Multicenter, Non-comparative Extension of Study AC-058B301, to Investigate the Long-term Safety, Tolerability, and Control of Disease of Ponesimod 20 mg in Subjects With Relapsing Multiple Sclerosis
Phase: PHASE3
Conditions: Multiple Sclerosis
Sponsor: Actelion

Actelion Pharmaceuticals Ltd
(a Janssen Pharmaceutical Company of Johnson & Johnson)*
CONFIDENTIAL - FOIA Exemptions Apply in U.S.
Ponesimod/ ACT-128800 / JNJ-67896153
Relapsing Multiple Sclerosis
Protocol AC-058B303
OPTIMUM-LT
Multicenter, non-comparative extension to study AC-058B301, to investigate the long-term
safety, tolerability, and control of disease of ponesimod 20 mg in subjects with relapsing
multiple sclerosis
Study Phase: 
3
EudraCT Number: 
2016-004719-10
Status and version: 
Approved;Version 6
Date: 
15March 2022
EDMS No.: 
EDMS-ERI-207656619; 7.0
* Actelion Pharmaceuticals Ltd (“Actelion”) is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Actelion studies may vary, such as, but not
limited to Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; or Janssen Research &
Development, LLC. The term “sponsor” is used throughout the protocol to represent these various legal entities; the
sponsor is identified on the Contact Information page that accompanies the protocol.
Confidentiality statement
The information provided herein contains Company trade secrets, commercial or financial information that the
Company customarily holds close and treats as confidential. The information is being provided under the assurance
that the recipient will maintain the confidentiality of the information under applicable statutes, regulations, rules,
protective orders or otherwise.
NCT03232073

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SPONSOR CONTACT DETAILS
SPONSOR  
Actelion Pharmaceuticals Ltd.*
Gewerbestrasse 16
CH-4123 Allschwil
Switzerland
 
+41 61 565 65 65
Clinical Trial Physician 
Contact details of the Clinical Trial Physician can
be found in the Investigator Site File
MEDICAL HOTLINE 
Site-specific toll telephone numbers and toll-free
numbers for the Medical Hotline can be found in
the Investigator Site File
ACTELION CONTRIBUTORS TO THE PROTOCOL
Clinical Leader 
Study Responsible Physician  
Principal Scientist 
Trial Statistician  
Medical Safety Officer 
* Actelion Pharmaceuticals Ltd. is a Janssen pharmaceutical company of Johnson & Johnson and
is hereafter referred to as the sponsor of the study.
PPD
PPD
PPD
PPD
PPD

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CONTRACT RESEARCH ORGANIZATIONS INFORMATION
CENTRAL LABORATORY 
CENTRAL ENROLLMENT  
CENTRAL MRI 
READING  
CENTRAL ECGs READING 
A list of site-specific contact details for Contract Research Organizations (CROs) can be found
in the Investigator Site File.
PPD
PPD
PPD
PPD

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Relapsing multiple sclerosis
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TABLE OF CONTENTS
SPONSOR CONTACT DETAILS.................................................................................................. 2
ACTELION CONTRIBUTORS TO THE PROTOCOL.................................................................2
CONTRACT RESEARCH ORGANIZATIONS INFORMATION ...............................................3
TABLE OF CONTENTS................................................................................................................. 4
LIST OF TABLES......................................................................................................................... 12
LIST OF FIGURES ....................................................................................................................... 12
LIST OF APPENDICES................................................................................................................ 12
LIST OF ABBREVIATIONS AND ACRONYMS ......................................................................13
GLOBAL AMENDMENT 5......................................................................................................... 17
PROTOCOL SYNOPSIS AC-058B303........................................................................................ 22
1 
BACKGROUND..................................................................................................................... 39
1.1 
Multiple sclerosis...................................................................................................... 39
1.1.1 
Pathogenesis.................................................................................................. 39
1.1.2 
Clinical course .............................................................................................. 39
1.1.3 
Epidemiology................................................................................................ 41
1.1.4 
Treatment of MS........................................................................................... 41
1.1.4.1 
Injectable disease-modifying therapies ...............................................41
1.1.4.2 
Orally administered disease-modifying therapies...............................42
1.2 
Sphingosine-1-phosphate receptors..........................................................................42
1.3 
Ponesimod ................................................................................................................ 43
1.3.1 
Nonclinical studies........................................................................................43
1.3.2 
Clinical studies.............................................................................................. 44
1.3.2.1 
Clinical pharmacology ........................................................................44
1.3.2.2 
Pharmacodynamics in humans............................................................44
1.3.2.3 
Efficacy in humans..............................................................................45
1.3.2.4 
Safety and tolerability .........................................................................46
1.4 
Purpose and rationale of the study............................................................................48
2 
STUDY OBJECTIVES........................................................................................................... 49

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2.1 
Safety objectives....................................................................................................... 49
2.2 
Efficacy objectives ................................................................................................... 49
3 
OVERALL STUDY DESIGN AND PLAN...........................................................................49
3.1 
Study design ............................................................................................................. 49
3.2 
Study periods............................................................................................................ 49
3.2.1 
Core study follow up period and transition into the extension study...........49
3.2.2 
Pre-treatment period .....................................................................................50
3.2.3 
Treatment period........................................................................................... 50
3.2.3.1 
End-of-treatment .................................................................................51
3.2.4 
Safety follow-up ...........................................................................................51
3.2.5 
Sub-studies.................................................................................................... 52
3.2.5.1 
Pulmonary function monitoring ..........................................................52
3.2.5.2 
Janssen COVID-19 vaccination sub-study..........................................53
3.3 
Study design rationale .............................................................................................. 53
3.4 
Site staff and their roles............................................................................................ 53
3.4.1 
Principal Investigator....................................................................................54
3.4.2 
Treating neurologist...................................................................................... 54
3.4.3 
Efficacy assessor........................................................................................... 55
3.4.4 
First-dose administrator................................................................................56
3.4.5 
Clinical coordinator / study nurse.................................................................56
3.4.6 
MRI staff....................................................................................................... 57
3.4.7 
Local neurologist/radiologist or neurologist with MRI expertise.................57
3.4.8 
Ophthalmologist............................................................................................ 57
3.4.9 
Pulmonary function laboratory technician or expert ....................................58
3.4.10 
Pulmonologist............................................................................................... 58
3.4.11 
Dermatologist................................................................................................ 58
3.5 
Study committees ..................................................................................................... 58
3.5.1 
Independent Data Monitoring Committee....................................................58
3.5.1.1 
Independent Statistical Analysis Center..............................................58
3.5.2 
Ophthalmology Safety Board .......................................................................59
3.5.3 
Major adverse cardiovascular events adjudication board.............................59
4 
SUBJECT POPULATION...................................................................................................... 59
4.1 
Subject population description................................................................................. 59
4.2 
Inclusion criteria....................................................................................................... 59
4.3 
Exclusion criteria...................................................................................................... 60
4.4 
Subjects of reproductive potential............................................................................61
4.4.1 
Women of childbearing potential .................................................................61
4.4.2 
Fertile male subject.......................................................................................62
4.5 
Medical history......................................................................................................... 62

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4.5.1 
Ongoing medical history from the core study ..............................................62
4.5.2 
Additional medical history not reported in the core study............................62
4.5.3 
MS disease history........................................................................................62
4.5.4 
MS disease changes ......................................................................................63
5 TREATMENTS ...................................................................................................................... 63
5.1 
Study treatment......................................................................................................... 63
5.1.1 
Investigational treatment: description and rationale.....................................63
5.1.2 
Study treatment administration.....................................................................63
5.1.2.1 
Up-titration (performed by IVRS).......................................................63
5.1.2.2 
Maintenance ........................................................................................64
5.1.3 
Treatment assignment...................................................................................64
5.1.4 
Blinding ........................................................................................................ 65
5.1.5 
Study treatment supply.................................................................................65
5.1.5.1 
Study treatment packaging and labeling .............................................65
5.1.5.2 
Study treatment distribution and storage.............................................65
5.1.5.3 
Study treatment dispensing .................................................................65
5.1.5.4 
Study treatment return and destruction ...............................................65
5.1.6 
Study treatment accountability and compliance with study treatment.........66
5.1.6.1 
Study treatment accountability............................................................66
5.1.6.2 
Study treatment compliance................................................................66
5.1.7 
Accelerated elimination of teriflunomide and duration of continued
contraception................................................................................................. 66
5.1.8 
Study treatment dose adjustments and interruptions ....................................67
5.1.9 
Guidance for re-initiation of study treatment in the event of study treatment
interruption.................................................................................................... 67
5.1.10 
Criteria for discharge from cardiac monitoring on Day 1, and on the first day
of re-initiation of the investigational study treatment following treatment
interruptions.................................................................................................. 70
5.1.11 
Premature discontinuation of study treatment..............................................70
5.1.12 
Study-specific criteria for interruption / premature discontinuation of study
treatment and management of clinically relevant events..............................71
5.1.12.1 
Cardiovascular.....................................................................................71
5.1.12.2 
Hematological abnormalities...............................................................72
5.1.12.3 
Respiratory system..............................................................................75
5.1.12.4 
Pregnancy............................................................................................77
5.1.12.5 
Planned pregnancy ..............................................................................77
5.1.12.6 
Liver abnormalities..............................................................................79
5.1.12.7 
Ocular abnormalities ...........................................................................81
5.2 
Concomitant therapy................................................................................................. 82
5.2.1 
Recommended concomitant therapy.............................................................82

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Relapsing multiple sclerosis
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5.2.2 
Allowed concomitant therapy.......................................................................82
5.2.3 
Forbidden study-treatment-concomitant therapy..........................................83
6 
STUDY ENDPOINTS ............................................................................................................ 84
6.1 
Efficacy endpoints.................................................................................................... 84
6.1.1 
Main clinical endpoints.................................................................................84
6.1.2 
MRI-based endpoints....................................................................................86
6.1.3 
Other endpoints............................................................................................. 86
6.2 
Safety endpoints ....................................................................................................... 86
7 
STUDY ASSESSMENTS....................................................................................................... 89
7.1 
Informed consent...................................................................................................... 89
7.2 
Demographics and medical history ..........................................................................90
7.3 
Study-concomitant therapies ....................................................................................90
7.4 
Efficacy assessments ................................................................................................90
7.4.1 
Neurological evaluation................................................................................90
7.4.2 
Detection and evaluation of relapses ............................................................91
7.4.3 
MRI evaluations............................................................................................ 94
7.4.4 
MSFC............................................................................................................ 94
7.4.5 
Symbol Digit Modalities Test.......................................................................95
7.5 
Safety assessments.................................................................................................... 95
7.5.1 
12-lead electrocardiogram ............................................................................95
7.5.2 
Blood pressure .............................................................................................. 96
7.5.3 
Body temperature.......................................................................................... 97
7.5.4 
Pulse rate....................................................................................................... 97
7.5.5 
Spirometry .................................................................................................... 97
7.5.6 
DLCO sub-study............................................................................................. 98
7.5.7 
Ophthalmologic assessments........................................................................99
7.5.8 
Optical Coherence Tomography.................................................................100
7.5.9 
Weight......................................................................................................... 100
7.5.10 
Physical examination..................................................................................100
7.5.11 
Dermatological examination.......................................................................101
7.5.12 
Laboratory assessments ..............................................................................101
7.5.12.1 
Type of laboratory.............................................................................101
7.5.12.2 
Laboratory tests.................................................................................102
7.6 
Electronic self-rated version of the Columbia-Suicide Severity Rating Scale.......104
7.7 
Quality of life assessments ..................................................................................... 105
7.7.1 
36-Item Short Form Health Survey v2 (SF-36v2™)..................................105
7.8 
Total blood volume................................................................................................. 106
8 
SCHEDULE OF VISITS ...................................................................................................... 107

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Relapsing multiple sclerosis
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8.1 
Core study follow up period and transition into the extension study.....................107
8.1.1 
Core study FU1........................................................................................107
8.1.2 
Core study abbreviated FU2....................................................................108
8.2 
Pre-treatment period............................................................................................... 108
8.2.1 
Visit 1 pre-dose........................................................................................108
8.3 
Treatment period..................................................................................................... 109
8.3.1 
Visit 1 post-dose (includes first dosing)..................................................109
8.3.2 
Visit 2 Day 15.......................................................................................... 110
8.3.3 
Visit 3 Week 4......................................................................................... 111
8.3.4 
Additional safety laboratory tests until Week 24 (Weeks 8, 16 and 20) ....112
8.3.5 
Visit 4 Week 12.......................................................................................112
8.3.6 
In-between-visit telephone calls until Week 240 (every 6 weeks).............113
8.3.7 
Visit 5 Week 24.......................................................................................113
8.3.8 
Visits 6, 8, 9, 10, 12, 13, 14, 16, 17, 18, 20, 21, 22; Weeks 36, 60, 72, 84,
108, 120, 132, 156, 168, 180, 204, 216, 228 ..............................................114
8.3.9 
Visits 7, 11, 15, 19 - Weeks 48, 96, 144, 192.............................................115
8.3.10 
EOT Visit Week 240 ...............................................................................116
8.4 
Follow-up period .................................................................................................... 118
8.4.1 
EOS Visit.................................................................................................... 118
8.5 
Unscheduled visits.................................................................................................. 119
8.5.1 
Unscheduled visits for relapses (Visits R1, R2, etc.)..................................119
8.5.2 
Unscheduled visits (any other assessment; U1, U2, U3, etc.) ....................120
8.5.3 
Additional unscheduled visits for re-initiation of study treatment (I1, I2,
etc.) ............................................................................................................. 121
8.5.4 
Additional unscheduled visit 30 days after study treatment interruption due
to planned pregnancy with intention of study treatment re-initiation
post-partum................................................................................................. 122
8.5.5 
Additional unscheduled visits for eligibility assessment for re-initiation of
study treatment for female subjects who interrupted the study treatment for
planned pregnancy and who wish to re-start the study treatment after
delivery....................................................................................................... 123
8.5.6 
Unscheduled visit for re-start of the study treatment after delivery...........125
9 
STUDY COMPLETION AND POST-STUDY TREATMENT/MEDICAL CARE ...........125
9.1 
Study completion.................................................................................................... 125
9.2 
Premature withdrawal from study ..........................................................................126
9.3 
Premature termination or suspension of the study..................................................126
9.4 
Medical care of subjects after study completion/withdrawal from study...............127
10 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS.....................................127

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10.1 
Adverse events........................................................................................................ 127
10.1.1 
Definitions of adverse events......................................................................127
10.1.2 
Intensity of adverse events..........................................................................128
10.1.3 
Relationship to study treatment ..................................................................129
10.1.4  
Adverse events associated to study design or protocol-mandated procedures
.................................................................................................................... 129
10.1.5 
Reporting of adverse events........................................................................129
10.1.6 
Reporting of MS relapse.............................................................................129
10.1.7 
Follow-up of adverse events.......................................................................130
10.2 
Serious adverse events............................................................................................ 130
10.2.1 
Definitions of serious adverse events .........................................................130
10.2.1.1 
Serious adverse events.......................................................................130
10.2.2 
Reporting of serious adverse events ...........................................................130
10.2.3 
Follow-up of serious adverse events...........................................................131
10.2.4 
After the 30-day follow-up period..............................................................131
10.2.5 
Reporting procedures..................................................................................131
10.3 
Pregnancy ............................................................................................................... 131
10.3.1 
Reporting of pregnancy ..............................................................................132
10.3.2 
Follow-up of pregnancy..............................................................................132
10.4 
Study safety monitoring.......................................................................................... 132
10.5 
Special reporting situations ....................................................................................132
10.6 
Product quality complaint handling........................................................................133
11 STATISTICAL METHODS................................................................................................. 133
11.1 
Analysis strategy..................................................................................................... 134
11.1.1 
Analysis strategy for efficacy.....................................................................134
11.1.2 
Analysis strategy for safety.........................................................................134
11.1.3 
Baseline definitions.....................................................................................134
11.1.4 
Analysis periods.......................................................................................... 135
11.1.4.1 
Extension analysis period..................................................................135
11.1.4.2 
Combined analysis period.................................................................135
11.2 
Analysis sets ........................................................................................................... 135
11.2.1 
Extension Set.............................................................................................. 135
11.2.2 
Full Analysis Set......................................................................................... 135
11.2.3 
Safety Set.................................................................................................... 135
11.2.4 
Per-Protocol Set.......................................................................................... 135
11.2.5 
Other analysis sets ......................................................................................136
11.2.6 
Usage of the analysis sets ...........................................................................136
11.3 
Variables................................................................................................................. 136
11.3.1 
Main efficacy variables...............................................................................136
11.3.1.1 
Annualized relapse rate (confirmed relapses) ...................................136

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11.3.1.2 
Time to first confirmed relapse .........................................................136
11.3.1.3 
Time to first 12 or 24-week CDA .....................................................136
11.3.1.4 
Cumulative number of combined unique active lesions ...................137
11.3.1.5 
Longitudinal percent change over time in brain volume from baseline
........................................................................................................... 137
11.3.2 
Other efficacy variables..............................................................................137
11.3.3 
Safety variables........................................................................................... 137
11.4 
Description of statistical analyses...........................................................................138
11.4.1 
Overall testing strategy...............................................................................138
11.4.2 
Analysis of the main efficacy variable .......................................................138
11.4.2.1 
Statistical model................................................................................138
11.4.2.2 
Handling of missing data...................................................................138
11.4.2.3 
Main analysis of ARR.......................................................................138
11.4.2.4 
Additional analyses of ARR..............................................................139
11.4.2.5 
Subgroup analyses.............................................................................139
11.4.3 
Time to first confirmed relapse...................................................................139
11.4.4 
Time to 12 and 24-week CDA....................................................................139
11.4.5 
Cumulative number of combined unique active lesions.............................139
11.4.6 
Percent change from baseline in brain volume...........................................139
11.4.7 
Analysis of the other efficacy variables......................................................139
11.4.8 
Analysis of the safety variables ..................................................................140
11.4.8.1 
Adverse events ..................................................................................140
11.4.8.2 
Cardiac safety....................................................................................141
11.4.8.3 
Pulmonary safety...............................................................................142
11.4.8.4 
Vital signs.......................................................................................... 143
11.4.8.5 
Laboratory endpoints.........................................................................143
11.4.8.6 
eC-SSRS............................................................................................ 143
11.4.8.7 
Other Safety Variables ......................................................................143
11.4.9 
Immunogenicity Analysis...........................................................................144
11.5 
Interim analyses...................................................................................................... 144
11.5.1 
Additional periodic analyses.......................................................................144
11.6 
Sample size............................................................................................................. 144
12 DATA HANDLING.............................................................................................................. 144
12.1 
Data collection........................................................................................................ 144
12.2 
Maintenance of data confidentiality.......................................................................145
12.3 
Database management and quality control.............................................................145
13 PROCEDURES AND GOOD CLINICAL PRACTICE.......................................................146
13.1 
Ethics and Good Clinical Practice..........................................................................146
13.2 
Independent Ethics Committee / Institutional Review Board................................146

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13.3 
Informed consent.................................................................................................... 146
13.4 
Compensation to subjects and investigators...........................................................147
13.5 
Protocol adherence/compliance..............................................................................147
13.6 
Protocol amendments ............................................................................................. 147
13.7 
Essential documents and retention of documents...................................................147
13.8 
Monitoring.............................................................................................................. 148
13.9 
Investigator site file ................................................................................................ 149
13.10 Audit....................................................................................................................... 150
13.11 Inspections.............................................................................................................. 150
13.12 
Reporting of study results and publication.............................................................150
14 REFERENCES...................................................................................................................... 152
15 APPENDICES....................................................................................................................... 155
Appendix 1 
Neurostatus® scoring sheet..........................................................................155
Appendix 2 
Guidance for concomitant treatment with QT-prolonging drugs with known
risk of Torsades de Pointes..................................................................................... 157
Appendix 3 
Prohibited anti-arrhythmic and HR-lowering drugs...................................158
Appendix 4  
Adverse events of special interest...............................................................159
Appendix 5 
Abnormalities for ECG, BP and laboratory variables ................................160
Appendix 6 
Multiple Sclerosis Functional Composite...................................................164
Appendix 7 
Symbol Digit Modalities Test.....................................................................168
Appendix 8 
Electronic self-rated version of the Columbia-Suicide Severity rating Scale
(eC-SSRS) .............................................................................................................. 169
Appendix 9 
SF-36v2™................................................................................................... 192
Appendix 10 
Relapse assessment questionnaire ..............................................................203
Appendix 11 
Relapse symptom form...............................................................................207
Appendix 12 
Guidance on study conduct during the COVID-19 (coronavirus) pandemic ...
.................................................................................................................... 211
INVESTIGATOR AGREEMENT............................................................................................... 216

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LIST OF TABLES
Table 1 
Visit and assessment schedule................................................................................32
Table 2 
Visit and assessment schedule (Part 2) ..................................................................35
Table 3 
Dosing scheme ....................................................................................................... 64
Table 4  
Guidance for subject monitoring and discontinuation for PFT decrease and
persistent respiratory AEs ...................................................................................... 76
Table 5 
Guidance for subject monitoring and discontinuation for liver enzyme
abnormalities.......................................................................................................... 80
Table 6 
Main clinical endpoints.......................................................................................... 85
Table 7 
MRI-based endpoints ............................................................................................. 86
Table 8 
Other endpoints ...................................................................................................... 86
Table 9 
Analysis of safety endpoints ..................................................................................87
Table 10 
Minimum total blood volume to be drawn per subject ........................................106
Table 11 
Thresholds for marked laboratory abnormalities .................................................161
LIST OF FIGURES
Figure 1 
Study design........................................................................................................... 52
Figure 2 
Algorithm for management of treatment interruptions ..........................................69
Figure 3 
Flow diagram for the detection and evaluation of relapses....................................93
LIST OF APPENDICES
Appendix 1 Neurostatus® scoring sheet...................................................................................155
Appendix 2 Guidance for concomitant treatment with QT-prolonging drugs with known risk
of Torsades de Pointes.......................................................................................... 157
Appendix 3 
Prohibited anti-arrhythmic and HR-lowering drugs.............................................158
Appendix 4  Adverse events of special interest........................................................................159
Appendix 5 Abnormalities for ECG, BP and laboratory variables..........................................160
Appendix 6 Multiple Sclerosis Functional Composite............................................................164
Appendix 7 Symbol Digit Modalities Test..............................................................................168
Appendix 8 
Electronic self-rated version of the Columbia-Suicide Severity rating Scale (eC-
SSRS)................................................................................................................... 169
Appendix 9 SF-36v2™............................................................................................................ 192
Appendix 10 Relapse assessment questionnaire........................................................................203
Appendix 11 Relapse symptom form......................................................................................... 207
Appendix 12 Guidance on study conduct during the COVID-19 (coronavirus) pandemic.......211

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LIST OF ABBREVIATIONS AND ACRONYMS
9-HPT  
9-Hole Peg Test
ACTH  
Adrenocorticotropic hormone
Ad26.COV2.S  
Janssen COVID-19 vaccine
AE 
Adverse event
ALT  
Alanine aminotransferase
ARR  
Annualized Relapse Rate
AST 
Aspartate aminotransferase
ATS  
American Thoracic Society
AV  
Atrioventricular
BP 
Blood pressure
bpm  
Beats per minute
CDA  
Confirmed disability accumulation
CI 
Confidence interval
CIS  
Clinically isolated syndrome
CNS  
Central nervous system
COVID-19 
coronavirus disease-2019
CRO  
Contract Research Organization
CSF  
Cerebrospinal fluid
CTCAE 
Common terminology criteria for adverse events
CUAL 
Combined unique active lesion
CYP  
Cytochrome P450
DBP  
Diastolic blood pressure
DDI 
Drug-drug interaction
DILI 
Drug-induced liver injury
DIR  
Double inversion recovery
DLCO  
Diffusing capacity for the lungs measured using carbon monoxide
DMT  
Disease-modifying therapy
DNA  
Deoxyribonucleic acid
ECG  
Electrocardiogram
eCRF  
Electronic case report form

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eC-SSRS  
Electronic self-rated version of the Columbia-Suicide Severity Rating
Scale
EDSS  
Expanded Disability Status Scale
ELISA  
Enzyme-linked immunosorbent assay
EMA  
European Medicines Agency
EOS  
End-of-Study
EOT  
End-of-Treatment
ERS  
European Respiratory Society
ETDRS  
Early Treatment Diabetic Retinopathy Study
EUA  
Emergency Use Authorization
EXTS  
Extension Set
FA  
Fluorescence angiography
FAS  
Full Analysis Set
FDA  
Food and Drug Administration
FEF  
Forced expiratory flow
FEV1 
Forced expiratory volume in 1 second
FS  
Functional system
FU  
Follow-up
FVC  
Forced vital capacity
GCP  
Good Clinical Practice
Gd 
Gadolinium
Gd 
Gadolinium-enhancing
Hb  
Hemoglobin
HIV  
Human immunodeficiency virus
HR  
Heart rate
I 
Re-initiation visit
i.m. 
Intramuscular
i.v. 
Intravenous
IB  
Investigator’s Brochure
ICF  
Informed Consent Form
ICH  
International Council for Harmonisation
IDMC  
Independent Data Monitoring Committee

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IEC  
Independent Ethics Committee
IFN  
Interferon
INR  
International Normalized Ratio
IRB  
Institutional Review Board
IRT  
Interactive response technology
ISAC  
Independent Statistical Analysis Center
ISF  
Investigator site file
JCV  
John Cunningham Virus
LT  
Long Term
M13 
ACT-338375 (ponesimod metabolite)
MACE 
Major Adverse Cardiovascular Events
MedDRA  
Medical Dictionary for Regulatory Activities
MIAC  
Medical Image Analysis Center
MRI 
Magnetic resonance imaging
MS  
Multiple sclerosis
MSFC  
Multiple Sclerosis Functional Composite
NK 
Natural killer
NMSS  
US National Multiple Sclerosis Society
o.d. 
Once a day
OCT  
Optical coherence tomography
OSB  
Ophthalmology Safety Board
P 
Pregnancy visit
PASAT  
Paced Auditory Serial Addition Test
PCBV  
Percent Change in Brain Volume
PCR  
Polymerase chain reaction
PD  
Pharmacodynamic
PFT  
Pulmonary function test
PK 
Pharmacokinetic
PML 
Progressive multifocal leukoencephalopathy
PP  
Primary progressive
PPMS  
Primary progressive multiple sclerosis
PPS  
Per-Protocol Set

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PRMS  
Progressive relapsing multiple sclerosis
QTc 
QT corrected
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
R 
Relapse visit
RMS  
Relapsing multiple sclerosis
RR  
Relapsing-remitting
RRMS 
Relapsing-remitting multiple sclerosis
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus-2
s.c. 
Subcutaneous
S1P  
Sphingosine-1-phosphate
SAE 
Serious adverse event
SAF  
Safety Set
SAP  
Statistical Analysis Plan
SBP 
Systolic blood pressure
SDMT  
Symbol Digit Modalities Test
SIV  
Site initiation visit
SPMS  
Secondary progressive multiple sclerosis
TTS  
Thrombosis with Thrombocytopenia Syndrome
U 
Unscheduled visit
ULN  
Upper limit of the normal range
VNA  
Virus neutralization assay
WOCBP  
Women of childbearing potential
WHO  
World Health Organization

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GLOBAL AMENDMENT 5
Amendment rationale
This amendment applies to global protocol AC-058B303 Version 5, dated 19 October 2020. The
resulting amended global protocol is Version 6, dated 15 March 2022, and all local protocol
versions:
 Final Version 5.GBR.A dated 22 July 2021
 Final Version 5.ESP.A dated 22 July 2021
The reasons for this amendment are:
 To update the requirement for optical coherence tomography (OCT) assessments to be
performed only in case presence of visual symptoms suggestive of macular edema or active
uveitis as consistent with observed dynamic of this event on S1P treatment.
 To acknowledge the decommission of the Ophthalmology Safety Board (OSB). The number
of cases of macular edema is expected to be low (most cases occur within the first 6 months
of treatment) and no new patients will initiate treatment in the study. Therefore, an OSB
review is no longer required and will be decommissioned for the ongoing long-term
extension studies, its status has been clarified and where appropriate reference to the OSB
has been removed.
 To correct a discrepancy in Section 8.5.2 to clarify that a sample for immunogenicity
evaluations should not be taken at unscheduled visits.
 To add clarification and description of periodic analyses in addition to interim analyses in
Section 11.5.
 Due to limited availability of COVID-19 vaccine-naïve MS patients, the COVID-19
vaccination sub-study is cancelled and removed from the protocol (Appendix 13 and
Appendix 14).
 To provide a clarification that based on available evidence (and the fact that all patients in the
study have already initiated treatment with ponesimod), additional ECG monitoring in
specific cases (ie, treatment with QT prolonging drugs) is no longer required (Sections 7.5.1,
Section 8.5.2, and Appendix 2).
 To introduce immunogenicity analyses into the statistical section (Section 11.4).
 To update the list of adverse events of special interest to include identified risks
(Appendix 4).
 To confirm the disbandment of the IDMC.
 To clarify that the EXTS will also be used for efficacy analyses of the Combined Analysis
Period in addition to the FAS (Section 11.2.6).
 Clarifications and minor corrections have been added to the protocol.

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Changes to the protocol:
Two versions of the amended protocol will be prepared: 1) a clean version, and 2) a comparison
document showing deletions and insertions in comparison to the previous protocol version.
Amended protocol sections
The main sections of the protocol affected by this amendment are listed below. Where applicable,
the same changes have also been made to the corresponding sections of the protocol synopsis:
ACTELION CONTRIBUTORS TO THE PROTOCOL
SIGNATURE PAGE FOR ACTELION PHARMACEUTICALS LTD.
Table 1 
Visit and assessment schedule
Table 2 
Visit and assessment schedule (Part 2)
3.2.5 
Sub-studies
3.2.5.2 
Janssen COVID-19 vaccination sub-study
3.4.8 
Opthalmologist
3.5.1 
Independent Data Monitoring Committee
3.5.2 
Ophthalmology Safety Board
5.1.8 
Study treatment dose adjustments and interruptions
5.1.12.7 
Ocular abnormalities
5.1.12.7.1 
Guidance for monitoring and management of subjects with uveitis
5.2.2. 
Allowed concomitant therapy
6. 
Study endpoints
7. 
Study assessments
7.5.1 
12-lead electrocardiogram
7.5.8 
Optical Coherence Tomography
7.5.12.2 
Laboratory tests
Table 10 
Minimum total blood volume to be drawn per subject
8. 
Schedule of visits
8.3.5 
Visit 4 - Week 12

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8.3.7 
Visit 5 - Week 24
8.3.9 
Visits 7, 11, 15, 19 - Weeks 48, 96, 144, 192
8.3.10 
EOT Visit - Week 240
8.4.1 
EOS Visit
8.5.2 
Unscheduled visits (any other assessment; U1, U2, U3, etc.)
8.5.4 
Additional unscheduled visit 30 days after study treatment interruption due
to planned pregnancy with intention of study treatment re-initiation post partum
9.3 
Premature termination or suspension of the study
10. 
Safety definitions and reporting requirements
10.4 
Study safety monitoring
11. 
Statistical methods
11.2.6 
Usage of the analysis sets
11.4.9 
Immunogenicity Analysis
11.5.1 
Additional periodic analyses
Appendix 4 Adverse events of special interest
Appendix 13 Protocol for the Janssen COVID-19 Vaccination (Ad26.COV2.S) Sub-study
Appendix 14 TTS Form

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Summary of previous amendments
Amendment Date 
Main reason(s)
1 
1 March 2018 
The main reason for this amendment was to modify the
pulmonary treatment discontinuation criteria based on
changes in pulmonary function variables during the study
treatment.
2 
14 May 2020 
The main reasons for this amendment were:
 To allow the analysis of biomarkers in the serum
sample taken at Visit 1 (Enrollment).
 To amend the guidance for re-initiation of study
treatment in the event of study treatment interruption
in order to allow patients without the identified
cardiovascular risk factors to re-initiate study drug at
home.
 The efficacy assessor role is no longer defined as
“independent” and, depending on site setting, can now
be assumed by the primary investigator / treating
neurologist.
 To provide guidance regarding conduct of the study
during the COVID-19 (coronavirus) pandemic.
3 
19 October 2020 The main reasons for this amendment were:
 To inform study sites that the Independent Data
Monitoring Committee (IDMC) will be disbanded
after the clinical database closure of the last
ponesimod double-blind study, in line with the
disbandment date agreed per the IDMC Charter.
 To provide further guidance on study conduct if/when
ponesimod becomes commercially available during
the study and patients are switched from study
treatment to commercially available ponesimod.
 To align the safety reporting procedures with Janssen
Safety processes and standards following the
integration of Actelion Safety into Janssen Safety.

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Amendment Date 
Main reason(s)
4 
20 July 2021 
The main reasons for this amendment were:
 To introduce vaccination sub-study for a sub-set of
subjects to investigate the immune response induced
by the Janssen COVID-19 vaccine (Ad26.COV2.S).
 Inclusion of additional serum samples for all subjects
at all scheduled visits for immunogenicity evaluations;
eg, to measure anti-severe acute respiratory syndrome
coronavirus-2 (SARS-CoV-2) antibody levels induced
by vaccination with any COVID-19 vaccination or
after recovery from COVID 19.
 Addition  of clarifications regarding conduct of the
study during the COVID-19 pandemic and the
administration of non-live and live vaccinations.
 To make updates with regard to teriflunomide testing
per the Aubagio® prescribing information.

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PROTOCOL SYNOPSIS AC-058B303
TITLE 
Multicenter, non-comparative extension of study AC-058B301, to investigate the
long-term safety, tolerability, and control of disease of ponesimod 20 mg in
subjects with relapsing multiple sclerosis
ACRONYM  
OPTIMUM-LT
OBJECTIVES
Safety objectives:
 To describe the long-term safety and tolerability of ponesimod 20 mg in
subjects with relapsing multiple sclerosis (RMS).
 To describe the effects of re-initiation of ponesimod treatment after
interruption in subjects with RMS.
Efficacy objectives:
 To describe the long-term disease control in subjects with RMS receiving
ponesimod 20 mg.
 To describe the effect of a switch from teriflunomide to ponesimod 20 mg on
disease control in subjects with RMS.
DESIGN  
Multicenter, non-comparative, single-arm, Phase 3 study, as an extension of the
AC-058B301 study
PERIODS
Pre-treatment period:
The Pre-treatment period includes all pre-dose assessments of Visit 1 and starts
when the subject completes the core study Follow-up (FU) visits FU1 or FU2
(whichever applies) and signs the informed consent. This should ideally occur on
the day of core study FU1 or FU2 (whichever applies), but no later than 1 day
after these visits. It continues until the first dosing of study treatment, which
should occur at latest 7 days after signing the informed consent.
Treatment period:
The treatment period starts with the first dose of study treatment, which defines
Day 1 (end of Visit 1) of the AC-058B303 study and post-dose assessments of
Visit 1. The treatment period may last for 240 weeks or until ponesimod is
commercially available for the treatment of MS in the subject’s country. After
Day 1, there will be visits at Day 15, Week 4, Week 12, and subsequently every
12 weeks until the End-of-Treatment (EOT).
EOT:
The EOT visit will take place at Week 240 or at the time ponesimod is
commercially available for treatment of MS in the subject’s country (whichever
occurs first).
The EOT visit should preferably take place 1 day after the last dose of study
treatment but no later than 14 days after the last dose of study treatment.

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For those subjects completing study treatment due to the availability of
commercially available ponesimod, an EOT visit should be conducted preferably
within 7 days after stopping study treatment. Commercially available ponesimod
may be initiated on the day after last intake of study treatment.
Safety follow-up / End-of-Study:
For an individual subject, End-of-Study (EOS) is reached when treatment and
30-day safety FU have been completed. The EOS Visit should be performed
30-44 days after the last dose of study treatment.
The EOS visit should also be conducted for subjects who have switched to
commercially available ponesimod.
PLANNED DURATION  
Approximately 330 weeks from First subject-First visit to Last subject-Last visit.
SITE(S)/COUNTRY(IES) 
Approximately 160 sites in 28 countries worldwide.
SUBJECTS / GROUPS  
Subjects, having completed the double-blind treatment AC-058B301 study (core
study) as scheduled and willing to participate in the AC-058B303 study
(extension study), will be enrolled into one group treated with ponesimod 20 mg.
INCLUSION CRITERIA  
1. Signed informed consent, prior to initiation of any study-mandated procedure.
2. Subjects with MS having completed the double-blind treatment in the core
study as scheduled (i.e., who completed the double-blind treatment period
until Week 108).
3. Compliance with teriflunomide elimination procedure assessed as sufficient
by the investigator at visit FU1 or abbreviated visit FU2 of the core study,
whichever occurred last.
4. For subjects of reproductive potential:
 
Women of childbearing potential (WOCBP):
– 
must have a negative pre-treatment urine pregnancy test on
Day 1;
– 
must agree to undertake 4-weekly urine pregnancy tests during
the study and until 6 weeks after the first of two consecutive
tests showing teriflunomide plasma level <0.02 mg/L and until
at least 30 days after study treatment discontinuation;
– 
must have been using reliable methods of contraception
uninterrupted since EOT in the core study and must agree to
continue using reliable methods of contraception throughout the
study until 6 weeks after the first of two consecutive tests
showing teriflunomide plasma level <0.02 mg/L and until at
least 30 days after discontinuation of study treatment.
 
Fertile male subjects participating in the study who are sexually
active with WOCBP must agree to use a condom until 6 weeks after

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the first of two consecutive tests confirming plasma teriflunomide
level <0.02 mg/L.
Definition of WOCBP, fertile male subjects and the acceptable methods of
contraception for this study are described in Section 4.4.
EXCLUSION CRITERIA  
1. Any of the following cardiovascular conditions on Day 1 pre-dose:
a. Resting heart rate <50 beats per minute as measured by the pre-dose
12-lead electrocardiogram (ECG);
b. Presence of second degree atrioventricular (AV) block or third-degree
AV block or a QT interval corrected for Fridericia’s formula >470 ms
(females), >450 ms (males) on pre-dose 12-lead ECG.
2. Any of the following alerts from central laboratory at Visit 14 of the core
study (EOT) which was confirmed as an alert at repeated testing or not
repeated prior to FU1 of the core study:
a. Lymphocyte count: <0.2 109/L (<200/mm3 blinded results);
b. Neutrophil count <1.0 × 109/L(<1000 cells/mm3);
c. Platelet count <50 × 109/L (<50 000 cells/mm3);
d. Creatinine clearance <30 mL/min (Cockroft-Gault).
3. At Visit 14 of the core study (EOT) >30% decrease from core study baseline
forced expiratory volume in 1 second and/or forced vital capacity.
4. Clinically significant, persistent respiratory adverse events (AEs; e.g.,
dyspnea) not resolved prior to first dosing in the extension study.
5. Macular edema at any time between Visit 1 (Screening) in the core study and
Day 1 of the extension study.
6. Presence of the following at core study Visit 14 (EOT, Week 108), FU1, or
abbreviated visit FU2, or on Day 1 of the extension study pre-dose:
a. Suspected opportunistic infection of the central nervous system or any
other infection which, in the opinion of the investigator, contraindicates
re-start of the study drug;
b. Stevens-Johnson syndrome or toxic epidermal necrolysis or drug
reaction with eosinophilia and systemic symptoms.
7. Need for and intention to administer forbidden study-treatment-concomitant
therapy

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 
Treatment of relapses with plasma exchange (i.e., plasmapheresis,
cytapheresis) is prohibited.
Allowed concomitant therapy
 
Administration of i.v. atropine in the event of symptomatic bradycardia.
 
Short-acting ß2-agonists for respiratory symptoms and/or reduced
pulmonary function during study treatment.
 
QT-prolonging drugs with known risk of Torsades de Pointes should be
used with caution since ponesimod may potentially enhance their effect on
QT interval (guidance is provided in Appendix 2).
 
Glatiramer acetate and interferon (IFN) β-1a are allowed only during
ponesimod interruptions for planned pregnancy. These treatments may be
started 7 days after ponesimod cessation and must be stopped 7 days before
ponesimod re-initiation).
 
Other treatments considered necessary for the subject’s well-being and not
categorized as prohibited concomitant medications.
 
Vaccination with non-live vaccines is allowed while on study treatment if
the vaccination is advised by the primary investigator / treating neurologist,
based on her/his clinical assessment of the risk/benefit for the individual
patient, and if supported by guidelines for vaccination relevant to this
patient population, as applicable.
Prohibited concomitant therapy
 
Systemic corticosteroids and ACTH, except for the treatment of MS relapses
(see Treatment of Relapses above) and for short-term treatment (up to 2
weeks per treatment cycle with at least 8 weeks’ interval between treatment
cycles and no more than 4 weeks per year of the study duration on average)
with low dose of corticosteroid (up to 10 mg of prednisone equivalent daily)
or inhaled corticosteroids for pulmonary conditions.
 
DMTs for MS (except glatiramer acetate or IFN β-1a during ponesimod
interruptions for planned pregnancy as described under “Allowed”).
 
Immunosuppressive treatment (e.g., cladribine, lymphocyte-depleting
biological agents such as rituximab or ocrelizumab, mitoxantrone, or other
systemic immunosuppressive treatments such as azathioprine,
cyclophosphamide, cyclosporine or methotrexate).
 
Intravenous immunoglobulin (except in women who have interrupted study
treatment for pregnancy; for these women i.v. immunoglobulin  will be
allowed after 30 days from interruption of the study treatment).
 
Plasmapheresis, cytapheresis, or total lymphoid irradiation;
 
Vaccination with live vaccines, except if performed during a temporary
treatment interruption period. In this case it must be performed not earlier
than 1 week after last dose of study treatment, and treatment can be re-
initiated only after at least 4 weeks from completion of vaccination.
 
-blockers, diltiazem, verapamil, digoxin, or any other anti-arrhythmic or
heart rate lowering systemic therapy (a non-exhaustive list of drugs is

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provided in Appendix 3) during the up-titration period (i.e., from Day 1 until
Day 14 included and during the first 14 days after re-initiation of study
treatment). Treatment with any of these therapies is also not recommended
during the maintenance treatment period (from Day 15 until EOT) and
should be considered with caution if an alternative medication cannot be
used.
 
Any other investigational drug.
 
Any investigational therapeutic procedure for MS (e.g., stent placement or
angioplasty for chronic cerebrospinal venous insufficiency, stem cell
transplantation).
Commercially available ponesimod may be initiated on the day following last
intake of study treatment. The start date of commercially available ponesimod
must be recorded on the Concomitant Medication page of the eCRF.
ENDPOINTS
Main Efficacy endpoint(s)
In order to monitor disease activity in subjects after long-term treatment with
ponesimod 20 mg, and to investigate the effect of switching from teriflunomide
14 mg to ponesimod 20 mg, the main analysis of efficacy will focus on the
Combined Analysis Period, i.e., including data from both the core and extension
studies. In addition, specific efficacy endpoints will also be analyzed over the
Extension Analysis Period. The full list of efficacy endpoints together with details
of which endpoints will be analyzed over which analysis periods is given in
Section 6.1. Analysis over the Combined Analysis Period will use the core study
baseline as a reference, while analysis over the Extension Analysis Period will use
the extension study baseline as a reference. Baseline definitions for efficacy
endpoints are provided in Section 11.1.3.
The main clinical and magnetic resonance imaging-based endpoints are:
 
Annualized confirmed relapse rate (ARR; based on the number of
confirmed relapses per subject-year).
 
