Clinical trial NCT04781816
Conditions: Cutaneous Lupus Erythematosus
Sponsor: Sanofi
Start date: 2021-04-01; Completion date: 2023-06-26
Enrollment: 78 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

* Assess the efficacy of SAR443122 in cutaneous lupus erythematosus (CLE)

Secondary Objectives:

* Assess the effect of SAR443122 on the physician's global assessment of disease activity (PhysGA - disease activity)
* Assess the effect of SAR443122 on CLE induced itch and overall pain
* Assess the effect of SAR443122 on the proportion of disease activity responders compared to placebo
* Assess the effect of SAR443122 on the CLASI components score
* Assess the effect of SAR443122 on the Investigator's global assessment for CLE (IGA-CLE)
* Assess oral cavities for patients with oral lesions
* Assess the disease specific quality of life (QoL)
* Assess the safety and tolerability of SAR443122 in patients with CLE
* Assess the pharmacokinetics (PK) exposure of SAR443122 in patients with CLE

Detailed description:
Total study duration per participant was up 20 weeks including:

* A screening period of up to 4 weeks
* A treatment period of 12 weeks
* A post treatment follow-up period of 4 weeks

Arms: arm 1: SAR443122 for 12 weeks arm 2: Matching placebo
Interventions: intervention 1: SAR443122 intervention 2: Placebo
Intervention descriptions: intervention 1: Pharmaceutical form: Capsule Route of administration: Oral intervention 2: Pharmaceutical form: Capsule Route of administration: Oral

Protocol documents:
Prot_000.pdf: 
 
 
 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to Template: Sanofi OneDocument Version 4.0, dated 27-JUL-2020 
Page 1 
f 
AMENDED CLINICAL TRIAL PROTOCOL 02 
Protocol title: 
A randomized, double-blind, placebo controlled, proof 
of concept study assessing the efficacy and safety of 
the RIPK1-inhibitor SAR443122 in patients with 
moderate to severe subacute or discoid/chronic 
cutaneous lupus erythematosus 
Protocol number: 
ACT16404 
Amendment number: 
02 
Compound number 
(INN/Trademark): 
SAR443122 
Brief title: 
Proof of concept study of SAR443122 in patients with 
cutaneous lupus erythematosus 
CLEan 
Study phase: 
Phase 2 
Sponsor name: 
Sanofi-Aventis Recherche & Développement 
Legal registered 
address:  
1 avenue Pierre Brossolette 
91385 Chilly Mazarin Cedex 
France 
Manufacturer: Same as Sponsor 
Monitoring team’s 
representative name and 
contact information 
   
Regulatory agency identifier number(s): 
IND: 
152733 
EudraCT: 
2020-004703-14 
NCT: 
NCT04781816 
WHO: 
U1111-1246-6784 
EUDAMED: 
Not applicable 
Other: 
Not applicable 
 
Date: 
22-Nov-2022 
Total number of pages: 126 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial protocol 02 
All 
22-Nov-2022, version 1 (electronic 2.0) 
Amended Clinical Trial protocol 01 
All 
10-Dec-2021, version 1 (electronic 1.0) 
Original Protocol 
 
11-Dec-2020, version 1 (electronic 2.0) 
Amended Clinical Trial protocol 02 (22 November 2022) 
This amended clinical trial protocol 02 (amendment 02) is considered to be not substantial based 
on the criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and 
the Council of the European Union. Because it does not significantly impact the safety or 
physical/mental integrity of participants, nor the scientific value of the study. 
OVERALL RATIONALE FOR THE AMENDMENT 
The main purpose of this amendment is to include an interim analysis. The sponsor will make use 
of this interim analysis to facilitate internal operational decision on the compound development. 
For the details of the interim analysis, see Section 9.4. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 9.3 Statistical 
analyses 
Added: 
The SAP will be developed and finalized prior to 
database lock or any interim analysis. 
To provide more precision. 
Section 9.4 Interim analysis  
Added: 
An interim analysis is planned for this study. The 
sponsor will make use of this interim analysis to 
facilitate internal operational decision on the 
compound development. The interim analysis will 
be performed when around 75% of the patients 
have completed study treatment or discontinued 
the study. The interim analysis will not lead to 
changes in the conduct of the protocol other than 
stopping recruitment for this proof of concept 
study due to clear efficacy signal at the time of 
the interim analysis or due to lack of an efficacy 
signal, indicating a lack of equipoise for continued 
recruitment of patients. The details including the 
pre-specified rules for stopping the recruitment 
will be described in the SAP.  
An interim analysis is planned to facilitate 
internal operational decision on the 
compound development. 
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Section # and Name 
Description of Change 
Brief Rationale 
The interim analysis will evaluate the mean 
percent change from baseline in CLASI-A at 
Week 12 and other selected secondary efficacy 
endpoints, as well as the safety endpoints as 
needed. The PK and PD relationship could also 
be explored. 
The interim analysis will be performed by 
a separate statistical team, independent of the 
study team. The PK/PD analysis will be 
performed by a sponsor internal modeling and 
simulation team, also independent of the study 
team. Only those necessary for conducting the 
interim analysis and those responsible for internal 
project planning/overall portfolio planning needs 
(eg, to aid in the planning of future studies) will 
have the access to the interim analyses results 
before study completion.  A list of these 
individuals will be maintained. 
All sponsor internal personnel with access to 
unblinding information will be asked to sign 
a study confidentiality agreement before having 
access to unblinding information. Study team and 
investigational sites will not have access to 
interim study results, and continue to be blinded 
to individual randomization codes until study 
completion and database lock 
Section 10.1.6 Dissemination 
of clinical study data; 
Study participants 
Replaced “clinicalstudydatarequest.com” to 
“vivli.org” 
To correct the website address for 
dissemination of clinical study data of 
study participants. 
 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 02 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 4 
LIST OF TABLES ........................................................................................................................................... 9 
LIST OF FIGURES .......................................................................................................................................... 9 
1 
PROTOCOL SUMMARY ............................................................................................................... 10 
1.1 
SYNOPSIS ..................................................................................................................................... 10 
1.2 
SCHEMA ........................................................................................................................................ 15 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 16 
2 
INTRODUCTION ............................................................................................................................ 21 
2.1 
STUDY RATIONALE...................................................................................................................... 24 
2.2 
BACKGROUND ............................................................................................................................. 24 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 25 
2.3.1 
Risk assessment ............................................................................................................................ 25 
2.3.2 
Benefit assessment ........................................................................................................................ 27 
2.3.3 
Overall benefit: risk conclusion ...................................................................................................... 27 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 29 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 30 
4 
STUDY DESIGN ............................................................................................................................ 33 
4.1 
OVERALL DESIGN ........................................................................................................................ 33 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 34 
4.2.1 
Participant input into design ........................................................................................................... 35 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 35 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 35 
5 
STUDY POPULATION .................................................................................................................. 36 
5.1 
INCLUSION CRITERIA .................................................................................................................. 36 
5.2 
EXCLUSION CRITERIA  ............................................................................................................... 38 
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5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 41 
5.3.1 
Meals and dietary restrictions ........................................................................................................ 41 
5.3.2 
Caffeine, alcohol, and tobacco ....................................................................................................... 41 
5.3.3 
Activity ............................................................................................................................................ 41 
5.4 
SCREEN FAILURES...................................................................................................................... 41 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
(ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION) ............. 42 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 43 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 44 
6.1.1 
Investigational medicinal product ................................................................................................... 44 
6.1.2 
Non-investigational medicinal product ........................................................................................... 45 
6.1.3 
Devices .......................................................................................................................................... 45 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 45 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 46 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 47 
6.5 
DOSE MODIFICATION .................................................................................................................. 47 
6.5.1 
Retreatment criteria........................................................................................................................ 47 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY....................... 47 
6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 48 
6.8 
CONCOMITANT THERAPY .......................................................................................................... 48 
6.8.1 
Prohibited medications ................................................................................................................... 48 
6.8.2 
Topical corticosteroids ................................................................................................................... 49 
6.8.3 
Systemic corticosteroids ................................................................................................................ 49 
6.8.4 
Intra-articular, intralesional, intranasal, and inhaled corticosteroids .............................................. 49 
6.8.5 
Chloroquine and hydroxychloroquine ............................................................................................ 49 
6.8.6 
Nonsteroidal anti-inflammatory drugs, topical anesthetics, acetaminophen and other 
analgesic ........................................................................................................................................ 49 
6.8.7 
Drug interaction .............................................................................................................................. 50 
6.8.8 
Rescue medications ....................................................................................................................... 50 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 51 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  ..................................................................... 51 
7.1.1 
Permanent discontinuation ............................................................................................................ 51 
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7.1.1.1 
Handling of participants after permanent intervention discontinuation .......................................... 52 
7.1.2 
Liver chemistry stopping criteria .................................................................................................... 52 
7.1.3 
QTc stopping criteria ...................................................................................................................... 52 
7.1.4 
Temporary discontinuation ............................................................................................................. 52 
7.1.5 
Rechallenge ................................................................................................................................... 52 
7.1.5.1 
Study intervention restart or rechallenge after liver stopping criteria met ...................................... 53 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 53 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 54 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 55 
8.1 
EFFICACY ASSESSMENTS  ........................................................................................................ 55 
8.1.1 
Cutaneous lupus Erythematosus Disease Area and Severity Index (CLASI) ............................... 55 
8.1.2 
Physician Global Assessment of disease activity (PhysGA- disease activity) for cutaneous 
lupus erythematosus ...................................................................................................................... 56 
8.1.3 
Physician Global Assessment of Change in cutaneous lupus erythematosus activity 
(PGAC) ........................................................................................................................................... 56 
8.1.4 
Patient-reported Numerical Rating Scale (NRS) ........................................................................... 57 
8.1.5 
Investigator’s Global Assessment for Cutaneous Lupus Erythematosus (IGA-CLE) .................... 57 
8.1.6 
Oral Health Impact Profile 14-item version (OHIP-14) ................................................................... 58 
8.1.7 
SKINDEX-29+3 .............................................................................................................................. 58 
8.1.8 
Patient Global Impression of disease severity (PGIS) and Patient Global Impression of 
Change (PGIC) in cutaneous lupus erythematosus ...................................................................... 59 
8.1.9 
28-Joint assessment ...................................................................................................................... 59 
8.1.10 
Safety of Estrogens in Lupus Erythematosus National Assessment - Systemic Lupus 
Erythematosus Disease Activity Index (SELENA-SLEDAI) ........................................................... 59 
8.1.11 
Genital Erosive Lichen Planus (GELP) score ................................................................................ 59 
8.1.12 
Photography of Index Lesion ......................................................................................................... 60 
8.2 
SAFETY ASSESSMENTS  ............................................................................................................ 60 
8.2.1 
Physical examinations ................................................................................................................... 60 
8.2.2 
Vital signs ....................................................................................................................................... 61 
8.2.3 
Electrocardiograms ........................................................................................................................ 61 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 61 
8.2.5 
Suicidal ideation and behavior risk monitoring .............................................................................. 62 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 62 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 62 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 63 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 63 
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8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 63 
8.3.5 
Pregnancy ...................................................................................................................................... 64 
8.3.6 
Cardiovascular and death events .................................................................................................. 64 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 64 
8.3.8 
Adverse event of special interest ................................................................................................... 64 
8.3.9 
Guidelines for reporting product complaints .................................................................................. 65 
8.3.9.1 
Medical device deficiencies ........................................................................................................... 65 
8.4 
PHARMACOKINETICS .................................................................................................................. 65 
8.4.1 
Pharmacokinetics handling procedure ........................................................................................... 66 
8.4.2 
Bioanalytical method ...................................................................................................................... 66 
8.4.3 
Pharmacokinetic parameters ......................................................................................................... 66 
8.5 
GENETICS ..................................................................................................................................... 66 
8.6 
BIOMARKERS ............................................................................................................................... 67 
8.7 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 68 
8.8 
HEALTH ECONOMICS .................................................................................................................. 68 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 68 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 70 
9.1 
SAMPLE SIZE DETERMINATION ................................................................................................. 70 
9.2 
POPULATIONS FOR ANALYSES ................................................................................................. 70 
9.3 
STATISTICAL ANALYSES ............................................................................................................ 70 
9.3.1 
General considerations .................................................................................................................. 71 
9.3.2 
Primary endpoint(s) ........................................................................................................................ 71 
9.3.3 
Secondary endpoint(s) ................................................................................................................... 72 
9.3.4 
Exploratory endpoint(s) .................................................................................................................. 72 
9.3.5 
Analyses of safety data .................................................................................................................. 72 
9.3.5.1 
Adverse events .............................................................................................................................. 73 
9.3.5.2 
Vital signs ....................................................................................................................................... 74 
9.3.5.3 
Clinical safety laboratory ................................................................................................................ 74 
9.3.5.4 
Electrocardiogram .......................................................................................................................... 75 
9.3.6 
Analyses of pharmacokinetic data ................................................................................................. 75 
9.3.6.1 
Pharmacokinetic parameters ......................................................................................................... 75 
9.3.6.2 
Pharmacokinetic/Pharmacodynamic analysis ............................................................................... 75 
9.4 
INTERIM ANALYSES  ................................................................................................................... 75 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 76 
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10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 76 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 76 
10.1.2 
Financial disclosure........................................................................................................................ 77 
10.1.3 
Informed consent process .............................................................................................................. 77 
10.1.4 
Data protection ............................................................................................................................... 78 
10.1.5 
Committee structure ....................................................................................................................... 80 
10.1.5.1 Internal Safety Review Committee ................................................................................................. 80 
10.1.6 
Dissemination of clinical study data ............................................................................................... 81 
10.1.7 
Data quality assurance .................................................................................................................. 81 
10.1.8 
Source documents ......................................................................................................................... 82 
10.1.9 
Study and site start and closure ..................................................................................................... 82 
10.1.10 Publication policy ........................................................................................................................... 83 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 83 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ......................................................................... 85 
10.3.1 
Definition of AE .............................................................................................................................. 85 
10.3.2 
Definition of SAE ............................................................................................................................ 87 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................... 88 
10.3.4 
Reporting of SAEs.......................................................................................................................... 90 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................... 91 
10.4.1 
Definitions ...................................................................................................................................... 91 
10.4.2 
Contraception guidance ................................................................................................................. 92 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 94 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS AND STUDY INTERVENTION RECHALLENGE GUIDELINES ....................... 95 
10.7 
APPENDIX 7: AES, ADES, SAES, SADES, USADES AND DEVICE DEFICIENCIES: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP, 
AND REPORTING IN MEDICAL DEVICE STUDIES .................................................................... 99 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 99 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................. 100 
10.10 
APPENDIX 10: ADDITIONAL APPENDICES .............................................................................. 102 
10.10.1 List of topical corticosteroids ........................................................................................................ 102 
10.10.2 Sample of Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) ........... 104 
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10.10.3 Sample of Physician Global Assessment of disease activity (PhysGA- disease activity) and 
Physician Global Assessment of changes in cutaneous lupus erythematosus activity 
(PGAC) ......................................................................................................................................... 105 
10.10.4 Sample of Patient-Reported Peak Pruritus Numerical Rating Scale (itch-NRS) and Peak 
Pain Numerical Rating Scale (Pain-NRS) .................................................................................... 106 
10.10.5 Sample of Oral Health Impact Profile (OHIP-14) ......................................................................... 107 
10.10.6 Sample of SKINDEX-29+3 ........................................................................................................... 111 
10.10.7 Sample of Patient Global Impression of Change (PGIC) and Severity (PGIS) in cutaneous 
lupus erythematosus .................................................................................................................... 114 
10.10.8 Sample of Investigator’s Global Assessment for Cutaneous Lupus Erythematosus Activity 
(IGA-CLE) .................................................................................................................................... 115 
10.11 
APPENDIX 11: ABBREVIATIONS ............................................................................................... 117 
10.12 
APPENDIX 12: PROTOCOL AMENDMENT HISTORY .............................................................. 118 
10.12.1 Amended protocol 01 (10 DEC 2021) .......................................................................................... 118 
11 
REFERENCES ............................................................................................................................. 121 
 
LIST OF TABLES  
Table 1 - Risk assessment ............................................................................................................................ 26 
Table 2 - Objectives and endpoints ............................................................................................................... 29 
Table 3 - Overview of study interventions administered ............................................................................... 44 
Table 4 - Strong CYP3A inducers ................................................................................................................. 50 
Table 5 - Populations for analyses ................................................................................................................ 70 
Table 6 - Primary endpoint analysis .............................................................................................................. 71 
Table 7 - Selected secondary endpoints analyses ........................................................................................ 72 
Table 8 - Safety analyses .............................................................................................................................. 74 
Table 9 - Protocol-required laboratory tests .................................................................................................. 84 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 15 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: 
A randomized, double-blind, placebo controlled, proof of concept study assessing 
the efficacy and safety of the RIPK1-inhibitor SAR443122 in patients with moderate 
to severe subacute or discoid/chronic cutaneous lupus erythematosus 
Brief title:  
Proof of concept study of SAR443122 in patients with cutaneous lupus erythematosus 
Rationale: 
SAR443122 is a novel, potent and selective Receptor-Interacting serine-threonine Protein Kinase1 
(RIPK1) inhibitor. The RIP Kinase function involved in pro-inflammatory signaling via 
phosphorylated RIPK1/3 (pRIPK1/3) and phosphorylated mixed lineage kinase domain-like 
protein (pMLKL) leading to membrane pore formation, cell death and the release of danger-
associated molecular patterns (DAMPs) is inhibited by SAR443122. 
In interface dermatitis (ID), a group of skin autoimmune diseases, which is characterized by 
immune cell infiltration close to the basal membrane of the epidermis and cell swelling and death 
of the basal keratinocytes. A dysregulated immune response to keratinocyte damage caused by 
ultraviolet (UV) light and potentially other stimuli are considered drivers of ID which includes 
most cutaneous lupus erythematosus (CLE) forms. 
All subtypes of cutaneous lupus can be triggered and worsened by sunlight. The manifestations of 
lupus on skin most often involves the scalp, face, ears, and/or other sun-exposed areas. Some 
patients may present oral and/or genital lesions. Sometimes patients may feel pain or itch. Skin 
lesion can lead to permanent damage such as depigmentation, scaring and even hair loss when the 
scalp is involved. CLE skin manifestations in sun exposed area like scalp and face can be 
disfiguring and are a significant cause of morbidity.  
In Europe and the USA, the incidence of isolated CLE is ~4 cases per 100 000 persons per year. 
Skin involvement occurs in 70%-80% of all patients with systemic lupus erythematosus (SLE) 
during the course of their disease and patients with CLE can progress to SLE with internal organ 
systems involvement.  
Existing options to treat subacute and chronic lupus are limited and the standards of care consist 
of repurposed drugs with limited evidence supporting their efficacy and with considerable safety 
issues. There is a high unmet need for therapies with novel mechanisms of action that target the 
inflammation in severe CLE and are more efficacious and safer than current treatment. 
SAR443122 is proposed to target the chronic inflammation in participants with CLE which 
manifests as interface dermatitis, namely chronic cutaneous lupus erythematosus (CCLE)/discoid 
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lupus erythematosus (DLE) or subacute cutaneous lupus erythematosus (SCLE). RIPK1 inhibition 
may prevent the damage inflicted on keratinocytes and reduce the pro-inflammatory response to 
this damage, thereby ameliorating skin lesions and associated symptoms. 
The available nonclinical and clinical data from the SAR443122 development program in healthy 
volunteers demonstrated that SAR443122 is well tolerated with a good safety profile which 
allows for high exposure and tissue penetration in the skin with the opportunity to achieve high 
exposure in target cells. 
Objectives and endpoints  
 
 
 
 
 
Objectives 
Endpoints 
Primary 
• 
Assess the efficacy of SAR443122 in CLE 
• 
Percent change from baseline in Cutaneous 
Erythematosus Disease Area and Severity Index 
activity (CLASI-A) sub-score at Week 12 
Secondary 
• 
Assess the effect of SAR443122 on the physician’s 
global assessment of disease activity 
(PhysGA - disease activity) 
• 
Proportion of patients with PhysGA - disease 
activity of 0 or 1 (disease free or almost disease 
free) at Week 12 
• 
Assess the effect of SAR443122 on CLE induced 
itch and overall pain 
• 
Change from baseline in patients reported daily 
worst itch using Peak Pruritus Numerical Rating 
Scale (itch-NRS) at Week 12 
• 
Change from baseline in patients reported daily 
worst pain using Peak Pain Numerical Rating 
Scale (Pain-NRS) at Week 12 
• 
Assess the effect of SAR443122 on the proportion 
of disease activity responders compared to 
placebo 
• 
Proportion of CLASI-A50 and CLASI-A75 
responders at Week 12 
• 
Assess the effect of SAR443122 on the CLASI 
components’ score 
• 
Change from baseline in CLASI components' score 
over time 
• 
Assess the effect of SAR443122 on the 
Investigator’s global assessment for CLE (IGA-
CLE) 
• 
Proportion of patients with IGA-CLE score of 0 or 1 
(clear or almost clear) at Week 12 
• 
Assess oral cavities for patients with oral lesions 
• 
Change from baseline to Week 12 in the Oral 
Health Impact Profile (OHIP-14) for patients with 
oral lesions at baseline 
• 
Assess the disease specific quality of life (QoL) 
• 
Change from baseline in SKINDEX-29+3 total 
score at Week 12 
• 
Assess the safety and tolerability of SAR443122 in 
patients with CLE 
• 
Total number and percent of treatment-emergent 
adverse events (TEAEs), serious adverse events 
(SAEs), adverse events of special interest (AESIs) 
• 
Percent of potentially clinically significant 
abnormalities (PCSAs) in laboratory tests, 
electrocardiogram (ECG) or vital signs through end 
of study (EOS) 
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Objectives 
Endpoints 
• 
Assess the pharmacokinetics (PK) exposure of 
SAR443122 in patients with CLE 
• 
SAR443122 plasma concentration 
• 
Pharmacokinetic parameters (maximum 
concentration [Cmax], time to Cmax [tmax], area under 
the curve over the dosing interval [AUC0-tau], and 
elimination half-life [t1/2z]) 
 
 
 
 
Overall design: 
This is a multinational, multi-center, randomized, double-blind parallel group 12-week treatment 
study to evaluate efficacy and safety of the RIPK1-inhibitor SAR443122 dosed at 300 mg 
twice a day (BID) compared to matching placebo in patients with moderate to severe SCLE or 
DLE.  
The target population for the study is patients with histologically confirmed SCLE or DLE. 
Patients with acute CLE, drug induced lupus, certain chronic CLE subtypes (eg, LE timidus, lupus 
profundus, chilblain LE, LE-lichen planus overlap) or lupus like syndrome are excluded. Patients 
with SLE may be included provided they do not have significant involvement of the central 
nervous system (CNS), lung or kidney such as lupus nephritis.  
The study will be blinded to investigators, patients and Sanofi as well as Sanofi contracted staff.  
Participants will be randomized in a ratio of 1:1 to either SAR443122 or placebo arm. The 
randomization will be stratified by subtype of CLE (DLE or SCLE), baseline use of chloroquine 
or hydroxychloroquine (yes/no) and by region. Up to 88 participants are expected to be randomly 
assigned to the investigational medicinal product (IMP), expecting a total of approximately 
80 evaluable participants with approximately 40 evaluable participants per group. 
Each participant will have a screening period of up to 4 weeks to assess eligibility, a treatment 
period of 12 weeks beginning from the day of randomization (Baseline, Day 1) and a 4-week post 
treatment follow-up period. 
At screening, participants without a documented histological diagnosis of CLE within 1 year prior 
to Screening will need a biopsy during Screening period with a histological confirmation of CLE 
diagnosis before randomization. For participants with a documented histological diagnosis of CLE 
within 1 year prior to Screening, a biopsy will be performed at Baseline, while the eligibility 
related to CLE diagnosis will be based upon the historical documented result. 
During the 12-week treatment period, participants will be assessed by investigators every 4 weeks 
and undergo clinical laboratory examinations for all protocol required assessments. Patient-reported 
disease symptoms (itch and pain) will be assessed on a daily basis within two weeks and at least 
4 days prior to baseline and during the treatment period. Details are in Section 1.3. 
The primary objective of the study is to assess disease activity compared with placebo at Week 12 
as measured by the Cutaneous Lupus Erythematosus Disease Area and Severity Index (2, 3) 
activity (CLASI-A ) sub-score. The secondary endpoints include Investigator’s Global 
Assessment of CLE (IGA-CLE), Physician’s Global Assessment of disease activity (PhysGA- 
disease activity) at Week 12, assessments of CLE-induced itch and pain evaluated separately daily 
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by a patient reported numerical rating scale, the comparison of CLASI-A50, CLASI-A75 
responder rate, and change from baseline of CLASI individual components score (4). A quality of 
life instrument SKINDEX-29+3 will be used for quality of life assessment (5). 
During the study, rescue medication may be used in cases where there is worsening of signs or 
symptoms of CLE per Investigator’s assessment. If feasible, rescue medication should not be used 
for at least 4 weeks following the first administration of study intervention. Details are provided 
in Section 6.8.8. 
An internal safety review committee (ISRC) will be established to oversee the welfare of the 
participants as well as the safety, scientific integrity of the trial. All members in the committee are 
independent of the study operational team members. Details regarding the composition, mandate 
and function of the internal safety review committee will be provided in the respective ISRC 
charter. 
Brief summary:  
This is a parallel, treatment, Phase 2, participants, outcome assessors and Investigator masked, 
2-arm study to assess the efficacy and safety of SAR443122 compared to placebo in male and 
female participants aged 18 to 80 years with moderate to severe SCLE or DLE. 
Number of participants: 
A maximum of 88 participants will be randomized to study intervention with the goal of 
approximately 80 participants to complete the study and that are evaluable for the analysis of the 
primary endpoint. 
Intervention groups and duration: 
This study will include two treatment groups: SAR443122 and Placebo. 
Total study duration per participant will be up 20 weeks including:  
• A screening period of up to 4 weeks  
• A treatment period of 12 weeks  
• A post treatment follow-up period of 4 weeks 
Study intervention(s) 
Investigational medicinal product(s) 
• Formulation: capsules of either SAR443122 100 mg or matching placebo 
• Route(s) of administration: Oral route 
• Dose regimen: 300 mg BID for 12 weeks  
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Non-investigational medicinal products(s) 
• Rescue treatment may be used per investigators’ judgement during the study. Topical 
corticosteroids and/or topical calcineurin inhibitors and/or one short course of oral 
corticosteroids of up to 10 days are allowed. Initiation of any new topical corticosteroids 
and/or topical calcineurin inhibitors and/or increase potency for treating CLE will be 
considered a rescue treatment. Only one course of oral corticosteroids of up to ten days 
duration is permitted. If other systemic rescue medications such as immunosuppressants 
(except initiation or increase the dose of chloroquine or hydroxychloroquine) are required, 
the patient should be permanently discontinued from the study drug but they should be 
encouraged to stay in the study until the end of the study. 
Devices: Not applicable 
Posttrial access to study medication: Not planned 
Statistical considerations: 
• The sample size was derived to address the primary endpoint (percent change from 
Baseline to Week 12 in the CLASI-A sub-score) by applying the Quantitative Decision 
Making approach. 
Data Monitoring/Other committee: Yes (ISRC - described previously) 
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1.2 
SCHEMA  
 
Figure 1 - Graphical study design  
 
 
4 weeks  
End of study 
(EOS) 
Screening 
Up to 
28 days 
Double-blind treatment period (12 weeks) 
4 weeks 
follow-up  
Screening D-28 
D1/WK0 
Randomization stratified by 
CLE subtype, baseline use 
of chloroquine or 
hydroxychloroquine 
(yes/no), and region 
Start of double-blind 
treatment  
D85/WK 12 
End of treatment (EOT) 
Primary Endpoint 
(%-Change in CLASI-A) 
N= 44   Placebo BID  
Patients with histologically 
proven subacute or 
discoid/chronic CLE 
•
CLASI-A >=10 
•
No major organ 
manifestations in 
patients with SLE 
N= 44   SAR443122, 300 mg BID   
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
 
 
 
Screening 
(4 weeks) 
Treatment phase 
Follow-up 
Visit 
V1 
V2  
Baseline 
V3a 
V4 
V5 (EOT)  
V6 (EOS)  
Day 
D-28 to D-1  
(Maximum 28 days) 
D1 
 
D29  
(±4) 
D57 
(±4) 
D 85 
 
D 113 (+4) 
 
Week 
 
Wk 0 
Wk 4 
Wk 8 
Wk 12 
Wk 16 
Informed consent 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
Patient demographics 
X 
 
 
 
 
 
Medical/surgical history (includes substance usageb) and Family 
history of premature CV disease 
X 
 
 
 
 
 
Prior medications history 
X 
 
 
 
 
 
Concomitant medication (including sun protectionc) 
X 
X 
X 
X 
X 
12-lead electrocardiogram (ECG)  
X 
 
 
X 
Xd 
Physical examination including vital signse 
X 
X 
X 
X 
X 
X 
Serology: Hepatitis B & C, and HIVf 
X 
 
 
 
 
 
Antiphospholipid antibodiesg 
 
X 
 
 
 
 
Antihistone autoantibodies 
X 
 
 
 
 
 
Tuberculosis (TB) testingh 
X 
 
 
 
 
 
COVID-19 testingh  
X 
 
 
 
 
 
Height 
X 
 
 
 
 
 
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Screening 
(4 weeks) 
Treatment phase 
Follow-up 
Visit 
V1 
V2  
Baseline 
V3a 
V4 
V5 (EOT)  
V6 (EOS)  
Day 
D-28 to D-1  
(Maximum 28 days) 
D1 
 
D29  
(±4) 
D57 
(±4) 
D 85 
 
D 113 (+4) 
 
Week 
 
Wk 0 
Wk 4 
Wk 8 
Wk 12 
Wk 16 
Weight 
X 
 
 
 
X 
 
Call IVRS  
X 
X  
Randomization 
X 
X 
X 
X 
Investigational medicinal product (IMP) 
IMP daily intake (BID)i 
 
X-----------------------------------------------------------------I 
 
IMP dispense 
 
X 
X 
X 
 
 
IMP compliance (Patient diary) 
 
