Clinical trial NCT03232073
Conditions: Multiple Sclerosis
Sponsor: Actelion
Start date: 2017-07-05; Completion date: 2024-01-16
Enrollment: 877 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study AC-058B301 (OPTIMUM; NCT02425644) has been designed to investigate the efficacy, safety and tolerability of ponesimod in subjects with relapsing multiple sclerosis (RMS). The AC-058B303 study is the long-term extension for the core study AC-058B301. The purpose of this long term extension of the core study AC-058B301 is to characterize the long-term safety, tolerability, and control of disease of ponesimod 20 mg in subjects with RMS.

Detailed description:
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 in the core study. 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.

Arms: arm 1: 20 mg administered orally once daily
Interventions: intervention 1: Ponesimod
Intervention descriptions: intervention 1: Ponesimod; Film-coated tablet; Oral use. From Day 1 to Day 14, ponesimod is gradually up-titrated until a maintenance dose of 20 mg is reached from Day 15

Protocol documents:
Prot_000.pdf: 
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


Ponesimod / ACT-128800 / JNJ-67896153
Relapsing multiple sclerosis
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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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Relapsing multiple sclerosis
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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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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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function in multiple sclerosis (MACFIMS). J Int Neuropsychol Soc 12(4): 549–58.
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[Brinkmann 2010] Brinkmann V, Billich A, Baumruker T, et al. Fingolimod (FTY720): discovery
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[Comi 2012] Comi G, Jeffery D, Kappos L, et al; ALLEGRO Study Group. Placebo-controlled
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[Compston 2002] Compston A, Coles A. Multiple sclerosis. Lancet 2002;359:1221–31.
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[Confavreux 2014] Confavreux C & Vukusic. The clinical course ofmultiple sclerosis. Handb
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[Cyster 2005] Cyster JG. Chemokines, sphingosine-1-phosphate, and cell migration in secondary
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[FDA 2009b] Guidance for Industry. Drug-induced liver injury: premarketing clinical evaluation.
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[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.
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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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Version 6
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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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Ponesimod / ACT-128800
Relapsing multiple sclerosis
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Version 6
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Confidential
EudraCT 2016-004719-10
EDMS-ERI-207656619
CONFIDENTIAL - FOIA Exemptions Apply in U.S.


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


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


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B303, OPTIMUM-LT
Version 6
15March 2022, page 181/216
Confidential
EudraCT 2016-004719-10
EDMS-ERI-207656619
CONFIDENTIAL - FOIA Exemptions Apply in U.S.
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


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B303, OPTIMUM-LT
Version 6
15March 2022, page 182/216
Confidential
EudraCT 2016-004719-10
EDMS-ERI-207656619
CONFIDENTIAL - FOIA Exemptions Apply in U.S.
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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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.
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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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.
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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Relapsing multiple sclerosis
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Version 6
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Confidential
EudraCT 2016-004719-10
EDMS-ERI-207656619
CONFIDENTIAL - FOIA Exemptions Apply in U.S.
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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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.
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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Relapsing multiple sclerosis
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Version 6
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Confidential
EudraCT 2016-004719-10
EDMS-ERI-207656619
CONFIDENTIAL - FOIA Exemptions Apply in U.S.
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


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B303, OPTIMUM-LT
Version 6
15March 2022, page 188/216
Confidential
EudraCT 2016-004719-10
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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Relapsing multiple sclerosis
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Version 6
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Confidential
EudraCT 2016-004719-10
EDMS-ERI-207656619
CONFIDENTIAL - FOIA Exemptions Apply in U.S.
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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Confidential
EudraCT 2016-004719-10
EDMS-ERI-207656619
CONFIDENTIAL - FOIA Exemptions Apply in U.S.
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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Relapsing multiple sclerosis
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Version 6
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Confidential
EudraCT 2016-004719-10
EDMS-ERI-207656619
CONFIDENTIAL - FOIA Exemptions Apply in U.S.
Please enter the number using your touch tone phone.
Exit
Thank you and Good bye.


