Clinical trial NCT03742037
Conditions: Systemic Lupus Erythematosus
Keywords: Musculoskeletal and connective tissue disorders
Sponsor: Idorsia Pharmaceuticals Ltd.
Start date: 2018-12-21; Completion date: 2022-08-25
Enrollment: 427 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to assess the efficacy and safety of 4 doses of cenerimod versus placebo in adult subjects with systemic lupus erythematosus (SLE).

Detailed description:
This is a Phase 2b, multicenter, multinational, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of 4 doses of cenerimod versus placebo in adult subjects with moderately to severely active, autoantibody-positive systemic lupus erythematosus (SLE).

Arms: arm 1: Participants will receive cenerimod 0.5 mg once daily in addition to background SLE therapy. Treatment Period 1 is 6 months long. It will start with the administration of the first dose of study treatment, after randomization, and end at the Month 6 visit. All randomized participants need to complete Treatment Period 1 before continuing in Treatment Period 2. In Treatment Period 2 participants will continue with cenerimod 0.5 mg for a further 6 months and end study treatment at the Month 12 visit. arm 2: Participants will receive cenerimod 1 mg once daily in addition to background SLE therapy. Treatment Period 1 is 6 months long. It will start with the administration of the first dose of study treatment, after randomization, and end at the Month 6 visit. All randomized participants need to complete Treatment Period 1 before continuing in Treatment Period 2. In Treatment Period 2 participants will continue with cenerimod 1 mg for a further 6 months and end study treatment at the Month 12 visit. arm 3: Participants will receive cenerimod 2 mg once daily in addition to background SLE therapy. Treatment Period 1 is 6 months long. It will start with the administration of the first dose of study treatment, after randomization, and end at the Month 6 visit. All randomized participants need to complete Treatment Period 1 before continuing in Treatment Period 2. In Treatment Period 2 participants will continue with cenerimod 2 mg for a further 6 months and end study treatment at the Month 12 visit. arm 4: Half the participants that complete treatment with cenerimod 4 mg in Treatment Period 1 will be re-randomized to cenerimod 2 mg once daily in addition to background SLE therapy during Treatment Period 2. Participants will receive cenerimod 2 mg for 6 months and end study treatment at the Month 12 visit. arm 5: Half the participants that complete treatment with cenerimod 4 mg in Treatment Period 1 will be re-randomized to placebo (matching cenerimod) once daily in addition to background SLE therapy during Treatment Period 2. Participants will receive cenerimod 2 mg for 6 months and end study treatment at the Month 12 visit. arm 6: Participants will received cenerimod 4 mg once daily in addition to background SLE therapy for up to 6 months in Treatment Period 1. The participants randomized to the 4 mg treatment who were still on treatment at Month 6 were re-randomized in a 1:1 ratio to placebo or cenerimod 2 mg to enter Treatment Period 2. The participants who did not complete 6 months of cenerimod 4 mg treatment will be analyzed in the "Non Re-randomized (Ex-4mg)" treatment group. arm 7: Participants will receive placebo (matching cenerimod) once daily in addition to background SLE therapy. Treatment Period 1 is 6 months long. It will start with the administration of the first dose of study treatment, after randomization, and end at the Month 6 visit. All randomized participants need to complete Treatment Period 1 before continuing in Treatment Period 2. In Treatment Period 2 participants will continue with placebo (matching cenerimod) for a further 6 months and end study treatment at the Month 12 visit.
Interventions: intervention 1: Cenerimod 0.5 mg intervention 2: Cenerimod 1 mg intervention 3: Cenerimod 2 mg intervention 4: Cenerimod 4 mg intervention 5: Placebo intervention 6: cenerimod 2 mg (ex-4 mg)
Intervention descriptions: intervention 1: Cenerimod will be supplied as a film-coated tablets at the dose of 0.5 mg intervention 2: Cenerimod will be supplied as a film-coated tablets at the dose of 1 mg intervention 3: Cenerimod will be supplied as a film-coated tablets at the dose of 2 mg intervention 4: Cenerimod will be supplied as a film-coated tablets at the dose of 4 mg intervention 5: Matching placebo will be supplied as identical film-coated tablets formulated with the same excipients but without the active ingredient, cenerimod intervention 6: Cenerimod will be supplied as a film-coated tablets at the dose of 2 mg

Protocol documents:
SAP_002.pdf: 
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: 
27 September 2022 


 
 
 
 
 
 
CENERIMOD (ACT-334441) 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
FOR CLINICAL STUDY REPORT 
 
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) 
 
 
Document Number: D-22.294 
 
 
 
 
 
Property of Idorsia Pharmaceuticals Ltd 
 
Confidential 
 
May not be used, divulged, published or otherwise disclosed  
without the consent of Idorsia Pharmaceuticals Ltd 
 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND ACRONYMS ......................................................... 10 
1 
INTRODUCTION ...................................................................................................... 13 
2 
STUDY DESIGN AND FLOW ................................................................................. 13 
2.1 
Study design ................................................................................................ 13 
2.1.1 
Echocardiography ancillary study ................................................... 14 
2.2 
Study visit and assessment schedule ........................................................... 14 
2.3 
Study periods ............................................................................................... 15 
2.3.1 
Screening period .............................................................................. 15 
2.3.2 
Treatment periods ............................................................................ 15 
2.3.3 
Follow-up period .............................................................................. 15 
2.4 
Overview of analysis periods ...................................................................... 16 
2.4.1 
Analysis periods for primary efficacy endpoint, secondary 
efficacy endpoints and other efficacy endpoints .............................. 16 
2.4.2 
Analysis periods for exploratory endpoints ..................................... 16 
2.4.3 
Analysis periods for safety and biomarker endpoints ...................... 16 
3 
OBJECTIVES ............................................................................................................ 17 
3.1 
Primary objective ......................................................................................... 17 
3.1.1 
Estimands ......................................................................................... 17 
3.2 
Secondary objectives ................................................................................... 19 
3.3 
Exploratory objectives ................................................................................. 19 
4 
ANALYSIS SETS ...................................................................................................... 19 
4.1 
Definitions of analysis sets .......................................................................... 19 
4.1.1 
Screened Analysis Set ...................................................................... 19 
4.1.2 
Full Analysis Set .............................................................................. 19 
4.1.3 
Full Analysis Set - TP2 .................................................................... 19 
4.1.4 
Per-Protocol Set ............................................................................... 19 
4.1.5 
Safety Analysis Set .......................................................................... 20 
4.1.6 
Safety Analysis Set - TP2 ................................................................ 20 
4.1.7 
Echocardiography Set ...................................................................... 20 
4.1.8 
PK Analysis Set ............................................................................... 20 
4.2 
Usage of the analysis sets ............................................................................ 20 
5 
GENERAL DEFINITIONS AND DERIVATIONS .................................................. 22 
5.1 
Study dates ................................................................................................... 22 
5.2 
Baseline ....................................................................................................... 23 


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5.3 
Treatment day .............................................................................................. 23 
5.4 
Analysis periods .......................................................................................... 24 
5.4.1 
Efficacy observation period ............................................................. 24 
5.4.2 
Safety observation period ................................................................ 24 
5.4.3 
Treatment groups for analysis according to treatment period ......... 24 
5.4.3.1 
TP1 ......................................................................................... 24 
5.4.3.2 
TP2 ......................................................................................... 24 
5.4.3.3 
TP1 and TP2 combined (and up to EOS) ............................... 25 
5.4.3.4 
Listings ................................................................................... 25 
5.4.4 
Visit windows .................................................................................. 25 
5.5 
Subgroups .................................................................................................... 26 
5.6 
Other derivations ......................................................................................... 27 
6 
STUDY SUBJECTS VARIABLES AND ANALYSES ........................................... 27 
6.1 
Screen failures ............................................................................................. 27 
6.1.1 
Variables .......................................................................................... 27 
6.1.2 
Analysis ........................................................................................... 27 
6.2 
Eligibility criteria ......................................................................................... 27 
6.2.1 
Variables .......................................................................................... 27 
6.2.2 
Analysis ........................................................................................... 27 
6.3 
Subject disposition ....................................................................................... 28 
6.4 
Study treatment discontinuation .................................................................. 29 
6.4.1 
Variables .......................................................................................... 29 
6.4.2 
Analysis ........................................................................................... 29 
6.5 
Study discontinuation .................................................................................. 29 
6.5.1 
Variables .......................................................................................... 29 
6.5.2 
Analysis ........................................................................................... 30 
6.6 
Protocol deviations ...................................................................................... 30 
6.7 
Inclusion/exclusion in analysis sets ............................................................. 30 
6.7.1 
Variables .......................................................................................... 30 
6.7.2 
Analysis ........................................................................................... 31 
6.8 
Subject characteristics ................................................................................. 31 
6.8.1 
Demographics .................................................................................. 31 
6.8.1.1 
Variables ................................................................................. 31 
6.8.1.2 
Analysis .................................................................................. 32 
6.8.2 
Stratification variables ..................................................................... 32 
6.8.2.1 
Variables ................................................................................. 32 
6.8.2.2 
Analysis .................................................................................. 32 
6.8.3 
Baseline disease characteristics ....................................................... 33 
6.8.3.1 
BILAG-2004 medical history ................................................. 33 
6.8.3.2 
ACR classification criteria for SLE ........................................ 33 
6.8.3.3 
mSLEDAI-2K at Screening .................................................... 33 


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6.8.3.4 
Physician’s Global Assessment of disease ............................. 34 
6.8.3.5 
British Isles Lupus Assessment Group ................................... 34 
6.8.3.6 
SELENA flare index .............................................................. 35 
6.8.4 
Other baseline characteristics .......................................................... 35 
6.8.4.1 
Discharge from medical monitoring on day of first study 
drug intake .............................................................................. 35 
6.8.4.2 
Other baseline characteristics ................................................. 36 
6.8.5 
Medical history and current medical conditions .............................. 36 
6.8.5.1 
Variables - medical history and cardiovascular medical 
history / risk factors ................................................................ 36 
6.8.5.2 
Analysis - medical history and cardiovascular medical 
history / risk factors ................................................................ 37 
6.8.6 
Previous and concomitant therapies ................................................ 37 
6.8.6.1 
Variables ................................................................................. 37 
6.8.6.2 
Analysis .................................................................................. 39 
6.9 
Study treatment exposure ............................................................................ 39 
6.9.1 
Exposure to treatment ...................................................................... 39 
6.9.1.1 
Variables ................................................................................. 39 
6.9.1.2 
Analysis .................................................................................. 39 
6.9.2 
Compliance ...................................................................................... 40 
6.9.2.1 
Variables ................................................................................. 40 
6.9.2.2 
Analysis .................................................................................. 40 
6.10 
Pharmacokinetic variables ........................................................................... 40 
6.10.1 
Variables .......................................................................................... 41 
6.10.2 
Analysis ........................................................................................... 41 
7 
EFFICACY VARIABLES AND ANALYSES .......................................................... 41 
7.1 
Overview ..................................................................................................... 41 
7.1.1 
Overall testing strategy .................................................................... 43 
7.2 
Primary endpoint analysis ........................................................................... 46 
7.2.1 
Overview of analyses ....................................................................... 46 
7.2.2 
Variables .......................................................................................... 47 
7.2.3 
Handling of missing data ................................................................. 47 
7.2.4 
Hypothesis, statistical model and assumptions ................................ 48 
7.2.5 
Main analysis ................................................................................... 48 
7.2.6 
Supplementary/sensitivity analyses ................................................. 49 
7.2.6.1 
Multiple imputation under MAR using mixed model for 
repeated measurements ........................................................... 49 
7.2.6.2 
Multiple imputation under MNAR using copy reference ...... 51 
7.2.6.3 
Multiple imputation under MNAR using jump to 
reference ................................................................................. 51 
7.2.6.4 
Analyses based on PPS ........................................................... 52 


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7.2.6.5 
Treatment effect over time ..................................................... 52 
7.2.6.6 
Complete case analysis ........................................................... 52 
7.2.6.7 
Hypothetical estimand analysis .............................................. 53 
7.2.6.8 
Analyses based on SLEDAI-2K ............................................. 53 
7.2.6.9 
Dose-response analysis ........................................................... 53 
7.2.7 
Subgroup analyses ........................................................................... 57 
7.2.7.1 
Variables ................................................................................. 57 
7.2.7.2 
Analysis .................................................................................. 57 
7.3 
Secondary endpoints analysis ...................................................................... 57 
7.3.1 
Response at Month 6 on SRI-4 ........................................................ 57 
7.3.1.1 
Overview of analyses ............................................................. 57 
7.3.1.2 
Variables ................................................................................. 59 
7.3.1.3 
Handling of missing data ........................................................ 60 
7.3.1.4 
Hypothesis, statistical model and assumptions ...................... 60 
7.3.1.5 
Analysis .................................................................................. 60 
7.3.1.6 
Supplementary/sensitivity analyses ........................................ 61 
7.3.1.7 
Subgroup analyses .................................................................. 63 
7.3.2 
Response (no worsening) at Month 6 on BILAG-2004 disease 
activity index .................................................................................... 63 
7.3.2.1 
Overview of analyses ............................................................. 63 
7.3.2.2 
Variables ................................................................................. 64 
7.3.2.3 
Handling of missing data ........................................................ 64 
7.3.2.4 
Hypothesis, statistical model and assumptions ...................... 65 
7.3.2.5 
Analysis .................................................................................. 65 
7.3.2.6 
Supplementary/sensitivity analyses ........................................ 65 
7.3.2.7 
Subgroup analyses .................................................................. 65 
7.4 
Other efficacy endpoints analysis ................................................................ 65 
7.4.1 
Response at Month 6 on the mSLEDAI-2K score ........................... 66 
7.4.1.1 
Variables ................................................................................. 66 
7.4.1.2 
Analysis .................................................................................. 66 
7.4.2 
Response (no worsening and improvement) at Month 6 on 
BILAG-2004 disease activity index ................................................ 66 
7.4.2.1 
Variables ................................................................................. 66 
7.4.2.2 
Analysis .................................................................................. 67 
7.4.3 
Response at Month 6 on SRI-5, -6, -7, -8 ........................................ 67 
7.4.3.1 
Variables ................................................................................. 67 
7.4.3.2 
Analysis .................................................................................. 67 
7.4.4 
Occurrence of mild/moderate and severe flares from baseline 
up to Month 6 ................................................................................... 67 
7.4.4.1 
Variables ................................................................................. 67 
7.4.4.2 
Analysis .................................................................................. 67 
7.4.5 
Time to first severe flare up to Month 6 .......................................... 67 


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7.4.5.1 
Variables ................................................................................. 67 
7.4.5.2 
Analysis .................................................................................. 68 
7.4.6 
Time to first flare up to Month 6 ..................................................... 69 
7.4.6.1 
Variables ................................................................................. 69 
7.4.6.2 
Analysis .................................................................................. 69 
7.4.7 
Change from baseline to Month 6 in PGA score ............................. 69 
7.4.7.1 
Variables ................................................................................. 69 
7.4.7.2 
Analysis .................................................................................. 69 
7.5 
Exploratory endpoints .................................................................................. 69 
7.5.1 
Sustained mSLEDAI-2K response defined as a reduction of at 
least 
 
 
 
 .................................................................................. 70 
7.5.1.1 
Variables ................................................................................. 70 
7.5.1.2 
Analysis .................................................................................. 70 
7.5.2 
Change from baseline to each post-baseline assessment up to 
Month 12 in mSLEDAI-2K score .................................................... 71 
7.5.2.1 
Variables ................................................................................. 71 
7.5.2.2 
Analysis .................................................................................. 71 
7.5.3 
Response at each post-baseline assessment on the 
mSLEDAI-2K .................................................................................. 71 
7.5.3.1 
Variables ................................................................................. 71 
7.5.3.2 
Analysis .................................................................................. 71 
7.5.4 
Response (no worsening and improvement) at each 
post-baseline assessment on BILAG-2004 disease activity 
index ................................................................................................. 72 
7.5.4.1 
Variables ................................................................................. 72 
7.5.4.2 
Analysis .................................................................................. 72 
7.5.5 
Response at each post-baseline assessment on SRI-4, -5, -6, -7, 
-8 ...................................................................................................... 72 
7.5.5.1 
Variables ................................................................................. 72 
7.5.5.2 
Analysis .................................................................................. 73 
7.5.6 
Change from baseline to each post-baseline assessment in 
PGA score ........................................................................................ 73 
7.5.6.1 
Variables ................................................................................. 73 
7.5.6.2 
Analysis .................................................................................. 73 
7.5.7 
Occurrence of flares and severe flares at each post-baseline 
assessment ........................................................................................ 73 
7.5.7.1 
Variables ................................................................................. 73 
7.5.7.2 
Analysis .................................................................................. 74 
7.5.8 
Time to first severe flare from baseline to Month 12 ...................... 74 


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7.5.8.1 
Variables ................................................................................. 74 
7.5.8.2 
Analysis .................................................................................. 74 
7.5.9 
Time to first flare from baseline to Month 12 ................................. 74 
7.5.9.1 
Variables ................................................................................. 74 
7.5.9.2 
Analysis .................................................................................. 75 
7.5.10 
Change from baseline to each post-baseline assessment up to 
Month 12 in prednisone or equivalent dose ..................................... 75 
7.5.10.1 
Variables ................................................................................. 75 
7.5.10.2 
Analysis .................................................................................. 76 
7.6 
Analysis of PRO/QoL variables .................................................................. 77 
7.6.1 
Change from baseline to each post-baseline assessment in 
FACIT-Fatigue Scale score ............................................................. 77 
7.6.1.1 
Variables ................................................................................. 77 
7.6.1.2 
Analysis .................................................................................. 77 
7.6.2 
Change from baseline to each post-baseline assessment in 
PGIS-F ............................................................................................. 77 
7.6.2.1 
Variables ................................................................................. 77 
7.6.2.2 
Analysis .................................................................................. 77 
7.6.3 
PGIC-F score at each post-baseline assessment .............................. 78 
7.6.3.1 
Variables ................................................................................. 78 
7.6.3.2 
Analysis .................................................................................. 78 
7.6.4 
Change from baseline to each post-baseline assessment in 
SF-36v2™ ........................................................................................ 78 
7.6.4.1 
Variables ................................................................................. 78 
7.6.4.2 
Analysis .................................................................................. 79 
7.6.5 
Change from baseline to each post-baseline assessment in the 
Lupus QoL questionnaire ................................................................. 79 
7.6.5.1 
Variables ................................................................................. 79 
7.6.5.2 
Analysis .................................................................................. 80 
7.6.6 
Change of mucocutaneous and musculoskeletal score from 
baseline (TP1) up to Month 12 ........................................................ 80 
7.6.6.1 
Variables ................................................................................. 80 
7.6.6.2 
Analysis .................................................................................. 81 
7.7 
Analysis of pharmacokinetic variables ........................................................ 81 
8 
SAFETY VARIABLES AND ANALYSES .............................................................. 81 
8.1 
Overview of safety analyses including subgroup analyses ......................... 81 
8.1.1 
Safety endpoints ............................................................................... 81 
8.2 
Adverse events ............................................................................................. 82 
8.2.1 
Variables .......................................................................................... 82 
8.2.1.1 
Missing values ........................................................................ 83 
8.2.2 
Analysis ........................................................................................... 83 


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8.2.2.1 
AESIs ...................................................................................... 86 
8.3 
Death ............................................................................................................ 86 
8.3.1 
Variables .......................................................................................... 86 
8.3.2 
Analysis ........................................................................................... 87 
8.4 
Laboratory tests ........................................................................................... 87 
8.4.1 
Measurements .................................................................................. 87 
8.4.2 
Variables .......................................................................................... 88 
8.4.3 
Analysis ........................................................................................... 88 
8.5 
Spirometry ................................................................................................... 89 
8.5.1 
Measurements .................................................................................. 89 
8.5.2 
Variables .......................................................................................... 89 
8.5.2.1 
Definition absolute change and percent change from 
baseline (TP1) ......................................................................... 89 
8.5.2.2 
Definition absolute change and percent change from 
baseline (TP2) ......................................................................... 90 
8.5.2.3 
Decrease of (percent predicted) FEV1 or FVC > 15% 
from baseline .......................................................................... 90 
8.5.3 
Analysis ........................................................................................... 90 
8.6 
Electrocardiography ..................................................................................... 91 
8.6.1 
Measurements .................................................................................. 91 
8.6.2 
Variables .......................................................................................... 91 
8.6.2.1 
Change from baseline in 12-lead ECG ................................... 91 
8.6.2.2 
Notable abnormalities (12-lead ECG) .................................... 92 
8.6.2.3 
Morphological ECG abnormalities/findings (12-lead 
ECG) ....................................................................................... 92 
8.6.2.4 
Holter ECG ............................................................................. 93 
8.6.3 
Analysis ........................................................................................... 93 
8.6.3.1 
12-lead ECG ........................................................................... 93 
8.6.3.2 
Holter ECG ............................................................................. 94 
8.7 
Vital signs and body weight ........................................................................ 94 
8.7.1 
Blood pressure ................................................................................. 95 
8.7.1.1 
Measurements ......................................................................... 95 
8.7.1.2 
Blood pressure over time ........................................................ 95 
8.7.1.3 
Notable blood pressure abnormalities .................................... 96 
8.7.2 
Body weight ..................................................................................... 97 
8.7.2.1 
Variables ................................................................................. 97 
8.7.2.2 
Analysis .................................................................................. 97 
8.8 
Echocardiography (sub-study) ..................................................................... 97 
8.8.1 
Measurements .................................................................................. 97 
8.8.2 
Variables .......................................................................................... 98 
8.8.3 
Analysis ........................................................................................... 98 
8.9 
Biomarker endpoints .................................................................................... 98 


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8.9.1 
Variables .......................................................................................... 98 
8.9.2 
Analysis ........................................................................................... 99 
9 
GENERAL STATISTICAL METHODOLOGY ....................................................... 99 
9.1 
General rules for data presentations ............................................................ 99 
10 INTERIM ANALYSES ........................................................................................... 100 
11 REFERENCES ......................................................................................................... 101 
12 APPENDICES .......................................................................................................... 102 
12.1 
Visit and assessment schedule ................................................................... 102 
12.2 
Definitions of AEs of special interest ........................................................ 110 
12.3 
SF-36v2™.................................................................................................. 113 
12.4 
FACIT-Fatigue scoring manual ................................................................. 117 
12.5 
Revision history ......................................................................................... 118 
 
LIST OF TABLES 
 
Table 1 
Study committees ...................................................................................... 13 
Table 2 
Estimands for the primary objective ......................................................... 18 
Table 3 
Overview of the different analysis sets and their usage ............................ 21 
Table 4 
Visit windows ............................................................................................ 26 
Table 5 
Overview of analyses for primary estimand ............................................. 46 
Table 6 
Parameterization of models considered in MCP-Mod analyses................ 54 
Table 7 
Overview of analyses for secondary estimand #1 ..................................... 58 
Table 8 
Overview of analyses for secondary estimand #2 ..................................... 64 
Table 9 
Daily prednisone or equivalent doses used for derivation of monthly 
scores ......................................................................................................... 76 
Table 10 
Lupus QoL domains .................................................................................. 80 
Table 11 
Notable abnormalities in ECG parameters ................................................ 92 
Table 12 
Notable abnormalities in blood pressure ................................................... 96 
Table 13 
Scoring and transforming scales ............................................................. 115 
 
LIST OF FIGURES 
 
Figure 1 
Study design ID-064A202 (CARE) .......................................................... 16 
Figure 2 
Control of Type I error rate within each endpoint and treatment 
group .......................................................................................................... 45 
Figure 3 
Dose-response curves considered in MCP-Mod procedure ...................... 55 
 
 


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LIST OF ABBREVIATIONS AND ACRONYMS 
ACR 
 
American College of Rheumatology 
AE 
 
Adverse event 
AESI 
 
Adverse event of special interest 
AIC 
 
Akaike’s Information Criterion 
anti-dsDNA 
 
Anti-double-stranded deoxyribonucleic acid 
ATC 
 
Anatomical Therapeutic Chemical 
BILAG(-200)4 
 
British Isles Lupus Assessment Group(-2004) 
BMI 
 
Body mass index 
BP  
Bodily pain 
bpm 
 
Beats per minute 
CARE 
 
Cenerimod Assessing S1P1 Receptor modulation in 
Systemic Lupus Erythematosus 
CDISC 
 
Clinical Data Interchange Standards Consortium 
CI 
 
Confidence interval 
CRO 
 
Contract Research Organization 
CSR 
 
Clinical study report 
CV 
 
Coefficient of variation 
DBP 
 
Diastolic blood pressure 
DV 
 
Protocol deviation 
ECG 
 
Electrocardiogram/graphy 
(e)CRF 
 
(Electronic) case report form 
ECS 
 
Echocardiography Set 
Emax 
 
Maximum effect 
EOS 
 
End-of-Study 
EOT 
 
End-of-Treatment 
FACIT 
 
Functional Assessment of Chronic Illness Therapy 
FAS 
 
Full Analysis Set Treatment Period 1 
FEV1 
 
Forced expiratory volume in 1 second 
FU 
 
Follow-up 


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FVC 
 
Forced vital capacity 
GH  
General health 
GLMM 
 
Generalized linear mixed model 
HIV 
 
Human immunodeficiency virus 
HLGT  
High-level group term 
HR 
 
Heart rate 
ICH 
 
International Council for Harmonisation 
IgA/G/M 
 
Immunoglobulin A/G/M 
IXRS 
 
Interactive Response System 
linlog  
Linear in log 
LSM 
 
Least Square Means 
MAR 
 
Missing at random 
MCMC 
 
Markov chain Monte Carlo 
MCP 
 
Multiple comparison procedures 
MCS  
Mental component summary 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
MH  
Mental health 
MMRM 
 
Mixed model for repeated measures 
MNAR 
 
Missing not at random 
Mod  
Modeling 
(m)SLEDAI-2K 
 
(Modified) Systemic Lupus Erythematosus Disease Activity 
Index-2000 
OCS 
 
Oral corticosteroids 
OR 
 
Odds ratio 
PCS  
Physical component summary 
PF  
Physical functioning 
PGA 
 
Physician’s Global Assessment 
PGIC-F  
Patient Global Impression of Change – Fatigue 
PGIS-F  
Patient Global Impression of Severity – Fatigue 


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PK 
 
Pharmacokinetic(s) 
PKS 
 
Pharmacokinetic Analysis Set 
PPS 
 
Per-Protocol Set 
PRO 
 
Patient-reported outcome 
PT 
 
Preferred term 
QoL 
 
Quality of life 
QTcB 
 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
 
QT interval corrected for heart rate using Fridericia’s formula 
RE  
Role-emotional 
RP  
Role-physical 
SAE 
 
Serious adverse event 
SAF 
 
Safety Analysis Set 
SAP 
 
Statistical analysis plan 
SBP 
 
Systolic blood pressure 
SCR 
 
Screened Analysis Set 
SDTM 
 
Study Data Tabulation Model  
SF  
Social functioning 
SF-36v2 
 
36-Item Short Form Health Survey version 2 
SI 
 
Standard International 
SLE 
 
Systemic lupus erythematosus 
SMQ  
Standardised MedDRA Query 
SOC 
 
System organ class 
SRI 
 
Systemic Lupus Erythematosus Responder Index 
TEAE 
 
Treatment-emergent adverse event 
TP1 
 
Treatment Period 1 
TP2 
 
Treatment Period 2 
US 
 
United States 
VT  
Vitality 
WHO 
 
World Health Organization 


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1 
INTRODUCTION 
This SAP for the clinical study report for study ID-064A202 (CARE) is based on global 
protocol Version 5, 4 February 2022 [D-22.031]. The SAP describes analyses of the 
primary, secondary, other, and exploratory efficacy endpoints as well as all safety, QoL, 
PK, and biomarker endpoints.  
Source data for the analyses will be provided as SAS® datasets in SDTM format following 
CDISC. Analysis data sets will be derived as SAS® data sets in Analysis Data Model format 
following CDISC. 
The clinical pharmacologist will perform the calculation of PK parameters and create 
figures of individual and mean concentration-time profiles. PK concentration data will be 
merged with the actual date/time of sampling by Idorsia Data Management. 
Table 1 summarizes the study committees involved during the conduct of the study. 
Table 1 
Study committees 
Committee 
Responsibility 
Independent Data Monitoring Committee 
Review of safety data and provision of 
recommendations on trial continuation and conduct. 
Ophthalmology Safety Board 
Review and adjudication of all data related to cases 
suggestive of macular edema. 
2 
STUDY DESIGN AND FLOW 
2.1 Study design 
This is 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 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 once daily of cenerimod, in addition to background SLE therapy.  
Once randomized, all subjects will enter a 6-month double-blind study treatment period 
defined as Treatment Period 1 (TP1). 
Subjects randomized to, and still receiving, placebo, 0.5, 1, or 2 mg at Month 6 will 
continue their study treatment up to an additional maximum of 6 months in 
Treatment Period 2 (TP2), for a total maximum of 12 months.  
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 


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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 
Subjects who discontinue treatment in TP1 will continue study FU, performing study 
assessments, up to maximum duration of 12 months. 
At EOT, subjects will enter a 6-month FU period (4-month before protocol Version 5). 
Treatment allocation is stratified by dose of OCS at Randomization (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). 
The study will be conducted at approximately 180 sites in 21 countries notably from the 
regions of Asia Pacific, Eastern Europe, Latin America, North America, and Western 
Europe. 
No interim analysis is planned. There will be three study analyses: the Month-6 analysis, 
the Month-12 analysis and the final EOS analysis. 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 post-treatment follow-up period or discontinued the study.  
After Month-6 analysis and Month-12 analysis, 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 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 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. 
2.1.1 
Echocardiography ancillary study 
At Randomization, approximately 175 subjects will be assigned to the echocardiography 
ancillary study through the IXRS 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 EOT 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. 
2.2 Study visit and assessment schedule 
See Appendix 12.1 for the visit and assessment schedule. 


