A Phase 2b, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Evaluate the Efficacy, Safety, and Tolerability of Cenerimod in Subjects With Moderate to Severe Systemic Lupus Erythematosus (SLE)
Phase: PHASE2
Conditions: Systemic Lupus Erythematosus
Sponsor: Viatris Innovation GmbH

Cover page 
 
 
 
Official Title: 
 
A Phase 2b, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study to evaluate the efficacy, safety, and tolerability of cenerimod in 
subjects with moderate to severe systemic lupus erythematosus (SLE) 
 
 
 
ClinicalTrials.gov identifier: 
NCT03742037 
 
 
 
Date of document: 
4 February 2022 

 
 
TPL-000052_v11 
 
Cenerimod / ACT-334441 
Systemic lupus erythematosus 
Protocol ID-064A202 
 
CARE: Cenerimod Assessing S1P1 Receptor modulation in 
Systemic Lupus Erythematosus 
A Phase 2b, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study to evaluate the efficacy, safety, and tolerability of cenerimod in 
subjects with moderate to severe systemic lupus erythematosus (SLE)  
 
 
Study Phase: 
2b 
EudraCT Number: 
2018-001808-11 
Status and version: 
Final Version 5 
Date: 
4 February 2022 
Document type: 
Global protocol  
Idorsia number (Doc No.): 
D-22.031 
 
 
 
Confidentiality statement 
The information contained in this document, especially unpublished data, is the property of the sponsor of 
this study, Idorsia Pharmaceuticals Ltd. It is therefore provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your personnel, and an independent ethics committee 
or institutional review board. It is understood that this information will not be disclosed to others without 
written authorization from Idorsia Pharmaceuticals Ltd, except to the extent necessary to obtain informed 
consent from those persons to whom the study treatment may be administered. 

Cenerimod / ACT-334441 
Systemic lupus erythematosus 
Protocol ID-064A202 
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SPONSOR CONTACT DETAILS 
Sponsor 
Idorsia Pharmaceuticals Ltd 
Hegenheimermattweg 91 
CH-4123 Allschwil 
Switzerland 
 
+41 58 844 00 00 
Clinical Trial Physician  
Contact details of the Clinical Trial Physician can 
be found in the Investigator Site File. 
Medical Emergency Hotline 
Toll phone number:  
Site-specific toll telephone numbers and toll-free 
numbers for the Medical Emergency Hotline can 
be found in the Investigator Site File. 
 
 
 
CONTRACT RESEARCH ORGANIZATIONS’ INFORMATION 
Some study activities will be delegated to Contract Research Organizations (CROs). A 
list of site-specific contact details can be found in the Investigator Site File. 
 
 

Cenerimod / ACT-334441 
Systemic lupus erythematosus 
Protocol ID-064A202 
Final Version 5 
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Doc No D-22.031 
 
INVESTIGATOR SIGNATURE PAGE 
 
Treatment name / number 
Cenerimod / ACT-334441 
Indication 
Systemic lupus erythematosus 
Protocol number, study acronym, study title 
ID-064A202, CARE 
A Phase 2b, multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study to evaluate the efficacy, safety, and tolerability of cenerimod in subjects with 
moderate to severe systemic lupus erythematosus (SLE).  
 
I agree to the terms and conditions relating to this study as defined in this protocol and any 
other protocol-related documents. I fully understand that any changes instituted by the 
investigator(s) without previous agreement with the sponsor would constitute a protocol 
deviation, including any ancillary studies or procedures performed on study subjects (other 
than those procedures necessary for the well-being of the subjects). 
I agree to conduct this study in accordance with the Declaration of Helsinki principles, 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, 
and applicable regulations and laws. 
 
 
Principal 
Investigator 
Country 
Site 
number 
Town 
Date 
 
Signature 
 
 
 
 
 
 
 
 
 
 
 
 

Cenerimod / ACT-334441 
Systemic lupus erythematosus 
Protocol ID-064A202 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................13 
NON-SUBSTANTIAL GLOBAL AMENDMENT 4 .......................................................18 
PROTOCOL SYNOPSIS ID-064A202 .............................................................................23 
PROTOCOL ......................................................................................................................47 
1 
BACKGROUND INFORMATION ............................................................................47 
1.1 
Systemic lupus erythematosus ......................................................................47 
1.2 
Unmet needs in SLE .....................................................................................48 
1.3 
Sphingosine-1-phosphate ..............................................................................49 
1.4 
Cenerimod (ACT-334441) ...........................................................................49 
1.4.1 
Nonclinical data ................................................................................49 
1.4.2 
Clinical studies in humans ................................................................50 
1.4.2.1 
Phase 1 study in healthy subjects: results ............................... 51 
1.4.2.2 
Phase 2 study in SLE subjects: results ................................... 53 
2 
STUDY OBJECTIVES ...............................................................................................56 
2.1 
Primary objective ..........................................................................................56 
2.2 
Secondary objectives ....................................................................................56 
2.3 
Exploratory objectives ..................................................................................56 
3 
OVERALL STUDY DESIGN AND PLAN ...............................................................57 
3.1 
Study design .................................................................................................57 
3.1.1 
Study periods ....................................................................................58 
3.1.1.1 
Screening period (allowing OCS optimization period for 
subjects receiving OCS) ......................................................... 58 
3.1.1.2 
Treatment period .................................................................... 59 
3.1.1.3 
Follow-up period .................................................................... 59 
3.1.2 
Echocardiography ancillary study ....................................................59 
3.2 
Study design rationale ..................................................................................60 
3.2.1 
General rationale ...............................................................................60 
3.2.2 
Rationale for the four doses tested ....................................................61 
3.2.3 
Rationale for the efficacy endpoints .................................................62 
3.2.4 
Rationale for treatment duration .......................................................63 
3.3 
Overall benefit-risk conclusion ....................................................................63 
3.4 
Study committee ...........................................................................................64 

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Systemic lupus erythematosus 
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3.4.1 
Independent Data Monitoring Committee ........................................64 
4 
SUBJECT POPULATION ..........................................................................................64 
4.1 
Rationale for the selection of the study population ......................................64 
4.2 
Inclusion criteria ...........................................................................................65 
4.3 
Exclusion criteria ..........................................................................................66 
4.4 
Contraception requirements for women of childbearing potential ...............70 
4.4.1 
Definition of childbearing potential ..................................................70 
4.4.2 
Highly effective methods of contraception .......................................70 
4.4.3 
Male contraception ...........................................................................72 
5 
STUDY TREATMENT ..............................................................................................72 
5.1 
Investigational treatment and matching placebo: description ......................72 
5.1.1 
Study treatment administration .........................................................72 
5.1.2 
Treatment assignment .......................................................................73 
5.1.3 
Blinding ............................................................................................74 
5.1.3.1 
Blinding of study drug material .............................................. 74 
5.1.3.2 
Functional blinding ................................................................. 74 
5.1.3.3 
Unblinding for final analyses ................................................. 75 
5.1.3.4 
Unblinding for IDMC ............................................................. 75 
5.1.3.5 
Unblinding before final analyses ............................................ 75 
5.1.3.6 
Unblinding for suspected unexpected serious adverse 
reactions .................................................................................. 75 
5.1.3.7 
Emergency procedure for unblinding ..................................... 76 
5.1.4 
Study treatment supply .....................................................................76 
5.1.4.1 
Study treatment packaging and labeling ................................ 76 
5.1.4.2 
Study treatment distribution and storage ................................ 77 
5.1.4.3 
Study treatment dispensing .................................................... 77 
5.1.4.4 
Study treatment return and destruction .................................. 77 
5.1.5 
Study treatment accountability and compliance with study 
treatment ...........................................................................................77 
5.1.5.1 
Study treatment accountability ............................................... 77 
5.1.5.2 
Study treatment compliance ................................................... 78 
5.1.6 
Study treatment interruptions ............................................................78 
5.1.6.1 
Study treatment interruption between Day 1 and Day 14 ...... 78 
5.1.6.2 
Study treatment interruption after Day 14 .............................. 79 
5.1.7 
Premature discontinuation of study treatment ..................................79 
5.1.8 
Study-specific criteria for interruption / premature 
discontinuation of study treatment ....................................................81 
5.1.8.1 
Cardiovascular ........................................................................ 81 

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Systemic lupus erythematosus 
Protocol ID-064A202 
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5.1.8.2 
Immune system ....................................................................... 82 
5.1.8.3 
Respiratory system ................................................................. 83 
5.1.8.4 
Pregnancy / lack of compliance with protocol methods of 
contraception .......................................................................... 84 
5.1.8.5 
Liver enzyme abnormalities ................................................... 84 
5.1.8.6 
Ocular abnormalities .............................................................. 86 
5.1.8.7 
Infections ................................................................................ 86 
5.1.8.8 
Other potential premature treatment discontinuation ............. 87 
5.1.9 
Measures for subject retention ..........................................................87 
5.2 
Previous and concomitant therapy ................................................................87 
5.2.1 
Definition of previous and concomitant therapy ..............................87 
5.2.2 
Background SLE therapy ..................................................................88 
5.2.2.1 
Oral corticosteroids ................................................................ 89 
5.2.3 
Allowed concomitant therapy ...........................................................90 
5.2.4 
Forbidden concomitant therapy ........................................................91 
6 
STUDY ENDPOINTS ................................................................................................91 
6.1 
Efficacy endpoints ........................................................................................91 
6.1.1 
Primary efficacy endpoint .................................................................91 
6.1.2 
Secondary endpoints .........................................................................92 
6.1.3 
Other efficacy endpoints ...................................................................92 
6.1.4 
PRO / Quality of life endpoints ........................................................92 
6.1.5 
Exploratory endpoints .......................................................................93 
6.2 
Safety endpoints ...........................................................................................94 
6.3 
Pharmacokinetic endpoints ...........................................................................95 
6.4 
Biomarker endpoints .....................................................................................95 
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS ................................................95 
7.1 
Study visits ...................................................................................................95 
7.1.1 
Screening ..........................................................................................96 
7.1.1.1 
Re-screening ........................................................................... 96 
7.1.2 
Visit 2 – Day 1 – Randomization and pre- and post-dose 
assessment .........................................................................................97 
7.1.3 
Scheduled study visits .......................................................................98 
7.1.4 
Follow-up visits and EOS visit .........................................................98 
7.1.5 
Unscheduled visits ............................................................................99 
7.1.6 
Additional visits for re-initiation of study treatment ........................99 
7.2 
Study assessments .......................................................................................109 
7.2.1 
Demographics / baseline characteristics .........................................109 
7.2.1.1 
Medical history ..................................................................... 110 

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Systemic lupus erythematosus 
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7.2.1.2 
Data to be collected for screening failure subjects ............... 111 
7.2.2 
Previous and concomitant therapies ...............................................111 
7.2.3 
Safety assessments ..........................................................................111 
7.2.3.1 
Weight and height ................................................................ 111 
7.2.3.2 
Physical examination ............................................................ 111 
7.2.3.3 
12-lead ECG ......................................................................... 112 
7.2.3.4 
ECG Holter ........................................................................... 113 
7.2.3.5 
Blood pressure ...................................................................... 113 
7.2.3.6 
Echocardiography ................................................................. 114 
7.2.3.7 
Spirometry ............................................................................ 114 
7.2.3.8 
Ophthalmological examination ............................................ 115 
7.2.3.9 
Optical coherence tomography ............................................. 116 
7.2.3.10 
Chest X-ray ........................................................................... 117 
7.2.3.11 
Test for tuberculosis ............................................................. 117 
7.2.4 
Laboratory assessments ..................................................................117 
7.2.4.1 
Type of laboratory ................................................................ 117 
7.2.4.2 
Laboratory tests .................................................................... 118 
7.2.5 
Pharmacodynamic and pharmacokinetic assessments ....................121 
7.2.6 
Disease activity assessments ...........................................................121 
7.2.6.1 
Systemic Lupus Erythematosus Activity Index-2000 .......... 121 
7.2.6.2 
Physician’s Global Assessment of disease ........................... 122 
7.2.6.3 
British Isles Lupus Assessment Group ................................. 122 
7.2.6.4 
SLE Flare Index .................................................................... 123 
7.2.7 
Patient Reported Outcomes ............................................................123 
7.2.7.1 
36-Item Short Form Health Survey v2 ................................. 123 
7.2.7.2 
Functional Assessment of Chronic Illness Therapy – 
Fatigue Scale ........................................................................ 124 
7.2.7.3 
Patient Global Impression of Severity – Fatigue .................. 124 
7.2.7.4 
Patient Global Impression of Change – Fatigue ................... 124 
7.2.7.5 
Lupus Quality of Life ........................................................... 125 
7.2.8 
Biomarker assessments ...................................................................125 
7.2.9 
Emerging SLE biomarkers (tested by the sponsor) ........................126 
8 
STUDY COMPLETION AND POST-STUDY TREATMENT / MEDICAL 
CARE ........................................................................................................................126 
8.1 
Study completion ........................................................................................126 
8.2 
Premature withdrawal from study ..............................................................126 
8.3 
Premature termination or suspension of the study ......................................127 
8.4 
Medical care of subjects after study completion / withdrawal from 
study ............................................................................................................128 

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9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS .........................128 
9.1 
Safety definition .........................................................................................128 
9.1.1 
Definitions of adverse events ..........................................................128 
9.1.2 
Definition of serious adverse events ...............................................129 
9.1.3 
Definition of suspected unexpected serious adverse reactions .......130 
9.1.4 
Intensity of adverse events ..............................................................130 
9.1.5 
Relationship to study treatment ......................................................130 
9.1.6 
Relationship to protocol-mandated procedure ................................130 
9.2 
Time period and frequency for adverse event / serious adverse event 
assessment and follow-up ...........................................................................131 
9.2.1 
Follow-up of adverse events ...........................................................131 
9.2.2 
Follow-up of serious adverse events ...............................................131 
9.3 
Reporting procedures ..................................................................................131 
9.3.1 
Reporting of adverse events ............................................................131 
9.3.2 
Additional reporting procedure for serious adverse events ............131 
9.4 
Pregnancy ...................................................................................................132 
9.4.1 
Reporting of pregnancy ..................................................................132 
9.4.2 
Follow-up of pregnancy ..................................................................132 
9.4.3 
Reporting of study treatment overdose, misuse, abuse and 
medication errors ............................................................................133 
9.5 
Study safety monitoring ..............................................................................133 
10 STATISTICAL METHODS .....................................................................................133 
10.1 
Analysis sets ...............................................................................................133 
10.1.1 
Screened Analysis Set .....................................................................133 
10.1.2 
Full Analysis Set .............................................................................133 
10.1.3 
Full Analysis Set – TP2 ..................................................................133 
10.1.4 
Per-Protocol Analysis Set (PPS) .....................................................134 
10.1.5 
Safety Analysis Set .........................................................................134 
10.1.6 
Safety Analysis Set – TP2 ..............................................................134 
10.1.7 
Echocardiography Set .....................................................................134 
10.1.8 
PK Analysis Set ..............................................................................134 
10.1.9 
Usage of the analysis sets ...............................................................134 
10.2 
Variables .....................................................................................................135 
10.3 
Description of statistical analyses ...............................................................135 
10.3.1 
Overall testing strategy ...................................................................135 
10.3.2 
Analysis of the primary efficacy variable .......................................137 
10.3.2.1 
Hypotheses ........................................................................... 137 
10.3.2.2 
Primary statistical analysis ................................................... 137 
10.3.2.3 
Handling of missing data ...................................................... 137 

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10.3.2.4 
Sensitivity analyses for missing data .................................... 137 
10.3.2.5 
Supportive analyses .............................................................. 138 
10.3.2.6 
Subgroup analyses ................................................................ 139 
10.3.3 
Analysis of the secondary efficacy variables ..................................139 
10.3.3.1 
Response at Month 6 based on SRI-4 .................................. 139 
10.3.3.2 
Response at Month 6 based on BILAG-2004 ...................... 140 
10.3.4 
Analysis of other efficacy variables ................................................140 
10.3.5 
Analysis of the safety variables ......................................................140 
10.3.5.1 
Adverse events ..................................................................... 140 
10.3.5.2 
Vital signs ............................................................................. 140 
10.3.5.3 
Electrocardiography ............................................................. 141 
10.3.5.4 
Laboratory data ..................................................................... 141 
10.3.6 
Analysis of other variables .............................................................141 
10.4 
Study analyses ............................................................................................141 
10.4.1 
Month-6 analysis .............................................................................141 
10.4.2 
Month-12 analysis ...........................................................................142 
10.4.3 
Final EOS analysis ..........................................................................142 
10.5 
Sample size .................................................................................................142 
11 DATA HANDLING ..................................................................................................143 
11.1 
Data collection ............................................................................................143 
11.2 
Maintenance of data confidentiality ...........................................................144 
11.3 
Database management and quality control .................................................144 
12 PROCEDURES AND GOOD CLINICAL PRACTICE ...........................................145 
12.1 
Ethics and Good Clinical Practice ..............................................................145 
12.2 
Independent Ethics Committee / Institutional Review Board ....................145 
12.3 
Informed consent ........................................................................................145 
12.4 
Compensation to subjects and investigators ...............................................146 
12.5 
Protocol adherence/compliance ..................................................................146 
12.6 
Protocol amendments .................................................................................147 
12.7 
Essential documents and retention of documents .......................................147 
12.8 
Monitoring ..................................................................................................148 
12.9 
Investigator Site File ...................................................................................149 
12.10 
Audit ...........................................................................................................149 
12.11 
Inspections ..................................................................................................150 
12.12 
Reporting of study results and publication .................................................150 
13 REFERENCES ..........................................................................................................151 

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Systemic lupus erythematosus 
Protocol ID-064A202 
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14 APPENDICES ...........................................................................................................158 
 
LIST OF TABLES  
Table 1 
AC-064A201: Lymphocyte count in peripheral blood (109/L) 
at baseline, EOT, and change from baseline to EOT (modified 
pharmacodynamic set), results from Part A, Part B and Part A 
and B combined placebo ........................................................................... 54 
Table 2 
Guidelines for FEV1 decrease ................................................................... 83 
Table 3 
Algorithm for reducing dose of prednisone .............................................. 90 
Table 4 
Visit and assessment schedule................................................................. 101 
Table 5 
Relationship among laboratory tests for proteinuria ............................... 121 
Table 6 
Statistical assumptions for endpoints at Month 6 .................................... 142 
Table 7 
Effect of testing multiple null hypotheses on power ............................... 143 
LIST OF FIGURES 
Figure 1 
Study design ID-064A202 ......................................................................... 58 
Figure 2 
Guidance for monitoring total lymphocyte count ..................................... 83 
Figure 3 
Guidance for monitoring liver test abnormalities ..................................... 85 
Figure 4 
Control of Type I error rate within each endpoint and treatment 
group ........................................................................................................ 136 
 
LIST OF APPENDICES 
Appendix 1 
Corticosteroid conversion table ............................................................... 158 
Appendix 2 
American College of Rheumatology (ACR) Criteria for SLE ................ 159 
Appendix 3 
Forbidden anti-arrhythmic or heart rate lowering medications ............... 161 
Appendix 4 
Forbidden medications with risk of torsade de pointes ........................... 162 
Appendix 5 
Adverse events of special interest ........................................................... 163 
Appendix 6 
Criteria for discharge from monitored setting on Day 1 and on 
the first day of re-initiation following treatment interruptions ............... 164 
Appendix 7 
Notable abnormalities for ECG, BP and laboratory variables ................ 165 
Appendix 8 
American College of Cardiology / American Heart Association 
/ American College of Physicians Training Requirements for 
Performance and Interpretation of Adult Transthoracic 
Echocardiography .................................................................................... 169 
Appendix 9 
SLEDAI-2K: Data Collection Sheet ....................................................... 170 
Appendix 10 Physician’s Global Assessment Visual Analog Scale ............................. 172 
Appendix 11 BILAG-2004 INDEX .............................................................................. 173 

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Appendix 12 SLE Flare Index ...................................................................................... 174 
Appendix 13 SF-36v2™ ................................................................................................ 175 
Appendix 14 FACIT-Fatigue Scale .............................................................................. 181 
Appendix 15 Lupus Quality of Life .............................................................................. 182 
Appendix 16 Patient Global Impression of Severity – Fatigue .................................... 184 
Appendix 17 Patient Global Impression of Change – Fatigue ...................................... 185 
Appendix 18 Premature study treatment discontinuation examples ............................. 186 
 
 
 

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LIST OF ABBREVIATIONS AND ACRONYMS 
ACR  
American College of Rheumatology 
AE  
Adverse event 
AESI  
Adverse event of special interest 
ALT  
Alanine aminotransferase 
ANA  
Anti-nuclear antibodies 
anti-dsDNA  
Anti-double-stranded deoxyribonucleic acid 
anti-Sm  
Anti-Smith 
AST  
Aspartate aminotransferase 
AUC  
Area under the plasma concentration-time curve 
AUC0-24  
Area under the plasma concentration-time curve from 0 to 
24 hours 
AV  
Atrioventricular 
BILAG-2004  
British Isles Lupus Assessment Group-2004 
BP  
Blood pressure 
bpm  
Beats per minute 
CFR  
Code of Federal Regulations (US) 
CI  
Confidence interval 
Cmax  
Maximum observed plasma concentration 
CNS  
Central nervous system 
COVID-19  
Coronavirus disease 2019 
CR  
Copy reference 
CRA  
Clinical Research Associate 
CRO  
Contract Research Organization 
cSFI  
Classic Safety of Estrogens in Lupus Erythematosus National 
Assessment (SELENA)-SLEDAI flare index 
CSR  
Clinical study report 
CTCAE  
Common Terminology Criteria for Adverse Events 
Ctrough  
Trough plasma concentration 

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CTT  
Clinical Trial Team 
CVA  
Cerebrovascular accident 
CXCL10  
C-X-C motif chemokine 10 
CYP  
Cytochrome protein 
DBP  
Diastolic blood pressure 
DDI  
Drug-drug interaction 
ECG  
Electrocardiogram 
eCRF  
Electronic Case Report Form 
ECS  
Echocardiography set 
EDTA  
Ethylenediaminetetraacetic acid 
EMA  
European Medicines Agency 
EOS  
End-of-Study 
EOT  
End-of-Treatment 
EU  
European Union 
FACIT  
Functional Assessment of Chronic Illness Therapy 
FAS  
Full analysis set 
FDA  
Food and Drug Administration (US) 
FEV1  
Forced expiratory volume in 1 second 
FU  
Follow-up 
FVC  
Forced vital capacity 
GCP  
Good Clinical Practice 
GGT  
Gamma glutamyl transferase 
HIV  
Human immunodeficiency virus 
HR  
Heart rate 
i.v.  
Intravenous(ly) 
IB  
Investigator’s Brochure 
ICF  
Informed consent form 
ICH  
International Council for Harmonisation 

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IDMC  
Independent Data Monitoring Committee 
IEC  
Independent Ethics Committee 
IFN  
Interferon 
Ig  
Immunoglobulin 
INR  
International normalized ratio 
IRB  
Institutional Review Board 
IRT  
Interactive Response Technology 
ISAC  
Independent Statistical Analysis Center 
ISF  
Investigator Site File 
J2R  
Jump to Reference 
LSM  
Least Squares Mean 
LT  
Liver test 
MAD  
Multiple-ascending dose 
MAR  
Missing at random 
MedDRA  
Medical Dictionary for Regulatory Activities 
MMRM  
Mixed model for repeated measures 
MNAR  
Missing not at random 
MoA  
Mode of action 
mSLEDAI-2K  
Modified Systemic Lupus Erythematosus Disease Activity 
Index-2000 
NSAID  
Non-steroidal anti-inflammatory drug 
NYHA  
New York Heart Association 
o.d.  
Once daily 
OCS  
Oral corticosteroids 
OCT  
Optical coherence tomography 
PD  
Pharmacodynamic(s) 
pEOT  
Premature discontinuation of study treatment or premature 
End-of-Treatment 
PFT  
Pulmonary function test 

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PGA  
Physician’s Global Assessment 
PGIC-F  
Patient Global Impression of Change – Fatigue 
PGIS-F  
Patient Global Impression of Severity – Fatigue 
PK  
Pharmacokinetic(s) 
PKS  
Pharmacokinetic analysis set 
PPS  
Per-protocol set 
PRO  
Patient Reported Outcome 
QoL  
Quality of Life 
QS  
Quality System 
QTcB  
QT corrected for heart rate using Bazett’s formula 
QTcF  
QT corrected for heart rate using Fridericia’s formula 
RBC  
Red blood cells 
RSI  
Reference Safety Information 
s.c.  
Subcutaneous(ly) 
S1P  
Sphingosine-1-phosphate 
S1P1  
Sphingosine-1-phosphate receptor 1 
SAE  
Serious adverse event 
SAF  
Safety analysis set 
SAP  
Statistical analysis plan 
SBP  
Systolic blood pressure 
SCR  
Screened analysis set 
SF-36v2™  
36-Item Short Form Health Survey version 2 
SFI  
SLE Flare Index 
SIV  
Site initiation visit 
SLE  
Systemic lupus erythematosus  
SLEDAI-2K  
Systemic Lupus Erythematosus Disease Activity Index-2000 
SOC  
System Organ Class 
SOP  
Standard Operating Procedure 

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SRBC  
Sheep red blood cell 
SRI  
Systemic Lupus Erythematosus Responder Index  
SUSAR  
Suspected unexpected serious adverse reaction 
t½  
Apparent terminal elimination half-life 
TB  
Tuberculosis 
TBIL  
Total bilirubin 
TEAE  
Treatment-emergent adverse event 
TP1  
Treatment Period 1 
TP2  
Treatment Period 2 
ULN  
Upper limit of normal 
USPI  
United States Prescribing Information 
WBC  
White blood cell 
WOCBP  
Women of childbearing potential 
 
 

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NON-SUBSTANTIAL GLOBAL AMENDMENT 4 
Amendment rationale 
The rationale of this amendment applies to the global protocol ID-064A202 Version 4 
dated 2 December 2020. The resulting amended global protocol is Version 5 dated 
4 February 2022. 
The main reasons for this amendment consist of the following:  
A) Month-12 analysis: 
The cut-off for the protocol planned ‘Month-12 analysis’ has been updated to allow an 
early readout of the efficacy and safety data. The Month-12 analysis readout will 
supplement the 6-month primary analysis to support the start of the upcoming Phase 3. The 
analysis will be performed when all randomized subjects have completed Treatment 
Period 2 (TP2) or discontinued the study. The Month-12 analysis will take place before the 
completion of the safety follow-up period by all subjects and final End-of-Study (EOS) 
analysis. 
After the Month-6 and the Month-12 analyses, the study will remain double-blinded. 
Investigators, site staff, subjects, and the sponsor staff responsible for the study conduct 
(with appropriate firewalls) will remain blinded to study treatment allocation until study 
closure.  
The final EOS analysis will be performed as initially planned, when all randomized 
subjects have completed the posttreatment follow-up period or discontinued the study.  
B) Extension of the follow-up period and the period that the use of highly effective 
contraception in women of childbearing potential (WOCBP) is required: 
The follow-up period during which the use of highly effective contraception in WOCBP is 
required has been extended from 4 to 6 months after EOS treatment (End‑of‑Treatment 
[EOT]) or after permanent study treatment discontinuation based on data from the Phase 1 
study ID-064-105. 
Recently available pharmacokinetic (PK) data from the clinically completed Phase 1 study 
ID-064-105 has shown that the geometric mean apparent terminal elimination half-life (t½) 
of cenerimod was approximately 33 days as compared to 22 days prior observed in the 
multiple-ascending-dose (MAD) study. This may be related to the longer sampling period 
for PK assessment after stopping treatment with cenerimod in study ID-064-105 (120 days) 
compared to the MAD study (60 days). 
A period of 5 half-lives after EOT or after permanent study treatment discontinuation is 
considered adequate to monitor adverse events (AEs), serious AEs (SAEs) as well as to 
define the period where the use of highly effective contraception in WOCBP is required. 

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This measure is in line with the recommendations of the Clinical Trial Facilitation Group 
to use highly effective methods of contraception until the end of relevant systemic exposure 
for teratogenic compounds. 
Thus, the follow-up period in the CARE study is extended by 2 months with 2 follow-up 
(FU) phone call visits (FU3a and FU3b) to be performed 4 and 5 months after EOT. The 
EOS visit should occur 6 months after the EOT or permanent treatment discontinuation. 
Furthermore, a summary of the PK results of the recently clinically completed ID-064-105 
has been added to the background information. 
In addition to this protocol and its amendments, a separate addendum to the protocol is in 
place to cover exceptional measures to ensure subject safety in the context of the 
coronavirus disease 2019 (COVID‑19) pandemic and counteract any trial conduct 
disruption that may occur. The addendum (Version 2 dated from 27 May 2020) applies to 
those sites affected by the COVID-19 outbreak and is limited to the time during which such 
sites are affected.  
Amendment protocol sections 
2 versions of the amended protocol will be prepared: 1) a clean version, and 2) a 
comparison document showing deletions and insertions in comparison to the previous 
protocol version. 
The main sections of the protocol affected by this global amendment are listed below. 
Where applicable, the same changes have also been made to the corresponding sections of 
the protocol synopsis: 
 
Sections 
Change 
1.4.2 
Updates of t½. 
3.1 
Description of Month-12 analysis and final EOS analysis. 
Extension of the follow-up period to 6 months. 
3.1, 5.1.3.1 
Blinding management after the Month-12 analysis was added. 
4 
Extension of the contraception post study drug discontinuation 
from 4 months to 6 months 

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7 
Update of the follow-up period to 6 months:  
• Addition of 2 FU visits (phone calls) at 4 months and 
5 months after EOT.  
• EOS visit performed 6 months after last study treatment 
intake. 
5.1, 6.3, 8.1, 8.4, 9 
Update of study completion according to the extension of the 
follow-up period to 6 months. 
10.4 
Details on Month-12 and final EOS analyses added. 
 
Furthermore, minor editorial changes have been made to improve clarity, and 
typographical errors have been corrected in other sections of the protocol.  
Summary of previous amendments 
Amendments Date 
Change/Rationale (covered in this amendment) 
3 
2 December 2020 Substantial global amendment: 
• Due to the slower than anticipated enrollment and 
the unpredictable future impact of the COVID-19 
pandemic, the sponsor has decided to reduce the 
sample size of the study from 500 to 
approximately 325 randomized subjects. With 
this sample size of approximately 65 subjects per 
treatment group (instead of the initially planned 
100 subjects per group), the study will retain 
adequate power for the analysis of the primary 
endpoint and will provide evidence of efficacy 
and safety to design the Phase 3 program. 
• Study treatment will be extended to 12 months for 
all randomized subjects in order to generate 
additional safety and efficacy data over time. 
Therefore, all subjects who complete Treatment 
Period 1 (TP1) will enter and complete TP2 for an 
additional 6 months. The study will end when all 
subjects 
have 
completed 
TP2 
and 
the 
posttreatment follow-up period.  
The study objectives remained unchanged. The 
primary analysis is the Month-6 analysis; it will 

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Amendments Date 
Change/Rationale (covered in this amendment) 
be performed when all randomized subjects have 
completed TP1 or discontinued the study. 
2 
3 March 2020 
Substantial global amendment: 
• Revision of the specific stopping criteria and 
discharge criteria on Day 1 / re‑initiation for 
systolic blood pressure to account for eligible 
subjects with historical and baseline pre-dose 
systolic blood pressure values < 90 mmHg. 
• Introduction of the re-screening procedure for 
subjects who failed screening due to a transient 
non-eligibility reason, to mitigate the screening 
failure rate. 
• Other modifications were made to improve 
consistency and accuracy of the protocol. 
1 
31 July 2019 
Substantial global amendment: 
• Addition of Functional Assessment of Chronic 
Illness Therapy (FACIT)-Fatigue questionnaire at 
Month 3 to allow for an earlier assessment of 
fatigue. 
• Inclusion of anchor patient global assessment 
questions for FACIT-Fatigue (Patient Global 
Impression of Severity – Fatigue [PGIS-F] and 
Patient Global Impression of Change – Fatigue 
[PGIC-F]), to inform definition of responders and 
clinical meaningfulness of difference between 
groups. 
• Other modifications were made to improve 
consistency, accuracy, clarity and readability of 
the protocol, including the changes covered by 
the non‑substantial local amendment below. 

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Amendments Date 
Change/Rationale (covered in this amendment) 
1.USA.A 
3 April 2019 
Non-substantial local amendment: 
• Belimumab information on the s.c. dosage was 
missing. Clarification was provided to account for 
the intravenous and s.c. dosage.  
• Additional information on allowed concomitant 
therapy was provided regarding the use of topical 
ocular treatment administration during the course 
of the study.  
• Clarification 
on 
premature 
discontinuation: 
footnote 14 of Table 4 was modified to ensure full 
alignment with the protocol text.  
 
 
 

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PROTOCOL SYNOPSIS ID-064A202 
TITLE 
A Phase 2b, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study to evaluate the 
efficacy, safety, and tolerability of cenerimod in subjects with 
moderate to severe systemic lupus erythematosus (SLE). 
ACRONYM 
CARE: Cenerimod Assessing S1P1 Receptor modulation in 
Systemic Lupus Erythematosus 
OBJECTIVES 
The primary objective is to assess the efficacy of 6 months’ 
cenerimod treatment given at 4 different dose levels (0.5, 1, 
2, and 4 mg once daily [o.d.]) on disease activity in adult 
subjects with moderate to severe SLE concurrently receiving 
background therapy. 
The secondary objectives of the study are to evaluate the 
following over 6 months in adult subjects with moderate to 
severe SLE concurrently receiving background therapy: 
• The safety and tolerability of cenerimod treatment. 
• The effect of cenerimod treatment on quality of life and 
fatigue using relevant Patient Reported Outcome (PRO) 
instruments. 
• The effect of cenerimod treatment on SLE biomarkers. 
DESIGN 
This is a Phase 2b, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study in adult subjects 
with moderate to severe SLE.  
Approximately 325 adult subjects with SLE will be 
randomized in a 1:1:1:1:1 ratio to placebo, 0.5, 1, 2, or 4 mg 
o.d. of cenerimod, in addition to background SLE therapy.  
Once randomized, all subjects will enter a 6-month 
double-blind study treatment period called Treatment 
Period 1 (TP1). 
Subjects randomized to, and still receiving placebo, 0.5, 1, or 
2 mg at Month 6 will be assigned to the same treatment arm 
for an additional 6 months in Treatment Period 2 (TP2), i.e., 
for a total maximum of 12 months. 