Time from core study randomization to first confirmed relapse.
 
Time from core baseline to first 12-week confirmed disability
accumulation (CDA).
 
Time from core baseline to first 24-week CDA.
 
Percent change from baseline in brain volume at all assessments.
 
Cumulative number of combined unique active lesions (CUAL, defined as
new gadolinium-enhancing T1 lesions plus new or enlarging T2 lesions
without double-counting the lesions) at all assessments.
Main Safety endpoints
In order to investigate the long-term safety of ponesimod and the changes in safety
in subjects on teriflunomide switching to ponesimod 20 mg, analysis will be
performed on all data in the core and extension studies combined, using the core
baseline as a reference. In addition, safety data collected in the extension study

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will be analyzed independently, using the extension baseline as a reference. The
full list of safety endpoints together with details of which endpoints will be
analysed over which analysis periods is given in Section 6.2.
The main safety endpoints are:
 
Treatment-emergent AEs, serious adverse events (SAEs), and AEs of
special interest.
 
AEs leading to premature discontinuation of study treatment.
Treatment-emergent period is defined as the time from first ponesimod
administration in the analysis period up to 15 days (inclusive) after last study
treatment administration. This definition applies regardless of whether the subject
receives commercially available ponesimod after completing study treatment.
ASSESSMENTS  
Refer to the schedule of assessments in Table 1 and Table 2.
STATISTICAL
METHODOLOGY
Analysis Strategy
In order to describe the disease activity in subjects after long-term treatment with
ponesimod 20 mg, and to investigate the effect of switching from teriflunomide
14 mg to ponesimod 20 mg, the main analysis of efficacy will focus on integrating
data from both the core and extension studies. Subjects will be analyzed according
to the treatment they were randomized to in the core study. In addition, specific
efficacy endpoints will be analyzed using data collected only from the extension
study.
Similarly, the long-term safety of ponesimod 20 mg and the changes in safety in
teriflunomide 14 mg subjects switching to ponesimod 20 mg will be investigated
by summarizing the integrated data from both the core and extension studies. In
addition, specific safety endpoints will also be analyzed using data collected only
from the extension study.
No hypotheses are pre-specified. All analyses conducted will be descriptive and
will be defined in detail in a Statistical Analysis Plan.
Sample Size
As the extension study is an extension of the confirmatory Phase 3 core study,
there are no sample size considerations. The sample size will be determined by
how many of the 1100 subjects planned to be enrolled in the core study enroll into
the extension study. Based on anticipated discontinuation rates in the core study,
approximately 800 subjects are expected to enter the extension study.
Analysis periods
Extension Analysis Period: This includes all available data collected on or after
the start date of ponesimod treatment in the extension study, up to the EOS date

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for efficacy variables or up to the last treatment date + 15 days in the extension
study for safety variables.
Combined Analysis Period: For efficacy, this period includes all available data
from randomization in the core up to the extension EOS date for subjects entering
the extension, or up to the core EOS date for subjects not entering the extension.
For safety this period includes all available data from the date of first study
treatment administration in the core study up to the last treatment date + 15 days
in the extension study for subjects entering the extension, or up to the last
treatment date + 15days in the core study for subjects not entering the extension.
Analysis Sets
Efficacy analysis described over the Combined Analysis Period will use the Full
Analysis Set. Safety analysis described over the Combined Analysis Period will
use the Safety Analysis Set. Efficacy and safety analysis described over the
Extension Analysis Period will use the Extension Set.
Extension Set (EXTS): The extension set includes all subjects who signed an
informed consent to enter the extension study and who received at least one dose
of ponesimod study treatment in the extension study.
Full Analysis Set (FAS): Following the intention-to-treat principle, the FAS
includes all subjects randomized in the core study. Subjects will be evaluated
according to the treatment they have been randomized to in the core study, which
may be different from the treatment they have received.
Safety Analysis Set (SAF): The SAF includes all subjects who received at least
one intake of core study treatment. Subjects will be evaluated according to the
treatment they received during the core study.
Analysis of Efficacy Endpoints
The following baseline definitions will be used:
 
Core study baseline for efficacy is defined as the last non-missing
assessment before randomization in the core study.
 
Extension study baseline is defined as the last non-missing assessment
before first administration of ponesimod in the extension study.
Analysis based on the Combined Analysis Period will use the core study baseline.
Analysis based on the Extension Analysis Period will use the extension study
baseline.
All data will be listed and endpoints will be summarized by appropriate
descriptive statistics.

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The main efficacy endpoints will be described by core study treatment for each
period using the appropriate analysis set as follows:
 
ARR will be described using a negative binomial regression model with log
of time as an offset variable.
 
Time to first relapse and time to 12 and 24-week CDA will be analyzed using
Kaplan-Meier estimates.
 
CUAL will be described using a negative binomial regression model with
the log of the number of scans used as an offset variable.
 
Percent Change in Brain Volume will be summarized descriptively over
time.
Analysis of safety endpoints
Analysis over the Combined Analysis Period will be based on the SAF, and
analysis over the Extension Analysis Period will be based on the EXTS.
Cumulative data such as AEs and SAEs will only be summarized for subjects
initially treated with ponesimod 20 mg in the core study. The analysis of the
change from baseline for safety endpoints assessed by visit will be analyzed by
core treatment group with the core baseline as the reference.
In addition, safety data collected in the extension study will be analyzed for the
Extension Analysis Period using the EXTS, and will be summarized both overall
and split by the core treatment group. The analysis of the change from baseline
for safety endpoints assessed by visit will be analyzed with the extension baseline
as the reference.
The following baseline definitions will be used:
 
The core baseline value for safety is defined as the last non-missing value
recorded before the first administration of study treatment in the core study.
 
The extension baseline value for safety is defined as the last non-missing
assessment before the first administration of ponesimod in the extension
study.
All data will be listed and endpoints will be summarized by appropriate
descriptive statistics.
STUDY COMMITTEES  
The Independent Data Monitoring Committee (IDMC) responsible for monitoring
the core study has continued its duties for the extension study, until its
disbandment which occurred on 30th September 2021. It was composed of
physicians with relevant medical expertise. The composition and operation of the
IDMC was described in the IDMC charter.

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An independent statistical analysis center (not otherwise involved with study
conduct or statistical analysis) will generate reports, exclusively for review by the
IDMC.
An Ophthalmology Safety Board (OSB) composed of two independent
ophthalmologists reviewed and evaluated any reported case of macular edema.
The OSB was decommissioned from the date of Protocol Version 6. The
composition and operation of the OSB was described in the OSB charter.
A Major Adverse Cardiovascular Events (MACE) adjudication board will review
and evaluate the MACE reported in the study. The selection of AEs that will be
sent for adjudication will be based on a pre-defined list of preferred terms
belonging to relevant Standardized Medical Dictionary for Regulatory Activities
(MedDRA) Queries. For each AE sent for MACE adjudication, the MACE
adjudication board will determine whether or not the event belongs to one of the
pre-specified categories including cardiovascular death, myocardial infarction,
and stroke.
The composition and operations of MACE adjudication board are described in the
MACE adjudication board charter.
SUB-STUDIES
Pulmonary function monitoring
A sub-study assessing the diffusing capacity of the lungs, measured using
carbon monoxide (DLCO), will be continued in these subjects
who participated in the sub-study in the core study.

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Table 1 
Visit and assessment schedule
Periods 
Name
AC-058B301
(core study)
AC-058B303 (extension study) TREATMENT PERIOD
Duration  
NA  
Treatment may continue until 240 weeks or until ponesimod is commercially available (whichever occurs first)
Visits
Number 
NA  
1 
2 
3 
4 
5 
6, 8-10, 12-14,
16-18, 20-22
7, 11, 15, 19 
23
Name 
FU1
Core 
Study
Abbreviated 
FU2 
Core Study 
(1) 
Enrollment 
W2 
W4 
W12 
W24 
W36, W60, W72, W84,
W108, W120, W132, 
W156, W168, W180, 
W204, W216, W228
W48, W96,
W144, W192
EOT
Time 
NA  
NA  
Day 1(2) 
Day 15 
Week 4 
Week 12 
Week 24
Every 12 weeks 
W240 or
earlier (14)
Every 48 weeks 
Visit window  
NA  
NA  
NA  
1 to +3
days
±7 days 
±7 days 
±14 days 
±14 days 
±14 days 
14 days
Informed consent* 
X
Inclusion/exclusion criteria* 
X
Demographics 
X
Medical History* 
X
EDSS/FS* 
X 
X 
X 
X 
X 
X
Relapse* 
X 
X 
X (3)
SDMT* 
X 
X 
X 
X
MSFC* 
X 
X
SF-36** 
X 
X 
X
eC-SSRS** 
X 
X
MRI**(15) 
X 
X
Concomitant medications* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Physical examination* 
X 
X 
X 
X
Dermatological examination* (4) 
X 
X
Body weight* 
X 
X
Body temperature* 
X 
X 
X 
X 
X 
X 
X 
X 
X
Systolic/diastolic blood
pressure*(5)
X 
X(5) 
X 
X 
X 
X 
X 
X 
X
12 Lead ECG**(6) 
X 
X 
X 
X
Pulse rate*  
X 
X 
X 
X 
X
Ophthalmological
examination/OCT* (7)
X 
X 
X 
X
Pulmonary function tests* (8) 
X 
X 
X 
X
Hematology/Chemistry** 
X 
X 
(9) 
X 
X 
X
Urinalysis* 
X 
X 
X 
X 
X

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Periods 
Name
AC-058B301
(core study)
AC-058B303 (extension study) TREATMENT PERIOD
Duration  
NA  
Treatment may continue until 240 weeks or until ponesimod is commercially available (whichever occurs first)
Visits
Number 
NA  
1 
2 
3 
4 
5 
6, 8-10, 12-14,
16-18, 20-22
7, 11, 15, 19 
23
Name 
FU1
Core 
Study
Abbreviated 
FU2 
Core Study 
(1) 
Enrollment 
W2 
W4 
W12 
W24 
W36, W60, W72, W84,
W108, W120, W132, 
W156, W168, W180, 
W204, W216, W228
W48, W96,
W144, W192
EOT
Time 
NA  
NA  
Day 1(2) 
Day 15 
Week 4 
Week 12 
Week 24
Every 12 weeks 
W240 or
earlier (14)
Every 48 weeks 
Visit window  
NA  
NA  
NA  
1 to +3
days
±7 days 
±7 days 
±14 days 
±14 days 
±14 days 
14 days
Pregnancy test*/** (10) 
X 
X 
X 
X 
X 
X 
X serum  
X serum
Elimination procedure compliance 
X 
X
Teriflunomide plasma concentration  
X (11)
Serum sample for immunogenicity
evaluations** (16)
X 
X 
X
Additional serum sample for viral
serology/biomarkers*
X
Study treatment dispensing &
accountability (12)*
X 
X 
X 
X 
X 
X 
X 
X
AEs* / SAEs*(13) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
* Data collected in the eCRF
** Electronically transferred to the sponsor
Day 1 (date of treatment start) is to be used as the reference date for the purpose of calculating the subsequent visit dates (and time windows).
1) 
This visit will only take place if the compliance with the teriflunomide elimination procedure in the core study was not sufficient and has to be re-assessed prior to the study drug administration on
Day 1.
2) 
Visit 1 includes a pre-treatment period which lasts from signing of the informed consent until first dosing of study treatment. Ideally, all assessments and procedures of Visit 1 (e.g., signing of the
informed consent, first study treatment dosing and post-dose cardiac monitoring) should occur on the same day as the core study FU1 or abbreviated FU2 (whichever applies). In all cases, informed
consent should be signed no later than one day after FU1 or FU2 visit (whichever applies) and all assessments and procedures of Visit 1 must be completed (i.e., study treatment start) no longer than
7 days after signing of the informed consent. The date of Day 1 corresponds to the date of the first dose of study treatment in the extension study. The investigator should make every effort to
minimize the duration between EOT of the core study and Day 1 of the extension study. Ideally the treatment interruption should last no longer than 15 days.
3) 
At every study visit, subjects are reminded to contact their principal investigator / treating neurologist at the clinical site immediately in the event of the appearance of any new or worsening
neurological symptoms. In addition, the site will contact the subject 6 weeks (7 days) after each visit starting with Visit 4 (Week 12) in order to proactively inquire about any new or worsened
neurological symptoms. Whenever, between visits, a subject experiences any new or worsening neurological symptoms, he/she must contact the principal investigator / treating neurologist, study
nurse or clinical coordinator as soon as possible in order to complete a relapse assessment questionnaire [see Appendix 10].
4) 
Dermatological examination to be performed by a dermatologist.
5) 
Systolic / diastolic blood pressure: Only pre-dose except Day 1. On Day 1 pre-dose and hourly (+/− 15 min) for at least 4 hours post-dose and up to 12 hours.
6) 
ECGs: Only pre-dose except Day 1. On Day 1 pre-dose and hourly (+/− 15 min) for at least 4 hours post-dose and up to 12 hours.

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7) 
OCT and/or ophthalmological examination to be performed at any visit in the presence of visual symptoms suggestive of macular edema or active uveitis. From Protocol Version 6, scheduled OCT
examinations at visits 4, 5, 7, 11, 15, 19, and 23 will not be required.
8) 
PFTs including spirometry to be performed in all subjects; DLCO  to be performed in a subset of subjects at selected sites only.
9) 
Monitoring of hematology/chemistry every 4 weeks for the first 24 weeks after enrollment (7 days).
10) Between visits, urine pregnancy tests are done every 4 weeks (7 days) at home. At all visits, the methods of contraception will be reviewed and the contraceptive method form entered in the eCRF
must be updated as applicable.
11) Blood sample for a teriflunomide test (results to be communicated to site only if needed, e.g., in the case of AEs where the measurement of exposure to teriflunomide is of relevance).
12) Scheduled study medication dispensing/return procedures may be adapted according to the site practice. No medication dispensed at EOT.
13) All AEs and SAEs that occur after signing the informed consent and up to 30 days after study treatment discontinuation (i.e., EOS) must be reported.
14) The EOT Visit will take place at Week 240 or earlier if ponesimod becomes commercially available in the subject’s country or the subject prematurely discontinues from the study. In all cases, the
EOT visit should take place 1 day after the last dose of study treatment but no later than 14 days after the last dose of study treatment. Commercially available ponesimod may be initiated on the day
following last intake of study treatment.
15) In case of premature study treatment discontinuation, the MRI assessment at EOT does not need to be performed if the EOT visit occurs within 4 weeks of the MRI assessment at Visits 7, 11, 15, or
19 (Weeks 48, 96, 144, or 196).
16) To be collected for all subjects at all scheduled visits after approval of protocol version 5.
AE = adverse event; DLCO  = diffusing capacity of the lungs, measured using carbon monoxide; ECG = electrocardiogram; eCRF = electronic case report form; eC-SSRS = electronic self-rated version of
the Columbia-Suicide Severity Rating Scale; EDSS = expanded disability status scale; EOS = End-of-Study; EOT = End-of-Treatment; FS = Functional System; FU = follow-up; MRI = magnetic
resonance imaging; MSFC = Multiple Sclerosis Functional Composite; NA = not applicable; OCT = optical coherence tomography; PFT = pulmonary function test; SAE = serious adverse event;
W = week.

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Table 2 
Visit and assessment schedule (Part 2)
Periods 
Name 
FOLLOW-UP
UNSCHEDULED
Duration  
30 Days
Visits 
Number 
24 
R1, R2, …  
U1, U2, …  
I1, I2, …(13) 
P1, P2, …(9)
D1 
D15
Name 
EOS 
Relapse 
Unscheduled 
(8) 
Re- 
initiation 
D1 
Re-initiation  
D15 
Interruption / planned 
pregnancy  
Eligibility for 
re-initiation / 
planned 
pregnancy
Re-initiation D1 
/ pregnancy  
Re-initiation
D15 /
pregnancy
Day 1 of 
re-initiation  
Day 15 of 
re-initiation  
Unscheduled visit after 
drug interruption for 
planned pregnancy  
Unscheduled 
visit prior to 
study drug re- 
initiation after 
interruption for 
planned 
pregnancy  
Unscheduled 
visit following 
study drug 
interruption for 
planned 
pregnancy for 
re-start 
Unscheduled
visit following
study drug
interruption
for planned
pregnancy for
re-start
Time 
Last study 
treatment intake 
+ 30 days 
Any day 
between 
Day 1 and 
EOS  
Any day 
between 
Day 1 and 
EOS  
Any day 
between 
Day 1 and 
EOS  
Any day 
between 
Day 1 and 
EOS  
Earliest after Visit 5 
(Week 24) and until 
6 weeks after the first 
of two consecutive 
tests showing
teriflunomide plasma
level <0.02 mg/L and
at least 30 days after
study treatment
discontinuation
30 days
(±5days) before
study drug
re-initiation
Visit window  
+14 days 
+7 days 
NA  
NA  
± 1 day  
± 7 days 
NA  
NA  
NA
EDSS/FS* 
X 
X 
X 
X 
X
Relapse* 
X 
X 
X(11) 
X(11) 
X(11) 
X(11) 
X 
X 
X(11)
MRI**  
X 
X 
X
Concomitant medications* 
X 
X 
X 
X 
X 
X 
X
Physical examination* 
X 
X 
X 
X
Dermatological
examination*
X 
X
Body weight*  
X 
X 
X 
X
Body temperature* 
X 
X 
X 
X 
X 
X 
X 
X 
X
Systolic/diastolic blood
pressure*
X 
X 
X 
X(1) 
X 
X 
X 
X(1) 
X
12 Lead ECG** 
X 
X 
X(2) 
X 
X 
X 
X(2) 
X
Pulse rate*  
X 
X(12) 
X(12)

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Periods 
Name 
FOLLOW-UP
UNSCHEDULED
Duration  
30 Days
Visits 
Number 
24 
R1, R2, …  
U1, U2, …  
I1, I2, …(13) 
P1, P2, …(9)
D1 
D15
Name 
EOS 
Relapse 
Unscheduled 
(8) 
Re- 
initiation 
D1 
Re-initiation  
D15 
Interruption / planned 
pregnancy  
Eligibility for 
re-initiation / 
planned 
pregnancy
Re-initiation D1 
/ pregnancy  
Re-initiation
D15 /
pregnancy
Day 1 of 
re-initiation  
Day 15 of 
re-initiation  
Unscheduled visit after 
drug interruption for 
planned pregnancy  
Unscheduled 
visit prior to 
study drug re- 
initiation after 
interruption for 
planned 
pregnancy  
Unscheduled 
visit following 
study drug 
interruption for 
planned 
pregnancy for 
re-start 
Unscheduled
visit following
study drug
interruption
for planned
pregnancy for
re-start
Time 
Last study 
treatment intake 
+ 30 days 
Any day 
between 
Day 1 and 
EOS  
Any day 
between 
Day 1 and 
EOS  
Any day 
between 
Day 1 and 
EOS  
Any day 
between 
Day 1 and 
EOS  
Earliest after Visit 5 
(Week 24) and until 
6 weeks after the first 
of two consecutive 
tests showing
teriflunomide plasma
level <0.02 mg/L and
at least 30 days after
study treatment
discontinuation
30 days
(±5days) before
study drug
re-initiation
Visit window  
+14 days 
+7 days 
NA  
NA  
± 1 day  
± 7 days 
NA  
NA  
NA
Ophthalmological
examination/OCT* (3)
X 
X 
X 
X
Pulmonary function tests*
(4)
X 
X 
X 
X
Hematology/Chemistry** 
X 
X 
X 
X
Serum sample for
immunogenicity 
evaluations**(14)
X
Urinalysis* 
X 
X 
X 
X
Teriflunomide plasma
concentration (5) **
X
Viral serology  
X
Pregnancy test*/** 
X serum  
X 
X serum
X urine (first 
assessment) 
X (first
assessment; 10)

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Periods 
Name 
FOLLOW-UP
UNSCHEDULED
Duration  
30 Days
Visits 
Number 
24 
R1, R2, …  
U1, U2, …  
I1, I2, …(13) 
P1, P2, …(9)
D1 
D15
Name 
EOS 
Relapse 
Unscheduled 
(8) 
Re- 
initiation 
D1 
Re-initiation  
D15 
Interruption / planned 
pregnancy  
Eligibility for 
re-initiation / 
planned 
pregnancy
Re-initiation D1 
/ pregnancy  
Re-initiation
D15 /
pregnancy
Day 1 of 
re-initiation  
Day 15 of 
re-initiation  
Unscheduled visit after 
drug interruption for 
planned pregnancy  
Unscheduled 
visit prior to 
study drug re- 
initiation after 
interruption for 
planned 
pregnancy  
Unscheduled 
visit following 
study drug 
interruption for 
planned 
pregnancy for 
re-start 
Unscheduled
visit following
study drug
interruption
for planned
pregnancy for
re-start
Time 
Last study 
treatment intake 
+ 30 days 
Any day 
between 
Day 1 and 
EOS  
Any day 
between 
Day 1 and 
EOS  
Any day 
between 
Day 1 and 
EOS  
Any day 
between 
Day 1 and 
EOS  
Earliest after Visit 5 
(Week 24) and until 
6 weeks after the first 
of two consecutive 
tests showing
teriflunomide plasma
level <0.02 mg/L and
at least 30 days after
study treatment
discontinuation
30 days
(±5days) before
study drug
re-initiation
Visit window  
+14 days 
+7 days 
NA  
NA  
± 1 day  
± 7 days 
NA  
NA  
NA
Study treatment dispensing
& accountability (6)*
X 
X 
X 
X 
X
AEs*/ SAEs* (7) 
X 
X 
X 
X 
X 
X 
X 
X 
X
* Data collected in the eCRF.
** Electronically transferred to the sponsor
Day 1 (date of enrollment visit) is to be used as the reference date for the purpose of calculating the subsequent visit dates (and time windows).
1) 
SBP/DBP: Pre-dose (all subjects) and hourly (+/− 15 min) for at least 4 hours post-dose and up to 12 hours (only mandated for subjects with cardiovascular risk factors and at the discretion of the
investigator / treating neurologist for subjects without cardiovascular risk factors [see Section 5.1.9]).
2) 
ECGs: Pre-dose (all subjects) and hourly (+/− 15 min) for at least 4 hours post-dose and up to 12 hours (only for subjects with cardiovascular risk factors (only mandated for subjects with
cardiovascular risk factors and at the discretion of the investigator / treating neurologist for subjects without cardiovascular risk factors [see Section 5.1.9]).
3) 
OCT and/or ophthalmological examination to be performed at any visit in the presence of visual symptoms suggestive of macular edema or active uveitis. From Protocol Version 6 scheduled OCT
examinations at visit 24, visits for Interruption / planned pregnancy, visits for Eligibility for re-initiation / planned pregnancy, and at unscheduled visits will not be required.
4) 
PFTs include spirometry to be performed in all subjects; DLCO  to be performed in a subset of subjects at selected sites only.
5) 
Teriflunomide testing no longer required with approval of protocol version 5. Under protocol versions 1 to 4, teriflunomide plasma concentration may be assessed at Week 19 ± 7 days and at Week
21 ± 7 days and may be repeated at Visit 5 (Week 24) and at following visits if necessary until two consecutive test results confirming plasma concentration of teriflunomide <0.02 mg/L are available.

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6) 
Scheduled study medication dispensing/return procedures may be adapted according to the site practice.
7) 
All AEs and SAEs up to 30 days after study treatment discontinuation must be reported.
8) 
Unscheduled visits may be performed at any time during the study and the indicated assessments are optional, based on the judgment of the investigator.
9) 
The wish to become pregnant and stay in the study must be communicated by the female subject to the principal investigator / treating neurologist during a scheduled visit. Interruption of contraception
for planned pregnancy may only take place after Visit 5 (Week 24) and at earliest 6 weeks after the first of two consecutive tests confirming plasma teriflunomide level <0.02 mg/L and at least
30 days after ponesimod interruption. Please note: teriflunomide testing is no longer required with the approval of protocol version 5.
10) Review and assess contraception methods and total duration of study treatment interruption, which should not exceed 81 weeks.
11) Only if the subject is meeting the principal investigator / treating neurologist at unscheduled visits.
12) Only if no 12-lead ECG is performed at this visit.
13) As described in detail in Section 5.1.9, subjects who miss taking the study drug for four or more consecutive days are required to re-initiate ponesimod using the original up-titration scheme. In such
cases, there will be one or two visits; one visit on the day of re-initiation (Day 1) for all subjects. An additional visit 14 days (±1 day) after the day of re-initiation (Day 15) only mandated for subjects
with cardiovascular risk factors (see Section 5.1.9), but may be scheduled for any subject at the discretion of the investigator / treating neurologist.
14) To be collected for all subjects at all scheduled visits after approval of protocol version 5.
AE = adverse event; DBP = diastolic blood pressure; DLCO  = diffusing capacity of the lungs, measured using carbon monoxide; ECG = electrocardiogram; EDSS = expanded disability status scale; EOS
= End-of-Study; FS = Functional System; I = re-initiation visit; HR = heart rate; MRI = Magnetic resonance imaging; OCT = Optical coherence tomography; P = pregnancy visit; PFT = pulmonary
function test; R = relapse visit; SAE = serious adverse event; SDMT = Symbol Digit Modalities Test; SBP = systolic blood pressure; U = unscheduled visit.

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PROTOCOL
1 
BACKGROUND
1.1 Multiple sclerosis
Multiple sclerosis (MS) is an inflammatory autoimmune disorder of the central nervous system
(CNS) and the most common cause of progressive neurological disability in young adults
[Compston 2008]. This chronic demyelinating disease is characterized by heterogeneous clinical
expression, an unpredictable course and a variable prognosis. In MS, the frequent and major
neurological disability has important personal, social, and financial consequences for patients,
their families, and health care systems.
1.1.1 Pathogenesis
Although the etiology of MS is still unknown, it is widely accepted that it is an immune-mediated,
demyelinating process precipitated by unknown environmental factors in genetically susceptible
people.
MS results from a cascade of events involving activation of the immune system, acute focal
inflammatory demyelination, and axonal loss with limited remyelination, culminating in chronic
multifocal sclerotic plaques in the brain and spinal cord.
1.1.2 Clinical course
The two main clinical features of MS are exacerbations (also called attacks or relapses) and
progressive loss of neurological function. Relapses are considered the clinical expression of acute,
inflammatory, focal lesions of the brain or spinal cord, corresponding to axonal demyelination,
which leads to the slowing or blockade of axonal conduction at diverse affected sites of the brain
and spinal cord. This inflammatory disease activity may translate to a large variety of clinical
symptoms and signs and/or acute lesions visualized on magnetic resonance imaging (MRI). Acute
MRI lesions may or may not be accompanied by clinical symptoms. The progressive loss of
neurological function (called progression or accumulation of disability) may result from
incompletely recovered relapses or may be independent from relapses [Lublin 2003]. It is thought
to reflect mainly neurodegeneration corresponding to demyelination, axonal loss and gliosis.
The natural history of MS suggests that there are different patterns of disease course
[Compston 2008]. In relapsing-remitting MS (RRMS), patients have acute exacerbations with full
or partial recovery [Lublin 2003] and are otherwise stable between exacerbations; this presentation
is observed in the majority of MS patients (80−85% of the MS population).
Approximately 65−70% of RRMS patients experience gradual accumulation of disability and
fewer relapses later in their disease, which evolves into a secondary progressive MS (SPMS) stage
characterized by less inflammatory and more pronounced neurodegenerative features. The median
time for patients with RRMS to progress into SPMS is about 10 years [Noseworthy 2000,
Compston 2008]. In primary progressive MS (PPMS), patients experience progression of

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disability from onset (approximately 10−20% of patients with MS). In progressive relapsing MS
(PRMS) occurring in approximately 5% of patients with MS, the disability progression starts from
the onset of the disease and is associated with occasional relapses.
The classification of MS subtypes and the related terminology has been subject to changes over
the last two decades. In 1996, the US National Multiple Sclerosis Society (NMSS) Advisory
Committee on Clinical Trials in Multiple Sclerosis defined the clinical subtypes of MS and
provided standardized definitions for four MS clinical courses: relapsing-remitting (RR),
secondary progressive, primary progressive (PP), and progressive relapsing [Lublin 1996]. The
Committee proposed to eliminate the PRMS category since it could reflect misclassification of
other MS categories (e.g., SPMS without recognition of the initial relapsing course), but the term
continued to be used by clinicians and in clinical trials. In 2011, the NMSS Advisory Committee,
also sponsored by the European Committee for Treatment and Research in MS, proposed defining
the MS course by adding modifiers based on disease activity and progression [Lublin 2014]. A
patient with RRMS who had a new gadolinium-enhancing (Gd+) lesion on a current MRI would
be considered to be RR–active. Conversely, the term ‘not active’ could be used to indicate a patient
with a relapsing course but no relapses, Gd+ activity, or new or unequivocally enlarging T2 lesions
during the assessment period. Inclusion of activity as a modifier also allows elimination of the
PRMS category. A patient with PPMS who has an acute attack (thus fulfilling prior criteria for
PRMS) would be considered to be PP-active. On the other hand, a patient with PPMS with no
acute attacks and no MRI activity would be considered to be PP-not active. In terms of progressive
disease, this new classification distinguishes between progressive accumulation of disability from
onset, which includes non-active PPMS (previously known as PPMS) and active PPMS
(previously known as PRMS) and progressive accumulation of disability after initial relapsing
course (SPMS). Further, the term disability progression is only reserved for patients who are in
the progressive phase of MS, while the term disability accumulation refers to worsening in
Expanded Disability Status Scale (EDSS) score, which can either be due to incomplete recovery
from relapses or occurring independent from relapses, disregarding the RR or progressive course
of MS.
The Diagnostic Criteria for MS have been modified with the 2010 revised version of McDonald
Criteria [Polman 2011]. Implementation of these Diagnostic Criteria allows for an earlier diagnosis
of MS, with equivalent or improved specificity and sensitivity compared to the 2005 revision of
McDonald Criteria [Polman 2011].
Historically, the term clinically isolated syndrome (CIS) applied to those patients who have
experienced a single clinical event, who have had other possible diagnoses excluded, and who did
not fulfill the Diagnostic Criteria for MS [Polman 2005]. With the 2010 revision of McDonald’s
Diagnostic Criteria, CIS patients with clinical and/or MRI signs of dissemination in space and MRI
signs of dissemination in time are now diagnosed with relapsing MS (RMS).

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1.1.3 Epidemiology
MS affects an estimated 2−2.5 million people worldwide, of whom approximately 630,000 are in
Europe and 250,000 to 350,000 in the United States [Milo 2010, WHO 2008].
The incidence of MS is about 7 cases per 100,000 persons per year. The prevalence rate varies
between races and geographical latitudes, ranging from 50 to 120 per 100,000 [Compston 2002,
Milo 2010]. The prevalence is highest in Northern Europe, Southern Australia, New Zealand and
North America. The reason for the changing prevalence with geographical latitude is unknown but
suggests the existence of environmental factors, in addition to genetic factors [Pugliatti 2002,
Compston 2008]. The highest prevalence is observed in Northern European descendants
(Scandinavia and Scotland) [Milo 2010], whereas MS is less common in Asian populations
[Pugliatti 2002].
MS is the most common chronic neurologic disease in adults between 20 and 50 years of age with
a peak onset of MS in the early thirties. Women are affected approximately twice as often as men.
In 2 to 5% of patients, disease presents before the age of 16 [Compston 2002, Renoux 2007].
1.1.4 Treatment of MS
Current medical practice encourages early intervention with disease-modifying treatments, with
the intent of optimizing long-term clinical outcomes [Gold 2012].
Key objectives in the management of MS are reducing the rate of relapses and preventing or at
least delaying disease progression [Gold 2012]. Most of the disease-modifying drugs approved for
MS must be administered by injection or infusion (subcutaneous [s.c.], intramuscular [i.m.], or
intravenous [i.v.] route). Recently, new disease-modifying drugs administered orally have been
approved for RMS. Currently, there are several disease-modifying therapies (DMTs) approved in
at least one country for the treatment of MS.
1.1.4.1 Injectable disease-modifying therapies
The following injectable drugs have been approved in at least one country for the treatment of MS:
 Interferon (IFN) β-1a 30 mcg i.m. once weekly (Avonex®)
 IFN β-1a 22 or 44 mcg s.c. 3 times weekly (Rebif®)
 IFN β-1b 250 mcg s.c. every other day (Betaferon®, Extavia®)
 Pegylated IFN β-1a 125 mcg s.c. every 2 weeks (Plegridy®)
 Glatiramer acetate 20 mg s.c. once a day (o.d.) or 40 mg subcutaneously 3 times weekly
(Copaxone®)
 Glatiramer acetate 20 mg s.c. o.d. (Glatopa®)
 Natalizumab 300 mg i.v. every 4 weeks (Tysabri®)
 Mitoxantrone i.v. every 3 months (Novantrone®)
 Alemtuzumab concentrate for solution for infusion, 12 mg alemtuzumab in 1.2 mL
(10 mg/mL; Lemtrada®)

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 Ocrelizumab 600 mg i.v. every 6 months (Ocrevus®)
 Ofatumumab 20 mg/0.4 mL Subcutaneous once monthly (Kesimpta®)
Additional injectable drug currently in late-stage development for the treatment of RMS include
AIN457 (secukinumab).
1.1.4.2 Orally administered disease-modifying therapies
Several oral drugs have been approved for MS:
 Fingolimod 0.5 mg o.d. (Gilenya®)
 Teriflunomide 7 mg, 14 mg o.d. (Aubagio®)
 Dimethyl fumarate (BG-12) gastro-resistant hard capsules 120/240 mg twice daily
(Tecfidera®)
 Cladribine 3.5 mg/kg body weight over 2 years (Mavenclad®)
 Siponimod 0.25 and 2 mg orally o.d. (Mayzent®)
 Ozanimod 0.92 mg orally o.d. (Zeposia®)
 Diroximel fumarate 231 mg twice daily (Vumerity®)
 Monomethyl fumarate 95 mg capsules (Bafiertam™)
1.2 Sphingosine-1-phosphate receptors
S1P plays a central role in lymphocyte trafficking [Cyster 2005, Brinkmann 2007,
Brinkmann 2010, Schwab 2007, and references therein]. S1P is synthesized and secreted by many
cell types, including platelets, erythrocytes, and mast cells, and elicits a variety of physiological
responses [Cyster 2005, Alvarez 2007]. Among other effects, lymphocyte egress from primary and
secondary lymphoid organs is dependent on the S1P1 receptor. S1P1 receptor modulators block
lymphocyte migration out of lymphoid tissue into the lymphatic and vascular circulation, thereby
reducing peripheral lymphocyte counts and preventing lymphocyte recruitment to sites of
inflammation. Following withdrawal of an S1P1 receptor agonist, the functional lymphocytes
return to the circulation from their sites of sequestration. Other functions that do not rely on homing
mechanisms, such as antibody generation by B lymphocytes, first-line immunological protection
by granulocytes and monocytes, and antigen-dependent T-cell activation and expansion, are not
affected by this mechanism [Pinschewer 2000].
S1P itself induces pleiotropic effects, which are mediated by a family of five G protein-coupled
receptors, S1P1S1P5, located on endothelial cells, vascular and cardiac smooth muscle cells, and
cardiac myocytes [Alvarez 2007, Brinkmann 2007, Brinkmann 2010]. The first S1P receptor
modulator, fingolimod (FTY720, Gilenya®), which has been approved by the FDA and the EMA
for the treatment of MS, is not selective for the S1P1 receptor but interacts with S1P3, S1P4, and
S1P5 [Brinkmann 2007, Brinkmann 2010]. Two other S1P receptor modulators - siponimod and
ozanimod (which bind to S1P1 and S1P5) have also been approved for MS in some countries.

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1.3 Ponesimod
Ponesimod, an iminothiazolidinone derivative, is an orally active, selective modulator of the S1P1
that induces a rapid, dose-dependent, and reversible reduction in peripheral blood lymphocyte
count by  blocking the egress of lymphocytes from lymphoid organs. T and B cells are most
sensitive to ponesimod-mediated sequestration. In contrast, monocyte, natural killer (NK) cell and
neutrophil counts are not reduced by ponesimod. The effect of ponesimod on circulating effector
T cells represents a promising therapeutic approach for diseases in which activated T cells play a
critical role.
More detailed information can be found in the Investigator’s Brochure (IB) [Ponesimod IB].
1.3.1 Nonclinical studies
The main findings in the nonclinical studies conducted with ponesimod are:
 Ponesimod causes a rapid and substantial reduction in circulating lymphocytes in rats and dogs,
which is also rapidly and fully reversible. The effect correlates well with the plasma
concentration of ponesimod.
 Studies with ponesimod in animal models of T-cell-mediated diseases, such as MS, rheumatoid
arthritis, type 1 diabetes and skin hypersensitivity, consistently indicated a therapeutic potential
of ponesimod at oral doses that lower peripheral blood lymphocyte counts.
 Ponesimod shows an oral bioavailability of 35−74%, low clearance, and a tissue distribution
greater than total body water in rats and dogs. Plasma protein binding is high (≥98.9%) in rats,
dogs, and humans.
 The metabolism of ponesimod is comparable in rats, dogs, and humans. The main metabolite,
ACT-338375 (M13), is present in plasma of mice, rats, and dogs at levels similar to or higher
than steady-state exposures in humans at 40 mg/day.
 Based on available nonclinical data, the potential for drug-drug interactions (DDIs) is limited.
The metabolite M13 has no liability for causing DDIs via inhibition of cytochrome P450 (CYP)
enzymes or transport proteins. M13 is not a time-dependent inhibitor of CYP3A4, CYP2D6 or
CYP2C9. Neither ponesimod nor the M13 metabolite approach plasma concentrations
expected to inhibit CYP2C9 or CYP2C19 after daily doses of 20 mg at steady state.
 The main targets for ponesimod-related toxicity after treatment of up to 4 weeks were the lung
(all species) and the nervous system (clinical signs in dogs). After 13, 26, and 52 weeks of
treatment, the heart and skin were identified as additional target organs in dogs. No-observed-
adverse-effect levels were established for all toxicologically relevant targets in rats, mice, and
dogs after 4, 13, 26, and 52 weeks of treatment, and resulting safety margins are considered
acceptable.

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 Embryo-fetal toxicity studies in rats and rabbits indicated that ponesimod has embryotoxic and
teratogenic potential. In rat fertility studies, ponesimod had no effects on female and male
fertility and did not produce any testicular morphologic changes.
More detailed information can be found in the IB [Ponesimod IB].
1.3.2 Clinical studies
The human clinical experience with ponesimod to date consists of studies assessing single- and
multiple-dose safety and tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) in
healthy subjects treated with a single dose of up to 75 mg, or multiple doses of up to 100 mg o.d.,
for up to 22 days, as well as studies in subjects with RRMS treated for up to 7 years and in subjects
with moderate-to-severe chronic plaque psoriasis treated for up to 28 weeks with doses up to 40
mg o.d. A proof-of-concept study (AC-058A200) and dose-finding study (AC-058A201) in
moderate-to-severe plaque psoriasis and a dose-finding study in RRMS (AC-058B201) have been
completed. An extension study evaluating long-term effects of ponesimod in RRMS subjects who
completed study AC-058B201 is ongoing (AC-058B202). Ponesimod may also be investigated in
subjects suffering from other lymphocyte-mediated diseases.
For results of the Phase 1 studies and Phase 2 study in chronic plaque psoriasis, please refer to the
IB [Ponesimod IB]. Study  AC-058B301/OPTIMUM was completed (last patient last visit) in
May 2019 and Study AC-058B302/POINT was prematurely terminated (announcement made in
November 2019) due to failure to meet recruitment targets.
1.3.2.1 Clinical pharmacology
The PK profile of ponesimod is characterized by low variability. The terminal elimination half-
life is about 32 h. There is approximately 22.5 fold accumulation of the drug with repeated daily
oral dosing, and steady state is achieved within 4−5 days. There is a good correlation between the
plasma concentration of ponesimod and the peripheral blood total lymphocyte count. Food, age,
race or sex do not appear to relevantly affect the PK and PD of ponesimod. The PK DDI potential
of ponesimod is judged to be low based on current nonclinical and clinical data.
More detailed information can be found in the IB [Ponesimod IB].
1.3.2.2 Pharmacodynamics in humans
Oral administration of ponesimod dose-dependently reduces the circulating lymphocyte count in
humans. The maximum reduction from baseline of approximately 65–80% is achieved after a
single dose of ≥50 mg, or 40 mg o.d. at steady state. The nadir in lymphocyte count is attained
within 610 hours following a given single dose. There is no evidence of tachyphylaxis on
lymphocyte count. Peripheral blood counts of both T and B cells are reduced by ponesimod, while
NK cells and neutrophils are not reduced. Food, race and gender do not appear to relevantly affect
the PD of ponesimod. Upon discontinuation of ponesimod, the lymphocyte count generally returns
to within the normal range within 1 week.