X 
X 
X 
X 
 
Safety 
Adverse event/SAE recording 
X----------------------------------------------------------------------------------------------------------------------------------------------------> 
Tuberculosis risk assessment 
X 
 
 
X 
 
Hematology, Chemistry 
X 
X 
X 
X 
X 
Xd 
Fasting lipids, glycosylated hemoglobin (HbA1c) 
X 
 
 
 
Urinalysisj 
X 
X 
X 
X 
X 
 
Serum pregnancy test (woman of childbearing potential 
[WOCBP] only) 
X 
 
 
 
 
 
Urine pregnancy test (WOCBP only) 
 
X 
X 
X 
X 
X 
Efficacy assessment 
CLASIk 
X 
X 
X 
X 
X 
X 
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Screening 
(4 weeks) 
Treatment phase 
Follow-up 
Visit 
V1 
V2  
Baseline 
V3a 
V4 
V5 (EOT)  
V6 (EOS)  
Day 
D-28 to D-1  
(Maximum 28 days) 
D1 
 
D29  
(±4) 
D57 
(±4) 
D 85 
 
D 113 (+4) 
 
Week 
 
Wk 0 
Wk 4 
Wk 8 
Wk 12 
Wk 16 
IGA-CLE 
X 
X 
X 
X 
X 
X 
PhysGA-disease activity 
X 
X 
X 
X 
X 
X 
28-Joint assessment 
 
X 
X 
X 
X 
X 
SELENA-SLEDAIl 
 
X 
 
 
X 
 
GELPn 
 
X 
 
 
X 
 
OHIP-14m 
 
X 
 
 
X 
 
SKINDEX 29+3 
 
X 
 
 
X 
 
Itch-NRS/Pain-NRSo 
<-------------------------------------------------daily---------------------------------------------------------------> 
 
Physician Global Assessment of Change in disease activity 
 
 
 
X 
 
Patient Global Impression of change in disease 
 
 
 
 
X 
 
Patient Global Impression of disease severity 
 
X 
 
 
X 
 
Skin examination with photography of index lesion(s) 
 
X 
 
 
Xu 
 
PK and exploratory Biomarkers 
PK (plasma)p 
 
X 
 
X 
Xu 
 
pS166-RIPK1 (PBMC)q 
 
X 
  
X 
X 
Cytokine panel (Plasma) r 
 
X 
X 
X 
X 
X 
Chemokine Panel (Plasma)r 
 
X 
X 
X 
X 
X 
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Screening 
(4 weeks) 
Treatment phase 
Follow-up 
Visit 
V1 
V2  
Baseline 
V3a 
V4 
V5 (EOT)  
V6 (EOS)  
Day 
D-28 to D-1  
(Maximum 28 days) 
D1 
 
D29  
(±4) 
D57 
(±4) 
D 85 
 
D 113 (+4) 
 
Week 
 
Wk 0 
Wk 4 
Wk 8 
Wk 12 
Wk 16 
RNA sequencing (Whole Blood) (optional) 
 
X 
 
 
X 
 
Marker for systemic lupus (anti-dsDNA-ab, C3, C4)s 
 
X 
 
 
X 
 
Markers for systemic lupus (antinuclear antibody [ANA], 
anti-Smith-ab)s 
 
X 
 
 
 
 
Skin biopsy for histology, and RNA sequencingt 
Xt 
Xt 
 
 
Xu 
 
DNA sample (optional) 
 
X 
 
 
 
 
Abbreviation: ANA = antinuclear antibody; BID = twice a day; CLASI = Cutaneous Erythematosus Disease Area and Severity Index; CV= cardiovascular; ECG = electrocardiogram; GELP= Genital Erosive Lichen 
Planus; HIV = human immunodeficiency virus; IGA-CLE = Investigator's Global Assessment of CLE; IMP = investigational medicinal product; NRS = Numerical Rating Scale ; OHIP = Oral Health Impact Profile; 
PBMC = peripheral blood mononuclear cell; PD = pharmacodynamics; PK = pharmacokinetics; SAE = serious adverse event; SELENA-SEDAI = Safety of Estrogens in Lupus Erythematosus National Assessment-
SLE Disease Activity Index ; SLE = systemic lupus erythematosus; TB = tuberculosis; WOCBP = woman of childbearing potential 
a In case of urgent COVID-19 pandemic situation requiring strict confinement of population, visit can be organized and done by video per PI’s judgement. Appropriate measure should be put in place for laboratory 
procedures (eg, home nursing). 
b Substances: drugs, alcohol, tobacco, and caffeine. 
c Sun protection information includes the level of daily sun exposure and means for UV protection. 
d Only if there are abnormal findings at Wk12 requiring follow-up. 
e Full physical examination at screening only, including skin, nasal cavities, eyes, ears, respiratory, cardiovascular, gastrointestinal, neurological, lymphatic, and musculoskeletal systems. A brief physical 
examination will be performed at remaining on-site visits and include, at a minimum, assessments of the skin, lungs, cardiovascular system, lymphatic system (include but not limited to cervical, axillary, inguinal 
and clavicular lymph nodes) and abdomen (liver and spleen).  
f 
HBV and HCV serologies include: hepatitis B surface antigen (HBs-Ag), hepatitis B surface antibody (HBs-Ab), total hepatitis B core antibody (HBc-Ab), and hepatitis C antibody (HCV-Ab). In case of HBc-Ab 
positive and HBs-Ag negative, to assess patient’s eligibility, HBV DNA will be performed locally as per Investigator’s judgement. 
g Antiphospholipid antibodies to be performed in patients with SLE. 
h TB testing method will follow local guidelines and will be performed locally, in case that local guidelines is not available, QuantiFERON TB gold test will be performed either locally or centrally. COVID-19 testing will 
follow local guidelines and will be performed locally. 
i 
Last IMP dose intake will be morning dose on-site on Day 85. 
j 
To use dipstick, if any abnormality, send sample to central lab for testing. Urine microscopic examination (including pyuria, hematuria and urinary casts) and spot urine protein/creatinine ratio test will be performed 
at Baseline, Week 12, and when the SELENA-SLEDAI is assessed. 
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k CLASI assessment includes CLASI-A and CLASI-D. 
l 
SELENA-SLEDAI will be assessed for all patients at Baseline and W12, if new suspicion of SLE during the study, additional assessment will be performed at the on-site visit closest to the suspicion. 
m Only in patients with oral lesions diagnosed as lupus related at baseline. 
n Only in patients with genital lesions as lupus related at baseline. 
o NRS daily assessment will start within 2 weeks and at least 4 days prior to baseline. 
p Sample collection : on Day 1, PK sampling within 2 to 5 hours after the first morning dose (around Cmax); on Day 57 PK sampling just before or within 1 h before the morning dosing, within 2 to 5 hours after the 
first morning dose (around Cmax) and within 7 to 10 hours after the morning doses , On Day 85 (or early EOT) for all participants, PK sampling just before or within 1 h before the morning dosing and within 2 to 
5 hours after the first morning dose (around Cmax).  
q PBMC assay will be performed in patients with CLE in a subset of qualified sites. 
r 
Cytokine panel and chemokine panel assays will be performed. Details of the assessment in the panels are provided in Section 8.6.  
s To be measured at V2 and as needed if suspicion of systemic lupus during the study. 
t 
Only skin lesion to be biopsied. For patients who have no documented histological diagnosis, biopsy will be performed at screening and at Week 12. For patients who have documented histological diagnosis, 
biopsy will be performed at V2 after other eligibility assessments done and at Week 12. In case that the patient is prematurely discontinued from IMP, biopsy will be performed at EOT instead of Week 12. 
u To be performed at the end of treatment only, not required at Week 12 in case of premature end of treatment.
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2 
INTRODUCTION  
SAR443122 is a novel, potent and selective Receptor-Interacting serine-threonine Protein Kinase1 
(RIPK1) inhibitor for oral administration. RIP Kinase1 inhibition with SAR443122 results in the 
inhibition of tumor necrosis factor (TNF), interferon (IFN), toll-like receptor (TLR) 3/4 mediated cell 
death (necroptosis or apoptosis) and inflammation triggered by the release of danger-associated 
molecular patterns (DAMPs). SAR443122 has no effect on the scaffolding function of RIPK1 which 
is important for the Nuclear factor kB (NF-kB) dependent cell survival signaling downstream of the 
TNF-TNF receptor-1 complex. On the other hand, the RIP Kinase function involved in pro-
inflammatory signaling via pRIPK1/3 and pMLKL leading to membrane pore formation, cell death 
and DAMP release is inhibited by SAR443122 (see SAR443122 Investigator Brochure for detailed 
information). 
In skin autoimmune disease, such as CLE, we hypothesize that RIPK1 inhibition would be 
beneficial by a generalized dampening of the local pro-inflammatory milieu. CLE is manifested in 
the skin by increases in several pro-inflammatory cytokines as well as other mechanisms of cell 
death. 
Normally, controlled cell death is a physiological mechanism to remove infected or damaged cells 
but is also exploited by pathogens to escape host defense. Interferon receptors and TLR3/4 
receptors function as pathogen sensors of viral or bacterial components (PAMPs) or cell damage 
(DAMPs). Some pathogens modulate pro-inflammatory response after TNF receptor stimulation 
to escape innate immunity. Similar to response to infection, this process appears to be involved in 
certain autoimmune diseases such as CLE. 
Interface dermatitis (ID), which includes most CLE forms, is characterized by immune cell 
infiltration close to the basal membrane of the epidermis and cell swelling and death of the basal 
keratinocytes. Initial stimulus might be different among certain skin diseases, but dominance of 
cytotoxic T cells and involvement of plasmacytoid dendritic cells are described in several ID 
positive skin diseases (6). Biopsy-derived T-cells from CLE patients are dominated by interferon 
gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) positive cells (7). It was also 
demonstrated that ID is characterized by a shared transcriptome signature and CLE points towards 
a strong type I immune response. RIPK1 gets activated downstream of TNF receptor and IFN 
receptor activation as well as TLRs. Hence, primary pro-inflammatory cytokines involved in the 
pathophysiology of CLE are strongly linked to RIPK1 activation and downstream signaling 
demonstrated by hallmarks of RIPK1 signaling, phosphorylated RIPK1 (pRIPK1) and pMLKL 
(8). In conclusion, inhibition of RIPK1 downstream of TNF and IFN receptor activation are 
considered as a potential target to modulate the pathophysiology of CLE. 
Three-month toxicity studies of SAR443122 in monkey and rat have shown no adverse events 
(AEs) at the highest doses tested (
 mg/kg/day and 
 mg/kg/day, respectively). In the 
3-month rat study, test article-related effects were limited to increases in mean body weight, mean 
body weight gain, and mean food consumption for males administered 
 mg/kg/day; a few 
minor clinical pathology changes in animals administered ≥
 mg/kg/day, with no microscopic 
correlates; microscopically increased germinal center lymphocytes in the spleen of males and 
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females administered ≥
 mg/kg/day, with correlative splenic weight increases in females 
administered 
 mg/kg/day; increased liver weights for males administered 
 mg/kg/day 
and females administered ≥
 mg/kg/day; and increased kidney weights for females 
administered ≥
 mg/kg/day. All findings exhibited reversibility and were considered not 
adverse. Due to the mild severity of findings and the lack of impact on the health and well-being 
of animals administered 
 mg/kg/day, effects for this dose were considered non-adverse. Thus, 
the no observed adverse effect level (NOAEL) is 
 mg/kg/day. This dose level corresponded 
to mean Cmax and AUC values of 
 µM and 
 h*µM, respectively, in males and 
 µM and 
 h*µM, respectively, in females during Week 13 of the dosing phase. 
In the 3-month monkey study, non-adverse, SAR443122-related, increases in the incidence and/or 
severity of mononuclear cell infiltrates or increased lymphocytes were observed in multiple 
tissues of animals administered ≥
 mg/kg/day. Many of the findings were not found after the 
recovery phase, indicating reversibility. However, increased incidences and/or severities of 
mononuclear cell infiltrates persisted in the pancreas, lacrimal gland, kidney, sternum marrow 
(focal), tongue, and vagina. None of the findings in any dose group were considered adverse, thus, 
the NOAEL is 
 mg/kg/day. This dose level corresponded to mean Cmax and AUC values of 
 µM and 
 h*µM, respectively, in males and 
 µM and AUC 
 h*µM, respectively, in 
females during Week 13 of the dosing phase. 
SAR443122 was safe and well tolerated in healthy volunteers at exposures of up to 800 mg during 
the single dose part of the study, and up to 600 mg given once a day for 14 days during the 
multiple dose part of the study. 
Following single oral dose administration of 10 to 800 mg SAR443122 in fasted conditions, 
median tmax was reached between 
 and 
-hours post dosing. AUCs increased without major 
deviation from dose proportionality from 
 mg and then increased less than expected from 
dose proportionality from 
 mg. Cmax increased less than expected by dose 
proportionality from 
 mg. 
After once daily repeated administration for 14 days, there is no drug accumulation. The mean 
elimination half-life was estimated between 
 hours. Concomitant intake of a high fat meal 
did not modify the bioavailability of SAR443122 at 100 mg. 
Sustained maximal target engagement, measured as RIPK1 phosphorylation inhibition (>90%), was 
sustained for 24, 48 and at least 72 hours after single doses of 100, 200 and 400 mg, respectively. 
During the multiple ascending dose (MAD) study the median inhibition achieved during the period 
of maximal inhibition of the 50 mg group was 88.5% whereas the 100 and 200 mg groups show a 
median inhibition greater than 90% (93.9% and 91.3% respectively). Duration of the period of 
maximal inhibition was longer in 100 and 200 mg groups (median: 58 hours and 65 hours 
respectively) than in 50 mg group (median: 22 hours) under multiple dosing. 
The favorable safety profile allows for high exposure with the opportunity to achieve high 
exposure (>IC90, over 24 h) in target cells of carefully selected indications. The projected AUC 
following 12-weeks of administration to patients at 300 mg BID is 
 µM*h. Therefore, 
projected animal:human exposure ratios based on AUC are 10X and 2.8X for the rat 3-month and 
monkey 3-month, respectively. 
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A phase 1b, randomized, double-blinded, placebo-controlled study to evaluate the safety and 
immunomodulatory effect of the RIPK1 inhibitor SAR443122 in hospitalized patients with severe 
COVID-19 has started in July 2020. 
In Europe and the USA, the incidence of isolated CLE is ~4 cases per 100 000 persons per year, 
which is slightly higher than the incidence of SLE (~3 cases per 100 000 persons per year) (9, 10, 
11). CLE most often affects middle aged adults with a mean age at diagnosis of 54 years old. Skin 
involvement occurs in 70%-80% of all patients with SLE during the course of their disease and 
skin lesions are the first disease manifestation to present in 20%-25% of patients with SLE (11). 
Patients with CLE can progress to SLE with internal organ systems involvement. The rate of 
systemic manifestations depends on the underlying subtype of CLE; for example, acute cutaneous 
lupus erythematosus (ACLE) has the highest rate of systemic involvement (~90%), whereas 
localized DLE has the lowest (<5%) (10, 12). 
All subtypes of cutaneous lupus can be triggered and worsened by sunlight. Acute CLE most 
often involves a prominent rash on the cheeks and nose (“butterfly rash”). Subacute CLE most 
often presents with an erythematous, scaly papules on sun-exposed areas of the body that evolve 
into plaques. It tends to have circular skin lesions or lesions that can look like psoriasis on 
sun-exposed skin. Discoid lupus starts out as a red to purple scaly rash on the scalp, face, ears, and 
other sun-exposed areas. Over time, discoid lupus may heal with discolored scarring and even hair 
loss when the scalp is involved. Sometimes patients may feel pain or itch (13). Skin lesion can 
lead to permanent damage such as depigmentation and scarring if not treated. CLE skin 
manifestations in sun exposed area like scalp and face can be disfiguring and are a significant 
cause of morbidity. 
The adverse effects associated with exposure to UV light, in triggering and worsening disease 
activity, protection from exposure to direct sunlight is recommended for all patients with 
cutaneous lupus; though photoprotection does not always work and is not always feasible. 
Additionally, reduced sun exposure results in a decreased activation of vitamin D and the 
continuous or frequent use of corticosteroids increases the risk of osteoporosis. The guideline 
from the European Academy of Dermatology and Venereology recommends vitamin D 
supplementation for all patients with CLE to protect CLE patients against an increased risk of 
osteoporosis (14). 
Topical glucocorticoids are the first-line treatment for CLE lesions because of their anti-
inflammatory properties (14, 15). The primary indication for topical glucocorticoids is a localized 
DLE, patients with more extensive disease may show an inadequate response and are more prone 
to adverse effects. While topical calcineurin inhibitors are not approved for the treatment of CLE, 
they are frequently used as an alternative to topical corticosteroids. Unlike corticosteroids, these 
inhibitors do not induce skin atrophy, however, they are less effective than corticosteroids and 
carry a black box warning due to a potential tumor risk. 
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2.1 
STUDY RATIONALE  
Established systemic treatment in CLE 
In the current guidelines, antimalarial drugs and glucocorticoids are both recommended as 
first-line treatment in patients with highly active or widespread lesions (14, 16). Antimalarial 
drugs (such as chloroquine, hydroxychloroquine and quinacrine) are the most frequently used 
systemic drugs in CLE. The mode of action of these relatively old antimalarial drugs is still under 
investigation, but all of these antimalarial drugs inhibit type I IFN production by immune-
activated peripheral blood mononuclear cells (17). Both chloroquine and hydroxychloroquine are 
associated with important adverse drug reactions including QTc-prolongation and with long-term 
use there is a risk of potentially irreversible retinopathy. 
The use of systemic glucocorticoids (SGCs) is recommended for severe or widespread active CLE 
lesions. However, to decrease the impact of adverse reactions associated with SGCs, there is an 
imperative to taper their use as soon as possible (14).  
In patients with long-standing disease or high disease activity, other immunosuppressive and 
immunomodulatory drugs such as methotrexate, retinoids and dapsone are used (15). 
Approximately 30%-40% of patients with CLE are refractory to antimalarials. Methotrexate is 
recommended for use in refractory CLE, primarily SCLE (13), dapsone for recalcitrant CLE and 
bullous lupus erythematosus, and retinoids for selected patients with CLE (particularly patients 
with hypertrophic DLE) when they are unresponsive to other treatments. All other drugs, 
including mycophenolate mofetil and cyclosporine, are considered third-line therapies because of 
the lack of supporting clinical studies in CLE (14). 
In summary, existing options to treat subacute and chronic cutaneous lupus are limited and the 
current mainstays of treatment are repurposed drugs with limited evidence supporting their 
efficacy and are associated with considerable safety issues, in particular if used long-term. 
Patients using chloroquine and hydroxychloroquine for chronic treatment require regular 
ophthalmological screening to avoid potentially irreversible retinopathies, which increase sharply 
after 5-7 years of use. Among many other adverse effects, the same drugs may also cause QTc 
prolongation, which may be potentiated by other drugs. 
Serious side effects such as fatal cardiac rhythm disturbances including Torsades de Pointes are 
uncommon but have been observed and may be underdiagnosed. Chronic use of oral 
corticosteroids has many serious adverse effects including osteoporosis, hypertension, diabetes, 
weight gain, increased vulnerability to infection, cataracts and glaucoma (eye disorders), and 
thinning of the skin. No drug has been specifically approved for the treatment of CLE and there is 
an unmet need for therapies with novel mechanisms of action that target the inflammation in 
severe CLE that are more efficacious and safer than current treatment. 
2.2 
BACKGROUND  
Preclinical data support the application of RIPK1-inhibitors in ID, which includes CLE. Interface 
dermatitis characterized by immune cell infiltration close to the basal membrane of the epidermis, 
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and cell swelling and death of the undermost keratinocytes. This cell death is thought to contribute 
and propagate the inflammation seen in the skin diseases associated with ID. While the initial 
stimulus might be different among certain skin diseases, all ID is characterized by the dominance 
of cytotoxic T cells in the inflamed tissue and involvement of plasmacytoid dendritic cells. 
Biopsy-derived T-cells from CLE patients are dominated by IFN-γ and TNF- α positive cells. It 
was also demonstrated that ID is characterized by a shared transcriptome signature across 
different skin diseases, and CLE is associated with a strong type I immune response. RIPK1 gets 
activated downstream of TNF receptor and IFN receptor as well as TLRs signaling. Hence, 
primary pro-inflammatory cytokines involved in the pathophysiology of CLE are strongly linked 
to RIPK1 activation and downstream signaling as demonstrated by hallmarks of RIPK1 signaling, 
namely pRIPK1, pRIPK3 and pMLKL. In conclusion, inhibition of RIPK1 activity downstream of 
TNF and IFN receptor signaling is considered an important target to modulate the 
pathophysiology of cutaneous lupus erythematosus. Additional primary cell culture work based on 
human keratinocytes is ongoing to demonstrate the beneficial effect of RIPK1 inhibition on 
preventing or attenuating cell death in ID. In these ongoing assays we aim to demonstrate that 
through RIPK1 inhibition, dysregulation of cell death (apoptosis/necroptosis) is blocked and 
reduces overall inflammation. 
2.3 
BENEFIT/RISK ASSESSMENT  
The available nonclinical and clinical data from the SAR443122 development program in healthy 
volunteers (78 receiving active drug) demonstrated that SAR443122 is well tolerated with a good 
safety profile to date. SAR443122 is proposed to target the chronic inflammation in participants 
with CLE which manifests as interface dermatitis, namely DLE or SCLE. A dysregulated immune 
response to keratinocyte damage caused by UV light and potentially other stimuli as described 
above are considered drivers of interface dermatitis. RIPK1 inhibition may prevent the damage 
inflicted on keratinocytes and reduce the pro-inflammatory response to this damage, thereby 
ameliorating skin lesions and associated itch and discoloration of said skin lesions. 
More detailed information about the known and expected benefits and risks of SAR443122 may 
be found in the Investigator’s Brochure. 
2.3.1 Risk assessment  
SAR443122 was safe and well tolerated in the first-in-human (FIH) study 
(TDU16339/TDR16341). There were no serious adverse events (SAEs), no severe treatment-
emergent adverse events (TEAEs) and no deaths. There were no relevant treatment emergent 
potentially clinically significant abnormalities (PCSAs) for the laboratory values, vital signs, and 
ECG parameters. 
TDU16339 Part 1a single dose ascending (SAD): Total of 
 healthy volunteers were enrolled: 
 subjects were enrolled into each of the 
, and treated with 
 mg, 
 mg, 
 mg, 
 mg, 
 mg or 
 mg of SAR443122 (or placebo), respectively. No adverse events of 
special interest (AESIs), or treatment related TEAEs leading to treatment discontinuation reported 
during the study. 
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TDU16339 Part 1b food effect and relative bioavailability study: Total of  healthy volunteers 
completed all three periods. There were no AESIs, or treatment related TEAEs leading to 
treatment discontinuation reported during the study. 
TDR16341-Part2-MAD: Total of 
 healthy volunteers randomized and treated: Placebo: ; 
SAR443122 
 mg: ; SAR443122 
 mg: ; SAR443122 
 mg: ; SAR443122 
 mg: . 
Treated 
 days with highest multiple dose at 
 mg QD x 
 days. 
• Two AESI of alanine transaminase (ALT) elevation >2 x upper limit of normal (ULN), but 
<3 x ULN were reported, 1x on 
 mg and 1x on 
 mg dose. Both recovered, were 
asymptomatic and mild. 
Based on the clinical FIH TDU16339-SAD and TDR16341-Part2-MAD, both in healthy 
volunteers, and nonclinical studies of SAR443122, no important risks were identified to date. 
Based on the nonclinical studies, the potential risks are effect on immune system and anemia. 
Table 1 - Risk assessment  
Potential risk of clinical 
significance 
Summary of data/rationale for 
risk 
Mitigation strategy 
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Potential risk of clinical 
significance 
Summary of data/rationale for 
risk 
Mitigation strategy 
2.3.2 Benefit assessment  
Currently, there are no approved drugs for CLE. Limited existing options including antimalarial 
drugs, glucocorticoids, immunosuppressants and immunomodulators are often tried. All these 
drugs are repurposed drugs with limited evidence supporting their efficacy and with considerable 
side-effects. There is a high unmet medical need in patients with moderate to severe CLE. 
Through RIPK1 kinase inhibition, SAR443122 is expected to inhibit the dysregulation of 
apoptosis/necroptosis observed in ID including CLE and downregulate the inflammation. Based 
on the mechanism of action, and even though the study is of short duration, the potential benefits 
would be: 
• Reduction in disease activity score (CLASI-A) 
• Reduction in itch 
• Reduction in pain 
• Reduction of cutaneous or systemic disease flares 
• Reduction in oral or genital lesions 
• Improvement in QoL 
2.3.3 Overall benefit: risk conclusion  
Based on the FIH clinical studies (TDU16339/TDR16341) SAR443122 was safe and well 
tolerated in healthy volunteers up to 
 mg given as a single dose and up to 
 mg given daily 
for 
 days. SAR443122 has demonstrated a satisfactory safety profile in the nonclinical toxicity 
studies and was not found to be genotoxic or phototoxic. The projected AUC following 
-weeks 
of administration to patients at 
 mg BID is 
 µM*h. Therefore, projected animal:human 
exposure ratios based on AUC are 
X and 
X for the rat -month and monkey -month, 
respectively. 
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Risk management procedures and specific safety monitoring in particular to mitigate the potential 
risk of immune system disorder or anemia will be implemented (Section 2.3.1). 
Based on the acceptable safety profile summarized above and the potential for considerable 
benefits on cutaneous lupus disease activity, on acute episodes and on long-term sequelae, the 
potential benefits outweigh the risks in the proposed study population. 
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3 
OBJECTIVES AND ENDPOINTS  
Table 2 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
Assess the efficacy of SAR443122 in CLE 
• 
Percent change from baseline in Cutaneous 
Erythematosus Disease Area and Severity Index 
activity (CLASI-A) sub-score at Week 12 
Secondary 
• 
Assess the effect of SAR443122 on the physician’s 
global assessment of disease activity 
(PhysGA - disease activity) 
• 
Proportion of patients with PhysGA - disease 
activity of 0 or 1 (disease free or almost disease 
free) at Week 12 
• 
Assess the effect of SAR443122 on CLE induced 
itch and overall pain 
• 
Change from baseline in patients reported daily 
worst itch using Peak Pruritus Numerical Rating 
Scale (itch-NRS) at Week 12 
• 
Change from baseline in patients reported daily 
worst pain using Peak Pain Numerical Rating 
Scale (Pain-NRS) at Week 12 
• 
Assess the effect of SAR443122 on the proportion 
of disease activity responders compared to 
placebo 
• 
Proportion of CLASI-A50 and CLASI-A75 
responders at Week 12 
• 
Assess the effect of SAR443122 on the CLASI 
components’ score 
• 
Change from baseline in CLASI components' score 
over time 
• 
Assess the effect of SAR443122 on the 
Investigator’s global assessment for CLE (IGA-
CLE) 
• 
Proportion of patients with IGA-CLE score of 0 or 1 
(clear or almost clear) at Week 12 
• 
Assess oral cavities for patients with oral lesions 
• 
Change from baseline to Week 12 in the Oral 
Health Impact Profile (OHIP-14) for patients with 
oral lesions at baseline 
• 
Assess the disease specific quality of life (QoL) 
• 
Change from baseline in SKINDEX-29+3 total 
score at Week 12 
• 
Assess the safety and tolerability of SAR443122 in 
patients with CLE 
• 
Total number and percent of treatment-emergent 
adverse events (TEAEs), serious adverse events 
(SAEs), adverse events of special interest (AESIs) 
• 
Percent of potentially clinically significant 
abnormalities (PCSAs) in laboratory tests, 
electrocardiogram (ECG) or vital signs through end 
of study (EOS) 
• 
Assess the pharmacokinetics (PK) exposure of 
SAR443122 in patients with CLE 
• 
SAR443122 plasma concentration 
• 
Pharmacokinetic parameters (maximum 
concentration [Cmax], time to Cmax [tmax], area under 
the curve over the dosing interval [AUC0-tau], and 
elimination half-life [t1/2z]) 
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Objectives 
Endpoints 
Exploratory 
•
Assess the effect of SAR443122 on physicians’
and patients’ overall impression of change of the
disease activity and of the severity, and specific
domains of health-related QoL
•
Change from baseline at Week 12 in each of the
sub-scores of the SKINDEX-29+3
•
Change from baseline at Week 12 in the patient's
global impression of disease severity (PGIS)
•
Evaluation of patient's global impression of change
(PGIC) in overall disease at Week 12
•
Evaluation of physician's global assessment of
change in disease activity (PhysGAC disease
activity) at Week 12
•
Assess the effect of SAR443122 on CLE related
joint inflammation
•
Change from baseline in active joint count
assessment (28 joint assessment) at Week 12
•
Assess the effect of SAR443122 on reducing
systemic lupus erythematosus activity
•
Change from baseline in Safety of Estrogens in
Lupus Erythematosus National Assessment -
Systemic Lupus Erythematosus Disease Activity
Index (SELENA-SLEDAI) over time
•
Change from baseline in transcriptomic biomarkers
from mRNA derived from skin biopsy and from
blood
•
Change from baseline of blood plasma biomarkers
(eg, cytokine and chemokine levels) over time
•
Demonstrate inhibition of pS166-RIPK1 in PBMC
lysates with SAR443122 treatment compared to
placebo in a subset of patients at Week 12
•
Change from baseline to Week 12 in Genital
Erosive Lichen Planus (GELP) total score for
female patients with genital lesions at baseline
•
Photographic assessment of index lesions (Central
imaging acquisition tool), oral lesions if present
•
Histologic changes in skin biopsies (Central
pathologist)
•
Assess the effect of SAR443122 on RNA 
expression levels from skin biopsy and from blood 
as an indicator of response/disease progression
•
Assess the effect of SAR443122 on biomarkers in 
blood plasma (eg, cytokine and chemokine levels) 
as an indicator of response/disease progression
•
Assess target engagement of SAR443122 as a 
function of RIPK1 kinase activity/inhibition achieved 
by SAR443122 in peripheral blood mononuclear 
cells (PBMCs) of patients with CLE in a subset of 
qualified sites
•
Assess the genital area for female participants with 
genital lesions
•
Assess the effect of SAR443122 on skin lesion by 
photographic assessment of index lesions, oral 
lesions if present
•
Exploration of histologic changes in skin biopsies
•
Assess the effect of SAR443122 on the use of 
rescue medication
•
The frequency of use of rescue medications by
category (eg, topical corticosteroids, topical
calcineurin inhibitors, oral corticosteroids)
3.1 
APPROPRIATENESS OF MEASUREMENTS 
The Cutaneous Erythematosus Disease Area and Severity Index (CLASI) is a validated clinical 
instrument with documented content validity and good psychometric properties (inter- and intra- rater 
reliability; ability to detect changes) (2, 18, 19, 20, 21). It is commonly used clinically to assess 
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disease activity (CLASI-A) and skin damage (CLASI-D) induced by CLE. The primary endpoint is 
to assess disease activity; measured by the CLASI-A sub-score. This choice is in line with the 
standard instrument for evaluation of disease activity and the study design publicly available. 
To assess changes in skin lesions and potential early skin lesion improvement, the change of 
CLASI individual components from baseline will be evaluated, which occurs typically faster than 
other features of skin lesions.  
As a secondary endpoint, overall disease activity will be assessed by the IGA-CLE. The IGA is 
widely used in several dermatological conditions with verbal descriptors specific for the 
assessment of the indication in which it is used. The IGA-CLE is under development to be 
specific for the assessment of CLE by expert dermatologists and rheumatologists. 
The 5 point-lickert scale Physician’s Global assessment of disease activity (PhysGA-disease 
activity) will provide a global evaluation of the disease activity as per investigator’s evaluation. 
This instrument will be a secondary endpoint. 
Numerical rating scale (NRS) is one of standard measurement instruments for evaluation of 
chronic symptoms and is a popular choice for all patients due to its simple format. The peak 
pruritus NRS (itch-NRS) assess worst itch in the past 24 hours features high reliability and 
concurrent validity. The peak pain NRS (pain-NRS) related to CLE is developed specifically for 
this study and will assess worst pain related to CLE in the past 24 hours. 
GELP score is a scoring system for clinical assessment of genital lesions in women and it has 
been developed in lichen planus. For both the targeted CLE subtypes of the present study and 
lichen planus (LP) manifest interface dermatitis, CLE patients may present oral and/or genital 
lesions. These two clinical instruments validated in LP are considered as appropriate to assess oral 
and/or genital lesions in CLE patients. The results obtained from this study can serve for the 
larger study in CLE in the future. 
As an exploratory endpoint, 28- joint assessment of tender and swollen joints has been frequently 
used to assess joints inflammation in patients with lupus. It has been identified to assess 
SAR443122 effect on joint involvement in CLE patients in this study. 
Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index 
(SELENA-SLEDAI) is an instrument for the assessment of systemic manifestations of lupus (22). 
It is a clinical instrument to assess the disease activity in patients with SLE. In the present study, 
SLE patients without major organ involvement will be allowed to participate, and CLE could 
progress to SLE in some patients. It is anticipated to administer the SELENA-SLEDAI in all 
patients enrolled in order to monitor the lupus disease activity and potential development of 
systemic disease. Potential effect of SAR443122 on the systemic manifestations of lupus will be 
explored with this instrument. 
A quality of life questionnaire Skindex 29+3 (also called SkindexLupus) (5) will evaluate the 
effect of SAR443122 on patient’s QoL. It includes Skindex-29 items and a set of 3 questions to 
assess lupus-specific issues, ie, photosensitivity and alopecia. 
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Patient’s global impression of disease severity (PGIS) instrument will evaluate patient-reported 
impression of the disease severity while patient’s global impression of change in disease activity 
(PGIC) and physician’s global assessment of change in disease activity (PGAC) will evaluate 
patients and physicians evaluation of change in disease since the start of study medication, 
respectively. These scales will be used as anchor measure to validate psychometric properties of 
CLASI and patient reported outcomes (PROs) assessments used in the study. 
The pharmacokinetic assessments used in this study are standard for the evaluation of the drug 
administrated BID. 
The exploratory assessments related to DNA, RNA and biomarkers are selected based on the 
current knowledge from the literature and in-house research. 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a multinational, multi-center, randomized, double-blind parallel group 12-week treatment 
study to evaluate efficacy and safety of the RIPK1-inhibitor SAR443122 dosed at 300 mg BID 
compared to matching placebo in patients with moderate to severe SCLE or DLE. 
The target population for the study are patients with histologically proven SCLE or DLE. Patients 
with acute CLE, intermittent disease or drug induced lupus are excluded. Patients with SLE may 
be included provided they do not have significant involvement of the central nervous system 
(CNS), lung or kidney such as lupus nephritis. 
The study will be blinded to investigators, patients and Sanofi as well as Sanofi contracted staff. 
Participants will be randomized in a ratio of 1:1 to either SAR443122 or placebo arm. The 
randomization will be stratified by subtype of CLE (DLE or SCLE), baseline use of chloroquine 
or hydroxychloroquine, and by region. Up to 88 participants are expected to be randomly assigned 
to the IMP, expecting a total of approximately 80 evaluable participants with approximately 
40 evaluable participants per group. 
Each participant will have an up to 4 weeks screening period to assess the eligibility, 12 weeks 
treatment period counting from the day of randomization (Baseline, Day 1) and a 4-week post 
treatment follow-up period. 
At screening, participants without a documented histological diagnosis of CLE within 1 year prior to 
Screening will have to perform biopsy and histological result should be obtained before 
randomization to confirm the eligibility related to CLE diagnosis. For participants who have a 
documented histological diagnosis of CLE within 1 year prior to Screening, biopsy will be performed 
at Baseline, the eligibility related to CLE diagnosis will be based upon the documented result. 
During the 12 weeks treatment period, participants will be assessed by investigators every 
4 weeks and undergo a series of clinical laboratory examinations for efficacy, safety, 
pharmacokinetic, pharmacodynamic and exploratory assessments. Patient reported daily disease 
symptoms (itch and pain) will be assessed on a daily basis within two weeks and at least 4 days 
prior to baseline and during treatment period. Details can be found in Section 1.3. 
The primary objective of the study is to assess disease activity compared with placebo at Week 12 
as measured by the CLASI-A sub-score, the Cutaneous Lupus Erythematosus Disease Area and 
Severity Index (2, 3) activity sub-score. The secondary endpoints include IGA-CLE score, 
PhysGA- disease activity at Week 12, assessments of CLE-induced itch and pain evaluated 
separately daily by a patient reported NRS, the comparison of CLASI-A50, CLASI-A75 
responder rate, and change from baseline of CLASI individual components score (4). The safety 
of SAR443122 will be assessed throughout the study. A quality of life instrument 
SKINDEX-29+3 will be used for quality of life assessment (5). 
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During the study, the rescue medication may be used in case of CLE worsening per investigator’s 
medical judgement. If feasible, rescue medication should not be used for at least 4 weeks 
following the first administration of study intervention. Details can be found in Section 6.8.8. 
An internal safety review committee (ISRC) will be established to oversee the welfare of the 
participants as well as the safety, scientific integrity of the trial. Details regarding the 
composition, mandate and function of the internal safety review committee will be provided in the 
respective charter. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
This Phase 2a study is designed as a proof-of-concept study aimed at evaluating efficacy and 
safety of RIPK1 kinase inhibitor SAR443122 in patients with moderate and severe CLE 
(CLASI-A ≥10). 
The target population are patients with CLE which manifest interface dermatitis, namely DLE or 
SCLE based upon the hypothesis that RIPK1 inhibition may prevent the damage inflicted on 
keratinocytes and reduce the pro-inflammatory response to this damage, thereby ameliorating skin 
lesions including oral and genital lesions and associated clinical manifestations such as itch and pain. 
The proposed 12 weeks treatment duration is supported by the available preclinical and FIH 
studies and is consistent with the generally accepted time period to assess the clinical effect in 
patients with CLE. 
Existing options for treatment of CLE are repurposed drugs with limited evidence supporting their 
efficacy and with considerable safety issues. A placebo-controlled and parallel arms study is 
appropriate to evaluate efficacy and safety of SAR443122 in this population. PK and various 
biomarkers will be evaluated in this early clinical development study as well. 
This study is double-blind to minimize potential for bias on the part of the investigator, 
participant, or sponsor. 
The randomization ratio is 1:1. Stratification by subtype of CLE, baseline use of chloroquine or 
hydroxychloroquine (yes/no), and by region allows to minimize the influence of potential 
confounding factors such as the disease subtype, background treatment and seasonality on the 
participant’s response to the study treatment. 
Given that the study is placebo-controlled and is the first study of SAR443122 in patients with 
CLE, during the study, rescue medication may be used, to mitigate any potential risk related to 
CLE worsening. 
An Internal Safety Review Committee which is independent to study team will oversee the 
welfare of the participants as well as adverse drug effects. 
While there is no formal statistical hypothesis testing performed, the sample size was derived with 
respect to the primary endpoint (see Section 9.1). Thus, it is anticipated that the current sample 
size of approximately 80 evaluable patients may demonstrate a reduction of disease activities in 
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the active treatment arm measured by CLASI-A sub-score at Week 12, among other secondary 
clinical outcomes. 
The knowledge gained from this study could be confirmed with a larger trial to demonstrate 
a clinically significant effect of RIPK1 inhibition in CLE. 
4.2.1 Participant input into design  
Potential participants have not been involved in the design of this clinical trial. 
4.3 
JUSTIFICATION FOR DOSE  
Recently released clinical data from a competitor (23) and internal preclinical data in chronic 
inflammatory CNS disease, suggest that very high levels of RIPK1 kinase activity inhibition are 
required to have a clinical effect and that exposure needed to reach this high level of inhibition is 
higher in chronic inflammatory disease than in healthy subjects. Therefore, a daily dose of 600 mg 
of SAR443122 administered as 300 mg twice daily orally for 12 weeks is proposed. A BID 
regimen is selected to optimize drug plasma concentrations and reduce PK fluctuation during the 
entire dosing interval and thus to maintain maximum levels of inhibition. SAR443122 was well 
tolerated after single oral doses up to 800 mg and at multiple daily doses up to 600 mg in healthy 
subjects. Of note, a maximal tolerated dose was not established in either of these clinical studies 
of healthy volunteers. Predicted exposure for a 300 mg dose administered BID provides a safety 
margin of 5 x in terms of Cmax and 2.8 x in terms of AUC as compared to the exposure reached at 
the NOAEL in monkeys. 
4.4 
END OF STUDY DEFINITION  
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the last visit (End of Study visit, EOS) as shown in the Schedule of Activities 
(Section 1.3). 
The end of the study is defined as the date of the last visit of the last participant in the study 
globally. 
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5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and 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 of the following criteria apply: 
Age 
I 01. Participant must be 18 to 80 years of age inclusive, at the time of signing the informed 
consent 
Type of participant and disease characteristics 
I 02. Participants with cutaneous lupus erythematosus either in the form of discoid/chronic 
cutaneous lupus erythematosus or subacute cutaneous lupus erythematosus for at least 
3 months before Screening 
I 03. Participants with histologically confirmed and documented diagnosis within one year prior 
to Screening or during Screening period prior to randomization 
I 04. Active cutaneous lupus erythematosus skin lesions and a CLASI-A ≥10 both at Screening 
and Baseline 
I 05. Participant who is candidate for systemic treatment per Investigator’s judgement 
  