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2.3 Study periods 
2.3.1 
Screening period  
The screening period starts with the signing of the informed consent form 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 protocol section 5.2.2.1, D-22.031].  
2.3.2 
Treatment periods  
The study comprises 2 treatment periods: TP1 and TP2. 
TP1 lasts for 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 for up to 6 months and ends at the Month 12 visit. 
If a randomized subject discontinues treatment prematurely in TP1 or TP2, the subject will 
have a premature EOT visit, stay in the study, and complete all protocol-mandated visits 
up to the Month 12 visit (unless the subject withdraws consent earlier). 
At the time of the Month 12 visit, the EOT visit will take place.  
Furthermore, at this time the EOS visit will take place for subjects with premature EOT 
occurring at least 6 months prior to the Month 12 visit. For subjects with premature EOT 
occurring less than 6 months prior to the Month 12 visit, the 6-month FU period must be 
completed in its entirety. For example, if a subject has premature EOT at Month 8 occurring 
four months prior to the Month 12 visit, Month 9, Month 10, Month 11 and Month 12 
visits, also functioning as FU1, FU2, FU3, and FU3a, are conducted as planned, along with 
FU3b and EOS visits after the Month 12 visit. This completes 6 months of follow-up. 
2.3.3 
Follow-up period 
This period starts after the EOT visit and lasts 6 months until the EOS visit.  
For the first 5 months after the EOT visit, subjects will have to conduct monthly FU visits 
or phone calls at FU1, FU2, FU3, FU3a, and FU3b, to collect information on AEs/SAEs 
and/or pregnancy. For subjects that discontinue treatment prematurely, some or all FU 
visits may be replaced by scheduled visits.  
EOS should occur 6 months after the EOT but can occur later for subjects that prematurely 
discontinue treatment before Month 8. Study periods are displayed in Figure 1. 


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Figure 1 
Study design ID-064A202 (CARE) 
EOS = End-of-Study; EOT = End-of-Treatment; R = Randomization; RR = re-randomization; pts = patients; V = 
visit. 
2.4 
Overview of analysis periods 
2.4.1 
Analysis periods for primary efficacy endpoint, secondary efficacy 
endpoints and other efficacy endpoints 
Primary, secondary, and other efficacy endpoints as well as PRO and QoL endpoints will 
be analyzed from start of treatment up to the Month 6 assessment during TP1. 
2.4.2 
Analysis periods for exploratory endpoints 
Exploratory and PRO endpoints will be analyzed from baseline up to a maximum of 
12 months on all available assessments according to the following 2 groups [as defined in 
the protocol, D-22.031]: 
• Group 1: All randomized subjects for whom baseline is defined as the last available 
measurement before the start of randomized treatment in TP1. 
• Group 2: Subjects re-randomized at Month 6 for whom baseline is defined as the last 
available measurement before the start of re-randomized treatment in TP2. 
The exploratory endpoints will be analyzed from first study drug intake in TP1 up to the 
Month 12 assessment (pooling TP1 and TP2 data), as well as from re-randomization (in 
TP2) at Month 6 up to the Month 12 assessment. 
2.4.3 
Analysis periods for safety and biomarker endpoints 
Safety and biomarker endpoints will be analyzed from start of treatment in TP1 up to the 
Month 6 assessment, from start of treatment in TP2 up to the Month 12 visit, and from start 
of treatment in TP1 up to the Month 12 visit (pooling TP1 and TP2 data).  


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3 
OBJECTIVES 
3.1 Primary objective 
The primary objective is to assess the efficacy of 6 months of cenerimod treatment given 
at 4 different dose levels (0.5, 1, 2, and 4 mg once daily) on disease activity in adult subjects 
with moderate to severe SLE concurrently receiving background therapy. 
3.1.1 
Estimands 
The three estimands for the primary objective of this study are defined by the five attributes 
as shown in Table 2 and specified in ICH E9 (R1). 
 


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Table 2 
Estimands for the primary objective 
Estimand 
Target population 
Treatment condition of 
interest 
Endpoint 
Strategy for addressing 
intercurrent events 
Population-level 
summary 
Primary Estimand 
Adult subjects with 
moderate to severe SLE 
concurrently receiving 
background therapy as 
defined by the inclusion 
and exclusion criteria in 
the study protocol. 
Cenerimod 0.5 mg, 1 mg, 
2 mg and 4 mg plus 
background SLE therapy 
which will be compared 
to placebo plus 
background SLE therapy. 
Change from 
baseline to Month 6 
in the mSLEDAI-2K 
score (primary 
endpoint). 
Treatment policy, i.e., all 
collected endpoint data are used 
regardless of early treatment 
discontinuation or other 
intercurrent events. Missing data 
will be handled as described in 
Section 7.2.3. 
Mean change from 
baseline to Month 6, 
summarized as the 
difference between 
cenerimod treatment 
given at 4 different dose 
levels (0.5, 1, 2 and 4 mg) 
and placebo. 
Secondary 
Estimand #1 
Adult subjects with 
moderate to severe SLE 
concurrently receiving 
background therapy as 
defined by the inclusion 
and exclusion criteria in 
the study protocol. 
Cenerimod 0.5 mg, 1 mg, 
2 mg and 4 mg plus 
background SLE therapy 
which will be compared 
to placebo plus 
background SLE therapy. 
Response at 
Month 6 on SRI-4 
(secondary 
endpoint). 
Treatment policy, i.e., all 
collected endpoint data are used 
regardless of early treatment 
discontinuation or other 
intercurrent events. Missing data 
will be handled as described in 
Section 7.3.1.3. 
Proportion of responders 
at Month 6, summarized 
as the ratio between 
cenerimod treatment 
given at 4 different dose 
levels (0.5, 1, 2 and 4 mg) 
and placebo. 
Secondary 
Estimand #2 
Adult subjects with 
moderate to severe SLE 
concurrently receiving 
background therapy as 
defined by the inclusion 
and exclusion criteria in 
the study protocol. 
Cenerimod 0.5 mg, 1 mg, 
2 mg and 4 mg plus 
background SLE therapy 
which will be compared 
to placebo plus 
background SLE therapy. 
Response at 
Month 6 on 
BILAG-2004 
(secondary 
endpoint). 
Treatment policy, i.e., all 
collected endpoint data are used 
regardless of early treatment 
discontinuation or other 
intercurrent events. Missing data 
will be handled as described in 
Section 7.3.2.3. 
Proportion of responders 
at Month 6, summarized 
as the ratio between 
cenerimod treatment 
given at 4 different dose 
levels (0.5, 1, 2 and 4 mg) 
and placebo. 
BILAG-2004 = British Isles Lupus Assessment Group-2004; mSLEDAI-2K = modified Systemic Lupus Erythematosus Disease Activity Index-2000; SLE = systemic lupus 
erythematosus; SRI = Systemic Lupus Erythematosus Responder Index. 


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3.2 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 QoL and fatigue using relevant PRO instruments. 
• The effect of cenerimod treatment on SLE biomarkers. 
3.3 Exploratory objectives 
To explore the sustainability of the treatment effect, 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, QoL, 
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. 
4 
ANALYSIS SETS 
4.1 Definitions of analysis sets 
4.1.1 
Screened Analysis Set 
The SCR includes all subjects who entered Screening and have a subject identification 
number. 
4.1.2 
Full Analysis Set  
The 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. 
4.1.3 
Full Analysis Set - TP2 
The 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. 
4.1.4 
Per-Protocol Set 
The PPS includes all subjects from the FAS without clinically important DVs 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 a separate document before breaking the randomization blind.  
The PPS will only be defined for the period TP1. 


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4.1.5 
Safety Analysis Set 
The 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. In the 
event of accidental intake of a treatment other than the randomized treatment, treatment 
received is defined as the highest dose received. 
4.1.6 
Safety Analysis Set - TP2 
The 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. In the event of accidental intake of a treatment other than the randomized 
treatment during TP2, treatment received is defined as the highest dose received. 
4.1.7 
Echocardiography Set 
The ECS includes subjects who were assigned to the echocardiography sub-study by IXRS 
with at least one post-baseline echocardiography assessment. Subjects will be analyzed 
based on the treatment received. In the event of accidental intake of a treatment other than 
the randomized treatment, treatment received is defined as the highest dose received. 
4.1.8 
PK Analysis Set 
The 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. 
The reason for excluding a PK sample from analysis will be documented by Idorsia Clinical 
Pharmacology before breaking the randomization blind. 
4.2 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 SAF 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. 
In the event of accidental intake of a treatment other than the randomized treatment 
occurring during TP2 while the treatment received during TP1 matched the randomized 
treatment, the subject will be analyzed under the actual treatment group during TP1 for 
safety analyses during TP1 only. Safety analyses during TP2 or TP1 and TP2 combined 
(and up to EOS) will use the highest dose received, as described in Section 4.1. 


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The SAF 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. 
An overview of the different analysis sets is provided in Table 3. 
Table 3 
Overview of the different analysis sets and their usage 
 
Analysis sets 
Analyses / Data Displays 
SCR 
FAS 
PPS 
SAF 
PKS 
Screen failures, Analysis sets 
X 
 
 
 
 
Protocol deviations 
 
X 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
Subject disposition 
 
X 
 
 
 
Demographics 
 
X 
 
 
 
Baseline disease characteristics 
 
X 
 
 
 
Medical history and current medical 
conditions 
 
X 
 
 
 
SLE medical history 
 
X 
 
 
 
SLE and previous and concomitant 
therapies 
 
X 
 
 
 
Other screening assessments (physical 
exam, PGA, height, weight, smoking,  
chest X-ray, …) 
 
X 
 
 
 
Study treatment exposure 
 
X 
 
X 
 
Efficacy: Primary endpoint 
 
X 
X 
 
 
Efficacy: Secondary endpoints 
 
X 
X 
 
 
Efficacy: Other endpoints 
 
X 
 
 
 
Efficacy: Exploratory endpoints 
 
Xa 
 
 
 
Efficacy: Subgroup analyses 
 
X 
 
 
 
PRO/QoL endpoints 
 
X 
 
 
 
Pharmacokinetic endpoints 
 
 
 
 
X 
Safety endpoints 
 
 
 
Xb 
 
Biomarker endpoints 
 
X 
 
 
 
All subject listings 
Xc 
Xc 
 
Xc 
 
Note: X: main analysis, (a): Exploratory efficacy endpoints will be analyzed using the FAS and/or FAS-TP2. (b): Safety 
endpoints will be analyzed using the SAF and/or SAF-TP2. (c): Some listings will not be produced using the SCR, 
because certain data will not be collected for screen failures. 
FAS = Full Analysis Set; FAS-TP2 = Full Analysis Set in Treatment Period 2; PGA = Physician’s Global Assessment; 
PKS = Pharmacokinetic Analysis Set; PPS = Per-Protocol Set; PRO = patient-reported outcome; QoL = quality of 
life; SAF = Safety Analysis Set; SAF-TP2 = Safety Analysis Set in TP2; SCR = Screened Analysis Set; SLE = 
systemic lupus erythematosus. 


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5 
GENERAL DEFINITIONS AND DERIVATIONS 
5.1 Study dates  
The ‘Date of informed consent’ is defined as the date at which the informed consent is 
signed by the subject. This date is collected on the Informed Consent eCRF page. 
The ‘Screening date’ is defined as the date where the subject was screened (visit date from 
IXRS subject eCRF page). If the subject was screened multiple times, the date of last 
screening attempt will be used. 
The ‘Randomization date’ is defined as the date when the subject was randomized to one 
of the four doses of cenerimod or placebo (at the start of TP1) and is taken from the IXRS 
subject eCRF page. 
The ‘Re-randomization date’ is defined as the date when the subject was re-randomized 
through the IXRS system. The re-randomization date is taken directly from this system. 
The re-randomization date will be populated for subjects who reach the Month 6 visit 
(on treatment) and are re-randomized.  
Note: Subjects on 4 mg are re-randomized to placebo or 2 mg cenerimod in TP2. All other 
subjects are re-randomized to their original randomized group from TP1. 
Definition of treatment start/end dates in TP1 
• The ‘Treatment start date (TP1)’ is defined as the date of the first study drug intake 
in TP1 (cenerimod or placebo), as documented in the eCRF Study Treatment Intake. 
• The ‘Treatment start time (TP1)’ is defined as the time on the date of the first study 
drug intake in TP1 (cenerimod or placebo), as documented in the eCRF Study 
Treatment Intake. 
• The ‘Treatment end date (TP1)’ is defined as the date of the last study drug intake in 
TP1 (cenerimod or placebo), as documented in the eCRF Study Treatment Log. 
Definition of treatment start/end dates in TP2 
Treatment start and end dates are defined in the same way as described for TP1. 
Due to the start of a conflict in Ukraine around the same time as the planned EOT of several 
subjects in this country, sites had to stop their activities before entering the treatment end 
date for TP2 in the eCRF. This concerns a maximum of 9 subjects. For these subjects, the 
missing treatment end date for TP2 will be imputed at the start date of Month-12 visit. NB: 
This date is identical to the treatment completion date entered in the IRT system, except 
for one subject for whom it is the day after. 
Overall EOT date 
A subject’s overall EOT date is defined as the latest of Treatment end date (TP1) and 
Treatment end date (TP2). 


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Re-initiation in TP1 (during first two weeks of treatment) 
• The ‘Date of re-initiation’ is defined as the date when the study treatment was 
re-initiated after a break of at least 7 days during the first two weeks of treatment in 
TP1. The date of re-initiation is taken from the Re-initiation / Study Drug Intake eCRF 
page. Only one re-initiation is permitted per subject during TP1. 
• The ‘Time of re-initiation’ is defined as the corresponding time recorded on the 
Re-initiation / Study Drug Intake eCRF page. 
EOS date 
• The ‘EOS date’ is taken from the eCRF End-of-Study / Visit Summary form. If this 
date is missing, the last recorded (follow-up) visit or phone call on the eCRF is 
considered to be the EOS date. 
5.2 Baseline 
• The ‘Baseline (TP1)’ value for efficacy and safety analyses is defined as the last 
non-missing value recorded prior to first study drug intake in TP1 for each endpoint 
and each subject individually. For subjects that were randomized but did not take any 
study drug, baseline (TP1) is defined as the last non-missing value recorded up to and 
including the day of Randomization. 
• The ‘Baseline (TP2)’ value for efficacy and safety analyses is defined as the last 
non-missing value recorded up to and including the day of re-randomization for each 
endpoint and each subject individually. This baseline is only defined for subjects that 
have been re-randomized by IXRS. 
For certain datasets/analyses an ‘intra-day baseline’ is derived (e.g., ECG, vital signs). 
This intra-day baseline is defined as the last non-missing assessment prior to study drug 
intake on the corresponding day. If there is no pre-dose assessment on the day (by time and 
date), then the intra-day baseline is considered to be missing. The intra-day baseline is 
calculated for parameters that are part of the hourly measurements on the day of first study 
drug intake (in TP1) and the day of first study drug intake of a re-initiated subject (in TP1). 
For datasets where multiple measurements exist for the selection of the baseline 
assessment, the definition(s) is/are provided in the corresponding sections (e.g., spirometry 
or ECG data). 
5.3 Treatment day 
• The ‘Treatment Day’ is defined as the day relative to the treatment start date in TP1, 
with the Treatment start date considered as ‘Treatment Day 1’, the day after the 
Treatment start date as ‘Treatment Day 2’ and so forth. There is no ‘Treatment Day 0’, 
so the day before the Start-of-Treatment date is ‘Treatment Day –1’. The treatment day 
is derived for assessments in both TP1 and TP2. 
• The ‘Treatment day in TP1’ is derived as above, but only considering data in TP1. 


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• The ‘Treatment day in TP2’ is derived based on the treatment start day in TP2 being 
‘Day 1’, the day after treatment start being ‘Day 2’ and so forth. There is no ‘Day 0’ 
and no negative treatment day values. TP2 data will be assigned a ‘Treatment day in 
TP2’ only for subjects treated in TP2. 
5.4 Analysis periods 
5.4.1 
Efficacy observation period 
Efficacy observation periods are defined as: 
• TP1: From treatment start date (TP1) to the date of last visit performed in TP1 (up to 
Month 6); 
• TP2: From treatment start date (TP2) to the date of last visit performed in TP2 (up to 
Month 12). This period is defined for all re-randomized subjects; 
• Pooled TP1/TP2: From treatment start date (TP1) to the date of last visit performed in 
TP1/TP2 (up to Month 12). 
5.4.2 
Safety observation period 
As the observation period may differ according to endpoint, safety observation periods are 
defined along with the description of each analysis in the safety section. 
5.4.3 
Treatment groups for analysis according to treatment period 
5.4.3.1 TP1 
Any TP1 analyses will be summarized using the following 5 treatment groups: 
• Cenerimod 0.5 mg 
• Cenerimod 1 mg 
• Cenerimod 2 mg 
• Cenerimod 4 mg 
• Placebo 
5.4.3.2 TP2 
Any TP2 analyses will be summarized using the following 2 treatment groups: 
• Cenerimod 2 mg / Ex-4 mg 
• Placebo / Ex-4 mg 
Some TP2 analyses (as indicated in the respective sections) will also include the following 
treatment groups: 
• Cenerimod 0.5 mg 
• Cenerimod 1 mg 


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• Cenerimod 2 mg 
• Placebo 
5.4.3.3 TP1 and TP2 combined (and up to EOS) 
Any analyses combining TP1 and TP2 data will be summarized using the following 
6 treatment groups: 
• Cenerimod 0.5 mg 
• Cenerimod 1 mg 
• Cenerimod 2 mg 
• Cenerimod 2 mg / Ex-4 mg 
• Placebo / Ex-4 mg 
• Placebo 
Outputs for CSR section 15.1, description of compliance and study treatment exposure 
during TP1+TP2, and outputs for CSR section 15.3 describing treatment-emergent data 
regardless of the time-period (e.g., Adverse Events, abnormalities) will also include the 
“Not re-randomized / Ex-4 mg” group. 
5.4.3.4 Listings 
Listings will be presented using the following treatment groups: 
• Cenerimod 0.5 mg 
• Cenerimod 1 mg 
• Cenerimod 2 mg 
• Cenerimod 2 mg / Ex-4 mg 
• Placebo / Ex-4 mg 
• Not re-randomized / Ex-4 mg 
• Placebo 
Listings presenting TP2 data only will use the following treatment groups: 
• Cenerimod 2 mg / Ex-4 mg 
• Placebo / Ex-4 mg 
5.4.4 
Visit windows 
Data will be assigned into time windows for efficacy and safety analyses. 
The windows are defined as shown in Table 4. 


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Table 4 
Visit windows 
Visit 
Treatment day 
First treatment day 
Last treatment day 
Baseline 
 
–60 
1 
Month 1 
30 
2 
45 
Month 2 
60 
46 
75 
Month 3 
90 
76 
105 
Month 4 
120 
106 
135 
Month 5 
150 
136 
165 
Month 6 
180 
166 
195 
Month 7 
210 
196 
225 
Month 8 
240 
226 
255 
Month 9 
270 
256 
285 
Month 10 
300 
286 
315 
Month 11 
330 
316 
345 
Month 12 
360 
346 
375 
In the event that two visits are assigned to the same time window, choose the visit closest 
to the scheduled ‘Treatment day’, as displayed in Table 4. In the event that two visits are 
the same number of days from the scheduled ‘Treatment day’ select the first visit, with the 
exception that a regular visit will always be selected over an unscheduled visit. 
5.5 Subgroups 
The category in bold type is the reference category used for the analysis of subgroups. 
The following subgroup variables are defined according to protocol: 
• Stratification variable: Daily dose of OCS (< 7.5 mg or ≥ 7.5 mg prednisone 
equivalent) from IXRS system; 
• Stratification variable: mSLEDAI-2K (< 10 or ≥ 10) from IXRS 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 or Alaska Native, Asian, and Black). 
Both stratification variables are taken from the IXRS system; sex, age (< 65 years vs 
≥ 65 years) and race are taken from the Demographics eCRF page. Region is derived based 
on the country of the sites. Belimumab treatment status is derived as a binary variable based 
on coding from the Previous/Concomitant Medication eCRF page. 


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5.6 Other derivations 
The following conversion factors will be used to convert days into months or years: 
1 month = 30.44 days, 1 year = 365.25 days. For time windows calculation, 1 month is 
expressed as 30 days. 
6 
STUDY SUBJECTS VARIABLES AND ANALYSES 
6.1 Screen failures 
6.1.1 
Variables 
Screen failures are defined as subjects, with a screen failure date in the database 
(Screening/Screen failure date present in the IXRS subject form), who are not randomized 
according to the eCRF Eligibility/Randomization form (“Was the subject randomized?” → 
‘No’), and who are not randomized according to the IXRS system (i.e., no randomization 
date/time and number in the IXRS ‘Subject Form’). 
6.1.2 
Analysis 
The number of subjects screened, screening failures, subjects re-screened and re-screening 
failures, and reasons for screening failure will be summarized and listed using the SCR. 
Only reasons for the last screening attempt will be summarized. All reasons for screen 
failures will be included in the listing along with: date of Screening, screening attempt, an 
indicator variable (‘Yes’, ‘No’) for a successful or failed screening attempt, randomization 
date, number of days from successful Screening to Randomization and the verbatim reason 
for screen failure. 
The same description will be provided for the screening failures related to COVID-19 
pandemic. 
6.2 Eligibility criteria 
6.2.1 
Variables 
The inclusion and exclusion criteria information are taken from the Eligibility / Inclusion 
and Exclusion Criteria eCRF pages. 
6.2.2 
Analysis 
All subjects with unmet eligibility criteria will be listed. Subjects randomized with unmet 
criteria will be flagged in the listing. 
Eligibility criteria for screen failures not eligible as per inclusion/exclusion criteria will 
also be summarized. The table will only include screen failures not eligible as per 
inclusion/exclusion criteria. 
In case a subject was screened multiple times with more than one screening failure, the last 
screening failure will be included in the summary. All screening attempts will be included 
in the listings. 


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6.3 Subject disposition 
Subject disposition during TP1 includes the following variables, summarized by treatment 
group and overall using the FAS: 
• 
Subjects randomized in TP1 (subjects with randomization date/time and number 
present in the IXRS ‘Subject Form’ for TP1). 
• 
Subjects treated in TP1 (subjects with at least one dose of study treatment in the eCRF 
Study Treatment Log in TP1). 
• 
Subjects who prematurely discontinued study treatment in TP1 (subjects with 
‘Discontinuation’ as reason for treatment stop in the eCRF Study Treatment Log). 
• 
Subjects who completed TP1 on-treatment (subjects without ‘Discontinuation’ as 
reason for treatment stop in the eCRF Study Treatment Log). 
• 
Subjects who completed TP1 off-treatment. 
• 
Subjects who prematurely discontinued study in TP1 (based on End of Study Status 
eCRF page with valid date and reason). 
• 
Subjects taking part in the echocardiography ancillary study (subjects who were 
assigned to the echocardiography sub-study by IXRS). 
Subject disposition during TP2 includes the following variables, summarized by treatment 
group (also including cenerimod 0.5 mg, 1 mg, 2 mg and placebo groups) and overall using 
the FAS-TP2: 
• 
Subjects who were re-randomized in TP2 (subjects with randomization number 
present in IXRS for TP2). 
• 
Subjects treated in TP2 (subjects with at least one dose of study treatment in the eCRF 
Study Treatment Log in TP2). 
• 
Subjects who prematurely discontinued study treatment in TP2 (subjects with 
‘Discontinuation’ as reason for treatment stop on the eCRF Study Treatment Log, 
occurring after start of TP2 treatment). 
• 
Subjects who completed TP2 on-treatment (subjects without ‘Discontinuation’ as 
reason for treatment stop in the eCRF Study Treatment Log). 
• 
Subjects who completed TP2 off-treatment. 
• 
Subjects who prematurely discontinued study in TP2 (based on End of Study Status 
eCRF page with valid date and reason, occurring after start of TP2 treatment). 
Subject disposition during TP1 and TP2 includes the following variables, summarized by 
treatment group and overall using the FAS: 
• 
Subjects randomized in TP1. 
• 
Subjects treated in TP1. 
• 
Subjects re-randomized in TP2. 
• 
Subjects treated in TP2. 


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• 
Subjects who prematurely discontinued treatment during TP1 or TP2 (subjects with 
‘Discontinuation’ as reason for treatment stop in the eCRF Study Treatment Log). 
• 
Subjects who prematurely discontinued study (based on End of Study Status eCRF 
page with valid date and reason). 
The number of randomized subjects will also be summarized by country and site, using the 
SCR. 
6.4 Study treatment discontinuation 
6.4.1 
Variables 
Study treatment discontinuations are collected on the eCRF Study Treatment Log. 
A premature permanent treatment discontinuation is defined as stopping treatment 
permanently prior to the scheduled Month 12 visit (Reason for treatment stop/dose change 
= ‘Discontinuation’). Subjects discontinuing early are identified by having a 
discontinuation date on the corresponding eCRF page. 
The primary reason for premature treatment discontinuation is selected from reasons listed 
in the eCRF.  
Treatment discontinuation variables are also defined, by treatment period, for TP1 and TP2. 
6.4.2 
Analysis 
The reasons for discontinuing treatment will be listed using the FAS and summarized as 
follows:  
• During TP1: by treatment group and overall using the FAS. 
• During TP2: by treatment group (also including cenerimod 0.5 mg, 1 mg, 2 mg and 
placebo groups) and overall using the FAS-TP2. 
• During TP1 and TP2: by treatment group and overall using the FAS. 
The same description will be provided for the treatment discontinuation related to COVID-
19 pandemic. 
In addition, the cumulative incidence of study treatment discontinuations during TP1 and 
TP2 by reason will be visualized. 
6.5 Study discontinuation 
6.5.1 
Variables 
A subject withdrawing from the study early is flagged ‘No’ for the question “Did the 
subject complete the study?” on the End of Study Status eCRF page, with a study 
withdrawal date entered. The primary reason for study withdrawal is selected from reasons 
listed in the eCRF.  