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Subjects randomized to the 4 mg arm will receive study 
treatment at this dose for a maximum of 6 months in TP1. 
Afterwards, subjects in this group still receiving this dose at 
Month 6 will be re-randomized in a 1:1 ratio to placebo or 
cenerimod 2 mg to enter TP2 and will continue for a total 
maximum of 12 months.  
Treatment allocation is stratified by dose of oral 
corticosteroids (OCS) at Randomization (OCS with two 
strata: 
< 7.5 mg/day 
or 
≥ 7.5 mg/day 
prednisone 
or 
equivalent), and by disease activity at Screening (with two 
strata: modified Systemic Lupus Erythematosus Disease 
Activity Index-2000 [mSLEDAI-2K] < 10 or ≥ 10). 
There will be three study analyses: the Month-6 analysis, the 
Month-12 analysis, and the final EOS (End-of‑Study) 
analysis [see Section 10.4].  
Month-6 analysis will be performed when all randomized 
subjects have completed TP1 or discontinued the study. 
Month-12 analysis will be performed when all randomized 
subjects have completed TP2 or discontinued the study. Final 
EOS analysis will be performed when all randomized subjects 
have completed the posttreatment follow-up or discontinued 
the study. 
After Month-6 and Month-12 analyses, ongoing subjects will 
continue to be treated and followed up in a double-blinded 
manner up to their EOS visit. Investigators, site staff, 
subjects, and the sponsor staff responsible for the study 
conduct (with appropriate firewalls) will remain blinded to 
study treatment allocation until study closure. To maintain the 
blinding of the study up to final EOS analysis, appropriate 
measures will be put in place to ensure the good conduct of 
this process.  

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Study periods 
The study comprises the following periods:  
Screening period and OCS optimization period for 
subjects receiving OCS 
The screening period starts with the signing of the informed 
consent form (ICF) and ends on the day of Randomization, 
before the first study drug intake. This period can last up to 
60 days. During this period, the subject’s SLE background 
medication should be maintained stable except for OCS 
which should be tapered to the minimum required dose and 
maintained stable for at least 15 days prior to Randomization 
[see Section 5.2.2.1].  
Treatment period  
This period comprises 2 periods – TP1 and TP2.  
TP1 lasts 6 months. It starts with the administration of the first 
dose of study treatment, after subject randomization, and ends 
at the Month 6 visit.  
Starting at the Month 6 visit, TP2 lasts 6 months and ends at 
the Month 12 visit.  
All randomized subjects in the study will have to complete 
TP1 before continuing in TP2. 
Follow-up period 
This period starts after the End-of-Treatment (EOT) and lasts 
6 months until the EOS. For the first 5 months after the EOT 
visit, subjects will have to conduct monthly follow-up (FU) 
visits, FU1, FU2, FU3, FU3a, and FU3b to collect 
information on adverse events (AEs) and serious AEs (SAEs) 
and/or pregnancy as well as efficacy data. The EOS visit 
should occur 6 months after the EOT.  
NUMBER OF SUBJECTS 
Approximately 325 subjects diagnosed with SLE will be 
randomized.  
PLANNED DURATION 
Approximately 44 months from First Patient First Visit to 
Last Patient Last Visit. 

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SITES / COUNTRIES 
Approximately 180 sites from 21 countries notably from the 
regions of Asia Pacific, Eastern Europe, Latin America, North 
America, and Western Europe. 
INCLUSION CRITERIA 
Screening criteria: 
1. Signed ICF prior to any study-mandated procedure. 
2. Diagnosis of SLE made at least 6 months prior to 
Screening, by fulfilling at least 4 of the 11 criteria for SLE 
as defined by the American College of Rheumatology 
(ACR) criteria [Appendix 2].  
3. Male and female subjects, age 18 to 75 years old (both 
inclusive).  
4. A mSLEDAI-2K score ≥ 6 of at least 2 points for 
musculoskeletal 
or 
mucocutaneous 
manifestations 
(i.e., myositis, arthritis, rash, alopecia, mucosal ulcers). 
Note: The mSLEDAI-2K score does not take into account 
“leukopenia”. 
5. History or presence of positive anti-nuclear antibodies 
(ANA) or anti-double-stranded deoxyribonucleic acid 
(anti-dsDNA) antibodies.  
6. Currently treated with stable doses of one or more of the 
following background medications: 
• Non-steroidal anti-inflammatory drugs (NSAIDs), 
• Anti-malarials (≤ 400 mg/day hydroxychloroquine, 
≤ 500 mg/day chloroquine, ≤ 100 mg/day quinacrine), 
• Mycophenolate mofetil (≤ 2 g/day), 
• Mycophenolic acid (≤ 1440 mg/day), 
• Azathioprine (≤ 2 mg/kg/day), 
• Methotrexate (≤ 20 mg/week), 
• Corticosteroids 
(≤ 40 mg/day 
prednisone 
or 
equivalent), 
• Belimumab (≤ 10 mg/kg every 4 weeks intravenously 
[i.v.], or 200 mg/week subcutaneously [s.c.]).  
7. Women of childbearing potential (WOCBP): 

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• Must have a negative serum pregnancy test at 
Screening. 
• Must agree to undertake monthly urine pregnancy tests 
during the study. 
• Must use highly effective methods of contraception 
from the Screening visit until 6 months after taking the 
last dose of study treatment as described in 
Section 4.4.2. 
Randomization criteria:  
8. A clinical mSLEDAI-2K score ≥ 4. 
Note: The clinical mSLEDAI-2K is the mSLEDAI-2K 
assessment score without the inclusion of points 
attributable to hematuria, proteinuria, pyuria, low 
complement, 
increased 
DNA 
binding 
and 
thrombocytopenia. 
9. Presence of at least one of the following autoantibodies 
measured by central laboratory defined as follows (based 
on the screening sample): (a) positive ANA test measured 
by immunofluorescence assay with titer ≥ 1:80; or (b) 
positive anti-dsDNA antibodies with titer ≥ 30 IU/mL.  
10. On a stable dose of background SLE medication 
consisting of any of the following medications (alone or 
in combination) for a period of at least 30 days (15 days 
for corticosteroids) prior to Randomization: 
• NSAIDs, 
• Anti-malarials (≤ 400 mg/day hydroxychloroquine, 
≤ 500 mg/day chloroquine, ≤ 100 mg/day quinacrine), 
• Mycophenolate mofetil (≤ 2 g/day), 
• Mycophenolic acid (≤ 1440 mg/day), 
• Azathioprine (≤ 2 mg/kg/day), 
• Methotrexate (≤ 20 mg/week), 
• Corticosteroids 
(≤ 
40 
mg/day 
prednisone 
or 
equivalent) [see Section 5.2.2.1], 

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• Belimumab (≤ 10 mg/kg every 4 weeks i.v., or 
200 mg/week s.c.).  
11. WOCBP: 
• Must have a negative urine pregnancy test at 
Randomization visit. 
EXCLUSION CRITERIA 
Screening criteria 
Disease/condition 
1. Female subjects who are breastfeeding or planning to 
become pregnant during the study. 
2. Active 
lupus 
nephritis 
(defined 
by 
proteinuria 
> 1.5 g/24 h, 
or 
equivalent 
using 
spot 
urine 
protein-to-creatinine ratio: > 150 mg/mmol) or a renal 
biopsy 
demonstrating 
immune 
complex-mediated 
glomerulonephritis compatible with lupus nephritis 
within 90 days prior to Screening.  
3. Severe active central nervous system (CNS) lupus 
requiring therapeutic intervention (including aseptic 
meningitis, 
seizures, 
psychosis, 
cerebritis, 
cerebrovascular accident [CVA], organic brain syndrome, 
CNS vasculitis) and severe forms of vasculitis requiring 
systemic immunosuppressive treatment (including retinal 
vasculitis, coronary vasculitis, pulmonary vasculitis, 
mesenteric vasculitis) within 90 days prior to Screening. 
4. A diagnosis of mixed connective tissue disease or any 
history of overlap syndromes of SLE with rheumatoid 
arthritis, erosive arthritis, scleroderma or autoimmune 
hepatitis. 
5. History or presence of Mobitz type II or third-degree 
atrioventricular block, sick sinus syndrome, symptomatic 
bradycardia or syncope associated with cardiac disorders. 
6. Subjects who experienced myocardial infarction, unstable 
angina pectoris, stroke, transient ischemic attack, vascular 
thrombosis, decompensated heart failure requiring 
hospitalization, or heart failure defined by the New York 

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Heart Association (NYHA) Class III/IV within 6 months 
prior to Screening.  
7. An elevated QT corrected for heart rate (HR) using 
Fridericia’s formula (QTcF) interval of > 470 ms 
(females) / > 450 ms (males).  
8. History or presence of severe respiratory disease or 
pulmonary fibrosis, based on medical history, lung 
function and chest X-ray performed at Screening or within 
6 months prior to Screening or medically significant 
abnormal pulmonary function test: forced expiratory 
volume in 1 second (FEV1) or forced vital capacity (FVC) 
< 70% of predicted normal value or FEV1/FVC ratio 
< 0.7. 
9. History of clinically relevant bronchial asthma or chronic 
obstructive pulmonary disease that has required treatment 
with oral or parenteral corticosteroids for more than a total 
of 2 weeks within the last 6 months prior to Screening. 
10. Active or latent tuberculosis (TB), as assessed by chest 
X-ray performed at Screening or within 6 months prior to 
Screening, and interferon (IFN) gamma release assay 
(QuantiFERON-TB-Gold Plus®), except if there is 
documentation that the subject has completed adequate 
and successful treatment for TB previously. 
11. Ongoing bacterial, viral or fungal infection that is of 
clinical concern in the judgment of the investigator or 
history 
of 
any 
serious 
infection, 
defined 
as 
life-threatening 
or 
requiring 
i.v. 
antibiotics 
or 
hospitalization.  
12. Positive results for serological markers for hepatitis A, B, 
C and E indicating acute or chronic infection: 
− Anti-HAV IgM 
− HBsAg 
− Anti-HCV IgG or IgM 
− Anti-HEV IgG or IgM (if positive IgM and/or IgG, 
perform HEV-RNA PCR and if negative patient can 
be randomized). 

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13. Subjects who have congenital or acquired severe 
immunodeficiency or known HIV infection or positive 
HIV testing.  
14. Negative antibody test for varicella-zoster virus. 
Vaccination of antibody-negative subjects may be 
considered, which must occur at least 30 days prior to 
re-test and Randomization. 
15. History or presence of malignancy (except for surgically 
excised basal or squamous cell skin or mucosal lesions, 
including 
dysplasia 
and 
carcinoma 
in 
situ), 
lymphoproliferative disease, or history of total lymphoid 
irradiation. 
16. History or presence of bone marrow or solid organ 
transplantation. 
17. Presence of macular edema or active uveitis. 
18. Type 1 or 2 diabetes that is poorly controlled according to 
investigator judgment, or diabetes complicated with organ 
involvement such as diabetic nephropathy or retinopathy. 
19. History of chronic liver or biliary disease (other than 
Gilbert’s 
Syndrome) 
or 
subjects 
with 
alanine 
aminotransferase 
or 
aspartate 
aminotransferase 
> 2 × upper limit of normal (ULN) or total bilirubin 
> 1.5 × ULN (unless in the context of known Gilbert’s 
Syndrome).  
20. Significant hematology abnormality: lymphocyte count 
< 800 /μL (0.8 × 109/L); hemoglobin < 9 g/dL; white 
blood cell count < 2500/μL (2.5 × 109/L) or platelets 
< 75,000/μL (75 × 109/L). 
21. Estimated glomerular filtration rate 
< 60 mL/min/1.73 m2.  
22. History of clinically significant drug or alcohol abuse. 
23. Known allergy to 
sphingosine-1-phosphate (S1P) 
receptor modulators or any of the cenerimod formulation 
excipients. 

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24. Any other clinically relevant medical condition that 
would put the subject at risk if participating in the study, 
or any other diseases that may confound the disease 
activity assessments.  
Medications 
25. Treatment with the following medications within 15 days 
or 5 half-lives of the medication (whichever is longer) 
prior to Randomization: 
a. β-blockers, diltiazem, verapamil, digoxin, digitoxin, 
or any other anti-arrhythmic or HR-lowering systemic 
therapy [list of drugs provided in Appendix 3]. 
b. QT-prolonging drugs with known risk of torsade de 
pointes irrespective of indication [list of drugs 
provided in Appendix 4]. 
26. Treatment with the following medications within 30 days 
or 5 half-lives of the medication (whichever is longer) 
prior to Randomization:  
a. Cyclophosphamide, 
ciclosporine, 
tacrolimus, 
sirolimus. 
b. Pulse methylprednisone. 
c. Vaccination with live vaccines. 
27. Intra-articular, intramuscular or i.v. glucocorticosteroids 
within 6 weeks prior to Randomization. 
28. Treatment with the following medications within 90 days 
or 5 half-lives of the medication (whichever is longer) 
prior to Randomization:  
a. Leflunomide. 
b. i.v. immunoglobulins. 
29. Treatment with any investigational agent within 90 days 
or 5 half-lives of the drug (whichever is longer) prior to 
Randomization. 
30. Treatment with B cell-depleting biological agents such as 
rituximab or ocrelizumab within 12 months prior to 
Randomization. 

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31. Treatment with any of the following medications any time 
prior to Screening: 
a. Alemtuzumab,  
b. S1P receptor modulators (e.g., fingolimod). 
Randomization exclusion criteria  
32. Resting HR < 50 bpm as measured by the pre-dose 
12-lead ECG.  
33. An elevated QTcF interval of > 470 ms (females) / 
> 450 ms (males) as measured by the pre-dose 12-lead 
ECG on Day 1. 
34. Severe 
active 
CNS 
lupus 
requiring 
therapeutic 
intervention (including aseptic meningitis, psychosis, 
seizures, cerebritis, CVA, organic brain syndrome, CNS 
vasculitis) and severe forms of vasculitis requiring 
systemic immunosuppressive treatment (including retinal 
vasculitis, coronary vasculitis, pulmonary vasculitis, 
mesenteric vasculitis).  
35. Clinically 
relevant 
bronchial 
asthma 
or 
chronic 
obstructive pulmonary disease. 
STUDY TREATMENTS 
Investigational treatment 
Cenerimod is supplied as film-coated tablets at the doses of 
0.5, 1, 2, and 4 mg to be administered orally o.d.  
Placebo 
Placebo matching cenerimod film-coated tablets administered 
orally o.d. in the morning.  
CONCOMITANT 
THERAPY 
Background SLE therapy 
To be eligible for the study, subjects must currently receive at 
least one of the below SLE background medication:  
• NSAIDs 
− Aspirin (acetylsalicylic acid), 
− Ibuprofen, 
− Naproxen, 
− Celecoxib, 
− Others. 

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• Corticosteroids (≤ 40 mg/day prednisone or equivalent 
[see Appendix 1]) 
− Prednisolone, 
− Prednisone, 
− Methylprednisolone, 
− Dexamethasone, 
− Betamethasone, 
− Hydrocortisone, 
− Triamcinolone, 
− Cortisone. 
• Anti-malarials  
− Hydroxychloroquine (≤ 400 mg/day),  
− Chloroquine (≤ 500 mg/day), 
− Quinacrine (≤ 100 mg/day). 
• Mycophenolate mofetil (≤ 2 g/day) 
• Mycophenolic acid (≤ 1440 mg/day) 
• Azathioprine (≤ 2 mg/kg/day) 
• Methotrexate (≤ 20 mg/week) 
• Belimumab (≤ 10 mg/kg every 4 weeks i.v., or 
200 mg/week s.c.) 
Treatment with anti-malarials, mycophenolate mofetil, 
mycophenolic acid, azathioprine, methotrexate or belimumab 
must have been started at least 90 days prior to Screening. All 
other background SLE therapies must have been started at 
least 30 days prior to Screening.  
Background SLE therapy doses must be stable for at least 
30 days prior to Randomization. For corticosteroids, doses 
must be stable for at least 15 days prior to Randomization. 
Oral corticosteroids  
Screening period / oral corticosteroid optimization period 
for subjects receiving OCS 
For subjects who are being treated with corticosteroids prior 
to enrollment in this study, an optimization period aiming to 
reduce the doses of OCS to (or as close as possible to) the 

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minimum effective dose should be considered during the 
screening period. This will allow minimization of OCS 
changes during the treatment period, which is the preferred 
approach. Dose reductions are at the investigator’s discretion 
and can be done up to 15 days prior to Randomization when 
the OCS dose must be stable for eligibility criteria.  
Treatment Period 1 (from Randomization to Month 6) 
For subjects who are being treated with corticosteroids, it is 
preferable that doses are maintained stable until the end of 
Month 6 of the study to avoid introducing confounding 
factors for the interpretation of the primary objective. The 
dose adjustment recommended during Screening aims to 
minimize the change in OCS dose during the treatment 
period.  
For subjects showing improving SLE disease activity for at 
least 8 weeks, OCS dose reduction may be considered at the 
investigator’s discretion during the first 3 months of TP1 [see 
suggested guidance in Table 3]. No steroid sparing is allowed 
between Month 3 and Month 6 (i.e., between Visit 5 and 8). 
Rationale for dose change and details of the change should be 
documented in the electronic Case Report Form (eCRF).  
Subjects with increased SLE disease activity may receive one 
OCS burst during the first 3 months of TP1, which should be 
tapered to the Randomization dosage within 2 weeks of the 
start of the upgrade/initiation of the OCS. Alternatively, a 
single intramuscular or i.v. dose of methylprednisone (80 to 
160 mg or equivalent) is permitted instead of OCS burst. 
Rationale for dose change and details of the change should be 
documented in the eCRF. 
Treatment Period 2 (after Month 6 of treatment) 
After the first 6 months of study, OCS dose reduction may be 
considered for subjects showing improving SLE disease 
activity for at least 8 weeks. Investigators should consider the 
guidance provided in Table 3. This table reflects the ACR 
draft guidance regarding steroid reduction during periods of 
stable SLE disease [see Section 5.2.2.1]. 

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Subjects with increased SLE disease activity may receive an 
OCS burst after Month 6, which should be tapered to 
Randomization dosage within 2 weeks of the start of the 
upgrade/initiation of the OCS. Alternatively, a single 
intramuscular or i.v. dose of methylprednisone (80 to 160 mg 
or equivalent) is permitted instead of OCS burst.  
Allowed concomitant therapy 
After Randomization, background medications should be 
kept stable throughout the study. However, if clinically 
required, changes in certain medications as outlined below are 
allowed: 
• Stable chronic NSAID therapy: therapy is not to be started 
or stopped during the study.  
− Temporary use and/or dose change for treatment of 
non-SLE-related conditions (e.g., headache, 
menstrual cramps) is allowed.  
• Stable immunosuppressant therapy (i.e., methotrexate, 
azathioprine, or mycophenolate mofetil, mycophenolic 
acid as well as belimumab). Therapy is not to be started 
or stopped during the study, and the dose should be kept 
stable. 
• Atropine (i.v.) in the event of symptomatic bradycardia. 
• Topical ocular therapy (e.g., chronic treatment for 
glaucoma, ocular inflammation), including dilating eye 
drops, mydriatics, parasympathetic antagonists (e.g., 
tropicamide) 
or 
sympathetic 
agonists 
(e.g., 
phenylephrine). 
• Vaccination with non-live vaccines. 
• Topical treatment therapy including topical, inhaled, and 
nasal use of corticosteroid. 
• All other medications that are not forbidden. 
Forbidden concomitant therapy 
• Immunosuppressive agents not listed in allowed 
concomitant medication such as cyclophosphamide, 
ciclosporine, leflunomide, sirolimus, tacrolimus, etc.  

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• Immunosuppressive or immunomodulatory biological 
agents (e.g., i.v. immunoglobulin, rituximab, S1P receptor 
modulators other than cenerimod). 
• β-blockers, diltiazem, verapamil, digoxin, digitoxin, or 
any other anti-arrhythmic or HR-lowering therapy. 
• QT-prolonging drugs with known risk of torsade de 
pointes. 
• Vaccination with live vaccines. 
• Inhibitors of the breast cancer resistance protein 
transporter: 
curcumin, 
ciclosporine, 
eltrombopag, 
elacridar, gefitinib, teriflunomide. 
For further details, see table of forbidden medications in 
Appendix 3 and Appendix 4. 
ENDPOINTS 
Efficacy  
Primary endpoint 
• Change from baseline to Month 6 in the mSLEDAI-2K 
score. 
This endpoint is based on the SLE Disease Activity 
Index-2000 (SLEDAI-2K) index, modified to exclude 
leukopenia.  
The SLEDAI-2K will be assessed by the investigator or 
delegate who will enter the relevant data into the SLEDAI-2K 
form of the eCRF. Further details are available in 
Section 7.2.6.1. 
Baseline is defined as the last available measurement before 
the start of randomized treatment. All values of 
mSLEDAI-2K from baseline through Month 6 visits will be 
accounted for in the assessment of this endpoint. 
Secondary endpoints 
• Response on SLE Responder Index (SRI)-4 at Month 6 as 
compared to baseline, defined as follows: 
− Reduction from baseline of at least 4 points in the 
mSLEDAI-2K. 

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AND 
− No new British Isles Lupus Assessment Group 
(BILAG) A organ domain score and no more than one 
new BILAG B organ domain score compared with 
baseline. 
AND 
− No increase of more than 0.3 points on the Physician’s 
Global Assessment (PGA) since baseline. 
• Response (no worsening) at Month 6 on BILAG-2004 
disease activity index defined as no new BILAG A organ 
domain score and no more than one new BILAG B organ 
domain score compared with baseline. 
Other efficacy endpoints 
• Response at Month 6 based on improvement in the 
mSLEDAI-2K score defined as a reduction from baseline 
of at least 4 points.  
• Response (no worsening and improvement) at Month 6 on 
BILAG-2004 disease activity index defined as follows: 
− No new BILAG A organ domain score and no more 
than one new BILAG B organ domain score compared 
with baseline. 
AND 
− Any BILAG A organ domain score at study baseline 
improved to B/C/D or any BILAG B organ domain 
score at study baseline improved to C/D. 
• SRI-5, -6, -7, -8 responses at Month 6. 
• Occurrence of mild, moderate and severe flares for 
6 months [see SLE Flare Index in Appendix 12]. 
• Time to first severe flare from baseline to Month 6 (severe 
flares defined as BILAG-2004 A organ domain score 
presence due to items that are new or worse). 
• Time to first flare from baseline to Month 6. 
• Change from baseline to Month 6 in PGA score. 

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PRO / Quality of life endpoints 
• Change from baseline to each post-baseline assessment in 
Functional Assessment of Chronic Illness Therapy 
(FACIT)-Fatigue Scale score.  
• Change from baseline to each post-baseline assessment in 
Patient Global Impression of Severity – Fatigue (PGIS-F). 
• Patient Global Impression of Change – Fatigue (PGIC-F) 
score at each post-baseline assessment. 
• Change from baseline to each post-baseline assessment in 
36-Item 
Short 
Form 
Health 
Survey 
version 
2 
(SF-36v2™).  
• Change from baseline to each post-baseline assessment in 
the Lupus Quality of Life questionnaire.  
Exploratory endpoints  
See Section 6.1.5. 
Safety endpoints 
• Occurrence of treatment-emergent AEs/SAEs, and AEs of 
special interest [see Appendix 5]. 
• Occurrence of AEs leading to premature discontinuation 
of study treatment. 
• Changes in 12-lead ECG variables (HR, PR, QRS, QT, 
QT corrected for heart rate using Bazett’s formula [QTcB] 
and QTcF), from baseline to each post-baseline 
assessment up to EOS (i.e., each post-dose time point on 
Day 1 / Re-initiation and each post-dose analysis visit up 
to EOS) for each parameter. 
• Occurrence of treatment-emergent 12-lead ECG notable 
abnormalities (e.g., HR, PR, QTc) [see Appendix 7]. 
• Occurrence 
of 
treatment-emergent 
12-lead 
ECG 
abnormal findings. 
• Change in supine systolic blood pressure and diastolic 
blood pressure from baseline to each post-baseline 
assessment up to EOS (i.e., each post-dose time point on 
Day 1 / Re-initiation and each post-dose analysis visit up 
to EOS). 

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• Change in FEV1 and FVC from baseline to each 
post-baseline assessment up to EOS. 
• Occurrence of treatment-emergent decrease of FEV1 or 
FVC > 15% from baseline values at any post-baseline 
assessment. 
• Change in laboratory parameters (hematology, blood 
chemistry, and urinalysis) from baseline to each 
post-baseline assessment up to EOS. 
• Occurrence of treatment-emergent laboratory notable 
abnormalities [see Appendix 7]. 
• Change in body weight from baseline up to EOS. 
• Change in left ventricular ejection fraction as assessed by 
Standard 2D echocardiography from Screening to 
Month 6 
in 
subjects 
randomized 
to 
ancillary 
echocardiography study.  
• Occurrence of clinically relevant abnormalities as 
assessed by Standard 2D/Doppler echocardiography from 
Screening to Month 6 in subjects randomized to ancillary 
echocardiography study. 
Pharmacokinetic endpoints 
• Cenerimod plasma concentrations post-dose on Day 1, 6 h 
after dosing.  
• Ctrough cenerimod plasma concentrations prior to dosing at 
Months 1, 2, 3, and 6 or at EOT visit after premature study 
treatment discontinuation (if applicable). 
• Cenerimod plasma concentration at the EOS visit 
(i.e., 6 months after last dose of study treatment). 
Biomarker endpoints 
• Change from baseline to each post-baseline assessment up 
to EOS in total lymphocyte count. 
• Change from baseline to each post-baseline assessment in 
the following biomarkers: ANA, anti-dsDNA, anti-Smith, 
and C3, C4 complement. 
ASSESSMENTS 
Refer to the schedule of assessments in Table 4. 

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STATISTICAL 
METHODOLOGY 
Analysis sets 
Screened Analysis Set 
The Screened analysis set (SCR) includes all subjects who 
entered Screening and have a subject identification number. 
Full Analysis Set 
The Full analysis set (FAS) includes all subjects who have 
been assigned (i.e., randomized) to double-blind study 
treatment at the start of TP1. Subjects will be analyzed based 
on their assigned study treatment. 
Full Analysis Set – TP2 
The Full analysis set TP2 (FAS-TP2) includes all subjects 
from the FAS who have been assigned (i.e., randomized) to 
double-blind study treatment at the start of TP2. Subjects will 
be analyzed based on their assigned study treatment. 
Per-Protocol Analysis Set 
The Per-protocol set (PPS) includes all subjects from the FAS 
without clinically important protocol deviations occurring 
during TP1 which could affect the analysis of the primary 
endpoint variable.  
The precise reasons for excluding subjects from the PPS will 
be fully defined and documented in the statistical analysis 
plan (SAP) before breaking the randomization blind. 
The PPS will only be defined for the period TP1. 
Safety Analysis Set 
The Safety analysis set (SAF) includes all subjects who 
received at least one dose of double-blind study treatment 
during TP1. Subjects will be analyzed based on the treatment 
received. 
Safety Analysis set – TP2 
The Safety analysis set TP2 (SAF-TP2) includes all subjects 
from the SAF who received at least one dose of double-blind 
study treatment during TP2. Subjects will be analyzed based 
on the treatment received. 

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Echocardiography Set 
The Echocardiography set (ECS) includes subjects who were 
assigned to the Echocardiography sub-study by Interactive 
Response Technology (IRT) with at least one post-baseline 
echocardiography assessment. Subjects will be analyzed 
based on the treatment received. 
Pharmacokinetic Analysis Set 
The Pharmacokinetic (PK) analysis set (PKS) includes all 
randomized subjects who received at least one cenerimod 
dose, had at least one blood sample for PK evaluation 
collected after cenerimod initiation, had evaluable plasma 
concentrations, and did not deviate from the protocol in a way 
that might affect the evaluation of the PK endpoint. Subjects 
will be analyzed based on actual dose taken, not the 
randomized dose. 
Usage of the analysis sets 
The analyses of efficacy endpoints including baseline and 
disease characteristics from TP1 will be performed using the 
FAS and the PPS for sensitivity analyses. FAS-TP2 will be 
used for specific analyses only including TP2 data. 
The FAS will be used for analyses which combine TP1 and 
TP2 data. 
The Safety Set will be used for the analysis of safety 
endpoints (including study treatment exposure) from TP1. 
SAF-TP2 will be used for specific analyses only including 
TP2 data. 
The Safety Set will be used for analyses which combine TP1 
and TP2 data. 
Subject data will be listed using the SCR, unless otherwise 
specified. 
Description of statistical analyses 
All available data for each subject will be used in all statistical 
analyses unless otherwise specified. 

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Overall testing strategy 
The Type I error rate will be controlled for the testing of 
multiple null hypotheses associated with the primary and 
secondary endpoints and the four dose levels included in this 
study: 0.5, 1, 2, and 4 mg. 
The four statistical null hypotheses associated with the 
primary efficacy endpoint are: 
Change of mSLEDAI-2K from Baseline to Month 6: 
H1mSLEDAI-2K: cenerimod0.5 mg – placebo = 0, 
H2 mSLEDAI-2K: cenerimod1.0 mg – placebo = 0, 
H3 mSLEDAI-2K: cenerimod2.0 mg – placebo = 0, 
H4 mSLEDAI-2K: cenerimod4.0 mg – placebo = 0. 
These hypotheses represent the difference in mean change 
from baseline to Month 6 in mSLEDAI-2K between the four 
doses of cenerimod and placebo. 
The eight statistical null hypotheses associated with the 
secondary efficacy endpoints are: 
SRI-4 
H1SRI-4: cenerimod0.5 mg / placebo = 1, 
H2SRI-4: cenerimod1.0 mg / placebo = 1, 
H3SRI-4: cenerimod2.0 mg / placebo = 1, 
H4SRI-4: cenerimod4.0 mg / placebo = 1, 
and BILAG 
H1BILAG: cenerimod0.5 mg / placebo = 1, 
H2BILAG: cenerimod1.0 mg / placebo = 1, 
H3BILAG: cenerimod2.0 mg / placebo = 1, 
H4BILAG: cenerimod4.0 mg / placebo = 1. 
These eight hypotheses represent the odds ratios of the 
secondary endpoints SRI-4 and BILAG-2004 between the 
four doses of cenerimod and placebo. 

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Each null hypothesis will be tested against the alternative 
hypothesis that a difference exists between cenerimod and 
placebo, at a given dose, in mSLEDAI-2K, SRI-4, and 
BILAG-2004. 
Within each primary and secondary endpoint analysis, the 
Hochberg procedure will be used to control the familywise 
error rate to ensure an overall two-sided Type I error rate of 
5% for the four treatment group comparisons vs placebo. 
Further control of the study-wise error rate is conducted such 
that, for a given hypothesis to be rejected at a two-sided 
Type I error rate of 5% the same dose-level hypothesis must 
have also been rejected for the previous endpoint(s), 
considering the above ordering of the endpoint hypotheses 
[see Figure 4]. 
Analysis of the primary efficacy variable 
The primary efficacy variable, based on the mSLEDAI-2K 
[Section 6.1.1], is continuous in definition such that higher 
scores indicate more severe SLE disease. 
Primary statistical analysis 
The primary statistical analysis will be performed on the FAS, 
according to the intent-to-treat approach. 
The null hypotheses for the primary endpoint will be tested 
using a mixed model for repeated measures on all available 
changes from baseline in mSLEDAI-2K for post-baseline 
scores from Months 1 to 6.  
The following terms will be included in the model: baseline 
mSLEDAI-2K score, treatment group, month, treatment 
group by month interaction, baseline mSLEDAI-2K score by 
month interaction, and the single stratification factor OCS 
(from IRT). The stratification factor mSLEDAI-2K (from 
IRT) will not be included in the model as the continuous 
baseline value is already included. An unstructured 
covariance matrix will be used to account for the correlation 
between repeated measurements from the same subject. 
The treatment effect for each cenerimod dose vs placebo will 
be estimated from the Least Squares Mean differences for 

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each dose vs placebo at Month 6 and their corresponding 95% 
confidence intervals (CIs).  
The hypothesis tests will be based on the associated p-values 
at the two-sided significance level of alpha of 5%, controlling 
for multiplicity using the Hochberg procedure as mentioned 
above. 
Analysis of the secondary efficacy variables 
Response at Month 6 based on SRI-4 
A repeated measurement generalized linear model will be 
fitted with the secondary endpoint SRI-4 as response (from 
Month 1 to Month 6). The model will include the treatment 
group, month, the treatment group by month interaction, and 
will be stratified by the OCS and mSLEDAI-2K stratification 
variables (from IRT).  
The odds ratios and corresponding 95% CI for each treatment 
group comparison vs placebo will be provided along with the 
p-values from the Wald test. 
Response at Month 6 based on BILAG-2004 
The analysis will be performed based on the same repeated 
measurement model as described above. 
Analysis of other efficacy variables 
The analyses of all other efficacy variables will be described 
in detail in the SAP. Other efficacy endpoints will be analyzed 
at each relevant time point as specified in Section 6.1.3.  
Analysis of the safety variables  
The Safety Set will be used to perform all safety analyses. 
Safety analysis may be split by treatment period 
[Section 10.3.5]. This will be further detailed in the SAP. 
If not otherwise stated, only treatment-emergent safety data 
will be considered in tables and figures. All safety data will 
be included in outputs, with flags for safety data not 
considered to be treatment-emergent.  

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STUDY COMMITTEES 
An Independent Data Monitoring Committee will be 
monitoring the benefit-risk ratio and making appropriate 
recommendations based on all the reported data and thus 
ensuring that the study is being conducted with the highest 
scientific and ethical standards.  
ECHOCARDIOGRAPHY 
ASSESSMENTS/ 
ANCILLARY STUDY 
Echocardiography assessments will be performed for all 
subjects within 30 days prior to Randomization. 
Echocardiography ancillary study 
An additional echocardiography assessment will be 
performed at Month 6 (or at premature EOT [pEOT] visit in 
the event of premature study treatment discontinuation during 
TP1) in approximately 175 subjects participating in the 
echocardiography sub-study.  
Standard 2D/Doppler echocardiography will assess cardiac 
morphology 
and 
function 
including 
regional 
wall 
abnormalities, aortic valve morphology and function, mitral 
valve morphology and function, and left ventricular ejection 
fraction. 
 