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The magnitude of lymphocyte-count reductions seen with ponesimod in MS subjects was
consistent with observations made after short-term treatment in healthy subjects. In the Phase 2
dose-finding study AC-058B201, at Week 24, the mean reductions from baseline in lymphocyte
count were 49.8%, 65.3% and 68.6% in the ponesimod 10 mg, 20 mg, and 40 mg groups,
respectively, compared to a mean increase of 3.3% in the placebo group. Lymphocyte counts
remained stable on treatment and returned to baseline levels within 1 week following ponesimod
treatment discontinuation.
More detailed information can be found in the IB [Ponesimod IB].
1.3.2.3 Efficacy in humans
Study AC-058B201 [Olsson  2014] was a prospective, multicenter, randomized, double-blind,
placebo-controlled, parallel-group, dose-finding Phase 2b study, in which efficacy, safety, and
tolerability of three doses of ponesimod administered for 24 weeks were investigated in subjects
with RRMS. A total of 464 subjects were randomized (1:1:1:1) to 10, 20, or 40 mg ponesimod as
the capsule formulation, or placebo. Study medication was administered orally o.d., with a starting
dose of 10 mg o.d. in all ponesimod arms and with up-titration to 20 and 40 mg on Days 8 and 15,
respectively.
Treatment with ponesimod at doses of 40, 20, and 10 mg was associated with a statistically
significant decrease in the cumulative number of new T1 Gd+ lesions at Weeks 12, 16, 20, and 24
(primary endpoint) compared to placebo. The observed effect was dose-dependent, reaching a risk
reduction vs placebo of 77%, 83%, and 43% in the 40, 20, and 10 mg groups, respectively vs
placebo (p <0.0001).
The study was not powered to detect a significant effect of ponesimod on clinical endpoints like
aggregate Annualized Relapse Rate (ARR) or time to first confirmed relapse. Treatment with
ponesimod was associated with a reduction in the aggregate ARR up to Week 24. The ARR
reduction in the 40 mg dose group was 52% (0.251 vs 0.525 for placebo; nominal p <0.05),
compared with 21% and 37% in the 20 mg and 10 mg groups, respectively. Treatment with
ponesimod was associated with an increase in time to first confirmed relapse on treatment. The
hazard ratio for subjects treated with 40 mg ponesimod was 0.42 (95% confidence interval [CI]
0.20–0.87, p = 0.0189). In the 20 mg and 10 mg groups, the hazard ratio was 0.79 (95% CI 0.43,
1.45) and 0.64 (95% CI 0.33, 1.22), respectively.
Study AC-058B202 is a randomized, double-blind, parallel-group extension to study
AC-058B201, in which the long-term safety, tolerability, and efficacy of ponesimod in subjects
with RRMS are being investigated. Subjects who completed 24 weeks of treatment with
ponesimod in the core study were offered to continue treatment with ponesimod. Subjects who
completed 24 weeks of treatment with placebo were randomized in a 1:1:1 ratio to either 10, 20 or
40 mg ponesimod daily. The 10 mg and 40 mg dose levels were subsequently discontinued during
the extension study and all subjects were transitioned to the 20 mg dose level.

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The results from an interim analysis of study AC-058B201/B202 with cut-off date of 31 March
2019 have shown sustained low rates of MRI and clinical disease activity as well as low rates of
relapse and disability accumulation during long-term treatment with ponesimod for up to 9 years.
The model--adjusted ARR estimated with ponesimod 20 mg was approximately 0.15.
Study AC-058B301/OPTIMUM was a prospective, multicenter, randomized, double-blind, active
controlled, parallel group, Phase 3, superiority study. The study was designed to compare the
efficacy, safety, and tolerability of ponesimod 20 mg vs teriflunomide 14 mg in adult subjects with
relapsing MS over a treatment period of 108 weeks.
Results showed that ponesimod 20 mg statistically significantly reduced ARR (confirmed relapses)
by 30.5% compared to teriflunomide 14 mg (ARR = 0.202 for ponesimod 20 mg vs. 0.290 for
teriflunomide 14 mg, rate ratio: 0.695 [99% CL: 0.536: 0.902], p = 0.0003).
In addition, the change from baseline to Week 108 in fatigue (based on the Fatigue Symptom and
Impact Questionnaire-Relapsing Multiple Sclerosis [FSIQ-RMS] weekly symptoms score) was
statistically significantly lower in the ponesimod 20 mg arm compared with the teriflunomide
14 mg arm (mean = -0.01 for ponesimod 20 mg vs 3.56 for teriflunomide 14 mg, mean difference:
-3.57 [95% CL: -5.83: -1.32], p = 0.0019, where an increase from baseline indicates worsening in
fatigue symptoms).
Ponesimod 20 mg also statistically significantly reduced by 56% the number of CUALs between
baseline and Week 108 compared to teriflunomide 14 mg (mean CUALs per year = 1.405 for
ponesimod 20 mg vs. 3.164 for teriflunomide 14 mg, rate ratio: 0.44 [95% CL: 0.36: 0.54],
p <0.0001).
A 12-week CDA was observed in 10.1%, and 12.4% of subjects up to EOS in the ponesimod
20 mg and teriflunomide 14 mg arms, respectively (hazard ratio: 0.83 [95% CL, 0.58 to 1.18]; log-
rank p = 0.2939). A 24-week CDA was observed in 8.1%, and 9.9% of subjects up to EOS in the
ponesimod 20 mg and teriflunomide 14 mg arms, respectively. Exploratory analysis (not formally
tested as per testing procedure) showed that the hazard ratio: 0.84 (95% CL, 0.57 to 1.24]; log-
rank p = 0.3720).
More detailed information can be found in the IB [Ponesimod IB].
1.3.2.4  Safety and tolerability
Clinical studies to date have identified transient changes in heart rate (HR) and atrioventricular
(AV) conduction as the most prominent safety-related signal with ponesimod. Oral doses of
ponesimod resulted in dose-dependent sinus rate reductions in all treated subjects; the changes
were transient and resolved largely within 6−10 hours after dosing. In some subjects, these HR
reductions were accompanied by a transient effect on AV conduction with prolongation of the PR
interval on the electrocardiogram (ECG) and, occasionally, second degree AV-block. The effects
on HR and AV conduction diminish with repeated administration of ponesimod, indicating

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desensitization. To minimize the first-dose effects on HR and AV conduction, a dose up-titration
regimen was successfully tested and has been implemented in current clinical trials.
Difficulty in inspiration (dyspnea) and related pulmonary function test (PFT) changes have also
been detected in humans. Mild transient dyspnea/cough was noted frequently
2−6 hours after an oral dose of 40 mg or higher, and was associated with a clinically relevant
forced expiratory volume in 1 second (FEV1) decrease from baseline. Symptoms resolved
spontaneously upon discontinuation of treatment with ponesimod, and PFTs returned to baseline
upon drug discontinuation.
Elevations of aspartate transaminase (AST) and/or alanine aminotransferase (ALT) without any
bilirubin increase have been noted with ponesimod; they have been reversible upon
discontinuation of dosing. The changes were asymptomatic.
Individual cases of macular edema associated with changes in visual acuity have been observed in
subjects treated with ponesimod. These events resolved upon discontinuation of ponesimod.
Safety results from the completed OPTIMUM study and the interim analysis of the ongoing
AC-058B201/B202 study were consistent with previous studies and provide support for the long-
term safety of ponesimod. Results of the AC-058B301/OPTIMUM study also support the safety
and tolerability of the gradual ponesimod up-titration regimen.
 In the OPTIMUM study, the proportion of subjects who experienced at least one TEAE
was similar in both treatment arms (88.8% and 88.2% of subjects in the ponesimod 20 mg
and the teriflunomide 14 mg arms, respectively). The most common TEAEs in the
ponesimod 20 mg arm were ALT increased (19.5%), nasopharyngitis (19.3%), headache
(11.5%) and upper respiratory tract infections (10.6%). Initiation of ponesimod using the
gradual uptitration regimen (starting with ponesimod 2 mg) was not associated with
clinically significant bradyarrhythmia events; none of the reported bradyarrhythmia events
was serious or leading to discontinuation of treatment; no second- or higher degree AV
blocks were reported.
 In the interim analysis of AC-058B201/B202 (cut-off date of 31 March 2019), long-term
treatment with ponesimod was not associated with new safety or tolerability concerns.
Study AC-058B202 is ongoing. The results of the interim analysis support the long-term
benefit/risk profile of the 20 mg dose as the most optimal dose of ponesimod. Ponesimod
20 mg was shown to be safe and well tolerated in adults with RRMS over long-term
treatment of up to 9 years (median exposure to ponesimod in the 20 mg dose group of 8.02
years, corresponding to a total of 817 subject-years).

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Nonclinical safety testing of ponesimod indicates an embryotoxic and teratogenic potential.
Pregnant or lactating women are excluded from clinical trials, and women of childbearing potential
(WOCBP) must use reliable methods of contraception  and must not become pregnant during
exposure to the study treatment and for at least 30 days after study treatment discontinuation. A
hormonal contraceptive is allowed as one of the required methods of contraception, as the PK
profile of hormonal contraceptives has been shown not to be substantially altered in the presence
of ponesimod.
More detailed information can be found in the IB [Ponesimod IB].
1.4 Purpose and rationale of the study
The AC-058B303 study (extension study) is the long-term extension for the AC-058B301 study
(core study). The core study has been designed to investigate the efficacy, safety and tolerability
of ponesimod in subjects with RMS. The subjects are treated with either ponesimod or the active
comparator, teriflunomide. The purpose of this long-term extension of the core study is to
characterize the long-term safety and control of disease of ponesimod in subjects with RMS. In
particular, the study will allow to observe potential adverse events which may only occur after
long-term treatment with ponesimod. The study will also investigate the effect of re-initiation of
ponesimod after a brief interruption in a relatively large population (all subjects treated with
ponesimod in the core study and eligible for the extension study) on disease activity in terms of
relapses and MS-related MRI lesions. There is currently limited guidance on when a new MS
treatment should be started after discontinuation of teriflunomide and the study will contribute
with data on safety and efficacy of switching from teriflunomide to ponesimod after an interruption
as mandated by the protocol. The study will also allow confirmation of sustained efficacy of
ponesimod in terms of relapses, MRI lesions and reduction of disability accumulation during long-
term treatment. In addition, combined data from the core study together with the results of the
current extension study will allow comparison of MS activity in subjects who were switched from
teriflunomide to ponesimod versus those who were treated with ponesimod in both studies.
Published data from Phase 2 dose finding study AC-058B201 and preliminary data from its
extension study (AC-058B202) indicate that ponesimod at the dose used in this study (20 mg once
daily) has adequate efficacy in reducing disease activity in RMS patients.
Study AC-058B201 showed that ponesimod had clinically important and statistically significant
effects on the primary endpoint, which was the cumulative number of new MRI T1 Gdlesions
per patient recorded every 4 weeks from Weeks 12 to 24 after study treatment initiation as
compared to placebo. T1 Gdlesions are a well-recognized marker of MS disease activity and
prognostic marker of relapses.
In addition, preliminary data (with treatment up to 6.25 years with median exposure of
approximately 5.3 years) from extension study AC-058B202 demonstrated sustained effect on
MRI lesions and sustained low relapse rate. The observed reduction in circulating lymphocyte

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count associated with ponesimod treatment provides the biological plausibility for the observed
efficacy results.
The magnitude of effect of this dose of ponesimod on MRI lesions and relapse rates observed in
the Phase 2 studies, viewed in the context of published results from Phase 3 studies with
teriflunomide, supports the hypothesis that ponesimod may be superior to teriflunomide in terms
of frequency of relapses. The core study (AC-058B301) will formally test this hypothesis.
Therefore it seems justified to switch subjects who were treated with teriflunomide in the core
study to open-label ponesimod in the extension study and to continue treatment for 240 weeks or
until ponesimod is commercially available in the respective countries (see Section 3.2.3.1), unless
the overall data that will be submitted to Health Authorities do not support the approval of
ponesimod in the intended indication.
2 
STUDY OBJECTIVES
2.1 Safety objectives
 To describe the long-term safety and tolerability of ponesimod 20 mg in subjects with RMS.
 To describe the effects of re-initiation of ponesimod treatment after interruption in subjects
with RMS.
2.2 Efficacy objectives
 To describe the long-term disease control in subjects with RMS receiving ponesimod 20 mg.
 To describe the effect of a switch from teriflunomide to ponesimod 20 mg on disease control
in subjects with RMS.
3 OVERALL STUDY DESIGN AND PLAN
3.1 Study design
This study is a prospective, multicenter, open-label, non-comparative, long-term extension of the
Phase 3 confirmatory core study.
Subjects who have completed the 108-week treatment period in the core study will be enrolled into
one group treated with ponesimod 20 mg o.d. Based on anticipated discontinuation rates in the
core study, approximately 800 subjects are expected to enter the extension study.
The study will be conducted in approximately 160 sites in 28 countries.
3.2 Study periods
The extension study consists of a pre-treatment period, a treatment period, and a safety follow-up.
3.2.1 Core study follow up period and transition into the extension study
Eligible subjects may enter the extension study following the safety follow-up (FU) period of the
core study. For subjects transitioning into the extension study, the core study safety FU period

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concludes with a safety Follow-up Visit 1 (FU1) or with an abbreviated Follow-up Visit 2 (FU2)
at 1422 and 2337 days, respectively, after the last dose of the study drug in the core study (End-
of-Treatment; EOT). The abbreviated FU2 visit will take place only if the compliance with
teriflunomide elimination procedure was deemed not sufficient by the investigator at FU1 visit but
transition to the extension study is still planned.
The core study FU period ends when all assessments of FU1 or FU2 (whichever applies) have
been completed. At FU1 or FU2 (whichever applies) the subject’s compliance with teriflunomide
elimination procedure needs to be assessed as sufficient by the investigator in order to confirm
eligibility for the extension study.
3.2.2 Pre-treatment period
The pre-treatment period includes all pre-dose assessments of Visit 1 and starts when the subject
completes the core study FU visits FU1 or FU2 (whichever applies) and signs the informed
consent. This will be considered as the enrollment into the extension study.
Ideally, signing of informed consent will occur on the day of FU1 or FU2 visit (whichever applies).
In all cases, informed consent should be signed no later than one day after FU1 or FU2 visit
(whichever applies). Ideally, the assessment results of all inclusion and exclusion criteria will be
available when the informed consent is signed. In all cases, the assessment results of all inclusion
and exclusion criteria must be available prior to first dosing of study treatment.
The pre-treatment period ends with the first dose of study treatment (i.e., Day 1). The pre-treatment
period must not last longer than 7 days (i.e., signing of the informed consent until study treatment
initiation ≤ 7 days).
3.2.3 Treatment period
The treatment period starts with the first dose of study treatment, which defines Day 1 of the
extension study. All post-dose assessments of Visit 1 will be conducted during the treatment
period.
Ideally, all assessments and procedures of Visit 1, including first study treatment dosing and post-
dose cardiac monitoring, should occur on the same day as the core study FU1 or abbreviated FU2
(whichever applies). In all cases, all assessments and procedures of Visit 1 must be completed (i.e.,
study treatment start) no longer than 7 days after signing of the informed consent (start of Visit 1).
The time from last dose of study treatment in the OPTIMUM study to the first dose of ponesimod
in this study will last at least 14 days, but can last up to 44 days. The investigator should make
every effort to minimize the duration of the treatment interruption between EOT of the core study
and Day 1 of the extension study. Ideally, the treatment interruption should not last longer than
15days.
The treatment period consists of 240 weeks of treatment with ponesimod including a 14-day
gradual up-titration beginning on Day 1, followed by daily treatment with 20 mg ponesimod.

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Treatment will stop before 240 weeks if ponesimod becomes commercially available for the
treatment of multiple sclerosis in the subject’s country.
The visits during the treatment period will consist of an enrollment visit; three visits at 2 (i.e.,
15 days), 4, and 12 weeks after enrollment; and visits every 12 weeks thereafter until the EOT.
The treatment period may include a study treatment interruption period of variable duration [see
Section 5.1.12]. The permitted maximum duration of the study treatment interruption is 81 weeks
for planned pregnancies and 12 weeks for other reasons (if exceeded, then the subject will be
prematurely discontinued from the study). During the treatment interruption the subject will follow
the planned visit schedule off-treatment with the corresponding assessments with exceptions of
assessments that are contra-indicated due to the subject’s condition (e.g., in the event of pregnancy,
scheduled MRI assessments will not be performed).
3.2.3.1 End-of-treatment
The EOT visit will take place at Week 240 or at the time ponesimod is commercially available for
treatment of MS in the subject’s country (whichever occurs first). The EOT visit should preferably
take place 1 day after the last dose of study treatment but no later than 14 days after the last dose
of study treatment. The EOT may take place in case:
 of premature discontinuation of study treatment for subjects meeting the study specific
criteria for permanent discontinuation of study treatment described in Section 5.1.12;
 the sponsor decides to stop the extension study;
 the subject or the investigator decides to discontinue the study treatment;
 ponesimod is commercially available for the treatment of MS in the subject’s country.
In some countries, additional reimbursement negotiations and central formulary approvals will be
needed before ponesimod becomes available. In this case, patients participating in the
AC-058B303 study can continue to receive ponesimod until ponesimod is available in their local
country, or for a maximum of 240 weeks. Patients will get access to the study drug for a maximum
of 240 weeks. If ponesimod becomes available locally before the end of the 240 weeks in the
AC-058B303 extension study, then patients will be considered as having completed the extension
study and will be switched to commercially available supply if they wish to continue ponesimod
treatment. For these patients, the switch to commercially available ponesimod should occur at the
EOT visit, and commercially available ponesimod may be initiated on the day following last intake
of study treatment.
3.2.4 Safety follow-up
For an individual subject, End-of-Study (EOS) is reached when treatment and safety FU have been
completed. The EOS Visit should be performed 3044 days after the permanent discontinuation
of study treatment. If during study treatment interruption, the subject fulfills the criteria for

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premature discontinuation, the EOS visit should be scheduled as soon as possible after the decision
to prematurely discontinue has been taken.
The EOS visit and all assessments will also be conducted for subjects who have switched to
commercially available ponesimod.
The overall study design is depicted in Figure 1.
Figure 1 
Study design
EOT = End-of-Treatment; EOS = End-of-Study; V = Visit; FU = Follow-up; - - - = no study treatment.
3.2.5 Sub-studies
One of the four sub-studies performed during the core study will continue during the extension
study (i.e., the DLCO sub-study).
3.2.5.1 Pulmonary function monitoring
A sub-study assessing the diffusing capacity of the lungs, measured using carbon monoxide
(DLCO), will be continued in these subjects who participated in the sub-study in the core study.
Eligible subjects choosing to continue participation will provide consent under a separate informed
consent.

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3.2.5.2 Janssen COVID-19 vaccination sub-study
A sub-study using the Janssen COVID-19 vaccine (Ad26.COV2.S) was cancelled from Protocol
Version 6 onwards.
3.3 Study design rationale
This study is an open-label long-term extension of the core study. The purpose of this extension
study is to collect long-term safety and efficacy data and to provide ponesimod treatment to
subjects who completed the core study. Eligible subjects who have completed the core study
treatment may be enrolled to receive ponesimod 20 mg for a period of 240 weeks or until
ponesimod is commercially available. The study will be open-label since all the subjects will
receive ponesimod 20 mg o.d., in order to maximize the safety population exposed to ponesimod.
Although 
this 
is 
an 
open-label, 
non-comparative 
study, 
until 
introduction 
of
Protocol Amendment 2, EDSS / Functional system (FS) assessments were performed with the
efficacy assessor being blinded to safety, efficacy and other data as described in Section 3.4.3 to
limit bias.
Switching from double-blind setting in the core study will require a wash out period between the
end of treatment in the core study and the first dose of ponesimod in the extension study. In order
to keep the blind until the database lock in the core study, all the subjects will need to undergo the
accelerated elimination procedure of teriflunomide after EOT in the core study. The compliance
with the accelerated elimination procedure of teriflunomide will be assessed by the investigator
after the completed elimination procedure at FU1 Visit of the core study and, if deemed not
sufficient by the investigator also at the abbreviated FU2. The recommended compliance should
include intake of 33 doses of cholestyramine (8 g or 4 g) or 22 doses of activated charcoal (50 g).
The elimination procedure may take approximately 3 weeks to be completed and may be initiated
up to 7 days after the last day of study drug intake in the core study. The maximum interval between
the last dose of study drug in core study and the first dose of ponesimod in the extension study
might be up to 44 days (considering a maximum of 37 days from EOT to FU2 and a maximum of
7 days from FU2 to first dosing in the extension study). Ideally, the treatment interruption should
last no longer than 15 days, and Visit 1 should be completed the same day as or a day after core
study FU1 or abbreviated FU2 visits, whichever applies, and no longer than 7 days after these
visits. During this time the subjects will not receive any DMT for MS. Given the short duration of
interruption, no clinically important impact of this treatment interruption on the course of MS is
expected.
3.4 Site staff and their roles
In order to facilitate the performance of efficacy and safety 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.

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It is recommended that the designated personnel remain unchanged throughout the entire course
of the study and that an adequately trained back-up be designated to perform the assessments in
the event of absence of any ofthe staff listed below.
For each site, the preferred study staff will consist of:
 A principal investigator
 A treating neurologist (who may be the principal investigator)
 An efficacy assessor (who may be the principal investigator or treating neurologist)
 First dose administrator
 A clinical coordinator/study nurse (if required)
 MRI staff
 A radiologist/neuroradiologist or neurologist with MRI expertise
 An ophthalmologist
 A pulmonary function laboratory technician or expert
 A pulmonologist (only at sites participating in the DLCO sub-study)
 A dermatologist
3.4.1 Principal Investigator
The principal investigator must be an experienced neurologist or must name a sub-investigator
who is an experienced neurologist. The principal investigator is responsible for the overall conduct
of the study at the site. It is her/his responsibility to assign appropriate personnel to the protocol-
requested assessments (including safety and efficacy) and define their roles. This includes the
supervision of any external facility delegated with any study procedure/assessment for a subject.
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.
3.4.2 Treating neurologist
The treating neurologist is an experienced neurologist who may be the principal investigator. The
treating neurologist is responsible for subject clinical care and management, e.g., eligibility
evaluation, supervision of study treatment administration, reporting MS relapses on the specific
MS relapses pages of the electronic case report form (eCRF) [see Section 7.4.2 and
Section 10.1.6], monitoring of safety including recording and treating of adverse events (AEs),
physical examination (including neurological examination), routine laboratory results,
concomitant medications, blood pressure (BP), and ECGs. The treating neurologist may perform
the role of the efficacy assessor if qualified (see Section 3.4.3). The treating neurologist will have
access to the subject’s MRI images and/or reports from the local neurologist/radiologist or
neurologist with MRI expertise but not to the results of the central reading from the Medical Image
Analysis Center (MIAC). The exception is incidental findings with safety concerns discovered
during central MRI reading. In this event, the central MRI reading will send an incidental finding
report to the site.

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It is the responsibility of the treating neurologist to explain the study in all its aspects to the subject
and obtain her/his informed consent. The treating neurologist will be responsible for emphasizing
the need for reliable contraception methods and explaining such methods to the female participants
who are WOCBP and for explaining to the fertile male participants the need for using condoms
and the need for their female partners of childbearing potential to use reliable methods of
contraception for the period defined in this protocol [Section 4.4].
The treating neurologist is responsible for the medical management of the subject experiencing
cardiac events of clinical concern occurring at any time during the study treatment and not already
evaluated by the first-dose administrator. In these events, the treating neurologist may consult with
the first-dose administrator and/or a cardiologist. In case of acute cardiac events, she/he may refer
the subject to a cardiologist to receive emergency care and treatment.
The same physician must maintain the role of the treating neurologist for a given subject
throughout the study. A back-up treating neurologist may conduct a subject study visit only if the
primary treating neurologist is not available.
3.4.3 Efficacy assessor
The efficacy assessor is a physician or a qualified health care provider with clinical experience in
the medical treatment and care of patients with MS. She/he will perform the detailed neurological
examination for obtaining the EDSS/FS scores using the “Neurostatus” scoring documents [see
Appendix 1] according to the protocol schedule, as well as EDSS/FS scores at every unscheduled
visit for confirmation of relapse. The treating neurologist may perform the role of the efficacy
assessor if qualified.
To ensure consistency across sites, the efficacy assessor must be trained and certified on EDSS/FS
scoring prior to enrollment of the first subject at the study site. Through this training, the efficacy
assessor will become familiar with the EDSS/FS scoring and “Neurostatus” scoring documents
using an interactive “Neurostatus” Training DVD-ROM that will be provided to the site.
Certification, consisting of the “Neurostatus e-Test” web-based interactive test, will be assessed
prior to enrollment of the first subject at the study site and every two years thereafter. Training and
certification achieved during the core study are acceptable.
A back-up efficacy assessor may conduct neurological examination and EDSS/FS scoring if the
primary efficacy assessor is not available. This back-up efficacy assessor must be trained and
certified in EDSS/FS scoring (see above) and capable to ensure consistency in EDSS/FS scoring
with the primary efficacy assessor.
The efficacy assessor may be in charge of administering the Multiple Sclerosis Functional
Composite (MSFC) test.

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3.4.4 First-dose administrator
The first-dose administrator must be a physician capable of making healthcare decisions based on
ECG interpretation reports provided in a timely manner by the central ECG laboratory, and
experienced in the evaluation of BP and clinical signs or symptoms. If the first-dose administrator
is adequately trained and experienced in cardiology, she/he will make healthcare decisions solely
based on her/his own interpretation of the ECG (in which case expedited central reading of the
ECGs by the central ECG laboratory will not be required).
He/she must be qualified and equipped to provide emergency treatment in cases of acute cardiac
events. In case of the occurrence of such events, and if first-dose administrator is not adequately
trained and experienced in cardiology and is not equipped to provide emergency treatment, she/he
will refer the subject to a cardiologist to receive emergency treatment. The principal investigator /
treating neurologist may perform this role if qualified. The first-dose administrator is not required
to dispense ponesimod to the subject.
She/he is responsible for oversight of all BP and ECG assessments requested by the protocol at
Visit 1 (Day 1) and at visits for re-initiation of study treatment. This includes the close monitoring
of the subject during the first 4 hours and up to 12 hours following study treatment intake [see
Sections 5.1.9 and 5.1.10]. She/he will independently assess eligibility for discharge or continued
subject management on Visit 1 and on visits for re-initiation of study treatment where post-dose
monitoring is required. The confirmation of discharge of the subject will be documented in the
source documents. Depending on the setting at the site, the first-dose administrator may also be
responsible for the conduct of all BP and ECG assessments requested by the protocol during the
study. While the exams themselves may be performed by a delegate (e.g., a study nurse), the
review and interpretation must be performed by the physician.
If applicable, he/she will support the principal investigator in making a decision on eligibility of
the subject prior to enrollment, and on providing adequate treatment in cases of cardiac events.
Significant findings, which in the view of the first-dose administrator meet the definition of an AE,
must be reported to the principal investigator and recorded on the Adverse Event page of the eCRF.
Any cardiac events of potential clinical concern on Day 1 and on the first day of re-initiation of
study drug must be assessed by the first-dose administrator for seriousness, reported to the
principal investigator, and recorded on the AE page of the eCRF. In addition, the first-dose
administrator should determine the need for medical management and assist the treating
neurologist in deciding what actions should be taken on study treatment, if any. In these events,
the first-dose administrator may consult with a cardiologist.
3.4.5 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 neurologist in all aspects of subject
management. She/he will be responsible for scheduling visits and assessments as planned in the

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study protocol, recording concomitant medications, maintaining source documentation, and
transcription of data into the eCRF. She/he will instruct the subjects on study treatment
administration, and collect, process, and send all blood samples to the central laboratory.
Additionally, she/he may be responsible for coordinating the conduct of:
 MRI
 PFTs
 Ophthalmological and cardiac examination [see Section 3.4.4]
 MSFC score
 Symbol Digit Modalities Test (SDMT)
In the absence of a clinical coordinator / study nurse, the above tasks will be performed by the
principal investigator or a treating neurologist.
3.4.6 MRI staff
The MRI staff will be responsible for performing the MRI investigations according to the study
MRI manual (separate document). Original data will be exported to the MIAC, c/o University
Hospital Basel, Switzerland, and primary data will be stored at the study site.
3.4.7 Local neurologist/radiologist or neurologist with MRI expertise
The local neuroradiologist or a neurologist with MRI expertise will review the MRI images for
safety purposes and provide access to the subject’s MRI images and/or reports to the principal
investigator / treating neurologist. Significant findings, which, in view of the local
neuroradiologist, meet the definition of an AE must be assessed for seriousness, reported to the
principal investigator / treating neurologist and recorded on the AE page of the eCRF. In the event
of safety findings of potential clinical concern observed on the MRI scans at any visit during the
study, the local neuroradiologist will conduct further examination, as per local standard practice,
to rule out or confirm the diagnosis. This also applies to incidental findings with safety concerns
that have been detected during central MRI reading at MIAC and communicated to the local
radiologist.
3.4.8 Ophthalmologist
The ophthalmologist will review and interpret the ophthalmological examinations and optical
coherence tomography (OCT)1 assessments as scheduled in the study protocol [see Section 7.5.7
and 7.5.8]. In the event of suspected clinically significant findings (e.g., macular edema or active
uveitis), an unscheduled OCT examination should be performed by the ophthalmologist, and the
principal investigator / treating neurologist will be notified for reporting of an AE on the AE page
of the eCRF. In the event of findings observed at any visit during the study, the ophthalmologist
1 
Scheduled OCT assessments are only applicable to Global Protocol version 1 to 5. The requirement for scheduled OCT
assessments was removed from Protocol Version 6 onwards.

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will conduct further examination, as per local standard practice, to rule out or confirm the
diagnosis.
3.4.9 Pulmonary function laboratory technician or expert
The PFTs must be performed by experienced staff, such as a pulmonary function technician or
expert, according to the American Thoracic Society / European Respiratory Society (ATS/ERS)
guidelines [Miller 2005a].
3.4.10 Pulmonologist
At sites participating in the DLCO sub-study, a pulmonologist or a physician adequately trained in
respiratory medicine will review DLCO  results. If clinically significant alterations in DLCO
variables indicating a pulmonary condition that could result in increased risk for the subject are
observed, she/he may be prematurely discontinued from the study treatment at the discretion of
the principal investigator / treating neurologist. Significant findings, which in view of the
pulmonologist meet the definition of an AE, must be reported to the principal investigator / treating
neurologist and recorded on the AE page of the eCRF. In the event of findings observed at any
visit during the study, the pulmonologist will conduct further examination, as per local standard
practice, to rule out or confirm the diagnosis.
3.4.11 Dermatologist
A dermatologist will perform a complete skin examination as indicated in Table 1 and Table 2.
Significant findings, which in view of the dermatologist meet the definition of an AE, must be
reported to the principal investigator / treating neurologist and recorded on the AE page of the
eCRF. In the event of findings observed at any visit during the study, the dermatologist will
conduct further examinations, as per local standard practice, to rule out or confirm the diagnosis.
3.5 Study committees
3.5.1 Independent Data Monitoring Committee
The Independent Data Monitoring Committee (IDMC) responsible for monitoring the core study
has continued its duties for the extension study, until its disbandment which occurred on 30th
September 2021. It was composed of physicians with relevant medical expertise. The composition
and operation of the IDMC was described in the IDMC charter.
3.5.1.1 Independent Statistical Analysis Center
An independent Statistical Analysis Center (ISAC, Frontier Science), not otherwise involved in
study conduct or statistical analysis, will generate all analysis reports required throughout the trial
period, exclusively for review by the IDMC (including if required unblinded analysis by treatment
allocation in the core study). The reports will be generated from efficacy and safety data
periodically transferred by the sponsor to the ISAC.

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3.5.2 Ophthalmology Safety Board
An Ophthalmology Safety Board (OSB) composed of two independent ophthalmologists will
review and evaluate any new or suspected cases of macular edema. The composition and operation
of the OSB is described in the OSB charter. From Protocol Version 6 onwards, the OSB will be
decommissioned as macular edema is considered a well characterized identified risk with
treatment with ponesimod.
3.5.3 Major adverse cardiovascular events adjudication board
A major adverse cardiovascular events (MACE) adjudication board will review and evaluate the
MACE reported in the study. The selection of AEs that will be sent for adjudication will be based
on a pre-defined list of preferred terms belonging to relevant Standardized MedDRA Queries. For
each AE sent for MACE adjudication, the MACE adjudication board will determine whether the
event belongs or does not belong to one of the pre-specified categories, including cardiovascular
death, myocardial infarction, or stroke.
The composition and operations of MACE adjudication board will be described in the MACE
adjudication board charter.
4 
SUBJECT POPULATION
4.1 Subject population description
This study will enroll adult male and female subjects who have completed the 108-week treatment
period in the core study. These subjects were determined to have an established diagnosis of MS,
as defined by the 2010 revision of McDonald Diagnostic Criteria [Polman 2011], with relapsing
course from onset (i.e., RRMS and SPMS with superimposed relapses).
4.2 Inclusion criteria
1. Signed informed consent, prior to initiation of any study-mandated procedure.
2. Subjects with MS having completed the double-blind treatment in the core study as scheduled
(i.e., who completed the double-blind treatment period until Week 108).
3. Compliance with the teriflunomide elimination procedure assessed as sufficient by the
investigator at visit FU1 or abbreviated visit FU2 of the core study, whichever occurred last
(the recommended compliance should include intake of 33 doses of cholestyramine (8 g or 4 g)
or 22 doses of activated charcoal (50 g).
4. For subjects of reproductive potential: #
 Women of childbearing potential (WOCBP):
 Must have a negative pre-treatment urine pregnancy test on Day 1;
 Must agree to undertake 4-weekly urine pregnancy tests during the study and until
6 weeks after the first of two consecutive tests showing teriflunomide plasma level
<0.02 mg/L and until at least 30 days after study treatment discontinuation;
 Must have been using reliable methods of contraception uninterrupted since EOT in the
core study and must agree to continue using reliable methods of contraception

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throughout the study until 6 weeks after the first of two consecutive tests showing
teriflunomide plasma level <0.02 mg/L and until at least 30 days after discontinuation
of study treatment.
 Fertile male subjects participating in the study who are sexually active with WOCBP must
agree to use a condom until 6 weeks after the first of two consecutive tests confirming
plasma teriflunomide level <0.02 mg/L.
Definition of WOCBP, fertile male subjects and the acceptable methods of contraception for
this study are described in Section 4.4.
Women who interrupt the study treatment because of planned pregnancy will be exempt from
any protocol-mandated pregnancy tests after the first positive urine pregnancy test and until
30 days before study drug re-initiation. These women will also interrupt contraception 30 days
after the study treatment interruption and until after delivery [see Section 5.1.12.4].
# The inclusion criterion 4 was valid for all subjects throughout the recruitment period. Following approval of
protocol version 5 (by which time all subjects had been off teriflunomide for over 2 years), teriflunomide plasma
testing is no longer required.
4.3 Exclusion criteria
1. Any of the following cardiovascular conditions on Day 1 pre-dose:
a. Resting heart rate (HR) <50 beats per minute (bpm) as measured by the pre-dose 12-lead
ECG;
b. Presence of second or third degree atrioventricular (AV) block or a QT interval corrected
for heart rate on the basis of Fridericia’s formula (QTcF) >470 ms (females), >450 ms
(males) on pre-dose 12-lead ECG.
2. Any of the following alerts from central laboratory at Visit 14 of the core study (EOT) which
was confirmed as an alert at repeated testing or not repeated prior to FU1 of the core study:
a. Lymphocyte count: <0.2 × 109/L (<200/mm3 blinded results);
b. Neutrophil count <1.0 × 109/L (<1000 cells/mm3);
c. Platelet count <50 × 109/L (<50 000 cells/mm3);
d. Creatinine clearance <30 mL/min (Cockroft-Gault).
3. At Visit 14 of the core study (EOT) >30% decrease from core study baseline FEV1 and/or
forced vital capacity (FVC);
4. Clinically significant, persistent respiratory AEs (e.g., dyspnea) not resolved prior to first
dosing in the extension study.
5. Macular edema at any time between Visit 1 (Screening) in the core study and Day 1 of
extension study.
6. Presence of the following at core study Visit 14 (EOT, Week 108), FU1, or abbreviated visit
FU2, or on Day 1 (pre-dose) of the extension study:

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a. Suspected opportunistic infection of the CNS or any other infection which, in the opinion
of the investigator, contraindicates re-start of the study drug;
b. Stevens-Johnson syndrome or toxic epidermal necrolysis or drug reaction with eosinophilia
and systemic symptoms.
7. Need for and intention to administer forbidden study-treatment-concomitant therapy;
8. Women who are pregnant or lactating;
9. Male subjects wishing to father a child any time before the 6 week period following the first
of two consecutive tests confirming plasma teriflunomide level <0.02 mg/L;
10. Treatment with any MS DMTs between core study EOT and first dosing in extension study;
11. Any other clinically relevant medical or surgical condition, which, in the opinion of the
investigator, would put the subject at risk by participating in the study;
12. Subjects unlikely to comply with protocol, e.g., uncooperative attitude, inability to return for
follow-up visits, or known likelihood of not completing the study including mental condition
rendering the subject unable to understand the nature, scope, and possible consequences of the
study.
4.4 Subjects of reproductive potential
WOCBP and fertile male subjects participating in the study must agree that they will take means
to reduce reproductivity risk as defined in the following sections.
4.4.1 Women of childbearing potential
A woman is considered to be of childbearing potential unless she meets at least one of the
following criteria:
 Previous 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).
WOCBP participating in the study must have been using one of the following reliable methods of
contraception uninterrupted since EOT in the core study, and must agree to continue using these
methods of contraception treatment until 6 weeks after the first of two consecutive tests showing
teriflunomide plasma level <0.02 mg/L and until at least 30 days after discontinuation of study
treatment:
 Two methods of contraception, one from Group 1 and one from Group 2, defined as follows:
– 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 30 days prior to enrollment.
– Group 2: Female or male condoms, diaphragm or cervical cap.
OR

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 True abstinence from intercourse with a male partner only when this is in line with the preferred
lifestyle of the subject.
OR
 Permanent female sterilization (tubal occlusion/ligation at least 6 weeks prior to enrollment).
OR
 Sterilization of the male partner with documented post-vasectomy confirmation of the absence
of sperm in the ejaculate.
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.
4.4.2 Fertile male subject
A fertile male is defined as physiologically capable of conceiving offspring.
Fertile male subjects participating in the study who are sexually active with WOCBP must agree
to use a condom for up to 6 weeks after the first of two tests showing teriflunomide plasma level
<0.02 mg/L# and not to father a child during this period. Female partners of fertile male subjects,
if WOCBP, will need to use effective methods of contraception# [Aubagio® USPI, Aubagio®
SmPC], as recommended by the investigator during the same period.
# Important note: Teriflunomide testing is no longer required with the approval of protocol version 5. In
consequence, there are no longer any restrictions with regards to male subjects who intend to have a child.
4.5 Medical history
4.5.1 Ongoing medical history from the core study
Clinically significant past or concomitant disease or diagnosis ongoing from the core study and
ongoing at enrollment of the extension study is collected in the extension study eCRF prior to
enrollment.
4.5.2 Additional medical history not reported in the core study
Any new or additional clinically significant past or concomitant disease or diagnosis that cannot
be reported in the core study database is collected in the extension study eCRF prior to enrollment.
4.5.3 MS disease history
Complications or symptoms associated with MS present within 24 months prior to the core study
and ongoing at enrollment of the extension study are collected in the extension study eCRF prior
to enrollment.

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4.5.4 MS disease changes
Any MS disease (e.g., RRMS or SPMS with superimposed relapses) changes since the subject
entered the core study are collected in the extension study eCRF prior to enrollment.
5 TREATMENTS
5.1 Study treatment
The study treatment is the investigational drug ponesimod. The treatment period consists of an up-
titration period (from Day 1 to 14) and a maintenance period (Day 15 until EOT). Ponesimod dose
is increased over 15 days until a maintenance dose of 20 mg is reached.
Note that the term “study treatment” or “study drug” refers to study medication provided by the
sponsor, as opposed to “commercially available ponesimod” that may be started after
discontinuation of study treatment.
5.1.1 Investigational treatment: description and rationale
Ponesimod is supplied as its free base, in oral film-coated tablets at the doses of 2, 3, 4, 5, 6, 7, 8,
9, 10, and 20 mg. One tablet of ponesimod 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg will be taken orally o.d.
during the up-titration period (Day 1 to 14). During the maintenance period, one tablet of
ponesimod 20 mg will be taken orally o.d.
5.1.2 Study treatment administration
5.1.2.1 Up-titration (performed by IVRS)
A gradual up-titration of ponesimod from a 2 mg starting dose to a 20 mg maintenance dose over
a period of 14 days was found to successfully mitigate first-dose effects. This 2 week up-titration
regimen will be implemented in the study on initiation of treatment (Day 1) and on days of re-
initiation of treatment following treatment interruption of 4 days or more [see Section 5.1.9].

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5.1.4 Blinding
The treatment groups in the core study remained blinded until the randomization list was revealed
for the core study.
5.1.5 Study treatment supply
Manufacturing, labeling, packaging, and supply of study treatment will be conducted according to
Good Manufacturing Practice (GMP), Good Clinical Practice (GCP), and any local or national
regulatory requirements.
All study treatment supplies are to be used only in accordance with this protocol, and not for any
other purpose.
5.1.5.1 Study treatment packaging and labeling
5.1.5.1.1 Studytreatment packaging
Study treatment is provided as tablets and supplied in blister packs or bottles.
5.1.5.1.2 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.
5.1.5.2 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.
5.1.5.3  Study treatment dispensing
The subjects will receive sufficient study treatment to cover the period up to the next scheduled
visit. Alternatively, scheduled study medication dispensing/return procedures may be adapted
according to the site practice (i.e., if the subject comes to the investigational site more frequently
than the scheduled visits, it is then possible to dispense medication in smaller quantities). Subjects
are asked to return all used, partially used and unused study treatment blister packs/bottles at each
visit. If the subject forgets to bring the remaining study treatment to a study visit, she/he must be
instructed not to take any tablets from the remaining study treatment, and to bring the remaining
study treatment to the next visit.
An accurate record of the date and amount of study treatment dispensed to each subject must be
available for inspection at any time.
5.1.5.4  Study treatment return and destruction
On an ongoing basis and/or on termination of the study, the monitor will collect used and unused
subject kits. The return to the sponsor of unused study drug, or used returned study drug for
destruction, will be documented on the investigational product destruction form. When the study

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site is an authorized destruction unit and study intervention supplies are destroyed on-site, this
must also be documented on the investigational product destruction form.
5.1.6 Study treatment accountability and compliance with study treatment
5.1.6.1 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 IMP dispensing and accountability log as well as in the eCRF, and
checked by the Clinical Research Associate (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 unit dispensed to the subject:
 Dispensed kit number
 Date dispensed / Number of tablets dispensed.
 Date returned / Number of tablets returned.
All study treatment supplies, including partially used or empty blisters/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 from the remaining study treatment and to bring it at the next visit.
5.1.6.2 Study treatment compliance
Study treatment compliance is based on study treatment accountability. Study treatment
compliance will be calculated at each visit using the formula defined below:
Compliance =
[(number of tablets dispensed number of tablets returned) / total number of tablets that should
have been taken during the period*] 100
*The period is defined as the number of days between visits and is equal to the number of tablets that
should have been taken.
5.1.7 Accelerated elimination of teriflunomide and duration of continued contraception
Approximately half of the subjects in the core study received teriflunomide as their study
treatment, but due to blinding, all subjects will undergo an accelerated elimination procedure
followed by an assessment of compliance to the elimination procedure prior to administration of
the first dose of ponesimod in the extension study.
During the early stages of the study (protocol versions 1 through 4), additional plasma
teriflunomide tests may have been required to confirm that teriflunomide plasma levels were
sufficiently low (<0.02 mg/L) before fertile male participants could stop contraceptive
requirements and in the case of planned pregnancies (see Section 5.1.12.5). Following approval of

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protocol version 5, these tests are no longer required now that all ongoing subjects have been off
teriflunomide for over 2 years (last subject entered this extension study on 20-May-2019)
[Aubagio® USPI, Aubagio® SmPC].
5.1.8 Study treatment dose adjustments and interruptions
Study treatment up-titration, other than described in Section 5.1.2, is prohibited. Study treatment
down-titration is not foreseen in any situation and is prohibited.
Study treatment interruption should be avoided. If study treatment intake is interrupted by the
subject for any reason, she/he must immediately inform the investigator / treating neurologist.
Study treatment may be temporarily interrupted in response to an AE, a diagnostic or therapeutic
procedure, a laboratory abnormality, vaccination (see Section 5.2.3), or for administrative reasons.
Study-specific criteria for interruption of study treatment are described in Section 5.1.12. The
permitted maximum duration of the study treatment interruption is 81 weeks for planned
pregnancies and 12 weeks for other reasons (if exceeded, the subject will then be prematurely
discontinued from the study).
Detailed guidance on how to re-initiate study treatment in the event of drug interruption is provided
in Section 5.1.9.
Study treatment dose interruptions must be recorded in the eCRF.
5.1.9 Guidance for re-initiation of study treatment in the event of study treatment
interruption
If study treatment intake (up-titration or maintenance phases) is interrupted by the subject for any
reason, she/he must immediately inform the principal investigator / treating neurologist.
The following guidance is provided for re-initiation of investigational study treatment after study
treatment interruptions.
A schematic overview of the re-initiation algorithm is given below in Figure 2.
Depending on the day, time, and duration of study treatment interruption, the following procedures
will be followed.
 If the subject missed taking the dose in the morning:
– The dose should be taken at any time on the same day.
– Regular dosing should be resumed with the morning dose on the following day.
 If the subject missed taking the dose for up to three consecutive days:
– Dosing should be resumed in the morning, with the same dose taken prior to study
treatment interruption.
– Study treatment intake may be re-initiated by the subject at home.

