Clinical trial NCT02472795
Conditions: Systemic Lupus Erythematosus
Keywords: Systemic lupus erythematosus
Sponsor: Idorsia Pharmaceuticals Ltd.
Start date: 2015-06-01; Completion date: 2017-02-28
Enrollment: 105 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
International trial to evaluate the biological activity and safety of cenerimod (ACT-334441) in systemic lupus erythematosus (SLE) patients.

Detailed description:
This multicentre, double-blind, placebo-controlled study will have a staggered approach (Part A and B).

In part A, eligible patients will be randomly assigned (1:1:1:1) to once daily oral administration of cenerimod (0.5, 1, 2 mg) or placebo. After all patients have completed 4 weeks of treatment during part A, an Independent Data Monitoring Committee will review non-blinded data in an interim analysis to evaluate the safety profile of cenerimod and recommend whether the study could proceed to part B.

In part B, additional patients will be randomized (3:1) to once daily oral administration of cenerimod 4 mg or placebo.

All participants will receive study medication for 12 weeks.

Arms: arm 1: Participants will receive cenerimod 0.5 mg capsules orally once daily for 12 weeks. arm 2: Participants will receive cenerimod 1 mg capsules orally once daily for 12 weeks. arm 3: Participants will receive cenerimod 2 mg capsules orally once daily for 12 weeks. arm 4: Participants will received cenerimod 4 mg capsules orally once daily for 12 weeks. This treatment arm will start after all patients in Part A have completed 4 weeks of placebo, 0.5 mg, 1 mg and 2 mg cenerimod treatment. arm 5: Capsules of matching placebo taken orally once daily for 12 weeks.
Interventions: intervention 1: Matching placebo intervention 2: Cenerimod
Intervention descriptions: intervention 1: One capsule of cenerimod to be taken once daily, irrespective of food intake. The capsule is to be swallowed whole. The capsule should be taken each day at approximately the same time (preferably each morning). intervention 2: One capsule of cenerimod to be taken once daily, irrespective of food intake. The capsule is to be swallowed whole. The capsule should be taken each day at approximately the same time (preferably each morning).

Protocol documents:
Prot_000.pdf: 
Protocol AC-064A201 
A multicenter, randomized, double-blind, placebo-controlled, dose-response study to investigate the 
biological activity, safety, tolerability, and pharmacokinetics of ACT-334441 in subjects with systemic 
lupus erythematosus 
 
ClinicalTrials.gov Identifier: NCT02472795 
 
 
This study was sponsored by Actelion Pharmaceuticals.  
Study sponsorship was transferred to Idorsia Pharmaceuticals in July 2018. 
 


 
 
TPL-000052_v10 
 
 
ACT-334441 
Systemic Lupus Erythematosus 
Protocol AC-064A201 
A multicenter, randomized, double-blind, placebo-controlled, dose-response study 
to investigate the biological activity, safety, tolerability, and pharmacokinetics of 
ACT-334441 in subjects with systemic lupus erythematosus 
 
 
Study Phase: 
1/2 
EudraCT Number: 
2014-002984-14 
Status and version: 
Final Version 2  
Date: 
25 March 2015 
Actelion 
document 
number 
(Doc No.): 
D-15.156 
 
Confidentiality statement 
The information contained in this document, especially unpublished data, is the property of the sponsor of 
this study, Actelion Pharmaceuticals Ltd. It is therefore provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an Ethics Committee or Institutional 
Review Board. It is understood that this information will not be disclosed to others without written 
authorization from Actelion Pharmaceuticals Ltd, except to the extent necessary to obtain informed consent 
from those persons to whom the study treatment may be administered. 








ACT-334441 
Systemic lupus erythematosus 
Protocol AC-064A201 
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INVESTIGATOR SIGNATURE PAGE 
Treatment name / number 
ACT-334441 
Indication 
Systemic Lupus Erythematosus 
Protocol number, study title  
AC-064A201, A multicenter, randomized, double-blind, placebo-controlled, dose-
response study to investigate the biological activity, safety, tolerability, and 
pharmacokinetics of ACT-334441 in subjects with systemic lupus erythematosus. 
I agree to the terms and conditions relating to this study as defined in this protocol, the 
electronic Case Report Form (eCRF), 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 
wellbeing of the subjects). 
I agree to conduct this study in accordance with the Declaration of Helsinki principles, 
International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) 
guidelines, and applicable regulations and laws. I will obtain approval by an Institutional 
Review Board or Independent Ethics Committee (IRB/IEC) prior to study start and 
signed informed consent from all subjects included in this study. If an amendment to the 
protocol is necessary, I will obtain approval by an IRB/IEC and ensure approval by 
regulatory authorities (if applicable) have been obtained before the implementation of 
changes described in the amendment. I will allow direct access to source documents and 
study facilities to sponsor representative(s), particularly monitor(s) and auditor(s), and 
agree to inspection by regulatory authorities or IRB/IEC representative. I will ensure that 
the study treatment(s) supplied by the sponsor are being used only as described in this 
protocol. I confirm herewith that the sponsor is allowed to enter and utilize my 
professional contact details and function in an electronic database for internal purposes 
and for submission to Health Authorities worldwide. 
 
Country 
Site 
number 
Town 
Date 
 
Signature 
Site Principal 
Investigator 
 
 
 
 
 
 


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Systemic lupus erythematosus 
Protocol AC-064A201 
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TABLE OF CONTENTS 
SPONSOR CONTACT DETAILS ......................................................................................2 
ACTELION CONTRIBUTORS TO THE PROTOCOL .....................................................2 
MAIN CONTRACT RESEARCH ORGANIZATIONS INFORMATION ........................3 
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................14 
PROTOCOL SYNOPSIS AC-064A201 ............................................................................18 
1 
BACKGROUND .........................................................................................................38 
1.1 
Systemic Lupus Erythematosus ....................................................................38 
1.1.1 
Clinical manifestations and diagnosis ...............................................38 
1.1.2 
Epidemiology ....................................................................................39 
1.1.3 
Current treatments of SLE ................................................................39 
1.1.3.1 
Nonsteroidal anti-inflammatory drugs ....................................40 
1.1.3.2 
Antimalarial drugs ...................................................................40 
1.1.3.3 
Glucocorticoids .......................................................................40 
1.1.3.4 
Immunosuppressives ...............................................................41 
1.1.3.5 
Biologics ..................................................................................41 
1.1.4 
Unmet needs in SLE .........................................................................42 
1.2 
Sphingosine-1-phosphate receptors ..............................................................43 
1.3 
ACT-334441 .................................................................................................43 
1.3.1 
Nonclinical data ................................................................................43 
1.3.2 
Clinical studies ..................................................................................44 
1.3.2.1 
Clinical pharmacokinetics .......................................................45 
1.3.2.2 
Pharmacodynamics in humans ................................................45 
1.3.2.3 
Safety and tolerability .............................................................46 
1.4 
Purpose and rationale of the study ................................................................47 
2 
STUDY OBJECTIVES ...............................................................................................48 
2.1 
Main objectives .............................................................................................48 
2.2 
Exploratory Objectives .................................................................................48 
3 
OVERALL STUDY DESIGN AND PLAN ...............................................................48 
3.1 
Study design .................................................................................................48 
3.1.1 
Study periods ....................................................................................49 


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3.1.1.1 
Screening period ......................................................................49 
3.1.1.2 
Treatment period .....................................................................50 
3.1.1.3 
Follow-up period .....................................................................50 
3.1.2 
Study duration ...................................................................................50 
3.2 
Study design rationale ..................................................................................50 
3.3 
Site personnel and their roles ........................................................................52 
3.3.1 
Principal investigator ........................................................................53 
3.3.2 
Treating physician .............................................................................53 
3.3.3 
Cardiac safety assessor .....................................................................53 
3.3.4 
Echocardiography specialist .............................................................54 
3.3.5 
Clinical coordinator / study nurse .....................................................54 
3.3.6 
Ophthalmologist ................................................................................55 
3.3.7 
Pulmonary function laboratory technician or expert ........................55 
3.4 
Study Committees .........................................................................................55 
3.4.1 
Independent Data Monitoring Committee ........................................55 
3.4.2 
Ophthalmology Safety Board ...........................................................56 
4 
SUBJECT POPULATION ..........................................................................................56 
4.1 
Subject population description .....................................................................56 
4.2 
Rationale for the selection of the study population ......................................57 
4.3 
Inclusion criteria ...........................................................................................57 
4.4 
Exclusion criteria ..........................................................................................58 
4.5 
Criteria for women of childbearing potential ...............................................61 
4.5.1 
Definition of childbearing potential ..................................................61 
4.5.2 
Acceptable methods of contraception ...............................................61 
4.6 
Medical history .............................................................................................62 
4.6.1 
General medical history ....................................................................62 
4.6.2 
SLE-relevant disease history ............................................................63 
5 
TREATMENTS ..........................................................................................................65 
5.1 
Study treatment .............................................................................................65 
5.1.1 
Investigational treatment: description and rationale .........................65 
5.1.2 
Study treatment administration .........................................................65 
5.1.3 
Treatment assignment .......................................................................65 
5.1.4 
Blinding ............................................................................................66 
5.1.4.1 
Study drug material related blinding .......................................66 
5.1.4.2 
Functional blinding ..................................................................66 
5.1.5 
Unblinding ........................................................................................68 
5.1.5.1 
Unblinding for final analyses ..................................................68 
5.1.5.2 
Unblinding for interim analyses ..............................................68 


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5.1.5.3 
Unblinding before final analyses .............................................68 
5.1.5.4 
Unblinding for suspected unexpected serious adverse 
reactions ...................................................................................68 
5.1.5.5 
Emergency procedure for unblinding ......................................68 
5.1.6 
Study treatment supply .....................................................................69 
5.1.6.1 
Study treatment packaging and labeling .................................69 
5.1.6.2 
Study treatment distribution and storage .................................69 
5.1.6.3 
Study treatment dispensing .....................................................69 
5.1.6.4 
Study treatment return and destruction ...................................69 
5.1.7 
Study treatment accountability and compliance with study 
treatment ...........................................................................................70 
5.1.7.1 
Study treatment accountability ................................................70 
5.1.7.2 
Study treatment compliance ....................................................70 
5.1.8 
Study treatment interruptions ............................................................71 
5.1.8.1 
Between Day 1 and Day 14 .....................................................71 
5.1.8.2 
After Day 14 ............................................................................72 
5.1.9 
Premature discontinuation of study treatment ..................................72 
5.1.10 
Management of clinical events and study-specific criteria for 
interruption / premature discontinuation of study treatment ............73 
5.1.10.1 
Cardiovascular .........................................................................73 
5.1.10.2 
Immune system ........................................................................74 
5.1.10.3 
Respiratory system ..................................................................75 
5.1.10.4 
Pregnancy ................................................................................76 
5.1.10.5 
Liver abnormalities ..................................................................76 
5.1.10.6 
Ocular abnormalities ...............................................................77 
5.1.10.7 
Infections .................................................................................77 
5.1.10.8 
Premature treatment discontinuation after study 
treatment interruption, background therapy changes, 
administration of forbidden therapies, or study drug mis-
dispensing ................................................................................78 
5.2 
Previous and concomitant therapy ................................................................79 
5.2.1 
Background SLE therapy ..................................................................79 
5.2.1.1 
Definition of background SLE therapy ...................................79 
5.2.1.2 
Reporting of background SLE therapy in eCRF .....................80 
5.2.2 
Previous SLE therapies .....................................................................80 
5.2.2.1 
Definition of previous SLE therapies ......................................80 
5.2.2.2 
Reporting of previous SLE therapies in eCRF ........................80 
5.2.3 
Study-concomitant therapy ...............................................................80 
5.2.3.1 
Definition of study-concomitant therapy ................................80 
5.2.3.2 
Reporting of study-concomitant therapy in eCRF ..................81 


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5.2.4 
Allowed concomitant therapy ...........................................................81 
5.2.5 
Forbidden concomitant therapy ........................................................82 
6 
STUDY ENDPOINTS ................................................................................................82 
6.1 
Pharmacodynamic endpoints ........................................................................82 
6.2 
Safety endpoints ...........................................................................................83 
6.3 
Pharmacokinetic endpoints ...........................................................................83 
6.4 
Exploratory disease activity endpoints .........................................................84 
6.5 
Quality of life endpoints ...............................................................................84 
6.6 
Exploratory biomarker endpoints .................................................................84 
7 
STUDY ASSESSMENTS ...........................................................................................84 
7.1 
Screening/baseline assessments ....................................................................85 
7.1.1 
Informed consent (Screening visit) ...................................................85 
7.1.2 
Baseline demographics and disease characteristics ..........................85 
7.1.3 
Previous and concomitant therapies .................................................86 
7.2 
Safety assessments ........................................................................................86 
7.2.1 
Laboratory assessments ....................................................................86 
7.2.1.1 
Type of laboratory ...................................................................86 
7.2.1.2 
Laboratory tests .......................................................................87 
7.2.2 
12-lead ECG .....................................................................................89 
7.2.3 
ECG Holter .......................................................................................91 
7.2.4 
Blood pressure ..................................................................................92 
7.2.5 
Echocardiography .............................................................................92 
7.2.6 
Spirometry ........................................................................................93 
7.2.7 
Ophthalmological examination .........................................................94 
7.2.8 
Optical coherence tomography .........................................................94 
7.2.9 
Chest X-ray .......................................................................................95 
7.2.10 
Test for tuberculosis ..........................................................................95 
7.2.11 
Weight and height .............................................................................96 
7.2.12 
Physical examination ........................................................................96 
7.3 
Pharmacodynamic and pharmacokinetic assessments ..................................96 
7.3.1 
Pharmacodynamic assessments ........................................................96 
7.3.2 
Pharmacokinetic assessments ...........................................................96 
7.4 
Disease activity assessments ........................................................................97 
7.4.1 
Systemic Lupus Erythematosus Activity Index-2000 ......................97 
7.4.2 
Physician’s Global Assessment of disease .......................................97 
7.5 
Quality of Life assessments: 36-Item Short Form Health Survey v2 ...........98 
7.6 
Biomarker assessments .................................................................................98 
7.7 
Total blood volume .......................................................................................99 


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8 
SCHEDULE OF VISITS ..........................................................................................100 
8.1 
Screening period .........................................................................................101 
8.1.1 
Visit 1 (Screening) ..........................................................................101 
8.2 
Treatment period .........................................................................................103 
8.2.1 
Visit 2 – Randomization Day 1.......................................................103 
8.2.1.1 
Visit 2 – Day 1 – pre-dose assessment ..................................103 
8.2.1.2 
Visit 2 – Day 1 – Randomization and post-dose 
assessment .............................................................................104 
8.2.2 
Visit 3 – Week 2 .............................................................................104 
8.2.3 
Visit 4 – Week 4 and Visit 5 – Week 8 ..........................................105 
8.2.4 
Visit 6 – EOT ..................................................................................106 
8.3 
Follow-up period ........................................................................................107 
8.3.1 
Visit 7 – EOS ..................................................................................107 
8.3.2 
Visit 8 and Visit 9– follow-up (telephone contact visits) ...............107 
8.4 
Unscheduled visits (U1, U2…) ..................................................................108 
8.5 
Additional visits for re-initiation of study treatment ..................................109 
9 
STUDY COMPLETION AND POST-STUDY TREATMENT / MEDICAL 
CARE ........................................................................................................................109 
9.1 
Study completion ........................................................................................109 
9.2 
Premature withdrawal from study ..............................................................110 
9.3 
Premature termination or suspension of the study ......................................110 
9.4 
Medical care of subjects after study completion / withdrawal from 
study ............................................................................................................113 
10 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS .........................113 
10.1 
Adverse events ............................................................................................113 
10.1.1 
Definitions of adverse events ..........................................................113 
10.1.2 
Intensity of adverse events ..............................................................114 
10.1.3 
Relationship to study treatment ......................................................114 
10.1.4 
Adverse events associated to study design or protocol-
mandated procedures ......................................................................115 
10.1.5 
Reporting of adverse events ............................................................115 
10.1.6 
Follow-up of adverse events ...........................................................115 
10.1.7 
Adverse events of special interest ...................................................115 
10.2 
Serious adverse events ................................................................................115 
10.2.1 
Definitions of serious adverse events .............................................115 
10.2.1.1 
Serious adverse events ...........................................................115 


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10.2.1.2 
Serious adverse events associated with the study design 
or protocol-mandated procedures ..........................................116 
10.2.2 
Reporting of serious adverse events ...............................................116 
10.2.3 
Follow-up of serious adverse events ...............................................116 
10.2.4 
After the 16-week follow-up period ...............................................116 
10.2.5 
Reporting procedures ......................................................................116 
10.3 
Pregnancy ...................................................................................................117 
10.3.1 
Teratogenicity .................................................................................117 
10.3.2 
Reporting of pregnancy ..................................................................117 
10.3.3 
Follow-up of pregnancy ..................................................................118 
10.4 
Study safety monitoring ..............................................................................118 
11 STATISTICAL METHODS .....................................................................................118 
11.1 
General considerations ...............................................................................118 
11.2 
Analysis Sets ...............................................................................................119 
11.2.1 
Screened Analysis Set .....................................................................119 
11.2.2 
PD Analysis Set ..............................................................................119 
11.2.3 
Full Analysis Set .............................................................................119 
11.2.4 
Per-Protocol Set ..............................................................................120 
11.2.5 
Safety Analysis Set .........................................................................120 
11.2.6 
PK Analysis Set ..............................................................................120 
11.2.7 
Other analysis sets ..........................................................................120 
11.2.8 
Usage of the analysis sets ...............................................................120 
11.3 
Variables .....................................................................................................120 
11.3.1 
Main pharmacodynamic variable ....................................................120 
11.3.2 
Other pharmacodynamic variables .................................................121 
11.3.3 
Safety variables ...............................................................................121 
11.3.4 
Pharmacokinetic variables ..............................................................122 
11.3.5 
Exploratory disease activity variables ............................................122 
11.3.6 
Quality of life variables ..................................................................122 
11.3.7 
Exploratory biomarker variables ....................................................122 
11.4 
Description of statistical analyses ...............................................................123 
11.4.1 
Overall testing strategy ...................................................................123 
11.4.2 
Analysis of the main pharmacodynamic variable(s) .......................123 
11.4.2.1 
Hypotheses and statistical model ..........................................123 
11.4.2.2 
Handling of missing data .......................................................123 
11.4.2.3 
Main analysis .........................................................................124 
11.4.2.4 
Supportive/sensitivity analyses .............................................124 
11.4.2.5 
Subgroup analyses .................................................................125 
11.4.2.6 
Other pharmacodynamic variables ........................................125 


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11.4.3 
Analysis of the safety variable(s) ....................................................125 
11.4.3.1 
Adverse events ......................................................................125 
11.4.3.2 
Cardiac safety ........................................................................126 
11.4.3.3 
Pulmonary safety ...................................................................127 
11.4.3.4 
Vital signs ..............................................................................127 
11.4.3.5 
Laboratory endpoints .............................................................127 
11.4.3.6 
Ocular safety ..........................................................................128 
11.4.4 
Analysis of the exploratory efficacy variables ...............................128 
11.4.5 
Analysis of other variable(s) ...........................................................128 
11.4.5.1 
Pharmacokinetic endpoints ....................................................128 
11.4.5.2 
Exploratory biomarkers .........................................................128 
11.4.5.3 
Exploratory analyses .............................................................129 
11.5 
Interim safety review ..................................................................................129 
11.5.1 
Objectives .......................................................................................129 
11.5.2 
Timing .............................................................................................129 
11.5.3 
Unblinded IDMC review ................................................................129 
11.5.4 
Variables .........................................................................................130 
11.6 
Sample size .................................................................................................130 
11.6.1 
Sample size justification .................................................................130 
12 DATA HANDLING ..................................................................................................131 
12.1 
Data collection ............................................................................................131 
12.2 
Maintenance of data confidentiality ...........................................................132 
12.3 
Database management and quality control .................................................132 
13 PROCEDURES AND GOOD CLINICAL PRACTICE ...........................................133 
13.1 
Ethics and Good Clinical Practice ..............................................................133 
13.2 
Independent Ethics Committee / Institutional Review Board ....................133 
13.3 
Informed consent ........................................................................................133 
13.4 
Compensation to subjects and investigators ...............................................134 
13.5 
Protocol adherence/compliance ..................................................................134 
13.6 
Protocol amendments .................................................................................135 
13.7 
Essential documents and retention of documents .......................................135 
13.8 
Monitoring ..................................................................................................136 
13.9 
Investigator site file ....................................................................................137 
13.10 
Audit ...........................................................................................................137 
13.11 
Inspections ..................................................................................................137 
13.12 
Reporting of study results and publication .................................................138 
14 REFERENCES ..........................................................................................................140 


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LIST OF TABLES 
Table 1 
Visit and assessment schedule (same for part A and part B) ........................35 
Table 2 
Guidelines for FEV1 and/or FVC decrease ...................................................75 
Table 3 
Expected total blood volume to be drawn per patient ................................100 
Table 4 
Safety areas of interest ................................................................................112 
Table 5 
Thresholds for marked laboratory abnormalities for 
ACT-334441 ...............................................................................................155 
 
 
LIST OF FIGURES 
Figure 1 
AC-064A201 study design ...........................................................................49 
Figure 2 
Algorithm for management of study treatment interruptions .......................72 
Figure 3 
Guidance for monitoring liver test abnormalities .........................................76 
Figure 4 
Reduction in total lymphocyte count dose-response shapes ......................131 
 
 
LIST OF APPENDICES 
 
Appendix 1 Prohibited anti-arrhythmic or heart rate lowering medications ..................147 
Appendix 2 List of medications with risk of torsades de pointes ..................................148 
Appendix 3 Adverse events of special interest ..............................................................149 
Appendix 4 Criteria for discharge from hospital on Day 1 and on the first 
day of re-initiation following treatment interruptions ................................150 
Appendix 5 American College of Cardiology / American Heart Association / 
American College of Physicians Training Requirements for 
Performance and Interpretation of Adult Transthoracic 
Echocardiography .......................................................................................151 
Appendix 6 SLEDAI-2K: DATA COLLECTION SHEET ...........................................152 
Appendix 7 Notable abnormalities for ECG, BP and laboratory variables ....................154 
Appendix 8 Corticosteroid conversion table ..................................................................158 
Appendix 9 Physician’s Global Assessment Visual Analog Scale ................................159 
Appendix 10 SF-36v2™...................................................................................................160 
 


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LIST OF ABBREVIATIONS AND ACRONYMS 
 
ACR  
American College of Rheumatology  
ADME  
Absorption, distribution, metabolism, excretion 
AE  
Adverse event 
AESI  
Adverse event of special interest 
ALT  
Alanine aminotransferase 
ANA  
Anti-nuclear antibodies 
ANCOVA  
Analysis of covariance 
anti-dsDNA  
Anti-double-stranded deoxyribonucleic acid 
anti-Sm  
Anti-Smith 
AST  
Aspartate aminotransferase 
ATS  
American Thoracic Society 
AUC0-24  
Area under the curve from 0 to 24 hours  
AV  
Atrioventricular 
BAFF  
B-cell activating factor 
BLyS  
B-lymphocyte stimulator 
BP  
Blood pressure 
bpm  
Beats per minute 
CD  
Cluster of differentiation 
CI  
Confidence interval 
Cmax  
Maximum observed plasma concentration 
CNS  
Central nervous system 
CRA  
Clinical research associate 
CRO  
Contract Research Organization 
CRP  
C-reactive protein 
CSA  
Cardiac safety assessor 
CTCAE  
Common Terminology Criteria for Adverse Events 
Ctrough  
Measured plasma concentration at the end of one dosing interval 
CTT  
Clinical Trial Team 


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CV  
Coefficient of variation 
CYP  
Cytochrome P450 
CXCL10  
C-X-C motif chemokine 10 
CXR  
Chest X-Ray 
DBP  
Diastolic blood pressure 
DILI  
Drug-induced liver injury 
ECG  
Electrocardiogram 
EDTA  
Ethylenediaminetetraacetic acid 
Emax  
Maximum effect 
eCRF  
Electronic Case Report Form 
ELISA  
Enzyme-linked immunosorbant assay 
EMA  
European Medicines Agency 
EOT  
End-of-Treatment 
EOS  
End-of-Study 
ERS  
European Respiratory Society 
EULAR  
European League Against Rheumatism 
FAS  
Full Analysis Set 
FDA  
Food and Drug Administration 
FEV1  
Forced expiratory volume in 1 second 
FSFV  
First Subject First Visit 
FVC  
Forced vital capacity 
GCP  
Good Clinical Practice 
GGT  
Gamma glutamyl transferase 
Hb  
Hemoglobin 
HIV  
Human immunodeficiency virus 
HR  
Heart rate 
IB  
Investigator’s Brochure 
ICF  
Informed Consent Form 
ICH  
International Conference on Harmonisation 
IDMC  
Independent Data Monitoring Committee 
IEC  
Independent Ethics Committee 


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INR  
International normalized ratio 
IRB  
Institutional Review Board 
IRT  
Interactive response technology 
ISAC  
Independent Statistical Analysis Center 
ISF  
Investigator site file 
i.v.  
Intravenous 
LSLV  
Last Subject Last Visit 
LT  
Liver test 
LOCF  
Last observation carried forward 
MAD  
Multiple-ascending dose 
MCP-Mod  
Multiple Comparison Procedure and Modelling 
MedDRA  
Medical Dictionary for Regulatory Activities 
NSAID  
Non-steroidal anti-inflammatory drug 
o.d.  
Once daily 
OCT  
Optical coherence tomography 
OSB  
Ophthalmology Safety Board  
PD  
Pharmacodynamic 
PDS  
Pharmacodynamics Analysis Set 
PFT  
Pulmonary funtion test 
PGA  
Physician’s Global Assessment 
PK  
Pharmacokinetic 
PPS  
Per-protocol Set 
QTcB  
QT corrected for heart rate on the basis of Bazett’s formula 
QTcF  
QT corrected for heart rate on the basis of Fridericia’s formula 
RBC  
Red blood cells 
S1P  
Sphingosine-1-phosphate 
S1P1  
Sphingosine-1-phosphate receptor 1 
SAE  
Serious adverse event 
SAP  
Statistical Analysis Plan 
SBP  
Systolic Blood Pressure 
SF-36v2  
36-Item Short Form Health Survey v2 


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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 
SRBC  
Sheep red blood cell 
SUSAR  
Suspected unexpected serious adverse reaction 
t½  
Terminal elimination half life 
TB  
Tuberculosis 
TBL  
Total bilirubin 
ULN  
Upper limit of the normal range 
WBC  
White blood cells 
WOCBP  
Women of childbearing potential 


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PROTOCOL SYNOPSIS AC-064A201 
TITLE 
A multicenter, randomized, double-blind, placebo-controlled, 
dose-response study to investigate the biological activity, 
safety, tolerability, and pharmacokinetics of ACT-334441 in 
subjects with systemic lupus erythematosus. 
OBJECTIVES 
Main objectives 
• To investigate the pharmacodynamics (PD) of ACT-334441 
in adult subjects with systemic lupus erythematosus (SLE).  
• To investigate the safety and tolerability of ACT-334441 in 
adult subjects with SLE. 
Exploratory objectives 
• To investigate the pharmacokinetics (PK) of ACT-334441 in 
adult subjects with SLE. 
• To investigate the effect of ACT-334441 treatment on 
disease activity in adult subjects with SLE. 
DESIGN 
Prospective, 
multicenter, 
multinational, 
randomized, 
double-blind, 
placebo-controlled, 
two-part, 
dose-response 
Phase 1/2 study.  
This study is divided in two parts:  
• Part A: Four parallel treatment groups (including 
0.5 mg, 1 mg, or 2 mg of ACT-334441 and placebo 
control). 
An interim safety review will be conducted by the Independent 
Data Monitoring Committee (IDMC) when all subjects enrolled 
into Part A have completed Visit 4, unless prematurely 
discontinued. The IDMC will then evaluate the safety profile of 
ACT-334441 in SLE patients and give a recommendation 
whether or not to continue the study as planned (i.e., proceed to 
Part B).   
• Part B: Two parallel treatment groups (including 4 mg 
ACT-334441 and placebo control). 
Note: Subjects enrolled in Part A are not eligible to participate 
in Part B. 


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PERIODS 
There will be three periods in Part A and Part B. 
Screening period:  
This period starts up to 30 days before randomization and 
includes the Screening visit and the pre-randomization 
assessments.  
Treatment period:  
The treatment period will last 12 weeks. Visits during the 
treatment period will consist of a Randomization visit and 
visits at Weeks 2, 4, 8, and 12.  
The End-of-Treatment (EOT) visit will take place at Week 
12, or earlier in case of premature discontinuation of study 
treatment. In all cases, the EOT visit should take place 1 day 
after the last dose of study treatment but no later than 7 days 
after the last dose of study treatment. 
Follow-up period: 
Subjects will undergo an End-of-Study (EOS) Visit 6 weeks 
after the last dose of study treatment.  
Follow-up assessments via telephone calls will be performed 11 
weeks and 16 weeks after the last dose of study treatment to 
evaluate potential serious adverse events (SAEs) and to assess 
pregnancy status (urine test).    
STUDY 
TREATMENT 
DISCONTINUATION 
CRITERIA AND STUDY-
SPECIFIC 
CRITERIA 
FOR INTERRUPTION / 
CLINICAL STUDY STOP 
Study treatment discontinuation 
At any time during the double-blind treatment period, subjects 
meeting 
the 
study-specific 
criteria 
for 
permanent 
discontinuation 
of 
study 
treatment 
as 
described 
in 
Sections 5.1.9 and 5.1.10 are to be permanently discontinued 
from study treatment and will perform EOT and EOS visits and 
will be followed up for a total of 16 weeks after last study 
treatment intake (follow-up telephone calls for pregnancy and 
SAEs). 
Study-specific criteria for interruption / stopping of the 
clinical study or Part B 
• Part A: if 12 or more subjects out of the planned 36 
subjects in the combined active treatment groups (0.5, 1, 
or 2 mg) or 6 or more subjects out of the planned 12 


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subjects in the high dose group (2 mg) have been 
discontinued from study treatment due to meeting any of 
the individual patient’s stopping rules as defined per 
safety area of interest [see Section 9.3], the entire study 
will be put on hold. A detailed safety signal assessment 
and 
recommendations 
from 
IDMC 
and 
Health 
Authorities may allow a potential restart of the study. 
• Part B: if 4 or more subjects out of the planned 
12 subjects in the active treatment group (4 mg) have 
been discontinued study treatment due to meeting any of 
the individual patient’s stopping rules as defined per 
safety area of interest [see Section 9.3], all subjects 
included in Part B will stop study treatment. A detailed 
safety signal assessment and recommendations from 
IDMC and Health Authorities may allow a potential 
restart of the Part B. 
PLANNED DURATION 
Part A: Approximately 11 months from First subject-First visit 
(FSFV) to Last Subject-Last Visit (LSLV). 
Part A and B: Approximately 20 months from FSFV to LSLV. 
SITE(S) 
/ COUNTRY(IES) 
Approximately 21 sites notably in the USA, Russia and Europe. 
SUBJECTS / GROUPS 
Part A: Approximately 48 subjects will be randomized 
(1:1:1:1) via an interactive response technology (IRT) system to 
one of four groups (i.e., 12 subjects in each group; three dose 
levels of 0.5 mg, 1 mg, or 2 mg ACT-334441, or placebo once 
daily [o.d.]). 
 
Part B: Approximately 16 subjects will be randomized (3:1) 
via an IRT system to one of two groups (i.e., 12 subjects 
receiving 4 mg ACT-334441 and 4 receiving placebo o.d.). 
INCLUSION CRITERIA 
1. Signed informed consent prior to initiation of any 
study-mandated procedure. 
2. Men or women ≥ 18 and ≤ 65 years of age. 
3. Women 
of 
childbearing 
potential 
as 
defined 
in 
Section 4.5.1: 
• must have a negative serum pregnancy test at 
Screening and a negative urine pregnancy test at 


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Randomization at least 3 weeks apart; 
• must agree to undertake a urine pregnancy test as 
indicated in Table 1 (bi-weekly/ monthly) during 
the study and up to 16 weeks after study treatment 
discontinuation; 
• must use methods of contraception, as described in 
Section 4.5.2, from the Screening visit until 
16 weeks after study treatment discontinuation.  
4. Presenting with a 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 (criteria are cumulative and do not need to 
be present concurrently) [Tan 1982; Hochberg 1997]. 
5. Presenting with a Systemic Lupus Erythematosus Disease 
Activity Index-2000 (SLEDAI-2K) score of at least 2 points 
for musculoskeletal or mucocutaneous manifestations (i.e., 
myositis, arthritis, rash, alopecia, mucosal ulcers) at 
Screening. 
6. History or presence at Screening of positive anti-nuclear 
antibodies 
(ANA) 
or 
anti-double-stranded 
DNA 
(anti-dsDNA) antibodies. 
7. Currently treated for at least 30 days prior to Randomization 
with stable doses of one or more of the following 
background medications: 
• Non-steroidal anti-inflammatory drugs (NSAIDs), 
• Corticosteroids (≤ 10 mg/day prednisolone or 
equivalent), 
• Anti-malarials (≤ 400 mg/day hydroxychloroquine, 
≤ 500 mg/day chloroquine, ≤ 100 mg/day 
quinacrine)#, 
• Mycophenolate mofetil (≤ 2 g/day)#, 
• Azathioprine (≤ 2 mg/kg/day)#, 
• Methotrexate (≤ 20 mg/week)#. 
 
#Treatment 
with 
anti-malarials, 
mycophenolate 
mofetil, 
azathioprine, or methotrexate must have been started at least 
90 days prior to Randomization and must not have been stopped 
within 30 days prior to Randomization. 
EXCLUSION CRITERIA 
Pregnancy and breastfeeding 
1. Breastfeeding, pregnant women or women planning to 


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become pregnant during the study. 
SLE disease 
2. Subjects with active lupus nephritis (defined by proteinuria 
> 
1 
g/24 
h, 
or 
equivalent 
using 
spot 
urine 
protein-to-creatinine 
ratio) within 
90 
days 
prior 
to 
randomization; subjects with central nervous system lupus 
(e.g., 
aseptic 
meningitis, 
seizures, 
cerebritis, 
polyneuropathy, cerebrovascular disease) within 90 days 
prior to Randomization; subjects with lupus vasculitis 
within 90 days prior to Randomization. 
3. Subjects presenting with a SLEDAI-2K score > 12 at 
Screening or at Randomization. 
Cardiovascular 
4. History or presence of cardiac rhythm disorders (e.g., 
sinoatrial 
heart 
block, 
second- 
or 
third-degree 
atrioventricular block, symptomatic bradycardia, atrial 
flutter or atrial fibrillation, ventricular arrhythmias, cardiac 
arrest). 
5. Resting heart rate (HR) < 55 bpm as measured by the 
pre-dose 12-lead electrocardiogram (ECG) on Day 1; an 
increased QT corrected for HR on the basis of Fridericia’s 
formula (QTcF) interval of > 470 ms (females), > 450 ms 
(males) at Screening, or on Day 1 ECG prior to study 
treatment initiation. 
6. History or presence of ischemic heart disease. 
7. History or presence of myocarditis or endocarditis. 
8. Presence of valvular heart disease associated with 
symptoms or hemodynamic change. 
9. History of syncope associated with cardiac disorders. 
10. History or presence of cardiac failure. 
11. Systemic arterial hypertension not controlled by medication 
according to investigator judgment. 
12. History or presence of vascular thrombosis at any time or a 
history of pregnancy morbidity in the context of 
anti-phospholipid antibody syndrome within 5 years prior to 
Randomization. 
13. Clinically relevant hypotension according to investigator’s 
judgment or orthostatic hypotension (i.e., > 20 mmHg 
decrease in systolic blood pressure [SBP] or > 10 mmHg 
decrease in diastolic blood pressure [DBP] from supine to 


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standing position measured between 1 and 3 minutes after 
standing) at Screening. 
14. Known pulmonary arterial hypertension of functional 
class III or IV.  
Pulmonary 
15. History or presence of severe respiratory disease or 
pulmonary fibrosis, based on medical history, lung function 
and chest X-ray (CXR) performed at Screening or within 3 
months prior to Screening. 
16. Bronchial asthma or chronic obstructive pulmonary disease.  
17. Abnormal pulmonary function tests: forced expiratory 
volume in 1 second (FEV1) or forced vital capacity (FVC) < 
70% of predicted normal value; FEV1/FVC ratio <0.7. 
Treatments 
18. Treatment or planned treatment with the following 
medications*: 
a. Within 15 days or 5 half-lives of the medication, 
whichever is longer, prior to Randomization: 
o β-blockers, diltiazem, verapamil, digoxin 
or 
any 
other 
anti-arrhythmic 
or 
HR-lowering systemic therapy (list of 
drugs provided in Appendix 1). 
o QT-prolonging drugs with known risk of 
torsades de pointes, for any indication 
(list of drugs provided in Appendix 2). 
o Short- and long-acting β2-agonists (e.g., 
albuterol, levalbuterol, formoterol, 
terbutaline salmeterol). 
b. Within 30 days or 5 half-lives of the medication, 
whichever is longer, prior to Randomization: 
o Cyclophosphamide, cyclosporine, 
tacrolimus, sirolimus, etc., 
o Pulse methylprednisolone  
o Vaccination with live vaccines. 
c. Within 90 days prior to Randomization: 
o Belimumab, leflunomide, 
o Any investigational immunosuppressive 
or immunomodulatory agent (within 
90 days or 5 half-lives of the drug prior 
to start of study treatment, whichever is 


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longer).  
d. Within 12 months prior to Randomization: 
o B cell-depleting biological agents such as 
rituximab or ocrelizumab. 
e. Any time prior to Randomization: 
o Alemtuzumab, sphingosine-1-phosphate 
(S1P) modulators (e.g., fingolimod). 
*For immunosuppressants or anti-inflammatory drugs not listed 
among the fordidden medications, the investigator should 
discuss adequate wash-out time with the sponsor. 
Infection and infection risk 
19. Active or latent tuberculosis (TB), as assessed by CXR 
performed at Screening or within 3 months prior to 
Screening, 
and 
interferon 
gamma 
release 
assay 
(QuantiFERON-TB-Gold®) at Screening, except if there is 
documentation that the subject has completed adequate and 
successful treatment for latent TB infection or TB disease 
previously. 
20. Ongoing known bacterial, viral or fungal infection that is of 
clinical concern in the judgment of the investigator. 
21. A 
history 
of 
any 
serious 
infection, 
defined 
as 
life-threatening or requiring intravenous (i.v.) antibiotics or 
hospitalization, within 30 days prior to Randomization.  
22. Hepatitis B and C, congenital or acquired severe 
immunodeficiency or known human immunodeficiency 
virus (HIV) infection or positive HIV testing at Screening. 
23. Negative antibody test for varicella-zoster virus at 
Screening. 
Malignancy 
24. History or presence of malignancy (except for surgically 
excised 
basal 
or 
squamous 
cell 
skin 
lesions), 
lymphoproliferative disease, or history of total lymphoid 
irradiation. 
Transplantation 
25. History or presence of bone marrow or solid organ  
transplantation. 
Ophthalmology 
26. Presence of macular edema or active uveitis. 
Metabolic and hepatic  
27. Type 1 or 2 diabetes that is poorly controlled according to 


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investigator judgment, or diabetes complicated with organ 
involvement such as diabetic nephropathy or retinopathy. 
28. Moderate or severe hepatic impairment defined as Child 
Pugh Score B or C, respectively, based on measurement of 
total bilirubin 
(TBL), 
serum 
albumin, 
international 
normalized ratio, as well as on presence/absence and 
severity of ascites and hepatic encephalopaty. 
29. TBL > 1.5-fold upper limit of normal (ULN; unless in the 
context of known Gilbert’s Syndrome). 
30. Alanine 
aminotransferase 
(ALT) 
or 
aspartate 
aminotransferase (AST) > 2-fold ULN. 
Hematology 
31. Hemoglobin < 9 g/dL. 
32. White blood cell count < 2500/µL (2.5 × 109/L). 
33. Lymphocyte count < 800 /µL (0.8 × 109/L). 
34. Platelets < 75,000/µL (75 × 109/L). 
Renal 
35. Proteinuria > 1.0 g/24 hour or equivalent using spot urine 
protein-to-creatinine ratio. 
36. Estimated glomerular filtration rate < 60 mL/min/1.73 m2. 
Other categories 
37. History of clinically significant drug or alcohol abuse. 
38. Known allergy to S1P receptor 1 modulators or any of the 
ACT-334441 formulation excipients. 
39. Any other clinically relevant medical or surgical condition 
that in the opinion of the investigator would put the subject 
at risk if participating in the study. 
40. Subjects 
unlikely 
to 
comply 
with 
protocol, 
e.g., uncooperative attitude, inability to return for follow-up 
visits or likelihood of not completing the study, including 
mental condition rendering the subject unable to understand 
the nature, scope, and possible consequences of the study. 
STUDY TREATMENTS 
Investigational treatment 
ACT-334441 0.5 mg, 1 mg, 2 mg capsules for Part A, and 4 mg 
capsules for Part B, administered orally o.d. in the morning. 
Placebo 
Placebo matching ACT-334441 capsules administered orally 
o.d. in the morning.  


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CONCOMITANT 
THERAPY 
Allowed concomitant therapy 
• i.v. atropine in the event of symptomatic bradycardia [see 
study-specific criteria for permanent discontinuation of study 
treatment in Section 5.1.10]; 
• Dilating eye drops, mydriatics, including parasympathetic 
antagonists (e.g., tropicamide) or sympathetic agonists (e.g., 
phenylephrine) for topical use; 
• Vaccination with non-live vaccines; 
• Stable systemic corticosteroid therapy; corticosteroids are 
not to be started or stopped during the study, and the dose 
should be kept stable. However, the investigator may see 
reason to initiate or increase the dose of systemic 
corticosteroid to treat an SLE flare or another condition. In 
such cases, the dose may be increased for a period of not 
more than 14 days up to double the baseline dose or a 
maximum of 20 mg/day prednisolone or equivalent (please 
refer to conversion table in Appendix 8); 
• Topical treatment therapy including topical use of 
corticosteroid;  
• Stable antimalarial therapy (e.g., hydroxychloroquine, 
chloroquine, quinacrine); therapy is not to be started or 
stopped during the study, and dose should be kept stable; 
• Stable NSAID chronic 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). Therapy is not to 
be started or stopped during the study, and dose should be 
kept stable. 
Forbidden concomitant medication 
• Immunosuppressives not listed in allowed concomitant 
medication 
such 
as 
cyclophosphamide, 
cyclosporine, 
leflunomide, sirolimus, tacrolimus, etc.; 


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• Immunosuppressive or immunomodulatory biological agents 
(e.g., belimumab, i.v. immunoglobulin, rituximab, S1P 
modulators other than ACT-334441); 
• β-blockers, diltiazem, verapamil, digoxin, or any other 
anti-arrhythmic or HR-lowering therapy (as listed in 
Appendix 1); 
• QT-prolonging drugs with known risk of torsades de pointes 
(list of drugs provided in Appendix 2); 
• Short- 
and 
long-acting 
β2-agonists 
(e.g., 
albuterol, 
levalbuterol, formoterol, terbutaline salmeterol); 
• Vaccination with live vaccines. 
ENDPOINTS 
Pharmacodynamic endpoints 
• Change in total lymphocyte count from baseline to EOT 
• Change in total lymphocyte count from baseline to each 
post-baseline assessment 
Safety endpoints 
The treatment-emergent period is defined as the time from first 
study treatment intake up to 6 weeks (inclusive) after last study 
treatment intake. 
• Treatment-emergent adverse events (AEs), SAEs, and 
adverse events of special interest (AESI#); 
• 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 Bazzett’s formula [QTcB] 
and QT corrected for HR on the basis of Fridericia’s formula 
[QTcF]), from pre-dose to selected post-dose assessments 
(1 h, 2 h, 3 h, 4 h, 5 h, 6 h) on Day 1 and on day of study 
drug re-initiation; 
• Occurrence of treatment-emergent 12-lead ECG outliers 
(e.g., HR, PR, QTc defined in the Statistical Analysis Plan 
[SAP]);  
• Occurrence 
of 
treatment-emergent 
12-lead 
ECG 
abnormalities;  
• Occurrence 
of 
treatment-emergent 
ECG-Holter 
abnormalities on Day 1;  


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• Change in SBP and DBP from baseline up to EOS; 
• Change in FEV1 and FVC, expressed in absolute value (L) 
and percent value from baseline up to EOS; 
• Occurrence of treatment-emergent decrease of FEV1 or FVC 
> 15% from baseline values; 
• Change in laboratory parameters (hematology, blood 
chemistry, and urinalysis) from baseline up to EOS; 
• Treatment-emergent laboratory abnormalities according to 
CTCAE 2010 v4.03 [CTCAE 2010] and Food and Drug 
Administration 
(FDA) 
guidelines 
[FDA 
2009] 
(for 
ALT/AST/TBL); 
• Change in protein-to-creatinine ratio from baseline to EOT; 
• Change in body weight from baseline to EOT. 
#AESI considered for the analyses are described in Appendix 3. 
 
Pharmacokinetic endpoints 
• Ctrough ACT-334441 plasma concentrations prior to dosing at 
Weeks 2, 4, 8, and 12 (EOT) or at EOT visit after premature 
study treatment discontinuation (if applicable); 
• ACT-334441 plasma concentration at EOS (i.e., 6 weeks 
after study treatment discontinuation). 
Exploratory disease activity endpoints 
• Change in SLEDAI-2K score from baseline to each 
post-baseline assessment; 
• Change in Physician’s Global Assessment (PGA) score 
from baseline to each post-baseline assessment; 
• Change 
in 
SLEDAI-2K 
mucocutaneous 
and/or 
muscoskeletal scorings from baseline to each post-baseline 
assessment. 
Quality of life endpoints 
• Change in SF-36v2™ Health Survey domain and 
component scores from baseline to EOT. 


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Exploratory biomarker endpoints 
• Change in immunoglobulin serum levels (IgG, IgM, IgA) 
from baseline to each post-baseline assessment;  
• Change in ANA and anti-dsDNA antibody titers from 
baseline to each post-baseline assessment;  
• Change in serum complement components C3 and C4, 
C-reactive protein, fibrinogen, B lymphocyte stimulator and 
C-X-C motif chemokine 10 from baseline to each post-
baseline assessment; 
• Change in blood lymphocyte subsets from baseline to EOT 
and EOS. 
ASSESSMENTS 
Refer to the schedule of assessments in Table 1. 
STATISTICAL 
METHODOLOGY 
All statistical analyses will be conducted by Actelion or by 
designated Contract Research Organizations supervised by 
Actelion. 
The SAP will be finalized prior to database lock. 
Baseline is defined as the last assessment prior to initiation of 
the study treatment. 
Analysis sets 
Screened Analysis Set: includes all subjects who were screened 
and received a subject number. 
Safety Analysis Set: includes all randomized subjects who 
received at least one dose of study treatment. Unless otherwise 
stated, any analysis using the Safety Analysis Set will use all 
available safety data up to 6 weeks after discontinuation of 
study treatment. Subjects will be analyzed based on actual dose 
taken, not the randomized dose. 
PD Analysis Set: includes all subjects who received at least 
3 weeks of study treatment and have at least one lymphocyte 
count measurement between the Week 4 visit and Week 12 
visit. Subjects will be analyzed according to the treatment they 
received. 
Full Analysis Set (FAS): includes all randomized subjects. 
Subjects will be analyzed according to their randomized 


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treatment.  
Per-Protocol Set (PPS): defined as subjects from the FAS 
without any major protocol deviations. Major protocol 
deviations are described in Section 11.2.4.  
PK Analysis Set: includes all randomized subjects who received 
at least one ACT-334441 dose and provided at least one blood 
sample for PK evaluation. Subjects will be analyzed based on 
actual dose taken, not the randomized dose.  
Pharmacodynamic variable 
The change in lymphocyte count from baseline to EOT is 
defined as:  
• Total lymphocyte count at EOT – total lymphocyte 
count at baseline  
Last observation carried forward (LOCF; using the Week 4 visit 
or later) will be used for subjects with a missing EOT 
assessment.  
Exploratory disease activity variables 
The change from baseline in the SLEDAI-2K (modified to 
exclude leukopenia) score at each visit is calculated as : 
• SLEDAI-2K score at each visit – SLEDAI-2K score at 
baseline. 
The change from baseline in PGA score and the SLEDAI-2K 
mucocutaneous and/or muscoskeletal score will be calculated in 
a similar manner. 
Overall testing strategy for the pharmacodynamic endpoint  
An optimized contrast test according to the Multiple 
Comparison Procedure (MCP)-Mod approach [Bretz 2005] for 
each considered dose-response model will be performed. The 
existence of dose-response effects will be tested using the 
maximum of the model-based contrast tests. Multiplicity 
adjusted p-values will be calculated using the Dunnett-
distribution.  
Pharmacodynamic endpoint analysis 
Null and alternative hypotheses 


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The null hypothesis is that there is no dose response in terms of 
lowering of lymphocyte count (p, which is a negative value for 
a lowering of the lymphocyte count) from baseline to EOT, and 
the alternative hypothesis is the existence of a dose response:  
 for all doses d = 0.5, 1, 2, 4 mg 
                                                vs 
 for at least 1 dose d = 0.5, 1, 2, 4 mg 
If Part B of the trial is not performed, the hypothesis will be 
 for all doses d = 0.5, 1, 2 mg 
                                                vs 
 for at least 1 dose d = 0.5, 1, 2 mg 
To meet the objective of demonstrating existence of a dose 
response of ACT-334441 on the lymphocyte count reduction 
from baseline in subjects with SLE, the null hypotheses must be 
rejected by the test with a one-sided significance level of 5%.  
Main pharmacodynamic analysis 
The MCP-Mod approach consists of a set of optimized contrast 
tests for establishing the existence of dose-response effects. The 
overall strategy is described as follows: 
Definition of a set of likely dose response relations (see sample 
size section for more details): 
• Maximum effect (Emax) with 50% of the maximum effect 
at dose 0.2 mg 
• Emax with 50% of the maximum effect at dose 0.4 mg 
• Emax with 50% of the maximum effect at dose 1.0 mg 
• Quadratic with maximum effect at dose 3.0 mg (only if 
the 4 mg dose is studied) 
• Sigmoid-Emax with 50% of the maximum effect at dose 
0.4 mg and 95% of the maximum effect at dose 2.0 mg 
The existence of dose-response effects will be assessed with the 
optimized contrast tests. Dose-response effects are established 
at one sided level α=5%, if the following condition on the p 


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value 
holds 
for 
at 
least 
one 
contrast 
i: 
, where 
describes the 
Dunnett-distribution with correlation matrix 
. 
The model with the minimum p-value will be fitted to the data. 
As a sensitivity analysis, all remaining significant models will 
be fitted to the data and model-based dose estimates will be 
calculated. 
Given established dose-response effects with MCP-Mod, PD 
effects will be analyzed based on pairwise comparisons of 
reduction in lymphocyte count from baseline for each active 
dose levels to placebo using an analysis of covariance 
(ANCOVA) model adjusted for baseline lymphocyte counts. 
Testing will be done with a two-sided significance level of 5%. 
The type-1 error will be controlled via a hierarchical ordering of 
the tests: pairwise comparison will be conducted in decreasing 
dose order.  
The dose-response data will be summarized with point-wise and 
model-based estimates, standard deviation and 95% confidence 
intervals (CI) on the reduction in lymphocytes from baseline at 
the examined dose levels. A plot of the estimated dose response 
curve with 95% credibility interval limits will be presented 
along with the observed response at each dose. 
This analysis will be performed on the PD analysis set, and a 
supportive analysis will be performed on the FAS and the PPS.  
Exploratory efficacy endpoint analysis 
The exploratory efficacy endpoint change from baseline in 
SLEDAI-2K score at Week 12 will be analyzed using an 
ANCOVA, with treatment and baseline score as factors. 
Missing values at Week 12 will be imputed using LOCF. The 
mean treatment difference including 95% CI for each 
ACT-334441 dose compared to placebo will be presented. A 
sensitivity analysis will be performed using observed data 
without imputation. 
Other changes from baseline variables will be analyzed in a 
similar manner using an ANCOVA. 
All exploratory efficacy endpoints will be analyzed on the FAS 


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and PPS populations. 
No multiplicity adjustments will be made on exploratory 
efficacy endpoints.  
Safety endpoints 
Safety endpoints will be mainly analyzed descriptively by 
treatment group on the Safety Set. 
Sample size 
The sample size for the study was determined based on 
simulations. A maximum % lymphocyte reduction compared to 
baseline of 70% was assumed based on results obtained in 
Phase 1 with ACT-334441 and with other S1P receptor 
modulators. A sample size of 64 subjects (12 in each 
ACT-334441 dose group of 0.5 mg, 1 mg, 2 mg, 4 mg, and 
16 in the placebo group) would provide an average power of at 
least 90% to show a significant dose response relationship at a 
one-sided significance level of 5%, under the assumption of a % 
lymphocyte reduction compared to baseline of 0% (mean at 
Week 12 = 2.0 × 109/L) for placebo and a maximum of 70% for 
any ACT-334441 dose (mean at Week 12 = 0.6 × 109/L). The 
pooled SD is assumed to be 0.45 × 109/L. This takes into 
account 10% of subjects being excluded from the PD analysis 
set.  
If Part B is not conducted and the 4 mg dose is not tested, then 
there will be an average power of at least 80% to show a 
significant dose-response relationship with three dose levels at a 
one-sided significance level of 5%, using the same assumptions 
as above (based on a total sample size of 48 subjects [12, 12, 12 
and 12 in placebo, 0.5 mg, 1 mg and 2 mg, respectively]). 
Assumptions on the placebo response rate, maximum effect 
sizes and candidate dose-response models are based on the 
observed lymphocyte count in study AC-064-101. 
STUDY COMMITTEES 
Independent Data Monitoring Committee 
An IDMC has the overall responsibility for safeguarding the 
interests of subjects by monitoring data obtained in the study in 
an unblinded fashion and making appropriate recommendations 
based on the reported data, thus ensuring that the study is being 


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conducted with the highest scientific and ethical standards. The 
IDMC will be fully operational prior to enrolment of the first 
subject into the study. The IDMC will review unblinded data at 
regular intervals, will provide recommendation to apply study 
stopping rules (if indicated) and in addition will review interim 
safety data collected when all subjects enrolled into Part A have 
completed Visit 4 (Week 4), unless prematurely discontinued 
[see Section 11.5]. The composition and operation of the IDMC 
is described in the IDMC charter. 
Ophthalmology Safety Board 
An Ophthalmology Safety Board (OSB) composed of two 
independent ophthalmologists will review and evaluate in a 
blinded fashion any new or suspected case of macular edema. 
The composition and operation of the OSB is described in the 
OSB charter. 
 