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Study discontinuation variables are also derived by period, for TP1 and TP2. 
6.5.2 
Analysis 
The reasons for study discontinuation will be listed using the FAS and summarized as 
follows: 
• During TP1: by treatment group and overall using the FAS. 
• During TP2: by treatment group (also including cenerimod 0.5 mg, 1 mg, 2 mg and 
placebo groups) and overall using the FAS-TP2. 
• During TP1, TP2 and follow-up period: by treatment group and overall using the FAS. 
The same description will be provided for the study discontinuation related to COVID-19 
pandemic. 
In addition, the cumulative incidence of study discontinuation by reason will be visualized. 
6.6 Protocol deviations 
DVs will be summarized by DV category and subcategory by treatment group and overall. 
There will be separate tables for DVs during TP1 (using FAS), during TP2 (using 
FAS-TP2, including cenerimod 0.5 mg, 1 mg, 2 mg and placebo groups) and during the 
study (using FAS).  
Important DVs will be summarized separately, in the same way. 
The above summaries will be repeated for DVs and important DVs related to the COVID-
19 pandemic. 
A summary for DVs related to the conflict in Ukraine will be created. 
DVs will be listed using the SCR. The listing will include a flag indicating whether a DV 
was related to the COVID-19 pandemic and whether a DV was related to the conflict in 
Ukraine.  
A separate listing will present all subjects that were unblinded during the study including 
the event that triggered the unblinding request and the action taken following the 
unblinding using the FAS. 
6.7 Inclusion/exclusion in analysis sets 
6.7.1 
Variables 
The following variables are used for the analysis set outputs: 
• Subjects in the FAS 
• Subjects in the FAS-TP2 
• Subjects in the PPS 


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• Subjects in the SAF 
• Subjects in the SAF-TP2 
• Subjects in the ECS 
• Subjects in the PKS 
Definitions of the analysis sets are presented in Section 4.1. 
6.7.2 
Analysis 
The number and percentage of subjects in the FAS, FAS-TP2 and PPS will be summarized 
by treatment group and overall, using the FAS. The number and percentage of subjects in 
the SAF, SAF-TP2, ECS and PKS will be summarized by treatment group and overall, 
using the SAF. 
Reasons for exclusion from any analysis set will be summarized and listed. 
Reasons for excluding subjects from the PPS will be summarized in a table showing the 
following categories: 
• Subject randomized but did not fulfill the entry criteria. 
• Subject developed withdrawal criteria during the study, but did not withdraw. 
• Incorrect treatment administration or any violation of treatment concept. 
• Subjects who received forbidden concomitant medication/treatment. 
• Key study procedures missed or performed out of time window. 
• Other. 
6.8 Subject characteristics 
6.8.1 
Demographics 
6.8.1.1 Variables 
The demographic variables are derived as follows: 
• Sex; 
• Age (years; continuous); 
• Age group 1 (18–64, 65–75); 
• Age group 2 (18–45, 46–64, 65–75); 
• Weight (kg), by gender (female, male); 
• Height (cm), by gender (female, male); 
• BMI (kg/m2; continuous); 
• BMI (< 18.5, ≥ 18.5 – < 25.0, ≥ 25.0 – < 30.0, ≥ 30.0); 


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• Race (categorized as: American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or other Pacific Islander, White, Other); 
• Ethnicity (categorized as: Hispanic or Latino, Not Hispanic or Latino, Unknown); 
• Country; 
• Region (Asia, Europe, Latin America, US, Rest of World);  
• Childbearing potential (for female subjects only); 
• Reason for not being of childbearing potential (for female subjects only); 
• Smoking status (never smoked, current smoker, former smoker); 
BMI is defined as: BMI = weight in kg / (height in m)2. 
Data are taken from the Demographics and Height and body weight (at Screening), 
Smoking/Alcohol eCRF pages. Region will be derived from the country of the site. 
6.8.1.2 Analysis 
Demographics will be summarized using descriptive statistics for continuous and 
categorical data using the FAS and PPS. Demographics will also be summarized by sex 
using the FAS. 
Summary tables will be presented by treatment group and overall. A demographics listing 
will be produced using the SCR.  
The percentages of women with childbearing potential will be based on number of female 
subjects in the study. The percentages of reasons for not being of childbearing potential 
will be based on the number of female subjects that have answered the eCRF question “Is 
the woman of childbearing potential?” with ‘No’. 
6.8.2 
Stratification variables 
6.8.2.1 Variables 
OCS are collected on the Previous/Concomitant Medications eCRF page and are identified 
via coding. The stratification variable ‘Dose of oral corticosteroids’ is derived as a binary 
variable (< 7.5 mg/day vs ≥ 7.5 mg/day) at Randomization. 
The mSLEDAI-2K data is collected on the mSLEDAI-2K eCRF page at Screening. 
mSLEDAI-2K is also derived as a binary variable (< 10 and ≥ 10). 
The stratification variables, as entered by the investigator, are transferred by the IXRS 
provider. 
6.8.2.2 Analysis 
Number and percentage of subjects for each stratification factor separately as well as within 
each of the four strata will be summarized in shift tables according to eCRF as well as 
according to IXRS using the FAS. 


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6.8.3 
Baseline disease characteristics 
6.8.3.1 BILAG-2004 medical history 
6.8.3.1.1 Variables 
No variables are to be created, as data will only be listed. 
6.8.3.1.2 Analysis 
BILAG-2004 medical history will be listed using the SCR. 
6.8.3.2 ACR classification criteria for SLE 
6.8.3.2.1 Variables 
The data are taken from the ACR Criteria eCRF specifications page. Binary variables are 
created for each of the categories listed on that eCRF page. 
6.8.3.2.2 Analysis 
ACR classification criteria will be summarized using descriptive statistics for categorical 
data using the FAS. Summary tables will be presented by treatment group and overall.  
ACR classification criteria will be listed using the SCR. 
6.8.3.3 mSLEDAI-2K at Screening 
6.8.3.3.1 Variables 
The mSLEDAI-2K relevant disease characteristics are recorded and derived from the data 
on the mSLEDAI-2K eCRF page at Visit 1 (Screening), and the variables include: 
• Presence / no presence of each active descriptor 
• Mucocutaneous score 
• Musculoskeletal score 
• Sum of the mucocutaneous and musculoskeletal score 
• mSLEDAI-2K total score 
• SLEDAI-2K total score 
• mSLEDAI-2K total score as a category (≥ 10 and < 10) 
• SLEDAI-2K total score as a category (≥ 10 and < 10) 
mSLEDAI-2K 
The SLEDAI-2K is a disease activity index of SLE based on the presence of 24 descriptors 
in 9 organ systems over the preceding 10 days.  
Descriptors of the SLEDAI-2K are documented as either present or absent (or not done). 
Each of the descriptors is weighted and the total score of SLEDAI-2K is the sum of all 


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24 (weighted) descriptor scores. The range of the total SLEDAI-2K score is 0 to 105, with 
higher scores representing higher disease activity.  
In this study, a modified SLEDAI-2K (mSLEDAI-2K) score is applied. The item related 
to leukopenia is excluded from the SLEDAI-2K scoring due to the mode of action of the 
compound (i.e., lymphocyte count reduction in peripheral blood). Therefore, the 
mSLEDAI-2K total score has only 23 descriptors and a maximum score of 104.  
6.8.3.3.2 Analysis 
The mSLEDAI-2K at Screening will be summarized using descriptive statistics for 
continuous and categorical data using the FAS.  
Summary tables will be presented by treatment group and overall.  
mSLEDAI-2K data will be listed using the SCR. 
6.8.3.4 Physician’s Global Assessment of disease 
6.8.3.4.1 Variables 
The PGA is taken from the Screening Physician’s Global Assessment (PGA) eCRF page. 
6.8.3.4.2 Analysis 
PGA at Screening will be summarized using descriptive statistics for continuous and 
categorical data using the FAS.  
Summary tables will be presented by treatment group and overall.  
PGA data will be listed using the SCR. 
6.8.3.5 British Isles Lupus Assessment Group 
6.8.3.5.1 Variables 
Data is taken from the derived BILAG-2004 screening summary eCRF page BILAG-2004 
Grading. The data is received from an external vendor. 
For each of the nine assessed BILAG-2004 categories gradings are displayed in 
6 categories (A, B, C, D, E, not gradable). 


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6.8.3.5.2 Analysis 
For each of the 9 subcategories descriptive summary statistics will be produced using the 
FAS, by treatment group and overall.  
Data will also be listed using the SCR. 
6.8.3.6 SELENA flare index 
6.8.3.6.1 Variables 
Data is taken from the SELENA Flare Index eCRF pages which are aggregated and 
provided by an external vendor. 
Data are categorized into the following flare categories: 
• No flare 
• Mild or moderate flare 
• Severe flare 
6.8.3.6.2 Analysis 
Flare data will be summarized using descriptive statistics using the FAS. 
Summary tables will be presented by treatment group and overall.  
Flare data will be listed using the SCR. 
6.8.4 
Other baseline characteristics 
6.8.4.1 Discharge from medical monitoring on day of first study drug intake 
Subjects fulfilling the discharge criteria at 6 hours on the day of first study drug intake may 
leave the hospital.  
Subjects not fulfilling the discharge criteria at 6 hours will stay in hospital until the 
discharge criteria are fulfilled. The discharge criteria are checked every hour up to 12 hours. 
If the discharge criteria are not met after 12 hours, the subject will be permanently 
discontinued from study treatment.  
Discharge information is taken from the eCRF pages “Discharge from Medical Monitoring 
- 6 hours” and “Discharge from Medical Monitoring - 12 hours”. 
6.8.4.1.1 Variables 
The number of subjects being discharged at 6 hours, between 6 and 12 hours and the 
number of subjects being discontinued after 12 hours of medical monitoring are derived on 
the day of first study drug intake.  
For subjects that needed to stay longer than 6 hours, the time leaving the hospital is 
categorized hourly. 


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6.8.4.1.2 Analysis 
The number of subjects being discharged at 6 hours, the number of subjects being 
discharged between 6 and 12 hours and the number of subjects being discontinued after 
12 hours will be summarized descriptively using the SAF.  
The number of subjects being discharged between 6 and 12 hours will be summarized 
hourly. For subjects not being discharged, reasons for not being discharged will be 
summarized in categories using the SAF.  
Discharge data from the day of first study drug intake and the day of re-initiation will be 
listed using the SAF. 
6.8.4.2 Other baseline characteristics 
Other baseline characteristics collected during Screening include chest X-ray, 
contraceptive methods, physical examination, ophthalmological assessments, tuberculosis 
test, viral serology results and urinalysis. These are defined as collected on the eCRF and 
no derivation is required. 
6.8.5 
Medical history and current medical conditions 
6.8.5.1 Variables - medical history and cardiovascular medical history / risk factors 
6.8.5.1.1 Medical history (except SLE history, cardiovascular medical history and 
cardiovascular risk factors) 
Medical history includes all diseases or diagnoses recorded on the Medical History (except 
SLE history, cardiovascular medical history and cardiovascular risk factors) eCRF page.  
Reported terms are mapped to PTs using MedDRA at time of database closure.  
The variables of interest are the PT and the primary SOC. 
Current medical conditions are diseases and diagnoses that are ticked as ongoing at 
Screening and without an end date before or equal to the study treatment start date. In the 
event of a partial end date that overlaps with first dose (e.g., ’May 2019’ and first dose 
occurred on ‘23 May 2019’) or if an end date is missing, the medical condition is 
considered to be current if ongoing is ticked ‘Yes’.  
6.8.5.1.2 Cardiovascular medical history 
Cardiovascular medical history is collected on the Cardiovascular Medical History eCRF 
page. The same definitions apply as defined for the medical history (except SLE history, 
cardiovascular medical history and cardiovascular risk factors). 


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6.8.5.1.3 Cardiovascular risk factors 
Cardiovascular risk factors are collected on the Cardiovascular Risk Factors eCRF page. 
The same definitions apply as defined for the medical history (except SLE history, 
cardiovascular medical history and cardiovascular risk factors). 
6.8.5.2 Analysis - medical history and cardiovascular medical history / risk factors 
Medical history and cardiovascular medical history / risk factors will be summarized using 
the FAS. 
Summaries will be presented by primary SOC and PT, sorted by descending frequency 
based on the total column. The MedDRA version used for reporting will be specified in the 
footnote of the applicable output.  
Medical history data will be listed using the SCR. 
6.8.6 
Previous and concomitant therapies 
6.8.6.1 Variables 
Previous and concomitant therapies are collected on the Previous/Concomitant 
Medications eCRF page. Both non-SLE and SLE therapies are collected on this page. 
Previous and concomitant medications are categorized as follows: 
• Previous non-SLE therapies. 
• Study-concomitant non-SLE therapies. 
• Study-concomitant non-SLE therapies at baseline. 
• Previous SLE therapies. 
• Study-concomitant (background) SLE therapies. 
• Study-concomitant (background) SLE therapies at baseline. 
• Previous cardiovascular therapies. 
• Study-concomitant cardiovascular therapies. 
• Study-concomitant cardiovascular therapies at baseline. 
A previous therapy is any therapy for which the end date of therapy is prior to first study 
drug intake in TP1. A study-concomitant therapy is any therapy, that is either ongoing at 
the start of study treatment or is initiated between the start of the study treatment and the 
EOS visit. A study-concomitant therapy at baseline is any therapy, that either started on, 
or is ongoing at, the study treatment start date.  
The reported names are coded using the WHO drug code dictionary and the ATC class 
according to the most current version at time of database closure. The variables of interest 
are the PT (standardized medication name) and the ATC code level 4.  


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The WHO drug version used for reporting is specified in the footnote of the applicable 
output. 
6.8.6.1.1 Non-SLE therapies 
A non-SLE therapy is any therapy collected on the Previous/Concomitant Medications 
eCRF page which is not a SLE therapy [see Section 6.8.6.1.2] and not a cardiovascular 
therapy [see Section 6.8.6.1.3]. 
6.8.6.1.2 SLE therapies  
SLE therapies are identified based on the protocol-defined background SLE therapies [see 
protocol section 5.2.2, D-22.031] and a list based on WHODrug Global B3/C3-format is 
maintained in a separate document for their identification.  
An SLE therapy is any therapy collected on the Previous/Concomitant Medications eCRF 
page which is included in the above-mentioned list and which is not a cardiovascular 
therapy [see Section 6.8.6.1.3]. All SLE therapies will also be classified into the categories 
mentioned in protocol section 5.2.2, using this list. 
6.8.6.1.3 Cardiovascular therapies 
A cardiovascular therapy is any therapy administered for cardiovascular conditions or risk 
factors, reported on the Previous/Concomitant Medications eCRF page as: 
• Cardiovascular medical history. 
• Cardiovascular risk factors. 
6.8.6.1.4 Duration of medications/therapies 
The duration of medication/therapy in years is defined as: 
• Duration of medication/therapy (years) = therapy end date – therapy start date + 1 day 
/ 365.25. 
6.8.6.1.5 Data imputation 
The purpose of imputing therapy dates is only to determine if a therapy is study-
concomitant and/or study-concomitant at baseline. 
Incomplete therapy end dates will be imputed with the latest date possible, e.g., if the day 
is missing, the last day of the respective month will be imputed, or if day and month are 
missing, the last day of the respective year will be imputed. End dates that are completely 
missing will not be imputed and the therapy is considered as ongoing. 
If a therapy start date is completely missing, the earliest of study treatment start date or 
(imputed) therapy end date will be imputed. 
Partial therapy start dates will be imputed as follows: 


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• Therapy start day missing: if the (imputed) therapy end date is on or after study 
treatment start date (or missing) and the partial therapy start date is in the same month 
and year as the study treatment start date, the study treatment start date is used. 
Otherwise, the first day of the month is used. 
• Therapy start day and month missing: if the (imputed) therapy end date is on or after 
study treatment start date (or missing) and the partial therapy start date is in the same 
year as the study treatment start date, the study treatment start date is used. Otherwise, 
the first day of the year is used. 
6.8.6.2 Analysis 
Number (%) of subjects having taken at least one previous, study-concomitant or 
study-concomitant at baseline treatment will be summarized by ATC class and individual 
PT within each ATC class using the FAS, by treatment group and overall. For tables 
describing background SLE therapies, the category from protocol section 5.2.2 and 
identified in the file mentioned in Section 6.8.6.1.2 will be used instead of the ATC class. 
In addition, a table summarizing changes in background SLE therapies during TP1 will be 
produced. 
All previous and concomitant therapies will be listed using the SCR. 
6.9 Study treatment exposure 
6.9.1 
Exposure to treatment 
6.9.1.1 Variables 
Duration of exposure (months) to study drug is defined as the time elapsing between the 
[date of first study drug intake and the date of last study drug intake + 1 (in days)] / 365.25 
 12, regardless of any treatment interruptions. 
Duration of exposure is also derived by treatment period (TP1 and TP2). 
Exposure to study drug is also derived in categories (≤ 3 months [91 days], > 3 months and 
≤ 6 months [183 days], > 6 months and ≤ 9 months [274 days], > 9 months) for analyses 
of TP1 and TP2 combined and in monthly categories for analyses of TP1 and TP2 
separately, using the variable ‘Duration of exposure (months) to study drug’. 
6.9.1.2 Analysis 
The following summaries will be provided: 
• Study treatment exposure during TP1 using the SAF. 
• Study treatment exposure during TP1 by subgroup (sex, SLE age group, race) using the 
SAF. 
• Study treatment exposure during TP2 using the SAF-TP2. 
• Study treatment exposure during TP1 and TP2 using the SAF. 


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Exposure data will be listed using the SAF. 
6.9.2 
Compliance 
6.9.2.1 Variables 
Overall compliance (%) will be assessed through study treatment accountability using the 
following formula: 
Accountability based compliance = [(number of tablets dispensed − number of tablets 
returned) / number of tablets that should have been taken during the period*] × 100 
*The period is defined as the number of days during which study treatment should be taken 
as per actual visit dates. 
If a subject did not return a kit, compliance will be set to missing for the respective period 
(e.g., between two visits). For the derivation of the overall compliance, the respective 
period will not be considered. 
If a kit is replaced (e.g., because initial kit was lost by the subject), the initial kit will be 
ignored for the derivation of compliance. 
The overall compliance will be categorized as: 
• < 80% 
• ≥ 80% 
6.9.2.2 Analysis 
Overall study compliance will be summarized using descriptive statistics by treatment 
group using the FAS. The “Not re-randomized / Ex-4 mg” group will also be displayed.  
Compliance will also be summarized by period using the FAS for TP1 and the FAS-TP2 
for TP2 (also including cenerimod 0.5 mg, 1 mg, 2 mg and placebo groups). 
Compliance will be listed using the FAS.  
6.10 Pharmacokinetic variables 
PK plasma concentrations are collected 6 h after study drug administration on Day 1 
(initiation or re-initiation) and pre-dose at Visits 3 (Month 1), 4 (Month 2), 5 (Month 3), 
8 (Month 6), 14 (Month 12 or premature EOT), and at EOS. 
To prevent unblinding, the results of the PK data are not communicated to the investigator, 
study personnel, subjects, Clinical Research Associates, or any sponsor or vendor/CRO 
personnel involved in the conduct of the study.  
Results will be transferred by the bioanalytical laboratory for PK measurements to the 
sponsor and CRO personnel involved in the conduct of the study only after database lock. 


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6.10.1 Variables 
Plasma concentrations are provided by the biomarker laboratory. Thus, no derivations are 
required. 
6.10.2 Analysis 
For PK variables quantitative descriptive statistics (including geometric mean and 95% CI) 
for plasma concentrations will be presented on the day of first study drug intake, the day 
of re-initiation and over time (Month 1, 2, 3, 6, 12, premature EOT, EOS), by visit and 
treatment group using the PKS. 
The plasma concentration-time profiles of the values over time will be provided in figures 
(boxplot per treatment group and visit, from baseline to EOS) using the PKS.  
A listing of PK data will be produced using the PKS. 
7 
EFFICACY VARIABLES AND ANALYSES 
7.1 Overview 
The primary efficacy variable of the study is the absolute change of the mSLEDAI-2K 
score from baseline to Month 6. Changes for all time points from Month 1 through Month 6 
will be derived and included in the statistical analysis model of the primary endpoint.  
There are two secondary endpoints that are analyzed in hierarchical manner for each dose 
level comparison following any rejections of dose level comparisons hypotheses of the 
primary endpoint: 
• Response at Month 6 on SRI-4 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. 
The other efficacy endpoints are described as follows: 
• Response at Month 6 on 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: 


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− 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. 
• Response at Month 6 on SRI-5, -6, -7, -8 defined as the secondary endpoint (response 
at Month 6 on SRI-4) with reductions in mSLEDAI-2K of 5, 6, 7 and 8, instead of a 
reduction of 4. 
• Occurrence of mild, moderate and severe flares from baseline up to Month 6. 
• Time to first severe flare from baseline to Month 6 (severe flares defined as BILAG 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. 
Exploratory endpoints will be analyzed from baseline to a maximum of 12 months on all 
available assessments according to two groups: 
• Group 1: All randomized subjects, for whom baseline is defined as the last available 
measurement before the start of randomized treatment in TP1. 
• Group 2: Subjects re-randomized at Month 6, for whom baseline is defined as the last 
available measurement before the start of re-randomized treatment in TP2. 
Endpoints for Group 1: 
• Sustained mSLEDAI-2K response defined as a reduction of at least 
 
 
 
 
• Change from baseline to each post-baseline assessment up to Month 12 in prednisone 
or equivalent dose. 
Endpoints for Groups 1 and 2: 
• Change from baseline to each post-baseline assessment up to Month 12 in 
mSLEDAI-2K score.  
• Response at each post-baseline assessment on improvement in the mSLEDAI-2K 
score, defined as a reduction from baseline of at least 4 points. 
• Response (no worsening and improvement) at each post-baseline assessment 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 


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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. 
• Response at each post-baseline assessment on SRI-4, -5, -6, -7, -8. 
• 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 A or 2 or more new BILAG B organ domain scores 
compared to the previous visit). 
• Time to first severe flare from baseline to Month 12 (severe flares defined as BILAG 
A organ domain score presence due to items that are new or worse). 
• Time to first flare from baseline to Month 12. 
The PRO/QoL endpoints are defined as follows: 
• Change from baseline to each post-baseline assessment in FACIT-Fatigue Scale score. 
• Change from baseline to each post-baseline assessment in PGIS-F. 
• PGIC-F score at each post-baseline assessment. 
• Change from baseline to each post-baseline assessment in SF-36v2™. 
• Change from baseline to each post-baseline assessment in the Lupus QoL 
questionnaire. 
7.1.1 
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 
The four alternative hypotheses are: 
• HA1mSLEDAI-2K: cenerimod0.5 mg – placebo ≠ 0 
• HA2 mSLEDAI-2K: cenerimod1.0 mg – placebo ≠ 0 
• HA3 mSLEDAI-2K: cenerimod2.0 mg – placebo ≠ 0 


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• HA4 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 / alternative 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 
vs 
• HA1SRI-4: cenerimod0.5 mg/placebo ≠ 1 
• HA2SRI-4: cenerimod1.0 mg/placebo ≠ 1 
• HA3SRI-4: cenerimod2.0 mg/placebo ≠ 1 
• HA4SRI-4: cenerimod4.0 mg/placebo ≠ 1 
and 
BILAG-2004 
• H1BILAG: cenerimod0.5 mg/placebo = 1 
• H2BILAG: cenerimod1.0 mg/placebo = 1 
• H3BILAG: cenerimod2.0 mg/placebo = 1 
• H4BILAG: cenerimod4.0 mg/placebo = 1 
vs 
• HA1BILAG: cenerimod0.5 mg/placebo ≠ 1 
• HA2BILAG: cenerimod1.0 mg/placebo ≠ 1 
• HA3BILAG: cenerimod2.0 mg/placebo ≠ 1 
• HA4BILAG: cenerimod4.0 mg/placebo ≠ 1 
These eight hypotheses represent the ORs 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 the OR is 
different from 1 between cenerimod and placebo, at a given dose, in SRI-4 and 
BILAG-2004. 


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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 2].  
This testing strategy protects the Type I error rate in the primary endpoint family with a 
slight increase in the Type I error rate in the secondary endpoint families.  
Testing all four null hypotheses in the secondary endpoint families irrespective of which 
dose groups where significant in the previous endpoint family is the conservative approach 
(as opposed to only testing the significant doses from the previous endpoint family).  
Claims for statistical significance will not be made on results from dose groups that have 
not been significant in a previous endpoint family. Such results are considered exploratory 
only. 
Figure 2 
Control of Type I error rate within each endpoint and treatment 
group 
 
BILAG 2004 = British Isles Lupus Assessment Group-2004; mSLEDAI-2K = modified Systemic Lupus Erythematosus 
Disease Activity Index-2000; SRI = Systemic Lupus Erythematosus Responder Index. 