Sex, contraceptive/barrier method and pregnancy testing requirements 
I 06. All 
Contraceptive use by men or women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. 
a) Male participants 
Male participants are eligible to participate if they agree to the following during the 
study intervention period and for at least 5 days after the last dose of IMP, corresponding 
to time needed to eliminate study intervention(s) (eg, 5 terminal half-lives)  
• Refrain from donating 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/barrier as detailed below 
- 
A male condom and an additional highly effective contraceptive method as 
described in Appendix 4 Contraceptive and barrier guidance (Section 10.4) when 
having sexual intercourse with a woman of childbearing 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-childbearing potential (WONCBP) as defined in Appendix 4 
Contraceptive and barrier guidance (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 
Appendix 4 Contraceptive and barrier guidance (Section 10.4) during the study 
intervention period and for at least 2 days, corresponding to the time needed to 
eliminate any study intervention(s) (eg, 5 terminal half-lives) plus 30 days (a menstrual 
cycle) after the last dose of study intervention and agrees not to donate eggs (ova, 
oocytes) for the purpose of reproduction during this period. 
- 
A WOCBP must have a negative highly sensitive pregnancy test (urine and/or 
serum as required by local regulations) at Screening and Baseline visits before 
the first administration of study intervention, see Section 10.2 Pregnancy 
testing. 
- 
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. 
c) Local regulations regarding contraception for male and female participants 
(see Section 10.4.2). 
Informed Consent 
I 07. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1) of 
the protocol which includes compliance with the requirements and restrictions listed in the 
informed consent form (ICF) and in this protocol. In countries where legal age of majority 
is above 18 years, a specific ICF must also be signed by the participant’s legally authorized 
representative. 
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5.2 
EXCLUSION CRITERIA   
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Systemic lupus erythematosus according to the 2012 SLICC criteria (24) with major organ 
involvement such as lupus nephritis, cardiopulmonary involvement (eg, interstitial lung 
disease, pulmonary hypertension, pleuritis, pericarditis, myocarditis, and endocarditis), 
neuropsychiatric involvement, vasculitis, antiphospholipid syndrome (APS) on or 
requiring chronic anticoagulation, significant hematological and/or gastrointestinal 
involvement. Concurrent findings of malar rash, constitutional symptoms, alopecia, 
arthralgia/arthritis, myalgia, oral/nasal ulcers, Sjogren syndrome, Raynaud's phenomenon, 
sub-clinical pericardial and/or pleural effusions are permitted. Please consult the Sponsor 
for related SLE manifestations if unclear related to eligibility. 
E 02. Suspected or proven drug induced lupus erythematosus, including patients with positive 
antihistone autoantibody tests. 
E 03. Diagnosed with certain subtypes of CCLE (such as Lupus erythematosus tumidus, 
Chilblain, lupus panniculitis, lichenoid cutaneous lupus/lichen planus overlap syndrome). 
E 04. Autoimmune disease(s) other than systemic lupus erythematosus (eg, systemic sclerosis, 
myositis, rheumatoid arthritis, inflammatory bowel disease, primary biliary cirrhosis, 
multiple sclerosis, Behcet’s disease etc). 
E 05. Active skin diseases that may interfere with the study or study assessments (eg, Psoriasis). 
E 06. History of significant cardiovascular diseases/conditions, clinically significant renal, hepatic, 
metabolic (eg, poorly controlled diabetes mellitus demonstrated by screening HbAc1 ≥9%), 
neurologic, hematologic, ophthalmologic, respiratory, gastrointestinal, cerebrovascular or 
other significant medical illness or disorder which, in the judgment of the Investigator, could 
interfere with the study or require treatment that might interfere with the study. 
E 07. History of any malignancy except history of adequately treated basal cell carcinoma or in 
situ cervical carcinoma. 
E 08. Patients with active tuberculosis (TB) or non-tuberculous mycobacterial infection, or a history 
of incompletely treated active or latent TB per local guidelines will be excluded from the 
study unless it is documented by a specialist that the participant has been adequately treated 
and can now start treatment with the RIPK1 kinase inhibitor. Also excluded from the study 
are patients with a positive PPD test, Mantoux test or Quantiferon-TB Gold test at Screening 
indicating latent tuberculosis or another mycobacterial infection. Positive PPD or Mantoux is 
acceptable if can be explained by a documented BCG-vaccination. The method of 
tuberculosis testing will be selected on a country-by country basis, according to local 
guidelines. If Quantiferon-TB Gold test is used as per local guidelines, patients with positive 
or 2 confirmed indeterminate Quantiferon-TB Gold tests at screening (regardless of prior 
treatment status) will be excluded. 
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E 09. History of HIV infection or positive HIV serology at screening. 
E 10. Participants with any of the following result at screening: 
- 
Positive (or indeterminate) HBs Ag or, 
- 
Positive total HBc Ab confirmed by positive HBV DNA or, 
- 
Positive HCV Ab. 
E 11. History of recurrent or recent serious infection (eg, pneumonia, septicemia) within 4 weeks 
of screening, infection requiring hospitalization or intravenous antibiotics, antivirals or 
antifungals within 4 weeks of screening or chronic bacterial infections deemed 
unacceptable, as per Investigator’s judgement. 
E 12. Recurrent or active herpes zoster within 2 months prior to screening. 
E 13. Prolonged QTcF ≥450 ms (by Fridericia formula) or clinically significant findings on ECG 
per Investigator's assessment at Screening or during Screening period. 
E 14. Exposure to another investigative drug (monoclonal antibodies as well as small molecules) 
prior to Visit 1, within the period specified as follows: an interval of less than 6 months or 
<5 PK half-lives for investigative monoclonal antibodies, and an interval of less than 
30 days or <5 PK half-lives, whichever is longer prior to Screening, for investigative small 
molecules. 
E 15. Surgery within 4 weeks prior to the screening visit or with planned surgery during the 
study. 
E 16. Positive COVID-19 screening test, suspected of COVID-19 infection or known exposure 
to COVID-19 during the screening period. 
E 17. History of COVID-19 infection within 4 weeks prior to Screening; history of mechanical 
ventilation or extracorporeal membrane oxygenation (ECMO) due to COVID-19 infection 
within 3 months prior to Screening or with residual significant complications from 
COVID-19 making it unsafe for the participant to enter this study. 
E 18. Cannot avoid excessive UV exposure (such as use of tanning equipment and/or sun 
exposure [eg, beach vacation]) 4 weeks prior to baseline and during the study. Routine sun 
exposure through work (eg, farmer, construction worker, etc) are permitted but requires the 
use of sun block (recommend to use sun block with SPF 50 or higher) to sun exposed areas 
for at least 4 weeks prior to baseline and during the study. 
Prior/concomitant therapy 
E 19. Concomitant treatment with topical immunosuppressants beyond a stable regimen of low 
to medium potency topical corticosteroids and/or topical calcineurin inhibitors during the 
study and two weeks before baseline visit. 
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E 20. Initiation and/or changes in dosage of chloroquine/hydroxychloroquine within 12 weeks 
prior to Screening visit (or during Screening period) and/or the dose exceeding 
2.3 mg/kg/day for chloroquine or 400 mg/day for hydroxychloroquine. 
E 21. Systemic treatments (except for the study medication) for cutaneous or systemic lupus 
erythematosus or immunosuppressive therapy for autoimmune disease other than the study 
medication including:  
- 
cyclosporin and dapsone within 4 weeks prior to baseline visit. 
- 
methotrexate within 6 weeks prior to baseline visit. 
- 
mycophenolate mofetil (MMF), thalidomide, azathioprine, systemic retinoids, 
belimumab as well as any anti-TNF mAbs, B and/or T cell targeted 
immunosuppressive therapies within 2 months or 5 half-lives prior to baseline visit, 
whichever is longer as well as during the study. 
E 22. Systemic corticosteroids treatment <4 weeks before baseline visit. 
E 23. Live vaccine(s) within 1 month prior to Screening, or plans to receive such vaccines during 
the study. 
Prior/concurrent clinical study experience 
E 24. Participation in another clinical study 60 days before baseline visit. 
Diagnostic assessments 
E 25. Any of the following laboratory abnormalities at the Screening visit: 
- 
Hemoglobin <10 g/dL. 
- 
Absolute neutrophil count (ANC) <1500 /mm3 (or <1000/mm3 for participants of 
African descent). 
- 
Platelet <100 000 /mm3. 
- 
Creatinine clearance <60 mL/min using Cockcroft-Gault equation. 
- 
ALT or AST or ALP >1.5 x ULN. 
- 
Total bilirubin >1.5 x ULN or total bilirubin between > ULN and ≤1.5 ULN and 
associated with > ULN conjugated bilirubin unless documented Gilbert's syndrome. 
Retest can be done to reassess the eligibility during Screening period as per investigator's 
judgement that observed abnormality is not clinically significant and not consistent with 
patient's medical history. 
Other exclusions 
E 26. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized. 
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E 27. Any country-related specific regulation that would prevent the participant from entering 
the study - see Appendix 8 of the protocol (Section 10.8 country-specific requirements). 
E 28. Individuals with established dependency on drugs or alcohol, per the judgement of the 
investigator. 
E 29. Participant not suitable for participation, whatever the reason, as judged by the 
Investigator, including medical or clinical conditions, or participants potentially at risk of 
noncompliance to study procedures. 
E 30. Participants are employees of the clinical study site or other individuals directly involved 
in the conduct of the study, or immediate family members of such 
individuals (in conjunction with Section 1.61 of the ICH-GCP Ordinance E6). 
E 31. Any specific situation during study implementation/course that may rise ethics 
considerations. 
E 32. 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. 
 
5.3 
LIFESTYLE CONSIDERATIONS  
5.3.1 Meals and dietary restrictions  
No restrictions are required. 
5.3.2 Caffeine, alcohol, and tobacco  
The information of one’s regular use of alcohol and tobacco should be recorded in eCRF. 
5.3.3 Activity  
Not applicable. 
5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond 
to queries from regulatory authorities. Minimal information includes demography, screen failure 
reasons, eligibility criteria, and any serious adverse event (SAE). 
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Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened 1 additional time. Rescreened participants should be assigned with a new participant 
number. The participant number for the initial screening will be recorded in the rescreening eCRF. 
Participants who are rescreened must sign a new informed consent and all screening visit 
procedures must be repeated except biopsy done in previous screening visit. There is no 
requirement for a waiting period between the screen failure date and the rescreen date. 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
(ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION)  
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 
Appendix 9 (Section 10.9): Contingency measures for a regional or national emergency that is 
declared by a governmental agency should be considered for screening, enrollment, 
randomization, and administration of study intervention. 
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6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
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6.1 
STUDY INTERVENTION(S) ADMINISTERED  
6.1.1 Investigational medicinal product  
Table 3 - Overview of study interventions administered  
Arm name 
SAR443122 
Placebo 
Intervention labels 
SAR443122 
Placebo 
Type 
Drug 
Drug 
Dose formulation 
Capsules 
Capsules 
Unit dose strength(s) 
100 mg 
N/A 
Dosage level(s) 
3 capsules (300 mg) BID 
3 capsules BID 
Route of administration 
Orala 
Oral 
Use 
Experimental 
Placebo 
IMP or NIMP 
IMP 
IMP 
Packaging and labeling 
IMP will be provided in double blind kit labeled as required per 
country requirement 
IMP will be provided in double blind kit labeled as required per 
country requirement 
[Current/Former name(s) or alias(es)] 
DNL758 
Not applicable 
a 
The IMP can be taken with or without food. 
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The SAR443122/placebo may be supplied at the site or from the PI/site/Sponsor to the participant 
via a Sponsor-approved courier company where 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 
Appendix 9 (Section 10.9): Contingency Measures for a regional or national emergency that is 
declared by a governmental agency. 
6.1.2 Non-investigational medicinal product  
Rescue treatment may be used per investigators’ judgement during the study. Topical 
corticosteroids and/or topical calcineurin inhibitors and/or one short course of oral corticosteroids 
of up to 10 days are allowed. Initiation of any new topical corticosteroids and/or topical 
calcineurin inhibitors and/or increase potency, or initiation of oral corticosteroid for treating CLE 
will be considered a rescue treatment.  
If other systemic rescue medications such as immunosuppressants are required (except initiation 
or increase the dose of chloroquine or hydroxychloroquine), the patient should be permanently 
discontinued from the study drug but they should be encouraged to stay in the study until the end 
of the study. 
6.1.3 Devices  
Not applicable. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention 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. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention 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 8.3.9). 
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A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party (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 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
Methods of assigning participants to treatment arm 
The randomized treatment kit number list is generated centrally by Sanofi. 
The IMPs are packaged in accordance with this list. 
All participants will be centrally assigned to randomized study intervention using an interactive 
response technology (IRT). The Sanofi Clinical Supply Chain team will provide the randomized 
treatment kit number list to the IRT. The IRT system generates the participant randomization list 
and allocates the intervention number and the corresponding treatment kits to the participants 
according to it. 
The Investigator or designee will obtain the treatment kit numbers at randomization (Day 1, 
Baseline) and subsequent scheduled dosing visits via IRT that will be available 24 hours/day. 
Although the kit numbers will vary for the individual participant, the treatment group assignment 
and randomization will not change throughout the study. 
Treatment kits will be dispensed at the study visits summarized in SoA (Section 1.3). Returned 
study treatment kits should not be re-dispensed to the participants. 
Participants will be randomized in 1:1 ratio to treatment arms described in Table 3. 
Randomization will take place on Baseline/Day 1 and will be stratified by subtype of CLE (DLE 
versus SCLE), baseline use of chloroquine or hydroxychloroquine (Yes versus No), and by 
region. Sub-type of CLE and baseline use of chloroquine or hydroxychloroquine will be entered 
in the IRT before randomization takes place. 
A participant cannot be randomized more than once in the study. 
Methods of blinding and code breaking during the study 
SAR443122 100 mg and matching placebo will be provided in identically and visually 
indistinguishable capsules. 
The investigator, other staff members, as well as the participant will remain blinded and will not 
know the participant’s intervention assignment during the study. 
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• The IRT 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 
intervention 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 his/her discretion, contact the Sponsor 
to discuss the situation prior to unblinding a participant’s intervention assignment unless 
this could delay emergency treatment of the participant. If a participant’s intervention 
assignment is unblinded, the Sponsor must be notified within 24 hours after breaking the 
blind. The date and reason that the blind was broken must be recorded in the source 
documentation and case report form, as applicable. 
6.4 
STUDY INTERVENTION COMPLIANCE  
When participants are dosed at the site, they will receive study intervention directly from the 
Investigator or designee, under medical supervision. The date and time of each dose administered 
in the clinic will be recorded in the source documents and patient’s e-Diary. The dose of study 
intervention 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 intervention. 
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. IMP kits are delivered by Investigator during on-site 
visits for the following 4 weeks administrations at home. IMP kits (used, unused and partially 
used) are returned by the participant at each visit. In case of DTP process, the IMP kits can be 
provided and returned by the carrier (if defined in the contract). Compliance will be assessed by 
e-Diary records and counting returned capsules during the site visits and documented in the source 
documents and eCRF. Deviation(s) from the prescribed dosage regimen should be recorded in the 
eCRF. 
A record of the number of SAR443122/placebo capsules dispensed to and taken by each 
participant must be maintained and reconciled with study intervention and compliance records. 
Intervention start and stop dates, including dates for intervention delays and/or dose reductions 
will also be recorded in the CRF. 
6.5 
DOSE MODIFICATION  
Not applicable for this study. 
6.5.1 Retreatment criteria  
Not applicable. 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY  
Not applicable. 
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6.7 
TREATMENT OF OVERDOSE  
Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the Investigator should assess the participant, and then: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
SAR443122 can no longer be detected systemically (at least 5 days). 
3. Obtain a plasma sample for PK analysis within 2 days from the date of the last dose of 
study intervention if requested by the Medical Monitor (determined on a case-by-case 
basis). 
4. Document appropriately in the eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
6.8 
CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
• Reason for use. 
• Dates of administration including start and end dates. 
• Dosage information including dose and frequency. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Participants must abstain from taking 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 
intervention until completion of the follow-up visit, unless, in the opinion of the Investigator and 
Sponsor, the medication will not interfere with the study. 
6.8.1 Prohibited medications  
Any medications listed in exclusion criteria (E 19, E 20, E 21, E 22 and E 23) should not be 
initiated during the study except what specifically mentioned in rescue medicine section 
(Section 6.8.8). 
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6.8.2 Topical corticosteroids  
Stable regimen of low to medium potency topical corticosteroids (Appendix 10, Section 10.10.1) 
are allowed from baseline if they are initiated 2 weeks before baseline. No modification including 
formulation or regimen change is allowed during the study, except that the patient develops an AE 
not related to CLE requiring the modification. The modification and AE must be recorded in the 
eCRF. 
Any increase of potency of principal active, initiation a new topical corticosteroid due to CLE 
worsening will be considered as rescue medication and should be appropriately recorded as 
described in Section 6.8.8. 
6.8.3 Systemic corticosteroids  
Participants should not receive systemic corticosteroids within 4 weeks prior to the baseline. 
During the study, oral corticosteroids can be used as rescue medication as described in 
Section 6.8.8. If the participant develops an AE for a condition not related to CLE that requires the 
oral corticosteroid treatment, the sponsor must be notified timely (eg, within 1 working day). The 
allowed cumulative dose of oral corticosteroid is equivalent prednisone <60 mg/day x 10 days, taking 
into account rescue oral corticosteroid if any. 
6.8.4 Intra-articular, intralesional, intranasal, and inhaled corticosteroids  
Intralesional and Intra-articular corticosteroids are not allowed during the study. 
Intranasal and inhaled corticosteroid are authorized as needed for treating conditions other than 
CLE. 
6.8.5 Chloroquine and hydroxychloroquine  
If patients receive chloroquine, hydroxychloroquine at baseline, the dose should be stable for at 
least 12 weeks prior to Screening visit and not exceed 2.3 mg/kg/day for chloroquine, 400mg/day 
for hydroxychloroquine. No change is allowed during the Screening period. Whenever possible, 
the dose should be stable during entire study period except that the patient develops an AE not 
related to CLE or SLE requiring the modification. The modification and AE must be recorded in 
the eCRF. 
6.8.6 Nonsteroidal anti-inflammatory drugs, topical anesthetics, acetaminophen and 
other analgesic  
Paracetamol/Acetaminophen, at doses of ≤2 grams/day, is permitted for use any time during the 
study. Other concomitant medication may be considered on a case-by-case basis by the 
Investigator, if they do not interfere with the study including any study assessments. 
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6.8.7 Drug interaction  
6.8.8 Rescue medications  
Topical corticosteroids and/or topical calcineurin inhibitors and/or one short course of oral 
corticosteroids of up to 10 days are allowed as rescue medications. If other systemic rescue 
medications such as immunosuppressants (except initiation or increase the dose of chloroquine or 
hydroxychloroquine) are required, the patient should be permanently discontinued from the study 
drug, but they should be encouraged to stay in the study until the end of the study. 
Subjects requiring rescue therapy (addition or increase of any systemic or topical treatments) 
beyond baseline will be considered non-responders. 
Rescue medication should not be used for at least 4 weeks following the first administration of 
study intervention, if feasible. The date and time of rescue medication administration as well as 
the name, route of administration, reason for starting and dosage regimen of the rescue medication 
must be recorded. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
  