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Table 1 
Visit and assessment schedule (same for part A and part B) 
Periods 
Name 
Pre-
randomization 
Treatment period 
FU 
Unscheduled 
Duration 
Up to 30 days 
12 weeks 
16 weeks 
NA 
Visits  
Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
U1, U2,... 
I  
Name 
Screening 
Randomization 
(15) 
W2 
W4 
W8 
EOT 
EOS  
Phone call 
FU  
Phone 
call  
FU 
Unscheduled 
(17)  
Re-initiation 
Time 
Day −30 to −1 
Day 1 
Week 2 
Week 4 
Week 8 
Week 12 or 
earlier in 
case of 
premature 
discontinuati
on (16) 
Last study 
treatment 
intake + 6 
weeks 
 
Last study 
treatment 
intake + 11 
weeks 
 
Last 
study 
treatment 
intake + 
16 weeks 
Any day 
between Day 
1 and EOS 
For study 
treatment 
interruptions 
that started up 
to Day 14 
Visit window 
 
 
± 3 days 
± 5 days 
± 5 days 
± 5 days 
± 5 days 
± 5 days 
± 5 days 
NA 
Informed consent* 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria* 
X 
X 
 
 
 
 
 
 
 
 
 
Demographics* 
X 
 
 
 
 
 
 
 
 
 
 
Medical history/smoking status* 
X 
 
 
 
 
 
 
 
 
 
 
SLE history* (1) 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant medications/SLE 
therapies* 
X 
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 
 
 
 
 
X 
 
 
 
 
 
Disease activity scales*: 
SLEDAI-2K, PGA 
X 
X 
 
X 
X 
X 
X 
 
 
X 
 
Quality of life questionnaire*: 
SF-36 v2™ 
 
X 
 
 
 
X 
 
 
 
 
 
Chest X-ray (4) 
X 
 
 
 
 
 
 
 
 
 
 
SBP/DBP* (5;6) 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
12-lead ECG** (5) 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
ECG-Holter** (7) 
X 
X 
 
 
 
 
 
 
 
 
 
Echocardiography* 
X 
 
 
 
 
X 
 
 
 
 
 
Spirometry** (8) 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
Ophthalmological examination*  
X 
. 
X 
X 
X 
X 
X 
 
 
 
 
OCT 
X 
 
 
 
 
X 
 
 
 
 
 
Hematology (9)/ blood 
Chemistry** 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Pregnancy test */** (10) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Viral serology / tuberculosis 
test** 
X 
 
 
 
 
 
 
 
 
 
 


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Periods 
Name 
Pre-
randomization 
Treatment period 
FU 
Unscheduled 
Duration 
Up to 30 days 
12 weeks 
16 weeks 
NA 
Visits  
Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
U1, U2,... 
I  
Name 
Screening 
Randomization 
(15) 
W2 
W4 
W8 
EOT 
EOS  
Phone call 
FU  
Phone 
call  
FU 
Unscheduled 
(17)  
Re-initiation 
Time 
Day −30 to −1 
Day 1 
Week 2 
Week 4 
Week 8 
Week 12 or 
earlier in 
case of 
premature 
discontinuati
on (16) 
Last study 
treatment 
intake + 6 
weeks 
 
Last study 
treatment 
intake + 11 
weeks 
 
Last 
study 
treatment 
intake + 
16 weeks 
Any day 
between Day 
1 and EOS 
For study 
treatment 
interruptions 
that started up 
to Day 14 
Visit window 
 
 
± 3 days 
± 5 days 
± 5 days 
± 5 days 
± 5 days 
± 5 days 
± 5 days 
NA 
Additional serum sample for 
viral serology*** 
 
X 
 
 
 
 
 
 
 
 
 
ANA, anti-dsDNA antibodies, 
complement C3 and C4** 
X 
X 
 
X 
X 
X 
X 
 
 
X 
 
Exploratory biomarkers** (10) 
 
X 
 
X 
X 
X 
X 
 
 
 
 
Lymphocyte subsets*** (11) 
 
X 
 
 
 
X 
X 
 
 
 
 
Urine protein-to-creatinine 
ratio** 
X 
X 
 
 
 
X 
 
 
 
X 
 
Urinalysis (dipstick)* 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
PK sampling (pre dose)*** 
 
 
X 
X 
X 
X 
X 
 
 
 
 
Study treatment dispensing & 
accountability* (13) 
 
X 
X 
X 
X 
X 
 
 
 
 
X 
AEs* (14) 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
SAEs* (14) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
* Data collected in the eCRF 
** Electronically transferred to sponsor 
*** Sample collection date recorded in the eCRF (for PK samples, time will also be recorded) 
 
Assessments in part A and B are identical. 
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. 
The intervals between Visit 4 (Week 4), Visit 5 (Week 8) and Visit 6 (EOT) should not exceed 36 days.  
(1) History of positive ANA / anti-ds DNA antibodies will be included. 
(2) Complete physical examination (i.e., inspection, percussion, palpation and auscultation) will be performed at Visit 1 (Screening) and Visit 6 (EOT). A symptom-driven, 
abbreviated physical examination will be performed at all other visits in order to capture assessments needed for the SLEDAI-2K 
(3) Height only at Screening.  


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(4) A chest X-ray that has been performed within 3 months prior to Screening can be used (in this case, no need to repeat chest X-ray at Screening). 
(5) On Day 1 and at re-initiation, 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 from the hospital 
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.  
(6) At Screening, SBP/DBP will be assessed in supine position and after 1 to 3 minutes in standing position to assess orthostatic hypotension. At all other visits, SBP/DBP will be 
assessed in supine position. 
(7) At Screening, 24 hour ECG-Holter will start before 12:00. On Day 1, 24 hour ECG-Holter will start immediately before dosing.  
(8) Two spirometry assessments will be performed at Visit 1 (Screening). The assessments should be at least 5 days apart. The last assessment will count as baseline. 
(9) Hematology assessments including coagulation tests will be performed at each visit until EOS 
(10) Serum pregnancy tests will be performed at Screening and EOS. Urine pregnancy tests will be performed at all other visits (including telephone calls FU, 11 weeks and 16 weeks 
after study treatment discontinuation).  
(11) IgM, IgG, IgA, CRP, fibrinogen, and BLyS will be measured in serum. At Randomization visit only, anti-Smith, anti-cardiolipin, and anti-ribosomal P will also be measured. 
EDTA plasma samples will be shipped via central laboratory to Actelion for analysis of CXCL10 and other soluble biomarkers potentially related to SLE and/or S1P1 modulation. 
(12) Blood samples will be shipped via central laboratory to Actelion for lymphocyte subsets analysis. 
(13) No study drug dispensing at V3 and re-initiation visit 
(14) All AEs and SAEs that occur after signing the Informed Consent Form and up to 6 weeks (AEs) or 16 weeks (SAEs) after study treatment discontinuation must be reported. 
(15) Prior to randomization, the following central laboratory results must be available to confirm eligibility: ANA, anti-dsDNA, Hepatitis B surface antigen, Hepatitis C, HIV1 and 
HIV2, varicella-zoster virus, urine protein-to-creatinine ratio, ALT/AST/TBIL, pregnancy test (if applicable).  
(16) EOT visit should preferably take place 1 day after last study treatment dose, and no later than 7 days. 
(17) Unscheduled visits may be performed at any time during the study. Recording of changes in concomitant medications and background SLE therapies since last visit needs to be 
performed at each unscheduled visit. Further assessments including 12-lead ECG, SBP/DBP, SLEDAI-2K, PGA, laboratory assessments for SLEDAI-2K scoring (i.e., 
hematology/blood biochemistry, urinalysis, anti-dsDNA, complement C3 and C4) may be performed at the discretion of the investigator. 
 
AE = adverse event; ALT = alanine aminotransferase; ANA = anti-nuclear antibodies; anti-dsDNA = anti-double-stranded DNA; AST = aspartate aminotransferase; BLyS = 
B lymphocyte stimulator; CRP = C-reactive protein; CXCL10 = C-X-C motif chemokine 10; ECG = electrocardiogram; eCRF = electronic Case Report Form; EDTA= 
ethylenediaminetetraacetic acid; DBP = diastolic blood pressure; EOS = End-of-Study; EOT = End-of-Treatment; FU = follow-up; HIV = human immunodeficiency virus; NA = not 
applicable; OCT = optical coherence tomography; PGA = Physician’s Global Assessment; PK = pharmacokinetic; SAE = serious adverse event; S1P1 = sphingosine-1-phosphate 
receptor 1; SBP = systolic blood pressure; SF-36 = Short-Form 36; SLE = systemic lupus erythematosus; SLEDAI-2K = Systemic Lupus Erythematosus Disease Activity Index-2000; 
TBIL = total bilirubin; WOCBP = women of childbearing potential. 
 
 


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PROTOCOL 
1 
BACKGROUND  
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. 
SLE is primarily a disease of young women with a peak incidence between the ages of 
15 and 40 years [Borchers 2010; Pons-Estel 2010] and an estimated male to female ratio 
of 1:7 to 1:10 [Govoni 2006].  
The natural history of SLE is characterized by relapses or flares, alternated with periods 
of remission. The outcome is highly variable, ranging from prolonged remission to high 
morbidity with progression of organ damage and death. 
Clinical manifestations of SLE include rash, arthritis, anemia, thrombocytopenia, 
serositis, nephritis, seizures, and psychosis among others [Rahman 2008]. Current 
treatment of SLE is based on the use of anti-inflammatory and immunosuppressive 
therapies. With improved diagnosis and treatment, 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]. 
1.1.1 Clinical manifestations and diagnosis 
The clinical presentation of SLE is highly heterogeneous and includes a constellation of 
signs and symptoms involving various organs with an undulating course and 
accumulation of organ involvement over time [Boumpas 1995a; Boumpas 1995b].  
The more commonly involved organ systems are mucocutaneous, musculoskeletal, renal, 
nervous, cardiovascular, pleura, and lungs. The mucocutaneous and musculoskeletal 
systems are involved in over 75% of SLE patients. While these common manifestations 
are debilitating and negatively impact the patients’ quality of life, they are generally not 
fatal.  
Renal involvement occurs in one-half to two-thirds of patients and is associated with a 
poor outcome and mortality. Neuropsychiatric manifestations occur in about two-thirds 
of patients with varying manifestations, such as mood disorders, anxiety, and psychosis. 
Central nervous system (CNS) vasculitis and transverse myelitis are less common but 
serious acute manifestations. Most patients with SLE also have general constitutional 
symptoms including fatigue, malaise, fever, anorexia, and weight loss.  


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The unifying laboratory abnormality of SLE is the presence of circulating autoantibodies 
including anti-nuclear antibodies (ANA). The American College of Rheumatology 
(ACR) has designated 11 classification criteria incorporating major clinical features 
(mucocutaneous, articular, serosal, renal, and neurologic) and laboratory findings 
(hematologic and immunologic), which have been recently validated for the diagnosis of 
SLE [Petri 2012; Tan 1982; Hochberg 1997]. The presence of four or more criteria 
occurring either simultaneously or in succession is strongly suggestive of the diagnosis of 
SLE.  
1.1.2 Epidemiology 
Epidemiological studies of incidence and prevalence of SLE have shown large 
differences in different regions of the world and within the same country. Of note, 
diagnostic criteria have been updated in 1997, and many of the available epidemiological 
studies are based on previous criteria. 
Recent publications (applying the most updated diagnostic criteria) reported overall 
prevalence rates (per 100,000 inhabitants) ranging from 45.3 in Australia to 100 in USA 
[Bossingham 2003; Lerang 2012; Chiu 2010; Mok 2011; Helmick 2008; Furst 2013]. 
Overall incidence rates (per 100,000 person-year) range from 3 in Norway to 7.2 in USA 
and 8.1 in Taiwan [Lerang 2012; Chiu 2010; Furst 2013]. There are great differences in 
prevalence and incidence based on race: most of the studies indicate that SLE more 
frequently affects non-Caucasian individuals (e.g., in USA, the occurrence of SLE was 
three to four times higher among African-American than Caucasian women 
[Alarcón 2002; Danchenko 2006]). 
Categorized as a fatal condition in the beginning of the last century, patients with SLE 
now live years if not decades after diagnosis. Since the mid-1970s, most studies in 
Europe, the USA, Canada, and Latin America have demonstrated 5-year survival rates 
among newly diagnosed patients of over 90%, and 15- to 20-year survival rates of around 
80% [Mok 2011; Pons-Estel 2010]. In addition to failure of controlling renal and 
neurologic disease, infections and thrombosis are the leading causes of death in SLE 
patients [Kataoka 2004; Cervera 2009; Ward 2006]. 
1.1.3 Current treatments of SLE 
The current standard of care for treatment of SLE includes the use of non-steroidal 
anti-inflammatory 
drugs 
(NSAIDs), 
antimalarials, 
glucocorticoids, 
and 
immunosuppressive drugs such as cyclophosphamide, mycophenolate mofetil, 
azathioprine, or methotrexate. Guidelines for the pharmacological treatment of SLE were 
developed by the ACR in 1999 [ACR 1999] and the EULAR task force in 2008 [Bertsias 
2008]. 


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The choice of therapy is highly individualized and depends on symptom manifestations, 
organ involvement, and disease severity. Life-threatening or organ-threatening 
manifestations of SLE, such as those involving the kidneys, CNS, or blood vessels are 
treated with high-dose corticosteroids, immunosuppressive drugs, and biologics. 
Prednisone, hydroxychloroquine, and belimumab are approved therapies for SLE; other 
therapies including immunosuppressive drugs, rituximab, and intravenous (i.v.) 
immunoglobulins are used off-label [Yildirim-Toruner 2011]. Management of disease 
refractory to standard treatments, especially nephritis, cutaneous and neuropsychiatric 
manifestations as well as the prevention of disease flares, remain unsatisfactory and new 
therapeutic options are needed. 
This study will require patients to receive stable doses of at least one standard SLE 
therapy, which may include NSAIDs, antimalarials, glucocorticoids, methotrexate, 
azathioprine, or mycophenolate mofetil.  
1.1.3.1 Nonsteroidal anti-inflammatory drugs  
NSAIDs are commonly used to relieve SLE manifestations including arthralgia, 
inflammation, serositis, and fever. They can be used in combination with low doses of 
steroids or antimalarial agents [Gurevitz 2013].  
1.1.3.2 Antimalarial drugs 
Chloroquine-based antimalarial drugs such as chloroquine and hydroxychloroquine, often 
in combination with NSAIDs, are generally used as a first-line treatment for patients with 
mild SLE. Hydroxychloroquine (Plaquenil®) is approved for the treatment of SLE in the 
USA [FDA Plaquenil] and in some European countries including United Kingdom, 
France and Belgium. 
Antimalarials were found to prevent lupus flares and increase long-term survival of 
patients with SLE [Ruiz-Irastorza 2010]. Antimalarials are most useful for constitutional 
symptoms (e.g., fatigue and fever), musculoskeletal, and skin manifestations. 
Antimalarials have also possible cardioprotective and thromboprotective effects 
[Jung 2010]. Common adverse effects are gastrointestinal discomfort and dermatological 
reactions. Rarely, retinal toxicity has been reported, and regular eye examinations are 
recommended. 
1.1.3.3 Glucocorticoids 
Glucocorticoids rapidly relieve inflammation and modulate the immune system. The dose 
of glucocorticoid treatment depends on the severity and organ involvement in SLE.  
Low doses of oral prednisone (e.g., 0.1–0.2 mg/kg/day) can be used for the treatment of 
cutaneous or musculoskeletal manifestations not responding to other treatments and can 
help to prevent flares in clinically stable but serologically active patients [Gurevitz 2013; 


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Amissah-Arthur 2010]. A medium dose of oral prednisone (e.g., 0.5 mg/kg/day) can be 
used for moderate SLE with cardiopulmonary or hematological involvement. Finally, a 
high dose of oral prednisone (e.g., 1 mg/kg/day) or pulse methylprednisolone i.v. is used 
to treat severe disease with major organ involvement including the kidneys, CNS, or 
blood vessels, often in conjunction with immunosuppressive agents such as 
cyclophosphamide or mycophenolate mofetil [Kalunian 2009]. 
Long-term treatment with glucocorticoids can have several adverse effects including 
hyperglycaemia, osteoporosis, hypertension, glaucoma, gastrointestinal discomfort, 
myopathy, and accelerated atherosclerosis for which patients should be monitored. The 
lowest dose and shortest effective duration of treatment should be used. 
1.1.3.4 Immunosuppressives 
Treatment with immunosuppressives is reserved for patients with severe manifestations. 
These drugs usually include methotrexate, cyclophosphamide, mycophenolate mofetil, 
and azathioprine. Cyclosporine, tacrolimus, and leflunomide are used less frequently. 
Methotrexate has anti-inflammatory effects and can be beneficial in patients with 
articular and cutaneous involvement, decreasing SLE activity and allowing the use of 
lower glucocorticoid dose [Fortin 2008; Yildirim-Toruner 2011]. Adverse effects include 
stomatitis, bone marrow suppression, hepatotoxicity, alopecia, and pneumonitis. 
Cyclophosphamide has a cytotoxic effect on lymphocytes. In conjunction with 
glucocorticoids, cyclophosphamide is the standard of care for treatment of severe 
organ-threatening manifestations including lupus nephritis, neuropsychiatric lupus, and 
systemic vasculitis [Kalunian 2009]. Adverse effects include cystitis, infertility, alopecia, 
malignancies, and infections. 
Mycophenolate (the active metabolite of mycophenolate mofetil) blocks the proliferation 
of lymphocytes. Mycophenolate mofetil is often used instead of cyclophosphamide in 
combination with glucocorticoids for the treatment of lupus nephritis. Mycophenolate 
mofetil can be used for maintenance of renal response in patients with lupus nephritis 
[Dooley 2011]. Adverse effects include nausea, abdominal pain, diarrhea, bone marrow 
suppression, and infections. 
Azathioprine blocks lymphocyte proliferation. It is effective for treatment of articular and 
cutaneous manifestations and is frequently used to manage mild lupus nephritis and as a 
steroid-sparing agent [Yildirim-Toruner 2011]. Adverse effects include bone marrow 
suppression, gastrointestinal intolerance, and hepatotoxicity. 
1.1.3.5 Biologics 
Belimumab is a human IgG1λ monoclonal antibody that inhibits B-cell activating factor 
(BAFF), also known as B-lymphocyte stimulator (BLyS). 


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Belimumab (Benlysta®) was approved by the FDA in 2011 for use in adult patients with 
active, autoantibody-positive SLE who are receiving standard therapy [FDA Benlysta] 
[Furie 2011; Navarra 2011]. In the EU, belimumab is approved as add-on therapy in adult 
patients with active, autoantibody-positive SLE with a high degree of disease activity 
(e.g., positive anti-double-stranded DNA [anti-dsDNA] and low complement) despite 
standard therapy [EMA Benlysta]. Adverse effects observed in the clinical studies were 
mainly injection reactions. Biologics have reported therapeutic effects in SLE clinical 
studies. Rituximab depletes CD20+ B cells including autoreactive B cells 
[Yildirim-Toruner 2011]. Although placebo-controlled trials in SLE failed to demonstrate 
clinical improvement with rituximab, a number of small studies have suggested 
therapeutic benefit, and the drug is often used for treatment of severe refractory SLE 
especially lupus nephritis. Adverse effects include lymphopenia, neutropenia, and severe 
infections. 
Small clinical trials have reported beneficial effects of i.v. immunoglobulins, and this is 
sometimes used to treat refractory SLE. Other biologics with immunomodulatory 
activity, including abatacept (an inhibitor of T-cell activation), epratuzumab (a 
monoclonal antibody to CD22), blisibimod (a peptide inhibitor of BAFF), have reported 
potential beneficial effects, and clinical studies are ongoing to confirm preliminary 
findings [Ding 2013].  
1.1.4 Unmet needs in SLE 
Despite the significant improvements in diagnosing and managing the disease, treatment 
of SLE remains an area of significant unmet need. With the exception of belimumab, no 
new drug has received an approval for treatment of SLE in the last 50 years. Therapies 
for SLE consist of relatively non-specific immunosuppressive and anti-inflammatory 
drugs that are not effective in some patients and can be associated with significant side 
effects. Novel treatment options are needed for patients with severe disease, especially 
renal and CNS manifestations, and for patients with disease refractory to conventional 
therapies. Although approved for treatment of SLE, belimumab has shown modest 
efficacy and slow onset of effect and is not approved for treatment of lupus nephritis or 
CNS lupus.  
There is a great need for effective and safe steroid-sparing therapies that can help reduce 
toxicity from long-term use of high-dose glucocorticoids. Accelerated atherosclerosis and 
cardiovascular disease represent significant burden for patients with SLE that may be 
exacerbated by chronic use of glucocorticoids. 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 has shown significant effects on fatigue. Furthermore, the 
prevention of disease flares represents also a high medical need. 






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The study has recently been completed, and main findings of the study are summarized in 
the next sections. More detailed information can be found in the Investigator's brochure 
[ACT-334441 IB]. 
1.3.2.1 Clinical pharmacokinetics 
Following administration of single doses to male healthy subjects, the PK profile of 
ACT-334441 was characterized by low inter-subject variability (coefficient of variation 
[CV] < 30% for area under the curve, maximum observed plasma concentration [Cmax], 
and half life [t½]). Cmax was achieved within 5–6 h after dosing and t½ was between 170 
and 199 h (~ 7–9 days). 
Following administration of multiple once daily (o.d.) doses, steady-state conditions were 
attained between 20–32 days of treatment, and the t½ after the last administration was 
between 12–22 days. ACT-334441 accumulated in plasma, with 5- to 9-fold higher Cmax 
and area under the curve 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 ACT-334441 was 
observed. 
Only limited clinical data are currently available regarding the metabolism of 
ACT-334441. No information is available regarding the effects of disease (e.g., renal or 
hepatic impairment), age, or ethnicity on the PK of ACT-334441. Only limited data are 
available on the effects of sex on the PK of ACT-334441 (examination of the data from 
the 2 female subjects who received ACT-334441 suggest that the PK profile is not 
influenced by sex). 
1.3.2.2 Pharmacodynamics in humans 
Effect on lymphocyte count 
Oral administration of ACT-334441 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 ACT-334441, the lymphocyte count generally returned to normal range 
within 6 days.  
Repeated o.d. dosing of ACT-334441 (0.5 mg, 1 mg, 2 mg, or 4 mg) for 35 days led to a 
gradual, dose-dependent reduction in absolute lymphocyte count. Compared to baseline, 
multiple doses of ACT-334441 induced a decrease ranging from 34% to 64% with doses 
from 0.5 mg to 4 mg. The time the mean lymphocyte counts returned to within normal 


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range (i.e., ≥ 1 × 109 cells/L) dose dependently increased and was 28 days for the 4 mg 
dose group. 
No relevant differences in the effect on lymphocyte count reduction were seen after 
single-dose administration of 1 mg ACT-334441 in the fed and fasted states. 
1.3.2.3 Safety and tolerability 
Single doses of 1 mg, 3 mg, 10 mg, and 25 mg were evaluated in healthy subjects. The 
10 mg dose was identified as the maximal tolerated single dose of ACT-334441. 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 mg, 1 mg, 2 mg, and 4 mg ACT-334441 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, non-cardiac 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 ACT-334441, 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 ACT-334441 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 ACT-334441. 
In Part D of study AC-064-101, repeated administration of 2 mg ACT-334441 o.d. 
reduced the effect on HR of subsequent administration of 10 mg ponesimod, another 
S1P1 modulator with first-dose effect on HR. This shows that chronic o.d. administration 
of a 2 mg ACT-334441 dose can lead to desensitization of S1P1.  
Effect on blood pressure 
Blood pressure (BP) reduction was observed following a single high-dose administration 
(10 mg 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 ACT-334441. 


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Effect on liver enzyme elevations 
A transient increase in alanine aminotransferase (ALT) and/or aspartate aminotransferate 
(AST) and/or gamma glutamyl transferase (GGT) was observed in 8 subjects on active 
treatment after multiple doses of ACT-334441 (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 
and/or 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. 
1.4 
Purpose and rationale of the study 
The central role of S1P1 in T and B lymphocyte trafficking and the ability of an S1P1 
modulator to reduce the availability of circulating lymphocytes create a promising 
therapeutic approach for several autoimmune diseases including SLE. S1P modulation 
has been proven effective for the treatment of multiple sclerosis [Kappos 2010] and has 
recently been shown to have therapeutic potential also in psoriasis [Vaclavkova 2014].  
S1P1 modulators, including fingolimod (non-selective), ponesimod and KRP203 (both 
selective for S1P1), have shown beneficial effects in mouse models of SLE. Positive 
effects have been observed on kidney disease, serological abnormalities, and survival 
[Okazaki 2002; Ando 2010; Alperovich 2007; Wenderfer 2008]. Based on these data, it is 
plausible to hypothesize a therapeutic effect of ACT-334441 in patients with SLE. 
Patients with SLE have a number of immune system abnormalities, with the disease 
involving multiple organs and systems. The complexity and heterogeneity of SLE 
manifestations make it important to initially characterize the safety and biological activity 
of a potential novel treatment. For these reasons, the main purpose of this study is to 
investigate the dose response for lymphocyte count reduction and the safety and 
biological activity of ACT-334441 in SLE patients.  
Data from the non-selective S1P modulator fingolimod have shown that a 70% decrease 
in lymphocyte count compared to baseline is associated with efficacy in multiple 
sclerosis. Other selective S1P1 modulators such as siponimod and ponesimod have also 
shown that a lymphocyte count reduction of 60–70% from baseline is associated with a 
plateau of efficacy in multiple sclerosis, while a 20–30% reduction in lymphocyte counts 
is associated with minimal efficacy [Olsson 2014; Selmaj 2013]. 
The dose levels of 0.5 mg, 1 mg, 2 mg, and 4 mg of ACT-334441 planned for this study 
were well tolerated and have shown lymphocyte count reduction from baseline in the 
range 34–64% in healthy subjects in Phase 1. This approach is expected to allow the 


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characterization of the safety and biological activity for a range of potentially efficacious 
doses of ACT-334441 in SLE patients, and to possibly enable the selection of dose(s) for 
subsequent studies. 
2 
STUDY OBJECTIVES 
2.1 
Main objectives 
• To investigate the PD of ACT-334441 in adult subjects with SLE.  
• To investigate the safety and tolerability of ACT-334441 in adult subjects with SLE. 
2.2 
Exploratory Objectives 
• To investigate the PK of ACT-334441 in adult subjects with SLE. 
• To investigate the effect of ACT-334441 treatment on disease activity in adult 
subjects with SLE. 
3 
OVERALL STUDY DESIGN AND PLAN 
3.1 
Study design  
This 
is 
a 
prospective, 
multicenter, 
multinational, 
randomized, 
double-blind, 
placebo-controlled, two-part, dose-response Phase 1/2 study.  
This study is divided in two parts:  
Part A 
Part A will consist of four parallel treatment groups (including 0.5 mg, 1 mg, or 2 mg of 
ACT-334441 and placebo control). 
Approximately 48 subjects will be randomized (1:1:1:1) via an interactive response 
technology (IRT) system to one of four groups (i.e., 12 subjects in each group; three dose 
levels of 0.5 mg, 1 mg, or 2 mg ACT-334441, or placebo o.d.). 
Interim safety review 
An interim safety review will be conducted by the Independent Data Monitoring 
Committee (IDMC) when all subjects enrolled into Part A have completed Visit 4 
(Week 4), unless prematurely discontinued. The IDMC will then evaluate the safety 
profile of ACT-334441 in SLE patients and give a recommendation whether or not to 
continue the study as planned (i.e., proceed to Part B) [see Section 11.5]. 
Part B  
Part B will consist of two parallel treatment groups (including 4 mg ACT-334441 and 
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Approximately 16 subjects will be randomized (3:1) via an IRT system to one of two 
groups (i.e., 12 subjects receiving 4 mg ACT-334441 and 4 receiving placebo o.d.). 
Subjects enrolled in Part A are not eligible for Part B. 
The overall study design is shown in Figure 1. 
Figure 1 
AC-064A201 study design 
 
 
 
 
EOT = End-of-Treatment; EOS = End-of-Study; FU = follow-up; IDMC= Independent Data Monitoring 
Committee.  
3.1.1 Study periods 
There will be three periods in Part A and Part B: 
3.1.1.1 Screening period  
This period starts up to 30 days before Randomization at the time of the Informed 
Consent Form (ICF) signing and ends with subject randomization. It includes the 
Screening visit and the pre-randomization assessments. 


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3.1.1.2 Treatment period  
The treatment period will last 12 weeks. Visits during the treatment period will include 
the post-randomization assessments of the Randomization visit and visits at Weeks 2, 4, 
8, 12.  
The End-of-Treatment (EOT) visit will take place at Week 12 or earlier in case of 
premature permanent discontinuation of study treatment. In all cases, the EOT visit 
should take place 1 day after the last dose of study treatment intake but no later than 
7 days after the last dose of study treatment intake. 
3.1.1.3 Follow-up period  
This period starts immediately after the last dose of study treatment intake and ends 
approximately 16 weeks after the last dose of study treatment intake. The End-of-Study 
(EOS) visit will take place 6 weeks after the last dose of study treatment intake. 
After EOS, the subject will be followed up for an additional 10 weeks and will be 
contacted by telephone for follow-up 11 weeks and 16 weeks after last dose of study drug 
intake for SAEs and pregnancy status assessments. 
3.1.2 Study duration 
The planned study duration for Part A is approximately 11 months from 
First subject-First Visit (FSFV) to Last Subject-Last Visit (LSLV) and approximately 
20 months until LSLV from Part B.  
3.2 
Study design rationale 
This Phase 1/2 study is the first ACT-334441 study in SLE patients and the first study of 
an S1P1 modulator in SLE. The study has been designed to investigate the dose response 
for lymphocyte count reduction, and the safety, tolerability, PK, and biological activity of 
ACT-334441 in subjects with SLE who have at least one mucocutaneous and/or 
musculoskeletal manifestation despite receiving standard therapy. Because side effects of 
ACT-334441 may overlap with major organ involvement in SLE, patients with renal, 
cardiac, CNS, lung, and liver involvement are excluded. Patients with high disease 
activity (SLEDAI-2K > 12) will not be allowed to enter the study. (For the rationale of 
the study population, see Section 4.2.) 
A randomized, placebo-controlled, double-blind approach is used to eliminate bias in 
reporting safety and biological activity data. During the study, several decisions and 
assessments will have to be performed. In order to limit the risk of bias, specific 
measures are implemented to reduce the risk of unblinding. These measures include 
preventing access to results of white blood cell (WBC) and lymphocyte counts to the 
study site personnel and sponsor’s team, and preventing access of first-dose HR data 


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(12-lead electrocardiogram [ECG] on Day 1 and day of re-initiation and 24-hour Holter 
ECG on Day 1) to the the investigator, unless deemed necessary for patient safety. 
The use of ACT-334441 as adjunctive therapy to the standard of care is a suitable 
approach that enables evaluation of ACT-334441 in the context of commonly used SLE 
medications. Background standard therapy for SLE is allowed to ensure feasibility and 
representativeness of the real-life setting, but the type and dose of background therapies 
are limited and required to be stable to avoid confounding the evaluation of safety and 
biological activity of ACT-334441.  
A 12-week treatment duration is considered adequate for the initial evaluation of 
potential risks associated with ACT-334441 treatment. Twelve weeks is a sufficient time 
for ACT-334441 to reach steady-state concentration and is expected to allow an 
evaluation of biological activity (e.g., lymphocyte count reduction), an assessment of 
acute effects on HR and atrioventricular (AV) conduction, as well as of potential effects 
on pulmonary function. A 6-week follow-up period is considered adequate based on 
results from the Phase 1 study in healthy volunteers, in which the lymphocyte count 
normalized within 28 days for the 4 mg dose group. Additional 11-week and 16-week 
follow-up telephone calls are implemented to further increase patients’ safety. 
The dose levels of 0.5 mg, 1 mg, 2 mg, and 4 mg of ACT-334441 planned for this study 
have shown a dose response for lymphocyte count reduction, with a decrease in the range 
from −34 to −64% from baseline in healthy subjects in Phase 1, and are expected to be 
efficacious doses of ACT-334441 in SLE patients. 
The study will be performed in two parts. The first part (Part A) consists of a 
parallel-group treatment period, in which approximately 48 patients are randomized in a 
1:1:1:1 ratio to receive 0.5, 1, 2 mg ACT-334441 or placebo for 12 weeks. The second 
part (Part B) consists of a parallel-group treatment period, in which approximately 
16 patients are randomized in a 3:1 ratio to receive 4 mg ACT-334441 or placebo for 
12 weeks. For safety reasons, the second part testing the highest dose of 4 mg will 
commence only after an interim safety review of data from Part A is completed by the 
IDMC. This interim safety review will take place once all patients randomized in Part A 
have completed the Week 4 visit, unless prematurely discontinued. Four weeks of 
treatment are selected for this interim review as, based on observations in healthy 
subjects, this is a sufficient time to approach a plateau in the reduction of lymphocyte 
counts and to detect the main adverse effects of ACT-334441 treatment, including acute 
effects on HR and AV conduction.  
Study-specific stopping rules will be applied separately for the first part (Part A) and the 
second part (Part B). For Part A, if 12 or more subjects out of the planned 36 subjects in 
the combined active dose groups (0.5, 1, or 2 mg), or 6 or more subjects out of the 


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planned 12 subjects in the 2 mg dose group, have been discontinued study treatment due 
to meeting any of the individual patient’s stopping rules as defined per safety area of 
interest [see Section 9.3], the entire study will be put on hold. A detailed safety signal 
assessment and recommendations from IDMC and Health Authorities may allow a 
potential restart of the study.  
For Part B, if 4 or more subjects out of the planned 12 subjects in the active dose group 
(4 mg), have been discontinued study treatment due to meeting any of the individual 
patient’s stopping rules as defined per safety area of interest [see Section 9.3], all subjects 
included in Part B will stop study treatment. A detailed safety signal assessment and 
recommendations from IDMC and Health Authorities may allow a potential restart of the 
Part B. 
This study has been designed in accordance with the FDA guidance [FDA 2010], draft 
EMA guidelines [EMA 2013] and EULAR recommendations [Bertsias 2008] for clinical 
investigations in SLE. 
3.3 
Site personnel and their roles 
In order to maintain the blind throughout the study [see Section 5.1.5] and to facilitate the 
performance of assessments required by the protocol, it is essential that: 
• the site personnel have the appropriate medical expertise to perform these 
assessments; 
• the roles are defined clearly upfront. 
 
It is recommended that the designated personnel remain unchanged throughout the entire 
course of the study and that an adequately trained back-up is designated in case of 
absence of any of the staff listed below. 
At each site, the study staff will consist of: 
• A principal investigator; 
• A treating physician (the principal investigator may be acting as treating 
physician); 
• A cardiac safety assessor (CSA) responsible for close cardiac monitoring of the 
subject on Day 1 after dosing and at study treatment re-initiation visits, as well as 
at other visits as needed (for a given subject, the roles of treating physician and 
CSA are irreconcilable and must be assumed by two distinct physicians); 
• An echocardiography specialist responsible for echocardiographies; 
• A clinical coordinator/study nurse (if required); 
• An ophthalmologist responsible for the ophthalmological assessments (incl. 
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• A pulmonary function laboratory technician or expert responsible for spirometry. 
3.3.1 Principal investigator 
The principal investigator is responsible for the overall conduct of the study at the clinical 
site. It is her/his responsibility to assign appropriate personnel to the protocol-requested 
assessments (including safety and efficacy) and to define their roles. The principal 
investigator oversees the accrual of appropriate subjects, the conduct of the study 
according to the trial protocol, and the collection of the required data. 
3.3.2 Treating physician 
The treating physician can be a rheumatologist or a physician with specific training and 
experience in the management of patients with SLE. The principal investigator may act as 
the treating physician.  
It is the responsibility of the treating physician to explain the study in all its aspects to the 
subject and to obtain her/his informed consent.  
The treating physician will be responsible for subject clinical care and management, e.g., 
eligibility evaluation, supervision of study drug administration, reporting of disease 
activity, safety monitoring (including recording and treating of AEs, SAEs, physical 
examination, and routine laboratory results), and concomitant medications monitoring 
and reporting.  
The treating physician will be responsible for completing the Systemic Lupus 
Erythematosus Disease Activity Index-2000 (SLEDAI-2K) and the Physician’s Global 
Assessment (PGA). She/he must be trained to use the the SLEDAI-2K. 
The treating physician can consult the CSA and/or a cardiologist for interpretation of 
12-lead ECG and 24-hour ECG assessments made at Visit 1 (Screening) and Visits 3 to 7. 
The same physician must maintain the role of the treating physician for a given subject 
throughout the study. A back-up treating physician may conduct a subject study visit only 
if the primary treating physician is not available. 
3.3.3 Cardiac safety assessor 
The CSA must be a physician adequately trained and experienced in cardiology or a 
physician who is experienced in making health care decisions based on ECG 
interpretation reports that may be provided by another cardiologically experienced 
person. She/he can support the principal investigator / treating physician in making a 
decision on eligibility of the subject prior to randomization, and in providing adequate 
treatment in case of cardiac events. 


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The CSA will be responsible to perform all BP, 12-lead ECGs and 24-hour Holter ECG 
assessments at Visit 2 (Day 1) or at study treatment re-initiation as requested by the 
protocol [see Sections 7.2.2, 7.2.3, and 7.2.4]. This includes the hourly 12-lead ECGs and 
systolic BP (SBP) / diastolic BP (DBP) assessments during the first 6 hours and up to 
12 hours following the first study treatment intake. She/he will independently assess the 
subject’s eligibility for discharge [see Appendix 4] or study drug discontinuation [see 
Sections 5.1.9 and 5.1.10].  
While the exams themselves may be performed by a delegate (e.g., study nurse), the 
review and/or interpretation of 12-lead ECGs and Holter ECG reports must be performed 
by the CSA only. The reporting of BP and dates and time of ECG assessments will be 
performed by a delegate (e.g., main study nurse or clinical coordinator) in the electronic 
Case Report Form (eCRF). 
Reports and alerts from 12-lead ECGs performed at Visit 2 (Day 1) or at study treatment 
re-initiation and from 24-hour Holter ECG performed at Visit 2 (Day 1) will be sent only 
to the CSA and must not be shared with the treating physician.  
At Visit 2 (Day 1) or at study treatment re-initiation, significant findings (e.g., new ECG 
abnormalities, bradycardia), which in the view of the CSA meet the definition of an AE, 
must be reported to the primary investigator / treating physician and recorded on an AE 
page of the eCRF. Any treatment administered by the CSA (if applicable) will be 
reported to the primary investigator / treating physician and recorded as concomitant 
medication in the eCRF. 
3.3.4 Echocardiography specialist 
The physician conducting and interpreting Standard 2D/Doppler echocardiography must 
have qualifications equivalent at least to those defined for Level 2 training by the 
American College of Cardiology Board / American Heart Association clinical 
competence statement on echocardiography [see Appendix 5; Quiñones 2003]. In case a 
sonographer conducts the examination, the physician must review and interpret the 
results. 
3.3.5 Clinical coordinator / study nurse 
Depending on the organization of the investigational site, a clinical coordinator / study 
nurse may be required to assist the principal investigator / treating physician in all aspects 
of subject management. She/he will be responsible for scheduling visits and assessments 
as planned in the study protocol, recording concomitant medications, maintaining source 
documentation, and transcription of data into the eCRF. She/he will instruct the subjects 
on study drug administration, and collect, process, and send all blood and urine samples 
to the central laboratory. Additionally, she/he may be responsible for coordinating the 
pulmonary function tests (PFTs), ophthalmological and cardiac examinations, and the  


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36-Item Short Form Health Survey v2 (SF-36v2™) questionnaire. In the absence of a 
clinical coordinator / study nurse, the above tasks will be performed by the principal 
investigator. 
Important note: A person supporting the principal investigator / treating physician in 
performing or reporting study assessments cannot be delegated by the CSA to conduct 
12-lead ECG and Holter ECG at Day 1 or study re-initiation with unblinding potential. 
3.3.6 Ophthalmologist 
The ophthalmologist will review and interpret the ophthalmological examinations 
including OCT assessments as scheduled in the study protocol [see Sections 7.2.7 and 
7.2.8]. In the event of findings observed at any visit during the study, the ophthalmologist 
will conduct further examination, as per local standard practice, to rule out or confirm the 
diagnosis, and the treating physician will be notified for reporting any AEs or SAEs. 
3.3.7 Pulmonary function laboratory technician or expert 
Spirometry testing will be performed by a PFT technician, respiratory therapist or expert, 
or by a person with qualifications equivalent to those defined for a Registered Pulmonary 
Function Technologist and/or Registered Respiratory Therapist by the American 
Thoracic Society (ATS) / European Respiratory Society (ERS) guidelines [Miller 2005a]. 
Minimum requirements include sufficient education and training to assure that the 
technician understands the fundamentals of the tests, the common signs of pulmonary 
diseases and the management of the acquired pulmonary function data [Miller 2005a] . 
To the extent logistically feasible, attempts should be made to have the same tester 
throughout the study for a subject. Back-up testers (PFT technician, respiratory therapist 
or expert, or an equally experienced person according to the ATS/ERS guidelines 
[Miller 2005a] may conduct spirometry if the primary tester is not available. All PFT 
technicians or other experienced persons participating in the study will be trained before 
study start on the specific study requirements and if compliance issues are identified. 
3.4 
Study Committees  
3.4.1 Independent Data Monitoring Committee 
An IDMC has overall responsibility for safeguarding the interests of subjects by 
monitoring safety data obtained in the study in an unblinded fashion and making 
appropriate recommendations based on the reported data, thus ensuring that the study is 
being conducted with the highest scientific and ethical standards. The IDMC will be fully 
operational prior to enrolment of the first subject into the study. The IDMC will review 
unblinded safety data at regular intervals, including frequency of AEs, adverse events of 
special interest (AESIs), SAEs, AEs leading to treatment discontinuation (by dose and 
safety area of interest dependent manner). The IDMC will provide recommendation to 


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apply study stopping rules (if indicated [see Section 9.3]). In addition, the IDMC will 
review interim data from Part A when all subjects enrolled into Part A have completed 
Visit 4 (Week 4), (unless prematurely discontinued) [see Section 11.5] and will 
recommend whether or not to continue the study as planned (i.e., proceed to Part B). 
The composition and operation of the IDMC is described in the IDMC charter. 
3.4.2 Ophthalmology Safety Board 
An Ophthalmology Safety Board (OSB) composed of two independent ophthalmologists 
will review and evaluate in a blinded fashion any new or suspected case of macular 
edema. The composition and operation of the OSB is described in the OSB charter. 
4 
SUBJECT POPULATION 
4.1 
Subject population description 
This Phase 1/2 study will enroll adult patients with a confirmed diagnosis of SLE 
≥ 6 months, as defined by the 1997 update of the 1982 ACR revised criteria for 
classification of SLE [Hochberg 1997; Tan 1982]. Per the classification, patients will 
have fulfilled ≥ 4 of the 11 ACR diagnostic criteria, either serially or simultaneously. 
Presence of at least one mucocutaneous or musculoskeletal manifestation including 
myositis, arthritis, rash, alopecia, mucosal ulcers will be required at Screening [see 
Appendix 6]. A positive serum antibody test (ANA or anti-dsDNA) at Screening or a 
documented history of positive test will also be needed to ensure correct SLE diagnosis. 
Background therapies for SLE are allowed and at least one background therapy is 
required, with ACT-334441 used as adjunctive treatment. This defines a target population 
with remaining active disease and an unmet need for additional treatment despite 
standard therapy. Concomitant background therapy for SLE is permitted if treatment has 
been stable for 30 days prior to randomization and will have to include at least one of the 
following: NSAIDs, glucocorticoids, anti-malarials (hydroxychloroquine, chloroquine, 
quinacrine), mycophenolate mofetil, azathioprine, or methotrexate. The dose of these 
medications will be required not to exceed certain thresholds [see Section 4.3] and will be 
kept stable during the study.  
Patients with underlying pulmonary, cardiac or liver disease as well as patients with 
severe lupus (SLEDAI-2K score > 12 points) will be excluded. Subjects with active lupus 
nephritis, as proteinuria > 1.0 g/24 h, or equivalent using spot urine protein-to-creatinine 
ratio or subjects with CNS lupus (e.g., aseptic meningitis, seizures, cerebritis, 
polyneuropathy, cerebrovascular disease) within 90 days prior to Randomization will be 
excluded from the study. 


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Please refer to Sections 4.3 and 4.4 for a complete listing of the inclusion/exclusion 
criteria for the study. 
4.2 
Rationale for the selection of the study population 
Clinical manifestations of SLE are highly heterogeneous, ranging from fatigue, 
arthralgia, oral ulcerations, skin rash to life-threatening renal, hematological, and 
neurological disease. Current treatments remain inadequate, with many patients having an 
incompletely controlled disease and suffering from debilitating side effects of therapies. 
Patients with active disease receiving standard therapies represent a significant unmet 
need for new therapeutic options.  
Involvement of skin and/or joints is present in over 75% of SLE patients [see 
Section 1.1.1]. Inclusion of patients with musculoskeletal or mucocutaneous 
manifestations at Screening ensures the inclusion of subjects representative of the major 
SLE population.  
Subjects with severe SLE, active lupus nephritis and CNS lupus are excluded due to 
potential increased risk for end-organ damage. In addition, subjects presenting organ 
manifestations (i.e., pulmonary, cardiac or liver disease) that could overlap with potential 
toxicities of ACT-334441 will be excluded. This approach is intended to minimize the 
risk of adverse effects and to limit the type and dose of glucocorticoids and 
immunosuppressive therapies that can confound the evaluation of safety, tolerability, and 
biological activity of ACT-334441. 
4.3 
Inclusion criteria 
For inclusion in the study, all of the following inclusion criteria must be fulfilled. It is not 
permissible to waive any of the criteria for any subject: 
1. Signed informed consent prior to initiation of any study-mandated procedure. 
2. Men or women ≥ 18 and ≤ 65 years of age. 
3. Women of childbearing potential (WOCBP) as defined in Section 4.5.1: 
• must have a negative serum pregnancy test at Screening and a negative urine 
pregnancy test at Randomization at least 3 weeks apart; 
• must agree to undertake a urine pregnancy test as indicated in Table 1 
(bi-weekly/ monthly) during the study and up to 16 weeks after study 
treatment discontinuation; 
• must use methods of contraception as described in Section 4.5.2 from the 
Screening visit until 16 weeks after study treatment discontinuation.  
4. Presenting with a 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 are 
cumulative and do not need to be present concurrently) [Tan 1982; Hochberg 1997]. 