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7.2 Primary endpoint analysis 
7.2.1 
Overview of analyses 
The main estimator as well as sensitivity and supplementary estimators for the primary 
estimand as defined in Section 3.1.1 are summarized in Table 5. 
Table 5 
Overview of analyses for primary estimand 
Estimator 
Section 
Endpoint 
Imputation 
method 
Analysis 
Main estimator 
7.2.5 
Change of 
mSLEDAI-2K from 
baseline to Month 6 
None (MAR 
assumption) 
Primary analysis (MMRM model) using 
the FAS. 
To ensure that the estimand based on the 
treatment policy strategy can be estimated, 
the value for the variable of change in 
mSLEDAI-2K is used regardless of 
occurrence of intercurrent events, such as 
treatment discontinuation. 
Sensitivity 
estimator #1 
7.2.6.1 
Change of 
mSLEDAI-2K from 
baseline to Month 6 
Multiple 
imputation under 
MAR 
Simulation of 100 datasets based on 
MMRM model 
Sensitivity 
estimator #2 
7.2.6.2 
Change of 
mSLEDAI-2K from 
baseline to Month 6 
Multiple 
imputation under 
MNAR using 
copy reference 
Simulation of 100 datasets based on 
MMRM model 
Sensitivity 
estimator #3 
7.2.6.3 
Change of 
mSLEDAI-2K from 
baseline to Month 6 
Multiple 
imputation under 
MNAR using 
jump to 
reference 
Simulation of 100 datasets based on 
MMRM model 
Sensitivity 
estimator #4 
7.2.6.4 
Change of 
mSLEDAI-2K from 
baseline to Month 6 
None (MAR 
assumption) 
Primary analysis (MMRM model) based 
on PPS 
Sensitivity 
estimator #5 
7.2.6.6 
Change of 
mSLEDAI-2K from 
baseline to Month 6 
None (MAR 
assumption) 
Primary analysis (MMRM model) based 
on complete case analysis 
Supplementary 
estimator #1 
(dose response) 
7.2.6.9 
Dose response of 
mSLEDAI-2K from 
baseline to Month 6 
None (MAR 
assumption) 
 
Supplementary 
estimator #2 
(hypothetical 
estimand) 
7.2.6.7 
Change of 
mSLEDAI-2K from 
baseline to Month 6 
(hypothetical 
estimand) 
None (MAR 
assumption) 
Primary analysis (MMRM model) for all 
on-treatment data. 
To ensure that the estimand based on the 
hypothetical strategy can be estimated, 
only values of mSLEDAI-2K prior to 


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Estimator 
Section 
Endpoint 
Imputation 
method 
Analysis 
occurrence of treatment discontinuation, 
the intercurrent event of interest, are used. 
Supplementary 
estimator #3 
(SLEDAI-2K) 
7.2.6.8 
Change of 
SLEDAI-2K from 
baseline to Months 
1, 2, 3, 4, 5 and 6 
None (MAR 
assumption) 
Primary analysis (MMRM model) 
Supplementary 
estimator #4 
(subgroups) 
7.2.7 
Change of 
mSLEDAI-2K from 
baseline to Month 6 
None (MAR 
assumption) 
Subgroup analyses 
Supplementary 
estimator #5 
(response over 
time) 
7.2.6.5 
Change of 
mSLEDAI-2K from 
baseline to Months 
1, 2, 3, 4, 5 and 6 
None (MAR 
assumption) 
Primary analysis (MMRM model)  
FAS = Full Analysis Set; MAR = missing at random; MMRM = mixed model for repeated measures; MNAR= missing 
not at random; mSLEDAI-2K = modified Systemic Lupus Erythematosus Disease Activity Index-2000; PPS = Per-
Protocol Set. 
7.2.2 
Variables 
The primary efficacy endpoint is the absolute change from baseline to Month 6 in the 
mSLEDAI-2K score.  
The null hypotheses for the primary endpoint will be tested using an MMRM on the change 
from baseline in mSLEDAI-2K for all available post-baseline scores from Months 1 to 6. 
This change is defined as the difference: 
Change in mSLEDAI-2K = post-baseline mSLEDAI-2K score – baseline mSLEDAI-2K 
score. 
Post-baseline visits will be assigned into time windows, as defined in Section 5.4.4, and 
the change from baseline will be computed based on the assigned visit labels.  
Following the treatment policy estimand all data will be included in the analysis regardless 
of early treatment discontinuation or other intercurrent events. 
The mSLEDAI-2K score is derived on the mSLEDAI-2K eCRF page for every visit and 
can be used without further derivation. 
7.2.3 
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 MAR.  


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Various sensitivity analyses will be performed to evaluate the robustness of this assumption 
[see Table 5]. 
A summary of the patterns of missingness from baseline up to Month 6 will be provided 
as well as a figure presenting the mean change from baseline in mSLEDAI-2K for study 
completers and withdrawals by reason. 
7.2.4 
Hypothesis, statistical model and assumptions 
The hypotheses for the primary endpoint mSLEDAI-2K are presented in Section 7.1.1. 
7.2.5 
Main analysis 
The primary statistical analysis will be performed using the FAS, according to the 
intention-to-treat approach. 
The null hypotheses for the primary endpoint will be tested using an MMRM on all 
available changes from baseline in mSLEDAI-2K for post-baseline scores from Months 1 
through 6.  
The following fixed effects will be included in the model:  
• Treatment group. 
• Month. 
• Baseline mSLEDAI-2K score. 
• Treatment group by month interaction. 
• Baseline mSLEDAI-2K score by month interaction (as continuous variable). 
• Stratification factor OCS (from IXRS).  
The stratification factor mSLEDAI-2K at Screening will not be included in the model as 
the continuous baseline value is already included in the model.  
A restricted maximum likelihood approach in combination with the Newton Raphson 
Algorithm will be used.  
An unstructured (UN) covariance matrix will be used to account for the correlation between 
repeated measurements from the same subject. If this analysis fails to converge, the 
following structures will be tested in a subsequent order until model-convergence is 
achieved: heterogeneous Toeplitz (TOEPH); Toeplitz (TOEP); autoregressive (AR(1)); 
compound symmetry (CS). The Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom. 
The treatment effect for each cenerimod dose vs placebo will be estimated from the LSM 
differences for each dose vs placebo at Month 6 and their corresponding 95% CIs.  


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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. 
This analysis will be implemented using the following SAS® code: 
proc mixed method=reml; 
 class subjid ocs treatment month; 
 model change = ocs sledai_bl treatment month treatment*month sledai_bl*month / ddfm=kr; 
 repeated month / type = UN subject=subjid(treatment); 
  
 slice treatment*month / sliceby=month pdiff cl; 
run; 
 
Efficacy data of the primary endpoint will be summarized descriptively and listed using 
the FAS. 
7.2.6 
Supplementary/sensitivity analyses 
For all supplementary and sensitivity analyses of the primary endpoint analysis, the 
variable change from baseline in mSLEDAI-2K to Month 6 is derived as defined in 
Section 7.2.1 for the primary analysis. 
7.2.6.1 Multiple imputation under MAR using mixed model for repeated 
measurements  
This analysis will be conducted with multiple imputations in 3 steps using the FAS. 
7.2.6.1.1 Step 1 (imputation) 
Missing monthly mSLEDAI-2K scores will be imputed using a multiple imputation 
method [Rubin 1987], based on a model including the treatment group, the stratification 
factor OCS (from IXRS), the baseline mSLEDAI-2K score, and all post-baseline monthly 
scores up to Month 6.  
Instead of imputing a single value for each missing observation, a set of values is generated 
from the model, resulting in as many distinct complete datasets without missing data.  
More specifically, the imputations will be performed in two steps: ‘intermittent’ missing 
data (a monthly score is missing but one or more monthly score[s] is [are] available at 
following month[s]) will be first imputed by a Markov chain Monte Carlo method using a 
non-informative Jeffreys Prior, thus creating 100 partially imputed ‘monotone’ datasets, 
then the remaining missing data will be imputed once in each of these 100 ‘monotone’ 
imputed datasets using monotone regression leading finally to 100 complete imputed 
datasets. Imputed values will be restricted to remain in the clinically relevant range of 
[0, 104] but will not be rounded to integers. 
The two-step multiple imputation procedure will be implemented by the following SAS® 
code: 


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proc mi data=h nimpute=100 seed=1234 minimum = . . 0 0 0 0 0 0 maximum = . . 104 104 104 
104 104 104 minmaxiter=1000 out=h2; 
  by trt; 
  mcmc impute = monotone chain=single nbiter=200 niter=100; 
  var ocs sledai_bl m1 -- m6; 
run; 
 
proc mi data=h2 nimpute=1 seed=1234 minimum = . . . 0 0 0 0 0 0 maximum = . . . 104 104 104 
104 104 104 minmaxiter=1000 out=h3; 
  by _imputation_; 
  class treatment ocs; 
  var treatment ocs sledai_bl m1 -- m6; 
  monotone regression; 
run; 
 
In each imputed dataset, the change from baseline in mSLEDAI-2K from baseline to each 
monthly visit will be computed, as described for the primary endpoint. Imputed changes 
from baseline might not be integers. 
7.2.6.1.2 Step 2 (analysis) 
The analysis, within each imputed dataset, of the change in mSLEDAI-2K from baseline 
to Month 6 will be implemented by the following SAS® code: 
proc mixed data=<data from step 1>; 
class subjid ocs treatment month; 
model change = ocs sledai_bl treatment month treatment*month sledai_bl*month / ddfm=kr; 
repeated month / type = UN subject=subjid(treatment); 
 
slice treatment*month / sliceby=month pdiff cl; 
by _imputation_; 
run; 
7.2.6.1.3 Step 3 (combination) 
Uncertainty in the imputations will be reflected appropriately in the analysis by combining 
the results on each imputed dataset into one summary measure. This method has been 
shown to be efficient in handling missing data if the missing data mechanism is missing 
completely at random or MAR Schafer 1999]. 
The summary results across the 100 complete datasets will be aggregated following 
Rubin’s rule. The final estimate is the mean of the 100 per-imputation estimates and the 
final variance is the sum of the average within-imputation variance and (1+1/100) times 
the between-imputation variance [Rubin 1987]. From the final point estimate and variance, 
the 95% CI will be determined. The corresponding p-value will be displayed. 
The results aggregation as the final step of the multiple imputation procedure after analysis 
of the 100 complete datasets will be implemented by the following SAS® code: 
proc mianalyze parms= <data from step 2 >; 
 class treatment month; 
 modeleffect treatment*month; 
run; 
 


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The robustness of this model will be assessed via several sensitivity analyses as described 
in the following sections. 
7.2.6.2 Multiple imputation under MNAR using copy reference  
This sensitivity analysis will be performed using the FAS. 
The analysis of the primary endpoint described in Section 7.2.6.1 is based on the MAR 
assumption that “missingness” is independent of missing responses conditionally on 
observed responses.  
The observed data cannot be used to distinguish between MAR and MNAR missing data 
mechanisms [NRC Report 2010] and in incomplete-data settings a definitive MNAR 
analysis does not exist [Molenberghs 2004]. However, a selected number of MNAR 
models can be used to check the robustness of the results to departures from the MAR 
assumption. 
An analysis based on a pattern-mixture model will be performed keeping a ‘MAR 
imputation’ in the placebo arm while using an ‘MNAR approach’ in the cenerimod arm. 
This pattern-mixture model will follow the multiple imputation procedure described in 
Section 7.2.6.1.1 but with a modification in the second imputation step (after imputation 
of the ‘intermittent’ missing data). The remaining missing data in subjects from the 
cenerimod arm will be imputed based on data from the placebo arm, assuming that subjects 
from the cenerimod arm who stop providing data will exhibit the same future trajectories 
as subjects in the placebo arm, while the remaining data in subjects from the placebo arm 
will be imputed under the MAR assumption [O’Kelly 2014]. This imputation model using 
the available post-baseline data of each cenerimod subject to be imputed is following the 
copy reference approach [Carpenter 2013]. 
Step 1 will be implemented by the following SAS® code: 
proc mi data=h nimpute=100 seed=6789 minimum = . . . 0 0 0 0 0 0 maximum = . . . 104 104 
104 104 104 104 minmaxiter=1000 out=h2; 
mcmc impute = monotone; 
var treatment ocs sledai_bl m1 -- m6; 
run; 
 
proc mi data=h2 nimpute=1 seed=6789 minimum = . . 0 0 0 0 0 0 maximum = . . 104 104 104 104 
104 104 minmaxiter=1000 out=h3; 
by imputation ; 
class treatment ocs; 
var ocs sledai_bl m1 –- m6; 
mnar model (m1 –- m6 / modelobs=(treatment=“placebo”)); 
monotone regression; 
run; 
Steps 2 and 3 will be implemented as in Section 7.2.6.1.2 and 7.2.6.1.3. 
7.2.6.3 Multiple imputation under MNAR using jump to reference  
This sensitivity analysis will be performed using the FAS. 


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Steps 1 to 3 are repeated as described for the copy reference model in Section 7.2.6.2, with 
a code change in step 1, as displayed below. The jump to reference model is implemented 
by missing value imputations, separately for every visit, i.e., the imputation procedure will 
be repeated 6 times, once for each of the monthly visits. 
proc mi data=h nimpute=100 seed=123 minimum = . . 0 0 0 0 0 0 maximum = . . 104 104 104 104 
104 104 minmaxiter=1000 out=h2; 
mcmc impute = monotone; 
var ocs sledai_bl m1 -- m6; 
run; 
 
proc mi data=h2 nimpute=1 seed=123 minimum = . . 0 maximum = . . 104 minmaxiter=1000 out=m1; 
by _imputation_; 
class treatment ocs; 
var ocs sledai_bl m1; 
mnar model (m1 / modelobs=(treatment=“placebo”)); 
monotone regression; 
run; 
 
proc mi data=m1 nimpute=1 seed=123 minimum = . . 0 maximum = . . 104 minmaxiter=1000 out=m2; 
by _imputation_; 
class treatment ocs; 
var ocs sledai bl m2; 
mnar model (m2 / modelobs=(treatment=“placebo”)); 
monotone regression; 
run; 
 
… 
 
proc mi data=m5 nimpute=1 seed=123 minimum = . . 0 maximum = . . 104 minmaxiter=1000 out=m6; 
by _imputation_; 
class ocs; 
var ocs sledai_bl m6; 
mnar model (m6 / modelobs=(treatment=“placebo”)); 
monotone regression; 
run; 
 
7.2.6.4 Analyses based on PPS 
The analysis of the primary endpoint as described in Section 7.2.5 will be conducted using 
the PPS. 
7.2.6.5 Treatment effect over time 
All monthly estimates related to the primary endpoint variable from the primary analysis 
model described in Section 7.2.5 will be reported as well. 
Figures presenting the LSM differences versus placebo and their 95% CIs over time will 
be produced by treatment group using the FAS. 
7.2.6.6 Complete case analysis 
Only data from subjects with the complete information available at all visits from baseline 
to Month 6 will be included in the analysis of the primary endpoint as described in 
Section 7.2.5 (based on the FAS). 


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7.2.6.7 Hypothetical estimand analysis 
This supplementary analysis does not use the treatment policy strategy to account for 
treatment discontinuation that is used for the primary analysis estimand, but rather, the 
hypothetical strategy. This means that all assessments collected after premature treatment 
discontinuation are not included in the analysis. 
The analysis will be conducted in the same way as the primary analysis as described in 
Section 7.2.5 (based on the FAS). 
7.2.6.8 Analyses based on SLEDAI-2K 
7.2.6.8.1 Variable 
The derivation of the ‘full’ SLEDAI-2K is based on the derived mSLEDAI-2K scores of 
the primary endpoint [see Section 7.2.1], including baseline and Month 1 to Month 6 
scores, and the leukocyte value (from the central laboratory) at the corresponding visit. 
If leukopenia is present at the corresponding visit the SLEDAI-2K score derives as: 
SLEDAI-2K at Visit X = mSLEDAI-2K at Visit X + 1. 
If leukopenia is not present or the leukocyte data are missing at the corresponding visit the 
SLEDAI-2K score is derived as: 
SLEDAI-2K at Visit X = mSLEDAI-2K at Visit X. 
Leukopenia is defined as a leukocyte value of < 3000  109/L (per visit). 
7.2.6.8.2 Analysis 
The analysis of the primary endpoint as described in Section 7.2.5 will be conducted on 
the SLEDAI-2K. 
7.2.6.9 Dose-response analysis 
7.2.6.9.1 Dose-response analysis 
The objective of this supplementary analysis is to assess overall dose-response using 
modeling and multiple comparison procedures on the primary efficacy endpoint (change 
in mSLEDAI-2K from baseline to Month 6). 
7.2.6.9.2 Hypothesis and model 
The null hypothesis is that there is no dose response for the primary efficacy endpoint from 
baseline to Month 6, and the alternative hypothesis is the existence of a dose response:  
𝐻0: 𝑝𝑑≥ 𝑝𝑃𝑙𝑎𝑐𝑒𝑏𝑜 for all doses d = 0.5, 1, 2, 4 mg 
vs 
𝐻1: 𝑝𝑑< 𝑝𝑃𝑙𝑎𝑐𝑒𝑏𝑜 for at least 1 dose d =0.5, 1.0, 2.0, 4.0 mg 


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To meet the objective of defining a dose response on the reduction of mSLEDAI-2K from 
baseline to Month 6, the null hypotheses must be rejected with an exploratory one-sided 
significance level of 5%. 
Dose-response data are analyzed using the MCP-Mod approach [Bretz 2005]. In brief, this 
methodology consists of three steps: 
1. MCP step to establish a dose-response signal (i.e., the dose-response curve is not flat). 
2. Mod step: Selecting the best dose-response model for the observed data out of a pre-
specified set of candidate models, and 
3. Mod step: Estimating target dose(s) of interest via modeling.  
Five candidate models are considered: linear, linlog, Emax, sigmoidal Emax and logistic. See 
Table 6 for the parameterization of the dose-response models and Figure 3 as an illustration 
of their basic shapes. The initial values for the parameters are needed in the MCP step of 
the procedure. They will be estimated in the Mod step based on the actual data. 
Table 6 
Parameterization of models considered in MCP-Mod analyses 
Model 
Response* 
Initial value(s) 
for parameters 
Linear 
E0 + delta • dose 
NA* 
Linear in log 
E0 + delta • log(dose + 0.5) 
NA* 
Emax 
E0 + Emax • dose/(ED50 + dose) 
ED50 = 1 
Sigmoidal Emax 
E0 + Emax • doseh/(ED50h + doseh) 
ED50 = 1.5, h = 0.3 
Logistic 
E0 + Emax/(1 + exp[{ED50 - dose}/delta]) 
ED50 = 1.5, delta = 0.3 
Dose = 0, 0.5, 1, 2 and 4 mg of cenerimod;  
*Not applicable for E0, delta (in linear and linlog models), and Emax  
ED50 = dose giving half of the asymptotic maximum effect; Emax = maximum effect; linlog = linear in log; MCP-Mod = 
multiple comparison procedures - modeling; NA = not applicable. 


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Figure 3 
Dose-response curves considered in MCP-Mod procedure 
  
Emax = maximum effect; linlog = linear in log; MCP-Mod = multiple comparison procedures - modeling. 
 
Note that the ‘Model means’ on the vertical axis are plotted on a scale from 0 to −0.5 for 
illustrative purposes. The actual scale will depend on the endpoint analyzed. 
The null hypothesis of ‘no dose response’ will be rejected if at least one of the five multiple 
contrast tests has a multiplicity adjusted p-value < 0.05.  
All statistically significant models (i.e., with a multiplicity adjusted p-value < 0.05) will be 
fitted in the Mod step and for each model AIC will be calculated. The smaller the value of 
AIC (= model deviance + 2 times the number of model parameters), the better the fit. The 
analysis will be performed using the R DoseFinding package [Bornkamp 2016].  
7.2.6.9.3 Handling of missing data 
Missing data will not be imputed but will be handled by the underlying MMRM model 
assuming that the data are MAR. 


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7.2.6.9.4 Variables 
The LSM estimates of the change from baseline to Month 6 of all treatment groups and 
placebo are taken from the model of the primary efficacy endpoint. In addition, the 
variance/covariance matrix of the LSM estimates at Month 6 is output by SAS®. Both the 
LSM estimates, and the variance/covariance matrix are transferred into and analyzed using 
the R DoseFinding package. 
7.2.6.9.5 Analysis 
The analysis will be based on the R-code ‘Mods’ and ‘MMfit’. 
In the ‘Mods function call’ the candidate models are specified, together with the assumed 
placebo and maximum effects. In the call to the MCPMod function,  
• doses is a vector of length 5, corresponding to Planned Dose for TP1 (increasing order),  
• est is a vector of length 5, corresponding to the LSM estimates of the change from 
baseline to Month 6 of all treatment groups and placebo (sorted by dose),  
• C is the variance/covariance matrix (of dimensions 5 × 5) of the LSM estimates at 
Month 6 (sorted by dose), 
• Delta is a target difference vs. placebo [see protocol section 10.5, D-22.031].  
The object MMfit is summarized to obtain the MCP test, parameter estimates, target dose 
and AIC. These elements will be summarized. The object will be plotted to display the 
fitted dose-response curves. 
The selected model will be fitted using the fitMod function and plotted together with the LSM 
estimates and confidence intervals from the primary analysis.  
doses <- c(0,0.5,1,2,4) 
# define candidate models 
mods2 <- Mods(linear = NULL, linlog = NULL, emax = 1, sigEmax = c(1.5, 0.3), logistic =  
c(1.5, 0.3), doses = doses, direction="decreasing") 
# MCPMod 
MMfit <- DoseFinding::MCPMod(type="general", dose=doses, resp=est, S=as.matrix(C), 
models=mods2, alpha=0.05, selModel="AIC", Delta=1.5) 
# fit the selected model 
MMsel <- fitMod(type="general", dose=doses, resp=est, S=as.matrix(C), model=MMfit$selMod) 
# extract predicted values to plot, together with CI 
pred <- predict (MMsel, se.fit=TRUE, doseSeq=seq(0,4,0.05),predType="ls-means") 
pred$LB <- pred$fit - qnorm(0.975)*pred$se.fit 
pred$UB <- pred$fit + qnorm(0.975)*pred$se.fit 


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7.2.7 
Subgroup analyses 
The aim of these exploratory subgroup analyses, classifying subjects according to 
important baseline characteristics, is to explore the consistency of treatment effect in a 
variety of relevant subject subgroups to support the efficacy evaluation of cenerimod in 
this indication. 
7.2.7.1 Variables 
Subgroup variables are defined as in Section 5.5. 
7.2.7.2 Analysis 
The same model as for the main analysis described in Section 7.2.5 will be fitted per 
subgroup. Stratification factor OCS will not be included as a fixed effect in the model for 
subgroup analysis by daily dose of OCS. 
Summary tables will be produced, similar to those produced for the primary efficacy 
analysis, by subgroup. 
Forest plots will be produced, displaying the LSM differences for each dose vs placebo 
including 95% CIs at Month 6. The forest plot will include an ‘overall’ treatment effect, 
based on the primary efficacy analysis and a reference line for the zero effect. 
7.3 Secondary endpoints analysis 
7.3.1 
Response at Month 6 on SRI-4 
The composite endpoint (SRI-4 response at Month 6) is a binary endpoint based on three 
variables, as defined below. 
The mSLEDAI-2K score is derived on the mSLEDAI-2K eCRF page for every visit and 
can be used without further derivation. The PGA data is taken from the Physician’s Global 
Assessment (PGA) eCRF page. 
A time windowing approach, as defined in Section 5.4.4, is applied for the variable 
derivation. 
7.3.1.1 Overview of analyses 
The main estimator as well as sensitivity and supplementary estimators for the secondary 
estimand #1 as defined in Section 3.1.1 are summarized in Table 7. 


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Table 7 
Overview of analyses for secondary estimand #1 
Estimator 
Section 
Endpoint 
Imputation 
method 
Analysis 
Main 
estimator 
7.3.1.5 
Response on SRI-4 
at Month 6 
None (MAR 
assumption) 
Repeated measurements 
GLMM. 
To ensure that the estimand 
based on the treatment policy 
strategy can be estimated, the 
value for the variable of SRI-4 
is used regardless of occurrence 
of intercurrent events, such as 
treatment discontinuation. 
Sensitivity 
estimator #1 
7.3.1.6.1 
Response on SRI-4 
at Month 6 
None (MAR 
assumption) 
Repeated measurements 
GLMM based on PPS. 
Sensitivity 
estimator #2 
7.3.1.6.2 
Response on SRI-4 
at Month 6 
MI assuming 
MAR 
Repeated measurements 
GLMM on complete data 
imputed using MI assuming 
MAR. 
Sensitivity 
estimator #3 
7.3.1.6.3 
Response on SRI-4 
at Month 6 
MI assuming 
MNAR 
(tipping point) 
Repeated measurements 
GLMM on complete data 
imputed using MI assuming 
MNAR. 
Supplementary 
estimator #1 
(response over 
time) 
7.3.1.6.4 
Response on SRI-4 
at Month 1, 2, 3, 4, 
5 and 6 
None (MAR 
assumption) 
Repeated measurements 
GLMM. 
Supplementary 
estimator #2 
(subgroups) 
7.3.1.7 
Response on SRI-4 
at Month 6 
None (MAR 
assumption) 
Subgroup analyses. 
GLMM = generalized linear mixed model; MAR = missing at random; MI = multiple imputation; PPS = Per-Protocol 
Set; SRI = Systemic Lupus Erythematosus Responder Index. 
 


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7.3.1.2 Variables 
The three variables are defined as follows: 
mSLEDAI-2K Responder 
The absolute change of the mSLEDAI-2K from baseline to Month 6 (using time window 
approach) is defined as: 
Change in mSLEDAI-2K = mSLEDAI-2K score at Month 6 – mSLEDAI-2K score at 
baseline. 
Subjects with a reduction from baseline to Month 6 of ≥ 4 are considered to be responders 
(Responder = 1), subjects with a reduction of < 4 or an increase are considered to be 
non-responders (Responder = 0).  
BILAG-2004 Responder 
A responder (1) is defined as having no new BILAG A organ domain score and at most 
one new BILAG B organ domain score assessed for the nine body systems. A responder 
can only be assessed if the full information of all body systems is available. 
Non-responders (0) are defined as having one or more new BILAG A organ domain scores 
or at least two or more BILAG B organ domain scores. In the event of incomplete data in 
at least one of the body systems, but sufficient information to fulfill the non-response 
criteria, the subject will be considered to be a non-responder.  
Subjects that fit none of the above criteria will be assigned a missing value. 
PGA Responder 
The absolute change of PGA from baseline to Month 6 is defined as follows: 
Change of PGA = PGA value at Month 6 – PGA value at baseline. 
A responder (1) is a subject with an increase of ≤ 0.3 compared to baseline. A 
non-responder (0) is defined as having an increase of > 0.3 compared to baseline. Subjects 
with missing data either at baseline or Month 6 will be assigned a missing value. 
Composite endpoint 
A responder (1) for the endpoint SRI-4 response at Month 6 is defined as a responder of 
all three variables, as defined above. If at least one of the three variables indicate non-
response, the subject is considered to be a non-responder (0). If at least one of the three 
variables is missing, the subject is assigned a missing value, unless at least one non-missing 
variables indicates non-response. 
Data of this endpoint is derived for all monthly post-baseline visits up to Month 6. 


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7.3.1.3 Handling of missing data 
Missing data will not be imputed but will be handled by the repeated measurements 
GLMM, assuming that the data are MAR. 
A summary of the patterns of missingness from baseline up to Month 6 will be provided. 
7.3.1.4 Hypothesis, statistical model and assumptions 
The hypotheses for the secondary endpoint (response at Month 6 based on SRI-4) are 
presented in Section 7.1.1.  
7.3.1.5 Analysis 
This secondary endpoint will be analyzed using the FAS. Following the treatment policy 
estimand all data will be included in the analysis regardless of early treatment 
discontinuation or other intercurrent events. 
A repeated measurements GLMM with the logit link function will be fitted with the 
secondary endpoint SRI-4 as dependent variable (from Month 1 to Month 6). The model 
will include the treatment group, month, the treatment group by month interaction, and the 
OCS and mSLEDAI-2K stratification variables (from IXRS) as fixed effects.  
An unstructured (UN) covariance structure will be used for estimation of the correlation 
between responses measured within the same subjects across multiple months. If this 
analysis fails to converge, the following structures will be tested in a subsequent order until 
model-convergence is achieved: heterogeneous Toeplitz (TOEPH); Toeplitz (TOEP); 
autoregressive (AR(1)); compound symmetry (CS).  
Parameters will be estimated using restricted pseudo-likelihood with Newton Raphson 
ridging optimization and the Kenward-Roger method for calculating the denominator 
degrees of freedom. 
The study treatment groups will be compared against placebo at each month using ORs 
and 95% CIs. The main comparisons are at Month 6.  
The analysis will be implemented by the following SAS® code: 
proc glimmix; 
  nloptions technique=nrridg; 
  class subjid ocs sledai_sc treatment month; 
  model response = ocs sledai_sc treatment month treatment*month / link=logit dist=bin   
ddfm=kr; 
  random month / type=un subject=subjid rside; 
  lsmeans treatment*month / ilink cl; /* estimates event rates */ 
  lsmeans treatment*month / oddsratio diff cl; /* estimates ORs */ 
run; 
 
Data for this endpoint will be summarized descriptively and listed using the FAS. 


