lipids panel and pre-dose-PK. 
 
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2 
INTRODUCTION  
SAR441566 is a small molecule that binds to a pocket in the center of the soluble TNFα trimer, 
resulting in allosteric stabilization of a naturally occurring asymmetric form of sTNFα that is 
naturally a transient intermediate. This asymmetric trimer has an impaired capacity to engage 
TNFR1 and therefore TNFR1 signaling is impaired. In contrast to biologic TNF inhibitors, this 
small molecule appears to preserve signaling through TNFR2, which might decrease infectious 
risks associated with biologic TNF inhibitors. In psoriasis, TNFα plays a key role in driving 
inflammation. Consequently, TNFα inhibitors, are currently a frequently used therapy option in 
the management of psoriasis. 
2.1 
STUDY RATIONALE  
The aim of this Phase 2 trial is to evaluate the safety and efficacy of SAR441566 in treating 
moderate to severe plaque psoriasis. The doses to be tested in this study are selected according to 
the assessments of preliminary safety, pharmacokinetic (PK), and pharmacodynamics (PD) of 
SAR441566 in previous single ascending dose (SAD, TDU16919) and multiple ascending dose 
(MAD, TDR16920) studies. In the proof-of-mechanism study (PDY16918), repeated 
administration of 200 mg BID SAR441566 over 28 days was safe and well-tolerated by 
participants with mild to moderate psoriasis. In first-in-human studies, SAR441566 demonstrated 
favorable safety and PK characteristics which supports the advancement of SAR441566 into 
clinical studies in participants with moderate to severe plaque psoriasis. Furthermore, psoriasis 
remains a chronic disease requiring novel therapeutic options that are efficacious, reliable, safe, 
and that can be administered orally. 
2.2 
BACKGROUND  
TNFα is a cytokine with pleiotropic effects on both pathologic and homeostatic processes. TNFα 
plays a key pathophysiological role in psoriasis (3). Consequently, biological TNFα inhibitors are 
often successfully used and approved to treat psoriasis. 
TNFα is a member of the TNF superfamily of cytokines. It is produced by a variety of cell types, 
most notably, T cells. It is initially expressed as a transmembrane protein, also known as 
membrane bound TNFα (mTNFα). At the cell surface, mTNFα may undergo cleavage by a 
TNFα-converting enzyme to generate sTNFα. Structurally, both mTNFα and sTNFα exist as 
homotrimers which can bind 3 cognate receptors. This trimeric engagement is critical for receptor 
multimerization and subsequent signal transduction. sTNFα mainly signals via TNFR1, which is 
expressed on most cell types. In contrast, mTNFα mainly uses TNFR2 for signaling. TNFR2 is 
expressed primarily on neurons, endothelial cells, and immune cells, with enrichment on certain 
subpopulations of regulatory T-cells (Tregs). 
Functionally, sTNFα and mTNFα play different roles in pathologic and homeostatic processes. 
sTNFα engagement of TNFR1 leads to activation of pro-inflammatory and pro-apoptotic 
pathways that play pivotal roles in the effect of TNFα in certain autoimmune conditions. In 
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contrast, mTNFα signaling contributes to a variety of homeostatic functions, including tissue 
regeneration and cell survival. From an inflammatory standpoint, mTNFα has been shown to 
enhance function and proliferation of specific subsets of suppressive Tregs. TNFR2 agonism has 
also been shown to promote death of autoreactive CD8+ T-cells. Of note, mTNFα mice, which 
express only a non-cleavable form of TNFα, have been generated to study the specific effects of 
mTNFα. In respiratory tuberculosis infection models, multiple studies have demonstrated reduced 
mortality and bacterial burden in mTNFα mice compared with TNFα knockout mice. Similar 
results have been demonstrated in Listeria monocytogenes, Mycobacterium bovis bacilli 
Calmette-Guérin, and Leishmania major murine infection models (4, 5). 
SAR441566 is a small molecule that binds to a pocket in the center of the sTNFα trimer. This 
results in allosteric stabilization of a naturally occurring, asymmetric form of sTNFα that is 
normally a transient intermediate. Using analytical size exclusion, O’Connell et al. (2019) (1) 
demonstrated that this asymmetric trimer has an impaired capacity to engage TNFR1. They 
further demonstrated that UCB-9260, a related molecule to SAR441566, impairs TNFR1 
signaling in vitro. Jurkat cells were treated with sTNFα, sTNFα pre-incubated with UCB-9260, or 
sTNFα preincubated with etanercept. TNFR1 signaling, as measured by Western Blot analysis of 
kinases receptor-interacting protein kinase 1 (RIPK-1) ubiquitination and nuclear factor kappa B 
(NF-κB) phosphorylation, was impaired in both the etanercept- and UCB-9260-treated samples as 
compared with the samples treated with sTNFα alone. Nonclinical studies have demonstrated that 
targeting of sTNFα with SAR441566 is effective in reducing disease severity in murine model of 
inflammatory arthritis (2). 
Psoriasis is a T cell-mediated disease with autoimmune properties modulated by genetic 
susceptibility and environmental triggers. Inflammatory pathways characterized by excessive 
production of the cytokines Interleukin (IL)-12 and IL-23 promote the differentiation of 
pathogenic T cell responses, resulting in TNF and IL-17 production. These cytokines are an 
integral part of the TNF/IL-23/IL-17 axis involved in maintaining inflammation in psoriatic skin 
(6). 
In summary, it has been shown that TNFR1 and TNFR2 signaling have differential impacts on the 
immune system. TNFR1 contributes to acute inflammation, whereas TNFR2 plays roles in 
homeostasis, Treg expansion and function, and host defense against a variety of pathogens. 
Nonclinical studies have demonstrated that specific targeting of TNFR1 is effective in reducing 
disease severity in a murine model of inflammatory arthritis. The evidence supports the 
advancement of SAR441566, an inhibitor of TNFR1 signaling, into clinical studies for further 
treatment of psoriasis and SAR441566 is expected to reduce the side effects compared with the 
other TNF inhibitors. 
2.3 
BENEFIT/RISK ASSESSMENT  
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of SAR441566 may be found in the Investigator’s brochure (IB). 
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2.3.1 Risk assessment  
. In completed Phase 1 
clinical studies (up to 600 mg single dose or 300 mg BID), there were four AESI of ALT 
elevation observed in the MAD study (Grade 1 in 3 participants at the dose level 100 mg QD and 
Grade 2 in one participant at the highest dose, 300 mg BID) and no AESI regarding QTc 
prolongation. However, 
In the clinical study with 
 is used as concomitant medication. Importantly in additional 
completed Phase 1 studies, INT17671 exploring DDI with a 
, there were no safety concerns reported throughout the studies. 
The PDY16918 study (200 mg BID for 28 days) in mild to moderate 
psoriasis is completed and there were no safety concerns. 
Based on the class effect of anti-TNF biologics, the following potential risks are considered: 
increased risk of serious infections leading to hospitalization and death, increased risk of serious 
infections including reactivation of tuberculosis (TB), bacterial sepsis, invasive fungal infections, 
malignancies, hepatitis B virus reactivation, demyelinating disease (exacerbation, or new onset), 
cytopenia, pancytopenia, heart failure (worsening or new onset), and lupus-like syndrome. 
2.3.2 Benefit assessment  
The administration of SAR441566 is expected to prevent sTNF from activating TNFR1, which is 
assumed to be a key pathway of inflammation in plaque psoriasis. Accordingly, SAR441566 
could provide to participants a reduction (improvement) of signs and symptoms of plaque 
psoriasis similar to current biological TNF inhibitors without any development of Anti-drug 
antibodies. In the proof-of-mechanism study (PDY16918), repeated administration of 200 mg 
BID SAR441566 over 28 days was safe and well-tolerated by participants with mild to moderate 
psoriasis. Furthermore, participants may benefit from having regular clinical and laboratory 
evaluations throughout the study. 
2.3.3 Overall benefit/risk conclusion  
SAR441566 is a small molecule inhibitor of TNFR1 signaling. It has been shown that TNFR1 and 
TNFR2 have differential impacts on the immune system. TNFR1 contributes to acute 
inflammation, whereas TNFR2 plays roles in homeostasis, Treg expansion and function, and host 
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defense against a variety of pathogens. Nonclinical studies have demonstrated that specific 
targeting of sTNFα, and therefore inhibition of TNFR1 is effective in reducing disease severity in 
a murine model of inflammatory arthritis (2). In addition, sTNFα occupancy levels as PD markers 
were in the range of 100% at all dose levels in MAD studies. 
SAR441566 was generally well tolerated with a good safety profile in clinical studies performed 
to date. Based on the clinical First-in-human TDU16919-SAD, TDR16920 -MAD and INT17025 
, INT17671 
 and 
BDR17662, in healthy participants and proof of mechanism phase 1 study (PDY16918) in 
participants with mild to moderate psoriasis, there are no identified safety concerns to date. 
To date, there are no identified risks for SAR441566, and appropriate risk mitigation strategies are 
in place for well-defined potential risks associated with SAR441566. These risk mitigation 
strategies include close monitoring of participants and monitoring for the emergence of any 
undesirable clinical signs or biologic effects. The available nonclinical and clinical data support 
further clinical development of SAR441566. 
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3 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS  
Table 1 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
 
• 
To demonstrate the superiority of SAR441566 over 
placebo in participants with moderate to severe 
plaque psoriasis, in the NTIP. 
• 
Proportion of participants with a 75% or greater 
PASI score (Psoriasis Area and Severity Index 
score) improvement (reduction) from baseline 
(PASI75) at Week 12. 
Secondary 
 
• 
To evaluate the efficacy of SAR441566 in plaque 
psoriasis as compared to placebo in the NTIP. 
• 
PASI percent change from baseline to Week 12. 
• 
Proportion of participants with static Psoriasis 
Global Assessment (sPGA) score 0 (complete 
clearance) or 1 (minimal disease) at Week 12. 
• 
To evaluate the safety of SAR441566. 
• 
Incidence of TEAE, SAEs, and AEs of AESIs. 
• 
Incidence of study IMP permanent discontinuations 
and study withdrawals due to TEAEs. 
• 
Participants with medically significant changes in 
vital signs, ECG, and/or laboratory evaluations. 
• 
To assess pharmacokinetics of SAR441566 in 
participants with moderate to severe plaque 
psoriasis. 
• 
Plasma pre-dose and post-dose concentrations of 
SAR441566. 
Exploratory/Tertiary 
 
• 
To evaluate the efficacy of SAR441566 in plaque 
psoriasis as compared to placebo change over time. 
• 
PASI change from baseline to Week 4 and 8. 
• 
 
• 
The proportion of participants with a 90% or greater 
PASI reduction from baseline (PASI90) at Week 4, 
8 and 12. 
• 
 
• 
The proportion of participants with PASI75 at 
Week 4, and 8. 
• 
 
• 
 
• 
• 
• 
 
• 
Proportion of participants with sPGA score of clear 
or almost clear (0 or 1) at Week 4, and 8. 
• 
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Objectives 
Endpoints 
• 
To characterize the pharmacodynamic profile of 
SAR441566 in participants with plaque psoriasis. 
• 
Change in peripheral blood soluble biomarkers 
(including but not limited to hsCRP, IL-17A, IL-17F, 
IL-22, IL-19) from baseline to Week 4 and 12. 
i
 
• 
To evaluate the impact of SAR441566 on health-
related quality of life. 
• 
Change in Dermatology Life Quality Index (DLQI) 
from baseline to Week 12. 
 
 
For China, see Section 10.7.1 for details. 
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Primary estimands defined for primary endpoint are summarized in Table 2 below. More details 
are provided in Section 9.2. 
For all these estimands, the comparison of interest will be the comparison of SAR441566 vs. 
placebo. 
Table 2 - Summary of primary estimands for main endpoints  
Endpoint 
Estimands 
Category 
(estimand) 
Endpoint 
Population 
Intercurrent event(s) 
handling strategy 
Population-level 
summary  
(Analysis and missing 
data handling) 
Primary objective: To demonstrate the superiority of SAR441566 over placebo in NTIP with moderate to severe plaque 
psoriasis. 
Primary endpoint 
(treatment policy/ 
composite 
estimand). 
Proportion of 
participants with 
PASI75 
response at 
Week 12. 
NTIP 
Initiation of selected concomitant 
medication which could have an 
impact on the efficacy of the IMP: It 
will be handled with the composite 
strategy, ie, participants will be 
considered as non-responders after 
such event. 
Difference in the percentage 
of participants achieving 
PASI75 response at Week 12 
between each active arm and 
placebo, using the Cochran-
Mantel-Haenszel test.  
 