 

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PROTOCOL 
1 
BACKGROUND INFORMATION 
1.1 Systemic lupus erythematosus 
Systemic lupus erythematosus (SLE) is a complex and heterogeneous autoimmune disease 
of unknown etiology, characterized by the production of pathogenic autoantibodies, tissue 
deposition of immune complexes, and tissue damage across multiple organ systems. The 
adaptive T and B cells and the innate immune system are considered to play a major 
pathophysiological role in this disease as demonstrated by increased levels of circulating 
plasmablasts, infiltration of autoreactive CD4 and CD8 T cells, B cells, and innate immune 
cells into tissues, formation of tertiary lymphoid structures, and increased resistance to 
apoptosis [Carroll 2004, Foster 2007, Shah 2010]. 
SLE occurs primarily in young women with a peak incidence during the reproductive age 
years [Borchers 2010, Pons-Estel 2010, Pons-Estel 2017] and an estimated female to male 
ratio of 7:1 to 10:1 [Govoni 2006]. The disease is more prevalent in African-Americans 
than Caucasians (as per the National Women’s Information Center and the Department of 
Health and Human Services) and the estimated overall incidence rate for SLE varies from 
approximately 0.3–23.7 per 100,000 person-years whereas prevalence rates ranges from 
6.5–178 per 100,000 [Pons-Estel 2017]. In the United States, the prevalence of SLE is 
higher among Asians, African-Americans, African-Caribbeans, and Hispanic Americans 
compared to Caucasians [Pons-Estel 2010, Danchenko 2006, Rus 2002, Petri 2002]. In 
European countries, the prevalence of SLE is also higher among people of Asian and 
African descent [Pons-Estel 2010].  
With improved diagnosis and management, the life expectancy of SLE patients has 
improved from an approximate 4-year survival rate of 50% in the 1950s to a 15-year 
survival rate of 80% [Abu-Shakra 1995, Mok 2011, Pons-Estel 2010].  
Clinical manifestations of SLE include rash, arthritis, anemia, thrombocytopenia, serositis, 
nephritis, seizures, and psychosis among others [Rahman 2008]. 
The natural history of SLE is characterized by relapses or flares, alternated with periods of 
remission. It results in considerable morbidity due to flares of disease activity and 
accumulated organ damage, and an increased risk of premature death, mostly due to renal 
and cardiovascular disease, and infection [Pons-Estel 2010, Yurkovich 2014]. 
SLE patients’ quality of life is directly influenced by the symptoms they experience. 
Between 80 and 90% of patients with lupus report fatigue to be the most debilitating 
symptom of their disease with wide ranging effects on quality of life [Bakshi 2017]. Studies 
have shown that the disease can affect emotions, social well-being, family, employment 
and leisure activities, cognition, appearance, and independence. SLE patients have 

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consistently reported lower scores on quality of life measures (36-Item Short Form Health 
Survey version 2 [SF-36v2™]) compared to the general population [Gallop 2012, 
Kiani 2013]. 
The current treatment of SLE comprises non-steroidal anti-inflammatory drugs (NSAIDs), 
anti-malarials, corticosteroids, and immunosuppressive drugs, often prescribed in that 
order as the disease progresses [Xiong 2014]. Acetylsalicylic acid, hydroxychloroquine, 
and belimumab are the only FDA-approved treatments for SLE, whereas rituximab 
(anti-CD20 monoclonal antibody) and other immunosuppressive therapies are commonly 
used off-label [Xiong 2014]. 
• 
NSAIDs and anti-malarials are often insufficient to control the disease, and the 
escalation to long-term corticosteroid use and to more and more potent 
immunosuppressants is the norm rather than the exception. 
• 
Corticosteroids are commonly used in SLE and are a cornerstone of treatment, but 
have serious side effects associated with long-term use [Lateef 2012]. 
• 
Immunosuppressive drugs commonly used as SLE background therapy in the 
treatment of SLE include azathioprine, methotrexate, mycophenolate mofetil, and 
cyclophosphamide. Potential risks of use of these drugs include bone marrow 
suppression and increased risk of infections. 
• 
Belimumab, the most recently approved treatment for SLE, demonstrated treatment 
effect at 52 weeks but not at 76 weeks of treatment in its pivotal trials.  
1.2 Unmet needs in SLE 
Despite the significant improvements in diagnosing and managing the disease, treatment 
of SLE remains an area of significant unmet need. Except for belimumab, no new drug has 
received approval for treatment of SLE in the last 50 years. Therapies for SLE consist of 
relatively non-specific immunosuppressive and anti-inflammatory drugs of modest 
efficacy, and are associated with significant side effects.  
Accelerated atherosclerosis and cardiovascular disease represent a significant burden for 
patients with SLE that may be exacerbated by chronic use of corticoids. Effective and safe 
steroid-sparing therapies that can help to reduce toxicity from long-term use of high-dose 
glucocorticoids remain an unmet medical need. 
Fatigue is a very common symptom of SLE that negatively affects quality of life in the 
majority of SLE patients; none of the currently available treatments have shown significant 
effects on fatigue. Furthermore, the prevention of disease flares also represents a high 
medical need. 

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1.3 Sphingosine-1-phosphate  
Sphingosine-1-phosphate (S1P) plays a central role in lymphocyte trafficking 
[Cyster 2005, Brinkmann 2007, Brinkmann 2010, Schwab 2007]. S1P is synthesized and 
secreted by many cell types, including platelets, erythrocytes, and mast cells and elicits a 
variety of physiological responses [Cyster 2005, Alvarez 2007]. Among other effects, 
lymphocyte egress from primary and secondary lymphoid organs is dependent on the S1P 
receptor. S1P receptor modulators block lymphocyte migration out of lymphoid tissue into 
the lymphatic and vascular circulation, thereby preventing lymphocyte recruitment to sites 
of inflammation. Following withdrawal of an S1P receptor modulator, the functional 
lymphocytes return to the circulation from their sites of sequestration. First-line 
immunological protection by granulocytes and monocytes, and antigen-dependent T-cell 
activation and expansion are not affected by this mechanism [Pinschewer 2011]. 
S1P itself induces pleiotropic effects, which are mediated by a family of five G 
protein-coupled receptors, S1P1-S1P5, located on endothelial cells, vascular and cardiac 
smooth muscle cells, and cardiac myocytes [Alvarez 2007, Brinkmann 2007, 
Brinkmann 2010]. The first S1P receptor modulator, fingolimod (FTY720, Gilenya®), 
which has been approved by the FDA [Gilenya® USPI] and the EMA [Gilenya® SmPC] 
for the treatment of multiple sclerosis, is a non-selective S1P receptor modulator with 
activity on S1P1, S1P3, S1P4, and S1P5 [Brinkmann 2007, Brinkmann 2010]. 
1.4 Cenerimod (ACT-334441) 
Cenerimod is a potent, orally active, selective S1P1 receptor modulator that blocks the 
egress of lymphocytes from lymphoid organs and thus reduces the tissue availability of 
circulating lymphocytes (T and B cells). This pharmacodynamic (PD) effect is sustained 
with continued daily oral dosing but is reversible upon drug discontinuation.  
Cenerimod is being developed for the treatment of SLE. The compound was selected on 
the basis of its potential for once daily (o.d.) oral administration and its high selectivity for 
the S1P1 receptor.  
1.4.1 Nonclinical data 
The main findings in the nonclinical studies conducted on cenerimod were: 
• Cenerimod dose-dependently reduced lymphocyte counts in peripheral blood of rats and 
dogs after oral administration, reaching maximal effect at single doses ≥ 3 mg/kg in both 
species. 
• Cenerimod had only a modest effect on antibody response to sheep red blood cell 
(SRBC) immunization in rats with a small effect on SRBC-specific IgM antibody 
production and no evident effect on IgG antibodies. 

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• Cenerimod is a lipophilic, highly plasma protein-bound compound and has a low 
clearance in rats and dogs. 
• Bioavailability increased from 8 to 23% over a dose range of 0.1–40 mg/kg in the dog 
and from 9.7 to 23% at 0.3 and 3 mg/kg in the rat. 
• Cenerimod is a moderate inhibitor of cytochrome protein (CYP)2C9 and CYP2C19, 
with inhibition constants of 18 μM and 15 μM, respectively. Cenerimod is neither an 
activator of human pregnane X receptor nor an inducer of CYP3A4 messenger 
ribonucleic acid or enzyme expression in human hepatocytes. 
• Considering the low cenerimod doses and the high degree of binding to plasma proteins, 
it is expected that cenerimod has a limited potential for pharmacokinetic (PK) drug-drug 
interactions (DDIs) with concomitant medications whose PK are dependent on CYP 
clearance. 
• Cenerimod induced lung findings in rats and dogs. The findings were related to S1P1 
modulators increasing pulmonary vascular permeability and consisted of increased lung 
weights, perivascular edema (both species, up to 4 weeks of treatment), and an increased 
incidence in alveolar histiocytosis (both species). In general, the findings appeared less 
pronounced after sub-chronic to chronic treatment and were not associated with clinical 
signs indicative of respiratory dysfunction. 
• Coronary arterial lesions were observed in papillary muscles of the left ventricle in the 
dog after 4 weeks of treatment at 30 mg/kg/day and after 13 and 39 weeks at 
≥ 10 mg/kg/day. The coronary arterial lesions were not observed in other species (rat) 
during nonclinical studies with cenerimod, and are considered to be an expression of 
dog-specific sensitivity to hemodynamic changes, with limited human relevance. 
• Embryo-fetal toxicity studies in rats and rabbits showed that cenerimod is embryotoxic 
and teratogenic but not genotoxic nor mutagenic. 
• Cenerimod did not affect fertility in rats.  
• Safety margins were considered appropriate to support clinical trials up to 4 mg. For 
more details, see section 4.3.9 of the Investigator’s Brochure (IB) [Cenerimod IB].  
More detailed information on the data collected thus far on cenerimod can be found in the 
IB [Cenerimod IB]. The sponsor will notify the principal investigator of important 
nonclinical safety data that may become available during the study. 
1.4.2 Clinical studies in humans 
The human clinical experience with cenerimod includes four completed Phase 1 studies in 
healthy subjects (AC-064-101, AC-064-102, AC-064-103 and ID-064-104), one clinically 
completed Phase 1 study (ID-064-105) and one Phase 2 study in SLE subjects 

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(AC-064A201) [Hermann 2019]. The main findings of the studies are summarized below. 
More detailed information can be found in the IB [Cenerimod IB]. 
1.4.2.1 Phase 1 study in healthy subjects: results 
Clinical pharmacokinetics 
Following administration of single doses to male healthy subjects, the PK profile of 
cenerimod was characterized by low inter-subject variability (coefficient of variation 
< 30% for area under the plasma concentration-time curve [AUC], maximum observed 
plasma concentration [Cmax], and apparent terminal elimination half-life [t½]). Cmax was 
achieved within 5–6 h after dosing and t½ was between 170–199 h (~7–9 days). 
Following administration of multiple o.d. doses, steady-state conditions were attained 
between 20–32 days of treatment. The t½ after the last administration was between  
12–22 days with 60 days sampling period for PK assessment after stopping treatment with 
cenerimod and approximately 33 days with 120 days sampling period for PK assessment 
after stopping treatment [see Cenerimod IB for further details]. Cenerimod accumulated in 
plasma, with 5- to 9-fold higher Cmax and AUC from 0 to 24 hours (AUC0‑24) at steady state 
when compared to the first day of treatment. Cmax and AUC0-24 were shown to be dose 
proportional across the 0.5–4 mg dose range. 
The effect of food on the PK of a single 1 mg dose was investigated in study AC-064-101. 
No relevant effect of food on the PK parameters of cenerimod was observed. 
Only limited clinical data is currently available regarding the metabolism of cenerimod. 
No information is available regarding the effects of disease (e.g., renal or hepatic 
impairment), age, or ethnicity on the PK of cenerimod. Only limited data is available on 
the effects of sex on the PK of cenerimod (examination of the data from the 2 female 
subjects who received cenerimod suggest that the PK profile is not influenced by sex). 
Pharmacodynamics in humans 
Oral administration of cenerimod at single doses ≥ 3 mg reduced lymphocyte count in 
humans. The extent of lymphocyte count reduction was dose-dependent. A reduction from 
baseline of approximately 76% was achieved after the highest single dose of 25 mg. The 
nadir in lymphocyte count was attained within 16 h following a given dose. After a single 
dose of cenerimod, the lymphocyte count generally returned to normal range within 6 days.  
Repeated o.d. dosing of cenerimod (0.5, 1, 2, or 4 mg) for 35 days led to a gradual, 
dose-dependent reduction in absolute lymphocyte count. Compared to baseline, multiple 
doses of cenerimod induced a decrease ranging from 34 to 64% with doses from  
0.5–4 mg. The time the mean lymphocyte counts returned to within normal range (i.e., 
≥ 1  109 cells/L) dose-dependently increased and was 28 days for the 4 mg dose group. 

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No relevant differences in the effect on lymphocyte count reduction were seen after 
single-dose administration of 1 mg cenerimod in the fed and fasted states. 
Safety and tolerability 
Single doses of 1, 3, 10, and 25 mg were evaluated in healthy subjects. The 10 mg dose 
was identified as the maximal tolerated single dose of cenerimod. In the 25 mg group, a 
serious life-threatening event of hypotensive shock (preferred term: circulatory collapse) 
was reported. Per study stopping criteria, dose escalation was halted after the 25 mg dose 
group. One event of non-serious syncope of moderate intensity was also reported in the 
10 mg treatment group.  
Multiple doses of 0.5, 1, 2, and 4 mg cenerimod were administered o.d. for up to 35 days. 
All doses were found to be well tolerated, with no serious adverse events (SAEs) and no 
adverse events (AEs) leading to treatment discontinuation. The most frequently reported 
AEs in the active treatment groups were headache (37.5%), chest pain (all combined chest 
pain, chest discomfort, musculoskeletal chest pain, noncardiac chest pain; 33.3%), 
followed by nasopharyngitis (16.7%), and dizziness (16.7%). 
Effect on heart rate 
In the single-ascending dose part of the study, a transient decrease in heart rate (HR) was 
observed as the most frequent drug-related effect with cenerimod, with maximal reduction 
reached approximately 4 h post-dose and resolved within 12 h after dosing. 
In the multiple-ascending dose (MAD) part of the study, a transient decrease in HR was 
observed on Day 1 following treatment with cenerimod in all dose groups, when compared 
to placebo. The HR changes from baseline were not clinically significant, did not increase 
with dose, and were followed by a return to baseline over time (between 7 and 14 days of 
treatment), with repeated administration of cenerimod. 
In Part D of study AC-064-101, repeated administration of 2 mg cenerimod o.d. reduced 
the effect on HR of subsequent administration of 10 mg ponesimod, another S1P1 receptor 
modulator with first-dose effect on HR. This shows that chronic o.d. administration of a 
2 mg cenerimod dose can lead to desensitization of S1P1 receptor.  
Effect on blood pressure 
Blood pressure (BP) reduction was observed following a single high-dose administration 
(10 and 25 mg), with a maximal reduction reached approximately 6–8 h post-dose. In the 
MAD study, no relevant changes in BP were observed in the 0.5–4 mg dose groups 
following multiple o.d. dosing of cenerimod. 

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Effect on liver enzyme elevations 
A transient increase in alanine aminotransferase (ALT) and/or aspartate aminotransferase 
(AST) and/or gamma glutamyl transferase (GGT) was observed in 8 subjects on active 
treatment after multiple doses of cenerimod (Part B). These changes were transient and not 
accompanied by an increase in bilirubin. No relevant changes in other clinical chemistry 
variables were observed. None of the out-of-normal-range values in ALT, AST and/or 
GGT were considered as clinically significant, therefore none were reported as an AE. 
Effect on pulmonary function test 
No relevant effects on mean forced expiratory volume in 1 second (FEV1) and forced vital 
capacity (FVC) were observed. 
Cardiodynamic effects 
In the pilot phase of AC-064-102 single-dose administration of 2 mg cenerimod on top of 
steady-state atenolol led to a mean maximum decrease from baseline in HR of 30 bpm 
(mean decrease of 11 bpm following 5 days of atenolol 50 mg o.d. and a further mean 
maximum decrease of 19 bpm following concomitant administration of cenerimod). The 
study was prematurely terminated by the sponsor after completion of the pilot phase based 
on the observed cardiodynamic effect of single-dose administration of cenerimod on top of 
atenolol [see section 1.4.3.2 of the Cenerimod IB for further details].  
1.4.2.2 Phase 2 study in SLE subjects: results 
AC-064A201 
was 
a 
prospective, 
multicenter, 
randomized, 
double-blind, 
placebo-controlled, dose-response Phase 2 study evaluating o.d. administration of 
cenerimod in SLE subjects. This study was conducted in two parts (Part A and Part B) with 
an interim safety review of Part A data prior to the start of Part B. 
Sixty-seven subjects in total were randomized into the study, 49 in Part A and 18 in Part B. 
In Part A, 12, 12, and 13 subjects were randomized to 0.5, 1, and 2 mg of cenerimod, 
respectively, and 12 to placebo. In Part B, 13 subjects were randomized to cenerimod 4 mg 
and 5 to placebo. Subjects were treated for 12 weeks (End-of-Treatment [EOT]), with a 
follow-up period of 16 weeks. The follow-up period included an End-of-Study (EOS) visit, 
6 weeks after the last dose of study drug intake (Week 18) and phone contacts at 11 and 16 
weeks after EOT. 
The study met its primary objective by establishing the dose-response relationship of 
cenerimod based on the reduction of lymphocyte count in peripheral blood. The 
AC-064A201 study demonstrated that cenerimod reduced lymphocyte counts in a dose-
dependent manner (p < 0.00001) as expected from its primary mode of action (MoA). At 
doses of 1, 2, and 4 mg, reduction of circulating lymphocytes in the peripheral blood of 
SLE subjects was statistically significant in pairwise comparisons with placebo. Results 

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expressed as absolute change from baseline, unadjusted or adjusted on the baseline values, 
and associated p-values are presented in Table 1. 
Table 1 
AC-064A201: Lymphocyte count in peripheral blood (109/L) at 
baseline, EOT, and change from baseline to EOT (modified 
pharmacodynamic set), results from Part A, Part B and Part A and B 
combined placebo  
BSL = baseline; CI = confidence interval; EOT = End-of-Treatment; SD = standard deviation; SE = standard error. 
* Based on an analysis of covariance model including baseline as a covariate and with treatment group as factor. 
 
The exploratory analysis of efficacy suggested clinical improvement, particularly with the 
higher cenerimod doses: a numerical reduction in the modified Systemic Lupus 
Erythematosus Disease Activity Index-2000 (mSLEDAI-2K) was observed for the 4 mg 
dose, and to a lesser extent the 2 mg dose, after 12 weeks of treatment, in addition to an 
improvement in the mucocutaneous SLEDAI-2K sub-score. The decrease in SLEDAI-2K 
score with the 4 mg dose was sustained 6 weeks after treatment cessation, in keeping with 
the long half-life of cenerimod. In addition, decrease in anti-double-stranded 
deoxyribonucleic acid (anti-dsDNA) was seen with the 2 mg than the 4 mg dose when 
compared to placebo, more pronounced with the latter than the former.  

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Cenerimod treatment was well tolerated in subjects with SLE at all doses tested. No death 
occurred in the trial.  
Treatment-emergent AEs (TEAEs) occurred in 58.8, 41.7, 41.7, 46.2, and 38.5% of 
subjects on placebo and cenerimod 0.5, 1, 2, and 4 mg, respectively. Four 
treatment-emergent 
SAEs 
(cholecystitis 
chronic, 
pancreatitis 
chronic 
[twice], 
post-cholecystectomy syndrome) were reported during the study and occurred in a single 
subject on placebo (1/17 = 5.9%). These SAEs were severe and none were reported as a 
clinical manifestation of SLE flare or were judged by the investigator to be related to study 
treatment. In addition, one subject in the cenerimod 2 mg group had an SAE of SLE flare 
reported on Day 151 (66 days after the EOT visit). Three TEAEs (cholecystitis chronic, 
pancreatitis chronic, dyspepsia) led to discontinuation of study treatment in two subjects 
receiving placebo (2/17 = 11.8%). One subject in the cenerimod 1 mg group, with ongoing 
lymphadenitis at baseline, had an AE of severe autoimmune hepatitis that was diagnosed 
pre-dose on Day 1. The same subject had TEAE of severe pneumonitis (Day 4). Both 
events occurred in the context of an SLE flare. The non-TEAE of severe autoimmune 
hepatitis led to the discontinuation of study treatment on Day 9.  
The analysis of safety areas of special interest (cardiovascular effects including HR on 
Day 1 and PR interval, systolic and diastolic BP [SDB/DBP], pulmonary function tests 
[PFTs; FEV1 and FVC], immunomodulation including malignancies and infections, 
macular edema and liver enzyme elevations) revealed no clinically relevant safety concern. 
Treatment-emergent AEs of special interest (AESIs) occurred in 2, 1, 1, and 1 subjects on 
cenerimod 0.5, 1, 2 and 4 mg, respectively, and in 1 subject on placebo, with all AESIs 
being liver or pulmonary events in both cenerimod and placebo groups. There was no 
evidence suggestive of a dose dependency of cenerimod on the occurrence of AESIs. 
Clinically irrelevant dose-dependent decreases in HR from time-matched baseline values 
were observed with cenerimod compared to placebo during 24-hour Holter and 12-lead 
ECG on Day 1. No subject in any treatment group had a HR < 40 bpm on 12-lead ECG at 
any time during the 6 hours post cenerimod administration. None of the cenerimod-treated 
subjects had a PR interval > 200 milliseconds (ms) during the 6 hours post cenerimod (vs 
1 subject in the placebo group). The incidences of ECG findings after Day 1 were generally 
similar among cenerimod- and placebo-treated subjects with no relationship to the 
administered cenerimod dose  
Small decreases in mean/median pulmonary function variables were observed with 
cenerimod at EOT, but notable abnormalities in FEV1 and FVC (i.e., a > 15% decrease in 
percentage change from baseline) occurred in few subjects. The few subjects who had a 
notable decrease in FEV1 and/or FVC usually did so at a single visit, which was most often 
the EOT visit. One subject on placebo had such a decrease at 2 visits (Weeks 2 and 12). 

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Three subjects on cenerimod 0.5 mg had a notable decrease in both FEV1 and FVC. No 
differences between cenerimod- and placebo-treated subjects or dose effect could be 
discerned. None of the cenerimod-treated subjects had notable decrease in FEV1 and FVC 
at 2 measurement time points.  
No pattern or dose response could be discerned in liver chemistry. 
No macular edema or malignancy were observed during the study. 
No SAEs and no AEs of severe intensity infections were reported during the study. No 
herpetic infections were observed during the study. 
None of the 45 women of childbearing potential became pregnant during the study. 
No subject in any treatment group met the protocol pre-defined safety stopping criteria. 
2 
STUDY OBJECTIVES 
2.1 Primary objective 
The primary objective is to assess the efficacy of 6 months’ cenerimod treatment given at 
4 different dose levels (0.5, 1, 2, and 4 mg o.d.) on disease activity in adult subjects with 
moderate to severe SLE concurrently receiving background therapy. 
2.2 Secondary objectives 
The secondary objectives of the study are to evaluate the following over 6 months in adult 
subjects with moderate to severe SLE concurrently receiving background therapy: 
• The safety and tolerability of cenerimod treatment. 
• The effect of cenerimod treatment on quality of life and fatigue using relevant Patient 
Reported Outcome (PRO) instruments. 
• The effect of cenerimod treatment on SLE biomarkers. 
2.3 Exploratory objectives  
Further objectives are assessed over a treatment period of up to 12 months: 
• The effect of cenerimod 0.5, 1, 2 mg on disease activity, safety and tolerability, quality 
of life, fatigue and SLE biomarkers. 
• Starting from Month 6, the effects of dose reduction and withdrawal in subjects 
randomized to 4 mg who are re-randomized to either 2 mg or placebo. 

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3 
OVERALL STUDY DESIGN AND PLAN 
3.1 Study design 
This is a Phase 2b, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study in adult subjects with moderate to severe SLE.  
Approximately 325 adult subjects with SLE will be randomized in a 1:1:1:1:1 ratio to 
placebo, 0.5, 1, 2, or 4 mg o.d. of cenerimod, in addition to background SLE therapy.  
Treatment allocation is stratified by dose of oral corticosteroids (OCS) at Randomization 
(OCS with two strata: < 7.5 mg/day or ≥ 7.5 mg/day prednisone or equivalent), and by 
disease activity at Screening (with two strata: mSLEDAI-2K < 10 or ≥ 10). 
Following successful completion of Screening, randomized subjects will enter a 6-month 
double-blind study treatment period called Treatment Period 1 (TP1). 
Subjects completing TP1 will continue treatment for an additional 6 months in TP2, i.e., 
for a total maximum of 12 months.  
Treatment allocation in TP2 will depend on the treatment allocation in TP1 as follows, and 
does not require unblinding of TP1:  
a) Subjects randomized in TP1 to placebo, 0.5, 1, or 2 mg arms will continue their study 
double-blind treatment unchanged during TP2. 
b) Subjects randomized to the 4 mg arm in TP1 will be re-randomized in a double-blinded 
fashion in TP2 in a 1:1 ratio to placebo or cenerimod 2 mg. 
The double-blinding of the entire study will be preserved by Interactive Response 
Technology (IRT) treatment allocation.  
At the end of treatment, subjects will enter a 6-month follow-up period.  
There will be three study analyses: the Month-6 analysis, the Month-12 analysis, and the 
final EOS analysis [see Section 10.4].  
Month-6 analysis will be performed when all randomized subjects have completed TP1 or 
discontinued the study. Month-12 analysis will be performed when all randomized subjects 
have completed TP2 or discontinued the study. Final EOS analysis will be performed when 
all randomized subjects have completed the posttreatment follow-up period or discontinued 
the study.  
After Month-6 and Month-12 analyses, ongoing subjects will continue to be treated and 
followed up in a double-blinded manner up to their EOS visit. Investigators, site staff, 
subjects, and the sponsor staff responsible for the study conduct (with appropriate 

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firewalls) will remain blinded to study treatment allocation until study closure. To maintain 
the blinding of the study up to final EOS analysis, two separate sponsor teams will be set
up; Team 1 will be unblinded at the time of the Month-6 analysis while Team 2 will remain 
blinded until final EOS analysis in order to continue to review the data being collected up 
to EOS. The measures put in place to ensure the good conduct of this process will be
described in a dedicated study document. 
The study will be conducted at approximately 180 sites in approximately 21 countries.
Figure 1
Study design ID-064A202
EOS = End-of-Study; EOT = End-of-Treatment; R = Randomization; RR = re-randomization; pts = patients; V = visit.
3.1.1
Study periods
The study comprises the following periods: 
3.1.1.1
Screening period (allowing OCS optimization period for subjects receiving 
OCS)
The screening period starts with the signing of the informed consent form (ICF) and ends 
on the day of Randomization, before the first study drug intake. This period can last up to 
60 days. 
During this period, the subject’s SLE background medication should be maintained stable 
except for OCS which should be tapered to the minimum required dose and then 
maintained stable for at least 15 days prior to Randomization [see Section 5.2.2.1]. 

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3.1.1.2 Treatment period  
This period comprises 2 periods – TP1 and TP2.  
TP1 lasts 6 months. It starts with the administration of the first dose of study treatment, 
after subject randomization, and ends at the Month 6 visit.  
Starting from the Month 6 visit, TP2 lasts 6 months and ends at the Month 12 visit.  
All randomized subjects in the study will have to complete TP1 before continuing in TP2.  
Subjects randomized to placebo, 0.5, 1, or 2 mg arms who are still on treatment at Month 6 
will continue their study treatment during another treatment period of 6 months duration 
called TP2, i.e., for a total maximum of 12 months.  
Subjects randomized to the 4 mg arm who are still on treatment at Month 6 will be 
re-randomized in a 1:1 ratio to placebo or cenerimod 2 mg to enter TP2 and will continue 
study treatment for a total maximum of 12 months.  
For details regarding premature discontinuation of study treatment, please refer to 
Section 5.1.7. 
3.1.1.3 Follow-up period 
This period starts after the EOT and lasts 6 months until the EOS. For the first 5 months 
after the EOT visit, subjects will have to conduct monthly follow-up (FU) visits, FU1, FU2, 
FU3, FU3a, and FU3b to collect information on AEs and SAEs and/or pregnancy as well 
as efficacy data.  
The EOS visit should occur 6 months after the EOT. 
3.1.2 Echocardiography ancillary study 
At Randomization, approximately 175 subjects will be assigned to the echocardiography 
ancillary study through the IRT system. The echocardiography ancillary study will run 
concurrently with the main study. Subjects assigned to the echocardiography ancillary 
study will undergo an echocardiography assessment at Month 6 or at premature 
End-of-Treatment (pEOT) visit in the event of premature study treatment discontinuation 
during TP1, in addition to echocardiography assessments that will be performed for all 
subjects during the screening period.  
Standard 2D/Doppler echocardiography will assess cardiac morphology and function 
including regional wall abnormalities, aortic valve morphology and function, mitral valve 
morphology and function, and left ventricular ejection fraction. 
See also echocardiography assessments in Section 7.2.3.6. 

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3.2 Study design rationale 
3.2.1 General rationale 
This study is a multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study in adult subjects with SLE with moderate to severe disease activity in addition to 
background therapy. 
A randomized, double-blind design is used to control for bias in reporting safety, efficacy, 
and biological activity data.  
Cenerimod therapy is intended as adjunctive treatment, hence all subjects in the study will 
receive cenerimod or placebo in addition to SLE background therapy. Given the early 
phase of cenerimod clinical development, the use of background therapy will ensure that 
all subjects, including subjects who are randomized to placebo, will have the benefit of 
being treated with available background therapy.  
The use of placebo will allow discrimination of the efficacy and safety profile of cenerimod 
treatment in conjunction with SLE background therapy and compared to use of SLE 
background therapy. 
Based on the available nonclinical and clinical data to date, there is no likely PK interaction 
between cenerimod and any of the co-administered background therapies allowed in this 
protocol [see Cenerimod IB]. A potential PD interaction between cenerimod and permitted 
immunosuppressive drugs cannot be excluded but will be monitored by white blood cell 
(WBC) and lymphocyte counts as well as AEs, particularly AEs denoting infections. 
An important goal of the SLE therapy is to reduce the use of steroids, given their associated 
morbidity. However, reduction of steroid dose during the treatment period may confound 
interpretation of study results. Hence OCS dose reductions are highly encouraged prior to 
Randomization during the screening phase, up to 15 days only prior to Randomization. 
This will ensure a stable baseline assessment. After Randomization it is highly preferable 
that OCS doses remain stable to avoid confounding factors for data interpretation of 
primary and secondary endpoints at Month 6. However, to account for current management 
practice, some flexibility in the steroid management is allowed if absolutely necessary and 
well documented during the first 3 months of TP1 and during TP2 [see Section 5.2.2.1 for 
further details]. Consequently, during the entire study duration (a maximum of 20 months 
from beginning of Screening to end of FU), adjustment of OCS dose will be disallowed for 
3 months only.  
Given cenerimod’s MoA and to limit the risk of introducing bias to the study due to 
unblinding, the study personnel and sponsor’s team will not have access to results of total 
WBC (including differentials) and lymphocyte counts of subjects participating in the study. 
In the event of very low lymphocyte count (< 200 cells/µL) the central laboratory will send 

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an alert to the investigator to ensure proper follow-up of the subject [see Section 5.1.8.2 
for details of management of low lymphocyte counts]. Based on data collected in the 
Phase 2a study, during which no cases of lymphocyte count < 200 cells/µL occurred, this 
is considered to be rare and not leading to significant unblinding of the trial. 
Treatment allocation during both TP1 and TP2 will remain unknown to study sites, 
subjects, and sponsor’s personnel until the end of the study. Treatment allocation will be 
stratified by dose of OCS, i.e., < 7.5 mg/day or ≥ 7.5 mg/day prednisone equivalent, and 
by disease activity, i.e., mSLEDAI-2K < 10 or ≥ 10, as both factors can influence SLE 
parameters that are used as study endpoints [van Vollenhoven 2012]. 
To protect the safety of the subject, strict subject-specific safety stopping rules are applied 
during the entire study as defined in the protocol for each safety area of interest.  
As part of the risk mitigation plan, an echocardiography ancillary study will run 
concurrently with the main study. Approximately 175 subjects will be assigned to the 
ancillary study through the IRT system at Randomization to ensure balanced numbers of 
subjects across all treatment arms. Subjects participating in the ancillary study will undergo 
an echocardiography assessment at Month 6 or pEOT visit [see Section 3.1.2], in addition 
to an echocardiography assessment during the screening period that will be done for all 
subjects enrolled in the study.  
3.2.2 Rationale for the four doses tested  
The rationale for including 0.5, 1, 2, and 4 mg doses in this protocol is based primarily on 
results from study AC-064A201, a 12-week treatment study in SLE subjects [see 
Section 1.4.2.2 for further details]: 
• No clinically relevant safety findings emerged in the completed Phase 1 and 2 studies 
in 97 healthy and 67 SLE subjects, respectively, at any of the doses proposed in this 
Phase 2 study. 
• The study results indicated that the 4 mg dose of cenerimod was associated with 
clinically relevant improvement in the mSLEDAI-2K at EOT (12 weeks) which was 
sustained until the EOS, i.e., 6 weeks after EOT. The clinical results were further 
supported by the reduction in lymphocyte count, a decrease in disease-relevant T and 
B lymphocyte subsets, and a statistically significant reduction in anti-dsDNA 
autoantibodies. Based on these data, the 4 mg dose, which is expected to be associated 
with clinically meaningful efficacy without safety concern, warrants further 
investigation. 
• Treatment with the intermediate doses of 1 and 2 mg resulted in approximately 50% 
reduction in lymphocyte count during the 12 weeks of treatment. For the 2 mg dose, a 
numerical clinical improvement (mSLEDAI-2K) and a reduction in anti-dsDNA 

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autoantibodies were also observed. Clinical efficacy may be anticipated with longer 
duration of treatment and justifies the further investigation of these doses. 
• In the Phase 2 study, the 0.5 mg dose did not show clinical improvement and no 
reduction in lymphocyte count was observed compared to placebo. However, in the 
healthy subject Phase 1 AC-064-101 study the effect on lymphocyte counts was more 
pronounced. Given the totality of the data, it cannot be excluded that the 0.5 mg dose 
be the minimum effective dose. This justifies further investigation of this dose. 
3.2.3 Rationale for the efficacy endpoints  
The primary efficacy endpoint is the change from baseline to Month 6 in the mSLEDAI-2K 
score. 
The SLEDAI-2K is a well-established and one of the Health Authority 
guideline-recommended clinical endpoints, allowing for rapid and standardized SLE 
disease activity assessment, and has been shown to be sensitive in clinical trials. It has an 
acceptable inter-observer variability and correlates well between individual subject scores 
[FDA 2009]. The SLEDAI-2K will be modified (m) to exclude leukopenia (reduction by 
1 point out of 105 total points) since cenerimod induces reduction in lymphocyte count as 
part of its MoA. This approach is identical to the one which was used in the previous 
cenerimod AC-064A201 Phase 2 study. The minimal modification of the SLEDAI-2K is 
not considered to change the validity of the instrument. SLEDAI-2K will be also assessed.  
Measurement of disease activity by a single index may be insufficient to fully describe the 
therapeutic effect of a product in SLE. Therefore, secondary efficacy endpoints at Month 6 
include: 
a) Responder on SLE Responder Index (SRI)-4, a Health Authority recommended 
composite endpoint, comprising:  
(i) reduction from baseline of at least 4 points in the mSLEDAI-2K, and 
(ii) no new British Isles Lupus Assessment Group (BILAG) A organ domain score and 
no more than one new BILAG B organ domain score compared with baseline, and  
(iii) no increase of more than 0.3 points on the Physician’s Global Assessment (PGA) 
since baseline.  
SRI-4 allows tracking of concomitant improvement and worsening in different organs. 
b) Response (no worsening) at Month 6 on BILAG-2004 disease activity index defined as 
no new BILAG A organ domain score and no more than one new BILAG B organ domain 
score as compared with baseline.  