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5. Presenting with a SLEDAI-2K score of at least 2 points for musculoskeletal or 
mucocutaneous manifestations (i.e., myositis, arthritis, rash, alopecia, mucosal ulcers) 
at Screening. 
6. History or presence at Screening of positive ANA or anti-dsDNA antibodies. 
7. Currently treated for at least 30 days prior to Randomization with stable doses of one 
or more of the following background medications: 
• NSAIDs; 
• Corticosteroids (≤ 10 mg/day prednisolone or equivalent), 
• Anti-malarials (≤ 400 mg/day hydroxychloroquine, ≤ 500 mg/day 
chloroquine, ≤ 100 mg/day quinacrine)#, 
• Mycophenolate mofetil (≤ 2 g/day)#, 
• Azathioprine (≤ 2 mg/kg/day)#, 
• Methotrexate (≤ 20 mg/week)#. 
 
#Treatment with anti-malarials, mycophenolate mofetil, azathioprine, or methotrexate 
must have been started at least 90 days prior to Randomization and must not have been 
stopped within 30 days prior to Randomization. 
4.4 
Exclusion criteria 
Subjects must not fulfill any of the following exclusion criteria. It is not permissible to 
waive any of the criteria for any subject: 
 
Pregnancy and Breastfeeding 
1. Breastfeeding, pregnant women or women planning to become pregnant during the 
study. 
SLE disease 
2. Subjects with active lupus nephritis (defined by proteinuria > 1 g/24 h, or equivalent 
using spot urine protein-to-creatinine ratio) within 90 days prior to Randomization; 
subjects 
with 
CNS 
lupus 
(e.g., 
aseptic 
meningitis, 
seizures, 
cerebritis, 
polyneuropathy, cerebrovascular disease) within 90 days prior to Randomization; 
subjects with lupus vasculitis within 90 days prior to Randomization. 
3. Subjects presenting with a SLEDAI-2K score > 12 at Screening or at Randomization.  
Cardiovascular 
4. History or presence of cardiac rhythm disorders (e.g., sinoatrial heart block, second or 
third degree AV block, symptomatic bradycardia, atrial flutter or atrial fibrillation, 
ventricular arrhythmias, cardiac arrest). 
5. Resting HR < 55 bpm as measured by the pre-dose 12-lead ECG on Day 1; an 
increased QT corrected for heart rate on the basis of Fridericia’s formula (QTcF) 
interval of > 470 ms (females), > 450 ms (males) at Screening, or on Day 1 ECG 
prior to study treatment initiation. 


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6. History or presence of ischemic heart disease. 
7. History or presence of myocarditis or endocarditis. 
8. Presence of valvular heart disease associated with symptoms or hemodynamic 
change. 
9. History of syncope associated with cardiac disorders. 
10. History or presence of cardiac failure. 
11. Systemic arterial hypertension not controlled by medication according to investigator 
judgment. 
12. History or presence of vascular thrombosis at any time or a history of pregnancy 
morbidity in the context of anti-phospholipid antibody syndrome within 5 years prior 
to Randomization. 
13. Clinically relevant hypotension according to investigator’s judgment or orthostatic 
hypotension (i.e., > 20 mmHg decrease in SBP or > 10 mmHg decrease in DBP from 
supine to standing position measured between 1 and 3 minutes after standing) at 
Screening. 
14. Known pulmonary arterial hypertension of functional class III or IV.  
Pulmonary 
15. History or presence of severe respiratory disease or pulmonary fibrosis, based on 
medical history, lung function and chest X-ray (CXR) performed at Screening or 
within 3 months prior to Screening. 
16. Bronchial asthma or chronic obstructive pulmonary disease.  
17. Abnormal PFTs: FEV1 or FVC < 70% of predicted normal value; FEV1/FVC ratio 
< 0.7. 
Treatments 
18. Treatment or planned treatment with the following medications*: 
a. Within 15 days or 5 half-lives of the medication, whichever is longer, 
prior to Randomization: 
o β-blockers, 
diltiazem, 
verapamil, 
digoxin 
or 
any 
other 
anti-arrhythmic or HR-lowering systemic therapy (list of drugs 
provided in Appendix 1). 
o QT-prolonging drugs with known risk of torsades de pointes, for 
any indication (list of drugs provided in Appendix 2). 
o Short- and long-acting β2-agonists (e.g., albuterol, levalbuterol, 
formoterol, terbutaline salmeterol). 
b. Within 30 days or 5 half-lives of the medication, whichever is longer, 
prior to Randomization: 
o Cyclophosphamide, cyclosporine, tacrolimus, sirolimus, etc.,  
o Pulse methylprednisolone, 
o Vaccination with live vaccines. 
c. Within 90 days prior to Randomization: 


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o Belimumab, leflunomide 
o Any investigational immunosuppressive or immunomodulatory 
agent (within 90 days or 5 half-lives of the drug prior to start of 
study treatment, whichever is longer).  
d. Within 12 months prior to Randomization: 
o B cell-depleting biological agents such as rituximab or 
ocrelizumab. 
e. Any time prior to Randomization: 
o Alemtuzumab, S1P modulators (e.g., fingolimod). 
*For immunosuppressants or anti-inflammatory drugs not listed among the fordidden 
medications, the investigator should discuss adequate wash-out time with the sponsor. 
Infection and infection Risk 
19. Active or latent tuberculosis (TB), as assessed by CXR performed at Screening or 
within 3 months prior to Screening, and interferon gamma release assay 
(QuantiFERON-TB-Gold®) at Screening, except if there is documentation that the 
subject has completed adequate and successful treatment for latent TB infection or 
TB disease previously. 
20. Ongoing known bacterial, viral or fungal infection that is of clinical concern in the 
judgment of the investigator. 
21. A history of any serious infection, defined as life-threatening or requiring i.v. 
antibiotics or hospitalization, within 30 days prior to Randomization.  
22. Hepatistis B, C, congenital or acquired severe immunodeficiency or known human 
immunodeficiency virus (HIV) infection or positive HIV testing at Screening. 
23. Negative antibody test for varicella-zoster virus at Screening. 
Malignancy 
24. History or presence of malignancy (except for surgically excised basal or squamous 
cell skin lesions), lymphoproliferative disease, or history of total lymphoid 
irradiation. 
Transplantation 
25. History or presence of bone marrow or solid organ  transplantation. 
Ophthalmology 
26. Presence of macular edema or active uveitis. 
Metabolic and hepatic  
27. 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. 
28. Moderate or severe hepatic impairment defined as Child Pugh Score B or C, 
respectively, based on measurement of total bilirubin (TBL), serum albumin, 
international normalized ratio (INR), as well as on presence/absence and severity of 
ascites and hepatic encephalopaty. 


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29. TBL > 1.5-fold upper limit of normal (ULN; unless in the context of known Gilbert’s 
Syndrome). 
30. ALT or AST > 2-fold ULN. 
Hematology 
31. Hemoglobin (Hb) < 9 g/dL. 
32. WBC count < 2500/µL (2.5 × 109/L). 
33. Lymphocyte count < 800 /µL (0.8 × 109/L). 
34. Platelets < 75,000/µL (75 × 109/L). 
Renal 
35. Proteinuria > 1.0 g/24 hour or equivalent using spot urine protein-to-creatinine ratio. 
36. Estimated glomerular filtration rate < 60 mL/min/1.73 m2. 
Other categories 
37. History of clinically significant drug or alcohol abuse. 
38. Known allergy to S1P1 modulators or any of the ACT-334441 formulation excipients 
[see Section 5.1.1]. 
39. Any other clinically relevant medical or surgical condition that in the opinion of the 
investigator would put the subject at risk if participating in the study. 
40. Subjects unlikely to comply with protocol, e.g., uncooperative attitude, inability to 
return for follow-up visits or likelihood of not completing the study including mental 
condition rendering the subject unable to understand the nature, scope, and possible 
consequences of the study. 
 
4.5 Criteria for women of childbearing potential 
4.5.1 Definition of childbearing potential 
A woman is considered to be of childbearing potential unless she meets at least one of the 
following criteria: 
• Previous bilateral salpingectomy, bilateral salpingo-oophorectomy or 
hysterectomy. 
• Premature ovarian failure confirmed by a specialist. 
• XY genotype, Turner syndrome, uterine agenesis. 
• Postmenopausal, defined as 12 consecutive months with no menses without an 
alternative medical cause (ICH M3 definition). 
4.5.2 Acceptable methods of contraception 
WOCBP [see Section 4.5.1] must use one of the following methods of contraception 
from Visit 1 (Screening) up to at least 16 weeks after study treatment discontinuation: 
i. 
Two methods of contraception, one from Group 1 and one from Group 2, defined as 
follows: 


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o 
Group 1: Oral, implantable, transdermal, or injectable hormonal contraceptives 
or intrauterine devices. If a hormonal contraceptive is chosen from this group, it 
must be taken for at least 1 month prior to Randomization. 
o 
Group 2: Female or male condoms, diaphragm or cervical cap.  
OR 
ii. 
Sterilization of the male partner with documented post-vasectomy confirmation of 
the absence of sperm in the ejaculate. 
OR 
iii. 
Permanent female sterilization (tubal occlusion/ligation at least 6 weeks prior to 
Screening). 
OR 
iv. 
True abstinence from intercourse with a male partner only when this is in line with 
the preferred lifestyle of the subject. 
Rhythm methods or the use of a condom by a male partner alone are not considered 
acceptable methods of contraception for this study. 
The methods of contraception used (including non-pharmacological methods) must be 
recorded in the eCRF. 
4.6 
Medical history 
4.6.1 General medical history 
Relevant medical history, as defined below, must be recorded in the eCRF: 
• Chronic medical conditions including cardiac, cardiovascular, pulmonary, CNS, liver 
function, renal function, eye disorder, and skin conditions at any time in the past  
• 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 baseline therapy [see Section 5.2]  
• History of chemotherapy, radiotherapy, operations, immunosuppression or any other 
relevant medical treatment 


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4.6.2 SLE-relevant disease history 
SLE disease characteristics as defined below, evidenced by documentation in the subject 
charts, will be recorded on the SLE history page of the eCRF: 
• Date of first SLE symptoms 
• Date of SLE diagnosis 
• SLE symptoms according to ACR criteria [ACR 1997] 
1. Malar rash 
Fixed erythema, flat or raised, over the malar 
eminences, tending to spare the nasolabial folds 
2. Discoid rash 
Erythematous raised patches with adherent 
keratotic scaling and follicular plugging; atrophic 
scarring may occur in older lesions 
3. Photosensitivity 
Skin rash as a result of unusual reaction to 
sunlight, 
by 
patient 
history 
or 
physician 
observation 
4. Oral ulcers 
Oral or nasopharyngeal ulceration, usually 
painless, observed by physician 
5. Nonerosive arthritis 
Involving 
2 
or 
more 
peripheral 
joints, 
characterized by tenderness, swelling, or effusion 
6. Pleuritis or Pericarditis 
1. Pleuritis--convincing history of pleuritic pain or 
rubbing heard by a physician or evidence of 
pleural effusion OR  
2. Pericarditis--documented by electrocardigram 
or rub or evidence of pericardial effusion 
7. Renal disorder 
1. Persistent proteinuria > 0.5 grams per day 
or > than 3+ if quantitation not performed 
OR 
2. Cellular casts--may be red cell, hemoglobin, 
granular, tubular, or mixed 
8. Neurologic Disorder 
1. Seizures--in the absence of offending drugs or 
known metabolic derangements; e.g., uremia, 
ketoacidosis, or electrolyte imbalance  
OR  
2. Psychosis--in the absence of offending drugs or 
or known metabolic derangements, e.g., uremia, 
ketoacidosis, or electrolyte imbalance 
9. Hematologic Disorder 
1. Hemolytic anemia--with reticulocytosis 
OR 
2. Leukopenia--< 4,000/mm3 on ≥ 2 occasions 


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OR 
3. Lymphopenia--< 1,500/ mm3 on ≥ 2 occasions 
OR 
4. Thrombocytopenia--<100,000/ mm3 in the 
absence of offending drugs 
10. Immunologic Disorder 
1. Anti-DNA: antibody to native DNA in 
abnormal titer 
OR  
2. Anti-Sm: presence of antibody to Sm nuclear 
antigen 1.  
OR  
3. Positive finding of antiphospholipid antibodies 
on:  
1. an abnormal serum level of IgG or IgM 
anticardiolipin antibodies,  
2. a positive test result for lupus anticoagulant 
using a standard method, or  
3. a false-positive test result for at least 6 
months confirmed by Treponema pallidum 
immobilization or fluorescent treponemal 
antibody absorption test 
11. Positive Antinuclear 
Antibody 
An abnormal titer of antinuclear antibody by 
immunofluorescence or an equivalent assay at any 
point in time and in the absence of drugs 
 
In the eCRF, the date of first documented appearance and duration of the above ACR 
criteria will be recorded (when applicable). 
• 
History of detectable ANA or anti-dsDNA testing.  
o ANA 
 Date of testing 
 Titer value 
 Reference range 
 Test kit (e.g., Hep-2 titer, ELISA) 
 Testing laboratory 
o Anti-dsDNA 
 Date of testing 
 Titer value 
 Reference range 
 Test kit (e.g., Far assay, ELISA) 
 Testing laboratory 


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Important notes: 
If, at the Screening visit, ANA and anti-dsDNA results are negative per central laboratory 
testing, a positive historical test must be recorded to assess patient eligibility [see 
Section 4.3, inclusion criterion 6]. A historical testing is considered positive if ANA 
and/or anti-dsDNA antibodies was/were measured above the detection limit of the 
specific test kit used. The elevated ANA and/or anti-dsDNA should unequivocally be due 
to SLE in the opinion of the investigator. 
5 
TREATMENTS 
5.1 
Study treatment 
Study treatments include ACT-334441 and matching placebo, which are administered 
during a 12-week double-blind treatment period. 
5.1.1 Investigational treatment: description and rationale 
ACT-334441 is supplied as capsules at the doses of 0.5 mg, 1 mg, 2 mg, or 4 mg. The 
matching placebo is supplied as identical capsules formulated with the same excipients 
but without the active ingredient, ACT-334441. 
The four treatment doses of 0.5 mg, 1 mg, 2 mg, or 4 mg were selected based on PK, PD, 
safety, and tolerability results from the Phase 1 study, where such doses were 
administered o.d. up to 35 days in healthy subjects [see Section 1.3.2].  
Inactive ingredients of ACT-334441 formulation are: methycellulose, sodium lauryl 
sulfate, mannitol, colloidal silicon dioxide and dipalmitoylphosphatidylcholine; the 
capsule shell contains hydroxypropylmethylcellulose and titanium dioxide.  
5.1.2 Study treatment administration 
One capsule of ACT-334441 or placebo will be taken orally irrespective of food intake. 
The capsule will be swallowed as a whole. It is preferable that the capsule be taken each 
day at approximately the same time (preferably each morning).  
On the day of the study visits, study drug must be taken only after the completion of the 
pre-dose safety assessments (SBP, DBP, ECGs, PFTs, laboratory tests) and PK sampling. 
5.1.3 Treatment assignment 
In Part A, a total of 48 eligible subjects will be randomized in a 1:1:1:1 ratio to 
ACT-334441 0.5 mg, 1 mg, and 2 mg or placebo. In Part B, a total of 16 eligible subjects 
will be randomized in a 3:1 ratio to ACT-334441 4 mg or placebo.  
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. After having confirmed 


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the eligibility of the subject and prior to the start of study treatment, the 
investigator/delegate contacts the IRT system at Visit 2 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 randomization list is generated by the independent IRT provider and is kept strictly 
confidential. 
5.1.4 Blinding 
5.1.4.1 Study drug material related blinding 
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 at Actelion and Contract Research Organizations (CROs) involved in the 
conduct of the study will remain blinded to the treatment allocation until study closure. 
Actelion staff responsible for clinical trial supply will need to be unblinded to ensure 
adequate distribution of study treatment. 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 the study set-up has been completed. 
Until the time of unblinding for final data analysis, the randomization list is kept strictly 
confidential and accessible only to authorized persons who are not involved in the 
conduct and analysis of the study [see Section 5.1.5]. A sealed randomization code is 
kept by Actelion Global Quality Management 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. 
The investigational treatment and its matching placebo are indistinguishable, and all 
bottles will be packaged in the same way. 
5.1.4.2 Functional blinding 
First-dose effects on HR and AV conduction and lymphocyte counts reduction have been 
identified as potentially unblinding information. Access to this information by the site’s 
staff and sponsor’s study team will be restricted.  
The following measures will be taken to ensure that the main site staff and the Actelion 
study team will remain blinded to lymphocyte counts and that the medical review of 
cardiac safety assessments with unblinding potential will be performed without 
introducing bias: 
• Results of the total WBC count and total lymphocyte count will not be 
communicated to the sites, sponsor, and CRO unless a total lymphocyte count 


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< 200 cells/µL at any study visits until EOT or < 800 cells/ µL at EOS, is 
recorded by the central laboratory. In these events an alert will be sent to the 
principal investigator and to the sponsor including lymphocyte count results. 
Follow-up monitoring must be provided as described in Section 5.1.10.2. 
• Blood samples for lymphocyte subset exploratory analysis will be analyzed by the 
sponsor within 6 days after sampling. In order to avoid potential unblinding, the 
blood samples will be shipped to Actelion via the central laboratory with 
scrambled identification numbers. The Actelion team performing the analysis will 
be separated from the Actelion study team and will not have access to the subject 
number, date and time of the sampling (i.e., baseline or EOT) prior to database 
lock. 
• At the site level: 
o  A CSA will perform and evaluate the cardiac safety assessments on Day 1 
(Randomization) and on days of study treatment re-initiation. 
o The subject will be instructed not to discuss any results related to the 
first-dose administration (i.e., ECG results) with the principal investigator 
/ treating physician or any other blinded site personnel.  
o The central reading reports on 12-lead ECG and 24-hour Holter ECG 
performed after first dosing will be sent to the CSA only and must not be 
shared with the principal investigator / treating physician. 
o The principal investigator / treating physician and the CSA must not 
discuss any issues related to subject care and management on Day 1 or 
first day of study drug re-initiation, unless mandated for subject safety 
reasons. The principal investigator should not access the blinded ECG 
results, unless medically mandated to ensure subject’s safety. 
• At the sponsor level: 
o  The medical review of all first-dose data assessed on Day 1 
(Randomization) or on days of study treatment re-initiation (including 
hourly post-dose 12-lead ECGs and 24-hour Holter ECG data with 
unblinding potential, as well as other relevant data) will be performed by a 
first-dose monitor. He/she will only discuss the first-dose data with the 
CSA, the site CRA and/or IDMC members. Further details on the role of 
the first-dose monitor are described in the first-dose monitor charter. 
o Other sponsor team members involved in the medical review of other 
study data will not have access to first-dose data.  


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5.1.5 Unblinding 
5.1.5.1 Unblinding for final analyses 
Full randomization information will be made available for data analysis only after 
database closure in accordance with Actelion standard operating procedures (SOPs). 
5.1.5.2 Unblinding for interim analyses 
An ISAC, not otherwise involved in the design, conduct and analysis of the study, will 
have access to the randomization code in order to prepare the interim analysis reports and 
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 
SOPs. 
5.1.5.3 Unblinding before final analyses 
The randomization code will be made available to the PK bioanalytic laboratory in 
accordance with the sponsor’s SOPs. 
5.1.5.4 Unblinding for suspected unexpected serious adverse reactions 
When a suspected unexpected serious adverse reaction (SUSAR) occurs for a subject 
participating in the study, Actelion Global Drug Safety will request the unblinding of the 
treatment assignment. The randomization code will not be communicated to the site staff 
or to the Actelion study team; unblinded SUSAR information will be anonymized and 
provided to Actelion Global Drug Safety, respective health authorities and Institutional 
Review Boards (IRBs) / Independent Ethics Committees (IECs), and the IDMC. SUSARs 
will be reported to investigators in a blinded fashion. 
5.1.5.5 Emergency procedure for unblinding 
The investigator, study staff and sponsor staff must remain blinded to the subject’s 
treatment assignment. The identity of the study treatment may be revealed only if the 
subject experiences a medical event, the management of which would require knowledge 
of the blinded treatment assignment. In this case, the investigator can receive the 
unblinded randomization code for study treatment allocation through the IRT system. In 
these situations, the decision to unblind resides solely with the investigator. Whenever it 
is possible and if it does not interfere with (or does not delay) any decision in the best 
interest of the subject, the investigator should discuss the intended code break with the 
sponsor. 
The occurrence of any code break during the study must be clearly justified and 
explained by the investigator. The investigator must not disclose the unblinded treatment 
in the eCRF or to the sponsor or its delegates. In all cases, the sponsor must be informed 
as soon as possible before or after the code break. 


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The circumstances leading to the code break must be documented in the site study file 
and eCRF. 
Refer to the IRT system guidelines for complete information regarding the IRT system 
procedures for randomization, study drug assignment, and unblinding. 
5.1.6 Study treatment supply 
Manufacture, labeling, packaging and supply of study treatments will be conducted 
according to Good Manufacturing Practice, Good Clinical 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. 
5.1.6.1 Study treatment packaging and labeling 
5.1.6.1.1 Study treatment packaging and preparation 
Study treatment (ACT-334441 or placebo) is provided as capsules and is supplied in 
childproof bottles. 
5.1.6.1.2 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 retest date (or expiry date) will be given on the study treatment 
labels.  
5.1.6.2 Study treatment distribution and storage  
Treatment supplies must be kept in an appropriate, secure area and stored according to 
the conditions specified on the medication labels.  
5.1.6.3 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. The protocol-mandated study drug dispensing/return 
procedures may not be altered without prior written approval from the sponsor. An 
accurate record of the date and amount of study treatment dispensed to each subject must 
be available for inspection at any time.  
5.1.6.4 Study treatment return and destruction  
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 
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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 
If the CRA is not able to reconcile the treatment due to lost or prematurely destroyed 
bottles prior to destruction, the site is to provide detailed documentation that describes the 
loss or premature destruction to justify treatment accountability. 
5.1.7 Study treatment accountability and compliance with study treatment 
5.1.7.1 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 capsules dispensed (pre-populated in eCRF) 
• Date returned / number of capsules returned 
All study treatment supplies, including partially used or empty bottles, must be retained 
at the site for review by the CRA. 
If the subject forgets to bring the remaining study treatment to a study visit, he/she must 
be instructed to not take any tablet/capsules from the remaining study treatment and to 
bring it to the next visit. 
5.1.7.2 Study treatment compliance  
Treatment compliance will be assessed based on study treatment accountability: 
Accountability based compliance =  
[(number of capsules dispensed at Visit n − number of capsules returned at Visit n+1) / 
number of capsules 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 
above 80%. If below 80%, without a medical justification (e.g., adverse event), this will 
be considered as a protocol deviation. The investigator must check with the subject the 


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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. 
At Visit 3 and re-initiation visits, a compliance review based on study drug 
accountability, will be performed by the investigator (or delegate) and recorded in the 
eCRF. 
5.1.8 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, she/he must immediately inform the principal 
investigator / treating physician. If a subject forgets to take study treatment in the 
morning, she/he should take it on the same day and resume regular dosing the next 
morning. 
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 capsule per day. 
5.1.8.1 Between Day 1 and Day 14 
• If the subject misses to take the dose for 1 day or more, he/she must interrupt the 
treatment and immediately inform the principal investigator / treating physician. A 
re-initiation visit should take place within 7 days after the first dose was missed. 
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 the study treatment cannot be re-initiated within 7 days after the treatment 
interruption, the subject should be permanently discontinued. (Note that re-initiation 
visits may be performed after Day 14 if initial missed dosing occurred between 
Day 7–14) 
• If, at any visits (scheduled or unscheduled), the subject reports to the investigator 
having missed to take the dose for one or more days during the initial 2 weeks of 
treatment (Day 1 to Day 14) but has then resumed study treatment without reporting 
promptly the interruption to the investigator, information on any event potentially 
related to the interruption should be collected and the subject should be counselled on 
the risks of non-compliance. Based on the information available, the investigator may 
decide to permanently discontinue the subject or to continue study treatment as 
planned. No re-initiation should be performed in such a case. 
Note that a subject can be re-initiated only once during the study duration. 


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5.1.8.2 After Day 14 
• If the subject missed doses for less than 7 consecutive days: 
o Regular dosing should be continued with the morning dose on the following 
day. 
o Subjects must be instructed to contact the investigator immediately if they 
experience any symptoms of bradycardia (e.g., dizziness, vertigo, syncope). 
 
• If the subject missed doses for more than 7 consecutive days: 
o The subject should be permanently discontinued. 
A schematic overview is provided in Figure 2. 
Figure 2 
Algorithm for management of study treatment interruptions 
 
5.1.9 Premature discontinuation of study treatment 
The decision to prematurely discontinue study treatment may be made by the subject, the 
investigator, or Actelion. The main reason and whether discontinuation of study 
treatment is the decision of the subject, the investigator, or Actelion must be documented 
in the eCRF. 
A subject has the right to prematurely discontinue study treatment at any time 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 9.2]). 


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The investigator should discontinue study treatment for a given subject if, on balance, 
she/he believes that continued administration would be contrary to the best interests of 
the subject. Study treatment may be discontinued in response to an AE, lack of efficacy 
(including disease progression, treatment failure, worsening of subject condition), a 
protocol deviation (including not meeting eligibility criteria, non-compliance with study 
requirements, such as non-compliance with study treatment intake or visit attendance), or 
if the subject is lost to follow-up. Study-specific criteria for discontinuation of study 
treatment are described in Section 5.1.10. 
Premature discontinuation of study treatment may also result from a decision by 
Actelion, e.g., in case of premature termination or suspension of the study [see 
Section 9.3]. A subject who prematurely discontinues study treatment is not considered as 
withdrawn from the study, provided that the subject’s consent for this limited 
participation in the study has not been withdrawn. Subjects who prematurely discontinue 
study treatment will be asked to return for an EOT visit within 7 days of last study 
treatment intake, to attend an EOS Visit 6 weeks after the last dose of study treatment and 
will be followed-up for a total of 16 weeks after last study treatment intake (telephone 
call follow-up for pregnanacy and SAEs). 
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 is described in Sections 9.2 and 9.4, respectively. 
5.1.10 Management of clinical events and study-specific criteria for interruption / 
premature discontinuation of study treatment 
5.1.10.1 Cardiovascular 
Subjects must be permanently discontinued from study treatment if any of the following 
occurs:  
• HR < 40 bpm at two consecutive hourly 12-lead ECG post-dose on Day 1 (or on 
days of re-initiation following study treatment interruptions), or 
• SBP < 90 mmHg at two consecutive hourly BP measurements post-dose on Day 1 
(or on days of re-initiation following study treatment interruptions), or 
• The subject does not meet the criteria for discharge from the hospital on Day 1 (or 
on days of re-initiation following study treatment interruptions) after 12-hour 
post-dose monitoring [see Appendix 4], or 


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• QTcF > 500 ms is observed at any time throughout the study, as documented by 
12-lead ECG. 
In addition, the investigator should consider permanent discontinuation of study 
treatment if a subject reports at any time symptomatic bradycardia or hypotension (e.g., 
syncope). 
Follow-up monitoring will have to be provided until the event resolves, the condition is 
stable, or the change is regarded as no longer clinically relevant.  
Continuous ECG monitoring is recommended for subjects who meet study treatment 
discontinuation criteria related to bradycardia or other arrhythmia. Subjects who are 
permanently discontinued should not be discharged from the monitored setting before 
vital signs return to near baseline values and until there is no persisting ECG abnormality 
(e.g., QT prolongation, AV block second degree or higher) or ongoing AE requiring 
(continued) hospitalization, or until medically indicated. Any clinically relevant findings 
meeting the definition of an AE will be recorded accordingly in the eCRF. 
In case of any signs and symptoms of bradycardia or other arrhythmia (e.g., syncope, 
palpitations, dizziness) at any time during the study treatment, the CSA should be 
consulted. In case a cardiac origin of any event is suspected, permanent discontinuation 
of study treatment should be considered. 
In case subjects develop new or worsening of pre-existing hypertension during the course 
of the treatment with the study treatment that in the opinion of the investigator cannot be 
adequately controlled by medications, study treatment should be permanently 
discontinued.  
5.1.10.2 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/µL 
Confirmation will be done as follows: 
Whenever a total lymphocyte count < 200 cells/µL, is recorded by the central laboratory, 
an alert will be sent to the principal investigator and the sponsor. The primary 
investigator will immediately contact the subject and ask her/him to return to the site 
within 48 hours at the latest to repeat the test at trough level (pre-dose) by the central 
laboratory (unless the clinical situation mandates an immediate local testing). If the 
repeat test confirms a total lymphocyte count < 200 cells/µL, the study treatment must be 
discontinued, and lymphocyte counts must be monitored on a regular basis (e.g., every 


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2 weeks) at least until the EOS visit (6 weeks after study drug discontinuation). If 
lymphocyte count is still < 800 cells/µl at the EOS visit, monitoring should continue on a 
regular basis (e.g., every 2 weeks) by the local laboratory until the lymphocyte count has 
returned to ≥ 800 cells/µL or until medically indicated. 
In the event that clinically relevant, persistent blood cell count abnormalities (e.g., a 
marked abnormal low value for neutrophils, RBC or platelets flagged “LLL”; see 
Appendix 7) are observed, the investigator should consider permanent discontinuation of 
study treatment and/or discontinuation of concomitant immunosuppressive medications. 
5.1.10.3 Respiratory system 
In case of abnormal spirometry results or persistent respiratory symptoms (e.g., dyspnea), 
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 and below. 
Table 2 
Guidelines for FEV1 and/or FVC decrease  
 
Item 
Parameter 
Guideline 
1 
If FEV1 and/or FVC > 15% decrease from the study 
baseline. 
Repeat spirometry assessments 
preferably within 1 week 
See item 1a, 1b. 
1a 
If at repeat spirometry assessment: 
FEV1 and/or FVC > 15% decrease from the study 
baseline. 
Permanently discontinue study 
treatment and perform FU 
spirometry assessments. 
1b 
If at repeat spirometry assessment: 
FEV1 and/or FVC ≤ 15% decrease from the study 
baseline. 
Resume regular spirometry assessment 
schedule.  
If at any other scheduled assessment 
FEV1 and/or FVC > 15% decrease 
from the study baseline: 
permanently discontinue study 
treatment and perform FU 
spirometry assessment. 
FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; FU = follow-up. 
 
If clinically significant, persistent respiratory AEs (e.g., dyspnea) are reported, PFTs must 
be performed and study treatment must be permanently discontinued. Further diagnostic 
work-up and consultation with a pulmonologist or other specialist should be considered 
according to local practice and the clinical situation.  
In all cases of permanent study treatment discontinuation, follow-up monitoring must be 
provided until respiratory AEs are resolved and changes in pulmonary function are no 
longer clinically relevant or until medically indicated. 


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5.1.10.4 Pregnancy 
If a subject becomes pregnant while on study treatment, study treatment must be 
permanently discontinued. 
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 study treatment interruptions section [see Section 5.1.8].  
5.1.10.5 Liver abnormalities 
In case of abnormal liver tests (LTs) or signs and symptoms suggestive of drug-induced 
liver injury (DILI), 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. 
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 
AST = aspartate aminotransferase, ALT= alanine aminotransferase, INR = international normalized ratio, LT = Liver 
test, TBL = total bilirubin, ULN = upper limit of normal.  


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When marked abnormalities levels for AST, ALT, TBL or INR are reached as indicated 
in Figure 3, an alert will be sent by the central laboratory, to the principal investigator and 
the sponsor, as defined in Appendix 7. The sponsor will contact the principal investigator 
to ensure that she/he will immediately contact the subject to enquire about symptoms and 
ask her/him to return to the site within 72 hours at the latest to repeat the test by the 
central laboratory (unless the clinical situation mandates immediate local testing). In the 
case of repeated abnormal LFTs 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 and the clinical situation.  
In all cases of permanent study treatment discontinuation, follow-up monitoring must be 
provided until signs and symptoms have resolved and changes in liver function 
abnormalities are no longer clinically relevant or until medically indicated. 
5.1.10.6 Ocular abnormalities 
Subjects with suspected macular edema or retinal vasculitis should be confirmed by 
diagnostic work-up as recommended by local guidelines (e.g., OCT, fluorescence 
angiography). The OSB will receive all information related to suspected cases of macular 
edema and will perform a review of OCT results and the subject’s data. In case of 
confirmed macular edema, study treatment must be permanently discontinued and the 
subject must be followed up until resolution or until medically indicated. 
5.1.10.7 Infections 
Infections are a leading cause for morbidity and mortality in subjects with SLE 
[Danza 2013]. Bacterial infections are most frequent, followed by viral and fungal 
infections. Disease activity, disease duration, leukopenia, use of glucocorticoids and 
immunosuppressives have been linked to increased risk of infections in SLE patients, in 
particular in the respiratory system and urinary tract as well as in the skin and soft tissues.  
Diagnosis of infections may be delayed because they may mimic an SLE flare, therefore 
the investigator needs to maintain a high level of vigilance [Mosca 2010].  
TB infection in SLE is mainly localized to the lung with upper lobe infiltrates, miliary 
lung disease, and pleural effusions, and may be confused with pulmonary lupus 
manifestations. Opportunistic infections caused by the reactivation of human herpes 
viruses 
(herpes 
simplex 
viruses, 
varicella-zoster 
virus, 
Epstein-Barr 
virus, 
cytomegalovirus) may be associated with cutaneous and neurological symptoms. The 
neurotropic herpes viruses (herpes simplex and varicella-zoster) are frequent human 
pathogens, and their reactivation can cause serious infections of the CNS, such as 
encephalitis and meningitis [Steiner 2007]. The most frequent characteristics of these 


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infections are of acute onset, associated with fever, headache, confusion, personality 
changes, and disorientation. These symptoms may be difficult to distinguish from CNS 
lupus manifestations, therefore heightened vigilance is required. Particular vigilance is 
required for rare and unusual neurological symptoms, as their recognition is crucial for 
the early diagnosis of neurotropic herpes viruses infections and progressive multifocal 
leucoencephalopathy, caused by reactivation of John Cunningham virus [Nived 2008].  
The physical examination and blood tests on the routine visits should be focused on any 
potential sign of skin, mucosal surfaces, lung, gastrointestinal tract, liver, CNS, 
hematological abnormality and organ dysfunction suggesting a potential opportunistic 
infection.  
Subjects should be advised to be pro-active and alert in reporting any unusual 
neurological symptoms and any signs and symptoms indicative of systemic infections, 
such as fever, malaise and fatigue. 
In the event of a suspected clinically relevant infection (e.g., serious infection, 
opportunistic infection), the subject should be treated as clinically indicated and study 
treatment must be permanently discontinued. 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, in the event of permanent discontinuation from 
study treatment due to any reason, subjects should not receive any of the prohibited 
systemic immunosuppressive treatment during the follow-up period of 16 weeks after last 
study drug intake, unless clinically indicated and justifiable in the opinion of the 
investigator. 
5.1.10.8 Premature treatment discontinuation after study treatment interruption, 
background therapy changes, administration of forbidden therapies, or study 
drug mis-dispensing 
A subject must be permanently discontinued from study treatment if study treatment has 
been interrupted between Day 1 and Day 14 and not re-initiated within 7 days after 
treatment interruption [see Section 5.1.8.1] or the subject missed doses for more than 
7 consecutive days after Day 14 [see Section 5.1.8.2].  


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In case of disease progression, treatment failure, worsening of subject condition requiring 
changes in the dose of background therapy outside of protocol-specified levels [see 
Section 5.2.4], the subject may be permanently discontinued from the study treatment at 
the discretion of the investigator and after discussion with the sponsor. In case of need to 
administer forbidden concomitant therapies, the subject must be permanently 
discontinued from the study treatment [see Section 5.2.5]. 
In case of study drug mis-dispensing (incorrect kit dispensed) and incorrect study drug 
intake, the subject must be permanently discontinued. 
Furthermore, in the event of permanent discontinuation from study treatment due to any 
reason, subjects should not receive any of the prohibited systemic immunosuppressive 
treatment or other forbidden therapies during the follow-up period of 16 weeks 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 16 weeks after last study drug 
intake, and may only be changed if clinically indicated and justifiable by the investigator. 
5.2 
Previous and concomitant therapy 
5.2.1 Background SLE therapy 
5.2.1.1 Definition of background SLE therapy 
In order to be eligible for the study, subjects must currently receive at least one of the 
below background treatments for SLE.  
• NSAIDs 
o Aspirin (acetylsalicylic acid) 
o Ibuprofen 
o Naproxen 
o Celecoxib 
o Others 
• Corticosteroids (≤ 10 mg/day prednisolone or equivalent; see Appendix 8) 
o Prednisolone 
o Prednisone 
o Methylprednisolone 
o Dexamethasone 
o Betamethasone 
o Hydrocortisone 
o Triamcinolone 
o Cortisone 
o Others 
• Anti-malarials  


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o Hydroxychloroquine (≤ 400 mg/day)  
o Chloroquine (≤ 500 mg/day)  
o Quinacrine (≤ 100 mg/day) 
• Mycophenolate mofetil (≤ 2 g/day) 
• Azathioprine (≤ 2 mg/kg/day) 
• Methotrexate (≤ 20 mg/week) 
 
Note: 
All background SLE therapies must have been started at least 30 days prior to 
randomization with stable doses. Treatment with anti-malarials, mycophenolate mofetil, 
azathioprine, or methotrexate must have been started at least 90 days prior to 
randomization and must not have been stopped within 30 days prior to randomization. 
5.2.1.2 Reporting of background SLE therapy in eCRF 
All background SLE therapies ongoing at baseline or started during the study will be 
reported in the background SLE therapies pages of the eCRF. 
The generic name, start/end dates of administration, route, dose and change in dose, 
frequency of administration, and reason for discontinuation will be recorded in the eCRF. 
5.2.2 Previous SLE therapies 
5.2.2.1 Definition of previous SLE therapies 
A previous SLE therapy is any treatment administered for SLE and/or SLE 
manifestations for which the end date is prior to the start of the study (i.e., signing of 
ICF). 
5.2.2.2 Reporting of previous SLE therapies in eCRF 
All previous SLE therapies administered within 24 months prior to Screening will be 
reported in the previous SLE therapies pages of the eCRF. 
The generic name, start/end dates of administration, route, dose, frequency, and reason 
for discontinuation will be recorded in the eCRF. 
5.2.3 Study-concomitant therapy 
5.2.3.1 Definition of study-concomitant therapy  
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 except SLE 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 7 
(EOS). 


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5.2.3.2 Reporting of study-concomitant therapy in eCRF 
All study-concomitant therapies administered for non-SLE reasons will be reported in the 
concomitant medications pages of the eCRF. 
The generic name, start/end dates of administration (as well as whether it was ongoing at 
start of treatment and/or EOS), route, dose, frequency, and indication will be recorded in 
the eCRF. 
5.2.4 Allowed concomitant therapy 
• i.v. atropine in the event of symptomatic bradycardia (see study-specific criteria for 
permanent discontinuation of study treatment in Section 5.1.10); 
• Dilating eye drops, mydriatics, including parasympathetic antagonists (e.g., 
tropicamide) or sympathetic agonists (e.g., phenylephrine) for topical use; 
• Vaccination with non-live vaccines (Note: although nonclinical data indicate no 
significant impairment of antibody response to immunization, no clinical data is 
currently available on vaccination efficacy under ACT-334441 treatment, therefore it 
is suggested that all planned/indicated vaccinations are completed more than 30 days 
before the start of treatment and, in case of vaccination during the study, titer control 
is recommended.); 
• Stable systemic corticosteroid therapy; corticosteroids are not to be started or stopped 
during the study and the dose should be kept stable. However, the investigator may 
see reason to initiate or increase the dose of systemic corticosteroid to treat an SLE 
flare or another condition. In such cases, the dose may be increased for a period of not 
more than 14 days up to double the baseline dose or a maximum of 20 mg/day 
prednisolone or equivalent (please refer to conversion table in Appendix 8); 
• Topical treatment therapy including topical use of corticosteroid is allowed.  
• Stable antimalarial therapy (e.g., hydroxychloroquine, chloroquine, quinacrine); 
therapy is not to be started or stopped during the study, and dose should be kept 
stable; 
• Stable NSAID chronic 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). Therapy is not to be started or stopped during the study, and dose should be 
kept stable; 


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Background medications must be kept stable until the end of the follow-up period 
(16 weeks after the last study treatment intake) unless clinically indicated and justifiable 
in the opinion of the investigator. In case of changes in the dose of background 
medications outside protocol-specified levels, discontinuation of study treatment may be 
considered on a case-by-case basis and after discussion with the sponsor. 
5.2.5 Forbidden concomitant therapy 
• Immunosuppressives not listed in Section 5.2.4 such as cyclophosphamide, 
cyclosporine, leflunomide, sirolimus, tacrolimus, etc.; 
• Immunosuppressive or immunomodulatory biological agents (e.g., belimumab, i.v. 
immunoglobulin, rituximab, S1P modulators other than ACT-334441); 
• β-blockers, diltiazem, verapamil, digoxin, or any other anti-arrhythmic or 
HR-lowering therapy (as listed in Appendix 1); 
• QT-prolonging drugs with known risk of torsades de pointes (list of drugs and specific 
rules provided in Appendix 2); 
• Short- and long-acting β2-agonists (e.g., albuterol, levalbuterol, formoterol, 
terbutaline, salmeterol); 
• Vaccination with live vaccines. 
The forbidden concomitant therapies are not allowed during the study until the end of the 
follow-up period (16 weeks after the last study treatment intake) unless clinically 
indicated and justifiable in the opinion of the investigator. 
In case of significant SLE worsening or significant disease flare requiring the 
administration of prohibited immunosuppressives or immunomodulatory biological 
agents, study treatment should be permanently discontinued. For guidance on the use of 
allowed concomitant medications following EOS, see Section 5.2.4.  
If patients require treatment with any of the forbidden concomitant therapies or need to 
receive a live vaccine, study treatment should be permanently discontinued and patients 
should be followed up as clinically indicated.  
6 
STUDY ENDPOINTS 
6.1 
Pharmacodynamic endpoints 
• Change in total lymphocyte count from baseline to EOT;  
• Change in total lymphocyte count from baseline to each post-baseline assessment. 


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6.2 
Safety endpoints 
Treatment-emergent period is defined as the time from first study treatment intake up to 
6 weeks (inclusive) after last study treatment intake. 
• Treatment-emergent AEs, SAEs, and AESIs#; 
• AEs leading to premature discontinuation of study treatment; 
• Changes in 12-lead ECG variables (HR, PR, QRS, QT, QT corrected for heart rate on 
the basis of Bazzett’s formula [QTcB] and QT corrected for heart rate on the basis of 
Fridericia’s formula [QTcF]), from pre-dose to selected post-dose assessments (1 h, 
2 h, 3 h, 4 h, 5 h, 6 h) on Day 1 and on day of study drug re-initiation; 
• Occurrence of treatment-emergent 12-lead ECG outliers (e.g., HR, PR, QTc defined in 
the Statistical Analysis Plan [SAP]); 
• Occurrence of treatment-emergent 12-lead ECG abnormalities; 
• Occurrence of treatment-emergent ECG-Holter abnormalities on Day 1;  
• Change in SBP and DBP from baseline up to EOS; 
• Change in FEV1 and FVC, expressed in absolute value (L) and percent value from 
baseline up to EOS; 
• Occurrence of treatment-emergent decrease of FEV1 or FVC > 15% from baseline 
values; 
• Change in laboratory parameters (hematology, blood chemistry, and urinalysis) from 
baseline up to EOS; 
• Treatment-emergent laboratory abnormalities according to CTCAE 2010 v4.03 
[CTCAE 2010] and FDA guidelines [FDA 2009] (for ALT/AST/TBL); 
• Change in protein-to-creatinine ratio from baseline to EOT; 
• Change in body weight from baseline to EOT. 
#AESI considered for the analyses are described in Appendix 3. 
6.3 
Pharmacokinetic endpoints 
• Ctrough ACT-334441 plasma concentrations prior to dosing at Weeks 2, 4, 8, and 12 
(EOT) or at EOT visit after premature study treatment discontinuation (if applicable). 
• ACT-334441 plasma concentration at EOS (i.e., 6 weeks after study treatment 
discontinuation). 


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6.4 
Exploratory disease activity endpoints 
• Change in SLEDAI-2K score (modified to exclude leukopenia) from baseline to each 
post-baseline assessment; 
• Change in PGA score from baseline to each post-baseline assessment; 
• Change in SLEDAI-2K mucocutaneous and/or muscoskeletal scorings from baseline 
to each post-baseline assessment. 
6.5 
Quality of life endpoints 
• 
Change in SF-36v2™ Health Survey domain and component scores from baseline to 
EOT. 
6.6 
Exploratory biomarker endpoints 
The following exploratory biomarkers will analyzed, but the analysis is not limited to 
these markers: 
• Change in immunoglobulin serum levels (IgG, IgM, IgA) from baseline to each 
post-baseline assessment;  
• Change in ANA and anti-dsDNA antibody titers from baseline to each post-baseline 
assessment;  
• Change in serum complement components C3 and C4, C-reactive protein (CRP), 
fibrinogen, BLyS and C-X-C motif chemokine 10 (CXCL10) from baseline to each 
post-baseline assessment. 
• Change in blood lymphocyte subsets from baseline to EOT and EOS. 
7 
STUDY ASSESSMENTS 
All study assessments are performed by an experienced study staff member: medical, 
nursing, or specialist technical staff, 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. 
Calibration certificates for the following devices used to perform study assessments must 
be available at the clinical site prior to the randomization of the first subject:  
• 
Temperature measurement devices for study medication storage area and freezer. 


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• 
Spirometer; in addition, a copy of the calibrations check (syringe check) of the 
day of measurement must be stored and a log of calibration check results must be 
maintained at the site [see Section 7.2.6]. 
• 
12-lead ECGs and 24-hour Holter ECG. 
• 
BP monitoring device. 
 
Calibration certificates for echocardiography and OCT devices should be available as 
indicated in Sections 7.2.5 and 7.2.8. 
7.1 
Screening/baseline assessments 
7.1.1 Informed consent (Screening visit) 
Prior to performing any study-specific procedure or assessment, the subject must provide 
written informed consent to participate in the study. If the signing of informed consent 
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 (i.e., time of procedures 
documented). If a study-specific procedure or assessment has been performed as part of 
routine assessments and the results are available prior to the subject’s signing of informed 
consent (e.g., SLE-relevant disease history, CXR; see Sections 4.6.2 and 7.2.9), such 
procedure or assessment may be used to assess eligibility and does not have to be 
repeated. In such cases, it must be clear from the source document when and for which 
reason the assessment was done prior to the signing of the informed consent. It is the 
responsibility of the principal investigator / treating physician to explain the study in all 
its aspects to the subject and obtain her/his informed consent. The informed consent 
process will be documented in the investigator site file. The language used in the oral and 
written information about the trial, and including the informed consent form, will be 
provided in a language that is fully understandable to the subject.  
7.1.2 Baseline demographics and disease characteristics 
At Visit 1 (Screening), the below data are to be recorded in the eCRF. 
• Baseline demographics (sex, age, race/ethnicity, body weight and height). 
• Complete, clinically relevant medical history and current conditions, as well as 
smoking status. 
• SLE-relevant disease history, ACR criteria [see Section 4.6.2] and SLE 
assessments (i.e., SLEDAI-2K and PGA) [see Section 7.4]. 


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7.1.3 Previous and concomitant therapies 
All background/previous SLE therapies, as well as all study-concomitant therapies [see 
Section 5.2], will be reported in the corresponding eCRF pages [see Section 5.2]. 
7.2 
Safety assessments 
The definitions, reporting and follow-up of AEs and SAEs are described in Section 10. 
7.2.1 Laboratory assessments 
7.2.1.1 Type of laboratory 
A central laboratory (see central laboratory manual for contact details) 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 
automatically transferred from the central laboratory database to the sponsor’s clinical 
database. Analysis of lymphocyte subsets will be performed by the sponsor [see 
Section 7.6]. 
In exceptional cases (e.g., subject is hospitalized in a different hospital from the study 
center due to a medical emergency, or missing central laboratory values), local laboratory 
results (with the corresponding normal ranges) will be entered into the clinical database 
via dedicated eCRF pages. Testing of WBC and total lymphocyte counts at a local 
laboratory should not performed unless deemed absolutely necessary by the investigator 
to ensure subject’s safety. In this particular case, the local results of WBC and total 
lymphocyte counts will be recorded in the eCRF. 
In case 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 case 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 3 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. Clinically relevant laboratory findings that are 
present at the time of signature of informed consent must be recorded on the medical 
history page of the eCRF. Any clinically relevant laboratory abnormalities detected after 
signature of informed consent must be reported as an AE or SAE as appropriate [see 
Section 10] and must be followed until the value returns to within the normal range or is 


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stable, or until the change is no longer clinically relevant. 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. 
7.2.1.2 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. 
Hematology 
• Hb  
• Hematocrit, MCH, MCV, and MCHC 
• Erythrocyte count (reticulocyte  count) 
• Leukocyte count with differential counts* 
• Platelet count 
*For the purpose of functional blinding [see Section 5.1.4.2], the WBC and the 
lymphocyte counts will not be available to sites and the sponsor during the study. This 
data will be available only after database lock. Non-lymphocyte differential counts will 
be available during the course of the study as specified in the laboratory manual. If a 
lymphocyte count < 200 cells/µl is recorded by the central laboratory, an alert including 
lymphocyte count results will be sent to the investigators and to the sponsor at any study 
visits until EOT. If lymphocyte count < 800 cells/µl at EOS visit, an alert including 
lymphocyte count results will be sent to the investigator and to the sponsor’s team, and 
lymphocyte count should be monitored on a regular basis (e.g., every 2 weeks) by the 
local laboratory until the lymphocyte count has returned to ≥ 800 cells/µL or until 
medically indicated. 
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 


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• Protein, albumin 
Test for tuberculosis 
• An interferon gamma release assay will be performed at Visit 1 (Screening) to screen 
for active or latent TB [see Section 7.2.10]. 
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 7 
(EOS), and if pregnancy is suspected during the study. Urine pregnancy tests will be 
performed at all other visits.  
In order to be randomized in the study, WOCBP must have a confirmed negative serum 
pregnancy test at Visit 1 (Screening) and a second confirmed negative urine pregnancy 
test prior to Randomization. The two tests must be performed a minimum of 3 weeks 
apart.  
At Visit 7 (EOS), two urine pregnancy test kits will be dispensed to WOCBP to perform 
the test at their home 1–2 days before the planned follow-up telephone calls (11 weeks 
and 16 weeks after study drug discontinuation). The result of the tests (positive/negative) 
will be communicated to the treating physician during the follow-up telephone calls. 
Serum pregnancy test results data will be automatically transferred from the central 
laboratory database to the sponsor’s clinical database. Urine pregnancy testing results 
will be recorded in the eCRF (except for the follow-up telephone calls). In case of 
pregnancy up to the follow-up telephone calls, a Pregnancy Form must be completed [see 
Section 10.3.2].  
Virus serology 
• Hepatitis B surface antigen, Hepatitis C antibodies, 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 case of positive testing results [e.g., positive 
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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, in order 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 
At Visit 1 (Screening), Visit 2 (Randomization) and Visit 6 (EOT), urine samples will be 
collected and sent to the central laboratory for protein and creatinine measures, and 
determination of the protein-to-creatinine ratio. 
7.2.2 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 ECG recording will be performed for all subjects at all scheduled study visits 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 (U1, U2, etc.) to the study protocol schedule. During the 
treatment period, 12-lead ECGs must be performed prior to dosing. The data records (i.e., 
flashcards) will be sent to the evaluation center for central reading. 