 
 
Discontinuation of IMP: It will be 
handled with the treatment policy 
strategy. The primary endpoint will 
be assessed based on all 
assessments irrespective of the 
IMP discontinuation. 
Missing data will be imputed 
to non-responders when the 
response to PASI75 is 
missing. 
 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
3.1.1 Measurements of disease severity and extension by the clinician  
PASI, sPGA and BSA have been the corner stone of drug evaluation and approval by health 
authorities in Psoriasis over the last ten years. 
3.1.1.1 Psoriasis Area and Severity Index (PASI)  
PASI represents a composite score of a variety of physical signs of psoriasis and their extension. 
PASI is currently the most often cited instrument of this type. It is recommended by the Guideline 
on Clinical Investigation of Products Indicated for the Treatment of Psoriasis 
(CHMP/EWP/2454/02). PASI is calculated using a formula for rating the skin surface area 
involved with psoriasis and the degree of erythema, desquamation, and induration of the psoriatic 
plaques. PASI was developed more than 40 years ago, and it has been largely used and validated 
to measure the severity and progression of plaque psoriasis (7). 
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3.1.1.2 static Psoriasis Global Assessment (sPGA)  
sPGA of psoriasis severity is used as a global static assessment of all lesions on 6- or 7-point scale 
(from severe to none); it gives a general impression of severity or improvement of psoriasis on 
treatment. It is part of the instruments recommended in the Guideline on Clinical Investigation of 
Products Indicated for the Treatment of Psoriasis (CHMP/EWP/2454/02). 
3.1.1.3 Body Surface Area (BSA)  
BSA is the most common measurement of efficacy used in clinical trials to support the approval 
of psoriasis drugs. The strengths of this metric are its ease of use, familiarity for physician and 
patient, and the low variability of test-retest statistics by the same observer. 
3.1.2 Appropriateness of patient reported outcome measures  
 
 
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3.1.2.5 Dermatology Life Quality Index (DLQI)  
The impact of the disease on patient’s quality of life will be assessed with the DLQI, which is a 
validated and widely used PRO in patients with dermatologic diseases. The instrument has good 
evidence of content validity and psychometric properties supporting its reliability, construct 
validity and responsiveness (11, 12). It has been widely recommended for inclusion as an 
endpoint in all psoriasis clinical trials in which Health-Related Quality of Life of patients is a 
relevant outcome. The DLQI data generated from this phase II study provides the opportunity to 
further validate the PSSD. 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
The DRI17849 study is a phase 2, international, multicenter, randomized, double-blind, placebo-
controlled, 6-arm dose-ranging study of efficacy and safety of SAR441566 in adult participants 
with moderate to severe plaque psoriasis. 
The objectives are to demonstrate that SAR441566, a small molecule specific inhibitor of TNFR1 
signaling, is effective and safe in the treatment of plaque psoriasis, and to define the best 
dose/dosage regimen for further development. 
Two populations of participants are eligible for this study: 
1. Naïve targeted Immunotherapy population (NTIP): Participants naïve to biologics and 
small molecules to treat psoriasis (refer to E 15). 
2. Experienced Targeted Immunotherapy population (ETIP): Participants who previously 
received targeted immunotherapy for psoriasis (refer to E 16 and E 19). 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
4.2.1 Patient input into design  
The preliminary abbreviated protocol was presented and discussed during 90 minutes to a panel of 
4 psoriasis patients (2 male, 2 female, age 24-60yo) from the Netherlands. They recommended to 
remove the 
. 
They recommended patient convenient organization such as light meals and working places 
during waiting times in the visits, which will be implemented where feasible. 
4.3 
JUSTIFICATION FOR DOSE  
SAR441566 has been well tolerated by all participants with an acceptable safety profile in 
First-in-human studies in healthy participants over the range of 5 to 600 mg single dose and 
repeated doses of 100 to 600 mg total daily (100 mg QD, 100/200/300 mg BID) administered over 
14 days. There were no safety concerns (SAEs or severe TEAEs) throughout additional studies in 
healthy participants: 
• Interaction study (INT17025) with a single dose of
 SAR441566 alone or 
co-administered with 
. 
• Interaction study (INT17671) with a single dose and repeated once daily doses of 
SAR441566 over 13 days, co-administered with a single dose of
). 
• Relative bioavailability study (BDR17662) comparing 
at a 
single dose of
 SAR441566. 
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In the proof-of-mechanism study (PDY16918), repeated administration of 200 mg BID 
SAR441566 over 28 days was safe and well-tolerated by participants with mild to moderate 
psoriasis. 
It is anticipated that up to a dose of 200 mg BID, SAR441566 can be co-administered 
 with negligible risk of clinically relevant increase in 
SAR441566 systemic exposure with the following rationale: 
• 
• There was an approximately 2-fold difference between the SAR441566 exposure observed 
at 200 mg BID as compared to 300 mg BID in the MAD study (TDR16920). 
• Repeated oral administration of 300 mg BID over 14 days has been well tolerated by 
healthy participants. 
Overall, SAR441566 showed consistent PK and PD characteristics which support advancement 
into further clinical studies in participants. Both QD and BID dosing without regard to food are 
deemed feasible considering SAR441566 t1/2z of approximately 20 to 30 hours, negligible food 
effect at 200 mg single dose. High target occupancy was observed across the investigated dose 
levels in the MAD study (100 mg QD, 100/200/300 mg BID). The published estimates of TNFα 
occupancy indicate >98% for marketed TNFα inhibiting biologics (13) at average steady state 
concentration of efficacious dose. The mean TNFα occupancy measured on Day 14 was ~95% for 
100 mg QD and at pre-dose (trough level) and ~100% for all other time points assessed across the 
investigated dose range, ie, at 3 hours post-dose (~Cmax) for 100 mg QD, at pre-dose and 3 hours 
post-dose for 100 mg, 200 mg and 300 mg BID, respectively, which is in line with the exposure-
occupancy relationship established by in vitro studies (see also IB Section 5.1.2.4). These results 
suggest that 100 mg to 400 mg total daily doses can be considered potential therapeutically 
relevant doses. 50 mg QD is considered a sub-therapeutic dose based on the target occupancy 
results of doses >100 mg. 
In the POM study (PDY16918) in participants with mild to moderate psoriasis, serum IL-17A, 
IL-17F and IL-22 levels markedly declined following 4-week treatment of 200 mg BID 
SAR441566, in contrast to placebo. Notably, the biomarker decreases were in line with the 
observed clinical improvement in TLS score of 17.7% with 90% CI [4.98 to 30.49] at Week 4 
compared to placebo. The adjusted mean % improvement of 19.4% with 90% CI [6.28 to 32.48] 
in PASI at Week 4 was consistent with the clinically relevant improvement in the TLS score. The 
results obtained in the proof-of-mechanism study support the initiation of Phase 2 dose ranging 
studies as part of the further clinical development of SAR441566. 
In summary, the dose levels selected for the current study are expected to be safe and, based on 
the target occupancy data from the MAD study, as well as the efficacy and biomarker outcomes 
from the proof-of-mechanism study, to span a range of potential therapeutically relevant as well 
as subtherapeutic doses which will allow to explore the dose-response relationship and the 
determination of the optimal therapeutic dose for future large-scale studies. 
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4.4 
END-OF-STUDY DEFINITION  
The end of the study is defined as the date of the last scheduled visit at the end of the 4-week 
post-treatment period (safety follow-up), as shown in the schedule of activities. 
A participant is considered to have completed the study if the participant has completed all 
periods of the study including the last visit. 
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5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA  
Participants are eligible to be included in the study only if all the following criteria apply: 
Age 
I 01. At least 18 years old [or the legal age of consent in the jurisdiction in which the study is 
taking place] to 75 years of age inclusive, at the time of signing the informed consent. 
Type of participant and disease characteristics 
I 02. Participants with moderate to severe plaque psoriasis for at least 6 months, meeting the 
following criteria at screening and D1 (prior to randomization): 
a) PASI ≥12 points; and 
b) sPGA score ≥3 points; and 
c) BSA score ≥10%. 
I 03. Must be a candidate for phototherapy or systemic therapy. 
Weight 
I 04. Total body weight >=50 kg (110 lb) and body mass index (BMI) within the range 
[18 - 35] kg/m2 (inclusive). 
Sex, contraceptive/barrier method and pregnancy testing requirements/breastfeeding 
I 05. All contraceptive methods used by men and women should be consistent with local 
regulations regarding the methods of contraception for those participating in clinical 
studies. 
a) Male participants 
Male participants are eligible to participate if they agree to the following during the 
study treatment period and for at least 3 months after the last administration of study 
IMP: 
- 
Refrain from donating or cryopreserving sperm; 
PLUS, either: 
- 
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent; 
OR 
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- 
Must agree to use contraception as detailed below: 
A male condom and an additional highly effective contraceptive method 
(as described in Section 10.4), when having sexual intercourse with a woman 
of child-bearing potential (WOCBP) who is not currently pregnant. 
b) Female participants 
- 
A female participant is eligible to participate if she is not pregnant or 
breastfeeding, and one of the following conditions applies: 
- Is a woman of non-child-bearing potential as defined in the Section 10.4; 
OR 
- Is a WOCBP and agrees to use a contraceptive method that is highly effective 
(with a failure rate of <1% per year), preferably with low user dependency 
(as described in Section 10.4) during the study intervention period (to be 
effective before starting IMP) and for at least 3 months after the last 
administration of study IMP and agrees not to donate or cryopreserve eggs (ova, 
oocytes) for the purpose of reproduction during this period. 
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) at screening and a negative urine pregnancy test before 
the first administration of study IMP. 
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive. 
Informed Consent 
I 06. Capable of giving signed informed consent as described in Section 10.1.3 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 
(see Section 10.7). 
Other inclusion criteria 
 
5.2 
EXCLUSION CRITERIA  
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Other forms of psoriasis than plaque psoriasis, such as guttate psoriasis, psoriatic arthritis, 
or pustular psoriasis. Nail psoriasis is accepted for inclusion. 
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E 02. Plaque psoriasis is restricted to scalp, palms, soles, or flexures only. 
E 03. Any other skin diseases that can interfere with psoriasis evaluation or treatment response 
(eg, atopic dermatitis, fungal or bacterial superinfection). 
E 04. Other immunologic (autoimmune or inflammatory) disorder, except medically controlled 
diabetes or thyroid disorder as per Investigator's judgement. 
E 05. History of recurrent or recent serious infection (eg, pneumonia, septicemia), or infection(s) 
requiring hospitalization or treatment with IV anti-infectives (antibiotics, antivirals, 
antifungals, antihelminthics) within 30 days prior to D1, or infections(s) requiring oral 
anti-infectives (antibiotics, antivirals, antifungals, antihelminthics) within 14 days prior to 
D1. 
E 06. Known history of or suspected significant current immunosuppression, including history of 
invasive opportunistic or helminthic infections despite infection resolution or otherwise 
recurrent infections of abnormal frequency or prolonged duration. 
E 07. Participant with personal or family history of long QT syndrome. 
E 08. History of moderate to severe congestive heart failure (New York Heart Association Class 
III or IV), or recent cerebrovascular accident, or any other condition in the opinion of the 
Investigator that would put the participant at risk by participation in the protocol. 
E 09. History of solid organ transplant. 
E 10. History of alcohol or drug abuse within the past 2 years. 
E 11. History of diagnosis of demyelinating disease such as but not limited to: 
• Multiple Sclerosis. 
• Acute Disseminated Encephalomyelitis. 
• Balo's Disease (Concentric Sclerosis). 
• Charcot-Marie-Tooth Disease. 
• Guillain-Barre Syndrome. 
• Human T-lymphotropic virus 1 Associated Myelopathy. 
• Neuromyelitis Optica (Devic's Disease). 
E 12. Planned surgery during the treatment period. 
E 13. Active malignancy, lymphoproliferative disease, or malignancy in remission for less than 5 
years, except adequately treated (cured) localized carcinoma in situ of the cervix or ductal 
breast, or squamous cell carcinoma, or basal cell carcinoma of the skin. 
E 14. Any live (attenuated) vaccine within 6 weeks prior to randomization (eg, varicella zoster 
vaccine, oral polio, rabies) or plan to receive one during the trial. 
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History of targeted immunotherapy for psoriasis 
E 15. For NTIP: previous or current use of biologics, biosimilars or small molecules to treat 
psoriasis [such as targeting IL-23, IL-17, IL-12, TNFα (eg, Ustekinumab, secukinumab, 
ixikizumab), or phosphodiesterase 4, janus kinase or tyrosine kinase 2 inhibitors 
(apremilast, tofacitinib, deucravacitinib)]. 
E 16. For ETIP: never received biologics, biosimilars or small molecules to treat psoriasis such 
as targeting IL-23, IL-17, IL-12, TNFα (eg, Ustekinumab, secukinumab, ixikizumab), or 
phosphodiesterase 4, janus kinase or tyrosine kinase 2 inhibitors (apremilast, tofacitinib, 
deucravacitinib). 
E 17. Deleted in Amended protocol 04. 
Prior/concomitant therapy 
E 18. Simultaneous treatment with phototherapy or the following systemic therapies, however 
participants can go through washout to be considered for the study. Participants should not 
be withdrawn from a treatment if the disease is well controlled in order to be considered 
for the study. Emollients are accepted, as much as needed, during the duration of the study 
(see Table 5). 
• Natalizumab, rituximab or agents that modulate B or T cells (eg, alemtuzumab, 
abatacept, visilizumab) requires washout of 6 months until D1. 
• Systemic immunosuppressants (eg, MTX, Azathioprine, cyclosporine, 6-thiouganine, 
mercaptopurine, mycophenolate mofetil, hydroxyurea, tacrolimus) or anakinra, or 
phototherapy requires washout of 4 weeks until D1. 
• Systemic medications/treatments (including but not limited to oral or (intramuscular, 
intravenous, or intraarticular) injectable corticosteroids, retinoids, 1,25-dihydroxy 
vitamin D3 and analogues when administered at high doses with the intent to treat 
psoriasis, psoralens, sulfasalazine, hydroxyurea, fumaric acid derivative, Lithium, 
antimalarias, gold injections, leflunomide) requires washout of 4 weeks until D1. 
• Topical Treatments (eg, corticosteroids, anthralin, calcipotriene, topical vitamin D 
derivatives, tazarotene, methoxsalen, trimethylpsoralens, picrolimus, tacrolimus, 
vitamin A analogues, retinoids, salicylvaseline, salicylic acid, lactic acid, tar, 
andanthralin, `-hydroxy, fruit acids). See Table 5, for considerations regarding topical 
corticosteroids. 
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. 
Prior/concurrent clinical study experience 
E 25. Participation in any other study of investigational drug within 30 days or 5 times the 
terminal half-life of the investigational drug, whichever was longer, prior to 
randomization. 
Diagnostic assessments 
E 26. At screening visit or Day 1 a marked prolongation of QTcF interval >450 milliseconds 
(ms) (Fridericia QT correction formula, mean of triplicate measurement). 
E 27. At screening visit, presence of any of the following laboratory findings: 
a) Hemoglobin <8.0 g/dL. 
b) Platelet count <100 000 platelets/microliter. 
c) White blood cells <3500 cells/microliter. 
d) Neutrophils <1500 cells/microliter (or<1000/mm3 for participants of African descent). 
e) AST or ALT ≥2 × ULN. 
f) Total Bilirubin >2 × ULN; unless the participant has been diagnosed with Gilbert 
disease documented by genetic testing. 
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g) Creatinine clearance <45 mL/min using Cockcroft-Gault equation. 
Retest can be done to reassess the eligibility during the Screening period as per 
Investigator's judgement that observed abnormality is not clinically significant and not 
consistent with patient's medical history. 
E 28. At the screening visit, participants with positive: 
• Hepatitis B surface antigen (HBsAg), or IgM Hepatitis B core antibody (HBcAb) or 
total HBcAb confirmed by positive HBV-DNA (for participants in Japan, 
see Section 10.7.3), or 
• Hepatitis C virus antibody (HCVAb) confirmed by positive HCV-RNA. 
E 29. Exclusion related to Human immunodeficiency virus (HIV): 
• Positive HIV-1 or HIV-2 serology without antiretroviral therapy and CD4 
count <200 cells per milliliter of blood (cells/mm3) (for participants in the 
Czech Republic, see Section 10.7.4). 
E 30. Exclusion related to TB (Section 8.3.5): 
• Active TB or a history of incompletely treated TB. 
• Undergoing treatment for latent TB infection (LTBI). 
• Positive QuantiFERON®-TB test at Screening visit. 
• Participants with current household contacts with active TB. 
• Indeterminate QuantiFERON®-TB may be repeated once during screening period and 
will be considered positive if retest results are positive or indeterminate. 
• Patient who received BCG-vaccination within 12 months prior to screening. 
• Participants meeting all the following criteria would not be excluded: 
a) documented completed appropriate LTBI treatment, OR treated for active TB 
infection (with a treatment regimen as per local guidelines), AND 
b) have obtained consultation with a specialist to rule out or treat active TB infection 
(for participants in the Czech Republic, see Section 10.7.4), AND 
c) for whom review and approval from Sponsor have been granted are eligible. 
Note: TB testing is mandatory to rule out active/latent TB and a blood sample for 
QuantiFERON® Tuberculosis Gold Interferon- Gamma Release Assay (IGRA) testing 
should be sent to the central laboratory. 
The screening period may be extended to 6 weeks (+/- 3 days) if participants are 
awaiting consultation with a specialist to rule out or treat active TB infection, or 
approval from Sponsor. 
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Other exclusion criteria 
E 31. Inability to tolerate oral medication. 
E 32. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized. 
E 33. Participant not suitable for participation, whatever the reason, as judged by the 
Investigator, including medical or clinical conditions, incapacitated or participants 
potentially at risk of noncompliance to study procedures. 
E 34. Participants who 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 ICH-GCP Ordinance E6). 
E 35. Sensitivity to any of the study interventions, or components thereof, or drug or other 
allergy that, in the opinion of the Investigator, contraindicates participation in the study. 
E 36. Any country-related specific regulation that would prevent the participant from entering 
the study – see Appendix 7 in Section 10.7 of the protocol (country-specific requirements). 
 