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BILAG, also recommended by Health Authorities, is a comprehensive tool to assess 
disease activity and is sensitive to small changes over time. 
3.2.4 Rationale for treatment duration  
Based on the AC-064A201 data and the clinical experience with other S1P receptor 
modulators in autoimmune diseases [Vaclavkova 2014, Sandborn 2016], the full clinical 
effect of cenerimod is expected to occur at 6 months of treatment. Hence, it is anticipated 
that a 6-month treatment period study will provide substantial evidence of clinical efficacy 
of cenerimod supporting the timing of the primary efficacy endpoint of this study.  
Without delaying the study results and identification of the dose(s) to be pursued, the study 
offers the possibility to perform the analysis of efficacy and safety at Month 6 after 
completion of TP1 while subjects continue to be treated in TP2 (i.e., 12 months in total). 
This will allow a faster decision on the conduct of the Phase 3 program, while also 
providing additional safety and efficacy data.  
Although no clinically relevant safety finding emerged in all 67 subjects in study 
AC-064A201, safety data in the 4 mg dose remain limited, hence a staggered approach for 
testing the cenerimod 4 mg dose will be implemented in this development program, with 
the 4 mg dose being tested for 6 months only, a duration of exposure that may be extended 
in future studies depending on the results of this Phase 2b trial. Therefore, subjects who 
received 4 mg for 6 months will be re-randomized to receive either placebo or 2 mg. This 
switch to placebo will also allow the collection of information on the potential effects of 
treatment withdrawal and data from subjects switching to 2 mg will contribute to the 
decision of dose(s) selection for the future Phase 3 study.  
3.3 Overall benefit-risk conclusion  
The AC-064A201 study results demonstrated a dose-related reduction of circulating 
lymphocytes in peripheral blood in keeping with the expected MoA of cenerimod.  
The exploratory analysis of efficacy of the AC-064A201 study suggested clinical 
improvement assessed by numerical reduction in the mSLEDAI-2K and improvement in 
the mucocutaneous SLEDAI-2K sub-score, particularly with the higher doses of cenerimod 
tested in study AC-064A201.  
Cenerimod treatment was well tolerated at all doses tested in the Phase 2 study (0.5, 1, 2, 
and 4 mg), with no associated clinically relevant safety finding.  
The totality of cenerimod data to date, i.e., nonclinical and clinical, justify further 
investigation of the clinical efficacy of cenerimod in the dose range proposed in the study: 
0.5, 1, 2, and 4 mg.  

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Cenerimod has the potential of being a new, complementary therapeutic approach for SLE 
patients with acceptable efficacy and safety profiles. The foreseeable benefit-risk balance 
supports the inclusion of all cenerimod doses studied in this protocol (0.5, 1, 2 and 4 mg) 
and a comprehensive plan to mitigate potential risks is included in this protocol. 
3.4 Study committee 
3.4.1 Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) will be monitoring the safety and 
efficacy data obtained in the study and making appropriate recommendations based on the 
reported (unblinded to the Committee as necessary) data.  
The IDMC will be fully operational prior to enrollment of the first subject into the study. 
The composition and operation of the IDMC will be described in an IDMC charter. 
4 
SUBJECT POPULATION 
4.1 Rationale for the selection of the study population 
The target population of this study are subjects with generalized SLE who are receiving 
background therapy and with active, autoantibody positive disease, anti-nuclear antibodies 
(ANA) titer ≥ 1:80 and/or anti-dsDNA ≥ 30 IU/mL at Screening.  
Subjects must have at least a 6-month history of SLE and meet the American College of 
Rheumatology (ACR) criteria for diagnosis [Hochberg 1997].  
Subjects will be included in the study if they have a sufficient level of activity to justify 
therapeutic intervention and to provide measurable room for improvement. This is based 
on biomarker of activity and clinical symptomatology based on an mSLEDAI-2K score of 
at least 6 points and at least 2 points on the musculoskeletal or mucocutaneous sub-scores. 
The selection of this population is supported by the Phase 2 study results in which 
cenerimod improved the mSLEDAI-2K at 12 weeks and showed a trend for improvement 
in the musculoskeletal and mucocutaneous sub-scores. 
However, in the context of a placebo-controlled study and the limited efficacy data 
available to date, it is premature to test cenerimod in the most severe spectrum of the 
disease. Subjects with active lupus nephritis and central nervous system (CNS) lupus are 
therefore excluded. It is possible that in the future, and assuming cenerimod provides 
benefit to SLE patients as defined in the present study, more studies will be done in more 
severe patients. 
Given the heterogeneity in SLE disease manifestations, treatment is often not standardized. 
In order not to confound the results of the study, subjects should have initiated background 
treatment at least 3 months prior to Screening and need to have stable doses at least 30 days 

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prior to Randomization and throughout the study. For OCS, dose must be stable at least 
15 days prior to Randomization [see Section 5.2.2.1 for details on OCS management in the 
study]. 
4.2 Inclusion criteria 
For inclusion in the study, all the following inclusion criteria must be fulfilled. It is not 
permitted to waive any of the criteria for any subject. 
Screening criteria: 
1. Signed ICF prior to any study-mandated procedure. 
2. Diagnosis of SLE made at least 6 months prior to Screening, by fulfilling at least 4 of 
the 11 criteria for SLE as defined by the ACR criteria [Appendix 2]. 
3. Male and female subjects, age 18 to 75 years old (both inclusive).  
4. A mSLEDAI-2K score ≥ 6 of at least 2 points for musculoskeletal or mucocutaneous 
manifestations (i.e., myositis, arthritis, rash, alopecia, mucosal ulcers). 
Note: The mSLEDAI-2K score does not take into account “leukopenia”. 
5. History or presence of positive ANA or anti-dsDNA antibodies.  
6. Currently treated with stable doses of one or more of the following background 
medications: 
• NSAIDs, 
• Anti-malarials (≤ 400 mg/day hydroxychloroquine, ≤ 500 mg/day chloroquine, 
≤ 100 mg/day quinacrine), 
• Mycophenolate mofetil (≤ 2 g/day), 
• Mycophenolic acid (≤ 1440 mg/day), 
• Azathioprine (≤ 2 mg/kg/day), 
• Methotrexate (≤ 20 mg/week), 
• Corticosteroids (≤ 40 mg/day prednisone or equivalent), 
• Belimumab (≤ 10 mg/kg every 4 weeks intravenously [i.v.], or 200 mg/week 
subcutaneously [s.c.]).  
7. Women of childbearing potential (WOCBP): 
• Must have a negative serum pregnancy test at Screening.  
• Must agree to undertake monthly urine pregnancy tests during the study. 

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• Must use highly effective methods of contraception from the Screening visit until 
6 months after taking the last dose of study treatment as described in Section 4.4.2. 
Randomization criteria:  
8. A clinical mSLEDAI-2K score ≥ 4. 
Note: The clinical mSLEDAI-2K is the mSLEDAI-2K assessment score without the 
inclusion of points attributable to hematuria, proteinuria, pyuria, low complement, 
increased DNA binding and thrombocytopenia. 
9. Presence of at least one of the following autoantibodies measured by central laboratory 
defined as follows (based on the screening sample): (a) positive ANA test measured 
by immunofluorescence assay with titer ≥ 1:80; or (b) positive anti-dsDNA antibodies 
with titer ≥ 30 IU/mL.  
10. On a stable dose of background SLE medication consisting of any of the following 
medications (alone or in combination) for a period of at least 30 days (15 days for 
corticosteroids) prior to Randomization: 
• NSAIDs, 
• Anti-malarials (≤ 400 mg/day hydroxychloroquine, ≤ 500 mg/day chloroquine, 
≤ 100 mg/day quinacrine), 
• Mycophenolate mofetil (≤ 2 g/day), 
• Mycophenolic acid (≤ 1440 mg/day), 
• Azathioprine (≤ 2 mg/kg/day), 
• Methotrexate (≤ 20 mg/week), 
• Corticosteroids (≤ 40 mg/day prednisone or equivalent) [see Section 5.2.2.1], 
• Belimumab (≤ 10 mg/kg every 4 weeks i.v., or 200 mg/week s.c.). 
11. WOCBP: 
• Must have a negative urine pregnancy test at Randomization visit. 
4.3 Exclusion criteria 
Subjects must not fulfill any of the following exclusion criteria. It is not permitted to waive 
any of the criteria for any subject. 
Screening criteria 
Disease/condition 
1. Female subjects who are breastfeeding or planning to become pregnant during the 
study. 

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2. Active lupus nephritis (defined by proteinuria > 1.5 g/24 h, or equivalent using spot 
urine protein-to-creatinine ratio: > 150 mg/mmol) or a renal biopsy demonstrating 
immune complex-mediated glomerulonephritis compatible with lupus nephritis within 
90 days prior to Screening.  
3. Severe active CNS lupus requiring therapeutic intervention (e.g., aseptic meningitis, 
seizures, psychosis, cerebritis, cerebrovascular accident [CVA], organic brain 
syndrome, CNS vasculitis) and severe forms of vasculitis requiring systemic 
immunosuppressive treatment (e.g., retinal vasculitis, coronary vasculitis, pulmonary 
vasculitis, mesenteric vasculitis) within 90 days prior to Screening. 
4. A diagnosis of mixed connective tissue disease or any history of overlap syndromes 
of SLE with rheumatoid arthritis, erosive arthritis, scleroderma or autoimmune 
hepatitis.  
5. History or presence of Mobitz type II or third-degree atrioventricular (AV) block, sick 
sinus syndrome, symptomatic bradycardia or syncope associated with cardiac 
disorders. 
6. Subjects who experienced myocardial infarction, unstable angina pectoris, stroke, 
transient ischemic attack, vascular thrombosis, decompensated heart failure requiring 
hospitalization, or heart failure defined by the New York Heart Association (NYHA) 
Class III/IV within six months prior to Screening.  
7. An elevated QT corrected for HR using Fridericia’s formula (QTcF) interval of 
> 470 ms (females) / > 450 ms (males).  
8. History or presence of severe respiratory disease or pulmonary fibrosis, based on 
medical history, lung function and chest X-ray performed at Screening or within 
6 months prior to Screening or medically significant abnormal PFTs: FEV1 or FVC 
< 70% of predicted normal value or FEV1/FVC ratio < 0.7. 
9. History of clinically relevant bronchial asthma or chronic obstructive pulmonary 
disease that has required treatment with oral or parenteral corticosteroids for more than 
a total of 2 weeks within the last 6 months prior to Screening. 
10. Active or latent tuberculosis (TB), as assessed by chest X-ray performed at Screening 
or within 6 months prior to Screening, and interferon (IFN) gamma release assay 
(QuantiFERON-TB-Gold Plus®), except if there is documentation that the subject has 
completed adequate and successful treatment for TB previously. 
11. Ongoing bacterial, viral or fungal infection that is of clinical concern in the judgment 
of the investigator or history of any serious infection, defined as life-threatening or 
requiring i.v. antibiotics or hospitalization.  

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12. Positive results for serological markers for hepatitis A, B, C and E indicating acute or 
chronic infection: 
− Anti-HAV IgM 
− HBsAg 
− Anti-HCV IgG or IgM 
− Anti-HEV IgG or IgM (if positive IgM and/or IgG, perform HEV-RNA PCR and 
if negative patient can be randomized). 
13. Subjects who have congenital or acquired severe immunodeficiency or known HIV 
infection or positive HIV testing. 
14. Negative antibody test for varicella-zoster virus. Vaccination of antibody-negative 
subjects may be considered, which must occur at least 30 days prior to re-test and 
Randomization. 
15. History or presence of malignancy (except for surgically excised basal or squamous 
cell skin or mucosal lesions, including dysplasia and carcinoma in situ), 
lymphoproliferative disease, or history of total lymphoid irradiation. 
16. History or presence of bone marrow or solid organ transplantation. 
17. Presence of macular edema or active uveitis.  
18. Type 1 or 2 diabetes that is poorly controlled according to investigator judgment, or 
diabetes complicated with organ involvement such as diabetic nephropathy or 
retinopathy. 
19. History of chronic liver or biliary disease (other than Gilbert’s Syndrome) or subjects 
with ALT or AST > 2 × upper limit of normal (ULN) or total bilirubin (TBIL) 
> 1.5 × ULN (unless in the context of known Gilbert’s Syndrome).  
20. Significant hematology abnormality: lymphocyte count < 800 /μL (0.8 × 109/L); 
hemoglobin < 9 g/dL; WBC count < 2500/μL (2.5 × 109/L) or platelets < 75,000/μL 
(75 × 109/L). 
21. Estimated glomerular filtration rate < 60 mL/min/1.73 m2.  
22. History of clinically significant drug or alcohol abuse. 
23. Known allergy to S1P receptor modulators or any of the cenerimod formulation 
excipients. 
24. Any other clinically relevant medical condition that would put the subject at risk if 
participating in the study, or any other diseases that may confound the disease activity 
assessments.  

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Medications 
25. Treatment with the following medications within 15 days or 5 half-lives of the 
medication (whichever is longer) prior to Randomization: 
a. 
β-blockers, diltiazem, verapamil, digoxin, digitoxin, or any other anti-arrhythmic 
or HR-lowering systemic therapy [list of drugs provided in Appendix 3]. 
b. QT-prolonging drugs with known risk of torsade de pointes irrespective of 
indication [list of drugs provided in Appendix 4]. 
26. Treatment with the following medications within 30 days or 5 half-lives of the 
medication (whichever is longer) prior to Randomization:  
a. 
Cyclophosphamide, ciclosporine, tacrolimus, sirolimus. 
b. Pulse methylprednisone. 
c. 
Vaccination with live vaccines. 
27. Intra-articular, intramuscular or i.v. glucocorticosteroids within 6 weeks prior to 
Randomization. 
28. Treatment with the following medications within 90 days or 5 half-lives of the 
medication (whichever is longer) prior to Randomization:  
a. Leflunomide. 
b. i.v. immunoglobulins. 
29. Treatment with any investigational agent within 90 days or 5 half-lives of the drug 
(whichever is longer) prior to Randomization. 
30. Treatment with B cell-depleting biological agents such as rituximab or ocrelizumab 
within 12 months prior to Randomization. 
31. Treatment with any of the following medications any time prior to Screening: 
a. Alemtuzumab,  
b. S1P receptor modulators (e.g., fingolimod). 
For further details, see table of forbidden medications in Appendix 3.  
Randomization exclusion criteria  
32. Resting HR < 50 bpm as measured by the pre-dose 12-lead ECG.  
33. An elevated QTcF interval of > 470 ms (females) / > 450 ms (males) as measured by 
the pre-dose 12-lead ECG on Day 1. 
34. Severe active CNS lupus requiring therapeutic intervention (e.g., aseptic meningitis, 
psychosis, seizures, cerebritis, CVA, organic brain syndrome, CNS vasculitis) and 

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severe forms of vasculitis requiring systemic immunosuppressive treatment (e.g., 
retinal vasculitis, coronary vasculitis, pulmonary vasculitis, mesenteric vasculitis).  
35. Clinically relevant bronchial asthma or chronic obstructive pulmonary disease.  
4.4 Contraception requirements for women of childbearing potential  
4.4.1 Definition of childbearing potential 
A woman is considered to be of childbearing potential (WOCBP), i.e., fertile, following 
menarches and until becoming post-menopausal unless permanently sterile. 
Permanent sterilization methods include hysterectomy, bilateral salpingectomy and 
bilateral oophorectomy.  
Post-menopausal state is defined as 12 consecutive months with no menses without an 
alternative medical cause (ICH M3 definition). 
The reason for not being of childbearing potential will be recorded in the electronic Case 
Report Form (eCRF).  
4.4.2 Highly effective methods of contraception 
WOCBP [see definition in Section 4.4.1] must follow a highly effective contraception 
scheme from Screening up to at least 6 months after taking the last dose of study treatment. 
In line with the Clinical Trials Facilitation Group recommendations, highly effective birth 
control methods are:  
1. Hormonal contraceptives 1 : Combined (estrogen- and progestogen-containing) or 
progestogen-only hormonal contraception associated with inhibition of ovulation2 using 
one of the following routes of administration: oral, intravaginal, transdermal, injectable, 
implantable3. 
Hormonal contraception must be supplemented with a barrier method such as male 
condom (preferred method), female condom, cervical cap or diaphragm. Cervical cap 
and diaphragm must be used in combination with a spermicide. In countries where 
spermicides are not available/authorized, cervical cap and diaphragm must not be used. 
                                                 
1 If a hormonal contraceptive is chosen from this group, it must be taken for at least 1 month prior to study 
treatment start day. If the subject switches to, or starts, a hormonal contraceptive method during the study 
treatment phase, caution must be taken to ensure a highly effective contraceptive method is used without 
discontinuation. 
2 Cenerimod has a limited potential for PK DDIs with concomitant medications whose PK are dependent on 
CYP clearance, hence no interaction with hormonal contraception is expected (in vitro). For further details 
see the IB [Cenerimod IB]. 
 

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2. Intrauterine device3. 
3. Intrauterine hormone-releasing system3. 
4. Bilateral tubal occlusion/ligation3. 
5. Vasectomized partner3,4. 
6. Sexual abstinence5. 
The following contraception schemes used alone are NOT considered as highly effective 
methods of contraception: 
• Male or female condom with or without spermicide 
• Cap, diaphragm, or sponge with spermicide 
The following methods are NOT allowed as methods of contraception for this study: 
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action  
• Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
• Withdrawal (coitus interruptus) 
• Spermicides only 
• Lactational amenorrhea method 
• Combination of female condom and male condom 
The methods of birth control used (including non-pharmacological methods) of the 
WOCBP and/or partner (if applicable) must be recorded in the eCRF. 
The investigator/delegate will record in the eCRF at monthly intervals the result of the 
pregnancy test, whether the method of contraception has changed, and will remind the 
subject to follow the protocol-mandated method of contraception up to at least 6 months 
after study treatment discontinuation. 
                                                 
3 Contraception methods considered to have low user dependency. 
4 Vasectomized partner is a highly effective birth control method provided that the partner is the sole sexual 
partner of the WOCBP trial participant and that the vasectomized partner has received medical assessment 
of the surgical success. 
5 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 treatments. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the subject, and whether this is locally accepted as a highly effective method of contraception. 

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Note: the documentation of method of contraception can be based on the site personnel’s 
review of the subject’s medical records, medical examination or medical history interview 
of the subject. 
If the investigator considers that the subject is not complying with the protocol methods of 
contraception instructions, study treatment must be permanently discontinued [see 
Section 5.1.8.4]. 
4.4.3 Male contraception 
Based on nonclinical data and human distribution models, it is considered very unlikely 
that a relevant dose of cenerimod would be delivered to the female by seminal fluid 
transfer. Therefore, despite the teratogenic effect of cenerimod, the risk of harm to a human 
fetus by seminal transfer of cenerimod is considered to be very low. In addition, cenerimod 
is neither genotoxic nor mutagenic. Therefore, there is no specific recommendation for 
male contraception regarding cenerimod [see section 4.3.8.8 of the Cenerimod IB]. 
5 
STUDY TREATMENT 
5.1 Investigational treatment and matching placebo: description 
Cenerimod is available for clinical study use in tablets. It will be supplied as identical 
film-coated tablets at the doses of 0.5, 1, 2, and 4 mg.  
The inactive ingredients of the cenerimod film-coated tablet formulation are: 
hydroxypropyl methylcellulose, polyvinylpyrrolidone, mannitol, colloidal silicon dioxide, 
and magnesium stearate. The film coating consists of hydroxypropyl methylcellulose, 
propylene glycol, titanium dioxide, iron oxide yellow, iron oxide red, and iron oxide black. 
The matching placebo is supplied as identical film-coated tablets formulated with the same 
excipients but without the active ingredient, cenerimod. 
5.1.1 Study treatment administration 
One tablet of cenerimod or placebo will be taken orally irrespective of food intake. The 
tablet will be swallowed whole. It is preferable that the tablet is taken each day in the 
morning.  
Subjects must be instructed not to take study treatment in the morning of study visit days. 
On the day of the study visits, study treatment must be administered only after the 
completion of the pre-dose assessments (i.e., SBP, DBP, ECGs, spirometry, laboratory 
tests, and PK sampling). 
To ensure compliance, the study personnel must remind subjects at each visit of the study 
treatment intake requirements. 

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5.1.2 Treatment assignment 
A total of approximately 325 subjects will be randomized in a 1:1:1:1:1 ratio to placebo, 
or to cenerimod 0.5, 1, 2, and 4 mg.  
Once randomized, all subjects will enter a 6-month double-blind study treatment period 
TP1. 
After the completion of the 6 months of study treatment, subjects randomized to placebo, 
0.5, 1, or 2 mg arms will continue to receive double-blind study treatment for a maximum 
of 12 months in total.  
Subjects randomized to the 4 mg arm will receive study treatment for a maximum of 
6 months in TP1. After completion of the 6 months of study treatment, subjects in this 
group will be re-randomized in a 1:1 ratio to placebo or cenerimod 2 mg to enter TP2 and 
will continue to receive double-blind treatment for a maximum of 12 months in total.  
For more details on premature discontinuation of study treatment, please refer to 
Section 5.1.7. 
Treatment allocation via IRT will ensure maintenance of the double-blinding during the 
entire study.  
Treatment allocation is stratified by: 
• Dose of OCS at Randomization (OCS with two strata: < 7.5 mg/day or ≥ 7.5 mg/day of 
prednisone or equivalent),  
and  
• Disease activity at Screening (with two strata: mSLEDAI-2K < 10 or ≥ 10). 
Each of the clinical study sites will be assigned a unique site number. At Visit 1 
(Screening), all screened subjects will be assigned a study-specific subject number by the 
IRT system, which identifies the subject throughout the study. 
At the Randomization visit (Visit 2), and after having verified that the subject meets all 
inclusion criteria and none of the exclusion criteria, the investigator/delegate contacts the 
IRT system to randomize the subject. The IRT system assigns a randomization number to 
the subject and assigns the bottle number that matches the treatment arm assigned by the 
randomization list to the randomization number. 
The IRT system is handled by an external independent vendor which will generate the 
randomization list. 

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5.1.3 Blinding 
5.1.3.1 Blinding of study drug material 
This study will be performed in a double-blind fashion. The investigator and study staff, 
the subjects, the Clinical Research Associates (CRAs), all Clinical Trial Team (CTT) 
members from the sponsor and Contract Research Organizations (CROs) involved in the 
conduct of the study will remain blinded to the treatment allocation until study closure. The 
investigational treatment and its matching placebo are indistinguishable, and all bottles will 
be packaged in the same way. 
To ensure adequate supply of study treatment, the IRT vendor personnel responsible for 
clinical study supply distribution need to be unblinded at site level. The sponsor individuals 
contributing to clinical supply distribution will be unblinded at depot level only (a depot 
may be used for the study treatment supply of several sites and countries). These persons 
will be clearly identified, their unblinding will be documented in the trial master file, and 
they will not take part in any CTT meetings after study set-up has been completed. 
Until the time of unblinding for final data analysis, the randomization list is kept strictly 
confidential, and is accessible only to the IRT vendor and limited sponsor authorized 
personnel (only from the bioanalytical laboratory group), who are not involved in any other 
aspects of the conduct of the study.  
A sealed randomization code is kept by the sponsor’s Global Quality Management 
department in a safe cabinet. A second set will be provided to the statistician of the 
Independent Statistical Analysis Center (ISAC) for the production of unblinded IDMC 
statistical outputs. 
To prevent unblinding, the results of the biomarker and PK data will not be communicated 
to the investigator, study personnel, subjects, CRAs, any sponsor or vendor/CRO personnel 
involved in the conduct of the study. Results will be transferred by the central laboratory 
(for biomarkers) and the bioanalytical laboratory for PK measurement to the sponsor and 
CRO personnel involved in the conduct of the study only after database lock. 
To maintain the blinding of the study up to final EOS analysis, two separate sponsor teams 
will be set up; Team 1 will be unblinded at the time of the Month-6 analysis while Team 2 
will remain blinded until final EOS analysis in order to continue to review the data being 
collected up to EOS. The measures put in place to ensure the good conduct of this process 
will be described in a dedicated study document. 
5.1.3.2 Functional blinding 
Lymphocyte counts reduction has been identified as potentially unblinding information. 
Site’s staff and sponsor’s study team will not have access to this information until database 
lock. 

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The following measures will be taken to ensure that the main site staff and the sponsor 
study team will remain blinded to lymphocyte counts: 
• 
After the first dose of study treatment until EOS, results of the total WBC (including 
differentials) and lymphocyte counts will not be communicated to the sites, sponsor, 
and CROs. Testing of total WBC (including differentials) and lymphocyte counts at a 
local laboratory should not be performed unless deemed absolutely necessary to ensure 
subject’s safety. 
• 
For safety reasons, if total lymphocyte count < 200 cells/µL at any study visit until 
EOT or < 800 cells/µL at EOS is recorded by the central laboratory, an alert will be 
sent to the principal investigator and to the sponsor including lymphocyte count. For 
further guidance, please refer to Section 5.1.8.2. 
5.1.3.3 Unblinding for final analyses 
Full randomization information will be made available for data analysis only after database 
lock, in accordance with the sponsor’s Quality System (QS) documents.  
5.1.3.4 Unblinding for IDMC 
An ISAC, not otherwise involved in the design, conduct, and analysis of the study, will 
have access to the randomization code to prepare unblinded periodic reports for review by 
the IDMC during the course of the trial. The randomization code will be made available to 
the ISAC in accordance with the sponsor’s Standard Operating Procedures (SOPs). 
5.1.3.5 Unblinding before final analyses 
The randomization code will be made available to the bioanalytical laboratory for PK 
measurement in accordance with the sponsor’s SOPs. 
5.1.3.6 Unblinding for suspected unexpected serious adverse reactions 
If a suspected unexpected serious adverse reaction (SUSAR) see definition in 
Section 9.1.3 occurs in a subject participating in the study, the sponsor’s Global Drug 
Safety department will request the unblinding of the treatment assignment to meet 
regulatory reporting requirements. 
The treatment assignment will not be communicated to site personnel, subjects, sponsor 
CTT or any vendor/CRO personnel involved in the conduct of the study. 
Unblinded SUSAR information will be reported to respective Health Authorities and 
Independent Ethics Committees (IECs) / Institutional Review Boards (IRBs). SUSARs will 
be notified to investigators in a blinded fashion. 

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5.1.3.7 Emergency procedure for unblinding 
The investigator, study personnel, subjects, CRAs, sponsor personnel, and any CRO 
personnel involved in the conduct of the study must remain blinded to the subject’s 
treatment assignment.  
The identity of the study treatment may be revealed only if the subject experiences an 
emergency medical event, the management of which would require knowledge of the 
blinded treatment assignment. In this case, the decision to unblind resides solely with the 
investigator and the investigator can receive the unblinded treatment assignment through 
the IRT system. Whenever possible and provided it does not interfere with (or does not 
delay) any decision in the best interest of the subject, the investigator is invited to discuss 
the intended unblinding with the sponsor personnel. 
The occurrence of any emergency unblinding during the study must be clearly justified and 
explained by the investigator. In all cases, the sponsor personnel must be informed about 
the occurrence of an emergency unblinding as soon as possible before or after the 
unblinding. The sponsor personnel should not be informed about the unblinded treatment 
code. 
The circumstances leading to unblinding must be documented in the hospital charts and in 
the Investigator Site File (ISF). 
5.1.4 Study treatment supply 
Manufacture, labeling, packaging, and supply of study treatments will be conducted 
according to Good Manufacturing Practice, GCP, and any local or national regulatory 
requirements. 
All treatment supplies are to be used only in accordance with this protocol and not for any 
other purpose. 
5.1.4.1 Study treatment packaging and labeling 
5.1.4.1.1 Study treatment packaging  
Study treatment (cenerimod or placebo) is provided as tablets and is supplied in childproof 
bottles. 
5.1.4.1.2 Study treatment labeling 
Study treatment is labeled to comply with the applicable laws and regulations of the 
countries in which the study sites are located.  
The batch number and the re-test date (or expiry date) will be indicated on the study 
treatment labels as required by local regulations.  

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5.1.4.2 Study treatment distribution and storage  
Treatment supplies must be kept in an appropriate, restricted area and stored according to 
the conditions specified on the medication labels.  
5.1.4.3 Study treatment dispensing 
The subjects will receive sufficient study treatment to cover the period up to the next 
scheduled visit. Subjects are asked to return all used, partially used, and unused study 
treatment bottles at each visit. Should the treatment bottle dispensed at a scheduled visit be 
lost or damaged, a replacement bottle can be requested via the IRT system. The 
protocol‑mandated study drug dispensing/return procedures may not be altered without 
prior written approval from the sponsor. 
In exceptional circumstances (e.g., if the subject lost the study treatment between two 
visits, or if the subject is unable to return to the site due to a medical emergency 
/ hospitalization at another hospital), unscheduled dispensing and delivery of study 
treatment may occur outside of a scheduled visit. An accurate study treatment record of the 
date and amount of study treatment dispensed to each subject must be available at the site 
for inspection at any time. 
5.1.4.4 Study treatment return and destruction  
The protocol-mandated study treatment return procedures may not be altered without prior 
written approval from the sponsor. On an ongoing basis and/or upon termination of the 
study, the CRA will collect used and unused subject kits, which will be sent to the 
warehouse, where the sponsor or a representative will check treatment reconciliation.  
In certain circumstances, used and unused treatment bottles may be destroyed at the site 
once treatment accountability is finalized and checked by the sponsor or a representative, 
and written permission for the destruction has been obtained from the sponsor. 
5.1.5 Study treatment accountability and compliance with study treatment 
5.1.5.1 Study treatment accountability 
The inventory of study treatment dispensed and returned (i.e., study treatment 
accountability) must be performed by the study staff on the day of the subject visit and 
before providing further study treatment. It is recorded on the investigational medicinal 
product dispensing and accountability log and in the eCRF and checked by the CRA during 
site visits and at the end of the study. The study treatment accountability log in the eCRF 
will include at least the following information for each study treatment bottle dispensed to 
the subject: 
• 
Dispensed bottle number 
• 
Date dispensed / number of tablets dispensed (pre-populated in eCRF) 

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• 
Date returned / number of tablets returned 
All study treatment supplies, including partially used or empty bottles, must be retained at 
the site for review by the CRA. 
If a subject omits to bring the remaining study treatment bottle to a study visit, he/she must 
be instructed to not take any tablets from the remaining study treatment bottle and to return 
it at one of the next visits.  
5.1.5.2 Study treatment compliance  
Treatment compliance will be assessed based on study treatment accountability: 
Accountability based compliance = [(number of tablets dispensed at Visit n − number of 
tablets returned at Visit n+1) / number of tablets that should have been taken during the 
period*]  100 
* The period is defined as the number of days elapsed between the respective visits.  
During the study, study treatment compliance based on accountability is expected to be 
80% or above. If below 80% without a medical justification (e.g., AE) this will be 
considered as a protocol deviation.  
The investigator must check with the subject the reasons for this non-compliance and 
discuss actions to be taken to avoid re-occurrence at the next visit. If the subject forgets to 
bring the remaining study treatment to a study visit, he/she will be asked to bring it to the 
next visit. 
5.1.6 Study treatment interruptions 
Study treatment should not be interrupted. If study treatment intake is interrupted by the 
subject for a day or more for any reason, he/she must inform the principal investigator.  
Study treatment may be temporarily interrupted in response to an AE, or other reasons 
(e.g., diagnostic or therapeutic procedure, study treatment forgotten). Interruptions of study 
treatment must be kept as short as possible. All study treatment interruptions must be 
recorded in the eCRF. 
The following guidance is provided for re-initiation of study treatment after study treatment 
interruptions.  
Note that under no circumstances should a subject take more than one tablet per day. 
5.1.6.1 Study treatment interruption between Day 1 and Day 14 
A re-initiating study visit is required after study drug interruption lasting more than 7 days 
between Day 1 and Day 14. 

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• During this period if the subject omits to take the dose for 7 or more consecutive days, 
the subject must inform the principal investigator and a re-initiation visit should take 
place no later than 7 days after the investigator is aware of the treatment interruption. 
Re-initiation of study treatment must be monitored on site following the cardiac 
assessment schedule and applying the discharge criteria as on Day 1. 
• If, at any visit (scheduled or unscheduled), the subject reports to the investigator that 
he/she missed taking the dose for one or more days during the initial 2 weeks of 
treatment (Day 1 to Day 14) but then resumed study treatment without reporting the 
interruption promptly, information on any event potentially related to the interruption 
should be collected and the subject should be counseled on the risks of non-compliance. 
Information on the treatment interruption must be recorded in the eCRF. No re-initiation 
should be performed in such a case. 
5.1.6.2 Study treatment interruption after Day 14 
If the subject missed doses after Day 14 a re-initiation visit is not required. Information on 
any event potentially related to the interruption should be collected and the subject should 
be counseled on the risks of non-compliance. Information on the treatment interruption 
must be recorded in the eCRF. Subjects must be instructed to contact the investigator 
immediately if they experience any symptoms that may be related to bradycardia (e.g., 
dizziness, vertigo, syncope). 
5.1.7 Premature discontinuation of study treatment 
The decision to prematurely discontinue study treatment may be made by the subject, the 
investigator, or Idorsia personnel. The main reason (e.g., AE, lack of efficacy) must be 
documented in the eCRF and in the subject’s medical charts. 
At the time of information to subject / informed consent process, the investigator should 
explain to the subject the importance of continuing treatment in compliance with the 
protocol once randomized for the scientific validity of the study. However, a subject has 
the right to prematurely discontinue study treatment at any time, without any justification, 
by withdrawal from study treatment only or by withdrawal from any further participation 
in the study (i.e., premature withdrawal from the study [see Section 8.2]). A subject who 
prematurely discontinues study treatment is not considered as withdrawn from the study 
provided that the subject’s consent for participation in the study has not been withdrawn.  
In the event of premature discontinuation of study treatment for any reason: 
• Subjects should perform the pEOT visit, which must take place preferably no later than 
7 days after the last dose of study treatment, and all assessments planned at the pEOT 
visit, must be performed.  