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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 physician responsible 
for the performance (i.e., principal investigator / treating physician or CSA) 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. The tracings signed by the CSA will be kept in a 
separate file and will not be made accessible to the principal investigator / treating 
physician.  
All ECG reports (received from central reader) must be signed and dated by the primary 
investigator / treating physician or CSA within 3 calendar days of receipt and filed with 
the source documentation. The investigator / treating physician or CSA must indicate on 
the ECG report whether abnormal values are considered clinically relevant or not. 
Clinically relevant ECG findings that are present at the time of signature of informed 
consent must be recorded on the medical history page of the eCRF. Any clinically 
relevant ECG abnormalities detected after signature of informed consent must be 
reported as an AE or SAE as appropriate [see Section 10] and must be followed until the 
value returns to within the normal range or is stable, or until the change is no longer 
clinically relevant. 
At all visits, except at Visit 2 (Randomization) and study treatment re-initiation visits 
(see below), the 12-lead ECGs will be performed under the responsibility of the treating 
physician who may consult the CSA.  
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 CSA who will interpret the results.  
The pre-dose 12-lead ECG interpretation (before Randomization) provided by the CSA 
will support the subject’s final eligibility decision made by the principal investigator / 
treating physician 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 hospital if they 
meet the discharge criteria [see Appendix 4], 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.  


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The CSA must ensure that the main study team at site including the principal investigator 
/ treating physician, clinical coordinator / study nurse, and other personnel involved in 
subjects’ clinical care and management do not access first-dose ECG data with 
unblinding potential, including hourly post-dose 12-lead ECGs and 24-hour Holter ECG 
data of Day 1 or at re-initiation (e.g., central reading reports, tracings). 
7.2.3 ECG Holter 
ECG Holter monitoring will be performed for 24 hours at Visit 1 (Screening) and Visit 2 
(Randomization). Testing at Visit 1 (Screening) can be performed at any time during the 
Screening period. 
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 1 (Screening), the 24-hour ECG Holter will be performed under the 
responsibility of the principal investigator / treating physician. The performance of the 
assessment may be delegated to the CSA. The recording must be initiated before 12 pm 
(noon) and must be obtained for 24 hours.  
At Visit 2 (Randomization / Day 1), the 24-hour ECG Holter will be performed under the 
responsibility of the CSA. The recording must be initiated immediately before first 
dosing. The subject will be allowed to leave the clinic with the Holter and to perform 
her/his usual daily activities. The recording will be stopped 24 hours post-dose. It is 
essential to have uninterrupted recording during the 24 hours (including sleep hours).  
The central reading results (including alert notifications in case of specific findings) of 
the ECG Holter performed at Visit 1 (Screening) will be sent to the principal investigator 
/ treating physician and to the CSA. The central reading results (including alert 
notifications in case of specific findings) of the Holter performed at Visit 2 
(Randomization) will be sent only to the CSA. 
The ECG Holter reports must be signed and dated by the primary investigator / treating 
physician (Visit 1) or the CSA (Visit 2) within 3 calendar days of receipt and filed with 
the source documentation. The ECG Holter reports signed by the CSA will be kept in a 
separate file. The physician signing the ECG Holter report must indicate on the report 
whether abnormal values are considered clinically relevant or not. Clinically relevant 
ECG Holter findings that are present at the time of signature of informed consent must be 
recorded on the medical history page of the eCRF. Any clinically relevant ECG Holter 
abnormalities detected after signature of informed consent must be reported as an AE or 
SAE as appropriate [see Section 10] and must be followed until the value returns to 
within the normal range or is stable, or until the change is no longer clinically relevant.  


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7.2.4 Blood pressure 
BP measurements include SBP and DBP. BP will be assessed at all scheduled 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 will be measured twice. 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 by the eCRF. Any clinically relevant BP abnormalities detected after informed 
consent signature must be reported as an AE or SAE as appropriate [see Section 10]. 
At all visits, except at Visit 2 (Randomization) and study treatment re-initiation visits 
(see below), the SBP/DBP assessments will be performed under the responsibility of the 
treating physician, who may consult the CSA.  
At Visit 1 (Screening), SBP and DBP will be measured sequentially once in supine and 
once in standing position to determine the presence of orthostatic hypotension (i.e., 
> 20 mmHg decrease in SBP or > 10 mmHg decrease in DBP from supine to standing 
position, measured between 1 and 3 minutes after standing; see exclusion criteria 13.) 
At Visit 2 (Randomization / Day 1) and visits for re-initiation of study treatment when 
post-dose monitoring will be required, the SBP/DBP assessments will be performed 
under the responsibility of the CSA who will interpret the results. 
The pre- and post-dose SBP/DBP assessments will be performed in parallel to 12-lead 
ECGs until subject discharge.  
The hourly post-dose assessments will only be measured once at each hourly timepoint. 
Single SBP measurements will be used for determining discharge criteria. 
7.2.5 Echocardiography 
Echocardiography will be performed at Visit 1 (Screening) and Visit 6 (EOT) using the 
equipment present at the clinical site. 
Standard 2D/Doppler echocardiography should assess 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 
and calibrated according to the manufacturer’s recommendations. A copy of the 
calibration certificates done before the day of assessment must be stored as source 
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The physician conducting and interpreting standard 2D/Doppler echocardiography must 
have a level of experience equivalent to at least a Level 2 training, as defined in the 
American College of Cardiology Board / American Heart Association clinical 
competence statement on echocardiography [Quiñones 2003]. In case an expert 
sonographer is conducting the examination, the physician must review and interpret the 
echocardiography results. 
In the eCRF, the date of the echocardiography performance will be recorded. 
Echocardiography results will be documented in the patient charts but will not be 
reported in the eCRF. The presence/absence (i.e., Yes/No) of any abnormality will be 
entered in the eCRF. Clinically relevant echocardiography findings that are present at the 
time of signature of informed consent must be recorded on the medical history page of 
the eCRF. Any clinically relevant echocardiography abnormalities detected after 
signature of informed consent must be reported as an AE or SAE as appropriate [see 
Section 10] and must be followed until the value returns to within the normal range or is 
stable, or until the change is no longer clinically relevant.  
7.2.6 Spirometry 
Spirometry will be performed at all scheduled visits except Visit 2 (Randomization). 
Spirometry at Visit 1 (Screening) will consist of two assessments performed at least 
5 days apart during the Screening period. Spirometry at Visit 3 (Week 2) can be 
performed up to 3 days prior to or after the visit date. Spirometry from Visit 4 (Week 4) 
to Visit 7 (EOS) can be performed up to 5 days prior to or after the visit date. All 
spirometry assessments should preferably be performed in the 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 
ATS/ERS criteria [Miller 2005a, Miller 2005b], 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 main endpoint 
derivations will be validated by the independent central readers prior to being 
electronically transferred to the sponsor. No 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 
informed consent must be reported as an AE or SAE as appropriate [see Section 10] and 


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must be followed until the value returns to within the normal range or is stable, or until 
the change is no longer clinically relevant. 
The predicted normal values for FEV1 and FVC used to determine the exclusion and 
discontinuation criteria [see Section 5.1.10.3] will be those as defined by the European 
Community for Coal and Steel including ethnic group adjustments [Quanjer 1993]. 
7.2.7 Ophthalmological examination 
An ophthalmological examination will be performed by an ophthalmologist at any time 
during the Screening period. Examination at Visit 3 can be performed up to 3 days prior 
to or after the visit date. Examinations from Visit 4 (Week 4) to Visit 7 (EOS) can be 
performed up to 5 days prior to or after the visit date.  
The ophthalmological examination should include previous eye history and ophthalmic 
condition, any new or current ophthalmological symptoms, assessment of best corrected 
visual acuity (Early Treatment Diabetic Retinopathy Study charts), measurement of 
Goldmann applanation tonometry (recommended, if not available other applanation 
tonometer allowed), slitlamp examination of the anterior segment, and dilated indirect 
funduscopy. While the visual acuity and measurement of applanation tonometry exams 
may be performed by a delegate (e.g., experienced technician, optometrician), 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. 
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 will be recorded. The results 
will be documented in the patient charts but will not be reported in the eCRF. The 
presence/absence of any abnormality (i.e., Yes/No) will be recorded in the eCRF. 
Clinically relevant findings that are present at the time of signature of informed consent 
must be recorded on the medical history page of the eCRF. Any clinically relevant 
ophthalmological abnormalities (including OCT findings [see Section 7.2.8]) detected 
after signature of informed consent must be reported as an AE or SAE as appropriate [see 
Section 10] and must be followed until the value returns to within the normal range or is 
stable, or until the change is no longer clinically relevant. 
7.2.8 Optical coherence tomography 
OCT will be assessed at Visit 1 (Screening) and Visit 6 (EOT). Testing at Visit 1 can be 
performed at any time during the Screening period. At Visit 6 (EOT), testing may be 


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performed up to 7 days prior to the visit date but no later than 7 days after the 
discontinuation of study drug. 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 in case of active uveitis diagnosed during 
the study. While the OCT exam may be performed by a delegate (e.g., experienced 
technician, optometrician), 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 will be recorded. The results will be 
documented in the patient charts but will not be reported in the eCRF. The 
presence/absence of any abnormality (i.e., Yes/No) will be recorded in the eCRF. Any 
clinically relevant abnormalities detected after signature of informed consent must be 
reported as an AE or SAE as appropriate [see Section 10]. 
The OSB 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. 
7.2.9 Chest X-ray 
A CXR will be performed at Visit 1 (Screening) and assessed by the local radiologist in 
order to exclude any subject with findings suggestive of active or latent TB. Any CXR 
that had been performed within 3 months prior to Screening can be used; if available, 
there is no need to repeat CXR at Screening. The report of the CXR must be recorded in 
the patient file. 
7.2.10 Test for tuberculosis 
An interferon gamma release assay (QuantiFERON-TB-Gold®) 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 electronically transferred to the eCRF database.  
Only subjects with a negative test at Screening and without CXR findings [see 
Section 7.2.9] at Screening or within the previous 3 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 


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(invalid, indeterminate, or borderline), the test may be repeated one time and a negative 
result must be obtained prior to randomization in order 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. 
7.2.11 Weight and height 
Height will be measured at Visit 1 (Screening). Body weight (in underwear) will be 
measured at Visit 1 (Screening) and at Visit 6 (EOT).  
7.2.12 Physical examination 
Complete physical examination (i.e., inspection, percussion, palpation and auscultation) 
will be performed at Visit 1 (Screening) and Visit 6 (EOT). A symptom-driven, 
abbreviated physical examination will be performed at all other visits in order to capture 
assessments needed for the SLEDAI-2K scoring (note: SLEDAI-2K not assessed Visit 3). 
The observations should be reported according to body system in the eCRF as either 
normal or abnormal. If an abnormality is found, it should be specified on the 
corresponding eCRF page, describing the signs related to the abnormality (e.g., systolic 
murmur) and not the diagnosis (e.g., mitral valve insufficiency). Clinically relevant 
findings that are present at study start (i.e., before signing of informed consent) 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 
Sections 10.1.1 and 10.1.2] must be recorded by the principal investigator / treating 
physician on an AE page of the eCRF and must be reported to Actelion Global Drug 
Safety department (SAEs only). 
7.3 
Pharmacodynamic and pharmacokinetic assessments 
7.3.1 Pharmacodynamic assessments 
The PD marker is total lymphocyte counts, which will be measured as part of the 
hematology tests [see Section 7.2.1.2]. 
7.3.2 Pharmacokinetic assessments 
PK samples will be collected pre-dose (except EOT and EOS) at all visits from Visit 3 
(Week 2) to Visit 7 (EOS).  
The date and the time of blood sample collection will be entered in the eCRF. The date 
and time of the last study treatment dosing before blood draw will be entered in the 
eCRF. 


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The site staff will ship the plasma samples to the central laboratory. The central 
laboratory will ship the samples to the CRO in charge of the PK analysis (see page 3 for 
contact details).  
7.4 
Disease activity assessments 
7.4.1 Systemic Lupus Erythematosus Activity Index-2000 
The SLEDAI-2K will be assessed by the treating physician at all visits except Visit 3 
(Week 2) [see Appendix 6].  
The original SLEDAI is a validated tool for global measure of disease activity introduced 
in 1985 [Bombardier 1992]. The SLEDAI-2K is an updated version of the original 
SLEDAI. It has been validated as a measure of global disease activity and is suitable for 
use in clinical trials [Gladman 2002]. 
The treating physician will perform physical examinations as required [see 
Section 7.2.12], question the subject on her/his 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 dipstick results are positive, urine sample 
will be further analyzed as clinically indicated (i.e., microscopic analysis of WBC, RBC, 
casts, and protein quantification). 
All relevant data will be entered in the SLEDAI-2K form of the eCRF [see Appendix 6]. 
In case of musculoskeletal symptoms, the number of affected joints will be assessed. 
Important note: 
Reduction in WBC count (lymphocytes) is the main PD effect of S1P1 modulators 
including ACT-334441. Therefore, leukopenia is not assessable in the present study and 
will be excluded from the SLEDAI-2K scoring.  
7.4.2 Physician’s Global Assessment of disease 
The PGA will be assessed by the treating physician at all visits except Visit 3 (Week 2). 
The PGA is a visual 100 mm analog scale for assessment of disease activity by the 
physician ranging from 0 to 3 [see Appendix 9]. The scale is anchored at 0=“None”, 
1=“mild”, 2=“moderate”, 3=“severe” [Petri 2005]. 
Paper sheets will be provided to clinical sites. The treating physician will rate the overall 
state of the subject and make a vertical mark on the scale. Only original sheets should be 
used (i.e., no photocopies). A metric ruler will be used to measure the length between 
0 and the vertical mark. The length will be entered into the eCRF. 


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7.5 
Quality of Life assessments: 36-Item Short Form Health Survey v2 
The SF-36v2™ questionnaire (SF-36v2™ Health Survey© 1996, 2000 by Medical 
Outcomes Trust and Quality Metric Incorporated) [see Appendix 10] is used to assess the 
subject’s quality of life. The SF-36v2™ will be completed by the subject at Visit 2 
(Randomization) and Visit 6 (EOT). Preferably, the SF-36v2™ questionnaire will be 
completed by the subject in the morning prior to any other protocol assessment and prior 
to any other discussion with the investigator or treating physician. 
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 past 4-week period will be used. A sample of 
the SF-36v2™ (in English) is provided in Appendix 10. The subject will complete the 
questionnaire in local language on a validated paper form that will be collected and 
transcribed in the eCRF. 
Actelion has been granted a license agreement for the use of the SF-36v2™ 
questionnaire. 
7.6 
Biomarker assessments 
Serum and ethylenediaminetetraacetic acid (EDTA) plasma samples will be drawn at 
indicated visits and will be tested by the central laboratory (except lymphocyte subsets, 
which will be analyzed by the sponsor). Sample collection date will be recorded in the 
eCRF. 
Details of the collection, labeling and shipment of the samples can be found in the 
laboratory manual provided to the investigator. The tubes and labels for the samples will 
be provided to the investigator and/or staff by the sponsor or the central laboratory. 
ANA, anti-dsDNA, complement factors and exploratory biomarkers 
ANA and anti-dsDNA are a hallmark of SLE, and titers of these autoantibodies have 
been found to correlate with clinical disease activity and the response to therapy 
[Ravirajan 2001]. Low C3 and C4 complement have also been found to correlate with 
clinical disease activity [Swaak 1986]. Immunoglobulins may be elevated in SLE 
patients, and cytokines and other soluble factors have been found to be elevated in serum 
of SLE patients. 


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The following biomarkers as indicated below (but not limited to) will be measured at 
baseline and during the course of study treatment in order to support the SLE diagnosis of 
involved subjects, to explore their predictive value for treatment response and to explore 
changes in response to ACT-334441 treatment. 
• ANA, anti-dsDNA, complement C3 and C4 (all visits except Visit 3) 
• IgM, IgG, IgA, CRP, fibrinogen, and BLyS (Visit 2 and Visits 4 to 7)  
• anti-Smith, anti-cardiolipin (IgA, IgG, IgM) , anti-ribosomal P, (Visit 2 only). 
• CXCL10 (EDTA-plasma; Visit 2 and Visits 4 to 7) 
At Visit 1 (Screening), ANA and/or anti-dsDNA antibody testing should be positive in 
order to fulfill inclusion criterion 6 [see Section 4.3] unless a documented historical 
positive testing is available to confirm the subject’s eligibility [see Section 4.6.2]. 
Aliquots of the EDTA plasma samples will be transferred to the sponsor for exploratory 
analysis of new soluble biomarkers potentially related to SLE and/or S1P1 modulation. 
Frozen samples will be kept for a maximum duration of 15 years and will be destroyed 
thereafter.  
Blood lymphocyte subsets 
S1P1 modulators such as ACT-334441 reduce total lymphocyte counts (T and B 
lymphocytes) in healthy subjects. T and B cells consist of different subsets with potential 
distinct functions in SLE disease manifestation and progression. Specific subsets of B 
and T cells such as recently activated short-lived plasma cells are increased in the 
circulation of SLE patients [Grammer 2003a; Grammer 2003b; Klinman 1991]. Analysis 
of specific blood lymphocyte subsets may provide a better understanding of the 
immunomodulatory effect of ACT-334441 in SLE patients. 
Blood samples for lymphocyte subset analysis will be taken at Visit 2 (Randomization) , 
Visit 6 (EOT) and Visist 7 (EOS). 
The site staff will ship the blood samples to the central laboratory. The central laboratory 
will then ship the samples to the sponsor for analysis. B and T cell subsets will be 
analyzed using a combination of cell surface markers (e.g., CD3, CD4, CD 19, CD 20). 
7.7 
Total blood volume 
The expected total blood volume to be drawn per subject during the entire course of the 
study is described in Table 3. 


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Table 3 
Expected total blood volume to be drawn per patient 
Test 
Number 
of tests 
Volume 
per test 
Total volume per 
scheduled study visits 
Viral serology at screening (including test confirmation) 
1 
 9 mL 
9 mL 
Interferon gamma release assay for tuberculosis at screening 
1 
3 x 1 mL 
 3 mL 
Serum sample at randomization1 
1 
 5 mL 
 5 mL 
Hematology (including coagulation) 
7 
6 mL 
42 mL 
Blood chemistry2 
7 
7.5 mL 
52.5 mL 
ACT-334441 PK 
5 
3 mL 
15 mL 
Complement C3/C4, ANA, anti-ds DNA 
6 
7.5 mL 
45 mL 
Exploratory biomarkers (serum) 
5 
5.5 mL 
27.5 mL 
Exploratory biomarkers (plasma) 
5 
5 mL 
25 mL 
Lymphocyte subsets 
3 
5 mL 
15 mL 
Total blood volume drawn at scheduled study visits: 239 mL3 
1. To be stored at the central laboratory for potential retrospective analyses of viral serology titers in the event of infections. 
2. Includes serum pregnancy. 
3. Total blood volume may vary depending on re-test and unscheduled samples 
ANA = anti-nuclear antibodies; anti-ds DNA = anti-double-stranded DNA; PK = pharmacokinetic. 
 
8 
SCHEDULE OF VISITS 
To ensure compliance, at each visit, the study personnel must remind WOCBP to use the 
methods of contraception defined for this study. The reminders must be documented in 
the hospital chart. 
A tabulated summary of all visits and assessments described in the following sections is 
provided in Table 1. The schedule of visit dates should be established at the time of 
Screening. It is recommended that subjects adhere to the established visit schedule. 
The timepoint for every visit is defined taking as a reference Day 1 (Visit 2), which is the 
day of randomization.  
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, and, when 
applicable, before administration of study drug.  
• The intervals between all visits following Visit 4 (Week 4) and up to EOT 
(Week 12) visit should not exceed 36 days.  
• At Visit 2 (Randomization; Day 1) and on the days of re-initiation of study drug 
(if applicable), the 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. 


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• At other visits, ECGs, SBP/DBP, spirometry, blood drawings for hematology and 
biochemistry, along with all other assessments, are to be performed at pre-dose.  
• All PK sampling should be done at pre-dose (except EOT and EOS). 
• Resting time: 
o When the subject is 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. 
o Sufficient time between blood drawing and cardiac assessments (i.e., 
ECGs and/or BP measurement) is to be allowed.  
Re-screening 
It is permitted to re-screen subjects once, if the reason for non-eligibility was transient 
(e.g., abnormal laboratory test, insufficient wash-out period of a forbidden medication, 
etc.), provided that documented authorization has been received from Actelion. Subjects 
who were not eligible due to a negative test for varicella zoster antibodies may also be 
re-screened once after having been vaccinated. All pre-randomization assessments should 
then be repeated at the time of re-screening (with the exception of CXR evaluation). 
A subject who failed the screening for Part A may be re-screened for Part A or screened 
for Part B. 
8.1 
Screening period 
The Screening period must take place within 30 days prior to Randomization and include 
the Visit 1 (Screening) and the pre-dose assessments of Visit 2 (Day 1).  
The start of the Screening period is defined as the day of the first Screening assessment 
(i.e., signature of informed consent). 
8.1.1 Visit 1 (Screening) 
Visit 1 will be performed up to 30 days prior to Randomization. Visit 1 date is defined as 
the date of the first assessment performed for the study (i.e., informed consent signature).  
During this visit, subject informed consent will be obtained, and the assessments required 
for subject eligibility will be performed. These assessments may generally be performed 
on separate days within the Screening period.  
Visit 1 includes: 
• After discussing the study with the investigator and after agreeing to participate, the 
subject must sign the ICF. It is the responsibility of the investigator to obtain written 


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informed consent prior to any screening assessment. Subjects will be assigned a 
subject number by the IRT provider, for identification throughout the study. In case 
of re-screening, the subject number assigned during the first screening procedure will 
be retained. 
• Recording of demographics, medical history, smoking status, and disease history 
(including documented history of ANA, anti-dsDNA antibodies) 
• Review of SLE diagnosis and ACR criteria 
• Recording of previous SLE therapies, concomitant medications and background SLE 
therapies 
• Complete physical examination 
• Body weight, and height 
• SLEDAI-2K and PGA 
• CXR (any CXR performed within 90 days prior to Screening can be used). In case of 
re-screening, CXR does not need to be repeated. 
• SBP/DBP (including supine and standing position to assess orthostatic hypotension; 
see excluion criterion 13) 
• 12-lead ECG 
• 24-hour ECG-Holter (starting before 12:00) 
• Echocardiography (under the responsibility of the echocardiography specialist) 
• Spirometry (under the responsibility of the pulmonary function laboratory technician 
or expert) 
• Ophthalmological examination (under the responsibility of the ophthalmologist) 
• OCT (under the responsibility of the ophthalmologist) 
• Hematology (including coagulation tests), blood chemistry, and serum pregnancy test 
for WOCBP 
• Viral serology 
• TB test 
• ANA, anti-dsDNA antibodies, complement C3 and C4 
• Urine protein-to-creatinine ratio 
• Urinalysis (dipstick) 
• Recording of AEs/SAEs: all AEs/SAEs occurring after signing of the ICF are to be 
reported in the eCRF and on an SAE form, if applicable.  
The principal investigator / treating physician must check inclusion/exclusion criteria. 
The next visit (Visit 2) will only be scheduled if the subject meets all the eligibility 
criteria. Date of screen failure will be collected in the IRT system and in the eCRF; 
additionally, the reasons for screen failure are documented in the eCRF (screening 
information is collected for all screen failure subjects). 


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8.2 Treatment period 
The treatment period consists of Visits 2 to 6 (Randomization – Day 1, Weeks 2, 4, 8, 
and 12 (EOT).  
8.2.1 Visit 2 – Randomization Day 1 
Visit 2 corresponds to the start of the treatment period (Day 1 of the study). The ECGs 
(pre- and post-dose), BP (pre- and post-dose), and first-dose administration must be 
performed on the same day and define the date of the visit. This date should preferably 
correspond to the date of randomization in the IRT system. The assessments during this 
visit will be divided into two parts: before (pre-dose) and after study drug administration 
(post-dose). 
Important note: For WOCBP, the serum pregnancy test at Visit 1 (Screening) must be 
performed at least 3 weeks before the urine pregnancy test performed at Visit 2 prior to 
Randomization. 
8.2.1.1 Visit 2 – Day 1 – pre-dose assessment 
The principal investigator / treating physician must check all inclusion/exclusion criteria. 
Pre-dose assessments include: 
• SF-36v2™ questionnaire (to be completed prior to any other assessment) 
• Recording of change in concomitant medications and background SLE therapies since 
Visit 1 
• Recording of methods of contraception (for WOCBP) 
• Abbreviated physical examination 
• SLEDAI-2K and PGA 
• Pre-dose SBP/DBP (under the responsibility of the CSA) 
• Pre-dose 12-lead ECG (under the responsibility of the CSA) 
• 24-hour ECG-Holter starting immediately before first dosing (under the responsibility 
of the CSA) 
• Hematology (including coagulation tests), blood chemistry 
• Urine pregnancy test (for WOCBP) 
• Additional serum sample for viral serology 
• ANA, anti-dsDNA antibodies, complement C3 and C4 
• Exploratory biomarkers 
• Lymphocyte subsets 
• Urine protein-to-creatinine ratio 
• Urinalysis (dipstick) 
• Recording of AEs/SAEs: all AEs/SAEs occurring after signing of the ICF are to be 
reported in the eCRF and on an SAE form, if applicable. 


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8.2.1.2 Visit 2 – Day 1 – Randomization and post-dose assessment 
After confirmation of eligibility (i.e., verification of all entry criteria) 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.  
Visit 2 post-dose assessments include: 
• Hourly 12-lead ECG and SBP/DBP assessments for 6 hours or until the patient meets 
the discharge criteria (under the responsibility of the CSA [see Appendix 4]). If 
discharge criteria are not met after 12 hours, the subject should be permanently 
discontinued. 
• Recording of AEs and SAEs. 
The subject will be instructed to contact the site if she/he has any questions or problems. 
WOCBP will be reminded to use the methods of contraception defined for this study. The 
reminders must be documented in the hospital chart. 
An appointment for next visit will be scheduled and the subject will be instructed to: 
o bring back the remaining study medication for drug accountability 
o come fasted to the site 
o not take study treatment on the day of study visit prior to coming to the site  
o contact the principal investigator / treating physician 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. 
8.2.2 Visit 3 – Week 2 
The time window for this visit is ± 3 days. The date of the visit will be registered by the 
investigator or study staff in the eCRF only (no IRT visit registration as no study drug 
dispensing at Visit 3). All assessments may be performed up to 3 days prior to or after 
this visit date. The visit includes: 
• Recording of change in concomitant medications and background SLE therapies since 
Visit 2 
• Recording of methods of contraception (for WOCBP) 
• Abbreviated physical examination 
• SBP/DBP 
• 12-lead ECG 
• Spirometry (under the responsibility of the pulmonary function laboratory technician 
or expert) 
• Ophthalmological examination (under the responsibility of the ophthalmologist) 


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• Hematology (including coagulation tests), blood chemistry 
• Urine pregnancy test (for WOCBP) 
• Urinalysis 
• PK sampling 
• Study drug accountability for compliance review 
• Recording of AEs and SAEs 
• Remind WOCBP to use the methods of contraception defined for this study 
• Schedule an appointment for the next visit and instruct the subject to: 
o bring back any remaining study medication for drug accountability 
o come fasted to the site 
o not take study treatment on the day of study visit prior to coming to the site 
(study drug will be taken at the clinical site)  
o contact the principal investigator / treating physician 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. 
8.2.3 Visit 4 – Week 4 and Visit 5 – Week 8 
The visit window for these visits is ± 5 days. The date of study treatment dispensing, 
preferably corresponding to the date of registration of the visit in the IRT system defines 
the date of the visit. All other assessments may be performed up to 5 days prior to or after 
this visit date. The visit includes: 
• Recording of changes in concomitant medications and background SLE therapies 
since previous visit 
• Recording of methods of contraception (for WOCBP) 
• Abbreviated physical examination 
• SLEDAI-2K and PGA 
• SBP/DBP 
• 12-lead ECG 
• Spirometry (under the responsibility of the pulmonary function laboratory technician 
or expert) 
• Ophthalmological examination (under the responsibility of the ophthalmologist) 
• Hematology (including coagulation tests) and blood chemistry 
• Urine pregnancy test (for WOCBP) 
• ANA, anti-dsDNA antibodies, complement C3 and C4 
• Exploratory biomarkers 
• Urinalysis 
• PK sampling  
• Study drug dispensing and accountability 


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• Recording of AEs/SAEs 
• Remind WOCBP to use the methods of contraception defined for this study 
• Schedule an appointment for the next visit and instruct the subject to: 
o bring back any remaining study medication for drug accountability 
o come fasted to the site 
o not take study treatment on the day of study visit prior to coming to the site 
(study drug will be taken at the clinical site)  
o contact the principal investigator / treating physician 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. 
8.2.4 Visit 6 – EOT 
The EOT visit will take place at Week 12 (± 5 days) or earlier in case of premature 
discontinuation of study treatment. In all cases, the EOT visit must preferably take place 
1 day after the last dose of study treatment intake but no later than 7 days after the last 
dose of study treatment intake. The visit includes: 
• SF-36v2™ questionnaire (to be completed prior to any other assessment) 
• Recording of changes in concomitant medications and background SLE therapies 
since Visit 5 
• Recording of methods of contraception (for WOCBP) 
• Complete physical examination 
• Body weight 
• SLEDAI-2K and PGA 
• SBP/DBP 
• 12-lead ECG 
• Echocardiography (under the responsibility of the echocardiography specialist) 
• Spirometry (under the responsibility of the pulmonary function laboratory technician 
or expert) 
• Ophthalmological examination (under the responsibility of the ophthalmologist) 
• OCT (under the responsibility of the ophthalmologist) 
• Hematology (including coagulation tests) and blood chemistry 
• Urine pregnancy test (for WOCBP) 
• ANA, anti-dsDNA antibodies, complement C3 and C4 
• Exploratory biomarkers 
• Lymphocyte subsets 
• Urine protein-to-creatinine ratio 
• Urinalysis 
• PK sampling 


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• Study drug accountability 
• Recording of AEs/SAEs 
• Remind WOCBP to use the methods of contraception defined for this study 
• Schedule an appointment for the next visit and instruct the subject to: 
o come fasted to the site 
o contact the principal investigator / treating physician 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. 
8.3 
Follow-up period 
8.3.1 Visit 7 – EOS 
The EOS visit will take place 6 weeks (± 5 days) after last study treatment dose. The visit 
includes: 
• Recording of changes in concomitant medications and background SLE therapies 
since Visit 6 
• Recording of methods of contraception (for WOCBP) 
• Abbreviated physical examination 
• SLEDAI-2K and PGA 
• SBP/DBP 
• 12-lead ECG 
• Spirometry (under the responsibility of the pulmonary function laboratory technician 
or expert) 
• Ophthalmological examination (under the responsibility of the ophthalmologist) 
• Hematology (including coagulation tests) and blood chemistry 
• Serum pregnancy test (for WOCBP) 
• ANA, anti-dsDNA antibodies, complement C3 and C4 
• Exploratory biomarkers 
• Lymphocyte subsets 
• Urinalysis 
• PK sampling 
• Recording of AEs/SAEs 
A urine pregnancy test will be dispensed to WOCBP. 
8.3.2 Visit 8 and Visit 9– follow-up (telephone contact visits) 
Eleven weeks ± 5 days and 16 weeks ± 5 days, after the last dose of study drug has been 
taken, telephone calls will be made and include: 


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• Recording of SAEs 
• Urine pregnancy test for WOCBP (performed at home prior to telephone contacts 
with test kits dispensed at Visit 7 – EOS) 
Note that the data reported at these visits will not be entered in the eCRF. Results of the 
urine pregnancy tests must be reported in the source data. SAEs will be reported to 
Global Drug Safety and will be presented separately in the Clinical Study Report. 
8.4 
Unscheduled visits (U1, U2…) 
Unscheduled visits may be performed at any time during the study. These visits include 
(but are not limited to) those performed due to safety (e.g., occurrence of an AE, 
laboratory abnormalities), and/or SLE disease exacerbations (e.g., renal 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 
Additional assessments may be performed at the discretion of the investigator including 
but not limited to:  
• Abbreviated physical examination 
• SLEDAI-2K and PGA 
• SBP/DBP 
• 12-lead ECG 
• Hematology (including coagulation tests) and blood chemistry 
• Urine pregnancy test (for WOCBP) 
• ANA, anti-dsDNA antibodies, complement C3 and C4 
• Urine protein-to-creatinine ratio 
• Urinalysis 
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. For the additional assessments performed during unscheduled visit which 
are not part of the standard study assessments, results are not to be reported in the eCRF. 
However, 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 


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unscheduled visit, the regular scheduled study visits must continue according to the 
planned visit and assessment schedule. 
8.5 
Additional visits for re-initiation of study treatment 
Subjects may need to be monitored at the study site when re-initiating study drug 
following a study drug treatment interruption. Re-initiation visits should be conducted for 
study treatment interruptions which started prior to Day 14 [see Section 5.1.8]. 
Note that a subject can be re-initiated only once during the study duration 
The same post-dosing procedure as described in Section 8.2.1.2 (Visit 2 – Day 1 – 
Randomization and post-dose assessment) must be followed:  
• Hourly 12-lead ECG and SBP/DBP assessments for 6 hours or until the patient meets 
the discharge criteria (under the responsibility of the CSA [see Appendix 4]). If 
discharge criteria are not met after 12 hours, the subject should be permanently 
discontinued. 
• Recording of AEs and SAEs (please refer to Sections 7.2.2, 7.2.4 and 10.1.5 for 
reporting of AEs with onset on Day 1). 
• Recording of changes in concomitant medications and background SLE therapies 
since previous visit. 
• Study drug accountability for compliance review. 
These visits for post-dose monitoring of the subjects when re-initiating study treatment 
are additional unscheduled visits. The regular scheduled study visits must be resumed 
according to the original visit and assessment schedule. If the visit occurs at the same 
time as a regular visit, all assessments of the regular visit have to be perfomed in 
addition. 
9 
STUDY COMPLETION AND POST-STUDY TREATMENT / 
MEDICAL CARE 
9.1 
Study completion 
For an individual subject, study completion is reached when EOT visit and EOS visit 
have been completed.  
Ten weeks after the EOS visit, subjects will be contacted by telephone to collect 
follow-up information on any SAE and/or pregnancy (follow-up).  
EOS on a study level occurs at the time all subjects have completed their EOS visits, as 
described above. 


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9.2 
Premature withdrawal from study 
Subjects may voluntarily withdraw from the study 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, they believe that continued participation in 
the study would be contrary to the best interests of the subject. Withdrawal from the 
study may also result from a decision by Actelion for any reason, including premature 
termination or suspension of the study [see Section 9.3]. 
If premature withdrawal occurs for any reason, the reason for premature withdrawal from 
the study, along with who made the decision to withdraw (subject, investigator or 
Actelion) must be recorded in the eCRF. 
If for whatever reason (except death or loss-to-follow-up) a subject was withdrawn from 
the study, the investigator should make efforts to conduct a last visit/contact to assess the 
safety and well-being of the subject, collect unused study drug and discuss follow-up 
medical care. Data obtained during this last appointment / telephone call will be recorded 
in the subject’s medical records but 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 9.4. 
Subjects are considered as lost to follow-up if all reasonable attempts by the investigator 
to communicate with the individual fail. The site must take preventive measures to avoid 
a subject being lost to follow-up (e.g., document different ways of contact such as 
telephone number, home address, e-mail address, person to be contacted in case the 
subject cannot be reached). If the subject cannot be reached, the site must make a 
reasonable effort to contact the subject, document all attempts and enter the loss of 
follow-up information into the eCRF. The following methods must be used: at least three 
telephone calls must be placed to the last available telephone number, and one 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., site staff visit to the 
subject’s home), respecting the subject’s right to privacy. If the subject is still 
unreachable after all contact attempts listed above, she/he will be considered tob e lost to 
follow-up.  
9.3 
Premature termination or suspension of the study 
Actelion 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. 


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Study-specific stopping rules will be applied separately for Part A and Part B: 
• Part A: the entire study will be put on hold (all subjects will stop study treatment) 
if in Part A, 12 or more subjects out of the planned 36 subjects in the combined 
active dose groups of Part A (0.5, 1, or 2 mg), or 6 or more subjects out of the 
planned 12 subjects in the 2 mg dose group of Part A, have been discontinued due 
to meeting any of the individual patient’s stopping rules as defined per safety area 
of interest [Table 4]. 
• Part B: if 4 or more subjects in the active dose group of Part B (4 mg), have been 
discontinued due to meeting any of the individual patient’s stopping rules as 
defined per safety area of interest [Table 4], all subjects included in Part B will 
stop study treatment.  
The entire study or Part B will be suspended and a detailed safety signal assessment will 
be conducted. An un-blinded data assessment reflecting the total study safety experience 
will be performed by the IDMC in a dose level specific way (as certain AEs are likely to 
be dose dependent and might occur in higher frequency with higher dose). 
Recommendations from IDMC and Health Authorities may allow a potential restart of 
the study or of the Part B. 
If the study is prematurely suspended or terminated, Actelion will promptly inform the 
investigators, the IRBs/IECs and health authorities, as appropriate, and provide the 
reasons for the suspension or termination. A potential restart of the study will be allowed 
only in agreement with Health Authorities and IRBs/IECs. 
The safety areas of interest have been defined by the clinical experience obtained for this 
class of compounds and are described in Section 5.1.10. Table 4 provides a summary of 
these events in these safety areas of interest that will trigger subject’s discontinuation or 
may results in the hold of the clinical study if a certain number of patients were to be 
discontinued from study treatment, as indicated above. 


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Table 4 
Safety areas of interest 
Safety area of interest  
[See Section 5.1.10] 
Specific study stopping criteria being applied to stop subject / study 
Cardiovascular 
 
• 
HR < 40 bpm at two consecutive hourly 12-lead ECG post-dose 
(Day 1 or re-initiation) 
• 
SBP < 90 mmHg at two consecutive hourly BP measurements 
post-dose (Day 1 or re-initiation) 
• 
Subject not meeting criteria for discharge from the hospital (Day 1 or 
re-initiation)  
• 
QTcF > 500 ms at any time as documented by 12-lead ECG 
• 
Symptomatic bradycardia or hypotension (e.g., syncope) 
Immune 
system 
and 
Infections 
• 
Confirmed total lymphocyte count < 200 cells/µL 
• 
Clinically relevant infection (e.g., serious infection, opportunistic 
infection) 
Respiratory system 
 
• 
FEV1 and/or FVC > 15% decrease from the study baseline values 
which has been confirmed at repeat testing 
• 
Persistent respiratory AEs (e.g., dyspnea) 
Liver 
• 
Abnormal LTs or signs and symptoms suggestive of DILI as 
explained in the study protocol [Section 5.1.10.5] 
Ocular 
• 
Macular edema confirmed by Ophthalmology Safety Board 
AE = adverse event; BP = blood pressure; DILI = drug-induced liver injury; ECG = electrocardiogram; FEV1 = forced expiratory 
volume in 1 second; FVC = forced vital capacity; HR = heart rate; LT  = liver test; SBP = systolic blood pressure.  
If the study is suspended or prematurely terminated for any reason, the investigator in 
agreement with Actelion must promptly inform all enrolled subjects, and ensure their 
appropriate treatment and follow-up, as described in Section 9.2 for subjects prematurely 
withdrawn from the study. The investigator may be informed of additional procedures to 
be followed in order to ensure that adequate consideration is given to the protection of the 
subjects’ interests. 
In addition, if the investigator suspends or terminates the study without prior agreement 
from Actelion, the investigator must promptly inform Actelion and the IRB/IEC, and 
provide both with a detailed written explanation of the termination or suspension. 
If the IRB/IEC suspends or terminates its approval / favorable opinion of a study, the 
investigator must promptly notify Actelion and provide a detailed written explanation of 
the termination or suspension. 


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9.4 
Medical care of subjects after study completion / withdrawal from 
study 
After the subject’s study completion or premature withdrawal from the study, whichever 
applies, the investigator/delegate will explain to subjects what treatment(s) / medical care 
is necessary and available according to local regulations.  
In case of premature discontinuation from the study, WOCBP should be instructed to 
continue the use of contraception methods for at least 16 weeks after the last dose of 
study drug. 
10 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
10.1 Adverse events 
10.1.1 Definitions of adverse events 
An AE is any adverse change, 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 (i.e., after signing the informed consent), whether or not considered 
by the investigator as related to study treatment.  
A treatment-emergent AE is any AE temporally associated with the use of study 
treatment (from study treatment initiation until 6 weeks after study treatment 
discontinuation) whether or not considered by the investigator as related to study 
treatment. 
AEs include: 
• 
Exacerbation of a pre-existing disease. 
• 
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. 
• 
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 was 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.  


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Overdose, misuse and abuse of the study treatment should be reported as an AE and, in 
addition, study treatment errors must be documented in the study drug log of the eCRF. 
10.1.2 Intensity of adverse events 
The intensity of clinical AEs is graded on a three-point scale – mild, moderate, severe – 
and is reported on specific AE pages of the eCRF.  
If the intensity of an AE worsens during study treatment administration, only the worst 
intensity should be reported on the AE page. If the AE lessens in intensity, no change in 
the severity is required. 
If the intensity of an AE with an onset date between informed consent signature and start 
of study treatment and which is ongoing at the start of treatment worsens after the start of 
study treatment, a new AE page must be completed. The onset date of this new AE 
corresponds to the date of worsening in intensity. 
The three categories of intensity are defined as follows: 
 Mild 
The event may be noticeable to the subject. It does not influence daily activities and 
usually 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 10.2]. 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 severity assessment, determines the regulatory reporting 
obligations. 
10.1.3 Relationship to study treatment  
Each AE 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. The determination of the likelihood that the study drug caused the AE will be 
provided by an investigator who is a qualified physician. 


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10.1.4 Adverse events associated to study design or protocol-mandated procedures 
An AE is defined as related to study design or protocol-mandated procedures if it appears 
to have a reasonable possibility of a causal relationship to either the study design or to 
protocol-mandated procedures. Examples include discontinuation of a subject’s previous 
treatment during a washout period leading to exacerbation of underlying disease. 
10.1.5 Reporting of adverse events 
All AEs occurring after study start (i.e., signing of informed consent) and up to 6 weeks 
after study treatment discontinuation must be recorded on specific AE pages of the eCRF.  
10.1.6 Follow-up of adverse events 
AEs still ongoing more than 6 weeks after study treatment discontinuation must be 
followed up until they are no longer considered clinically relevant. 
10.1.7 Adverse events of special interest 
A list of AESIs is provided in Appendix 3. 
10.2 Serious adverse events 
10.2.1 Definitions of serious adverse events 
10.2.1.1 Serious adverse events 
An SAE is defined by the International Conference on Harmonisation (ICH) guidelines as 
any AE fulfilling at least one 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 inpatient 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 to be SAEs when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in the definitions above.  
The following reasons for hospitalization are exempt from being reported:  
• 
Hospitalization for cosmetic elective surgery, or social and/or convenience 
reasons. 


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• 
Hospitalization for pre-planned (i.e., planned prior to signing informed consent) 
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). 
10.2.1.2 Serious adverse events associated with the study design or protocol-mandated 
procedures  
An SAE is defined as related to study design or protocol-mandated procedures if it 
appears to have a reasonable possibility of a causal relationship to either the study design 
or to protocol-mandated procedures. Examples include discontinuation of a subject’s 
previous treatment during a washout period leading to exacerbation of underlying disease 
or a complication of an invasive procedure that is specifically required by the protocol. 
10.2.2 Reporting of serious adverse events  
All SAEs occurring after study start (i.e., signing of informed consent) up to 16 weeks 
after study treatment discontinuation must be reported to the Actelion drug safety 
department within 24 hours of the investigator’s knowledge of the event on an SAE form, 
regardless of the investigator-attributed causal relationship with study treatment or study-
mandated procedures. 
All SAEs occurring after study start (i.e., signing of informed consent) up to 6 weeks 
after study treatment discontinuation must also be reported using AE pages in the eCRF. 
10.2.3 Follow-up of serious adverse events  
SAEs still ongoing at the end of the 16-week follow-up period must be followed up until 
resolution or stabilization, or until the event outcome is provided, e.g., death.  
10.2.4 After the 16-week follow-up period  
New SAEs occurring after the 16-week follow-up period must be reported to the Actelion 
drug safety department within 24 hours of the investigator’s knowledge of the event, only 
if considered causally related to previous exposure to the study treatment by the 
investigator.  
10.2.5 Reporting procedures 
All SAEs must be reported by the investigator to the Actelion drug safety department 
within 24 hours of the investigator’s first knowledge of the event. 
All SAEs must be recorded on an SAE form, irrespective of the study treatment received 
by the subject, and whether or not this event is considered by the investigator to be 
related to study treatment.  


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The SAE forms must be faxed to the Actelion drug safety department (contact details are 
provided on the SAE form). The investigator must complete the SAE form in English and 
must assess the causal relationship of the event to study treatment. 
Follow-up information about a previously reported SAE must also be reported within 
24 hours of receiving it. The Actelion drug safety department may contact the 
investigator to obtain further information.  
If the subject is hospitalized in a hospital other than the study site, it is the investigator’s 
responsibility to contact this hospital to obtain all SAE-relevant information and 
documentation. 
The reference safety document to assess expectedness of a suspect serious adverse 
reaction and reported by the sponsor to health authorities, IRBs/IECs and investigators is 
the reference safety information section of the IB [ACT-334441 IB].  
SLE exacerbations or SLE flares and associated symptoms are anticipated SAEs in this 
study as commonly seen with the underlying disease and therefore expected to occur in 
this subject population. These SAEs will be treated as “disease-related” and expected 
(unless fatal) and will therefore not require systematic unblinding or expedited reporting 
to health authorities, IRBs/IECs, and investigators. However, these events will be 
monitored during the study by the sponsor and by the IDMC [see Section 10.4]. These 
SAEs are treated as waived SAEs for this study. 
10.3 Pregnancy 
10.3.1 Teratogenicity 
In embryo-fetal studies in rats and rabbits, ACT-334441 shows teratogenic potential. 
Therefore, appropriate precautions must be taken by WOCBP. Women must not become 
pregnant during the study and up to 16 weeks after study drug discontinuation. The 
investigator must explain and stress the importance of using methods of contraception 
[see Section 4.5.2]. 
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.  
10.3.2 Reporting of pregnancy 
Irrespective of the treatment received by the subject, any pregnancy occurring during the 
study including during the 16 weeks following study treatment discontinuation must be 
reported within 24 hours of the investigator’s knowledge of the event.  


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Pregnancies must be reported on the Actelion Pregnancy form up to 16 weeks following 
study treatment discontinuation, which is faxed to the Actelion drug safety department 
(see contact details provided on the Actelion Pregnancy form), and on an AE page in the 
eCRF up to 6 weeks following study treatment discontinuation (EOS).  
Male contraception 
Based on nonclinical data and human distribution models [see Section 1.3], it is 
considered very unlikely that a significant dose of ACT-334441 would be delivered to the 
female by seminal transfer. Furthermore, the potential risk of harm to a human fetus by 
ACT-334441 is considered to be very low, based on the high safety margins 
[ACT-334441 IB]. Therefore, there is no specific recommendation for male contraception 
regarding ACT-334441. (Note: For allowed concomitant therapies during this trial that 
require contraception, the respective method of contraception must be applied.) 
10.3.3 Follow-up of pregnancy  
Any pregnancy must be followed to its conclusion, and its outcome must be reported to 
the Actelion drug safety department. 
Any AE associated with the pregnancy occurring during the follow-up period after study 
drug discontinuation must be reported on separate AE pages in the eCRF up to 6 weeks 
following study treatment discontinuation (EOS). Any SAE occurring during the 
pregnancy must be reported on an SAE form as described in Section 10.2.5. 
10.4 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 Actelion Clinical team (in charge of ensuring subjects’ safety as 
well as data quality) by periodically monitoring clinical studies’ activities from protocol 
conception to database closure. In addition, an IDMC is monitoring safety data [see 
Section 3.4.1]. 
11 STATISTICAL METHODS 
11.1 General considerations 
All statistical analyses will be conducted by Actelion or by designated CROs supervised 
by Actelion. 
The SAP for final analysis will be approved prior to database lock. The SAP for the 
interim safety review will be finalized prior to unblinding the study by the independent 
ISAC. The SAPs provide the full details of all analyses, data displays, and algorithms to 
be used for data derivations. 