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Relapsing multiple sclerosis
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Version 6
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Confidential
EudraCT 2016-004719-10
EDMS-ERI-207656619
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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Relapsing multiple sclerosis
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Version 6
15March 2022, page 193/216
Confidential
EudraCT 2016-004719-10
EDMS-ERI-207656619
CONFIDENTIAL - FOIA Exemptions Apply in U.S.
CCI


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B303, OPTIMUM-LT
Version 6
15March 2022, page 194/216
Confidential
EudraCT 2016-004719-10
EDMS-ERI-207656619
CONFIDENTIAL - FOIA Exemptions Apply in U.S.
CCI


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B303, OPTIMUM-LT
Version 6
15March 2022, page 195/216
Confidential
EudraCT 2016-004719-10
EDMS-ERI-207656619
CONFIDENTIAL - FOIA Exemptions Apply in U.S.
CCI


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B303, OPTIMUM-LT
Version 6
15March 2022, page 196/216
Confidential
EudraCT 2016-004719-10
EDMS-ERI-207656619
CONFIDENTIAL - FOIA Exemptions Apply in U.S.
CCI


Ponesimod / ACT-128800
Relapsing multiple sclerosis
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Version 6
15March 2022, page 197/216
Confidential
EudraCT 2016-004719-10
EDMS-ERI-207656619
CONFIDENTIAL - FOIA Exemptions Apply in U.S.
CCI


Ponesimod / ACT-128800
Relapsing multiple sclerosis
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Version 6
15March 2022, page 198/216
Confidential
EudraCT 2016-004719-10
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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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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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


















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Version 6
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EDMS-ERI-207656619
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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EDMS-ERI-207656619
CONFIDENTIAL - FOIA Exemptions Apply in U.S.
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.


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B303, OPTIMUM-LT
Version 6
15March 2022, page 213/216
Confidential
EudraCT 2016-004719-10
EDMS-ERI-207656619
CONFIDENTIAL - FOIA Exemptions Apply in U.S.
 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.


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B303, OPTIMUM-LT
Version 6
15March 2022, page 214/216
Confidential
EudraCT 2016-004719-10
EDMS-ERI-207656619
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.


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B303, OPTIMUM-LT
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

SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 04 March 2024
Janssen Research & Development
Statistical Analysis Plan
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
Short Title
Long-term Safety and Efficacy Study of ponesimod 20 mg in subjects with relapsing multiple 
sclerosis
Protocol AC-058B303; Phase 3
JNJ-67896153  (ponesimod)
Status:
Approved
Date:
04 March 2024
Prepared by:
Janssen Research & Development, LLC
Document No.: EDMS-RIM-1099966, 1.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
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