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• Subjects must be followed up as per the original planned scheduled visits up to 
12 months after study treatment initiation. Subjects will have to perform all 
assessments of scheduled visits as planned and data should be collected. 
• Subjects who are no longer on treatment at Month 6 will not require re-randomization 
through the IRT system and will continue to be followed up during TP2 as per protocol 
schedule. 
• For subjects who were followed up for at least 6 months after last dose of study 
treatment, the EOS visit should be performed at Month 12. 
• For subjects who perform the pEOT visit less than 6 months prior to the Month 12 visit, 
the 6-month posttreatment follow-up period must be completed in its entirety. For 
example, if a subject completes pEOT visit at Month 8, the visits originally scheduled 
for Month 9, Month 10, Month 11 and Month 12 are conducted as planned, in 
replacement of FU1, FU2, FU3 and FU3a visits, respectively. After the Month 12 visit, 
FU3b and EOS visits are conducted, which corresponds to 6 months of posttreatment 
follow-up. For further examples, please refer to Appendix 18. 
It is also recommended that the investigator explains to the subject the importance of 
continuing in the study even if the subject wishes to be withdrawn from study treatment. 
This will reduce the amount of missing data. Measures in place to increase subject retention 
in the study are described in Section 5.1.9.  
Although a subject is not obliged to give his/her reason for prematurely withdrawing from 
the treatment or the study, it is recommended that the investigator makes a reasonable effort 
to ascertain the reason(s), while fully respecting the subject’s rights. 
The investigator should discontinue study treatment for a given subject if, on balance, 
he/she believes that continued administration would be contrary to the best interests of the 
subject. Study-specific criteria for discontinuation of study treatment are described in 
Section 5.1.8. 
Premature discontinuation of study treatment may also result from a decision by the 
sponsor (e.g., in the event of premature termination or suspension of the study [see 
Section 8.3]). 
A subject who prematurely discontinues study treatment and withdraws consent to 
participate in any further study assessments is considered as withdrawn from the study. 
Subjects who die or are lost to follow-up are also considered as withdrawn from the study. 
Withdrawal from the study and follow-up medical care of subjects withdrawn from the 
study are described in Sections 8.2 and 8.4, respectively. 

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5.1.8 Study-specific criteria for interruption / premature discontinuation of study 
treatment 
5.1.8.1 Cardiovascular 
All clinically relevant ECG or vital sign abnormalities as per investigator’s judgment must 
be recorded as an AE in the eCRF as per protocol AE definitions [see Section 9.1.1]. 
5.1.8.1.1 Day 1 specific stopping criteria 
Subjects must be permanently discontinued from study treatment if any of the following 
occurs on Day 1 of treatment or on days of re-initiation following study treatment 
interruptions [see Appendix 6]:  
• HR < 40 bpm at two consecutive hourly 12-lead ECG post-dose assessments. 
• SBP < 90 mmHg at two consecutive hourly BP measurements post-dose 
− For subjects with baseline pre-dose SBP < 90 mmHg: decrease in SBP of 
> 5 mmHg from pre-dose SBP value at two consecutive hourly BP measurements 
post-dose. 
• The subject does not meet the criteria for discharge from the monitored setting at 12-
hour post-dose. 
• Continuous ECG monitoring is recommended for subjects who meet study treatment 
discontinuation criteria related to bradycardia, arrhythmia or low BP on Day 1. Subjects 
who are permanently discontinued should not be discharged from the monitored setting 
before vital signs return to near baseline values, there is no persisting ECG abnormality 
(e.g., AV block second degree or higher) and/or the ongoing AE requiring (continued) 
hospitalization is resolved [see Appendix 6]. 
5.1.8.1.2 Other cardiovascular stopping criteria 
• If QTcF > 500 ms (females) or > 480 ms (males) is observed at any time throughout the 
study, as documented by 12-lead ECG (one immediate re-test is allowed). If at the re-
test, QTcF is confirmed > 500 ms, (females) or > 480 ms (males), the subject must be 
permanently discontinued from study treatment. Subjects with QTcF prolongation 
should be monitored until the absence of the persisting ECG abnormality can be 
confirmed. 
• Symptomatic bradycardia or hypotension (e.g., syncope) at any time.  
Follow-up monitoring will have to be provided until the AE resolves and the subject’s 
condition is stable. 

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5.1.8.2 Immune system 
Subjects must be permanently discontinued from study treatment at any time throughout 
the study in the event of confirmed total lymphocyte count < 200 cells/L, according to 
the guidance provided below and in Figure 2.  
Whenever a total lymphocyte count < 200 cells/L is recorded by the central laboratory, 
an alert containing the lymphocyte count result will be sent to the site / principal 
investigator and the sponsor. The principal investigator will immediately contact the 
subject and ask him/her to return to the site within 48 hours at the latest to repeat the test 
at trough level (pre-dose) at the central laboratory (unless the clinical situation mandates 
immediate local testing). If the repeat test confirms a total lymphocyte count 
< 200 cells/L, the study treatment must be permanently discontinued, and lymphocyte 
counts must be monitored on a regular basis (e.g., every 2 weeks). If the lymphocyte count 
is still < 800 cells/µL at the EOS visit, monitoring should be continued on a regular basis 
(e.g., every 2 weeks) by the local laboratory until the lymphocyte count has returned to 
≥ 800 cells/L.  

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Figure 2
Guidance for monitoring total lymphocyte count
5.1.8.3
Respiratory system
In the event of abnormal spirometry results the subject will be closely observed, spirometry 
assessments will be repeated, and study treatment must be permanently discontinued, 
according to the guidance provided in Table 2.
Table 2
Guidelines for FEV1 decrease 
Item
Parameter
Guideline
1
If FEV1 15% decrease from Visit 1.
Repeat spirometry assessments 
preferably within 1 week.
See item 1a, 1b.
1a
If at repeat spirometry assessment:
FEV1 15% decrease from Visit 1.
Permanently discontinue study 
treatment and perform FU spirometry 
assessments.
1b
If at repeat spirometry assessment:
FEV1 15% decrease from Visit 1.
Resume regular spirometry assessment 
schedule. 
FEV1 = forced expiratory volume in 1 second; FU = follow-up.

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Further diagnostic work-up and consultation with a pulmonologist or other specialist 
should be considered according to local practice.  
In all cases of permanent study treatment discontinuation, follow-up monitoring must be 
provided until respiratory AEs are resolved and/or changes in pulmonary function are 
resolved, or steadily resolving. 
5.1.8.4 Pregnancy / lack of compliance with protocol methods of contraception 
If a subject becomes pregnant while on study treatment, study treatment must be 
permanently discontinued. The investigator/delegate must counsel the subject and discuss 
the risks of continuing with the pregnancy and the possible effects on the fetus. 
If a subject has a positive urine pregnancy test, study treatment must be interrupted 
immediately. A serum pregnancy test must be performed as soon as possible. If the 
pregnancy is confirmed, study treatment must be permanently discontinued (apart from 
study drug, also some co-medications may have to be considered for discontinuation). If 
the result of the serum pregnancy test is negative, study drug may be re-initiated as 
indicated in the study treatment interruptions section. 
If the investigator considers that the subject is not complying with the protocol methods of 
contraception instructions, study treatment must be permanently discontinued. 
5.1.8.5 Liver enzyme abnormalities 
In the event of abnormal liver tests (LTs) or signs and symptoms suggestive of 
drug-induced liver injury, the subject will be closely observed, LTs will be repeated, and 
study treatment must be permanently discontinued, according to the guidance provided in 
Figure 3. 

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Figure 3
Guidance for monitoring liver test abnormalities
* Symptoms include unusual lethargy or fatigue, nausea, vomiting, right upper quadrant pain or tenderness, jaundice, 
anorexia, dark urine, fever, rash, itching and/or eosinophilia (> 5%).
** Investigator may consider permanent discontinuation.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR = international normalized ratio; LT = liver 
test; TBIL = total bilirubin; ULN = upper limit of normal. 
When marked abnormalities for AST, ALT, TBIL, or international normalized ratio (INR)
are reached as indicated in Figure 3, an alert will be sent by the central laboratory to the 
site / principal investigator and the sponsor. The sponsor will contact the site / principal 
investigator to ensure that he/she will immediately contact the subject to enquire about 
symptoms and ask him/her to return to the site within 72 hours at the latest to repeat the 
test at the central laboratory (unless the clinical situation mandates immediate local 
testing). 
In the event of repeated abnormal LTs within 72 hours, the subject will be closely observed 
and liver enzyme and bilirubin tests will be repeated by the central laboratory or locally 
according to the scheme illustrated in Figure 3. Further diagnostic work-up and 
consultation with a hepatologist or other specialist should be considered according to local 
practice. 

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In all cases of permanent study treatment discontinuation, follow-up monitoring must be 
conducted until signs and symptoms have resolved and/or changes in liver function 
abnormalities have resolved or are steadily improving. 
5.1.8.6 Ocular abnormalities 
Subjects with suspected macular edema or retinal vasculitis: 
• 
The diagnosis should be confirmed by diagnostic work-up as recommended by local 
guidelines (e.g., optical coherence tomography [OCT] or fluorescence angiography).  
• 
The Ophthalmology Safety Board will receive all available, required information 
related to suspected cases of macular edema or any other relevant ophthalmologic 
cases and will perform a central, blinded review of OCT results and the subject’s data.  
• 
The study drug must be temporarily interrupted during the case assessment. In the 
event the Ophthalmology Safety Board assess the case as confirmed or suspicious 
macular edema, study treatment must be permanently discontinued. The subject must 
be followed up until resolution or condition is considered non-clinically significant by 
the investigator.  
5.1.8.7 Infections 
Subjects should be advised to be pro-active and alert in reporting any signs and symptoms 
indicative of systemic infections such as fever, malaise, and fatigue or any unusual 
neurological symptoms suggestive of brain infection. 
In the event of a serious infection as per investigator judgment (e.g., opportunistic infection 
or serious infection requiring i.v. medication or hospitalization), the subject should be 
treated as clinically indicated and the investigator should consider permanent 
discontinuation of study treatment. Concomitant immunomodulatory medications may also 
be discontinued at the discretion of the investigator. The decision to permanently 
discontinue study treatment will be made after evaluation of all available information 
concerning all potential causes of infection and the clinical status of the subject. Further 
diagnostic work-up and consultation with an infectious disease specialist or other specialist 
should be considered according to local practice and the clinical situation.  
In the event of permanent discontinuation from study treatment due to infection, adequate 
treatment needs to be provided, and the subject must be monitored until complete 
resolution of the infection. Furthermore, subjects should not receive any of the prohibited 
systemic immunosuppressive treatments during the follow-up period of 6 months after last 
study drug intake, unless clinically indicated and justifiable in the opinion of the 
investigator. 

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5.1.8.8 Other potential premature treatment discontinuation  
In the event of incorrect study drug dispensing (incorrect kit dispensed) and incorrect study 
drug intake detected before assignment of a new kit, the subject must be permanently 
discontinued from study treatment. 
Furthermore, in the event of permanent discontinuation from study treatment for any 
reason, subjects should not receive any of the prohibited systemic immunosuppressive 
treatments or other forbidden therapies during the follow-up period of 6 months after last 
study drug intake, unless clinically indicated and justifiable in the opinion of the 
investigator. Also, the allowed concomitant therapies should stay within the 
protocol‑defined ranges during the follow-up period of 6 months after last study drug intake 
and may only be changed if clinically indicated and justifiable by the investigator. 
5.1.9 Measures for subject retention 
Subjects withdrawn from study treatment are encouraged to remain in the study until its 
completion.  
In order to ensure compliance with the study procedures, subjects that are prematurely 
discontinued from study treatment should continue to be followed up as per the original 
planned visits [see Section 5.1.7].  
The investigator is encouraged to explain to the subjects the importance of remaining in 
the study for data accuracy purposes and scientific relevance of the study results. The ICF 
will also highlight the scientific importance of the subject’s data. 
5.2 Previous and concomitant therapy 
5.2.1 Definition of previous and concomitant therapy 
A previous therapy is any treatment for which the end date is prior to start of study 
treatment. Relevant previous therapies (e.g., SLE treatment) for which the end date is less 
than 12 months prior to ICF signature will be recorded in the eCRF. 
A study-concomitant therapy is any treatment (including methods of contraception and 
traditional and alternative medicines, i.e., plant-, animal-, or mineral-based medicines) 
given for any reason including the background SLE therapy that is either ongoing at the 
start of study treatment or is initiated during the study treatment period, or during the 
follow-up period up to Visit 18 (EOS). All study-concomitant therapies administered will 
be reported in the eCRF.  
The generic name, start/end dates of administration (as well as whether it started prior to 
first study treatment administration and/or was ongoing at EOS), route, dose, frequency, 
and indication for use will be recorded in the eCRF. 

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5.2.2 Background SLE therapy 
To be eligible for the study, subjects must currently receive at least one of the below SLE 
background medications:  
• NSAIDs 
− Aspirin (acetylsalicylic acid), 
− Ibuprofen, 
− Naproxen, 
− Celecoxib, 
− Others. 
• Corticosteroids (≤ 40 mg/day prednisone or equivalent [see Appendix 1]) 
− Prednisolone, 
− Prednisone, 
− Methylprednisolone, 
− Dexamethasone, 
− Betamethasone, 
− Hydrocortisone, 
− Triamcinolone, 
− Cortisone. 
• Anti-malarials  
− Hydroxychloroquine (≤ 400 mg/day),  
− Chloroquine (≤ 500 mg/day), 
− Quinacrine (≤ 100 mg/day). 
• Mycophenolate mofetil (≤ 2 g/day) 
• Mycophenolic acid (≤ 1440 mg/day) 
• Azathioprine (≤ 2 mg/kg/day) 
• Methotrexate (≤ 20 mg/week) 
• Belimumab (≤ 10 mg/kg every 4 weeks i.v., or 200 mg/week s.c.) 
Treatment with anti-malarials, mycophenolate mofetil, mycophenolic acid, azathioprine, 
methotrexate or belimumab must have been started at least 90 days prior to Screening. All 
other background SLE therapies must have been started at least 30 days prior to Screening.  
Background SLE therapy doses must be stable for at least 30 days prior to Randomization. 
For corticosteroids, doses must be stable for at least 15 days prior to Randomization [see 
Section 5.2.2.1]. 

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Subjects must be reminded of the importance of the adherence to SLE background 
medication starting at the Screening visit and throughout the duration of the study. The 
non-adherence to SLE background therapy may confound interpretation of study results.  
5.2.2.1 Oral corticosteroids  
Eligibility criteria related to corticosteroids 
For subjects who are being treated with corticosteroids prior to enrollment in this study, it 
is required for eligibility that corticosteroids: 
• Were started for at least 30 days prior to Screening. 
• Doses are stable for at least 15 days prior to Randomization. 
• Doses are ≤ 40 mg/day prednisone or equivalent [see equivalence in Appendix 1]. 
Screening period / oral corticosteroid optimization period for subjects receiving 
OCS 
For subjects who are being treated with corticosteroids prior to enrollment in this study, an 
optimization period aiming to reduce the doses of OCS to (or as close as possible to) the 
minimum effective dose should be considered during the screening period. This will allow 
the minimization of the OCS changes during the treatment period, which is the preferred 
approach.  
Dose reductions are at the investigator’s discretion and can be done up to 15 days prior to 
Randomization when the OCS dose must be stable as per eligibility criteria.  
Investigators should consider the guidance provided in Table 3. This table reflects the ACR 
draft guidance regarding steroid reduction during periods of stable SLE disease.  
Treatment Period 1 (from Randomization to Month 6) 
For subjects who are being treated with corticosteroids, it is preferable that doses are 
maintained stable until the end of Month 6 of the study to avoid introducing confounding 
factors for the interpretation of the primary objective. The dose adjustment recommended 
during Screening aims to minimize the change in OCS dose during the treatment period.  
For subjects showing improving SLE disease activity for at least 8 weeks, OCS dose 
reduction may be considered at the investigator’s discretion during the first 3 months of 
TP1 [see suggested guidance in Table 3]. No steroid sparing is allowed between Month 3 
and Month 6 (i.e., between Visit 5 and 8). Rationale for dose change and details of the 
change should be documented in the eCRF.  
Subjects with increased SLE disease activity may receive one OCS burst during the first 
3 months of TP1, which should be tapered to the Randomization dosage within 2 weeks of 

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initiation of the upgrade / initiation of the OCS. Alternatively, a single intramuscular or i.v. 
dose of methylprednisone (80 to 160 mg or equivalent) is permitted instead of OCS burst. 
Rationale for dose change and details of the change should be documented in the eCRF. 
Treatment Period 2 (after Month 6 of treatment) 
After the first 6 months of study, OCS dose reduction may be considered for subjects 
showing improving SLE disease activity for at least 8 weeks. Investigators should consider 
the guidance provided in Table 3. This table reflects the ACR draft guidance regarding 
steroid reduction during periods of stable SLE disease.  
Subjects with increased SLE disease activity may receive one OCS burst after Month 6, 
which should be tapered to Randomization dosage within 2 weeks of initiation of the 
upgrade / initiation of the OCS. Alternatively, a single intramuscular or i.v. dose of 
methylprednisone (80 to 160 mg or equivalent) is permitted instead of OCS burst.  
Table 3 
Algorithm for reducing dose of prednisone  
Daily dose (mg) 
Dose reduction (mg) 
Up to 7.5 
1.0 
> 7.5 to 15 
2.5 
> 15 to 30 
5.0 
> 30 to 40 
10.0 
> 40 
Taper at the investigator’s discretion using draft guidelines 
prepared for ACR  
ACR = American College of Rheumatology. 
 
5.2.3 Allowed concomitant therapy 
After Randomization, background medications should be kept stable throughout the study. 
However, if clinically required, changes in certain medications as outlined below are 
allowed: 
• Stable chronic NSAID therapy: therapy is not to be started or stopped during the study.  
− Temporary use and/or dose change for treatment of non-SLE-related conditions 
(e.g., headache, menstrual cramps) is allowed.  
• Stable immunosuppressant therapy (i.e., methotrexate, azathioprine, or mycophenolate 
mofetil, mycophenolic acid as well as belimumab). Therapy is not to be started or 
stopped during the study, and the dose should be kept stable. 

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• Atropine (i.v.) in the event of symptomatic bradycardia. 
• Topical ocular therapy (e.g., chronic treatment for glaucoma, ocular inflammation), 
including dilating eye drops, mydriatics, parasympathetic antagonists (e.g., 
tropicamide) or sympathetic agonists (e.g., phenylephrine). 
• Vaccination with non-live vaccines. 
• Topical treatment therapy including topical, inhaled, and nasal use of corticosteroid. 
• All other medications that are not forbidden [see Section 5.2.4]. 
5.2.4 Forbidden concomitant therapy 
• Immunosuppressive agents not listed in allowed concomitant medication such as 
cyclophosphamide, ciclosporine, leflunomide, sirolimus, tacrolimus, etc. 
• Immunosuppressive 
or 
immunomodulatory 
biological 
agents 
(e.g., 
i.v. 
immunoglobulin, rituximab, S1P receptor modulators other than cenerimod). 
• β-blockers, diltiazem, verapamil, digoxin, digitoxin, or any other anti-arrhythmic or 
HR-lowering therapy. 
• QT-prolonging drugs with known risk of torsade de pointes. 
• Vaccination with live vaccines.  
• Inhibitors of the breast cancer resistance protein transporter: curcumin, ciclosporine, 
eltrombopag, elacridar, gefitinib, teriflunomide. 
For further details, see table of forbidden medications in Appendix 3 and Appendix 4. 
6 
STUDY ENDPOINTS 
6.1 Efficacy endpoints 
6.1.1 Primary efficacy endpoint 
• 
Change from baseline to Month 6 in the mSLEDAI-2K score. 
This endpoint is based on the SLEDAI-2K index, modified to exclude leukopenia.  
The SLEDAI-2K will be assessed by the investigator or delegate who will enter the 
relevant data into the SLEDAI-2K form of the eCRF. Further details are available in 
Section 7.2.6.1. 
Baseline is defined as the last available measurement before the start of randomized 
treatment. All values of mSLEDAI-2K from baseline through Month 6 visits will be 
accounted for in the assessment of this endpoint. 

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6.1.2 Secondary endpoints 
• Response on SRI-4 at Month 6 as compared to baseline, defined as follows: 
− Reduction from baseline of at least 4 points in the mSLEDAI-2K. 
AND 
− No new BILAG A organ domain score and no more than one new BILAG B 
organ domain score compared with baseline. 
AND 
− No increase of more than 0.3 points on the PGA since baseline. 
• Response (no worsening) at Month 6 on BILAG-2004 disease activity index defined as 
no new BILAG A organ domain score and no more than one new BILAG B organ 
domain score compared with baseline. 
6.1.3 Other efficacy endpoints 
• Response at Month 6 based on improvement in the mSLEDAI-2K score defined as a 
reduction from baseline of at least 4 points.  
• Response (no worsening and improvement) at Month 6 on BILAG-2004 disease 
activity index defined as follows: 
− 
No new BILAG A organ domain score and no more than one new BILAG B 
organ domain score compared with baseline.  
AND 
− 
Any BILAG A organ domain score at study baseline improved to B/C/D or any 
BILAG B organ domain score at study baseline improved to C/D. 
• SRI-5, -6, -7, -8 responses at Month 6. 
• Occurrence of mild, moderate and severe flares for 6 months [see SLE Flare Index 
(SFI) in Appendix 12]. 
• Time to first severe flare from baseline to Month 6 (severe flares defined as 
BILAG-2004 A organ domain score presence due to items that are new or worse). 
• Time to first flare from baseline to Month 6. 
• Change from baseline to Month 6 in PGA score. 
6.1.4 PRO / Quality of life endpoints 
• Change from baseline to each post-baseline assessment in Functional Assessment of 
Chronic Illness Therapy (FACIT) Fatigue Scale score.  

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• Change from baseline to each post-baseline assessment in PGA score. 
• Occurrence of flares and severe flares at each post-baseline assessment (defined as 
either 1 or more new BILAG-2004 A or 2 or more new BILAG-2004 B items compared 
to the previous visit). 
• Time to first severe flare from baseline to Month 12 (severe flares defined as 
BILAG-2004 ‘A’ score presence due to items that are new or worse). 
• Time to first flare from baseline to Month 12. 
6.2 Safety endpoints 
• Occurrence of treatment-emergent AEs/SAEs, and AESIs [see Appendix 5]. 
• Occurrence of AEs leading to premature discontinuation of study treatment. 
• Changes in 12-lead ECG variables (HR, PR, QRS, QT, QT corrected for heart rate 
using Bazett’s formula [QTcB] and QTcF), from baseline to each post-baseline 
assessment up to EOS (i.e., each post-dose time point on Day 1 / Re-initiation and each 
post-dose analysis visit up to EOS) for each variable. 
• Occurrence of treatment-emergent 12-lead ECG notable abnormalities (e.g., HR, PR, 
QTc) [see Appendix 7]. 
• Occurrence of treatment-emergent 12-lead ECG abnormal findings. 
• Change in supine SBP and DBP from baseline to each post-baseline assessment up to 
EOS (i.e., each post-dose time point on Day 1 / Re-initiation and each post-dose 
analysis visit up to EOS). 
• Change in FEV1 and FVC from baseline to each post-baseline assessment up to EOS. 
• Occurrence of treatment-emergent decrease of FEV1 or FVC > 15% from baseline 
values at any post-baseline assessment. 
• Change in laboratory variables (hematology, blood chemistry, and urinalysis) from 
baseline to each post-baseline assessment up to EOS. 
• Occurrence of treatment-emergent laboratory notable abnormalities [see Appendix 7]. 
• Change in body weight from baseline up to EOS. 
• Change in left ventricular ejection fraction as assessed by Standard 2D 
echocardiography from Screening to Month 6 in subjects randomized to ancillary 
echocardiography study.  
• Occurrence of clinically relevant abnormalities as assessed by Standard 2D/Doppler 
echocardiography from Screening to Month 6 in subjects randomized to ancillary 
echocardiography study. 

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6.3 Pharmacokinetic endpoints 
• Cenerimod plasma concentrations post-dose on Day 1, 6 h after dosing.  
• Ctrough cenerimod plasma concentrations prior to dosing at Months 1, 2, 3, and 6 or at 
EOT visit after premature study treatment discontinuation (if applicable). 
• Cenerimod plasma concentration at the EOS visit (i.e., 6 months after last dose of study 
treatment). 
6.4 Biomarker endpoints 
• Change from baseline to each post-baseline assessment up to EOS in total lymphocyte 
count. 
• Change from baseline to each post-baseline assessment in the following biomarkers: 
ANA, anti-dsDNA, anti-Smith (anti-Sm), and C3, C4 complement. 
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS 
7.1 Study visits 
The study visits and their respective assessments and time windows are listed in Table 4.  
All efforts should be made to keep subjects on schedule, based on the date of their Day 1 
(Visit 2), which is the day of Randomization. 
To ensure compliance, at each visit the study personnel must remind WOCBP to use the 
methods of contraception defined for this study. When scheduling the different assessments 
for a subject visit, the following should be taken into account: 
• The subject must come to the clinic in a fasted condition for all visits except for EOT, 
FU1, EOS and unscheduled visits. Subjects should be instructed not to take the study 
medication in the morning of the day of the visit.  
• At Visit 2 (Randomization, Day 1) and at the Re-initiation visit (if applicable [see 
Section 7.1.2]), assessments during the visits will be divided into two parts: before 
(pre-dose) and after (post-dose) the administration of the study drug, which will be taken 
at the site [see Sections 7.1.2 and 7.1.5]. 
• At other visits, SBP/DBP, ECGs, spirometry, blood draws for hematology/biochemistry 
and PK, are to be performed pre-dose.  
• Resting time: 
− When a subject has to go to another department within the hospital for a specific 
test, sufficient time should be allowed for the subject to rest prior to the 
examination. 

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− Sufficient time between blood drawing and cardiac assessments (i.e., ECGs and/or 
BP measurement) is to be allowed.  
• All PK sampling should be done pre-dose except for Day 1. 
• Safety follow-up information will be collected during the FU1 visit; FU2, FU3, FU3a, 
and FU3b visits (phone call visit), and at the EOS visit (6 months after last study drug 
intake). Efficacy data will be collected at FU1 and EOS visits. 
7.1.1 Screening 
The date of the Screening visit is the date when the ICF is signed see Section 12.3 for the 
informed consent procedure. 
The subjects who agree to participate in the study and the investigator/delegate must sign 
the ICF prior to any study-related assessment or procedure. 
If the signing of the ICF and performance of the first study-specific procedures or 
assessments take place on the same day, it must be clear from the source documents that 
informed consent was obtained prior to any study-specific procedures being performed. If 
a study-specific procedure or assessment has been performed as part of routine assessments 
on the day of the Screening visit or before the Screening visit, and the results are available 
prior to the subject signing the ICF, such procedure or assessment may be used and does 
not have to be repeated (e.g., vital signs). In such cases, it must be clear from the source 
documents when and for which reason the assessment was done prior to the signing of the 
ICF. 
For convenience reasons, study-specific procedures or assessments can take place on 
different days during the screening period. 
Subjects who sign the ICF when the enrollment target has already been met may still be 
randomized. 
Within the 60 days of the screening period, subjects may repeat abnormal laboratory tests 
and abnormal PFT (FEV1 or FVC) required to meet eligibility criteria.  
For subjects who are being treated with corticosteroids prior to enrollment in this study, an 
optimization period aiming to reduce the doses of OCS to (or as close as possible to) the 
minimum effective dose, should be considered during the screening period [see 
Section 5.2.2.1]. 
7.1.1.1 Re-screening 
Subjects who did not meet the criteria for participation in the study (i.e., screen failure) 
may be re-screened once if the reason for non-eligibility was transient (e.g., laboratory test 

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result outside protocol limit, abnormal pulmonary function test, insufficient wash-out 
period of a forbidden medication, etc.).  
Eligibility assessments must be repeated at the time of re-screening if more than 3 months 
have elapsed from the initial screening assessment. 
Subjects who were not eligible due to a negative test for varicella-zoster antibodies may 
also be re-screened once after completing all required vaccination doses, which must occur 
at least 30 days prior to re-test and Randomization. 
A new ICF must be signed prior to re-screening the subject if more than 3 months have 
elapsed since the first ICF signature. Re-screened subjects will be assigned the same 
subject number as for the initial screening. 
7.1.2 Visit 2 – Day 1 – Randomization and pre- and post-dose assessment 
After confirmation of eligibility (i.e., verification of all entry criteria before dosing) by the 
investigator, randomization should occur via IRT to obtain randomization and study 
treatment kit numbers. Study treatment should then be dispensed and the subject should 
take the first dose of study treatment at site after pre-dose assessments are completed.  
Visit 2 pre-dose assessments include: 
• Inclusion/exclusion criteria 
• Physical examination 
• Clinical mSLEDAI-2K, BILAG, PGA, and SFI 
• PRO and quality of life (FACIT-Fatigue Scale, PGIS-F, SF-36v2™ and Lupus QoL) 
• Hematology and blood chemistry 
• SLE biomarkers serum sampling 
• Urine pregnancy test 
• Urinalysis 
• Urine protein-to-creatinine ratio 
• SBP/DBP assessment 
• 12-lead ECG 
• Start 24 hours ECG Holter  
• Recording of AEs and SAEs 
• Recording of changes in concomitant medications and background SLE therapies since 
previous visit. 

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Visit 2 post-dose assessments include: 
• Hourly 12-lead ECG and SBP/DBP assessments for 6 hours or until the subject meets 
the discharge criteria [see Appendix 6].  
• After 6 hours, subjects may be discharged from the monitored setting if they meet the 
discharge criteria, otherwise SBP/DBP assessments and 12-lead ECG will be performed 
hourly until discharge criteria are met. If discharge criteria are not met after 12 hours, 
the subject must be permanently discontinued from study treatment.  
• PK sample 6 hours after dosing. 
• Recording of AEs and SAEs.  
The subject will be instructed to contact the site if he/she has any questions or problems. 
WOCBP will be reminded to use the methods of contraception defined for this study.  
An appointment for the next visit will be scheduled and the subject will be instructed to: 
• Bring back the remaining study medication for drug accountability, 
• Come fasted to the site, 
• Not take study treatment on the day of study visit prior to coming to the site, 
• Contact the principal investigator immediately in the event of the appearance of any 
symptoms (e.g., suggestive of an SLE flare) or any AEs or SAEs or if a study treatment 
dose is missed. 
7.1.3 Scheduled study visits 
Study visit assessments from Visit 3 up to Visit 13 should be performed as described in 
Table 4.  
• Study medication should be taken at the site.  
• Whenever applicable, SBP/DBP, ECGs, spirometry, blood draws for hematology and 
biochemistry and PK, should be performed pre-dose. 
• PK sampling at Visit 3, 4, 5 and 8 should be done pre-dose. 
• All other scheduled assessments can be performed pre-dose or post-dose. 
7.1.4 Follow-up visits and EOS visit 
Five follow-up visits (FU1, FU2, FU3, FU3a, and FU3b) will be performed after the EOT 
visit and before the EOS visit. 
FU1 visit will be performed at the site one month after EOT.  

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FU2, FU3, FU3a, and FU3b visits will be phone call visits and will be done 2 months, 
3 months, 4 months and 5 months after EOT, respectively.  
Assessments at FU visits will include:  
• Recording of AEs and SAEs.  
• Urine pregnancy test for WOCBP (performed at home prior to phone contacts with test 
kits dispensed at Visit 14/EOT). 
• Recording of changes in concomitant medications and background SLE therapies since 
previous visit – FU1 and EOS only. 
• Efficacy data: mSLEDAI-2K, BILAG, PGA, SFI (FU1 and EOS only) and 
FACIT‑Fatigue, PGIS-F, PGIC-F, SF-36v2™, and Lupus QoL (EOS only). 
EOS visit assessments will be performed 6 months after the last dose of study treatment as 
per schedule of assessment Table 4. 
7.1.5 Unscheduled visits  
Unscheduled visits (U1, U2, and others) may be performed at any time during the study 
based on medical needs. These visits include, but are not limited to, those performed due 
to safety (e.g., occurrence of an AE/SAE, laboratory abnormalities), and/or SLE disease 
exacerbations (e.g., flare). 
The date of the visit and the reason for such visits as well as any data related to study 
assessments performed at unscheduled visits will be recorded in the eCRF. 
During an unscheduled visit, the following assessments must be performed:  
• Recording of changes in concomitant medications and background SLE therapies since 
last visit. 
• Recording of AEs/SAEs. 
Depending on the reason for the unscheduled visit (e.g., AE), additional assessments will 
be performed based on the judgment of the investigator, and the results will be recorded in 
the eCRF. Any clinically relevant abnormalities detected must be reported as an AE or 
SAE as appropriate in the corresponding Adverse Event form of the eCRF. After an 
unscheduled visit, the regular scheduled study visits must continue according to the 
planned visit and assessment schedule. 
7.1.6 Additional visits for re-initiation of study treatment 
Re-initiation visits should be conducted for study treatment interruption lasting more than 
7 consecutive days between Day 1 and Day 14 [see Section 5.1.6]. 

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Note that a subject can be re-initiated only once during the study duration. 
The re-initiation post-dosing procedure must be followed:  
• Hourly 12-lead ECG and SBP/DBP assessments for 6 hours or until the subject meets 
the discharge criteria. If discharge criteria are not met after 12 hours, the subject should 
be permanently discontinued. 
• PK sample 6 hours after dosing. 
• Recording of AEs and SAEs. 
• Recording of changes in concomitant medications and background SLE therapies since 
previous visit. 
• Study drug accountability for compliance review. 
 