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7.3.1.6 Supplementary/sensitivity analyses 
7.3.1.6.1 Analyses based on PPS 
The analysis of the secondary endpoint will be repeated using the PPS. 
7.3.1.6.2 Multiple imputation under MAR  
7.3.1.6.2.1 Step 1 (imputation) 
Missing monthly SRI-4 scores will be imputed using a multiple imputation method 
[Rubin 1987], based on a model including the treatment group, the stratification factors 
OCS and mSLEDAI-2K (from IXRS), and all post-baseline monthly scores up to Month 6.  
Instead of imputing a single value for each missing observation, a set of values is generated 
from the model, resulting in as many distinct complete datasets without missing data.  
More specifically, the imputations will be performed in two steps: first, ‘intermittent’ 
missing data (a score is missing but one or more score[s] is [are] available at following 
month[s]) will be first imputed by a MCMC method using a non-informative Jeffreys Prior, 
thus creating 100 partially imputed ‘monotone’ datasets. 
MCMC assumes multivariate normality for the SRI-4 scores at subsequent visits. This 
assumption is not satisfied for this binary endpoint. However, if the proportion of non-
monotone data is not large, this will have a limited impact on the overall results. The values 
imputed by the MCMC will be rounded using adaptive rounding [Bernaards 2007]. In 
adaptive rounding, instead of using a fixed threshold of 0.5, the threshold is based on the 
imputed data using a normal approximation for a binomial distribution. This threshold is 
defined as follows, where µ is the mean of the imputed variable (including available binary 
observations and imputed continuous values) computed using unrounded values and Φ-1 
(µ) is the z value from a standard normal distribution (inverse of the standard normal 
cumulative distribution): 
𝑡ℎ𝑟𝑒𝑠ℎ𝑜𝑙𝑑=  𝜇− Φ−1(𝜇)√𝜇(1 −𝜇) 
Values greater or equal to the threshold are rounded to 1, and values smaller than the 
threshold are rounded to 0. 
In the second step, the remaining missing data will be imputed once in each of these 
100 ’monotone’ imputed datasets using logistic regression leading finally to 100 complete 
imputed datasets. 


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The multiple imputation procedure will be implemented by the following SAS® code: 
proc mi data=h nimpute=100 seed=12345 out=h2; 
  by treatment; 
  mcmc impute = monotone chain=single nbiter=200 niter=100; 
  var ocs sledai m1 -- m6; 
run; 
 
< Round imputed values in h2, using adaptive rounding > 
 
proc mi data=h2 nimpute=1 seed=12345 out=h3; 
  by_imputation_; 
  class treatment ocs sledai m1 -- m6; 
  var treatment ocs sledai m1 -- m6; 
  monotone logistic; 
run; 
 
7.3.1.6.2.2 Step 2 (analysis) 
Each imputed dataset will be analyzed using the same model as for the main analysis of 
SRI-4 described in Section 7.3.1.5. 
7.3.1.6.2.3 Step 3 (combination) 
Uncertainty in the imputations will be reflected appropriately in the analysis by combining 
the results on each imputed dataset into one summary measure. This method has been 
shown to be efficient in handling missing data if the missing data mechanism is missing 
completely at random or MAR Schafer 1999]. 
The summary results across the 100 complete datasets will be aggregated following 
Rubin’s rule. The final estimate is the mean of the 100 per-imputation estimates and the 
final variance is the sum of the average within-imputation variance and (1+1/100) times 
the between-imputation variance [Rubin 1987]. From the final point estimate and variance, 
the 95% CI will be determined. The corresponding p-value will be displayed. 
The results aggregation as the final step of the multiple imputation procedure after analysis 
of the 100 complete datasets will be implemented by the following SAS® code: 
proc mianalyze parms(classvar=classval)=<data from step 2 >; 
  class treatment month; 
  modeleffect treatment*month; 
  ods output parameterestimates=<result dataset>; 
run; 
7.3.1.6.3 Tipping point analysis  
This analysis will be implemented in three steps as described in Section 7.3.1.6.2. 
The difference here is that, at the end of step 1, a “non-responder” status is imposed at 
Month 6 on withdrawals with an extra probability above that is modeled by the MAR 
assumption in the active treatment groups. Imputations under MAR in the placebo arm are 
not changed. This is implemented using the following example SAS® code: 


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data h4; 
  set h3; 
  * delta represents a probability of resetting imputed responder status to non-responder; 
  delta = 0.05; 
  call streaminit(1234); 
  if m6_miss = “Y” and trt ne “Placebo” then do; * if responder status was missing (i.e., 
imputed) and treatment group is not placebo; 
    if rand("Uniform") < delta then m6 = 0; 
  end; 
run; 
For example, if this probability is set to 10%, for every 10 subjects imputed as responders 
in the active treatment groups under the MAR assumption, 1 subject is randomly re-
imputed as a non-responder. Note, that some subjects are of course imputed as non-
responders directly under MAR. 
To stress test the result from the main analysis, we impose a succession of probability 
adjustments starting at 5%, incrementing by 5% up to 100%. 
7.3.1.6.4 Treatment effect over time 
7.3.1.6.4.1 Variables 
To assess the treatment effect over time on SRI-4, the composite endpoint SRI-4 response 
will be calculated as described in Section 7.3.1.2 for all post-baseline visits from Months 1 
to 6. 
7.3.1.6.4.2 Analysis 
The analysis will be performed based on the same repeated measurements model as 
described in Section 7.3.1.5. 
A figure presenting OR (95% CI) vs placebo over time will be produced. 
7.3.1.7 Subgroup analyses 
The same model as for the main analysis described in Section 7.3.1.5 will be fitted per 
subgroup. 
A forest plot will be produced, displaying the OR for each dose vs placebo including 95% 
CIs at Month 6. The forest plot will include an ‘overall’ treatment effect, based on the 
secondary efficacy analysis and a reference line for no treatment effect at OR = 1. 
For the analyses of the OCS and mSLEDAI-2K subgroups, the corresponding subgroup 
will not be included as a stratification factor in the model. 
7.3.2 
Response (no worsening) at Month 6 on BILAG-2004 disease activity index 
7.3.2.1 Overview of analyses 
The main estimator as well as sensitivity and supplementary estimators for the secondary 
estimand #2 as defined in Section 3.1.1 are summarized in Table 8. 


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Table 8 
Overview of analyses for secondary estimand #2 
Estimator 
Section 
Endpoint 
Imputation 
method 
Analysis 
Main 
estimator 
7.3.2.5 
Response on 
BILAG-2004 at 
Month 6 
None (MAR 
assumption) 
Repeated measurements GLMM. 
To ensure that the estimand based 
on the treatment policy strategy 
can be estimated, the value for the 
variable of BILAG-2004 is used 
regardless of occurrence of 
intercurrent events, such as 
treatment discontinuation. 
Sensitivity 
estimator #1 
7.3.2.6.1 
Response on 
BILAG-2004 at 
Month 6 
None (MAR 
assumption) 
Repeated measurements GLMM 
based on PPS 
Sensitivity 
estimator #2 
7.3.2.6.2 
Response on 
BILAG-2004 at 
Month 6 
MI assuming 
MAR 
Repeated measurements GLMM 
on complete data imputed using 
MI assuming MAR 
Sensitivity 
estimator #3 
7.3.2.6.3 
Response on 
BILAG-2004 at 
Month 6 
MI assuming 
MNAR (tipping 
point) 
Repeated measurements GLMM 
on complete data imputed using 
MI assuming MNAR 
Supplementary 
estimator #1 
(response over 
time) 
7.3.2.6.4 
Response on 
BILAG-2004 at 
Month 1, 2, 3, 4, 
5 and 6 
None (MAR 
assumption) 
Repeated measurements GLMM. 
Supplementary 
estimator #2 
(subgroups) 
7.3.2.7 
Response on 
BILAG-2004 at 
Month 6 
None (MAR 
assumption) 
Subgroup analyses 
BILAG-2004 = British Isles Lupus Assessment Group-2004; GLMM = generalized linear mixed model; MAR = missing 
at random; MI = multiple imputation; PPS = Per-Protocol Set. 
 
7.3.2.2 Variables 
The binary response variable of this endpoint is derived as described in Section 7.3.1.2 for 
the BILAG-2004 endpoint. 
7.3.2.3 Handling of missing data 
Missing data will not be imputed but will be handled by the repeated measurement’s 
GLMM assuming that the data are MAR. 


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A summary table of the patterns of missingness from baseline up to Month 6 will be 
provided. 
7.3.2.4 Hypothesis, statistical model and assumptions 
The hypotheses for the secondary endpoint (response at Month 6 based on BILAG-2004) 
are presented in Section 7.1.1.  
7.3.2.5 Analysis 
The analysis will be performed based on the same repeated measurements model as 
described in Section 7.3.1.5. 
Data of this endpoint will be summarized descriptively and listed using the FAS. 
7.3.2.6 Supplementary/sensitivity analyses 
7.3.2.6.1 Analyses based on PPS 
The analysis of the secondary endpoint will be repeated using the PPS. 
7.3.2.6.2 Multiple imputation under MAR  
This analysis will be implemented as described in Section 7.3.1.6.2. 
7.3.2.6.3 Tipping point analysis  
This analysis will be implemented as described in Section 7.3.1.6.3. 
7.3.2.6.4 Treatment effect over time 
7.3.2.6.4.1 Variables 
The same variable definitions as for the secondary endpoint are used. No imputation 
methods are applied. The endpoint is also derived for the time points Month 1 to Month 5. 
7.3.2.6.4.2 Analysis 
The repeated measurements analysis will be conducted in the same way as for the 
secondary endpoint described in Section 7.3.1.5.  
A figure presenting OR (95% CI) vs placebo over time will be produced. 
7.3.2.7 Subgroup analyses 
Subgroup analyses will be conducted in the same way as defined for the secondary 
endpoint SRI-4. 
7.4 Other efficacy endpoints analysis 
No imputation methods are applied for the other efficacy endpoints. All other efficacy 
endpoints will be summarized descriptively and listed using the FAS. Additional analyses 
for the other efficacy endpoints are described in the sections below. 


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The time window approach, as defined in Section 5.4.4, is applied for the derivation of the 
following variables. 
7.4.1 
Response at Month 6 on the mSLEDAI-2K score 
7.4.1.1 Variables 
The binary response variable of this endpoint is derived as described in Section 7.3.1.2 for 
the mSLEDAI-2K endpoint. 
7.4.1.2 Analysis 
The analysis will be conducted in the same way as the analysis in Section 7.3.1.5. 
7.4.2 
Response (no worsening and improvement) at Month 6 on BILAG-2004 
disease activity index 
7.4.2.1 Variables 
The composite endpoint (response at Month 6 based on the BILAG-2004 disease activity 
index) is a binary endpoint based on two variables, as defined below. 
BILAG-1 
A responder (1) is defined as having no new BILAG A organ domain score and at most 
one new BILAG B organ domain score assessed for the nine body systems. A responder 
can only be assessed if the full information of all body systems is available. 
Non-responders (0) are defined as having one or more new BILAG A organ domain scores 
or at least two or more BILAG B organ domain scores. In the event of incomplete data in 
at least one of the body systems, but sufficient information to fulfill the non-response 
criteria, the subject is considered to be a non-responder.  
Subjects that fit none of the above criteria are assigned a missing value. 
BILAG-2 
A responder (1) is defined as having an improvement of at least one BILAG A organ 
domain score to either B, C or D or as having an improvement of at least one BILAG B 
organ domain score to C or D. A responder can only be assessed if the full information of 
all body systems is available. 
A non-responder (0) is defined as having no improvement in any BILAG A or BILAG B 
organ domain scores. In the event of incomplete data in at least one of the body systems, 
but sufficient information to fulfill the non-response criteria, the subject is considered to 
be a non-responder. 
Subjects without any BILAG A or BILAG B organ domain scores at baseline are defined 
as responders. 


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Composite endpoint 
A responder (1) for the endpoint response at Month 6 based on the BILAG-2004 scale 
(alternative definition) is defined as a responder of both variables, as defined above. If at 
least one of the two variables equal a non-response, the subject is considered to be a 
non-responder (0). In the event of at least one of the two variables being missing, the 
subject is assigned a missing value, unless it is clear that the subject is a non-responder. 
7.4.2.2 Analysis 
The analysis will be conducted in the same way as the analysis in Section 7.3.1.5. 
7.4.3 
Response at Month 6 on SRI-5, -6, -7, -8 
7.4.3.1 Variables 
The binary response variables of these endpoints are derived as described in Section 7.3.1.2 
with a reduction in mSLEDAI-2K of 5, 6, 7 or 8, instead of a reduction of 4.  
For SRI-X (X = 5, 6, 7 or 8) subjects with a baseline value of less than X will be excluded 
from the analysis. 
7.4.3.2 Analysis 
The analysis will be conducted in the same way as the analysis in Section 7.3.1.5.  
7.4.4 
Occurrence of mild/moderate and severe flares from baseline up to Month 6 
7.4.4.1 Variables 
Derived data for this endpoint is provided by an external vendor. Data is categorized into 
mild/moderate or severe flares. 
The definition of flares is provided in appendix 12 of the protocol [D-22.031]. 
7.4.4.2 Analysis 
The number and percentage of subjects with no flare, mild/moderate flare and severe flare 
from baseline up to Month 6 overall as well as at every visit will be summarized by 
treatment group. 
7.4.5 
Time to first severe flare up to Month 6 
7.4.5.1 Variables 
The time to first severe flare during TP1, from baseline to Month 6 visit (in days) is defined 
as: 
[Date of first severe flare − Date of treatment start date + 1] in days. 


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The start date of the first severe flare must be within TP1. Missing dates are imputed as 
follows: 
• Day missing: Impute first day of the month or if earlier than first study drug intake, 
impute day of first study drug intake. 
• Day and month missing: If the year is in the interval of (First study drug intake; 
Month 6) impute the first study drug intake date, otherwise keep as missing. 
• If the date is completely missing, then include severe flare in the analysis and set the 
date to the first study drug intake date. 
For subjects without any severe flares, the time to the first severe flare is censored at the 
Month 6 visit date or at the time of last available observation without any severe flares in 
TP1 if the subject discontinues study prior to Month 6. 
Subjects with a severe flare during TP1 are considered as having an event (‘1’), censored 
subjects as having no event (‘0’). 
7.4.5.2 Analysis 
The number of subjects with events and subjects with censored observations will be 
presented by treatment group.  
A Kaplan-Meier plot will be produced showing all five treatment arms and p-values.  
The treatment effect will be estimated using a stratified Cox proportional hazard model 
(displaying hazard ratios and 95% CI), stratified by OCS and mSLEDAI-2K (from IXRS). 
Hazard ratios and 95% CI will also be displayed in the Kaplan-Meier plot. 
 
* KM; 
proc lifetest; 
 strata treatment; 
 id subjid; 
 time time*censor(1); 
 ods select productlimitestimates quartiles; 
run; 
 
* cox proportional hazard model; 
proc phreg; 
 class treatment (ref=“placebo”); 
 model time*censor(1) = treatment / ties=exact rl; 
 strata ocs sledai_sc; 
 ods select ParameterEstimates; 
run; 
 
 
The analysis will be conducted for data collected during TP1 up to both Month 6 and EOT.  


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7.4.6 
Time to first flare up to Month 6 
7.4.6.1 Variables 
Variables for the endpoint ‘time to first flare from baseline to Month 6’ are derived exactly 
in the same way as in the previous section, with the only difference that all flares instead 
of only severe flares are included. Variables are derived up to EOT (during TP1) and up to 
Month 6. 
7.4.6.2 Analysis 
The Cox proportional hazards model will be repeated as described in Section 7.4.5.2 for 
data collected during TP1 up to both Month 6 and EOT. 
7.4.7 
Change from baseline to Month 6 in PGA score 
7.4.7.1 Variables 
The absolute change from baseline to Month 6 in PGA score is derived as: 
Change in PGA = PGA score at Month 6 − PGA score at baseline. 
In the event of missing values at one of the assessments, the variable is set to missing. 
7.4.7.2 Analysis 
An MMRM model will be used to analyze this endpoint including all monthly visits 
(similar to primary efficacy analysis in Section 7.2.5).  
The following fixed effects will be included in the model: PGA baseline value, the two 
stratification factors (OCS and mSLEDAI-2K from IXRS), treatment group, month, 
treatment group by month interaction and PGA baseline value by month interaction.  
7.5 Exploratory endpoints 
All exploratory endpoints will be summarized descriptively and listed using the FAS or 
FAS-TP2 unless otherwise stated.  
Additional analyses for the exploratory endpoints are described in the sections below.  
Exploratory endpoints will be analyzed from baseline up to a maximum of 12 months on 
all available assessments according to 2 Groups: 
• Group 1: All randomized subjects, for whom baseline is defined as the last available 
measurement before the start of randomized treatment in TP1. 
• Group 2: Subjects re-randomized at Month 6, for whom baseline is defined as the last 
available measurement before the start of re-randomized treatment in TP2. 
A time window approach will be applied to the endpoints where data will be analyzed at 
protocol-mandated visits [as defined in Section 5.4.4]. 


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The display of treatment groups in the summary tables is as defined in Section 5.4.3. 
Group 1 will be analyzed based on 5 treatment groups (Placebo, 0.5, 1, 2, 4 mg), whereas 
Group 2 will be analyzed based on 6 treatment groups (Placebo, 0.5, 1, 2, 4 mg / 2 mg and 
4 mg / placebo). 
7.5.1 
Sustained mSLEDAI-2K response defined as a reduction of at least 
 
 
 
 
7.5.1.1 Variables 
A binary response variable is derived for this endpoint. The following criteria apply for a 
responder (1): 
• Subject must have at least 
mSLEDAI-2K assessments 
 
 
• Subject must have a reduction of the mSLEDAI-2K of at least 
 
 
• Subject must have a reduction of the mSLEDAI-2K of at least 
 
 
 
 
 
 
7.5.1.2 Analysis 
This endpoint will only be analyzed for Group 1 using the FAS with a logistic regression 
model. 
The logistic regression model will include the treatment group [as defined in 
Section 5.4.3.1] and will be stratified by the OCS and mSLEDAI-2K stratification 
variables (from IXRS). 
The estimates of the ORs between each cenerimod dose group and placebo will be reported 
with their 95% CIs. In addition, the proportion of responders will be reported by treatment 
group. 


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7.5.2 
Change from baseline to each post-baseline assessment up to Month 12 in 
mSLEDAI-2K score 
7.5.2.1 Variables 
Group 1 
The variable is derived as defined in the primary endpoint Section 7.2.1, for each visit up 
to Month 12. 
Group 2 
The variable is derived as defined in the primary endpoint Section 7.2.1 for each visit from 
Month 6 up to Month 12 based on the TP2 baseline value for all subjects in FAS-TP2. 
7.5.2.2 Analysis 
Group 1 
An MMRM analysis will be performed as described in Section 7.2.5, including visits up to 
Month 12 using 5 treatment groups as defined in Section 5.4.3.3. 
Group 2 
An MMRM analysis will be performed similar to the one described in Section 7.2.5, but 
only including data from Month 7 up to Month 12 and from treatment groups Cenerimod 
2 mg / Ex-4 mg and Placebo / Ex-4 mg. The model will include treatment group, month, 
TP2 baseline mSLEDAI-2K score, treatment group by month interaction and TP2 baseline 
mSLEDAI-2K score by month interaction as fixed effects. 
All other aspects of the model are as described in Section 7.2.5. 
7.5.3 
Response at each post-baseline assessment on the mSLEDAI-2K 
7.5.3.1 Variables 
Group 1 
The variable is derived as in Section 7.4.1.1 for each visit up to Month 12. 
Group 2 
The variable is derived as in Section 7.4.1.1 for each visit from Month 6 up to Month 12 
based on the TP2 baseline value for all subjects in FAS-TP2.  
7.5.3.2 Analysis 
Group 1 
A repeated measurements GLMM model for binary response variables will be performed 
as described in Section 7.3.1.5 based on 5 treatment groups as described in Section 5.4.3.3. 
Group 2 
A repeated measurements GLMM model for binary response variables will be performed 
as described in Section 7.3.1.5. The model will be fitted including data from Month 7 up 


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to Month 12 and from treatment groups Cenerimod 2 mg / Ex-4 mg and Placebo / Ex-4 mg. 
The model will include treatment group, month, TP2 baseline mSLEDAI-2K score, 
treatment group by month interaction and TP2 baseline mSLEDAI-2K score by month 
interaction as fixed effects. 
All other aspects of the model are as described in Section 7.3.1.5. 
7.5.4 
Response (no worsening and improvement) at each post-baseline assessment 
on BILAG-2004 disease activity index 
7.5.4.1 Variables 
Group 1 
The variable is derived as defined in Section 7.4.2 for each visit up to Month 12. 
Group 2 
The variable is derived as defined in Section 7.4.2 for each visit from Month 6 up to 
Month 12 based on the TP2 baseline value for all subjects in FAS-TP2. 
7.5.4.2 Analysis 
Group 1 
A repeated measurements GLMM model for binary response variables will be performed 
as described in Section 7.3.1.5 based on 5 treatment groups as described in Section 5.4.3.3. 
Group 2 
A repeated measurements GLMM model for binary response variables will be performed, 
as described in Section 7.3.1.5. The model will be fitted including data from Month 7 up 
to Month 12 and from treatment groups Cenerimod 2 mg / Ex-4 mg and Placebo / Ex-4 mg. 
The model will include treatment group, month and treatment group by month interaction 
as fixed effects. 
All other aspects of the model are as described in Section 7.3.1.5. 
7.5.5 
Response at each post-baseline assessment on SRI-4, -5, -6, -7, -8 
7.5.5.1 Variables 
Group 1 
The variables are derived as defined in Sections 7.3.1.2 and 7.4.3.1 for each visit from 
Month 1 up to Month 12. 
Group 2 
The variables are derived as defined in Sections 7.3.1.2 and 7.4.3.1 for each visit from 
Month 6 up to Month 12 based on the TP2 baseline value for all subjects in FAS-TP2. 


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7.5.5.2 Analysis 
Group 1 
A repeated measurements GLMM model for binary response variables will be performed 
as described in Section 7.3.1.5 based on 5 treatment groups as described in Section 5.4.3.3. 
Group 2 
A repeated measurements GLMM model for binary response variables will be performed, 
as described in Section 7.3.1.5. The model will be fitted including data from Month 7 up 
to Month 12 and from treatment groups Cenerimod 2 mg / Ex-4 mg and Placebo / Ex-4 mg. 
The model will include treatment group, month and treatment group by month interaction 
as fixed effects. 
All other aspects of the model are as described in Section 7.3.1.5.  
7.5.6 
Change from baseline to each post-baseline assessment in PGA score 
7.5.6.1 Variables 
Group 1 
The variable is derived as defined in Section 7.4.7.1 for each visit from Month 1 up to 
Month 12. 
Group 2 
The variable is derived as defined in Section 7.4.7.1 for each visit from Month 6 up to 
Month 12 based on the TP2 baseline value for all subjects in FAS-TP2. 
7.5.6.2 Analysis 
Group 1 
The analysis will be based on an MMRM model, similar to the one used for the primary 
analysis [Section 7.2.5] based on 5 treatment groups as described in Section 5.4.3.3. 
Group 2 
The analysis will be based on an MMRM model, similar to the one used for the primary 
analysis [Section 7.2.5]. The model will be fitted including data from Month 7 up to 
Month 12 and from treatment groups Cenerimod 2 mg / Ex-4 mg and Placebo / Ex-4 mg. 
The model will include treatment group, month, TP2 baseline PGA score, treatment group 
by month interaction and TP2 baseline PGA score by month interaction as fixed effects. 
All other aspects of the model are as described in Section 7.2.5. 
7.5.7 
Occurrence of flares and severe flares at each post-baseline assessment 
7.5.7.1 Variables 
Derived data for this endpoint is provided by an external vendor. Data will be categorized 
into mild/moderate or severe flares. 


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The definition of flares is provided in appendix 12 of the protocol [D-22.031]. 
7.5.7.2 Analysis 
Group 1 
Data will be analyzed descriptively as described in Section 7.4.4.2 for data up to Month 12 
using treatment groups as described in Section 5.4.3.3. 
Group 2 
Data will be analyzed descriptively for all subjects in FAS-TP2 as described in 
Section 7.4.4.2 using treatment groups as defined in Section 5.4.3.2 for data from baseline 
TP2 up to Month 12. 
7.5.8 
Time to first severe flare from baseline to Month 12 
7.5.8.1 Variables 
Group 1 
The variable is derived as defined in Section 7.4.5.1, for visits up to EOT (including TP2) 
and up to Month 12. 
Group 2 
The variable is derived as defined in Section 7.4.5.1, from the Month 6 visit up to EOT and 
up to Month 12 for all subjects in FAS-TP2. The censoring is derived from start of TP2, 
instead of start of TP1. 
7.5.8.2 Analysis 
Group 1 
A Cox proportional hazards model will be performed as described in Section 7.4.5.2 based 
on 5 treatment groups as described in Section 5.4.3.3 for data up to EOT and up to 
Month 12. 
Group 2 
A Cox proportional hazards model will be performed with treatment as a factor, only 
including treatment groups Cenerimod 2 mg / Ex-4 mg and Placebo / Ex-4 mg. 
7.5.9 
Time to first flare from baseline to Month 12 
7.5.9.1 Variables 
Group 1 
The variable is derived as defined in Section 7.4.6.1, for visits up to EOT + 180 days 
(including TP2) and up to Month 12. 


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Group 2 
The variable is derived as defined in Section 7.4.6.1, from the Month 6 visit up to 
EOT + 180 days and up to Month 12 for all subjects in FAS-TP2. The censoring is derived 
from start of TP2, instead of start of TP1. 
7.5.9.2 Analysis 
Group 1 
A Cox proportional hazards model will be performed as described in Section 7.4.6.2 based 
on 5 treatment groups as described in Section 5.4.3.3 for data up to EOT and up to Month 
12. 
Group 2 
A Cox proportional hazards model will be performed with treatment as a factor, only 
including treatment groups Cenerimod 2 mg / Ex-4 mg and Placebo / Ex-4 mg. 
7.5.10 Change from baseline to each post-baseline assessment up to Month 12 in 
prednisone or equivalent dose 
7.5.10.1 Variables 
Group 1 
Steroids are collected on the Previous/Concomitant Medications eCRF page. OCS will be 
identified using the WHODrug Global B3/C3-format Standardized Drug Grouping named 
“Corticosteroids” and with CM.CMROUTE equal “ORAL”. Doses that are not taken daily 
will be transformed according to CM.CMDOSFRQ. OCS are converted to prednisone 
equivalent doses using the table in the protocol, appendix 1 [D-22.031]. If subjects are 
taking OCS during the study that are not covered in the table in the protocol, conversion 
factors are retrieved from the literature.  
The prednisone or equivalent dose at each visit from baseline up to Month 12 will be 
derived as the monthly average of the daily prednisone or equivalent dose as shown in 
Table 9. 