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– 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 taking the dose of ponesimod for four or more consecutive days, then the
original up-titration scheme for the investigational study treatment needs to be re-applied.
1. Subjects with cardiovascular risk factors (i.e., meeting any of the below-listed Criteria for
Cardiac Monitoring at Site) will require cardiac monitoring and therefore must have their re-
initiation of study drug performed at the site. On the day of the re-initiation of ponesimod, the
subject must be monitored for at least 4 hours post-dose, following the cardiac assessment
schedule and applying the discharge criteria as described in Section 5.1.10.
Criteria for Cardiac Monitoring at Site (cardiovascular risk factors):
 Sinus bradycardia HR <55 bpm
 History or presence during the study of first or second-degree Mobitz type I AV block
 History or presence during the study of myocardial infarction or heart failure
In the event of a re-initiation, the treating neurologist may consult with the first-dose
administrator and/or a cardiologist to determine the most appropriate monitoring strategy.
Cardiology advice should be sought in case of history or presence during the study of the
following conditions or abnormalities:
 Atrial flutter, fibrillation or any other arrhythmias treated with anti-arrhythmic drugs;
 Unstable ischemic heart disease or cardiac decompensated failure;
 Cardiac arrest or cerebrovascular disease (e.g., transient ischemic attack, stroke);
 Mobitz Type II second-degree heart block, sick sinus syndrome or sino-atrial heart block;
 Subjects receiving concomitant therapy with drugs that decrease HR (e.g., beta-blockers,
calcium channel blockers and other drugs that may decrease HR).
2. Subjects who do not meet any of the Criteria for Cardiac Monitoring at Site (as confirmed at
pre-dose ECG assessment) may either re-initiate the study drug at home after receiving up-
titration kit from the site or re-initiate study drug at site and be monitored for at least 4 hours
post-dose at the discretion of the investigator / treating neurologist (see Section 8.5.3). Subjects
re-initiating study drug at home must be instructed to contact the investigator or local

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emergency facilities immediately if they experience any cardiac adverse effects including
symptoms of potential bradycardia (e.g., dizziness, vertigo, syncope). The additional visit
14 days (1 day) after the day of re-initiation (Day 15) (see Section 8.5.3) may be scheduled
at the discretion of the investigator / treating neurologist.
Figure 2 
Algorithm for management of treatment interruptions
Whenever the investigator / treating neurologist becomes aware that the subject did not report
having missed the study treatment intake for one or more days during up-titration or four or more
days during maintenance and has continued dosing, the subject should be interviewed by the
investigator / treating neurologist for any symptoms related to bradycardia, and further
examinations (e.g., 12-lead ECG, BP measurement) may be performed at the discretion of the
investigator / treating neurologist. Based on an assessment of the clinical findings and the
likelihood of subject’s adherence to treatment, the investigator / treating neurologist will determine
whether the subject can continue regular dosing, needs to re-initiate treatment, or should
permanently discontinue treatment.

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5.1.10 Criteria for discharge from cardiac monitoring on Day 1, and on the first day of
re-initiation of the investigational study treatment following treatment interruptions
At the time of discharge from cardiac monitoring (i.e., when the evaluation of the pre-dose and all
the hourly post-dose ECGs until 4 hours post-dose have been obtained) 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 and QTcF increase from pre-dose <60 ms;
 No persisting significant ECG abnormality (e.g., AV block second or third degree) or ongoing
AE requiring continued cardiac monitoring or prohibiting study continuation as an out-patient.
If the subject does not meet the discharge criteria (as described above) at 4 hours post-dose, the
subject should be carefully monitored for an additional period, and a 12-lead ECG and BP
measurement must be performed every hour. The subject can be discharged from  cardiac
monitoring as soon as the above criteria are met.
Should the subject not meet the criteria for discharge from cardiac monitoring at 12 hours post-
dose, she/he must be prematurely discontinued from study treatment. Subjects who are
prematurely discontinued should not be discharged from cardiac monitoring before vital signs
return to near baseline values in the extension study, or until there is no persisting ECG
abnormality (e.g., AV block second degree or higher), ongoing AE requiring continued cardiac
monitoring, or until medically indicated.
5.1.11 Premature discontinuation of study treatment
In the study, the premature discontinuation of study treatment is defined as a permanent
discontinuation of study treatment earlier than the planned treatment duration of 240 weeks or
ponesimod is commercially available. The decision to prematurely discontinue study treatment
may be made by the subject, the investigator, or the sponsor.
A subject has the right to prematurely discontinue study treatment at any time by withdrawal from
treatment only, or by withdrawal from treatment and any further participation in the study.
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. In the
event of clinically significant progression of the disease as judged by the investigator, the
investigator should consider switching to another potentially more effective therapy, discuss
alternative treatment options with the subject, and document the outcome of this discussion in the
medical records.

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Premature discontinuation of study treatment may also result from a decision by the sponsor, e.g.,
in the event of premature termination or suspension ofthe study [see Section 9.3].
The main reason for discontinuation of study treatment, and whether the discontinuation of study
treatment is the decision of the subject, the investigator, or the sponsor must be documented in the
eCRF.
A subject who prematurely discontinues study treatment and withdraws consent to participate in
any further study assessments is considered withdrawn from the study. Subjects who die or are
lost to FU are also considered as withdrawn from the study. Withdrawal from the study and FU
medical care of subjects withdrawn from the study is described in Sections 9.2 and 9.4,
respectively.
In the event of premature discontinuation from study treatment due to any reason, the investigator
should consider prescribing appropriate treatment for MS according to the local clinical practice
and availability. The investigator should exercise caution when considering the switch to another
immunomodulatory MS treatment.
5.1.12 Study-specific criteria for interruption / premature discontinuation of study
treatment and management of clinically relevant events
5.1.12.1 Cardiovascular
Subjects must be prematurely discontinued from study treatment if:
 The following change in HR is observed at any time throughout the study, as documented by
12-lead ECG:
– HR <30 bpm, or
– HR <40 bpm is sustained for at least 1 hour and is associated with symptoms of
bradycardia (e.g., syncope, dizziness, or vertigo), or
 QTcF >500 ms is observed at any time throughout the study, as documented by 12-lead ECG,
or
 The subject does not meet the criteria for discharge from cardiac monitoring on Day 1, or on
the first day of re-initiation of study treatment following drug interruptions, if applicable, after
12 hours post dose monitoring.
FU monitoring must be provided until the event leading to study treatment discontinuation
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 in the extension study and until there is no persisting ECG abnormality (e.g., QT
prolongation, AV block second degree or higher) or ongoing AE requiring (continued) cardiac

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monitoring, or until medically indicated. Any clinically relevant finding meeting the definition of
an AE will be recorded accordingly in the eCRF.
In the event of any clinical signs or symptoms of bradycardia or other arrhythmia (e.g., syncope,
palpitations, etc.), at any time during the study treatment, the first-dose administrator and/or a
cardiologist may be consulted. If a cardiac origin is suspected, premature discontinuation of study
treatment should be considered.
If subjects experience sustained de novo or worsening of pre-existing hypertension during the
course of treatment with the study treatment which, in the opinion of the investigator, cannot be
adequately controlled by medication, study treatment should be prematurely discontinued.
5.1.12.2 Hematological abnormalities
Subjects must be prematurely discontinued from study treatment at any time throughout the study
in the event of:
 Confirmed total lymphocyte count <0.2 × 109/L (<200 cells/mm3)
Confirmation will be carried out as follows:
Whenever a total lymphocyte count <0.2 × 109/L, is recorded by the central laboratory, an alert
will be sent to the principal investigator and the sponsor. The principal investigator will
immediately contact the subject and ask her/him to return to the site preferably within 48 hours
but no later than within 1 week to repeat the test at trough level (pre-dose) with the central
laboratory (unless the clinical situation mandates immediate local testing). If the repeat test
confirms a total lymphocyte count <0.2 × 109/L the study treatment must be discontinued.
Lymphocyte counts must be monitored at least once a week by the central laboratory until the
lymphocyte count has returned to ≥0.8 × 109/L or ≥80% of the baseline value in the extension
study. Any clinically relevant finding meeting the definition of an AE will be recorded accordingly
in the eCRF.
In the event of a clinically relevant infection (e.g., opportunistic infection, serious infection), the
study treatment may be interrupted and the subject referred to an expert in infectious diseases for
further examination and treatment at the discretion of the investigator. In the event of study
treatment interruption, the subject will be closely observed, and if the infection is resolved or not
confirmed and the benefit/risk balance is considered acceptable for the subject to resume study
treatment, the study treatment may be re-initiated at the discretion of the investigator.
In the event of premature discontinuation from study treatment due to infection, adequate treatment
needs to be provided and the subject monitored until complete resolution of the infection.
A guidance for screening and monitoring of subjects for opportunistic infection is provided in
Sections 5.1.12.2.1 and 5.1.12.2.2. Subjects must be advised to be proactive and alert in reporting

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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 opportunistic infection in the CNS, unscheduled brain MRI scans may
be performed at the investigator’s request.
5.1.12.2.1 Guidance for exclusion and on-treatment monitoring of subjects for progressive
multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the CNS that
can lead to death or severe disability. Active replication of the human polyoma John Cunningham
Virus (JCV) in glial cells of the brain, causing lytic death in oligodendrocytes, is the underlying
pathobiology of PML. The infection typically arises in severely immunocompromised subjects,
e.g., those with HIV infection, malignant disease, or transplanted organs. Development of PML is
extremely rare in immunocompetent individuals. People with autoimmune rheumatic diseases,
especially systemic lupus erythematosus, are also at higher risk of PML [Kappos 2011].
MS subjects treated with natalizumab are at increased risk of developing PML. In addition to
natalizumab, cases of PML have been reported in subjects treated with various drugs, usually in
combination with corticosteroids, including alkylating agents (e.g., cyclophosphamide,
carmustine, and dacarbazine), purine analogues (e.g., fludarabine, cladribine, and azathioprine),
immunosuppressants (e.g., ciclosporin, tacrolimus, sirolimus, and mycophenolate), therapeutic
monoclonal antibodies (e.g., rituximab, infliximab, etanercept, basiliximab, daclizumab,
efalizumab, alemtuzumab, and muromonab-CD3) [Kappos 2011] and, in rare instances in subjects
treated with fingolimod or dimethyl fumarate.
Clinical features indicative of PML are:
 Subacute onset;
 Occurs over several weeks and is progressive;
 Clinical presentation includes aphasia, behavioral and neurophysiological alteration,
retrochiasmal visual deficits, hemiparesis, and seizures.
For subjects with prior exposure to natalizumab or other immunosuppressive agents who have
been enrolled in the core study and who, under the study treatment, present new neurological
symptoms suggestive of pathology other than MS, the investigator should consider PML or another
opportunistic infection of the CNS and, in the event of clinical features indicative of these
conditions, the following diagnostic procedures are recommended:
 Perform MRI including T1 sequences with Gd (and additional sequences if needed), and
include comparison with the previous MRI images in the interpretation of the MRI results;
 Interrupt study treatment until PML or other opportunistic CNS infection has been excluded
with confidence;

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 Perform  lumbar puncture and send cerebrospinal fluid (CSF) for JCV DNA testing by
polymerase chain reaction (PCR) with an ultrasensitive assay. The JCV DNA assay should be
based on quantitative real time PCR to maximize sensitivity and specificity for detection, and
an assay with a maximum lower limit of quantification of 50 DNA copies per mL should be
used.
Detection of JCV DNA in the CSF of a symptomatic subject confirms the diagnosis. However, a
negative JCV PCR result should not exclude a possible diagnosis ofPML.
If the CSF is negative but clinical signs and symptoms and/or MRI are still suggestive of PML:
 Consider repeating CSF analysis;
 Consider other opportunistic infections with CNS manifestations;
 Manage the subject on suspicion of PML or other opportunistic CNS infections according to
local guidelines.
If,
 There are no suspicious signs of PML or other opportunistic infections on MRI and
 Lumbar puncture, if done, is negative for JC DNA, and
 The neurological signs and symptoms show improvement and are no longer suspicious of PML
and can be explained by MS or an alternative, not infectious etiology,
the suspicion of PML is not supported. Other causes of the atypical neurological signs or symptoms
or MRI findings need to be considered. Re-starting the study treatment should be considered if the
benefit/risk is still favorable, according to the investigator.
However, if the investigator is still NOT able to rule out PML or another CNS opportunistic
infection, the study treatment should be permanently discontinued, and the subject should be
managed according to the local standard of care.
The PML cases should be reported to the sponsor as serious adverse events (SAEs).
If at the scheduled visit the MRI shows signs atypical for MS, PML or other opportunistic infection
should be considered based on the clinical signs and symptoms, MRI results, previous exposure to
natalizumab or immunosuppressants, and laboratory tests including CSF analysis, if indicated. As
long as there is suspicion of PML or other opportunistic infection, the study treatment should be
interrupted and should not be re-introduced until this suspicion has been ruled out.
5.1.12.2.2General guidance for monitoring of subjects for opportunistic infections other than
PML during treatment
Heightened vigilance is required for opportunistic infections, with particular attention to be paid
to viral infections. However, investigators and physicians following subjects should also be alert
to potential systemic infections caused by fungi and bacteria. In the event of an opportunistic

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infection, the subject must be referred to an expert in infectious diseases for further examination
and treatment. The study treatment must be permanently discontinued in case of opportunistic CNS
infections. For any other opportunistic infections, the study treatment may be interrupted or
permanently discontinued at the discretion of the investigator.
It is important to recognize that opportunistic infections caused by the reactivation of human herpes
viruses (herpes simplex viruses, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus) may be
associated primarily with 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. The most frequent characteristics of these
infections are an acute onset, associated with fever, headache, confusion, personality changes, and
disorientation. Any suspicion of these infections must lead to immediate discontinuation of study
treatment and to early initiation of antiviral treatment [Steiner 2007].
Particular vigilance is required for rare and unusual neurological symptoms, as their recognition is
crucial for the early diagnosis of neurotropic herpes viruses infections.
The thorough physical examination and blood tests on the routine visits should be focused on any
potential sign of skin, mucosal surfaces, gastrointestinal tract, liver, hematological etc, abnormality
and organ dysfunction suggesting a potential opportunistic infection.
Subjects should be advised to be proactive and alert in reporting any unusual neurological
symptoms and any signs and symptoms indicative of systemic infections, such as fever, malaise
and fatigue [Kappos 2007].
5.1.12.3 Respiratory system
In the event of abnormal spirometry results or persistent respiratory symptoms (e.g., dyspnea), the
subject will be closely observed, spirometry will be repeated, and study treatment discontinuation
should be considered, according to the guidance provided in Table 4.

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Table 4 
Guidance for subject monitoring and discontinuation for PFT decrease and
persistent respiratory AEs
Item  
Parameter 
Guidance
1 
If: 
30% decrease from the study baseline 
FEV1 and/or FVC. 
Repeat PFT within the next 2 weeks or
earlier if clinically indicated.
See item 1a, 1b.
1a 
If at repeat PFT: 
30% decrease from the study baseline 
FEV1 and/or FVC and, in the
opinion of the investigator, this
change is clinically significant
Discontinue study treatment and perform
FU PFTs.
1b 
If at repeat PFT: 
30% decrease from the study baseline
FEV1 and/or FVC
and
the subject does not have respiratory
symptoms (e.g., cough, dyspnea).
Resume regular PFTs schedule.
Baseline = assessment done at Visit 2 (Baseline) of the core study; AE = adverse event; FEV1 = forced expiratory volume in 1
second; FU = follow-up; FVC = forced vital capacity; PFT = pulmonary function test.
If clinically significant, persistent respiratory AEs (e.g., dyspnea) are reported, PFTs must be
performed and study treatment may be interrupted at the discretion of the investigator. In the event
of study treatment interruption, the subject will be closely observed, FU PFTs will be performed,
and further diagnostic work-up and consultation with a pulmonologist or other specialist should
be considered according to local practice and the clinical situation. Following study treatment
interruption, if PFTs normalize and lung toxicity is unlikely, study treatment may be re-initiated
at the discretion of the investigator.
The decision to permanently discontinue study treatment will be made after evaluation of all
available information concerning concomitant medication, other potential causes of respiratory
AEs, and the clinical status of the subject. Further diagnostic work-up and consultation with a
pulmonologist or other specialist should be considered according to local practice and the clinical
situation.
Subjects experiencing respiratory symptoms and/or reduced pulmonary function during the course
of the treatment with the study treatment may be prescribed short-acting β2 agonist (to be used on
an ‘as needed’ basis’ use), at the investigator’s discretion. If a subject fails to show symptom relief
and/or reversibility, additional diagnostic work up (e.g., high-resolution computerized
tomography, DLCO) and/or permanent study treatment discontinuation should be considered at the
discretion of the investigator.

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In all cases of permanent discontinuation, FU monitoring must be provided until respiratory AEs
have resolved and changes in pulmonary function are no longer regarded as clinically relevant, or
until medically indicated.
5.1.12.4 Pregnancy
If a subject becomes pregnant while on study drug, study treatment must be permanently
discontinued. The investigator must counsel the subject and discuss the risks of continuing with
the pregnancy and the possible effects on the fetus. All initial reports of pregnancy in female
participants must be reported to the sponsor by the study site personnel within 24 hours of their
knowledge of the event (see Section 10.3.1).
5.1.12.5 Planned pregnancy
Female subjects participating in the study and wishing to become pregnant during the study may
stay in the study and will have the study treatment interrupted prior to pregnancy and re-started
after delivery.
Before becoming pregnant the following protocol requirements must be met:
 The wish to become pregnant and stay in the study must be communicated by the female
subject to the principal investigator / treating neurologist during a scheduled visit.
 Prior to interrupting contraception, the subject must have 2 negative urine pregnancy tests: one
at the scheduled visit on the day of study treatment interruption and one 30 days after study
treatment interruption.
 The total duration of the study treatment interruption due to planned pregnancy must not
exceed 81 weeks, otherwise the study treatment will be discontinued.
 The interruption of contraception must take place after Visit 5 (Week 24) and at earliest
6 weeks after the first of two consecutive tests confirming plasma teriflunomide level
<0.02 mg/L# and at least 30 days after ponesimod interruption.
 The subject must agree to be followed by an appropriate health care professional (e.g.,
gynecologist, obstetrician and/or midwife) during pregnancy according to local practice, to
have the reports from pregnancy assessments communicated to the principal investigator
/ treating neurologist and to have the information on the subject’s MS status communicated by
the principal investigator / treating neurologist to that health care professional.
# Important note: Teriflunomide testing is no longer required with the approval of protocol version 5

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In addition to the protocol requirements above, the principal investigator / treating neurologist
must explain the following to the subject:
 The potential impact of pregnancy and the post-partum period on the subject’s MS and
potential medical treatments that would be available for the subject while the study treatment
is interrupted.
 Re-initiation of study treatment can only take place after delivery and breastfeeding has ended,
if applicable, and will require a medical evaluation of subject’s eligibility for study treatment
re-initiation.
 Timing of the interruption and possible re-initiation of study treatment and of contraception,
related urine pregnancy tests and unscheduled visits.
 The need for re-uptitration at the study treatment re-initiation.
 Breastfeeding must be completely stopped prior to the re-initiation of the study treatment.
 The need to follow the visit schedule as per protocol during pregnancy, including all scheduled
assessments and procedures except MRI, PFTs, and without study treatment dispensing.
The re-start of study treatment after delivery requires the following eligibility criteria to be met:
 The subject has completely stopped breastfeeding prior to re-start of the study treatment.
 The subject must have been using the reliable methods of contraception as described in
Section 4.4.1 for at least 30 days prior to re-start of study treatment.
 The subject must have had 2 negative urine pregnancy tests performed 30 days apart; the
second one must be during the re-start visit.
 The subject did/does not fulfill any protocol criteria for permanent study treatment
discontinuation [see Section 5.1.12] at any of the previous visits or at the unscheduled visit for
re-start of the study treatment, except the planned pregnancy.
 If the subject received another DMT (IFN β or glatiramer acetate) during pregnancy and post-
partum, this treatment must be discontinued at least 7 days before study treatment re-start.
If the subject agrees to all of the above, the study treatment will be interrupted at the scheduled
visit once the subject, after having received the above explanation from the principal investigator
/ treating neurologist, has confirmed the wish to become pregnant and interrupt and potentially re-
start the study treatment. The sponsor must be contacted in each particular case in order to confirm
that the subject who wishes to become pregnant can continue in the study.
The above requirements for re-initiation of study drug after delivery apply to all cases of study
treatment interruption for planned pregnancy irrespective of the duration of pregnancy, and also

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to all cases where planned pregnancy did not occur but where contraception was interrupted for
any duration, and the subject thereafter wishes to re-start study treatment.
5.1.12.6 Liver abnormalities
In the event of abnormal liver tests or signs and symptoms suggestive of drug-induced liver injury
(DILI), the subject will be closely observed, liver tests will be repeated, and study treatment
discontinuation should be considered according to the guidance provided in Table 5.
Note: All events of ALT or AST 3xULN and total bilirubin 2xULN (>35% direct bilirubin) or
ALT or AST 3xULN and INR >1.5 may indicate severe liver injury (possible ‘Hy’s Law’) and
must be reported to sponsor in an expedited manner and as an SAE if SAE criteria are met. The
INR stated threshold value will not apply to participants receiving anticoagulants.

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Table 5 
Guidance for subject monitoring and discontinuation for liver enzyme
abnormalities
Item  Laboratory parameter 
Guidance
1 
ALT or AST ≥3 ULN * 
Start close observation. Repeat labs
within 72 hours. See items 1a and 1b.
* if ALT or AST ≥8 × ULN OR
ALT or AST ≥3 × ULN and TBL
≥2 × ULN or INR 1.5a OR
ALT or AST ≥3 × ULN with the
appearance of fatigue, nausea,
vomiting, right upper quadrant pain or
tenderness, fever, rash, and/or
eosinophilia (5%) and retest cannot
be done within 72 hours, permanently
discontinue study treatment, and
perform FU
1a 
If at repeated labs, ALT or AST ≥3 ULN 
8 ULN 
Continue close observation. Repeat
labs twice weekly. See items 2a and
2b.
1b 
If at repeated labs, ALT or AST <3 ULN 
Resume regular labs schedule.
2a 
If at repeated labs, ALT or AST ≥5ULN 
for 2 weeks 
Permanently discontinue study
treatment, and perform FU.
2b 
If at repeated labs, 
ALT or AST ≥3 ULN <5ULN for 
2 weeks
Continue close observation. Repeat
labs once or twice weekly.
3 
If at repeated labs: 
 ALT or AST ≥8 × ULN  
 ALT or AST ≥3 × ULN and TBL
≥2 × ULN or INR 1.5a
 ALT or AST ≥3 × ULN with the
appearance of fatigue, nausea, vomiting,
right upper quadrant pain or tenderness,
fever, rash, and/or eosinophilia (5%)
Permanently discontinue study
treatment, and perform FU.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; FU = follow-up; INR = International Normalized Ratio; TBL
= total bilirubin; ULN = upper limit of normal range.
a 
Note: All events of ALT or AST 3xULN andtotal bilirubin 2xULN (>35% direct bilirubin) or ALT or AST 3xULN and
INR >1.5 may indicate severe liver injury (possible ‘Hy’s Law’) andmust be reported to sponsor in an expedited manner
and as an SAE if SAE criteria are met. The INR stated threshold value will not apply to participants receiving anticoagulants.

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Whenever AST or ALT ≥3 × the upper limit of normal range (ULN) are recorded by the central
laboratory, an alert will be sent to the principal investigator and the sponsor. The sponsor will
contact the principal investigator to ensure that she/he will immediately contact the subject, and
ask the subject about any potential symptoms. The subject will be closely observed and will be
asked to return to the site as soon as possible after the time of receipt of the alert to repeat the liver
enzyme and bilirubin tests by the central laboratory (unless the clinical situation mandates
immediate local testing) according to the scheme illustrated in Table 5. Further diagnostic work-
up (including hepatitis serological testing by the central lab) and consultation with a hepatologist
or other specialist should be considered, and adequate medical management should be provided
according to local practice and the clinical situation. Any clinically relevant finding meeting the
definition of an AE will be recorded accordingly in the eCRF.
In the event of study treatment interruption, the subject will be closely observed and FU liver tests
will be performed. Following study treatment interruption, if liver tests normalize and drug-related
hepatotoxicity is unlikely, study treatment may be re-initiated at the discretion of the investigator.
The decision to permanently discontinue study treatment will be made after evaluation of all
available information concerning concomitant medications, other potential causes of
hepatotoxicity, and the clinical status of the subject. NB: The re-initiation is not permitted for
situations where the study treatment should be permanently discontinued according to Table 5. In
all cases of permanent study treatment discontinuation, FU monitoring must be provided until
signs and symptoms have resolved and changes in liver function are no longer regarded as
clinically relevant or until medically indicated.
5.1.12.7Ocular abnormalities
In the event of suspected clinically significant findings (e.g., macular edema or active uveitis), an
unscheduled OCT examination should be performed. In the case of macular edema, confirmed by
the local ophthalmologist, the subject must be permanently discontinued from study treatment and
will be managed and followed up until resolution. Any clinically relevant finding meeting the
definition of an AE will be recorded accordingly in the eCRF.
Subjects with active uveitis but without macular edema may continue on the study treatment but
will require additional ophthalmologic assessments as detailed below:
5.1.12.7.1 Guidance for monitoring and management of subjects with uveitis
If active uveitis (ocular pain, floaters, blurred vision, increased intraocular pressure) is suspected
at EOT or FU1 visit in the core study, or during a scheduled ophthalmological assessment, or at
an unscheduled assessment due to ophthalmological symptoms in the extension study,
fluorescence angiography (FA) should be performed (unless contra-indicated according to the
ophthalmologist) in addition to the scheduled ophthalmological assessment in order to characterize
the uveitis. Subjects with suspicion of uveitis occurring during the study treatment but outside
scheduled ophthalmological assessment should have a full ophthalmological assessment
performed together with FA (unless contra-indicated) and OCT as soon as possible. If active

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uveitis can be confirmed and macular edema can be ruled out, the subject may continue in the
study without interrupting the study treatment. Such subjects will need to be controlled by the
ophthalmologist 1 week, 2 weeks, and 4 weeks after the diagnosis of uveitis has been confirmed,
and then every 4 weeks throughout the study or until the condition has resolved. These
ophthalmological exams should include full ophthalmological assessment (ophthalmological
symptoms, assessment of best corrected visual acuity (Early Treatment Diabetic Retinopathy
Study [ETDRS] charts), measurement of tonometry (Goldmann applanation tonometry is
recommended, slitlamp examination of the anterior segment, and dilated indirect funduscopy), as
well as OCT. FA may be repeated at the ophthalmologist’s discretion. The ophthalmologist will
decide what treatment should be given to the subject. If the subject needs to be treated by
immunosuppressants prohibited by the protocol, the study treatment must be discontinued. If
uveitis is progressing in spite of treatment, the investigator may consider interrupting or
permanently discontinuing the study treatment.
5.2 Concomitant therapy
A therapy that is concomitant to study-treatment is any treatment that is either ongoing at the start
of study treatment or is initiated during the study treatment period, or up to 30 days after the end
of study treatment. All study treatment concomitant therapies will be recorded on the Concomitant
Medications page of the eCRF. In addition, all medication taken by the subject at EOS of the core
study, i.e., all medication ongoing or started at this time, will be recorded on the Concomitant
Medications page of the eCRF.
5.2.1 Recommended concomitant therapy
Treatment of relapses:
 If a relapse requires treatment with corticosteroids, methylprednisolone 1 g i.v. daily for 3 to
5 days is recommended. Treatment with other corticosteroids, another dose, other routes of
administration, or adrenocorticotropic hormone (ACTH) is not recommended unless deemed
absolutely necessary, and must be documented in the subject charts by the investigator. Oral
taper with corticosteroids is not permitted.
 Treatment of relapses with plasma exchange (i.e., plasmapheresis, cytapheresis) is prohibited.
5.2.2 Allowed concomitant therapy
 Administration of i.v. atropine in the event of symptomatic bradycardia;
 Short-acting ß2-agonists for respiratory symptoms and/or reduced pulmonary function during
study treatment;
 QT-prolonging drugs with known risk of Torsades de Pointes should be used with caution as
ponesimod may potentially enhance their effect on QT interval [guidance is provided in
Appendix 2];

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 Glatiramer acetate and INF β-1a are allowed only during ponesimod interruptions for planned
pregnancy. These treatments may be started 7 days after ponesimod cessation and must be
stopped 7 days before ponesimod re-initiation;
 Other treatments considered necessary for the subject’s wellbeing and not categorized as
prohibited concomitant medications.
 Vaccination with non-live vaccines is allowed while on study treatment if the vaccination is
advised by the primary investigator / treating neurologist, based on her/his clinical assessment
of the risk/benefit for the individual patient, and if supported by guidelines for vaccination
relevant to this patient population, as applicable.
5.2.3 Forbidden study-treatment-concomitant therapy
 Systemic corticosteroids and ACTH, except for the treatment of MS relapses [see
Section 5.2.1] and for short-term treatment (up to 2 weeks per treatment cycle with at least
8 weeks’ interval between treatment cycles and no more than 4 weeks per year of the study
duration on average) with low dose of corticosteroid (up to 10 mg of prednisone equivalent
daily) or inhaled corticosteroids for pulmonary conditions;
 Disease-modifying drugs for MS other than prescribed as per protocol (except glatiramer
acetate or INF β-1a during ponesimod interruptions for planned pregnancy as described under
“Allowed”).
 Immunosuppressive treatment (e.g., cladribine, lymphocyte-depleting biological agents such
as rituximab or ocrelizumab, mitoxantrone, or other systemic immunosuppressive treatments
such as azathioprine, cyclophosphamide, cyclosporine or methotrexate);
 i.v. immunoglobulin (except in women who have interrupted study treatment for pregnancy;
for these women i.v. immunoglobulin will be allowed after 30 days from interruption of the
study treatment);
 Plasmapheresis, cytapheresis, or total lymphoid irradiation;
 Vaccination with live vaccines, except if performed during a temporary treatment interruption
period. In this case it must be performed not earlier than 1 week after last dose of study
treatment, and treatment can be re-initiated only after at least 4 weeks from completion of
vaccination;
 β-blockers, diltiazem, verapamil, digoxin, digitoxin or any other anti-arrhythmic or HR
lowering systemic therapy (a non-exhaustive list of drugs provided in Appendix 3) during the
up-titration period (i.e., from Day 1 until Day 14 included, and during the first 14 days after
re-initiation of study treatment). Treatment with any of these therapies is also not
recommended during the maintenance treatment period (from Day 15 until EOT) and should
be considered with caution if an alternative medication cannot be used;

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 Any other investigational drug;
 Any investigational therapeutic procedure for MS (e.g., stent placement or angioplasty for
chronic cerebrospinal venous insufficiency, stem-cell transplantation).
Commercially available ponesimod may be initiated on the day following last intake of study
treatment. The start date of commercially available ponesimod must be recorded on the
Concomitant Medication page of the eCRF.
In the event that a subject takes any of these forbidden medications, the investigator must contact
the sponsor to discuss further FU actions, including stopping/interrupting study treatment as
appropriate.
6 STUDY ENDPOINTS
Endpoints for the main part of this study are summarized below.
6.1 Efficacy endpoints
In order to monitor disease activity with long-term treatment with ponesimod, and to investigate
the effect of switching from teriflunomide to ponesimod, the main analysis of efficacy will focus
on the Combined Analysis Period, i.e., including data from both the core and extension studies. In
addition, specific efficacy endpoints will also be analysed over the Extension Analysis Period, i.e.,
only including data from the extension study. Analysis over the Combined Analysis Period will
use the core study baseline as a reference, while analysis over the Extension Analysis Period will
use the extension study baseline as a reference. Baseline definitions for efficacy endpoints are
provided in Section 11.1.3.
The tables below detail which endpoints will be analyzed for the Extension Analysis Period, and
which for the Combined Analysis Period. See Section 11.1 for further details regarding the analysis
strategy.
6.1.1 Main clinical endpoints
The main clinical endpoints are those relating to disease activity (relapses, disability accumulation,
and composite of the latter including MRI).

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Table 6 
Main clinical endpoints
Endpoints
Combined 
Analysis 
Period 
Extension
Analysis
Period
 ARR (based on the number of confirmed relapses* per
subject-year)
Y 
Y 
 Time from core study randomization to first confirmed 
relapse*
Y 
N
 Time from core baseline to 12-week CDA  
Y 
N
 Absence of relapses* 
Y 
Y
 Time from core baseline to 24-week CDA  
Y 
N
 Change from baseline in EDSS at all assessments 
Y 
Y
 NEDA status at EOS according to NEDA 3 (defined by the 
absence of confirmed relapse, Gd+ T1 lesions, new or
enlarging T2 lesions and 12-week CDA)
Y 
N
 NEDA status at EOS according to NEDA 4 (defined by the 
absence of confirmed relapse, Gd+ T1 lesions, new or
enlarging T2 lesions, 12-week CDA, and annual brain
volume change ≥0.4% from baseline to all assessments)
Y 
N
*Definition of relapse
 
A relapse is defined as new, worsening or recurrent neurological symptoms that occur at least 30 days after the onset of a
preceding relapse, and that last at least 24 hours, in the absence of fever or infection.
 
The new, worsening or recurrent neurological symptoms are to be evaluated by the treating neurologist and, if all the elements
of the above definition have been verified, and in the absence of another, better explanation of the subject’s symptoms, the
event is considered as a relapse [see Section 7.4.2]. The onset date of the relapse corresponds to the onset date of the symptoms.
 
A relapse will be confirmed by the treating neurologist only when the subjects’ symptoms are accompanied by an increase in
EDSS/FS scores, which is consistent with the subject’s symptoms, from a previous clinically stable EDSS/FS assessment (i.e.,
performed at least 30 days after the onset of any previous relapse), obtained by the efficacy assessor and consistent with the
following:
 
An increase of at least half a step (0.5 points; unless EDSS = 0, then an increase of at least 1.0 points is required) or
 
An increase of at least 1.0 point in at least two FS scores, or
 
An increase of at least 2.0 points in at least one FS score (excluding bladder/bowel and cerebral).
ARR = annualized relapse rate; CDA = confirmed disability accumulation; EDSS = Expanded Disability Status Scale; EOS = End-
of-Study; FS = functional system; NEDA = no evidence of disease activity.

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6.1.2 MRI-based endpoints
Table 7 
MRI-based endpoints
Endpoints
Combined
Analysis
Period
Extension
Analysis
Period
 PCBV at all assessments 
Y 
Y
 CUAL, defined as new Gd+ T1 lesions plus new or 
enlarging T2 lesions without double-counting the
lesions) at all assessments
Y 
Y
 Number of Gd+ T1 lesions at all assessments 
Y 
Y
 Cumulative number of new or enlarging T2 lesions 
(relative to baseline) at all assessments
Y 
Y
 Volume of MRI lesions (T2 lesions, T1 hypointense 
lesions) at all assessments
Y 
Y
 Absence of MRI lesions (Gd+ T1 lesions, new or 
enlarging T2 lesions) at all assessments
Y 
Y
 Proportion of Gd+ lesions at baseline evolving to PBHs 
at all assessments
Y 
Y
CUAL = cumulative number of combined unique active lesions; MRI = magnetic resonance imaging PBH = persistent black holes;
PCBV = percent change from baseline in brain volume.
6.1.3 Other endpoints
Table 8 
Other endpoints
Endpoints 
Combined 
Analysis 
Period 
Extension
Analysis
Period
 Change from baseline in MSFC Z-score at all
assessments
Y 
Y 
 Change in the SDMT score at all assessments 
Y 
Y
 Change from baseline in SF-36v2™ Health Survey 
domain and component scores
Y 
Y
MSFC = Multiple Sclerosis Functional Composite; SDMT = Symbol Digit Modalities Test.
6.2 Safety endpoints
In order to investigate the long-term safety of ponesimod and the changes in safety in teriflunomide
subjects switching to ponesimod 20 mg, analysis will be performed on all data in the core and
extension studies combined, using the core baseline as a reference. In addition, safety data

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collected in the extension study will be analyzed independently, using the extension baseline as a
reference.
Table 9 details which endpoints will be analyzed for the Extension Analysis Period, and which for
the Combined Analysis Period.
Table 9 
Analysis of safety endpoints
Endpoints 
Combined 
Analysis 
Period 
Extension
Analysis
Period
Adverse events
 Treatment-emergent AEs, SAEs, and AEs of special interest# 
Y* 
Y
 AEs leading to premature discontinuation of study treatment 
Y 
Y
Cardiac safety
 Treatment-emergent morphological ECG abnormalities (as 
defined by the ECG provider)
Y* 
Y
 Absolute values by visit for 12-lead ECG parameters (HR, 
PR, QRS, QT, QTcB, QTcF)
Y 
Y
 Change from baseline values by visit for ECG parameters 
(HR, PR, QRS, QT, QT QTcB, QTcF)
Y 
Y
 Change in ECG parameters (HR, PR, QRS, QT, QT QTcB, 
QTcF) from pre-dose to selected post-dose assessments (1 h,
2 h, 3 h, 4 h) on Day 1 and on day of re-initiation of study
treatment
N 
Y
Pulmonary safety
 Absolute values and percent change from baseline in FEV1 
and FVC at all assessments
Y 
Y
 Treatment-emergent decrease from baseline >20% and 
>30% in FEV1 or FVC
Y 
Y
 Treatment-emergent decrease from baseline >20 percentage 
points in % of predicted FEV1 and FVC
Y 
Y
 Among subjects with a decrease of ≥200 mL or ≥12% in 
FEV1 or FVC from baseline to EOT, reversibility defined as
a decrease of <200 mL or <12% in FEV1 or FVC from
baseline to EOS**
Y 
N

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Table 9 
Analysis of safety endpoints
Endpoints
Combined 
Analysis 
Period 
Extension
Analysis
Period
 Absolute change from baseline to EOS versus change from
baseline to EOT in FEV1 and FVC (absolute and % of
predicted)**
Y 
N
 Change in lung diffusion capacity as assessed by DLCO  (at
selected sites only) expressed in absolute change (mL) and
% of predicted value from baseline at all assessments
Y 
Y
 Change from baseline to EOS versus change from baseline
to EOT in DLCO  (absolute and % of predicted) (at selected
sites only)**
Y 
N
Other endpoints
 Absolute values and change from baseline for HR, SBP, 
DBP and body weight at all assessments
Y 
Y
 Treatment-emergent notable blood pressure abnormalities##  
Y 
Y
 Absolute values and change from baseline for laboratory 
tests (hematology, blood chemistry, urinalysis) at all
assessments
Y 
Y
 Treatment-emergent notable laboratory abnormalities##  
Y 
Y
 Change from baseline to EOS versus change from baseline 
to EOT in lymphocyte counts (absolute and percent
change)**
Y 
N
 Treatment-emergent eC-SSRS suicidal ideation score of 4 or 
above, or a “yes” response on the eC-SSRS suicidal behavior
item
Y 
N
* Cumulative safety data, i.e., AEs for the combined analysis period will only be presented for subjects who received 20 mg
ponesimod in the core study.
# 
The selection of AEs of special interest [see Appendix 4] is based on the anticipated risks of treatment with ponesimod; the
final list of AEs of special interest will be defined in the SAP.
## The selection of notable abnormalities considered for the analyses is based on standard definitions and the anticipated risks of
treatment with ponesimod; the final list of abnormalities will be defined in the SAP.
** Only for subjects who have no exposure to commercially available ponesimod prior to the EOS visit.
AE = adverse event; DBP = diastolic blood pressure; DLCO  = diffusing capacity for the lungs measured using carbon monoxide;
eC-SSRS = electronic self-rated version of the Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; EOS =
End-of-Study; EOT = End-of-Treatment; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; HR =
heart rate; 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; SAE = serious adverse event; SAP = statistical analysis plan; SBP = systolic blood pressure.

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The treatment-emergent period is defined as the time from first ponesimod administration in the
applicable Analysis Period up to 15 days (inclusive) after last study treatment administration. This
definition applies regardless of whether the subject receives commercially available ponesimod
after completing study treatment.
7 STUDY ASSESSMENTS
The assessments pertaining to a visit may be performed within the allowed time window.
All study assessments are performed by a qualified 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,
MRI, blood sampling etc., to an external facility, she/he should inform the sponsor of the
delegation. 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.
Any incidental finding of an abnormality discovered by an external facility must be shared with
the principal investigator, who is responsible for reporting the event (e.g., AE) in the eCRF as
appropriate. Clinically relevant incidental findings will be followed up per local medical practice.
Calibration certificates for the following devices used to perform study assessments must be
available prior to enrolling the first subject:
 Temperature measurement devices for study medication storage area and lab sample storage
(e.g., freezer).
 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 7.5.5].
 DLCO gas analyzer (if applicable); in addition, a copy ofthe calibrations of the day of test must
be stored and a log of calibration results must be maintained at the site. Frequent testing
involving the same healthy subject control (biological quality check) or a DLCO simulator will
ensure continuous monitoring of the gas analyzer measurement accuracy over time [see
Section 7.5.6].
 ECGs.
 BP monitoring device.
7.1 Informed consent
Prior to performing any study-specific procedures or assessments, the subject must provide written
informed consent to participate in the extension study.