JNJ-67896153  (ponesimod)
Statistical Analysis Plan AC-058B303
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved, Date: 04 March 2024
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
VERSION HISTORY..................................................................................................................................... 7
1.
INTRODUCTION.................................................................................................................................. 8
1.1.
Objectives and Endpoints ................................................................................................................ 8
1.1.1.
Safety objectives and endpoints................................................................................................... 8
1.1.2.
Efficacy objectives and endpoints ................................................................................................ 9
1.1.2.1.
Main clinical endpoints ............................................................................................................ 10
1.1.2.2.
MRI-based endpoints .............................................................................................................. 10
1.1.2.3.
Other endpoints ....................................................................................................................... 11
1.2.
Study Design and treatment period ............................................................................................... 12
1.2.1.
Core study follow up period and transition into the extension study .......................................... 12
1.2.2.
Pre-treatment period................................................................................................................... 12
1.2.3.
Treatment period ........................................................................................................................ 12
1.2.3.1.
End-of-treatment visit .............................................................................................................. 13
1.2.4.
Safety follow-up .......................................................................................................................... 13
1.3.
Procedures for Randomization and Stratification .......................................................................... 14
1.4.
Blinding .......................................................................................................................................... 14
2.
STATISTICAL HYPOTHESES.......................................................................................................... 14
3.
SAMPLE SIZE DETERMINATION.................................................................................................... 14
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS..................................................................... 15
4.1.
Definitions of analysis sets............................................................................................................. 15
4.1.1.
Extension set (EXTS) ................................................................................................................. 15
4.1.2.
DLCO sub-study extension set (DLCO EXTS)............................................................................. 15
4.1.3.
Full analysis set (FAS)................................................................................................................ 15
4.1.4.
Safety set (SAF) ......................................................................................................................... 15
4.1.5.
DLCO sub-study safety set (DLCO SAF) ..................................................................................... 15
4.2.
Usage of the analysis sets ............................................................................................................. 15
5.
STATISTICAL ANALYSES............................................................................................................... 17
5.1.
General Considerations ................................................................................................................. 17
5.1.1.
Analysis Periods ......................................................................................................................... 17
5.1.1.1.
Extension Analysis Period....................................................................................................... 17
5.1.1.2.
Combined Analysis Period ...................................................................................................... 17
5.1.1.3.
Core Analysis Period ............................................................................................................... 18
5.1.1.4.
Post-treatment analysis Period................................................................................................ 18
5.1.2.
Labels for treatment group.......................................................................................................... 18
5.1.3.
Baseline and change-from-baseline........................................................................................... 18
5.1.3.1.
Extension Baseline .................................................................................................................. 18
5.1.3.2.
Core Baseline .......................................................................................................................... 19
5.1.4.
Visit Windows ............................................................................................................................. 19
5.1.5.
Analysis Strategy........................................................................................................................ 22
5.1.5.1.
Analysis strategy for efficacy................................................................................................... 22
5.1.5.2.
Analysis strategy for safety...................................................................................................... 22
5.1.6.
Definition of treatment-emergent ................................................................................................ 23
5.1.7.
Study Day ................................................................................................................................... 23
5.1.7.1.
Extension Study Day ............................................................................................................... 23
5.1.7.2.
Combined Study Day............................................................................................................... 24
5.1.8.
Coding......................................................................................................................................... 24
5.1.9.
Dates........................................................................................................................................... 24
5.1.9.1.
Extension enrollment date....................................................................................................... 24