7.1 
DISCONTINUATION OF STUDY INTERVENTION   
7.1.1 Permanent discontinuation  
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study intervention. If study intervention is definitively discontinued, the 
participant will remain in the study to be evaluated. Remaining visits will be performed, details 
are in Section 7.1.1.1. 
See the SoA for data to be collected at the time of discontinuation of study intervention and 
follow-up and for any further evaluations that need to be completed. 
The IMP will be permanently discontinued in case of the following events: 
• Clinically significant infections such as: 
- 
Opportunistic infections 
- 
Active TB 
- 
COVID-19 infections (positive-PCR or suspected active COVID-19 infection) 
• New adenopathy of unknown cause 
• New diagnosed malignancies 
• Initiation of systemic rescue medication except one short course of oral corticosteroid 
<10 days and/or chloroquine or hydroxychloroquine 
• Significant laboratory abnormalities (See Appendix 6 [Section 10.6]): 
- 
ALT >5 ULN or ALT >3 ULN with concomitant total bilirubin >2 ULN (unless 
patient with documented Gilbert’s syndrome) 
• Hb <8 g/dl of unknown cause 
• Symptomatic overdose 
• Pregnancy in female participant 
• Any AEs, per Investigator’s judgement that discontinuation of study intervention is in best 
interest of the participant 
Any abnormal laboratory value or ECG parameter will be immediately rechecked for 
confirmation before making a decision of definitive discontinuation of the IMP for the concerned 
participant. 
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7.1.1.1 Handling of participants after permanent intervention discontinuation  
Participants will be followed-up according to the study procedures specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
If possible, and after the definitive early discontinuation of intervention, the participants will be 
assessed using the procedure normally planned for the last dosing day with the IMP (end of 
treatment [EOT] visit) including skin biopsy sample and PK sample, if appropriate. Then, all the 
remaining visits and associated procedures prespecified in the SOA will be performed, except skin 
biopsy, pharmacokinetic samples, and photography at Week 12. 
All cases of permanent intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the eCRF when considered as confirmed. 
7.1.2 Liver chemistry stopping criteria  
Discontinuation of study intervention for abnormal liver tests is required by the Investigator when 
a participant meets one of the conditions outlined in the algorithm (Section 10.6) or in the 
presence of abnormal liver chemistries not meeting protocol-specified stopping rules if the 
Investigator believes that it is in best interest of the participant. 
7.1.3 QTc stopping criteria  
If a clinically significant finding is identified (including, but not limited to changes from baseline 
in QT interval after enrollment), the Investigator or qualified designee will determine if the 
participant can continue in the study and if any change in participant management is needed. This 
review of the ECG printed at the time of collection must be documented. Any new clinically 
relevant finding should be reported as an AE or AESI (Section 8.3.8). 
7.1.4 Temporary discontinuation  
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs (Section 10.6) or disruption of the clinical trial due to a regional or national 
emergency declared by a governmental agency (Appendix 9: Contingency measures for a regional 
or national emergency that is declared by a governmental agency [Section 10.9]). For all 
temporary intervention discontinuations, duration should be recorded by the Investigator in the 
appropriate pages of the eCRF. 
A temporary discontinuation >7 consecutive days will lead to permanent discontinuation. 
7.1.5 Rechallenge  
Reinitiation of intervention with 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(s) in the occurrence of the concerned event was 
unlikely and if the selection criteria for the study are still met. 
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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 
Appendix 9 (Section 10.9): Contingency Measures for a regional or national emergency that is 
declared by a governmental agency. 
7.1.5.1 Study intervention restart or rechallenge after liver stopping criteria met  
Study intervention restart or rechallenge after liver chemistry stopping criteria (Section 7.1.2) are 
met by any participant in this study is not allowed. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
• A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral or 
compliance reasons. This is expected to be uncommon. 
• 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 for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, 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 intervention should be explicitly asked about the 
contribution of possible AEs to their decision, and any AE information elicited must be 
documented. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
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 intervention 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 re-randomized (treated) in the study. 
Their inclusion and intervention numbers must not be reused. 
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7.3 
LOST TO FOLLOW UP  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 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, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 1 (Section 10.1). 
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8 
STUDY ASSESSMENTS AND PROCEDURES  
• Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed. The clinician reported outcome (ClinRO) 
mentioned in the SoA will be used when copyright is obtained (if applicable). 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 
• Patient-reported outcome (PRO) questionnaires should be completed by the participants 
before the consultation and/or clinical tests, in a quiet place (at home in e-diary and at 
clinic). The questionnaires should be completed by the participants themselves, 
independently from their physician, the study nurse, or any other medical personnel and 
without any help from friends or relatives. 
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 
Appendix 9 (Section 10.9): Contingency Measures for a regional or national emergency that is 
declared by a governmental agency. 
8.1 
EFFICACY ASSESSMENTS   
Planned time points for all efficacy assessments are provided in the SoA (Section 1.3). 
8.1.1 Cutaneous lupus Erythematosus Disease Area and Severity Index (CLASI)  
The CLASI is a clinician rated scale designed to assess the disease activity and damage in CLE in 
adults. It is composed of 56 items covering two dimensions (2): the disease activity (CLASI-A) 
and the disease damage (CLASI-D). The domains covered by the two as follows: 
• CLASI-A disease activity 
- 
Erythema 
- 
Scale/Hypertrophy 
- 
Recent hair loss/Alopecia (clinically not obviously scarred) 
- 
Mucous membrane lesions 
• CLASI-D disease damage 
- 
Dyspigmentation 
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• Scarring/Atrophy/Panniculitis 
• Clinically judged scarring of the scalp (including scarring alopecia) 
It has a current recall period and takes approximately 5 minutes to complete. Each of the 
two domains can be scored individually, with a higher score indicating a more severe skin disease. 
CLASI-A sub-score ranges from 0 to 70, with the following cut-offs: 0-9 indicating mild disease, 
10-20 indicating moderate disease, and 21-70 indicating severe disease (3). Damage is scored on 
a scale of 0-56, using the parameters of dyspigmentation and scarring, with higher scores 
indicating worse disease damage. Scores are given for different anatomical locations and are 
based on the worst area involved. 
The CLASI is a validated clinical instrument with documented content validity and good 
psychometric properties (inter- and intra- rater reliability; ability to detect changes) (2, 18, 19, 20, 
21). A 4-point or 20% decrease in CLASI-A score represents the minimal clinically important 
change (MCIC) (3). 
The CLASI-A50/75 response is defined as a patient achieved a decrease by at least 50%/75% of 
CLASI-A sub-score from baseline. 
Whenever possible, the same patient should be assessed by the same Investigator throughout the 
study. 
The CLASI is provided in Appendix 10 (Section 10.10.2). 
Clinicians will complete the CLASI as per SoA (Section 1.3). 
8.1.2 Physician Global Assessment of disease activity (PhysGA- disease activity) for 
cutaneous lupus erythematosus  
The Physician’s Global Assessment of disease activity (PhysGA- disease activity) is a 5 point-
Lickert scale instrument designed to assess physician-reported disease activity ranging from “Not 
active at all” to “Extremely active”. This instrument has been developed internally for this study 
in CLE. Whenever possible, the same patient should be assessed by the same Investigator 
throughout the study. 
The PhysGA-disease activity is provided in Appendix 10 (Section 10.10.3). 
Clinicians will complete the PhysGA-disease activity as per SoA (Section 1.3). 
8.1.3 Physician Global Assessment of Change in cutaneous lupus erythematosus activity 
(PGAC)  
The Physician’s Global Assessment of Change in cutaneous lupus erythematosus (PGAC) is 
a 7-Point Likert scale instrument designed to assess physician-reported evaluation of change in 
patient’s cutaneous lupus erythematosus activity overall in regards of start of treatment. The scale 
is ranged from “Very much improved” to “Very much worse”. 
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Whenever possible, the same patient should be assessed by the same Investigator throughout the 
study. 
The PGAC is provided in Appendix 10 (Section 10.10.3). 
Clinicians will complete the PGAC as per SoA (Section 1.3). 
8.1.4 Patient-reported Numerical Rating Scale (NRS)  
The Peak Pruritus NRS (itch-NRS) is a single item PRO tool that patients will use to report the 
intensity of their pruritus (itch) during a daily recall period. Patients will be asked to rate their 
worst itch on a 0 (“No itch”) to 10 (“Worst itch imaginable”) NRS by answering the following 
question: “On a scale of 0 to 10, with 0 being ‘no itch’ and 10 being the ‘worst itch imaginable’, 
how would you rate your itch at the worst moment during the previous 24 hours?” 
The Peak Pruritus NRS has been validated in atopic dermatitis adult and adolescent patients; 
a threshold for clinically relevant, within-person response was found to be 2-4 points (25). 
The Peak Pain NRS (Pain-NRS) is a single item PRO tool that patients will use to report the 
intensity of their CLE-related pain (skin, oral, genital) during a daily recall period. Patients will be 
asked to rate their worst pain on a 0 (“No pain”) to 10 (“Worst pain imaginable”) NRS by 
answering the following question: “On a scale of 0 to 10, with 0 being ‘no pain’ and 10 being the 
‘worst pain imaginable’, how would you rate your pain at the worst moment due to your lupus 
during the previous 24 hours?”. 
The Pain-NRS has been developed specifically for the present study. 
The itch-NRS and Pain-NRS are provided in Appendix 10 (Section 10.10.4). 
Patients will complete the Peak Pruritus NRS and Peak Pain NRS daily, as per the SoA (Section 1.3). 
If acetaminophen or other analgesics or topical anesthesia are used for pain relief, the participant 
will be requested to rate his/her pain just before the next administration. 
8.1.5 Investigator’s Global Assessment for Cutaneous Lupus Erythematosus (IGA-CLE)  
Investigator’s Global Assessment for Cutaneous Lupus Erythematosus (IGA-CLE) is a ClinRO 
that allows for clinicians to assess the overall disease activity of CLE using a 5-point scale: 
0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), and 4 (severe). The Severity of CLE is 
determined by descriptions of a combination of 3 plaque characteristics: erythema, scale, 
elevation. Erythema is the primary characteristic that should influence the rating, with other 
characteristics considered secondarily. Telangiectatic change should not be considered in the 
rating. The assessment does not require the presence of all four characteristics, the severity is 
averaged over the observed characteristics. 
Whenever possible, the same patient should be assessed by the same Investigator throughout the 
study. 
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The IGA-CLE is provided in the Appendix 10 (Section 10.10.8) 
Clinicians will complete the IGA-CLE as per SoA (Section 1.3). 
8.1.6 Oral Health Impact Profile 14-item version (OHIP-14)  
The OHIP-14 is a PRO questionnaire that measures people’s perception of dysfunction, 
discomfort and disability attributed to oral conditions in adults (26). It is composed of 14 items 
that assess seven different dimensions, considering the perception of the individual in relation to 
the impact of oral conditions in the physical, psychological and social well-being in the last 
month. Each of the 14 items has a set of possible answers distributed in a Likert scale (0 = never, 
1 = hardly ever. 2 = occasionally 3 = fairly often, 4 = very often), which represents the frequency 
that the individual perceives the impact of oral health on seven dimensions: functional limitation 
(2 items), physical pain (2 items), psychological discomfort (2 items), physical disability 
(2 items), psychological disability (2 items), social disability (2 items) and handicap (2 items) 
(26). The OHIP-14 scores can range from 0 to 56 and are calculated by summing the ordinal 
values for the 14 items. The domain scores can range from 0 to 8. Higher OHIP-14 scores indicate 
worse oral-health-related quality of life. OHIP-14 shows good reliability, validity and precision. 
The OHIP-14 is provided in Appendix 10 (Section 10.10.5). 
Patients will complete the OHIP-14 as per the SoA (Section 1.3). 
8.1.7 SKINDEX-29+3  
Skindex-29 is a PRO measure designed to assess the effects of skin disease on patients’ 
health-related quality of life in adults (27, 28). It is a generic instrument for skin and connective 
tissue diseases. It contains 29 items, distributed across the following domains: emotions 
(10 items), symptoms (7 items), functioning (12 items); and one item about treatment that is not 
part of the total score. Recall period is “during the past week”. Each item is rated on a 5-point 
Likert scale (never, rarely, sometimes, often, all the time). Individual items are scored from 
0 to100 in 25-point increments with 100 representing maximal disability. 
The measurement properties of the instrument have been extensively documented in various skin 
diseases, including CLE and SLE patients (3, 29, 30, 31). No data is available on the ability of the 
instrument to detect changes in CLE/SLE. Important impact on health-related quality of life is 
defined as a 9.38-point and a 7.37-point improvement in the Emotions and Symptoms subscales of 
Skindex-29, respectively (32). 
The Skindex 29+3 (also called SkindexLupus) (5). It includes a fourth subscale (3 questions) to 
assess lupus-specific issues, ie, photosensitivity and alopecia. Two items, ‘‘I worry about going 
outside because the sun might flare my disease’’ and ‘‘My skin disease prevents me from doing 
outdoor activities’’ relate to photosensitivity. The average of these two items was used to generate 
a photosensitivity subscale. Construct validity (item-total correlations; known-group validity) has 
been documented (33, 34, 35). 
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The SKINDEX-29+3 is provided in Appendix 10 (Section 10.10.6). 
Patients will complete the SKINDEX-29+3 as per the SoA (Section 1.3). 
8.1.8 Patient Global Impression of disease severity (PGIS) and Patient Global Impression 
of Change (PGIC) in cutaneous lupus erythematosus  
The PGIS is a 4-Point Likert scale instrument designed to assess patient’s evaluation of the 
severity their disease over the past week ranging from “None” to “Severe”. 
The PGIC is a 7-Point Likert scale instrument designed to assess patient’s-reported evaluation of 
change in their disease overall in regard to start of study medication. The scale is ranging from 
“Very much better” to “Very much worse”. 
The PGIS and PGIC are provided in Appendix 10 (Section 10.10.7). 
Patients will complete the PGIS and PGIC as per the SoA (Section 1.3). 
8.1.9 28-Joint assessment  
Twenty- eight-joint assessment will be used to assess CLE related joint inflammation by counting 
the number of active swollen and tender joints. An active joint is defined as joint with swelling 
within joint not due to deformity and/or joint with tenderness. 
Twenty- eight joints include proximal interphalangeal joints (10 joints), metacarpophalangeal 
joints (10), wrists (2), elbows (2), shoulders (2) and knees (2). 
8.1.10 Safety of Estrogens in Lupus Erythematosus National Assessment - Systemic 
Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI)  
The SELENA-SLEDAI has been developed to measure the disease activity in patients with SLE 
for use in clinical trials (22). It has been developed to determine global improvement and 
performed in effective and reliable manners in studies (36). 
This is a weighted index in which signs and symptoms, laboratory tests for each of the nine organ 
systems are given a weighted score and summed up if present at the time of the visit or in the 
preceding 10 days. The maximum theoretical score for the SELENA-SLEDAI is 105 (all 
24 descriptors present simultaneously) with 0 indicating inactive disease. A reduction of ≥4 points 
in the SELENA-SLEDAI score from baseline is considered to be a clinically meaningful 
improvement (37). 
Clinicians will complete the SELENA-SLEDAI as per the SoA (Section 1.3). 
8.1.11 Genital Erosive Lichen Planus (GELP) score  
Genital Erosive Lichen Planus score is a scoring system for clinical assessment of GELP in 
women (38). The GELP scoring system is based on a simple grading (0-3) of area of involvement, 
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degree of erythema, number of erosions, number of striae and patient-reported pain induced by 
pressuring the involved area with a cotton swab. Area of genital involvement, erythema, striae, 
number of erosions and pain are registered and scored 0-3 (0 is none) for each parameter. Vulval 
and vaginal involvement is assessed separately, resulting in a maximum GELP score of 30. 
Clinicians will complete the GELP as per the SoA (Section 1.3). 
8.1.12 Photography of Index Lesion  
Index lesions will be photographed at baseline. The same lesions will be photographed at EOT 
visit to evaluate their progression. 
Index lesion should include at least biopsied lesion and non-biopsied lesions. The lesion with the 
highest disease activity score as assessed by CLASI-A by Investigator at baseline should be 
selected. If more than one lesion is evaluated with the same highest score, it is up to Investigator 
to select some of those lesions or decide to photography all of them. If oral lesions present at 
baseline, oral lesion should be selected as well. 
The body site(s) and lesion features assessed by Investigator of photographed skin lesion will be 
recorded in the eCRF. 
The detailed information will be provided in the photography user guide. 
8.2 
SAFETY ASSESSMENTS   
This section presents safety assessments other than AEs which are presented in Section 8.3. 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1 Physical examinations  
A targeted physical examination including lung auscultation and assessment of consciousness will 
be performed at time points according to Section 1.3. Care should be taken to examine and assess 
any abnormalities that may be present, as indicated by the participant’s medical history. 
• A full physical examination will include, at a minimum, assessments of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems, skin, nasal 
cavities, eyes, and ears. Height (screening only) and weight will also be measured and 
recorded. 
• A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, lymphatic system (include but not limited to cervical, axillary, 
inguinal and clavicular lymph nodes) and abdomen (liver and spleen). 
• Investigators should pay special attention to clinical signs related to previous serious illnesses. 
• Any new finding or worsening of previous finding should be reported as a new adverse event. 
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8.2.2 Vital signs  
Vital signs, including systolic and diastolic blood pressure, pulse rate, temperature and respiration 
rate, will be collected and recorded at the time points according to Section 1.3. 
• Temperature, pulse rate, respiratory rate, and blood pressure will be assessed. The site of 
temperature measurement should be recorded in the eCRF, and the same site should be 
used throughout the study for the same patient. 
• Blood pressure and pulse measurements will be assessed in semi-supine position 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). 
• Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse 
and 3 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 on the eCRF. 
8.2.3 Electrocardiograms  
A standard 12-lead ECG will be performed at time points according to Section 1.3. Heart rate will 
be recorded from the ventricular rate and the PR, QRS, and QT (identify QTcF) intervals will be 
recorded in the eCRF. The ECG strips or reports will be retained with the source. 
• Single 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. Refer to Section 7 for QTcF withdrawal criteria and any additional QTcF 
readings that may be necessary. 
8.2.4 Clinical safety laboratory assessments  
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency. Additional clinical laboratory tests may be performed based on 
the investigator’s clinical judgement. 
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the participant’s condition. 
A laboratory manual will be provided to study sites with additional information for laboratory 
parameters assessed centrally. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 14 days after the last dose of study intervention should be repeated until the 
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values return to normal or baseline or are no longer considered clinically significant by the 
Investigator or medical monitor. 
• If such values do not return to normal/baseline within a period of time judged reasonable 
by the Investigator, the etiology should be identified, and the Sponsor notified. 
• All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), 
must be conducted in accordance with the laboratory manual and the SoA. 
• If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the Investigator (eg, SAE or severe AE or dose modification), then 
the results must be recorded in the eCRF. 
8.2.5 Suicidal ideation and behavior risk monitoring  
Not applicable. 
8.3 
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 8.3.8. 
The definitions of unsolicited and solicited adverse events can be found in Appendix 3 
(Section 10.3). 
AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study (see Section 7). 
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). 
8.3.1 Time period and frequency for collecting AE and SAE information  
All SAEs will be collected from the signing of the informed consent form (ICF) until the 
follow-up visit at the time points specified in the SoA (Section 1.3). 
All AE will be collected from the signing of the ICF at the time points 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). 
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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 AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor. 
8.3.2 Method of detecting AEs and SAEs  
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3 Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. At the pre-specified study end-date, all SAEs, and AEs of 
special interest (as defined in Section 8.3.8), 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). 
8.3.4 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• Adverse events that are considered expected will be specified in the reference safety 
information (Investigator’s Brochure). 
• 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. 
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• An Investigator who receives an Investigator safety report describing a SAE, SUSAR or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
will review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. It is the responsibility of the 
Sponsor to assess whether an event meets the criteria for a SUSAR, and therefore, is 
expedited to regulatory authorities. 
8.3.5 Pregnancy  
It is the responsibility of the investigator to report to the sponsor (or designee), any pregnancy 
occurring in a female study participant or a female partner of male participant, during the study. 
• Details of all pregnancies in female participants and female partners of male participants 
will be collected after the start of study intervention and until the outcome of the 
pregnancy. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. 
• If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4). 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6 Cardiovascular and death events  
Cardiovascular and death events should be reported to the sponsor and/or health authority per 
reporting rules for AEs or SAEs if seriousness criteria met. 
8.3.7 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs  
Not applicable. 
8.3.8 Adverse event of special interest  
Adverse event of special interest 
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
Investigator to the Sponsor is required. Such events may require further investigation in order to 
characterize and understand them. Adverse events of special interest may be added, modified or 
removed during a study by protocol amendment. 
• 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; 
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- 
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 Appendix 4 
[Section 10.4]) 
• Symptomatic overdose (serious or nonserious) with IMP. 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the participant (not based on systematic pills 
count) and defined as at least 50% more than intended daily dose within one day. 
• Increase in alanine transaminase (ALT) 
- 
≥3 X ULN (for participants with normal baseline) or 
- 
>3 X ULN AND at least 2-fold increase from baseline value (for participants with 
abnormal baseline). 
• Other AESI: 
- 
Anemia (Hb <8 g/dL). 
• Other project specific AESI(s) 
- 
QTc ≥500 ms (per QTcF). 
- 
New Lymphadenopathy. 
8.3.9 Guidelines for reporting product complaints  
Any defect in the IMP must be reported as soon as possible by the Investigator to the monitoring 
team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
8.3.9.1 Medical device deficiencies  
Not applicable. 
8.4 
PHARMACOKINETICS  
Samples for SAR443122 PK analyses will be collected at the following timepoints as mentioned 
in (Section 1.3): 
• On Day 1, PK sampling within 2 to 5 hours after the first morning dose (around Cmax); 
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• On Day 57 PK sampling just before or within 1 h before the morning dosing, within 2 to 
5 hours after the first morning dose (around Cmax) and within 7 to 10 hours after the 
morning doses; 
• On Day 85, PK sampling just before or within 1 h before the morning dosing and within 
2 to 5 hours after the first morning dose (around Cmax). 
Procedures for PK sample management and analysis will be described in the laboratory manual. 
A maximum of 2 samples may be collected at additional time points during the study if warranted 
and agreed upon between the Investigator and the Sponsor. The timing of sampling may be altered 
during the course of the study based on newly available data (eg, to obtain data closer to the time 
of peak plasma concentrations) to ensure appropriate monitoring. 
The actual date and time (24-hour clock time) of each sample, and associated IMP intake will be 
recorded. 
8.4.1 Pharmacokinetics handling procedure  
Instructions for the collection and handling of biological samples will be provided by the Sponsor 
in the laboratory manual. 
Genetic analyses will not be performed on these plasma samples. Participant confidentiality will 
be maintained. At visits during which plasma samples for the determination of multiple aspects of 
study intervention will be taken, one sample of sufficient volume can be used. 
Drug concentration information that would unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. 
8.4.2 Bioanalytical method  
SAR443122 will be assayed by a validated LC/MS method. The details of the bioanalytical 
method will be specified in the laboratory manual. 
8.4.3 Pharmacokinetic parameters  
SAR443122 concentrations at selected time points after IMP intake will be reported using 
descriptive statistics. Additional PK parameters such as Cmax, tmax, and AUC0-tau and elimination 
half-life [t1/2z] at steady state will be estimated using a population PK approach. These parameters 
will be presented in a separate, stand-alone report. 
8.5 
GENETICS  
All participants will undergo skin punch biopsies. The first biopsy will be before the 
randomization (either at screening or at Baseline) and the second at EOT visit. Transcriptomic 
analysis (RNA sequencing) will be performed on skin samples obtained from biopsies, to explore 
changes related to treatment and/or disease progression compared to baseline and placebo controls 
to evaluate their association with the observed clinical responses to SAR443122. 
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Participants will be asked whether they will consent to the collection of an optional blood sample 
for the isolation of DNA and RNA. These materials will be used for exploratory genomic and 
transcriptomic analysis, respectively. 
Blood samples for DNA or RNA isolation will be collected at the timepoints indicated in SoA 
(Section 1.3) from participants who have consented to participate in the genetic analysis 
component of the study. Participation is optional. Participants who do not wish to participate in 
the genetic research may still participate in the study. 
Blood samples for RNA isolation will be collected at the timepoints indicated in SoA from 
participants who have consented to participate in the gene expression analysis component of the 
study. Participation is optional. Participants who do not wish to participate in the genetic research 
may still participate in the study. 
In the event of DNA or RNA seq extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a replacement 
sample unless it was included in the original consent. 
See Appendix 5 (Section 10.5) for information regarding genetic research. Details on processes 
for collection and shipment and destruction of these samples can be found in the laboratory 
manual. 
8.6 
BIOMARKERS  
Blood and skin biopsy samples collected from subjects in this study may be used to identify and 
measure biomarkers (including optional collections of blood for DNA and/or RNA as discussed 
in Section 8.5) related to the study drug. These samples will be used for scientific research to 
support this study protocol. The information gained from these samples may be used to design or 
improve methods for analyzing, comparing, or combining study data. Plasma from whole blood 
will be used for exploratory research including the development of PD assays and/or exploration 
of target- and disease-related exploratory biomarkers related to RIP kinase-1 inhibition such as 
cytokines, lipids, metabolites, proteome, cellular markers, immune cell phenotypes, and other 
inflammatory biomarkers. All samples, including any for assay development will be shipped to 
the Sponsor or a designated laboratory. 
Blood samples for biomarkers related to CLE will be collected by venipuncture at the timepoints 
indicated in SoA (Section 1.3). Procedures for collecting, processing and shipping of these 
samples are provided in the laboratory manual. 
Samples will be tested for changes related to treatment and/or disease progression compared to 
baseline and placebo controls to evaluate their association with the observed clinical responses to 
SAR443122, including: 
• PBMC: Whole blood will be collected for PBMC isolation. RIPK1 phosphorylation at 
Serine-166 (pS166-RIPK1) will be measured in lysates prepared from collected PBMCs 
using a qualified fit-for-purpose assay. 
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• Cytokines Panel, Chemokines Panel, and disease related biomarkers: Blood plasma 
will be used for the tests. 
- 
The cytokine panel includes validated assays for: 
 
 
- 
The chemokine panel includes validated assays for: 
 
. 
- 
The disease related biomarkers are referred to as C3, C4, anti-dsDNA-Ab as well as 
other CLE biomarkers. 
• Skin Biopsy for Immunohistochemistry (IHC): Skin samples obtained from punch 
biopsies will be used for Immunohistochemistry and histology analysis. 
Samples will remain confidential. These samples, and any additional samples derived from the 
original samples, may be stored and analyzed for up to 15 years after the study ends and the final 
results are reported (or according to local regulations). The Sponsor and its authorized 
representatives will ensure that samples are destroyed at the end of the storage period. 
The timing of the PD assessments, including blood collections, to be performed during the study 
may be subject to change based on the ongoing review of the data. Furthermore, additional blood 
samples may be taken from each subject per treatment period per safety purpose. Any changes to 
the scheduled timepoints of PD assessments will be agreed with the Sponsor. 
8.7 
IMMUNOGENICITY ASSESSMENTS  
Not applicable. 
8.8 
HEALTH ECONOMICS  
Not applicable. 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH  
Future research may help further the understanding of disease subtypes, disease biology, related 
conditions, drug response and toxicity, and can help identify new drug targets or biomarkers that 
predict participant response to treatment. Therefore, data and biological samples will be stored 
and used for future research when consented to by participants (see Section 10.1.3) unless 
prohibited by local laws or IRBs/IECs (in such case, consent for future use of sample will not be 
included in the local ICF). 
For participants who consent to the future use of biological samples, the left-over samples may be 
used after the study ends for future research related either to the drug, the mechanism of action, 
and the disease or its associated conditions. Such research may include, but is not limited to, 
performing assessments on DNA, RNA, proteins or metabolites. If future research on genetic 
material is performed, this will also be limited to the purpose of addressing research questions 
related to the drug, the mechanism of action, the disease or its associated conditions. 
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For this same purpose above, some clinical laboratory data generated in this study from 
participants who consent to will be shared with researchers as a third part. Participant’s coded data 
sets provided to researchers for a specific research project will be available to the researchers for 
a maximum of 25 years after the end of their specific project (end of project is defined by 
publication of the results or finalization of the future research project report). 
In the event future research is conducted for other purposes not listed above, the study participants 
will be informed of those purposes and will be given means to object to those research projects. 
An additional written consent will be obtained from participants if this is the case. 
Data and samples will be used in compliance with the information provided to participants in the 
ICF Part 2 (future research) and any applicable data protection laws. 
All study participant data and samples will be coded such that no participant direct identifiers will be 
linked to them. Coded data and samples may be transferred to a Sponsor site (or a subcontractor site), 
which may be located outside of the country where the study is conducted. The Sponsor adopts 
safeguards for protecting participant confidentiality and personal data (see Section 10.1.4). 
The samples will be stored for a maximum of 15 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. 
Study participant coded data will be stored for future research for up to 25 years after the end of 
the study. If data are still considered of important scientific value after this period, coded data 
already available will be anonymized unless otherwise required by applicable laws (the same will 
apply to the data of a study participant who has requested the destruction of his/her samples). 
Participant’s coded data sets provided to researchers for a specific research project will be available 
to the researchers for a maximum of 25 years after the end of their specific project (end of project is 
defined by publication of the results or finalization of the future research project report). 
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9 
STATISTICAL CONSIDERATIONS  
  