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Table 4 
Visit and assessment schedule 
PERIODS 
Name 
SCREENING 
TREATMENT PERIOD 1 
From Day 1 to Month 6  
 
Duration 
Up to 60 days 
VISITS 
Number 
1 
2 
2a 
3 
4 
5 
6 
7 
8 
 
 
Name 
 
Screening 
 
Randomization (1) 
 
Month 1 
 
Month 2 
 
Month 3 
 
Month 4 
 
Month 5 
 
Month 6 
 
Time 
 
Day –60 to  
Day –1 
 
Day 1 
 
Day 2 
 
Day 30 
(2 days) 
 
Day 60 
(7 days) 
 
Day 90 
(7 days) 
 
Day 120 
(7 days) 
 
Day 150 
(7 days) 
 
Day 180 
(7 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Smoking and alcohol consumption status 
X 
 
 
 
 
 
 
 
 
Medical history and SLE history 
X 
 
 
 
 
 
 
 
 
SLE and previous/concomitant therapies 
X 
X 
 
X 
X 
X 
X 
X 
X 
Physical examination (2) 
X 
X 
 
X 
X 
X 
X 
X 
X 
Body weight and height (3) 
X 
 
 
 
 
 
 
 
 
mSLEDAI-2K, BILAG, PGA, SFI 
X 
X 
 
X 
X 
X 
X 
X 
X 
FACIT-Fatigue, PGIS-F 
 
X 
 
 
 
X 
 
 
X 
PGIC-F 
 
 
 
 
 
X 
 
 
X 
SF-36v2™ and Lupus QoL 
 
X 
 
 
 
 
 
 
X 
Chest X-ray (5) 
X 
 
 
 
 
 
 
 
 
Vital signs: SBP/DBP* (6) (7) 
X 
X 
 
X 
X 
X 
 X 
X 
X 
12-lead ECG* (7) 
X 
X 
 
 
 
X 
 
 
X 
ECG Holter* (8) 
 
X 
X 
 
 
 
 
 
 
Echocardiography (4) 
X 
 
 
 
 
 
 
 
X 
Spirometry* 
X 
 
 
 
 
X 
 
 
X 
Ophthalmological examinations 
X 
 
 
 
 
X 
 
 
X 
OCT 
X 
 
 
 
 
X 
 
 
 

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PERIODS 
Name 
SCREENING 
TREATMENT PERIOD 1 
From Day 1 to Month 6  
 
Duration 
Up to 60 days 
VISITS 
Number 
1 
2 
2a 
3 
4 
5 
6 
7 
8 
 
 
Name 
 
Screening 
 
Randomization (1) 
 
Month 1 
 
Month 2 
 
Month 3 
 
Month 4 
 
Month 5 
 
Month 6 
 
Time 
 
Day –60 to  
Day –1 
 
Day 1 
 
Day 2 
 
Day 30 
(2 days) 
 
Day 60 
(7 days) 
 
Day 90 
(7 days) 
 
Day 120 
(7 days) 
 
Day 150 
(7 days) 
 
Day 180 
(7 days) 
PK sampling* (9)  
 
X  
 
X 
X 
X 
 
 
X 
Hematology and blood chemistry* (10) 
X 
X 
 
X 
X 
X 
X 
X 
X 
Pregnancy test (11) 
X 
X 
 
X 
X  
X 
X 
X 
X 
Viral serology / TB test 
X 
 
 
 
 
 
 
 
 
Additional sample for virology 
 
X 
 
 
 
 
 
 
 
SLE biomarkers  
X 
X (13) 
 
X 
X 
X (13) 
X 
X 
X (13) 
Urine protein-to-creatinine ratio 
X 
X 
 
X 
X 
X 
X 
X 
X 
Urinalysis (dipstick) 
X 
X 
 
X 
X 
X 
X 
X 
X 
Study treatment dispensing/return and accountability 
 
X 
 
X 
X 
X 
X 
X 
X 
AEs (12) / SAEs (12) 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 

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PERIODS 
Name 
TREATMENT PERIOD 2  
From Month 6 to Month 12 
 
Duration 
VISITS 
Number 
9 
10 
11 
12 
13 
14 
 
Name 
Month 7 
Month 8 
Month 9 
Month 10 
Month 11 
Month 12 / End-of-Treatment (EOT) / premature 
discontinuation of study treatment (pEOT) (14) 
 
Time 
Day 210 
(7 days) 
Day 240 
(7 days) 
Day 270 
(7 days) 
Day 300 
(7 days) 
Day 330 
(7 days) 
 
SLE and previous/concomitant therapies  
X 
X 
X 
X 
X 
X 
Physical examination (2) 
X 
X 
X 
X 
X 
X 
Body weight (3) 
 
 
 
 
 
X 
mSLEDAI-2K, BILAG, PGA, SFI 
X 
X 
X 
X 
X 
X 
FACIT-Fatigue, PGIS-F, PGIC-F, SF-36v2™ and 
Lupus QoL  
 
 
X 
 
 
X 
Echocardiography (4) 
 
 
 
 
 
X 
Vital signs: SBP/DBP* (6) (7) 
X 
X 
X 
X 
X 
X 
12-lead ECG* (7) 
 
 
X 
 
 
X 
Spirometry* 
 
 
X 
 
 
X 
Ophthalmological examinations 
 
 
 
 
 
X 
OCT 
 
 
 
 
 
X 
Hematology and blood chemistry* (10) 
X 
X 
X 
X 
X 
X 
Pregnancy test (11) 
X 
X 
X 
X 
X  
X 
Urinalysis (dipstick) 
X 
X 
X 
X 
X 
X 
SLE biomarkers 
X 
X 
X 
X 
X 
X (13) 
Urine protein-to-creatinine ratio 
X 
X 
X 
X 
X 
X 
PK sampling* 
 
 
 
 
 
X (9) 
Study treatment dispensing/return and accountability 
X 
X 
X 
X 
X 
X 
AEs (12) / SAEs (12) 
X 
X 
X 
X 
X 
X 

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PERIODS 
Name 
FOLLOW-UP 
 
Duration 
6 months 
VISITS 
Number 
15 
16 
17 
17a 
17b 
18 
 
 
Name 
FU1 
FU2 
PHONE CALL 
FU3 
PHONE CALL 
FU3a 
PHONE CALL 
FU3b 
PHONE CALL 
EOS 
 
Time 
1 month after last 
dose (16) 
(7 days) 
2 months after last 
dose (16) 
(7 days) 
3 months after last 
dose (16) 
(7 days) 
4 months after last 
dose (16) 
(7 days) 
5 months after 
last dose (16) 
(7 days) 
6 months after last 
dose (16) 
(7 days) 
SLE and concomitant therapies 
X 
 
 
 
 
X 
Physical examination (2) 
X 
 
 
 
 
X 
Body weight (3) 
 
 
 
 
 
X 
mSLEDAI-2K, BILAG, PGA, SFI 
X 
 
 
 
 
X 
FACIT-Fatigue, PGIS-F, PGIC-F, SF-36v2™, and Lupus 
QoL  
 
 
 
 
 
X 
Vital signs: SBP/DBP* (6) (7) 
X 
 
 
 
 
X 
12-lead ECG* (7) 
 
 
 
 
 
X 
ECG Holter* (8) 
 
 
 
 
 
 
Echocardiography (4) 
 
 
 
 
 
 
Spirometry* 
 
 
 
 
 
X 
Ophthalmological examinations 
 
 
 
 
 
X 
OCT 
 
 
 
 
 
 
PK sampling* (9)  
 
 
 
 
 
X 

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PERIODS 
Name 
FOLLOW-UP 
 
Duration 
6 Months 
VISITS 
Number 
15 
16 
17 
17a 
17b 
18 
 
 
 
Name 
FU1 
FU2 
PHONE CALL 
FU3 
PHONE CALL 
FU3a 
PHONE CALL 
FU3b 
PHONE CALL 
EOS 
 
Time 
1 month after last 
dose (16) 
(7 days) 
2 months after last 
dose (16) 
(7 days) 
3 months after last 
dose (16) 
(7 days) 
4 months after last 
dose (16) 
(7 days) 
5 months after 
last dose (16) 
(7 days) 
6 months after last 
dose (16) (7 days) 
Hematology and blood chemistry* (10) 
X 
 
 
 
 
X 
Pregnancy test (11) 
X 
X 
X 
X 
X 
X 
Viral serology / TB test 
 
 
 
 
 
 
Urinalysis (dipstick) 
X 
 
 
 
 
X 
SLE biomarkers 
X 
 
 
 
 
X 
Urine protein-to-creatinine ratio 
X 
 
 
 
 
X 
Study treatment dispensing/return and accountability 
 
 
 
 
 
 
AEs (12)/ SAEs (12) 
X 
X 
X 
X 
X 
X 
 
 
 

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PERIODS 
Name 
UNSCHEDULED 
 
Duration 
NA 
VISITS 
Number 
U1, U2, … 
I1 
I2 
 
 
Name 
Unscheduled (15) 
Re-initiation 
 
Time 
Any day between Day 1 and EOS 
(assessments to be performed as applicable) 
Re-initiating study drug after interruption lasting 
more than 7 days between Day 1 and Day 14 
SLE and concomitant therapies 
X 
X 
 
Physical examination (2) 
X 
X 
 
Body weight (3) 
X 
 
 
mSLEDAI-2K, BILAG, PGA, SFI 
X 
 
 
FACIT-Fatigue, PGIS-F, PGIC-F, SF-36v2™, and Lupus QoL  
X 
 
 
Chest X-ray (5) 
X 
 
 
Vital signs: SBP/DBP* (6) (7) 
X 
X 
 
12-lead ECG* (7) 
X 
X 
 
ECG Holter* (8) 
 
X 
X 
Echocardiography (4) 
X 
 
 
Spirometry* 
X 
 
 
Ophthalmological examinations 
X 
 
 
OCT 
X 
 
 
PK sampling* (9)  
 
X 
 

Cenerimod / ACT-334441 
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Protocol ID-064A202 
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Doc No D-22.031 
 
 
PERIODS 
Name 
UNSCHEDULED 
 
Duration 
NA 
VISITS 
Number 
U1, U2, … 
I1 
I2 
 
 
 
Name 
Unscheduled (15) 
Re-initiation 
 
Time 
Any day between Day 1 and EOS 
(assessments to be performed as applicable) 
Re-initiating study drug after  
interruption lasting more than 7 days between 
Day 1 and Day 14 
Hematology and blood chemistry* (10) 
X 
 
 
Pregnancy test (11) 
X 
 
 
Viral serology / TB test 
X 
 
 
Urinalysis (dipstick) 
X 
 
 
SLE biomarkers 
X 
 
 
Urine protein-to-creatinine ratio 
X 
 
 
Study treatment dispensing/return and accountability 
 
X 
 
AEs (12)/ SAEs (12) 
X 
X 
 
 
One month is considered to be 30 days. 
Day 1 (date of Randomization visit) is to be used as the reference date for the purpose of calculating the subsequent visit dates (and time windows). 
For WOCBP, the serum pregnancy test at Visit 1 must be performed at least 3 weeks before the urine pregnancy test performed at Visit 2 prior to Randomization. 
* Study treatment should not be taken before the assessment (i.e., SBP/DBP, ECGs, spirometry, laboratory tests, and PK sampling). 
 
(1) Prior to Randomization, the following central laboratory results must be available to confirm eligibility: ANA, anti-dsDNA, anti-HAV IgM, Hepatitis B surface antigen, Hepatitis C 
antibodies (anti-HCV IgG or IgM), anti-HEV IgM and/or IgG, HEV-RNA PCR (as needed), HIV1 and HIV2, varicella-zoster virus IgM antibody, urine protein-to-creatinine ratio, 
ALT/AST/TBIL and pregnancy test (if applicable). 
(2) A complete physical examination (i.e., inspection, percussion, palpation, and auscultation) will only be performed at Visits 1, 2, 3, 5, 8, 11, 14, and 15. For all other visits, a 
symptom-driven abbreviated physical examination will be performed in order to capture assessments needed for the SLEDAI-2K, the PGA, the BILAG, and the SFI. 
(3) Height only at Screening. Body weight should be measured as part of BILAG assessment at each applicable visit and recorded in the source documentation. If clinically relevant, body 
weight collected outside Screening, EOT and EOS visits may be reported as an Unscheduled assessment. 
(4) Echocardiography will be performed at Visit 1 (Screening) preferably within 30 days prior to Randomization for all subjects and at Visit 8 (Month 6) in approximately 175 subjects, as 
part of the ancillary study. In the event of premature study treatment discontinuation during TP1 (i.e., before Visit 8), echocardiography will be performed at pEOT visit and will not be 
required at Visit 8. 

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(5) A chest X-ray that has been performed within 6 months prior to Screening can be used (in this case, there is no need to repeat the chest X-ray at Screening). 
(6) At each pre-dose assessment, SBP/DBP measurements will be performed twice in the supine position. 
(7) On Day 1 and at Re-initiation visit, SBP/DBP assessment and 12-lead ECG will be done pre-dose and hourly until 6 h post-dose; after 6 h, subjects may be discharged if they meet the 
discharge criteria, otherwise SBP/DBP assessments and 12-lead ECG will be performed hourly until discharge criteria are met. If discharge criteria are not met after 12 h, the subject 
must be permanently discontinued. At all other visits, only pre-dose SBP/DBP assessments and 12-lead ECG will be performed. 
(8) On Day 1 and at Re-initiation visit, 24-hour ECG Holter should start before dosing. The subject must return to the site on Day 2 (Visit 2a) / Re-initiation (Visit I2) for removal of the 
device after 24-hour recording. 
(9) On Day 1 and at Re-initiation visit, PK samples will be collected 6 hours after dosing. At Visits 3, 4, 5, and 8, PK samples will be collected pre-dose. At pEOT visit, in the event of 
premature treatment discontinuation during TP1 (i.e., before Visit 8) and at EOS visit, PK samples will be collected at any time during the visit and will not be required at Visit 8. 
(10) Hematology assessments, including coagulation tests will be performed at each visit until EOS, except FU2, FU3, FU3a, and FU3b visits. 
(11) Serum pregnancy tests will be performed at Screening and EOS. Urine pregnancy tests will be performed at all other visits. To ensure compliance, the study personnel must remind 
WOCBP at each visit to use the methods of contraception defined for this study from the Screening visit until 6 months after taking the last dose of study treatment. 
(12) All AEs and SAEs occurring after signing the ICF and up to 6 months after study treatment discontinuation must be reported. 
(13) Sample for SLE biomarkers analyses will include: SLE biomarkers serum sample, serum EDTA sample and PAXgene sample.  
(14) If the subject discontinues study treatment prematurely, the pEOT visit should preferably take place no later than 7 days after last study drug intake. Subjects who prematurely 
discontinue treatment will remain in the study and continue to perform all assessments as per planned visit schedule. See Section 5.1.7 for additional details on premature discontinuation 
of study treatment. 
(15) Unscheduled visits may be performed at any time during the course of the study. Recording the changes in concomitant medications and in background SLE therapies since the last visit 
needs to be performed at each unscheduled visit. Further assessment including body weight, chest X-ray, 12-lead ECG, SBP/DBP, echocardiography, SLEDAI-2K, PGA, BILAG, 
FACIT-Fatigue Scale, PGIS-F, PGIC-F, SF-36v2™, Lupus QoL, laboratory assessments and other disease activity assessments may be performed at the discretion of the investigator. 
(16) Applicable for subjects having completed TP2 according to the protocol schedule up to Month 12 / EOT (Visit 14). 
 
AE = adverse event; ALT = alanine aminotransferase; ANA = anti-nuclear antibodies; anti-dsDNA = anti-double-stranded deoxyribonucleic acid; anti-HAV = anti-hepatitis A virus; 
anti‑HCV = anti-hepatitis C virus; anti-HEV = anti-hepatitis E virus; AST = aspartate aminotransferase; BILAG = British Isles Lupus Assessment Group; DBP = diastolic blood 
pressure; ECG = electrocardiogram; EDTA = ethylenediaminetetraacetic acid; EOS = End-of-Study; EOT = End-of-Treatment; FACIT-Fatigue = Functional Assessment of Chronic 
Illness Therapy-Fatigue Scale score; FU = follow-up; HEV-RNA PCR = hepatitis E virus ribonucleic acid polymerase chain reaction; HIV = human immunodeficiency virus; 
I =re‑initiation; ICF = informed consent form; Ig = immunoglobulin; mSLEDAI-2k = modified Systemic Lupus Erythematosus Disease Activity Index-2000; NA = not applicable; OCT 
= optical coherence tomography; pEOT = premature discontinuation of study treatment or premature End-of-Treatment; PFT = pulmonary function test; PGA= Physician’s Global 
Assessment; PGIC-F = Patient Global Impression of Change – Fatigue; PGIS-F = Patient Global Impression of Severity – Fatigue; PK = pharmacokinetic(s); QoL = Quality of life; 
SAE = serious adverse event; SBP = systolic blood pressure; SF-36v2™ = 36-Item Short Form Health Survey version 2; SFI = SLE Flare Index; SLE = systemic lupus erythematosus; 
SLEDAI-2K = Systemic Lupus Erythematosus Disease Activity Index-2000; TB = tuberculosis; TBIL = total bilirubin; U = unscheduled; WOCBP = women of childbearing potential. 
 

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7.2 Study assessments 
The study assessments are listed in Table 4.  
All study assessments performed during study visits (scheduled or unscheduled) are done 
by the investigator/delegate and are recorded in the eCRF, unless otherwise specified. 
Study assessments performed during unscheduled visits will also be recorded in the eCRF.  
If the principal investigator delegates any study procedure/assessment for a subject (e.g., 
ECG, OCT, blood sampling, etc.) to an external facility, he/she should inform the sponsor 
to whom these tasks are delegated. The set-up and oversight will be agreed upon with the 
sponsor. The supervision of any external facilities remains under the responsibility of the 
principal investigator. At Visit 2 (Randomization / Day 1) and at study treatment 
re-initiation visits where post-dose monitoring is required, the pre- and post-dose 12-lead 
ECG assessments will be performed under the responsibility of the investigator who will 
interpret the results. The pre-dose 12-lead ECG interpretation (before Randomization) will 
support the subject’s final eligibility decision made by the investigator according to the 
inclusion/exclusion criteria.  
The post-dosing 12-lead ECGs will be performed together with BP assessments hourly 
until 6 hours post-dose. At this time, subjects may be discharged from the monitored setting 
if they meet the discharge criteria [see Appendix 6], otherwise 12-lead ECG and BP will 
be assessed hourly until discharge criteria are met. If the subject does not meet the defined 
discharge criteria at 12 hours post-dose, the subject will be permanently discontinued from 
the study treatment and will be kept in the hospital for observation.  
7.2.1 Demographics / baseline characteristics 
Demographic and baseline characteristic data to be collected on all subjects including 
screening failure subjects. 
The below data are to be recorded in the eCRF: 
• Baseline demographics and anthropometric variables (sex, age, race, and ethnicity [if 
allowed in the country]), body weight, and height.  
• Relevant medical history / current medical conditions other than those related to SLE 
(e.g., chronic and ongoing acute conditions, serious past conditions) present before 
signing of the ICF. Where possible, main diagnoses and not symptoms will be recorded. 

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7.2.1.1 Medical history 
7.2.1.1.1 General medical history 
Relevant medical history, as defined below, must be recorded in the eCRF: 
• Chronic medical conditions including pulmonary, CNS, liver function, renal function, 
eye disorder, and skin conditions at any time in the past. Cardiovascular medical 
conditions are to be recorded in a dedicated eCRF page [see Section 7.2.1.1.2]. 
• New acute medically relevant conditions including any serious infection, defined as 
life-threatening or requiring i.v. antibiotics or hospitalization in the past 6 months. 
• Exposure to healthcare settings in the past 3 months (e.g., hospitalization, emergency 
care admissions, visit to emergency medical services facility). 
• Pregnancy morbidity (e.g., fetus loss, spontaneous abortion, premature birth). 
• Previous and concomitant therapy [see Section 5.2].  
• History of chemotherapy, radiotherapy, operations, immunosuppression or any other 
relevant medical treatment. 
7.2.1.1.2 Cardiovascular medical history 
Relevant cardiovascular medical history, as defined below, must be recorded in the eCRF: 
• Valvular heart disease, arrhythmias, tachycardia, bradycardia, atrial fibrillation, atrial 
flutter, PR interval shortened, QTc prolonged, left ventricular hypertrophy, right 
ventricular hypertrophy, angina pectoris, myocardial infarction, coronary artery disease, 
heart failure (current NYHA class should be provided), cardiomegaly, pericarditis, 
myocarditis, endocarditis, idiopathic cardiomyopathy, congenital heart disease, 
previous heart surgery, stroke, transient ischemic attack, peripheral vascular disease, 
deep vein thrombosis. 
• Cardiovascular risk factors: hypertension, hypercholesterolemia, atherosclerosis, 
diabetes mellitus, sedentary lifestyle, overweight, obese, family history of heart disease. 
7.2.1.1.3 SLE-relevant medical history 
SLE disease characteristics as defined below, evidenced by documentation in the subject 
charts, will be recorded in the eCRF: 
• Date of first SLE symptoms. 
• Date of SLE diagnosis. 
• SLE symptoms according to ACR criteria [ACR 1997, Appendix 2]. 

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7.2.1.2 Data to be collected for screening failure subjects 
A minimal set of screening failure information is required to ensure transparent reporting 
of screening failure subjects. 
For subjects who failed Screening, the following data will be recorded in the eCRF: 
• Age, sex, race, and ethnicity (if allowed in the country); 
• Inclusion criteria not met and/or exclusion criteria met; 
• SAEs. 
7.2.2 Previous and concomitant therapies 
All background/previous SLE therapies, as well as all study-concomitant therapies will be 
reported in the corresponding eCRF pages [see Section 5.2]. 
7.2.3 Safety assessments 
The definitions, reporting, and follow-up of AEs and SAEs are described in Section 9.1.1. 
7.2.3.1 Weight and height 
Height will be measured at Visit 1 (Screening).  
Body weight (in underwear) will be measured at Visit 1 (Screening), Visit 14 (EOT) and 
Visit 18 (EOS) and recorded in the eCRF. Body weight should be measured as part of 
BILAG assessment at each applicable visit [see Section 7.2.6.3] and recorded in the source 
documentation. If clinically relevant, body weight collected outside Visit 1 (Screening), 
Visit 14 (EOT) and Visit 18 (EOS) may be reported as an Unscheduled assessment in the 
eCRF. 
7.2.3.2 Physical examination 
Complete physical examination (i.e., inspection, percussion, palpation, and auscultation) 
will be performed at Visits 1, 2, 3, 5, 8, 11, 14 and 15. For all other visits, a symptom-driven 
abbreviated physical examination will be performed in order to capture assessments needed 
for the SLEDAI-2K, the PGA, the BILAG, and the SFI. 
The observations should be reported in the eCRF as either normal or abnormal. If an 
abnormality is found, it should be specified on the corresponding eCRF page. All findings, 
including clinically not relevant findings that are present at study start (i.e., before signing 
the ICF), must be recorded on the Medical History or SLE-relevant disease history eCRF 
page. Physical examination findings made after study start that meet the definition of an 
AE/SAE [see Section 9.1] must be recorded by the principal investigator on an AE page of 
the eCRF and must be reported to the sponsor’s Global Drug Safety department (SAEs 
only). 

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7.2.3.3 12-lead ECG 
Digital 12-lead ECG devices will be provided to each site by the central ECG laboratory 
for the duration of the study. 
Digital 12-lead ECG recordings will be performed at pre-dose for all subjects at Visits 1, 
2, 5, 8, 11, 14/EOT and 18/EOS with the subject in a fully rested supine position after the 
subject has been allowed to rest for a minimum of 5 minutes prior to the measurement. 
Pre-dose ECGs also need to be performed at unscheduled visits and re-initiation visits, if 
applicable. The data records will be sent to the evaluation center for central reading. 
Details will be provided in the 12-lead ECG laboratory manual. 
The following parameters will be evaluated: HR (bpm), PR (ms), QRS (ms), QT (ms), QTc 
(ms), and any ECG findings. QTc (ms) will be calculated according to Bazett’s and 
Fridericia’s formula (QTcB = QT/(RR) 0.5 and QTcF = QT/(RR)0.33, respectively. 
ECG printout tracings must be reviewed, signed, and dated by the investigator as soon as 
possible after the examinations; a copy of the tracing should be made and both original and 
copy will be kept in the subject file.  
All ECG reports (received from central reader) must be signed and dated by the investigator 
and filed with the source documentation. The investigator must indicate on the ECG report 
whether abnormal values are considered clinically relevant or not. All ECG findings 
including clinically not relevant findings that are present at the time of signing the ICF 
must be recorded on the cardiovascular medical history page of the eCRF [see 
Section 7.2.1.1.2]. Any clinically relevant ECG abnormalities detected after signature of 
the ICF must be reported as an AE or SAE as appropriate [see Section 9.3]. The 12-lead 
ECGs will be performed under the responsibility of the investigator.  
At Visit 2 (Randomization / Day 1) and at study treatment re-initiation visits where 
post-dose monitoring is required, the pre- and post-dose 12-lead ECG assessments will be 
also performed under the responsibility of the investigator who will interpret the results.  
The pre-dose 12-lead ECG interpretation (before Randomization) will support the subject’s 
final eligibility decision made by the investigator according to the inclusion/exclusion 
criteria.  
The post-dosing 12-lead ECGs will be performed together with BP assessments hourly 
until 6 hours post-dose. At this time, subjects may be discharged from the monitored setting 
if they meet the discharge criteria [see Appendix 6], otherwise 12-lead ECG and BP will 
be assessed hourly until discharge criteria are met. If the subject does not meet the defined 
discharge criteria at 12 hours post-dose, the subject will be permanently discontinued from 
the study treatment and will be kept in the monitored setting for observation.  

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7.2.3.4 ECG Holter 
ECG Holter monitoring will be performed for 24 hours at Visit 2 (Randomization) and at 
Re-initiation visit.  
Digital ECG Holter devices will be provided to the sites for the duration of the study. The 
data records will be sent to the ECG Holter core laboratory for central reading.  
At Visit 2 (Randomization / Day 1) and Re-initiation visit, the 24-hour ECG Holter will be 
performed under the responsibility of the investigator. The recording must be initiated 
before first dosing. The subject will be allowed to leave the clinic with the Holter and to 
perform his/her usual daily activities. The recording will be stopped 24 hours post-dose. It 
is essential to have an uninterrupted recording during the 24 hours (including sleep hours).  
The central reading results (including alert notifications in the event of specific findings) 
of the ECG Holter performed at Visit 2 (Randomization) and Re-initiation visit will be sent 
to the investigator. 
The ECG Holter reports must be signed and dated by the investigator and filed with the 
source documentation. The investigator signing the ECG Holter report must indicate on the 
report whether abnormal values are considered clinically relevant or not. All Holter ECG 
findings including clinically not relevant findings that are present at the time of signature 
of the ICF must be recorded on the cardiovascular medical history page of the eCRF. Any 
clinically relevant Holter ECG abnormalities detected after signature of the ICF must be 
reported as an AE or SAE as appropriate [see Section 9.1.1] and must be followed until the 
event is resolved and/or the value returns to within the normal range or is steadily 
improving.  
7.2.3.5 Blood pressure 
BP measurements including SBP and DBP will be performed under the responsibility of 
the investigator and will be assessed at all scheduled visits except FU2 and FU3 visits. 
BP assessment will be performed using the same type of device throughout the study on 
the same arm with the subject in a fully rested supine position after the subject has been 
allowed to rest for a minimum of 5 minutes prior to the measurement. At each pre-dose 
assessment, SBP and DBP measurements will be performed twice. Each of the two 
obtained measurements (i.e., two SBP measurements and two DBP measurements) and the 
position and arm used are to be recorded in the eCRF. The means of the two obtained 
measurements will be calculated in the eCRF. Any clinically relevant BP abnormalities 
detected after informed consent signature must be reported as an AE or SAE as appropriate 
[see Section 9.1.1]. 
At Visit 2 (Randomization / Day 1), the pre- and post-dose SBP/DBP assessments will 
be performed in parallel to 12-lead ECGs until subject discharge. Pre-dose measurements 

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will be performed twice and recorded in the eCRF as described above for pre-dose 
assessments at all relevant scheduled visits. 
The hourly post-dose assessments will only be measured once at each hourly time point. 
Single SBP measurements will be used for determining discharge criteria. 
7.2.3.6 Echocardiography 
An echocardiography assessment will be performed during the screening period for all 
subjects, 
preferably 
within 
30 
days 
prior 
to 
Randomization. 
Unscheduled 
echocardiography examinations may be conducted at any time during the study as judged 
by the investigator. 
Standard 2D/Doppler echocardiography should assess cardiac morphology and function 
including regional wall abnormalities, aortic valve morphology and function, mitral valve 
morphology and function, and left ventricular ejection fraction. The echocardiography 
equipment needs to be maintained with preventive maintenance service occurring at least 
yearly.  
The physician conducting standard 2D/Doppler echocardiography must have a level of 
experience equivalent to at least Level 2 training, as defined in the American College of 
Cardiology Board / American Heart Association clinical competence statement on 
echocardiography. In case an expert sonographer is conducting the examination, the expert 
physician must review the echocardiography results. 
An echocardiography monitoring plan was developed for the study to ensure standardized 
data collection and assessment. The evaluation of the echocardiography data will be done 
by a central imaging laboratory.  
All echocardiography findings at Screening including clinically not relevant findings must 
be recorded on the cardiovascular medical history page of the eCRF. Any clinically 
relevant echocardiography abnormalities detected after Randomization must be reported 
as an AE or SAE as appropriate [see Section 9.1.1]  
Detailed instructions on procedures, standardization, qualification, recording, and transfer 
of data will be provided in a separate manual. 
For echocardiography ancillary study see Section 3.1.2. 
7.2.3.7 Spirometry 
Spirometry will be performed at Visit 1 (Screening), Visit 5 (Month 3), Visit 8 (Month 6), 
Visit 11 (Month 9), at EOT visit, at EOS visit and at unscheduled visits if required.  
Spirometry assessments after the Randomization visit can be performed up to 7 days prior 
to or after the visit date. All spirometry assessments should preferably be performed in the 

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morning at approximately the same time to avoid diurnal variation, and prior to study drug 
intake. Spirometry testing will assess FVC and FEV1. 
A central reader will provide equipment and a PFT manual with detailed instructions for 
the procedures, calibration, and validation of spirometers. All recorded spirometry values 
will be transmitted to the centralized provider, and will be reviewed by independent central 
readers. Quality of the assessments will be evaluated for compliance with the American 
Thoracic Society / European Respiratory Society criteria and queries may be sent to the 
sites for clarification. If quality issues are identified, additional training will be provided. 
The selection of the highest (largest) FEV1 and FVC values to be used for the endpoint 
derivations will be validated by the independent central readers prior to being electronically 
transferred to the sponsor. The date and time of the assessment will be reported in the 
eCRF. No other data will be reported in the eCRF. 
PFT values that trigger study drug discontinuation will be flagged and sent to the sites and 
the sponsor. Any clinically relevant PFT abnormality detected after signature of the ICF 
must be reported as an AE or SAE as appropriate [see Section 9.1.1] and must be followed 
until the value returns to within the normal range or is steadily improving. 
The predicted normal values for FEV1 and FVC used to determine the exclusion criteria 
and the study treatment interruption/premature discontinuation criteria [see Section 4.3 and 
Section 5.1.8, respectively] will be those as defined by the European Community for Coal 
and Steel including ethnic group adjustments [Quanjer 1993]. 
7.2.3.8 Ophthalmological examination 
An ophthalmological examination will be performed by an ophthalmologist at any time 
during the screening period but results must be available prior to the Randomization visit 
(Visit 2). Examinations after Screening will be performed at Visits 5, 8, 14/EOT, and 
Visit 18/EOS. The scheduled visits can be performed up to 7 days prior to or after the visit 
date [see Table 4]. 
The ophthalmological examination should include previous eye history and ophthalmic 
condition, any new or current ophthalmological symptoms, assessment of best corrected 
visual acuity per local standard practice, measurement of Goldmann applanation tonometry 
(recommended, if not available other applanation tonometer allowed), slit lamp 
examination of the anterior segment, and fundoscopy. While the visual acuity and 
measurement of applanation tonometry exams may be performed by a delegate (e.g., 
experienced technician, optometrist), the review and interpretation must be performed by 
the ophthalmologist. Conduct, review, and interpretation of all other ophthalmological 
exams must be performed by the ophthalmologist. 

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The purpose of the assessment prior to Randomization is to exclude subjects with macular 
edema or active uveitis from the study and to document a baseline assessment. Assessments 
at each visit will ensure that any new ophthalmological abnormality is detected and treated 
at an early stage.  
In the eCRF, the date of the ophthalmological examination and the presence/absence of 
any abnormality (i.e., Yes/No) will be recorded. The results will be documented in the 
subject charts but will not be reported in the eCRF. Clinically relevant findings that are 
present at the time of signature of the ICF must be recorded on the medical history page of 
the eCRF. Any clinically relevant ophthalmological abnormalities (including OCT findings 
detected after signature of the ICF) must be reported as an AE or SAE as appropriate [see 
Section 9.1.1] and must be followed until the value returns to within the normal range or 
is steadily improving. 
7.2.3.9 Optical coherence tomography 
OCT will be performed at Visit 1 (Screening), Visit 5 (Month 3), and at EOT visit. Testing 
at Visit 1 can be performed at any time during the screening period. At Visit 5 and EOT 
visit, testing may be performed up to 7 days prior to the visit date but no later than 7 days 
after the visit. In addition, unscheduled OCT examination will have to be assessed in the 
event of visual symptoms or findings suggestive of macular edema according to the 
ophthalmologist’s decision or if active uveitis is diagnosed during the study. While the 
OCT exam may be performed by a delegate (e.g., experienced technician, optometrist), the 
review and interpretation must be performed by the ophthalmologist.  
The purpose of the assessment prior to Randomization is to exclude subjects with macular 
edema or active uveitis from the study, and to document a baseline assessment. The site 
will use the OCT device available locally and must ensure it is working properly. A copy 
of the calibration certificates done before the day of assessment must be stored as source 
documents at the site. To the extent that is logistically feasible, the same OCT machine is 
to be used for each individual subject throughout the study.  
In the eCRF, the date of the OCT assessment and the presence/absence of any abnormality 
(i.e., Yes/No) will be recorded. The results will be documented in the subject charts but 
will not be reported in the eCRF. Any clinically relevant abnormalities detected after 
signature of the ICF must be reported as an AE or SAE as appropriate [see Section 9.1.1]. 
An Ophthalmology Safety Board will receive all information related to suspected cases of 
macular edema and will perform a central, blinded review of OCT images and subject’s 
data of suspected cases of macular edema. 