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All data will be listed, and endpoints will be summarized by appropriate descriptive 
statistics (tables or figures), typically including: 
• number of non-missing observations, number of missing observations, mean, standard 
deviation, median, Q1 (first quartile), Q3 (third quartile), minimum and maximum for 
continuous endpoints; 
• number of non-missing observations, number of missing observations and frequency 
with percentage per category (percentages based on the number of non-missing 
observations) for categorical endpoints; 
• number of subjects at risk, cumulative number of events, cumulative number of 
censored observations and Kaplan-Meier estimates of the survival function for 
time-to-event endpoints. 
Baseline is defined as the last assessment prior to initiation of the study treatment. 
Absolute changes from baseline are defined as: post-baseline value minus baseline value, 
i.e., a positive sign indicates an increase as compared to baseline. 
A percentage (relative) change from baseline is defined as the absolute change from 
baseline divided by the baseline value (if the baseline value does not equal 0) multiplied 
by 100. 
11.2 Analysis Sets 
11.2.1 Screened Analysis Set 
This analysis set includes all subjects who were screened and received a subject number. 
11.2.2 PD Analysis Set 
The Pharmacodynamics Analysis Set (PDS) includes all subjects who received at least 
3 weeks of study treatment and have at least one lymphocyte count measurement between 
the Week 4 visit and Week 12 visit. Subjects will be analyzed according to the treatment 
they received. 
11.2.3 Full Analysis Set 
The Full Analysis Set (FAS) includes all randomized subjects. In order to adhere to the 
intention-to-treat principle as much as possible:  
• Subjects will be evaluated according to the dose they have been randomized to (which 
may be different to the dose they have received)  
• Unless otherwise stated, all available efficacy data up to the EOS date will be 
included, irrespective of whether a subject has stopped study treatment earlier or has 
received any SLE treatment other than that to which the subject was randomized to.  


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11.2.4 Per-Protocol Set 
The Per-Protocol Set (PPS) comprises data from all subjects included in the FAS without 
selected major protocol deviations including but not limited to : 
• Subjects not adhering to the treatment regimen for mandatory concomitant 
medication; 
• Subjects with < 80% compliance to study treatment; 
• Start of any prohibited systemic SLE therapies during the course of the trial.  
A complete list will be provided in the SAP. 
11.2.5 Safety Analysis Set 
The Safety Analysis Set includes all randomized subjects who received at least one dose 
of study treatment. Unless otherwise stated, any analysis using the Safety Analysis Set 
will use all available safety data up to 6 weeks  after discontinuation of study treatment. 
Subjects will be analyzed based on actual dose taken, not the randomized dose.  
11.2.6  PK Analysis Set 
The PK Analysis Set will include all randomized subjects who received at least one 
ACT-334441 dose and provided at least one blood sample for PK evaluation. Subjects 
will be analyzed based on actual dose taken, not the randomized dose.  
11.2.7 Other analysis sets 
Other analysis datasets are defined in the corresponding SAPs, e.g., Biomarker analysis 
sets. 
11.2.8 Usage of the analysis sets 
The primary analysis and supportive analysis of PD endpoints will be carried out on the 
PDS. 
All exploratory efficacy analyses will be performed using the FAS. Sensitivity analyses 
of PD endpoints will also be performed on the FAS. 
Supplementary analysis to test the robustness of the results for selected PD endpoints and 
for all exploratory efficacy endpoints will be performed based on the PPS. 
All safety data will be analyzed using the Safety Analysis Set. 
All PK analysis be analyzed using the PK Analysis Set. 
11.3 Variables 
11.3.1 Main pharmacodynamic variable 
The main variable is the change in lymphocyte count from baseline to EOT, defined as:  


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• Total lymphocyte count at EOT – total lymphocyte count at baseline  
Last observation carried forward (LOCF; using data from the Week 4 visit or later) will 
be used for subjects with a missing EOT assessment.  
11.3.2 Other pharmacodynamic variables 
Other PD variables comprise: 
• Absolute values of total lymphocyte count at each timepoint; 
• Change in total lymphocyte count from baseline to each post-baseline assessment 
(expressed as absolute change from baseline and percent change from baseline).  
Absolute change and percentage changes are calculated as defined in Section 11.1. 
11.3.3 Safety variables 
The treatment-emergent period is defined as the time from first study treatment intake up 
to 6 weeks (inclusive) after last study treatment intake. 
• Treatment-emergent AEs, SAEs, and AESIs [described in Appendix 3]; 
• AEs leading to premature discontinuation of study tretment; 
• Change in 12-lead ECG variables (heart rate, PR, QRS, QT, QTcB and QTcF), 
from pre-dose to selected post-doses assessments (1 h, 2 h, 3 h, 4 h, 5 h, 6 h) on 
Day 1 and on day of study drug re-initiation; 
• Occurrence of treatment-emergent 12-lead ECG outliers. Full details of all outlier 
definitions will be provided in the SAP; 
• Occurrence of treatment-emergent 12-lead ECG abnormalities at each scheduled 
assessment timepoint;  
• Occurrence of treatment-emergent ECG-Holter abnormalities on Day 1;  
• Change in SBP and DBP from baseline up to EOS; 
• Change in FEV1 and FVC, expressed in absolute value (L) and percent value from 
baseline up to EOS; 
• Occurrence of treatment-emergent decrease of FEV1 or FVC > 15% from baseline 
values; 
• Change in laboratory parameters (hematology, blood chemistry, and urinalysis) 
from baseline up to EOS; 
• Change in protein-to-creatinine ratio from baseline to EOT; 
• Treatment-emergent laboratory abnormalities according to CTCAE 2010 v4.03 
[CTCAE 2010] and FDA guidelines [FDA 2009] (for ALT/AST/TBL); 
• Change in body weight from baseline to EOT. 


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11.3.4 Pharmacokinetic variables 
PK variables comprise 
• Ctrough ACT-334441 plasma concentrations prior to dosing at Weeks 2, 4, 8, and 
12 (EOT); 
• ACT-334441 plasma concentration at EOS (i.e., 6 weeks after study treatment 
discontinuation). 
 
11.3.5 Exploratory disease activity variables 
Exploratory disease activity variables comprise the following markers, including but not 
limited to: 
• Change from baseline in the SLEDAI-2K (modified to exclude leukopenia) score 
at each scheduled post-baseline assessment; the SLEDAI-2K score at each visit is 
calculated as the sum of all individual item score/weight;  
• Change from baseline in PGA score at each scheduled post-baseline assessment; 
• Change from baseline in SLEDAI-2K mucocutaneous and/or muscoskeletal score 
at each scheduled post-baseline assessment. The SLEDAI-2K mucocutaneous 
and/or muscoskeletal score is calculated as the sum of each individual 
mucocutaneous (mucosal ulcers, rash, alopecia) and/or muscoskeletal (arthritis 
and myositis) score/weight. 
All exploratory disease activity variables are calculated as the score at each visit minus 
the score at baseline. 
11.3.6 Quality of life variables 
Exploratory disease activity variables comprise: 
• Change from baseline to EOT in SF-36v2™ Health Survey domain and 
component scores, calculated as the score at EOT minus the score at baseline. 
Calculation of the domain and component scores will be detailed in the SAP.  
11.3.7 Exploratory biomarker variables 
Exploratory biomarker variables comprise but not limited to: 
• Change in immunoglobulin serum levels (IgG, IgM, IgA) from baseline to each 
post-baseline assessment;  
• Change in ANA and anti-dsDNA antibody titers from baseline to each 
post-baseline assessment;  
• Change in serum complement components C3 and C4, CRP, fibrinogen, BLyS 
and CXCL10 from baseline to each post-baseline assessment; 
• Change in blood lymphocyte subsets from baseline to EOT and EOS (expressed 


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as absolute change from baseline and percent change from baseline); 
Change from baseline is calculated as the measurement reported at each visit minus the 
measurement reported at baseline. 
11.4 Description of statistical analyses 
11.4.1 Overall testing strategy 
An optimized contrast test according to the Multiple Comparison Procedure and 
Modelling (MCP-Mod) approach [Bretz 2005] for each considered dose-response model 
will be performed. The existence of dose-response effects will be tested using the 
maximum of the model-based contrast tests. Multiplicity adjusted p-values will be 
calculated using the Dunnett-distribution. 
11.4.2 Analysis of the main pharmacodynamic variable(s) 
11.4.2.1 
Hypotheses and statistical model 
The null hypothesis is that there is no dose response in terms of lowering of lymphocyte 
counts (p, which is a negative value for a lowering of the lymphocyte count) from 
baseline to EOT, and the alternative hypothesis is the existence of a dose response:  
 for all doses d = 0.5, 1, 2, 4 mg 
                                                vs 
 for at least 1 dose d =0.5, 1, 2, 4 mg 
If Part B of the trial is not performed, the hypothesis will be 
 for all doses d = 0.5, 1, 2 mg 
                                                vs 
 for at least 1 dose d =0.5, 1, 2 mg 
To meet the objective of demonstrating existence of a dose response of ACT-334441 on 
the lymphocyte count reduction from baseline in subjects with SLE, the null hypotheses 
must be rejected by the test with a one-sided significance level of 5%.  
11.4.2.2 
Handling of missing data 
In the primary analysis, missing lymphocyte count at EOT visit will be imputed utilizing 
LOCF techniques (using data from the Week 4 visit or later). Patients with missing 
baseline lymphocyte count and/or no lymphocyte count at or after Visit 4 will be 
excluded from the primary analysis. 


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11.4.2.3 
Main analysis 
The MCP-Mod approach consists of a set of optimized contrast tests for establishing the 
existence of dose-response effects. The overall strategy is described as follows: 
Definition of a set of likely dose-response relations [see Section 11.6 for more details] 
(the method allows for characteristics of the curve, such as maximum effect, to be 
defined at doses not studied): 
• Maximum effect (Emax) with 50% of the maximum effect at dose 0.2 mg 
• Emax with 50% of the maximum effect at dose 0.4 mg 
• Emax with 50% of the maximum effect at dose 1.0 mg 
• Quadratic with maximum effect at dose 3.0 mg (only if the 4 gm dose is studied) 
• Sigmoid-Emax with 50% of the maximum effect at dose 0.4 mg and 95% of the 
maximum effect at dose 2.0 mg. 
The existence of dose-response effects will be assessed with the optimized contrast tests. 
Dose-response effects are established at one-sided level α=5%, if the following condition 
on the p value holds for at least one contrast i: 
, where 
describes the Dunnett-distribution with correlation matrix 
. 
The model with the minimum p-value will be fitted to the data. As a sensitivity analysis, 
all remaining significant models will be fitted to the data, and model-based dose 
estimates will be calculated. 
Given established dose-response effects with MCP-Mod, PD effects will be analyzed 
based on pairwise comparisons of reduction in lymphocyte count from baseline for each 
active dose levels to placebo using an analysis of covariance (ANCOVA) model, adjusted 
for baseline lymphocyte counts. Testing will be done with two-sided significance level 
5%. The type-1 error will be controlled via a hierarchical ordering of the tests: pairwise 
comparison will be conducted in decreasing dose order.  
The dose-response data will be summarized with point-wise and model-based estimates, 
standard deviation and 95% confidence-intervals (CI) on the reduction in lymphocytes 
from baseline at the examined dose levels. A plot of the estimated dose-response curve 
with 95% credibility interval limits will be presented along with the observed response at 
each dose. 
This analysis will be performed on the PDS.  
11.4.2.4 
Supportive/sensitivity analyses 
A supportive analysis will be performed on the FAS and PPS. The analysis described in 
Section 11.4.2.3 will also be repeated on observed data with no missing data imputation. 
Further analysis will be described in the SAP. 


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11.4.2.5 
Subgroup analyses 
Any subgroup analysis will be described in the SAP. 
11.4.2.6 Other pharmacodynamic variables 
Absolute values, absolute change from baseline and percent change from baseline of total 
lymphocyte counts and blood lymphocyte subsets at each timepoint will be summarized 
descriptively. An ANCOVA model adjusted for baseline counts will be used to compare 
each dose to placebo at the EOT visit only. 
11.4.3 Analysis of the safety variable(s) 
The Safety Analysis Set will be used to perform all safety analyses.  
If not otherwise stated, only treatment-emergent safety data (observations with onset or 
assessment dates at/after first intake of study drug up to 6 weeks after study drug 
discontinuation) will be considered in tables and figures. All safety data will be included 
in listings, with flags for safety data not considered to be treatment-emergent. 
Specific safety events (AEs, laboratory tests, ECG findings, etc.) will be considered. In 
general, they consist of one or more well-defined safety events that are similar in nature 
and for which there is a specific clinical interest in connection with ACT-334441.  
For specific AESIs, the number and percentage of subjects with at least one event will be 
reported. Point estimates and 95% CIs for safety-event incidences and the relative risk 
ratio relative to placebo will be provided without adjustment for multiplicity. 
Exploratory analysis of time to first onset of safety events of interest may be displayed by 
Kaplan-Meier estimates. Subjects not experiencing the safety event will be censored at 
the minimum of the EOS date and 6 weeks after last dose of study drug. Where 
applicable, study treatment doses will be compared with placebo by hazard ratios and 
corresponding 95% CIs from Cox’s regression model.  
11.4.3.1 
Adverse events 
All AEs will be coded using the latest version of the Medical Dictionary for Regulatory 
Activities (MedDRA) available at the time of database closure. 
11.4.3.1.1 Treatment-emergent AEs and SAEs  
Treatment-emergent AEs, SAEs and AEs leading to premature discontinuation of study 
drug will be tabulated by study dose, 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 
each ACT-334441 dose or placebo.  


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11.4.3.1.2 AEs and SAEs for screening failure patients  
AEs and SAEs during screening will be listed for patients who are screening failures and 
do not enter the study treatment period. 
11.4.3.1.3 AESIs 
The number and percentage of subjects who experienced at least one AESI, at least one 
AESI within each category and at least one AESI within each preferred term will be 
summarized by dose. The relative risk of having an AESI in each dose group compared to 
placebo will be summarized using forest plots. 
11.4.3.1.4 Post-treatment AEs and SAEs 
Post-treatment (S)AEs occurring over 6 weeks after treatment discontinuation will be 
summarized in a similar manner as described in Section 11.4.3.1.1.  
11.4.3.1.5 Deaths 
Fatal SAEs occurring any time after the start of treatment will be summarized in a similar 
manner as described in Section 11.4.3.1.1.  
11.4.3.2 
Cardiac safety 
11.4.3.2.1 12-lead ECG assessments 
Descriptive summary statistics by visit and study treatment will be provided for observed 
treatment-emergent values and absolute changes from pre-dose in numeric 12-lead ECG 
values (HR, PR, QRS, QT, QTcB, QTcF). Data will be summarized from pre-dose to 
each post-dose assessments on Day 1 and also at the re-initiation of study drug. 
Notable abnormalities for selected 12-lead ECG parameters (HR, PR, QT, QTcF) will be 
summarized for all data on Day 1, Week 12 and also at the re-initiation of study drug.  
In addition treatment-emergent morphological ECG abnormalities will be summarized 
descriptively (using data from the ECG provider).  
11.4.3.2.2 Cardiac safety events 
Cardiac safety events will include:  
• treatment-emergent QTc > 450 ms (male), > 470 ms (female), > 500 ms (male), and 
> 520 ms (female) 
• treatment-emergent QTc increase from baseline > 30 ms, > 60 ms 
• other treatment-emergent abnormalities observed by 12-lead ECG 
• treatment-emergent (serious) cardiac AESIs. 
 
Cardiac safety events will be summarized descriptively.  


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11.4.3.2.3 24-hour Holter ECG 
Treatment-emergent abnormalities as assessed by 24-hour Holter ECG monitoring will be 
summarized by dose group and presented similarly to AEs. Hourly mean HRs will be 
summarized descriptively.   
11.4.3.3 
Pulmonary safety 
11.4.3.3.1 Pulmonary function testing 
Descriptive summary statistics by visit and study dose will be provided for observed 
treatment-emergent values and changes from baseline by visit in FEV1, FVC and 
FEV1/FVC ratio (all expressed in absolute change, % change and % of predicted value).  
The number and proportion of treatment-emergent decrease of percent-predicted FEV1 or 
FVC > 15 percentage points from baseline at any time up to the last treatment will be 
summarized by dose. 
11.4.3.3.2 Pulmonary safety events 
Pulmonary safety events will include:  
• treatment-emergent decrease of FEV1 or FVC to < 85% of baseline values 
• (serious) pulmonary AESIs  
• withdrawal due to pulmonary reasons / AE 
 
Pulmonary safety events will be summarized descriptively.  
11.4.3.4 
Vital signs 
Descriptive summary statistics by visit and study dose will be provided for observed 
treatment-emergent values and absolute changes from baseline in HR, BP and body 
weight. 
Treatment-emergent notable BP abnormalities will also be summarized. The definition 
for notable abnormalities is provided in Appendix 7. 
11.4.3.5 
 Laboratory endpoints 
11.4.3.5.1 Laboratory tests 
Descriptive summary statistics by visit and study dose will be provided for observed 
treatment-emergent values and absolute changes from baseline for laboratory tests 
(hematology, blood chemistry, urinalysis). Data will be displayed in Standard 
International units whenever possible, and graphical approaches will be applied. 
11.4.3.5.2 Laboratory safety events 
Laboratory safety events will include:  


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• treatment-emergent laboratory test abnormalities based on normal ranges of the central 
laboratory and according to CTCAE 2010 v4.03 [CTCAE 2010]  
• treatment-emergent laboratory test abnormalities based on FDA guidance for DILI 
[FDA 2009] (for ALT/AST/TBL) 
• lymphocyte count reversibility after EOT, expressed in absolute change and percent 
change from baseline 
 
The definitions for marked abnormalities is provided in Appendix 7. Laboratory safety 
events will be summarized descriptively.  
11.4.3.6 
Ocular safety 
Ocular safety events will include: 
• treatment-emergent ocular AESIs 
11.4.4 Analysis of the exploratory efficacy variables 
The analysis of the exploratory efficacy endpoint change from baseline in SLEDAI-2K 
score at Week 12 will be performed using an ANCOVA with treatment and baseline 
score as factors. Missing values at Week 12 will be imputed using LOCF. The mean 
treatment difference including 95% CI for each ACT-334441 dose compared to placebo 
will be presented. A sensitivity analysis will be performed using observed data without 
imputation. 
Other changes from baseline variables will be analyzed in a similar manner using an 
ANCOVA. 
All exploratory efficacy endpoints will be analyzed on the FAS and PPS. 
No multiplicity adjustments will be made on exploratory efficacy endpoints. Other 
analyses will be described in the SAP. 
11.4.5 Analysis of other variable(s) 
11.4.5.1 Pharmacokinetic endpoints 
Concentrations will be summarized by descriptive statistics. 
11.4.5.2 Exploratory biomarkers 
Descriptive statistics of mean, median, CV, standard error of the mean, 95% CI for each 
time point and variable will be summarized. 
Statistical analysis of means (time-point and variable) for each ACT-334441 dose group 
against placebo will be conducted. 
Statistical analysis on the exploratory disease activity endpoint SLEDAI-2K will be 
performed on the difference between subjects with an exploratory biomarker value ≤ the 


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25th percentile compared to subjects with a value ≥ the 75th percentile. Depending on the 
shape of the dose-response curve observed for the main PD endpoint, dose groups may be 
combined to increase the power to observe differences.  
Modeling of exploratory biomarkers together with PK, PD or efficacy variables might be 
conducted and will be described in the SAP. 
The list of statistical analysis on exploratory biomarkers data is not exclusive. 
11.4.5.3 Exploratory analyses 
Exploratory, data-driven analyses may be performed and will be described in the SAP. 
The relationship between ACT-334441 concentrations and any safety or tolerability, 
disease activity, biomarker, or PD data might be investigated on an exploratory basis. 
Whenever possible, a model will be established to describe these relationships. 
11.5 Interim safety review 
Prior to enrolling any subject into study Part B, the ISAC will perform an interim analysis 
of Part A data, which will be reviewed by the IDMC.  
The IDMC will operate according to an IDMC charter jointly agreed between the IDMC 
members and Actelion. 
11.5.1 Objectives 
The objective of the interim safety review is to evaluate the safety profile of ACT-334441 
in SLE patients and to determine if the study should continue as planned with initiation of 
Part B or if the study should be amended with protocol changes or if the study should be 
discontinued to ensure subject safety. 
11.5.2 Timing 
The interim safety review will be conducted when all subjects enrolled into Part A have 
completed Visit 4 (Week 4), unless prematurely discontinued.  
11.5.3 Unblinded IDMC review 
After blinded data review by blinded Actelion staff, an ISAC (a CRO or an Academic 
Research Organization not otherwise involved with study conduct or statistical analysis) 
will generate an unblinded interim analysis report exclusively for review by the IDMC.  
No interim database lock will occur. Actelion staff will remain blinded to study treatment 
after the interim safety review is performed. 


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Based on the interim safety review with cut-off at Visit 4 and an IDMC recommendation, 
the study will continue as planned with Part B initiation or be amended (protocol changes 
or study discontinued to ensure subject safety). 
11.5.4 Variables 
The interim data will include the following variables: 
• Demographics and disease characteristics 
• Patient disposition 
• Background and concomitant medications 
• SAEs, AEs (including AESI), and AEs leading to study treatment discontinuation 
• 12-lead ECGs and 24-hour ECG Holter data 
• Spirometry data 
• Hematology data including total lymphocyte counts, neutrophils and platelet 
counts 
• Blood clinical chemistry data including liver function parameters and 
immunoglobulin levels (IgM, IgG, IgA) 
• ACT-334441 plasma concentration data. 
 
Data will be displayed using summary tables, listings, figures and patient profiles. 
11.6 Sample size 
11.6.1 Sample size justification 
The sample size for the study was determined based on simulations. A sample size of 
64 subjects (12 in each ACT-334441 dose group of 0.5 mg, 1 mg, 2 mg, 4 mg and 16 in 
the placebo group) would provide an average power of at least 90% to show a significant 
dose-response relationship at a one-sided alpha significance level of 5%, under the 
assumption of a lymphocyte % reduction compared to baseline of 0% (mean at Week 12 
= 2.0 × 109/L) for placebo and a maximum of 70% for any ACT-334441 dose (mean at 
Week 12 = 0.6 × 109/L). A maximum lymphocyte % reduction compared to baseline of 
70% was assumed based on results obtained in Phase 1 with ACT-334441 and with other 
S1P modulators. The pooled standard deviation is assumed to be 0.45 × 109/L. This takes 
into account 10% of subjects being excluded from the PDS.  
If Part B is not conducted and the 4 mg dose is not tested then there will be an average 
power of at least 80% to show a significant dose-response relationship with three doses at 
a one-sided significance level of 5%, using the same assumptions as above (based on a 
total sample size of 48 subjects [12, 12, 12 and 12 in placebo, 0.5 mg, 1 mg and 2 mg, 
respectively]). 


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Assuming a % reduction in lymphocyte counts of between 25% to 70% (and pooled 
standard deviation = 0.45 × 109/L) compared to placebo, any single pairwise dose 
comparison will have between 77% and 100% power to detect a difference at a 2-sided 
significance level of 5%.  
Assumptions on the placebo response rate, maximum effect sizes and candidate 
dose-response models are based on the observed lymphocyte counts in study 
AC-064-101. 
Figure 4 
Reduction in total lymphocyte count dose-response shapes 
 
 
12 DATA HANDLING 
12.1 Data collection 
The investigator/delegate is responsible to ensure the accuracy, completeness, and 
timeliness 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 


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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 fail to complete the study. If a subject withdraws from the study, the reason must be 
noted on the eCRF.  
12.2 Maintenance of data confidentiality 
The investigator/delegate must ensure that data confidentiality is maintained. On eCRFs 
or other documents submitted to Actelion, subjects must be identified only by number, 
and never by name or initials, hospital numbers or any other identifier. The 
investigator/delegate must keep a subject identification code list at the site, showing the 
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 Actelion, and must be kept in strict confidence by the investigator/delegate. 
12.3 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 Actelion 
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 Actelion 
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. 


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This process will continue until database closure. 
Laboratory samples, 12-lead ECG, 24-hour Holter ECG, and spirometry will be 
processed through a central reader, and the results will be sent electronically to Actelion.  
After the database has been declared complete and accurate, the database will be closed. 
Any changes to the database after that time may only be made as described in the 
appropriate SOP. After database closure, the investigator will receive the eCRF of the 
subjects of her/his site (including all data changes made) on electronic media or as a 
paper copy. 
13 PROCEDURES AND GOOD CLINICAL PRACTICE 
13.1 Ethics and Good Clinical Practice 
Actelion 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 research is conducted.  
13.2 Independent Ethics Committee / Institutional Review Board 
The investigator will submit this protocol and any related document provided to the 
subject (such as Subject Information Leaflet used to obtain informed consent) to an IRB 
or IEC. Approval from the committee 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 IRB/IEC in accordance with local procedures and 
regulations [see Section 13.6]. 
A list of members participating in the IRB/IEC 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. 
13.3 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. 
The ICF will be provided in the country local language(s). 


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Site staff authorized to participate to the consent process and/or to obtain consent from 
the subject and/or legal representative will be listed on an Actelion Delegation of 
Authority form. A study physician must always be involved in the consent process.  
The subject and/or legal representative must sign, personally date and time (if 
appropriate) the ICF before any study-related procedures (i.e., any procedures required by 
the protocol) begin. The ICF must also be signed, personally dated and timed (if the first 
study-mandated procedure was performed on the same day informed consent was 
obtained) by the authorized site staff listed on the Actelion Delegation of Authority form. 
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 Actelion 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 case 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. Actelion, the regulatory authorities (if 
applicable) and the IRB/IEC 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 IRB/IEC, according to procedures and before subjects are recruited.  
13.4 Compensation to subjects and investigators 
Actelion 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. 
13.5 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 Actelion or its 
representative in a timely manner. The investigator/delegate must document and explain 


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any deviation from the approved protocol. IRB/IEC and regulatory authorities must be 
informed, according to their requirements, but no later than 15 calendar days after the 
event. 
13.6 Protocol amendments 
Any change to the protocol can only be made through a written protocol amendment. A 
protocol amendment must be submitted to the IRB/IEC and regulatory authorities, 
according to their requirements. 
13.7 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: 
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 
Actelion’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 Actelion to store these documents outside the site, so 
that they can be retrieved in case of a regulatory inspection. No study document should 
be destroyed without prior written approval from Actelion. Should the investigator wish 
to assign the study records to another party, or move them to another location, Actelion 
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 
for verification by the CRA. The printouts will be considered as the official clinical study 
records and must be filed either with the subject medical records or with the subject’s 
eCRF.  


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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 Actelion’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. The printouts should be 
filed either with the subject medical records or with the subject’s eCRF. 
13.8 Monitoring 
Prior to study start, a site initiation visit (SIV) will be performed after the required 
essential study documents are approved by Actelion. 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 investigator site file (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. 
Actelion 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 plan. 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 
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 


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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 closure at the discretion of 
Actelion. 
13.9 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 Actelion. 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 Actelion immediately.  
If the principal investigator changes, or if the site relocates, the CRA must be notified as 
soon as possible.  
13.10 Audit 
Actelion’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 Actelion’s requirements (e.g., SOPs) will also be verified. Prior to initiating 
this audit, the investigator will be contacted by Actelion to arrange a time for the audit.  
The investigator and staff must cooperate with the auditor(s) and allow access to all study 
documentation (e.g., subject records) and facilities. 
13.11 Inspections 
Health authorities and/or IRB/IEC may also wish to conduct an inspection of Actelion’s 
clinical study (during the study or after its completion).  


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Should an inspection be requested by a health authority and/or IRB/IEC, the investigator 
must inform Actelion 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. 
13.12 Reporting of study results and publication  
Study results will be documented in a Clinical Study Report that will be signed by 
Actelion representatives and the coordinating investigator (or principal investigator for 
single-center studies). 
The coordinating investigator, if any, will have the opportunity to review the analysis of 
the data and to discuss the interpretation of the study results with Actelion prior to 
publication. 
Actelion will post results from its clinical studies on Actelion’s Clinical Trial Register 
and on external/national registries, as required by law. 
Actelion’s Policy on Disclosure of Clinical Research Information can be found at:  
http://www.actelion.com/documents/corporate/policies_charters/policy_clinical-research-
information.pdf 
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 
Actelion and will be determined by mutual agreement. 
Any study-related publication written independently by investigators must be submitted 
to Actelion for review at least 30 days prior to submission for publication or presentation. 
Upon review, Actelion may provide comments and may also request alterations and/or 


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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. 
Actelion’s policy on scientific publications can be found at: 
http://www.actelion.com/documents/corporate/policies-charters/policy-scientific-
publications.pdf 


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Appendix 1 
Prohibited anti-arrhythmic or heart rate lowering medications  
The use of the following drugs at any time during the study is prohibited [see 
Section 5.2.5]: 
•         Adenosine 
 
•         Ivabradine 
•         Acetobulol 
 
•         Lidocaine 
•         Ajmaline 
 
•         Lorajmine 
•         Amiodarone 
 
•         Lorcainide 
•         Aprinidine 
 
•         Metoprolol 
•         Atenolol 
 
•         Mexiletine 
•         Azimilide 
 
•         Morcizine 
•         Bepridil 
 
•         Nadolol 
•         Bisiprolol 
 
•         Phenytoin 
•         Betaxolol 
 
•         Pilocarpin 
•         Bretylium 
 
•         Prajmaline 
•         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 2 
List of medications with risk of torsades de pointes 
The use of the following QT-prolonging medications with a known risk of torsades de 
pointes at any time during the study is prohibited [see Section 5.2.5]: 
 
• 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 3 
Adverse events of special interest 
AESIs will include the anticipated risks of treatment with ACT-334441 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 disorders 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 4 
Criteria for discharge from hospital 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; 
• QTcF < 500 ms; 
• 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, she/he 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. 


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Appendix 5 
American College of Cardiology / American Heart Association / 
American College of Physicians Training Requirements for 
Performance and Interpretation of Adult Transthoracic 
Echocardiography 
 
 
Cumulative Duration of 
Training 
Minimum Total Number of 
Examinations Performed 
Minimum Number of 
Examinations Interpreted 
Level 1 
3 months 
75 
150 
Level 2 
6 months 
150 (75 additional) 
300 (150 aditional) 
Level 3 
12 months 
300 (150 aditional) 
750 (450 aditional) 
 
From: Quiñones 2003 


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Appendix 6 
SLEDAI-2K: DATA COLLECTION SHEET 
Enter weight in SLEDAI-2K score column if descriptor is present at the time of the visit 
or in the preceding 10 days. 


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Note that Leukopenia will not be evaluated for reasons of functional blinding [see 
Section 5.1.4.2] 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 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 
ACT-334441 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 (2010 v4.03) 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 2010].  
The term ALERT here corresponds to protocol-defined test result threshold requiring an 
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. Parameters for which no 
threshold is defined in Table 5 below may be defined in the central laboratory manual. 










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Appendix 9 
Physician’s Global Assessment Visual Analog Scale 
From: Petri 2005 


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Appendix 10 
SF-36v2™ 
United States (English) SF-36v2 Standard 


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SAP_001.pdf: 
Statistical Analysis Plan AC-064A201 
A multicenter, randomized, double-blind, placebo-controlled, dose-response study to investigate the 
biological activity, safety, tolerability, and pharmacokinetics of ACT-334441 in subjects with systemic 
lupus erythematosus 
 
ClinicalTrials.gov Identifier: NCT02472795 
 
 
This study was sponsored by Actelion Pharmaceuticals.  
Study sponsorship was transferred to Idorsia Pharmaceuticals in July 2018. 
 


TPL-000241 v02 
STATISTICAL ANALYSIS PLAN 
FOR CSR  
A multicenter, randomized, double-blind, placebo-controlled, dose-response study 
to investigate the biological activity, safety, tolerability, and pharmacokinetics of 
ACT-334441 in subjects with systemic lupus erythematosus 
Purpose of Analysis 
Clinical Study Report 
Investigational Drug 
Cenerimod (ACT-334441) 
Protocol Number 
AC-064A201 
Actelion Document Number 
D-17.230
Document Status/Version Number 
Final 1.0
Date 
20 April 2017
Author 
, Trial Statistician 
Author 
, Project Statistician 
Reviewer 
 
Reviewer 
 
Reviewer 
 
Reviewer 
 
Reviewer 
 
Reviewer 
 
Reviewer 
 
Reviewer 
 
Reviewer 
 
Reviewer 
 
Reviewer 
 
Reviewer 
 
Reviewer 
 
Confidential 
Property of Actelion Pharmaceuticals Ltd. May not be used, divulged, published or 
otherwise disclosed without the consent of Actelion Pharmaceuticals Ltd. 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND ACRONYMS ............................................................8 
1 
INTRODUCTION .......................................................................................................11 
2 
STUDY DESIGN AND FLOW ..................................................................................11 
2.1 
Study design .................................................................................................12 
2.2 
Study visit and assessment schedule ............................................................13 
3 
OBJECTIVES .............................................................................................................17 
3.1 
Main objective(s) ..........................................................................................17 
3.2 
Exploratory objectives ..................................................................................17 
4 
CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN THE 
STUDY PROTOCOL .................................................................................................17 
4.1 
Changes to the analyses planned in the study protocol ................................17 
4.1.1 
Pharmacodynamic analysis set definition .........................................17 
4.1.2 
Per-protocol analysis set definition ...................................................17 
4.1.3 
Adverse events of special interest .....................................................21 
4.2 
Changes in the conduct of the study / data collection ..................................21 
4.3 
Clarifications concerning endpoint definitions and related variables or 
statistical methods .........................................................................................21 
4.3.1 
Analysis visits ...................................................................................21 
4.3.2 
Systemic Lupus Erythematosus Activity Index-2000 
(SLEDAI-2K) ...................................................................................22 
4.3.3 
Exploratory biomarkers variables .....................................................23 
4.3.4 
24 hour Holter-ECG ..........................................................................23 
5 
DEFINITIONS OF VARIABLES ..............................................................................23 
5.1 
Screening failures .........................................................................................23 
5.2 
Subject characteristics ..................................................................................23 
5.2.1 
Demographics and other characteristics ...........................................23 
5.2.2 
Baseline disease characteristics ........................................................24 
5.2.2.1 
SLE relevant disease history ...................................................24 
5.2.2.2 
Modified SLEDAI-2K and PGA .............................................25 
5.2.2.3 
Exploratory disease biomarker ................................................26 
5.2.3 
Other baseline characteristics ...........................................................27 
5.2.4 
Medical history .................................................................................27 
5.2.5 
Previous and concomitant therapies .................................................27 
5.2.5.1 
Previous non-SLE therapies ....................................................27 


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5.2.5.2 
Study-treatment concomitant non-SLE therapies ....................27 
5.2.5.3 
Previous SLE therapies ...........................................................28 
5.2.5.4 
Study-treatment concomitant SLE therapies ...........................28 
5.3 
Study treatment exposure and compliance ...................................................28 
5.3.1 
Exposure ...........................................................................................28 
5.3.2 
Compliance with study treatment .....................................................28 
5.3.3 
Study treatment discontinuation .......................................................29 
5.3.4 
Study treatment interruptions and re-initiations ...............................29 
5.4 
Study discontinuation of the subject .............................................................29 
5.5 
Pharmacodynamic variables .........................................................................29 
5.5.1 
Main pharmacodynamic variable ......................................................29 
5.5.2 
Other pharmacodynamic variables ...................................................30 
5.6 
Pharmacokinetic variables ............................................................................30 
5.7 
Efficacy variables .........................................................................................30 
5.7.1 
Primary efficacy variable ..................................................................30 
5.7.2 
Secondary efficacy variables ............................................................31 
5.7.3 
Other efficacy variables ....................................................................31 
5.7.3.1 
Exploratory disease activity variables .....................................31 
5.7.3.2 
Exploratory biomarker variables .............................................31 
5.8 
Safety variables .............................................................................................33 
5.8.1 
Adverse events ..................................................................................33 
5.8.1.1 
Treatment-emergent adverse events ........................................33 
5.8.1.2 
Related treatment-emergent adverse events ............................33 
5.8.2 
Deaths ...............................................................................................33 
5.8.2.1 
All deaths .................................................................................33 
5.8.2.2 
Adverse events leading to death ..............................................33 
5.8.3 
Serious adverse events ......................................................................34 
5.8.3.1 
Fatal serious adverse events ....................................................34 
5.8.4 
Adverse events leading to discontinuation of study treatment .........34 
5.8.5 
Other significant adverse events .......................................................34 
5.8.5.1 
AE of special interest ..............................................................34 
5.8.5.2 
SLE flares reported as AEs .....................................................34 
5.8.6 
Vital signs and body weight ..............................................................34 
5.8.6.1 
Blood pressure .........................................................................34 
5.8.6.2 
Body weight ............................................................................35 
5.8.7 
Electrocardiogram .............................................................................36 
5.8.7.1 
12-lead ECG variables and findings ........................................36 
5.8.7.2 
24 hour Holter-ECG ................................................................37 
5.8.8 
Echocardiography .............................................................................37 
5.8.9 
Discharge from hospital at day 1/re-initiation ..................................38 
5.8.10 
Laboratory .........................................................................................38 
5.8.11 
Spirometry ........................................................................................39 


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5.8.12 
Optical coherence tomography test ...................................................40 
5.8.13 
Ophthalmological examination .........................................................40 
5.8.14 
Physical examination ........................................................................40 
5.9 
Quality of life variables ................................................................................40 
6 
DEFINITION OF PROTOCOL DEVIATIONS .........................................................41 
7 
ANALYSIS SETS .......................................................................................................41 
7.1 
Definitions of analysis sets ...........................................................................41 
7.1.1 
Screened analysis set ........................................................................41 
7.1.2 
Full analysis set .................................................................................41 
7.1.3 
Per-protocol analysis set ...................................................................41 
7.1.4 
Safety analysis set .............................................................................44 
7.1.5 
Other analysis sets ............................................................................44 
7.1.5.1 
Pharmacodynamic Analysis Set ..............................................44 
7.1.5.2 
Pharmacokinetic Analysis Set .................................................44 
7.2 
Usage of the analysis sets .............................................................................44 
8 
DEFINITION OF SUBGROUPS ................................................................................46 
9 
GENERAL STATISTICAL METHODOLOGY ........................................................46 
9.1 
Statistical methods for binary data ...............................................................46 
9.1.1 
Confidence interval for a proportion ................................................46 
9.2 
Statistical methods for continuous data ........................................................46 
9.2.1 
Multiple Comparison Procedure and Modeling (MCP-Mod) 
approach ............................................................................................46 
9.2.2 
Analysis of Variance .........................................................................48 
9.2.3 
Analysis of Covariance .....................................................................49 
10 STATISTICAL ANALYSES ......................................................................................51 
10.1 
Overall testing strategy .................................................................................51 
10.2 
General rules for data presentations .............................................................52 
10.3 
Display of subject disposition, protocol deviations and analysis sets ..........52 
10.3.1 
Subject disposition ............................................................................53 
10.3.1.1 
Screening failures ....................................................................53 
10.3.1.2 
Discontinuation from study .....................................................53 
10.3.1.3 
Discontinuation of study treatment .........................................53 
10.3.2 
Protocol deviations ...........................................................................53 
10.3.3 
Analysis sets .....................................................................................54 
10.4 
Analyses of subject characteristics ...............................................................54 
10.4.1 
Demographics ...................................................................................54 
10.4.2 
Baseline disease characteristics ........................................................54 


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10.4.3 
Other baseline characteristics ...........................................................54 
10.4.4 
Medical history .................................................................................54 
10.4.5 
Previous and concomitant therapies .................................................55 
10.4.6 
Other subject characteristics .............................................................55 
10.5 
Analysis of study treatment exposure and compliance.................................55 
10.5.1 
Exposure ...........................................................................................55 
10.5.2 
Compliance with study treatment .....................................................55 
10.6 
Analysis of the main pharmacodynamic variable(s) ....................................56 
10.6.1 
Hypothesis and statistical model .......................................................56 
10.6.2 
Handling of missing data ..................................................................56 
10.6.3 
Main analysis ....................................................................................56 
10.6.4 
Supportive/sensitivity analyses .........................................................57 
10.6.5 
Subgroup analyses ............................................................................57 
10.7 
Analysis of the other pharmacodynamic variables .......................................58 
10.8 
Analysis of other efficacy variables .............................................................58 
10.8.1.1 
Exploratory disease activity endpoints ....................................58 
10.8.1.2 
Exploratory biomarker ............................................................59 
10.9 
Analysis of safety variables ..........................................................................59 
10.9.1 
Adverse events ..................................................................................59 
10.9.2 
Deaths and other serious adverse events ...........................................60 
10.9.2.1 
Death .......................................................................................60 
10.9.2.2 
Serious adverse events .............................................................61 
10.9.2.3 
Adverse events leading to study treatment 
discontinuation ........................................................................61 
10.9.2.4 
Other significant adverse events ..............................................61 
10.9.3 
Electrocardiography (ECG) ..............................................................62 
10.9.3.1 
12-lead ECG variables and findings ........................................62 
10.9.3.2 
24 hour Holter-ECG ................................................................62 
10.9.4 
Laboratory tests .................................................................................63 
10.9.5 
Vital signs and body weight ..............................................................64 
10.9.6 
Spirometry ........................................................................................64 
10.9.7 
Physical examination ........................................................................65 
10.9.8 
Ophthalmological examination and OCT .........................................65 
10.9.9 
Echocardiography .............................................................................65 
10.10 
Analysis of quality of life variables ..............................................................65 
10.11 
Analysis of pharmacokinetic variables .........................................................65 
11 GENERAL DEFINITIONS AND DERIVATIONS ...................................................66 
11.1 
Phases, periods, visits ...................................................................................66 
11.1.1 
Analysis visits ...................................................................................66 
11.1.2 
Retests and multiple assessments in the same visit window ............68 
11.2 
Analysis variables .........................................................................................69 


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General ..............................................................................................69 
11.2.2 
Subject Level Data ............................................................................69 
Subject demographics ...................................................................................69 
Population flags ............................................................................................70 
Treatment variables ......................................................................................71 
Trial dates 
 .................................................................................................71 
Death variables .............................................................................................72 
Screening variables .......................................................................................72 
Conditional (if there is at least one re-screening visit performed) ........72 
End of treatment variables ............................................................................72 
End of study variables ..................................................................................73 
Accidental unblinding variables ...................................................................73 
11.2.3 
Protocol Deviations Data ..................................................................73 
11.2.4 
Concomitant medications Data .........................................................76 
11.2.5 
Study treatment exposure and compliance .......................................77 
11.2.5.1 
Exposure ..................................................................................77 
11.2.5.2 
Compliance (based on drug accountability) ............................77 
11.2.6 
Pharmacodynamic data .....................................................................77 
11.2.7 
Adverse event data ............................................................................77 
Adverse Events of special interest (AESI) ...................................................78 
11.2.8 
Medical history data (general) ..........................................................79 
11.2.9 
Medical history data, SLE specific ...................................................79 
11.2.10 
Discharge from hospital data ............................................................80 
11.2.11 
12-lead ECG, parameters data ..........................................................81
11.2.12 
12-lead ECG, findings data ...............................................................82
11.2.13 
24 hour Holter-ECG, parameters data ..............................................82 
11.2.14 
24 hour Holter-ECG, findings data ...................................................83 
11.2.15 
Laboratory Data (Safety labs) ...........................................................84 
11.2.16 
Exploratory biomarker data ..............................................................85 
11.2.16.1 
Baseline disease characteristics, Exploratory disease 
biomarker .................................................................................86 
11.2.16.2 
Exploratory biomarker variables .............................................86 
11.2.17 
Vital Signs Data ................................................................................89 
11.2.17.1 
Blood pressure .........................................................................89 
11.2.17.2 
Body weight ............................................................................89 
11.2.18 
Questionnaires Data ..........................................................................89 
11.2.19 
Spirometry Data ................................................................................92 
11.2.20 
Pharmacokinetics Concentrations Data ............................................93 
11.2.21 
Physical examination data ................................................................94 
11.2.22 
Childbearing potential data, contraception, and pregnancy test 
data ....................................................................................................94 


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12 HANDLING OF MISSING/INCOMPLETE DATE AND TIME FIELDS ...............94 
13 LIST OF SUMMARY TABLES, LISTINGS AND FIGURES .................................96 
14 REFERENCES ............................................................................................................97 
15 APPENDICES .............................................................................................................98 
15.1 
Protocol Synopsis .........................................................................................98 
15.2 
Discussion and further considerations of the applied statistical 
methods .......................................................................................................114 
15.2.1 
Clinical laboratory evaluation .........................................................114 
15.2.2 
Definitions of AEs of special interest, S1P1 compounds (09-
Sep-2016) ........................................................................................118 
15.2.3 
SF-36 scoring ..................................................................................121 
15.3 
Document history .......................................................................................125 
LIST OF TABLES 
Table 1 
Associated Documents ....................................................................................11 
Table 2 
Visit and assessment schedule (same for part A and part B) ..........................14 
Table 3 
Protocol deviations leading to exclusion from the PPS ..................................18 
Table 4 
Exploratory disease biomarker evaluated at baseline only (in categories) .....26 
Table 5 
Exploratory biomarker variables evaluated during the study .........................32 
Table 6 
Notable abnormalities in blood pressure .........................................................35 
Table 7 
Notable abnormalities in ECG parameters......................................................36 
Table 8 
Protocol deviations leading to exclusion from the PPS ..................................42 
Table 9 
Overview of the different analysis sets and their usage ..................................45 
Table 10 
Parameterization of Models considered in MCP-Mod analyses .....................47 
Table 11 
Study phases, period and analysis visits .........................................................67 
Table 12 
Protocol deviations leading to exclusion from the PPS ..................................74 
Table 13 
Potential Holter-ECG Findings .......................................................................83 
Table 14 
Lymphocyte subsets: parameters and units .....................................................87 
Table 15 
Handling of missing date and time .................................................................94 
Table 16 
Clinical laboratory evaluation: Marked abnormalities in laboratory 
parameters (adapted from Table 5 from the Clinical Study Protocol) ..........114 
LIST OF FIGURES 
Figure 1 
Study design of AC-064A201 investigating ACT-334441 in SLE 
subjects ............................................................................................................13 
Figure 2 
Dose-response curves considered in MCP-Mod procedure ............................47 


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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 
ALP 
Alkaline Phosphatase  
ANA 
Anti-nuclear antibodies 
ANCOVA 
Analysis of covariance 
anti-dsDNA 
Anti-double-stranded deoxyribonucleic acid 
APL 
Immunoglobulin A Phospholipid 
AST 
Aspartate aminotransferase 
ATC 
Anatomic therapeutic chemical 
BLyS 
B-lymphocyte stimulator
BP 
Blood pressure
bpm 
Beats Per Minute
CCM 
Central Clinical Monitoring
CI 
Confidence interval
CRP 
C-reactive protein
CL 
Confidence limit(s)
CSR 
Clinical study report
CTCAE 
Common Terminology Criteria for Adverse Events
Ctrough 
Measured plasma concentration at the end of one dosing interval
CXCL10 
C-X-C motif chemokine 10
DBP 
Diastolic blood pressure
ECG 
Electrocardiogram
eCRF 
Electronic case report form
EDTA 
Ethylenediaminetetraacetic acid
Emax 
Maximum effect


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EOS 
End-of-study 
EOT 
End-of-treatment 
FAS 
Full analysis set 
FDA 
(US) Food and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FSFV 
First subject first visit 
FU 
Follow-up 
FVC 
Forced vital capacity 
GPL 
Immunoglobulin G Phospholipid 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
INR 
International Normalized Ratio 
IR 
Interim safety review 
IRT 
Interactive response technology  
LLN 
Lower limit of the normal ranges 
LLOQ 
Lower limit of quantification 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCP 
multiple comparison procedures 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPL 
Immunoglobulin M Phospholipid 
LSLV 
Last subject last visit 
NA 
Not applicable 


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OCT 
Optical coherence tomography 
PD 
Pharmacodynamic 
PGA 
Physician’s Global Assessment 
PK 
Pharmacokinetic 
PPS 
Per-protocol analysis set 
QTcB 
QT corrected for heart rate on the basis of Bazett’s formula 
QTCF 
QT interval corrected for heart rate using Fridericia’s formula 
S1P 
Sphingosine-1-phosphate 
S1P1 
Sphingosine-1-phosphate receptor 1 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis system 
SBP 
Systolic blood pressure 
SF-36v2 
36-Item Short Form Health Survey v2
SLE 
Systemic lupus erythematosus
SLEDAI-2K 
Systemic Lupus Erythematosus Disease Activity Index-2000
SOC 
System organ class
SDTM 
Study Data Tabulation Model
SI 
Standard International
TEAE 
Treatment-emergent adverse event
TB 
Tuberculosis
TBL 
Total bilirubin
ULN 
Upper limit of the normal ranges
ULQ 
Upper limit of quantification
VPCs 
Ventricular premature complexes
WBC 
White blood cells
WHO 
World Health Organization
WOCBP 
Women of childbearing potential


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1 
INTRODUCTION 
This statistical analysis plan (SAP) describes in detail the analyses and data presentation 
of all endpoints for the final clinical study report (CSR) of study AC-064A201.  
This analysis plan is based on or refers to the following documents: 
Table 1 
Associated Documents 
Two additional SAPs were developed for: 
•
Closed sessions of the independent data monitoring committee (IDMC) and Interim
Safety Review (IR). This is based on this CSR SAP and is written by the Independent
Statistical Analysis Center and is not reviewed by Actelion.
•
Periodic reviews for Central Clinical Monitoring (CCM) and open sessions of the
IDMC. This document describes specific and dedicated analyses as documented in
the CCM Plan and refers mainly to this CSR SAP in terms of statistical methods and
data presentation.
The source data for the analyses described in this SAP are the Study Data Tabulation 
Model (SDTM) datasets, provided by CDDM as Statistical Analysis System (SAS) 
datasets. 
2 
STUDY DESIGN AND FLOW 
Further details can be found in the protocol synopsis in Appendix A. 


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2.1 Study design 
This 
is 
a 
prospective, 
multicenter, 
multinational, 
randomized, 
double-blind, 
placebo-controlled, two-part, dose-response Phase 1/2 study. This study is divided in two 
parts:  
Part A 
Part A consists of four parallel treatment groups (including 0.5 mg, 1 mg, or 2 mg of 
ACT-334441 and placebo control). Approximately 48 subjects were randomized (1:1:1:1) 
via an interactive response technology (IRT) system to one of the four groups (i.e., 
12 subjects in each group; three dose levels of 0.5 mg, 1 mg, or 2 mg ACT-334441, or 
placebo o.d.). 
Subjects received ACT-334441 or placebo once daily (o.d.) for 12 weeks. 
Interim safety review 
An Interim Review (IR) was conducted by the IDMC when all subjects enrolled into Part 
A completed Visit 4 (Week 4), unless prematurely discontinued. The IDMC evaluated the 
safety profile of ACT-334441 in systemic lupus erythematosus (SLE) subjects and gave a 
recommendation to continue the study as planned (i.e., proceed to Part B). 
Part B 
Part B consists of two parallel treatment groups (including 4 mg ACT-334441 and 
placebo control). 
Approximately 16 subjects were randomized (3:1) via an IRT system to one of the two 
groups (i.e., 12 subjects receiving 4 mg ACT-334441 and 4 subjects receiving placebo 
o.d.). Subjects enrolled in Part A were not eligible for Part B.
The study design is shown in Figure 1.