JNJ-67896153  (ponesimod)
Statistical Analysis Plan AC-058B303
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Approved, Date: 04 March 2024
5.1.9.2.
First study drug intake date/time in extension study ............................................................... 24
5.1.9.3.
Extension End-of-Treatment (EOT) date................................................................................. 24
5.1.9.4.
Extension End-of-Study (EOS) date........................................................................................ 25
5.1.10.
Re-assignment of EOT visits / visit windowing........................................................................... 25
5.2.
Subject Dispositions....................................................................................................................... 27
5.2.1.
Definition of disposition variables ............................................................................................... 27
5.2.1.1.
Enrolled subjects in the extension study ................................................................................. 27
5.2.1.2.
Treated subjects in the extension study.................................................................................. 27
5.2.1.3.
Subjects completing the core treatment and study as per protocol and not entering 
the extension ........................................................................................................................... 27
5.2.1.4.
Subjects prematurely discontinued from treatment in the extension....................................... 28
5.2.1.5.
Subjects completed study in the extension as per protocol .................................................... 28
5.2.1.6.
Subjects prematurely discontinued from study in the extension ............................................. 28
5.2.1.7.
Subjects prematurely discontinued from treatment or study in the extension......................... 28
5.2.1.8.
Subjects interrupted treatment for planned pregnancy in the extension................................. 28
5.2.1.9.
Last study drug intake date prior to pregnancy interruption date............................................ 28
5.2.1.10.
Time in study ........................................................................................................................... 28
5.2.2.
Analysis of subject disposition.................................................................................................... 29
5.2.2.1.
Subject disposition................................................................................................................... 29
5.2.2.2.
Study treatment and study discontinuation ............................................................................. 30
5.2.3.
Analysis sets............................................................................................................................... 31
5.2.4.
Time in study .............................................................................................................................. 31
5.3.
Analysis of efficacy variables ......................................................................................................... 31
5.3.1.
Definition of Endpoint(s) ............................................................................................................. 31
5.3.1.1.
Relapse-related variables........................................................................................................ 31
5.3.1.1.1.
Annualized Relapse Rate (ARR).......................................................................................... 31
5.3.1.1.2.
Time to first (confirmed) relapse .......................................................................................... 33
5.3.1.1.3.
Duration of (confirmed) relapse............................................................................................ 33
5.3.1.2.
MRI-related variables .............................................................................................................. 33
5.3.1.2.1.
T1 Gd+ lesions ..................................................................................................................... 34
5.3.1.2.2.
New or enlarging T2 lesions................................................................................................. 35
5.3.1.2.3.
Combined unique active lesions (CUAL) and cumulative CUAL ......................................... 36
5.3.1.2.4.
Percent Change of Brain Volume from Baseline ................................................................. 36
5.3.1.3.
Neurological variables ............................................................................................................. 37
5.3.1.3.1.
CDA: 12/24-week confirmed disability accumulation........................................................... 37
5.3.1.3.2.
Time to first 12 or 24-week CDA.......................................................................................... 39
5.3.1.3.3.
Change from baseline in EDSS ........................................................................................... 39
5.3.1.4.
Other efficacy variables ........................................................................................................... 39
5.3.1.4.1.
NEDA-3 status up to extension EOS ................................................................................... 39
5.3.1.4.2.
NEDA-4 status up to extension EOS ................................................................................... 39
5.3.1.4.3.
Change in Multiple Sclerosis Functional Composite (MSFC) Z-score from baseline 
by visit up to Extension EOS................................................................................................ 40
5.3.1.4.4.
Change in the symbol digit modalities test (SDMT) score from baseline by visit up 
to Extension EOS................................................................................................................. 40
5.3.2.
Analysis Methods........................................................................................................................ 41
5.3.2.1.
Statistical methodology............................................................................................................ 41
5.3.2.1.1.
Statistical methodology for count data ................................................................................. 41
5.3.2.1.2.
Statistical methodology for time to event data ..................................................................... 41
5.3.2.2.
Analysis of relapse-related variables....................................................................................... 42
5.3.2.2.1.
Main analysis of ARR........................................................................................................... 42
5.3.2.2.2.
Additional analyses of ARR.................................................................................................. 42
5.3.2.2.3.
Time to first (confirmed) relapse .......................................................................................... 43
5.3.2.3.
Analysis of MRI-related variables............................................................................................ 43
5.3.2.3.1.
T1 Gd+ lesions ..................................................................................................................... 43
5.3.2.3.2.
New or enlarging T2 lesions................................................................................................. 44
5.3.2.3.3.
Combined unique active lesions (CUAL) ............................................................................. 45
5.3.2.3.4.
Percent Change of Brain Volume from Baseline ................................................................. 45
5.3.2.4.
Analysis of neurological variables ........................................................................................... 46