5.3 
LIFESTYLE CONSIDERATIONS  
Participants will be asked to inform the Investigator or sub-investigator during the screening visit 
about their vaccination history. Based on the provided information, the Investigator or 
Sub-investigator will determine if the participants received the appropriate immunization for their 
age according to the current immunization guideline in place in the participant’s local country. 
. 
5.3.1 Meals and dietary restrictions  
• Refrain from 
 before the start of IMP until after the final dose. 
• Participants should come to Visits 2, 4 and 6 in fasting conditions (except water) and 
abstain from caffeine containing beverages/foods for 8 hours prior to arrival. A light meal 
will be provided by the site after the laboratory tests, lipids panel and pre-dose-PK. 
• It is recommended to record the ECG under fasting conditions (except water). If this is not 
possible, a light snack with minimal carbohydrate content (eg, crackers, fruit, or yogurt, 
maximum 100-200 calories, no caffeine containing beverages or foods) can be consumed 
at least 2 hours prior to the ECG assessment. 
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5.3.2 Fasting, caffeine, alcohol, and tobacco  
• Fasting: During Visit 2, 4 and 6 (Week 0, 4 and 12), participant should be fasting (except 
water), and abstain from caffeine containing beverages/foods for 8 hours prior to arrival. 
•
. 
• Alcohol: During each dosing session, participants will abstain from alcohol for 24 hours 
before the start of dosing until after collection of the final PK and/or pharmacodynamic 
sample. 
• Tobacco: Participants who use tobacco products will be instructed that use of nicotine-
containing products (including nicotine patches) will not be permitted while they are in the 
clinical unit. 
5.3.3 Activity  
• No restrictions on activity. 
5.4 
SCREEN FAILURES  
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidating Standards of 
Reporting Trials publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure reasons, eligibility criteria, and any 
SAE. 
The Investigator will maintain a screening log to record reasons for screening failure, as 
applicable. 
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5.5 
RE-TESTING: LABORATORY INCLUSION/EXCLUSION CRITERIA  
In cases where original screen failure was due to reasons expected to change at re-screening and 
based upon the Investigator’s clinical judgment, the participant may be rescreened only once for 
this study after notification of the Sponsor. Rescreened participants will be assigned a new 
participant number for the re-screening event. There is no requirement for a waiting period 
between the screen-failure and the re-screening. A new consent form must be signed and Visit 1 
procedures that did not initially meet eligibility criteria or that were performed earlier than 
28 days before randomization must be repeated for re-screened participants. 
If a hematology/chemistry laboratory value falls outside the normal range and is judged by the 
Investigator to be clinically significant, it may be repeated once and if the repeat value is no 
longer considered clinically significant then that specific laboratory testing result should not 
disqualify a participant from the study. Consultation with the medical monitor may help to 
identify whether repeat testing of any parameter is clinically relevant. 
Any new result will override the previous result (ie, the most current result prior to 
Randomization) and is the value by which study inclusion will be assessed, as it represents the 
participant’s most current, clinical state. 
5.6 
CRITERIA FOR TEMPORARILY DELAYING 
ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY IMP  
During a regional or national emergency declared by a governmental agency, if the site is unable 
to adequately follow protocol mandated procedures, contingency measures are proposed in 
Section 10.8.  
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6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY  
Study interventions are all pre-specified, IMPs and AxMPs, medical devices and other 
interventions (eg, surgical and behavioral) intended to be administered to the study participants 
during the study conduct. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
Table 3 - Study intervention administered  
Intervention label 
SAR441566 
 mg and 
 mg 
Placebo 
Intervention name 
SAR441566 
SAR441566 matching placebo 
Intervention description 
Type 
Drug 
Drug 
Dose formulation 
Tablet 
Tablet 
Unit dose strengths 
0 mg 
Dosage levels 
Route of administration 
Oral 
Oral 
Use 
Experimental 
Placebo 
IMP and AxMP 
IMP 
IMP 
Packaging and labeling 
Study IMP will be provided in wallet. Each 
wallet will be labeled as required per 
country requirements. 
Study IMP will be provided in wallet. 
Each wallet will be labeled as required 
per country requirements. 
[Current/former name(s) or 
alias(es)] 
Not applicable 
Not applicable 
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Table 4 - Study arms  
Arm title 
200 mg BID 
100 mg BID 
200 mg QD 
100 mg QD 
50 mg QD 
Placebo 
Arm type 
Experimental 
Experimental 
Experimental 
Experimental 
Experimental 
Placebo 
Arm 
description 
Participants 
will receive 
200 mg of 
SAR441566 
BID for 
12 weeks 
Participants 
will receive 
100 mg of 
SAR441566 
BID for 
12 weeks 
Participants 
will receive 
200 mg of 
SAR441566 
QD for 
12 weeks 
Participants 
will receive 
100 mg of 
SAR441566 
QD for 
12 weeks 
Participants 
will receive 
50 mg of 
SAR441566 
QD for 
12 weeks 
Participants 
will receive 
Placebo for 
12 weeks 
 
The SAR441566 or placebo may be supplied at the site or from the PI/site/Sponsor to the 
participant via a Sponsor-approved courier company when allowed by local regulations and 
agreed upon by the participant. 
For a regional or national emergency declared by a governmental agency that results in travel 
restrictions, confinement, or restricted site access, contingency measures are included in 
Section 10.8. 
6.1.1 Devices  
• Not Applicable. 
6.2 
PREPARATION, HANDLING, STORAGE, AND ACCOUNTABILITY  
1. The Investigator or designee must confirm appropriate conditions (eg, temperature) have 
been maintained during transit for all study IMP received and any discrepancies are 
reported and resolved before use of the study IMP. 
2. Only participants enrolled in the study may receive study IMP and only authorized site 
staff may supply, prepare, or administer study IMP. 
3. All study 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. 
4. The Investigator, institution, the head of the medical institution (where applicable), or 
authorized site staff is responsible for study IMP accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records). 
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 8.4.10). 
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, to recall the IMP and eliminate potential hazards. 
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Under no circumstances will the Investigator supply IMP to a third party (except for DTP 
shipment, for which a courier company has been approved by the Sponsor), allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
6.3 
ASSIGNMENT TO STUDY TREATMENT  
• At Visit 2 (Week 0), after all baseline evaluations have been completed, participants will 
be randomly assigned to study IMP (SAR441566 or matching placebo). 
• The list of randomized IMP kit numbers is generated centrally by Sanofi. The IMPs 
(SAR441566 and placebo) are packaged in accordance with this list. 
• The randomization and IMP allocation are performed centrally by an IWRS. Before the 
study is initiated the log in information, and directions for the IWRS will be provided to 
each site. 
• The IWRS generates the participant randomization list and allocates the IMP number and 
the corresponding intervention kits to the participants according to it. 
• Participant’s randomization list will be stratified by prior targeted immunotherapy use 
history (NTIP vs. ETIP). 
• Study IMP will be dispensed at the study visits as summarized in the SoA (see 
Section 1.3). Returned study IMP should not be re-dispensed to the participants. Details of 
the IWRS procedure will be provided in the IWRS site manual. 
• During the treatment period, several IMP kit numbers will be allocated to participants by 
the IWRS across visits, in the same arm as assigned at randomization. 
• A randomized participant is defined as a participant from screened population who has 
been allocated to a randomized IMP regardless of whether the IMP is received or not. 
• Time of randomization for a participant is defined as the time recorded by IWRS. 
• A participant cannot be randomized more than once in the study. Due to the study 
duration, several IMP kits numbers will be allocated to participants by the IWRS across 
visits in the same arm assigned at the randomization visit. That is, in these cases, the 
IMP/kit number varies but the arm assignment at randomization does not change. 
6.4 
BLINDING  
This is a double-blind study in which the participants and Investigators are blinded to study IMP. 
Investigators will not have access to the randomization (treatment) codes except under exceptional 
medical circumstances. 
The IWRS will be programmed with blind-breaking instructions. In case of an emergency, the 
Investigator has the sole responsibility for determining if unblinding of a participant’s IMP 
assignment is warranted (eg, in case of available antidote). Participant safety must always be the 
first consideration in making such a determination. If the Investigator decides that unblinding is 
warranted, he/she may, at the Investigator’s discretion, contact the Sponsor to discuss the situation 
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prior to unblinding a participant’s IMP assignment unless this could delay emergency treatment 
for the participant. If a participant’s intervention assignment is unblinded, the Sponsor must be 
notified within 24 hours of this occurrence. The date and reason for the unblinding must be 
recorded in the source documentation and eCRF, as applicable. 
At the assay institutions (bioanalytical labs) responsible for PK measurements, only samples 
collected from participants on active drug may be analyzed leading to unblinding of responsible 
bioanalysts prior to the database lock. Bioanalysts are excluded from the clinical study operation’s 
team and a process will be set up to prevent any potential unblinding, ie, no unblinded data will be 
shared with the clinical study operational team prior to database lock. 
The Investigator and the Sponsor will also be blinded to PK and hsCRP data. In addition, 
population PK analysis may be conducted prior to data base lock leading to unblinding of 
personnel in charge of dataset creation and data analysis. These personnel will be excluded from 
the clinical trial team. 
Sponsor safety staff may unblind the IMP assignment for any participant with an SAE for the 
purpose of expedited regulatory reporting (see Section 8.4.4). Sponsor staff involved in the 
conduct of the study will remain blinded to the participant IMP assignment. 
Methods of blinding 
• The placebo tablet will be identical to the SAR441566 tablet in appearance, quantity, taste, 
odor, packaging, and labeling. SAR441566 and placebo will be provided in 
indistinguishable wallets, in identical kits labeled with an IMP kit number. 
• The IDMC will have access to unblinded data if deemed necessary by the IDMC. No 
unblinding information will be shared by the IDMC with the study team. Details about the 
distribution of unblinding data to the IDMC while protecting the blind are described in the 
IDMC charter. 
• In case of an interim analysis, a Statistician, Programmer, and the Clinical Research 
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. 
• Laboratory assessments listed as PD markers and biomarkers in the SoA (Section 1.3) will 
be blinded from baseline/Day 1 throughout the study, except for those which are needed 
for screening (see Section 10.2). In case of a safety concern, unblinding can be performed 
by the Investigator and/or Sponsor for the PD marker. 
6.5 
STUDY IMP COMPLIANCE  
When participants are dosed at the site, the Investigator or the designee will provide IMP to the 
participant from a new IMP kit, and not from a previous IMP kit. The date and time of each dose 
administered in the clinic will be recorded in the source documents. The dose of study 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 study IMP. 
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Compliance of IMP: 
When participants self-administer study IMP at home, compliance with study IMP will be 
assessed at each visit. Compliance will be assessed by counting returned tablets in each pack 
during the site visits and documented in the source documents and relevant form. A participant is 
determined compliant with the treatment if the participant took 80% or more of scheduled IMP 
during the treatment period. 
Omissions or deviations from the prescribed dosage regimen should be recorded in the medication 
administration questionnaire. 
Accountability of IMP provided by the Sponsor: 
• The Investigator counts the number of remaining tablets in the returned packs, and then 
fills in the IMP log form. 
• The Investigator also checks the IMP administration questionnaire to evaluate patient 
compliance. 
A record of the quantity of tablets dispensed to and administered by each participant must be 
maintained and reconciled with study IMP and compliance records. IMP start and stop dates, 
including dates for IMP delays and/or dose reductions will also be recorded. 
6.6 
DOSE MODIFICATION  
Dose modification is not allowed. 
6.7 
CONTINUED ACCESS TO IMP AFTER THE END OF THE STUDY  
Not applicable. 
6.8 
TREATMENT OF OVERDOSE  
For this study, any dose of SAR441566 greater than 50% more than the intended daily dose 
within 24-hour period ±2 hours will be considered an overdose. 
Participants who are overdosed should be treated symptomatically. Currently, there is no known 
antidote for SAR441566. 
In the event of an overdose, the Investigator should: 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities. 
• Evaluate the participant to determine whether study IMP should be interrupted. 
• Obtain a plasma sample for PK analysis as soon as possible. 
• Document appropriately in the eCRF. 
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• Contact the Sponsor as soon as possible. Of note: Asymptomatic overdose must be 
reported as standard AE. 
6.9 
PRIOR AND CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter or prescription medicines, recreational 
drugs, vitamins, minerals and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded in the eCRF and Source Data along 
with: 
• Drug generic name. 
• Reason for use. 
• Dates of administration including start and end dates. 
• Dosage information including dose and frequency. 
The Sponsor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
Participants should abstain from taking prescription or nonprescription drugs (including vitamins, 
recreational drugs, and dietary or herbal supplements) 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 study IMP until 
completion of the EoS visit, unless, in the opinion of the Investigator and Sponsor, the medication 
will not interfere with the study. 
Treatments in addition to the IMPs should be kept to a minimum during the study. However, if 
these are considered necessary for the participant’s welfare and are unlikely to interfere with the 
IMPs, they may be given at the discretion of the Investigator, with a stable dose (when possible). 
Participant should report in their IMP administration questionnaire any change in the ongoing 
specific treatment or newly taken concomitant medication(s), if any between the on-site study 
visits. The investigator can request 
 during the study (Day 1 to EoS). 
6.9.1 Prior Therapy  
Prior therapies restricted for participants eligible for this study are detailed in the exclusion 
criteria (Section 5.2). 
6.9.2 Prohibited concomitant therapy  
Refer to the exclusion criteria (Section 5.2) and Table 5. For China, refer to Section 10.7.1. 
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i
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For China: Any Chinese medicine containing Tripterygium and/or Total 
glucosides of peony, or other Chinese medicine aimed at treating psoriasis. 
1 month 
1. There is no restriction on corticosteroids that only have a topical effect to treat other 
indications than psoriasis (eg, inhalant corticosteroids to treat asthma or corticosteroid 
drops used in the eye or ear). 
2. Use of 1,25-dihydroxy vitamin D3 and analogues is prohibited only when administered at 
high doses with the intent to treat psoriasis. Oral intake of vitamin D for the treatment of 
other indications is not prohibited. Ensure any type of vitamin D administration is 
recorded on the eCRF. 
3. Exception: Topical corticosteroids of US class 6 (mild, such as desonide) or US Class 7 
(least potent, such as hydrocortisone) will be permitted for limited use to the face, axilla, 
and/or genitalia with a restriction of use within 24 hours prior to clinic visits on D1, W4, 
W8 and W12. 
6.9.3 Permitted concomitant therapy  
There is no restriction on topical corticosteroids used to treat other indications than psoriasis 
(eg, inhaled corticosteroids to treat asthma or corticosteroid drops used in the eye or ear). 
Topical corticosteroids of US class 6 (mild, such as desonide) or US class 7 (least potent, such as 
hydrocortisone) will be permitted for use limited to the face, axilla, and/or genitalia with a 
restriction of use within 24 hours prior to clinic visits on Day 1, Week 4, 8 and 12. 
Any therapy other than the prohibited concomitant therapy that may be given at the discretion of 
the Investigator has to be recorded in the source data (Section 10.1.8) and the eCRF. 
 