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Figure 1 
Study design of AC-064A201 investigating ACT-334441 in SLE 
subjects 
EOT = End-of-Treatment; EOS = End-of-Study; FU = follow-up; IDMC= Independent Data Monitoring 
Committee.  
2.2 Study visit and assessment schedule 
See Table 2 for a detailed plan of the visit and assessment schedule. 


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Table 2 
Visit and assessment schedule (same for part A and part B) 
Perio
ds 
Name 
Pre-
randomizatio
n 
Treatment period 
FU 
Unscheduled 
Duration 
Up to 30 
days 
12 weeks 
16 weeks 
NA 
Visits  
Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
U1, U2,... 
I 
Name 
Screening 
Randomizati
on (15) 
W2 
W4 
W8 
EOT 
EOS 
Phone 
call FU 
Phone 
call  
FU 
Unschedul
ed (17)  
Re-
initiation 
Time 
Day −30 to 
−1 
Day 1 
Week 
2 
Week 4 
Week 8 
Week 12 
or earlier 
in case of 
premature 
discontinu
ation (16) 
Last study 
treatment 
intake + 6 
weeks 
Last 
study 
treatment 
intake + 
11 weeks 
Last 
study 
treatme
nt 
intake 
+ 16
weeks
Any day 
between 
Day 1 and 
EOS 
For study 
treatment 
interruptio
ns that 
started up 
to Day 14 
Visit window 
± 3 
days 
± 5 days 
± 5 days 
± 5 days 
± 5 days 
± 5 days 
± 5 
days 
NA 
Informed consent* 
X 
Inclusion/exclusion 
criteria* 
X 
X 
Demographics* 
X 
Medical history/smoking 
status* 
X 
SLE history* (1) 
X 
Concomitant 
medications/SLE therapies* 
X 
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 
X 
Disease activity scales*: 
SLEDAI-2K, PGA 
X 
X 
X 
X 
X 
X 
X 
Quality of life 
questionnaire*: 
SF-36 v2™ 
X 
X 
Chest X-ray (4) 
X 
SBP/DBP* (5;6) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG** (5) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG-Holter** (7) 
X 
X 
Echocardiography* 
X 
X 
Spirometry** (8) 
X 
X 
X 
X 
X 
X 
Ophthalmological 
examination*  
X 
. 
X 
X 
X 
X 
X 


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Perio
ds 
Name 
Pre-
randomizatio
n 
Treatment period 
FU 
Unscheduled 
Duration 
Up to 30 
days 
12 weeks 
16 weeks 
NA 
Visits  
Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
U1, U2,... 
I 
Name 
Screening 
Randomizati
on (15) 
W2 
W4 
W8 
EOT 
EOS 
Phone 
call FU 
Phone 
call  
FU 
Unschedul
ed (17)  
Re-
initiation 
Time 
Day −30 to 
−1 
Day 1 
Week 
2 
Week 4 
Week 8 
Week 12 
or earlier 
in case of 
premature 
discontinu
ation (16) 
Last study 
treatment 
intake + 6 
weeks 
Last 
study 
treatment 
intake + 
11 weeks 
Last 
study 
treatme
nt 
intake 
+ 16
weeks
Any day 
between 
Day 1 and 
EOS 
For study 
treatment 
interruptio
ns that 
started up 
to Day 14 
Visit window 
± 3 
days 
± 5 days 
± 5 days 
± 5 days 
± 5 days 
± 5 days 
± 5 
days 
NA 
OCT 
X 
X 
Hematology (9)/ blood 
Chemistry** 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test */** (10) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Viral serology / 
tuberculosis test** 
X 
Additional serum sample 
for viral serology*** 
X 
ANA, anti-dsDNA 
antibodies, complement C3 
and C4** 
X 
X 
X 
X 
X 
X 
X 
Exploratory biomarkers** 
(11) 
X 
X 
X 
X 
X 
Lymphocyte subsets*** 
(12) 
X 
X 
X 
Urine protein-to-creatinine 
ratio** 
X 
X 
X 
X 
Urinalysis (dipstick)* 
X 
X 
X 
X 
X 
X 
X 
X 
PK sampling (pre dose)*** 
X 
X 
X 
X 
X 
Study treatment dispensing 
& accountability* (13) 
X 
X 
X 
X 
X 
X 
AEs* (14) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SAEs* (14) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
* Data collected in the eCRF 
** Electronically transferred to sponsor
*** Sample collection date recorded in the eCRF (for PK samples, time will also be recorded) 


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Assessments in part A and B are identical. 
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. 
The intervals between Visit 4 (Week 4), Visit 5 (Week 8) and Visit 6 (EOT) should not exceed 36 days.  
(1) History of positive ANA / anti-ds DNA antibodies will be included. 
(2) Complete physical examination (i.e., inspection, percussion, palpation and auscultation) will be performed at Visit 1 (Screening) and Visit 6 (EOT). A symptom-driven,
abbreviated physical examination will be performed at all other visits in order to capture assessments needed for the SLEDAI-2K 
(3) Height only at Screening. 
(4) A chest X-ray that has been performed within 3 months prior to Screening can be used (in this case, no need to repeat chest X-ray at Screening).
(5) On Day 1 and at re-initiation, 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 from the hospital 
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.
(6) At Screening, SBP/DBP will be assessed in supine position and after 1 to 3 minutes in standing position to assess orthostatic hypotension. At all other visits, SBP/DBP will be 
assessed in supine position. 
(7) At Screening, 24 hour ECG-Holter will start before 12:00. On Day 1, 24 hour ECG-Holter will start immediately before dosing.
(8) Two spirometry assessments will be performed at Visit 1 (Screening). The assessments should be at least 5 days apart. The last assessment will count as baseline. 
(9) Hematology assessments including coagulation tests will be performed at each visits until EOS 
(10) Serum pregnancy tests will be performed at Screening and EOS. Urine pregnancy tests will be performed at all other visits (including telephone calls FU, 11 weeks and 16 weeks
after study treatment discontinuation). 
(11) IgM, IgG, IgA, CRP, fibrinogen, and BLyS will be measured in serum. At Randomization visit only, anti-Smith, anti-cardiolipin, and anti-ribosomal P will also be measured.
EDTA plasma samples will be shipped via central laboratory to Actelion for analysis of CXCL10 and other soluble biomarkers potentially related to SLE and/or S1P1 modulation. 
(12) Blood samples will be shipped via central laboratory to Actelion for lymphocyte subsets analysis.
(13) No study drug dispensing at V3 and re-initiation visit 
(14) All AEs and SAEs that occur after signing the Informed Consent Form and up to 6 weeks (AEs) or 16 weeks (SAEs) after study treatment discontinuation must be reported. 
(15) Prior to randomization, the following central laboratory results must be available to confirm eligibility: ANA, anti-dsDNA, Hepatitis B surface antigen, Hepatitis C, HIV1 and
HIV2, varicella-zoster virus, urine protein-to-creatinine ratio, ALT/AST/TBL, pregnancy test (if applicable).
(16) EOT visit should preferably take place 1 day after last study treatment dose, and no later than 7 days.
(17) Unscheduled visits may be performed at any time during the study. Recording of changes in concomitant medications and background SLE therapies since last visit needs to be 
performed at each unscheduled visit. Further assessments including 12-lead ECG, SBP/DBP, SLEDAI-2K, PGA, laboratory assessments for SLEDAI-2K scoring (i.e.,
hematology/blood biochemistry, urinalysis, anti-dsDNA, complement C3 and C4) may be performed at the discretion of the investigator.
AE = adverse event; ALT = alanine aminotransferase; ANA = anti-nuclear antibodies; anti-dsDNA = anti-double-stranded DNA; AST = aspartate aminotransferase; BLyS = 
B lymphocyte stimulator; CRP = C-reactive protein; CXCL10 = C-X-C motif chemokine 10; ECG = electrocardiogram; eCRF = electronic Case Report Form; EDTA= 
ethylenediaminetetraacetic acid; DBP = diastolic blood pressure; EOS = End-of-Study; EOT = End-of-Treatment; FU = follow-up; HIV = human immunodeficiency virus; NA = not 
applicable; OCT = optical coherence tomography; PGA = Physician’s Global Assessment; PK = pharmacokinetic; SAE = serious adverse event; S1P1 = sphingosine-1-phosphate 
receptor 1; SBP = systolic blood pressure; SF-36 = Short-Form 36; SLE = systemic lupus erythematosus; SLEDAI-2K = Systemic Lupus Erythematosus Disease Activity Index-
2000; TBL = total bilirubin; WOCBP = women of childbearing potential.


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3 
OBJECTIVES 
3.1 Main objective(s) 
•
To investigate the pharmacodynamics (PD) of ACT-334441 in adult subjects with
SLE.
•
To investigate the safety and tolerability of ACT-334441 in adult subjects with
SLE.
3.2 Exploratory objectives 
•
To investigate the pharmacokinetics (PK) of ACT-334441 in adult subjects with
SLE.
•
To investigate the effect of ACT-334441 treatment on disease activity in adult
subjects with SLE.
4 
CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN 
THE STUDY PROTOCOL 
4.1 Changes to the analyses planned in the study protocol 
4.1.1 Pharmacodynamic analysis set definition 
Previously Read 
The pharmacodynamics analysis set (PDS) includes all subjects who received at least 
3 weeks of study treatment and have at least one lymphocyte count measurement between 
the Week 4 visit and Week 12 visit.  
Now Reads: 
The pharmacodynamics analysis set (PDS) includes all subjects who received at least 
21 days of uninterrupted study treatment, with lymphocyte count measurements at 
baseline and post-baseline (namely, one sample taken at least 21 days after the first study 
treatment intake and no later than 7 days after the last study treatment intake and no study 
treatment interruption documented in the first 21 days). 
Rationale for change: 
To allow analysis of the primary endpoint, the change from baseline to end of treatment 
(EOT) in lymphocyte count, based on a value at baseline and a value ‘under treatment’ so 
that the expected drug dependent effect on the lymphocyte count is biologically 
meaningful and has sufficient time to reach the full effect on lymphocyte reduction.  
4.1.2 Per-protocol analysis set definition 
Previously Read 
The Per-Protocol Set (PPS) comprises data from all subjects included in the Full Analysis 
Set (FAS) without selected important protocol deviations including but not limited to: 


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•
Subjects not adhering to the treatment regimen for mandatory concomitant
medication;
•
Subjects with < 80% compliance to study treatment;
•
Start of any prohibited systemic SLE therapies during the course of the trial.
Now Reads: 
The Per-Protocol Set (PPS) comprises data from all subjects included in the Full Analysis 
Set (FAS) without relevant deviations which could affect the evaluation of the 
pharmacodynamic parameters (lymphocyte count) and the exploratory disease activity 
parameters (SLEDAI-2K, PGA). 
The protocol deviations leading to exclusion from the PPS are listed in the below table. 


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Please note: 
•
If a subject is excluded from the PDS then he is also excluded from the PPS.
Rationale: Insufficient pharmacodynamic effect is unlikely to show e.g. clinical
improvement, but will confound the results.
•
 If a subject presents with such protocol deviation (specifically,
pregnancy test not performed 3 weeks apart), but no pregnancy occurred and all
subsequent pregnancy tests were consistently negative during the trial, the subject
can be included into the PPS.
Rationale: Biologically this subject is not different from included subjects.
However, an important protocol deviation has to be reported.
•
: If a subject presents with such protocol deviation, but the change
of the immunologically active medication occurred at or after EOT, the subject
can be included in the PPS.
Rationale: The primary endpoint compares the change from baseline to EOT.
Rationale for change: 
The definition of the PPS has been adapted to fully account for the study eligibility 
criteria.  




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4.3.2 Systemic Lupus Erythematosus Activity Index-2000 (SLEDAI-2K) 
Naming convention 
In this study, a modified SLEDAI-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). 
Rationale for change: To make it more clear that the full SLEDAI-2K score has not been 
used in the study.  
Additional variables/endpoints related to SLEDAI 
For the modified SLEDAI-2K score, additional variables/endpoints are added: 
•
Value at baseline categorized as ‘≥ 6’ and ‘< 6’;
•
Occurrence of an increase from baseline > 3 at each post-baseline analysis visit.
Rationale for change:  
More granularity in the SLEDAI-2K categories is provided to better describe the disease 
severity and to assess lupus flares during the study.  
A SLEDAI score of 6 is considered to be clinically relevant, because a score of > 5 has 
> 50% probability of requiring lupus-directed therapy [Nuttall 2013]. In turn, a
SLEDAI-2K of < 6 is considered as mild disease, whereas a SLEDAI-2K of ≥6 points
corresponds to moderate or severe SLE disease activity.
Reduction in the flare rate is a useful clinical trial endpoint even in a small trial. An 
increase in the global SLEDAI-2K score of >3 points is considered to distinguish SLE 
patients with persistently active disease versus those having a disease flare [Nuttall 2013, 
Nikpour 2009]. 
Additional endpoint related to arthritis 
For subjects presenting arthritis, the number of affected joints is collected in the eCRF. 
The following endpoints not listed in the protocol are defined: 
o
Number of affected joints, value at baseline;
o
Number of affected joints and change from baseline to each post-baseline
analysis visit.
Rationale for change: 
Positive proof of concept (PoC) of the S1P1 receptor modulator ponesimod was achieved 
in the skin auto-immune disease psoriasis [Vaclavkova 2014]. In the subgroup of 
psoriasis patients with concomitant psoriatic arthritis, ponesimod also improved the joint 
pain score, giving rise to the hypothesis that S1P receptor modulation may improve 
arthritis. Accordingly, the number of arthritis affected joints in SLE patients is assessed 
during the study and proposed to be analyzed statistically. 


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4.3.3 Exploratory biomarkers variables 
For exploratory biomarkers such as ANA titers or C-reactive protein (CRP), the planned 
analyses encompass the description of the values as a continuous variable (absolute 
value, absolute change from baseline and percent change from baseline). A selection of 
these biomarkers will be summarized as categorical variables.  
Rationale for change: During the conduct of the study, it was realized that, for some 
biomarkers (ANA titers, CRP, anti-ribosomal P), more than one-third of the values are 
either recorded below the lower limit of quantification (‘<1’; BLQ) or above upper limit 
of quantification (‘>100’; ULQ). Considering this, descriptive results may be biased 
when the total number of BLQ and ULQ values is large; in these circumstances, the 
variables are described only as categorical variables. 
4.3.4 24 hour Holter-ECG 
An additional (exploratory) endpoint is defined for ‘ECG Mean Heart rate (beats/min)’, 
recorded during the diary period:  
•
Absolute time-matched change in ECG Mean Heart rate (beats/min) from Visit 1
(Screening) to Visit 2 (Randomization/ Day 1) at each hourly time point up to
24 hours post-dose.
Rationale for change: The descriptive analysis of hourly mean heart rate during screening 
and on Day 1 was planned but the analysis of the absolute time-matched change from 
Screening to Day 1 was subsequently considered to be relevant. 
5 
DEFINITIONS OF VARIABLES 
5.1 Screening failures 
A subject is considered a screening failure if the subject is screened but not subsequently 
randomized in the IRT System. Subjects screened twice (allowed by the protocol) and 
subsequently randomized are not counted as screening failures. 
The primary reason for screening failure is documented on the ‘Randomization’ eCRF 
page (as the ‘Primary reason why the subject was not randomized’). If a subject is 
considered a screening failure but no reason for screening failure is reported, the reason is 
categorized as ‘Unknown’. 
5.2 Subject characteristics 
In the event that a subject is re-screened and the re-screening pages are completed, the 
data on the re-screening page supersedes that on the original screening page.  
5.2.1 Demographics and other characteristics 
The following characteristics are collected on the ‘Demographics’, ‘Smoking Status’ and 
‘Body Weight and Height’ eCRF pages at Visit 1 (Screening):  


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•
Age (years);
•
Sex (categorized as: Male, Female);
•
Woman of childbearing potential (No/Yes) ;
•
Smoking status (categorized as: Current smoker/ Former smoker/ Never smoked);
•
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);
•
Body weight (kg);
•
Height (cm);
•
Country of enrolment (assigned in the eCRF based on the list of sites).
In addition, the following variables are derived: 
•
Age (years) in categories, mandatory for EudraCT (12 - 17, 18 - 64, 65 - 84);
•
Age (years) in categories (18 - 30, 31 - 45, 46 - 65);
•
Body mass index (kg/m2); derived weight (kg) / [height (cm) / 100]2.
•
Body mass index (kg/m2) in categories, based on the WHO classification
(< 18.5, 18.5 – <25.0, 25.0 – <30.0, 30.0 – <35.0, 35.0 – <40.0, ≥ 40.0).
5.2.2 Baseline disease characteristics 
5.2.2.1 SLE relevant disease history 
SLE relevant disease characteristics (as recorded or derived from the data captured on the 
‘Systemic Lupus Erythematosus Relevant Disease History’ and ‘History of Detectable 
ANA or Anti‐dsDNA Testing’ eCRF pages at Visit 1 [Screening]) include: 
•
Time from first SLE symptoms (years) calculated as follows:
(date of informed consent - date of first SLE symptoms)/365.25.
•
Time from SLE diagnosis (years) calculated as follows:
(date of informed consent - date of SLE diagnosis)/365.25.
•
Number of SLE symptoms according to ACR criteria [ACR 1997]:
-
met in the past
-
started more than 6 months prior to screening
-
ongoing at screening
-
met either serially or simultaneously (i.e., met in the past and started more
than 6 months prior to screening)
Number of SLE symptoms according to ACR criteria [ACR 1997] met in the past 
is calculated for each subject as the number of criteria for which the box ‘Was this 
criterion ever met in the past?’ is ticked ‘Yes’. This number is categorized as 
0-3, 4-11.


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Number of SLE symptoms according to ACR criteria [ACR 1997] started more 
than 6 months prior to screening is calculated for each subject as the number of 
criteria for which the box ‘Did it start more than 6 months prior to Screening?’ is 
ticked ‘Yes’. This number is categorized as 0-3, 4-11.  
Number of SLE symptoms according to ACR criteria [ACR 1997] ongoing at 
screening is calculated for each subject as the number of criteria for which the box 
‘Ongoing at Screening?’ is ticked ‘Yes’. This number is categorized as 0-3, 4-11.  
Number of SLE symptoms according to ACR criteria [ACR 1997] met either 
serially or simultaneously is calculated for each subject as the number of criteria 
for which the box ‘Ongoing at Screening?’ or ‘Was this criterion ever met in the 
past?’ is ticked ‘Yes’. This number is categorized as 0-3, 4-11.  
•
Presence of a documented historical positive ANA or anti-dsDNA testing
Presence of a documented historical positive ANA is equal to ‘Yes’ when the box
‘ANA: Was a documented historical positive testing available?’ is ticked ‘Yes’ on
‘History of Detectable ANA or Anti-dsDNA Testing’ eCRF. If there is no
documented evidence of a test we do not know if the subject was positive or
negative and therefore they are counted as having ‘No documented evidence of a
test’.
Presence of a documented historical positive anti-dsDNA is equal to ‘Yes’ when
the box ‘Anti-dsDNA: Was a documented historical positive testing available?’ is
ticked ‘Yes’ on ‘History of Detectable ANA or Anti-dsDNA Testing’ eCRF. If
there is no documented evidence of a test we do not know if the subject was
positive or negative and therefore they are counted as having ‘No documented
evidence of a test’.
5.2.2.2 Modified SLEDAI-2K and PGA 
The modified SLEDAI-2K relevant disease characteristics (as recorded and derived from 
the data on the ‘Modified SLEDAI-2K’ and ‘Physician’s Global Assessment’ eCRF 
pages at Visit 1 [Screening]) include: 
•
SLEDAI-2K:
o
presence or not of each active descriptor,
o
mucocutaneous score,
o
musculoskeletal score,
o
sum of the mucocutaneous and musculoskeletal scores,
o
modified SLEDAI-2K total score,
o
modified SLEDAI-2K total score as a category (≥ 6 and < 6)
•
Physician’s Global Assessment (PGA) score.




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5.2.3 Other baseline characteristics 
Other baseline characteristics, collected during screening include chest X-ray,  
contraceptive methods, tuberculosis test and optionally viral serology results. These are 
defined as collected on the eCRF and no derivation is required.   
5.2.4 Medical history 
Medical history includes clinically significant previous and/or concomitant diseases or 
diagnoses recorded on the ‘Medical History (except SLE)’ eCRF page. Reported terms 
are mapped to preferred terms using the most current version of the Medical Dictionary 
for Regulatory Activities (MedDRA) at time of database closure.  
The variables of interest are the preferred term and the primary System Organ Class 
(SOC). 
Previous medical history are those diseases or diagnoses that are not ticked as ongoing at 
screening on the eCRF and with 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., May2013 and 
first dose occurred on 23May2013) or if an end date is missing, the medical history is 
considered as previous if ongoing is ticked ‘No’. All other medical history terms are 
considered concomitant. 
5.2.5 Previous and concomitant therapies 
Therapies are collected on several dedicated eCRF pages: 
•
‘Previous non-SLE therapies’
•
‘Concomitant non-SLE therapies’
•
‘Previous SLE therapies’
•
‘Concomitant (Background) SLE therapies
The reported names are coded using the WHO drug code dictionary and the anatomic 
therapeutic chemical (ATC) class according to the most current version at time of 
database closure. The variables of interest are the preferred term (standardized 
medication name) and the ATC code level 4. 
5.2.5.1 Previous non-SLE therapies 
A previous non-SLE therapy is any therapy for which the end date of therapy is prior to 
the start of study (i.e., signed informed consent) and reported in the ‘Previous Non SLE 
therapies’ page of the eCRF.  
5.2.5.2 Study-treatment concomitant non-SLE therapies 
A study-treatment concomitant non-SLE therapy is any therapy given for any reason 
except SLE that is either ongoing at the start of study treatment or is initiated between the 
start of the study treatment and Visit 7 (EOS) reported on the ‘Concomitant medications’ 
page of the eCRF. 


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5.2.5.3 Previous SLE therapies 
A previous SLE therapy is any therapy administered for SLE and/or SLE manifestations 
as described in protocol section 5.2.2.1 reported on the ‘Previous SLE therapies’ page of 
the eCRF.  
5.2.5.4  Study-treatment concomitant SLE therapies 
A concomitant (background) SLE therapy is any therapy administered for SLE and/or 
SLE manifestations as described in protocol section 5.2.1.1 reported on the ‘Background 
SLE therapies’ page of the eCRF.   
5.3 Study treatment exposure and compliance 
Study treatment duration and compliance are defined for the treatment period. 
5.3.1 Exposure 
For each subject, the following exposure-related variables are derived from the ‘Study 
Drug Log’ eCRF form: 
•
Study treatment duration, defined as the number of days between start of study
treatment and permanent treatment discontinuation of study treatment (both
inclusive), regardless of interruption(s).
•
Study treatment duration excluding treatment interruptions (days), defined as the
study treatment duration minus study treatment interruptions.
Study treatment duration is also categorized (cumulatively) as: at least one day, at least 1 
week, at least 4 weeks, at least 8 weeks, at least 11 weeks and at least 12 weeks.  
5.3.2 Compliance with study treatment 
Study treatment compliance is computed within the ‘Study Drug Log Dispensing & 
Accountability’ form of the eCRF at each dispensing/return visit as well as for the whole 
treatment period based on the visit dates.  
In case of low compliance with the study drug (below 80%), the reason is collected in the 
eCRF (e.g., Treatment interrupted due to AE, Bottle not returned and study drug not 
taken).  
The actual compliance over the study treatment period needs to be re-computed based on 
the actual study treatment duration according to the following formula: 
Compliance (%) = 100 x 
Total number of capsules dispensed - Total number of capsules returned
Study treatment duration (days) x number of capsules prescribed per day (1)


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5.3.3 Study treatment discontinuation 
Reasons for premature discontinuation of study treatment are recorded on the ‘Premature 
Discontinuation of Study Treatment’ page of the eCRF.  
A subject is considered to have discontinued from the study treatment prematurely if at 
least one reason is reported, or the reason for treatment discontinuation on the ‘Study 
Drug Log’ page of the eCRF is ‘premature discontinuation’. 
Subjects who complete study treatment as per protocol are those with a record in the 
eCRF Study Drug Log of ‘Completed as per protocol’.  
5.3.4 Study treatment interruptions and re-initiations 
Study treatment interruptions at any time and re-initiations between Day 1 and Week 2 
are recorded on the ‘Study Drug Log’ page of the eCRF. 
A subject is considered to have had a study treatment interruption if the reason for 
treatment end is either ‘Temporarily interrupted due to an AE’ or ‘Temporarily 
interrupted not due to an AE’. 
5.4 Study discontinuation of the subject 
Reasons for study discontinuation are recorded on the ‘End of Study’ page of the eCRF. 
A subject is considered to have completed the study if ‘Did the subject complete the 
study?’ has been ticked as ‘Yes’. A subject is considered to have discontinued from the 
study prematurely if ‘Did the subject complete the study?’ has been ticked as ‘No’.  
5.5 Pharmacodynamic variables 
In this section, the variables include all lymphocyte count values as transferred by the 
central laboratory (i.e., all planned visits plus unscheduled visits) but exclude the local 
laboratory results (which are included in the safety analyses).  
Details of the general computation rules for pharmacodynamic variables can be found in 
Section 11. 
5.5.1 Main pharmacodynamic variable 
The main variable is the change in lymphocyte count in peripheral blood from baseline to 
EOT, defined as:  
•
Total lymphocyte count at EOT – total lymphocyte count at baseline
The value at baseline is defined as the last non-missing value obtained from a sample 
taken prior to the first study treatment intake. 


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The value at EOT is defined last post-baseline value from a sample taken at least 21 days 
after the first study treatment intake (with no interruptions) and no later than 7 days after 
the last study treatment intake for the analyses on the PDS and on the PPS. 
The value at EOT is defined as the last post-baseline value up to Week 12 for the 
analyses on the FAS (application of the intention-to-treat principle [ITT] utilizing the 
Last observation carried forward [LOCF] technique for missing data).  
5.5.2 Other pharmacodynamic variables  
Other PD variables comprise: 
•
Absolute values of total lymphocyte count at each analysis visit;
•
Absolute change in total lymphocyte count from baseline at each analysis visit;
•
Percentage change in total lymphocyte count from baseline at each analysis visit.
The analysis visits are defined in Section 11.1.1. Absolute change and percentage 
changes are calculated as defined in Section 11.  
5.6 Pharmacokinetic variables 
PK samples are collected at Visit 3 (Week 2), Visit 4 (Week 4), Visit 5 (Week 8), Visit 6 
(Week 12/ EOT), and Visit 7 (EOS). 
PK variables comprise 
•
Ctrough ACT-334441 plasma concentrations prior to dosing at Weeks 2, 4, 8, and
12 (EOT);
•
ACT-334441 plasma concentration at EOS (i.e., 6 weeks after study treatment
discontinuation).
The following PK endpoint is defined:  
•
Cenerimod (ACT-334441) plasma concentrations at each analysis visit.
For analysis visits Weeks 2, 4, 8, samples must be taken 1 calendar day after the previous 
dose and before the next dose (see Section 11 for details of how this is handled).  
For analysis visit Week 12, samples must be taken within 1 to 7 calendar days after the 
last dose (see Section 11 for details of how this is handled). 
5.7 Efficacy variables 
For the endpoints defined below, further details concerning the derivation of the 
corresponding analysis variables can be found in Section 11. 
5.7.1 Primary efficacy variable 
Not applicable. 


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5.7.2 Secondary efficacy variables 
Not applicable. 
5.7.3 Other efficacy variables 
All efficacy variables evaluated in this study are considered exploratory. 
5.7.3.1 Exploratory disease activity variables 
•
Modified Systemic Lupus Erythematosus Activity Index-2000 (SLEDAI-2K)
The following endpoints are defined: 
o
Absolute values, absolute change and percent change in modified total
SLEDAI-2K score from baseline to each post-baseline analysis visit
(including EOT);
o
Absolute values, absolute change and percent change in SLEDAI-2K
mucocutaneous subscore, musculoskeletal subscore, and combined
mucocutaneous and musculoskeletal subscores from baseline to each post-
baseline analysis visit (including EOT).
In addition, for the modified total SLEDAI-2K score, the following endpoints are 
defined:  
o
Occurrence of an increase from baseline of > 3.
In addition, for subjects presenting with arthritis, the following endpoint is defined: 
o
Number of affected joints at baseline;
o
Number of affected joints and change from baseline to each post-baseline
analysis visit.
•
Physician’s Global Assessment of disease (PGA)
The following endpoints are defined: 
o
Absolute value, absolute change and percent change in PGA score from
baseline to each post-baseline analysis visit (including EOT).
5.7.3.2 Exploratory biomarker variables 
•
ANA, anti-dsDNA, complement factors and exploratory biomarkers
The following parameters are assayed by the central laboratory: 
o
ANA, anti-dsDNA, complement C3 and C4 (all visits except Visit 3);
o
IgM, IgG, IgA, CRP, fibrinogen, and B lymphocyte stimulator (BLyS) (Visit
2 and Visits 4 to 7).
The following parameter is assayed by Translational Science Biology: 




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•
Blood lymphocyte subsets
Blood samples for lymphocyte subset analysis are taken at Visit 2 (Randomization/ Day 
1), Visit 6 (EOT) and Visit 7 (EOS) and assayed by Translational Science Biology at 
Actelion. 
The following endpoints are defined: 
o
Change in blood lymphocyte subsets from baseline to EOT and EOS.
The complete list of parameters and units is provided in Section 11.  
5.8 Safety variables 
More details of the computation of safety variables can be found in Section 11. 
5.8.1 Adverse events 
All adverse events (AEs) occurring during the study period (from informed consent 
signature up to the EOS visit) are recorded on the eCRF. The original verbatim terms 
used by investigators to identify AEs are mapped to preferred terms (PT) using the most 
current version of the MedDRA dictionary at the time of database closure.  
5.8.1.1 Treatment-emergent adverse events 
A treatment-emergent adverse event (TEAE) is any AE temporally associated with the 
use of study treatment (from study treatment initiation until Visit 7 [EOS]) irrespective 
whether considered by the investigator to be related to study treatment or not.  
An AE is considered a TEAE if the start date is after (>) the first study treatment intake 
or the start date is on the same day as the first study treatment intake and the answer to 
‘Did this adverse event start at visit 2 or on first day of re-initiation following study drug 
intake?’ is equal to ‘Yes’ indicating that the AE started after first intake of study 
treatment.  
5.8.1.2 Related treatment-emergent adverse events 
An AE is considered related if the investigator ticked ‘Yes’ to the question ‘Relationship 
to study treatment’ or if it is missing. 
5.8.2 Deaths 
5.8.2.1 All deaths 
Date of death and primary cause are recorded on the ‘Death’ eCRF page. 
5.8.2.2 Adverse events leading to death 
AEs with an outcome reported as ‘death’ are considered as AEs leading to death. 


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5.8.3 Serious adverse events 
An AE is considered serious if the investigator ticked ‘Yes’ on the question ‘Serious?’ on 
the Adverse Event eCRF or if it is missing. 
5.8.3.1 Fatal serious adverse events 
An AE is considered fatal and serious if the investigator ticked ‘Yes’ on the question 
‘Serious?’ and if the outcome is equal to ‘Death’ on the Adverse Event eCRF. 
5.8.4 Adverse events leading to discontinuation of study treatment 
These are AEs with ‘Action taken with study drug’ recorded as ‘permanently 
discontinued’ on the Adverse Event eCRF. 
5.8.5 Other significant adverse events 
5.8.5.1 AE of special interest 
An AE is considered to be an AE of special interest (AESI) if it is treatment emergent 
and belongs to any of the categories listed below (the list of corresponding MedDRA PT 
is defined in the latest AESI list enclosed in Appendix 15.2.2):  
•
Effect on heart rate and rhythm AESI (including hypotension)
•
Cardiovascular AESI
•
Hypertension AESI
•
Liver AESI (Hepatobiliary disorders/ liver enzyme abnormality)
•
Pulmonary AESI
•
Macular edema AESI
•
Infection AESI
•
Herpetic infections AESI
•
Skin malignancy AESI
•
Non-Skin malignancy AESI
•
Stroke AESI
•
Seizure AESI
5.8.5.2 SLE flares reported as AEs  
These are AEs with ‘Does this Adverse Event represent a clinical manifestation of SLE 
flare?’ ticked ‘Yes’ on the ‘Adverse Event’ eCRF page. 
5.8.6 Vital signs and body weight 
Vital signs include Systolic Blood Pressure (SBP) (mmHg), Diastolic Blood Pressure 
(DBP) (mmHg) and body weight (kg).  
5.8.6.1 Blood pressure 
SBP and DBP are collected at all visits. At Visit 1 (Screening), SBP and DBP are 
measured sequentially, twice in the supine and twice in the standing position. In this case 






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12-lead ECG findings
For each ECG, the cardiologist provides his overall interpretation (Normal/ Abnormal) 
and describes the potential findings by category. All findings reported post first dose are 
considered as treatment-emergent.  
5.8.7.2 24 hour Holter-ECG 
Holter-ECG monitoring is performed for 24 hours at Visit 1 (Screening) and at Visit 2 
(Randomization/ Day 1). The 24 hour Holter-ECG parameter collected is the hourly 
mean heart rate (bpm). 
The hourly records are time-matched between these two visits and the corresponding 
change for each matched time point is computed.  
The following endpoints are defined: 
•
Occurrence of treatment-emergent Holter-ECG-Holter abnormalities on Day 1;
•
Absolute time-matched hourly mean heart rate (bpm) change from Visit 1
(Screening) to Visit 2 (Randomization/ Day 1) at each hourly timepoint up to
24 hours post-dose for;
-
Holter-ECG- variables
The following analysis parameter is defined:
•
ECG Mean Heart rate (beats/min) .
For this analysis parameter, the following analysis variables are defined (see Section 11 
for further details): 
•
Baseline value at each hourly time point (i.e. hourly measurements at Visit 1)
•
Analysis value at each post-baseline assessment (i.e., hourly measurements at
Visit 2)
•
Absolute time-matched change from Visit 1 (Screening) to Visit 2
(Randomization/ Day 1) at each hourly time point.
-
Holter-ECG qualitative findings
For each Holter-ECG, the cardiologist provides his overall interpretation (Normal/ 
Abnormal) and describes the potential findings in the comment section. Each finding 
reported for the Holter-ECG performed on Day 1 are considered treatment-emergent.  
5.8.8 Echocardiography  
Echocardiography is performed at Visit 1 (Screening) and Visit 6 (EOT). The 
presence/absence (i.e., Yes/No) of any abnormality is recorded in the eCRF.  


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5.8.9 Discharge from hospital at day 1/re-initiation 
The subject’s eligibility for discharge or study drug discontinuation at Visit 2 
(Randomization/ Day 1) or study treatment re-initiation is independently assessed by the 
cardiac safety assessor and collected in the ‘Discharge from Hospital at Day 
1/Re-Initiation’. The variables of interest are: 
•
Actual time from first study treatment intake to discharge (hours);
•
Time from first study treatment intake to discharge, derived from the actual time
computed above (at 6 hours, after 6 through 12 hours, after 12 hours);
•
Reason for non-discharge at 6 hours, as collected in the eCRF;
•
Reason for non-discharge from 6 to 12 hours, as collected in the eCRF;
5.8.10 Laboratory 
Laboratory test results are transferred from the central laboratory or, if assayed locally, 
entered in local laboratory eCRF. Assessments are performed at each scheduled visit 
from Visit 1 (Screening) to Visit 7 (EOS), and at unscheduled visits if required. 
The following parameters are assayed: 
•
Hematology: 
Hemoglobin, 
hematocrit, 
platelets, 
MCH, 
MCV, 
MCHC,
reticulocytes/erythrocytes, erythrocytes, leukocytes count with differential count
(basophils, eosinophils, lymphocytes, neutrophils, monocytes,  and basophils/
leukocytes, eosinophils/ leukocytes, lymphocytes/ leukocytes, monocytes/ leukocytes,
neutrophils/ leukocytes);
•
Blood chemistry: Aspartate aminotransferase (AST), alanine aminotransferase
(ALT), alkaline phosphatase, total bilirubin (TBL), direct bilirubin, lactate
dehydrogenase, creatinine, blood urea nitrogen, urate, glucose, cholesterol,
triglycerides, sodium, potassium, chloride, calcium, protein, albumin, creatinine
clearance;
•
Coagulation tests: prothrombin time, INR, activated partial thromboplastin time;
•
Urine protein-to-creatinine ratio (Visits 1, 2 and 6): Creatinine, protein, protein/
creatinine.
For women of childbearing potential, serum pregnancy tests are performed at Visit 1 
(Screening) and Visit 7 (EOS) (central laboratory), and urinary pregnancy tests are 
performed at all other visits and collected in the dedicated eCRF page.  
Urine dipsticks are used to perform the urinalysis at all visits (e.g., pH, glucose, proteins, 
blood, leukocytes) and the results are recorded in the dedicated eCRF page. 


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The following endpoints are defined: 
•
Absolute value and absolute change from baseline in laboratory parameters
(hematology, blood chemistry, and urinalysis) at each post-baseline analysis visit
up to EOS;
•
Treatment-emergent laboratory test abnormalities based on reference ranges
(central laboratory) and abnormality thresholds (as defined in appendix 7 of the
study protocol and in Section 15.2).
For these abnormalities, additional criteria are defined to characterize the occurrence of 
treatment-emergent abnormalities during the treatment period in each direction separately 
(low and high).  
Treatment-emergent liver function abnormalities occurring at any time post-baseline are 
identified according to the following criteria, where a subject is considered to have met 
the criteria if they have at least one abnormality based on the worst post-baseline value 
measured (up to EOS): 
•
ALT ≥ 3, ≥ 5, ≥ 8 x ULN;
•
AST ≥ 3, ≥ 5, ≥ 8 x ULN;
•
AST or ALT ≥ 3, ≥ 5, ≥ 8, x ULN;
•
ALP ≥ 2 x ULN;
•
TBL ≥ 2 x ULN;
•
TBL ≥ 2 ULN combined with ALT ≥ 3 ULN;
•
TBL ≥ 2 ULN combined with AST ≥ 3 ULN;
•
INR ≥ 1.5, ≥2.5 x ULN;
•
INR ≥ 1.5, ≥2.5 x baseline;
•
INR ≥ 1.5 ULN combined with ALT ≥ 3 ULN;
•
INR ≥ 1.5 ULN combined with AST ≥ 3 ULN;
•
ALT ≥ 3 x ULN + TBL ≥ 2 x ULN + ALP < 2 x ULN;
•
AST ≥ 3 x ULN + TBL ≥ 2 x ULN + ALP < 2 x ULN;
Please note that for criteria combining several parameters, the abnormality must be 
reported at the same visit (same sample date).  
5.8.11 Spirometry 
Spirometry is performed at all scheduled visits except Visit 2 (Randomization/ Day 1). 
Two spirometry assessments are performed at Visit 1 (Screening). For each test, the best 
values for 12 parameters are provided: Forced Expiratory Volume in 1 Second (FEV1)  
(L), Forced Vital Capacity (FVC) (L), percent-predicted FEV1 (%), percent-predicted 
FVC (%), FEV1/FVC, Predicted FEV1 (L), Predicted FVC (L), Peak Expiratory Flow 
(L/s), Forced Expiratory Flow 25-75% (FEF) (L/s), Forced Expiratory Flow 25% (FEF) 


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(L/s), Forced Expiratory Flow 50% (FEF) (L/s) and Forced Expiratory Flow 75% (FEF) 
(L/s). 
The following endpoints are defined: 
•
Absolute value, absolute change and percent change in FEV1 and FVC from
baseline at any post-baseline analysis visit (up to EOS);
•
Occurrence of treatment-emergent decrease in FEV1 or FVC of > 15% from
baseline values at any post-baseline analysis visit.
The analysis visits are defined in Section 11.1.1 ‘Analysis visits’. Absolute value, 
absolute change and percentage change are calculated for all parameters as defined in 
Section 11.  
The occurrence of treatment emergent abnormalities is assessed at each post-baseline 
analysis visit for FEV1 (L) and FVC (L), on the value of the percent change from baseline 
as a decrease greater than 15%.  
5.8.12 Optical coherence tomography test 
The optical coherence tomography test (OCT) is performed at Visit 1 (Screening) and 
Visit 6 (EOT). The presence/ absence of any abnormality (i.e., Yes/No) and whether the 
finding is clinically significant is recorded in the eCRF.  
5.8.13 Ophthalmological examination 
Ophthalmological examinations are performed at each visit except Visit 2 
(Randomization/ Day 1). The presence/ absence of any abnormality (i.e., Yes/No) and 
whether the finding is clinically significant is recorded in the eCRF.  
5.8.14 Physical examination 
A complete physical examination is performed at Visit 1 (Screening) and Visit 6 (EOT). 
A symptom-driven, abbreviated physical examination is performed at all other visits.  
The observations are reported according to body system in the eCRF as either normal or 
abnormal, and whether the finding is clinically significant.  
5.9 Quality of life variables 
The SF-36v2™ questionnaire is used to assess the subject’s quality of life. The SF-
36v2™ is completed by the subject at Visit 2 (Randomization/ Day 1) and at Visit 6 
(EOT).  
The following endpoint is defined: 
•
Change in SF-36v2™ Health Survey domain and component scores from baseline
to EOT


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Full details of the derivations of the raw and norm-based domain scores and physical and 
mental component scores, and handling of missing data, are described in Section 11 and 
Appendix 15.2. 
6 
DEFINITION OF PROTOCOL DEVIATIONS 
This section refers to all protocol deviations as recorded in a database according to the 
specifications provided in the protocol violations code list. They are categorized as:  
•
Important protocol deviations
o
Protocol deviation at screening before randomization
o
Protocol deviation for eligibility criteria at screening (only for randomized
subjects)
o
Protocol deviation after randomization
•
Minor protocol deviations
Deviations that lead to exclusion of subjects from the Per-protocol set are described in 
Section 7.1.3 and in more detail in Section 11.2.3. 
7 
ANALYSIS SETS 
7.1 Definitions of analysis sets 
7.1.1 Screened analysis set  
The screened analysis set (SCR) includes all subjects who were screened and received a 
subject number. 
7.1.2 Full analysis set 
The full analysis set (FAS) includes all subjects randomized to a study treatment. In order 
to adhere to the intention-to-treat (ITT) principle as far as possible:  
•
Subjects are evaluated according to the study treatment to which they were
randomized (which may be different from the study treatment they have
received).
7.1.3 Per-protocol analysis set  
The Per-Protocol Set (PPS) comprises data from all subjects included in the FAS without 
relevant deviations which could affect the evaluation of the PD parameters (lymphocyte 
count) and the exploratory disease activity parameters (SLEDAI-2K, PGA). 
The protocol deviations leading to exclusion from the PPS are listed in the below table. 


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Please note: 
•
If a subject is excluded from the PDS then he is also excluded from the PPS.
Rationale: Insufficient pharmacodynamic effect is unlikely to show e.g. clinical
improvement, but will confound the results.
•
 If a subject presents with such protocol deviation (specifically,
pregnancy test not performed 3 weeks apart), but no pregnancy occurred and all
subsequent pregnancy tests were consistently negative during the trial, the subject
can be included into the PPS.
Rationale: Biologically this subject is not different from included subjects.
However, an important protocol deviation has to be reported.
•
: If a subject presents with such protocol deviation, but the change
of the immunologically active medication occurred at or after EOT, the subject
can be included in the PPS.
Rationale: The primary endpoint compares the change from baseline to EOT.
7.1.4 Safety analysis set 
The safety analysis set (SAF) includes all subjects who received at least one dose of 
study treatment. Unless otherwise stated, any analysis using the SAF uses all available 
safety data up to EOS.  
Subjects are analyzed based on treatment actually received. 
7.1.5 Other analysis sets  
7.1.5.1 Pharmacodynamic Analysis Set  
The Pharmacodynamics Analysis Set (PDS) includes all subjects who received at least 21 
days of study treatment, with lymphocyte count measurements at baseline and post-
baseline (namely, one sample taken at least 21 days after the first study treatment intake 
and no later than 7 days after the last study treatment intake with no treatment 
interruption documented in the first 21 days). 
Subjects are analyzed according to the treatment received. 
7.1.5.2 Pharmacokinetic Analysis Set  
The pharmacokinetic analysis set (PKS) includes all randomized subjects who received at 
least one dose of ACT-334441 and provided at least one blood sample for PK evaluation.  
Subjects are analyzed based on treatment received.  
7.2 Usage of the analysis sets 
Overall summary of study disposition, screening failures and including reasons for 
screening failure are summarized using the SCR.  




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8 
DEFINITION OF SUBGROUPS 
Not applicable as no subgroups were defined in the protocol. Due to the small number of 
subjects per dose it was decided that subgroups would not be explored in the CSR SAP.  
9 
GENERAL STATISTICAL METHODOLOGY 
This section describes in general terms the statistical models and methods applied. 
9.1 Statistical methods for binary data 
9.1.1 Confidence interval for a proportion 
Statistical considerations.  
For proportions, two-sided (
)
α
−
1
% Clopper-Pearson Confidence Intervals (CIs)
[Clopper 1934] are calculated.  
SAS Code 
The Clopper-Pearson CIs are calculated using SAS code similar to: 
data events; 
  set events; * containing – for each group – numbers of subjects (n) and ‘events’ (e); 
  p=round(100*e/n); 
  lo=round(100*betainv(.025, e, n-e+1)); 
  up=round(100*betainv(.975, e+1, n-e)); 
  if lo=. then lo=0; 
  if up=. then up=100; 
run; 
9.2 Statistical methods for continuous data 
9.2.1 Multiple Comparison Procedure and Modeling (MCP-Mod) approach 
Dose-response data are analyzed using the MCP-Mod approach [Bretz 2005]. In brief, 
this methodology consists of two steps: 
1. Multiple Comparisons Procedures (MCP) step to establish a dose-response signal
(i.e., the dose-response curve is not flat) using multiple comparison procedures.
2. Modeling (Mod) step to estimate the dose-response curve and target doses using
modeling techniques.
In this study five models have been pre-specified in the protocol for consideration in all 
MCP-Mod analyses: Emax (with three different starting values for ED50), quadratic, and 
sigmoidal Emax. See Table 10 for the parameterization of the dose-response models and 
Figure 2 as 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.  




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The basic R-code is similar to: 
library(DoseFinding) 
doses <- c(0, 0.5, 1.0, 2.0, 4.0) 
s <- sEmax(ed50=0.4, ed95=2) 
candMod <- Mods(      emax = c(0.2, 0.4, 1.0) 
,   sigEmax = s 
, quadratic = -0.167 
,     doses = doses 
,   placEff = 0 
,    maxEff = -70% reduction from of the mean baseline value 
, direction = “decreasing” 
) 
MMfit <- MCPMod(       dose = TRTDOSEP 
,      resp = CHG 
,      data = LYM 
, addCovars = ~BASE 
,    models = candMod 
,     delta = -1.4(arbitrary to run model, target dose not estimated) 
) 
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, LYM is a data frame 
with objects TRTDOSEP (Planned Dose for Period 01), CHG (for Absolute change from 
baseline), and BASE (for Baseline Value) and delta is a target difference vs. placebo. The 
object MMfit is summarized to obtain the MCP test, parameter estimates, target dose and 
AIC. These elements go in a summary table. The object is plotted to display the fitted 
dose-response curves. 
9.2.2 Analysis of Variance 
For the analysis of quality of life variables, on the absolute change from baseline for each 
score, the mean treatment differences for each ACT-334441 dose compared to placebo 
and their corresponding 95% confidence intervals are provided using a One-way analysis 
of variance (ANOVA) with treatment group as a factor in the model. 
Statistical considerations 
In analysis of variance, a continuous response variable, known as a dependent variable, is 
measured under experimental conditions identified by classification variables, known as 
independent variables. The variation in the response is assumed to be due to effects in the 
classification, with random error accounting for the remaining variation. 
Adjusted means are calculated by fitting the following fixed effects analysis of variance 
(ANOVA) model,  
Yik = µ + αi + εik 
where 
-
Yik is the absolute change from baseline of the kth subject in treatment group i;
-
µ is the overall mean;
-
αi is the main effect of treatment group i;


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εik are error terms which are normally distributed with a mean of zero and variance
2
σ (
(
)
2
,0
~
σ
ε
N
ijk
(
(
)
2
,0
~
σ
ε
N
ijk
(
(
)
2
,0
~
σ
ε
N
ijk
). 
Validation:  
The normal distribution of the variables is evaluated by means of the Shapiro-Wilk test 
and graphically (stem and leaf plot and normal probability plot) in each treatment group. 
The homogeneity of variances across treatment groups is assessed using Hartley’s test. 
SAS Code 
The SAS statements used to calculate the means and the between-group differences are 
similar to: 
ods output ESTIMATES = DIFF; 
ods output LSMeanCL = LSM; 
proc glm data = changes ; 
  by TESTNO TESTCD TEST  ; 
  class TRTGRPPS; 
  model CHANGE = TRTGRPPS/ss3; 
  lsmeans TRTGRPPS / tdiff stderr cl; 
  estimate “Group A minus Group E” TRTGRPPS  1   0   0   0  -1; 
  estimate “Group B minus Group E” TRTGRPPS  0   1   0   0  -1; 
  estimate “Group C minus Group E” TRTGRPPS  0   0   1   0  -1; 
  estimate “Group D minus Group E” TRTGRPPS  0   0   0   1  -1; 
run; 
quit; 
9.2.3 Analysis of Covariance 
For analyses involving the absolute and/or the percent changes from baseline for a 
studied parameter, the mean treatment differences for each ACT-334441 dose compared 
to placebo and their corresponding 95% confidence intervals are provided using an 
Analysis of Covariance (ANCOVA) including baseline value as a covariate and with 
treatment group as a factor in the model. 
Statistical considerations 
The model used for this analysis is a general linear model studying treatment effect with 
baseline value of studied parameter (as fixed effect) as covariate: 
Yik = γ Xik + ai + εik 
where: 
-
Yik is the response from the kth subject that received treatment i,
-
Xik is the baseline value of the analysed variable for the kth subject that received
treatment i,
-
γ denotes the common slope of the baseline covariate,


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-
ai denotes the intercept of the ith treatment,
-
εik ~ iid N(0, σε
2) denotes the experimental unit error associated with the kth subject
that received treatment i.
The model can also be written in matrix notation as: 
Y = Xβ + ε 
where: 
-
Y is the vector of observations,
-
X is the design matrix of the fixed effects and baseline factors,
-
β is the unknown vector of the fixed effects and baseline factors,
-
ε is the unobserved vector of independent and identically distributed random
errors, such as 
,R)
0
N(
~
ε
 where R = 
2
ε
σ
2
ε
σ
2
ε
σ In.
Estimations:  
The estimate βˆ of β is given by: 
C
X
R
X
Var
Y
X
X
X
ˆ
)
ˆ
(
)ˆ
(
with 
)
(
ˆ
1
=
′
=
′
′
=
−
−
−
β
β
Confidence interval: 
The Sum of Squares (SS) using a LS-means contrast is used for computing SS(H0: Lβ = 0) 
(where Lβ denotes a linear estimable combination of the fixed effects): 
The 95% confidence interval of βˆ βˆ βˆ  is given by: 
'
ˆ
ˆ
975
0,ˆ
L
C
L
t
L
ν
β ±
where: 
-
νˆ  denotes the approximate degrees of freedom by Satterthwaite,
-
975
0,νˆt
is the 0.975th quantile of the t-distribution with νˆ degrees of freedom.
The least-squares approach provides estimates of the linear parameters that are 
unbiased and have minimum variance among linear estimators. 
The treatment effect is estimated by the difference of the LS-means of each studied 
treatment group. 
Validation:  
Residual normality and homoscedasticity will be studied using graphs and descriptive 
statistics. 