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It is recommended to hand out the informed consent form to the subject at core study EOT (or
earlier) in order to allow ample time for reading and discussion prior to core study FU1 visit.
Ideally, signing of informed consent will occur on the day of FU1 or FU2 visit (whichever applies).
In all cases, informed consent should be signed no later than one day after FU1 or FU2 visit
(whichever applies) and it must be clear from the source documents that informed consent was
obtained prior to any study-specific procedures being performed. If a study-specific procedure or
assessment has been performed as part of routine assessment or as part of the core study, and the
results are available prior to the subject’s signing of informed consent, such procedures or
assessments may be used to assess eligibility, and do 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
neurologist 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 (ICF),
must be provided in a language that is fully understandable to the subject.
Additional informed consents must be obtained from those subjects continuing participation in the
DLCO sub-study.
7.2 Demographics and medical history
Demographics (age, gender and childbearing potential) and medical history [see Section 4.5] are
to be recorded in the eCRF at Visit 1.
7.3 Study-concomitant therapies
All study-concomitant therapy (including contraceptives and traditional and alternative medicines,
i.e., plant-, animal-, or mineral-based medicines, vaccinations) taken by the subject from the EOS
of the core study until the end of their participation in the study (i.e., EOS) will be recorded in the
Concomitant Therapies pages of the eCRF. This includes all ongoing therapies and those initiated
or stopped during this period. The corresponding dates of initiation and discontinuation will be
recorded.
7.4 Efficacy assessments
7.4.1 Neurological evaluation
EDSS and FS scores [Kurtzke 1983] are based on a standard neurological examination for
assessing neurologic disability and impairment in MS. The seven FS scores are ordinal clinical
rating scales ranging from 0 to 5 or 6, assessing visual, brain stem, pyramidal, cerebellar, sensory,
bowel and bladder, and cerebral functions while ambulation is an ordinal scale ranging from 0 to
12 assessing walking distance and assistance. The ratings of the individual FS scores are then used,
in conjunction with ambulation score, to obtain the EDSS score. EDSS is an ordinal clinical rating
scale ranging from 0 (normal neurological examination) to 10 (death due to MS) in half-point
increments.

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EDSS and FS assessments will only be performed at visits indicated in Table 1 and by the efficacy
assessor who should preferably maintain this role for a given subject throughout the study [see
Section 3.4.3]. The efficacy assessor must not consult prior EDSS/FS scores when performing the
current EDSS/FS assessment. In no case will the treating neurologist alter the EDSS/FS score
obtained by the efficacy assessor. The examination will be based on the modified neurological
examination ‘Neurostatus’ [Appendix 1] using the corresponding scoring documents. The
EDSS/FS scoring will be recorded in the eCRF. NB: Fatigue, which is an optional part of the
‘Neurostatus’ assessment, will not contribute to the Cerebral FS score.
7.4.2 Detection and evaluation of relapses
Detection and evaluation of relapses will be done as follows [see Figure 3]:
Step 1:At every study visit, subjects are reminded to contact their principal investigator / treating
neurologist immediately in the event of the appearance of any new or worsening neurological
symptoms. In addition, the site will contact the subject 6 weeks (7 days) after each of the visits
following Visit 4 (Week 12) in order to proactively inquire about any new or worsened
neurological symptoms. If applicable, this may occur on site during blood sampling visits.
Whenever a subject experiences any new or worsening neurological symptoms between visits,
he/she must contact the principal investigator / treating neurologist, study nurse or clinical
coordinator as soon as possible in order to complete a telephone questionnaire for relapse
assessment [see Appendix 10].
If, during the call from the site inquiring about symptoms suggestive of potential new relapses, the
subject reports occurrence of such symptoms, a telephone questionnaire for relapse assessment
will also be completed.
If a relapse is suspected, the subject will be required to come to the site for an unscheduled relapse
assessment visit. The completed telephone questionnaire will be collected in the eCRF.
Step 2:At every visit (including unscheduled visits at which the subject is attended by the principal
investigator / treating neurologist), the principal investigator / treating neurologist will interview
and examine the subject to determine whether or not a relapse may have occurred since last visit
using a dedicated relapse assessment questionnaire [see Appendix 10] and the relapse symptom
form [see Appendix 11]. NB: Visits for laboratory re-test (due to a non-evaluable assessment, e.g.,
a non-analyzable blood sample, MRI rejected by MIAC for quality reasons), or repeated test (e.g.,
repeated test of serum leucocyte level or repeated PFT as required per protocol) are not considered
scheduled or unscheduled visits. Unscheduled visits for safety reasons such as unscheduled
ophthalmology assessments, unscheduled PFTs or unscheduled MRIs do not require relapse
assessments unless in connection with or as a consequence of these assessment the subject is seen
at the site by the principal investigator / treating neurologist.
Based on the interview and examination, the principal investigator / treating neurologist will
determine if symptoms are likely to be due to a relapse (i.e., all elements from the relapse definition

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in Section 6.1 have been verified, in the absence of another, better explanation of the subject’s
symptoms), the subject will be referred to the efficacy assessor for an EDSS assessment (NB: at
scheduled visits the EDSS assessment planned for this visit will be used). The completed
questionnaire and the outcome of the examination will be collected in the eCRF.
Step 3: The efficacy assessor will perform the EDSS/FS assessment within 7 days of the onset of
new or worsening neurological symptom(s) [see Section 7.4.1]. Important note:EDSS and FS
assessments will be performed only by the efficacy assessor. The efficacy assessor must not
consult prior EDSS/FS scores when performing the current EDSS/FS assessment. In no case will
the treating neurologist alter the EDSS/FS score obtained by the efficacy assessor. If the relapse
requires treatment with corticosteroids [see Section 5.2.1], treatment should be initiated as early
as recommended by local clinical practice. The neurological examination by the efficacy assessor
must always be performed prior to the treatment start.
Step 4: The treating neurologist will review the EDSS/FS score obtained by the efficacy assessor
and determine presence or absence of qualifying increase in EDSS/FS (i.e., of the magnitude
described in Section 6.1 from a previously clinically stable EDSS/FS score and consistent with the
subject’s new symptoms). Based on this review, the treating neurologist will decide if the relapse
is confirmed or not, according to the protocol definition of confirmed relapse [see Section 6.1].
Once step 1 of the relapse detection has been initiated (whether by subject calling the site, by
interview of the subject at scheduled visit, or by scheduled calls from the site to the subject), the
final result of the relapse detection and confirmation process will be captured as one of the
following three outcomes: no relapse, unconfirmed relapse, or confirmed relapse. New or
worsened neurological symptoms reported by the subject and for which there is another and better
explanation for the subject’s current symptoms than an MS relapse will be captured on an AE
page.
All MS relapses, whether or not confirmed, must be reported on specific relapse pages of the eCRF.
MS relapses and associated symptoms are not to be entered on the AE page of the eCRF with the
following exceptions:
 MS relapses with fatal outcome (these must always be recorded as an AE on the AE page in
addition to being reported as SAEs).
 MS relapses that, in the view of the investigator, warrant specific notice due to unusual
frequency, severity or remarkable clinical manifestations (these should be reported as an AE
on the AE page of the eCRF and, if applicable, on the SAE form).

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Figure 3 
Flow diagram for the detection and evaluation of relapses

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7.4.3 MRI evaluations
MRI scans will be performed at Visits indicated in Table 1 and Table 2. In case of premature study
treatment discontinuation, the MRI assessment at EOT does not need to be performed if the EOT
visit occurs within 4 weeks of the MRI assessment at Visits 7, 11, 15, or 19 (Weeks 48, 96, 144,
or 196). All MRI data will be analyzed by the MIAC, c/o University Hospital Basel, Switzerland
for MRI efficacy outcomes.
MRI variables include the number and volume of new and total Gdlesions on T1-weighted MRI
scans, number of new and enlarging lesions and lesion volume on T2-weighted MRI, and global
measures of loss of brain tissue.
T1-weighted imaging before and after i.v. administration of 0.1 mmol/kg body weight
(= 0.2 mL/kg) of Gd as well as T2-weighted imaging will be performed. Gd may cause nausea and
vomiting, and in very rare cases allergic reactions that could require immediate anti-anaphylactic
therapy (such as steroids, epinephrine/adrenaline, etc.). It is recommended to use macrocyclic
gadolinium-based contrast agents (e.g., gadobutrol, gadoterate, gadoteridol) as described in the
MRI manual.
Detailed instructions on procedures, standardization, qualification, recording, and transfer of data,
etc., will be provided in the study MRI manual (separate document).
Incidental, non-MS-related findings identified by central reading will be communicated to the
principal investigator / treating neurologist. Furthermore, all MRI scans performed for the study
must be reviewed and documented for safety by the local neuroradiologist. The principal
investigator / treating neurologist must have access to the MRI images and/or reports, and be
informed of any findings of concern for the subject’s safety including non-MS-related findings
detected on the MRI scan. Study participants with clinically relevant findings on MRI will be
followed up until establishing the final diagnosis and managed as per local medical practice. Other
diagnostic procedures may be performed as a FU assessment according to local standard
procedures when considered necessary by the investigator. Incidental clinically relevant findings
on MRI will be reported as an AE.
7.4.4 MSFC
The MSFC score consists of 3 clinical examinations: the Timed 25-Foot Walk, the Paced Auditory
Serial Addition Test (PASAT-3” version), and the 9-Hole Peg Test (9 HPT). The timed 25-foot
(7.62 meters) walk is a quantitative measure of lower extremity function. The 9-HPT is a
quantitative measure of upper extremity (arm and hand) function. The PASAT is a measure of
cognitive function that specifically assesses auditory information processing speed and flexibility,
as well as calculation ability.
MSFC will be assessed at visits indicated in Table 1 and Table 2.

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MSFC will be administered in combination with SDMT [see Section 7.4.5] in the following
sequence:
1. 
Timed 25-Foot Walk (7.62 meter)
2. 
9-HPT
3. 
PASAT
4. 
SDMT
A full description of the administration of the scale, sequence of tests and scoring will be given in
a separate document provided to each site. The test will only be administered by a trained
administrator and the results will be collected in the eCRF.
A more comprehensive description of the test and its administration is provided in Appendix 6.
7.4.5 Symbol Digit Modalities Test
The SDMT [Smith 1982, Benedict 2006] measures attention and processing speed much like the
PASAT. It will be administered at visits indicated in Table 1 and Table 2.
The SDMT includes a reference key of nine symbols, each paired with a single digit. Below the
reference key are rows of the symbols arranged randomly. The subject is given 90 seconds to say
the number that corresponds to each symbol. The test administrator records the answers and the
number of correct answers is recorded as the score.
Study personnel will be trained to administer and score the SDMT.
A sample of the SDMT is provided as Appendix 7. The rater will record the subject’s responses
on a validated paper form that will be collected and transcribed in the eCRF.
The sponsor has been granted a license agreement for the use of the SDMT. The individual
questionnaires will be completed by all subjects in all countries, as it does not require language
translation.
7.5 Safety assessments
The definitions, reporting and follow-up of AEs, SAEs and potential pregnancies are described in
Section 10.
7.5.1 12-lead electrocardiogram
A standard 12-lead ECG will be recorded at visits indicated in Table 1 and Table 2, 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 ECG may also be performed at unscheduled visits.
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 must be performed for all subjects according to the

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study protocol schedule. The data records will be sent to the central ECG laboratory for central
reading. The reports from the central ECG laboratory will be sent to the site within a few days.
Details will be provided in the ECG laboratory manual.
The following variables 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] ½ and QTcF = QT/[RR] ⅓, respectively).
During the treatment period ECGs must be performed at pre-dose.
At Visit 1 (Day 1) (and on the day of re-initiation of study treatment [see Section 5.1.9]), ECGs
must be performed at pre dose, and hourly (+/− 15 min) thereafter for a minimum of 4 hours and
up to 12 hours post-dose#. Subjects may be discharged from the cardiac monitoring if they meet
the discharge criteria before 12 hours post dose but no sooner than the (report of) ECG at 4 hours
post-dose has been evaluated. 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 but will continue
to be monitored, and additional ECG measurements will be performed until changes in ECG
variables are no longer clinically relevant (i.e., discharge criteria are met; see Section 5.1.10), or
until medically indicated.
#Subjects who do not meet any of the Criteria for Cardiac Monitoring at Site (See protocol Section 5.1.9) may re-
initiate the study drug at home without post-dose cardiac monitoring.
7.5.2 Blood pressure
BP measurements include SBP and DBP.
BP monitoring will be performed using the same type of device throughout the study on the same
arm with the subject preferably in a fully rested supine position after the subject has been allowed
to rest for a minimum of 5 minutes prior to the measurement. It is highly recommended to use the
same position (supine or sitting) at all BP measurements. At each pre-dose assessment, SBP and
DBP will be measured twice (i.e., two SBP measurements and two DBP measurements). 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. Post-dose assessments at Visit 1 (Day 1) and at
visits for re-initiation of study treatment will only be measured once at each timepoint. This single
obtained SBP measurement is to be used for determining discharge criteria on Day 1 and on day
of re-initiation of study treatment.

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BP measurements will be performed at all scheduled study visits. In addition, unscheduled BP
measurements may be performed at any time during the study. At Visit 1 (Day 1) and on days of
re-initiation of study treatment, [see Section 5.1.10], SBP and DBP will be measured at pre-dose
and hourly (+/− 15 min) thereafter for a minimum of 4 hours and up to 12 hours post-dose.#
#Subjects who do not meet any of the Criteria for Cardiac Monitoring at Site (See protocol Section 5.1.9) may
re-initiate the study drug at home without post-dose cardiac monitoring
Subjects may be discharged from cardiac monitoring if they meet the discharge criteria before
12 hours post-dose but no sooner than 4 hours post-dose [see Section 5.1.10]. 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, but will continue the cardiac monitoring. Additional BP
measurements will be performed until changes are no longer clinically relevant (i.e., discharge
criteria are met; see Section 5.1.10), or until medically indicated.
7.5.3 Body temperature
Body temperature will be assessed at all scheduled study visits. Body temperature will also be
assessed at unscheduled visits for relapses. In addition, body temperature measurements may be
performed at any time during the study, as part of unscheduled visits.
All body temperature assessments will be documented in the source documents of the subject. All
body temperature values should also be recorded in the eCRF as normal or abnormal. If an
abnormality is found, it should be specified on the corresponding eCRF page. Clinically relevant
findings meeting the definition of an AE (new AE, or worsening of previously existing condition)
[see Section 10.1], must be recorded on the AE page of the eCRF.
7.5.4 Pulse rate
Pulse rate will be assessed at visits where no 12-lead ECG is performed as indicated in Table 1
and Table 2. Pulse rate may also be assessed at any time during the study, as part of unscheduled
visits when 12-lead ECG may not be performed.
All pulse rate examinations will be documented in the source documents of the subject. All pulse
rates should also be recorded in the eCRF as normal or abnormal. If an abnormality is found, it
should be specified on the corresponding eCRF page. Clinically relevant findings meeting the
definition of an AE (new AE, or worsening of previously existing condition) [see Section 10.1],
must be recorded on the AE page of the eCRF.
7.5.5 Spirometry
Spirometry tests will be performed at visits indicated in Table 1 and Table 2. In addition,
unscheduled spirometry must be conducted in the event of persistent respiratory symptoms (e.g.,
dyspnea).
It is highly recommended that all spirometry assessments are performed in the morning, and prior
to study treatment intake. Subjects must refrain from taking short-acting-beta-agonists (e.g.,

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salbutamol) for 6 hours and long-acting-beta-agonists for 24 hours prior to spirometry testing. If
taken, the test should be rescheduled. To perform the spirometry test, subjects will be rested for a
minimum of 5 minutes prior to start.
Spirometry testing will consist of assessing FVC and FEV1. Further indices, part of the collected
flow-volume curves, may be explored and/or used for spirometry quality control measures. The
following flow-volume curve indices will be collected at each timepoint: FEV1; FVC; the
instantaneous forced expiratory flow (FEF) at 25%, 50% and 75% of the FVC (FEF25%, FEF50%,
FEF75%, respectively); the mean FEF between 25% and 75% of the FVC (FEF25–75%); and the
peak exploratory flow.
Spirometry tests willbe conducted according to the ATS/ERS guidelines [Miller 2005a, Miller 2005b].
The pulmonary function facility will ensure that the spirometer is functioning properly and is calibrated
according to manufacturer instruction and ATS/ERS guidelines.
Spirometry testing will be performed by a PFT technician, respiratory therapist or expert, or an
equally experienced person according to the ATS/ERS guidelines (e.g., for the US, a registered
pulmonary function technologist and/or a registered respiratory therapist). 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) may conduct spirometry if the primary tester is not
available.
Clinically relevant findings meeting the definition of an AE (new AE, or worsening of previously
existing condition) [see Section 10.1], must be recorded on the AE page of the eCRF.
7.5.6 DLCO sub-study
Subjects who participated in the DLCO  sub-study during the core study will be asked to continue
their participation in the DLCO  sub-study during the extension study. The subjects may choose to
continue participation by providing consent under a separate informed consent for the DLCO  sub-
study. The assessment will be conducted at visits indicated in Table 1 and Table 2. In addition,
unscheduled DLCO tests may be performed at any time during the study.
DLCO  tests will be performed by a PFT technician, respiratory therapist or expert or an equally
experienced person according to the ATS/ERS guidelines [Miller 2005a]. DLCO  results will be
reviewed by a pulmonologist or a physician adequately trained in pulmonology.
DLCO  tests will be conducted according to the ATS/ERS guidelines and will be assessed by the
single breath method [Macintyre 2005]. DLCO efforts, up to a maximum of five, will be performed
to produce at least two technically acceptable and repeatable traces (according to ATS/ERS
guideline criteria). There must be a minimal interval of at least 4 minutes between each effort
performed. Data from all DLCO efforts collected during a session will be captured in the eCRF.

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The mean of two best within session DLCO  efforts will be selected and calculated by the sponsor
as the value for this session. If only one acceptable effort is achieved, this will be selected by the
sponsor for this session. If no acceptable effort is achieved, the effort with the highest inspiratory
vital capacity will be selected by the sponsor for this session. For the analysis, the results will be
corrected for hemoglobin (Hb) concentration and reported at a standard Hb concentration using
the Cotes method [Macintyre 2005] (calculated by the sponsor in the database using the Hb value
from the central laboratory).
The sites participating in the sub-study will use their own DLCO gas analyzer and must ensure it is
calibrated and working properly. The gas analyzer will need to fulfill the technical requirements
and recommendations for range and accuracy for DLCO assessment from the ATS/ERS guidelines
[Macintyre 2005]. A copy of the calibrations of the day of a test must be stored as source
documents in the subject charts at each subject visit, and a log of calibration results must be
maintained at the site. In addition, frequent testing involving the same healthy subject control
(biological quality check) or a DLCO  simulator will ensure continuous monitoring of the gas
analyzer measurement accuracy over time.
If clinically significant alterations in DLCO  variables indicating a pulmonary condition that could
result in increased risk for the subject are observed, she/he may be prematurely discontinued from
the study treatment at the discretion of the investigator. Clinically relevant findings meeting the
definition of an AE (new AE, or worsening of previously existing condition) [see Section 10.1],
must be recorded on the AE page of the eCRF.
A back-up tester (PFT technician, respiratory therapist, or expert or an equally experienced person
according to the ATS/ERS guidelines [Miller 2005a]) may conduct DLCO  if the primary tester is
not available. This back-up tester must be trained on the specific requirements and have had
refreshment on ATS/ERS recommendations before starting on the study. DLCO  conduct,
documentation, performance, training details (of the responsible PFT site personnel), and quality
control procedures are described in the PFT manual.
7.5.7 Ophthalmologic assessments
Ophthalmologic assessments will be performed at visits indicated in Table 1. In addition,
unscheduled ophthalmological examination will be done in the event of visual symptoms or
findings suggestive of active uveitis [see Section 5.1.12.7.1].
The safety ophthalmological assessment includes previous eye history and ophthalmic condition,
any new or current ophthalmological symptoms, assessment of best corrected visual acuity
(ETDRS charts), measurement of ocular pressure with Goldmann applanation tonometry
(recommended, if not available other tonometry methods are allowed), slitlamp examination of the
anterior segment, and dilated indirect funduscopy. Additionally, the safety ophthalmological
assessment will include fluorescence angiography if there is a suspicion of active uveitis during
the study (unless contra-indicated according to the ophthalmologist) [see Section 5.1.12.7]. While
the visual acuity and ocular pressure measurement themselves may be performed by a delegate

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(e.g., 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. Fluorescence angiography (if applicable) may be performed by
a delegate (e.g., technician, optometrician) but always in the presence of the ophthalmologist who
will review and interpret the results.
All ophthalmological examinations will be documented in the source documents of the subject.
All parameters assessed at the ophthalmological examination should also be recorded in the eCRF
as normal or abnormal. If an abnormality is found on any of the assessed parameters, it should be
specified on the corresponding eCRF page. Clinically relevant findings meeting the definition of
an AE (new AE, or worsening of previously existing condition) [see Section 10.1], must be
recorded on the AE page of the eCRF.
7.5.8 Optical Coherence Tomography
OCT was assessed at visits indicated in Table 1 and Table 2 in Protocol Versions 1 to 5. The
requirement for scheduled OCT assessments was removed from Protocol Version 6 onwards.
Unscheduled OCT examination will have to be assessed in the event of visual symptoms or
findings suggestive of macular edema according to the ophthalmologist’s decision, or if active
uveitis is diagnosed during the study [see Section 5.1.12.7]. While the OCT exam may be
performed by a delegate (e.g., technician, optometrician), the review and interpretation must be
performed by the ophthalmologist.
All examinations will be documented in the source documents of the subject. OCT examination
should also be recorded in the eCRF as normal or abnormal. If an abnormality is found, it should
be specified on the corresponding eCRF page. Clinically relevant findings meeting the definition
of an AE (new AE, or worsening of previously existing condition) [see Section 10.1], must be
recorded on the AE page of the eCRF.
7.5.9 Weight
Body weight will be measured at visits indicated in Table 1. In addition, unscheduled body weight
measurement may be performed at any time during the study. Data will be collected in the eCRF.
7.5.10 Physical examination
Physical examination is performed by the principal investigator or treating neurologist at visit
indicated in Table 1 and Table 2. In addition, unscheduled physical examination may be performed
at any time during the study.
Physical examination includes the examination of the general appearance, head, eyes, ears, nose,
throat, neck, heart, lungs, abdomen, lymph nodes, extremities, skin, neurological and
musculoskeletal functions. Other exams will be performed if indicated, based on medical history
and/or symptoms.

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Information for all physical examinations must be included in the source documentation at the
study site. The observations should be reported by body system in the eCRF as 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). Clinically relevant findings meeting the
definition of an AE (new AE, or worsening of previously existing condition) must be recorded on
the AE page of the eCRF.
Note:
The standardized neurological evaluation based on EDSS and FS scores conducted by the efficacy
assessor [see Section 7.4.1] does not obviate the requirement for the examination of the
neurological function as part of the physical examination by the treating neurologist.
7.5.11 Dermatological examination
A complete skin examination will be performed by a dermatologist at visits indicated in Table 1
and Table 2. In addition, unscheduled complete skin examination may be performed by the
dermatologist at any time during the study, if indicated.
In the event of findings of suspicious or pre-cancerous or cancerous skin disorders observed at any
visit during the study, the dermatologist will conduct further examination, as per local standard
practice, including the taking of skin biopsies if required to rule out or confirm a diagnosis.
All examinations will be documented in the source documents of the subject. Dermatological
examination should be recorded in the eCRF as normal or abnormal. If an abnormality is found, it
should be specified on the corresponding eCRF page. Clinically relevant findings meeting the
definition of an AE (new AE, or worsening of previously existing condition) [see Section 10.1]
will be recorded accordingly on the AE page of the eCRF.
7.5.12 Laboratory assessments
7.5.12.1 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.
Under specific circumstances, laboratory samples could be drawn in a local laboratory close to
where the subject lives and analyzed at the central laboratory. In such circumstances, the local
laboratory must be provided with the central laboratory kits, which must be used for blood
collection. The blood samples collected locally will be shipped by the local laboratory to the central
laboratory for analysis. Such a local laboratory shall be identified as soon as possible, but no later
than upon enrollment of the subject in the study.
Local laboratory results will only be collected in exceptional cases (e.g., subject is hospitalized in
a different hospital from the study center due to a medical emergency). In cases where a local

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laboratory is used for the collection and analysis of blood samples, the local laboratory results
(with the corresponding normal ranges) will be entered into the clinical database via dedicated
eCRF pages.
If a central laboratory sample is lost, has deteriorated or cannot be analyzed for whatever reason,
the investigator will collect an additional sample as soon as possible for repeat analysis if still
clinically relevant.
The central laboratory will provide all laboratory results by fax or normal mail to the site. Any
alerts will be indicated on the report [see Section 5.1.12].
 Teriflunomide plasma concentration: A plasma sample will be taken on Day 1 for a
teriflunomide test (results to be communicated to site only if needed, e.g., in the case of AEs
where the measurement of exposure to teriflunomide is of relevance).
 Important note: Additional teriflunomide testing is no longer required with the approval of
protocol version 5. Under protocol versions 1 to 4, teriflunomide plasma concentration may be
assessed at Week 19 ± 7 days and at Week 21 ± 7 days and may be repeated at Visit 5 (Week
24) and at following visits if necessary until two consecutive test results confirming plasma
concentration of teriflunomide <0.02 mg/L are available.
All laboratory reports must be signed and dated by the principal investigator or delegate within
5calendar 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 meeting the definition of an AE [see Section 10.1] must be
reported as an AE or SAE as appropriate, 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. Further laboratory
analyses should be performed as indicated and according to the judgment of the investigator.
Details about the collection, sampling, storage, shipment procedures, and reporting of results and
abnormal findings can be found in the laboratory manual.
7.5.12.2 Laboratory tests
Blood samples will be drawn when applicable, before the morning administration of study
medication visits indicated in Table 1. Fasting conditions are recommended but not required.
Unscheduled laboratory tests may be performed at any time during the study.
Urinalysis will be assessed using dipsticks at visits indicated in Table 1 and Table 2. In addition,
unscheduled urinalysis may be performed at any time during the study.
Hematology
 Red blood cell count
 Total and differential white blood cell counts (basophils, eosinophils, lymphocytes,
monocytes, neutrophils, band forms)

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 Platelet count
 Hb
 Hematocrit
Clinical chemistry
 Glucose
 ALT, AST, AP, total bilirubin, lactate dehydrogenase
 International Normalized Ratio
 Creatinine
 Calculated creatinine clearance (Cockroft-Gault)
 Urea
 Uric acid
 Total cholesterol
 Triglycerides
 Sodium, potassium, chloride, calcium
 Total protein, albumin
 C-reactive protein
Biomarkers and additional analyses in the event of infections
 A serum sample will be taken at Visit 1 to be 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 and for analysis of biomarkers.
Immunogenicity evaluations
 At every scheduled visit after approval of protocol version 5, a 5 mL serum sample will be
taken for immunogenicity evaluations (e.g., anti-SARS-CoV-2 antibody titers, SARS-CoV-2
neutralization assays).
Pregnancy test
A serum and urine pregnancy tests for WOCBP and will be performed at visits indicated in Table 1
and Table 2 and if pregnancy is suspected during the study. Additionally, urine pregnancy tests will
be performed at home every 4 weeks (7 days) between the visits. Subjects will communicate the
result (telephone call) of the tests to the principal investigator / treating neurologist.
Female subjects who interrupt the study treatment because of planned pregnancy will be exempted
from any protocol-mandated pregnancy tests after the first positive pregnancy test and until
30 days before study drug re-initiation.

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Serum pregnancy testing results 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. In the event of pregnancy, a Pregnancy Form must be completed [see Section 10.3].
Urinalysis
 pH
 Glucose
 Proteins
 Blood
 Leukocytes
 Bilirubin, urobilinogen
Urine dipsticks provided by the central laboratory will be used to perform the urinalysis. The test
should be performed and analyzed at the site. The results must be documented in the source
documents / subject charts and should be recorded in the eCRF as normal or abnormal. If an
abnormality is found, it should be specified on the corresponding eCRF page and the results for
the abnormal parameter will be reported in the eCRF. Clinically relevant findings meeting the
definition of an AE (new AE, or worsening of previously existing condition) [see Section 10.1]
will be recorded accordingly on the AE page of the eCRF.
Teriflunomide plasma level tests:
The results of the teriflunomide test conducted with the plasma sample taken on Day 1 will be
communicated to site only if needed, e.g., in the case of AEs where the measurement of exposure
to teriflunomide is of relevance.
During the early stages of the study (protocol versions 1 through 4), additional plasma
teriflunomide tests may have been required to confirm that teriflunomide plasma levels were
sufficiently low (<0.02 mg/L) before fertile male participants could stop contraceptive
requirements and in the case of planned pregnancies (see Section 5.1.12.5). Following approval of
protocol version 5, these tests are no longer required now that all ongoing subjects have been off
teriflunomide for over 2 years (last subject entered this extension study on 20-May-2019)
[Aubagio® USPI, Aubagio® SmPC].
The plasma teriflunomide concentration will be determined by using a high-performance liquid
chromatography method [Sobhani 2010].
7.6 Electronic self-rated version of the Columbia-Suicide Severity Rating Scale
The electronic self-rated version of the Columbia-Suicide Severity Rating Scale (eC-SSRS) is used
to reliably and consistently monitor subjects for suicidal ideation and behavior during the study. It
will be completed at visits indicated in Table 1 and Table 2.

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The eC-SSRS assesses lifetime suicidality during an initial baseline evaluation, and then
prospectively monitors ideations and behaviors at subsequent follow-up assessments. At each visit
the eC-SSRS is completed, the treating neurologist will review the responses provided by the
subject and assess the findings. The eC-SSRS is a fully structured clinical interview designed and
developed for electronic administration. Subjects will be asked to respond to standardized clinical
questions aimed at measuring the severity of suicidal ideation (rated on a 5-point ordinal scale),
the levels of suicidal behavior, and the category self-injurious behavior without suicidal intent.
Any subjects who reaches an eC-SSRS suicidal ideation score of 4 or above, or who responds
“yes” on the eC-SSRS suicidal behavior item must be referred to an appropriate health professional
who should make a decision on the management of the suicidal symptoms and recommend whether
or not the subject should continue the treatment with the study drug.
It is recommended that the eC-SSRS is completed prior to any clinical assessments, and after the
SF-36v2™ has been completed. Preferably, subjects would complete the eC-SSRS while waiting
for their appointment before any interaction with health care providers.
The clinical site will provide either a telephone, tablet, or computer for the subject to complete
the eC-SSRS. A sample of the telephone administered eC-SSRS (in English) is provided as
Appendix 8. The data will be collected by a vendor who will send the results to the sponsor.
In exceptional cases only (e.g., problem with the server), a clinician administered C-SSRS (paper
version) may be administered by an adequately qualified and trained clinician. The clinician
administered C-SSRS (paper version) does not need to be recorded in the eCRF. However, any
subject who reaches a C-SSRS suicidal ideation score of 4 or above, or who responds “yes” on the
C-SSRS suicidal behavior item must be referred to an appropriate health professional, as described
above. Furthermore, an eC-SSRS should be completed at the next applicable visit (provided the
reason for conducting a paper C-SSRS is no longer applicable).
The sponsor has been granted a license agreement for the use of the eC-SSRS and the clinician
administered C-SSRS (paper version).
7.7 Quality of life assessments
7.7.1 36-Item Short Form Health Survey v2 (SF-36v2™)
The SF-36v2™ Questionnaire (SF-36v2™ Health Survey© 1996, 2000 by Medical Outcomes
Trust and Quality Metric Incorporated) is used to assess the subject’s quality of life. The SF-
36v2™ will be completed by the subject at visits indicated in Table 1 and Table 2.
In the SF-36v2TM Questionnaire, subjects are instructed to rate their health and capacity to perform
activities of daily living 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 [Maruish 2011]. Individual domain scores are used to

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8 SCHEDULE OF VISITS
A tabulated summary of all visits and assessments described in the following sections is provided
in Table 1 and Table 2.
The schedule of visit dates should be established at the time of enrollment (Visit 1). To the extent
possible, subjects will be expected to adhere to the established visit schedule. The assessments
pertaining to a visit may be performed within the allowed time window.
 The timepoint for every visit refers to Day 1 (first dosing of study treatment).
 When scheduling the different assessments for a subject visit, the following should be taken
into account:
 At Day 1 (first dosing of study treatment) and on the days of re-initiation of study treatment
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 treatment, which will be
taken at the site on the day of visits.
 At other visits, ECGs, SBP/DBP, PFTs, blood drawings for hematology and biochemistry,
along with all other assessments, are to be performed pre-dose.
 Recommended resting time:
 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.
 Sufficient resting time should be allowed between the walking assessments for MSFC and
EDSS and other assessments (PFTs, ECGs, and BP).
 Sufficient time between blood drawing and cardiac assessments (i.e., ECGs and/or BP
measurement) is to be allowed.
To ensure compliance, at each visit the study personnel must remind WOCBP and fertile men to
use the methods of contraception defined for this study. The reminders must be documented in the
hospital chart.
Unscheduled visits may be performed at any time during the study. Depending on the reason for
the unscheduled visit (e.g., AE), appropriate assessments may be performed based on the judgment
of the investigator and must be recorded in the eCRF. After an unscheduled visit, the regular
scheduled study visits must continue according to the planned visit and assessment schedule.
8.1 Core study follow up period and transition into the extension study
8.1.1 Core study FU1
Subjects eligible for this study will have completed the FU1 visit of the core study (14–22 days after
the last dose of the study drug in the core study). Day 1 (Visit 1) of the extension may occur on the
same day as the core study FU1 visit provided the results from assessments required for eligibility
[see Section 4.3] are available and based on investigator judgment, the accelerated elimination
procedure has been successfully completed prior to the first dose administration in the extension

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study. The investigator should make every effort to minimize the duration between EOT of the core
study and Day 1 of the extension study. Ideally the treatment interruption should last no longer than
15 days.
The core study FU1 visit includes the following assessments:
 MS relapse
 Recording of changes in concomitant medications
 Assessment and recording in the eCRF of methods of contraception (for WOCBP only)
 Body temperature
 SBP/DBP
 12-lead ECG
 Spirometry
 DLCO (if applicable; under the responsibility of the pulmonologist)
 Hematology, blood chemistry
 Urinalysis
 Accelerated elimination procedure compliance assessment
 Urine pregnancy test for WOCBP
 Recording of AEs and SAEs.
8.1.2 Core study abbreviated FU2
For subjects transitioning to the extension study, an abbreviated FU2 visit will take place only if
the compliance with teriflunomide elimination procedure was deemed not sufficient by the
investigator at the core study FU1. The core study abbreviated FU2 visit should occur 23–37 days
after last drug intake and includes the following assessments:
 Recording of changes in concomitant medications
 Accelerated elimination procedure compliance assessment
 Recording of AEs and SAEs
 MS relapse assessment.
8.2 Pre-treatment period
The pre-treatment period is included within Visit 1 and begins with the subject signing the
informed consent at Visit 1. It continues until the administration of study treatment on Day 1. Visit
1 would ideally start on the day of the core study FU1 or abbreviated FU2 visits (whichever
applies), but no later than 1 day after these visits.
8.2.1 Visit 1 pre-dose
Enrollment and Visit 1 starts with the signing of the informed consent, which would ideally occur
on the day of FU1 or FU2 visit (whichever applies). In all cases, informed consent should be signed
no later than one day after FU1 or FU2 visit (whichever applies).

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The following assessment must be performed pre-dose at Visit 1: inclusion/exclusion criteria
concomitant medications, MS relapse, body temperature, ECG, SBP/SDP and pregnancy test. The
remaining assessments (i.e., medical history, EDSS/FS and physical examination) can be
performed up to 7 days after the subject has signed informed consent and before the first dose of
study treatment.
The following assessments must be performed pre-dose:
 Informed consent
 Inclusion/exclusion criteria
 Demographics
 Medical History
 EDSS/FS
 MS relapse (pre-dose Day 1)*/**
 Recording of concomitant medications*/**
 Assessment and recording in the eCRF of methods of contraception (for WOCBP only)
 Physical examination
 12-lead ECG (pre-dose Day 1)
 Body temperature (pre-dose Day 1)*
 SBP/DBP (pre-dose Day 1)*
 Urine pregnancy test (pre-dose Day 1)*/**
 Recording of AEs/SAEs
*These assessments do not need to be repeated if Day 1 occurs the same day as the core study FU1 visit.
**These assessments do not need to be repeated if Day 1 occurs the same day as the core study abbreviated FU2 visit.
8.3 Treatment period
The treatment period consists of Visit 1 to the EOT visit.
8.3.1 Visit 1 post-dose (includes first dosing)
The treatment period starts with the first dosing of study treatment, which defines Day 1 of the
extension study. Visit 1 transitions into the treatment period with the administration of study
treatment on Day 1.
Ideally, all assessments and procedures of Visit 1 including first dosing of study treatment and
post-dose cardiac monitoring would occur on the same day as the core study FU1 or abbreviated
FU2 (whichever applies). In all cases, all assessments and procedures of Visit 1 must be completed
(i.e., study treatment start) no later than 7 days after signing the informed consent.
The following assessments are performed:
 Enroll via IRT to obtain study treatment kit number;
 Dispensing of study treatment;

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 SBP/DBP hourly (+/− 15 min) for up to 12 hours post-dose with a minimum of 4 hours post-
dose;
 12-lead ECG hourly (+/− 15 min) until the evaluation ofthe ECG performed at 4 hours post-
dose is available. For subjects not meeting the discharge criteria at 4 hours post-dose, further
ECGs will be performed every hour for up to 12 hours post-dose until the discharge criteria
are met;
 Recording of AEs/SAEs;
 Blood sample for teriflunomide test (results to be communicated to site only if needed, e.g., in
the case of AEs where the measurement of exposure to teriflunomide is of relevance);
 Blood sample for virology (to be analyzed in case of a viral infection and the virus can be
identified);
 Remind WOCBP and fertile men to use the methods of contraception defined for this study
(for WOCBP throughout the study until at least 30 days after study treatment discontinuation
and until 6 weeks after the first of two consecutive tests confirming plasma teriflunomide level
<0.02 mg/L#, and for fertile men, until 6 weeks after the first of two consecutive tests
confirming plasma teriflunomide level <0.02 mg/L#). The reminders must be documented in
the hospital chart;
 Schedule an appointment for next visit and instruct subject to:
 come fasted to the site (recommended)
 bring back all blister packs (used, partially used and unused blister packs)
 not take study treatment on the day of study visit prior to coming to the site
 contact their principal investigator / treating neurologist at the clinical site immediately
in the event of the appearance of any symptoms suggestive of an MS exacerbation.
Subjects will need to gradually up-titrate from 2 mg to 10 mg during Day 1 to 14. As there is no
site visit planned until Day 15, subjects will be instructed during Visit 1 on how to perform the
gradual up-titration. The subject will be instructed to contact the site if she/he has any questions
or problems.
# Important note: Teriflunomide testing is no longer required with the approval of protocol version 5
8.3.2 Visit 2 Day 15
The visit window for this visit is −1 / +3 days. The date of drug 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 3 days prior to or after this visit date. The visit
includes:
 MS relapse
 Recording of changes in concomitant medications
 Assessment and recording in the eCRF of methods of contraception (for WOCBP only)
 Body temperature
 SBP/DBP (pre-dose)

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 Pulse rate (pre-dose)
 Hematology, blood chemistry
 Study medication accountability and compliance review
 IRT call and study treatment dispensing
 Recording of AEs and SAEs
 Remind WOCBP and fertile men to use the methods of contraception defined for this study
(for WOCBP throughout the study until at least 30 days after study treatment discontinuation
and until 6 weeks after the first of two consecutive tests confirming plasma teriflunomide level
<0.02 mg/L#, and for fertile men, until 6 weeks after the first of two consecutive tests
confirming plasma teriflunomide level <0.02 mg/L#). The reminders must be documented in
the hospital chart.
 Schedule an appointment for next visit and instruct subject to:
 Come fasted to the site (recommended)
 Bring back all bottles
 Not take study treatment on the day of study visit prior to coming to the site
 Contact their principal investigator / treating neurologist at the clinical site immediately
in the event of the appearance of any symptoms suggestive of an MS exacerbation.
# Important note: Teriflunomide testing is no longer required with the approval of protocol version 5
8.3.3 Visit 3 Week 4
The visit window for these visits is ± 7 days. Measurement of SBP/DBP (pre-dose) defines the
date of the visit. All other assessments may be performed up to 7 days prior to or after this visit
date. The visits include:
 MS relapse
 Recording of changes in concomitant medications
 Assessment and recording in the eCRF of methods of contraception (for WOCBP only)
 Body temperature
 SBP/DBP (pre-dose)
 Pulse rate (pre-dose)
 Spirometry (pre-dose)
 DLCO (if applicable; pre-dose, under the responsibility of the pulmonologist)
 Hematology, blood chemistry
 Urine pregnancy test for WOCBP
 Study medication accountability and compliance review
 Recording of AEs and SAEs
 Remind WOCBP and fertile men to use the methods of contraception defined for this study
(for WOCBP throughout the study until at least 30 days after study treatment discontinuation
and until 6 weeks after the first of two consecutive tests confirming plasma teriflunomide level
<0.02 mg/L# and for fertile men, until 6 weeks after the first of two consecutive tests

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confirming plasma teriflunomide level <0.02 mg/L#). The reminders must be documented in
the hospital chart.
 Schedule an appointment for next visits, including hematology, blood chemistry to be collected
at Week 8, and instruct subject to:
 Come fasted to the site (recommended)
 Bring back all study treatment bottles
 Not take study treatment on the day of study visit prior to coming to the site
 Contact their principal investigator / treating neurologist at the clinical site immediately
in the event of the appearance of any symptoms suggestive of an MS exacerbation.
# Important note: Teriflunomide testing is no longer required with the approval of protocol version 5
8.3.4 Additional safety laboratory tests until Week 24 (Weeks 8, 16 and 20)
The test window is ± 7 days. Under specific circumstances (e.g., subject lives far away from the
site and cannot return every 4 weeks during the first 24 weeks), laboratory samples could be drawn
in a local laboratory close to where the subject lives, and analyzed at the central laboratory [see
Section 7.5.12.1].
8.3.5 Visit 4 Week 12
The visit window for these visits is ± 7 days. The IRT call defines the date of the visit. All other
assessments may be performed up to 7 days prior to or after this visit date. The visits include:
 EDSS/FS
 MS relapse
 SDMT
 Recording of changes in concomitant medications
 Assessment and recording in the eCRF of methods of contraception (for WOCBP only)
 Body temperature
 SBP/DBP (pre-dose)
 Pulse rate (pre-dose)
 Ophthalmological examination (under the responsibility of the ophthalmologist)
 OCT (under the responsibility of the ophthalmologist)2
 Hematology, blood chemistry
 Urine pregnancy test for WOCBP
 Study medication accountability and compliance review
 IRT call and study treatment dispensing
 Recording of AEs and SAEs
2 
Scheduled OCT assessments are only applicable to Global Protocol Version 1 to 5. The requirement for OCT assessments
was removed from Global Protocol Version 6 onwards.