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Table 9 
Daily prednisone or equivalent doses used for derivation of monthly 
scores 
Monthly score 
First treatment day 
Last treatment day 
Baseline 
–30 
–1 
Month 1 
1 
30 
Month 2 
31 
60 
Month 3 
61 
90 
Month 4 
91 
120 
Month 5 
121 
150 
Month 6 
Month 6 visit* – 29 days 
Month 6 visit 
Month 7 
Month 6 visit + 1 day 
Month 6 visit + 30 days 
Month 8 
Month 6 visit + 31 day 
Month 6 visit + 60 days 
Month 9 
Month 6 visit + 61 day 
Month 6 visit + 90 days 
Month 10 
Month 6 visit + 91 day 
Month 6 visit + 120 days 
Month 11 
Month 6 visit + 121 day 
Month 6 visit + 150 days 
Month 12 
Month 6 visit + 151 day 
Month 6 visit + 180 days 
* If a subject has a visit recorded after Month 6 but the Month 6 visit was not done, Month 6 visit will be replaced by 
Day 180. 
It may be noted that for subjects with a Month 6 visit performed earlier than Day 180, there 
will be an overlap between the 29 days used to derive the Month 5 monthly score and the 
29 days used to derive the Month 6 monthly score. 
The absolute change in prednisone or equivalent dose from baseline (in TP1) is computed 
as follows: 
Change in prednisone or equivalent dose = Prednisone or equivalent dose at 
Visit X − prednisone or equivalent dose at baseline (in TP1). 
7.5.10.2 Analysis 
Group 1 
The change in prednisone or equivalent dose during TP1 will be analyzed descriptively, by 
visit and treatment groups as defined in Section 5.4.3.1. In addition, a figure by visit and 
treatment group will be produced, containing the change in prednisone or equivalent dose. 


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The change in prednisone or equivalent dose during TP1 and TP2 will be analyzed 
descriptively, by visit and treatment groups as defined in Section 5.4.3.3. 
7.6 Analysis of PRO/QoL variables 
A time window approach will be applied to the PRO endpoints [as defined in 
Section 5.4.4]. Data will be listed using the FAS. 
All PRO endpoints will be analyzed during TP1 by treatment groups as defined in 
Section 5.4.3.1 and during TP1 and TP2 by treatment groups as defined in Section 5.4.3.3. 
7.6.1 
Change from baseline to each post-baseline assessment in FACIT-Fatigue 
Scale score  
The FACIT-Fatigue Scale is collected at Randomization, Month 3, Month 6, Month 9 and 
Month 12/premature EOT. The FACIT-Fatigue Scale score is based on a questionnaire 
with 13 questions. 
7.6.1.1 Variables 
Calculation of FACIT-Fatigue Scale score 
The FACIT-Fatigue Scale score will be derived as described in Appendix 12.4. 
The absolute change in FACIT-Fatigue Scale score is computed as follows: 
Change in FACIT-Fatigue Scale score = FACIT-Fatigue Scale score at 
Visit X – FACIT-Fatigue Scale score at baseline (in TP1) 
7.6.1.2 Analysis 
The change in FACIT-Fatigue Scale score will be analyzed descriptively, by visit and 
treatment group using the FAS.  
A figure of the change in FACIT-Fatigue Scale score over time will be produced using the 
FAS, by visit and treatment group. 
7.6.2 
Change from baseline to each post-baseline assessment in PGIS-F 
7.6.2.1 Variables 
 
. The PGIS-F is collected as defined in the visit and assessment schedule [see 
Appendix 12.1]. 
7.6.2.2 Analysis 
The change from baseline to each post-baseline assessment in the PGIS-F will be analyzed 
descriptively by visit and treatment group using the FAS with a shift table. 


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7.6.3 
PGIC-F score at each post-baseline assessment 
7.6.3.1 Variables 
 
 
The PGIC-F is collected as defined in the visit and assessment schedule [see 
Appendix 12.1]. 
7.6.3.2 Analysis 
The PGIC-F will be analyzed descriptively by visit and treatment group using the FAS 
with summary statistics as defined in Section 9.1 for categorical variables. 
7.6.4 
Change from baseline to each post-baseline assessment in SF-36v2™ 
SF-36v2™ data is collected using a paper CRF. Data is collected at Randomization, 
Month 6, Month 9 and Month 12 / premature EOT. 
According to the questionnaire manual [Ware 2000], the following scores are considered: 
• SF-36v2™ domain scores (0–100 scale): physical functioning, role physical, bodily 
pain, general health, vitality, social functioning, role emotional and mental health. 
• SF-36v2™ domain scores norm-based: physical functioning, role physical, bodily pain, 
general health, vitality, social functioning, role emotional and mental health. 
• SF-36v2™ PCS and MCS measures norm-based. 
• SF-36v2™ reported health transition score. 
7.6.4.1 Variables 
The SF-36v2™ is a multi-purpose, short-form health survey with 36 questions. It yields an 
8-scale profile of the functional health and well-being scores (i.e., physical functioning, 
role physical, bodily pain, general health, vitality, social functioning, role emotional and 
mental health) as well as psychometrically based physical and mental health summary 
measures and a preference-based health utility (health rated as ‘much better now than one 
year ago’, ‘somewhat better now than one year ago’, ‘about the same as one year ago’, 
‘somewhat worse now than one year ago’, and ‘much worse now than one year ago’).  
The following scores/measures are derived inhouse as described in the SF-36v2™ scoring 
manual using 1998 US population norms [Ware 2000] and detailed in Appendix 12.3 for 
the analysis: 
• SF-36v2™ domain scores transformed to a 0–100 scale. 
• SF-36v2™ domain scores norm-based (also known as T-scores). 
• SF-36v2™ PCS and MCS measures norm-based (also known as T-scores). 
• SF-36v2™ reported health transition score. 


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Missing items of incomplete questionnaires are imputed as described in Appendix 12.3. If, 
after applying imputation rules, the value at a given time point is missing (domain scores 
or component summary measures) then the value is considered missing.  
Except for the reported health transition score (which is expressed as a subjective change 
in the question), the absolute change from baseline is defined as: 
Change of SF-36v2™ score = SF-36v2™ individual score at visit − SF-36v2™ 
individual score at baseline 
Baseline is defined as the last valid assessment prior to first study drug intake (by time and 
date). 
7.6.4.2 Analysis 
SF-36v2™ data will be analyzed using the FAS by visit and treatment group. 
Summary statistics, by visit and treatment group, will be produced for all sub-scores and 
normalized sub-scores (physical functioning, role physical, bodily pain, general health, 
vitality, social functioning, role emotional and mental health, PCS and MCS). The health 
transition score will only be described at Month 12, and will be listed for all visits. Changes 
from baseline will be summarized for sub-scores and normalized sub-scores. 
7.6.5 
Change from baseline to each post-baseline assessment in the Lupus QoL 
questionnaire 
The Lupus QoL questionnaire will be collected at Randomization, Month 6, Month 9 and 
Month 12/premature EOT. The Lupus QoL score is based on a questionnaire with 
34 questions.  
7.6.5.1 Variables 
Calculation of Lupus QoL score 
 
 
1. 
The Lupus QoL consists of 34 items in eight domains. The number of items in each domain 
and the item numbers that refer to each domain are shown in Table 10. 


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Table 10 
Lupus QoL domains 
7.6.5.2 Analysis 
The change in Lupus QoL score will be analyzed descriptively, by visit and treatment 
group, using the FAS. A figure of the change in Lupus QoL score over time will be 
produced using the FAS, by visit and treatment group. 
7.6.6 
Change of mucocutaneous and musculoskeletal score from baseline (TP1) 
up to Month 12 
7.6.6.1 Variables 
The mucocutaneous score is defined as the weighted sum of each of the individual 
descriptors for the applicable organ class, i.e., mucosal ulcers, rash, and alopecia. The score 
is computed by summing up the standardized results for each descriptor. 


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The musculoskeletal score is defined as the weighted sum of each of the individual 
descriptors for the applicable organ class, i.e., arthritis and myositis. The score is computed 
by summing up the standardized result for each descriptor. 
The mucocutaneous and musculoskeletal score is defined as the sum of the mucocutaneous 
and the musculoskeletal scores (computed above).  
The absolute change from baseline (TP1) is computed as: 
Change in mSLEDAI-2K sub-score = mSLEDAI-2K sub-score at Visit X − 
mSLEDAI-2K sub-score at baseline (in TP1). 
7.6.6.2 Analysis 
The change in mucocutaneous and musculoskeletal score will be analyzed descriptively, 
by visit and treatment group, using the FAS. 
7.7 Analysis of pharmacokinetic variables 
See Section 6.10. 
8 
SAFETY VARIABLES AND ANALYSES 
8.1 Overview of safety analyses including subgroup analyses 
8.1.1 
Safety endpoints 
The following endpoints are defined according to protocol: 
• Occurrence of TEAEs/SAEs, and AESIs [see protocol appendix 5, D-22.031]. 
• Occurrence of AEs leading to premature discontinuation of study treatment. 
• Changes in 12-lead ECG variables (HR, PR, QRS, QT, QT corrected for HR on the 
basis of 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 protocol appendix 7, D-22.031]. 
• Occurrence of treatment-emergent 12-lead ECG abnormal findings. 
• Change in supine SBP/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 parameters (hematology, blood chemistry, and urinalysis) from 
baseline to each post-baseline assessment up to EOS. 


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• Occurrence of treatment-emergent laboratory notable abnormalities [see protocol 
appendix 7, D-22.031]. 
• Change in body weight from baseline up to EOS. 
• Change in left ventricular ejection fraction as assessed by Standard 2D/Doppler 
echocardiography from Screening to Month 6 in subjects randomized to ancillary 
echocardiography study. 
• Occurrence of abnormalities as assessed by Standard 2D/Doppler echocardiography 
from Screening to Month 6 in subjects randomized to ancillary echocardiography 
study. 
8.2 Adverse events 
An AE is any event reported by the investigator on the Adverse Event eCRF page.  
All AEs will be coded using MedDRA (most current version at time of database 
closure/snapshot). 
AEs are classified according to the period of occurrence of the event. Periods are defined 
as: 
• TEAEs 
• AEs with onset during TP1 
• AEs with onset during TP2 
A more detailed description of rules for assigning AEs to the different periods is described 
below. 
All AE tables will be summarized using the SAF. AE listings (all AEs, AEs leading to 
premature discontinuation of study treatment, SAEs, AESIs) will be produced using the 
SAF. A separate listing will be produced using the SCR to present AEs for non-treated 
subjects. 
8.2.1 
Variables 
AEs are classified as ‘Treatment-emergent AEs’ if the start date of the AE is on or after 
the date of first study drug intake (by time and date) up to EOT + 180 days (inclusive).  
AEs with onset during TP1 are defined in the interval: 
[First study drug intake (by time and date); Month 6 visit or EOT  
(if EOT date is on or before Month 6 visit date)] 
AEs with onset during TP2 are defined in the interval: 
[Month 6 visit + 1 day; EOT]. 


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Any AE prior to start of treatment (by time and date) in TP1 and AEs 121 days or more 
after EOT are considered non-treatment-emergent AEs. 
TEAEs on Day 1 are reported up to 24 hours after first study drug intake in TP1 and on or 
after the time of first study drug intake.  
TEAEs on the day of re-initiation are defined in the same way, but for the day of the 
re-initiation. 
8.2.1.1 Missing values 
Missing or partial dates for TEAEs are imputed as follows for the purpose of the treatment-
emergent definition: 
• AE start day missing: If the month and year is on or after the time and date of the first 
study drug intake month and year, and before or during the month and year of EOT + 
180 days, consider the AE as treatment-emergent and impute the first day of the month, 
and if it is earlier than the first study drug intake, impute the first study drug intake 
date. 
• AE start day and month missing: If the year is the same year as the year of first study 
drug intake or later, and if the year is prior to or in the same year as the year of EOT + 
180 days, consider the AE as treatment-emergent and impute the date of first study drug 
intake. 
• If the AE start date is completely missing then the AE is considered to be 
treatment-emergent (for TP1, but not for TP2). 
If the time of an AE occurring on the day of first study drug intake is not recorded, the AE 
is considered to be treatment-emergent. 
The same rule applies for AEs on the day of re-initiation. 
8.2.2 
Analysis 
An overview of AEs with onset during TP1 will be provided, showing number and 
percentage of subjects with at least one: 
• AE with onset during TP1 
• Treatment-emergent AE on day of first study drug intake 
• Treatment-emergent AE on day of re-initiation 
• AE with onset during TP1 related to study treatment 
• Severe AE with onset during TP1 
• AE of special interest with onset during TP1 
• SAE with onset during TP1 
• SAE related to study treatment with onset during TP1 


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• Fatal AE with onset during TP1 
• AE leading to study drug discontinuation with onset during TP1 
• AE leading to study drug interruption with onset during TP1 
An overview of AEs with onset during TP2 will be provided, showing number and 
percentage of subjects with at least one: 
• AE with onset during TP2 
• AE with onset during TP2 related to study treatment 
• Severe AE with onset during TP2 
• AE of special interest with onset during TP2 
• SAE with onset during TP2 
• SAE related to study treatment with onset during TP2 
• Fatal AE with onset during TP2 
• AE leading to study drug discontinuation with onset during TP2 
• AE leading to study drug interruption with onset during TP2 
An overview of TEAEs will be provided, showing number and percentage of subjects with 
at least one: 
• Treatment-emergent AE 
• Treatment-emergent AE related to study treatment 
• Treatment-emergent severe AE 
• Treatment-emergent AE of special interest 
• Treatment-emergent SAE 
• Treatment-emergent SAE related to study treatment 
• Treatment-emergent fatal AEs 
• AE leading to study drug discontinuation 
• AE leading to study drug interruption 
AEs will be summarized by presenting the number and percentage of subjects with at least 
one event, having an AE in each primary SOC, and having each individual AE (PT), for 
each treatment group.  
AEs will be sorted by descending frequency in the highest dose group, then second highest 
dose group, and so on until the placebo group, and then alphabetically.  


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Summary tables will be provided for the following: 
• AEs with onset during TP1 (by SOC and PT) 
• AEs with onset during TP2 (by SOC and PT) 
• TEAEs (by SOC and PT) 
• TEAEs (by PT) 
• TEAEs on day of first study drug intake (by SOC and PT) 
• TEAEs on day of re-initiation (by SOC and PT) 
• AEs related to study treatment with onset during TP1 (by SOC and PT) 
• AEs related to study treatment with onset during TP2 (by SOC and PT) 
• TEAEs related to study treatment (by SOC and PT) 
• AEs with onset during TP1 (by SOC, PT and intensity) 
• AEs with onset during TP2 (by SOC, PT and intensity) 
• TEAEs (by SOC, PT and intensity) 
• AEs of special interest with onset during TP1 (by SOC and PT) 
• AEs of special interest with onset during TP2 (by SOC and PT) 
• TEAEs of special interest (by SOC and PT) 
• AEs of special interest with onset during TP1 (by category and PT) 
• AEs of special interest with onset during TP2 (by category and PT) 
• TEAEs of special interest (by category and PT) 
• SAEs with onset during TP1 (by SOC and PT) 
• SAEs with onset during TP2 (by SOC and PT) 
• TESAEs (by SOC and PT) 
• Treatment-emergent deaths and SAEs (by SOC and PT) 
• Non-serious TEAEs (frequency threshold  5%; by SOC and PT) 
• TESAEs (by PT) 
• SAEs related to study treatment with onset during TP1 (by SOC and PT) 
• SAEs related to study treatment with onset during TP2 (by SOC and PT) 
• TESAEs related to study treatment (by SOC and PT) 
• Fatal AEs with onset during TP1 (by SOC and PT) 
• Fatal AEs with onset during TP2 (by SOC and PT) 
• Fatal TEAEs (by SOC and PT) 
• AEs leading to temporary interruption of study treatment with onset during TP1 (by 
SOC and PT) 


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• AEs leading to temporary interruption of study treatment with onset during TP2 (by 
SOC and PT) 
• AEs leading to temporary interruption of study treatment (by SOC and PT) 
• AEs leading to premature discontinuation of study treatment with onset during TP1 (by 
SOC and PT) 
• AEs leading to premature discontinuation of study treatment with onset during TP1 (by 
PT) 
• AEs leading to premature discontinuation of study treatment with onset during TP2 (by 
SOC and PT) 
• AEs leading to premature discontinuation of study treatment with onset during TP2 (by 
PT) 
• AEs leading to premature discontinuation of study treatment (by SOC and PT) 
8.2.2.1 AESIs 
AESIs include important identified or potential risks of the treatment with cenerimod, the 
known class effects or events that may be related to SLE comorbidities (e.g., cardiovascular 
AEs). 
AESIs include the following safety categories:  
• Effect on HR- and rhythm-related AEs 
• Hypotension-related AEs 
• Hypertension-related AEs 
• Hepatobiliary disorder- / liver enzyme abnormality-related AEs 
• Pulmonary-related AEs 
• Macular edema- / Eye disorder-related AEs 
• Infection-related AEs 
• Malignancy (skin)-related AEs 
• Malignancy (non-skin)-related AEs 
• Cardiovascular-related AEs 
AESIs are identified via PTs provided by the Idorsia Drug Safety department [see 
Appendix 12.2].  
8.3 Death 
8.3.1 
Variables 
Data are taken from the Death eCRF page. 


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8.3.2 
Analysis 
Deaths will be summarized using the SAF and listed using the SCR Actual treatment group 
will be displayed in the listing. Deaths will be summarized by treatment group, SOC and 
PT. 
8.4 Laboratory tests 
Laboratory test results are transferred from the central laboratory or, if assayed locally, 
entered in local laboratory eCRF (in exceptional cases). Local laboratory data will only be 
listed (as local laboratory data is only requested in specific rare circumstances for medical 
evaluation of an individual subject). 
Laboratory assessments are performed at each scheduled visit from Screening up to the 
EOS visit (except FU2, FU3, FU3a, and FU3b), and at unscheduled visits if required. 
A time window approach will be applied to the laboratory data [as defined in Section 5.4.4]. 
8.4.1 
Measurements 
The following parameters are assayed at any scheduled visit according to the protocol: 
Hematology: 
• Hemoglobin 
• Hematocrit, mean corpuscular hemoglobin, mean corpuscular volume, and mean 
corpuscular hemoglobin concentration 
• Erythrocyte count (reticulocyte count) 
• Leukocyte count with differential counts (only available after database lock) 
• Platelet count 
Blood chemistry: 
• Aspartate aminotransferase and alanine aminotransferase, alkaline phosphatase, total 
and direct bilirubin, lactate dehydrogenase 
• Creatinine 
• Blood urea nitrogen 
• Uric acid 
• Glucose 
• Cholesterol, triglycerides 
• Sodium, potassium, chloride, calcium 
• Protein, albumin 
Urinalysis (including but not limited to):  
• pH 


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• Glucose 
• Proteins 
• Blood 
• Leukocytes 
Tests for tuberculosis, viral serology tests (Hepatitis B surface antigen, Hepatitis C 
antibodies, HIV1 and HIV2 antibodies, varicella-zoster virus IgG antibodies), coagulation 
tests (prothrombin time, international normalized ratio, activated partial thromboplastin 
time, urine-protein-to-creatinine ratio), other laboratory tests in the event of infection and 
pregnancy tests are also carried out during the study. 
8.4.2 
Variables 
The absolute change and percent change from baseline in laboratory parameters 
(hematology, blood chemistry, and urinalysis) at each post-baseline analysis visit up to 
EOS is calculated as follows: 
• Absolute change in laboratory parameters = Laboratory value at Visit X − Laboratory 
value at baseline (TP1) 
• Percent change in laboratory parameters = (Laboratory value at Visit X − Laboratory 
value at baseline [TP1]) / Laboratory value at baseline (TP1)  100 
Absolute and percent changes are also derived based on the TP2 baseline. 
Laboratory test abnormalities are defined as summarized in protocol appendix 7, for the 
following periods: 
• During TP1: up to Month 6 for subjects who complete TP1 on treatment and up to EOT 
for subjects who discontinue study treatment during TP1. 
• During TP2: up to EOT. 
• Treatment-emergent (combining TP1 and TP2 data): up to EOT + 180 days. 
8.4.3 
Analysis 
Laboratory parameters will be summarized using the SAF (for TP1 and for TP1+TP2 
combined) and using the SAF-TP2 (for TP2) by visit and treatment group [as defined in 
Section 5.4.3]. Data will be displayed in SI units as provided by the central laboratory.  
Treatment-emergent marked laboratory abnormalities (up to EOT + 180 days) as well as 
marked laboratory abnormalities during TP1 and during TP2 will be summarized by 
treatment group.  
A subject will be counted only once in the most severe category of a given parameter. 
However, it is possible that, for a given parameter, the same subject is counted as a high 
marked abnormality for an observed value and as a low marked abnormality for a different 


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observed value. An abnormality is only counted as treatment-emergent if the criterion itself 
and all more severe criterion for the same parameter were not already present at baseline. 
Percentages will be based on the number of subjects at risk, i.e., those not meeting the 
criterion or a more severe criterion for the same parameter at baseline (or having a missing 
baseline value) and having at least one post-baseline value for a given parameter. For 
criteria that are not only based on absolute values but also on changes from baseline, 
subjects with a missing baseline value are not included in the number of subjects at risk. 
A standard laboratory listing will be produced using the SAF containing all central and 
local laboratory data collected in the database. Local laboratory data will only be listed. 
8.5 Spirometry 
Spirometry measurements are performed every three months during the double-blind study 
treatment period and at the EOS visit. 
Spirometry test results will be transferred from a vendor including information on the 
quality of the measurements. 
A time window approach will be applied to the spirometry data [as defined in 
Section 5.4.4]. 
8.5.1 
Measurements 
FEV1 (in L) and FVC (in L) are assessed in this study.  
The percent predicted FEV1 and FVC is computed based on the formula defined by Quanjer 
[Quanjer 1993]. 
8.5.2 
Variables 
8.5.2.1 Definition absolute change and percent change from baseline (TP1) 
The absolute change from baseline for FEV1, FVC, percent predicted FEV1 and percent 
predicted FVC is calculated as follows: 
• Change from baseline = FEV1 at post-baseline visit − FEV1 at baseline 
• Change from baseline = FVC at post-baseline visit − FVC at baseline 
Percent change from baseline for FEV1, FVC, percent predicted FEV1 and percent 
predicted FVC is calculated as follows: 
• Percent change from baseline = (FEV1 at post-baseline visit − FEV1 at baseline) / FEV1 
at baseline  100 
• Percent change from baseline = (FVC at post-baseline visit − FVC at baseline) / FVC 
at baseline  100 


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Percent change from baseline expressed as percent of predicted baseline for FEV1 and FVC 
is calculated as follows: 
• Percent change from baseline = (FEV1 at post-baseline visit − FEV1 at baseline) / 
predicted FEV1 at baseline  100 
• Percent change from baseline = (FVC at post-baseline visit − FVC at baseline) / 
predicted FVC at baseline  100 
8.5.2.2 Definition absolute change and percent change from baseline (TP2) 
The absolute change and percent change from baseline (TP2) is calculated in the same way 
as described above. 
8.5.2.3 Decrease of (percent predicted) FEV1 or FVC > 15% from baseline 
A percent change decrease  > 15% is defined for the following periods: 
• During TP1: up to Month 6 for subjects who complete TP1 on treatment and up to EOT 
for subjects who discontinue study treatment during TP1. 
• During TP2: up to EOT. 
• Treatment-emergent (combining TP1 and TP2 data): up to EOT + 180 days. 
8.5.3 
Analysis 
Spirometry outputs will be produced using the SAF (for TP1 and for TP1+TP2) and 
SAF-TP2 (for TP2). 
Observed values, changes from baseline and percent changes from baseline of FEV1 and 
FVC will be summarized by visit and treatment group, during TP1 using the FAS, during 
TP2 using the FAS-TP2, and combining TP1 and TP2 for each post-baseline assessment 
up to EOS using the FAS.  
For percentage changes from baseline, summary statistics will be derived from the 
geometric mean of the ratio to baseline, and from the geometric mean of the ratio to 
predicted value at baseline for the percentage change expressed as percent of predicted 
baseline. Geometric mean will be computed and transformed into a percentage change by 
using the transformation x – > ((x-1) × 100) as described in Section 8.9.2.  
The CV of the geometric mean will also be presented [see Section 8.9.2 for calculation]. 
All outputs defined above will be repeated for percent predicted FEV1 and FVC.  
Summary statistics will be produced showing the number of subjects with a treatment-
emergent decrease of at least 15% from baseline for FEV1 and FVC and percent predicted 
FEV1 and FVC. Decreases during TP1 and during TP2 will be summarized as well. 
Spirometry data will be listed using the SAF. 


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8.6 Electrocardiography 
The 12-lead ECG measurements and qualitative ECG findings (e.g., rhythm, ectopy, 
conduction and morphology) are provided by the ECG central reader, along with the 
overall interpretation of the ECG (Normal/Abnormal). 
ECG Holter monitoring data and findings are also provided by a central reader. 
8.6.1 
Measurements 
12-lead ECG is measured at visits defined in the visit and assessment schedule [see 
Appendix 12.1].  
The following parameters will be evaluated: HR (bpm), PR (ms), QRS (ms), QT (ms), QTc 
(ms), and any ECG findings. QTc (ms) is calculated according to Bazett’s and Fridericia’s 
formula. Data is received in derived form by the vendor. 
A time window approach will be applied to the ECG data [as defined in Section 5.4.4]. 
ECG Holter monitoring is performed for 24 hours at Visit 2 (Randomization). 
8.6.2 
Variables 
8.6.2.1 Change from baseline in 12-lead ECG 
Change of ECG measurements is derived on the day of first study drug intake, on the day 
of re-initiation and generally from the baseline (in TP1) to each pre-dose assessment at any 
visit during the conduct of the study. Changes are derived for any ECG parameter provided 
by the vendor (mean HR, PR interval, QRS duration, QT interval, QTcB and QTcF 
interval). 
The intra-day change is defined for the day of first study drug intake and the day of 
re-initiation, by hour: 
Hourly intra-day change = Value at hourly post-dose assessment − value at pre-dose 
assessment. 
ECG values at the pre-dose assessment must have been assessed on the day of first study 
drug intake / day of re-initiation, otherwise they are considered to be missing. Some 
subjects might stay longer in hospital than the expected 6 hours. Intra-day changes are also 
calculated for assessments performed later than 6 hours after first study drug intake.  
Changes compared to a derived baseline value are defined as: 
Change = Value at post-baseline visit (pre-dose) − derived baseline value. 
The derived baseline value is defined as the last valid value measured prior to first study 
drug intake in TP1 (by date and time). For HR, the mean ECG HR is used to derive the 
baseline value. For the remaining ECG parameters (PR interval, QRS duration, QT 


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interval, QTcB and QTcF interval) aggregate values are provided by the ECG central 
reader that are used to derive the baseline value. 
Changes from baseline are also derived based on the TP2 baseline. 
8.6.2.2 Notable abnormalities (12-lead ECG) 
Table 11 
Notable abnormalities in ECG parameters 
Analysis 
parameter 
Analysis variable(s) 
Analysis criterion 
QTcB (ms) and 
QTcF (ms) 
Analysis value 
- Value > 450 and ≤ 480 (male), > 470 and ≤ 480 (female) 
- Value > 480 and ≤ 500 
- Value > 500 and ≤ 520 (female) 
- Value > 500 (male), > 520 (female) 
 
Change from baseline 
- Increase from baseline > 30 and ≤ 60 
- Increase from baseline > 60 
 
Analysis value and 
change from baseline  
- Value > 450 and increase from baseline > 30 and ≤ 60 
- Value > 450 and increase from baseline > 60 
Heart rate (bpm) 
Analysis value 
- Value < 40  
PR duration (ms) 
Analysis value 
- Value > 200  
 
Change from baseline 
- Increase from baseline > 20 
 
Analysis value and 
change from baseline 
- Value > 200 and increase from baseline > 20  
bpm = beats per minute; ECG = electrocardiogram; QTcB = QT interval corrected for heart rate using Bazett’s formula; 
QTcF = QT interval corrected for heart rate using Fridericia’s formula. 
 