Caution should be exercised with 
. 
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If the patient has been using any allowed concomitant therapy, he/she should continue it at the 
same dose and regimen throughout the entire study (if reasonable from the medical point of view). 
On days when blood samples are taken, the patient should continue the usual regimen of his/her 
concomitant therapy (except the use of topical corticosteroids of US class 6/mild or 
US Class 7/least potent, which cannot be used 24 hours prior to clinic visits). 
6.9.4 Rescue medicine  
Topical corticosteroids of class least potent or mild (US class 6 or 7) (such as hydrocortisone) are 
permitted for use limited to the face, axilla, and/or genitalia with a restriction of use within 24 
hours prior to clinic visits on Day 1, Week 4, 8 and 12. 
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7 
DISCONTINUATION OF STUDY IMP AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL  
Discontinuation of specific sites or of the study are detailed in Appendix 1 (Section 10.1.9). 
7.1 
DISCONTINUATION OF STUDY IMP   
An individual should discontinue study IMP if any of the following occurs: 
• At the request of the participant, ie, withdrawal of consent. 
• Pregnancy of a female participant. 
• Occurrence of SAE if further participation could jeopardize the safety of the participant. 
• Any clinically relevant safety laboratory deviation, including but not limited to 
 (refer to Section 7.1.3). 
• Worsening of psoriasis requiring intensification of therapy outside of substances permitted 
in the study (refer to Section 6.9.2 and Section 6.9.3). 
• Any other medically important AE in the judgement of the investigator. 
All study IMP withdrawals should be recorded by the Investigator on the appropriate case report 
form screens for eCRF when considered as confirmed. 
In case of premature study IMP discontinuation, see Section 7.1.1 below. 
For any participant who fails to return to the site, the Investigator should make every effort to 
recontact the participant (eg, contact the participant’s family or private physician, review available 
registries or health care database), and to determine his/her health status, including at least his/her 
vital status. Attempts to contact the participant must be documented in the participant’s records 
(eg, times and dates of attempted telephone contact, receipt for sending a registered letter). 
7.1.1 Permanent discontinuation  
It may be necessary for a participant to permanently discontinue study IMP. In this case the 
participant must be followed up as described below. 
Abnormal laboratory value or ECG parameter should be rechecked for confirmation, according to 
Investigator’s judgement before deciding on possible permanent discontinuation of the IMP for 
the concerned participant. 
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Handling of participants after permanent IMP discontinuation 
Participants who discontinue IMP treatment prior to completing the 12-week treatment period 
should be assessed as per the EoT visit at the earliest opportunity and no later than 7 days from 
the last dose of IMP. After the EoT visit: 
a) Participants who accept to stay on study without IMP intake: all remaining visits described 
in the SoA should be performed until the EoS, but only clinical assessments, AE and 
concomitant medication review and patient reported outcomes should be carried out at the 
study visits. 
b) Participants who withdraw consent from the study: should have an EoS visit 4 weeks after 
their last dose of IMP. 
All cases of permanent IMP discontinuation must be recorded by the Investigator in the 
appropriate pages of the eCRF when considered as confirmed. 
The recommended wash out period for SAR441566 is
 (>5 x the half-life of SAR441566). 
 