9.1 
SAMPLE SIZE DETERMINATION  
The sample size was derived with respect to the primary endpoint (percent change from Baseline 
in CLASI-A sub-score at Week 12) by applying the Quantitative Decision Making approach as 
described by Quan et al (39). Assuming a standard deviation of 45% and a reducing effect of 
28% under active treatment, a sample size of 80 evaluable participants results in an overall 
probability for a positive decision of more than 50% and a negative decision probability of 20%. 
Up to 88 participants are expected to be randomly assigned to the IMP, expecting a total of 
80 evaluable participants with approximately 40 evaluable participants per group. 
9.2 
POPULATIONS FOR ANALYSES  
The following populations are defined (Table 5): 
Table 5 - Populations for analyses  
Population 
Description 
Screened 
All participants who sign the ICF. 
Randomized 
All screened participants who are randomly assigned to the IMP (by IRT) regardless 
of whether the intervention was received or not. 
Efficacy 
All randomized participants exposed to the IMP, with available Baseline 
assessment of the CLASI-A who did actually receive at least 1 complete dose of 
IMP and with at least 1 post IMP administration measurement. Participants will be 
analyzed according to the intervention they actually received. 
Safety 
All randomized participants exposed to the IMP (regardless of the amount of 
treatment administered) are included in the safety population. Participants will be 
analyzed according to the intervention they actually received. 
Pharmacokinetic (PK) 
All randomized and treated participants without any important deviation related to 
IMP administration, for whom the PK data are considered interpretable. Participants 
having received only placebo will not be part of the PK population. 
CLASI-A: Cutaneous Lupus Erythematosus Disease Area and Severity Index - A, ICF: informed consent form, IMP: investigational medicinal 
product, PK: pharmacokinetic. 
Note: “Screened” means a participant's, or their legally acceptable representative’s, agreement to 
participate in a clinical study following completion of the informed consent process. 
9.3 
STATISTICAL ANALYSES  
The statistical analysis plan (SAP) will include a more technical and detailed description of the 
statistical analyses described in this section. This section is a summary of the planned statistical 
analyses of the most important endpoints including primary and a subset of secondary endpoints. 
The SAP will be developed and finalized prior to database lock or any interim analysis. 
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For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9 (Section 10.9): Contingency measures for a regional or national 
emergency that is declared by a governmental agency. 
9.3.1 General considerations  
Descriptive analyses will include summarization of quantitative variables (using n, mean, standard 
deviation, inter quartile range, median, minimum, and maximum) and qualitative data 
(by reporting absolute and relative frequencies). 
The baseline value of efficacy parameters is defined as the Day 1 pre-dose assessment value 
unless otherwise specified. 
The baseline value of the other parameters is defined as the last available value prior to the first 
dose of investigational medicinal product (IMP) if the participant is treated, or the last available 
value up to randomization if the participant is not exposed to IMP. 
9.3.2 Primary endpoint(s)  
The primary analysis will be performed on the Efficacy population through a mixed model with 
repeated measurements (MMRM) will be fitted to estimate the difference in percent change in 
CLASI-A from Baseline at Week 12. The model includes fixed effects for baseline CLASI-A, 
post-baseline visit, geographical region, disease subtype, baseline use of chloroquine or 
hydroxychloroquine, intervention group, visit by intervention group interaction, and visit-by-
baseline CLASI-A interaction. Stratification factors will be included in the analysis model if 
a sufficient number of participants per stratum is available. Details will be specified in the SAP. 
Repeated measurements for each post-baseline visit are taken within subject (Table 6). Point 
estimate and two-sided 90% confidence interval for the difference of mean percent change 
between the 2 groups (SAR443122 versus placebo) will be derived from the linear model 
framework. 
Table 6 - Primary endpoint analysis  
Primary endpoint 
Statistical analysis methods 
Percent change in CLASI-A score 
from Baseline to Week 12. 
The difference to placebo of mean percent change from Baseline in CLASI-A at Week 12 
will be derived using a mixed model with repeated measurements (MMRM) including 
fixed effects for baseline CLASI-A, post-baseline visit, geographical region, disease 
subtype, baseline use of chloroquine or hydroxychloroquine, intervention group, 
visit-by- intervention group interaction, and visit-by-baseline-CLASI-A interaction. 
Repeated measurements for each post-baseline visit are taken within subject. Point 
estimate with 90% confidence interval for the difference of mean percent change at 
Week 12 between the 2 groups (SAR443122 versus placebo) will be derived. 
CLASI-A: Cutaneous Lupus Erythematosus Disease Area and Severity Index - A. 
Observed mean and mean percent change from Baseline in the primary endpoint will be 
summarized descriptively by intervention group and visit. 
Details on the handling of participants requiring rescue medication will be detailed in the SAP. 
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9.3.3 Secondary endpoint(s)  
Analysis of secondary efficacy endpoints will be performed on the Efficacy population. 
The secondary endpoints defined as proportion of patients with Phys-GA disease activity being 
either 0 or 1 at Week 12 and proportion of patients with IGA-CLE of 0 or 1 (clear or almost clear) at 
Week 12 (Table 7) will be calculated using a logistic regression model with treatment, geographical 
region, disease subtype, baseline use of chloroquine or hydroxychloroquine, and subtype by 
intervention group interaction as fixed effects. Stratification factors will be included in the analysis 
model if a sufficient number of participants per stratum is available. Details will be specified in the 
SAP. A 90% confidence interval for the difference in proportions will be provided by back-
transformation to the natural scale of the corresponding 90% confidence interval for the log-odds ratio. 
Table 7 - Selected secondary endpoints analyses  
Secondary endpoint 
Statistical analysis methods 
Proportion of patients with 
PhysGA-disease activity at 
Week 12 being either 0 or 1 
The difference in proportion of subjects with PhysGA-disease activity in 0 or 1 will be 
estimated based on a logistic regression model with treatment, geographical region, disease 
subtype, baseline use of chloroquine or hydroxychloroquine, and subtype-by-intervention group 
interaction as fixed effects. A 90% confidence interval for the difference will be provided. 
Proportion of patients with 
IGA-CLE score of 0 or 1 (clear 
or almost clear) at Week 12 
The difference in proportion of subjects with IGA-CLE score of 0 or 1 will be estimated 
based on a logistic regression model with treatment, geographical region, disease subtype, 
baseline use of chloroquine or hydroxychloroquine, and subtype by intervention group 
interaction as fixed effects. A 90% confidence interval for the difference will be provided. 
PhysGA-disease activity: Physicians Global Assessment of disease activity; IGA-CLE: Investigator’s Global Assessment for Cutaneous Lupus 
Erythematosus. 
The observed proportion of subjects with PhysGA-disease activity in 0 or 1 and with IGA-CLE 
score in 0 or 1 will be summarized descriptively by intervention group and visit, respectively. 
Secondary endpoints other than adverse events, PCSAs, laboratory tests, ECG parameters, vital 
signs or pharmacokinetic parameters will be summarized descriptively by intervention group and 
visit, and their change from baseline will be presented where applicable. 
Summaries of adverse events, PCSAs, laboratory tests, ECG parameters, vital signs as well as 
pharmacokinetic parameters are described in Section 9.3.5 below. 
Additional details on further analyses of secondary endpoints will be provided in the SAP. 
9.3.4 Exploratory endpoint(s)  
Details on the analysis of exploratory endpoints will be provided in the SAP. 
9.3.5 Analyses of safety data  
The safety evaluation will be based upon the review of the individual values (clinically significant 
abnormalities), descriptive statistics (summary tables, figures) and, if needed, on statistical 
analysis (appropriate estimations, confidence intervals). No statistical significance tests will be 
performed on safety data. 
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Potentially clinically significant abnormality (PCSA) values are defined as abnormal values 
considered medically important by the Sponsor, according to predefined criteria/thresholds based 
on literature reviews and defined by the Sponsor for clinical laboratory tests, vital signs, and ECG 
parameters. 
All the safety analyses will be performed using the safety population. 
For all safety data variables, the following observation periods are defined and used for 
classification of AEs, determination of on-treatment PCSA values, and the last on-treatment value 
for laboratory and vital sign parameters: 
• The pre-treatment period is defined as the time between informed consent signature and 
the first IMP administration. 
• The treatment-emergent (TE) period is defined as the time from the first IMP 
administration up to the EoS visit (EoS included). It may be split further into the following 
periods: 
- 
On treatment period, defined as the time from the first IMP administration up to the 
last administration of the IMP +5 days (last day included). 
- 
Residual treatment period, defined as the time after end of the on-treatment period to 
the EoS visit (EoS included). 
• The post treatment period is defined as the time starting after the TE period. 
9.3.5.1 Adverse events  
9.3.5.1.1 Definitions  
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA; version in use by the Sponsor at the time of database lock). Clinical judgment should 
be used to determine the severity of AEs as described in Section 10.3.3. 
Adverse events will be analyzed in the following 3 categories: 
• Pre-treatment AEs: AEs that developed, worsened or became serious during the 
pre-treatment period. 
• Treatment emergent AEs: 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 
period. 
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Analysis of all adverse events 
Adverse event 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 if applicable. 
Analysis of AEs, SAEs, AESIs, deaths and PCSAs are summarized in Table 8 and will be detailed 
in the SAP. 
Table 8 - Safety analyses  
Safety measures 
Statistical analysis methods 
Adverse events  
• 
AEs  
• 
TEAEs  
• 
SAEs  
• 
AEs leading to IMP discontinuation or study 
withdrawal 
• 
AEs leading to death  
• 
AESIs  
• 
PCSAs 
Treatment-emergent adverse event incidence tables will be 
presented by system organ class, high-level group term, high-level 
term, and preferred term for each intervention group and overall, 
showing the number (n) and percentage (%) of participants 
experiencing a TEAE.  
Multiple occurrences of the same event in the same participant will 
be counted only once in the tables. The denominator for 
computation of percentages will be the safety population within 
each intervention group. In addition, TEAEs will be described 
according to maximum intensity and relation to the IMP.  
Adverse events that occur outside the treatment emergent period 
will be listed separately. 
Proportion of patients with at least 1 TEAE, treatment emergent 
SAE, AESI, TEAE leading to death, and TEAE leading to definitive 
treatment discontinuation will be tabulated by intervention group 
and overall.  
The incidence of PCSAs occurring during the TE period will be 
summarized by intervention group overall and by baseline status. 
AE: adverse event, AESI: adverse event of special interest, IMP: investigational medicinal product, PCSA: potentially clinically significant 
abnormality, SAE: serious adverse event, TEAE: treatment-emergent adverse event. 
9.3.5.2 Vital signs  
Vital signs (respiration rate, temperature, pulse rate and blood pressure) will be summarized by 
baseline and change from baseline to each scheduled assessment time with descriptive statistics 
for each intervention group. 
9.3.5.3 Clinical safety laboratory  
Laboratory results (hematology or clinical chemistry) will be summarized by baseline and change 
from baseline to each scheduled assessment time with descriptive statistics for each intervention 
group. 
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9.3.5.4 Electrocardiogram  
Electrocardiogram parameters will be summarized by intervention group as raw data and change 
from baseline to each assessment time with descriptive statistics based on the data collected. 
9.3.6 Analyses of pharmacokinetic data  
9.3.6.1 Pharmacokinetic parameters  
SAR443122 concentrations at selected time points will be reported by intervention group using 
descriptive statistics on the Pharmacokinetic population. 
Further details on the analysis of PK parameters will be described in the SAP. 
9.3.6.2 Pharmacokinetic/Pharmacodynamic analysis  
The analysis of PK/PD relationship will be described in the SAP. 
9.4 
INTERIM ANALYSES   
An interim analysis is planned for this study. The sponsor will make use of this interim analysis to 
facilitate internal operational decision on the compound development. The interim analysis will be 
performed when around 75% of the patients have completed study treatment or discontinued the 
study. The interim analysis will not lead to changes in the conduct of the protocol other than 
stopping recruitment for this proof of concept study due to clear efficacy signal at the time of the 
interim analysis or due to lack of an efficacy signal, indicating a lack of equipoise for continued 
recruitment of patients.  The details including the pre-specified rules for stopping the recruitment 
will be described in the SAP.  
The interim analysis will evaluate the mean percent change from baseline in CLASI-A at Week 12 
and other selected secondary efficacy endpoints, as well as the safety endpoints as needed. The 
PK and PD relationship could also be explored. 
The interim analysis will be performed by a separate statistical team, independent of the study 
team. The PK/PD analysis will be performed by a sponsor internal modeling and simulation team, 
also independent of the study team. Only those necessary for conducting the interim analysis and 
those responsible for internal project planning/overall portfolio planning needs (eg, to aid in the 
planning of future studies) will have the access to the interim analyses results before study 
completion. A list of these individuals will be maintained. 
All sponsor internal personnel with access to unblinding information will be asked to sign a study 
confidentiality agreement before having access to unblinding information. Study team and 
investigational sites will not have access to interim study results, and continue to be blinded to 
individual randomization codes until study completion and database lock. 
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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. 
- 
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation - GDPR). 
• The protocol, protocol amendments, ICF, Investigator Brochure, [IDFU] 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: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
- 
Determining whether an incidental finding (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 so designated by the participant) is consistent with all 
applicable national, state, or regional laws and regulations in the country where 
the study is being conducted, and 
- 
The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical validity. 
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- 
The participant in a clinical study has the right to opt out of being notified by the 
Investigator of such incidental findings. In the event that the participant has 
opted out of being notified and the finding has consequences for other 
individuals, eg, the finding relates to a communicable disease, Investigators 
should seek independent ethical advice before determining next steps. 
- 
In case the participant has decided to opt out, the Investigator must record in the 
site medical files that she/he does not want to know about such findings. 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), European Medical Device Regulation 
2017/745 for clinical device research (if applicable), and all other applicable local 
regulations. 
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical trial participants or on the scientific value of the trial) prior to their implementation. 
10.1.2 Financial disclosure  
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3 Informed consent process  
• The Investigator or his/her representative will explain the nature of the study to the 
participants, and answer all questions regarding the study, including what happens to the 
participant when his/her participation ends (post-trial access strategy for the study). 
• Participants must be informed that their participation is voluntary. Participants 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 Global Data Protection Regulation (GDPR) and of the French law, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center. 
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
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• 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. 
Participants who are rescreened are required to sign a new ICF. 
The ICF contains 2 separate sections that addresses the use for research of participants’ data 
and/or samples (remaining mandatory ones or new extra samples collected for optional research). 
Optional exploratory research must 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 a checkbox in 
CSICF Part 3. 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. 
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 
Appendix 9 (Section 10.9): Contingency Measures for a regional or national emergency that is 
declared by a governmental agency. 
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 (General Data Protection Regulation). 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 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 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 and because they are required by regulatory agencies (eg, on African American 
population for the FDA). They will not be collected in the countries where this is prohibited by 
local regulation. 
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• 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 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. 
• The participant must be informed that his/her 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. 
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• 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 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: 
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- 
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. 
• 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. 
• In order 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 all 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 Committee structure  
10.1.5.1 Internal Safety Review Committee  
This study will establish an unblinded ISRC which is independent from study team and 
Investigators to conduct the review of safety data (all AEs, including SAE and AESIs) as well as 
selected clinical laboratory parameters, and to make recommendations to the study team regarding 
the continuation, modification including additional safety measures, a temporary halt or 
termination of the trial. The assessment of available safety data and selected clinical laboratory 
data (as defined in the ISRC charter) will be done periodically. Enrollment may be held during the 
safety review only on the recommendation of the ISRC at their discretion. The ISRC chair may 
call for Ad hoc meetings at any point if the ongoing safety report data warrants this measure in 
their judgement. The structure, membership and exact responsibilities of the ISRC are detailed in 
the respective charter. 
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10.1.6 Dissemination of clinical study data  
Study participants 
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, EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance and intellectual property. 
For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to vivli.org. 
Individual 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 Organizations”. 
10.1.7 Data quality assurance  
• All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
• Guidance on completion of CRFs will be provided in CRF completion instructions. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in separate study documents. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
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• 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 longer retention period. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
10.1.8 Source documents  
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data reported on the CRF or entered in the 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 the Monitoring Plan. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.9 Study and site start and closure  
First act of recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is considered the first act of screening and will be the study start date. 
Study/Site termination 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
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Reasons for study termination by the Sponsor, as well as reasons for the early closure of a study 
site by the Sponsor or Investigator may include but are not limited to: 
• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio. 
- 
Discontinuation of further study intervention development. 
• For site termination: 
- 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines. 
- 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator. 
- 
Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.10 Publication policy  
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments. 
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
• The tests detailed in Table 9 will be performed. 
• For tests to be performed by the central laboratory, local laboratory results are only 
required in the event that the central laboratory results are not available in time for either 
study intervention administration and/or response evaluation. Additionally, if the local 
laboratory results are used to make either a study intervention decision or response 
evaluation, the results must be entered into the CRF. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
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• Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
• Pregnancy testing. 
Table 9 - Protocol-required laboratory tests  
 
Laboratory tests 
Parameters 
Hematology 
 
 
Platelet count 
 
Red blood cell (RBC) count 
 
Hemoglobin 
 
Hematocrit 
 
RBC indices: 
 
MCV 
 
MCH 
 
%Reticulocytes 
 
White blood cell (WBC) count with differential: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
Clinical chemistry 
 
 
Blood urea nitrogen (BUN) 
 
Creatinine 
 
Creatinine phosphokinase (CPK) 
 
Glucose [fasting] 
 
Potassium 
 
Sodium 
 
Calcium 
 
Aspartate aminotransferase (AST)/Serum glutamic-oxaloacetic transaminase (SGOT) 
 
Alanine aminotransferase (ALT)/Serum glutamic-pyruvic transaminase (SGPT) 
 
Alkaline phosphatasea 
 
Total and direct bilirubin 
 
Total protein 
Urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte 
esterase] by dipstick 
• 
Microscopic examination (including pyuria, hematuria and urinary casts) 
Spot Urine test 
• 
Urine protein test 
• 
Urine creatinine test  
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Laboratory tests 
Parameters 
Pregnancy testing 
• 
Serum or highly sensitive urine human chorionic gonadotropin (hCG) pregnancy 
test (as needed for women of childbearing potential)b 
Other screening tests 
• 
Please refer to Section 1.3 for a complete list of screening test 
• 
All study-required laboratory tests will be performed by a central laboratory with 
the exception of: 
- 
TB screening testing 
- 
COVID-19 screening testing 
- 
Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only) 
- 
Hepatitis B DNA testing as needed 
The results of each test must be entered into the eCRF. 
NOTES: 
a 
If alkaline phosphatase is elevated, consider fractionating. 
b 
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. 
Laboratory/analyte results (eg, PK/PD) that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded. 
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 patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Definition of unsolicited and solicited AE 
• An unsolicited adverse event is an adverse event that was not solicited using a participant 
diary and that is communicated by a participant who has signed the informed consent. 
Unsolicited AEs include serious and non-serious AEs. 
• Potential unsolicited AEs may be medically attended (ie, symptoms or illnesses requiring 
a hospitalisation, or 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 concern. Detailed information about reported unsolicited AEs will be collected 
by qualified site personnel and documented in the participant’s records. 
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• Unsolicited AEs that are not medically attended nor perceived as a concern by participant 
will be collected during 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 diary. 
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), 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 conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE. 
• 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. Also, “lack of 
efficacy” or “failure of expected pharmacological action” also constitutes an AE or SAE. 
Events NOT meeting the AE definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
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• 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 adverse event that, at any dose: 
a) Results in death 
b) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been 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) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 
f) Other situations: 
- 
Medical or scientific judgment should be exercised by the Investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant 
medical events that 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. 
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- 
Note: The following list of medically important events is intended to serve as 
a guideline for determining which condition has to 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 as a consequence of 
blood sampling) 
- 
Bullous cutaneous eruptions 
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, with the exception of 
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. 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories: 
• Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
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• Moderate: An event that causes sufficient discomfort to interfere with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. “Severe” is a category used for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than that a relationship cannot be ruled 
out. 
• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The Investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor and/or health authority. 
However, it is very important that the Investigator always make an assessment of 
causality for every event before the initial transmission of the SAE data to the 
Sponsor and/or health authority. 
• The Investigator may change his/her opinion of causality in light of 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 health authority and the Sponsor with a copy of 
any post-mortem 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 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form (see next section) or to 
the Sponsor’s representative by telephone. 
• Contacts for SAE reporting can be found in Investigator study 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 time frames. 
• Contacts for SAE reporting can be found in Investigator study file. 
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10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE  
10.4.1 Definitions  
A woman is considered WOCBP (fertile) from the time of menarche until becoming 
postmenopausal (see below) unless permanently sterile (see below). 
• A postmenopausal state is defined as the period of time after a woman has experienced no 
menses for 12 consecutive months without an alternative medical cause. 
• A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be used 
to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT). 
• Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment. 
Permanent sterilization methods include: 
• 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. 
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 intervention, additional evaluation should be 
considered. 
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10.4.2 Contraception guidance  
• If locally required, acceptable contraceptive methods are limited to those which inhibit 
ovulation as the primary mode of action 
 
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 
• 
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 intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant. 
a 
Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for those 
participating in clinical studies. 
b 
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when used consistently and 
correctly. 
c 
Male condoms must be used 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). 
• For the Unite Kingdom, acceptable forms of effective contraception include: 
- 
Established use of oral, injectable, or implantable progestogen-only hormonal 
contraception associated with inhibition of ovulation; 
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- 
Placement of an intrauterine device (IUD) or intrauterine hormone-releasing system 
(IUS); 
- 
Bilateral tubal occlusion; 
- 
Male sterilization (provided that the partner is the sole sexual partner of the WOCBP 
study participant and that the sterilized partner has received medical assessment of the 
surgical success). 
• True abstinence: When this is in line with the preferred and usual lifestyle of the subject. 
(Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and 
withdrawal are not acceptable methods of contraception). 
COLLECTION OF PREGNANCY INFORMATION: 
Male participants with partners who become pregnant 
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive the IMP. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
Female participants who become pregnant 
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the Sponsor within 24 hours of learning 
of a participant's pregnancy. 
• The participant will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the Sponsor. Generally, follow-up will not be required 
for longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of 
pregnancy will be reported, regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure. 
• Any pregnancy complication or elective termination of a pregnancy for medical reasons 
will be reported as an AE or SAE. 
• A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring at 
>22 weeks gestational age) is always considered to be an SAE and will be reported as 
such. 
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• Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described 
in Section 8.3.5. While the Investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 
10.5 
APPENDIX 5: GENETICS  
Use/Analysis of DNA/RNA 
• Genetic variation may impact a participant’s response to study intervention, susceptibility 
to, and severity and progression of disease. Variable response to study intervention may be 
due to genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular subtype of 
the disease being treated. Therefore, where local regulations and IRB/IEC allow, a blood 
sample will be collected for DNA and RNA analysis from consenting participants. Skin 
biopsy sample will be collected for RNA analysis from study participant. 
• DNA/RNA samples will be used for research related to SAR443122 or CLE and related 
diseases. They may also be used to develop tests/assays including diagnostic tests related 
to SAR443122 and/or RIPK1 kinase class and CLE. Genetic research may consist of the 
analysis of one or more candidate genes or the analysis of genetic markers throughout the 
genome or analysis of the entire genome (as appropriate). 
• DNA/RNA samples will be analyzed for changes related to treatment and/or disease 
progression compared to baseline and placebo controls to evaluate their association with 
the observed clinical responses to SAR443122. Additional analyses may be conducted if it 
is hypothesized that this may help further understand the clinical data. 
• The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to SAR443122 or study interventions of this class to understand 
study disease or related conditions. 
• The results of genetic analyses may be reported in the clinical study report (CSR) or in 
a separate study summary. 
• The Sponsor will store the genetic samples in a secure storage space with adequate 
measures to protect confidentiality. 
• The samples will be retained while research on SAR443122 or study interventions of this 
class or CLE and related diseases continues but no longer than 15 years or other period as 
per local requirements. 
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10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND 
FOLLOW-UP ASSESSMENTS AND STUDY INTERVENTION 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 10.3.3 is met. 
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Thrombocytopenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting adverse events in Section 10.3.3 is met. 
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*If unable to retest in 72 hours, use original lab results to decide on further reporting/monitoring/discontinuation. 
Note: 
“Baseline” refers to ALT sampled at baseline visit; or if baseline value unavailable, to the latest ALT sampled before the baseline visit. The 
algorithm does not apply to the instances of increase in ALT during screening. 
See Section 10.3.3 for guidance on safety reporting. 
Normalization is defined as ≤ ULN or baseline value, if baseline value is > ULN. 
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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 10.3.3 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 10.3.3 is met. 
10.7 
APPENDIX 7: AES, ADES, SAES, SADES, USADES AND DEVICE DEFICIENCIES: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP, 
AND REPORTING IN MEDICAL DEVICE STUDIES  
Not applicable. 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS  
For country-specific contraceptive guidance, see Section 10.4.2. 
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10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY  
A regional or national emergency declared by a governmental agency (eg, public health emergency, 
natural disaster, pandemic, terrorist attack) may prevent access to the clinical trial site. 
Contingency procedures are suggested for an emergency that prevents access to the study site, to 
ensure the safety of the participants, to consider continuity of the clinical study conduct, protect 
trial integrity, and assist in maintaining compliance with Good Clinical Practice in Conduct of 
Clinical Trials Guidance. Sponsor agreement must be obtained prior to the implementation of 
these procedures for the duration of the emergency. 
During the emergency, if the site will be unable to adequately follow protocol mandated 
procedures, alternative treatment outside the clinical trial should be proposed, and 
screening/enrollment/randomization/administration of study intervention may be temporarily 
delayed. 
Attempts should be made to perform all assessments in accordance with the approved protocol to 
the extent possible. In case this is not possible due to a temporary disruption caused by 
an emergency, focus should be given to assessments necessary to ensure the safety of participants 
and those important to preserving the main scientific value of the study. 
Contingencies implemented due to emergency will be documented. 
The participant or their legally authorized representative should be verbally informed prior to 
initiating any changes that are to be implemented for the duration of the emergency (eg, study 
visit delays/treatment extension, use of local labs). 
Study assessments and procedures 
Use of local clinic or laboratory locations may be allowed when central labs analyses cannot be 
performed due to a government declared national emergency. 
If onsite visits are not possible: 
• remote visits (eg, phone call, virtual consultation, etc) or home visits (eg, home nurses, 
home health vendor, etc) may be planned for the collection of possible safety and/or 
efficacy data (eg, adverse events, blood sampling, patient-reported questionnaires, etc) 
• visit windows may be extended for assessment of safety and/or efficacy data that cannot 
be obtained remotely [eg, vital signs, physical examination, ECG, CLASI-assessment and 
other physician-assessed questionnaires, index lesion photography, biopsy]. Possibility of 
visit extension and duration of such extension must be discussed on a case by case basis 
with the Sponsor considering first of all subject’s safety and best interests. 
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If onsite visits are possible and there is a need to reduce the time spent on site to a minimum, 
combined-approach can be considered: 
• during onsite visit, the focus should be on IMP dispensation, collection of safety 
information (vital signs, physical examination, adverse events), safety blood collection 
(mainly biochemistry and hematology) and efficacy endpoints (eg, CLASI, PhyGA- 
disease activitiy, IGA-CLE if applicable, etc). However, all efforts should be made to 
perform the measurements of other parameters for efficacy endpoints. These would 
include photography and biopsy. 
• And to complete other assessments that can be obtained in a remote fashion. 
Study intervention 
The following contingencies may be implemented to make clinical supplies available to the 
participant for the duration of the emergency. 
• The Direct-to-Patient (DTP) supply of IMP from the PI/site/Sponsor via a Sponsor-
approved courier company where allowed by local regulations and agreed upon by the 
participant. 
• Delivery by authorized staff during home visits, following clear defined procedures (IMP 
shipment process, safety protection of patients and staff, data protection etc). 
If a participant has to stop IMP due to a regional or national emergency (eg, COVID-19), 
reinitiation of IMP can only occur once the Investigator has determined, according to his/her best 
judgement, that the contribution of the IMP(s) to the occurrence of the epidemic event 
(eg, COVID-19) was unlikely and the selection criteria for the study are still met. Reinitiation of 
the study intervention will be done under close and appropriate clinical/and or laboratory 
monitoring. 
Statistical analyses 
The impact of the regional or national emergency declared by a governmental agency on study 
conduct will be summarized (eg, study discontinuation or discontinuation/delay/omission of the 
intervention due to the emergency). Any additional analyses and methods required to evaluate the 
impact on efficacy (eg, missing data due to the emergency) and safety will be detailed in the SAP. 
 
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10.10 APPENDIX 10: ADDITIONAL APPENDICES  
10.10.1 List of topical corticosteroids  
This list is indicative and not exhaustive. 
 