Notable ECG abnormalities are derived as described in Table 11 and defined for the 
following periods: 
• Day of first study drug intake (up to 24 hours after first study drug intake). 
• During TP1: up to Month 6 for subjects who complete TP1 on treatment and up to EOT 
for subjects who discontinue study treatment during TP1. 
• During TP2: up to EOT. 
• Treatment-emergent (combining TP1 and TP2 data): up to EOT + 180 days. 
Values and changes derived above will be used to characterize abnormalities. 
8.6.2.3 Morphological ECG abnormalities/findings (12-lead ECG) 
Morphological ECG findings are defined for: 
• Day of first study drug intake (up to 24 hours after first study drug intake). 
• During TP1: up to Month 6 for subjects who complete TP1 on treatment and up to EOT 
for subjects who discontinue study treatment during TP1. 


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• During TP2: up to EOT. 
• Treatment-emergent (combining TP1 and TP2 data): up to EOT + 180 days. 
Due to the automatic transfer of data from the hospital to the vendor all date and time 
information should be complete. In the unlikely event of missing date and time, the missing 
information is imputed in the same way as the date and time information for TEAEs. 
8.6.2.4 Holter ECG 
Due to the HR-lowering effect of cenerimod on the first day of study drug intake the 
baseline Holter value and all other post-baseline values are derived dependent on the time 
of the first study drug intake. Baseline is defined as the average HR prior to first study drug 
intake. 
Hourly averages of the HR after baseline are also calculated based on the time of the first 
study drug intake. 
Example: 
If the start time of first study drug intake is 8:22:00 am, the mean HR in the interval 
[7:22:00 am (or start of recording); 8:21:59 am] is considered as the baseline value and the 
mean HR in the interval [8:22:00 am; 9:21:59 am] is considered as the first hourly interval. 
The mean HR is calculated for 24 intervals (if data available). 
For each Holter ECG, a cardiologist will provide an overall interpretation 
(Normal/Abnormal) and will describe potential findings. 
Each finding reported for the Holter ECG performed on the day of first study drug intake 
is considered to be treatment-emergent (up to 24 hours after the start of recording). 
Absolute changes of the mean hourly HR are defined as follows: 
Changes of the mean hourly HR = mean hourly HR at hour X − mean hourly HR at 
baseline 
8.6.3 
Analysis 
8.6.3.1 12-lead ECG 
All ECG outputs will be summarized using the SAF and SAF-TP2. 
Standard summary tables will be produced, by time point, for any ECG parameter provided 
by the vendor on the day of first study drug intake by treatment group. A similar summary 
table will be produced by study visit, for TP1, for TP2 and for TP1 and TP2 combined. 
Figures over time will be produced to support the summary tables. 
The incidence of ECG outliers / notable ECG abnormalities and morphological ECG 
findings will be summarized for the periods defined above. 


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A subject will be counted only once in the most severe category of a given parameter. An 
abnormality is only counted as treatment-emergent if the criterion itself and all more severe 
criterion for the same parameter were not already present at baseline. 
Percentages will be based on the number of subjects at risk, i.e., those not meeting the 
criterion or a more severe criterion for the same parameter at baseline (or having a missing 
baseline value) and having at least one post-baseline value for a given parameter. For 
criteria that are based on an increase from baseline, subjects with a missing baseline value 
are not included in the number of subjects at risk. 
For QTcB and QTcF, a shift table from baseline to worst value post-baseline will be 
produced based on the abnormalities. 
The incidence of ECG outliers/notable ECG abnormalities and morphological ECG 
findings will be summarized for TP2 as well. Outputs will be displayed in the same way as 
described above, based on 6 treatment groups using the SAF-TP2. 
ECG data (parameters and findings) will be listed by treatment group, subject and visit 
using the SAF.  
All post-treatment notable abnormalities will be flagged and qualitative abnormalities (as 
transferred by the ECG central reader) will be listed using the SAF. 
8.6.3.2 Holter ECG 
Standard summary tables of the mean hourly HR observed values and changes from 
baseline will be produced, by time point and treatment group, for the day of first study drug 
intake. Figures over time will support the summary tables. 
Holter ECG findings (with codes from [001] to [019] in SDTM CO domain) will be 
summarized by treatment group. When mentioned in the finding, number of episodes will 
not be included in the finding verbatim for the summary table but will be displayed as 
collected in the listing. 
Holter ECG data will be listed by treatment group, subject and visit using the SAF. A listing 
of all Holter ECG abnormalities will also be provided. 
8.7 Vital signs and body weight 
Blood pressure data are collected on the Vital Signs eCRF page.  
Weight is collected on the Body Weight eCRF page.  
The HR is only collected in the ECG data and therefore not analyzed in this section. 
A time window approach will be applied to the vital signs / weight data [as defined in 
Section 5.4.4]. 


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8.7.1 
Blood pressure 
8.7.1.1 Measurements 
For SBP and DBP two measurements will be performed pre-dose at every visit (except 
FU2, FU3, FU3a, and FU3b).  
For the randomization visit and the re-initiation visit, where the subject stays in the hospital 
for an extended period of time, single hourly post-dose measurements will be performed. 
8.7.1.2 Blood pressure over time 
8.7.1.2.1 Variables 
Absolute change of blood pressure is derived on the day of first study drug intake, on the 
day of re-initiation and generally from the last valid assessment prior to first study drug 
intake to each pre-dose assessment at any visit during the conduct of the study.  
Absolute changes are derived for SBP and DBP separately, based on measurements at each 
(hourly) visit. In the event of two available measurements the mean of those two 
measurements is computed. 
Intra-day change is defined for the day of first study drug intake and the day of re-initiation, 
by hour: 
Hourly intra-day change = Blood pressure value at hourly post-dose assessment − mean 
blood pressure value at pre-dose assessment 
The mean blood pressure value at the pre-dose assessment must be assessed on the day of 
first study drug intake / day of re-initiation, otherwise it is considered to be missing.  
Some subjects might stay longer in hospital than the expected 6 hours. Intra-day changes 
are also calculated for assessments performed later than 6 hours after first study drug 
intake. 
Pre-dose assessments are identified by date and time. Blood pressure is assessed twice at 
each pre-dose visit and the mean of those two measurements is used to calculate the change. 
In the event that only one measurement is performed at any (hourly) visit, this single 
measurement is used for analysis instead of the mean. 
Changes compared to the derived mean baseline value are defined as: 
Change = Mean blood pressure value at post-baseline visit (pre-dose) − derived mean 
baseline value 
The derived mean baseline value is the mean of the last two blood pressure values measured 
on the same day before first study drug intake (by date and time). In the event of missing 
pre-dose data on the day of first study drug intake, the mean of the closest measurements 
prior to first study drug intake (e.g., at Screening) is used. 


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Changes from TP2 baseline will be derived in the same way. 
All data independent of the position (sitting, standing, supine) and location (right arm, left 
arm) are included in the derivation. 
8.7.1.2.2 Analysis 
Blood pressure parameters will be summarized using the SAF (for day of first study drug 
intake, for TP1 and for TP1+TP2 combined) and using the SAF-TP2 (for TP2) by time 
point / visit and treatment group [as defined in Section 5.4.3]. 
Blood pressure data will be listed using the SAF. 
8.7.1.3 Notable blood pressure abnormalities 
8.7.1.3.1 Variables 
For SBP and DBP, the occurrence of notable abnormalities (up to EOT + 180 days) is 
assessed according to the criteria defined in Table 12. Values and changes derived above 
will be used to characterize abnormalities. 
Table 12 
Notable abnormalities in blood pressure 
Analysis parameter 
Analysis criterion 
SBP (mmHg) 
Value ≤ 90 and decrease ≥ 20 from baseline 
 
Value ≥140 and increase ≥ 20 from baseline 
 
Value ≥ 160 
DBP (mmHg) 
Value ≤ 50 and decrease ≥ 15 from baseline 
 
Value ≥ 90 and increase ≥ 15 from baseline 
 
Value ≥ 100 
DBP = diastolic blood pressure; SBP = systolic blood pressure. 
 
Abnormalities are defined for:  
• Treatment-emergent on day of first study drug intake: up to 24 hours after first study 
drug intake. 
• During TP1: up to Month 6 for subjects who complete TP1 on treatment and up to EOT 
for subjects who discontinue study treatment during TP1. 
• During TP2: up to EOT. 
• Treatment-emergent (combining TP1 and TP2 data): up to EOT + 180 days. 


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8.7.1.3.2 Analysis 
Treatment-emergent notable blood pressure abnormalities will be summarized 
descriptively using the SAF (treatment-emergent on day of first study drug intake, during 
TP1, and during TP1 and TP2) and the SAF-TP2 (during TP2).  
An abnormality is only counted as treatment-emergent if the criterion was not already 
present at baseline. 
Percentages will be based on the number of subjects at risk, i.e., those not meeting the 
criterion at baseline (or having a missing baseline value) and having at least one post-
baseline value for a given parameter. For criteria that are based on the change from 
baseline, subjects with a missing baseline value are not included in the number of subjects 
at risk. 
8.7.2 
Body weight 
8.7.2.1 Variables 
Weight is summarized over time and changes are derived as follows: 
Change = Weight at post-baseline visit − baseline weight. 
Changes are also derived based on TP2 baseline. 
8.7.2.2 Analysis 
Absolute values and changes from baseline up to EOS will be summarized using the SAF. 
Absolute values and changes from baseline during TP1 will be summarized using the SAF 
and during TP2 using the SAF-TP2. 
Weight data will be listed using the SAF. 
8.8 Echocardiography (sub-study) 
Standard 2D/Doppler data are collected for all subjects at Screening and for approximately 
175 subjects in the study at Month 6 or premature EOT visit. 
8.8.1 
Measurements 
Cardiac morphology and function including regional wall abnormalities, aortic valve 
morphology and function, mitral valve morphology and function, and left ventricular 
ejection fraction are collected in this study. 
Abnormalities from Screening to Month 6 are assessed by Standard 2D/Doppler 
echocardiography.  
Abnormalities and cardiac data (as defined above) will be received by a vendor. 
A time window approach will be applied [as defined in Section 5.4.4]. 


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8.8.2 
Variables 
The change in left ventricular ejection fraction is computed as: 
Change in left ventricular ejection fraction (%) = Left ventricular ejection fraction (%) at 
Month 6 or premature EOT visit − Left ventricular ejection fraction (%) at Screening. 
8.8.3 
Analysis 
Standard summary tables will be produced using the ECS, by treatment group, for the 
change in left ventricular ejection fraction from Screening to Month 6 or premature EOT 
visit. 
Abnormalities will be summarized descriptively using the ECS. 
Echocardiography data will be listed using the SAF. 
8.9 Biomarker endpoints 
The following biomarkers are assessed:  
• total lymphocyte count 
• anti-cardiolipin antibodies (IgA, IgG, IgM) 
• Anti-nuclear antibodies 
• anti-dsDNA antibodies 
• anti-Smith antibodies 
• C3 and C4 complement 
The following biomarkers will be included in summaries (numerically).  
• Anti-nuclear antibodies 
• anti-dsDNA antibodies 
• anti-Smith antibodies 
• C3 and C4 complement 
Qualitative assessments (e.g., Normal/Abnormal) will only be listed. 
A time window approach will be applied [as defined in Section 5.4.4]. 
8.9.1 
Variables 
The absolute change and percent change from baseline in biomarker parameters at each 
post-baseline analysis visit up to EOS is calculated as follows: 
• Change in biomarker parameters = Biomarker value at Visit X − Biomarker value at 
baseline 


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• Percent change in biomarker parameters = (Biomarker value at Visit X − Biomarker 
value at baseline) / Biomarker value at baseline  100 
Baseline is defined as the last valid biomarker value prior to first study drug intake, by time 
and date. 
8.9.2 
Analysis 
Biomarker data will be analyzed using the FAS and data up to the EOS visit. 
For biomarkers standard summary statistics for absolute values, absolute change and 
percent change from baseline will be presented, by visit and treatment group.  
Summary statistics of percentage changes will be derived from the geometric mean of the 
ratio to baseline. Because geometric mean of data is equivalent to exp(mean of log-
transformed data), the geometric mean of the ratio to baseline is equivalent to exp(mean of 
log[post-baseline/baseline]), 
equivalent 
to 
exp(mean 
of 
(log[post-baseline] 
– 
log[baseline])). Geometric mean of the ratio to baseline will be transformed into a 
percentage change by using the transformation x – > ((x-1) × 100).  
The CV of the geometric mean will be derived as: 
100 × √exp ((𝑆𝐷𝑙𝑜𝑔)
2) −1 
Note that anti-cardiolipin antibodies are only collected at baseline and therefore only the 
baseline summaries will be presented for this parameter. 
Biomarkers will be listed using the FAS. 
9 
GENERAL STATISTICAL METHODOLOGY  
9.1 General rules for data presentations 
Unless otherwise specified, data will be summarized using appropriate descriptive 
statistics: 
• For continuous variables: number of non-missing observations, mean, standard 
deviation, minimum, first quartile, median, third quartile and maximum. 
Results will be displayed in the format of the eCRF for median, percentiles, minimum 
and maximum values. They will be displayed with one additional digit for the mean 
and the 95% CIs. The standard deviation will be displayed with one more digit than the 
mean. 
• For dichotomous or categorical variables: number of non-missing observations, and 
frequency with percentage per category. Denominators for percentages are the number 
of subjects in the pertinent analysis set and treatment group, unless otherwise specified. 


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• For time-to-event variables: number of events, number at risk, number of censored 
observations and Kaplan-Meier estimates of the survival function. 
In listings, subject number is presented as “SUBJID/SEX/AGE”. 
A percentage change from baseline is defined as the absolute change from baseline divided 
by the baseline value (if the baseline value is > 0) and then multiplied by 100. In the event 
of baseline and post-baseline value both equal to 0, the ratio to baseline will be set to 1 (i.e., 
the percent change from baseline will be set to 0%). If baseline is equal to 0 and 
post-baseline value greater than 0 (infinite ratio) or if baseline greater than 0 and 
post-baseline equal to 0 (log[ratio] = minus infinity), the percent change will be missing. 
10 INTERIM ANALYSES 
No interim analyses are planned according to protocol. 


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11 REFERENCES 
[D-22.031] 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). Idorsia 
Pharmaceuticals Ltd. Protocol ID-064A202 Version 5, 4 February 2022. 
[Bernaards 2007] Bernaards CA, Belin TR, Schafer JL. Robustness of multivariate normal 
approximation for imputation of incomplete binary data. Stat Med 2007;26:1368-82.  
[Bornkamp 2016] Bornkamp B, Pinheiro J, Bretz F. Design and Analysis of Dose-Finding 
Studies. 5 August 2017 [accessed on 12 July 2019]. Available from:  
ftp://cran.r-project.org/pub/R/web/packages/MCPMod/MCPMod.pdf 
[Bretz 2005] Bretz F, Pinheiro JC, Branson M. Combining Multiple Comparisons and 
Modeling Techniques in Dose-Response Studies. Biometrics 2005;61:738–48. 
[Carpenter 2013] Carpenter JR, Roger JH, Kenward MG. Analysis of longitudinal trials 
with protocol deviation: a framework for relevant, accessible assumptions, and 
inference via multiple imputation. J Biopharm Stat. 2013;23(6):1352–71. 
[Molenberghs 2004], Molenberghs G, Thijs H, Jansen I, Beunckens C, Kenward MG, 
Mallinckrodt C, et al. Analyzing incomplete longitudinal clinical trial data. 
Biostatistics. 2004;5:445–64. 
[NRC Report 2010] National Research Council, Panel on Handling Missing Data in 
Clinical Trials; Committee on National Statistics; Division of Behavioral and Social 
Sciences and Education. The prevention and treatment of missing data in clinical 
trials. The National Academies Press, 2010 Washington DC, USA. 
[O’Kelly 2014] O’Kelly M, Ratitch B. Clinical Trials with Missing Data: A Guide for 
Practitioners. John Wiley & Sons, Ltd; 2014. 
[Quanjer 1993] Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault 
JC. Lung volumes and forced ventilatory flows. Report Working Party 
Standardization of Lung Function Tests, European Community for Steel and Coal. 
Official Statement of the European Respiratory Society. Eur Respir J Suppl. 1993 
Mar;16:5–40. 
[Rubin 1987] Rubin DB. Multiple imputation for nonresponse in surveys. New York, NY, 
USA: John Wiley & Sons; 1987. 
[Schafer 1999] Schafer JL. Multiple imputation: a primer. Stat Methods Med Res. 
1999;8:3–1 
[Ware 2000] Ware JE, Kosinski M, Dewey JE. How to Score Version 2 of the SF-36® 
Health Survey. Lincoln, RI: QualityMetric Incorporated, 2000. 
 


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12 APPENDICES 
12.1 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 up 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 
 


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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 
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. 
(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. 


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(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 and 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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12.2 Definitions of AEs of special interest  
The definitions for AESIs are based on a systematic approach using SMQs. The additional 
relevant term can be added to the search or deleted appropriately providing the rationale 
for the change. The current proposal is based on MedDRA version 25.0. The following 
safety areas are addressed by the pre-defined AESIs. Note that all SMQs are considered as 
broad searches (i.e., including broad and narrow terms) unless noted otherwise.  
Narratives will be written for all SAEs, pregnancy and death events reported to Global 
Drug Safety, including those not meeting the definition of AESIs. 
• Effect on HR and rhythm AESI  
Effect on HR and rhythm AESI are identified by the PTs in the following SMQ: 
Bradyarrhythmias (incl conduction defects and disorders of sinus node function) 
(SMQ). Note that this SMQ only has narrow scope defined. 
In addition, to the PTs included in Bradyarrhythmias (including conduction defects and 
disorders of sinus node function [SMQ]), the following PTs will be added to the search for 
AEs addressing effects on HR and rhythm:  
“BRADYCARDIA”, “ELECTROCARDIOGRAM RR INTERVAL PROLONGED”, 
“HEART 
RATE 
DECREASED”, 
“CHRONOTROPIC 
INCOMPETENCE”, 
“PRESYNCOPE”, “SYNCOPE”, “LOSS OF CONSCIOUSNESS”, and “CENTRAL 
BRADYCARDIA”.  
AESI Narratives will be written for AEs of confirmed symptomatic events on HR and 
rhythm (e.g., symptomatic bradycardia, etc.). Narratives will be written for AV block 2nd 
and 3rd degree, but not for AV block 1st degree. 
• Hypotension AESI 
The following PTs will be added to the search for AEs addressing hypotension: “BLOOD 
PRESSURE DECREASED”, “BLOOD PRESSURE DIASTOLIC DECREASED”, 
“BLOOD PRESSURE ORTHOSTATIC DECREASED”, “BLOOD PRESSURE 
SYSTOLIC DECREASED”, “DIASTOLIC HYPOTENSION”, “MEAN ARTERIAL 
PRESSURE DECREASED”, “ORTHOSTATIC HYPOTENSION”, “PROCEDURAL 
HYPOTENSION”, “HYPOTENSION”, “CIRCULATORY COLLAPSE”, “BLOOD 
PRESSURE 
AMBULATORY 
DECREASED”, 
“BLOOD 
PRESSURE 
IMMEASURABLE”, 
“BLOOD 
PRESSURE 
SYSTOLIC 
INSPIRATORY 
DECREASED”, “CT HYPOTENSION COMPLEX”, “DISTRIBUTIVE SHOCK”, 
“PROCEDURAL SHOCK”, “SHOCK”, “SHOCK HAEMORRHAGIC”, and “SHOCK 
SYMPTOM”, “HYPOTENSIVE CRISIS”, “POST PROCEDURAL HYPOTENSION”, 
“HYPOVOLAEMIC 
SHOCK”, 
“CARDIOGENIC 
SHOCK”, 
“PERIPHERAL 
CIRCULATORY FAILURE”. 
AESI Narratives will be written for confirmed symptomatic hypotension events. 


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• Cardiovascular AESI 
Cardiovascular AESI are identified by any PT in the following SMQs: Ischaemic heart 
disease (SMQ, narrow scope) or Torsade de pointes/QT prolongation (SMQ, broad 
scope) or Cardiac failure (SMQ, narrow scope).  
AESI Narratives will be written for these AESIs only if reported as SAE. 
• Hypertension AESI 
Hypertension AESIs are identified by the PTs in the following SMQ: Hypertension 
(SMQ, narrow scope). 
AESI Narratives will be written for these AESIs only if reported as SAE. 
• Hepatobiliary disorders / Liver enzyme abnormality AESI 
Hepatobiliary disorders/ Liver enzyme abnormality AESIs are identified by the PTs in the 
following SMQ: Drug related hepatic disorders - comprehensive search (SMQ). 
AESI Narratives will be written for lab abnormalities or AEs of ALT or AST >= 3 × ULN. 
No narrative will be written for AEs declared without ALT or AST being >= 3 × ULN. 
• Pulmonary AESI 
These AEs are identified by the PTs the in the following SMQs: Asthma/bronchospasm 
(SMQ) or Interstitial lung disease (SMQ).  
The PTs “DYSPNOEA AT REST”, “DYSPNOEA” and “DYSPNOEA EXERTIONAL” 
which are not included in the above-mentioned SMQs are added to the search.  
SMQs related to respiratory system do not cover all the PTs on investigation (i.e., AEs 
based on pulmonary function test or chest X-ray or computerized tomography scan). 
Therefore, the PT from the MedDRA SOC ‘Investigations’ identified by the following 
HLGT are added to the search: ‘Respiratory and pulmonary investigations (excl blood 
gases)’ (HLGT) with the exception of the following PTs: “CAPNOGRAM NORMAL”, 
“END-TIDAL CO2 NORMAL”, “EXPIRATORY RESERVE VOLUME NORMAL”, 
“FORCED EXPIRATORY VOLUME NORMAL”, “FORCED VITAL CAPACITY 
NORMAL”, “FUNCTIONAL RESIDUAL CAPACITY NORMAL”, “INSPIRATORY 
CAPACITY NORMAL”, “MAXIMAL VOLUNTARY VENTILATION NORMAL”, 
“PEAK EXPIRATORY FLOW RATE NORMAL”, “PULMONARY FUNCTION 
CHALLENGE TEST NORMAL”, “PULMONARY FUNCTION TEST NORMAL”, 
“RHINOMANOMETRY NORMAL”, “SPIROMETRY NORMAL”, “TOTAL LUNG 
CAPACITY NORMAL”, “VITAL CAPACITY NORMAL”. 
AESI Narratives will be written for Pulmonary Functional Tests meeting the study 
treatment discontinuation criteria defined in protocol section 5.1.8.3. 


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• Macular edema AESI 
Macular edema AESI are identified by the following PTs: “MACULAR OEDEMA”, 
“MACULAR HOLE”, “MACULAR PSEUDOHOLE”, “MACULAR RUPTURE”, 
“MACULAR 
THICKENING”, 
“MACULAR 
CYST”, 
“RETINAL 
OEDEMA”, 
“DIABETIC 
RETINAL 
OEDEMA”, 
“CYSTOID 
MACULAR 
OEDEMA”, 
“PAPILLOEDEMA”, and “PSEUDOPAPILLOEDEMA”. 
AESI Narratives will be written for cases reviewed by the Ophthalmology Safety Board. 
• Eye disorder AESI 
Eye disorder AESI are identified by the PTs in the following SMQ: Retinal disorders 
(SMQ, narrow scope).  
AESI Narratives will be written for cases reviewed by the Ophthalmology Safety Board. 
• Infection AESI 
Infection AESI are identified by the PTs in the following SMQ: Opportunistic infection 
(SMQ). 
AESI Narratives will be written for all these AESIs, except for COVID-19 cases that are 
not reported as SAE. 
• Skin malignancy AESI 
Skin malignancy AESI are identified by the PTs in the following SMQs: Skin neoplasms, 
malignant and unspecified (SMQ) or Skin premalignant disorders (SMQ) (broad and 
narrow scope, including all sub SMQs). 
AESI Narratives will be written for all these AESIs. 
• Non-skin malignancy AESI 
Non-skin malignancy AESI are identified by the PTs in the following SMQs: Malignant 
tumours (SMQ) or Malignant lymphomas (SMQ; Narrow scope) excluding the PTs 
included in the ‘Skin malignancy AESI’. 
AESI Narratives will be written for all these AESIs. 
 
 
 


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12.3 SF-36v2™ 


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Computing domain scores 
 
Computing normalized domain scores 


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Computing PCS and MCS measures  
Missing data 




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12.5 Revision history  
Version 
Date 
Version 
Implemented Change(s) 
5-Aug-2019 
1.0 
New 
27-Aug-
2020 
2.0 
• 
Section 2.1: added paragraph on the echocardiography ancillary study.  
• 
Section 3.1.1: the final ICH E9 addendum was not available when 
version 1 of this SAP was prepared. The draft ICH E9 addendum did not 
include the “treatment condition of interest” attribute. This was now 
added in this SAP. 
• 
Section 4.1: clarified definition of ‘treatment received’ and updated 
analysis set labels to remove ‘TP1’ as these analysis sets are also used 
for analyses that combine data from TP1 and TP2. 
• 
Section 5.4.3: updated treatment groups for exploratory analyses of TP2 
data and TP1 + TP2 data combined. Clarified treatment groups used in 
listings. 
• 
Section 6.1: updated to account for re-screening which was not allowed 
in previous protocol version. 
• 
Section 6.2.2: removed summary table of eligibility criteria. 
• 
Sections 6.3, 6.4, 6.5, 6.6, 6.9: data will be presented separately during 
TP1, during TP2 and during TP1 + TP2. 
• 
Section 6.6: added listing for subjects unblinded during the study; added 
summaries of DVs related to COVID-19 pandemic. 
• 
Section 6.7.2: clarified that analysis sets will be summarized separately 
by randomized group and treatment received. Separate tables for re-
randomized groups added. Added tables for reasons of exclusion. 
• 
Section 6.8.1.2: added demographics by sex table. 
• 
Section 6.8.2.2: clarified that stratification factors will be presented as 
shift table. 
• 
Section 6.8.6: added summaries for concomitant at baseline therapies; 
clarified definition of SLE therapies; clarified date imputation; added 
summary of changes in background medications. 
• 
Section 7.2.3: added patterns of missingness table and figure showing 
mean change from baseline by study completers and withdrawals. 
• 
Section 7.2.5: added further details for MMRM specification. 
• 
Section 7.2.7.2, 7.3.1.7: clarified subgroup analyses (separate models per 
subgroup). 
• 
Sections 7.3.1.3, 7.3.2.3: added patterns of missingness table. 
• 
Section 7.3.1.5: added further details for GLMM specification. 
• 
Sections 7.3.1.6.2, 7.3.1.6.3, 7.3.2.6.2, 7.3.2.6.3: added additional 
sensitivity analyses. 
• 
Sections 7.5.2.2, 7.5.3.2, 7.5.4.2, 7.5.5.2, 7.5.6.2, 7.5.8.2, 7.5.9.2: 
clarified that only re-randomized groups are included in models of TP2 
data. 