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SAS Code 
The SAS statements used to calculate the adjusted means and the between-group 
differences are similar to: 
ods output ESTIMATES = DIFF; 
ods output LSMeanCL = LSM; 
proc glm data = changes ; 
  by TESTNO TESTCD TEST  ; 
  class TRTGRPPS; 
  model CHANGE = TRTGRPPS BASELINE /ss3; 
  lsmeans TRTGRPPS / tdiff stderr cl; 
  estimate “Group A minus Group E” TRTGRPPS  1   0   0   0  -1; 
  estimate “Group B minus Group E” TRTGRPPS  0   1   0   0  -1; 
  estimate “Group C minus Group E” TRTGRPPS  0   0   1   0  -1; 
  estimate “Group D minus Group E” TRTGRPPS  0   0   0   1  -1; 
run; 
quit; 
10 STATISTICAL ANALYSES 
This study is performed in two parts: part A with four treatment groups (including 0.5 
mg, 1 mg, or 2 mg of ACT-334441 and placebo control) and part B with two treatment 
groups (including 4 mg of ACT-334441 and placebo control). In all analyses the 
assumption is made that the data from part A and part B can be combined, in particular 
the subjects randomized to placebo in any part of the study are analyzed as one group. 
This assumption is investigated for the main pharmacodynamics endpoint in a sensitivity 
analysis. 
10.1 Overall testing strategy 
An optimized contrast test according to the Multiple Comparison Procedure and 
Modeling (MCP-Mod) approach [Bretz 2005] for each considered dose-response model 
is performed. The existence of dose-response effects on the change from baseline in 
lymphocytes counts at EOT is tested using the maximum of the model-based contrast 
tests using a one-sided 0.05 alpha. Multiplicity adjusted p-values are calculated using the 
Dunnett-distribution which controls the type 1 error. 
All other statistical testing are performed at a two-sided significance level of 0.05 using 
95% Confidence Limits (CLs).  
In all analyses of secondary and other efficacy variables, no correction will be made for 
multiple testing. 


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10.2 General rules for data presentations 
This section describes the general rules applied for all data displays, unless otherwise 
specified in each corresponding section. 
SAS version 9.4 is used for the preparation of all tables, listings and figures.  
Listings are sorted by country, site, treatment group, subject number and timing (dates, 
times and/or visits as applicable) and will display all subjects.  
Names of outputs begin with T for Table, F for Figure and L for Listing, the next 2 digits 
represent the ADaM dataset the output is based on (e.g. LB for laboratory), followed by a 
numerical number and finally there is a suffix that indicates the analysis set (e.g., SAF for 
Safety Analysis Set). 
Data are listed and summarized using appropriate descriptive statistics: 
•
Number of non-missing observations, mean, standard deviation, minimum, Q1,
median, Q3 and maximum for continuous variables.
•
Number of non-missing observations, and frequency with percentage per category for
categorical variables. Denominators for percentages are the number of subjects in the
pertinent analysis set and treatment group, unless otherwise specified.
Table layout and format 
• Placebo is the first column on the left with  ACT-334441 dose groups ordered (left to
right) in ascending order of dose and where appropriate the total is in the right most
column.
• Placebo corresponds to the pooled subjects randomized in ‘Placebo Control (Part A)’
and ‘Placebo Control (Part B)’.
Example table layout: 
Placebo
ACT-334441
ACT-334441
ACT-334441
ACT-334441
Total
0.5 mg
1.0 mg
2.0 mg
4.0 mg
(N=XX)
(N=XX)
(N=XX)
(N=XX)
(N=XX)
(N=XX)
<XXXXXXXXXX>   
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
XX (XX.X)
10.3 Display of subject disposition, protocol deviations and analysis sets 
A listing of the randomization scheme and codes is produced for randomized subjects 
only (ICH E3 16.1.7).  


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10.3.1 Subject disposition 
An overview of the recruitment for each country/site is presented for the FAS by 
treatment group and overall in a table. 
An overview of the subject disposition over the course of the study is presented for the 
SCR by treatment group (except for Screened and Re-Screened which are only 
summarized for the total column) and overall in a table and comprises the number of 
subjects: 
•
Screened,
•
Re-screened
•
Randomized
•
Treated
•
Completed/ prematurely discontinued the study treatment
•
Completed/ prematurely discontinued the study
10.3.1.1 Screening failures 
The number of subjects screened, randomized, failed screening and reasons for screening 
failure are summarized for the SCR in a table and in a listing. For subjects that fail 
screening twice, only the reason of the last failure is reported in the summary table. All 
reasons for screening failure are included in the listing together with the screening failure 
date.  
10.3.1.2 Discontinuation from study 
For the FAS, the number and percentage of subjects who completed the study as per 
protocol, discontinued the study and the reasons for study discontinuation are 
summarized by treatment group and overall. Study completion/discontinuation details  
and the reasons for study discontinuation are also presented in a listing.  
10.3.1.3 Discontinuation of study treatment 
For the SAF, the number and percentage of subjects who completed the study treatment 
as per protocol, discontinued the treatment prematurely and the reasons for study 
treatment discontinuation are summarized by treatment group and overall. The study 
treatment completion/discontinuation details and reasons for study treatment 
discontinuation are also presented in a listing.  
10.3.2 Protocol deviations 
Minor and important protocol deviations are displayed in a listing. This listing includes 
all deviation descriptions, identifiers and categories. A second listing may be generated to 
list the ‘other’ protocol deviations. Subjects without any protocol deviations are not 
included in these listings.  


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Protocol deviations (minor and important) are summarized by treatment group and 
overall for the FAS. Protocol deviations are also summarized by country and treatment 
group for the FAS.  
10.3.3 Analysis sets 
The number and percentage of subjects included and excluded in each analysis set are 
summarized in a table, by treatment group and overall for the FAS.  
The inclusion/ exclusion of subjects in each analysis set and the reasons are listed for all 
screened subjects. 
In addition, the number and percentage of subjects included in the FAS but excluded 
from the PPS are summarized in a table as well as the reason of exclusion. 
A listing is produced to present the subjects for whom the randomization code was 
broken at site or sponsor office. It contains the date of unblinding and the reason for 
unblinding.  
10.4 Analyses of subject characteristics 
10.4.1 Demographics 
Demographic characteristics [variables defined in Section 5.2.1] are summarized by 
treatment group and overall, using descriptive statistics for continuous and categorical 
data using the FAS. Body weight and height are tabulated by gender. 
A listing is produced on the SCR for the demographic characteristics. Smoking habits are 
presented in a separate listing for the SCR. 
10.4.2 Baseline disease characteristics 
Baseline disease characteristics [defined in Section 5.2.2] are summarized by treatment 
group and overall using appropriate descriptive statistics for the FAS. The variables 
related to the SLE relevant disease history and history of detectable ANA or anti‐dsDNA 
testing are summarized in one table, and the variables related to modified SLEDAI-2K at 
baseline (active descriptors, sub-scores and scores) and PGA in a second table, and 
exploratory biomarkers (anti-Smith, anti-cardiolipin [IgA, IgG, IgM], anti-ribosomal P) 
in a third table. Listings are presented for the SCR. 
10.4.3 Other baseline characteristics 
Other baseline disease characteristics [defined in Section 5.2.3] are listed for the SCR. 
10.4.4 Medical history 
Previous and concomitant medical history (diseases/diagnoses) [defined in Section 5.2.4] 
are summarized separately, by treatment group and overall using the FAS. The number 
and percentage of subjects with at least one medical history are presented overall and by 
SOC and individual PT within each SOC.  


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SOCs/PTs are sorted by descending frequency of the number of subjects in the highest-
dose group. If the frequencies of SOCs or PTs are the same, alphabetical order is used.  
One listing is produced for the SCR.  
10.4.5 Previous and concomitant therapies 
Previous and concomitant therapies [defined in Section 5.2.5] are summarized separately 
as follows: 
•
‘Previous non-SLE therapies’
•
‘Study treatment concomitant non-SLE therapies’
•
‘Previous SLE therapies’
•
‘Study treatment concomitant (Background) SLE therapies’
Number and percentage of subjects having received at least one therapy are presented 
overall, by ATC class (level 4) and PT within each ATC class. ATC classes are sorted by 
descending  frequency of the number of subjects in the highest-dose treatment group. If 
the frequencies of ATC class are the same, alphabetical order is used. The same rule 
applies for PTs within ATC class.  
10.4.6 Other subject characteristics 
The information ‘woman of childbearing potential’ as well as the contraceptive methods 
and the results of the serum and urinary pregnancy tests conducted during study are 
presented in a listing for the SCR. 
10.5 Analysis of study treatment exposure and compliance 
10.5.1 Exposure 
Exposure characteristics for the study treatment [defined in Section 5.3.1] are 
summarized by treatment group using descriptive statistics for continuous and categorical 
data, for the SAF. The listing is produced for the SCR The study treatment duration 
(days) is also tabulated by end of treatment status (completed, premature discontinuation) 
and overall. 
Study treatment interruptions data [defined in Section 5.3.4] are summarized by treatment 
group using descriptive statistics for categorical data using the SAF. The reasons for 
treatment interruptions are included in the exposure listing.  
10.5.2 Compliance with study treatment 
The overall compliance to the study treatment [defined in Section 5.3.2] is summarized 
by treatment group using descriptive statistics for continuous and categorical data, for the 
FAS. The listing is produced for the SCR. 


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10.6 Analysis of the main pharmacodynamic variable(s) 
This section describes the analysis of the main pharmacodynamic endpoint (i.e., change 
in lymphocyte count from baseline to EOT), as defined in in Section 5.5.1. 
The objective is to demonstrate a dose response of ACT-334441 on the lymphocyte count 
reduction from baseline in peripheral blood in subjects with SLE. 
10.6.1 Hypothesis and statistical model 
The null hypothesis is that there is no dose response in terms of lowering the lymphocyte 
count (p, which is a negative value for lowering of the lymphocyte count) from baseline 
to EOT, 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, 2, 4 mg- 
To meet the objective of demonstrating a dose response of ACT-334441 on the 
lymphocyte count reduction from baseline to EOT, the null hypotheses must be rejected 
by the test with a one-sided significance level of 5%.  
10.6.2 Handling of missing data 
In the main analysis the lymphocyte count is analyzed at EOT which for the majority of 
patients is Week 12. This is effectively imputation utilizing the LOCF technique i.e., 
using data from Week 4 (i.e. at least 21 days after the first study treatment intake) later to 
impute for missing Week 12 values. This is justified given the maximum effect on 
lymphocyte counts is expected to be achieved at 4 weeks, since in the AC-064-101 study 
that investigated cenerimod in healthy subjects, multiple doses resulted in mean 
lymphocyte count-time profiles that “plateaued” at 20–23 days of treatment in all dose 
groups [Cenerimod IB, section 5.2.5.2]. Subjects with missing baseline lymphocyte 
counts and/or no lymphocyte count at or after Week 4 are excluded from the main 
analysis on the PDS.  
The analysis by visit includes a ‘Complete Case’ analysis at Week 12 which allows for an 
assessment of the effect of LOCF. The analysis on the FAS is also at EOT which uses 
LOCF from the last post-baseline visit with no time restriction.  
10.6.3 Main analysis 
The MCP-Mod approach consists of a set of optimized contrast tests for establishing the 
existence of dose-response effect. The overall strategy is described as follows: 
Definition of a set of likely dose-response relations (the method allows for characteristics 
of the curve, such as maximum effect, to be defined at doses not studied): 
•
Maximum effect (Emax) with 50% of the maximum effect at dose 0.2 mg


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•
Emax with 50% of the maximum effect at dose 0.4 mg
•
Emax with 50% of the maximum effect at dose 1.0 mg
•
Quadratic with maximum effect at dose 3.0 mg
•
Sigmoid-Emax with 50% of the maximum effect at dose 0.4 mg and 95% of the
maximum effect at dose 2.0 mg.
The existence of dose-response effects is assessed with the optimized contrast tests. 
Dose-response effects are established at one-sided level α=5%, if the following condition 
on the p value holds for at least one contrast i: 𝑝𝑖: = 1 −𝐹𝛴𝐷𝑢𝑛𝑛𝑒𝑡𝑡 (𝑍𝑖) < 0.05, where 
𝐹𝛴𝐷𝑢𝑛𝑛𝑒𝑡𝑡 describes the Dunnett-distribution with correlation matrix 𝛴𝐷𝑢𝑛𝑛𝑒𝑡𝑡. 
The model with the minimum p-value is fitted to the data. As a sensitivity analysis, all 
remaining significant models are fitted to the data, and model-based dose response 
estimates are calculated. A table summarizing the t-statistic and adjusted p-value for each 
curve is presented by decreasing adjusted p-value.  
A plot of the estimated dose-response curve with 95% CIs is presented along with the 
observed response at each dose. A table summarizing the estimates (and standard error) 
of each dose-response curve parameters and the AIC will also be presented.   
Given established dose-response effects with MCP-Mod, PD effects are analyzed based 
on pairwise comparisons of reduction in lymphocyte count from baseline to EOT for each 
active dose level to placebo using an analysis of covariance (ANCOVA) model, adjusted 
for baseline lymphocyte count. Testing is done with two-sided significance level 5%. The 
type-1 error is controlled via a hierarchical ordering of the tests: pairwise comparison is 
conducted in decreasing dose order. The analysis described in this paragraph is repeated 
for the % change from baseline to EOT in lymphocyte counts. 
This analysis is performed on the PDS.  
10.6.4 Supportive/sensitivity analyses 
These analyses (MCP-Mod and ANCOVA) are replicated on the FAS. 
The assumption that the data from part A and part B can be pooled in a single analysis 
[Section 10] is investigated by performing separate ANCOVAs for the two parts. Within 
part A, comparisons are conducted between first 3 treatment groups (0.5 mg, 1.0 mg and 
2.0 mg) and placebo (Part A) and within part B between the 4th treatment group (4.0 mg) 
and placebo (Part B). The differences vs. placebo obtained from these models are 
compared with the corresponding differences from the main analysis. This sensitivity 
analysis is performed for the PDS and FAS. 
10.6.5 Subgroup analyses 
Not applicable.  


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10.7 Analysis of the other pharmacodynamic variables 
Quantitative descriptive statistics for absolute value, absolute change from baseline and 
percent change from baseline are presented by analysis visit and treatment group. These 
analyses are performed on the FAS.  
10.8 Analysis of other efficacy variables 
10.8.1.1 Exploratory disease activity endpoints 
•
Main analysis
For all the SLEDAI-2K variables (including number of affected joints) and the PGA 
variable [defined in Section 5.7.3.1], an ANCOVA model including baseline value as a 
covariate and treatment group as a factor is applied to the absolute change from baseline 
to EOT for each variable on the FAS and PPS. The difference in least squares means 
between each ACT-334441 dose and placebo is computed and the 95% confidence 
intervals for the differences are estimated. 
•
Secondary analysis
For the SLEDAI-2K (including number of affected joints) and PGA variables [defined in 
Section 5.7.3.1], separate summaries of quantitative descriptive statistics for absolute 
values, absolute change from baseline and percent change from baseline are presented by 
analysis visit and treatment group.  
For modified SLEDAI-2K total score, the summaries are also presented stratified by 
baseline category (baseline total SLEDAI-2K score < 6, baseline total SLEDAI-2K score 
≥ 6, overall). 
In addition, for the modified total SLEDAI-2K total score, the occurrence of an increase 
from baseline > 3is tabulated by analysis visit and treatment group. 
The evolution of the values over time (PGA score, modified SLEDAI-2K score and 
number of affected joints) is provided in graphical format for each parameter from 
baseline to EOS visit (one figure per endpoint, one boxplot per treatment group and 
analysis visit).  
All these analyses are performed on the FAS. 
Listings are produced on the SCR. For PGA and SLEDAI-2K score, it displays the 
absolute values, the absolute change and the percent change from baseline to each post-
baseline assessment, the values taken into account for the analysis are flagged.  
In addition, for the modified SLEDAI-2K, the value at each analysis visit for each 
descriptor is included in a listing. 


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10.8.1.2 Exploratory biomarker 
For exploratory biomarkers [defined in Section 5.7.3.2], separate summaries of 
quantitative descriptive statistics for absolute values, absolute change and percent change 
from baseline are presented by analysis visit and treatment group (including geometric 
mean and associated 95% CI).  
For exploratory biomarkers for which categories have been used, the number and 
percentage of subjects with a value in each category are summarized by analysis visit and 
treatment group.  
10.9 Analysis of safety variables 
The SAF is used to perform all safety analyses. 
For the tabulations by analysis visit and time points (e.g. values over time for blood 
pressure measurements, ECG), if multiple values are available (unscheduled visits/ 
retests), the examination closest to the planned visit/ time point is chosen [see Section 11 
for more details]. 
However, for the summaries of treatment-emergent abnormalities over the study period, 
all safety data collected up to EOS are considered.  
All safety data are included in listings, with specific flags for the treatment-emergent or 
values taken into account in the analyses. 
10.9.1 Adverse events 
All AEs captured from signature of informed consent up to EOS are reported in the 
subject listings which include data collected in eCRF as well as the coded terms (SOC, 
PT) and a flag for treatment-emergent.  
For displays of AEs summarizing counts on the event level (i.e. total number of events), 
the denominator for calculating percentage is the number AEs occurring in a given 
treatment group. For displays of events by period of onset, the denominator is the number 
of AEs occurring in a given treatment group during the relevant period of onset. For 
displays of AEs summarizing counts on the subject level (i.e. total number of subjects 
experiencing events), the denominator for percentages is the number of subjects in the 
SAF for a given treatment group. 
For all tables, aggregate counts for total number of subjects, events and associated 
percentages, and total number of subjects, events and associated percentages per SOC 
and PT are also included (as applicable). 
For tables presented by SOC and PT, SOCs/PTs are sorted by descending frequency of 
the number of subjects in the highest-dose group. If the frequencies of SOCs or PTs are 
the same, alphabetical order is used.  


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For tables presented by PT, PTs are sorted by descending frequency of the number of 
subjects in the highest-dose treatment group. If the frequencies of PTs are the same, 
alphabetical order is used.  
The following displays of adverse events are provided: 
•
An overview of treatment-emergent adverse events (TEAEs) by treatment group with
the following counts and percentages:
-
Subjects with at least one TEAE;
-
Subjects with at least one serious TEAE;
-
Subjects with fatal serious TEAE;
-
Subjects with at least one non-serious TEAE;
-
Subjects with at least one severe TEAE;
-
Subjects with at least one drug-related TEAE;
-
Subjects with at least one drug-related serious TEAE;
-
Subjects with at least one TEAE leading to study drug discontinuation.
•
The number and percentage of TEAEs, and subjects experiencing TEAEs, by period
of onset (on Day 1 post-dose, after Day 1, overall), treatment group, SOC and PT.
•
The number and percentage of subjects with TEAEs by treatment group and PT.
•
The number and percentage of subjects with related TEAEs, by treatment group and
PT. If an adverse event (PT) occurs more than once for a subject during the treatment
period, the strongest relationship to study treatment is taken into account.
•
The number of subjects with TEAEs, by treatment group, severity/ intensity and PT.
If an adverse event (PT) occurs more than once for a subject during the treatment
period, the maximal severity is taken into account.
10.9.2 Deaths and other serious adverse events 
10.9.2.1 Death 
All deaths 
The number and percentage of subjects who died after the start of the treatment are 
summarized per treatment group, including the reported causes of death. A listing 
including all deaths is provided.  
Fatal SAEs 
The following displays of fatal SAEs are provided: 
•
The number and percentage of subjects with fatal SAEs by treatment group, SOC and
PT.


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•
The number and percentage of subjects with fatal SAEs, by treatment group and PT.
•
The number and percentage of subjects with related fatal TEAEs by treatment group
and PT.
Fatal SAEs are included and flagged in the listing of all SAEs. 
10.9.2.2 Serious adverse events 
The following displays of SAEs are provided: 
•
The number and percentage of treatment-emergent SAEs, and subjects experiencing
treatment-emergent SAEs, by period of onset (on Day 1 post-dose, after Day 1,
overall), treatment group, SOC and PT.
•
The number and percentage of subjects with treatment-emergent SAEs by treatment
group and PT.
•
The number and percentage of subjects with related treatment-emergent SAEs, by
treatment group and PT. If an adverse event (PT) occurs more than once for a subject
during the treatment period, the strongest relationship to study treatment is taken into
account.
A listing including all SAEs is provided. 
10.9.2.3 Adverse events leading to study treatment discontinuation 
The following displays of TEAEs leading to study treatment discontinuation are 
provided: 
•
The number and percentage of subjects experiencing TEAEs leading to study
treatment discontinuation, by period of onset (on Day 1 post-dose, after Day 1,
overall), treatment group, SOC and PT.
•
The number and percentage of subjects with TEAEs leading to study treatment
discontinuation by treatment group and PT.
•
The number and percentage of subjects with related TEAEs leading to study
treatment discontinuation, by treatment group and PT
A listing including all AEs leading to study treatment discontinuation is provided. 
10.9.2.4 Other significant adverse events 
The number and percentage of subjects who experienced after the first study treatment at 
least one adverse event of special interest (AESI), at least one AESI within each category 
and at least one AESI within each preferred term is summarized by treatment group.  


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The relative risk of having a specific AESI in each dose group compared to placebo is 
summarized in a table and presented in a figure (forest plots). 
A listing including all AESIs is provided. 
10.9.3 Electrocardiography (ECG) 
10.9.3.1 12-lead ECG variables and findings 
The following displays of ECGs are provided: 
•
Quantitative descriptive statistics for absolute values of ECG parameters by treatment
group and analysis visit and time point.
•
Quantitative descriptive statistics for the absolute change from baseline to 1h, 2h, 3h,
4h, 5h and 6 h post-dose on Day 1 and each post-baseline analysis visit by treatment
group and parameter.
•
Boxplots of absolute values at baseline and all post-baseline analysis visits and time
points: one figure per parameter and per treatment group. Notable abnormality
thresholds are displayed on the plots as an overlay.
•
Notable ECG abnormalities for QTcB, QTcF, HR, PR and QRS are summarized by
treatment group by presenting the number and percentage of subjects with any
abnormality at each post-baseline analysis visit and time point, at any time on Day 1
(from 1 hour post-dose to discharge), at any time after Day 1 (from discharge on Day
1 up to EOT), and at any time post-baseline (from 1 hour post-dose to EOS), 95%
Clopper-Pearson confidence intervals are presented for the proportions.
•
The number and percentage of subjects with any treatment-emergent ECG qualitative
abnormalities at any time (ECG findings) by category and reported term are
summarized by treatment group.
The denominator for percentages is the number of subjects with at least one post-baseline 
assessment in the considered interval. 
All ECG data (parameters and findings) are listed by treatment group, subject and visit. 
All post-treatment notable abnormalities are flagged and qualitative abnormalities (as 
transferred by the ECG central reader) are listed. 
10.9.3.2 24 hour Holter-ECG 
Quantitative descriptive statistics are presented for the hourly mean heart rate (bpm) by 
time interval for measurements performed on Visit 2 (Randomization/ Day 1).  
The hourly records are time-matched between Visit 1 (Screening) and Visit 2 
(Randomization/ Day 1) and quantitative descriptive statistics for the corresponding 
change by time interval are presented.  


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The evolution of the values over time for the hourly mean heart rate (bpm) on Visit 2 
(Randomization/ Day 1) is provided in graphical format (mean and 95% CI for the 
absolute value for each time interval and treatment group). 
The evolution of the change from time-matched screening holter on day 1 for the hourly 
mean heart rate (bpm) is similarly provided in a graphical format (mean and 95%CI for 
the time-matched change for each time interval and treatment group) 
Treatment-emergent Holter-ECG findings are tabulated by treatment group. 
All Holter-ECG data are listed by treatment group, subject and visit. A listing of all 
Holter-ECG abnormalities is also provided. 
10.9.4 Laboratory tests 
Descriptive summary statistics by analysis visit and treatment group are provided for 
observed values and absolute changes from baseline by category (hematology/ 
coagulation, chemistry, urinalysis). Data are displayed in SI units as provided by the 
central laboratory. 
Values from local labs are not included in the different summaries but are included in the 
listings.  
For categorical urinalysis parameters (dipstick), qualitative descriptive statistics for 
recorded values are presented by parameter and visit.  
Treatment-emergent laboratory abnormalities are summarized by lab category, parameter 
and severity over the study treatment period. For each parameter, the severity is based on 
the position of the value against reference ranges (central laboratory) and additional 
thresholds for significance (see appendix 7 of the study protocol) and the worst 
abnormality is considered in each direction separately (Low and High). In addition, for 
the liver tests, the number and percentages of subjects with values above the normal 
ranges, or with abnormal values that are of a certain size (e.g., twice the upper limit of the 
normal ranges; see section 5.1.10.5, figure 3 of the study protocol) are presented along 
with their 95% Clopper-Pearson confidence intervals. For each parameter, the maximum 
highest value recorded during the treatment period is taken into account.  
The denominator for percentages is the number of subjects with at least one post-baseline 
assessment. 
All data are presented in the listings: 
•
hematology, chemistry, coagulation, urinalysis
•
urinary dipstick
•
viral serology (if assay is required)/ tuberculosis test results are listed along with
the other baseline characteristics


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•
serum and urinary pregnancy tests results are listed along with the childbearing
potential information
10.9.5 Vital signs and body weight 
For body weight, a summary table presenting the value at baseline, value at Visit 6 (EOT) 
and the change from baseline is produced by treatment group. 
Standing SBP and DBP (mmHg) are not included in the summary tables but included in 
the listings. 
For supine SBP and DBP (mmHg), the following displays are provided: 
•
Quantitative descriptive statistics for absolute values by treatment group and analysis
visit and time point.
•
Quantitative descriptive statistics for the absolute change from baseline to 1h, 2h, 3h,
4h, 5h and 6 h post-dose on Day 1 and each post-baseline analysis visit by treatment
group and parameter. This table is repeated for the measurements taken on day of
study drug re-initiation, if applicable.
•
Boxplots of absolute values at baseline and all post-baseline analysis visits and time
points: one figure per parameter and per treatment group. Notable abnormality
thresholds are displayed on the plots as an overlay.
•
Notable BP abnormalities are summarized by treatment group by presenting the
number and percentage of subjects with any abnormality at each post-baseline
analysis visit and time point, at any time on Day 1 (from 1 hour post-dose to
discharge), at any time after Day 1 (from discharge on Day 1 up to EOT), and at any
time post-baseline (from 1 hour post-dose to EOS), 95% Clopper-Pearson confidence
intervals are presented for the proportions.
The denominator for percentages is the number of subjects with at least one post-baseline 
assessment in the considered interval. 
All data (values and changes) are listed by treatment group, subject and visit. All marked 
abnormalities are flagged. 
10.9.6 Spirometry 
Quantitative descriptive statistics are presented by parameter, by analysis visit and 
treatment group. In addition, a summary table presenting the absolute change from 
baseline to each visit up to EOS is produced. Similarly the percent change from baseline 
to each visit up to EOS are presented by visit and by treatment group. 
The number and percentage of subjects with a decrease in FEV1 or FVC of > 15% from 
baseline value is provided for each visit, by analysis visit and treatment group, each with 
95% Clopper-Pearson confidence intervals. In addition, the number and percentage of 


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subjects with a 15% decrease in FEV1 or FVC at one visit, 2 consecutive visits, 3 
consecutive visits, and more than 3 visits during the treatment period is presented. 
The evolution of the values over time is provided in graphical format for FEV1 (L), FVC 
(L) and FEV1/FVC (one figure per parameter: one boxplot per treatment group and
analysis visit, from baseline to EOS).
All data (values and changes) are listed by treatment group, subject and visit. All marked 
abnormalities are flagged. 
10.9.7 Physical examination 
A listing presents the findings of physical examination (Clinical significance and details) 
by treatment group, subject number, body system and visit number. 
10.9.8 Ophthalmological examination and OCT 
A listing presents the findings of ophthalmological examination (Clinical significance 
and details) by treatment group, subject number, visit and by type of examination (optical 
coherence tomography test, ophthalmological examination). 
10.9.9 Echocardiography 
A listing presents the findings of echocardiography (Clinical significance and details) by 
treatment group, subject number and visit. 
10.10 Analysis of quality of life variables 
For each score (8 domain scores, 2 component scores), quantitative descriptive statistics 
are presented for each analysis visit (baseline and EOT) and for the change from baseline 
to EOT by treatment group for the SAF. Additionally, the mean treatment differences for 
each ACT-334441 dose compared to placebo and their corresponding 95% CIs are 
provided using an ANOVA with treatment group as a factor in the model.  
If the data are non-normally distributed or should the assumptions underlying the 
ANOVA model (normality of the residuals, homogeneity of the variance) not be fulfilled, 
the same comparisons between treatment groups will also be performed using a non-
parametric one-way ANOVA. 
For the reported health transition item, qualitative descriptive statistics are presented for 
each visit by treatment group.  
10.11 Analysis of pharmacokinetic variables 
For PK variables [defined in Section 5.6], quantitative descriptive statistics (including 
geometric mean and 95% CI) for ACT-334441 plasma concentrations are presented by 
visit and treatment group for the PKS. It includes only data from samples that are taken 
according to the protocol i.e.,  


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•
For Week 2, 4 and 8: trough samples, i.e., samples taken before dosing and one day
after the previous dose
•
For Week 12: samples taken within 1 to 7 days following the last dose.
The evolution of the values over time is provided in graphical format (one figure: one 
boxplot per treatment group and analysis visit, from baseline to EOS).  
A listing of individual data is produced on the SCR.  
11 GENERAL DEFINITIONS AND DERIVATIONS 
11.1 Phases, periods, visits 
Assessments that are summarized in the report are those defined in the study protocol and 
recorded at the corresponding visits in the eCRF.  
11.1.1 Analysis visits 
To allow analysis of data at the relevant planned (scheduled) visits, all recorded 
assessments, including unscheduled ones, are assigned to the most appropriate analysis 
visit according to the best fitting time-window for that visit [see Table 11]. The visit 
windows are based on the number of days from first study treatment intake. In the 
majority of cases it is expected that the analysis visit is the same as the scheduled visit.  
Analysis Relative Day is estimated for several assessments (e.g., vital signs, laboratory 
data, physical examination). It refers to the number of days elapsed since first study 
treatment intake date plus 1 (e.g., Day 1 is the day of first study treatment intake). For 
dates prior to first study treatment intake, study day is the negative number of days 
elapsed between the date under consideration and the day of first study treatment intake. 
Therefore, the study day is never 0. 
Analysis Relative Day to EOT is estimated for several assessments (e.g., vital signs, 
laboratory data, physical examination). It refers to the number of days elapsed since last 
study treatment intake date (e.g., Analysis Relative Day to EOT is null when the date of 
assessment and the date of last study treatment intake are equal).  
Analysis Window Difference from Target is defined as the absolute difference between 
Analysis Relative Day and Analysis Window Target. It is necessary to adjust for the 
fact that there is no day 0 in the event that Analysis Relative Day and Analysis Window 
Target are not of the same sign.  




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On Day 1 (post-dose) 
For 12 lead ECG and blood pressure measurements, an additional observation (AVISITN 
= 2.5, AVISIT = ‘During day 1’, DTYPE = ‘MINIMUM’ and/or DTYPE = 
‘MAXIMUM’) is created for all subjects with at least one post-baseline assessment 
performed on Day 1, after first study treatment intake, and is populated according to the 
worst observation carried forward (WOCF) principle.  
From discharge on day 1 through EOT 
For 12 lead ECG and blood pressure measurements, an additional observation (AVISITN 
= 7.1, AVISIT = ‘From Week 2 through Week 12’, DTYPE = ‘MINIMUM’ or/and 
DTYPE = ‘‘MAXIMUM’) is created for all subjects with at least one post-baseline 
assessment performed after discharge on Day 1 and up to Week 12 and is populated 
according to the WOCF principle.  
During Study Period 
For 12 lead ECG and blood pressure measurements, an additional observation (AVISITN 
= 7.2, AVISIT = ‘During study period’, DTYPE = ‘MINIMUM’ and/or DTYPE = 
‘‘MAXIMUM’) is created for all subjects with at least one post-baseline assessment 
performed from Day 1, after first study treatment intake, up to EOS and is populated 
according to the WOCF principle.  
11.1.2 Retests and multiple assessments in the same visit window 
Unless specified otherwise, for findings (e.g., 12 lead ECG, laboratory data), in the case 
of multiple results in the same analysis visit/ time point, the results included in summary 
tables are selected according to the following rules: 
•
Prior to first study drug administration
For the same parameter and the same subject, only the latest non-missing result
available prior to first study drug administration is retained for analysis.
•
After first study drug administration
For the same parameter and the same subject in the same visit window, only the result
of the first non-missing assessment (closer to the target day) is retained for analysis.
In case of equidistant values from the planned time point, the last assessment is
considered for the analyses. Where multiple assessments fall on the same day, then
the latest is used.
The records to be taken into account in the analysis are to be flagged (the variable 
Analysis Record Flag is defined to support the selection of the right assessment). All 
results are listed. 


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11.2 Analysis variables 
11.2.1 General 
Baseline value is defined as the last non-missing value before date and time of first dose 
intake of double-blind treatment.  
Analysis value is defined as the value at the visit (numeric result in standard units). 
Absolute change from baseline is defined as post-baseline value minus baseline value, 
i.e., a positive sign indicates an increase as compared to baseline.
Percent 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. 
Ratio to baseline is defined as the value at the visit divided by the value at baseline (if 
the baseline value is > 0). 
Analysis Date is defined as the numeric SAS date derived from the Date/Time of 
assessment. It can be an imputed date [cf. section 12 for more details]. 
Analysis Start Date is defined as the numeric SAS date derived from the Start 
Date/Time of an event. It can be an imputed date [cf. section 12 for more details]. 
Analysis End Date is defined as the numeric SAS date derived from the End Date/Time 
of an event. It can be an imputed date [cf. section 12 for more details]. 
Analysis End Relative Day is estimated for several assessments, including AE end, 
treatment interruptions, concomitant medication end. It refers to the number of days 
between the end of the specific event and the first study treatment intake.  
11.2.2 Subject Level Data 
This dataset regroups information from Demographics (DM), Disposition (DS), Death 
Details (DD), Vital Signs (VS), Exposure (EX), Subject Visits (SV), Reproductive 
System (RP), Substance Use (SU) domains and their supplemental domains.  
Subject demographics 
Age, Age Units, Sex: retrieved from the DM domain or, in case of re-screening, retrieved 
from the supplemental domain. 
Childbearing potential: latest information to be retrieved from the RP domain (the 
information recorded for a RE-SCREENING supersedes information collected at 
SCREENING). 
Race, Ethnicity, Country: the information has to be retrieved from the DM domain. 
Variables to facilitate the production of the summary tables have to be created (e.g., 
numeric code to enable the correct display order or the long value in proper case).  


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Variables related to substance use (Smoking habits, Number of cigarettes smoked, 
Number of years quit, Year quit) are retrieved from Substance Use domain.   
Weight (kg) and Height (cm) at baseline: the latest information has to be retrieved from 
the VS domain (prior to first intake). 
Population flags 
Screened Subject Flag is assigned to Y for all subjects who have a record in the DM 
domain. 
Re-Screened Subject Flag is assigned to: 
•
Y for subjects who have a record in the SV domain with a visit number equal to 1.1
•
N otherwise.
Randomized Population Flag is assigned to:
•
Y for all subjects who have a record in DS domain with a Standardized Disposition
Term equal to RANDOMIZED
•
N otherwise.
Full Analysis Set Population Flag is assigned to:
•
Y for all subjects who have a record in DS domain with a Standardized Disposition
Term equal to RANDOMIZED
•
N otherwise.
Safety Analysis Set Population Flag is assigned to
•
Y for all subjects who have a record in EX domain corresponding to the first study
treatment administration (Group ID =DAY 1 /RE-INITIATION)
•
N otherwise.
Per-protocol Population Flag is assigned to:
•
Y for all subjects included in the Full Analysis Set who have no record in the DV
domain flagged as ‘leading to exclusion from PPS’
•
N otherwise.
Pharmacokinetic Analysis Set Population Flag is assigned to:
•
Y for all subjects included in the Safety Analysis Set who have at least one non-
missing ACT-33341 concentration available post-baseline
•
N otherwise.
Pharmacodynamic Analysis Set Population Flag is assigned to:




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Death variables 
Date of Death is extracted from the DS domain, where there is a record with 
Standardized Disposition Term equal to DEATH. 
Death Relative Day to EOT is computed as the number of days between the date of first 
exposure to treatment and the end of treatment date.  
Death Relative Day is computed as the number of days between the date of first 
exposure to treatment and the date of death.  
Death Dictionary-Derived Term is extracted from the Death Details domain. It is equal 
to ‘Character Result/Finding in Std Format’ where Death Detail Assessment Name equals 
to Primary Diagnosis. 
Death Reported Term is extracted from the Death Details domain. It is equal to Result 
or Finding as Collected where Death Detail Assessment Name equals to Primary 
Diagnosis. 
Screening variables 
Date of Screening is extracted from the SV domain as the start date of visit 1. 
Date of Screen Failure is extracted from the DS domain. 
Reason for Screen Failure is extracted from the DS domain. It is equal to: 
-
Subject withdrew consent, when there is a record with subcategory equal to
RANDOMIZATION 
and 
a 
Standardized 
Disposition 
Term 
equal 
to
WITHDRAWAL BY SUBJECT,
-
Subject not eligible, when there is a corresponding record in the DS domain with
a Standardized Disposition Term equal to SCREEN FAILURE and a Reported
Term equal to NOT ELIGIBLE PER INCLUSION/EXCLUSION CRITERIA,
-
Other, when there is a corresponding record in the DS domain with a category
equal to OTHER EVENT and a Standardized Disposition Term equal to OTHER.
Reason Spec for Screen Failure is extracted from the DS domain. It is equal to the 
Reported Term from the record with a category equal to OTHER EVENT and a 
Standardized Disposition Term equal to OTHER.  
Conditional (if there is at least one re-screening visit performed) 
Date of Re-Screening is extracted from the SV domain as the start date of visit 1.1 
End of treatment variables 
End of Treatment Date is derived from DS domain where category equals to 
DISPOSITION EVENT epoch equals to TREATMENT. 
End of Treatment Day is computed as the number of days between the date of first 
exposure to treatment and the end of treatment date.  


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End of Treatment Status is defined as Completed, Discontinued or Ongoing. It is equal 
to: 
-
Ongoing, as long as there is no corresponding record in the DS domain
-
Completed, when there is a corresponding record in the DS domain with a
Standardized Disposition Term equals to COMPLETED
-
Discontinued, when there is a corresponding record in the DS domain with a
Standardized Disposition Term not equals to COMPLETED.
End of study variables 
End of Study Date is derived from DS domain where category equals to DISPOSITION 
EVENT, subcategory equals to STUDY and epoch equals to FOLLOW-UP. 
End of Study Day is computed as the number of days between the date of first exposure 
to treatment and the end of study date.  
End of Study Status is defined as Completed, Discontinued or Ongoing. It is equal to: 
-
Ongoing, as long as there is no corresponding record in the DS domain
-
Completed, when there is a corresponding record in the DS domain with a
Standardized Disposition Term equals to COMPLETED
-
Discontinued, when there is a corresponding record in the DS domain with a
Standardized Disposition Term not equals to COMPLETED.
Accidental unblinding variables 
Unblinding category is populated, if there is a record in DS with a Standardized 
Disposition Term equals to equal UNBLINDED TREATMENT, with the contents of the 
Category for Disposition Event. 
Unblinding date/ time is populated, if there is a record in DS with a Standardized 
Disposition Term equals to equal UNBLINDED TREATMENT, with the contents of the 
Start date/ time of the Disposition Event. 
Event that Triggered the Request is populated, if there is a record in DS with a 
Standardized Disposition Term equals to equal UNBLINDED TREATMENT, with the 
contents of the Reported Term for the Disposition Event. 
Action Taken Following the Unblinding is populated, if there is a record in DS with a 
Standardized Disposition Term equals to equal UNBLINDED TREATMENT, with the 
Data Value where the Variable Qualifier Name is equal to DSACNOTH. 
11.2.3 Protocol Deviations Data  
This dataset contains information from Protocol Deviations (DV) Domain and its 
supplemental domain, in an Occurrence Data Structure (OCCDS). 
The presence of deviations affecting the assessment the efficacy leads to exclusion from 
the PPS. The following codes have been selected:  


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Please note: 
•
If a subject is excluded from the PDS then he is also excluded from the PPS.
Rationale: Insufficient pharmacodynamic effect is unlikely to show e.g. clinical
improvement, but will confound the results.
•
 If a subject presents with such protocol deviation (specifically,
pregnancy test not performed 3 weeks apart), but no pregnancy occurred and all
subsequent pregnancy tests were consistently negative during the trial, the subject
can be included into the PPS.
Rationale: Biologically this subject is not different from included subjects.
However, an important protocol deviation has to be reported.
•
: If a subject presents with such protocol deviation, but the change
of the immunologically active medication occurred at or after EOT, the subject
can be included in the PPS.
Rationale: The primary endpoint compares the change from baseline to EOT.
11.2.4 Concomitant medications Data 
This dataset regroups information from Concomitant/Prior Medications (CM) and its 
supplemental domain, in an Occurrence Data Structure (OCCDS).  
Previous therapy flag is equal to Y when the therapy is reported on the corresponding 
eCRF ‘Previous Non SLE Therapies’ page (corresponds to Category equal to 
‘GENERAL’ and Subcategory equal to ‘PRIOR’)  
Concomitant therapy flag is equal to Y when the therapy is reported on the 
corresponding eCRF ‘Concomitant Medication’ page (Category equal to ‘GENERAL’ 
and Subcategory equal to ‘CONCOMITANT’)  
Previous SLE therapies flag is equal to Y when the therapy is reported on the 
corresponding eCRF ‘Previous SLE Therapies’ page (Category equal to ‘SLE SPECIFIC’ 
and Subcategory equal to ‘PRIOR’)  


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Concomitant (Background) SLE therapy flag is equal to Y when the therapy is 
reported on the corresponding eCRF ‘Background SLE Therapies’ page (Category equal 
to ‘SLE SPECIFIC’ and Subcategory equal to ‘CONCOMITANT’)  
11.2.5 Study treatment exposure and compliance  
11.2.5.1 Exposure  
This dataset regroups information from Exposure (EX) Domain and its supplemental 
domain, in a Basic Data Structure (BDS).  
The following parameters are defined: 
Re-initiation performed is defined to Y if there is more than one record in the EX 
domain with Group ID equals to ‘DAY 1 /RE-INITIATION’, equals to N otherwise.  
Study treatment duration (days) is defined as the number of days between start of 
study treatment and permanent treatment discontinuation of study treatment (both 
inclusive), regardless of interruption, i.e.,  
Latest end date of Treatment -  Earliest start date of treatment intake +1. 
It is also categorized as (non-exclusive mutually): at least 1 day, at least 1 week (7 days), 
at least 4 weeks (28 days), at least 8 weeks (56 days) and at least 11 weeks (77 days). 
Study treatment duration (days), excluding interruptions, is defined as the total number 
of days of all treatment intervals (end date of interval minus start date of interval + 1 [in 
days], excluding overlaps). 
11.2.5.2 Compliance (based on drug accountability) 
This dataset regroups information from Drug Accountability (DA) Domain and its 
supplemental domain, in a Basic Data Structure (BDS).  
11.2.6 Pharmacodynamic data 
This dataset contains information from Laboratory Test Findings (LB) domain in a BD 
structure. It is limited to the parameter named ‘Lymphocyte’ as measured by the central 
laboratory.  
Baseline, Absolute value at each post-baseline assessment, Absolute and percent 
change from baseline to each post-baseline assessment variables are populated as 
described in the general section.  
11.2.7 Adverse event data 
This dataset contains information from Adverse Events (AE), its supplemental domain 
and Healthcare Encounters (HO) domain in an Occurrence Data Structure. 






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•
Time from SLE diagnosis (years) to informed consent signature is calculated as
follows: (Informed consent date - date of SLE diagnosis)/365.25.
•
Number of SLE symptoms according to ACR criteria [ACR 1997] met in the past
is calculated for each subject as the number of observations with Event Pre-Specified
equal to Y and Occurrence equal to Y and End Relative to Reference Time Point
equal to BEFORE.
•
Number of SLE symptoms according to ACR criteria [ACR 1997] started more
than 6 months prior to screening is calculated for each subject as the number of
observations with Event Pre-Specified equal to Y and Occurrence equal to Y and Did
it start more than 6 months prior? equal to Y.
•
Number of SLE symptoms according to ACR criteria [ACR 1997] ongoing at
screening is calculated for each subject as the number of observations with Event
Pre-Specified equal to Y and Occurrence equal to Y and End Relative to Reference
Time Point equal to ONGOING.
•
Number of SLE symptoms according to ACR criteria [ACR 1997] met either
serially or simultaneously is calculated for each subject as the number of
observations with Event Pre-Specified equal to Y and Occurrence equal to Y.
For each Number of SLE symptoms computed, the analysis value is further
categorized in 0-3 and 4-11.
•
Presence of a documented historical positive ANA is equal to Y when there is at
least one observation in LB Domain with Group ID equal to ‘PREVIOUS
TESTINGS’ and Lab Test or Examination Short Name equal to ‘ANA’.
•
Presence of a documented historical positive anti-dsDNA is equal to Y when there
is least one observation  in LB Domain with Group ID equal to ‘PREVIOUS
TESTINGS’ and Lab Test or Examination Short Name equal to ‘ADSDNA’.
11.2.10 
Discharge from hospital data 
The dataset is an extraction from the HO domain (Reported terms equal to 
‘HOSPITALIZATION AT RANDOMIZATION’), merged to its supplemental domain, 
in a basic data structure. 
The following parameters/ analysis value are defined: 
Actual time from first study treatment intake to discharge (hours) is calculated as 
follows: (date/ time of first study treatment intake - date/ time of discharge)/ 3600. 
Time from first study treatment intake to discharge is defined as follows: 
•
Equal to ‘6 hours’ when the answer to ‘Was the subject discharge at 6h after study
drug intake?’ is equal to ‘Yes’,




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abnormality is derived on the subject level at the following time points: from 1 hour post-
dose on Day 1 up to discharge, from discharge on Day 1 through EOT  and at any time 
post-baseline.  
There is also a parameter defined corresponding to the interpretation of the cardiologist. 
Additional comments he may have are extracted from the Comments (CO) Domain.  
11.2.12 
12-lead ECG, findings data
The dataset contains the observations extracted from the EG Domain with Category 
equals to ‘FINDING’ and Method equals to ‘12 LEAD STANDARD’, in an occurrence 
data structure. Each finding is mapped now into an event. 
Findings are considered ‘Treatment Emergent’ if the date/time of the ECG is after the 
first study treatment intake. 
11.2.13 
24 hour Holter-ECG, parameters data 
This dataset contains, in a basic data structure, only 2 tests extracted from EG Domain for 
Method equal to ‘12 LEAD HOLTER’:  
•
‘ECG Mean Heart Rate’, on observations with Category equal to
‘MEASUREMENT’ and Subcategory equal to ‘DIARYP’ (Diary Period)
•
‘Holter Overall Interpretation’
For parameter equal to ‘Mean Heart Rate (bpm)’, the following variables are defined: 
Analysis Flag  
If several ECG (ECG reference ID) are available for ‘V1 - Screening visit’, only the most 
recent is taken into account (Group ID equal to ‘‘REPEAT’). 
Analysis time point 
For Holters performed during screening period, the analysis time point for each hourly 
measurement is defined with respect to the study treatment intake on Day 1. Let’s assume 
a Holter (screening) starting on 05-FEB-2017 at 11:03 and a first study treatment intake 
on 03-MAR-2017 at 10:53. On Day 1, the 1st hour starts at 10:53 and ends at 11:53. It is 
time-matched with the screening record starting at 11:03 and ending at 12:03.  
For Holters performed on day 1, the analysis time point for each hourly measurement is 
defined with respect to the study drug intake. It is equal to 0 for records with a start time 
of the interval prior to time of study drug intake.  
Absolute change from baseline (time-matched change from Visit 1 (Screening) to Visit 
2 (Randomization/ Day 1)’ ) is defined as post-baseline value minus baseline value for 
each hourly time-matched measurement, i.e., a positive sign indicates an increase as 
compared to baseline.  