Topical corticosteroid 
Formulation(s) 
Strength 
Super High potency (For Rescue only) 
 
 
Betamethasone dipropionate, augmented 
Ointment 
0.05% 
Clobetasol propionate 
Solution, Foam, Cream, Ointment 
0.05% 
Diflorasone diacetate 
Ointment 
0.05% 
Halobetasol propionate 
Cream, Ointment 
0.05% 
High (For Rescue Only) 
 
 
Amcinonide 
Lotion, Cream, Ointment 
0.1% 
Betamethasone dipropionate 
Foam, Cream, Ointment 
Cream, Ointment 
Cream, Ointment, Solution, Lotion, Gel 
0.05% 
0.025% 
0.064% 
Betamethasone butyrate propionate 
Lotion, Cream, Ointment 
0.05% 
Betamethoasone valerate 
Ointment, Foam 
Cream, Ointment 
0.05% 
0.12% 
Deprodone propionate 
Cream, Ointment 
0.3% 
Desoximetasone 
Cream, Ointment 
0.25% 
Dexamethasone propionate 
Lotion, Cream, Ointment 
0.1% 
Dexamethasone valerate 
Cream, Ointment 
0.12% 
Diflorasone diacetate 
Cream, Ointment 
0.05% 
Diflorcortolone valerate 
Solution, Cream, Ointment 
0.01% 
Difluprednate 
Lotion, Cream, Ointment 
0.05% 
Fluocinonide 
Solution, Gel, Cream, Ointment 
0.05% 
Halcinonide 
Solution, Cream, Ointment 
0.1% 
Mometasone furoate 
Ointment 
0.1% 
Medium Potency 
 
 
Betamethasone dipropionate 
Lotion 
0.02% 
Betamethasone valerate 
Foam, Lotion, Cream 
Lotion, Cream 
0.1% 
0.12% 
Clobetasone butyrate 
Lotion, Cream, Ointment 
0.05% 
Desoximetasone 
Cream 
0.05% 
Fludroxycortide 
Cream, Tape 
0.05%, 4 μg/m2 
Flumethasone pivalate 
Lotion, Cream, Ointment 
0.02% 
Fluocinolone acetonide 
Solution, Cream, Ointment 
0.025% 
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Topical corticosteroid 
Formulation(s) 
Strength 
Hydrocortisone butyrate 
Lotion, Cream, Ointment 
0.1% 
Hydrocortisone valerate 
Cream, Ointment 
0.2% 
Mometasone furoate 
Lotion, Cream 
0.1% 
Prednicarbate 
Cream  
0.1% 
Prednisolone 
Cream, Ointment 
0.5% 
Prednisolone acetate 
Ointment 
0.25% 
Prednisolone valerate acetate 
Lotion, Cream, Ointment 
0.3% 
Triamcinolone acetonide 
Lotion, Cream, Ointment 
0.1% 
Low Potency 
 
 
Alclometasone dipropionate 
Cream, Ointment 
Ointment 
0.05% 
0.1% 
Desonide 
Foam, Gel, Cream, Ointment 
0.05% 
Dexamethasone sodium phosphate 
Lotion, Cream, Ointment 
Cream, Ointment 
0.1% 
0.05% 
Fluocinolone acetonide 
Solution, Cream 
Spray 
0.01% 
0.007% 
Hydrocortisone acetate 
Lotion, Cream, Ointment 
≤1% 
Methylprednisolone 
Ointment 
0.1% 
 
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A m e n d e d Cli ni c al Tri al Pr ot o c ol 0 2  
S A R 4 4 3 1 2 2 -A C T 1 6 4 0 4  
2 2 -N o v -2 0 2 2  
V er si o n n u m b er: 1  
 
Pr o p ert y of t h e S a n ofi gr o u p - stri ctl y c o nfi d e nti al  
P a g e 1 0 4  
1 0. 1 0. 2  S a m pl e of C ut a n e o u s L u p u s Er yt h e m at o s u s Di s e a s e Ar e a a n d S e v erit y I n d e x 
( C L A SI)  
 
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10.10.3 Sample of Physician Global Assessment of disease activity (PhysGA- disease 
activity) and Physician Global Assessment of changes in cutaneous lupus 
erythematosus activity (PGAC)  
 
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10.10.4 Sample of Patient-Reported Peak Pruritus Numerical Rating Scale (itch-NRS) and 
Peak Pain Numerical Rating Scale (Pain-NRS)  
 
 
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10.10.5 Sample of Oral Health Impact Profile (OHIP-14)  
 
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10.10.6 Sample of SKINDEX-29+3  
 
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10.10.7 Sample of Patient Global Impression of Change (PGIC) and Severity (PGIS) in 
cutaneous lupus erythematosus  
 
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10.10.8 Sample of Investigator’s Global Assessment for Cutaneous Lupus 
Erythematosus Activity (IGA-CLE)  
Instructions:  
Severity is determined by a combination of 3 plaque characteristics (erythema, scale, elevation) 
based on descriptions of each characteristic. Scalp involvement includes an assessment of peri-
follicular keratosis as noted.  Scarring alopecia / areas of permanent scarring on the scalp are NOT 
counted. 
Erythema is the PRIMARY characteristic that should influence the rating, with plaque 
elevation, scaling and other secondary characteristics considered secondarily. 
Telangiectatic change should NOT be considered. 
Assessment does NOT require all four characteristics to be present. 
Severity of the morphologic features are AVERAGED over the burden of lesions. 
 
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Cutaneous Lupus Activity Investigator’s Global Assessment (IGA-CLE)  
Score 
Description 
0 – Clear  
Erythema – none  
Scale – none  
Edema/infiltration – none  
Follicular involvement – follicular plugging/follicular hyperkeratosis – absent   
Secondary change – no vesicles, erosion, crusting  
1 – Almost clear   
Erythema – faint  
Scale – minimal   
Edema/infiltration – minimal (barely palpable)  
Follicular involvement – follicular plugging/follicular hyperkeratosis - minimal and diffuse  
Secondary change – no vesicles, erosion, crusting   
2 – Mild  
Erythema – pink/mild  
Scale – thin, patchy  
Edema/infiltration – mild, palpable, barely visible  
Follicular involvement – follicular plugging/follicular hyperkeratosis (recent) in one quadrant of scalp  
Secondary change – mild superficial erosion, crusting present; no vesicles   
3 – Moderate  
Erythema – red erythema  
Scale – thick, patchy  
Edema/infiltration – moderately raised, palpable, visible   
Follicular involvement – follicular plugging/follicular hyperkeratosis in more than one quadrant of scalp  
Secondary change – moderate, superficial erosion, crusting: no vesicles  
4 – Severe  
Erythema – violaceous/bright red erythema  
Scale – thick, confluent  
Edema/infiltration – thick, raised, easily palpable, easily visible  
Follicular involvement – follicular plugging/follicular hyperkeratosis in more than two quadrants of scalp  
Secondary change – marked erosion, crusting and/or vesicular change present  
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10.11 APPENDIX 11: ABBREVIATIONS  
 
AE: 
adverse events 
AESI: 
adverse event of special interest 
ALT: 
alanine transaminase 
ANA: 
antinuclear antibody 
BID: 
twice a day 
CCLE: 
chronic cutaneous lupus erythematosus 
CLASI: 
Cutaneous Erythematosus Disease Area and Severity Index 
CLASI-A: 
Cutaneous Erythematosus Disease Area and Severity Index - Activity  
CLASI-D: 
Cutaneous Erythematosus Disease Area and Severity Index-skin damange 
CLE: 
cutaneous lupus erythematosus 
ClinRO: 
clinician reported outcome 
CNS: 
central nervous system 
DAMP: 
danger-associated molecular pattern 
DLE: 
discoid lupus erythematosus 
ECG: 
electrocardiogram 
EOS: 
end of study 
EOT: 
End of Treatment 
EOT: 
end of treatment 
FIH: 
first-in-human 
GELP: 
Genital Erosive Lichen Planus 
ID: 
interface dermatitis 
IGA-CLE: 
Investigator’s Global Assessment of CLE  
IMP: 
Investigational medicinal product 
INF: 
interferon 
ISRC: 
internal safety review committee 
itch-NRS: 
Peak Pruritus Numerical Rating Scale 
LP: 
lichen planus 
MAD: 
multiple ascending dose 
NOAEL: 
no observed adverse effect level 
NRS: 
numerical rating scale 
OHIP-14: 
Oral Health Impact Profile 
pain-NRS: 
 Peak Pain Numerical Rating Scale  
PBMC: 
peripheral blood mononuclear cell 
PCSA: 
 potentially clinically significant abnormality 
PD: 
pharmacodynamics 
PGAC: 
physician’s global assessment of change in disease activity 
PGIC: 
patient's global impression of change 
PGIS: 
patient's global impression of disease severity 
PhysGA-disease activity: 
physician’s global assessment of disease activity 
PK: 
pharmacokinetics 
pMLKL: 
phosphorylated mixed lineage kinase domain-like protein 
PRO: 
patient reported outcomes 
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QoL: 
quality of life 
RIPK1: 
Receptor-Interacting serine-threonine Protein Kinase 1 
SAE: 
serious adverse event 
SCLE: 
subacute cutaneous lupus erythematosus 
SELENA-SLEDAI: 
Safety of Estrogens in Lupus Erythematosus National 
Assessment-SLE Disease Activity Index 
SGC: 
systemic glucocorticoid 
SLE: 
systemic lupus erythematosus 
TB: 
tuberculosis 
TE: 
treatment-emergent 
TEAE: 
treatment-emergent adverse event 
TLR: 
toll-like receptor 
TNF: 
tumor necrosis factor 
ULN: 
upper limit of normal 
UV: 
ultraviolet 
WOCBP: 
woman of childbearing potential 
 
10.12 APPENDIX 12: PROTOCOL AMENDMENT HISTORY  
The Protocol amendment summary of changes table for the current amended protocol 02 is 
located directly before Table of Contents. 
10.12.1 Amended protocol 01 (10 DEC 2021)  
This amended clinical trial protocol 01 (amendment 01) is considered to be not substantial based 
on the criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and 
the Council of the European Union. Because it does not significantly impact the safety or 
physical/mental integrity of participants, nor the scientific value of the study. 
Overall Rationale for the Amendment 
The main purpose of this amendment is to remove the 50% randomization cap for the discoid 
cutaneous lupus erythematosus (DLE) subtype.  
Cutaneous Lupus erythematosus (CLE) is a heterogeneous skin disease with a wide spectrum of 
presenting cutaneous manifestations that have been subdivided into several subtypes. The present 
study is targeting the subacute cutaneous lupus erythematosus (SCLE) and discoid cutaneous 
lupus erythematosus (DLE) subtypes. While the pathophysiology of CLE is not fully understood, 
some publications suggest that the treatment response might be subtype dependent (40). DLE is 
known to be the most common subtype (9). To optimize the differential assessments of both 
subtypes, the original protocol included a cap at 50% for the DLE subtype. The sponsor now 
decided to remove the cap for the DLE subtype patients for a study population being more 
reflective of the natural distribution of the CLE population and to allow completion of the study 
within a reasonable time. 
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It is mentioned in the section 8 that “The clinician reported outcome (ClinRO) mentioned in the 
SoA will be used when copyright is obtained (if applicable)”. Modified Oral Mucositis Index 
(MOMI) will not be used in the study as its full copyright has not been obtained. To improve the 
readability, the sponsor takes this opportunity to remove the text related to MOMI throughout the 
document. Other corrections of discrepancies, minor editorial errors identified during initial 
protocol submission and wording clarity have been made as well. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Cover page 
Added NCT number 
Regulatory agency identifier number(s) is 
available 
Section 1.1 Synopsis, Section 
4.1 Overall Design, Section 
6.3 Measures to minimize 
bias: randomization and 
blinding 
Context related to “a cap of 50% for patients with 
histologically proven DLE will be implemented” 
was removed. 
To be more reflective of the natural 
distribution of the CLE population and to 
allow completion of the study within a 
reasonable time. 
Section 1.1 Synopsis, Section 
3 Objectives and Endpoints 
Section 1.3 Schedule of 
Activities (SoA), Section 3.1 
Appropriateness of 
Measurements, Section 8.1.6 
Modified Oral Mucositis Index 
(MOMI), Section 10.9 
Appendix 9: Contingency 
measures for a regional or 
national emergency that is 
declared by a governmental 
agency 
Secondary Endpoint: “Change from baseline to 
Week 12 in Modified Oral Mucositis Index 
(MOMI) at Week 12 for patients with oral lesions 
at baseline” is deleted. 
Context related to MOMI was deleted. 
To improve the readability as the MOMI 
will not be used in the study because 
copyright wasn’t obtained (as per initial 
plan highlighted in Section 8: The 
clinician reported outcome (ClinRO) 
mentioned in the SoA will be used when 
copyright is obtained (if applicable)).  
Section 2.3.1 Risk 
assessment: table 1 
Reorganized table 1 
To improve the clarity without content 
change 
Section 6.3 Measures to 
minimize bias: randomization 
and blinding 
Replaced “the Investigator should make every 
effort to contact the Sponsor” by “he/she may, at 
his/her discretion, contact the Sponsor to discuss 
the situation” 
To improve the appropriateness of 
language related to the unblinding 
process as per a health authority’s 
comment 
Section 7.1.1.1 Handling of 
participants after permanent 
intervention discontinuation 
Modified “skin biopsy and pharmacokinetics 
sample” to “skin biopsy, pharmacokinetic 
samples, and photography at Week 12”. 
Foot note “u” was newly inserted in Section 1.3. 
To improve the clarity 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.1.5 Investigator’s 
Global Assessment for 
Cutaneous Lupus 
Erythematosus (IGA-CLE), 
Section 10.10.8 Sample of 
Investigator’s Global 
Assessment for Cutaneous 
Lupus Erythematosus 
(IGA-CLE) 
Added more detailed information on IGA-CLE 
assessment and provided an example in 
appendix. 
To provide a more detailed description of 
IGA-CLE assessment in order to improve 
the clarity 
Section 8.2.3 
Electrocardiograms 
Section 8.3.8 Adverse event 
of special interest 
Clarified “QTcB or QTcF” to “QTcF”. 
 
Added reference of calculation formula (per 
QTcF) to “QTc ≥500 ms”. 
To provide more precision 
Section 8.6 Biomarkers 
“Immunohistochemistry analysis” was replaced 
by “Immunohistochemistry and histology 
analysis”. 
To provide more precision 
Section 9 Statistical 
Considerations  
Aligned the names of the analysis populations 
with current Sponsor’s standard. 
Removed a duplicated content in Section 9.3.5.3 
(The same content is provided in Table 8) 
Added more detail description throughout the 
section 
To improve precision and clarity 
All sections throughout 
Minor editorial and typographical error 
corrections.  
To improve readability and overall quality 
of the document 
 
 
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11 
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12. Patel P, Werth V. Cutaneous lupus erythematosus: a review. Dermatol Clin. 2002;20(3):373-
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21. Namas R, Powell C, Kahlenberg JM. Anti-Ro Positivity Is a Predictor of Responsiveness to 
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receptor-interacting protein kinase 1 (RIPK1) in active plaque psoriasis: A randomized 
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24. Petri M, Orbai AM, Alarcón GS, Gordon C, Merrill JT, Fortin PR, et al. Derivation and 
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Discontinuation of hydroxychloroquine in older patients with systemic lupus erythematosus: a 
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37. Gladman DD, Urowitz MB, Kagal A, Hallett D. Accurately describing changes in disease 
activity in systemic lupus erythematosus. J Rheumatol. 2000;27:377-9. 
38. Helgesen A, Warloe T, Pripp A, Kirschner R, Peng Q, Tanbo T, et al. Vulvovaginal 
photodynamic therapy vs. topical corticosteroids in genital erosive lichen planus: a 
randomized controlled trial. Br J Dermatol, 2015;173:1156-62. 
39. Quan H, Chen X, Lan Y, Luo X, Kubiak R, Bonnet N, et al. Applications of bayesian analysis 
to proof-of-concept trial planning and decision making. Pharm Stat. 2020;19(4):468-81. 
40. Nanes BA, Zhu JL, Chong BF. Robust measurement of clinical improvement in patients with 
cutaneous lupus erythematosus. Lupus Sci Med. 2020;7(1):e000364. 
 
 
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Any and all information presented in this document shall be treated as confidential and shall remain the exclusive 
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According to template: QSD-002644 VERSION 9.0 (01-FEB-2022) 
Page 1 
 
STATISTICAL ANALYSIS PLAN       
Protocol title: 
A randomized, double-blind, placebo controlled, 
proof of concept study assessing the efficacy and 
safety of the RIPK1-inhibitor SAR443122 in patients 
with moderate to severe subacute or discoid/chronic 
cutaneous lupus erythematosus 
Protocol number: 
ACT16404 
Compound number 
(INN/Trademark): 
SAR443122 
Study phase: 
Phase 2 
Short title: 
Proof of concept study of SAR443122 in patients 
with cutaneous lupus erythematosus 
CLEan 
Statistician: 
 
Statistical Project Leader: 
 
Date of issue: 
19-Jan-2023 
Regulatory agency identifier number(s): 
IND: 
152733 
EudraCT: 
NCT: 
WHO: 
EUDAMED: 
Other: 
2020-004703-14 
NCT04781816 
U1111-1246-6784 
Not applicable 
Not applicable 
 
 
Total number of pages: 46 
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Statistical Analysis Plan  
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Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 4 
VERSION HISTORY ....................................................................................................................................... 5 
1 
INTRODUCTION .............................................................................................................................. 6 
1.1 
STUDY DESIGN .............................................................................................................................. 6 
1.2 
OBJECTIVE AND ENDPOINTS ...................................................................................................... 6 
2 
ANALYSIS POPULATIONS ............................................................................................................ 9 
3 
STATISTICAL ANALYSES ........................................................................................................... 11 
3.1 
GENERAL CONSIDERATIONS .................................................................................................... 11 
3.2 
PRIMARY ENDPOINT(S) ANALYSIS ............................................................................................ 12 
3.2.1 
Definition of endpoint ..................................................................................................................... 12 
3.2.2 
Main analytical approach ............................................................................................................... 13 
3.2.3 
Sensitivity analysis ......................................................................................................................... 14 
3.2.4 
Supplementary analyses ................................................................................................................ 15 
3.3 
SECONDARY ENDPOINT(S) ANALYSIS ..................................................................................... 17 
3.3.1 
Definition of endpoints ................................................................................................................... 17 
3.3.2 
Main analytical approach ............................................................................................................... 19 
3.4 
EXPLORATORY ENDPOINT(S) ANALYSIS ................................................................................. 21 
3.4.1 
Definition of endpoints ................................................................................................................... 21 
3.4.2 
Main analytical approach ............................................................................................................... 23 
3.5 
MULTIPLICITY ISSUES ................................................................................................................ 24 
3.6 
SAFETY ANALYSES ..................................................................................................................... 24 
3.6.1 
Extent of exposure ......................................................................................................................... 24 
3.6.2 
Adverse events .............................................................................................................................. 25 
3.6.3 
Additional safety assessments ....................................................................................................... 28 
3.6.3.1 
Laboratory variables, vital signs and electrocardiograms (ECGs) ................................................. 28 
3.7 
OTHER ANALYSES....................................................................................................................... 29 
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3.7.1 
Other variables and/or parameters ................................................................................................ 29 
3.7.1.1 
PK analyses ................................................................................................................................... 29 
3.7.1.2 
Biomarkers analyses ...................................................................................................................... 30 
3.7.1.3 
PK/PD analyses ............................................................................................................................. 30 
3.7.2 
Subgroup analyses ........................................................................................................................ 30 
3.8 
INTERIM ANALYSES .................................................................................................................... 31 
3.9 
CHANGES TO PROTOCOL-PLANNED ANALYSES .................................................................... 33 
4 
SAMPLE SIZE DETERMINATION ................................................................................................ 34 
5 
SUPPORTING DOCUMENTATION .............................................................................................. 35 
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS ..................................................................................... 35 
5.2 
APPENDIX 2 PARTICIPANT DISPOSITIONS .............................................................................. 36 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS .................................................................................................. 37 
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS ........................................................................ 39 
5.5 
APPENDIX 5 SAMPLE SAS CODE............................................................................................... 40 
5.6 
APPENDIX 6 SELECTION CRITERIA FOR RESCUE MEDICATION CATEGORIES ................. 41 
5.7 
APPENDIX 7 SAMPLE OF CUTANEOUS LUPUS ERYTHEMATOSUS DISEASE AREA 
AND SEVERITY INDEX (CLASI) ................................................................................................... 43 
5.8 
APPENDIX 8 SAMPLE OF SAFETY OF ESTROGEN IN LUPUS ERYTHEMATOSUS 
NATIONAL ASSESSMENT – SYSTEMIC LUPUS ERYTHEMATOSUS DISEASE 
ACTIVITY INDEX (SELENA-SLEDAI) ........................................................................................... 44 
5.9 
APPENDIX 9 SAMPLE OF GENITAL EROSIVE LICHEN PLANUS (GELP) SCORE .................. 45 
6 
REFERENCES ............................................................................................................................... 46 
 
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LIST OF TABLES  
Table 1 - Objectives and endpoints ................................................................................................................. 6 
Table 2 - Populations for analyses .................................................................................................................. 9 
Table 3 - Prohibited medications/rescue medications that impact efficacy ................................................... 14 
Table 4 - Sorting of AE tables ....................................................................................................................... 26 
Table 5 - Analyses of adverse events ........................................................................................................... 27 
Table 6 - Selections for AESIs ...................................................................................................................... 27 
 
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Statistical Analysis Plan  
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VERSION HISTORY  
 
This statistical analysis plan (SAP) for study ACT16404 is based on the Amended Clinical Trial 
protocol 02 dated 22-Nov-2022. This section summarizes the major changes to the statistical 
analysis features in the SAP. 
The first participant was randomized on 16-Jun-2021. Version 1.0 of this SAP is approved before 
code release for the interim analysis is performed. 
Major changes in statistical analysis plan 
SAP Version 
Approval Date 
Changes 
Rationale 
1 
Current 
Changed analysis method for binary 
secondary endpoints from logistic 
regression to Cochran-Mantel-Haenszel 
(CMH) 
To accommodate anticipated 
participant distribution across 
stratums  
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1 
INTRODUCTION  
1.1 
STUDY DESIGN  
This study is a Phase 2a multinational, multi-center, randomized, double-blind parallel group 
12-week treatment study to evaluate efficacy and safety of the RIPK1-inhibitor SAR443122 dosed 
at 300 mg twice a day (BID) compared to matching placebo in patients with moderate to severe 
subacute cutaneous lupus erythematosus (SCLE) or discoid lupus erythematosus (DLE).  
Participants are randomized to receive SAR443122 or placebo in a 1:1 ratio. The randomization is 
stratified by subtype of CLE (DLE or SCLE), baseline use of chloroquine or hydroxychloroquine 
(yes/no) and by region (Asia Pacific, Eurasia, Europe, Latin America, North America).  
Up to 88 participants are expected to be randomly assigned to the investigational medicinal 
product (IMP), expecting a total of approximately 80 evaluable participants with approximately 
40 evaluable participants per study intervention group. 
1.2 
OBJECTIVE AND ENDPOINTS  
Table 1 - Objectives and endpoints  
 
Objectives 
Endpoints 
Primary 
 
 
 
• 
Assess the efficacy of SAR443122 in CLE 
• 
Percent change from baseline in Cutaneous 
Erythematosus Disease Area and Severity Index 
activity (CLASI-A) sub-score at Week 12 
Secondary 
 
 
 
• 
Assess the effect of SAR443122 on the 
physician’s global assessment of disease 
activity (PhysGA – disease activity) 
• 
Proportion of patients with PhysGA – disease 
activity of 0 or 1 (disease free or almost disease 
free) at Week 12 
 
• 
Assess the effect of SAR443122 on CLE 
induced itch and overall pain 
• 
Change from baseline in patients reported daily 
worst itch using Peak Pruritus Numerical Rating 
Scale (itch-NRS) at Week 12 
• 
Change from baseline in patients reported daily 
worst pain using Peak Pain Numerical Rating 
Scale (Pain-NRS) at Week 12 
 
• 
Assess the effect of SAR443122 on the 
proportion of disease activity responders 
compared to placebo 
• 
Proportion of CLASI-A50 and CLASI-A75 
responders at Week 12 
 
• 
Assess the effect of SAR443122 on the 
CLASI components’ score 
• 
Change from baseline in CLASI components’ 
score over time 
 
• 
Assess the effect of SAR443122 on the 
Investigator’s global assessment for CLE 
(IGA-CLE) 
• 
Proportion of patients with IGA-CLE score of 0 or 
1 (clear or almost clear) at Week 12 
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Objectives 
Endpoints 
 
• 
Assess oral cavities for patients with oral 
lesions 
• 
Change from baseline to Week 12 in the Oral 
Health Impact Profile (OHIP-14) for patients with 
oral lesions at baseline 
 
• 
Assess the disease specific quality of life 
(QoL) 
• 
Change from baseline in SKINDEX-29+3 total 
score at Week 12 
 
• 
Assess the safety and tolerability of 
SAR443122 in patients with CLE 
• 
Total number and percent of treatment-emergent 
adverse events (TEAEs), serious adverse events 
(SAEs), adverse events of special interest 
(AESIs) 
• 
Percent of potentially clinically significant 
abnormalities (PCSAs) in laboratory tests, 
electrocardiogram (ECG) or vital signs through 
end of study (EOS) 
 
• 
Assess the pharmacokinetics (PK) 
exposure of SAR443122 in patients with 
CLE 
• 
Sar443122 plasma concentration 
• 
Pharmacokinetic parameters (maximum 
concentration [Cmax], time to Cmax [tmax], area 
under the curve over the dosing interval 
[AUC0-tau], and elimination half-life [t1/2z]) 
Exploratory 
 
 
 
• 
Assess the effect of SAR443122 on 
physicians’ and patients’ overall impression 
of change of the disease activity and of the 
severity, and specific domains of health 
related QoL 
• 
Change from baseline at Week 12 in each of the 
sub-scores of the SKINDEX-29+3 
• 
Change from baseline at Week 12 in the patient’s 
global impression of disease severity (PGIS) 
• 
Evaluation of patient’s global impression of 
change (PGIC) in overall disease at Week 12 
• 
Evaluation of physician’s global assessment of 
change in disease activity (PhysGAC disease 
activity) at Week 12 
 
• 
Assess the effect of SAR443122 on CLE 
related joint inflammation 
• 
Change from baseline in active joint count 
assessment (28 joint assessment) at Week 12 
 
• 
Assess the effect of SAR443122 on 
reducing systemic lupus erythematosus 
activity 
• 
Change from baseline in Safety of Estrogens in 
Lupus Erythematosus National Assessment – 
Systemic Lupus Erythematosus Disease Activity 
Index (SELENA-SLEDAI) over time 
 
• 
Assess the effect of SAR443122 on RNA 
expression levels from skin biopsy and from 
blood as an indicator of response/disease 
progression 
• 
Change from baseline in transcriptomic 
biomarkers from mRNA derived from skin biopsy 
and from blood 
 
• 
Assess the effect of SAR443122 on 
biomarkers in blood plasma (eg, cytokine 
and chemokine levels) as an indicator of 
response/disease progression 
• 
Change from baseline of blood plasma 
biomarkers (eg, cytokine and chemokine levels) 
over time 
 
• 
Assess target engagement of SAR443122 
as a function of RIPK1 kinase 
activity/inhibition achieved by SAR443122 
in peripheral blood mononuclear cells 
(PBMCs) of patients with CLE in a subset of 
qualified sites 
• 
Demonstrate inhibition of pS-166-RIPK1 in 
PBMC lysates with SAR443122 treatment 
compared to placebo in a subset of patients at 
Week 12 
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Objectives 
Endpoints 
 
• 
Assess the genital area for female 
participants with genital lesions 
• 
Change from baseline to Week 12 in Genital 
Erosive Lichen Planus (GELP) total score for 
female patients with genital lesions at baseline 
 
• 
Assess the effect of SAR443122 on skin 
lesion by photographic assessment of index 
lesions, oral lesions if present 
• 
Photographic assessment of index lesions 
(Central imaging acquisition tool), oral lesions if 
present 
 
• 
Exploration of histologic changes in skin 
biopsies 
• 
Histologic changes in skin biopsies (Central 
pathologist) 
 
• 
Assess the effect of SAR443122 on the use 
of rescue medication 
• 
The frequency of use of rescue medications by 
category (eg, topical corticosteroids, topical 
calcineurin inhibitors, oral corticosteroids) 
 