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• 
Section 7.5.10: added more details for derivation of monthly prednisone 
equivalent dose. 
• 
Section 8: safety events will be presented as occurring during TP1, 
occurring during TP2 and treatment-emergent. 
• 
Section 8.2.2: defined 3 overview tables instead of only one (AEs with 
onset during TP1, AEs with onset during TP2, treatment-emergent AEs) 
and replaced several subsections by bullet list of outputs. 
• 
Sections 8.4.3, 8.6.3, 8.7.1.3.2: clarified definition of emergent events. 
• 
Section 11: removed these exploratory analyses which will not be 
performed for CSR. 
• 
Appendix 12: removed laboratory abnormalities table and refer to 
protocol appendix instead. 
• 
Appendix 12.4: added FACIT-Fatigue scoring manual. 
• 
Other minor clarifications and editorial updates. 
09-Sep-2021 
3.0 
• 
Section 2 (Study design): Updated following protocol amendment 
(protocol version 4.0): 
- 
Sample size reduced from 500 to 325 
- 
Planned end of TP2 will be 12 months after initial randomization, 
for all subjects 
- 
Describe Month-6 and Month-12 analyses milestones 
• 
Section 4.1.4 (Per-Protocol Set): criteria for exclusion from the PP set are 
detailed in an excel file, to facilitate the reading 
• 
Section 4.2 (Usage of analysis sets): Clarify that in the event of accidental 
intake of a treatment other than the randomized treatment occurring 
during TP2, actual treatment group for TP1 only will be the randomized 
treatment 
• 
Section 5.1 (Study dates) and section 6.2 (Eligibility criteria): Updated 
to include possibility for re-screening introduced in a protocol 
amendment 
• 
Section 5.4.3 (Treatment groups for analysis according to treatment 
period): Labels for treatment groups updated after team review during 
dry-run 1 
• 
Section 5.4.3 (Treatment groups for analysis according to treatment 
period): Treatment group of those randomized to cenerimod 4mg during 
TP1 and not re-randomized will be displayed in a selection of outputs 
(disposition, treatment-emergent safety events) 
• 
Section 6.1: added description of screening failures related to COVID-19 
pandemic. 
• 
Section 6.2 (Eligibility criteria): Added summary of eligibility criteria for 
screen failures not eligible as per inclusion/exclusion criteria 
• 
Section 6.3 (Subject disposition): Disposition updated following dry-run 
1 comments 
• 
Section 6.4: added description of study treatment discontinuation related 
to COVID-19 pandemic. 


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• 
Section 6.5: added description of study discontinuation related to 
COVID-19 pandemic. 
• 
Section 6.8.6 (Previous and concomitant therapies): Description of 
background SLE therapies by ATC and PT was replaced by a description 
by categories mentioned in the protocol and PT 
• 
Section 6.9.2 (Compliance): Clarifications on derivation of compliance 
when the kit is not returned or was replaced 
• 
Section 7 (Efficacy analyses): subject random effect was removed from 
all models 
• 
Number of replicated for multiple imputation was reduced from 500 to 
100 for all analyses using MI 
• 
Section 7.2.6.9 (Dose-response analysis): MCP-Mod analyses to be 
performed were clarified and piece of code added  
• 
Section 7.4.5 (Time to first severe flare up to Month 6), section 7.4.6 
(Time to first flare up to Month 6): Log-rank test was removed 
• 
Section 7.5.1 (Sustained mSLEDAI-2K response): Added the definition 
of subjects with enough assessments to be assessed for this endpoint 
• 
Section 7.5.10 (Change from baseline to each post-baseline assessment 
up to Month 12 in prednisone or equivalent dose): Clarification of the 
analysis windows: If a subject has a visit recorded after Month 6 but the 
Month 6 visit was not done, Month 6 visit will be replaced by Day 180. 
• 
Section 7.6.1 (FACIT-Fatigue): Month-3 analysis timepoint was added 
following protocol amendment (protocol version 4.0) 
• 
Section 7.6.4 (SF 36v2™): The health transition score will only be 
described at Month 12, as it rates the current state compared to one year 
before 
• 
Section 7.6.5 (Lupus QoL): Scoring details were described as per scoring 
manual  
• 
Section 7.6.6 (mucocutaneous and musculoskeletal score): The sum of 
the mucocutaneous and musculoskeletal score will also be described 
• 
Section 8.5 (Spirometry): Formula for percent change from baseline 
expressed as percent of predicted baseline for FEV1 and FVC was 
corrected 
• 
Section 8.5 (Spirometry): Geometric mean and CV for percent change 
from Baseline were added following dry-run 1 review 
• 
Section 8.8 (Echocardiography sub-study): Sample size increased from 
125 to 175 following protocol amendment (protocol version 4.0) 
• 
Section 8.8 (Echocardiography sub-study): All abnormalities will be 
described, not only clinically relevant ones 
• 
Section 8.9 (Biomarkers): List of selected biomarkers (quantitative 
variables) to be described was added. All other biomarkers (qualitative 
variables) will only be listed  
• 
Section 8.9 (Biomarkers): Derivation of geometric mean for percent 
change from baseline was clarified 


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• 
Section 9.1 (General rules for data presentations): Derivation of 
percentage change from baseline was added 
• 
Section 12.1 (Visit and assessment schedule): Updated following 
protocol amendment (protocol version 4.0) 
• 
Section 12.2 (Definitions of AEs of special interest): AESI list was 
updated following the last criteria for research provided by safety 
department, based on the last version of MedDRA used (v24.0) + AESIs 
for which narratives will be written was added 
21-Mar-2022 
4.0 
Updates as per protocol Version 5 (protocol amendment 4): 
• 
Follow-up extended from 4 months to 6 months, with two new FU visits 
taking place (FU3a and FU3b): 
– Section 2.1 (Study design) 
– Section 2.3 (Study periods) 
– Section 8.4 (Laboratory tests) 
– Section 8.5 (Spirometry) 
– Section 8.7.1 (Blood pressure) 
– Section 12.1 (Visits and assessment schedule) 
• 
Month-12 analysis to be performed at last EOT (instead of EOS). The 
Final EOS analysis will take place at EOS. 
– Section 2.1 (Study design) 
• 
Minor wording updates  
– Section 4.2 (Usage of analysis sets) 
– Section 5.1 (Study dates) 
 
Added a rule in Section 5.1 (Study dates) to handle missing EOT dates in the 
eCRF due to the start of the conflict in Ukraine. 
27-Sep-2022 
5.0 
• 
Update of the ‘treatment-emergent’ period (applicable for AEs, 
abnormalities, findings, etc.) following evidence for longer half-life for 
cenerimod (longer than the known half-life until then). 
• 
Section 6.4.1 (Study treatment discontinuation): wording update which 
should have been corrected in previous version (following protocol v4.0 
Planned end of TP2 will be 12 months after initial randomization, for all 
subjects). 
• 
Section 6.6 (Protocol Deviations): Added a table of PDs related to the 
conflict in Ukraine + flag in listing. 
• 
Section 8.6.3 (Holter ECG): Remove number of episodes from the 
summary table of findings, as it is not relevant for summary and makes 
the table uninterpretable.  
• 
Section 12.2 (Definition of AESI): Updated as per upgraded MedDRA 
version (v25.0). 
 

Prot_001.pdf: 
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: 
27 May 2020 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADDENDUM 2 TO PROTOCOL 
ID-064A202 
 
Exceptional measures to ensure subject safety and counteract 
potential trial conduct disruption due to the COVID-19 
pandemic 
 
 
 
Document Number: D-20.100 
27 May 2020 
 
 
 
 
 
Property of Idorsia Pharmaceuticals Ltd 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Idorsia Pharmaceuticals Ltd 
 
 
 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND ACRONYMS ............................................................. 3 
UPDATE TO THE ADDENDUM ...................................................................................... 4 
1 
INTRODUCTION ........................................................................................................ 5 
2 
RECOMMENDATIONS AND INSTRUCTIONS ...................................................... 5 
2.1 
Conduct of on-site visits ................................................................................ 5 
2.2 
Conduct of home visits or remote visits ........................................................ 6 
2.2.1 
Obtaining subject’s consent to provide his/her name and home 
address to a third party ....................................................................... 9 
2.3 
Subjects infected with SARS-CoV-2 ............................................................. 9 
2.4 
Efficacy assessments .................................................................................... 10 
2.4.1 
Study assessments related to the primary and secondary 
endpoints. ......................................................................................... 10 
2.5 
Reporting of protocol deviations related to COVID-19 pandemic .............. 11 
2.6 
Monitoring ................................................................................................... 11 
3 
REFERENCES ........................................................................................................... 11 


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LIST OF ABBREVIATIONS AND ACRONYMS 
 
AE 
Adverse event 
BILAG 
British Isles Lupus Assessment Group 
COVID-19 
Coronavirus disease 2019 
CRA 
Clinical research associate 
DDI 
Drug-drug interaction 
eCRF 
Electronic case report form 
FDA 
(US) Food and Drug Administration 
GCP 
Good Clinical Practice 
HMA 
(EU) Heads of Medicines Agencies 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
PD 
Protocol deviation 
PGA 
Physician’s Global Assessment 
PRO 
Patient Reported Outcome 
QoL 
Quality of Life 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SLE 
Systemic lupus erythematosus 
SLEDAI-2K 
Systemic Lupus Erythematosus Disease Activity Index-2000 
SRI 
Systemic Lupus Erythematosus Responder Index 
WBC 
White blood cell 
WHO 
World Health Organization 


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UPDATE TO THE ADDENDUM 
This amendment applies to the addendum, dated 8 April 2020, to the protocol ID-064A202, 
issued to implement “Exceptional measures to ensure subject safety and counteract 
potential trial conduct disruption due to the COVID-19 pandemic”. 
The resulting document is: Addendum 2 to protocol ID-064A202, dated 27 May 2020. 
Rationale 
The main reason for the changes to the addendum is to implement the IDMC 
recommendations sent to Idorsia on 18 May 2020, consisting of screening all new patients 
for SARS-CoV-2 prior to entry in study ID-064A202. Hence, subjects who test positive 
for SARS-CoV-2 should be considered as screen failures and discontinued from the study. 
Changes to the Addendum 
The section “Subjects infected with SARS-CoV-2”of the addendum is updated to include 
the following new instructions: 
2.3   Subjects infected with SARS-CoV-2 
• During screening, subjects must be tested for SARS-CoV-2 unless the subject has 
tested negative within a week prior to screening. Subjects will be screen failed and 
discontinued from screening if she/he tests positive for SARS-CoV-2. 
• It is the responsibility of the investigator/delegate to obtain the subject’s consent using 
a specific ICF if the testing for SARS-CoV-2 is performed as part of the trial-mandated 
procedures during screening. The SARS-CoV-2 test can be performed at the site or in 
a local laboratory using a prescription provided by the investigator. 
• After subject randomization, testing for SARS-CoV-2 should follow local guidance. 
Two versions of the updated addendum will be provided: 
1) a clean version and 2) a comparison document showing deletions and insertions in 
comparison to the previous addendum version. 


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1 
INTRODUCTION 
As a consequence of the pandemic of respiratory infectious disease (COVID-19; declared 
a pandemic by the WHO on 11 March 2020) caused by a novel coronavirus 
(SARS-CoV-2), Idorsia provided instructions and guidance in communication letters sent 
to ID-064A202 (CARE) study investigators on 19 March 2020 and 31 March 2020. These 
measures and instructions are in line with health authority guidelines (FDA, HMA and 
individual national health authorities) released in March 2020 on how to address the 
challenges caused by the pandemic itself. 
These measures, which also constitute PDs, are introduced to preserve subject safety, trial 
integrity and interpretability, as well as compliance with regulatory requirements. 
Idorsia tracks these deviations from the protocol as “PDs related to COVID-19”. This will 
allow, at the end of the trial, a reconstruction of the impact that such deviations had on the 
trial integrity and interpretability. This requires that the instructions and measures included 
in this addendum continue to be collected as PDs as per original protocol definition, and 
will be identified as due to COVID-19 even after the implementation of this addendum. 
The objective of this addendum is to document those measures and instructions in the 
protocol. The addendum applies to those sites affected by the COVID-19 outbreak and 
is limited to the time during which such sites are affected. 
This addendum is therefore limited in scope and in duration. 
The recommendations and instructions that have been provided to the investigators are 
described below with reference to the protocol sections affected: 
2 
RECOMMENDATIONS AND INSTRUCTIONS 
2.1 Conduct of on-site visits 
For subjects who are continuing to participate in the ID-064A202 (CARE) study, it is 
important that the protocol visit schedule is adhered to in order to ensure subject safety and 
trial integrity during the COVID-19 pandemic outbreak. 
The preferred option is to maintain on-site visits, provided that the subject is allowed and 
can travel to the site [see protocol section 7.1]. To ensure safety of the subject on his/her 
way to the site, the site staff will remind the subject to adhere to local laws and 
recommendations (e.g., not using public transportation). Alternatively, subjects can use 
taxis or private cars, the cost of which will be reimbursed by Idorsia. 
On-site visits should be performed according to the protocol [see protocol section 7.2, 
table 4]. To facilitate on-site visits, scheduled visits might be brought forward or visit 
windows extended (e.g., ±7 days from scheduled visit, or even longer if the subject has 
enough study treatment). The reason for this delayed scheduled visit must be documented 
in the subject’s medical chart. 


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If the subject can travel to the investigational site for his/her study site visit, the investigator 
should: 
• 
Ensure the subject’s safety on his/her way to the site in compliance with local/country 
instructions (e.g., not using public transportation). 
• 
Perform the on-site visit assessments according to the protocol [protocol section 7.1 
and 7.2]. 
• 
If blood and urine samples cannot be collected by the courier for shipment to the 
central laboratory, the analysis can be performed by the site’s local laboratory*. 
*If done by site local laboratory, the investigator should make sure that the site personnel has an “unblinded” staff 
member who is not involved in the conduct of ID-064A202 (CARE) study and who can check for any WBC (including 
differentials) and lymphocyte counts and redact these parameters from the laboratory report. If this option is not available, 
the site local laboratory analysis should still be performed. 
Note that new subjects may be considered for screening only after thorough 
evaluation of the benefit-risk for the subject participation in the context of the 
COVID-19 pandemic. Screening visit should only take place if a complete on-site visit 
can be organized. If this is not possible, the preferred option is to reschedule the 
screening visit to a time when all components of the site visit can be performed in full 
compliance with the protocol. 
2.2 Conduct of home visits or remote visits 
If the subject cannot, is not allowed, or is not willing to travel to the investigational site 
due to the COVID-19 pandemic, remote visits (telephone call or video call) may be 
conducted as described below. 
• 
If possible, it is preferable to have the remote visit performed as a video call instead 
of a telephone call. 
• 
The IEC or IRB must be notified in advance of remote visits if this is a local 
requirement. 
• 
During the remote visit, the investigator will interview the subject to: 
− Check for the occurrence of any new AE or worsening of existing ones. When 
asking for AEs, the same process as that used for site visits is to be followed [see 
protocol section 9.3], i.e., use open-ended questions such as “Have you had any 
new symptoms or experienced any worsening of your disease since the last study 
visit?”. 
o If the subject spontaneously reports symptoms of worsening of disease activity 
or symptoms that could be related to the safety areas of special interest [refer 
to protocol appendix 5] follow the instructions below, as relevant: 


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▪ Symptoms potentially related to SLE flare: a visit by site staff / or home 
nurse to the subject’s home should take place if allowed or the subject 
should be asked to come to the site if this is allowed in emergency cases. 
▪ Bradycardia (e.g., dizziness, vertigo, syncope): treatment medication 
interruption and restart should be verified, and the subject should be asked 
to check their pulse. If severe bradycardia is suspected, a visit by site staff / 
home nurse to the subject’s home should take place if allowed. 
▪ Hypertension/hypotension (e.g., severe headache, fatigue, confusion, vision 
problems, chest pain, difficulty breathing, irregular heartbeat, dizziness or 
lightheadedness, fainting): the subject should be asked about availability of 
a home-based automated blood pressure instrument for self-assessment or 
such a device should be delivered to the subject’s home. 
▪ Dyspnea: if severe dyspnea is observed, the subject should be asked about 
other potential symptoms that could be linked to COVID-19 (e.g., fever) to 
act accordingly. If this is not possible a home nurse service should be 
organized to perform spirometry at the subject’s home. 
▪ Visual disturbances: if reduced or blurred vision is reported, the investigator 
should consider whether waiting for site to return to normal site operation 
is acceptable. The investigator may consult the study ophthalmologist for 
the most appropriate action to be taken. 
▪ Symptoms that may indicate hepatotoxicity: (e.g., unusual lethargy or 
fatigue, nausea, vomiting, upper right quadrant pain or tenderness, jaundice, 
anorexia, dark urine, fever, rash, itching) blood sampling at home is to be 
conducted. 
− Check for changes in any ongoing medication or start of new medication(s) 
− Check if the subject has enough study medication to ensure no study medication 
holiday. 
− Make sure that subjects who are women of childbearing potential have enough 
home pregnancy kits (send them along with study medications to subject’s home if 
necessary) and remind them to perform the test monthly. 
− Ask the subject to perform the blood and urine sampling in a local laboratory for 
analysis using a prescription provided by the investigator**. 
** If possible, in this situation laboratory results and reports should be sent to an “unblinded” site staff member who is 
not involved in the conduct of (ID-064A202) CARE study and who can check for any WBC (including differential) and 
lymphocyte count and redact these parameters from local laboratory report. If this option is not available, site local 
laboratory analysis results and reports should still be sent to the site. 
• 
If closer monitoring of any of the above symptoms is not possible within the 
foreseeable future, depending on the severity of the symptoms observed and on the 


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investigator’s assessment of the benefit-risk for the subject’s participation in the trial, 
the investigator may consider discontinuing the study medication. 
• 
A subject who permanently discontinues study treatment is not considered as having 
withdrawn from the study, provided that the subject’s consent to participate in the 
study has not been withdrawn. Hence, the subject remains in the study, and study 
protocol assessments should continue to be performed until the end of the study 
following the planned scheduled of assessments. This will reduce the amount of 
missing data and should ensure data accuracy and scientific relevance of the study 
results. 
• 
The site staff should organize the delivery of study treatment and pregnancy tests (if 
applicable) to the subject’s home using either the institutional internal process or a 
home nurse, if allowed by local laws and regulation or by using the express courier 
service contracted by the sponsor. Shipment to subject’s home can only occur after 
obtaining subject’s consent [see Section 2.2.1]. 
• 
For those subjects for whom study medication is provided at home due to the inability 
to perform on-site visits, a solution must be identified to perform, at a minimum, the 
WBC and lymphocyte count assessments (preferably the entire chemistry and 
hematology panel) as close as possible to the original protocol schedule, preferably 
using the study central laboratory, or a local laboratory if necessary. 
• 
During the remote visit, the investigator also ensures that the subject understands that 
the new study medication kit is to be used instead of the one used previously, even if 
there is remaining medication. The unused medication will have to be brought back to 
the center at the next safe opportunity. 
• 
The remote visit must be entered as an Unscheduled visit in the eCRF and documented 
in detail (day, time and conversation) in the subject’s medical charts. 
• 
The remote visit is not meant to replace an on-site visit. If in the foreseeable future 
on-site visits can be resumed, planned on-site visits can be re-scheduled as long as the 
subject has enough study treatment and SLE background therapy. As soon as possible 
following the remote visit, the corresponding on-site visit must be performed. If the 
corresponding on-site visit can only be scheduled relatively close to the next scheduled 
study visit (e.g. within 1 week of the next study visit), this study visit will be skipped 
to the next scheduled on-site visit. 
Idorsia is providing the option to have home nurses visiting the subject at home (also 
called “flying nurses”) 
In addition to the remote visit, Idorsia will support the sites to organize home nurses 
to visit the subjects at home if allowed. Home nurse visits can be performed in order to 
keep close contact with the subjects at least as frequently as required by the protocol 
mandated on-site visits: 


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The home nurses will: 
• 
Handle the shipping logistics of the central laboratory kits for blood and urine 
sampling. 
• 
Handle the delivery of the study medication to subject’s home. 
• 
Assess blood pressure measurement at subject’s home. 
• 
Make sure that subjects who are women of childbearing potential have enough home 
pregnancy kits (send them or bring them along with study medications to subject’s 
home if necessary) and remind them to perform the test monthly. 
• 
Perform the blood and urine sampling and will organize the shipping logistics to the 
central laboratory. If blood and urine samples cannot be collected by the courier for 
shipment to the central laboratory, the analysis will be performed by the site local 
laboratory**. 
• 
Provide PRO and QoL questionnaires to the subject at home. 
2.2.1 Obtaining subject’s consent to provide his/her name and home address to a 
third party 
In line with the protocol section 12.3, it is the responsibility of the investigator/delegate to 
obtain the subject`s consent to provide his/her name and home address to any third party 
(e.g., courier service, home nurse) responsible for delivering study treatment (and 
pregnancy tests if applicable). In the event of verbal consent, the date and time verbal 
consent was obtained must be documented in the subject’s medical chart. If according to 
the local regulation the subject’s consent must be obtained in writing, investigator must act 
accordingly (e.g., request subject’s consent by mail) and document it in the subject medical 
charts. 
2.3 Subjects infected with SARS-CoV-2 
• During screening, subjects must be tested for SARS-CoV-2 unless the subject has 
tested negative within a week prior to screening. Subjects will be screen failed and 
discontinued from screening if she/he tests positive for SARS-CoV-2. 
• It is the responsibility of the investigator/delegate to obtain the subject’s consent using 
a specific ICF if the testing for SARS-CoV-2 is performed as part of the trial-mandated 
procedures during screening. The SARS-CoV-2 test can be performed at the site or in 
a local laboratory using a prescription provided by the investigator. 
• After subject randomization, testing for SARS-CoV-2 should follow local guidance. 
In addition to the provisions described in Sections 2.1 and 2.2, should a subject become 
infected with SARS-CoV-2 / contract COVID-19: 
• Information about COVID-19 positivity to SARS-CoV-2, and its corresponding 
diagnosis (symptoms or pneumonia related to COVID-19) as well as administered 


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medications will be collected on the AE and Concomitant Medication pages of the 
eCRF (refer to protocol sections 9 and 5.2, respectively). 
• If a subject is confirmed to be infected with SARS-CoV-2, the precautionary principle 
suggests that study treatment should be stopped. No unblinding is deemed necessary. 
In the event that the subject is on active therapy, the effect of cenerimod will disappear 
gradually. 
• Given the long half-life of cenerimod (12−22 days) [see section 1.4.2 of the 
Cenerimod IB], Idorsia has evaluated the potential DDI with the current, available, 
most frequently used medications for COVID-19 (e.g., remdesivir, lopinavir/ritonavir, 
IFN beta1b, corticosteroids, hydroxychloroquine). Based on our current knowledge, 
cenerimod and the anti-COVID-19 drugs are not expected to mutually affect their PK 
properties based on an effect on metabolizing enzymes or transporters, therefore 
subjects can be treated as per current practice. Refer to the IB for full description of 
potential DDIs with cenerimod [Cenerimod IB]. 
• When shipping samples from subjects who tested positive or had high potential to test 
positive for SARS-CoV-2 virus infection to the study central laboratory, the central 
laboratory manual and the most updated COVID-19 regional guidance provided by 
 should be followed. 
2.4 Efficacy assessments 
2.4.1 Study assessments related to the primary and secondary endpoints. 
It is important to ensure that efficacy assessments, especially assessments related to 
primary (SLEDAI-2K) and secondary endpoints (i.e., BILAG and SRI-4) are performed as 
per protocol. They should ideally not be performed later than one month after the protocol 
planned schedule of assessment [see protocol section 7]. 
If the investigator is not able to arrange on-site visits to perform the planned efficacy 
evaluations, the following should be implemented: 
• Organize the remote visit as described above, at approximately the time of the planned 
visit assessment. 
• During the remote visit, the investigator should collect the SLEDAI-2K components 
even if not all assessments are possible [protocol section 7.2.6]. Record the outcome of 
the SLEDAI-2K assessment in the eCRF and report a PD related to COVID-19 in the 
event of missing values. If this is not possible, the investigator should contact the CRA 
or sponsor study team. 
• The same procedures should be followed to perform the assessments (e.g., BILAG, 
PGA, SLE Flare Index) related to the secondary efficacy endpoints. These 
measurements should be collected at that time as well [protocol section 7.2.6]. 


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Very important note: as soon as the study site can resume activity, ask the subject to come 
to the site at the closest scheduled visit, to perform a full SLEDAI-2K assessment and all 
other assessments (such as BILAG, PGA, ...) which will be recorded in the eCRF. 
2.5 Reporting of protocol deviations related to COVID-19 pandemic 
PDs due to COVID-19 are expected to occur during the pandemic and fall under the ICH 
GCP 4.5.4 “The investigator may implement a deviation from, or change of, the protocol 
to eliminate an immediate hazard(s) to trial subjects”. Any PD occurring due to COVID-19 
must be documented according to ICH GCP 4.5.3 and clearly recorded as related to 
COVID-19. All PDs will be reported to the sponsor, IEC/IRB and regulatory authorities 
according to local requirements. 
2.6 Monitoring 
If on-site monitoring cannot be performed by the CRA as described in protocol section 12.8 
and if acceptable under local law with the IEC/IRB, the CRA will conduct remote 
monitoring and remote source data verification, provided that the subject´s confidentiality 
is maintained throughout the process [as per protocol section 11.2] and all local approvals 
to do so are in place. If remote monitoring or remote source data verification are not 
allowed, alternatives as applicable according to local regulations might be agreed with the 
investigator to ensure data integrity. 
3 
REFERENCES 
[Cenerimod IB] Investigator’s Brochure for cenerimod (ACT-334441), version 10. Idorsia 
Pharmaceuticals, Ltd, January 2020. 

Prot_000.pdf: 
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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4 February 2022, page 2/186 
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Doc No D-22.031 
 
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 
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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 
 
 
 
 
 
 
 
 
 
 
 
 


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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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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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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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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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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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Systemic lupus erythematosus 
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Doc No D-22.031 
 
 
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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Systemic lupus erythematosus 
Protocol ID-064A202 
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Doc No D-22.031 
 
 
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 
Systemic lupus erythematosus 
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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Doc No D-22.031 
 
 
(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. 
 


Cenerimod / ACT-334441 
Systemic lupus erythematosus 
Protocol ID-064A202 
Final Version 5 
4 February 2022, page 109/186 
Confidential 
EudraCT 2018-001808-11 
Doc No D-22.031 
 
 
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. 


Cenerimod / ACT-334441 
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Doc No D-22.031 
 
 
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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[KDIGO 2012] Kidney Disease Improving Global Outcomes (KDIGO) 2012 Clinical 
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Semin Arthritis Rheum. 2010 Feb;39(4):257–68. 


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[Pons-Estel 2017] Pons-Estel GJ, Ugarte-Gil MF, Alarcón GS. Epidemiology of systemic 
lupus erythematosus. Expert Rev Clin Immunol. 2017 Aug;13(8):799–814.  
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AS, et al. ACC/AHH clinical competence statement on echocardiography: a report 
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Clinical Competence (Committee on Echocardiography). J Am Coll Cardiol 
2003,41:687–708. 
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Erratum in BMJ 1998 Nov 28;317(7171);1491. 
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Lippincott Williams and Wilkins, Philadelphia 2002. 
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SB, et al. Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis. N 
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balance of Th17 and Th1 cells in systemic lupus erythematosus. Arthritis Res Ther. 
2010;12(2):R53. 


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[Strand 2014] Strand V, Levy RA, Cervera R, Petri MA, Birch H, Freimuth WW, et al. 
Improvements in health-related quality of life with belimumab, a B-lymphocyte 
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Assessment of Global Fatigue in Multiple Sclerosis: A Spanish Language Version of 
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(Hoboken). 2011 Nov; 63 Suppl 11:S413–9. 


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[Yurkovich 2014] Yurkovich M, Vostretsova K, Chen W, Aviña-Zubieta JA. Overall and 
cause-specific mortality in patients with systemic lupus erythematosus: a 
meta-analysis of observational studies. Arthritis Care Res (Hoboken). 2014 Apr; 
66(4):608–16. 
 


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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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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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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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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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Appendix 11 BILAG-2004 INDEX 


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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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Appendix 16 Patient Global Impression of Severity – Fatigue 


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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.