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7.1.4 Temporary discontinuation  
Temporary IMP discontinuation may be considered by the Investigator because of suspected AEs 
or disruption of the clinical trial due to a regional or national emergency declared by a 
governmental agency (Section 10.8). For all temporary IMP discontinuations, duration should be 
recorded by the Investigator in the appropriate pages of the eCRF. 
Temporary IMP discontinuation decided by the Investigator corresponds to ≥2 consecutive IMP 
doses not administered to the participant. 
7.1.5 Rechallenge  
Reinitiating the IMP will be done under close and appropriate clinical and/or laboratory 
monitoring once the Investigator will have considered according to his/her best medical judgment 
that the responsibility of the IMP in the occurrence of the concerned AE was unlikely and if the 
selection criteria for the study are still met (refer to Section 5.1 and Section 5.2). 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.8. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
• A participant may withdraw from the study at any time at the participant’s own request for 
any reason (or without providing any reason). 
• A participant may be withdrawn at any time at the discretion of the Investigator for safety, 
behavioral, or compliance reasons. 
• At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA (Section 1.3). See SoA for data to be collected 
at the time of study discontinuation and follow-up and for any further evaluations that 
need to be completed. 
• If the participant withdraws consent from the study, the Sponsor will retain and continue 
to use any data collected before such a withdrawal of consent, as per applicable clinical 
regulation(s). 
• If a participant withdraws from the study, the participant may request destruction of any 
samples taken and not tested, and the Investigator must document this in the site study 
records. 
If participants no longer wish to take the IMP, they will be encouraged to remain in the study. 
The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. 
Participants who withdraw from the study IMP should be explicitly asked about the contribution 
of possible AEs to their decision, and any AE information elicited must be documented. 
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All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
eCRF 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. 
Withdrawal of consent for IMP should be distinguished from withdrawal of consent for follow-up 
visits and from withdrawal of consent for non-participant contact follow-up, eg, medical record 
checks. The site should document any case of withdrawal of consent. 
Participants who have withdrawn from the study cannot be rerandomized/reallocated (treated) in 
the study. Their inclusion and intervention numbers will not be reused. 
7.3 
LOST TO FOLLOW UP  
A participant will be considered lost to follow-up if the participant 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, counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether 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 (when possible, 3 telephone calls, and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
Should the participant continue to be unreachable, the participant will be considered to 
have withdrawn from the study. 
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8 
STUDY ASSESSMENTS AND PROCEDURES  
• Study procedures and their timing are summarized in the SoA. 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 should 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, blood 
count, urine tests) and obtained before signing of the ICF cannot be utilized for screening 
or baseline purposes even if they were performed within the timeframe defined in the SoA, 
Central laboratory analysis is required. See Section 8.3.6 for pregnancy testing 
and Section 8.3.5 for local Quantiferon Testing. 
• In the event of a significant study-continuity issue (eg, caused by a pandemic), alternate 
strategies for participant visits, assessments, medication distribution and monitoring may 
be implemented by the Sponsor or the Investigator, as per local Health 
Authority/independent ethics committee requirements (Section 10.8). 
• Safety/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. 
• Blood sampling details including volume for all laboratory assessments will be provided in 
the laboratory manual and the ICF. 
• Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
8.1 
ADMINISTRATIVE AND GENERAL/BASELINE PROCEDURES  
Baseline demographic characteristics will consist of: 
1. Age (years) 
2. Height (cm) 
3. Weight (kg) 
4. Race and Ethnicity 
5. Gender, if applicable 
6. Psoriasis history including date of symptom onset, date of the diagnosis, previous 
treatments (medication generic name, doses, clinical efficacy response [responder or 
no-responder], reason for discontinuation [side effects, lack of clinical efficacy, 
medication interaction with other concomitant therapy, remission/lack of symptoms, and 
other] and length of the therapy), and current treatments. 
7. History of psoriasis in the family. 
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8. Concomitant disease such as diabetes mellitus, arterial hypertension, obesity, 
dyslipidemia, myocardial infarction, etc. 
9. Details regarding current therapies and vitamins for concomitant therapies. 
10. Smoking status, specifying if participant is current, former, or never smoker. 
Study participant race or ethnicity will be collected in this study because analysis of results 
according to race/ethnicity are required by several Regulatory Authorities (eg, African American 
population for FDA in United States, Japanese population for the Pharmaceuticals and Medical 
Devices Agency [PMDA] in Japan or Chinese population for the National Medical Products 
Administration [NMPA] in China). 
8.2 
EFFICACY ASSESSMENTS   
Planned timepoints for all efficacy assessments are provided in the SoA. 
To minimize any bias, it is recommended participants to complete their PRO measures before 
clinician assessments and discussion of their clinical condition, treatment plan, AEs, and any other 
related topics that could influence participant’s perception and feelings prior to responding to the 
questions. There will be a specific training on ePRO technology. For the ePRO data it is 
mandatory that a key person (for example research nurse) at each site is responsible for ePRO data 
collection, to optimize participant compliance and to ensure data completeness. Reason for 
non-completion will be documented in the eCRF. 
8.2.1 Psoriasis area and severity index (PASI)  
The PASI is an established measure of clinical efficacy for psoriasis medications (7). The PASI is 
a tool that provides a numeric scoring for participants’ overall psoriasis disease state, ranging 
from 0 to 72. It is a linear combination of percent of surface area of skin that is affected and the 
severity of erythema, induration, and desquamation over four body regions. 
The endpoints used are based on the percent reduction from baseline, generally summarized as a 
dichotomous outcome based on achieving over an X% reduction (or PASIX), where X is 50, 75, 
90 and 100. 
To calculate the PASI, the four main body areas are assessed: head (h), trunk (t), upper 
extremities (u) and lower extremities (l). These correspond to 10, 30, 20 and 40% of the total body 
area respectively. 
The physician quantifies the percentage of the considered body area covered by plaque psoriasis. 
This percentage of psoriatic involvement is translated into a numerical value “Ax” for each body 
area: 0 = no involvement, 1 = <10%, 2 = 10 to <30%, 3 = 30 to <50%, 4 = 50 to <70%, 5 = 70 to 
<90%, and 6 = 90 to 100% involvement. These scores are noted Ah, At, Au, and Al in the formula 
below. 
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The signs of severity, erythema (E), induration (I) and desquamation (D) of lesions are assessed 
using a numeric scale 0-4 where 0 is a complete lack of cutaneous involvement and 4 is the 
severest possible involvement; scores are made independently for each of the areas, h, t, u, and 
l and represents a composite score for each area. An illustration of judging erythema follows: 
0 = no erythema, 1 = slight erythema, 2 = moderate erythema, 3 = striking erythema, and 
4 = exceptionally striking erythema. 
The PASI score is calculated according to the following formula: 
PASI = 0.1(Eh+Ih+Dh)Ah + 0.3(Et+It+Dt)At + 0.2(Eu+Iu+Du)Au + 0.4(El+Il+Dl)Al 
8.2.2 static Psoriasis Global Assessment (sPGA)  
The sPGA is a 5-point score ranging from 0 to 4, based on the physician’s assessment of the 
average thickness, erythema, and scaling of all psoriatic lesions (14). The assessment is 
considered “static”, which refers to the participant’s disease state at the time of the assessments, 
without comparison to any of the participant’s previous disease states, whether at Baseline or at a 
previous visit. A lower score indicates less body coverage, with 0 being clear and 1 being almost 
clear. 
Erythema 
• 0 Normal (post-inflammatory hyper/hypopigmentation may be present). 
• 1 Faint, diffuse pink or slight red coloration. 
• 2 Mild (light red coloration). 
• 3 Definite red coloration (Dull to bright red). 
• 4 Bright to Deep red coloration of lesions. 
Induration (plaque elevation) 
• 0 None. 
• 1 Just detectable (slight elevation above normal skin). 
• 2 Mild thickening (slight but definite elevation, typically edges are indistinct or sloped). 
• 3 Clearly distinguishable to moderate thickening (marked definite elevation with rough or 
sloped edges). 
• 4 Severe thickening with hard edges (marked elevation typically with hard or sharp edges). 
Desquamation 
• 0 No scaling. 
• 1 Minimal focal scaling (surface dryness with some desquamation). 
• 2 Predominately fine scaling (fine scale partially or mostly covering lesions). 
• 3 Moderate scaling (coarser scale covering most or all of the lesions). 
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Overall Scoring resulting of the average of the Erythema, Induration and Desquamation score: 
• Clear 0 = 0 for all three symptoms. Post-inflammatory hyper/hypopigmentation may be 
present. 
• Almost clear 1 = mean >0, <1.5. Normal to pink coloration; just detectable (possible slight 
elevation above normal skin). No to minimal focal scaling. 
• Mild 2 = mean >= 1.5, <2.5. Pink to light red coloration; mild thickening (slight but 
definite elevation, typically edges are indistinct or sloped). Predominantly fine scaling. 
• Moderate 3 = mean >=2.5, <3.5. Dull to bright red coloration; clearly distinguishable to 
moderate thickening; moderate scaling. 
• Severe 4 = mean >=3.5. Bright to deep dark red coloration; severe thickening with hard 
edges; severe coarse scaling covering almost all or all lesions. 
8.2.3 Body surface Area (BSA)  
BSA will be calculated from the integrated BSA within the PASI assessment. 
Percent BSA will be evaluated as the percent involvement of psoriasis on each patient’s BSA on a 
continuous scale from 0% (no involvement) to 100% (full involvement), where 1% corresponds to 
the size of the patient’s hand (including the palm, fingers, and thumb) (15). 
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8.2.8 Dermatology Life Quality Index (DLQI)  
The DLQI is one of the most widely used measures in dermatology populations to evaluate 
participants’ Health-Related Quality of Life. It is a patient-reported outcome instrument consisting 
of 10 items exploring six dimensions: ‘Symptoms and feelings” (2 items), “Daily activities” 
(2 items), “Leisure” (2 items), “Work and school” (1 item), “Personal relationships” (2 items), 
“Treatment” (1 item). Each item is rated on a dichotomous: Yes/No and 3- and 4-point 
Likert/Likert-type scale for capturing skin symptom-related experiences over the previous weeks. 
Scores are computed overall and for the six domains. The total DLQI score ranges from 0 to 
30 which higher scores indicating better QoL. The instrument has good evidence of content 
validity and psychometric properties supporting its reliability, construct validity and 
responsiveness (16). 
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The DLQI questionnaires are provided in Section 10.10.1. 
8.3 
SAFETY ASSESSMENTS   
This section presents safety assessments other than AEs which are presented in Section 8.4. 
Planned timepoints for all safety assessments are provided in the SoA. 
8.3.1 Physical examinations  
• The complete physical examination will consist of evaluation of the following systems: 
general, head, eyes, ears, nose, throat, neck, cardiovascular, lungs, abdominal, extremities, 
neurologic, psychiatric, skin, and musculoskeletal. 
• The targeted physical exam will consist of evaluation of the following systems: general, 
eyes, throat, cardiovascular, lungs, abdominal, extremities, and skin, musculoskeletal. 
• Complete and targeted physical examinations may be performed by a Doctor of Medicine, 
Doctor of Osteopathy, Physician's Assistant, or a Nurse Practitioner. A targeted physical 
examination may note any changes in the participant's condition since the last assessment 
and does not preclude examination of any of the body systems as clinically indicated. 
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8.3.2 Vital signs  
• Vital signs include body temperature (°C), heart rate (beats per minute), and systolic and 
diastolic blood pressure (mm Hg) (before blood collection for laboratory tests). 
• Blood pressure and pulse measurements will be assessed sitting with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (eg, television, cell phones). 
• For blood pressure measurements, 3 consecutive blood pressure readings will be recorded 
at intervals of at least 1 minute. The average of the 3 blood pressure readings will be 
recorded. 
8.3.3 Electrocardiograms  
• Standard 12-lead ECGs are recorded after at least 10 minutes of rest in supine position 
using an electrocardiographic device. The electrodes will be positioned at the same place 
for each ECG recording throughout the study (eg, attachment sites of the leads will be 
visualized on a transparent paper). 
• Triplicate 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and 
QTcF intervals. 
. 
• At each timepoint at which triplicate ECGs are required, 3 individual ECG tracings should 
be obtained within 5 minutes, with at least 1 minute between 2 replicates. 
• The ECG should be recorded 
• 
. 
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• Each ECG consists of a 10-second recording of the 12 leads simultaneously, leading to: 
- 
A single 12-lead ECG (50 mm/s, 10 mm/mV) printout with heart rate, PR, QRS, 
QT, QTcF automatic correction evaluation using Fridericia formula (by the ECG 
device), including date, time, number of the participant, and at least 3 complexes 
for each lead. The Investigator should revise the results of the printout and his/hers 
medical opinion together with the automatic values will be recorded in the eCRF. 
This printout will be retained at the site. A second printout may be performed also, 
if needed. 
- 
A digital storage that enables potential further reading by an ECG central 
laboratory: each digital file will be identified by theoretical time (day and time Dxx 
Txx Hxx), real date and real time (recorder time), Sponsor study code, participant 
number (eg, 3 digits), and site and country numbers, if relevant. The digital 
recording, data storage, and transmission (whenever requested) need to comply 
with all applicable regulatory requirements (ie, FDA 21 code of federal regulations 
[CFR], Part 11). 
8.3.4 Clinical safety laboratory tests  
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed by 
central laboratory and the SoA (Section 1.3) for the timing and frequency. 
• The Investigator must review the laboratory results, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory results 
must be retained with source documents. See Appendix 3 (Section 10.3) for abnormal 
laboratory results reporting. All laboratory tests with values considered clinically 
significantly abnormal during participation in the study or within 3 days after the last dose 
of study IMP should be repeated until the values return to normal or baseline or are no 
longer considered clinically significant by the Investigator. 
- 
If values do not return to normal/baseline within a period judged reasonable by the 
Investigator, the etiology should be identified, and the Sponsor notified. 
- 
All protocol-required laboratory tests, as defined in Appendix 2 (Section 10.2), 
must be conducted in accordance with the central laboratory manual and the SoA 
(Section 1.3). 
- 
If laboratory values from non-protocol specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in eCRF. 
8.3.5 Tuberculosis assessment and QuantiFERON®  
Medical history, including assessment of active TB, history of incompletely treated TB, 
undergoing treatment for latent TB or with current household contacts with active TB is 
considered part of the process to assess a participant’s eligibility as outlined in E 30 at the 
screening visit. All participants will have a screening test, the QuantiFERON® (an interferon 
gamma release assay, IGRA), performed centrally. If unable to obtain central lab results 
(eg, repeated test due to indeterminate result), an IGRA test could be obtained locally 
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(eg, T-spot®, QuantiFERON®), after consultation with the study medical monitor. Indeterminate 
IGRA may be repeated once during screening period and will be considered positive if retest 
results are positive or indeterminate. 
Participants with a positive screening test will not be eligible for the study unless participants 
have documented completed appropriate active/latent TB treatment and consultation with a 
specialist has been obtained to rule out or treat active TB infection (for participants in the Czech 
Republic, see Section 10.7.4) and Sponsor approval has been granted in writing (Refer to 
exclusion criteria E 30). 
8.3.6 Pregnancy testing  
• Refer to Section 5.1 Inclusion criteria for pregnancy testing entry criteria; the Investigator 
is responsible for review of medical history, menstrual history, and recent sexual activity 
to decrease the risk for inclusion of a woman with an early undetected pregnancy. 
• Pregnancy testing (urine or serum as required by local regulations) should be conducted at 
prespecified intervals described in SoA during IMP treatment. 
• Pregnancy testing (urine or serum as required by local regulations) should be conducted 
corresponding with the time frame for female participant contraception in Section 5.1 
Inclusion Criteria. 
• Additional serum or urine pregnancy tests may be performed, as determined necessary by 
the Investigator, or required by local regulation, to establish the absence of pregnancy at 
any time during the participant’s participation in the study. 
8.4 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING  
The definitions of AEs and SAEs can be found in Appendix 3 (Section 10.3). The definition of 
AESI is provided in Section 8.4.8. 
The definitions of unsolicited and solicited AEs can be found in Appendix 3 (Section 10.3). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant’s legally authorized representative) that meet the definition of an AE or SAE and 
remain responsible for following up all AEs, considered related to the study IMP or study 
procedures, or that caused the participant to discontinue the study IMP (see Section 7). This 
includes events reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative). 
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). 
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8.4.1 Time period and frequency for collecting AE and SAE information  
All AEs (serious or nonserious) will be collected from the signing of the ICF until the EoS visit at 
the timepoints specified in the SoA (Section 1.3). 
All SAEs and AESI 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 information on 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 the Investigator considers the 
event to be reasonably related to the study IMP or study participation, the Investigator must 
promptly notify the Sponsor. 
8.4.2 Method of detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.4.3 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 pre-specified study end-date, all SAEs and AEs of 
special interest (as defined in Section 8.4.8), will be followed until resolution, stabilization, the 
event is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
Further information on follow-up procedures is provided in Appendix 3 (Section 10.3). 
8.4.4 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study IMP under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study IMP under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Boards (IRB)/Independent 
Ethics Committees (IEC), and Investigators. 
• Serious adverse events that are considered expected will be specified in the reference 
safety information (IB). 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing an SAE, SUSAR or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
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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. 
8.4.5 Pregnancy  
• Details of all pregnancies in female participants and female partners of male participants 
will be collected after the start of study IMP and until and until EoS visit. 
• If a pregnancy is reported, the Investigator will record pregnancy information on the 
appropriate form and submit it to the Sponsor within 24 hours of learning of the pregnancy 
and should follow the procedures outlined in Appendix 4 “contraception and barrier 
guidance” (Section 10.4). 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
• The participant/pregnant female partner will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant/pregnant 
female partner and the neonate, and the information will be forwarded to the Sponsor. 
• Any post-study pregnancy-related SAE considered reasonably related to the study IMP by 
the Investigator will be reported to the Sponsor as described in Section 8.4.4. While the 
Investigator is not obligated to actively seek this information in former 
participant/pregnant female partner, 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 IMP or be withdrawn from the study. 
Prior to continuation of study IMP following pregnancy, the following must occur: 
• The Sponsor and the relevant IRB/IEC give written approval. 
• The participant gives signed informed consent. 
• The Investigator agrees to monitor the outcome of the pregnancy and the status of the 
participant and her offspring. 
8.4.6 Cardiovascular and death events  
Cardiovascular events should be reported if they meet AE/SAE criteria. Events with fatal outcome 
events should be reported as SAEs. 
8.4.7 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs  
Not applicable. 
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8.4.8 Adverse events 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 to 
characterize and understand them. AESIs may be added, modified, or removed during a study by 
protocol amendment. 
• 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/AxMP; 
- 
Pregnancy occurring in a female participant entered in the clinical trial or in a female 
partner of a male participant entered in the clinical trial. 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 Section 8.4.5). 
• Symptomatic overdose (serious or nonserious) with IMP/AxMP (see definition of an 
overdose in Section 6.8). 
). 
8.4.9 Medication errors or misuses of medicinal product  
All reports of medication error or misuse in relation to the IMP with or without an AE must be 
recorded on the corresponding page(s) of the eCRF and transmitted to the Sponsor’s 
representative following standard processes. 
A medication error is an unintended failure in the drug treatment process (ie, mistake in the 
process of prescribing, storing, dispensing, preparing, or administering medicinal products in 
clinical practice) that leads to, or has the potential to lead to harm to the participant. This includes 
situations in which a participant was involved or not (eg, even if the error was recognized and 
intercepted before the participant received or used the product), and whether it resulted in harm to 
the participant or not. 
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A misuse refers to situations where the medicinal product is intentionally and inappropriately 
used, ie, not in accordance with the terms of the marketing authorization or outside what is 
foreseen in the protocol, by the participant for a therapeutic purpose. 
Of note, if a medication error or misuse meets the protocol definition of an overdose, it will be 
recorded in the overdose page of the eCRF. 
8.4.10 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 the quality issue must be reported together with an AE or SAE. 
8.4.11 Medical device deficiencies  
Not applicable. 
8.5 
PHARMACOKINETICS  
• Whole blood samples will be collected for measurement of plasma concentrations of 
SAR441566 as specified in the SoA (Section 1.3). 
• A maximum of 5 samples may be collected at additional timepoints during the study if 
warranted and agreed upon between the Investigator and the Sponsor. The timing of 
sampling may be altered during the study based on newly available data (eg, to obtain data 
closer to the time of peak plasma concentrations or to optimize PK timepoints during the 
course of the study based on the updated knowledge of drug behavior) to ensure 
appropriate monitoring. 
• Instructions for the collection and handling of biological samples will be provided by the 
Sponsor in a separate document. The actual date and time of each sample will be recorded. 
PK samples will be tested by the Sponsor or Sponsor's designee. 
• Samples collected for analyses of SAR441566 concentration may also be used to evaluate 
safety or efficacy aspects related to concerns arising during or after the study. 
PK samples could be used for testing analytical method performance such as comparability and 
incurred sample reproducibility and for possible exploratory analysis of drug metabolites and/or 
drug interaction. The exploratory data will not be included in the study report but will be kept on 
file. 
SAR441566 concentrations at selected time points after IMP administration will be reported using 
descriptive statistics. Population PK and PK/PD approaches will be used for the estimation of PK 
parameters such as Cmax, tmax, and AUC0-tau, and for possible exposure-response analyses if 
appropriate. These results will be presented in a separate stand-alone report. 
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Drug concentration information that would unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. 
For China, see Section 10.7.1 for details.  
8.6 
PHARMACODYNAMICS  
See Section 8.7 Genetics and Section 8.8 Biomarkers for a description of pharmacodynamic 
parameters. 
. 
Details on processes for collection and shipment and destruction of these samples can be found in 
the laboratory manual. Results will be presented in reports separate from the clinical study report 
(CSR). See Appendix 5 (Section 10.5) [Genetics] for information regarding genetic research. 
Genetic analyses will not be done for participants enrolled in China (Section 10.7.1). 
8.8 
BIOMARKERS  
Whole blood, plasma and serum blood samples will be collected to assess the
 of systemic inflammation associated to 
psoriasis, as well as disease markers and their correlation with clinical response. Samples will be 
collected pre-IMP dose and at the timepoints specified in the SoA, as detailed in a laboratory 
manual provided separately to sites. 
Quantitative analysis of soluble blood proteins associated with psoriasis and/or SAR441566 
activity will be performed in serum or plasma including but not limited to: 
• IL-17A, IL-17F, IL-22, IL-19,
 IL-17A and IL-17F are 
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released by skin infiltrating immune cells and are commonly accepted as key disease 
drivers. IL-22 is released by lesional psoriatic skin, whereby high concentrations correlate 
with disease activity. IL-19 is a component of IL-23/IL-17 cascade, which is increased in 
psoriasis and correlated to PASI. 
Soluble protein biomarkers will be assessed through standardized methods. Instructions for the 
collection and handling of the biological samples will be provided in a separate document. 
Whole blood samples will also be collected for
 