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2 
ANALYSIS POPULATIONS  
The following populations for analyses are defined: 
Table 2 - Populations for analyses  
Population 
Description 
Screened 
All participants who signed the ICF. 
Randomized 
All screened participants who are randomly assigned to the IMP (by IRT) regardless 
of whether the intervention was received or not. 
ITT 
Same definition as above. 
Efficacy 
All randomized participants exposed to the IMP, with available Baseline 
assessment of the CLASI-A who did actually receive at least 1 complete dose of 
IMP and with at least 1 post IMP administration measurement. Participants will be 
analyzed according to the intervention they actually received. 
Pharmacodynamic (PD) 
All randomized and treated participants with at least one post-baseline value of the 
PD endpoint analyzed*. Participants will be analyzed according to the intervention 
they actually received. 
Pharmacokinetic (PK) 
All randomized and treated participants without any important deviation related to 
IMP administration, for whom the PK data are considered interpretable. Participants 
having received only placebo will not be part of the PK population. 
PK/PD 
All participants being included in both the PK and the PD populations will be 
included in the PK/PD population. In addition, participants being included in the PD 
population and having received only placebo will be part of the PK/PD population. 
Safety 
All randomized participants exposed to the IMP (regardless of the amount of 
treatment administered) are included in the safety population. Participants will be 
analyzed according to the intervention they actually received. 
Population without trial impact 
(disruption) due to COVID-19 
Any participant: 
• 
without any critical or major deviation related to COVID19  
• 
and who didn’t permanently discontinue treatment due to COVID19  
• 
and who didn’t permanently discontinue study due to COVID19.  
CLASI-A: Cutaneous Lupus Erythematosus Disease Area and Severity Index - A, ICF: informed consent form, IMP: investigational medicinal 
product, PK: pharmacokinetic, PD: pharmacodynamic 
Note: “Screened” means a participant's, or their legally acceptable representative’s, agreement to participate in a clinical study following 
completion of the informed consent process. 
*PD endpoints include exploratory biomarkers 
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 
will be used in any analysis population. The safety experience associated with any later randomization 
will be reported separately. 
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For participants receiving more than one study intervention during the study, the intervention 
group for as-treated analyses will be the intervention group of the study intervention received the 
most (based on the amount of study intervention administered). In case of equality, the 
SAR443122 intervention group will be used. The intervention group for as-randomized analyses 
will be the as-randomized intervention group. 
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3 
STATISTICAL ANALYSES  
3.1 
GENERAL CONSIDERATIONS  
In general, unless otherwise specified, continuous data will be summarized using the number of 
observations available, mean, Standard Deviation (SD), median, Q1, Q3, minimum, and 
maximum. Categorical and ordinal data will be summarized using the count and percentage of 
participants, as appropriate. 
The baseline value of efficacy parameters is defined as the Day 1 assessment value except for 
e-Diary data (Peak Pruritus NRS and Peak Pain NRS) or otherwise specified. If not available, the 
last available Screening assessment value will be used. Day 1 is defined as the day of first IMP. 
For participants randomized and not exposed to IMP, Day 1 is defined as the day of 
randomization. 
The baseline for weekly average Peak Pruritus NRS and Peak Pain NRS is defined as the average 
of daily non-missing scores obtained during the week prior to first IMP intake (Day 1). 
The baseline value of the other parameters is defined as the last available value prior to the 
first dose of investigational medicinal product (IMP) if the participant is treated, or the 
last available value up to randomization if the participant is not exposed to IMP. 
Unless otherwise specified, analyses will be performed by intervention group (and overall, for 
baseline and demographics characteristics). 
Participants whose stratification data are entered incorrectly within the IRT system 
(eg, participant randomized in stratum “baseline use of chloroquine or hydroxychloroquine = no” 
instead of “baseline use of chloroquine or hydroxychloroquine = yes”) will nonetheless be 
considered as randomized and analyzed using the correct stratum values for all analyses.  
Given the potentially low number of participants per stratum, the following modifications may be 
conducted for all analyses: 
• Disease subtype stratification factor may be removed from the analysis model; 
• The following combination of geographical regions and countries may be performed: 
Europe + North America + Australia versus Latin America + Eurasia + India. 
Observation period  
The observation period will be divided into 3 segments:  
• The pre-treatment period is defined as the time between informed consent signature and 
first Investigational Medicinal Product (IMP) administration. 
• The Treatment-Emergent (TE) period is defined as the period from the first IMP 
administration up to the End-Of-Study (EOS) visit (included). It may be split further into 
the following periods: 
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- 
On-treatment period, defined as the time from the first IMP administration to the 
last administration of the IMP + 5 days (last day included). 
- 
Residual treatment period, defined as the time after end of the on-treatment period to 
the EOS visit (EOS included). 
• The post-treatment period is defined as the time starting after the TE period. 
3.2 
PRIMARY ENDPOINT(S) ANALYSIS  
3.2.1 Definition of endpoint  
The primary endpoint is the percent change from baseline in Cutaneous Erythematosus Disease 
Area and Severity Index activity (CLASI-A) sub-score at Week 12. 
The CLASI (see Section 5.7) is a clinician rated scale designed to assess the disease activity and 
damage in CLE in adults. It is composed of 56 items covering two dimensions: the disease 
activity (CLASI-A) and the disease damage (CLASI-D). The domains covered by the two as 
follows: 
• CLASI-A disease activity 
- 
Erythema 
- 
Scale/Hypertrophy 
- 
Recent hair loss/Alopecia (clinically not obviously scarred) 
- 
Mucous membrane lesions 
• CLASI-D disease damage 
- 
Dyspigmentation 
- 
Scarring/Atrophy/Panniculitis 
- 
Clinically judged scarring of the scalp (including scarring alopecia) 
Each of the two domains can be scored individually, with a higher score indicating a more severe 
skin disease. CLASI-A sub-score ranges from 0 to 70, with the following cut-offs: 0-9 indicating 
mild disease, 10-20 indicating moderate disease, and 21-70 indicating severe disease. Damage is 
scored on a scale of 0-56, using the parameters of dyspigmentation and scarring, with higher 
scores indicating worse disease damage. Scores are given for different anatomical locations and 
are based on the worst area involved. 
Besides mucocutaneous ulcerations and hair loss, active inflammatory skin pathology scored in 
the CLASI-A includes erythema and scale/hypertrophy in 13 distinct body areas (scalp, ears, nose 
and malar area, rest of face, V-area neck (frontal), post neck and shoulders, chest, abdomen, back 
and buttocks, arms, hands, legs, feet), mucous membrane lesions and alopecia due to active lupus. 
The CLASI-A is the sum of the above item scores.  
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The CLASI-D considers dyspigmentation, skin scarring and/or panniculitis of the aforementioned 
13 body areas. 
The CLASI is assessed at Screening, Day 1, Week 4, Week 8, Week 12 (EOT) and Week 16 
(EOS) visits. 
Missing item(s) will lead to missing domain(s) and total score(s). 
3.2.2 Main analytical approach  
The primary analysis of the percent change from baseline in CLASI-A at Week 12 will be 
performed on the Efficacy population through a mixed model with repeated measurements 
(MMRM) over time within participant. All post-baseline available data of planned visits until 
Week 12 (EOT) will be taken into account. 
The model will include fixed effects for disease subtype (DLE, SCLE), baseline use of 
chloroquine or hydroxychloroquine (Yes, No), geographical region (Asia Pacific, Eurasia, 
Europe, Latin America, North America), post-baseline visit, study intervention group, baseline 
CLASI-A, visit by study intervention group interaction, and visit-by-baseline CLASI-A 
interaction.  
This model will be run assuming an unstructured covariance pattern. Parameters will be estimated 
using restricted maximum likelihood method with the Newton-Raphson algorithm. Denominator 
degrees of freedom will be estimated using Kenward-Roger adjustment.  
Point estimate and two-sided 90% confidence interval (CI) for the difference of mean percent 
change between the 2 groups (SAR443122 versus placebo) at Week 12 will be derived from the 
linear model framework.  
If MMRM model fails to achieve convergence due to complexity of model specification, other 
covariance structures may be tested by order of decreasing complexity (eg, heterogeneous 
Toeplitz (TOEPH), antedependence (ANTE(1)), heterogeneous autoregressive ((ARH(1)), 
Toeplitz (TOEP), autoregressive (AR(1)), compound symmetry (CS) or variance components 
(VC)); some fixed effect (eg, visit-by-baseline CLASI-A interaction) might also be removed from 
the model. 
If model assumptions appear not to be met, alternative statistical methods may be applied, 
eg, robust ANCOVA may be conducted instead. 
The following “intercurrent event” strategy will be followed: 
• Taking selected prohibited/rescue medication (see Table 3) prior to Week 12: data after 
event occurrence will be set to missing. Data after event occurrence will be set to missing 
for descriptive statistics. 
• Discontinuation of study treatment prior to Week 12 for any other reason: Off-study 
treatment data up to Week 12 will be included in the analysis. 
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Table 3 - Prohibited medications/rescue medications that impact efficacy  
Medication 
Comment 
Data to be set as missing after 
taking medication in the main 
statistical analysisa 
Topical corticosteroids and/or topical calcineurin 
inhibitors initiated after Day 1 
No IMP discontinuation 
Yes (Ticked 'RESCUE THERAPY' in 
CRF page) 
One short course of oral corticosteroids of up to 
10 days initiated after Day 1 
No IMP discontinuation 
Yes (Ticked 'RESCUE THERAPY' in 
CRF page) 
Initiation or increase the dose of chloroquine or 
hydroxychloroquine or any other anti-malarial 
used for CLE treatment after Day 1 
No IMP discontinuation 
Yes (Ticked 'RESCUE THERAPY' in 
CRF page) 
Topical immunosuppressants beyond a stable 
regimen of low to medium potency topical 
corticosteroids and/or topical calcineurin 
inhibitors initiated after Day 1 
IMP to be discontinued 
Yes (Identified during blinded review of 
deviations) 
Discontinuation or decrease the dose of 
chloroquine or hydroxychloroquine after Day 1 
No IMP discontinuation 
Yes (Identified during blinded review of 
deviations) 
Systemic treatments for cutaneous or systemic 
lupus erythematosus or immunosuppressive 
therapy for autoimmune disease 
(eg, cyclosporin, dapsone, methotrexate, 
mycophenolate mofetil, thalidomide, 
azathioprine, systemic retinoids, belimumab, 
anti-TNF mAbs, B and/or T cell targeted 
immunosuppressive therapies) initiated after 
Day 1 
IMP to be discontinued 
Yes (Identified during blinded review of 
deviations) 
Systemic corticosteroids for more than 10 days 
initiated after Day 1 
IMP to be discontinued 
Yes (Identified during blinded review of 
deviations) 
Intralesional and intra-articular corticosteroids 
initiated after Day 1 
IMP to be discontinued 
Yes (Identified during blinded review of 
deviations) 
a When yes, data to be set as missing after taking medication. When no, data is not set to missing. 
Blinded review of prohibited/rescue treatment (medication or procedure) based on Table 3 will be 
implemented before database lock by considering the type of medication or procedure, indication, 
dose, timing and frequency.  
In addition, no imputation of missing endpoint data will be done as they will be handled directly 
in the mixed model with repeated measurements assuming they are missing at random (MAR). 
The reason for non-available primary endpoint might be provided in a table (including premature 
study discontinuation, premature EOT visit, taking selected prohibited/rescue medication [see 
Table 3] prior to Week 12). 
3.2.3 Sensitivity analysis  
No sensitivity analysis will be performed. However, supplementary analyses will be performed as 
described in the section below. 
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3.2.4 Supplementary analyses  
The following supplementary analyses will be performed: 
Intent-to-treat analysis (including all data after taking the prohibited and/or rescue medications) 
The data collected after taking selected prohibited/rescue medications will be included in this 
supplementary analysis to evaluate the robustness of the primary analysis results with respect to 
the method of handling data while taking the prohibited/rescue medications. This analysis will be 
performed on the ITT population where the participants will be analyzed according to the 
intervention they were allocated to. All post-baseline available data of planned visits until 
Week 12 (EOT) will be included into the analysis. Participants with missing CLASI-A at baseline 
will not be included in the analysis. 
Hybrid method analysis (the worst-observation carried forward (WOCF) and last-observation 
carried forward (LOCF)) 
The percent change from baseline in CLASI-A at Week 12 will be analyzed on the Efficacy 
population using an analysis of covariance (ANCOVA) model with disease subtype, baseline use 
of chloroquine or hydroxychloroquine, geographical region, study intervention group and baseline 
CLASI-A as fixed effects. 
A hybrid method will be used to handle data while taking the prohibited/rescue medications and 
missing data:  
• Data after event occurrence will be set to missing and imputed using the WOCF approach: 
the participant’s worst postbaseline value on or before the time of the event will be used to 
impute missing endpoint value (for participants whose postbaseline values are all missing, 
the participant’s baseline will be used to impute the missing endpoint value).  
• Missing endpoint data will be imputed using the LOCF approach. 
Point estimate and two-sided 90% confidence interval for the mean differences between the 
2 groups (SAR443122 versus placebo) at Week 12 will be provided. 
Additional covariates (smoking status at baseline and average postbaseline sun exposure without 
sun protection) 
A supplementary analysis of the percent change from baseline in CLASI-A at Week 12 will be 
explored by introducing smoking status at baseline (yes, no) and average postbaseline sun 
exposure without sun protection (in hours) as fixed effects to the analysis model defined above. 
The average postbaseline sun exposure without sun protection will be calculated based on the 
non-missing values up to Week 12. For participants whose postbaseline values are all missing, the 
participant’s baseline will be used to impute the missing value. Participants whose postbaseline 
and baseline values are all missing will be excluded from the analysis. 
Point estimate and two-sided 90% confidence interval for the mean differences between the 
2 groups (SAR443122 versus placebo) at Week 12 will be provided. 
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Tipping point analysis 
In addition to the supplementary analyses planned above, a tipping point analysis based on 
multiple imputation (MI) method might be explored on the Efficacy population to evaluate the 
robustness of the results from the primary analysis to deviations from the MAR assumption.  
The steps to perform the tipping point analysis will be as follows: 
1. Data collected after taking selected prohibited/rescue medications will be set to missing 
while off-study treatment data up to Week 12 will be included in the analysis; 
2. Missing data will be imputed using MI under the MAR assumption. The imputation 
number will be 1000; 
3. All imputed Week 12 percent change from baseline in CLASI-A in the SAR443122 
intervention group will be artificially penalized by adding a penalty term in each complete 
dataset; 
4. The percent change from baseline in CLASI-A at Week 12 will be analyzed using 
an analysis of covariance (ANCOVA) model with disease subtype, baseline use of 
chloroquine or hydroxychloroquine, geographical region, study intervention group and 
baseline CLASI-A as fixed effects in each complete dataset; 
5. Results will be combined across complete datasets using Rubin’s rule; 
6. Steps 3 to 5 will be repeated with penalty increased as needed to evaluate the impact on 
decision making. 
See Section 5.5 for the sample SAS code for the imputation and the analysis. 
Other analyses 
Point estimate and two-sided 90% confidence interval (CI) for the difference of mean percent 
change between the 2 groups (SAR443122 versus placebo) at Week 4 and Week 8 will be derived 
from the MMRM model as presented for the primary analysis and intent-to-treat supplementary 
analysis. 
Time profile plots of point estimates of the mean percent change from baseline in CLASI-A 
(+/- SE) will be presented by study intervention group and visit, and for the difference between 
the 2 groups (SAR443122 versus placebo) (with 90% CI). 
The cumulative distribution function of the percent change from baseline in CLASI-A will be 
plotted by study intervention group at Week 12. 
Descriptive statistics of raw data, change and percent change from baseline will be provided by 
visit and study intervention group. Additional descriptive statistics could be provided by stratum 
and combination of stratum if applicable. A listing of data observed after taking selected 
prohibited/rescue medication (see Table 3) will be provided as well. 
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In addition, mean raw data, change and percent change from baseline in CLASI-A with the 
corresponding standard error will be plotted over time by study intervention group. Spaghetti plots 
may be provided as well to visualize the behaviors of the participants. 
3.3 
SECONDARY ENDPOINT(S) ANALYSIS  
The secondary endpoints analyses described in this section will be performed on the Efficacy 
population. 
3.3.1 Definition of endpoints  
The secondary endpoints are as follows: 
• The proportion of patients with PhysGA disease activity of 0 or 1 (disease free or almost 
disease free) at Week 12 
The Physician’s Global Assessment of disease activity (PhysGA- disease activity) is a 5 point-
Likert scale instrument designed to assess physician-reported disease activity ranging from 
0 (“Not active at all”) to 4 (“Extremely active”).  
The PhysGA disease activity is assessed at Screening, Day 1, Week 4, Week 8, Week 12 (EOT) 
and Week 16 (EOS) visits. 
• The change from baseline in patients reported daily worst itch using itch-NRS at Week 12 
• The change from baseline in patients reported daily worst pain using pain-NRS at 
Week 12 
The Peak Pruritus NRS is a single item PRO tool that patients will use to report the maximal 
intensity of their pruritus (itch) daily, using a 24-hour recall period. Patients will be asked to rate 
their worst itch on a 0 (“No itch”) to 10 (“Worst itch imaginable”) NRS. 
The Peak Pain NRS is a single item PRO tool that patients will use to report the maximal intensity 
of their CLE-related pain (skin, oral, genital) during a daily 24-hour recall period. Patients will be 
asked to rate their worst pain on a 0 (“No pain”) to 10 (“Worst pain imaginable”) NRS. 
Patients will complete the Peak Pruritus NRS and Peak Pain NRS daily up to Week 12 (EOT) 
visit. 
The weekly average Peak Pruritus NRS and Peak Pain NRS scores at each postbaseline visit will 
be used for analyses. It will be defined as the average of daily non-missing scores within the week 
preceding the given visit. 
In case a patient does not attend a visit, the theoretical visit date will be used for derivation. 
• The proportion of CLASI-A50 and CLASI-A75 responders at Week 12 
The CLASI-A50/75 response is defined as a patient achieved a decrease by at least 50%/75% of 
CLASI-A sub-score from baseline. 
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• The change from baseline in CLASI components’ score over time  
See Section 3.2.1 for a description of the CLASI.  
CLASI component’s scores used for analysis will be CLASI-A, CLASI-D and CLASI 
subcomponent’s scores (eg, Erythema, Scale/Hypertrophy, Scarring/Atrophy/Panniculitis scores). 
• The proportion of patients with IGA-CLE score of 0 or 1 (clear or almost clear) at 
Week 12 
Investigator’s Global Assessment for Cutaneous Lupus Erythematosus (IGA-CLE) is a ClinRO 
that allows for clinicians to assess the overall disease activity of CLE using a 5-point scale: 
0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), and 4 (severe). The Severity of CLE is 
determined by descriptions of a combination of 3 plaque characteristics: erythema, scale, 
elevation. Erythema is the primary characteristic that should influence the rating, with other 
characteristics considered secondarily. Telangiectatic change should not be considered in the 
rating. The assessment does not require the presence of all four characteristics, the severity is 
averaged over the observed characteristics. 
The IGA-CLE ClinRO was added in this study following FDA’s demand. Since the 
implementation of this specifically developed ClinRO on sites happened after study start, some 
participants had already performed their Week 12 visit beforehand. As a result, participants with 
missing data resulting from the implementation, at their respective site, of the IGA-CLE ClinRO 
after their Week 12 visit will not be included into the analysis of this endpoint. 
The IGA-CLE is assessed at Screening, Day 1, Week 4, Week 8, Week 12 (EOT) and Week 16 
(EOS) visits. 
• The change from baseline to Week 12 in the Oral Health Impact Profile (OHIP-14) for 
patients with oral lesions at baseline  
The OHIP-14 is a PRO questionnaire that measures people’s perception of dysfunction, 
discomfort and disability attributed to oral conditions in adults. It is composed of 14 items that 
assess seven different dimensions, considering the perception of the individual in relation to the 
impact of oral conditions in the physical, psychological and social well-being in the last month. 
Each of the 14 items has a set of possible answers distributed in a Likert scale (0 = never, 
1 = hardly ever. 2 = occasionally 3 = fairly often, 4 = very often), which represents the frequency 
that the individual perceives the impact of oral health on seven dimensions: functional limitation 
(2 items), physical pain (2 items), psychological discomfort (2 items), physical disability 
(2 items), psychological disability (2 items), social disability (2 items) and handicap (2 items). 
The OHIP-14 scores can range from 0 to 56 and are calculated by summing the ordinal values for 
the 14 items. The domain scores can range from 0 to 8. Higher OHIP-14 scores indicate worse 
oral-health-related quality of life. 
Item(s) answered “Don’t know” will be considered as missing. Missing item(s) will lead to 
missing domain(s) and total score. 
The OHIP-14 is assessed at Day 1 and Week 12 (EOT) visits. 
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• The change from baseline in SKINDEX-29+3 total score at Week 12 
SKINDEX-29 is a PRO measure designed to assess the effects of skin disease on patients’ 
health-related quality of life in adults. It is a generic instrument for skin and connective tissue 
diseases. It contains 29 items, distributed across the following domains: emotions (10 items: 3; 6; 
9; 12; 13; 15; 21; 23; 26; 28), symptoms (7 items: 1; 7; 10; 16; 19; 24; 27), functioning (12 items: 
2; 4; 5; 8; 11; 14; 17; 20; 22; 25; 29; 30); and one item about treatment that is not part of the total 
score (Item 18). Recall period is “during the past week”. Each item is rated on a 5-point Likert 
scale (never, rarely, sometimes, often, all the time). Individual items are scored from 0 to 100 in 
25-point increments with 100 representing maximal disability. The Skindex 29+3 (also called 
SkindexLupus) includes a fourth subscale (3 items: 31-33) to assess lupus-specific issues, 
ie, photosensitivity (Items 31; 33) and alopecia (Item 32). Domain scores are the average of items 
in a given domain. The total score (0 to 100, with a higher score indicating a worse quality of life) 
is defined as the average of all items. 
More than 25% of items missing in a given domain (resp. overall) will lead to missing domain 
score (resp. total score). Any participant for whom emotions, symptoms and functioning domains 
score are missing will lead to exclusion of the participant from the analysis. 
The SKINDEX-29+3 is assessed at Day 1 and Week 12 (EOT) visits. 
3.3.2 Main analytical approach  
Secondary efficacy endpoints that measure binary responses 
Each binary endpoint (PhysGA-disease activity, IGA-CLE, CLASI-A50 and CLASI-A75) will be 
analyzed using a Cochran-Mantel-Haenszel (CMH) method stratified by disease subtype (DLE, 
SCLE), baseline use of chloroquine or hydroxychloroquine (Yes, No) and geographical region 
(Asia Pacific, Eurasia, Europe, Latin America, North America).  
Point estimate and two-sided 90% confidence interval for the treatment difference (SAR443122 
versus placebo) in proportion at Week 12 will be provided based on the weighted average of 
treatment differences from each strata using CMH weights as described below. 
Let 
 denote the proportions of responders in the SAR44322 and placebo intervention 
groups from strata i, and 
 be the sample sizes in the SAR44322 and placebo 
intervention groups from strata i. Then the weighted average of treatment differences between 
SAR44322 and placebo will be estimated as 
 where 
 and 
 is CMH 
weight for strata i. The associated two-sided 90% CI for the difference can be calculated as 
, where 
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In case of no event in a cell for a strata, continuity correction will be made (ie, 0.5 will be added 
to each cell of the 2x2 table) for that strata for variance calculation only. No continuity adjustment 
will be applied for estimating the weighted average of treatment difference. The continuity 
correction will be applied to estimate variance for constructing 90% CI for the overall difference. 
The proportion of responders in each study intervention group will be provided as well. 
Participants who took prohibited/rescue medication (see Table 3) prior to Week 12 will be 
considered as non-responders.  
Participants with missing binary endpoint data at Week 12 will be considered as non-responders. 
Descriptive statistics 
The observed proportion of CLASI-A50 and CLASI-A75 responders will be summarized 
descriptively by visit and study intervention group.  
In, addition, PhysGA-disease activity and IGA-CLE scores will be summarized as ordinal 
variables by visit and study intervention group. Bar charts showing the distribution of severity 
categories will be provided as well by visit and study intervention group. If needed, a missing 
category will be included.  
Data after taking selected prohibited/rescue medications (see Table 3) will be set to missing for 
descriptive statistics. 
Secondary efficacy endpoints that measure continuous or ordinal responses 
Secondary efficacy endpoints that measure continuous or ordinal responses (Peak Pruritus NRS, 
Peak Pain NRS, CLASI-A, SKINDEX-29+3) other than CLASI-D, CLASI subcomponent’s 
scores and OHIP-14 will be analyzed using an analysis of covariance (ANCOVA) model with 
disease subtype (DLE, SCLE), baseline use of chloroquine or hydroxychloroquine (Yes, No), 
geographical region (Asia Pacific, Eurasia, Europe, Latin America, North America), study 
intervention group and relevant baseline endpoint measurement as fixed effects. 
Point estimate and two-sided 90% confidence interval for the mean differences between the 
2 groups (SAR443122 versus placebo) at Week 12 will be provided. 
Endpoint data after taking prohibited/rescue medication (see Table 3) prior to Week 12 will be set 
to missing and imputed using the worst-observation carried forward (WOCF) approach as 
described in Section 3.2.4. 
Missing endpoint data at Week 12 will be imputed using the LOCF approach.  
Specifically for Peak Pruritus NRS and Peak Pain NRS, a multiple imputation (MI) approach may 
be used in addition to impute missing endpoint data (including missing data at baseline).  
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Descriptive statistics 
As appropriate, descriptive statistics of raw data and change from baseline will be provided by 
visit and study intervention group.  
In addition, mean raw data and change from baseline with the corresponding standard error will 
be plotted over time by study intervention group for weekly-averages Peak Pruritus NRS and Peak 
Pain NRS. 
For CLASI-D and CLASI subcomponent’s scores, only descriptive statistics of raw data and 
change from baseline may be provided by visit and study intervention group. 
For OHIP-14, only descriptive statistics of raw data and change from baseline will be provided on 
the total score by visit and study intervention group. 
Data after taking selected prohibited/rescue medications (see Table 3) will be set to missing for 
descriptive statistics. 
Other secondary endpoints analyses are defined in Section 3.6.2 (AE, SAE, AESI), 
Section 3.6.3.1 (laboratory, vital signs and ECG abnormalities) and Section 3.7.1.1 (PK). 
3.4 
EXPLORATORY ENDPOINT(S) ANALYSIS  
3.4.1 Definition of endpoints  
The exploratory endpoints are as follows: 
• Change from baseline at Week 12 in each of the sub-scores of the SKINDEX-29+3 
See Section 3.3.1 for a description of the SKINDEX-29+3. Each of the four sub-scores of the 
SKINDEX-29+3 (emotion, symptoms, functioning, lupus specific) will be used for descriptive 
analysis. 
• Change from baseline at Week 12 in the patient’s global impression of disease severity 
(PGIS) 
The PGIS is a 4-Point Likert scale instrument designed to assess patient’s evaluation of the 
severity of their disease over the past week ranging from “None” to “Severe”. 
The PGIS is assessed at Day 1 and Week 12 visits. 
• Evaluation of patient’s global impression of change (PGIC) in overall disease at Week 12 
The PGIC is a 7-Point Likert scale instrument designed to assess patient’s-reported evaluation of 
change in their disease overall in regard to start of study medication. The scale is ranging from 
“Very much better” to “Very much worse”. 
The PGIC is assessed at Week 12 visit. 
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• Evaluation of physician’s global assessment of change in disease activity (PhysGAC 
disease activity) at Week 12 
See Section 3.3.1 for a description of the PhysGA - disease activity. 
The Physician’s Global Assessment of Change in disease activity is a 7-Point Likert scale 
instrument designed to assess physician-reported evaluation of change in patient’s cutaneous 
lupus erythematosus activity overall in regards of start of treatment. The scale is ranged from 
“Very much improved” to “Very much worse”. 
The PhysGAC disease activity is assessed at Week 12 visit. 
• Change from baseline in active joint count assessment (28 joint assessment) at Week 12 
Twenty-eight-joint assessment is used to assess CLE related joint inflammation by counting the 
number of active swollen and tender joints. An active joint is defined as joint with swelling within 
joint not due to deformity and/or joint with tenderness. 
The 28 joint assessment is done at Day 1, Week 4, Week 8, Week 12 and Week 16 visits. 
• Change from baseline in Safety of Estrogens in Lupus Erythematosus National 
Assessment – Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) 
over time 
The SELENA-SLEDAI (see Section 5.8) has been developed to measure the disease activity in 
patients with SLE for use in clinical trials. It has been developed to determine global improvement 
and performed in effective and reliable manners in studies. This is a weighted index in which 
signs and symptoms, laboratory tests for each of the nine organ systems are given a weighted 
score and summed up if present at the time of the visit or in the preceding 10 days. The maximum 
theoretical score for the SELENA-SLEDAI is 105 (all 24 descriptors present simultaneously) with 
0 indicating inactive disease.  
The SELENA-SLEDAI is assessed at Day 1 and Week 12 visits. 
Missing item(s) will lead to missing total score. 
• Change from baseline to Week 12 in Genital Erosive Lichen Planus (GELP) total score for 
female patients with genital lesions at baseline 
Genital Erosive Lichen Planus score (see Section 5.9) is a scoring system for clinical assessment 
of GELP in women. The GELP scoring system is based on a simple grading (0-3) of area of 
involvement, degree of erythema, number of erosions, number of striae and patient-reported pain 
induced by pressuring the involved area with a cotton swab. Area of genital involvement, 
erythema, striae, number of erosions and pain are registered and scored 0-3 (0 is none) for each 
parameter. Vulval and vaginal involvement is assessed separately, resulting in a maximum GELP 
score of 30, with higher score indicating a higher symptom severity. 
The GELP is assessed at Day 1 and Week 12 visits. 
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Missing item(s) will lead to missing total score. 
• Photographic assessment of index lesions (Central imaging acquisition tool), oral lesions if 
present 
As a minimum the body site(s) and lesion features assessed by Investigator of photographed skin 
lesion will be recorded. The Photographic assessment of index lesions is done at Baseline and 
Week 12 visits. 
• The frequency of use of rescue medications by category (eg, topical corticosteroids, 
topical calcineurin inhibitors, oral corticosteroids) 
Rescue medications will be assigned to the following categories (“topical corticosteroids”, 
“topical calcineurin inhibitors”, “oral corticosteroids”, “anti-malarial”,” immunosuppressants”) 
according to the algorithm presented in Section 5.6. 
3.4.2 Main analytical approach  
Exploratory efficacy endpoints (28 joint assessment, SELENA-SLEDAI) will be analyzed on the 
Efficacy population using the same methodology as secondary efficacy for similar data 
(continuous or ordinal) except the endpoints below: 
• Change from baseline at Week 12 in each of the sub-scores of the SKINDEX-29+3 
Descriptive statistics of raw data and change from baseline will be provided for each sub-score by 
visit and study intervention group. Data after taking selected prohibited/rescue medications 
(see Table 3) will be set to missing for descriptive statistics. 
• Change from baseline at Week 12 in the patient’s global impression of disease severity 
(PGIS) 
PGIS will be summarized as an ordinal variable by visit and study intervention group. Data after 
taking selected prohibited/rescue medications (see Table 3) will be set to missing for descriptive 
statistics. 
• Evaluation of patient’s global impression of change (PGIC) in overall disease at Week 12 
PGIC will be summarized as an ordinal variable at Week 12 by study intervention group. Data 
after taking selected prohibited/rescue medications (see Table 3) will be set to missing for 
descriptive statistics. 
• Evaluation of physician’s global assessment of change in disease activity (PhysGAC 
disease activity) at Week 12 
PhysGAC disease activity will be summarized as an ordinal variable at Week 12 by study 
intervention group. Data after taking selected prohibited/rescue medications (see Table 3) will be 
set to missing for descriptive statistics. 
• Change from baseline to Week 12 in Genital Erosive Lichen Planus (GELP) total score for 
female patients with genital lesions at baseline 
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Descriptive statistics of raw data and change from baseline will be provided for GELP total score 
as well as vulval and vaginal involvement scores by visit and study intervention group. Data after 
taking selected prohibited/rescue medications (see Table 3) will be set to missing for descriptive 
statistics. 
• The frequency of use of rescue medications by category (eg, topical corticosteroids, 
topical calcineurin inhibitors, oral corticosteroids) 
The number (%) of participants experiencing at least one use of rescue medication after D1 and 
prior to Week 12 (and prior to Week 16 as needed) will be summarized for each category and 
overall by study intervention group.  
In addition, if at least 5 events as mentioned above occur, the time (week) to first rescue 
medication for those participants will also be analyzed using Kaplan-Meier method and the 
duration of the rescue medication use may be summarized if applicable. 
• Photographic assessment of index lesions (Central imaging acquisition tool), oral lesions if 
present 
Listing of participants with index lesions will be provided. Further descriptive analyses may be 
explored if applicable. 
3.5 
MULTIPLICITY ISSUES  
No multiplicity adjustment will be performed for this study. 
3.6 
SAFETY ANALYSES  
All safety analyses will be performed on the safety population as defined in Section 2, unless 
otherwise specified, using the following common rules: 
• The analysis of the safety variables will be essentially descriptive, and no testing is 
planned.  
• Safety data in participants who do not belong to the safety population (eg, exposed but not 
randomized) will be provided separately. 
3.6.1 Extent of exposure  
The extent of IMP exposure will be assessed by the duration of IMP exposure and summarized 
within the safety population and within the efficacy population if relevant. 
The following listings will be provided: 
• Participants receiving IMP from specified batch. 
• Randomization scheme (Strata, Block number, Order within the block, Randomization 
number, Study intervention group, Randomization date and time, Participant identifier, 
and Comments [if needed]). 
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Duration of IMP exposure 
Duration of IMP exposure is defined as last IMP administration date – first IMP administration 
date + 1 days, regardless of unplanned intermittent discontinuations. If the date of the last dose of 
IMP is missing, the duration of IMP will be left as missing. 
Duration of IMP exposure will be summarized quantitatively and categorically: <1, 1 to 2, 2 to 4, 
4 to 8, 8 to 12, and >12 weeks.  
Treatment compliance 
A given administration will be considered noncompliant if the participant did not take the planned 
dose of treatment as required by the protocol until the date of last administration of IMP 
(ie, 6 capsules in the day). Missing exposure between first recorded on-site dosing date and 
first recorded e-Diary dosing date, identified during blinded review of the deviations before 
database lock, will be assumed to be exposure as planned for participants whom e-Diary device 
was initiated late. No other imputation will be made for participants with missing or incomplete 
data. 
Percentage of treatment compliance for a participant will be defined as the number of days that 
the participant was compliant divided by the total number of days that the participant was planned 
to take from the first administration of IMP up to the actual last administration of IMP. 
Treatment compliance will be summarized quantitatively and categorically: <80%, <90%, 
<95% and ≥95%. 
Cases of symptomatic overdose (defined as at least 50% more than intended daily dose within 
one day) will be considered an AESI and will be listed as such. 
3.6.2 Adverse events  
General common rules for adverse events 
All adverse events (AEs) will be coded to a Lower-Level Term (LLT), Preferred Term (PT), 
High-Level Term (HLT), High-Level Group Term (HLGT), and associated primary System 
Organ Class (SOC) using the Medical Dictionary for Regulatory Activities (MedDRA) version 
currently in effect at Sanofi at the time of database lock. 
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. 
• Treatment-Emergent Adverse Events (TEAE)s: 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  
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Similarly, the AE leading to deaths will be analyzed in the pre-treatment, treatment-emergent and 
post-treatment periods if applicable.  
The primary focus of AE reporting will be on TEAEs. 
An AE with incomplete or missing date/time of onset (occurrence, worsening, or becoming 
serious) will be classified as a TEAE unless there is definitive information to determine it is a pre-
treatment or a post-treatment AE.  
If the assessment of the relationship to IMP is missing for an AE, this AE will be assumed as 
related to IMP. If the severity is missing for an AE, the severity will be left as missing. 
The AE tables will be sorted as indicated in Table 4.  
Table 4 - Sorting of AE tables  
AE presentation 
Sorting rules 
SOC, HLGT, HLT and PT 
By the internationally agreed SOC order and by alphabetic order of HLGTs, HLTs and PTsa, b 
a Sorting will be based on the SAR443122 intervention group 
b The table of all TEAEs presented by SOC, HLGT, HLT and PT will define the presentation order for all other tables (eg, treatment-
emergent SAE), unless otherwise specified. 
Analysis of all adverse events 
The overview of TEAE with the details below will be generated: 
• Any TEAE 
• Any severe TEAE 
• Any treatment emergent SAE 
• TEAE leading to death, if any 
• Any TEAE leading to permanent intervention discontinuation  
• Any TEAE leading to permanent study discontinuation 
• Any treatment emergent AESI 
• Any TEAE considered by the investigator as related to IMP 
The AE summaries of Table 5 will be generated with number (%) of participants experiencing at 
least one event and sorted by the internationally agreed SOC order and by alphabetic order of 
HLGTs, HLTs and PTs. Sorting will be based on SAR443122 intervention group (see Table 4).  
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Table 5 - Analyses of adverse events  
Type of AE 
MedDRA levels 
All TEAE 
Primary SOC, HLGT, HLT and PT 
Common TEAE (≥5% across all groups) 
Primary SOC, HLGT, HLT and PT 
TEAE related to IMP as per Investigator’s judgment 
Primary SOC, HLGT, HLT and PT 
TEAE by maximal intensity 
Primary SOC, HLGT, HLT and PT 
Treatment emergent SAE [optional] 
Primary SOC, HLGT, HLT and PT 
Treatment emergent SAE related to IMP as per Investigator’s 
judgment [optional] 
Primary SOC, HLGT, HLT and PT 
TEAE leading to permanent intervention discontinuation [optional] 
Primary SOC, HLGT, HLT and PT 
TEAE leading to death (death as an outcome of the AE as reported 
by the Investigator in the AE page) [optional] 
Primary SOC, HLGT, HLT and PT 
Treatment emergent COVID19 related AE [optional] 
Primary SOC, HLGT, HLT and PT 
In addition, the all TEAE summary by Primary SOC, HLGT, HLT and PT will be performed by 
trial impact (disruption) due to COVID-19 and according to baseline use of chloroquine or 
hydroxychloroquine.  
Optional tables mentioned in Table 5 are to be done in case of sufficient number of events. 
Otherwise only listings will be provided.  
Adverse events of special interest 
Adverse events of special interest (AESIs) will be selected for analyses as indicated in Table 6. 
In case of sufficient number of events, the number (%) of participants experiencing at least 
one event will be provided for each event of interest. Otherwise only listings will be provided. 
Tables will be sorted as indicated in Table 4.  
Table 6 - Selections for AESIs  
AESIs 
Selection 
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 
e-CRF specific tick box on the AE page 
Symptomatic overdose (serious or non-
serious) with IMP 
e-CRF specific tick box on the AE page 
Increase in ALT 
e-CRF specific tick box on the AE page 
Anemia 
Combined AESIs eCRF tick-box 
QTc ≥500 ms 
Combined AESIs eCRF tick-box 
New Lymphadenopathy 
Combined AESIs eCRF tick-box 
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A listing of all AEs will be provided for participants treated but not considered as randomized, if 
any.  
Adverse events that occur outside of the treatment emergent period will be listed separately.  
3.6.3 Additional safety assessments  
3.6.3.1 Laboratory variables, vital signs and electrocardiograms (ECGs)  
The following variables will be analyzed. They will be converted into standard international units. 
• Hematology: 
- 
Red blood cells and platelets and coagulation: hemoglobin, hematocrit, mean 
corpuscular volume, mean corpuscular hemoglobin, reticulocyte count, red blood cell 
count, platelet count 
- 
White blood cells: white blood cell count, neutrophils, lymphocytes, monocytes, 
basophils, eosinophils 
•  Clinical chemistry: 
- 
 Metabolism: glucose [fasting], total protein, creatine phosphokinase 
- 
Electrolytes: sodium, potassium, calcium 
- 
Renal function: creatinine, creatinine clearance, blood urea nitrogen. Creatinine 
clearance will be derived with the equation of Cockroft and Gault using weight 
assessed at the same visit as creatinine 
- 
Liver function: alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, total and direct bilirubin 
• Urinalysis: 
- 
Urinalysis for quantitative analysis: pH, specific gravity, proteins and glucose  
• Vital signs: pulse rate, systolic and diastolic blood pressure according to position (semi- 
supine), respiratory rate, temperature 
• ECG variables: heart rate, PR, QRS, QT, and corrected QTc (according to Fridericia) 
Quantitative analyses 
For laboratory variables, vital signs and ECG variables above, descriptive statistics for results and 
changes from baseline as appropriate will be provided for each planned visit, and for the last value 
during the on-treatment period. These analyses will be performed using central measurements 
only (when available), for laboratory variables and ECG variables.  
For hemoglobin, neutrophils, platelet count, creatinine clearance, alanine aminotransferase, 
aspartate aminotransferase, alkaline phosphatase, total and direct bilirubin and QTcF, mean 
changes from baseline with the corresponding standard error will be plotted over time.  
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Analyses according to PCSA 
Potentially Clinically Significant Abnormality (PCSA) analyses will be performed based on the 
PCSA list currently in effect at Sanofi at the time of the database lock for patients. For laboratory 
parameters for which no PCSA criteria are defined, similar analyses will be done using out-of-
normal ranges, if applicable.  
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 above, 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 
Additional analyses for potential drug-induced liver injury 
If any, an intext listing of liver function tests data for participants with potential drug-induced 
liver injury (“ALT >3 ULN and Total bilirubin >2ULN” or “Direct bilirubin>35% of Total 
bilirubin and Total bilirubin >1.5 ULN”) will be provided. 
Additionally, listing of ALT increase documentation (including specific medical history, alcohol 
habits, associated signs and symptoms, trigger factors…) will also be provided for participants 
with one or more ALT increases greater than or equal to 2 ULN. 
Listing of participants with QTc >480 msec and/or change from baseline QTc >60 msec 
If any, an intext listing of participants with QTc >480 msec and/or change from baseline 
QTc >60 msec will be provided. 
3.7 
OTHER ANALYSES  
3.7.1 Other variables and/or parameters  
3.7.1.1 PK analyses  
SAR443122 concentrations will be described in the SAR443122 intervention group on the PK 
population for each planned visit using the following descriptive statistics: mean, geometric mean, 
median, standard deviation, coefficient of variation, minimum, and maximum. These analyses will 
be performed by specific subgroups (eg, gender, BMI, age) if appropriate.  
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All concentration values below the lower limit of quantitation (LLOQ) will be treated as zero in 
all summary statistics. Geometric mean will not be computed in case at least one concentration is 
below LLOQ. 
3.7.1.2 Biomarkers analyses  
The Biomarker endpoints are as follows: 
• Change from baseline in transcriptomic biomarkers from mRNA derived from skin biopsy 
and from blood 
• Change from baseline of blood plasma biomarkers (eg, cytokine and chemokine levels) 
over time 
• Demonstrate inhibition of pS166-RIPK1 in PBMC lysates with SAR443122 treatment 
compared to placebo in a subset of patients at Week 12 
• Histologic changes in skin biopsies (Central pathologist) 
Biomarker analyses will be described in a specific Biomarker SAP and reported separately. 
3.7.1.3 PK/PD analyses  
The analysis of PK/PD relationship will be described and reported separately. 
3.7.2 Subgroup analyses  
Analyses will be performed on the primary endpoint across the following subgroups if relevant 
(categories with fewer than 5 participants may be combined with other categories) using the same 
methodology as for the primary endpoint: 
• Age group (<65, ≥65 years) 
• Gender (Male, Female) 
• Geographical region (Asia Pacific, Eurasia, Europe, Latin America, North America).  
• Disease subtype (SCLE, DLE) 
• Baseline use of chloroquine or hydroxychloroquine (yes, no) 
• Baseline CLASI-A (severe, moderate) 
The subgroup factor term and the subgroup-by-intervention group, subgroup-by-visit and 
subgroup-by-intervention group-by-visit interaction terms will be added in the primary model. In 
the case that the subgroup factor is identical or similar to a randomization strata factor, the strata 
factor will not be kept in the model.  
If needed simpler modelling (eg, ANCOVA) may be considered instead. 
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In each subgroup, the treatment effects for the primary endpoint will be provided, as well as the 
corresponding 90% CI, using the same method as applied to the primary analysis. Forest plots will 
be provided. 
3.8 
INTERIM ANALYSES  
An interim analysis is planned for this study.  
The sponsor will make use of this interim analysis to facilitate internal operational decision on the 
compound development. The interim analysis will be performed when around 75% of the 
participants have completed study treatment or discontinued the study. The PK and PD 
relationship could also be explored before final database lock. The cut-off for the interim analysis 
is once the 65th participant reaches its Week 12 (EOT) visit (09-Jan-2023) or prematurely 
discontinue study intervention. The interim analysis or PK/PD analysis will not lead to changes in 
the conduct of the protocol other than stopping recruitment for this proof-of-concept study due to 
a positive decision based on the interim analysis or due to negative decision, indicating a lack of 
equipoise for continued recruitment of patients. The statistical analyses efficacy results based on 
this interim analysis will be considered as the main analyses for the study. As a result, any 
additional analyses performed in the future with additional patients will be considered as 
supplementary analyses only.  
The interim analysis will evaluate the mean percent change from baseline in CLASI-A at Week 12 
and other selected secondary efficacy endpoints on the Efficacy population, as well as the safety 
endpoints on the Safety population defined below:  
Efficacy: 
• The proportion of patients with PhysGA disease activity of 0 or 1 (disease free or almost 
disease free) at Week 12 
• The change from baseline in patients reported daily worst itch using Peak Pruritus 
Numerical Rating Scale (itch-NRS) at Week 12. 
• The change from baseline in patients reported daily worst pain using Peak Pain Numerical 
Rating Scale (pain-NRS) at Week 12. 
• The proportion of CLASI-A50 and CLASI-A75 responders at Week 12. 
• The proportion of patients with IGA-CLE score of 0 or 1 (clear or almost clear) at 
Week 12. 
Safety: 
• Total number and percent of treatment-emergent adverse events (TEAEs), serious adverse 
events (SAEs), adverse events of special interest (AESIs), and TEAEs leading to 
permanent study intervention discontinuation through end of study (EOS).  
• Percent of potentially clinically significant abnormalities (PCSAs) in laboratory tests, 
electrocardiogram (ECG) or vital signs through end of study (EOS). 
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All analysis performed for this interim analysis are described in the Statistical Analysis Plan, but 
the following additional rules will apply for analyses performed at interim analysis: 
• Efficacy and safety analyses will be conducted on all participants who did complete the 
treatment period or prematurely discontinued the study intervention at cut-off date. 
The interim analysis will be performed by a separate statistical team, independent of the study 
team. The PK/PD analysis will be performed by a sponsor internal modeling and simulation team, 
also independent of the study team. Only those necessary for conducting the interim analysis, 
PK/PD analysis and those responsible for internal project planning/overall portfolio planning 
needs (eg, to aid in the planning of future studies) will have the access to the interim analyses 
results before study completion. A list of these individuals will be maintained.  
All sponsor internal personnel with access to unblinding information will be asked to sign a study 
confidentiality agreement before having access to unblinding information. Study team and 
investigational sites will not have access to interim study results and continue to be blinded to 
individual randomization codes until study completion and database lock. Therefore the interim 
analysis will not lead to changes in the conduct of the protocol. 
Result distribution, code release process and blinding strategy will be described in a pre-defined 
dissemination plan. 
 