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 Remind WOCBP and fertile men to use the methods of contraception defined for this study
(for WOCBP throughout the study until at least 30 days after study treatment discontinuation
and until 6 weeks after the first of two consecutive tests confirming plasma teriflunomide level
<0.02 mg/L# and for fertile men, until 6 weeks after the first of two consecutive tests
confirming plasma teriflunomide level <0.02 mg/L#). Schedule an appointment for next visits,
including hematology, blood chemistry to be collected at Weeks 16 and 20, and instruct subject
to:
 Come fasted to the site (recommended)
 Bring back all study treatment bottles
 Not take study treatment on the day of study visit prior to coming to the site
 Contact their principal investigator / treating neurologist at the clinical site immediately
in the event of the appearance of any symptoms suggestive of an MS exacerbation.
# Important note: Teriflunomide testing is no longer required with the approval of protocol version 5
8.3.6 In-between-visit telephone calls until Week 240 (every 6 weeks)
The site will contact the subject in between 12-weekly visits (e.g., Visit 5-Week 24, Visit 6-Week
36). These telephone calls will be conducted either at Weeks 18, 30, 42, and up to Week 234
(+/−7 days), or 6 weeks after the last 12-weekly visit (± 7 days). During these telephone calls, the
site will proactively inquire about any new or worsened neurological symptoms.
8.3.7 Visit 5 Week 24
The visit window for these visits is ± 14 days. The IRT call defines the date of the visit. All other
assessments may be performed within the visit window of this visit date. The visits include:
 EDSS/FS
 MS relapse
 SDMT
 SF-36 v2
 Recording of changes in concomitant medications
 Assessment and recording in the eCRF of methods of contraception (for WOCBP only)
 Physical examination
 Body temperature
 SBP/DBP (pre-dose)
 Pulse rate (pre-dose)
 Ophthalmological examination (under the responsibility of the ophthalmologist)
 OCT (under the responsibility of the ophthalmologist)3
 Hematology, blood chemistry
3 
Scheduled OCT assessments are only applicable to Global Protocol version 1 to 5. The requirement for OCT assessments
was removed from Protocol Version 6 onwards.

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 Urinalysis
 Urine pregnancy test for WOCBP
 Study medication accountability and compliance review
 IRT call and study treatment dispensing
 Recording of AEs and SAEs
 Remind WOCBP and fertile men to use the methods of contraception defined for this study
(for WOCBP throughout the study until at least 30 days after study treatment discontinuation
and until 6 weeks after the first of two consecutive tests confirming plasma teriflunomide level
<0.02 mg/L# and for fertile men, until 6 weeks after the first of two consecutive tests
confirming plasma teriflunomide level <0.02 mg/L#, if applicable). Schedule an appointment
for next visit and instruct subject to:
 Come fasted to the site (recommended)
 Bring back all study treatment bottles
 Not take study treatment on the day of study visit prior to coming to the site
 Contact their principal investigator / treating neurologist at the clinical site immediately
in the event of the appearance of any symptoms suggestive of an MS exacerbation.
# Important note: Teriflunomide testing is no longer required with the approval of protocol version 5
8.3.8 Visits 6, 8, 9, 10, 12, 13, 14, 16, 17, 18, 20, 21, 22; Weeks 36, 60, 72, 84, 108, 120, 132,
156, 168, 180, 204, 216, 228
The visit window for these visits is ± 14 days. The IRT call defines the date of the visit. All other
assessments may be performed within the window of this visit date. The visits include:
 EDSS/FS
 MS relapse
 Recording of changes in concomitant medications
 Assessment and recording in the eCRF of methods of contraception (for WOCBP only)
 Body temperature
 SBP/DBP (pre-dose)
 Pulse rate (pre-dose)
 Hematology, blood chemistry, and (following approval of protocol version 5) a serum sample
for immunogenicity evaluations (e.g., anti SARS-CoV-2 antibody testing) will be collected for
all subjects
 Urinalysis
 Urine pregnancy test for WOCBP (NB: female subjects who interrupt the study treatment
because of planned pregnancy will be exempted from any protocol-mandated pregnancy tests
after the first positive pregnancy test and until 30 days before study drug re-initiation. Study
medication accountability and compliance review
 IRT call and study treatment dispensing
 Recording of AEs and SAEs

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 Remind WOCBP and fertile men to use the methods of contraception defined for this study
(for WOCBP throughout the study until at least 30 days after study treatment discontinuation
and until 6 weeks after the first of two consecutive tests confirming plasma teriflunomide level
<0.02 mg/L# and for fertile men, until 6 weeks after the first of two consecutive tests
confirming plasma teriflunomide level <0.02 mg/L#, if applicable). Schedule an appointment
for next visit and instruct subject to:
 Come fasted to the site (recommended)
 Bring back all study treatment bottles
 Not take study treatment on the day of study visit prior to coming to the site
 Contact their principal investigator / treating neurologist at the clinical site immediately
in the event of the appearance of any symptoms suggestive of an MS exacerbation.
# Important note: Teriflunomide testing is no longer required with the approval of protocol version 5
8.3.9 Visits 7, 11, 15, 19 - Weeks 48, 96, 144, 192
The visit window for these visits is ± 14 days. The IRT call defines the date of the visit. All other
assessments may be performed within the window of this visit date. The visits include:
 EDSS/FS
 MS relapse
 MSFC
 SDMT
 SF-36 v2
 eC-SSRS
 MRI
 Recording of changes in concomitant medications
 Assessment and recording in the eCRF of methods of contraception (for WOCBP only)
 Physical examination
 Dermatological examination
 Body weight
 Body temperature
 SBP/DBP (pre-dose)
 12-lead ECG (pre-dose)
 Ophthalmological examination (under the responsibility of the ophthalmologist)
 OCT (under the responsibility of the ophthalmologist)4
 Spirometry (pre-dose)
 DLCO (if applicable; pre-dose, under the responsibility of the pulmonologist)
4 
Scheduled OCT assessments are only applicable to Global Protocol version 1 to 5. The requirement for OCT assessments
was removed from Protocol Version 6 onwards.

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 Hematology, blood chemistry, and (following approval of protocol version 5) a serum sample
for immunogenicity evaluations (e.g., anti SARS-CoV-2 antibody testing) will be collected for
all subjects
 Urinalysis
 Serum pregnancy test for WOCBP (NB: female subjects who interrupt the study treatment
because of planned pregnancy will be exempted from any protocol-mandated pregnancy tests
after the first positive pregnancy test and until 30 days before study drug re-initiation. Study
medication accountability and compliance review
 IRT call and study treatment dispensing
 Recording of AEs and SAEs
 Remind WOCBP and fertile men to use the methods of contraception defined for this study
(for WOCBP throughout the study until at least 30 days after study treatment discontinuation
and until 6 weeks after the first of two consecutive tests confirming plasma teriflunomide level
<0.02 mg/L# and for fertile men, until 6 weeks after the first of two consecutive tests
confirming plasma teriflunomide level <0.02 mg/L#, if applicable). Schedule an appointment
for next visit and instruct subject to:
– Come fasted to the site (recommended)
– Bring back all study treatment bottles
– Not take study treatment on the day of study visit prior to coming to the site
– Contact their principal investigator / treating neurologist at the clinical site immediately
in the event of the appearance of any symptoms suggestive of an MS exacerbation.
# Important note: Teriflunomide testing is no longer required with the approval of protocol version 5
8.3.10 EOT Visit Week 240
The visit window for this visit is ± 14 days. The ECG assessment defines the date of the visit. All
other assessments may be performed within the window of this visit date. If a study treatment
interruption is transformed into a permanent premature discontinuation, the EOT visit should be
done as soon as possible, preferably 7 days after the decision to discontinue was made.
For those subjects completing study treatment due to the availability of commercially available
ponesimod, an EOT visit should be conducted preferably within 7 days after stopping study
treatment. Commercially available ponesimod may be initiated on the day after last intake of study
treatment.
The visits include:
 EDSS/FS
 MS relapse
 MSFC
 SDMT

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 SF-36 v2
 eC-SSRS
 MRI (in case of premature study treatment discontinuation, the MRI assessment at EOT does
not need to be performed if the EOT visit occurs within 4 weeks of the MRI assessment at
Visits 7, 11, 15, or 19 (Weeks 48, 96, 144, or 196)
 Recording of changes in concomitant medications
 Assessment and recording in the eCRF of methods of contraception (for WOCBP only)
 Physical examination
 Dermatological examination
 Body weight
 Body temperature
 SBP/DBP
 12-lead ECG
 Ophthalmological examination (under the responsibility of the ophthalmologist)
 OCT (under the responsibility of the ophthalmologist)5
 Spirometry
 DLCO (if applicable; pre-dose, under the responsibility of the pulmonologist)
 Hematology, blood chemistry, and (following approval of protocol version 5) a serum sample
for immunogenicity evaluations (e.g., anti SARS-CoV-2 antibody testing) will be collected for
all subjects
 Urinalysis
 Serum pregnancy test for WOCBP (NB: female subjects who interrupt the study treatment
because of planned pregnancy will be exempted from any protocol-mandated pregnancy tests
after the first positive pregnancy test and until 30 days before study drug re-initiation. Study
medication accountability and compliance review
 Recording of AEs and SAEs
 Remind WOCBP and fertile men to use the methods of contraception defined for this study
(for WOCBP throughout the study until at least 30 days after study treatment discontinuation
and until 6 weeks after the first of two consecutive tests confirming plasma teriflunomide level
<0.02 mg/L# and for fertile men, until 6 weeks after the first of two consecutive tests
confirming plasma teriflunomide level <0.02 mg/L#, if applicable). Schedule an appointment
for next visit and instruct subject to:
 Come fasted to the site (recommended)
 Bring back all study treatment bottles
 Contact their principal investigator / treating neurologist at the clinical site immediately
in the event of the appearance of any symptoms suggestive of an MS exacerbation.
5 
Scheduled OCT assessments are only applicable to Global Protocol version 1 to 5. The requirement for OCT assessments
was removed from Protocol Version 6 onwards.

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# Important note: Teriflunomide testing is no longer required with the approval of protocol version 5
8.4 Follow-up period
The follow-up period includes the EOS visit 30 days after the last day of study treatment intake.
8.4.1 EOS Visit
This visit will be conducted 30–44 days after the permanent discontinuation of study treatment.
All assessments should be conducted within the visit window. The last assessment conducted for
the study will define the visit date.
The EOS visit should also be conducted for subjects who have switched to commercially available
ponesimod.
The visits include:
 EDSS/FS
 MS relapse
 Recording of changes in concomitant medications
 Assessment and recording in the eCRF of methods of contraception (for WOCBP only)
 Body temperature
 SBP/DBP
 12-lead ECG
 Ophthalmological examination (under the responsibility of the ophthalmologist)
 OCT (under the responsibility of the ophthalmologist)6
 Spirometry
 DLCO (if applicable; under the responsibility of the pulmonologist)
 Hematology, blood chemistry, and (following approval of protocol version 5) a serum sample
for immunogenicity evaluations (e.g., anti SARS-CoV-2 antibody testing) will be collected for
all subjects
 Urinalysis
 Serum pregnancy test for WOCBP
 Recording of AEs and SAEs
 Remind WOCBP and fertile men to use the methods of contraception defined for this study
until 6 weeks after the first of two consecutive tests confirming plasma teriflunomide level
<0.02 mg/L# if such test results have not been obtained prior to EOS visit.
# Important note: Teriflunomide testing is no longer required with the approval ofprotocol version 5
6 
Scheduled OCT assessments are only applicable to Global Protocol version 1 to 5. The requirement for OCT assessments
was removed from Protocol Version 6 onwards.

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8.5 Unscheduled visits
An unscheduled site visit may be performed at any time during the study (between scheduled
visits), as necessary, at the investigator’s discretion, or may be required such as in the case of a
planned pregnancy. These visits include (but are not limited to) those performed due to safety (e.g.,
occurrence of an AE, laboratory abnormalities, planned study treatment interruption),
administration of study treatment (e.g., re-initiation, return of unused study medication, need to
initiate treatment with a QT-prolonging drug), and/or MS related issues (e.g., relapses).
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.
8.5.1 Unscheduled visits for relapses (Visits R1, R2, etc.)
Subjects will be reminded to contact their treating neurologist at the clinical site immediately in
the event of appearance of any new or worsened neurological symptoms. Whenever a subject
contacts the principal investigator / treating neurologist reporting the appearance of any symptoms
suggestive of an MS exacerbation, the principal investigator / treating neurologist will interview
the subject and determine the necessity of an unscheduled visit for relapse. An unscheduled visit
will be organized as soon as possible after onset or worsening of the symptom(s) as follows:
 The principal investigator / treating neurologist will interview and examine the subject to
determine whether or not a relapse may  have occurred since last visit using the dedicated
relapse assessment questionnaire [see Appendix 10] and the relapse symptoms form [see
Appendix 11] and decide whether the subject has to be referred to the efficacy assessor.
 In order to exclude potential other reasons for the symptom(s) observed, the principal
investigator / treating neurologist will need to perform the following assessments:
 Physical examination
 Vital signs: SBP/DBP, pulse rate, body temperature
 In the event of the subject’s referral to the efficacy assessor, the latter will perform the EDSS
and FS within 7 days from the onset or worsening of the symptom(s). The decision regarding
whether the new or worsened neurological symptoms are considered as confirmed or
unconfirmed relapse will be made by the principal investigator / treating neurologist by
assessing the compatibility of the symptoms reported by the subject and the presence or
absence of a qualifying increase in the EDSS/FS (i.e., and increase of the magnitude described
in Section 6.1.1) resulting from comparison between the current and previous, clinically stable
EDSS/FS assessment performed by the efficacy assessor.
All MS relapses, whether confirmed or unconfirmed during the study, must be reported on specific
relapse pages of the eCRF. MS relapses and associated symptoms are not to be entered on the AE
page of the eCRF with the following exceptions:

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MS relapses with fatal outcome (these must always be recorded as AEs on the AE page in addition
to being reported as SAEs).
MS relapses that, in the view of the investigator, warrant specific notice due to unusual frequency,
severity or remarkable clinical manifestations (these should be reported as AEs on the AE page of
the eCRF and, if applicable, on the SAE form).
Additionally, the following assessments must be done during those visits:
 Recording of changes in concomitant medications
 Recording of AEs and SAEs
 Schedule an appointment for next visit, unless already done and instruct subject to:
 Preferably come fasted to the site and contact their principal investigator / treating
neurologist at the clinical site immediately in the event of the appearance of any
symptoms suggestive of an MS exacerbation.
If a relapse visit is within 5 days prior to the date of a regular visit where MRI is assessed, efforts
should be made to perform the MRI assessments prior to the start of treatment with i.v.
corticosteroids. However, if this is not possible, then the MRI should be delayed until at least
14 days after the last dose of corticosteroids.
These visits for relapses are additional unscheduled visits. The regular scheduled study visits must
be resumed according to the original visit and assessment schedule. If the visit is within the visit
window of a regular visit, the assessments for the relapse unscheduled visit count as the ones of
this regular visit.
8.5.2 Unscheduled visits (any other assessment; U1, U2, U3, etc.)
An unscheduled site visit may be performed at any time during the study (between scheduled
visits), as necessary, at the investigator’s discretion. 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 such visits, any of the following assessments may be performed at
the investigator’s discretion:
 EDSS/FS
 MS Relapse (if the subject is meeting the principal investigator / treating neurologist)
 MRI
 Assessment of concomitant medications
 Assessment of methods of contraception (for WOCBP only)
 Physical examination
 Dermatological examination
 Body temperature
 Body weight
 SBP/DBP

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 Teriflunomide plasma concentration#
 Pulse rate (to be assessed only if no 12-lead ECG is performed)
 Ophthalmological examination (e.g., presence of visual symptoms suggestive of active uveitis
[see Section 5.1.12.7])
 OCT (e.g., presence of visual symptoms suggestive of macular edema or active uveitis [see
Section 5.1.12.7])
 Complete laboratory tests including: hematology, blood chemistry, viral serology, urinalysis,
urine or serum pregnancy test (for WOCBP only).
 IRT call – return of study treatment bottles and unused medication, and dispensing of new
bottles, if appropriate.
 Assessment of AEs and SAEs.
# Important note: Teriflunomide testing is no longer required with the approval of protocol version 5
Additional unscheduled spirometry will have to be conducted in the event of respiratory symptoms
(e.g., dyspnea) and in the event of FEV1 or FVC at a scheduled visit showing decrease from
extension study baseline by >30% during the course of the study. Administration of inhaled
short-acting β2 agonist (e.g., albuterol/salbutamol) for symptom relief may be performed at the
discretion of the investigator. Administration of short-acting β2 agonist will be collected in the
eCRF.
If any of the laboratory variables listed in Section 7.5.12.2 need to be analyzed, this must be done
at the central laboratory, except in case of emergency; if it has been done at a local laboratory,
results must be recorded in the eCRF [see Section 7.5.12].
8.5.3 Additional unscheduled visits for re-initiation of study treatment (I1, I2, etc.)
As described in detail in Section 5.1.9, subjects who miss taking the dose of study drug for 4 or
more consecutive days will need to re-initiate study drug using the original up-titration scheme.
In such cases, there will be one or two visits:
 One visit on the day of re-initiation (D1) for all subjects;
 An additional visit 14 days (1 day) after the day of re-initiation (D15) only mandated for
subjects with cardiovascular risk factors (see Section 5.1.9) but may be scheduled for any
subject at the discretion of the investigator / treating neurologist.
The following assessments/procedures must be done during the visit on the day of re-initiation (D1):
 MS relapse (if the subject is meeting the principal investigator / treating neurologist)
 Body temperature;
 SBP/DBP pre-dose and hourly (+/− 15 min) for up to 12 hours post-dose (under the
responsibility of the first-dose administrator)*;

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 12-lead ECG pre-dose and hourly (+/− 15 min) for up to 12 hours post-dose (under the
responsibility of the first-dose administrator)*;
 IRT call and study treatment dispensing§;
 Recording of AEs and SAEs;
 Recording of changes in concomitant medications;
 The discharge criteria will be applied as described for Day 1. Subjects may be discharged from
cardiac monitoring if they meet the discharge criteria before 12 hours post-dose but no sooner
than 4 hours post-dose [see Section 5.1.10].
* All subjects are required to have a pre-dose assessment. Only subjects with cardiovascular risk factors [see
Section 5.1.9] are required to be monitored for at least 4 hours and up to 12 hours post-dose at the study site. In this
case, discharge criteria will be applied as described for Day 1 [see Section 5.1.10]. Subjects without cardiovascular
risk factors may re-initiate study drug at home or at site and be monitored for at least 4 hours post-dose at the discretion
of the investigator / treating neurologist.
§ Subjects with cardiovascular risk factors [see Section 5.1.9] will receive only the up-titration kit. Subjects without
cardiovascular risk factors [see Section 5.1.9] and who re-initiated at home will receive both the up-titration kit and
blisters/bottles for maintenance.
For subjects attending the visit 14 days after the day of re-initiation (if applicable), the following
assessments need to be done:
 MS relapse (if the subject is meeting the principal investigator / treating neurologist);
 Body temperature;
 SBP/DBP (pre-dose);
 12-lead ECG (pre-dose);
 IRT call – return of study treatment blisters/bottles and unused medication, and dispensing of
new blisters/bottles, if appropriate;
 Recording of AEs and SAEs.
The date of visit and any data related to study assessments performed during this visit (12-lead
ECGs, SBP/DBP) will be reported on the specific eCRF pages for unscheduled visit for re-
initiation of study treatment.
These visits for 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 must be
performed in addition.
8.5.4 Additional unscheduled visit 30 days after study treatment interruption due to
planned pregnancy with intention of study treatment re-initiation post-partum
As described in Section 5.1.12.4, female participants who wish to become pregnant must have a
negative pregnancy test at an unscheduled visit 30 days after they interrupt study treatment before
they can interrupt the contraception. In addition, interruption of contraception should take place

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after Visit 5 (Week 24) and at earliest 6 weeks after the first of two consecutive tests confirming
plasma teriflunomide level <0.02 mg/L# and at least 30 days after study treatment discontinuation.
During this visit, the following assessment will be performed:
 EDSS/FS
 MS Relapse (if the subject is meeting the principal investigator / treating neurologist)
 MRI
 Assessment of concomitant medications
 Assessment of methods of contraception (for WOCBP only)
 Physical examination
 Dermatological examination
 Body temperature
 Body weight
 SBP/DBP
 Spirometry
 Pulse rate (to be assessed only if no 12-lead ECG is performed)
 Ophthalmological examination (e.g., presence of visual symptoms suggestive of active uveitis
[see Section 5.1.12.7])
 OCT (e.g., presence of visual symptoms suggestive of macular edema or active uveitis [see
Section 5.1.12.7])
 Complete laboratory tests including: hematology, blood chemistry, viral serology, urinalysis
and serum pregnancy test.
 Recording of AEs and SAEs.
The principal investigator / treating neurologist or the study nurse must instruct/remind the subject
to interrupt the contraception until after delivery and to follow all the visits scheduled as per
protocol during the drug interruption period and until the study treatment has been re-started or
permanently discontinued
# Important note: Teriflunomide testing is no longer required with the approval of protocol version 5
8.5.5 Additional unscheduled visits for eligibility assessment for re-initiation of study
treatment for female subjects who interrupted the study treatment for planned
pregnancy and who wish to re-start the study treatment after delivery
As described in Section 5.1.12.4, female subjects who interrupted the study treatment for planned
pregnancy and who wish to re-start the study treatment after delivery will need to be assessed for
the eligibility for the study treatment restart. Unless the subject has been treated with a DMT
(interferon β or glatiramer acetate) during the pregnancy and post-partum, this visit should take
place as soon as possible after delivery in order to minimize the post-partum period without MS
treatment. In addition, this visit should take place 30 (± 5) days before the study drug re-initiation.

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During this visit, the following assessments must be performed before study drug administration:
Urine pregnancy test first and, if urine pregnancy test is negative:
 EDSS/FS assessment
 MS relapse
 MRI examination
 Recording of changes in concomitant medications, if any
 Assessment and recording in the eCRF of methods of contraception
 Physical examination
 Body temperature
 Body weight
 SBP/DBP
 Ophthalmological examination (under the responsibility of the ophthalmologist)
 OCT (e.g., presence of visual symptoms suggestive of macular edema or active uveitis [see
Section 5.1.12.7])
 Spirometry, DLCO (if applicable; under the responsibility of the pulmonologist)
 Hematology, blood chemistry
 12-lead ECG
 Urinalysis
 Recording of AEs and SAEs
 Remind the subject to use the methods of contraception defined for this study. The reminders
must be documented in the hospital chart.
 Confirmation that the subject did/does not fulfill any protocol criteria for permanent study
treatment discontinuation [see Section 5.1.12] at any of the previous visits or at the
unscheduled visit for re-start of the study medication except the planned pregnancy.
 If the subject has been treated with a DMT (interferon β or glatiramer acetate) during and after
pregnancy, the subject must be instructed to interrupt the treatment 7 days before re-start of
ponesimod and this instruction must be documented in the hospital records.
If all the eligibility criteria for study treatment restart which are assessable at this visit are fulfilled,
schedule an appointment for next visit (i.e., additional unscheduled visits for re-initiation of study
treatment) 25–35 days later and instruct the subject to contact their principal investigator / treating
neurologist at the clinical site immediately in the event of the appearance of any symptoms
suggestive of an MS exacerbation.
The subject must be instructed/reminded that that breastfeeding must be completely stopped before
study drug re-initiation.
If the urine pregnancy test is positive, the subject is not eligible for ponesimod re-start.
This visit must be performed in all cases of study drug interruption for planned pregnancy,
irrespective of the duration of pregnancy, and also in all cases where planned pregnancy did not

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occur but where the contraception was interrupted for any duration and the subject wishes to re-
start study treatment.
8.5.6 Unscheduled visit for re-start of the study treatment after delivery
The following assessments/procedures must be performed during the visit:
Urine pregnancy test first, and, if negative:
 Assessment and recording in the eCRF of methods of contraception and confirmation that that
the subject has been using reliable methods of contraception as described in Section 4.4.1 for
at least 30 days;
 Assessment of total duration of study treatment interruption (which should not exceed
81 weeks);
 Confirmation that breastfeeding has been completely stopped;
 If the subject has been treated with a DMT (interferon β or glatiramer acetate) during and after
pregnancy, confirmation that this treatment has been discontinued not less than 7 days prior to
study drug re-initiation;
 12-lead ECG and SBP/DBP (under the responsibility of the physician evaluating cardiac safety
assessments) at pre-dose and every hour (+/− 15 min) for 4-hours post-dose*;
 The discharge criteria will be applied as described for first day of re-initiation
[see Section 5.1.10]*;
 Body temperature;
 Body weight;
 Recording of AEs and SAEs;
 Recording of changes in concomitant medications;
 MS relapse;
 Dispensing of study treatment.
If the urine pregnancy test is positive, the subject is not eligible for ponesimod re-start. The regular
scheduled study visits must continue according to the original visit and assessment schedule.
* All subjects are required to have a pre-dose assessment. Only subjects with cardiovascular risk factors [see
Section 5.1.9] are required to be monitored for at least 4 hours and up to 12 hours post-dose at the study site. In this
case, discharge criteria will be applied as described for Day 1 [see Section 5.1.10]. Subjects without cardiovascular
risk factors may re-initiate study drug at home.
9 STUDY COMPLETION AND POST-STUDY TREATMENT/MEDICAL
CARE
9.1 Study completion
For an individual subject, EOS is reached when treatment and FU periods have been completed.
The reason(s) for discontinuing the study along with who made the decision, if applicable, (i.e.,
subject, investigator or the sponsor) must be recorded in the eCRF.

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EOS on a study level occurs at the time all subjects have completed their EOS visits, as described
above.
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, die, or are lost to FU for any other reason. 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 the sponsor for any reason,
including premature termination or suspension of the study [see Section 9.3].
Subjects are considered as lost to FU 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 FU
(e.g., document different ways of contact such as telephone number, home address, e-mail address,
person to be contacted if the subject cannot be reached). If the subject cannot be reached, the site
must make a reasonable effort to contact the subject, document all attempts and enter the loss of
FU 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 to be lost to FU.
If premature withdrawal occurs for any reason, the reason for premature withdrawal from the
study, along with who made the decision (subject, investigator or the sponsor), must be recorded
in the eCRF.
If for whatever reason (except death or loss to FU) a subject was withdrawn from the study, the
investigator should make efforts to conduct a last visit/contact to assess the safety and wellbeing
of the subject, collect unused study treatment and discuss (FU) post-study medical care. Data
obtained during this last appointment / telephone call will be recorded in the subjects’ medical
records but it will not be collected in the eCRF. The investigator must provide FU 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.
9.3 Premature termination or suspension of the study
The sponsor reserves the right to terminate the study at any time globally or locally. Investigators
can terminate the participation of their site in the study at any time.

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If the study is suspended or prematurely terminated, the sponsor will promptly inform the
investigators, the Institutional Review Boards (IRBs) / Independent Ethics Committees (IECs) and
health authorities as appropriate, and provide the reasons for the suspension or termination.
If the study is suspended or prematurely terminated for any reason, the investigator in agreement
with the sponsor must promptly inform all enrolled subjects and ensure their appropriate treatment
and FU, as described in Section 9.2. 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 the
sponsor, the investigator must promptly inform the sponsor 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 the study, the investigator
must promptly notify the sponsor and provide a detailed written explanation of the termination or
suspension.
Any suspension or premature termination of the study was to be discussed with the IDMC until its
disbandment which occurred on 30th September 2021.
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.
10 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS
Safety definitions and reporting requirements for all subjects participating in this study are
summarized below.
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,
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 15 days after study treatment discontinuation) whether or not
considered by the investigator as related to study treatment. This definition applies regardless of
whether the subject receives commercially available ponesimod after completing study treatment.
Treatment-emergence is considered with respect to the relevant Analysis Period, i.e., relative to
the first dose of ponesimod in the core study for the Combined Analysis Period, and relative to the
first dose of ponesimod in the extension study for the Extension Analysis Period.

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AEs include:
 Exacerbation of a pre-existing disease with the exception of MS relapse and associated
symptoms [see Section 10.1.6].
 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 (i.e., signing of informed consent).
 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.
Special reporting situations are described in Section 10.5.
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 prior to start of extension study treatment and which is
ongoing at the start of treatment worsens after the start of study treatment, a new AE must be
recorded in the eCRF. 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.

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 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 10.3.1]. 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 subsequently reported as either related or
unrelated. The determination of the likelihood that the study treatment caused the AE will be
provided by an investigator who is a qualified physician.
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 treatment start (Day 1) and up to 30 days after permanent study
treatment discontinuation (i.e., EOS) must be recorded on specific AE pages of the eCRF. This
also applies to AEs occurring during the treatment interruption (e.g., due to planned pregnancy),
for example, all AEs during study treatment interruption should be reported in the eCRF. If, during
study treatment interruption which lasted >30 days the subject fulfills the criteria for permanent
study treatment discontinuation, the reporting of AEs should continue until the EOS visit, which
should be scheduled as soon as possible after the decision for permanent study treatment
discontinuation has been taken. The sponsor may contact the investigator to obtain further
information concerning AEs.
10.1.6 Reporting of MS relapse
All MS relapses during the study must be reported on specific relapse pages of the eCRF. MS
relapses and associated symptoms are not to be entered on the AE page of the eCRF with the
following exceptions:
 MS relapses with fatal outcome (these must always be recorded as AEs on the AE page in
addition to being reported as SAEs).
 MS relapses that, in the view of the investigator, warrant specific notice due to unusual
frequency, severity or remarkable clinical manifestations (these should be reported as AEs on
the AE page of the eCRF and, if applicable, on the SAE form).

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10.1.7 Follow-up of adverse events
AEs still ongoing more than 30 days after permanent study treatment discontinuation must be
followed up until they are no longer considered clinically relevant.
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 Council for 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 in-patient hospitalization, or prolongation of existing hospitalization.
 Resulting in persistent or significant disability or incapacity.
 Congenital anomaly or birth defect.
 Is a suspected transmission of any infectious agent via a medicinal product
 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 exempted from being reported:
 Hospitalization for cosmetic elective surgery, or social and/or convenience reasons.
 Hospitalization for MS relapse (with the exceptions described in Section 10.1.6).
 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 (for example, if a
complication prolongs hospitalization).
10.2.2 Reporting of serious adverse events
All SAEs occurring after study treatment start (Day 1) and up to 30 days after permanent study
treatment discontinuation must be reported on AE pages in the eCRF and on SAE forms, regardless

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of the investigator-attributed causal relationship with study treatment or study-mandated
procedures.
10.2.3 Follow-up of serious adverse events
Serious adverse events still ongoing at the EOS visit must be followed up until resolution or
stabilization, or until the event outcome is provided, e.g., death.
10.2.4 After the 30-day follow-up period
New SAEs occurring after the 30-day FU period must be reported to the sponsor within 24 hours
of the investigator’s knowledge of the event, only if considered by the investigator to be causally
related to previous exposure to the study treatment.
10.2.5 Reporting procedures
All SAEs, as well as product quality complaints (PQCs), occurring during the study must be
reported to the appropriate sponsor contact person by study site personnel within 24 hours of their
knowledge of the event.
MS relapses and associated symptoms are exempt from being reported on an SAE form by the
investigator to the sponsor with the exceptions described in Section 10.1.6.
All SAEs must be recorded on an SAE form by the investigator, and whether or not this event is
considered by the investigator to be related to study treatment. The SAE forms must be completed
and signed by a physician from the study site and transmitted to the sponsor (contact details are
provided on the SAE form) within 24 hours. The investigator must complete the SAE form in
English, and must assess the causal relationship of the event to study treatment.
FU information about a previously reported SAE must also be reported within 24 hours of
receiving it. The sponsor 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 safety information section of the IB [Ponesimod IB] is the reference safety document to assess
expectedness of a suspect serious adverse reaction and reporting by the sponsor to health
authorities, IRBs/IECs and investigators.
10.3 Pregnancy
If a woman becomes pregnant while on study treatment, study treatment must be permanently
discontinued. The investigator must counsel the subject and discuss the risks of continuing with
the pregnancy and the possible effects on the fetus.
Women who wish to interrupt the study treatment because of planned pregnancy and restart the
study treatment after delivery and lactation, if applicable, will be allowed to stay in the study
provided the conditions mentioned in the Section 5.1.12.5are fulfilled.

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10.3.1 Reporting of pregnancy
Any pregnancy (irrespective if planned or not) occurring during the entire study including during
30 days following permanent study treatment discontinuation, must be reported to the sponsor by
study site personnel within 24 hours of their knowledge of the event. Pregnancies must be reported
on the appropriate pregnancy notification form, which is transmitted to the sponsor, and on the AE
page in the eCRF.
10.3.2 Follow-up of pregnancy
Any pregnancy must be followed to its conclusion and its outcome reported to the sponsor.
Any AE associated with the pregnancy occurring during the FU period after study treatment
discontinuation or during study treatment interruption for planned pregnancy must be reported on
separate AE pages in the eCRF. Any SAE occurring during the pregnancy must be reported using
an SAE form as described in Section 10.2.2. Abnormal pregnancy outcomes (e.g., spontaneous
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs and
must be reported using an SAE form.
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
sponsor’s clinical team (in charge of ensuring subjects’ safety as well as data quality) by
periodically monitoring clinical study activities from protocol conception to database closure. In
addition, an IDMC monitored safety data until its disbandment which occurred on 30th September
2021 [see Section 3.5.1]. The sponsor may request additional data pertaining to the diagnostic
work-up of an AE or SAE (e.g., medical imaging, local laboratory values) for the purpose of safety
monitoring. Such additional data may be shared with external experts.
10.5 Special reporting situations
Safety events of interest on a sponsor study drug in an interventional study that may require
expedited reporting or safety evaluation include, but are not limited to:
 
Overdose of a sponsor study drug (defined as the intake of >1 pills on the same calendar day)
 
Suspected abuse/misuse of a sponsor study drug
 
Accidental or occupational exposure to a sponsor study drug
 
Medication error, intercepted medication error, or potential medication error involving a
Johnson & Johnson medicinal product (with or without patient exposure to the Johnson &
Johnson medicinal product, e.g., product name confusion, product label confusion, intercepted
prescribing or dispensing errors)
 
Exposure to a sponsor study drug from breastfeeding

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Special reporting situations should be recorded on the AE pages of the eCRF, and study treatment
errors must be documented in the study treatment log of the eCRF. Any special reporting situation
that meets the criteria of an SAE should be recorded as an SAE.
10.6 Product quality complaint handling
Definition
A PQC is defined as any suspicion of a product defect related to manufacturing, labeling, or
packaging, i.e., any dissatisfaction relative to the identity, quality, durability, reliability, or
performance of a distributed product, including its labeling, drug delivery system, or package
integrity. A PQC may have an impact on the safety and efficacy of the product. In addition, it
includes any technical complaints, defined as any complaint that indicates a potential quality issue
during manufacturing, packaging, release testing, stability monitoring, dose preparation, storage
or distribution of the product or the drug delivery system.
Procedures
All initial PQCs must be reported to the sponsor by the study site personnel within 24 hours after
being made aware of the event.
A sample of the suspected product should be maintained under the correct storage conditions until
a shipment request is received from the sponsor.
11 STATISTICAL METHODS
All statistical analyses will be conducted by the sponsor or by designated Contract Research
Organizations supervised by the sponsor.
The Statistical Analysis Plan (SAP) will provide the full details of all analyses, data displays, and
algorithms to be used for data derivations. The extension study database will be combined with
the core study database, with indicator variables in the database to distinguish between the two
studies. Statistical analyses will be descriptive and no inferential statistics are planned in the
protocol.
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, minimum, median, Q1, Q3, 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.

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11.1 Analysis strategy
11.1.1 Analysis strategy for efficacy
In order to describe the disease activity in subjects after long-term treatment with ponesimod 20
mg, and to investigate the effect of switching from teriflunomide 14 mg to ponesimod 20 mg, the
main analysis of efficacy will focus on combined data from both the core and extension studies.
Subjects will be analyzed according to the treatment they were randomized to in the core study.
This will allow the assessment of the effect of early long-term treatment with ponesimod 20 mg
compared with delaying the treatment with ponesimod 20 mg for 2 years.
Following 108 weeks of treatment with either ponesimod 20 mg or teriflunomide 14 mg in the
core study, it must be assumed that the two populations will not be similar in terms of baseline
characteristics at the start of the extension study, split by core study randomized treatment and
overall. With this limitation acknowledged, specific efficacy endpoints will be analysed only for
the extension study. Section 6.1 details which efficacy endpoints will be analysed for the combined
core and extension studies, and which additionally will be analyzed for the extension study.
11.1.2 Analysis strategy for safety
The long-term safety of ponesimod and the changes in safety in teriflunomide 14 mg subjects
switching to ponesimod 20 mg will be investigated by summarizing the combined data from both
the core and extension studies. Cumulative data such as AEs and SAEs will only be summarized
for subjects initially treated with ponesimod 20 mg in the core study to allow a long-term
assessment of up to 6 years. To assess trends over time and to assess the switch from teriflunomide
14 mg to ponesimod 20 mg, the analysis of the change from baseline for safety endpoints will be
assessed by visit from core baseline up to last treatment + 15 days, and will be analyzed by core
treatment group.
In addition, all safety data collected in the extension study will be analyzed for the extension study
only, and will be summarized both overall and split by the core treatment group. For this analysis,
the extension study baseline is used as the reference.
Section 6.2 details which safety endpoints will be analyzed for the combined core and extension
studies, and which will be analyzed for the extension study.
11.1.3 Baseline definitions
The following baseline definitions will be used:
 
The core baseline value for efficacy is defined as the last non-missing value recorded before
randomization in the core study for each endpoint and each subject individually.
 
The core baseline value for safety is defined as the last non-missing value recorded before the
first study treatment administration in the core study for each endpoint and each subject
individually.

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 
The extension baseline value for efficacy and safety is defined as the last non-missing value
recorded in either the core or extension studies before the first administration of ponesimod
in the extension study (unless otherwise specified in the SAP).
Analysis over the Extension Analysis Period will use the extension study baseline, whilst analysis
over the Combined Analysis Period will use the core study baseline.
11.1.4 Analysis periods
11.1.4.1 Extension analysis period
This period includes all available data collected on or after the first date of ponesimod treatment
in the extension study, up to the extension EOS date for efficacy variables or up to the last study
treatment date + 15 days in the extension study for safety variables. This definition applies
regardless of whether the subject receives commercially available ponesimod after completing
study treatment.
11.1.4.2 Combined analysis period
For efficacy this period includes all available data from randomization in the core study up to the
extension EOS date for subjects entering the extension, or up to the core EOS date for subjects not
entering the extension. For safety this period includes all available data from the date of first
treatment administration up to the last treatment date + 15 days in the extension study for subjects
entering the extension, or up to the last treatment date + 15 days in the core study for subjects not
entering the extension.
11.2 Analysis sets
11.2.1 Extension Set
The Extension Set (EXTS) includes all subjects who signed an informed consent to enter the
extension study and who received at least one dose of ponesimod study medication in the extension
study.
11.2.2 Full Analysis Set
Following the intention-to-treat (ITT) principle, the Full Analysis Set (FAS) includes all subjects
randomized in the core study. Subjects will be evaluated according to the treatment they have been
randomized to in the core study, which may be different from the treatment they have received.
11.2.3 Safety Set
The Safety Set (SAF) includes all subjects who received at least one administration of core study
treatment. Subjects will be analyzed according to the treatment they received during the core study.
11.2.4 Per-Protocol Set
The Per-Protocol Set (PPS) comprises all subjects included in the FAS without any major protocol
deviations, that impact the assessment of the main efficacy endpoints, occurring prior to or at
randomization in the core study. Only the data for a subject collected after a major protocol

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deviation for subjects developing protocol deviations during either study will be excluded for the
PPS analysis.
All reportable protocol deviations will be defined in the SAP.
11.2.5 Other analysis sets
Other analysis sets will be described in the study SAP.
11.2.6 Usage of the analysis sets
The EXTS will be used for efficacy and safety analyses of the Extension Analysis Period. The
FAS and EXTS will be used for efficacy analyses of the Combined Analysis Period. The SAF will
be used for the safety analysis of the Combined Analysis Period in an as-treated approach.
11.3 Variables
11.3.1 Main efficacy variables
11.3.1.1 Annualized relapse rate (confirmed relapses)
ARR for each period is defined using the following variables:
 The number of confirmed relapses per subject between the start and end of the period.
 The subject’s length of observation in the period in years, defined as: [end of period date minus
start of period date + 1] divided by 365.25.
The ARR will be calculated for the following periods:
 Combined Analysis Period;
 Extension Analysis Period.
11.3.1.2 Time to first confirmed relapse
The time to first confirmed relapse is defined as:
 Date of first confirmed relapse (in either the core or extension study) minus date of
randomization in the core + 1 in days.
Time to first confirmed relapse is calculated over the Combined Analysis Period. Subjects who
entered the extension study and remained free of relapses will be censored at the extension EOS
date, subjects who did not enter the extension and ended the core study free of relapses will be
censored at the core study EOS date. For censored subjects the time is defined as EOS date minus
date of randomization + 1 in days.
11.3.1.3 Time to first 12 or 24-week CDA
Time to 12 or 24-week CDA from core baseline to EOS (extension EOS for subjects entering the
extension study or core EOS for subjects not entering the extension) is defined as:

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 Increase of at least 1.5 in EDSS for subjects with a baseline EDSS score of 0;
 Increase of at least 1.0 in EDSS for subjects with a baseline EDSS score of 1.0 to 5.0;
 Increase of at least 0.5 in EDSS for subjects with a baseline EDSS score ≥5.5;
confirmed after 12 or 24 weeks.
Time to first 12 or 24-week CDA is defined as start date of the first 12 or 24-week CDA minus
date of randomization in the core study + 1 in days. For a subject without a 12 or 24-week CDA,
the censored time to 12 or 24-week CDA is defined as:
 [date of last EDSS assessment for subjects without an EDSS increase (as defined above) at
their last visit or date of EDSS visit prior to the last visit if there is an increase at the last visit]
minus date of randomization in the core study + 1.
Further details of the derivation of this variable will be provided in the SAP.
11.3.1.4 Cumulative number of combined unique active lesions
Cumulative number of combined unique active lesions (CUAL) [defined in Section 6.1.2] will be
calculated for the following periods:
 Combined Analysis Period;
 Extension Analysis Period.
Cumulative number of CUAL is calculated as the sum of lesions at all post baseline MRI visits
up to the end of each analysis period.
11.3.1.5 Longitudinal percent change over time in brain volume from baseline
Percent change in brain volume (PCBV) will be calculated at each visit using the skull as scaling
constraint by performing halfway registration between images from the MRI assessments from
baseline to the end of both the Combined Analysis Period and the Extension Analysis Period:
 
Percent change from the mean brain surface displacement between the MRI scans (SIENA
method).
Further details of the derivation of this variable will be provided in the SAP.
11.3.2 Other efficacy variables
All other efficacy variables will be described in the SAP.
11.3.3 Safety variables
All safety variables will be defined in detail in the SAP. See Section 6.2 for the safety endpoint
definitions.