Blood samples will be collected for 
With specific consent, optional blood samples will be collected for future biomarker analysis 
and/or retrospective safety follow-up, potentially including but not limited to 
 exploratory analysis reflecting effects of SAR441566 and/or to identify markers 
potentially predictive of clinical response. Participation is optional. Participants who do not wish 
to participate in the research may still participate in the study. 
Analyses may also seek to identify which markers are associated with clinical response to 
SAR441566, or can be predictive of clinical response, or correlate to clinical response and clinical 
features. 
For China, see Section 10.7.1 for details. 
8.9 
IMMUNOGENICITY ASSESSMENTS  
Not applicable. 
8.10 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS  
Health economics are not evaluated in this study. 
8.11 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH  
Future research may help further the understanding of disease and the development of new 
medicines. Reuse of coded data and biological samples (leftover and additional) will be limited to 
future scientific research conducted under a research plan for the purpose of diagnosing, 
preventing, or treating diseases (Section 10.7.1 for specification related to China). The future 
research projects will be conducted under the Sponsor’s and/or its affiliates’ and/or, if applicable, 
the partner of the Sponsor which has licensed the study drug to the Sponsor or which is 
co-developing the study drug with the Sponsor’s control, acting alone or in collaboration with 
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research partners such as universities, research institutions or industrial partners with whom the 
coded data may be shared. 
Data and biological samples will be stored and used for future research only when consented to by 
participants (see Section 10.1.3) and, when applicable, further information on the future research 
has been provided to the study participant, unless prohibited by local laws or IRBs/IECs (in such 
case, consent for future use of data/sample will not be included in the local ICF). The conditions 
for reuse will be adapted locally with the appropriate language in the ICF. 
In any case, a specific consent will be collected for the performance of genetic analyses on 
leftover and/or additional samples. 
Data protection – Processing of coded clinical data 
The study participant will be provided will all mandatory details of the data processing in Section 
2 of the core ICF. 
The Sponsor adopts safeguards for protecting participant confidentiality and personal data 
(see Section 10.1.4). 
Use of leftover samples and additional samples for future research 
Remaining leftover samples will be used only after the study ends, ie, end of study as defined in 
the study protocol, upon consent of the participant. Additional/extra samples can be collected and 
used during the study conduct at a given timepoint (eg, at randomization visit) as defined in the 
study protocol. 
The study participant will be provided with all mandatory details of the use of the human 
biological samples (leftover and additional) in Section 2 of the Core ICF. 
Study participant data will be stored for up to 25 years for regulatory purposes and future 
research. Biological samples for future use will be stored for up to 25 years after the end of the 
study. Any samples remaining at the end of retention period will be destroyed. If a participant 
requests destruction of his/her samples before the end of the retention period, the Investigator 
must notify the Sponsor (or its contract organization) in writing. In such case, samples will be 
destroyed, and related coded data will be anonymized unless otherwise required by applicable 
laws. 
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9 
STATISTICAL CONSIDERATIONS  
The statistical analysis plan (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. 
9.1 
POPULATIONS FOR ANALYSES  
The following populations for analyses are defined. 
Table 6 - Populations for analyses  
Population 
Description 
Screened 
All participants who signed the ICF. 
Randomized 
All participants from screened population who have been allocated to a randomized 
intervention by IWRS regardless of whether the intervention was received. 
Intent-to-treat (ITT) 
All randomized participants. Participants will be analyzed according to the intervention 
allocated by randomization.  
Safety 
All randomized participants who have taken at least 1 dose of study intervention, regardless 
of the amount of intervention administered. Participants will be analyzed according to the 
intervention they received. 
Pharmacokinetic (PK) 
All participants from the safety population with at least one post-baseline PK result with 
adequate documentation of dosing and sampling dates and times. 
Participants having received only placebo will not be part of the PK population. 
Participants will be analyzed according to the intervention they received. 
Naive targeted Immunotherapy 
population (NTIP)  
All randomized participants who have never received targeted immunotherapy for psoriasis. 
Participants will be analyzed according to the intervention allocated by randomization. 
Experienced Targeted 
Immunotherapy population 
(ETIP) 
All randomized participants who previously received targeted immunotherapy for psoriasis. 
Participants will be analyzed according to the intervention allocated by randomization. 
Participants exposed to study intervention before or without being randomized will not be 
considered randomized and will not be included in any analysis population. The safety experience 
of these participants will be reported separately. 
Randomized participants for whom it is unclear whether they took the study intervention will be 
considered as exposed and will be included in the safety population as randomized. 
For any participant randomized more than once, only the data associated with the first 
randomization (except if the first randomization is done by error) will be used in any analysis 
population. The safety experience associated with any later randomization will be reported 
separately. 
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9.2 
STATISTICAL ANALYSES  
This section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints. 
9.2.1 General considerations  
The baseline value is defined as the last available value before the first dose of double-blind IMP. 
For participants randomized but not treated, the baseline value is defined as the last available 
value before randomization. 
Unless otherwise specified, analyses will be performed by intervention group/dose level and 
overall, for baseline and demographics characteristics. 
The observation period will be divided into 3 segments: 
• The pre-treatment period is defined as the period up to first double-blind IMP 
administration. 
• The treatment-emergent period is defined as the period from the first IMP 
administration to the last IMP administration +5 days. The treatment-emergent period 
includes the following 2 periods: 
- 
The on-treatment period is defined as the period from the first IMP 
administration to the last administration of the IMP +1 day. 
- 
The residual treatment period is defined as the period from the end of the 
on-treatment period to the end of the treatment-emergent period. 
• The post-treatment period is defined as the period from the end of the 
treatment-emergent period. 
9.2.2 Primary endpoint analyses  
9.2.2.1 Definition of endpoint  
The primary endpoint is the response in PASI75, which is defined by proportion of participants 
with a 75% or greater PASI improvement from baseline at Week 12. 
9.2.2.2 Main analytical approach  
The primary endpoint will be analyzed with the primary estimand defined according to the 
following attributes: 
• Endpoint: Proportion of participants with a 75% or greater PASI score improvement from 
baseline at Week 12. 
• Intervention condition: SAR441566 200 mg BID, 100 mg BID, 200 mg QD, 100 mg QD 
and 50 mg QD will be compared to placebo. 
• Analysis population: NTIP population 
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• Intercurrent events: 
- 
The IMP discontinuation: It will be handled with the treatment policy strategy. The 
primary endpoint will be assessed based on all assessments irrespective of the IMP 
discontinuation. 
- 
Starting the selected concomitant medication which could have an impact on the 
efficacy of IMP: It will be handled with the composite variable strategy. For primary 
endpoint, participants who receive selected concomitant medications will be 
considered as non-responders for time points after the medication usage. For other 
participants, all available data including those collected during the off-treatment period 
will be used to determine the responder/non-responder status. 
Of note, details of selection of concomitant medications which could have an impact on 
the efficacy of IMP will be specified in the SAP. 
• Population-level summary: Difference in the percentage of participants achieving PASI75 
response at Week 12 between each active arm and placebo. The Cochran-Mantel-Haenszel 
test will be used for the primary endpoint analysis. Multiplicity adjustment will be 
provided (See Section 9.2.5). Further details will be specified in the SAP. 
Missing data will be imputed to non-responders when the response to PASI75 is missing. 
9.2.2.3 Sensitivity/Supplementary analysis  
Supplementary/sensitivity analyses to assess the robustness of the conclusion of the primary 
analysis might be performed. To assess the consistency of treatment effects across different 
subgroup levels, subgroup analyses will be performed for the primary efficacy endpoint, such as 
age, gender, etc. Further details will be specified in SAP. 
9.2.3 Secondary endpoints analyses  
Categorical secondary endpoints will be analyzed using Cochran-Mantel-Haenszel test including 
treatment group in the NTIP. 
Continuous secondary endpoints will be analyzed by fitting an Analysis of Covariance model with 
the Baseline covariates in NTIP. Further details on missing data and intercurrent events handling 
will be specified in SAP. 
Other secondary analyses will be defined in Section 9.2.6.1 (AE, SAE, AESIs), Section 9.2.6.2 
(laboratory abnormalities), Section 8.5 (PK). 
No multiplicity adjustment for the secondary efficacy endpoints will be made. 
9.2.4 Exploratory/Tertiary endpoint(s) analyses  
The details about the analysis of tertiary endpoints will be described in the study SAP. The 
primary and key secondary endpoints will also be analyzed in ETIP population for exploratory 
purpose. 
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9.2.5 Multiplicity adjustment  
To control the overall Type I error of 0.05 under circumstance of multiple comparisons for the 
primary endpoint in the NTIP, the comparison between each dose of SAR441566 three doses 
(200 mg BID, 100 mg BID, 200 mg QD) and placebo will be conducted in a pairwise manner 
following a step-down procedure. The hierarchy will be 200 mg BID vs placebo, 100 mg BID vs 
placebo and 200 mg QD vs. Placebo. The testing will continue to the next level only if the 
previous comparison is statistically significant.  
9.2.6 Safety analyses  
All safety analysis will be based on the safety population according to the intervention group to 
which the participants are exposed. 
9.2.6.1 Adverse events  
General common rules for adverse events 
The AEs will be analyzed in the following 3 categories: 
• Pre-treatment AEs: AEs that developed, worsened, or became serious during the 
pre-treatment period. 
• TEAEs: AEs that developed, worsened, or became serious during the treatment-emergent 
period. 
• Post-treatment AEs: AEs that developed, worsened, or became serious during the 
post-treatment period. 
Similarly, the deaths will be analyzed in the pre-treatment, treatment-emergent and post-treatment 
periods. 
Analysis of all adverse events 
AE incidence table will be provided by treatment group for all types of TEAEs: all TEAEs, all 
treatment-emergent AESI (defined with a PT or a prespecified grouping), all treatment-emergent 
SAEs and all TEAEs leading to permanent treatment discontinuation. 
The AE summaries will be generated with number (%) of participants experiencing at least one 
event. 
Deaths will also be analyzed. 
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9.2.6.2 Laboratory variables, vital signs, and electrocardiograms (ECGs)  
Quantitative analyses 
When relevant, for laboratory variables, vital signs and ECG variables, descriptive statistics for 
results and changes from baseline will be provided for each planned visit/each analysis window, 
the last value, and the worst value (minimum and/or maximum value depending on the parameter) 
during the on-treatment period. These analyses will be performed using central measurements 
only (when available) for laboratory variables. For ECG variables, only the on-site automatic 
reading will be used in the quantitative analysis. 
Analyses according to PCSA 
PCSA analyses will be performed based on the PCSA list currently in effect at Sanofi at the time 
of the database lock. 
Analyses according to PCSA will be performed based on the worst value during the treatment-
emergent period, using all measurements either local or central, either scheduled, nonscheduled or 
repeated). 
For laboratory variables, vital signs and ECG variables, the incidence of participants with at least 
one PCSA during the treatment-emergent period will be summarized regardless of the baseline 
level and according to the following baseline status categories: 
• Normal/missing. 
• Abnormal according to PCSA criterion or criteria. 
For ECG, the incidence of participants with at least one abnormal ECG during the 
treatment-emergent period will be summarized regardless of the baseline level and according to 
the following baseline status categories: 
• Normal/missing. 
• Abnormal. 
9.2.7 Other analyses  
Data collected regarding the impact of the COVID-19 or other pandemics, on the participants will 
be summarized (eg, discontinuation due to COVID-19). Any additional analyses and methods 
required to investigate the impact of COVID-19 or other pandemics requiring public health 
emergency on the efficacy (eg, missing data due to COVID-19) and safety will be detailed in the 
SAP. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.8. 
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9.3 
INTERIM ANALYSES   
An interim analysis will be performed when approximately
f the participants in the primary 
analysis population have completed the EoS visit. The purpose of the interim analysis would be to 
provide early information for the Sponsor to plan for future development. The results of the 
interim analysis will not impact the conduct of the study. The SAP will describe the planned 
interim analysis in greater details. 
9.4 
SAMPLE SIZE DETERMINATION  
A total sample size of approximately 207 participants will be randomized to the intervention 
groups in two different strata, ie, NTIP vs. ETIP. 
In the stratum of NTIP, approximately 144 participants will be randomized in a randomization 
ratio 1:1:1:1:1:1 to SAR441566 200 mg BID, SAR441566 100 mg BID, SAR441566 200 mg QD, 
SAR441566 100 mg QD, SAR441566 50 mg QD and placebo, ie, 24 participants in each of six 
groups. The NTIP is the primary population for efficacy analysis. 
In the stratum of ETIP, approximately 63 participants will be randomized in a randomization ratio 
2:2:2:1 to SAR441566 200 mg BID, SAR441566 200 mg QD, SAR441566 100 mg QD and 
placebo, ie, 18 participants in each of SAR441566 200 mg BID, 200 mg QD and 100 mg QD 
groups and 9 participants in the placebo group. The ETIP is for exploratory purpose only. 
In the NTIP, assuming a
 dropout rate, the sample size of 24 participants per group will 
provide about 
% power to demonstrate superiority of SAR441566 200 mg BID or 100 mg BID 
or 200 mg QD versus placebo with a
with the following assumptions on the primary endpoint: 
• PASI75 Placebo rate of 
. 
• PASI75 SAR441566 rate of
. 
To estimate the dose-response curve on QD regimen in the NTIP, the sample size of 
24 participants per group will provide an minimum power of
% to detect the presence of a dose 
response, based on the assumption of a maximum effect in terms of PASI75 of treatment 
difference of 
% in SAR441566 comparing with placebo rate of 
%, using 
 