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3.9 
CHANGES TO PROTOCOL-PLANNED ANALYSES  
This section summarizes major statistical changes in the protocol amendment(s). 
Major statistical changes in protocol amendment(s) 
Amendment 
Number 
Approval 
Date 
Changes 
Rationale 
1 
10-Dec-2021 
Aligned the names of the analysis 
populations with current Sponsor’s 
standard 
To improve precision and clarity 
2 
22-Nov-2022 
Added an interim analysis 
To facilitate internal operational decision on 
the compound development 
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4 
SAMPLE SIZE DETERMINATION  
The sample size was derived with respect to the primary endpoint (percent change from Baseline 
in CLASI-A sub-score at Week 12) by applying the Quantitative Decision Making approach as 
described by Quan et al (1). Assuming a standard deviation of 45% and a reducing effect of 28% 
under active treatment, a sample size of 80 evaluable participants results in an overall probability 
for a positive decision of more than 50% and a negative decision probability of 20%. Up to 
88 participants are expected to be randomly assigned to the IMP, expecting a total of 80 evaluable 
participants with approximately 40 evaluable participants per group. 
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5 
SUPPORTING DOCUMENTATION  
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS  
 
AE: 
adverse event 
AESIs: 
adverse events of special interest 
ANCOVA: 
analysis of covariance 
BID: 
twice a day 
CI: 
confidence interval, confidence interval 
CLASI: 
cutaneous erythematosus disease area and severity index 
CLE: 
cutaneous lupus erythematosus 
ClinRO: 
clinician reported outcome 
CMH: 
Cochran-Mantel-Haenszel 
CRF: 
case report form 
DLE: 
discoid lupus erythematosus 
EOS: 
end of study 
EOT: 
end of treatment 
GELP: 
genital erosive lichen planus 
HLT: 
high level term 
ICF: 
Informed consent form 
IGA-CLE: 
investigator’s global assessment for cutaneous lupus erythematosus 
IMP: 
investigational medicinal product 
IRT: 
interactive response technology 
ITT: 
intent to treat 
LLOQ: 
lower limit of quantification 
LLT: 
lower-level term 
LOCF: 
last observation carried forward 
MAR: 
missing at random 
MCMC: 
Markov Chain Monte Carlo 
MedDRA: 
medical dictionary for regulatory activities 
MI: 
multiple imputation 
MMRM: 
mixed model with repeated measurements 
OHIP-14: 
oral health impact profile 
PCSA: 
potentially clinically significant abnormality 
PD: 
pharmacodynamic 
PGIC: 
patient’s global impression of change 
PGIS: 
patient’s global impression of disease severity 
PhysGA: 
physician’s global assessment of disease activity 
PhysGAC: 
physician’s global assessment of change in disease activity 
PK: 
pharmacokinetic 
PRO: 
patient reported outcome 
PT: 
preferred term 
SAP: 
statistical analysis plan 
SCLE: 
subacute lupus erythematosus 
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SD: 
standard deviation 
SELENA-SLEDAI: 
safety of estrogens in lupus erythematosus national assessment 
SLE: 
systemic lupus erythematosus 
SOC: 
system organ class 
TE: 
treatment-emergent 
TEAE: 
treatment-emergent adverse event 
ULOQ: 
upper limit of quantification 
WHO-DD: 
World Health Organization-drug dictionary 
WOCF: 
worst observation carried forward 
 
5.2 
APPENDIX 2 PARTICIPANT DISPOSITIONS  
The number (%) of participants included in the analysis populations listed in Table 2 will be 
summarized. All exclusions from any analysis populations will be fully documented in the CSR. 
Screen failures are defined as participants who consent to participate in the study but are not 
subsequently randomized. The number (%) of screen failures with inclusion criteria not met 
and/or exclusion criteria met will be provided in the screened population.  
The number (%) of participants in the following categories will be provided:  
• Screened participants 
• Randomized but not exposed participants 
• Randomized and exposed participants 
• Participants who completed the study treatment period as per protocol  
• Participants who did not complete the study treatment period as per protocol and main 
reason for permanent intervention discontinuation.  
• Participants who completed the study period as per protocol. 
• Participants who did not complete the study period as per protocol and main reason for 
study discontinuation. 
Reasons for permanent study intervention and study discontinuation “adverse event” and “other 
reasons” will be split as related versus not related to COVID-19. 
The number (%) of exposed and not randomized participants will also be summarized. In addition, 
the number (%) of participants screened, screened-failed, randomized, randomized and exposed, 
with permanent intervention discontinuation and with early study discontinuation will be provided 
by geographical region, country and site.  
Listing of participants with permanent intervention discontinuation or with premature end of study 
(ie, who did not complete the study period as per protocol) will be provided for the safety 
population along with the main reason of discontinuations and related to COVID-19 or not, 
respectively. 
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Protocol deviations 
All critical or major deviations potentially impacting efficacy analyses, randomization, and drug 
dispensing irregularities, and other major or critical deviations will be summarized in tables 
giving numbers and percentages of deviations by treatment group. In addition the summary will 
be displayed separately as related versus not related to COVID-19, if applicable. They will also be 
listed in the randomized population. They will be displayed separately as related versus not 
related to COVID-19. 
Emergency situation impact 
A summary of visits impacted by COVID-19 pandemic will be provided for the safety population 
along with the description of the impact (visit not done, visit partially done on site/by phone, visit 
done but delayed), if applicable. 
In addition, a listing of participants excluded from the population without trial impact (disruption) 
due to COVID-19 will be provided for the safety population along with the main reasons of 
exclusion. 
If any, similar summary of visits and listing of participants impacted by any other emergency 
situation (eg, war in Ukraine) will be provided for the safety population. 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS  
Demographics, baseline characteristics, medical surgical history 
The following demographics and baseline characteristics, medical and surgical history and disease 
characteristics at baseline will be summarized using descriptive statistics in the safety population 
and in the efficacy population if relevant. 
Demographic and baseline characteristics  
• Age in years as quantitative variable and in categories (18 to <65, 65 to <85) 
• Gender (Male, Female) 
• Race (White, Black or African American, Asian, Native Hawaiian or Other Pacific 
Islander, American Indian or Alaska Native, Multiple) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino) 
• CLE subtype (DLE, SCLE) 
• Geographical region (Asia Pacific, Eurasia, Europe, Latin America, North America) 
• Baseline use of chloroquine or hydroxychloroquine (Yes, No) 
• Average daily sun exposure without sun protection in hours 
• CLASI-A severity (Moderate [10-20], Severe [21-70]) 
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Baseline safety and efficacy/PD parameters (apart from those listed above) will be presented 
along with the safety and efficacy/PD summaries. 
All medical and surgical history will be coded to a LLT, PT, HLT, HLGT, and associated primary 
SOC using the MedDRA version currently in effect at Sanofi at the time of database lock. All 
medical history will be summarized by primary SOC and PT using a frequency table (number and 
% of participants) by study intervention group. 
The following baseline disease characteristics will be summarized by study intervention group: 
• Time since diagnosis of CLE in years (defined as randomization date – diagnosis date) 
• Time since diagnosis of SLE in years (defined as randomization date – diagnosis date) 
Partial diagnosis dates will be imputed as follows: 
• Missing day will be imputed as 15th of the corresponding month, if only month is 
available. 
• Missing month will be imputed as July of the corresponding year. 
• Missing both month and day will be imputed as July 1st of the corresponding year. 
• Missing year won’t be imputed. 
In case an imputed date of diagnosis is after the participant’s screening date, the screening date 
will be used instead. 
Prior or concomitant or post-treatment medications 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database lock. 
• Prior medications are those the participant used prior to first IMP intake. Prior medications 
can be discontinued before first administration or can be ongoing during study intervention 
period. 
• Concomitant medications are any medications received by the participant concomitantly to 
the IMP during the on-treatment period. 
• Post-treatment medications are those the participant took in the period running from the 
end of the concomitant medications period up to the end of the study. 
A given medication can be classified as a prior medication and/or as a concomitant medication 
and/or as post-treatment medication. If it cannot be determined whether a given medication was 
taken prior or concomitantly or post, it will be considered as prior, concomitant, and post-
treatment medication. 
The prior and concomitant and post-treatment medications will be summarized for the safety 
population and in the efficacy population if relevant, by anatomic and therapeutic level. 
Participants will be counted once in each ATC category (anatomic or therapeutic) linked to the 
medication. 
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5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS  
General data handling conventions 
For parameters with evaluations before administration and in cases of rechecked value(s) for 
one participant, only the last observation will be used as baseline in descriptive statistics and 
derivations of other parameter values. After baseline, only observations planned in the protocol 
will be used in descriptive statistics. 
The premature EOT visit is entered in eCRF if a patient prematurely discontinues the study 
intervention. These measurements may not be used in descriptive statistics but could be added in 
table footnote. 
Furthermore, EOS visit measurements from patients who prematurely discontinue the study 
(“Subject Status” in “Completion of End of Study/Follow-up” page is not “Completed”) may not 
be used in descriptive statistics as well, but could be added in table footnote. 
For clinical laboratory parameters with nonnumeric values, the imputed values used for the 
descriptive statistics and/or the flags will be determined by considering the following rules: 
• If database value is ‘ <X’, the value used will be X/2 
• If database value is ‘ >X’, the value used will be X 
• If database value is a range (eg, ‘X – Y’), the values used will be (Y + X)/2 
Heart rate is the generic term used indifferently for pulse rate or heart rate from vital signs or ECG 
assessments. 
Data below the Lower Limit Of Quantitation/detection limit (LLOQ) will be replaced by half of 
the LLOQ, data above the Upper Limit Of Quantification will be replaced by ULOQ value. 
Unscheduled visits 
Unscheduled visit measurements of laboratory data, vital signs and ECG will be used for 
computation of baseline, the last on-treatment value and analysis according to PCSAs grades, and 
the shift summaries for safety.  
Efficacy 
The baseline value of efficacy parameters is defined as the Day 1 (the day of first IMP) 
assessment value unless otherwise specified. If not available, the last available Screening 
assessment value will be used. Single domains/(sub)scales of efficacy parameters may have 
baseline on a different visit than the overall score. 
EOS visits will only be included (if available) in descriptive statistics and not in efficacy models. 
Premature EOT visits will not be included in efficacy models as well. 
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5.5 
APPENDIX 5 SAMPLE SAS CODE  
Variables 
Assuming disease subtype stratification factor is removed from the analysis model and the 
following combination of geographical regions and countries are performed: Europe + North 
America + Australia versus Latin America + Eurasia + India. 
* treat                              – treatment (Placebo [0]; SAR443122 [1]); 
* strata1                           – baseline use of chloroquine or hydroxychloroquine (Yes [1]; No [0]); 
* strata2                           – region (Latin America + Eurasia + India [0]; Europe + North America 
+ Australia [1]); 
* value0                           – CLASI-A value at baseline; 
* pchange1 … pchange3 – CLASI-A percent change from baseline at each post-baseline visit; 
If multivariate normality assumption appears not to be met for the percent change from baseline in 
CLASI-A, the raw CLASI-A values may be used in the imputation model instead. Alternative 
statistical methods may be applied as well, eg, data may be transformed for analysis. 
Tipping point analysis 
1. 1000 datasets with a monotone missing pattern will be obtained, induced by Markov Chain 
Monte Carlo (MCMC) method.  
* Partial imputation to render monotone missing; 
proc mi data= data out=monotone nimpute=1000 seed=35791; 
 
var strata1 strata2 treat value0 pchange:; 
 
mcmc chain=multiple impute=monotone; 
run; 
2. For each of the imputed dataset with monotone missing pattern in step 1, the remaining 
missing data will be imputed using the regression method for the monotone pattern with 
adjustment for covariates. Missing data will be imputed with penalty in SAR443122 
intervention group. 
* To impute the missing data at post-baseline visits with penalty in SAR443122 
intervention group; 
proc mi data= monotone out= dat_imp nimpute=1 seed=57913; 
by _imputation_; 
 
class strata1 strata2 treat; 
 
var strata1 strata2 treat value0 pchange:; 
 
monotone method=reg; 
 
mnar adjust (pchange3 / shift=&shift. adjustobs=(treat=’1’)); *1 denotes 
SAR443122 intervention group; 
run; 
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3. Each of the 1000 imputed datasets will be analyzed using the appropriate ANCOVA 
model.  
proc glm data= dat_imp; 
 
by _imputation_; 
 
class strata1 strata2 treat; 
 
model value3 = strata1 strata2 treat value0; 
 
lsmeans treat / stderr; 
 
estimate ‘Diff SAR443122 versus Placebo’ treat -1 1; 
 
ods output LSMeans=implsmeans Estimates=implsmeansdiff; 
run; 
4. Applying Rubin’s rule to combine analysis results (point estimates and standard errors) 
from 1000 imputations using PROC MIANALYZE for the LS means and difference in LS 
means between SAR443122 and placebo. 
proc sort data=implsmeans; by treat _imputation_; run; 
 
proc mianalyze data=implsmeans; 
 
by treat; 
 
modeleffects lsmean; 
 
stderr stderr; 
 
ods output ParameterEstimates=lsmeans; 
run; 
 
proc mianalyze data=implsmeandiff; 
 modeleffects estimate; 
stderr stderr; 
ods output ParameterEstimates=lsmeandiff; 
run; 
5.6 
APPENDIX 6 SELECTION CRITERIA FOR RESCUE MEDICATION CATEGORIES  
Rescue medications identified with the following groupings will be assigned to category “anti-
malarial”: 
• CDG00132 “HYDROXYCHLOROQUINE_mono_and_multi_ingredients”; 
• CDG30011 “CHLOROQUINE_mono_and_multi_ingredients”; 
• CDG40130 “MEPACRINE_mono_and_multi_ingredients”;  
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Rescue medications identified with the following groupings will be assigned to category “topical 
corticosteroids”: 
• CDG10390 “Super High potency Topical corticosteroid (For Rescue only)” with 
Route=“TOPICAL”; 
• CDG10391 “High Topical corticosteroid (For Rescue Only)” with Route=“TOPICAL”; 
• CDG40052 “Medium potency topical corticosteroids_Study level” with 
Route=“TOPICAL”; 
• CDG40053 “Low potency topical corticosteroids_Study level” with Route=“TOPICAL”. 
Rescue medications identified with following groupings will be assigned to category “topical 
calcineurin inhibitors”: 
• Chemical class “TOPICAL CALCINEURIN INHIBITOR” and Route=“TOPICAL”; 
Rescue medications identified with following groupings will be assigned to category “oral 
corticosteroids”: 
• Chemical class “CORTICOSTEROIDS” and Route=“ORAL”; 
Rescue medications identified with following groupings will be assigned to category 
“immunosuppressant”: 
• CDG00039 “AZATHIOPRINE_mono_and_multi_ingredients”; 
• CDG00120 “MYCOPHENOLATE_mono_and_multi_ingredients”; 
• CDG10270 “Thalidomide_mono_and_multi_ingredients”; 
• Chemical class “SELECTIVE IMMUNOSUPPRESSANTS”; 
• Standardized Medication Name “LENALIDOMIDE”; 
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St ati sti c al A n al y si s Pl a n   
1 9 -J a n -2 0 2 3  
S A R 4 4 3 1 2 2 -A C T 1 6 4 0 4  
V er si o n n u m b er: 1  
Pr o p ert y of t h e S a n ofi gr o u p - stri ctl y c o nfi d e nti al  
P a g e 4 3  
5. 7  
A P P E N DI X 7  S A M P L E O F C U T A N E O U S  L U P U S E R Y T H E M A T O S U S  DI S E A S E A R E A 
A N D S E V E RI T Y I N D E X ( C L A SI)   
 
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5.8 
APPENDIX 8 SAMPLE OF SAFETY OF ESTROGEN IN LUPUS ERYTHEMATOSUS 
NATIONAL ASSESSMENT – SYSTEMIC LUPUS ERYTHEMATOSUS DISEASE 
ACTIVITY INDEX (SELENA-SLEDAI)  
 
 
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5.9 
APPENDIX 9 SAMPLE OF GENITAL EROSIVE LICHEN PLANUS (GELP) SCORE  
 
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6 
REFERENCES  
1. Quan H, Chen X, Lan Y, Luo X, Kubiak R, Bonnet N, et al. Applications of bayesian analysis 
to proof-of-concept trial planning and decision making. Pharm Stat. 2020;19(4):468-81. 
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