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11.4 Description of statistical analyses
11.4.1 Overall testing strategy
This extension study is exploratory in nature and no hypotheses are pre-specified. No multiplicity
adjustments will be made for the efficacy endpoints.
11.4.2 Analysis of the main efficacy variable
11.4.2.1 Statistical model
A generalized linear model with negative binomial distribution for the number of confirmed
relapses will be assumed.
Tj 
denotes the length of observation for subject j
Y j 
denotes the number of relapses for subject j during tj
µ j 
denotes the mean of the negative binomial distribution of Y  
j.
The mean for the distribution of the ARR for subject j, denoted by µj /tj, will be modeled by the
following equation:


θ
xj 
j 
j t 



log
, i.e., 


j
j 
j 
t
μ
log
log



θ
x
, where
xj 
is the vector denoting study treatments and covariates for subject j
θ 
is the vector of unknown fixed model parameters.
A negative binomial regression model will be used to calculate the ARRs by the core study
treatment for the appropriate analysis set and period. Two-sided 95% Wald CIs will be calculated
for the ARRs.
11.4.2.2 Handling of missing data
All confirmed relapses from randomization in the core study up to the EOS visit in either core or
extension studies for all subjects in the full analysis set (FAS) will be used in the main analysis of
the ARR endpoint regardless of study treatment compliance; therefore, no data will be excluded
from the analysis.
Every effort will be made to collect relapse information as completely as possible, with a focus on
collecting all start dates and all EDSS/FS data required for the relapses to make a correct evaluation
of relapse confirmation. All relapses with missing or incomplete start dates will be included in the
efficacy analysis, unless it is clear that they have occurred prior to the start of the analysis period.
No missing data imputation is defined for the analysis of ARR variable.
11.4.2.3 Main analysis of ARR
The main statistical analysis will be performed on the FAS using all data in the Combined Analysis
Period. The model described in Section 11.4.2.1 for confirmed relapses will be used, with core

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study treatment as a factor and the logarithm of time on study up to the end of the Combined
Analysis Period as an offset variable. Sensitivity analysis will be described in the SAP.
11.4.2.4 Additional analyses of ARR
The same analysis as described in Section 11.4.2.3 will also be performed using all data in the
Extension Analysis Period based on the EXTS with the logarithm of time on study during the
Extension Analysis Period as an offset variable. The SAP will describe in more detail extension
baseline covariates that will be considered in case of extension baseline imbalances.
No follow-up relapse data will be available in the extension study for subjects who discontinue
study early in the core study or for subjects who complete the core study and choose not to enter
the extension study, which could lead to biases in any treatment effect estimates. The SAP will
describe imputation methods including a worst case, best case and most plausible case to address
this.
11.4.2.5 Subgroup analyses
All subgroup analysis will be defined in the SAP.
11.4.3 Time to first confirmed relapse
The analysis of time from randomization in the core study to first relapse during the Combined
Analysis Period will be performed on the FAS using Kaplan-Meier methods; estimates for the
survival functions will be plotted using KM curves and will be tabulated by 12-week intervals.
11.4.4 Time to 12 and 24-week CDA
The analysis of time from core study baseline to first 12- and 24-week CDA will be summarized
in a similar manner to the time to first relapse variable.
11.4.5 Cumulative number of combined unique active lesions
The statistical analysis of CUAL will be performed for each analysis period based on the associated
analysis set using a similar model as described in Section 11.4.2.1 for the main analysis of the
confirmed relapses with core study treatment as a factor and the log of the number of scans in the
period used as an offset variable. The SAP will describe in more detail extension baseline
covariates that will be considered in case of extension baseline imbalances.
11.4.6 Percent change from baseline in brain volume
PCBV will be summarized descriptively by core treatment group for the Combined Analysis
Period using the FAS and for the Extension Analysis Period for the EXTS.
11.4.7 Analysis of the other efficacy variables
The analysis of all other efficacy variables will be detailed in the SAP.

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11.4.8 Analysis of the safety variables
If not otherwise stated, only safety data considered treatment-emergent (up to 15 days after the last
treatment administration) in the respective analysis period [as defined in Section 11.1.4] will be
included in tables and figures. All safety data will be included in listings, with flags for safety data
not considered to be treatment-emergent to a specific analysis period.
Generally, safety data is presented as follows:
Safety data collected in the extension study will be analyzed based on the Extension Analysis
Period using the EXTS and will be summarized for all subjects overall and split by core study
treatment group. The analysis of change from baseline for safety endpoints assessed by visit will
use the extension baseline as reference.
Furthermore, the long-term safety of ponesimod 20 mg and the changes in safety for teriflunomide
14 mg subjects switching to ponesimod 20 mg will be assessed by summarizing all data in the
Combined Analysis Periodusing the SAF. Cumulative data such as AEs and SAEs will only be
summarized for subjects initially treated with ponesimod 20 mg in the core study. Safety endpoints
assessed by visit will be summarized by core study treatment group. Analysis of change from
baseline for safety endpoints assessed by visit will use the core baseline as reference.
11.4.8.1 Adverse events
All AEs will be coded using the latest version of MedDRA available at the time of database
closure.
11.4.8.1.1 Treatment-emergent AEs and SAEs
Treatment-emergent AEs and SAEs will be tabulated by 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 study treatment.
AEs and SAEs will be summarized over the:
 Extension Analysis Period by core study treatment and overall, using the EXTS;
 Combined Analysis Period for subjects who received ponesimod 20 mg in the core study only,
using the SAF.
11.4.8.1.2AEs of special interest and MACE
AEs of special interest and MACE will be summarized in the same way as described in
Section 11.4.8.1.1. The list of AEs of special interest is provided in Appendix 4.

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11.4.8.1.3AEs leading to premature discontinuation of study treatment
(S)AEs leading to premature discontinuation of study treatment will be summarized by core study
treatment and overall for the Extension Analysis Period based only on the EXTS, in a similar
manner as that described in Section 11.4.8.1.1.
11.4.8.1.4 Post-treatment AEs and SAEs
Post-treatment (S)AEs occurring after the last treatment administration + 15 days up to EOS will
be summarized based on the EXTS in a similar manner as described in Section 11.4.8.1.1.
11.4.8.1.5 Deaths
Fatal SAEs occurring any time after the start of treatment in the extension study will be
summarized by core study treatment and overall, based on the EXTS in a similar manner as
described in Section 11.4.8.1.1.
11.4.8.2 Cardiac safety
11.4.8.2.1 Treatment-emergent abnormalities
Treatment-emergent morphological ECG abnormalities will be summarized in a similar manner to
AEs, and will include the cardiac safety events:
 Treatment-emergent QTcF 450 ms, 480 ms, 500 ms
 Treatment-emergent QTcF increase from baseline 30 ms, 60 ms
 Other treatment-emergent abnormalities observed by 12-lead ECG
 Treatment-emergent (serious) cardiac AEs of special interest.
11.4.8.2.2Absolute values and change from baseline by visit
Descriptive summary statistics for observed treatment-emergent absolute values and absolute
change from core baseline in numeric 12-lead ECG values for the parameters HR, PR, QRS, QT,
QTcB and QTcF by visit will be provided for the Combined Analysis Period by core study
treatment using the SAF.
In addition, descriptive summary statistics by core study treatment and overall for absolute change
from extension baseline for pre-dose parameters by visit will be provided for the Extension
Analysis Period using the EXTS.
11.4.8.2.3Change from pre-dose to post-dose
The change from pre-dose to post-dose assessments at 1 h, 2 h, 3 h, and 4 h on the day of initiation
of ponesimod in the extension study will be summarized by core study treatment and overall for
the following parameters: HR, PR, QT, QTcB, QTcF. This analysis will be based on the Extension
Analysis Period using the EXTS.

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11.4.8.3 Pulmonary safety
11.4.8.3.1 Absolute values and change from baseline
Descriptive summary statistics by visit for the Combined Analysis Period using the SAF will be
provided for observed (absolute and percent of predicted) treatment-emergent values and changes
from core baseline for FEV1, FVC and FEV1/FVC ratio (all expressed in absolute change, %
change).
The mean (and 95% CIs) for change from core baseline to EOS and from core baseline to EOT for
FEV1 and FVC (absolute change, percent change and absolute change in % predicted)** will be
plotted by core study treatment for the Combined Analysis Period using the SAF.
** applies only to subjects who have no exposure to commercially available ponesimod prior to the EOS visit.
11.4.8.3.2Treatment-emergent decreases in FEV 
1 and FVC
The number and proportion of treatment-emergent decreases of % of predicted FEV1 or FVC 20
percentage points from core baseline at any time during the Combined Analysis Period for subjects
who received ponesimod 20 mg in the core study based only on the SAF will be summarized in a
similar manner to the AEs as described in Section 11.4.8.1.1.
11.4.8.3.3Reversibility of treatment-emergent decreases in FEV 
1 and FVC
For the subset of subjects with a decrease of ≥200 mL or ≥12% in FEV1 or FVC from core baseline
at EOT, the number and percentage of subjects with a decrease of <200 mL and <12% from core
baseline to EOS** in FEV1 or FVC will be summarized for subjects who received ponesimod
20 mg in the core study only for the Combined Analysis Period using the SAF.
** applies only to subjects who have no exposure to commercially available ponesimod prior to the EOS visit.
11.4.8.3.4 Lung diffusion capacity
Descriptive summary statistics for observed treatment-emergent values and changes from core
baseline (expressed in absolute change and % of predicted value) in DLCO by visit will be provided
by core study treatment for the Combined Analysis Period using the SAF.
11.4.8.3.5 Pulmonary safety events
Treatment-emergent pulmonary safety events over the Combined Analysis Period for subjects who
received ponesimod 20 mg in the core study only, will be summarized in a similar manner to AEs
and will include the events:
 Pulmonary AEs or SAEs of special interest;
 Withdrawal due to pulmonary reasons/AE.
The analysis of other pulmonary variables will be described in the SAP.

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11.4.8.4 Vital signs
Descriptive summary statistics by visit will be provided for observed treatment-emergent values
and absolute change from core baseline for HR, sBP, dBP and body weight by core study treatment
for the Combined Analysis Period using the SAF. These parameters will also be summarized
descriptively for the Extension Analysis Period by core study treatment, and overall using the
EXTS.
Treatment-emergent notable BP abnormalities will also be summarized for both analysis periods.
The definition for notable abnormalities is provided in Appendix 5.
11.4.8.5 Laboratory endpoints
Descriptive summary statistics by visit will be provided for observed treatment-emergent values
and absolute change from core baseline for laboratory tests (hematology, blood chemistry,
urinalysis) by core study treatment for the Combined Analysis Period using the SAF. These
parameters will also be summarized descriptively for the Extension Analysis Period by core study
treatment and overall using the EXTS.
Treatment-emergent laboratory notable abnormalities will be summarized for subjects who
received ponesimod 20 mg in the core study only for the Combined Analysis Period using the
SAF.
The definition for notable abnormalities is provided in Appendix 5and include:
 Treatment-emergent laboratory test abnormalities based on normal ranges of the central
laboratory, project-specific ranges, and common terminology criteria for adverse events
(CTCAE) [CTCAE 2010; see Appendix 5]
 Treatment-emergent laboratory test abnormalities based on FDA guidance for DILI [FDA 2009b]
(for ALT / AST / total bilirubin).
Lymphocyte count reversibility after EOT will be summarized descriptively by comparing the
mean (and 95% CIs) for absolute change in lymphocyte counts from core baseline to EOS, and
from core baseline to EOT.** This analysis will be performed for the Combined Analysis Period
by core study treatment using the SAF.
** applies only to subjects who have no exposure to commercially available ponesimod prior to the EOS visit.
11.4.8.6 eC-SSRS
The number and percentage of subjects with a treatment-emergent eC-SSRS suicidal ideation score
of 4 or above, or a “yes” response on the eC-SSRS suicidal behavior item will be summarized
descriptively by core study treatment for the Combined Analysis Period.
11.4.8.7 Other Safety Variables
The analysis of all other safety variables will be described in detail in the SAP.

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11.4.9 Immunogenicity Analysis
The following humoral immune responses are measured, based on the COVID-19 immunogenicity
samples, including S- and N-ELISA assays and titers of neutralizing antibodies in a subset of
samples.
 SARS-CoV-2 binding antibodies to S protein (ELISA): Analysis of antibodies binding to
SARS-CoV-2 S protein
 SARS-CoV-2 seroconversion based on antibodies to N protein (ELISA): Analysis of
antibodies binding to SARS-CoV-2 N protein
 SARS-CoV-2 neutralization (wtVNA): Analysis of neutralizing antibodies to the wild-type
virus
Descriptive statistics of assays will be presented overall, by vaccination type, and by COVID-19
AE status as applicable.
11.5 Interim analyses
An unblinded interim analysis will be performed after the randomization list unblinding of the core
study. Further interim analyses may be performed subsequent to this date.
11.5.1 Additional periodic analyses
During the conduct of the study, data analyses might be performed at specified intervals of time
(eg, all patients who complete 12 months of treatment).
11.6 Sample size
As the extension study is an extension of the confirmatory Phase 3 core study, there are no sample
size statistical considerations. The sample size will be pragmatically determined by how many of
the 1100 subjects planned in the core phase enroll into the extension study. Based on anticipated
discontinuation rates in the core study, approximately 800 subjects are expected to enter the
extension study.
12 DATA HANDLING
12.1 Data collection
The investigator/delegate is responsible for ensuring 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 (EDC; using the Rave system provided by
Medidata Solutions, Inc., a web-based tool). The investigator and site staff will be trained to enter
and edit the data via a secure network, with secure access features (username, password, and
identification –  an electronic password system). A complete electronic audit trail will be
maintained. The investigator/delegate will approve the data (i.e., confirm the accuracy of the data
recorded) using an electronic signature (ref. to 21 CFR Part 11).

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Subject pre-treatment and treatment data will be completed for all subjects (i.e., eligible and non-
eligible) through the eCRF.
For each subject enrolled (i.e., from whom an informed consent has been obtained), 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 (e.g., documents attached to SAE reports) submitted to the sponsor and any external
service providers, 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 enrollment number, the subject’s name, date of
birth, and address or any other locally accepted identifiers. Documents identifying the subjects
(e.g., signed informed consent forms) must not be sent to the sponsor, and must be kept in strict
confidence by the investigator/delegate.
12.3 Database management and quality control
Electronic CRFs will be used for all subjects. The investigator will have access to the site eCRF
data until the database is locked. Thereafter, they will have read-only access. The eCRF must be
kept current to reflect subject status at any timepoint during the course of the study.
While entering the data, the investigator/delegate will be instantly alerted to data queries by
validated programmed checks. Additional data review will be performed by the sponsor on an
ongoing basis to look for unexpected patterns in data and study monitoring. If discrepant data are
detected, a query specifying the problem and requesting clarification will be issued and visible to
the investigator/delegate via the eCRF. All electronic queries visible in the system either require a
data correction (when applicable) and a response from the investigator/delegate to clarify the
queried data directly in the eCRF, or simply a data correction in the eCRF. The
investigator/delegate must, on request, supply the sponsor with any required background data from
the study documentation or clinical records. This is particularly important when errors in data
transcription are suspected. In the case of health authority queries, it is also necessary to have
access to the complete study records, provided that subject confidentiality is protected.
This process will continue until database closure.
Laboratory samples, ECGs, SF-36v2TM,eC-SSRS assessments will be processed through a central
laboratory/provider and the results will be sent electronically to the sponsor. Any data received
from central laboratory or central ECG facility generated in relation to follow up on adverse events
which are ongoing at end of study should be entered in the database even if obtained after the EOS
visit.

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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 eCRFs 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
The sponsor and the investigators will ensure that the study is conducted in full compliance with
ICH-GCP Guidelines, the principles of the “Declaration of Helsinki”, and with the laws and
regulations of the country in which the 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 Institutional Review Board
(IRB) or Independent Ethics Committee (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 or subject information leaflet 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).
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 the Actelion Delegation of Authority form and the
Janssen Delegation Log. 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

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performed on the same day informed consent was obtained) by the authorized site staff listed on
the Actelion Delegation of Authority form/Janssen Delegation Log.
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. This must include the study reference, the subject number, the date and,
if applicable, time when the subject was first introduced to the clinical study, the date and, if
applicable, time 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), a copy
of the signed ICF given to the subject / legal representative.
13.4 Compensation to subjects and investigators
The sponsor provides insurance in order to indemnify (with both legal and financial coverage) the
investigator/site against claims arising from the study, except for claims that arise from malpractice
and/or negligence.
The compensation of the subject in the event of study-related injuries will comply with applicable
regulations.
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 the sponsor or its
representative, in a timely manner. The investigator/delegate must document and explain any
deviation from the approved protocol. Deviations considered to be a violation of GCP must be
reported to the IRB/IEC and regulatory authorities according to the sponsor or (overruling) local
requirements.
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 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.

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These records are to be classified into two different categories of documents: investigator site file
(ISF) and subject clinical source documents.
These records must be kept by the investigator for as long as is necessary to comply with the
sponsor’s requirements (i.e., 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 site for any or all of the documents, special
arrangements, respecting the data confidentiality, must be made between the investigator and the
sponsor to store these documents outside the site, so that they can be retrieved in the event of a
regulatory inspection. No study document should be destroyed without prior written approval from
the sponsor. Should the investigator wish to assign the study records to another party, or move
them to another location, the sponsor must be notified in advance.
If the site is using an electronic/computerized system to store subject medical records, it can be
used for the purpose of the clinical study if it is validated (as per 21 CFR Part 11 or equivalent
standard) and if the monitor 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 monitor could not be provided access to the
system, the site is requested to print the complete set ofsource data needed for verification by the
monitor. The print-outs must be numbered, stapled together with a coversheet, signed and dated
by the investigator/delegate to confirm that these certified copies are exact copies containing the
same information as the original subject’s data. 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.
In order to verify that the process the site uses to prepare certified copies is reliable, the monitor
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 monitor does not need to verify this process
for all data of all subjects but at least for some of them (e.g., first subject; regular check during the
study of critical data like inclusion/exclusion criteria, endpoints for some subjects) as per the
sponsor’s instructions. If it were not possible for the monitor to observe this process, it would not
be possible to rely on the site’s certified copies, and therefore the site cannot be selected for the
clinical study.
13.8 Monitoring
Prior to study start, a site initiation visit (SIV) will be performed after the required essential study
documents are approved by the sponsor. The study treatment will be shipped to the site upon
approval of the required essential documents.

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The principal investigator must ensure that all site personnel involved in the study are present
during the SIV and will dedicate enough time to it. Site Information Technology (IT) support
should also be available during the initiation visit.
The SIV must be completed before the site can start the screening of study subjects. Following the
SIV, a copy of the completed initiation visit report and follow-up letter will be provided to the
principal investigator and filed in the ISF.
During the study, the monitor will contact and visit the site regularly and must be permitted, on
request, to have access to study facilities and all source documents needed to verify adherence to
the protocol and the completeness, consistency, and accuracy of the data being entered in the
eCRFs and other protocol-related documents. The sponsor monitoring standards require full
verification that informed consent has been provided, 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 (site visit
or phone call), 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
monitor. The required site personnel must be available during monitoring visits and allow adequate
time to meet with the monitor to discuss study related issues.
The investigator agrees to cooperate with the monitor(s) to ensure that any issues detected in the
course of these monitoring visits are resolved. If the subject is hospitalized or dies in a hospital
other than the study site, the investigator is responsible for contacting that hospital in order to
document the SAE, in accordance with local regulations.
A close-out visit will be performed for any initiated site when there are no more active subjects
and all FU issues have been resolved. If a site does not enroll any subjects, the close-out visit may
be performed prior to study database closure at the discretion of the sponsor.
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 E6 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 monitor 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.

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The ISF must be stored in a secure and access-restricted area during and after the study. It must be
kept by the site for as long as needed to comply with any applicable rules and regulations, ICH-
GCP, as well as instructions from the sponsor. If the site needs to transfer the ISF to another
location and/or if site facility can no longer store the ISF, the principal investigator must inform
the sponsor immediately.
If the principal investigator changes, or if the site relocates, the monitor must be notified as soon
as possible.
13.10 Audit
Representatives of the sponsor's clinical quality assurance department may audit the investigator
site (during the study or after its completion). The purpose of this visit will be to determine the
investigator’s adherence to ICH-GCP, the protocol, and applicable regulations; adherence to the
sponsor’s requirements (e.g., SOPs) will also be verified. Prior to initiating this audit, the
investigator will be contacted by the sponsor to arrange a time for the audit.
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 conduct an inspection of the sponsor’s clinical study
(during the study or after its completion).
Should an inspection be announced by a health authority and/or IRB/IEC, the investigator must
inform the sponsor immediately, (usually via the monitor), that such a request has been made.
The investigator and staff must cooperate with inspector(s) and allow access to all study
documentation (e.g., subject records) and study facilities.
13.12 Reporting of study results and publication
All information, including but not limited to information regarding ponesimod or the sponsor's
operations (e.g., patent application, formulas, manufacturing processes, basic scientific data, prior
clinical data, formulation information) supplied by the sponsor to the investigator and not
previously published, and any data, including exploratory research data, generated as a result of
this study, are considered confidential and remain the sole property of the sponsor. The investigator
agrees to maintain this information in confidence and use this information only to accomplish this
study and will not use it for other purposes without the sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the
sponsor in connection with the continued development of ponesimod, and thus may be disclosed
as required to other clinical investigators or regulatory agencies. To permit the information derived
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all
data obtained in the study.

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The results of the study will be reported in a Clinical Study Report generated by the sponsor and
will contain data from all study sites that participated in the study as per protocol. Recruitment
performance or specific expertise related to the nature and the key assessment parameters of the
study will be used to determine a coordinating investigator for the study. Results of exploratory
analyses performed after the Clinical Study Report has been issued will be reported in a separate
report and will not require a revision of the Clinical Study Report.
Study participant identifiers will not be used in publication of results. Any work created in
connection with performance of the study and contained in the data that can benefit from copyright
protection (except any publication by the investigator as provided for below) shall be the property
of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary (multicenter)
data and information without approval from the investigator. The investigator has the right to
publish study site-specific data after the primary data are published. If an investigator wishes to
publish information from the study, a copy of the manuscript must be provided to the sponsor for
review at least 60 days before submission for publication or presentation. Expedited reviews will
be arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in
writing, the investigator will withhold such publication for up to an additional 60 days to allow for
filing of a patent application. In the event that issues arise regarding scientific integrity or
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will
not mandate modifications to scientific content and does nothave the right to suppress information.
For multicenter study designs and sub-study approaches, secondary results generally should not
be published before the primary endpoints of a study have been published. Similarly, investigators
will recognize the integrity of a multicenter study by not submitting for publication data derived
from the individual study site until the combined results from the completed study  have been
submitted for publication, within 18 months after the study end date, or the sponsor confirms there
will be no multicenter study publication. Authorship of publications resulting from this study will
be based on the guidelines on authorship, such as those described in the ICMJE Recommendations
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which
state that the named authors must have made a significant contribution to the conception or design
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the
work or revised it critically for important intellectual content; and given final approval of the
version to be published; and agreed 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.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required
by law. The disclosure of the final study results will be performed after the end of study in order
to ensure the statistical analyses are relevant.

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14 REFERENCES
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phosphate. Trends Endocrinol Metab 2007;18:300–7.
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_Product_Information/human/002514/WC500148682.pdf
[Aubagio® USPI] Aubagio® (teriflunomide) oral tablets –  Full prescribing information;
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202992s000lbl.pdf
[Benedict 2006] Benedict RH, Cookfair D, et al. Validity of the minimal assessment of cognitive
function in multiple sclerosis (MACFIMS). J Int Neuropsychol Soc 12(4): 549–58.
[Brinkmann 2007] Brinkmann V. Sphingosine 1-phosphate receptors in health and disease:
Mechanistic insights from gene deletion studies and reverse pharmacology. Pharmacol Ther
2007;9 (11):883–897.
[Brinkmann 2010] Brinkmann V, Billich A, Baumruker T, et al. Fingolimod (FTY720): discovery
and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov 2010;115:84-105.
[Comi 2012] Comi G, Jeffery D, Kappos L, et al; ALLEGRO Study Group. Placebo-controlled
trial of oral laquinimod for multiple sclerosis. N Engl J Med 2012;366(11):1000–9.
[Compston 2002] Compston A, Coles A. Multiple sclerosis. Lancet 2002;359:1221–31.
[Compston 2008] Compston A, Coles A. Multiple sclerosis. Lancet 2008;372:1502–18.
[Confavreux 2014] Confavreux C & Vukusic. The clinical course ofmultiple sclerosis. Handb
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[CTCAE 2010] Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
Published: May 28, 2009 (v4.03: June 14, 2010); U.S.DEPARTMENT OF HEALTH AND
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[Cyster 2005] Cyster JG. Chemokines, sphingosine-1-phosphate, and cell migration in secondary
lymphoid organs. Annu Rev Immunol 2005;23:127–59.
[FDA 2009b] Guidance for Industry. Drug-induced liver injury: premarketing clinical evaluation.
FDA CDER July 2009.
[Gold 2012] Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12
for relapsing multiple sclerosis. N Engl J Med 2012;367:1098–107.
[Kappos 2007] Kappos L, Bates D, Hartung HP, et al. Natalizumab treatment for multiple
sclerosis: recommendations for subject selection and monitoring. Lancet Neurol 2007;6:431–41.

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[Kappos 2011] Kappos L, Bates D, Edan G, et al. Natalizumab treatment for multiple sclerosis:
updated recommendations for patient selection and monitoring. Lancet Neurol 2011;10:745–58.
[Kurtzke 1983] Kurtzke JF. Rating neurologic impairment in multiple sclerosis: An expanded
disability status scale (EDSS). Neurology 1983;33:1444–1452.
[Lublin 1996] Lublin FD, Reingold SC, et al. Defining the clinical course of multiple sclerosis:
results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee
on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 1996;46(4):907–11.
[Lublin 2003] Lublin FD, Baier M, Cutter G. Effect of relapses on development of residual deficit
in multiple sclerosis. Neurology 2003;61:1528–32.
[Lublin 2014] Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple
sclerosis: The 2013 revisions. Neurology 2014 [Epub ahead of print].
[Macintyre 2005] Macintyre N, Crapo RO, Viegi G, et al. ATS/ERS Task Force. Standardisation
of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J
2005;26(4):720–35.
[Maruish 2011] Maruish ME (Ed.). User’s manual for the SF-36v2 Health Survey (3rd ed.).
Lincoln, RI: QualityMetric Incorporated; 2011.
[Miller 2005a] Miller MR, Crapo R, Hankinson J, et al,; ATS/ERS Task Force. General
considerations for lung function testing. Eur Respir J. 2005 Jul;26(1):153–61. Review.
[Miller 2005b] Miller MR, Hankinson J, Brusasco V, et al; ATS/ERS Task Force. Standardisation
of spirometry. Eur Respir J. 2005 Aug;26(2):319–38.
[Milo 2010] Milo R, Kahana E. Multiple sclerosis: geoepidemiology, genetics and the
environment. Autoimmun Rev 2010;9(5):A387–394.
[Noseworthy 2000] Noseworthy JH, Lucchinetti CF, Rodriguez M, et al. Multiple sclerosis. N
Engl J Med 2000;343:938–52.
[Olsson 2014] Olsson T, Boster A, Fernandez O, Freedman O, Freedman MS, Pozzilli C, Bach D,
Berkani O, Mueller MS, Sidorenko T, Radue EW, Melanson M. Oral ponesimod in relapsing-
remitting multiple sclerosis: a randomised phase II trial. J Neurol Neurosurg Psychiatry
2014;85(11):1198-208.
[Pinschewer 2000] Pinschewer DD, Ochsenbein AF, Odermatt B, et al. FTY720
immunosuppression impairs effector T cell peripheral homing without affecting induction,
expansion, and memory. J Immunol 2000;164:5761–70.
[Polman 2005] Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis:
2005 revisions to the “McDonald Criteria.” Ann Neurol 2005;58:840–846.

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[Polman 2011] Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple
sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292–302.
[Ponesimod IB] Investigator’s Brochure for ponesimod S1P1 receptor agonist, Actelion
Pharmaceuticals Ltd., a Janssen Pharmaceutical Company of Johnson & Johnson (current version
on file).
[Pugliatti 2002 Pugliatti M, Sotgiu S, Rosati G. The worldwide prevalence of multiple sclerosis.
Clin Neurol Neurosurg 2002;104(3):182–91.
[Renoux 2007 Renoux C, Vukusic S, et al. Natural history of multiple sclerosis with childhood
onset. N Engl J Med 2007 Jun 21;356(25):2603–13.
[Schwab 2007] Schwab JM, Cyster JG. Finding a way out: lymphocyte egress from lymphoid
organs. Nat Immunol 2007;8:1295–301.
[Smith 1982] Smith, A. Symbol digit modalities test: Manual, (Western Psychological Services,
Los Angeles, 1982).
[Sobhani 2010] Sobhani K, Garrett DA, Liu DP, Rainey PM. A rapid and simple high-performance
liquid chromatography assay for the leflunomide metabolite, teriflunomide (A77 1726), in renal
transplant recipients. Am J Clin Pathol 2010;133(3):454–7.
[Steiner 2007] Steiner I, Kennedy PG, Pachner AR. The neurotropic herpes viruses: herpes
simplex and varicella-zoster. Lancet Neurol 2007;6:1015–28.
[WHO 2008] Thompson AJ, Rompani P, Dua T, et al. WHO/MSIF: Atlas of MS: multiple sclerosis
resources across the world. Mult Scler 2008; S153.

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15 APPENDICES
Appendix 1 Neurostatus® scoring sheet

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Appendix 2 
Guidance for concomitant treatment with QT-prolonging drugs with
known risk of Torsades de Pointes
QT-prolonging medications with known risk of Torsades de Pointes (e.g., azithromycin,
citalopram, clarithromycin, erythromycin, escitalopram, moxifloxacin, etc.) should be
administered with caution since ponesimod may potentially enhance their effect on QT interval. A
list of QT-prolonging medications with known risk of TdP is published by AZCERT [University
of Arizona CERT http://crediblemeds.org/]. The investigator should also take into account other
relevant risk factors such as hypokalemia, bradycardia or QTc interval prolongation when
considering treatment with a QT-prolonging drug. Based on the available evidence, the additional
ECG monitoring will no longer be required for re-initiating or increasing the dose of a QT-
prolonging drugs with known risk of Torsades de Pointes from Protocol Version 6 onwards.

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Appendix 3 Prohibited anti-arrhythmic and HR-lowering drugs
The following anti-arrhythmic and HR-lowering drugs (systemic administration) are prohibited
during the up-titration period (i.e., from Day 1 until Day 14 included and during the first 14 days
after re-initiation of study treatment) [see Section 5.2.3]:
Adenosine 
Lidocaine
Acebutolol 
Lorajmine
Ajmaline 
Lorcainide
Amiodarone 
Metoprolol
Aprinidine 
Mexiletine
Atenolol 
Morcizine
Azimilide 
Nadolol
Bepridil 
Phenytoin
Betaxolol 
Pilocarpine
Bisprolol 
Prajmaline
Bretylium 
Procainamide
Bunaftine 
Propafenone
Carvedilol 
Propranolol
Cibenzoline 
Quinidine
Disopyramide 
Sotalol
Dofetilide 
Sparteine
Dronedarone 
Tedisamil
Encainide 
Timolol
Esmolol 
Tocainide
Flecainide 
Vernakalant
Ibutilide
Ivabradine
This list is not exhaustive; other anti-arrhythmic or HR-lowering drugs are also prohibited during
uptitration. In case of doubt, please discuss the use of any potential anti-arrhythmic or HR-
lowering drug with the sponsor.
Treatment with any of these therapies is also not recommended during maintenance treatment with
ponesimod (i.e., 20 mg) and should be considered with caution if an alternative medication cannot
be used.

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Appendix 4 Adverse events of special interest
AEs of special interest will include the anticipated risks of treatment with ponesimod, and the
events that may be related to MS comorbidities (e.g., seizures or stroke). The following safety
areas were updated from Protocol version 6 onwards to include identified risks:
 Bradyarrhythmia occurring post-first dose
 Macular edema
 Bronchoconstriction
 Severe liver injury
 Serious opportunistic infections including PML
 Skin cancer
 Convulsions
 Unexpected neurological or psychiatric symptoms/signs (PRES, ADEM, atypical MS relapses)
A list of AEs of special interest (MedDRA preferred terms) will be defined in the SAP.

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Appendix 5 Abnormalities for ECG, BP and laboratory variables
Notable abnormalities for ECG and BP that are related to the potential effects of ponesimod 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), QTcB or QTcF
 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) [CTCAE 2010] grading system and, in
specific cases (e.g., lymphocyte levels), are adjusted based on the known PD effect of the study
treatments (e.g., LLL threshold for lymphocytes).
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 treatment) 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 central laboratory manual. Parameters for which no threshold is defined in
Table 11 below may be defined in the central laboratory manual.

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Table 11 
Thresholds for marked laboratory abnormalities
Parameter (SI unit) 
LL  
LLL  
HH  
HHH
Hemoglobin (g/L) 
<100 
<80 
Increase in >20 g/L above 
ULN or above baseline (for 
pre-treatment assessments, 
and post-treatment 
assessments when baseline 
≤ULN) or increase from 
baseline >20 g/L (for post- 
treatment assessments when 
baseline is >ULN)
Increase in >40 g/L above
ULN (for pre- treatment
assessments, and post-
treatment assessments when
baseline ≤ ULN) or increase
from baseline >40 g/L (for
post-treatment assessments
when baseline is >ULN)
MCH (pg/Cell) 
ND  
ND  
ND  
ND
MCV (fL) 
ND  
ND  
ND  
ND
Hematocrit (L/L) 
<0.28 (female) 
<0.32 (male) 
<0.20 
>0.55 (female) 
>0.60 (male)
>0.65
Platelet count (109 /L) 
<75 
<50 
>600 
>999
RBC count (1012 /L) 
ND  
ND  
ND  
ND
WBC count (109 /L) 
NA  
<1.9 
>20.0 
>100.0
Lymphocyte (109 /L) 
ND  
<0.2 
ALERT:
<0.2
>4.0 
≥8.0
Neutrophils (109 /L) 
<1.5 
<1.0 
ND  
ND
Eosinophils (109 /L) 
ND  
ND  
>5.0 
ND
Monocytes (109 /L) 
ND  
ND  
ND  
ND
Basophils (109 /L) 
ND  
ND  
ND  
ND
Polymorphonuclear leucocyte/Band cells (%) 
ND  
ND  
>90%  
>95%
AST (U/L)* 
ND  
ND  
≥3 ULN  
ALERT: 
≥3 ULN  
≥5 ULN
ALERT:
≥5 ULN
≥8 ULN

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Parameter (SI unit) 
LL  
LLL  
HH  
HHH
ALT (U/L)* 
ND  
ND  
≥3 ULN  
ALERT:
≥3 ULN
≥5ULN
ALERT:
≥5 ULN
≥8 ULN
Total bilirubin (umol/L) 
ND  
ND  
≥2 ULN
ALERT:
≥2 ULN combined with
ALT or AST ≥3ULN
≥5 ULN  
Alkaline Phosphatase (U/L) 
ND  
ND  
>2.5 ULN  
>5 ULN
INR* 
ND  
ND  
≥1.5 ULN 
ALERT:
≥1.5 combined with ALT
or AST ≥3 ULN
≥2.5 ULN
Lactate dehydrogenase 
ND  
ND  
ND  
ND
Creatinine (umol/L)* 
ND  
ND  
>1.5 ULN or >1.5 baseline 
>3 ULN or >3 baseline
Creatinine clearance (mL/min) 
<60 
<30 
ND  
ND
Urea (mmol/L) 
ND  
ND  
>2.5 ULN  
>5 ULN
Albumin (g/L) 
<30 
<20 
ND  
ND
Protein total (g/L) 
ND  
ND  
ND  
ND
C-reactive protein (mg/L) 
ND  
ND  
ND  
ND
Glucose (mmol/L) 
<3.0 
<2.2 
>8.9 
>13.9
Potassium (mmol/L) 
<3.2 
<3.0 
>5.5 
>6.0
Sodium (mmol/L) 
ND  
<130 
>150 
>155
Calcium (mmol/L) 
<2.0 
<1.75 
>2.9 
>3.1
Chloride (mmol/L) 
ND  
ND  
ND  
ND
Triglyceride (mmol/L) 
ND  
ND  
>3.42 
>11.4
Cholesterol (mmol/L) 
ND  
ND  
>7.75 
>12.92
Serum pregnancy test 
ND  
ND  
ND  
Positive
ALERT:

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Parameter (SI unit) 
LL  
LLL  
HH  
HHH
Positive
Teriflunomide (ng/mL) 
ND  
ND  
ND  
>20
ALERT:
>20
* HH and HHH based on CTCAE 2010 v4.03 [CTCAE 2010]. An ALERT will be sent when INR ≥1.5 based on the guidance for monitoring liver test abnormalities from FDA
[FDA 2009b]. Note: All events of ALT or AST 3xULN andtotal bilirubin 2xULN (>35% direct bilirubin) or ALT or AST 3xULN andINR >1.5 may indicate severe liver
injury (possible ‘Hy’s Law’) andmust be reported to sponsor in an expedited manner and as an SAE if SAE criteria are met. The INR stated threshold value will not apply
to participants receiving anticoagulants.
ALERT = study-specific alerts that trigger specific actions by the investigator [see Sections 5.1.12]; ALT = alanine aminotransferase; AST = aspartate aminotransferase; ND = not
defined; may be complemented by definitions provided by the central laboratory (see central laboratory manual); ULN = upper limit of normal.

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Appendix 6 Multiple Sclerosis Functional Composite
The MSFC consists of the three following assessments:
1) Timed 25-Foot walk;
The Timed 25-Foot Walk is a quantitative measure of lower extremity function. It is the first
component of the MSFC administered at each visit. The subject is directed to one end of a clearly
marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The task
is immediately administered again by having the subject walk back the same distance. Subjects
may use assistive devices when doing this task. In clinical trials, it is recommended that the treating
neurologist select the appropriate assistive device for each subject.
2) 9-Hole Peg Test (9-HPT);
The 9-HPT is a quantitative measure of upper extremity (arm and hand) function. The 9-HPT is
the second component of the MSFC to be administered. Both the dominant and non-dominant
hands are tested twice (two consecutive trials of the dominant hand, followed immediately by two
consecutive trials of the non-dominant hand). It is important that the 9-HPT be administered on a
solid table (not a rolling hospital bedside table) and that the 9-HPT apparatus be anchored.
3) Paced Auditory Serial Addition Test (PASAT-3” version).
The PASAT is a measure of cognitive function that specifically assesses auditory information
processing speed and flexibility, as well as calculation ability. The PASAT is presented on
audiocassette tape or compact disc to control the rate of stimulus presentation. Single digits are
presented either every 3 seconds and the subject must add each new digit to the one immediately
prior to it. The test score is the number of correct sums given (out of 60 possible) in each trial. To
minimize familiarity with stimulus items in clinical trials and other serial studies, two alternate
forms have been developed; the order of these should be counterbalanced across testing sessions.
The PASAT is the last measure of the MSFC that is administered at each visit.
Test administration:
The MSFC should be administered as close to the beginning of a study visit as possible but
definitely before the subject does a distance walk. MSFC components should be administered in
the following order:
1. Trial 1, Timed 25-Foot Walk
2. Trial 2, Timed 25-Foot Walk
3. Trial 1, Dominant Hand, 9-HPT
4. Trial 2, Dominant Hand, 9-HPT
5. Trial 1, Non-Dominant Hand, 9-HPT

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6. Trial 2, Non-Dominant Hand, 9-HPT
7. PASAT-3”
Scoring:
There are three components to the MSFC: (1) the average scores from the four trials on the 9-HPT
(the two trials for each hand are averaged, converted to the reciprocals of the mean times for each
hand and then the two reciprocals are averaged); (2) the average scores of two Timed 25-Foot
Walk trials; (3) the number correct from the PASAT-3. The MSFC is based on the concept that
scores for these three dimensions – arm, leg, and cognitive function – are combined to create a
single score (the MSFC score) that can be used to detect change over time in a group of MS
subjects. This is done by creating Z-scores for each component of the MSFC.
MSFC Score = {Zarm, average + Zleg, average + Zcognitive} / 3.0
Where Zxxx =Z-score

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Appendix 7 Symbol Digit Modalities Test
The SDMT [Smith 1982, Benedict 2006] measures attention and processing speed much like the
PASAT. The SDMT includes a reference key of 9 symbols, each paired with a single digit. Below
the reference key are rows of the symbols arranged randomly. The subject is given 90 seconds to
say the number that corresponds with each symbol. The test administrator records the answers and
the number of correct answers is recorded as the score.
The SDMT will be performed after the MSFC. Study personnel will be trained to administer and
score the SDMT. A sample of the SDMT is provided below. Subjects will complete the test on a
validated paper form that will be collected and transcribed in the eCRF.