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7.2.3.10 Chest X-ray 
A chest X-ray will be performed at Visit 1 (Screening) and assessed by the local radiologist 
to exclude any subject with findings suggestive of active or latent TB and it is also part of 
the assessments of severe respiratory disease and pulmonary fibrosis. Any chest X-ray that 
had been performed within 6 months prior to Screening can be used; if available, there is 
no need to repeat the chest X-ray at Screening. The report of the chest X-ray must be 
recorded in the subject file. 
7.2.3.11 Test for tuberculosis 
An IFN gamma release assay (QuantiFERON-TB-Gold Plus®) will be performed at Visit 1 
(Screening) to screen for active or latent TB. The test will be analyzed and interpreted at 
the central laboratory and transferred to the principal investigator.  
Only subjects with a negative test at Screening and without chest X-ray findings [see 
Section 4.3] at Screening or within the previous 6 months suggestive of active or latent TB 
can be included in the study. If the test result is positive, subjects must not be included in 
the study, except if there is documentation that the subject has completed adequate and 
successful treatment for TB previously. If the test result is inconclusive (invalid, 
indeterminate, or borderline), the test may be repeated one time and a negative result must 
be obtained prior to Randomization to include the subject. If the result of the repeated test 
is inconclusive, subjects must not be included in the study. 
Details on the performance of the test for TB will be provided in the specific central 
laboratory manual. 
7.2.4 Laboratory assessments 
7.2.4.1 Type of laboratory 
A central laboratory will be used for all protocol-mandated laboratory tests, including 
re-tests due to laboratory abnormalities and laboratory tests performed at unscheduled 
visits. Central laboratory data will be transferred from the central laboratory database to 
the sponsor. See central laboratory manual for contact details. 
In exceptional cases (e.g., subject is hospitalized in a different hospital from the study 
center due to a medical emergency), local laboratory results (with the corresponding 
normal ranges) will be entered into the clinical database via dedicated eCRF pages. Due to 
functional blinding [see Section 5.1.3.2], testing of total WBC (including differentials) and 
lymphocyte counts at a local laboratory should not be performed unless deemed absolutely 
necessary to ensure subject’s safety. In this case, the local results of total WBC (including 
differentials) and lymphocyte counts collected until EOS visit will be recorded in the 
eCRF. 

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If a central laboratory sample is lost or cannot be analyzed for whatever reason, the 
investigator will collect an additional sample as soon as possible for repeat analysis, unless 
a local laboratory sample was collected within the same time window and these test results 
are available. 
Central laboratory reports will be sent to the investigator. In the event of specific 
(pre-defined) laboratory abnormalities, the central laboratory will alert the sponsor and the 
concerned clinical site. Values that will trigger such alert notification are displayed in 
Appendix 7. 
All laboratory reports must be signed and dated by the primary investigator or delegate 
within 10 working days of receipt and filed with the source documentation. The 
investigator/delegate must indicate on the laboratory report whether abnormal values are 
considered clinically relevant or not. Laboratory findings that are present at the time of 
signature of the ICF must be recorded on the medical history page of the eCRF. Any 
clinically relevant laboratory abnormalities detected after signature of the ICF must be 
reported as an AE or SAE as appropriate [see Section 9.1.1] and must be followed until the 
value returns to within the normal range or is steadily improving. Further laboratory 
analyses should be performed as indicated and according to the judgment of the 
investigator. 
Details about the collection, sampling, storage, shipment procedures, reporting of results, 
and abnormal findings can be found in the laboratory manual. 
7.2.4.2 Laboratory tests 
Blood samples will be drawn at all scheduled visits. At unscheduled visits, blood samples 
will be collected at the investigator’s discretion. Sample collection dates will be recorded 
in the eCRF [for biomarkers see Section 7.2.8]. 
Hematology 
• Hemoglobin 
• Hematocrit, mean corpuscular hemoglobin, mean corpuscular volume, and mean 
corpuscular hemoglobin concentration 
• Erythrocyte count (reticulocyte count) 
• Leukocyte count with differential counts* 
• Platelet count. 
* For the purpose of functional blinding [see Section 5.1.3.2], total WBC (including 
differentials) and lymphocyte counts will not be available to sites and to the sponsor during 
the study. This data will be available only after database lock. For the management of 
lymphocyte count < 200 cells/µL, please refer to Section 5.1.8.2 for more details.  

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Clinical chemistry 
• Aminotransferases (AST/ALT), alkaline phosphatase, total and direct bilirubin, lactate 
dehydrogenase 
• Creatinine 
• Blood urea nitrogen 
• Uric acid 
• Glucose 
• Cholesterol, triglycerides 
• Sodium, potassium, chloride, calcium 
• Protein, albumin. 
Test for tuberculosis 
• An IFN gamma release assay will be performed at Visit 1 (Screening) to screen for 
active or latent TB [see Sections 4.3 and 7.2.3.11]. 
Coagulation tests 
• Prothrombin time and INR. 
• Activated partial thromboplastin time. 
Pregnancy test 
A serum pregnancy test for WOCBP will be performed at Visit 1 (Screening) and Visit 18 
(EOS), and if pregnancy is suspected during the study. Urine pregnancy tests will be 
performed at all other visits.  
WOCBP must have a confirmed negative serum pregnancy test at Visit 1 (Screening) and 
a second confirmed negative urine pregnancy test prior to Randomization (Visit 2). The 
two tests must be performed at least 3 weeks apart.  
Serum pregnancy test results data will be automatically transferred from the central 
laboratory database to the sponsor. Urine pregnancy testing results will be recorded in the 
eCRF. In the event of pregnancy up to 6 months after the last dose of study medication, a 
Pregnancy form must be completed [see Section 9.4].  
Virus serology 
• Anti-HAV IgM, Hepatitis B surface antigen, Hepatitis C antibodies (anti-HCV IgG or 
IgM), anti-HEV IgG, anti-HEV IgM, HEV-RNA PCR (if positive anti-HEV IgM and/or 
IgG), HIV1 and HIV2 antibodies, varicella-zoster virus IgG antibodies will be assessed 
in serum at Visit 1 (Screening) (a confirmatory test might be required in the event of 
positive testing results [e.g., positive Hepatitis C antibodies]). 

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Additional analyses in the event of infections 
• A serum sample will be taken at Visit 2 (Randomization) and stored at the central 
laboratory for potential retrospective analyses of viral serology titers in the event of 
infections (e.g., suspected opportunistic infection) during the study. 
Urinalysis  
Including but not limited to: 
• pH 
• Glucose 
• Proteins 
• Blood 
• Leukocytes 
A midstream urine sample (approximately 30 mL) will be obtained, to avoid contamination 
with epithelial cells and sediments. Urine dipsticks provided by the central laboratory will 
be used to perform the urinalysis at all visits. The test will be performed and analyzed at 
the site, and the results will be recorded in the eCRF. 
If the dipstick results are positive for protein, leukocytes, or blood, the urine sample will 
be subject to further analysis as clinically indicated (i.e., microscopic analysis of WBC, red 
blood cells [RBC], casts, and protein quantification). The results of any further analysis 
must be documented in the source documents / subject charts and can be used for 
assessment of the SLEDAI-2K score.  
Urine protein-to-creatinine ratio is to be performed at all scheduled visits except FU2, FU3, 
FU3a, and FU3b visits. Urine samples will be collected and sent to the central laboratory 
for protein and creatinine measures, and determination of the protein-to-creatinine ratio. 
For the assessment of proteinuria, the protein-to-creatinine ratio in a single urine sample 
has been demonstrated as strongly correlated with the protein content of a 24-hour urine 
collection [Ginsberg 1983, Ruggenenti 1998, KDIGO 2012, Price 2005]. Due to this 
reason, the result from urine protein-to-creatinine ratio can be used in this study for 
assessment of both the SLEDAI-2K and BILAG scores. The relationship among these 
laboratory tests for proteinuria is provided below in Table 5 [KDIGO 2012]. 

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Table 5 
Relationship among laboratory tests for proteinuria 
Measure 
Unit 
Conversion factor 
24-hour urine protein excretion rate 
g/24 hours 
1 
mg/24 hours 
1000 
Urine protein-to-creatinine ratio 
mg/g 
1000 
mg/mmol 
100* 
* The conversion is rounded for pragmatic reasons. For an exact conversion from mg/g of creatinine to mg/mmol of 
creatinine, multiply by 0.113. 
 
7.2.5 Pharmacodynamic and pharmacokinetic assessments 
The PD marker is total lymphocyte counts, which will be measured as part of the 
hematology tests [see Section 7.2.4]. 
PK samples will be collected post-dose on Day 1 (Visit 2, Randomization) 6 hours after 
dosing.  
PK samples will be collected pre-dose at Visit 3 (Month 1), Visit 4 (Month 2), Visit 5 
(Month 3), and at Visit 8 (Month 6) or at EOT visit in the event of premature 
discontinuation of study treatment. 
PK sample will also be collected at EOS visit (i.e., 6 months after last dose of study 
treatment). 
The date and the time of blood sample collection will be entered in the eCRF.  
Details about the collection, sampling, storage, and shipment procedures can be found in 
the laboratory manual. Sites will receive required material from the central laboratory 
before the start of the study (e.g., tubes, labels, shipment materials). The site personnel will 
take care of the shipment of the plasma samples to the central laboratory who will forward 
the PK samples to the Idorsia bioanalytical laboratory at a time interval agreed with the 
sponsor.  
7.2.6 Disease activity assessments 
7.2.6.1 Systemic Lupus Erythematosus Activity Index-2000 
The SLEDAI-2K will be assessed by the principal investigator at all visits except Day 2, 
FU2, FU3, FU3a, and FU3b visits, and Re-initiation visit [see Appendix 9].  
The principal investigator will perform physical examinations, question the subject on 
his/her current state and about any potential SLE symptoms and/or manifestation that may 
have occurred during the past 10 days, and collect all laboratory parameters relevant to the 
scoring (e.g., protein-to-creatinine ratio, anti-dsDNA titer, dipstick urinalysis). If the 

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7.2.6.4 SLE Flare Index 
The classic Safety of Estrogens in Lupus Erythematosus National Assessment 
(SELENA)-SLEDAI Flare Index (cSFI) was originally developed specifically for the 
SELENA study [Buyon 2005, Petri 2005] with the aim of sensitively capturing flares of all 
types as well as distinguishing severe flares. Mild and moderate flares are not discriminated 
in the cSFI. 
The SFI is defined by an increase in the SLEDAI of 3 or more points (mild or moderate 
flare) or a 12 point increase (severe), a 0–3 visual analog scale with anchors for the 
physician global assessment (none, mild, moderate or severe flare) with an increase in 
1 (for mild/moderate) or 2.5 (for severe) and adding NSAIDs or hydroxychloroquine (for 
mild) or steroids, but no more than 0.5 mg/kg/day and/or adding a new immunosuppressant 
(for severe) [Buyon 2005, Petri 2002].  
The SFI will be assessed by the principal investigator at all visits except Day 2, FU2, FU3, 
FU3a, FU3b and re-initiation visits. The investigator will assess the SLE flare index [see 
Appendix 12] and relevant data will be entered in the SFI form of the eCRF. 
7.2.7 Patient Reported Outcomes 
All PRO questionnaires will be completed by the subject prior to any other protocol 
assessment and prior to any other discussion with the investigator or principal investigator. 
7.2.7.1 36-Item Short Form Health Survey v2 
The SF-36v2™ questionnaire [see Appendix 13] will be used to assess the subject’s quality 
of life. The SF-36v2™ will be completed by the subject at Visit 2 (Randomization), at 
Visit 8 (Month 6), Visit 11 (Month 9), Visit 14 (Month 12/EOT; for subjects completing 
12 months of treatment), Visit 18 (EOS) and unscheduled visit.  
In the SF-36v2™ questionnaire, subjects are instructed to rate their health and capacity to 
perform daily living activities in eight domains including physical functioning, physical 
role limitations, bodily pain, general health, vitality, social functioning, emotional role 
limitations, and mental health during the last 4 weeks. Raw domain scores are determined 
and transformed to a 0–100 scale as described in the SF-36v2™ manual, and individual 
domain scores are used to determine the physical and mental component summary scores 
as described in the SF-36v2™ manual [Maruish 2011].  
The standard SF-36v2™ considering the previous 4-week period will be used. A sample 
of the SF-36v2™ (in English) is provided in Appendix 13. The subject will complete the 
questionnaire in the local language on a validated paper form that will be collected. 

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7.2.9 Emerging SLE biomarkers (tested by the sponsor) 
SLE subject heterogeneity and the lack of disease activity biomarkers led to increasing 
efforts to identify biomarkers to characterize subjects and to investigate treatment response. 
CXCL10 and Type-I IFN, among others emerged as promising biomarkers. EDTA plasma 
samples will be collected at Randomization and at Visits 5, 8 and 14 (EOT). Samples will 
be frozen and stored by the sponsor for exploratory analysis of new emerging biomarkers. 
Samples will be kept for a maximum duration of 15 years and will be destroyed thereafter. 
Whole blood (PAXgene) samples will be collected at Randomization and at Visits 5, 8 and 
14 (EOT). Samples will be frozen and stored by the sponsor for exploratory analysis of 
biomarkers, e.g., Type-I IFN gene expression signature and antibody-secreting cells gene 
expression signature. Samples will be kept for a maximum duration of 15 years and will 
be destroyed thereafter. 
8 
STUDY COMPLETION AND POST-STUDY TREATMENT / 
MEDICAL CARE 
8.1 Study completion 
For an individual subject, study completion is reached when EOT visit and EOS visit have 
been completed as per protocol. 
The EOT visit of the last subject randomized in the study corresponds to Visit 14 and will 
occur at Month 12, or earlier if the study treatment is prematurely discontinued. 
For the first 5 months after the EOT visit, subjects will have to undergo FU1, FU2, FU3, 
FU3a, and FU3b visits, respectively, to collect information on any SAE and/or pregnancy 
(follow-up) and on efficacy. The FU2, FU3, FU3a, and FU3b visits are conducted by phone 
and will occur 2, 3, 4 and 5 months after EOT, respectively. EOS should occur 6 months 
after the EOT visit. 
The EOS at study level occurs at the time all subjects have completed their EOS visit, as 
described above. 
8.2 Premature withdrawal from study 
Subjects may voluntarily withdraw from the study without justification for any reason at 
any time. Subjects are considered withdrawn if they state an intention to withdraw further 
participation in all components of the study (i.e., withdrawal of consent), die, or are lost to 
follow-up. If a subject withdraws consent, no further data will be collected in the eCRF 
from the date of withdrawal onward. The investigator may withdraw a subject from the 
study (without regard to the subject’s consent) if, on balance, he/she believes that continued 
participation in the study would be contrary to the best interests of the subject. Withdrawal 

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from the study may also result from a decision by the sponsor for any reason, including 
premature termination or suspension of the study. 
Subjects are considered as lost to follow-up if all repeated attempts by the investigator to 
communicate with the individual have failed. The site must take preventive measures to 
avoid a subject being lost to follow-up (e.g., document different ways of contact such as 
phone number, home address, e-mail address, person to be contacted if the subject cannot 
be reached). If the subject cannot be reached, the site must make reasonable repeated efforts 
to contact the subject. The following methods must be used: at least 3 attempts at contact 
(e.g., phone calls, or e-mails) must be placed to the last available phone number or e-mail 
address and 1 registered letter must be sent by post to the last available home address. 
Additional methods may be acceptable if they are compliant with local rules/regulations 
(e.g., a visit by site personnel to the subject’s home), respecting the subject’s right to 
privacy. If the subject is still unreachable after all contact attempts listed above he/she will 
be considered lost to follow-up. 
The reason for premature withdrawal from the study must be recorded in the eCRF. 
If for whatever reason (except death or loss-to-follow-up) a subject is withdrawn from the 
study, the investigator should make best efforts to schedule a last appointment / phone call 
to assess the safety and well-being of the subject, collect unused study treatment and 
discuss follow-up medical care. Data obtained during this last appointment / phone call 
will be recorded in the subjects’ medical records but it will not be collected in the eCRF. 
The investigator must provide follow-up medical care for all subjects who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care, as described 
in Section 8.4. 
8.3 Premature termination or suspension of the study 
The sponsor reserves the right to terminate the study at any time globally or locally. 
Investigators can terminate the participation of their site in the study at any time. 
If the study is prematurely suspended or terminated, the sponsor will promptly inform the 
investigators, the IECs/IRBs, and Health Authorities, as appropriate, and provide the 
reasons for the suspension or termination. 
If the study is suspended or prematurely terminated for any reason, the investigator, in 
agreement with the sponsor, must promptly inform all enrolled subjects and ensure their 
appropriate treatment and follow-up, as described in Section 8.2. The sponsor may inform 
the investigator of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the subjects’ interests. 

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In addition, if the investigator suspends or terminates the study without prior agreement 
from the sponsor, the investigator must promptly inform the sponsor personnel and the 
IEC/IRB, and provide both with a detailed written explanation of the termination or 
suspension. 
If the IEC/IRB suspends or terminates its approval / favorable opinion of the study, the 
investigator must promptly notify the sponsor personnel and provide a detailed written 
explanation of the termination or suspension. 
A potential restart of the study will be allowed only in agreement with Health Authorities 
and IRBs/IECs. 
Study-specific subject’s criteria for interruption / premature discontinuation of study 
treatment are described in Section 5.1.8. Hold of the clinical study may occur if a certain 
number of subjects are discontinued from study treatment due to study-specific criteria for 
interruption / premature discontinuation. 
8.4 Medical care of subjects after study completion / withdrawal from study 
After the subject’s study completion or premature withdrawal from the study the 
investigator/delegate will explain to subjects what treatment(s) / medical care is necessary 
and available according to local practice.  
In the event of premature discontinuation from the study, WOCBP should be instructed to 
continue the use of contraception for at least 6 months after the last dose of study drug. 
9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
9.1 Safety definition 
9.1.1 Definitions of adverse events 
An AE is any untoward medical occurrence, i.e., any unfavorable and unintended sign, 
including an abnormal laboratory finding, symptom, or disease that occurs in a subject 
during the course of the study, whether or not considered by the investigator as related to 
study treatment. 
AEs include: 
• Exacerbation of a pre-existing disease if considered relevant. 
• Increase in frequency or intensity of a pre-existing episodic disease or medical 
condition. 
• Disease or medical condition detected or diagnosed during the course of the study, even 
though it may have been present prior to the start of the study. 

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• Continuous persistent disease or symptoms present at study start that worsen following 
the start of the study.  
• Abnormal assessments, e.g., change on physical examination, ECG findings, if they 
represent a clinically significant finding that was not present at study start or worsened 
during the course of the study. 
• Laboratory test abnormalities if they represent a clinically significant finding, 
symptomatic or not, which were not present at study start or worsened during the course 
of the study or led to dose reduction, interruption or permanent discontinuation of study 
treatment.  
In addition, all reports of intentional misuse and abuse of the study treatment are also 
considered an AE irrespective of whether a clinical event occurs. 
9.1.2 Definition of serious adverse events 
An SAE is defined by the ICH guidelines as any AE fulfilling at least 1 of the following 
criteria: 
• Fatal; 
• Life-threatening: refers to an event in which the subject was at risk of death at the time 
of the event. It does not refer to an event that hypothetically might have caused death 
had it been more severe; 
• Requiring in-patient hospitalization or prolongation of existing hospitalization; 
• Resulting in persistent or significant disability or incapacity; 
• Congenital anomaly or birth defect; 
• Medically significant: refers to important medical events that may not immediately 
result in death, be life-threatening, or require hospitalization but may be considered 
medically significant based upon appropriate medical judgment, as they may jeopardize 
the subject, and/or may require medical or surgical intervention to prevent one of the 
outcomes listed in the definitions above. 
The following reasons for hospitalization are not considered as SAEs: 
• Hospitalization for cosmetic elective surgery, or social and/or convenience reasons; 
• Hospitalization for pre-planned (i.e., planned prior to signing the ICF) surgery or 
standard monitoring of a pre-existing disease or medical condition that did not worsen, 
e.g., hospitalization for coronary angiography in a subject with stable angina pectoris. 
However, complications that occur during hospitalization are AEs or SAEs (e.g., if a 
complication prolongs hospitalization). 

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9.1.3 Definition of suspected unexpected serious adverse reactions 
The expectedness of an SAE is determined by the sponsor according to the Reference 
Safety Information (RSI) section provided in the most recent version of the IB.  
Any SAE that is assessed as related and unexpected against the RSI is known as a SUSAR. 
9.1.4 Intensity of adverse events 
The intensity of AEs is graded on a three-point scale — mild, moderate, severe — as 
follows: 
❑ 
Mild 
The event may be noticeable to the subject. It does not usually influence daily activities, 
and normally does not require intervention. 
❑ 
Moderate 
The event may make the subject uncomfortable. Performance of daily activities may be 
influenced, and intervention may be needed. 
❑ 
Severe 
The event may cause noticeable discomfort and usually interferes with daily activities. The 
subject may not be able to continue in the study, and treatment or intervention is usually 
needed. 
A mild, moderate, or severe AE may or may not be serious [see Section 9.1.2]. These terms 
are used to describe the intensity of a specific event. Medical judgment should be used on 
a case-by-case basis. 
Seriousness, rather than intensity assessment, determines the regulatory reporting 
obligations.  
9.1.5 Relationship to study treatment  
Each AE/SAE must be assessed by the investigator as to whether or not there is a 
reasonable possibility of causal relationship to the study treatment, and reported as either 
related or unrelated.  
9.1.6 Relationship to protocol-mandated procedure  
An AE/SAE is defined as related to protocol-mandated procedure if it appears to have a 
reasonable possibility of a causal relationship to either the study design or to a 
protocol-mandated procedure. 

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The determination of the likelihood that a protocol-mandated procedure caused the 
AE/SAE will be provided by the investigator. 
9.2 Time period and frequency for adverse event / serious adverse event 
assessment and follow-up 
The occurrence of an AE/SAE may come to the attention of study personnel during study 
visits, phone calls or interviews of subjects presenting for medical care.  
At each study visit (scheduled or unscheduled), the investigator will inquire about the 
occurrence of AE/SAEs since the last visit. 
9.2.1 Follow-up of adverse events  
AEs still ongoing at the EOS visit must be followed up until resolution, are no longer 
considered clinically relevant or until stabilization.  
9.2.2 Follow-up of serious adverse events 
SAEs still ongoing at the EOS visit must be followed up until resolution, stabilization, or 
until the event outcome is provided.  
9.3 Reporting procedures 
9.3.1 Reporting of adverse events  
All AEs with an onset date after signing of the ICF and up to 6 months after study treatment 
discontinuation must be recorded on specific AE forms of the eCRF.  
Information to be collected in an AE form in the eCRF includes seriousness, date of onset, 
action taken with the study treatment, outcome of AE, date of resolution (if applicable) and 
investigator’s assessment of intensity, and relationship to study treatment, study design or 
protocol-mandated procedures. 
Information on worsening of intensity will be collected on a new AE form. If the AE 
lessens in intensity, no change in the severity is required to be reported. 
Follow-up information on ongoing AEs obtained after the subject’s EOS visit will not be 
collected in the eCRF. 
9.3.2 Additional reporting procedure for serious adverse events 
All SAEs must be reported by the investigator to the sponsor’s Global Drug Safety 
department within 24 hours of the investigator’s first knowledge of the event. 
All SAEs occurring after signing of the ICF up to 6 months after study treatment 
discontinuation must be recorded on an SAE form, regardless of the investigator‑attributed 
causal relationship with study treatment or study-mandated procedures. 

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The SAE forms must be sent to the sponsor’s Global Drug Safety department (see contact 
details on the SAE form). The investigator must complete the SAE form in English, and 
must assess the event’s causal relationship to the study treatment. 
Any relevant information from source documents regarding the SAE, e.g., hospital notes 
or discharge summaries, etc., must be summarized on the SAE form. 
Follow-up information about a previously reported SAE must also be reported within 
24 hours of receiving it. The sponsor’s Global Drug Safety personnel may contact the 
investigator to obtain further information. 
If the subject is hospitalized in a hospital other than that of the study site, it is the 
investigator’s responsibility to contact this hospital to obtain all SAE-relevant information 
and documentation. 
New SAEs occurring after the 6-month follow-up period must be reported to the sponsor’s 
Global Drug Safety department within 24 hours of the investigator’s knowledge of the 
event, only if considered by the investigator to be causally related to previous exposure to 
the study treatment. 
9.4 Pregnancy 
Women must not become pregnant during the study and up to 6 months after study drug 
discontinuation. The investigator must explain and remind female subjects of the 
importance of using methods of contraception at every study visit. 
If a woman becomes pregnant while on study treatment, study treatment must be 
discontinued. The investigator must counsel the subject and discuss the risks of continuing 
with the pregnancy and the possible effects on the fetus. 
9.4.1 Reporting of pregnancy 
Any pregnancy occurring in a female subject after signing of the ICF and up to 6 months 
following study treatment discontinuation must be reported to the sponsor’s Global Drug 
Safety department within 24 hours of the investigator’s knowledge of the event. 
Pregnancies must be reported on the sponsor Pregnancy form, which is faxed to the 
sponsor’s Global Drug Safety department (see contact details provided on the Pregnancy 
form).  
9.4.2 Follow-up of pregnancy  
Any pregnancy must be followed to its conclusion, and its outcome must be reported to the 
sponsor’s Global Drug Safety department. 

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Any AE associated with the pregnancy occurring during the follow-up period after study 
drug discontinuation must be reported on separate AE forms in the eCRF up to 6 months 
following study treatment discontinuation (EOS).  
Any SAE occurring during the pregnancy must be reported on an SAE form as described 
in Section 9.3.2. 
9.4.3 Reporting of study treatment overdose, misuse, abuse and medication errors 
Study treatment overdose (defined as higher than the dose of study treatment prescribed), 
and study treatment errors will be reported as an AE when associated with signs or 
symptoms. 
In addition, study treatment errors must be documented in the study drug log of the eCRF. 
Misuse and abuse of the study treatment will be reported as an AE/SAE as determined. 
9.5 Study safety monitoring 
Clinical study safety information (AEs, SAEs, laboratory values, ECGs, vital signs, and 
project-specific labs/examinations as required) is monitored and reviewed on a continuous 
basis by the sponsor (in charge of ensuring subjects’ safety as well as data quality). The 
sponsor may request additional data pertaining to the diagnostic work-up of an AE or SAE 
(e.g., medical imaging, local laboratory values).  
In addition, an IDMC is periodically monitoring the study data [see Section 3.4.1]. 
10 STATISTICAL METHODS 
10.1 Analysis sets 
10.1.1 Screened Analysis Set 
The Screened analysis set (SCR) includes all subjects who entered Screening and have a 
subject identification number. 
10.1.2 Full Analysis Set 
The Full analysis set (FAS) includes all subjects randomized to double-blind study 
treatment at the start of TP1. Subjects will be analyzed based on their assigned study 
treatment. 
10.1.3 Full Analysis Set – TP2 
The Full analysis set TP2 (FAS-TP2) includes all subjects from the FAS who have been 
randomized to double-blind study treatment at the start of TP2. Subjects will be analyzed 
based on their assigned study treatment. 

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10.1.4 Per-Protocol Analysis Set (PPS) 
The Per-protocol set (PPS) includes all subjects from the FAS without clinically important 
protocol deviations occurring during TP1 which could affect the analysis of the primary 
endpoint variable.  
The precise reasons for excluding subjects from the PPS will be fully defined and 
documented in the statistical analysis plan (SAP) before breaking the randomization blind. 
The PPS will only be defined for the period TP1. 
10.1.5 Safety Analysis Set 
The Safety analysis set (SAF) includes all subjects who received at least one dose of 
double-blind study treatment during TP1. Subjects will be analyzed based on the treatment 
received. 
10.1.6 Safety Analysis Set – TP2 
The Safety analysis set TP2 (SAF-TP2) includes all subjects from the SAF who received 
at least one dose of double-blind study treatment during TP2. Subjects will be analyzed 
based on the treatment received. 
10.1.7 Echocardiography Set 
The Echocardiography set (ECS) includes subjects who were assigned to the 
Echocardiography sub-study by IRT with at least one post-baseline echocardiography 
assessment. Subjects will be analyzed based on the treatment received. 
10.1.8 PK Analysis Set 
The PK analysis set (PKS) includes all randomized subjects who received at least one 
cenerimod dose, had at least one blood sample for PK evaluation collected after cenerimod 
initiation, had evaluable plasma concentrations, and did not deviate from the protocol in a 
way that might affect the evaluation of the PK endpoint. Subjects will be analyzed based 
on actual dose taken, not the randomized dose. 
10.1.9 Usage of the analysis sets 
The analyses of efficacy endpoints including baseline and disease characteristics from TP1 
will be performed using the FAS and the PPS for sensitivity analyses. FAS-TP2 will be 
used for specific analyses only including TP2 data. 
The FAS will be used for analyses which combine TP1 and TP2 data (and FU data when 
applicable). 
The Safety Set will be used for the analysis of safety endpoints (including study treatment 
exposure) from TP1. SAF-TP2 will be used for specific analyses only including TP2 data. 

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The Safety Set will be used for analyses which combine TP1 and TP2 data (and FU data 
when applicable). 
Subject data will be listed using the SCR, unless otherwise specified. 
10.2 Variables 
Detailed description of study efficacy and safety endpoints can be found in Section 6. 
10.3 Description of statistical analyses 
All available data for each subject will be used in all statistical analyses unless otherwise 
specified. 
10.3.1 Overall testing strategy 
The Type I error rate will be controlled for the testing of multiple null hypotheses 
associated with the primary and secondary endpoints and the four dose levels included in 
this study: 0.5, 1, 2, and 4 mg. 
The four statistical null hypotheses associated with the primary efficacy endpoint are: 
Change of mSLEDAI-2K from Baseline to Month 6: 
H1mSLEDAI-2K: cenerimod0.5 mg – placebo = 0 
H2 mSLEDAI-2K: cenerimod1.0 mg – placebo = 0 
H3 mSLEDAI-2K: cenerimod2.0 mg – placebo = 0 
H4 mSLEDAI-2K: cenerimod4.0 mg – placebo = 0 
These hypotheses represent the difference in mean change from baseline to Month 6 in 
mSLEDAI-2K between the four doses of cenerimod and placebo. 
The eight statistical null hypotheses associated with the secondary efficacy endpoints are: 
SRI-4 
H1SRI-4: cenerimod0.5 mg / placebo = 1 
H2SRI-4: cenerimod1.0 mg / placebo = 1 
H3SRI-4: cenerimod2.0 mg / placebo = 1 
H4SRI-4: cenerimod4.0 mg / placebo = 1 
and BILAG 
H1BILAG: cenerimod0.5 mg / placebo = 1 
H2BILAG: cenerimod1.0 mg / placebo = 1 
H3BILAG: cenerimod2.0 mg / placebo = 1 
H4BILAG: cenerimod4.0 mg / placebo = 1 

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These eight hypotheses represent the odds ratios of the secondary endpoints SRI-4 and 
BILAG-2004 between the four doses of cenerimod and placebo. 
Each null hypothesis will be tested against the alternative hypothesis that a difference exists 
between cenerimod and placebo, at a given dose, in mSLEDAI-2K, SRI-4, and 
BILAG-2004. 
Within each primary and secondary endpoint analysis, the Hochberg procedure will be 
used to control the familywise error rate to ensure an overall two-sided Type I error rate of 
5% for the four treatment group comparisons vs placebo. Further control of the study-wise 
error rate is conducted such that, for a given hypothesis to be rejected at a two-sided Type I 
error rate of 5%, the same dose-level hypothesis must have also been rejected for the 
previous endpoint(s), considering the above ordering of the endpoint hypotheses [see 
Figure 4]. 
Figure 4 
Control of Type I error rate within each endpoint and treatment 
group 
 
 

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10.3.2 Analysis of the primary efficacy variable 
The primary efficacy variable, based on the mSLEDAI-2K [Section 6.1.1], is continuous 
in definition such that higher scores indicate more severe SLE disease. 
10.3.2.1 Hypotheses 
The hypothesis for the primary mSLEDAI-2K endpoint comparisons between the four 
doses of cenerimod and placebo are formulated in Section 10.3.1. 
10.3.2.2 Primary statistical analysis 
The primary statistical analysis will be performed on the FAS, according to the 
intent-to-treat approach. 
The null hypotheses for the primary endpoint will be tested using a mixed model for 
repeated measures (MMRM) on all available changes from baseline in mSLEDAI-2K for 
post-baseline scores from Months 1 to 6. The following terms will be included in the 
model: baseline mSLEDAI-2K score, treatment group, month, treatment group by month 
interaction, baseline mSLEDAI-2K score by month interaction, and the single stratification 
factor OCS (from IRT). The stratification factor mSLEDAI-2K (from IRT) will not be 
included in the model as the continuous baseline value is already included. An unstructured 
covariance matrix will be used to account for the correlation between repeated 
measurements from the same subject. 
The treatment effect for each cenerimod dose vs placebo will be estimated from the Least 
Squares Mean (LSM) differences for each dose vs placebo at Month 6 and their 
corresponding 95% confidence intervals (CIs).  
The hypothesis tests will be based on the associated p-values at the two-sided significance 
level of alpha of 5%, controlling for multiplicity using the Hochberg procedure as 
mentioned above. 
10.3.2.3 Handling of missing data  
Based on the Phase 2 study, AC-064A201, it is expected that 6% of subjects will have a 
missing mSLEDAI-2K result at Month 6. Missing data will not be imputed but will be 
handled by the MMRM assuming that the data are missing at random (MAR). 
10.3.2.4 Sensitivity analyses for missing data  
The impact of missing data on the MAR assumption from the MMRM will be assessed to 
check the robustness of the primary endpoint results and to ensure that missing data have 
not had an influence on the results.  