Calculations for Chi-square test were done using 
. 
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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 ICH Good Clinical Practice (GCP) guidelines. 
- 
The Regulation (EU) No 536/2014 of the European Parliament and the Council of 
16 April 2014 on clinical trials on medicinal products for human use, as applicable. 
- 
The General Data Protection Regulation (GDPR) and any other applicable data 
protection laws. 
- 
Any other applicable laws and regulations. 
• The protocol, protocol amendments, ICF, IB, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed 
and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard 
to study participants. 
• The Investigator will be responsible for the following, as applicable: 
- 
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. 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, Regulation No 536/2014 of the 
European Parliament and the Council of the European Union for clinical studies, 
European Medical Device Regulation 2017/745 for clinical device research, and all 
other applicable local regulations. 
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- 
Determining whether an incidental finding (as per Sanofi policy) 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 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 concerned 
reproductive importance, AND has analytical validity, AND has clinical validity. 
- 
The participant in a clinical study has the right to opt out of being notified by the 
Investigator of such incidental findings. If 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. 
As applicable, according to requirements of the Regulation No536/2014 of the European 
Parliament and the Council of the European Union, 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. 
According to the Regulation No 536/2014 of the European Parliament and the Council of the 
European Union and as specified by the applicable regulatory requirements in non-EU/ European 
Economic Area countries, Sanofi, as the clinical trial Sponsor, needs to report to the concerned 
regulatory agency/ies serious breaches without undue delay but not later than 7 calendar days of 
becoming aware of that breach. A serious breach is defined as a deviation of the version of the 
protocol applicable at the time of the breach or the applicable clinical trial regulation that is likely 
to affect to a significant degree the safety and rights of a participant or the reliability and 
robustness of the data generated in the clinical trial. 
The Sponsor shall ensure that all parties involved in the conduct of the clinical trial promptly 
report any events that might meet the definition of a serious breach. 
Therefore, Investigators shall within 48h after being aware of a deviation that might meet the 
definition of a serious breach, report to the Sponsor any suspected serious breach to enable the 
Sponsor to carry out the required assessment and notify the regulatory agency/ies in the event of a 
confirmed serious breach. To that extent, the principal Investigator must have a process in place to 
ensure that the site staff or service providers engaged by the principal Investigator/institution are 
able to identify the occurrence of a (suspected) serious breach and that a (suspected) serious 
breach is promptly reported to the Sponsor through the contacts (e-mail address or telephone 
number) provided by the Sponsor. 
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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  
The ICF will be provided to the study participant in paper version. 
• The Investigator or the Investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the potential participants, and answer all questions 
regarding the study, including what happens to the participants when their participation 
ends (post-trial access strategy for the study). 
• Potential participants must be informed that their participation is voluntary. They will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, Privacy and Data Protection requirements including 
those of the GDPR and of the French law, 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 enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• In case of ICF amendment while the participants are still included in the study, they must 
be re-consented to the most current version of the ICF(s). Where participants are not in the 
study anymore, teams in charge of the amendment must define if those participants must 
or not re-consent or be informed of the amendment (eg, if the processing of personal data 
is modified, if the Sponsor changes, etc). 
• A copy of the ICF(s) must be provided to the participant. 
The ICF contains 2 separate sections that address the use for future research of participants’ data 
and/or samples (remaining mandatory ones or new extra samples collected for optional research). 
Optional exploratory research should be detailed in the section “Optional tests/procedures” and 
future research is to be defined in Core Study Informed Consent Form (CSICF) Part 2. Each 
option is subject to an independent consent and must be confirmed by ticking checkboxes in 
CSICF Part 3, each checkbox corresponding to a specific use: consent for the performance of an 
optional exploratory research; consent for storage and use of coded data for future research; 
consent for use of leftover samples and associated coded data for future research; consent for 
collection of additional biological samples for storage and use for future research, and consent for 
performance of genetic analyses on biological samples. The Investigator or authorized designee 
will explain to each participant the objectives of the exploratory research and why data and 
samples are important for future 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. 
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For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.8. 
For Germany, please refer to Section 10.7.2. 
10.1.4 Data protection  
All personal data collected and/or processed in relation to this study will be handled in 
compliance with all applicable Privacy & Data Protection laws and regulations, including the 
GDPR. The study Sponsor is the Sanofi company responsible for ensuring compliance with this 
matter, when processing data from any individual who may be included in the Sanofi databases, 
including trial participants, Investigators, nurses, experts, service providers, Ethics Committee 
members, etc. 
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor takes all appropriate measures to safeguard and prevent access to this 
data by any unauthorized third party. 
Protection of participant personal data 
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 they are expected to modify 
the drug response/because they are required by regulatory agencies (eg, on African American 
population for the FDA or on Japanese population for the PMDA in Japan or Chinese population 
for the NMPA in China). They will not be collected in the countries where this is prohibited by 
local regulation. 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or its service providers, when applicable, will 
be identifiable only by the unique identifier; participant names or any information which 
would make the participant identifiable will not be transferred to the Sponsor. 
• Participants must be informed that their personal study-related data will be used by the 
Sponsor in accordance with applicable data protection laws. The level of disclosure must 
also be explained to the participant as described in the informed consent. 
• Participants must be informed that their 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. 
• The contract between Sponsor, Investigators, and study sites specifies responsibilities of 
the parties related data protection, including handling of data security breaches and 
respective communication and cooperation of the parties. Accordingly, the Investigator 
and the institution will promptly notify the Sponsor about any data security breaches and 
detail in the notification the nature of the breach, the categories (eg, Sponsor’s personnel, 
study participants or their relatives, healthcare professionals, etc), the approximate number 
of participants concerned, the type and approximate number of data records concerned and 
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the likely consequences of the breach. The institution and/or Investigator will investigate 
the causes of the data security breach and take actions to minimize the effects of said 
breach. The institution and/or Investigator will record all information relating to the 
breach, including the results of their own investigations and investigations by authorities, 
as applicable, and will take all measures as necessary to prevent future data security 
breaches. 
• Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access. 
• Participants must be informed that their study-related data will be used for the whole “drug 
development program”, ie, for this trial as well as for the following steps necessary for the 
development of the investigational product, including to support negotiations with payers 
and publication of results. 
Protection of personal data related to professionals involved in the study 
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to allow 
Sanofi to manage involvement in the study and/or the related contractual or 
pre-contractual relationship. They may be communicated to any company of the Sanofi 
group (“Sanofi”) or to Sanofi service providers, where needed. 
• Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (link available at 
Sanofi.com). 
• In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. 
The same rule applies in case the professionals are listed on a regulatory agencies 
disqualification list. 
• Personal data can be communicated to the following recipients: 
- 
Personnel within Sanofi or partners or service providers involved in the study. 
- 
Judicial, administrative and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in the 
framework of judicial or administrative procedures. Contact details and identity may 
also be published on public websites in the interest of scientific research transparency. 
• Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering an 
adequate level of protection. Those transfers are safeguarded by Sanofi in accordance with 
the requirement of European law including, notably: 
- 
The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers. 
- 
Sanofi’s Binding Corporate Rules for intra-group transfers. 
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• Professionals have the possibility to lodge a complaint with Sanofi leading Supervisory 
Authority, the “Commission Nationale de l’Informatique et des Libertés” (CNIL) or with 
any competent local regulatory authority. 
• Personal data of professionals will be retained by Sanofi for up to thirty (30) years, unless 
further retention is required by applicable regulations. 
• To facilitate the maintenance of Investigators personal data, especially if they contribute to 
studies sponsored by several pharmaceuticals companies, Sanofi participates in the Shared 
Investigator Platform (SIP) and in the TransCelerate Investigator Registry (IR) project 
(https://transceleratebiopharmainc.com/initiatives/investigator-registry) Therefore, 
personal data will be securely shared by Sanofi with other pharmaceutical company 
members of the TransCelerate project. This sharing allows Investigators to keep their data 
up to date once for across pharmaceutical companies participating in the project, with the 
right to object to the transfer of the data to the TransCelerate project. 
• Professionals have the right to request the access to and the rectification of their personal 
data, as well as their erasure (where applicable) by contacting the Sanofi Data Protection 
Officer: Sanofi DPO - 54 rue La Boétie - 75008 PARIS - France (to contact Sanofi by 
email, visit https://www.sanofi.com/en/our-responsibility/sanofi-global-privacy-
policy/contact). 
10.1.5 Committees structure  
10.1.5.1  Data Monitoring Committee  
The Sponsor will implement an IDMC for the duration of this study. The IDMC will be charged 
with monitoring the safety of patients participating in this clinical trial. The IDMC will review the 
safety and associated data (eg, labs) from the study at established frequencies, as defined in the 
IDMC charter. The IDMC will identify any concerning safety signals that merit further evaluation 
and make recommendations to the Sponsor on all safety aspects, based on their independent 
evaluation of unblinded data from study groups. 
During this process, the IDMC will also institute any measures that may be required for ensuring 
the integrity of the study results during the execution of its primary mission. 
The IDMC will be comprised of at least 5 external members who specialize in the following 
areas: 
Members of the IDMC will be independent of those performing the study, being neither 
investigators nor employees of the Sponsor, and without conflict of interest regarding study 
outcome. The details of IDMC composition, schedule of meetings, and functions will be detailed 
in the IDMC charter. The IDMC’s specific activities will be defined by a mutually agreed charter, 
which will define the IDMC membership, conduct and meeting schedule. 
Sanofi retains final decision-making authority on all aspects of the study. 
Follow-up actions may be taken based on data and recommendations generated by the IDMC 
including any change in the study design or communication with health authorities, as indicated. 
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10.1.6 Dissemination of clinical study data and results  
Study participants 
At the end of the clinical study, the Sponsor may publish the study results in scientific journal(s). 
As part of the review for publication, independent scientists may need to use “coded” data of all 
the study participants to independently verify the study’s results. 
Sanofi shares information about clinical trials and results on publicly 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, euclinicaltrials.eu, and sanofi.com, as well as some national 
registries. For pediatric and adult trials, the results will generally be submitted/released 6 and 12 
months respectively, after the end of the clinical trial worldwide (ie, the last active, participating 
country). 
In addition, results from clinical trials in participants 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 vivli.org. 
Individual anonymized participant data and supporting clinical documents are available for 
request at vivli.org. 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: vivli.org. 
Professionals involved in the study or in the drug development program 
 
Sanofi may publicly disclose, and communicate to relevant authorities/institutions, the funding, 
including payments and transfers of value, direct or indirect, made to healthcare organizations and 
professionals and/or any direct or indirect advantages and/or any related information or document 
if required by applicable law, by regulation or by a code of conduct such as the “EFPIA Code on 
Disclosure of Transfers of Value from Pharmaceutical Companies to Healthcare Professionals and 
Healthcare Organisations”. 
10.1.7 Data quality assurance  
• All participant data relating to the study will be recorded on eCRF 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 electronically signing 
the eCRF. 
• Guidance on completion of eCRFs will be provided in eCRF Completion Instructions. 
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• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Quality tolerance limits (QTLs) will be pre-defined to identify systematic issues that can 
impact participant safety and/or reliability of study results. These pre-defined parameters 
will be monitored during the study and important deviations from the QTLs and remedial 
actions taken will be summarized in the clinical study report. 
• Monitoring details describing strategy, including definition of study critical data items and 
processes (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). 
• 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 different 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 entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The Investigator may 
need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available. 
• Definition of what constitutes source data can be found in monitoring guidelines. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• The Sponsor or designee will perform monitoring to confirm that data entered the eCRF 
by authorized site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of participants are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.9 Study and site start and closure  
First act of recruitment 
The first act of recruitment is the first participant screened and will be the study start date. 
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Study/Site termination 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for 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 IMP 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. 
 
 
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10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
• The tests detailed in Table 7 will be performed by the central laboratory. 
• Local laboratory results are only required if the central laboratory results are not available 
in time for either study 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 a study IMP 
decision or response evaluation, the results must be recorded. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and Section 5.2. 
• Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
Table 7 - Protocol-required laboratory tests  
Laboratory tests 
Parameters 
Hematology 
Platelet count 
 
Red blood cell (RBC) count 
 
RBC indices: 
 
Mean corpuscular volume (MCV) 
 
Mean corpuscular hemoglobin (MCH) 
 
%Reticulocytes 
 
White blood cell (WBC) count with differential: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
 
Hemoglobin 
 
Hematocrit 
Clinical chemistrya 
Bicarbonate 
 
Blood urea nitrogen (BUN) 
 
Potassium 
 
Creatinine 
 
Creatinine clearance 
 
Glucose non-fasting 
 
Sodium 
 
Calcium 
 
Chloride 
 
Phosphate 
 
AST/Serum glutamic-oxaloacetic transaminase 
 
ALT/Serum glutamic-pyruvic transaminase 
 
ALPb 
 
Albumin 
 
Total bilirubin 
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Laboratory tests 
Parameters 
 
Conjugated bilirubin 
 
Unconjugated bilirubin 
 
Total protein 
 
CPK 
 
Total cholesterol fasting 
 
 
 
Pregnancy testing 
[Serum or highly sensitive urine] human chorionic gonadotropin (hCG) pregnancy test (as 
needed for women of childbearing potential)c 
Other screening tests 
FSH (as needed in women of nonchildbearing potential only) 
Serology (QuantiFERON®, HIV (HIV-1 and HIV-2) antibodies/CD4 count, HBsAg, IgM and 
total HBcAb and HCVAb. In case of HBcAb positivity, HBV-DNA testing must be performed. 
In case of HCVAb positivity, HCV-RNA testing must be performed (for Japan, HBsAb needs 
to be tested in addition to HBsAg and (IgM or total) HBcAb - Section 10.7.3) 
hsCRP 
All study-required laboratory tests will be performed by a central laboratory except for urine 
pregnancy. 
NOTES: 
a Details of liver chemistry stopping criteria and required actions and follow-up are given in Section 7.1.2 Liver Chemistry 
Stopping Criteria and Appendix 6 (Section 10.6). 
b If alkaline phosphatase is elevated, consider fractionating. 
c Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
Investigators must document their review of each laboratory safety report. 
10.3 
APPENDIX 3: AES AND SAES: 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 clinical study participant, temporally 
associated with the use of study IMP, whether considered related to the study IMP. 
• 
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 IMP. 
Definition of unsolicited and solicited AE 
• 
An unsolicited AE is an AE that was not solicited using a participant questionnaire and 
that is communicated by a participant who has signed the informed consent. Unsolicited 
AEs include serious and nonserious AEs. 
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• 
Potential unsolicited AEs may be medically attended (ie, symptoms or illnesses requiring 
a hospitalization, emergency room visit, or visit to/by a health care provider). The 
participants will be instructed to contact the site as soon as possible to report medically 
attended event(s), as well as any events that, though not medically attended, are of 
participant’s concern. Detailed information about reported unsolicited AEs will be 
collected by qualified site personnel and documented in the participant’s records. 
• 
Unsolicited AEs that are not medically attended nor perceived as a concern by the 
participant will be collected during an interview with the participants and by review of 
available medical records at the next visit. 
• 
Solicited AEs are predefined local and systemic events for which the participant is 
specifically questioned, and which are noted by the participants in their questionnaire. 
Events meeting the AE definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, 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, or more severe than expected for the participant’s condition), 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 pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New condition detected or diagnosed after study IMP 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 IMP or 
a concomitant medication. 
• 
Signs, symptoms, or the clinical sequelae of any medication errors, misuse, and abuse 
with the IMP. 
• 
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. 
• 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as an AE or SAE if they fulfill the definition of an AE or SAE. Lack of efficacy 
or failure of expected pharmacological action also constitutes an AE or SAE. 
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Events NOT meeting the AE definition 
• Any abnormal laboratory findings or other abnormal safety assessments that 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 pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2 Definition of SAE  
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or more of 
the criteria listed: 
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 admitted (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 pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d) Results in persistent or significant 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) that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect. 
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f) Other situations: 
Medical or scientific judgment should be exercised by the Investigator 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. 
The following list of medically important events is intended to serve as a guideline for 
determining which condition could be considered as a medically important event. The 
list is not intended to be exhaustive: 
• Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm. 
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc). 
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc). 
• Development of drug dependence or drug abuse. 
• ALT >3 × ULN + total bilirubin >2 × ULN or asymptomatic ALT increase >10 × ULN. 
• Suicide attempt or any event suggestive of suicidality. 
• Syncope, loss of consciousness (except if documented because of blood sampling). 
• Bullous cutaneous eruptions. 
• Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study. 
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. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor’s representative in lieu of completion of the required form. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor’s representative. In this case, all participant identifiers, except for the 
participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor’s representative. 
• 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. 
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Assessment of intensity 
The Investigator will assess intensity for each AE and SAE reported during the study and assign it 
to one of the following categories: 
• Mild: A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
• Moderate: A type of adverse event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research participant. 
• Severe: A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic intervention. 
Assessment of causality 
• The Investigator is obligated to assess the relationship between study IMP and each 
occurrence of each AE/SAE. The Investigator will use clinical judgment to determine the 
relationship. 
• A reasonable possibility of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than that a relationship cannot be ruled 
out. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study IMP administration will 
be considered and investigated. 
• For causality assessment, the Investigator will also consult the IB and/or product 
information, for marketed products. 
• The Investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes. 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’s representative. However, it is very important that the Investigator always 
assess causality for every event before the initial transmission of the SAE data to the 
Sponsor’s representative. 
• The Investigator may change his/her opinion of causality considering follow-up 
information and send an 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’s 
representative to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
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• 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 postmortem findings 
including histopathology. 
• New or updated information will be recorded in the originally submitted documents. 
• 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’s representative 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) 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 
offline 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 
offline, then the site can report this information on a paper SAE form (see next section) or 
to the Sponsor’s representative by telephone. 
• Contacts for SAE reporting can be found in investigator site file. 
SAE reporting to the Sponsor via paper data collection tool 
• Facsimile transmission of the SAE paper data collection tool is the preferred method to 
transmit this information to the Sponsor’s representative. 
• 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 data collection tool within the designated reporting timeframes]. 
• Contacts for SAE reporting can be found in the protocol cover page (Sponsor Monitoring 
team). 
 