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Some parameters being assayed in the serum and in the urine (assay and dipstick), 
parameters need to be renamed depending on Category, Method and Specimen Type: 
The parameter code (no longer than 8 characters) corresponds to: 
•
the Test Code for Category equal to ‘CHEMISTRY’, ‘COAGULATION’ and
‘HEMATOLOGY’,
•
the concatenation of ‘U’ and the Test Code for Category equal to
‘URINALYSIS’,
•
the concatenation of ‘UD’ and the Test Code for Category equal to
‘URINALYSIS’ and Method equal to ‘DIPSTICK’.
The parameter corresponds to the concatenation of: 
•
the Category,
•
the Lab Test or Examination Name,
•
the Standard Units in brackets.
For the parameters assayed as a continuous variable, Baseline, Absolute value at each 
post-baseline assessment, Absolute and percent change from baseline to each post-
baseline assessment variables are populated as described in the general section. 
For the parameters assayed as a categorical variable (e.g., Protein), the analysis value is 
defined only as a character value.  
Analysis Reference Range Indicator is derived to identify marked abnormalities 
according the Adapted table 5 from the study protocol [included in Section 15]. It is only 
defined for results coming from the central laboratory, it is based on the normal range 
indicator provided by ACM (L, LL, H, HH) and augmented or modified according to the 
adapted table 5. 
11.2.16 
Exploratory biomarker data 
This dataset contains the following parameters, assayed by the central laboratory, except 
for Blood lymphocyte subsets, from the LB Domain, mapped into a basic data structure.  
Baseline is defined as the last non-missing value (numeric result in standard units) before 
date and time of first dose intake of double-blind treatment. Values below the lower limit 
of quantification (for example: LLQ = 2) recorded as “< LLQ” are set to half that limit 
(i.e., LLQ/2). Values recorded above or equal the upper limit of quantification are set to 
the upper limit. No imputation is performed for values recorded greater than the ULQ.  
Baseline value in categories is defined from numeric and character results in standard 
units using the categorization depicted in the corresponding sections. 
Analysis value is defined as the value at the visit (numeric result in standard units). 
Values below the lower limit of quantification (for example: LLQ = 2) recorded as “< 








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11.2.17 
Vital Signs Data 
This dataset contains information from the Vital Signs (VS) Domain, mapped into a basic 
data structure.  
11.2.17.1 Blood pressure  
For Supine SBP / DBP (mmHg): 
Baseline is defined as the mean (computed in the eCRF) of the 2 measurements 
performed on Visit Day 1, at pre-dose (Category equal to ‘MEAN’). If missing, it is 
replaced by the last non missing value recorded prior to the first dose.  
Analysis value is defined as the value at the visit/ time point (numeric result in standard 
units). For assessments performed on Visit Day 1, after pre-dose, the analysis value at the 
time point is retrieved from the record available. For all visits performed after Day 1, the 
analysis value is retrieved from the record populated with VSCAT = ‘MEAN’. 
Abnormalities, as defined in table ‘treatment emergent notable abnormalities’ are 
populated for each post-baseline assessment individually. In addition, the occurrence of 
at least one ‘Low’ and at least one ‘High’ treatment-emergent abnormality is derived on 
the subject level for the following time intervals: on Day 1 (from 1 hour post-dose up to 
discharge), after Day 1 (from discharge on Day 1 through Visit 7 (EOS)) and at any time 
post-baseline.  
For Standing SBP / DBP (mmHg), only the Analysis value at the visit is populated. 
11.2.17.2 Body weight 
For Body weight (kg), Baseline, Absolute value at each post-baseline analysis visit 
and Absolute change from baseline to each post-baseline analysis visit variables are 
populated as described in the general section. 
11.2.18 
Questionnaires Data 
This dataset contains information from the Questionnaire (QS) Domain and its 
supplemental domain, mapped into a basic data structure.  
•
Modified Systemic Lupus Erythematosus Activity Index-2000 (SLEDAI-2K)
The QS Domain contains the 23 individual descriptors but also the total SLEDAI-2K 
score and the combined musculoskeletal and mucocutaneous manifestations subscores.  
Two additional parameters are created: 
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. It can be 
computed by summing up the standardized result for each descriptor.  


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The Muscoloskeletal Score is defined as the weighted sum of each of the individual 
descriptors for the applicable organ class, i.e. arthritis and myositis. It can be computed 
by summing up the standardized result for each descriptor.  
The usual Baseline, Absolute value at each post-baseline analysis visit, Absolute and 
percent change from baseline to each post-baseline analysis visit variables are defined 
for the total score and for the 3 sub-scores based on the numeric result (standardized).  
The Baseline Category is defined, for the total score only, as ‘≥ 6’ and ‘< 6’. 
The Occurrence of an increase from baseline > 3, > 6, > 12 are defined, for the total 
score only, at each visit, based on the absolute change from baseline. 
•
Physician’s Global Assessment of disease (PGA)
The QS Domain contains the original value recorded on the eCRF (length from 0 to 100 
mm) and the standardized value (from 0.00 to 3.00).
The usual Baseline, Absolute value at each post-baseline analysis visit, Absolute and 
percent change from baseline to each post-baseline analysis visit variables are defined 
based on the numeric result (standardized).  
•
36-Item Short Form Health Survey v2 (SF 36v2™) questionnaire
The QS Domain contains the original value (decode format) recorded on the eCRF (eg., 
‘Excellent’, ‘All of the time’) and the standardized value as specified in the SF-36 v2 
manual.  
Cenerimod: AC-064A201 SAP Version 1
90 of 139


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The latest set of ‘best’ values carrying the highest FVC (L), with the highest 
quality, is retained for analysis.  
If more than one set of ‘best’ values is done on the same day then an ‘Acceptable’ 
test is taken in preference to a ‘Borderline’ test. If all sets on one day have the 
same quality (BTR Grade Code equal to ‘Acceptable’ or ‘Borderline’) then the 
highest value is taken. If after this, there are still two sets with either the same 
value and the same quality then the last set using the time of assessment is used. 
-
After first study drug administration
The first set of ‘best’ values carrying the highest FVC (L), with the highest
quality, is retained for analysis.
If more than one set of ‘best’ values is done on the same day then an ‘Acceptable’
test is taken in preference to a ‘Borderline’ test. If all sets on one day have the
same quality (BTR Grade Code equal to ‘Acceptable’ or ‘Borderline’) then the set
of ‘best’ values carrying the lowest FVC (L) is taken.
For each parameter, the Baseline Value is extracted from the same set of ‘best’ values 
identified thanks to the Analysis Record Flag defined above. It can be defined as the 
highest of the best value(s) populated by the independent central reader (Sponsor-Defined 
Identifier equal to ‘0’) on valid assessments (BTR Grade Code equal to ‘Acceptable’ or 
‘Borderline’) performed before first study treatment intake. If more than one set of tests 
is done on the same day then an ‘Acceptable’ test is taken in preference to a ‘Borderline’ 
test. If all tests on one day have the same quality (BTR Grade Code equal to ‘Acceptable’ 
or ‘Borderline’) then the highest value is taken. If after this, there are still two tests with 
either the same value and the same quality then the last test using the time of test is used. 
For each parameter, the Analysis value is extracted from the same set of ‘best’ values 
identified thanks to the Analysis Record Flag defined above. It can be defined as the 
best value populated by the independent central reader (Sponsor-Defined Identifier equal 
to ‘0’) on valid assessments (BTR Grade Code equal to ‘Acceptable’ or ‘Borderline’) at 
each post-baseline visit. If several best values of the same quality are available at the 
same visit, the highest value is taken in preference to a highest value (i.e., the value 
leading to the lowest change from baseline). 
Absolute and percent change from baseline to each post-baseline analysis visit 
variables are populated as described in the general section (except for Predicted FVC (L) 
and Predicted FEV1 (L) which hold constant values). 
For FVC (L) and FEV1 (L), for each post-baseline assessment, if the percent change from 
baseline is lower than -15%, the criterion ‘Decrease from baseline > 15%’ is populated to 
Y.  
11.2.20 
Pharmacokinetics Concentrations Data 
The dataset contains the information from the Pharmacokinetics Concentration (PC) and 
its supplemental domain, in a basic data structure. 








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14 REFERENCES 
[Cenerimod IB] Investigator’s Brochure for cenerimod, version 7. Actelion 
Pharmaceuticals, January 2017. 
[Bretz 2005] Bretz F, Pinheiro JC, Branson M. Combining Multiple Comparisons and 
Modeling Techniques in Dose-Response Studies; Biometrics 2005; 61; 738-748. 
[Clopper 1934] Clopper CJ, Pearson ES. The use of confidential or fiducial limits 
illustrated in the case of the binomial. Biometrika 1934; 26:404-413. 
[Nikpour 2009] Nikpour M, Urowitz MB, Ibanez D, Gladman DD. Frequency and 
determinants of flare and persistently active disease in systemic lupus 
erythematosus. Arthritis & Rheumatism 2009 Sep 15;61(9):1152–8. 
[Nuttall 2013] Nuttall A, Isenberg DA. Assessment of disease activity, damage and 
quality of life in systemic lupus erythematosus: new aspects. Best Pract Res Clin 
Rheumatol. 2013 Jun; 27(3):309-18. 


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15 APPENDICES 
15.1 Protocol Synopsis 
A. 
TITLE 
A multicenter, randomized, double-blind, placebo-controlled, 
dose-response study to investigate the biological activity, 
safety, tolerability, and pharmacokinetics of ACT-334441 in 
subjects with systemic lupus erythematosus. 
OBJECTIVES 
Main objectives 
•
To investigate the pharmacodynamics (PD) of ACT-
334441 
in 
adult 
subjects 
with 
systemic 
lupus
erythematosus (SLE).
•
To investigate the safety and tolerability of ACT-
334441 in adult subjects with SLE.
Exploratory objectives 
•
To investigate the pharmacokinetics (PK) of ACT-
334441 in adult subjects with SLE.
•
To investigate the effect of ACT-334441 treatment on
disease activity in adult subjects with SLE.
DESIGN 
Prospective, 
multicenter, 
multinational, 
randomized, 
double-blind, 
placebo-controlled, 
two-part, 
dose-response 
Phase 1/2 study.  
This study is divided in two parts:  
•
Part A: Four parallel treatment groups (including
0.5 mg, 1 mg, or 2 mg of ACT-334441 and placebo
control).
An interim safety review will be conducted by the Independent 
Data Monitoring Committee (IDMC) when all subjects enrolled 
into Part A have completed Visit 4, unless prematurely 
discontinued. The IDMC will then evaluate the safety profile of 
ACT-334441 in SLE patients and give a recommendation 
whether or not to continue the study as planned (i.e., proceed to 
Part B).   
•
Part B: Two parallel treatment groups (including 4 mg
ACT-334441 and placebo control).
Note: Subjects enrolled in Part A are not eligible to participate 


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in Part B. 
PERIODS 
There will be three periods in Part A and Part B. 
Screening period:  
This period starts up to 30 days before randomization and 
includes the Screening visit and the pre-randomization 
assessments.  
Treatment period: 
The treatment period will last 12 weeks. Visits during the 
treatment period will consist of a Randomization visit and 
visits at Weeks 2, 4, 8, and 12.  
The End-of-Treatment (EOT) visit will take place at Week 
12, or earlier in case of premature discontinuation of study 
treatment. In all cases, the EOT visit should take place 1 day 
after the last dose of study treatment but no later than 7 days 
after the last dose of study treatment. 
Follow-up period: 
Subjects will undergo an End-of-Study (EOS) Visit 6 weeks 
after the last dose of study treatment.  
Follow-up assessments via telephone calls will be performed 11 
weeks and 16 weeks after the last dose of study treatment to 
evaluate potential serious adverse events (SAEs) and to assess 
pregnancy status (urine test).    
STUDY 
DISCONTINUATION 
CRITERIA AND STUDY-
SPECIFIC 
CRITERIA 
FOR INTERRUPTION / 
CLINICAL STUDY STOP 
Study treatment discontinuation 
At any time during the double-blind treatment period, subjects 
meeting 
the 
study-specific 
criteria 
for 
permanent 
discontinuation of study treatment as described in Sections 
5.1.9 and 5.1.10 are to be permanently discontinued from study 
treatment and will perform EOT and EOS visits and will be 
followed up for a total of 16 weeks after last study treatment 
intake (telephone calls follow-up for pregnancy and SAEs). 
Study-specific criteria for interruption / stopping of the 
clinical study or Part B 
•
Part A: if 12 or more subjects out of the planned 36
subjects in the combined active treatment groups (0.5, 1,
or 2 mg) or 6 or more subjects out of the planned 12
subjects in the high dose group (2 mg) have been
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individual patient’s stopping rules as defined per safety 
area of interest [see Section 9.3], the entire study will be 
put on hold. A detailed safety signal assessment and 
recommendations from IDMC and Health Authorities 
may allow a potential restart of the study. 
•
Part B: if 4 or more subjects out of the planned
12 subjects in the active treatment group (4 mg) have
been discontinued study treatment due to meeting any of
the individual patient’s stopping rules as defined per
safety area of interest [see Section 9.3], all subjects
included in Part B will stop study treatment. A detailed
safety signal assessment and recommendations from
IDMC and Health Authorities may allow a potential
restart of the Part B.
PLANNED DURATION 
Part A: Approximately 11 months from First subject-First visit 
(FSFV) to Last Subject-Last Visit (LSLV). 
Part A and B: Approximately 20 months from FSFV to LSLV. 
SITE(S) 
/ COUNTRY(IES) 
Approximately 21 sites notably in the USA, Russia and Europe. 
SUBJECTS / GROUPS 
Part A: Approximately 48 subjects will be randomized 
(1:1:1:1) via an interactive response technology (IRT) system to 
one of four groups (i.e., 12 subjects in each group; three dose 
levels of 0.5 mg, 1 mg, or 2 mg ACT-334441, or placebo once 
daily [o.d.]). 
Part B: Approximately 16 subjects will be randomized (3:1) 
via an IRT system to one of two groups (i.e., 12 subjects 
receiving 4 mg ACT-334441 and 4 receiving placebo o.d.). 
INCLUSION CRITERIA 
1. Signed informed consent prior to initiation of any
study-mandated procedure.
2. Men or women ≥ 18 and ≤ 65 years of age.
3. Women of childbearing potential as defined in Section
4.5.1:
•
must have a negative serum pregnancy test at
Screening and a negative urine pregnancy test at
Randomization at least 3 weeks apart;
•
must agree to undertake a urine pregnancy test as
indicated in Table 1 (bi-weekly/ monthly) during


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the study and up to 16 weeks after study treatment 
discontinuation; 
•
must use methods of contraception, as described in
Section 4.5.2, from the Screening visit until
16 weeks after study treatment discontinuation.
4. Presenting with a 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 (criteria are cumulative and do not need to
be present concurrently) [Tan 1982; Hochberg 1997].
5. Presenting with a Systemic Lupus Erythematosus Disease
Activity Index-2000 (SLEDAI-2K) score of at least 2 points
for musculoskeletal or mucocutaneous manifestations (i.e.,
myositis, arthritis, rash, alopecia, mucosal ulcers) at
Screening.
6. History or presence at Screening of positive anti-nuclear
antibodies 
(ANA) 
or 
anti-double-stranded 
DNA
(anti-dsDNA) antibodies.
7. Currently treated for at least 30 days prior to Randomization
with stable doses of one or more of the following
background medications:
•
Non-steroidal anti-inflammatory drugs (NSAIDs),
•
Corticosteroids (≤ 10 mg/day prednisolone or
equivalent),
•
Anti-malarials (≤ 400 mg/day hydroxychloroquine,
≤ 500 mg/day chloroquine, ≤ 100 mg/day
quinacrine)#,
•
Mycophenolate mofetil (≤ 2 g/day)#,
•
Azathioprine (≤ 2 mg/kg/day)#,
•
Methotrexate (≤ 20 mg/week)#.
#Treatment 
with 
anti-malarials, 
mycophenolate 
mofetil, 
azathioprine, or methotrexate must have been started at least 
90 days prior to Randomization and must not have been stopped 
within 30 days prior to Randomization. 
EXCLUSION CRITERIA 
Pregnancy and breastfeeding 
1. Breastfeeding, pregnant women or women planning to
become pregnant during the study.
SLE disease 
2. Subjects with active lupus nephritis (defined by proteinuria
>
1 
g/24 
h, 
or 
equivalent 
using 
spot 
urine


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protein-to-creatinine 
ratio) within 
90 
days 
prior 
to 
randomization; subjects with central nervous system lupus 
(e.g., 
aseptic 
meningitis, 
seizures, 
cerebritis, 
polyneuropathy, cerebrovascular disease) within 90 days 
prior to Randomization; subjects with lupus vasculitis 
within 90 days prior to Randomization. 
3. Subjects presenting with a SLEDAI-2K score > 12 at
Screening or at Randomization.
Cardiovascular 
4. History or presence of cardiac rhythm disorders (e.g.,
sinoatrial 
heart 
block, 
second- 
or 
third-degree
atrioventricular block, symptomatic bradycardia, atrial
flutter or atrial fibrillation, ventricular arrhythmias, cardiac
arrest).
5. Resting heart rate (HR) < 55 bpm as measured by the
pre-dose 12-lead electrocardiogram (ECG) on Day 1; an
increased QT corrected for HR on the basis of Fridericia’s
formula (QTcF) interval of > 470 ms (females), > 450 ms
(males) at Screening, or on Day 1 ECG prior to study
treatment initiation.
6. History or presence of ischemic heart disease.
7. History or presence of myocarditis or endocarditis.
8. Presence of valvular heart disease associated with
symptoms or hemodynamic change.
9. History of syncope associated with cardiac disorders.
10. History or presence of cardiac failure.
11. Systemic arterial hypertension not controlled by medication
according to investigator judgment.
12. History or presence of vascular thrombosis at any time or a
history of pregnancy morbidity in the context of
anti-phospholipid antibody syndrome within 5 years prior to
Randomization.
13. Clinically relevant hypotension according to investigator’s
judgment or orthostatic hypotension (i.e., > 20 mmHg
decrease in systolic blood pressure [SBP] or > 10 mmHg
decrease in diastolic blood pressure [DBP] from supine to
standing position measured between 1 and 3 minutes after
standing) at Screening.
14. Known pulmonary arterial hypertension of functional
class III or IV.
Pulmonary 
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pulmonary fibrosis, based on medical history, lung function 
and chest X-ray (CXR) performed at Screening or within 3 
months prior to Screening. 
16. Bronchial asthma or chronic obstructive pulmonary disease.
17. Abnormal pulmonary function tests: forced expiratory
volume in 1 second (FEV1) or forced vital capacity (FVC) <
70% of predicted normal value; FEV1/FVC ratio <0.7.
Treatments 
18. Treatment or planned treatment with the following
medications*:
a.
Within 15 days or 5 half-lives of the medication,
whichever is longer, prior to Randomization:
o β-blockers, diltiazem, verapamil, digoxin
or 
any 
other 
anti-arrhythmic 
or 
HR-lowering systemic therapy (list of 
drugs provided in Appendix 1). 
o QT-prolonging drugs with known risk of
torsades de pointes, for any indication 
(list of drugs provided in Appendix 2). 
o Short- and long-acting β2-agonists (e.g.,
albuterol, levalbuterol, formoterol, 
terbutaline salmeterol). 
b. Within 30 days or 5 half-lives of the medication,
whichever is longer, prior to Randomization:
o Cyclophosphamide, cyclosporine,
tacrolimus, sirolimus, etc., 
o Pulse methylprednisolone
o Vaccination with live vaccines.
c.
Within 90 days prior to Randomization:
o Belimumab, leflunomide,
o Any investigational immunosuppressive
or immunomodulatory agent (within 
90 days or 5 half-lives of the drug prior 
to start of study treatment, whichever is 
longer).  
d. Within 12 months prior to Randomization:
o B cell-depleting biological agents such as
rituximab or ocrelizumab. 
e.
Any time prior to Randomization:
o Alemtuzumab, sphingosine-1-phosphate
(S1P) modulators (e.g., fingolimod). 


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*For immunosuppressants or anti-inflammatory drugs not listed
among the fordidden medications, the investigator should
discuss adequate wash-out time with the sponsor.
Infection and infection risk
19. Active or latent tuberculosis (TB), as assessed by CXR
performed at Screening or within 3 months prior to
Screening, 
and 
interferon 
gamma 
release 
assay
(QuantiFERON-TB-Gold®) at Screening, except if there is
documentation that the subject has completed adequate and
successful treatment for latent TB infection or TB disease
previously.
20. Ongoing known bacterial, viral or fungal infection that is of
clinical concern in the judgment of the investigator.
21. A 
history 
of 
any 
serious 
infection, 
defined 
as
life-threatening or requiring intravenous (i.v.) antibiotics or
hospitalization, within 30 days prior to Randomization.
22. Hepatitis B and C, congenital or acquired severe
immunodeficiency or known human immunodeficiency
virus (HIV) infection or positive HIV testing at Screening.
23. Negative antibody test for varicella-zoster virus at
Screening.
Malignancy 
24. History or presence of malignancy (except for surgically
excised 
basal 
or 
squamous 
cell 
skin 
lesions),
lymphoproliferative disease, or history of total lymphoid
irradiation.
Transplantation 
25. History or presence of bone marrow or solid organ
transplantation.
Ophthalmology 
26. Presence of macular edema or active uveitis.
Metabolic and hepatic
27. 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.
28. Moderate or severe hepatic impairment defined as Child
Pugh Score B or C, respectively, based on measurement of
total bilirubin 
(TBL), 
serum 
albumin, 
international
normalized ratio, as well as on presence/absence and
severity of ascites and hepatic encephalopaty.
29. TBL > 1.5-fold upper limit of normal (ULN; unless in the
context of known Gilbert’s Syndrome).


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30. Alanine 
aminotransferase 
(ALT) 
or 
aspartate
aminotransferase (AST) > 2-fold ULN.
Hematology 
31. Hemoglobin < 9 g/dL.
32. White blood cell count < 2500/µL (2.5 × 109/L).
33. Lymphocyte count < 800 /µL (0.8 × 109/L).
34. Platelets < 75,000/µL (75 × 109/L).
Renal
35. Proteinuria > 1.0 g/24 hour or equivalent using spot urine
protein-to-creatinine ratio.
36. Estimated glomerular filtration rate < 60 mL/min/1.73 m2.
Other categories
37. History of clinically significant drug or alcohol abuse.
38. Known allergy to S1P receptor 1 modulators or any of the
ACT-334441 formulation excipients.
39. Any other clinically relevant medical or surgical condition
that in the opinion of the investigator would put the subject
at risk if participating in the study.
40. Subjects 
unlikely 
to 
comply 
with 
protocol,
e.g., uncooperative attitude, inability to return for follow-up
visits or likelihood of not completing the study, including
mental condition rendering the subject unable to understand
the nature, scope, and possible consequences of the study.
STUDY TREATMENTS 
Investigational treatment 
ACT-334441 0.5 mg, 1 mg, 2 mg capsules for Part A, and 4 mg 
capsules for Part B, administered orally o.d. in the morning. 
Placebo 
Placebo matching ACT-334441 capsules administered orally 
o.d. in the morning.


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CONCOMITANT 
THERAPY 
Allowed concomitant therapy 
•
i.v. atropine in the event of symptomatic bradycardia
[see 
study-specific 
criteria 
for 
permanent
discontinuation of study treatment in Section 5.1.10;
•
Dilating 
eye 
drops, 
mydriatics, 
including
parasympathetic antagonists (e.g., tropicamide) or
sympathetic agonists (e.g., phenylephrine) for topical
use;
•
Vaccination with non-live vaccines;
•
Stable systemic corticosteroid therapy; corticosteroids
are not to be started or stopped during the study, and the
dose should be kept stable. However, the investigator
may see reason to initiate or increase the dose of
systemic corticosteroid to treat an SLE flare or another
condition. In such cases, the dose may be increased for a
period of not more than 14 days up to double the
baseline dose or a maximum of 20 mg/day prednisolone
or equivalent (please refer to conversion table in
Appendix 8);
•
Topical treatment therapy including topical use of
corticosteroid;
•
Stable antimalarial therapy (e.g., hydroxychloroquine,
chloroquine, quinacrine); therapy is not to be started or
stopped during the study, and dose should be kept
stable;
•
Stable NSAID chronic 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). Therapy is not
to be started or stopped during the study, and dose
should be kept stable.
Forbidden concomitant medication 
•
Immunosuppressives not listed in allowed concomitant
medication such as cyclophosphamide, cyclosporine,


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leflunomide, sirolimus, tacrolimus, etc.; 
•
Immunosuppressive or immunomodulatory biological
agents 
(e.g., 
belimumab, 
i.v. 
immunoglobulin,
rituximab, S1P modulators other than ACT-334441);
•
β-blockers, diltiazem, verapamil, digoxin, or any other
anti-arrhythmic or HR-lowering therapy (as listed in
Appendix 1);
•
QT-prolonging drugs with known risk of torsades de
pointes (list of drugs provided in Appendix 2);
•
Short- and long-acting β2-agonists (e.g., albuterol,
levalbuterol, formoterol, terbutaline salmeterol);
•
Vaccination with live vaccines.
ENDPOINTS 
Pharmacodynamic endpoints 
•
Change in total lymphocyte count from baseline to EOT
•
Change in total lymphocyte count from baseline to each
post-baseline assessment
Safety endpoints 
The treatment-emergent period is defined as the time from first 
study treatment intake up to 6 weeks (inclusive) after last study 
treatment intake. 
•
Treatment-emergent adverse events (AEs), SAEs, and
adverse events of special interest (AESI#);
•
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 Bazzett’s formula
[QTcB] and QT corrected for HR on the basis of
Fridericia’s formula [QTcF]), from pre-dose to selected
post-dose assessments (1 h, 2 h, 3 h, 4 h, 5 h, 6 h) on
Day 1 and on day of study drug re-initiation;
•
Occurrence of treatment-emergent 12-lead ECG outliers
(e.g., HR, PR, QTc defined in the Statistical Analysis
Plan [SAP]);
•
Occurrence 
of 
treatment-emergent 
12-lead 
ECG
abnormalities;
•
Occurrence 
of 
treatment-emergent 
ECG-Holter


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abnormalities on Day 1; 
•
Change in SBP and DBP from baseline up to EOS;
•
Change in FEV1 and FVC, expressed in absolute value
(L) and percent value from baseline up to EOS;
•
Occurrence of treatment-emergent decrease of FEV1 or
FVC > 15% from baseline values;
•
Change in laboratory parameters (hematology, blood
chemistry, and urinalysis) from baseline up to EOS;
•
Treatment-emergent laboratory abnormalities according
to CTCAE 2010 v4.03 [CTCAE 2010] and Food and
Drug Administration (FDA) guidelines [FDA 2009] (for
ALT/AST/TBL);
•
Change in protein-to-creatinine ratio from baseline to
EOT;
•
Change in body weight from baseline to EOT.
#AESI considered for the analyses are described in Appendix 3. 
Pharmacokinetic endpoints 
•
Ctrough ACT-334441 plasma concentrations prior to
dosing at Weeks 2, 4, 8, and 12 (EOT) or at EOT visit
after premature study treatment discontinuation (if
applicable);
•
ACT-334441 plasma concentration at EOS (i.e., 6 weeks
after study treatment discontinuation).
Exploratory disease activity endpoints 
•
Change in SLEDAI-2K score from baseline to each
post-baseline assessment;
•
Change in Physician’s Global Assessment (PGA) score
from baseline to each post-baseline assessment;
•
Change 
in 
SLEDAI-2K 
mucocutaneous 
and/or
muscoskeletal scorings from baseline to each post-
baseline assessment.
Quality of life endpoints 
•
Change in SF-36v2™ Health Survey domain and


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component scores from baseline to EOT. 
Exploratory biomarker endpoints 
•
Change in immunoglobulin serum levels (IgG, IgM,
IgA) from baseline to each post-baseline assessment;
•
Change in ANA and anti-dsDNA antibody titers from
baseline to each post-baseline assessment;
•
Change in serum complement components C3 and C4,
C-reactive protein, fibrinogen, B lymphocyte stimulator
and C-X-C motif chemokine 10 from baseline to each
post-baseline assessment;
•
Change in blood lymphocyte subsets from baseline to
EOT and EOS.
ASSESSMENTS 
Refer to the schedule of assessments in Table 1. 
STATISTICAL 
METHODOLOGY 
All statistical analyses will be conducted by Actelion or by 
designated Contract Research Organizations supervised by 
Actelion. 
The SAP will be finalized prior to database lock. 
Baseline is defined as the last assessment prior to initiation of 
the study treatment. 
Analysis sets 
Screened Analysis Set: includes all subjects who were screened 
and received a subject number. 
Safety Analysis Set: includes all randomized subjects who 
received at least one dose of study treatment. Unless otherwise 
stated, any analysis using the Safety Analysis Set will use all 
available safety data up to 6 weeks after discontinuation of 
study treatment. Subjects will be analyzed based on actual dose 
taken, not the randomized dose. 
PD Analysis Set: includes all subjects who received at least 
3 weeks of study treatment and have at least one lymphocyte 
count measurement between the Week 4 visit and Week 12 
visit. Subjects will be analyzed according to the treatment they 
received. 
Full Analysis Set (FAS): includes all randomized subjects. 
Subjects will be analyzed according to their randomized 


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treatment. 
Per-Protocol Set (PPS): defined as subjects from the FAS 
without any major protocol deviations. Major protocol 
deviations are described in Section 11.2.4.  
PK Analysis Set: includes all randomized subjects who received 
at least one ACT-334441 dose and provided at least one blood 
sample for PK evaluation. Subjects will be analyzed based on 
actual dose taken, not the randomized dose.  
Pharmacodynamic variable 
The change in lymphocyte count from baseline to EOT is 
defined as:  
•
Total lymphocyte count at EOT – total lymphocyte
count at baseline
Last observation carried forward (LOCF; using the Week 4 visit 
or later) will be used for subjects with a missing EOT 
assessment.  
Exploratory disease activity variables 
The change from baseline in the SLEDAI-2K (modified to 
exclude leukopenia) score at each visit is calculated as : 
•
SLEDAI-2K score at each visit – SLEDAI-2K score at
baseline.
The change from baseline in PGA score and the SLEDAI-2K 
mucocutaneous and/or muscoskeletal score will be calculated in 
a similar manner. 
Overall testing strategy for the pharmacodynamic endpoint 
An optimized contrast test according to the Multiple 
Comparison Procedure (MCP)-Mod approach [Bretz 2005] for 
each considered dose-response model will be performed. The 
existence of dose-response effects will be tested using the 
maximum of the model-based contrast tests. Multiplicity 
adjusted p-values will be calculated using the Dunnett-
distribution.  
Pharmacodynamic endpoint analysis 
Null and alternative hypotheses 
The null hypothesis is that there is no dose response in terms of 


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lowering of lymphocyte count (p, which is a negative value for 
a lowering of the lymphocyte count) from baseline to EOT, 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, 2, 4 mg 
If Part B of the trial is not performed, the hypothesis 
will be 
𝐻0: 𝑝𝑑≥ 𝑝𝑃𝑙𝑎𝑐𝑒𝑏𝑜 for all doses d = 0.5, 1, 2 mg 
vs 
𝐻1: 𝑝𝑑< 𝑝𝑃𝑙𝑎𝑐𝑒𝑏𝑜 for at least 1 dose d =0.5, 1, 2 mg 
To meet the objective of demonstrating existence of a 
dose response of ACT-334441 on the lymphocyte count 
reduction from baseline in subjects with SLE, the null 
hypotheses must be rejected by the test with a one-
sided significance level of 5%.  
Main pharmacodynamic analysis 
The MCP-Mod approach consists of a set of optimized contrast 
tests for establishing the existence of dose-response effects. The 
overall strategy is described as follows: 
Definition of a set of likely dose response relations (see sample 
size section for more details): 
•
Maximum effect (Emax) with 50% of the maximum effect
at dose 0.2 mg
•
Emax with 50% of the maximum effect at dose 0.4 mg
•
Emax with 50% of the maximum effect at dose 1.0 mg
•
Quadratic with maximum effect at dose 3.0 mg (only if
the 4 mg dose is studied)
•
Sigmoid-Emax with 50% of the maximum effect at dose
0.4 mg and 95% of the maximum effect at dose 2.0 mg
The existence of dose-response effects will be assessed with the 
optimized contrast tests. Dose-response effects are established 
at one sided level α=5%, if the following condition on the p 
value holds for at least one contrast i: 𝑝𝑖: = 1 −𝐹𝛴𝐷𝑢𝑛𝑛𝑒𝑡𝑡 (𝑍𝑖) <
0.05, where 𝐹𝛴𝐷𝑢𝑛𝑛𝑒𝑡𝑡 describes the Dunnett-distribution with 


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correlation matrix 𝛴𝐷𝑢𝑛𝑛𝑒𝑡𝑡. 
The model with the minimum p-value will be fitted to the data. 
As a sensitivity analysis, all remaining significant models will 
be fitted to the data and model-based dose estimates will be 
calculated. 
Given established dose-response effects with MCP-
Mod, PD effects will be analyzed based on pairwise 
comparisons of reduction in lymphocyte count from 
baseline for each active dose levels to placebo using an 
analysis of covariance (ANCOVA) model adjusted for 
baseline lymphocyte counts. Testing will be done with a 
two-sided significance level of 5%. The type-1 error will 
be controlled via a hierarchical ordering of the tests: 
pairwise comparison will be conducted in decreasing 
dose order.  
The dose-response data will be summarized with point-wise and 
model-based estimates, standard deviation and 95% confidence 
intervals (CI) on the reduction in lymphocytes from baseline at 
the examined dose levels. A plot of the estimated dose response 
curve with 95% credibility interval limits will be presented 
along with the observed response at each dose. 
This analysis will be performed on the PD analysis set, 
and a supportive analysis will be performed on the FAS 
and the PPS.  
Exploratory efficacy endpoint analysis 
The exploratory efficacy endpoint change from baseline in 
SLEDAI-2K score at Week 12 will be analyzed using an 
ANCOVA, with treatment and baseline score as factors. 
Missing values at Week 12 will be imputed using LOCF. The 
mean treatment difference including 95% CI for each 
ACT-334441 dose compared to placebo will be presented. A 
sensitivity analysis will be performed using observed data 
without imputation. 
Other changes from baseline variables will be analyzed in a 
similar manner using an ANCOVA. 
All exploratory efficacy endpoints will be analyzed on the FAS 
and PPS populations. 


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No multiplicity adjustments will be made on exploratory 
efficacy endpoints.  
Safety endpoints 
Safety endpoints will be mainly analyzed descriptively by 
treatment group on the Safety Set. 
Sample size 
The sample size for the study was determined based on 
simulations. A maximum % lymphocyte reduction compared to 
baseline of 70% was assumed based on results obtained in 
Phase 1 with ACT-334441 and with other S1P receptor 
modulators. A sample size of 64 subjects (12 in each 
ACT-334441 dose group of 0.5 mg, 1 mg, 2 mg, 4 mg, and 
16 in the placebo group) would provide an average power of at 
least 90% to show a significant dose response relationship at a 
one-sided significance level of 5%, under the assumption of a % 
lymphocyte reduction compared to baseline of 0% (mean at 
Week 12 = 2.0 × 109/L) for placebo and a maximum of 70% for 
any ACT-334441 dose (mean at Week 12 = 0.6 × 109/L). The 
pooled SD is assumed to be 0.45 × 109/L. This takes into 
account 10% of subjects being excluded from the PD analysis 
set.  
If Part B is not conducted and the 4 mg dose is not tested, then 
there will be an average power of at least 80% to show a 
significant dose-response relationship with three dose levels at a 
one-sided significance level of 5%, using the same assumptions 
as above (based on a total sample size of 48 subjects [12, 12, 12 
and 12 in placebo, 0.5 mg, 1 mg and 2 mg, respectively]). 
Assumptions on the placebo response rate, maximum effect 
sizes and candidate dose-response models are based on the 
observed lymphocyte count in study AC-064-101. 
STUDY COMMITTEES 
Independent Data Monitoring Committee 
An IDMC has the overall responsibility for safeguarding the 
interests of subjects by monitoring data obtained in the study in 
an unblinded fashion and making appropriate recommendations 
based on the reported data, thus ensuring that the study is being 
conducted with the highest scientific and ethical standards. The 
IDMC will be fully operational prior to enrolment of the first 
subject into the study. The IDMC will review unblinded data at 


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regular intervals, will provide recommendation to apply study 
stopping rules (if indicated) and in addition will review interim 
safety data collected when all subjects enrolled into Part A have 
completed Visit 4 (Week 4), unless prematurely discontinued 
[see Section 11.5]. The composition and operation of the IDMC 
is described in the IDMC charter. 
Ophthalmology Safety Board 
An Ophthalmology Safety Board (OSB) composed of two 
independent ophthalmologists will review and evaluate in a 
blinded fashion any new or suspected case of macular edema. 
The composition and operation of the OSB is described in the 
OSB charter. 
15.2 Discussion and further considerations of the applied statistical methods 
15.2.1 Clinical laboratory evaluation 
Table 16 
Clinical laboratory evaluation: Marked abnormalities in laboratory 
parameters (adapted from Table 5 from the Clinical Study Protocol) 
Category 
Test 
Code 
Test Name 
Standard 
Unit 
Se
x 
LLL 
LL 
LO 
HI 
HH 
HHH 
CHEMISTRY 
ALB 
Albumin  
g/L  
< 20  
< 30 
35 
52 
71 
NA 
CHEMISTRY 
ALP 
Alkaline 
Phosphatase  
U/L  
F 
NA 
NA 
42 
98 
> 2.5 
ULN
> 5 
ULN
CHEMISTRY 
ALP 
Alkaline 
Phosphatase  
U/L  
M 
NA 
NA 
53 
129 
> 2.5 
ULN 
> 5 
ULN
CHEMISTRY 
ALT 
Alanine 
Aminotransfera
se  
U/L  
F 
NA 
NA 
0 
33 
≥ 3 
ULN 
≥ 5 
ULN 
CHEMISTRY 
ALT 
Alanine 
Aminotransfera
se  
U/L  
M 
NA 
NA 
0 
44 
≥ 3 
ULN 
≥ 5 
ULN 
CHEMISTRY 
AST 
Aspartate 
Aminotransfera
se  
U/L  
F 
NA 
NA 
14 
34 
≥ 3 
ULN 
≥ 5 
ULN 
CHEMISTRY 
AST 
Aspartate 
Aminotransfera
se  
U/L  
M 
NA 
NA 
14 
39 
≥ 3 
ULN 
≥ 5 
ULN 


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Category 
Test 
Code 
Test Name 
Standard 
Unit 
Se
x 
LLL 
LL 
LO 
HI 
HH 
HHH 
CHEMISTRY 
BILI  
Bilirubin  
umol/L  
NA 
NA 
5.1 
20.5 
≥ 2 
ULN 
≥ 5 
ULN 
CHEMISTRY 
BUN  
Blood Urea 
Nitrogen 
mmol/L  
NA 
NA 
3.2 
8 2 
20.5 
41.0 
CHEMISTRY 
CA  
Calcium  
mmol/L  
< 1.75  
< 2.0  
2.15 
2 55 
> 2.9 
> 3.1 
CHEMISTRY 
CHOL  
Cholesterol 
mmol/L  
NA 
NA 
0 
5 2 
> 7.75
> 
12.92  
CHEMISTRY 
CL  
Chloride  
mmol/L  
NA 
74 
99 
109 
131 
NA 
CHEMISTRY 
CREAT  
Creatinine  
umol/L  
F 
NA 
NA 
44 
97 
> 1.5 
ULN 
or >
1 5 × 
baselin
e 
> 3
ULN 
or > 3 
×
baselin
e 
CHEMISTRY 
CREAT  
Creatinine  
umol/L  
M 
NA 
NA 
62 
115 
> 1.5 
ULN 
or >
1 5 × 
baselin
e 
> 3
ULN 
or > 3 
×
baselin
e 
CHEMISTRY 
GRFE 
Creatinine 
Clearance  
mL/min/1.73
m2  
<30  
<60  
60 
NA. 
NA 
NA 
CHEMISTRY 
GLUC 
Glucose  
mmol/L  
< 2.2  
< 3.0  
3.3 
5 5 
> 8.9 
> 13.9
CHEMISTRY 
K  
Potassium  
mmol/L  
< 3.0  
< 3.2  
3.5 
5 1 
> 5.5 
> 6.0 
CHEMISTRY 
LDH 
Lactate 
Dehydrogenase  
U/L  
NA 
NA 
120 
246 
>=524 
NA 
CHEMISTRY 
PROT  
Protein  
g/L  
NA 
39 
64 
83 
101 
NA 
CHEMISTRY 
SODIUM 
Sodium  
mmol/L  
< 130  
NA 
136 
145 
> 150
> 155
CHEMISTRY 
TRIG  
Triglycerides 
mmol/L  
NA 
NA 
0 
1.68 
> 3.42
> 11.4
CHEMISTRY 
URATE 
Urate  
umol/L  
F 
NA 
NA 
137 
393 
> 590 
> 720
CHEMISTRY 
URATE 
Urate  
umol/L  
M 
NA 
NA 
262 
452 
> 590 
> 720
COAGULATI
ON 
APTT  
Activated 
Partial 
Thromboplastin 
Time  
sec 
NA 
14.0 
24 
37 
> 1.5 - 
2 5 × 
ULN 
> 2.5 ×
ULN 


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Category 
Test 
Code 
Test Name 
Standard 
Unit 
Se
x 
LLL 
LL 
LO 
HI 
HH 
HHH 
COAGULATI
ON 
FIBRINO 
Fibrinogen  
g/L  
< 0.25 
LLN or 
< 75% 
decreas
e from 
baselin
e or 
absolut
e value 
< 0.5 
< 0.75 
- 0.5
LLN or
25 - < 
50%
decreas
e from 
baselin
e
2.1 
4.7 
6.0 
NA 
COAGULATI
ON 
INR 
Prothrombin 
Intl. 
Normalized 
Ratio 
Fraction of 1 
NA 
NA 
0.8 
1 2 
≥ 1.5 
ULN 
≥ 2.5 
ULN 
COAGULATI
ON 
PT  
Prothrombin 
Time  
sec 
NA 
NA 
9.4 
13 
NA 
100.1 
HEMATOLOG
Y  
EOS 
Eosinophils 
10e9/L  
NA 
NA 
0 
0 5 
> 5.0
ND 
HEMATOLOG
Y  
HCT  
Hematocrit  
L/L 
F 
< 20 
< 28  
0.36
4 
0.48
9 
> 55 
> 65 
HEMATOLOG
Y  
HCT  
Hematocrit  
L/L 
M 
< 20 
< 32  
0.41
6 
0 54
1 
> 60 
> 65 
HEMATOLOG
Y  
HGB 
Hemoglobin  
g/L  
F 
< 80 
g/L  
< 100 
g/L  
115 
160 
Increas
e in > 
20 g/L 
above 
ULN 
or 
Increas
e in > 
20 g/L 
above 
baselin
e (if 
baselin
e is 
above 
ULN) 
Increas
e in > 
40 g/L 
above 
ULN 
or 
Increas
e in 
>40g/L 
above 
baselin
e (if
baselin
e is
above 
ULN)


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Category 
Test 
Code 
Test Name 
Standard 
Unit 
Se
x 
LLL 
LL 
LO 
HI 
HH 
HHH 
HEMATOLOG
Y  
HGB 
Hemoglobin  
g/L  
M 
< 80  
< 100 
130 
175 
Increas
e in > 
20 g/L 
above 
ULN 
or 
Increas
e in > 
20 g/L 
above 
baselin
e (if 
baselin
e is 
above 
ULN) 
Increas
e in > 
40 g/L 
above 
ULN 
or 
Increas
e in > 
above 
baselin
e (if 
baselin
e is 
above 
ULN) 
HEMATOLOG
Y  
NEUT  
Neutrophils  
10e9/L  
< 1.0  
< 1.5 
1.8 
7.7 
15.4 
NA 
HEMATOLOG
Y  
PLAT  
Platelets 
10e9/L  
< 50.0  
< 75 
130 
400 
> 600 
> 999 
HEMATOLOG
Y  
RBC  
Erythrocytes 
10e12/L 
NA 
NA 
3.8 
5 2 
NA 
NA 
HEMATOLOG
Y  
RBC  
Erythrocytes 
10e12/L 
M 
NA 
NA 
4.5 
5 9 
NA 
NA 
HEMATOLOG
Y 
WBC 
Leukocytes 
10e9/L 
F 
< 1.9  
NA 
4.5 
11.0 
> 20.0
> 
100.0  
HEMATOLOG
Y 
LYM 
Lymphocytes 
10e9/L 
< 0.2  
NA 
1.00 
4.80 
> 4.0 
≥ 8 
URINALYSIS 
PROT  
Protein  
mg/L  
NA 
NA 
10 
140 
1000 
3500 
URINALYSIS 
PROTCR
T  
Protein/Creatini
ne  
g/mol  
NA 
NA 
1.1 
12.1 
>100 
>300 
URINALYSIS 
PROTCR
T  
Protein/Creatini
ne  
g/mol  
NA 
NA 
1.7 
7.7 
>100 
>300 


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15.2.2 Definitions of AEs of special interest, S1P1 compounds (09-Sep-2016) 
The definitions for adverse events of special interest are based on systematic approach 
using Standardized MedDRA Queries (SMQ).  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 19.0. The following safety areas are addressed by 
the pre-defined adverse events of special interest: 
•
Effect on heart rate and rhythm AESI (including hypotension)
Effect on heart rate and rhythm AESI are identified by the preferred terms in the 
following SMQ: Bradyarrhythmias (incl conduction defects and disorders of sinus 
node function) (SMQ). In addition, to the preferred terms included in Bradyarrhythmias 
(including conduction defects and disorders of sinus node function (SMQ)), the following 
preferred terms will be added to the search for AEs addressing effects on heart rate and 
rhythm: 
“BRADYCARDIA”, 
“ELECTROCARDIOGRAM 
RR 
INTERVAL 
PROLONGED”, 
“HEART 
RATE 
DECREASED”, 
“CHRONOTROPIC 
INCOMPETENCE”, 
“PRESYNCOPE”, 
“SYNCOPE” 
and 
“LOSS 
OF 
CONSCIOUSNESS”.   
The following preferred terms 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 
FLUCTUATION”, “LABILE BLOOD PRESSURE” and “BLOOD PRESSURE 
AMBULATORY DECREASED”.  
•
Cardiovascular AESI
Cardiovascular AESI are identified by any preferred term in the following SMQs: 
Ischemic heart disease (SMQ) or Cardiomyopathy (SMQ) or Cardiac failure (SMQ) 
excluding the preferred term “DYSPNOEA” .  
•
Hypertension AESI
Hypertension AESI are identified by the preferred terms in the following SMQ: 
Hypertension (SMQ) 
•
Hepatobiliary disorders / Liver enzyme abnormality AESI


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Hepatobiliary disorders/ Liver enzyme abnormality AESI are identified by the preferred 
terms in the following SMQ: Drug related hepatic disorders - comprehensive search 
(SMQ) This SMQ is included in the SMQ Hepatic disorder (SMQ) but only the preferred 
terms included in Drug related hepatic disorders - comprehensive search (SMQ) are 
included to identify hepatobiliary disorders / Liver enzyme abnormality AESI. 
•
Pulmonary AESI
These AEs are identified by the preferred terms the in the following SMQs: 
Asthma/bronchospasm (SMQ) or Interstitial lung disease (SMQ). The preferred terms 
“DYSPNOEA AT REST”, “DYSPNOEA” and “DYSPNOEA EXERTIONAL” are 
added to the search pre-defined by SMQs Asthma/bronchospasm or Interstitial lung 
disease.  SMQs related to respiratory system do not cover the preferred terms on 
investigations (i.e., AEs based on PFT or chest X Ray or CT scan). Therefore, any 
preferred term from the MedDRA System Organ Class (SOC) ‘Investigations’ identified 
by the following high level terms (HLT) are added to the search: ‘Respiratory tract and 
thoracic histopathology procedures’ (HLT) or ‘Respiratory tract and thoracic 
imaging procedures’ (HLT) and ‘Respiratory and pulmonary function diagnostic 
procedures’ (HLT) with the exception of the following preferred terms: 
‘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’. 
•
Macular edema AESI
Macular edema AESI are identified by the following preferred terms:  “MACULAR 
OEDEMA”, “MACULAR HOLE”, “MACULAR PSEUDOHOLE”, “MACULAR 
RUPTURE”, “MACULAR CYST”, “RETINAL OEDEMA”, “DIABETIC RETINAL 
OEDEMA”, 
“CYSTOID 
MACULAR 
OEDEMA”, 
“PAPILLOEDEMA”, 
and 
“PSEUDOPAPILLOEDEMA”. 
•
Infection AESI
Infection AESI are identified by the adverse events belonging to the SOC (System Organ 
Class) Infections and Infestations (SOC), only if reported as serious or severe. 


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Doc D-17.230 
•
Herpetic infection AESI
Herpetic infection AESI are identified by the preferred terms in the following high level 
terms: Herpes viral infections (HLT) and the following preferred term will be added to 
the search for AEs addressing varicella zoster infection: “ENCEPHALITIS POST 
VARICELLA”, “HERPES GESTATIONIS”, “HERPES SIMPLEX TEST POSITIVE”, 
“HUMAN HERPES VIRUS 6 SEROLOGY POSITIVE”, and “HUMAN HERPES 
VIRUS 8 TEST POSITIVE”. 
•
Skin malignancy AESI
Skin malignancy AESI are identified by the preferred terms in the following SMQs: Skin 
neoplasmsm malignant and unspecified (SMQ) or Skin premalignant disorders 
(SMQ). 
•
Non-skin malignancy AESI
Non-skin malignancy AESI are identified by the preferred terms in the following SMQ: 
Malignant tumours excluding the preferred terms included in the following SMQs: Skin 
neoplasms, malignant and unspecified (SMQ) or Skin premalignant disorders 
(SMQ). 
•
Stroke AESI
Stroke AESI are identified by any preferred term in the following SMQ: Central 
nervous system haemorrhages and cerebrovascular conditions (SMQ). This SMQ 
consists of 3 following SMQs: Conditions associated with central nervous system 
haemorrhages and cerebrovascular accidents (SMQ), Haemorrhagic cerebrovascular 
conditions (SMQ) and Ischaemic cerebrovascular conditions (SMQ).  
•
Seizure AESI
Seizure AESI are identified by any preferred term in the following SMQ: Convulsions 
(SMQ). 




ACT-334441 
Study AC-064A201 
20 April 2017, page 122/125 
Confidential 
Statistical Analysis Plan 
Doc D-17.230 


ACT-334441 
Study AC-064A201 
20 April 2017, page 123/125 
Confidential 
Statistical Analysis Plan 
Doc D-17.230