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An analysis based on a pattern-mixture model will be performed keeping a MAR 
imputation in the placebo arm while using a missing not at random (MNAR) approach in 
the cenerimod arms.  
Multiple imputation analyses will be performed assuming a monotone missing data pattern, 
such that, if data are missing at a given visit, they are assumed to be missing at all remaining 
visits. Any non-monotone missing data, i.e., missing values which occur between 
non-missing values will first be imputed under MAR. This is considered reasonable 
because the proportion of non-monotone missing data is expected to be low. 
Two control-based multiple imputation analyses will then be performed under MNAR 
using both Jump to Reference (J2R) and Copy Reference (CR) approaches 
[Carpenter 2013]. In these approaches, multiple imputation of missing values will be 
performed based on the assumption that subjects with missing data in the cenerimod groups 
follow the trajectory of the placebo arm, conditional on subject data available prior to 
discontinuation (baseline mSLEDAI-2K for the J2R approach; baseline as well as available 
post-baseline mSLEDAI-2K for the CR approach). 
10.3.2.5 Supportive analyses 
A series of additional analyses based on the mSLEDAI-2K are presented below and will 
support the primary endpoint results by analyzing the primary endpoint variable using 
various other methods and assumptions. 
Impact of the use of different analysis sets 
The primary endpoint analysis will be repeated on the PPS in order to assess the impact of 
important protocol deviations on the assessment of the primary endpoint. This analysis will 
address the issue of the lack of adherence to the protocol and lack of compliance to study 
treatment.  
Examination of treatment effect over time 
A supportive analysis using the above MMRM will be conducted to characterize the 
treatment effect over time such that the monthly changes from baseline in mSLEDAI-2K 
will be analyzed on all available data from all visits from Month 1 to Month 6 without 
replacement of missing values.  
The model will enable: 
• Estimation of the treatment differences (cenerimod dose vs placebo) in the mean 
changes from baseline to Month 6 along with the corresponding two-sided 95% CI. 
• Characterization of the patterns of change over time in the mean change from baseline 
in mSLEDAI-2K by treatment group. 
• No multiplicity adjustment is applied as this analysis is descriptive in nature. 

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Complete case analysis 
To assess the impact of missing data on the primary endpoint analysis the MMRM analysis 
of the primary endpoint will be conducted on the subset of subjects with the complete 
monthly score data for Months 1 to 6. 
Dose-response analysis 
As a supportive analysis, the overall dose-response will be assessed using modeling and 
multiple comparison procedures. Details of this analysis will be described in the SAP. 
10.3.2.6 Subgroup analyses 
The aim of the subgroup analyses is to explore the consistency of treatment effect in 
relevant subgroups: 
• Daily dose of OCS (< 7.5 mg or ≥ 7.5 mg prednisone equivalent) from IRT system 
• mSLEDAI-2K (< 10 or ≥ 10) from IRT system 
• Sex (male/female) 
• Geographical region (Europe, US, Rest of World)  
• Age (< 65 years vs ≥ 65 years) at Screening 
• Belimumab treatment status (“treated” vs “not treated”) at Screening 
• Race (white, American Indian, Asian, and black) 
Results of the subgroup analyses will be displayed in a forest plot and will include: 
• An estimate of the treatment effect for each cenerimod dose vs placebo with 
corresponding 95% CI for each level of the subgroup. It will be calculated as the LSM 
difference vs placebo at Month 6 obtained separately for each subgroup level. 
• A vertical reference line displayed at the level of the overall treatment effect. 
• For the analyses of the OCS and mSLEDAI-2K subgroups, the corresponding subgroup 
will not be included as a stratification factor in the MMRM. 
10.3.3 Analysis of the secondary efficacy variables 
10.3.3.1 Response at Month 6 based on SRI-4 
A repeated measurement generalized linear model will be fitted with the secondary 
endpoint SRI-4 as response (from Month 1 to Month 6). The model will include the 
treatment group, month, the treatment group by month interaction, and will be stratified by 
the OCS and mSLEDAI-2K stratification variables (from IRT).  

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The odds ratios and corresponding 95% CI for each treatment group comparison vs placebo 
will be provided along with the p-values from the Wald test. 
10.3.3.2 Response at Month 6 based on BILAG-2004 
The analysis will be performed based on the same repeated measurement model as 
described in Section 10.3.3.1. 
10.3.4 Analysis of other efficacy variables 
The analyses of all other efficacy variables will be described in detail in the SAP. Other 
efficacy endpoints will be analyzed at each relevant time point [see Section 6.1.3]. 
10.3.5 Analysis of the safety variables  
The Safety Set will be used to perform all safety analyses. 
Safety analysis may be split by treatment period [defined in Section 3.1.1.2]. This will be 
further detailed in the SAP. 
If not otherwise stated, only treatment-emergent safety data will be considered in tables 
and figures. All safety data will be included in outputs, with flags for safety data not 
considered to be treatment-emergent.  
10.3.5.1 Adverse events 
10.3.5.1.1 Treatment-emergent adverse events and serious adverse events 
Treatment-emergent AEs and SAEs will be tabulated by study treatment, system organ 
class (SOC), and preferred terms within each SOC: the number and percentage of subjects 
who experienced at least one (S)AE, at least one (S)AE within each SOC and at 
least one (S)AE within each preferred term will be displayed. (S)AEs will also be 
summarized by decreasing frequency of preferred term. (S)AEs will also be tabulated by 
maximum intensity and relationship to cenerimod dose or placebo. 
10.3.5.1.2 Adverse events leading to premature discontinuation of study drug 
(S)AEs leading to premature discontinuation of study drug will be summarized in a similar 
manner as that described in Section 10.3.5.1.1. 
10.3.5.2 Vital signs 
Descriptive summary statistics by visit and study treatment will be provided for observed 
treatment-emergent values and absolute changes from baseline in HR, SBP, DBP, and body 
weight. 
Treatment-emergent notable BP abnormalities will also be summarized descriptively. 

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10.3.5.3 Electrocardiography 
Descriptive summary statistics by visit and study treatment will be provided for observed 
treatment-emergent values and absolute changes from baseline in numeric 12-lead ECG 
values (HR, PR, QRS, QT, QTcB, QTcF). 
Changes in 12-lead ECG variables (HR, PR, QRS, QT, QTcB, QTcF) from pre-dose to 
post-dose will be summarized.  
Treatment-emergent notable abnormalities for 12-lead ECG variables (HR, PR, QRS, QT, 
QTcB, QTcF) will be summarized at all visits and pre-/post-dose time points.  
In addition, summaries of treatment-emergent ECG abnormal findings that were not 
present before first study treatment intake (using data from the ECG provider) will be 
provided.  
10.3.5.4 Laboratory data 
10.3.5.4.1 Changes from baseline in laboratory variables 
Descriptive summary statistics by visit and study treatment will be provided for observed 
treatment-emergent values and absolute and percentage changes from baseline for 
laboratory tests (hematology, blood chemistry, urinalysis). 
Data will be displayed in SI units whenever possible and graphical approaches will be 
applied for certain variables. 
10.3.5.4.2 Treatment-emergent marked laboratory abnormalities 
Laboratory abnormalities will be summarized descriptively by study treatment as 
categorical variables.  
10.3.6 Analysis of other variables 
A full description of all other analyses will be described in the SAP.  
10.4 Study analyses 
Three study analyses will be performed: the Month-6 analysis, the Month-12 analysis and 
the final EOS analysis. 
10.4.1 Month-6 analysis 
Month-6 analysis will be performed when all randomized subjects have completed TP1 or 
discontinued the study, using all data collected up to that time. 
All analyses planned in the SAP will be performed including data beyond the Month-6 
visit. This includes the analyses of the confirmatory efficacy endpoints described in 
Sections 10.3.2 and 10.3.3. 

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Prior to the database lock for Month-6 analysis, a full data cleaning will be performed. 
Thereafter, the data used for Month-6 analysis will not change and Type I error control will 
be maintained, as described in Section 10.3.1. 
10.4.2 Month-12 analysis 
Month-12 analysis will be performed when all randomized subjects have completed TP2 
or discontinued the study, using all data collected up to that time. 
All analyses planned in the SAP and including data beyond the Month-6 visit will be 
performed, including data beyond the Month-12 visit (i.e., analyses on TP2 data or on 
combined TP1 and TP2 [and FU when applicable] data). Analyses on TP1 data only, 
including analyses of the confirmatory efficacy endpoints, will not be repeated as the data 
used for Month-6 analysis will have been locked [see section 10.4.1]. Prior to the database 
lock for Month-12 analysis, a full data cleaning will be performed. 
10.4.3 Final EOS analysis 
Final EOS analysis will be performed when all randomized subjects have completed the 
posttreatment follow-up period or discontinued the study. 
All analyses planned in the SAP will be performed, including all data collected.  
10.5 Sample size 
Assumptions used to calculate power are provided in Table 6. 
Table 6 
Statistical assumptions for endpoints at Month 6 
Continuous endpoints 
Expected mean 
difference vs placebo 
SD per treatment 
group 
Effect size (mean/SD) 
mSLEDAI-2K 
 
 
 
Response endpoint 
Placebo response rate 
 
Expected difference 
vs placebo 
SRI-4 
40% 
 
20% 
BILAG-2004 
40% 
 
20% 
Effect size calculated as 
 
  
BILAG = British Isles Lupus Assessment Group-2004; mSLEDAI-2K = modified Systemic Lupus Erythematosus 
Disease Activity Index-2000; SD = standard deviation; SRI-4 = Systemic Lupus Erythematosus Responder Index 4. 
 
Assumptions for the expected mean difference and corresponding between-subject 
standard deviation for the mSLEDAI-2K primary endpoint are based on the recently 
completed 12-week Phase 2 study, AC-064A201 conducted in SLE subjects receiving 0.5, 
1, 2, or 4 mg of cenerimod or placebo. The resulting effect size of 
 is in line with that 
seen at higher doses of cenerimod at 12 weeks in AC-064A201. Such a difference is greater 

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than that seen 
in other treatments 
approved for the treatment 
of SLE 
[GlaxoSmithKline 2018]. 
Based on the above effect size assumption for the continuous mSLEDAI-2K primary 
endpoint, 10,000 simulations using analysis of covariance to test four doses vs placebo 
indicate that 325 subjects (65 per group) will provide 89.6% power at a two-sided 5% level 
of significance to reject at least one of the four treatment hypotheses.  
Under the same conditions, for the response based secondary endpoints, this sample size 
provides 71.4% power to reject at least one of the four treatment hypotheses.  
All power calculations provided account for multiplicity of the four comparisons vs 
placebo, using the Hochberg procedure. 
With an increasing number of null hypotheses being tested the power to reject these 
hypotheses decreases, as shown in Table 7.  
Table 7 
Effect of testing multiple null hypotheses on power  
Endpoint 
Power (%) related to the number of hypotheses rejected 
 
At least one 
2 or more 
3 or more 
All 4 
Primary 
89.6 
79.9 
70.7 
58.3 
Secondary 
71.4 
57.4 
45.2 
29.8 
11 DATA HANDLING 
11.1 Data collection 
The investigator/delegate is responsible for ensuring the accuracy, completeness, and 
timelines of the data reported. All source documents should be completed in a neat, legible 
manner to ensure accurate interpretation of the data. Data reported in the eCRF derived 
from source documents must be consistent with the source documents. 
eCRF data will be captured via electronic data capture using the Rave system provided by 
Medidata Solutions, Inc., a web-based tool. The investigator and site staff will be trained 
to enter and edit the data via a secure network, with secure access features (username, 
password and identification – an electronic password system). A complete electronic audit 
trail will be maintained.  
Physician-reported entries recorded in the PGA are considered source data.  
Subject Screening and Enrollment data will be completed for all subjects (i.e., eligible and 
non-eligible) through the IRT system and eCRF. 
For each subject enrolled, regardless of study treatment initiation, an eCRF must be 
completed and signed by the investigator/delegate. This also applies to those subjects who 

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fail to complete the study. If a subject withdraws from the study, the reason must be noted 
on the eCRF.  
11.2 Maintenance of data confidentiality 
The investigator/delegate must ensure that data confidentiality is maintained. On eCRFs or 
other documents (e.g., documents attached to SAE forms / Pregnancy forms) submitted to 
the sponsor and any vendors or CROs, subjects must be identified only by number and 
never by their name or initials, date of birth, hospital numbers, or any other personal 
identifier. The investigator/delegate must keep a subject identification code list at the site, 
showing the screening/randomization number, the subject’s name, date of birth, and 
address or any other locally accepted identifiers. Documents identifying the subjects (e.g., 
signed ICFs) must not be sent to the sponsor, any vendor or CROs, and must be kept in 
strict confidence by the investigator/delegate.  
11.3 Database management and quality control 
eCRFs will be used for all subjects. The investigator will have access to the site eCRF data 
until the database is locked. Thereafter, they will have read-only access. The eCRF must 
be kept current to reflect subject status at any timepoint during the course of the study. 
While entering the data, the investigator/delegate will be instantly alerted to data queries 
by validated programmed checks. Additional data review will be performed by the sponsor 
on an ongoing basis to look for unexpected patterns in data and study monitoring. If 
discrepant data are detected, a query specifying the problem and requesting clarification 
will be issued and visible to the investigator/delegate via the eCRF. All electronic queries 
visible in the system either require a data correction (when applicable) and a response from 
the investigator/delegate to clarify the queried data directly in the eCRF, or simply a data 
correction in the eCRF. The investigator/delegate must, on request, supply the sponsor with 
any required background data from the study documentation or clinical records. This is 
particularly important when errors in data transcription are suspected. In the case of Health 
Authority queries, it is also necessary to have access to the complete study records, 
provided that subject confidentiality is protected. 
This process will continue until database lock. 
Laboratory samples, standard biomarkers, 12-lead ECG, 24-hour Holter ECG, 
echocardiography and spirometry will be processed through a central laboratory or vendor 
and the results of the randomized subjects will be electronically sent to the sponsor at 
pre-specified intervals with a final transfer prior to database lock. During the course of the 
study, the site staff and sponsor representatives can access the data in a view-only mode on 
the central server of the respective vendor. 

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AEs and medical history are coded according to the latest MedDRA version used by the 
sponsor or its delegate. Medications are coded according to the latest WHO Drug 
Dictionary version used by the sponsor or its delegate. 
After the database has been declared complete and accurate, the database will be locked. 
Any changes to the database after that time may only be made as described in the 
appropriate sponsor QS docs. After database lock, the investigator will have read-only 
access to the site eCRF subject data, until receipt of an electronic copy of the site eCRFs 
(including the audit trail) on electronic media. 
12 PROCEDURES AND GOOD CLINICAL PRACTICE 
12.1 Ethics and Good Clinical Practice 
The sponsor and the investigators will ensure that the study is conducted in full compliance 
with ICH GCP guidelines, the principles of the ‘Declaration of Helsinki’ and with the laws 
and regulations of the country in which the study is conducted.  
12.2 Independent Ethics Committee / Institutional Review Board 
The investigator will submit this protocol and any related document(s) provided to the 
subject (such as Subject Information Leaflet used to obtain informed consent) to an 
IRB/IEC. Approval from the committee/board must be obtained before starting the study 
and must be documented in a dated letter to the investigator, clearly identifying the study, 
the documents reviewed, and the date of approval.  
Modifications made to the protocol after receipt of the approval must also be submitted as 
amendments by the investigator to the IEC/IRB in accordance with local procedures and 
regulations. 
A list of members participating in the IEC/IRB meetings must be provided, including the 
names, qualifications and functions of these members. If that is not possible, the attempts 
made to obtain this information along with an explanation as to why it cannot be obtained 
or disclosed must be documented in the study documentation. If a study staff member was 
present during a meeting, it must be clear that this person did not vote. 
12.3 Informed consent 
It is the responsibility of the investigator/delegate to obtain informed consent according to 
ICH GCP guidelines and local regulations from each individual participating in this study 
and/or legal representative. The investigator/delegate must explain to subjects that they are 
completely free to refuse to enter the study, or to withdraw from it at any time for any 
reason without having to provide any justification. 
The ICF will be provided in the country local language(s). 

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Site personnel authorized (according to local regulations) to participate in the consent 
process and/or to obtain consent from the subject and/or legal representative will be listed 
on a Sponsor Delegation of Authority form. A study physician must always be involved in 
the consent process.  
The subject and/or legal representative and authorized site personnel must sign, personally 
date and time (if the first study-mandated procedure was performed on the same day 
informed consent was obtained, and as per local regulations) the ICF before any 
study-related procedures (i.e., any procedures required by the protocol) begin.  
A copy of the signed and dated ICF is given to the subject and/or legal representative; the 
original is filed in the site documentation.  
The informed consent process must be fully documented in the subject’s medical records, 
including study reference, subject number, date/time (if applicable) when the subject was 
first introduced to the sponsor’s clinical study, date/time (if applicable) of consent, who 
participated in the consent discussion, who consented the subject and any additional person 
present during the consent process (e.g., subject family member), copy of the signed ICF 
given to the subject / legal representative. 
In the event that the site would like to recruit a subject who would be considered as 
vulnerable (e.g., subject cannot read or write, does not speak or understand the ICF 
language), additional measures must be implemented in order to ensure subject rights are 
respected and the consent obtained is legally valid. The sponsor, the regulatory authorities 
(if applicable) and the IEC/IRB must be informed prior to the recruitment. The consent 
process (e.g., involvement of an impartial witness) must be fully described, submitted to, 
and approved by the IEC/IRB, according to procedures and before subjects are recruited.  
12.4 Compensation to subjects and investigators 
The sponsor provides insurance in order to indemnify (with both legal and financial 
coverage) the investigator/site against claims arising from the study, except for claims that 
arise from malpractice and/or negligence. 
The compensation of the subject in the event of study-related injuries will comply with 
applicable regulations. 
12.5 Protocol adherence/compliance 
The investigator must conduct the study in compliance with the approved version of the 
protocol and must not implement any deviation/change from the protocol, except when 
deviation is necessary to eliminate an immediate hazard to the subject.  
If a protocol deviation occurs, the investigator/delegate will inform the sponsor or its 
representative in a timely manner. The investigator/delegate must document and explain 

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any deviation from the approved protocol. Deviations considered to be a violation of ICH 
GCP must be reported to IEC/IRB and regulatory authorities according to the sponsor or 
(overruling) local requirements. 
All protocol deviations will be reported in the Clinical Study Report (CSR). IECs/IRBs 
will be provided with listings of protocol deviations as per local requirements. 
12.6 Protocol amendments 
Any change to the protocol can only be made through a written protocol amendment. A 
protocol amendment must be submitted to the IEC/IRB and regulatory authorities, 
according to their requirements. 
12.7 Essential documents and retention of documents 
The investigator/delegate must maintain adequate records necessary for the reconstruction 
and evaluation of the study. A number of attributes are considered of universal importance 
to source data and the records that hold those data. These include that the data and records 
are accurate, legible, contemporaneous, original (or certified copy), attributable, complete, 
consistent, enduring and available when needed. 
These records are to be classified into two different categories of documents: the 
investigator’s file and subject clinical source documents.  
These records must be kept by the investigator for as long as is necessary to comply with 
the sponsor’s requirements (e.g., as specified in the clinical study agreement) and national 
and/or international regulations, whichever would be the longest period. If the investigator 
cannot guarantee this archiving requirement at the investigational site for any or all of the 
documents, special arrangements, respecting the data confidentiality, must be made 
between the investigator and the sponsor to store these documents outside the site, so that 
they can be retrieved in the event of a regulatory inspection. No study document should be 
destroyed without prior written approval from the sponsor. Should the investigator wish to 
assign the study records to another party, or move them to another location, the sponsor 
must be notified in advance.  
If the site is using an electronic/computerized system to store subject medical records, it 
can be used for the purpose of the clinical study if it is validated (as per 21 CFR Part 11 or 
equivalent standard) and if the CRA has been provided personal and restricted access to 
study subjects only, to verify consistency between electronic source data and the eCRF 
during monitoring visits. 
If the site is using an electronic/computerized system to store subject medical records but 
it could not be confirmed that the system is validated or if the CRA could not be provided 
access to the system, the site is requested to print the complete set of source data needed 

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for verification by the CRA. The printouts must be numbered, stapled together with a 
coversheet, signed and dated by the investigator/delegate to confirm that these certified 
copies are exact copies having the same information as the original source data. The 
printouts will be considered as the official clinical study records and must be filed either 
with the subject’s medical records or with the subject’s eCRF.  
In order to verify that the process the site uses to prepare certified copies is reliable, the 
CRA must be able to observe this process and confirm that the comparison of the source 
documents and the certified copy did not reveal inconsistencies. The CRA does not need 
to verify this process for all data of all subjects but at least for some of them (e.g., first 
subject, regular check during the study of critical data like inclusion/exclusion criteria, 
endpoints for some subjects) as per the sponsor’s instructions. If it were not possible for 
the monitor to observe this process, it would not be possible to rely on the site’s certified 
copies, therefore the site cannot be selected for the clinical study. 
12.8 Monitoring 
Prior to study start, a site initiation visit (SIV) will be performed after all the required 
approvals are obtained and the required essential study documents are approved by the 
sponsor. The study treatment will be shipped to the site upon approval of the required 
essential documents.  
The principal investigator must ensure that all site personnel involved in the study will be 
present during the SIV and will dedicate enough time to it. Site Information Technology 
support should also be available during the initiation visit.  
The SIV must be completed before the site can start the screening of study subjects. 
Following the SIV, a copy of the completed initiation visit report and follow-up letter will 
be provided to the principal investigator and filed in the ISF. 
During the study, the CRA will contact and visit the investigational site regularly and, on 
request, must be permitted to have access to trial facilities and all source documents needed 
to verify adherence to the protocol and the completeness, consistency and accuracy of the 
data being entered in the eCRFs and other protocol-related documents. The sponsor’s 
monitoring standards require full verification that informed consent has been provided and 
verification of adherence to the inclusion/exclusion criteria, documentation of SAEs, and 
the recording of the main efficacy, safety and tolerability endpoints. Additional checks of 
the consistency of the source data with the eCRFs will be performed according to the 
study-specific monitoring guidelines. The frequency of the monitoring visits will be based 
on subject recruitment rate and critical data collection times. 
The principal investigator must ensure that the eCRF is completed after a subject’s visit to 
the site and that all requested subject files (e.g., ICFs, medical notes/charts, other 

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documentation verifying the activities conducted for the study) are available for review by 
the CRA. The required site personnel must be available during monitoring visits and allow 
adequate time to meet with the CRA to discuss study-related issues.  
The investigator agrees to cooperate with the CRA(s) to ensure that any issues detected in 
the course of these monitoring visits are resolved. If the subject is hospitalized or dies in a 
hospital other than the study site, the investigator is responsible for contacting that hospital 
in order to document the SAE, in accordance with local regulations. 
A close-out visit will be performed for any initiated site and when there are no more active 
subjects and after all study data have been accepted by medical review and all follow-up 
issues have been resolved. In case a site does not enroll any subjects, the close-out visit 
may be performed prior to study database lock at the discretion of the sponsor. 
12.9 Investigator Site File 
Each site will be provided with an ISF prior to the initiation visit. It will contain all the 
essential documents that are required to always be up-to-date and filed at site as per ICH 
GCP section 8. 
The ISF will include a table of contents listing the essential documents. All study-related 
documentation must be maintained in the ISF. 
In some cases, exceptions can be discussed with the CRA regarding the filing of the study 
documents outside the ISF. It should be clearly documented where each document is filed. 
This note to file should be present in the specific tab of the document in the ISF. 
The ISF must be stored in a secure and access-restricted area during and after the study. It 
must be kept by the site for as long as needed to comply with any applicable rules and 
regulations, ICH GCP as well as instructions from the sponsor. If the site needs to transfer 
the ISF to another location and/or if site facility can no longer store the ISF, the principal 
investigator must inform the sponsor immediately.  
If the principal investigator changes, or if the site relocates, the CRA must be notified as 
soon as possible.  
12.10 Audit 
The sponsor’s Global Quality Management representatives may audit the investigator site 
(during the study or after its completion). The purpose of this visit will be to determine the 
investigator’s adherence to ICH GCP, the protocol, and applicable regulations; adherence 
to the sponsor’s requirements (e.g., SOPs) will also be verified. Prior to initiating this audit, 
the investigator will be contacted by the sponsor to arrange a time for the audit.  

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The investigator and staff must cooperate with the auditor(s) and allow access to all study 
documentation (e.g., subject records) and facilities. 
12.11 Inspections 
Health Authorities and/or IECs/IRBs may also wish to conduct an inspection of the 
sponsor’s clinical study (during the study or after its completion).  
Should an inspection be requested by a Health Authority and/or an IEC/IRB, the 
investigator must inform the sponsor immediately (usually via the CRA) that such a request 
has been made.  
The investigator and staff must cooperate with the inspector(s) and allow access to all study 
documentation (e.g., subject records) and study facilities. 
12.12 Reporting of study results and publication  
The sponsor will post the key elements of this protocol and the summary of results within 
the required timelines on publicly accessible databases (e.g., clinicaltrials.gov, EU 
database), as required by law and regulation. 
Study results will be documented in a CSR that will be signed by the sponsor’s 
representatives and the Coordinating Investigator.  
In accordance with the Good Publication Practices and ethical practice, the results of the 
study will be submitted for publication in a peer-reviewed journal. Study results can be 
submitted for presentation at a congress before publication in a peer-reviewed journal. 
Authorship will be determined in accordance with the International Committee of Journal 
Editors criteria and be based on: 
• Substantial contributions to: the conception or design of the study, or the acquisition, 
analysis or interpretation of data; and 
• Drafting of the publication or critical review for important intellectual content; and  
• Providing final approval of the version to be published; and 
• Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately investigated 
and resolved.  
The list of authors of any publication of study results may include representatives of the 
sponsor and will be determined by mutual agreement. 
Any study-related publication written independently by investigators must be submitted to 
the sponsor for review at least 30 days prior to submission for publication or presentation. 

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Upon review, the sponsor may provide comments and may also request alterations and/or 
deletions for the sole purpose of protecting its confidential information and/or patent rights. 
Neither the institution nor the investigator should permit publication during such a review 
period. 
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14 APPENDICES 
Appendix 1 
Corticosteroid conversion table 
[Dixon 1991, Meikle 1977, Webb 2005] 

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Appendix 2 
American College of Rheumatology (ACR) Criteria for SLE 
The ACR Criteria for the Classification of SLE [Tan 1982, Hochberg 1997].  

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Appendix 3 
Forbidden anti-arrhythmic or heart rate lowering medications  
The use of the following drugs at any time during the study is prohibited [see 
Section 5.2.4]: 
•         Adenosine 
 
•         Ivabradine 
•         Acebutolol 
 
•         Lidocaine 
•         Ajmaline 
 
•         Lorajmine 
•         Amiodarone 
 
•         Lorcainide 
•         Aprinidine 
 
•         Metoprolol 
•         Atenolol 
 
•         Mexiletine 
•         Azimilide 
 
•         Moracizine 
•         Bepridil 
 
•         Nadolol 
•         Bisoprolol 
 
•         Phenytoin 
•         Betaxolol 
 
•         Pilocarpin 
•         Bretylium 
 
•         Prajmalium 
•         Bunaftine 
 
•         Procainamide 
•         Cibenzoline 
 
•         Propafenone 
•         Diltiazem 
 
•         Propranolol 
•         Digoxin 
 
•         Quinidine 
•         Disopyramide 
 
•         Sotalol 
•         Dofetilide 
 
•         Sparteine 
•         Dronedarone 
 
•         Tedisamil 
•         Encainide 
 
•         Timolol 
•         Esmolol 
 
•         Tocainide 
•         Flecainide 
 
•         Verapamil 
•         Ibutilide 
 
•         Vernakalant 
 
If, in the judgment of the investigator, it is in the best interests of the subject to receive any 
of the drugs listed above, study drug must be permanently discontinued. 

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Appendix 4 
Forbidden medications with risk of torsade de pointes 
The use of the following QT-prolonging medications with a known risk of torsade de 
pointes at any time during the study is prohibited [see Section 5.2.4]: 
• Arsenic trioxide  
 
• Halofantrine 
• Astemizole  
 
• Haloperidol  
• Anagrelide 
 
• Levomethadyl 
• Azithromycin 
 
• Mesoridazine 
• Bepridil  
 
• Methadone 
• Chlorpromazine  
 
• Moxifloxacin 
• Cisapride 
 
• Ondansetron 
• Citalopram 
 
• Pentamidine  
• Clarithromycin 
 
• Pimozide 
• Cocaine 
 
• Probucol 
• Domperidone 
 
• Sevoflurane 
• Dronedarone 
 
• Sparfloxacin 
• Droperidol  
 
• Sulpiride 
• Erythromycin  
 
• Terfenadine 
• Escitalopram 
 
• Thioridazine 
• Flecainide 
 
• Vandetanib 
 
If, in the judgment of the investigator, it is in the best interests of the subject to receive any 
of the drugs listed above, study treatment must be permanently discontinued. 
 
 
 

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Systemic lupus erythematosus 
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Doc No D-22.031 
 
 
Appendix 5 
Adverse events of special interest 
AESIs will include the anticipated risks of treatment with cenerimod or the known class 
effects or the events that may be related to SLE comorbidities (e.g., cardiovascular AEs) 
and will address the following safety areas: 
• Effect on HR and rhythm‑related AEs 
• Hypotension-related AEs 
• Hypertension-related AEs 
• Hepatobiliary disorders / liver enzyme abnormality‑related AEs 
• Pulmonary-related AEs  
• Eye disorder-related AEs 
• Infection-related AEs 
• Skin malignancy-related AEs 
• Malignancy- (non-skin) related AEs 
• Cardiovascular-related AEs 
A list of AESIs (MedDRA preferred terms) will be defined in the SAP. 
 
 

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Appendix 6 
Criteria for discharge from monitored setting on Day 1 and on the 
first day of re-initiation following treatment interruptions 
At the time of discharge (i.e., 6 h post-dose) on Day 1 and on the first day of re-initiation 
of study treatment following drug interruptions, the following criteria must be met: 
• ECG-derived resting HR > 45 bpm; and if HR < 50 bpm it must not be the lowest value 
post-dose; 
• SBP ≥ 90 mmHg; 
− For subjects with baseline pre-dose SBP < 90 mmHg: decrease in SBP of ≤ 5 mmHg 
from pre-dose SBP value; 
• QTcF < 500 ms (females) or < 480 ms (males); 
• No persistent ECG abnormality (e.g., AV block second degree or higher) or ongoing 
AE requiring continued hospitalization. 
Should the subject not meet the criteria for discharge 6 h post-dose, he/she will be 
monitored until 12 h post-dose with 12-lead ECG and BP measurements performed hourly 
and may be discharged after any of the hourly measurements, provided that discharge 
criteria are met until 12 h post-dose. If at 12 h post-dose the subject does not meet discharge 
criteria, he/she must be permanently discontinued from study treatment. Subjects who are 
permanently discontinued should not be discharged from the monitored setting before vital 
signs return to near baseline values and until there are no persistent ECG abnormalities 
(e.g., AV block second degree or higher) or ongoing AE requiring continued 
hospitalization, or until a diagnosis is established. 
Discharge criteria will be recorded in the eCRF. 
 
 

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Systemic lupus erythematosus 
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Appendix 7 
Notable abnormalities for ECG, BP and laboratory variables 
Notable abnormalities for ECG and BP 
Notable abnormalities for ECG and BP that are related to the potential effects of cenerimod 
will address the following variables: 
• Morphological ECG findings (defined as any abnormal finding not present prior to start 
of treatment) 
• HR outliers (bpm), based on ECG 
• PR interval (ms) 
• QT/QTc interval (ms), based on Bazett’s or Fridericia’s formula 
• BP (mmHg) 
The definition of the abnormal values to be reported will be described in the SAP. 
Laboratory abnormalities 
Laboratory values below or above the normal range will be graded at three levels (H, HH, 
HHH for values above normal range and L, LL, LLL for values below the normal range) 
where L stands for “low”, H for “high”. 
The term “marked abnormality” describes laboratory values above or below the thresholds, 
with grading of abnormalities at two levels: LL/HH and LLL/HHH. These thresholds have 
been defined by the sponsor in order to flag and/or communicate abnormal laboratory 
results from the central laboratory to the investigators, and for the purpose of standardized 
data analysis and reporting by the sponsor. The definitions of marked abnormal values are 
based mainly on the Common Terminology Criteria for Adverse Events (CTCAE) grading 
system (2017 v5.0) and, in specific cases (e.g., lymphocyte levels), are adjusted based on 
the known PD effect of the study drugs (e.g., LLL threshold for lymphocytes) 
[CTCAE 2017].  
The term ALERT here corresponds to the protocol-defined test result threshold requiring 
action from the investigator as described in the protocol (e.g., repeat the test, interrupt or 
discontinue the study drug) and should not be confused with the term “call alert” used by 
the central laboratory for laboratory results, which will be communicated to the 
investigator. Not all ALERTs listed in this table will be “call alerts” from the central 
laboratory and vice versa. 
PLEASE NOTE: Thresholds for abnormality of level L or H are not provided in this 
appendix but will be provided in the laboratory manual. 
 
 

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Systemic lupus erythematosus 
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Appendix 8 
American College of Cardiology / American Heart Association / 
American College of Physicians Training Requirements for 
Performance and Interpretation of Adult Transthoracic 
Echocardiography 
Source: [Quiñones 2003].
 
 

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Appendix 9 
SLEDAI-2K: Data Collection Sheet 

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Note that leukopenia will not be evaluated for reasons of functional blinding [see 
Section 5.1.3.2] and CH50 will not assessed by central laboratory. 
Hematuria, proteinuria and pyuria are evaluated by dipstick at each visit assessing 
SLEDAI-2K. If the dipstick results are positive, urine sample will be further analyzed as 
clinically indicated (i.e., microscopic analysis of WBC, RBC, casts, and protein 
quantification).  
 
 

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Systemic lupus erythematosus 
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Appendix 11 BILAG-2004 INDEX 

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Protocol ID-064A202 
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Appendix 12 SLE Flare Index  
Source: [Petri 2005]. 
 
 
 

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Appendix 15 Lupus Quality of Life 

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Protocol ID-064A202 
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Systemic lupus erythematosus 
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Appendix 16 Patient Global Impression of Severity – Fatigue 

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Protocol ID-064A202 
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Appendix 17 Patient Global Impression of Change – Fatigue 

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Appendix 18
Premature study treatment discontinuation examples
Note: If pEOT occurs within the visit window of next scheduled visit, the next scheduled visit is to be replaced with the pEOT visit.
EOS = End-of-Study, EOT = End-of-Treatment, FU = Follow-up, M = month, pEOT = premature End-of-Treatment, Rand = Randomization, 
RR = re‑randomization.