 
 
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10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE  
10.4.1 Definitions  
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
• Premenarchal. 
• 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, gonadal 
dysgenesis), investigator discretion should be applied to determining study entry 
eligibility. 
• Postmenopausal 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
- 
A high FSH level in the postmenopausal range may be used to confirm a postmenopausal 
state in women not using hormonal contraception or hormone replacement treatment 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH measurement 
is insufficient. 
- 
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-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 enrolment. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first administration of study IMP, additional evaluation should be considered. 
10.4.2 Contraception guidance  
• Participants should be given advice about donation and cryopreservation of germ cells 
prior to the start of the study IMP, in line with the fact that study IMP may affect ova up to 
3 months and sperm up to 3 months (see inclusion criteria). 
• If locally required, acceptable contraceptive methods are limited to those which inhibit 
ovulation as the primary mode of action. 
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CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly effective methodsb that have low user dependency Failure rate of <1% per year when used 
consistently and correctly. 
• Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS)c 
• Bilateral tubal occlusion or ligation 
• Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia 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. 
Note: documentation of azoospermia for a male participant can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history interview. 
Highly effective methodsb that are user dependent Failure rate of <1% per year when used 
consistently and correctly. 
• 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 IMP. 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 Male or female condoms must be used only in addition to hormonal contraception. 
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 from friction). 
 
 
 
 
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10.6 
APPENDIX 6: LIVER AND OTHER SAFETY SUGGESTED ACTIONS AND FOLLOW-
UP ASSESSMENTS AND STUDY IMP RESTART/RECHALLENGE GUIDELINES  
 
Neutropenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting adverse events in Section 8.4 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 adverse events in Section 8.4 is met. 
 
 
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*If unable to retest in 72 hours, use original lab results to decide on further reporting/monitoring/discontinuation. 
** Unless a protocol-defined criterion for permanent discontinuation is met. 
*** See box below 
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 Section 8.4 for guidance on safety reporting. 
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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 adverse events in Section 8.4 is met. 
 
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Increase in CPK is to be recorded as an AE only if at least 1 of the criteria in the general 
guidelines for reporting adverse events in Section 8.4 is met. 
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10.7 
APPENDIX 7: COUNTRY-SPECIFIC/REGION REQUIREMENTS  
10.7.1 China  
Exploratory/Tertiary biomarker samples to characterize immune cell populations including Th17, 
Treg, CD4 and CD8 as described in Section 1.3 and Section 8.8 will be optionally collected for 
participants in China. 
Exploratory/Tertiary genetic and protein biomarker samples for future research, including RNA 
and DNA sequencing, and proteomics as described in Section 1.3, Section 8.7 and Section 8.8 are 
not applicable for participants in China. 
In accordance with local requirements, the use of biological samples as described in Section 8.11 
are not applicable for participants in China. 
For prohibited concomitant medication refer to Section 6.9.2. 
Furthermore, any Chinese medicine containing Tripterygium and/or Total glucosides of peony are 
not allowed 1 month prior to V1 or during the trial period. Other Chinese medicine aimed at 
treating psoriasis also cannot be used 1-month prior V1 or during the trial period. 
10.7.2 Germany  
Informed consent process: All references to "legally authorized representative" are not applicable 
in Germany; only participants who can give written consent themselves are included in the study. 
References to "legally authorized representative" are found in Section 10.1.3. 
10.7.3 Japan  
Participants in Japan need to be tested for HBsAb, in addition to HBsAg and (IgM or total) 
HBcAb. Positive results for HBsAb, or IgM or total HBcAb need to be confirmed by positive 
HBV-DNA. 
Participants with positive HBsAg are excluded. 
Participants with positive HBsAb or (IgM or total) HBcAb but negative (no detectable) 
HBV-DNA, are required to undergo HBV-DNA testing at Week 4, Week 8, Week 12. 
10.7.4 Czech Republic  
Participants with positive HIV-1 or HIV-2 serology are excluded. 
Complete and targeted physical examinations may be performed only by a physician. 
Participants with documented completed appropriate active or latent TB treatment would not be 
excluded from enrolment if their enrolment is approved by a TB specialist or an infectious 
diseases specialist. 
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10.8 
APPENDIX 8: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY  
For European countries contingency measures are currently only applicable for the COVID-19 
pandemic. 
10.9 
APPENDIX 9: COLLECTION, STORAGE AND FUTURE USE OF DATA AND HUMAN 
BIOLOGICAL SAMPLES  
10.9.1 Compliance with Member State applicable rules for the collection, storage, and 
future use of human biological samples (Article 7.1h)  
This appendix is provided separately. 
10.9.2 Compliance with Member State applicable rules for the collection, storage, and 
future use of (personal) data (article 7 (1 d) of EU Regulation 536/2014)  
This appendix is provided separately. 
 
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10.11 APPENDIX 11: LISTS OF CYP3A AND P-GP INHIBITORS AND INDUCERS  
 
Concomitant administration of medications that are 
 of the study. 
 which triggered at least 2-fold 
changes of AUC of the victim probe
 of the study. 
The following lists were extracted from the Drug Interaction Database from the University of 
Washington (www.druginteractionsolutions.org). 
Note that the lists provided may not be exhaustive and that the product information of drugs 
intended for concomitant use should be consulted. 
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10.13 APPENDIX 13: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the table of contents (TOC). 
10.13.1 Amended protocol 03 (04 December 2023)  
This amended protocol (amendment 03) is considered to be non-substantial based on the criteria 
set forth in Article 2(2)(13) of the Regulation of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
This amendment is the result of the European Union (EU) consideration. It incorporates a specific 
country requirement for Czech Republic relative to TB exclusion criteria. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
5.2 Exclusion Criteria – 
E30 
The following statement has been added: ”b) have obtained 
consultation with a specialist to rule out or treat active TB 
infection (for participants in the Czech Republic, see 
Section 10.7.4), AND” 
Country specific requirement 
8.3.5 Tuberculosis 
assessment and 
QuantiFERON® 
The last paragraph of the section has been amended to 
“Participants with a positive screening test will not be eligible 
for the study. Participants with documented completed 
appropriate active/latent TB treatment would not be excluded if 
consultation with a specialist has been obtained to rule out or 
treat active TB infection (for participants in the Czech 
Republic, see Section 10.7.4) and Sponsor approval has 
been granted in writing (Refer to exclusion criteria E 30).” 
Country specific requirement 
10.7.4 Czech Republic 
The current section has been updated with the following 
wording: “Participants with documented completed appropriate 
active or latent TB treatment would not be excluded from 
enrolment if their enrolment is approved by a TB specialist or 
an infectious diseases specialist.” 
Country specific requirement 
10.13.2 Amended protocol 02 (22 November 2023)  
This amended protocol (amendment 02) is considered to be non-substantial based on the criteria 
set forth in Article 2(2)(13) of the Regulation of the European Parliament and the Council of the 
European Union. 
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OVERALL RATIONALE FOR THE AMENDMENT 
This amendment is the result of the European Union (EU) consideration. It incorporates the 
recommendation to extend the follow-up period, update the frequency of urine pregnancy testing, 
clarify exclusion criteria related to washout period rules, incorporate drugs list that prolong QT 
interval, exclude incapacitated participants, clarify the rescue medication, clarify the process for 
including participants with active/latent TB treatment, provide interim analysis details, and to 
include specific country requirements for Czech Republic. In addition, medical photography 
assessments are no longer planned in this protocol and have been removed. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
Considering the safety follow-up period, the previous wording 
“2 weeks” has been replaced by “4 weeks” 3 times in this 
section.  
Extending the follow-up period 
to 4 weeks 
1.2 Schema 
Post-treatment has been changed from “2 weeks”, “Week14” 
to “4 weeks”, “Week 16” 
Extending the follow-up period 
to 4 weeks 
1.3 Schedule of Activities 
(SoA) 
Post-treatment has been changed from “2 weeks” to “4 
weeks”; corresponding End of Study day has been updated 
accordingly to Day 113 and “Week 14” to “Week 16”. 
Extending the follow-up period 
to 4 weeks 
1.3 Schedule of Activities 
(SoA) 
The row “Optional: Medical Photographyq” has been deleted. 
Medical photography is no 
longer planned in this protocol 
1.3 Schedule of Activities 
(SoA) 
Initial urine pregnancy testing planned at “Screening and 
Weeks 0, 12” have been updated to “Screening and Weeks 0, 
4, 8, 12 and 16 (EoS)” 
Setting-up the interval of the 
urine pregnancy testing to 4 
weeks during IMP treatment in 
WOCBP, including at the EoS.  
1.3 Schedule of Activities 
(SoA) - Footnotes 
Footnote “q” related to “Optional Medical Photography” has 
been deleted. The order of the footnotes that followed has 
been updated both in the footnote part and in the SoA. 
Medical photography is no 
longer planned in this protocol 
4.4 End-of-study definition 
Post-treatment period has been updated from “2-week”, “4- 
week” 
Extending the follow-up period 
to 4 weeks 
5.2 Exclusion Criteria – 
E18 
The first sentence of the E18 has been updated from 
“Simultaneous treatment with phototherapy or the following 
systemic therapies, however participants can go through 
washout to be considered for the study. Emollients are 
accepted, as much as needed, during the duration of the study 
(see Table 5).” to “Simultaneous treatment with phototherapy 
or the following systemic therapies, however participants can 
go through washout to be considered for the study. 
Participants should not be withdrawn from a treatment if 
the disease is well controlled in order to be considered for 
the study. Emollients are accepted, as much as needed, 
during the duration of the study (see Table 5).” 
Wording update to avoid 
misinterpretation of E18 
5.2 Exclusion Criteria – 
E20 
Insert a reference to Appendix 12: QT prolonging drug list 
Clarification 
5.2 Exclusion Criteria – 
E29 
The following statement has been added:”(for participants in 
the Czech Republic, see Section 10.7.4).” 
Country specific requirement 
5.2 Exclusion Criteria – 
E33 
“incapacitated” has been explicitly added to the list of reasons 
indicating that a participant is not suitable for participation. 
Wording update to avoid 
misinterpretation of E33 
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Section # and Name 
Description of Change 
Brief Rationale 
6.9.4 Rescue medicine 
The following indication has been added “Topical 
corticosteroids of class least potent or mild (US class 6 or 7) 
(such as hydrocortisone) are permitted for use limited to the 
face, axilla, and/or genitalia with a restriction of use within 24 
hours prior to clinic visits on Day 1, Week 4, 8 and 12.” 
Wording about the rescue 
medication needed to be 
explicit  
8.2.11 Medical 
Photography (Optional) 
[deleted] 
This section has been removed from the protocol. 
Medical photography is no 
longer planned in this protocol 
8.3.3 Electrocardiograms 
Considering the safety follow-up period, the previous wording 
“Week 14” has been replaced by “Week 16”. 
Extending the follow-up period 
to 4 weeks 
8.3.5 Tuberculosis 
assessment and 
QuantiFERON® 
The last paragraph of the section has been amended to 
“Participants with documented completed appropriate 
active/latent TB treatment would not be excluded if 
consultation with a specialist has been obtained to rule 
out or treat active TB infection and Sponsor approval has 
been granted in writing (Refer to exclusion criteria E 30).” 
Clarification that participants 
with documented completed 
appropriate active/latent TB 
treatment would not be 
excluded from enrolment if a 
specialist consultation has been 
obtained as well as Sponsor 
approval. 
9.3 Interim Analyses 
An interim analysis will be performed. The section has been 
amended to: “An interim analysis will be performed when 
approximately 70% of the participants in the primary analysis 
population have completed the Week 12 visit. The purpose of 
the interim analysis would be to provide early information for 
the Sponsor to plan for future development. The results of the 
interim analysis will not impact the conduct of the study. The 
SAP will describe the planned interim analysis in greater 
details.” 
Clarification 
10.7.4 Czech Republic 
The current section has been added with the following 
wording: “Participants with positive HIV-1 or HIV-2 serology 
are excluded. Complete and targeted physical examinations 
may be performed only by a physician.” 
Country specific requirement 
10.12 Appendix 12: QT 
prolonging drug list 
Appendix 10.12 has been included in the protocol to provide a 
list of drugs that prolong the QTcF interval with known risk for 
Torsades de Pointes or that can prolong the QT interval 
Explicitly listing the concomitant 
medications known to prolong 
the QTcF interval 
10.13 Appendix 13: 
Protocol amendment 
history 
Appendix 12: Protocol amendment history is referred to 
Appendix13: Protocol amendment history in the current 
amendment 
Table of Contents update 
10.13.3 Amended protocol 01 (19 October 2023)  
This amended protocol (amendment 01) is considered to be non-substantial based on the criteria 
set forth in Article 2(2)(13) of the Regulation of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The main rationale for the amendment pertaining to Japan is to align with the PMDA request. 
Following initial submissions in Japan, the PMDA requested changes to the HBsAg related 
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inclusion criteria for Japanese participants only. This amendment affects Appendix 10.7.3 of the 
study protocol. Japanese participants with a positive HBsAg are excluded. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
10.7.3 Japan 
(5.2 Exclusion Criteria 
E28; 1.3 Schedule of 
Activities; and Table 7) 
“Participants in Japan need to be tested for HBsAb, in addition 
to HBsAg and (IgM or total) HBcAb. Positive results for 
HBsAb, or HBsAg, or IgM or total HBcAb need to be confirmed 
by positive HBV-DNA. 
Participants with positive HBsAb or HBsAg or (IgM or total) 
HBcAb but negative (no detectable) HBV-DNA, are required to 
undergo HBV-DNA testing at Week 4, Week 8, Week 12.” 
has been replaced by 
“Participants in Japan need to be tested for HBsAb, in addition 
to HBsAg and (IgM or total) HBcAb. Positive results for 
HBsAb, or HBsAg, or IgM or total HBcAb need to be 
confirmed by positive HBV-DNA. 
Participants with positive HBsAg are excluded. 
Participants with positive HBsAb or HBsAg or (IgM or total) 
HBcAb but negative (no detectable) HBV-DNA, are required to 
undergo HBV-DNA testing at Week 4, Week 8, Week 12.” 
According to PMDA request, 
Japanese participants with a 
positive HBsAg are excluded. 
 
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11 
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14. Langley RG, Feldman SR, Nyirady J, van de Kerkhof P, Papavassilis C. The 5-point 
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