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Appendix 8 Electronic self-rated version of the Columbia-Suicide Severity rating
Scale (eC-SSRS)
Usage Notes:
When the interval between calls exceeds 120 days the number of days since the last call
is not repeated to the subject.
Core Language: US English
Introduction
NRT01
The last time you called this telephone system to answer questions about thoughts or
actions related to wanting to be dead or killing yourself was [date]. That was [num] days
ago. During this call I want you to only consider thoughts or actions that have occurred
since that call. In answering the following questions, only report your thoughts and
actions over the past [num] days or since [date].
If days SLC >120
The last time you called this telephone system to answer questions about thoughts or
actions related to wanting to be dead or killing yourself was [date]. During this call I
want you to only consider thoughts or actions that have occurred since that call. In
answering the following questions, only report your thoughts and actions since [date].
Passive Suicide Ideation
Q01
Since your last call, have you wished you were dead or wished you could go to sleep and
not wake up?
If Yes, press 1
If No, press 2
Ideation Level = 1

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Active Suicide Ideation
Q02
Since your last call on [date], [num] days ago have you actually had any thoughts of
killing yourself?
If days SLC >120
Since your last call on [date], have you actually had any thoughts of killing yourself?
If Yes, press 1
If No, press 2
Ideation Level = 2
Q03
Have you thought about how you might do this?
If Yes, press 1
If No, press 2
Ideation Level = 3
Q03.1
What way of killing yourself did you think of most often?
If with medication, press 1
If by hanging, press 2
If by jumping, press 3
If with a gun, press 4
If by some other method, press 5
Q04
Since your last call, have you had any intention of acting on these thoughts of killing
yourself? As opposed to you have the thoughts, but you definitely would not act on them?
If Yes, press 1
If No, press 2

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Ideation Level = 4
Q05
Have you started to work out, or actually worked out, the specific details of how to kill
yourself since your last call?
If Yes, press 1
If No, press 2
Q05q
Did you actually intend to carry out the details of your plan?
If Yes, press 1
If No, press 2
Ideation Level = 5
Q05r
How did you intend to kill yourself?
If with medication, press 1
If by hanging, press 2
If by jumping, press 3
If with a gun, press 4
If by some other method, press 5
Ideation Probing
Q01aNRT
You just indicated that since your last call, you had wished you were dead or wished that
you could go to sleep and not wake up. I want to ask you a few more questions about
that. When responding to these questions, I want you to think about the time when these
thoughts were most severe in the past [num] days.
If days SLC >120

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You just indicated that since your last call, you had wished you were dead or wished that
you could go to sleep and not wake up. I want to ask you a few more questions about
that. When responding to these questions, I want you to think about the time when these
thoughts were most severe since your last call.
Q01a
When your wishes to be dead or to go to sleep and not wake up were most severe, how
often did the thoughts occur?
If these thoughts occurred less than once a week, press 1
If about once a week, press 2
If these thoughts occurred 2 to 5 times a week, press 3
If daily or almost daily, press 4
If these thoughts occurred many times a day, press 5
Q01b
How long did the thoughts last?
If these thoughts were fleeting, lasting seconds to minutes, press 1
If less than an hour, press 2
If these thoughts lasted between 1 and 4 hours, press 3
If between 4 and 8 hours, press 4
If these thoughts lasted more than 8 hours, press 5
Q01c
Did you make any attempt to try to control these thoughts about wanting to die or going
to sleep and not waking up, whether you were successful in controlling them or not?
If Yes, press 1
If No, press 2
Q01d
How easily could you control or stop these thoughts?

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If you could easily control these thoughts, press 1
If with a little difficulty, press 2
If you could control these thoughts, but with some difficulty, press 3
If with a lot of difficulty, press 4
If you were unable to control these thoughts, press 5
Q01e.1
Did you think about things like family, religion, or fear of pain or death that might affect
your wish to be dead or going to sleep and not waking up?
If Yes, press 1
If No, press 2
Q01e
Choose one of the following statements that best describes whether anyone or anything
did or did not stop you from wishing you were dead or that you could fall asleep and not
wake up.
If something definitely stopped you from wishing you were dead or that you could fall
asleep and not wake up, press 1
If something probably stopped you, press 2
If you are uncertain whether something stopped you from wishing you were dead or that
you could fall asleep and not wake up, press 3
If something most likely did not stop you, press 4
If something definitely did not stop you from wishing you were dead or that you could
fall asleep and not wake up, press 5
Q01f.1
When you thought about wishing to be dead or going to sleep and not waking up, did you
have a reason in mind like ending your pain or getting attention or revenge?
If Yes, press 1
If No, press 2

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Q01f
What sort of reasons did you have for thinking about wanting to die? Was it to end the
pain or stop the way you were feeling? In other words, you could not go on living with
this pain or how you were feeling? Was it to get attention, revenge or a reaction from
others? Or both?
If it was completely to get attention, revenge or a reaction from others, press 1
If it was mostly to get attention, revenge or a reaction from others, press 2
If equally to get attention, revenge or a reaction from others and to end or stop the pain,
press 3
If mostly to end or stop the pain (that is, you could not go on living with the pain or how
you were feeling), press 4
If completely to end or stop the pain, press 5
Q02aNRT
You indicated before that since your last call you had thought of killing yourself. I want
to ask you a few more questions about that. When responding to these questions, I want
you to think about the time you were feeling most suicidal in the past [num] days.
If days SLC >120
You indicated before that since your last call you had thought of killing yourself. I want
to ask you a few more questions about that. When responding to these questions, I want
you to think about the time you were feeling most suicidal since your last call.
Q02a
When you were feeling most suicidal, how often did you think of killing yourself?
If these thoughts occurred less than once a week, press 1
If about once a week, press 2
If these thoughts occurred 2 to 5 times a week, press 3
If daily or almost daily, press 4
If these thoughts occurred many times a day, press 5
Q02b
How long did these thoughts of killing yourself last?

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If these thoughts were fleeting, lasting seconds to minutes, press 1
If less than an hour, press 2
If these thoughts lasted between 1 and 4 hours, press 3
If between 4 and 8 hours, press 4
If these thoughts lasted more than 8 hours, press 5
Q02c
Did you make any attempt to try to control or stop these thoughts, whether you were
successful in controlling them or not?
If Yes, press 1
If No, press 2
Q02d
How easily could you control or stop thinking about killing yourself?
If you could easily control these thoughts, press 1
If with a little difficulty, press 2
If you could control these thoughts, but with some difficulty, press 3
If with a lot of difficulty, press 4
If you were unable to control these thoughts, press 5
Q02e.1
Did you think about things like family, religion, or fear of pain or death that might affect
your decision about killing yourself?
If Yes, press 1
If No, press 2
Q02e
Choose one of the following statements that best describes whether anyone or anything
did or did not stop you from acting on your thoughts of committing suicide.

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If something definitely stopped you from attempting suicide, press 1
If something probably stopped you, press 2
If you are uncertain whether something stopped you from attempting suicide, press 3
If something most likely did not stop you, press 4
If something definitely did not stop you from attempting suicide, press 5
Q02f.1
When you thought about killing yourself, did you have a reason in mind like ending your
pain or getting attention or revenge?
If Yes, press 1
If No, press 2
Q02f
What sort of reasons did you have for thinking about wanting to kill yourself? Was it to
end the pain or stop the way you were feeling? In other words, you could not go on living
with this pain or how you were feeling? Or was it to get attention, revenge or a reaction
from others? Or both?
If it was completely to get attention, revenge or a reaction from others, press 1
If it was mostly to get attention, revenge or a reaction from others, press 2
If equally to get attention, revenge or a reaction from others and to end or stop the pain,
press 3
If mostly to end or stop the pain (that is, you could not go on living with the pain or how
you were feeling), press 4
If completely to end or stop the pain, press 5
Q03aNRT
You indicated before that since your last call you had thought about how you might kill
yourself. I want to ask you a few more questions about that. When responding to these
questions, I want you to think about the time you were feeling the most suicidal in the
past [num] days.
If days SLC >120
You indicated before that since your last call you had thought about how you might kill
yourself. I want to ask you a few more questions about that. When responding to these
questions, I want you to think about the time you were feeling the most suicidal since
your last call.

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Q03a
When you were feeling most suicidal, how often did you think about how you might kill
yourself?
If these thoughts occurred less than once a week, press 1
If about once a week, press 2
If these thoughts occurred 2 to 5 times a week, press 3
If daily or almost daily, press 4
If these thoughts occurred many times a day, press 5
Q03b
When you had these thoughts, how long did they last?
If these thoughts were fleeting, lasting seconds to minutes, press 1
If less than an hour, press 2
If these thoughts lasted between 1 and 4 hours, press 3
If between 4 and 8 hours, press 4
If these thoughts lasted more than 8 hours, press 5
Q03c
Did you make any attempt to try to control or stop these thoughts, whether you were
successful in controlling them or not?
If Yes, press 1
If No, press 2
Q03d
How easily could you control or stop thinking about how you might kill yourself?
If you could easily control these thoughts, press 1
If with a little difficulty, press 2
If you could control these thoughts, but with some difficulty, press 3
If with a lot of difficulty, press 4
If you were unable to control these thoughts, press 5

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Q03e.1
Did you think about things like family, religion, or fear of pain or death that might affect
your decision about killing yourself?
If Yes, press 1
If No, press 2
Q03e
Choose one of the following statements that best describes whether anyone or anything
did or did not stop you from acting on your thoughts of committing suicide.
If something definitely stopped you from attempting suicide, press 1
If something probably stopped you, press 2
If you are uncertain whether something stopped you from attempting suicide, press 3
If something most likely did not stop you, press 4
If something definitely did not stop you from attempting suicide, press 5
Q03f.1
When you thought about killing yourself, did you have a reason in mind like ending your
pain or getting attention or revenge?
If Yes, press 1
If No, press 2
Q03f
What sort of reasons did you have for thinking about wanting to kill yourself? Was it to
end the pain or stop the way you were feeling? In other words, you could not go on living
with this pain or how you were feeling? Or was it to get attention, revenge or a reaction
from others? Or both?
If it was completely to get attention, revenge or a reaction from others, press 1
If it was mostly to get attention, revenge or a reaction from others, press 2
If equally to get attention, revenge or a reaction from others and to end or stop the pain,
press 3
If mostly to end or stop the pain (that is, you could not go on living with the pain or how
you were feeling), press 4
If completely to end or stop the pain, press 5

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Q04aNRT
You indicated before that since your last call you thought about killing yourself and that
you had some intention of acting on these thoughts. I want to ask you a few more
questions about that. When responding to these questions, I want you to think about the
time you were feeling the most suicidal in the past [num] days.
If days SLC >120
You indicated before that since your last call you thought about killing yourself and that
you had some intention of acting on these thoughts. I want to ask you a few more
questions about that. When responding to these questions, I want you to think about the
time you were feeling the most suicidal since your last call.
Q04a
When you were feeling most suicidal and had some intention of acting on those thoughts
of killing yourself, how often did those thoughts occur?
If these thoughts occurred less than once a week, press 1
If about once a week, press 2
If these thoughts occurred 2 to 5 times a week, press 3
If daily or almost daily, press 4
If these thoughts occurred many times a day, press 5
Q04b
How long did the thoughts last?
If these thoughts were fleeting, lasting seconds to minutes, press 1
If less than an hour, press 2
If these thoughts lasted between 1 and 4 hours, press 3
If between 4 and 8 hours, press 4
If these thoughts lasted more than 8 hours, press 5
Q04c
Did you make any attempt to try to control or stop these thoughts about actually killing
yourself, whether you were successful in controlling them or not?

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If Yes, press 1
If No, press 2
Q04d
How easily could you control or stop thinking about killing yourself?
If you could easily control these thoughts, press 1
If with a little difficulty, press 2
If you could control these thoughts, but with some difficulty, press 3
If with a lot of difficulty, press 4
If you were unable to control these thoughts, press 5
Q04e.1
Did you think about things like family, religion, or fear of pain or death that might affect
your decision about killing yourself?
If Yes, press 1
If No, press 2
Q04e
Choose one of the following statements that best describes whether anyone or anything
did or did not stop you from acting on your thoughts of committing suicide.
If something definitely stopped you from attempting suicide, press 1
If something probably stopped you, press 2
If you are uncertain whether something stopped you from attempting suicide, press 3
If something most likely did not stop you, press 4
If something definitely did not stop you from attempting suicide, press 5
Q04f.1
When you thought about killing yourself, did you have a reason in mind like ending your
pain or getting attention or revenge?
If Yes, press 1
If No, press 2

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Q04f
What sort of reasons did you have for thinking about wanting to kill yourself? Was it to
end the pain or stop the way you were feeling? In other words, you could not go on living
with this pain or how you were feeling? Or was it to get attention, revenge or a reaction
from others? Or both?
If it was completely to get attention, revenge or a reaction from others, press 1
If it was mostly to get attention, revenge or a reaction from others, press 2
If equally to get attention, revenge or a reaction from others and to end or stop the pain,
press 3
If mostly to end or stop the pain (that is, you could not go on living with the pain or how
you were feeling), press 4
If completely to end or stop the pain, press 5
Q05aNRT
You indicated before that since your last call you had started working on plans or had
actually worked out the details of how to kill yourself and had some intention to act on
them. I want to ask you a few more questions about that. When responding to these
questions, I want you to think about the time you were feeling the most suicidal in the
past [num] days.
If days SLC >120
You indicated before that since your last call you had started working on plans or had
actually worked out the details of how to kill yourself and had some intention to act on
them. I want to ask you a few more questions about that. When responding to these
questions, I want you to think about the time you were feeling the most suicidal since
your last call.
Q05a
When you were feeling the most suicidal and started planning or worked out details of
how to kill yourself, how often did you think about killing yourself?
If these thoughts occurred less than once a week, press 1
If about once a week, press 2
If these thoughts occurred 2 to 5 times a week, press 3
If daily or almost daily, press 4
If these thoughts occurred many times a day, press 5

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Q05b
How long did the thoughts last?
If these thoughts were fleeting, lasting seconds to minutes, press 1
If less than an hour, press 2
If these thoughts lasted between 1 and 4 hours, press 3
If between 4 and 8 hours, press 4
If these thoughts lasted more than 8 hours, press 5
Q05c
Did you make any attempt to try to control or stop these thoughts about actually killing
yourself, whether you were successful in controlling them or not?
If Yes, press 1
If No, press 2
Q05d
How easily could you control or stop thinking about killing yourself?
If you could easily control these thoughts, press 1
If with a little difficulty, press 2
If you could control these thoughts, but with some difficulty, press 3
If with a lot of difficulty, press 4
If you were unable to control these thoughts, press 5
Q05e.1
Did you think about things like family, religion, or fear of pain or death that might affect
your decision about killing yourself?
If Yes, press 1
If No, press 2
Q05e
Choose one of the following statements that best describes whether anyone or anything
did or did not stop you from acting on your thoughts of committing suicide.

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If something definitely stopped you from attempting suicide, press 1
If something probably stopped you, press 2
If you are uncertain whether something stopped you from attempting suicide, press 3
If something most likely did not stop you, press 4
If something definitely did not stop you from attempting suicide, press 5
Q05f.1
When you thought about killing yourself, did you have a reason in mind like ending your
pain or getting attention or revenge?
If Yes, press 1
If No, press 2
Q05f
What sort of reasons did you have for thinking about wanting to kill yourself? Was it to
end the pain or stop the way you were feeling? In other words, you could not go on living
with this pain or how you were feeling? Or was it to get attention, revenge or a reaction
from others? Or both?
If it was completely to get attention, revenge or a reaction from others, press 1
If it was mostly to get attention, revenge or a reaction from others, press 2
If equally to get attention, revenge or a reaction from others and to end or stop the pain,
press 3
If mostly to end or stop the pain (that is, you could not go on living with the pain or how
you were feeling), press 4
If completely to end or stop the pain, press 5
Midpoint Transition
We are almost finished. So far I have been asking about thoughts and feelings you may
have had. Now I would like to know about things you may have done to try to hurt
yourself since your last call.
Suicidal Behavior
Q06a
Since your last call on [date] have you made a suicide attempt?

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If Yes, press 1
If No, press 2
Q06b
Use the number keys on your telephone to enter the number of suicide attempts you have
made since your last call.
Q06cNRT01
If attempts >= 3
Consider your most recent attempt, your first attempt, and your most serious attempt
separately.
Q06cNRT02
If attempts = 2
Consider your most recent attempt and your first attempt separately
Q06c
If loop = 1
When you made your most recent attempt, were you trying to end your life?
If Yes, press 1
If No, press 2
If loop = 2
When you made your first attempt, were you trying to end your life?
If Yes, press 1
If No, press 2
If loop = 3
When you made your most serious attempt, were you trying to end your life?
If Yes, press 1
If No, press 2
Q06e

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Did you think it was possible that you could have died from what you did?
If Yes, press 1
If No, press 2
Q06d
So then, if you wanted to die, even a little, when you did this, Press 1.
If you did it purely for other reasons, like to relieve stress, feel better, get sympathy, or
get something else to happen to you, without any intention of killing yourself, Press 2.
Q07a
Since your last call, have you done anything to intentionally hurt or harm yourself?
If Yes, press 1
If No, press 2
Q07b
Use the number keys on your telephone to enter the number of times you have
intentionally hurt or harmed yourself since your last call. If you cannot remember the
exact number, enter your best estimate.
Q07cNRT01
Just consider the three most recent times you have intentionally harmed or hurt yourself.
Q07c_Attempt
If loop = 1
Think about the time you intentionally hurt or harmed yourself most recently.
If loop >1
Consider the time you hurt or harmed yourself before that
Q07c
Were you trying to end your life?

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If Yes, press 1
If No, press 2
Q07e
Did you think it was possible that you could have died from what you did?
If Yes, press 1
If No, press 2
Q07d
So then, if you wanted to die, even a little, when you did this, Press 1.
If you did it purely for other reasons, like to relieve stress, feel better, get sympathy, or
get something else to happen to you, without any intention of killing yourself, Press 2.
Q08a
Since your last call, have you done anything dangerous where you could have died?
If Yes, press 1
If No, press 2
Q08b
Use the number keys on your telephone to enter the number of times you have done
dangerous activities where you could have died in the past [num] days.
Use the number keys on your telephone to enter the number of times you have done
dangerous activities where you could have died since your last call.
Q08c_NRT01
Just consider the three most recent times you have done something dangerous where you
could have died.
Q08c_Attempt
If loop = 1
Think about the most recent time you did a dangerous activity where you could have died

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If loop >1
Consider the time you did something dangerous before that
Q08c_1
Were you trying to harm yourself when you did this?
If Yes, press 1
If No, press 2
Q08c
Were you trying to end your life?
If Yes, press 1
If No, press 2
Q08d
So then, if you wanted to die, even a little, when you did this, Press 1.
If you did it purely for other reasons, like to relieve stress, feel better, get sympathy, or
get something else to happen to you, without any intention of killing yourself, Press 2.
Lethality
Q09
If Q06a = YES
As a result of your most serious attempt since your last call, were you injured more
seriously than surface scratches or mild nausea?
If Yes, press 1
If No, press 2
If Q06a = NO
As a result of the most serious time you tried to hurt yourself since your last call, were
you injured more seriously than surface scratches or mild nausea?
If Yes, press 1
If No, press 2

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EDMS-ERI-207656619
CONFIDENTIAL - FOIA Exemptions Apply in U.S.
Q09a
Were you hospitalized for medical treatment of the physical injury you suffered? For
example, were you comatose from an overdose, or did you suffer extensive blood loss
that required a transfusion, or severe damage to your head or a vital organ? If you were
hospitalized for psychiatric evaluation, but not for medical treatment of a severe physical
injury, answer No.
If Yes, press 1
If No, press 2
Q09b
Were you injured so severely that you would have died without treatment in an intensive
care unit, or did you suffer permanent physical damage from which you will never
completely recover, such as paralysis or disfigurement?
If Yes, press 1
If No, press 2
Q09c
Did your injury cause you to be extremely drowsy, or result in broken bones, or severe
bleeding?
If Yes, press 1
If No, press 2
Q09.10
Although you were not injured during the most serious time, how serious could your
injuries have been?
If what you did was not likely to cause injury, Press 1
If what you did was likely to cause physical injury, but probably not death, Press 2
If what you did was likely to cause death with or without medical help, for example
trying to shoot yourself in the head but the gun failed to fire, Press 3

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Interrupted Attempts
Q10
Since your last call, was there a time when you started to do something to end your life
but someone or something stopped you before you actually did anything?
If Yes, press 1
If No, press 2
Q10a
About how many times have you been stopped from ending your life by someone or
something since your last call?
Please enter the number using your touch tone phone.
Aborted Attempts
Q11
Since your last call, has there been a time when you started to do something to try to end
your life but you stopped yourself before you actually did anything?
If Yes, press 1
If No, press 2
Q11a
About how many times have you stopped yourself from ending your life in the last [num]
days, since your last call?
If days SLC >120
About how many times have you stopped yourself from ending your life since your last
call?
Please enter the number using your touch tone phone.
Preparatory Acts or Behaviors
Q12NRT
Assess prior responses and present introduction:

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Other than the times you have already told me about since your last call when you did
things intending to kill yourself or thought you might have died, when you started to do
something to end your life but someone or something stopped you, and when you started
to do something to end your life but stopped yourself,
Other than the times you have already told me about since your last call when you did
things intending to kill yourself or thought you might have died, and when you started to
do something to end your life but stopped yourself,
Other than the times you have already told me about since your last call when you did
things intending to kill yourself or thought you might have died and when you started to
do something to end your life but someone or something stopped you,
Other than the times you have already told me about since your last call when you started
to do something to end your life but someone or something stopped you and when you
started to do something to end your life but stopped yourself,
Other than the times you have already told me about since your last call when you did
things intending to kill yourself or thought you might have died,
Other than the times you have already told me about since your last call when you started
to do something to end your life but someone or something stopped you,
Other than the times you have already told me about since your last call when you started
to do something to end your life but stopped yourself,
Q12
Have you taken any steps toward making a suicide attempt or preparing to kill yourself
such as collecting pills, getting a gun, giving valuables away or writing a suicide note?
If Yes, press 1
If No, press 2
Q12a
About how many times?

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Please enter the number using your touch tone phone.
Exit
Thank you and Good bye.

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CONFIDENTIAL - FOIA Exemptions Apply in U.S.
Appendix 9 SF-36v2™
SF-36v2® Health Survey © 1992, 1996, 2000, 2010
Medical Outcomes Trust and
QualityMetric Incorporated.
All Rights Reserved.
SF-36® is a registered trademark of
Medical Outcomes Trust.
(SF-36v2® Health Survey Standard,
United States (English))
CCI

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EDMS-ERI-207656619
CONFIDENTIAL - FOIA Exemptions Apply in U.S.
CCI

Ponesimod / ACT-128800
Relapsing multiple sclerosis
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Version 6
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EudraCT 2016-004719-10
EDMS-ERI-207656619
CONFIDENTIAL - FOIA Exemptions Apply in U.S.
CCI

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Relapsing multiple sclerosis
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Version 6
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EDMS-ERI-207656619
CONFIDENTIAL - FOIA Exemptions Apply in U.S.
CCI

Ponesimod / ACT-128800
Relapsing multiple sclerosis
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Version 6
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CONFIDENTIAL - FOIA Exemptions Apply in U.S.
CCI

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Relapsing multiple sclerosis
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Version 6
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CONFIDENTIAL - FOIA Exemptions Apply in U.S.
CCI

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Relapsing multiple sclerosis
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Version 6
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EDMS-ERI-207656619
CONFIDENTIAL - FOIA Exemptions Apply in U.S.
CCI

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Relapsing multiple sclerosis
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Version 6
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EudraCT 2016-004719-10
EDMS-ERI-207656619
CONFIDENTIAL - FOIA Exemptions Apply in U.S.
CCI

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Relapsing multiple sclerosis
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Version 6
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CONFIDENTIAL - FOIA Exemptions Apply in U.S.
CCI

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Relapsing multiple sclerosis
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EDMS-ERI-207656619
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CCI

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Relapsing multiple sclerosis
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CCI

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CONFIDENTIAL - FOIA Exemptions Apply in U.S.
Appendix 12 Guidance on study conduct during the COVID-19 (coronavirus)
pandemic
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on
the conduct of this clinical study due to, for example, self-isolation/quarantine by participants and
study-site personnel; travel restrictions/limited access to public places, including hospitals; study
site personnel being reassigned to critical tasks.
In alignment with recent health authority guidance, the sponsor is providing options for
study-related participant management in the event of disruption to the conduct of the study. This
guidance does not supersede any local or government requirements or the clinical judgment of the
investigator to protect the health and well-being of participants and site staff. If at any time a
participant’s safety is considered to be at risk, study intervention will be discontinued, and study
follow-up will be conducted.
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each
contact, participants will be interviewed to collect safety data. Key efficacy endpoint assessments
should be performed if required and as feasible. Participants will also be questioned regarding
general health status to fulfill any physical examination requirement.
Every effort should be made to adhere to protocol-specified assessments for participants on study
intervention, including follow up. Modifications to protocol-required assessments may be
permitted via COVID-19 Appendix after consultation with the participant, investigator, and the
sponsor. Missed assessments/visits will be captured in the clinical trial management / EDC system
for protocol deviations. Discontinuations of study interventions and withdrawal from the study
should be documented with the prefix “COVID-19-related” in the case report form (CRF).
The sponsor will continue to monitor the conduct and progress of the clinical study, and any
changes will be communicated to the sites and to the health authorities according to local guidance.
If a participant has tested positive for COVID-19, the investigator should contact the sponsor’s
responsible medical officer to discuss plans for study intervention and follow-up. Modifications
made to the study conduct as a result of the COVID-19 pandemic should be summarized in the
clinical study report.
GUIDANCE SPECIFIC TO THIS PROTOCOL:
 Patient Visits & Assessments
Assessments that may be completed over the phone include assessment of relapse, eC-SSRS,
review of adverse events and concomitant medications. Vital signs can be collected in a remote

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setting by the subject, caregiver, delegated site staff/in-home nurse, or general practitioner, as
feasible. Please ensure the remote method you choose is allowable per local regulations and fully
documented in the subject source files.
It is important for safety monitoring of laboratory parameters to continue according to the protocol
schedule. If access to the study site (and therefore the central lab) is not possible, local laboratories
may be used to monitor laboratory parameters. An alternative, if allowed per local regulations, is
to use delegated site staff/in-home nursing to collect blood samples at the subject’s home and ship
to either the central laboratory or an accredited local laboratory for testing. Where local
laboratories are used, it’s important to ensure appropriate documentation of laboratory reference
ranges. If abnormal laboratory values requiring follow-up in the protocol, or any other abnormality
deemed critical by the investigator, are unable to be followed-up, it is recommended to temporarily
interrupt (for a maximum of 12 weeks) until the abnormality can  be considered resolved or
permanently discontinue study treatment.
Other protocol-required examinations and assessments not conducive to remote administration can
be conducted as soon as it is feasible for the subject to come to the site for a visit. As clinically
indicated, other local resources such as the subject’s general practitioner or delegated site staff/in-
home nursing can be considered.
 Study Drug Dispensation
If a subject is unable to travel to the site for a scheduled visit where study drug would be dispensed,
the following alternate measures should be discussed with the sponsor and may be considered to
ensure continuity of treatment:
- A caregiver or family member may pick up study drug on behalf of the subject if first
discussed and agreed by the subject. The conversation with the subject must be documented
in the source files. The subject must name the individual who will pick up study drug on
their behalf. This is necessary for site staff to confirm the study drug is provided to the
appropriate individual, ensure proper chain of custody of study drug, and to maintain
subject privacy. This must be confirmed and documented in the subject source file.
- Investigative site staff may deliver study drug directly to the subject’s home. The chain of
custody and transit conditions must be clearly documented within the subject source file.
- If no other alternative is feasible, direct-to-patient shipment of study drug from the site may
be considered with prior approval from the sponsor and relevant health authority, as
applicable.
- It is important to remind subjects that in case of treatment interruption of 4 or more
consecutive days, they should inform the investigator and/or site staff immediately.
Ponesimod treatment can only be restarted with uptitration and on-site cardiac monitoring,
as applicable, as described in the protocol.

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 COVID-19 Infection in MS Patients:
There is currently no available data suggesting that patients treated with ponesimod should have
treatment interrupted during the COVID-19 pandemic. In general, patients receiving
immunomodulators should continue treatment and continue to exercise precautionary measures to
minimize the risk of infection. If a subject develops symptoms associated with coronavirus
infection, it is recommended to confirm the diagnosis using locally approved laboratory kits and
reported to the local health authorities, as required. Subjects with positive test results for
coronavirus should have this recorded as an AE, and if hospitalized, this should be reported as an
SAE. It is important to notify the treating physician of the subject’s participation in this clinical
study and details of the study treatment. It is also recommended to follow local MS Society
recommendations.
 On-site Monitoring Visits:
In case on-site monitoring visits are not possible, your monitor may arrange remote site monitoring
activities with you until the point at which regular on-site monitoring visits may resume.
All of the above measures are recommended for consideration on a temporary basis during the
COVID-19 pandemic to enable continuity of treatment and to ensure that subject assessments,
particularly those assessing relapse and safety, continue as outlined in the protocol without
imposing health risk to subjects, their families, and site staff. Every effort should be made to
complete all protocol-required assessments. Investigators should use their clinical judgment and
benefit risk assessment in determining if a subject can continue study treatment in the absence of
on-site clinic visits. If remote visits are not possible, or if in the investigator’s judgment,
appropriate safety monitoring is not feasible in a remote setting, the investigator should consider
temporarily interrupting study treatment (for a maximum of 12 weeks per protocol) or
discontinuing study treatment and initiating treatment with another available disease modifying
treatment (DMT).
STUDY CONDUCT RELATED TO COVID-19 VACCINE DEPLOYMENT FOR
NONCOVID-19 CLINICAL TRIALS
Current guidelines from global MS societies recommended that people with MS should be
vaccinated against COVID-19.1,2,3 Having MS does not increase the risk of COVID-19 virus
infection or the risk to develop severe forms of the infection more than the general population and
it is important that DMT in MS patients is continued and maintained.4 It is therefore recommended
that people with MS currently taking a DMT, including ponesimod, continue with their treatment
unless advised to stop by their treating physicians (e.g., MS patients on DMT with risk factors for
severe COVID-19 infections).
No clinical data are available on the efficacy and safety of vaccinations in patients taking
ponesimod.

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Relapsing multiple sclerosis
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CONFIDENTIAL - FOIA Exemptions Apply in U.S.
Based on preclinical data, vaccinations may be less effective if administered during treatment.
There are 4 main types of COVID-19 vaccines (all non-live) that are currently available (see
below). For a complete overview of the COVID-19 vaccine landscape, please refer to the WHO
website.5
 mRNA vaccines are based on the SARS-CoV-2 spike glycoprotein antigen encoded by
RNA and formulated in lipid nanoparticles;
 Protein subunit vaccines based on full-length spike protein (S), receptor-binding domain
(RBD), non-RBD S protein fragments, and non-S structural proteins;
 Vector vaccines consisting of a recombinant adenovirus carrying the gene for
SARS-CoV-2 virus spike glycoprotein;
 Inactivated vaccines use viruses whose genetic material has been destroyed so they cannot
replicate, but can still trigger an immune response.
As stated in Section 5.2.2, vaccination with non-live vaccines is allowed while on study treatment
if the vaccination is advised by the primary investigator / treating neurologist, based on her/his
clinical assessment of the risk/benefit for the individual patient, and if supported by guidelines for
vaccination relevant to this patient population, as applicable.
Therefore, all above mentioned COVID-19 vaccines may be administered to study subjects.
Important notes and reminders:
 Vaccination with live vaccines is prohibited, except if performed during a temporary
treatment interruption period. In this case it must be performed not earlier than 1 week after
the last dose of study treatment, and treatment can be reinitiated only after at least 4 weeks
from completion of vaccination (see Section 5.2.3).
 Please report any administered vaccines on a Concomitant Medication page in the CRF.
If a patient is eligible for COVID-19 vaccination in accordance with their local regulations their
participation in the study should be modified as required.
The reporting of any AEs (including SARS-CoV-2 infection or those associated with COVID-19
vaccination) should be reported as described in Section 10.
References:
1. 
MS International Federation 2021. MS, the coronavirus and vaccines – updated global advice.
Available from: https://www.msif.org/news/2020/02/10/the-coronavirus-and-ms-what-you-need-to-
know/ews today 2021. Accessed 19 July 2021.
2. 
National MS Society 2021. COVID-19 vaccine guidance for people living with MS.
https://www.nationalmssociety.org/coronavirus-covid-19-information/multiple-sclerosis-and-
coronavirus/covid-19-vaccine-guidance#section-1. Accessed 19 July 2021.

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Relapsing multiple sclerosis
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Version 6
15March 2022, page 215/216
Confidential
EudraCT 2016-004719-10
EDMS-ERI-207656619
CONFIDENTIAL - FOIA Exemptions Apply in U.S.
3. National MS Society 2021. MS treatment guidelines during coronavirus. Available from:
https://www.nationalmssociety.org/coronavirus-covid-19-information/multiple-sclerosis-and-
coronavirus/ms-treatment-guidelines-during-coronavirus. Accessed 19 July 2021.
4. Zheng C, Kar I, Chen CK, et al. Multiple Sclerosis Disease-Modifying Therapy and the COVID-19
Pandemic: Implications on the Risk of Infection and Future Vaccination. CNS Drugs.
2020;34(9):879-896.
5. WHO 2021. COVID-19 vaccine tracker and landscape. Available from:
https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines. Accessed
19 July 2021.

Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B303, OPTIMUM-LT
Version 6
15March 2022, page 216/216
Confidential
EudraCT 2016-004719-10
EDMS-ERI-207656619
CONFIDENTIAL - FOIA Exemptions Apply in U.S.
INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study drug, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Actelion Pharmaceuticals Ltd
Signature: 
[electronic signature appended at the end of the 
protocol]
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course of the study, written
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD

Signature
User 
Date 
Reason
 
17-Mar-2022
20:00:35
(GMT)
Document Approval
PPD

CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved,  Date: 12 May 2022
Janssen Research & Development *
Clinical Protocol
GUIDANCE ON STUDY CONDUCT DURING MAJOR DISRUPTION
Multicenter, Non-Comparative Extension to Study AC-058B301, to Investigate the Long-
Term Safety, Tolerability, and Control of Disease of Ponesimod 20 mg in Subjects With
Relapsing Multiple Sclerosis
Protocol AC-058B303; Phase 3
ACT-128800 / JNJ-67896153  ponesimod
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen Biologics,
BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen Sciences Ireland
UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term “sponsor” is used
throughout the protocol to represent these various legal entities; the sponsor is identified on the Contact
Information page that accompanies the protocol.
United States (US) sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
EudraCT NUMBER:  2009-011470-15
Status: 
Approved
Date: 
12 May 2022
Prepared by: Janssen Research & Development, LLC
EDMS number: 
EDMS-RIM-736230, 2.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory
requirements.
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or
otherwise.
NCT03232073

Guidance on Study Conduct During Major Disruption Due to the Regional Crisis
ACT-128800 / JNJ-67896153  ponesimod 
Clinical Protocol AC-058B303
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status: Approved,  Date: 12 May 2022
Study Conduct During Major Disruption Due to the Regional Crisis
It is recognized that the regional crisis may have an impact on the conduct of this clinical study
due to, for example, travel restrictions/limited access to public places, including hospitals; study
site personnel being unavailable, or reassigned to critical tasks.
The sponsor is providing options for study related participant management in the event of
disruption to the conduct of the study. This guidance does not supersede any local or government
requirements or the clinical judgement of the investigator to protect the health and well-being of
participants and site staff. In case it is not possible to obtain initial informed consent of potential
participant or updated written informed consent of study participant due to movement restrictions,
study participant may provide consent verbally in the presence of an impartial witness. If, at any
time, a participant’s travel to the study site is considered to be dangerous, study participation may
be interrupted, and study follow-up conducted. If it becomes necessary to discontinue participation
in the study, the procedures outlined in the protocol for discontinuing study intervention will be
followed.
If, as a result ofthe regional crisis scheduled visits cannot be conducted in person at the study site,
they will be performed to the extent possible remotely/virtually or delayed until such time that
on-site visits can be resumed. At each contact, participants will be interviewed to collect safety
data. Key efficacy endpoint assessments should be performed if required and as feasible.
Participants will also be questioned regarding general health status to fulfill any physical
examination requirement.
Every effort should be made to adhere to protocol-specified assessments for participants on study
intervention, including follow-up. Modifications to protocol-required assessments may be
permitted after consultation with the participant, investigator, and the sponsor. All protocol
deviations related to the regional crisis should be documented with the prefix “Regional Crisis” in
the CRF. Missed/remote assessments/visits will be captured in the clinical trial management
system for protocol deviations. Discontinuations of study interventions and withdrawal from the
study should be documented with the prefix “Regional Crisis” in the CRF.
The sponsor will continue to monitor the conduct and progress of the clinical study, and any
changes will be communicated to the sites and to the health authorities according to local guidance.
Modifications made to the study conduct as a result of the regional crisis should be summarized in
the clinical study report.
All of the described measures are recommended for consideration on a temporary basis during the
regional crisis to enable continuity of treatment and to ensure that patient assessments, particularly
those assessing relapse and safety, continue as outlined in the protocol without imposing health
risk to patients, their families, and site staff. Every effort should be made to complete all protocol-
required assessments. Investigators should use their clinical judgment and benefit risk assessment
in determining if a patient can continue study treatment in the absence of on-site clinic visits. If
remote visits are not possible, or if in the investigator’s judgment, appropriate safety monitoring
is not feasible in a remote setting, the investigator should consider transferring the patient to

Guidance on Study Conduct During Major Disruption Due to the Regional Crisis
ACT-128800 / JNJ-67896153  ponesimod 
Clinical Protocol AC-058B303
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
3
Status: Approved,  Date: 12 May 2022
another clinical trial site, temporarily interrupting study treatment (for a maximum of 12 weeks
per protocol) or discontinuing study treatment and initiating treatment with another available
disease modifying treatment (DMT). Alternatively, the patient may be shared with another site,
especially if a return to the original site is feasible. If study treatment is interrupted or a patient
discontinues from the study the investigator must check the availability of subsequent standard of
care.
Patient Visits and Assessments
The investigator should assess the feasibility and risk of maintaining scheduled treatment visits on
a case-by-case basis, depending on local conditions and guidance by local authorities, and should
not hesitate to contact the study sponsor for additional guidance. Assessments that may be
completed over the phone include assessment of relapse, review of adverse events and concomitant
medications. Vital signs can be collected in a remote setting by the patient, caregiver, delegated
site staff/in-home nurse, or general practitioner, as feasible. Please ensure the remote method you
choose is allowable per local regulations and fully documented in the patient source files.
Other protocol-required examinations and assessments not conducive to remote administration can
be conducted as soon as it is feasible for the patient to come to the site for a visit. As clinically
indicated, other local resources such as the patient’s general practitioner or delegated site staff/in-
home- nursing can be considered.
Specific Laboratory Instructions
It is important for safety monitoring of laboratory parameters to continue according to the protocol
schedule. If access to the study site (and therefore the central laboratory) is not possible, local
laboratories may be used to monitor laboratory parameters. An alternative, if allowed per local
regulations, is to use delegated site staff/in-home nursing to collect blood samples at the patient’s
home and ship to either the central laboratory or an accredited local laboratory for testing. Where
local laboratories are used, it is important to ensure appropriate documentation of laboratory
reference ranges. If abnormal laboratory values requiring follow-up in the protocol, or any other
abnormality deemed critical by the investigator, are unable to be followed up, it is recommended
to temporarily interrupt (for a maximum of 12 weeks) until the abnormality can be considered
resolved or permanently discontinue study treatment.
At times when courier support is not available to move samples to the central laboratory, then
laboratory assessments should focus on the following order of priority:
1. Utilize local laboratory assessments required to ensure participant safety. Generally, this
includes CBC (complete blood count) and serum chemistry assessments, as per protocol
assessment schedule and investigator clinical judgement.
2. All samples such as biopsy tissue which have long-term stability should continue to be
collected and stored at the study site. Other labs considered investigational, such as
immunogenicity samples, can be collected and stored as per the protocol until a time where
transportation services are restored.

Guidance on Study Conduct During Major Disruption Due to the Regional Crisis
ACT-128800 / JNJ-67896153  ponesimod 
Clinical Protocol AC-058B303
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
4
Status: Approved,  Date: 12 May 2022
3. Should local laboratories be used, please refer to the study protocol on what is to be collected
in terms of local laboratory documentation, ie, laboratory ranges.
Study Drug Dispensation and Other Trial Supplies
Study drug supply is monitored via IWRS. It is imperative for ongoing management, any study
medications dispensed is recorded in IWRS. Any interruptions of patient treatment due to supply
availability, should be alerted to the Site Manager. Damaged supplies should be reported as soon
as possible so managing re-supply can be prioritized. Trial related supplies such as laboratory kits
may be interrupted. Local laboratory supplies may be utilized as outlined in the Study Laboratory
Manual. For other supplies, consult with the Site Manager to discuss feasible options.
To ensure uninterrupted treatment, consider performing an early (unscheduled) study drug
dispensation for your patients as soon as possible at your discretion ensuring that the material will
not expire before the next scheduled visit. This is important since an interruption of ponesimod
treatment may be associated with return of MS disease activity. Also, due to the known risk of
bradyarrhythmia upon treatment re-initiation after an interruption of 4 days or longer, treatment
must be restarted using the up-titration kit. If a patient is unable to travel to the site for a scheduled
visit where study drug would be dispensed, the following alternate measures should be discussed
with the sponsor and may be considered to ensure continuity of treatment:
 
A caregiver or family member may pick up study drug on behalf of the patient if first discussed
and agreed by the patient. The conversation with the patient must be documented in the source
files. The patient must name the individual who will pick up study drug on their behalf. This
is necessary for site staff to confirm the study drug is provided to the appropriate individual,
ensure proper chain of custody of study drug, and to maintain patient privacy. This must be
confirmed and documented in the patient source file.
 
Investigative site staff may deliver study drug directly to the patient’s home. The chain of
custody and transit conditions must be clearly documented within the patient source file.
 
If no other alternative is feasible, direct-to-patient shipment of study drug from the site may
be considered with prior approval from the sponsor and relevant health authority, as
applicable.
 
It is important to remind patients that in case of treatment interruption of 4 or more consecutive
days, they should inform the investigator and/or site staff immediately. Ponesimod treatment
can only be restarted with up-titration and on-site cardiac monitoring, as applicable, as
described in the protocol.
On-site Monitoring Visits:
In case on-site monitoring visits are not possible, your Site Manager may arrange remote site
monitoring activities with you until the point at which regular on-site monitoring visits may
resume.
SAE reporting should continue as usual until further notification through any of the following
methods:

Guidance on Study Conduct During Major Disruption Due to the Regional Crisis
ACT-128800 / JNJ-67896153  ponesimod 
Clinical Protocol AC-058B303
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
5
Status: Approved,  Date: 12 May 2022
 
Secure! email
 
If secure email is not possible, please call your Site Manager or Local Trial Manager
For sites not impacted, please continue to adhere to all protocol and contractual agreements
(protocol compliance to treatment, safety and efficacy evaluations, safety reporting and data entry
timelines).

Guidance on Study Conduct During Major Disruption Due to the Regional Crisis
ACT-128800 / JNJ-67896153  ponesimod 
Clinical Protocol AC-058B303
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
6
Status: Approved,  Date: 12 May 2022
INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study.
I will conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to
me who assist in the conduct of this study. I will discuss this material with them to ensure that they
are fully informed regarding the study intervention, the conduct of the study, and the obligations
of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Actelion Pharmaceuticals Ltd
Signature: [electronic signature appended at the end of the protocol] 
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course of the study, written
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD

Signature
User 
Date 
Reason
 
12-May-2022
20:48:52
(GMT)
Document Approval
PPD