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5.3.2.4.1.
Analysis of disability progression (12/24-week CDA) .......................................................... 46
5.3.2.4.2.
Change in EDSS from baseline by visit up to EOS.............................................................. 46
5.3.2.5.
Analysis of other efficacy variables ......................................................................................... 46
5.3.2.5.1.
NEDA-3 status up to EOS.................................................................................................... 46
5.3.2.5.2.
NEDA-4 status up to EOS.................................................................................................... 46
5.3.2.5.3.
Change in MSFC Z-score from baseline by visit up to Extension EOS............................... 46
5.3.2.5.4.
Change in the SDMT score from baseline by visit up to Extension EOS ............................ 46
5.4.
Safety Analyses ............................................................................................................................. 47
5.4.1.
Extent of Exposure ..................................................................................................................... 47
5.4.1.1.
Definition of extent of exposure............................................................................................... 47
5.4.1.1.1.
Exposure (Time on treatment) ............................................................................................. 47
5.4.1.1.2.
Compliance with study treatment......................................................................................... 48
5.4.1.1.3.
Treatment duration (days with intake documented) during up-titration period 
(extension study).................................................................................................................. 48
5.4.1.1.4.
Treatment duration (days with intake documented) during maintenance period 
(extension study).................................................................................................................. 49
5.4.1.1.5.
Study treatment completion/discontinuation ........................................................................ 49
5.4.1.1.6.
Study treatment interruptions............................................................................................... 49
5.4.1.1.7.
Re-initiation of ponesimod.................................................................................................... 50
5.4.1.1.8.
Study completion/discontinuation......................................................................................... 50
5.4.1.2.
Analysis of extent of exposure................................................................................................. 50
5.4.1.2.1.
Exposure .............................................................................................................................. 50
5.4.1.2.2.
Compliance with study treatment......................................................................................... 51
5.4.2.
Adverse Events........................................................................................................................... 51
5.4.2.1.
General consideration in adverse events ................................................................................ 51
5.4.2.2.
Analysis variables in AE .......................................................................................................... 52
5.4.2.2.1.
Frequency of adverse events and AEs per 100 subject-years ............................................ 52
5.4.2.2.2.
Treatment-emergent adverse events................................................................................... 52
5.4.2.2.3.
Serious adverse events........................................................................................................ 53
5.4.2.2.4.
Adverse events leading to permanent discontinuation of study treatment .......................... 53
5.4.2.2.5.
Adverse events leading to temporary interruption of study treatment ................................. 53
5.4.2.2.6.
Adverse events leading to hospitalization............................................................................ 53
5.4.2.2.7.
Fatal adverse events............................................................................................................ 53
5.4.2.2.8.
Deaths .................................................................................................................................. 53
5.4.2.2.9.
Post-treatment AEs and SAEs............................................................................................. 53
5.4.2.2.10.
Adverse events of special interest (AESI)............................................................................ 53
5.4.2.2.11.
Major adverse cardiovascular events (MACE)..................................................................... 54
5.4.2.2.12.
Intensity of adverse events .................................................................................................. 54
5.4.2.2.13.
Relationship of adverse events............................................................................................ 54
5.4.2.3.
Analysis of safety variables ..................................................................................................... 54
5.4.2.3.1.
Adverse events..................................................................................................................... 55
5.4.2.3.2.
Deaths .................................................................................................................................. 56
5.4.2.3.3.
Serious adverse events (SAEs) ........................................................................................... 56
5.4.2.3.4.
Treatment-emergent adverse events leading to study treatment discontinuation............... 56
5.4.2.3.5.
Adverse events of special interest (AESIs).......................................................................... 57
5.4.2.3.6.
Major adverse cardiovascular events (MACE)..................................................................... 57
5.4.3.
Additional Safety Assessments .................................................................................................. 57
5.4.3.1.
Clinical Laboratory Tests......................................................................................................... 57
5.4.3.1.1.
Laboratory Test variables..................................................................................................... 57
5.4.3.1.2.
Analysis of Laboratory Tests................................................................................................ 59
5.4.3.2.
Vital Signs................................................................................................................................ 62
5.4.3.2.1.
Definition of Vital Signs variables......................................................................................... 62
5.4.3.2.1.1.
Blood Pressure.................................................................................................................. 62
5.4.3.2.1.2.
Weight............................................................................................................................... 63
5.4.3.2.1.3.
Body Temperature ............................................................................................................ 64
5.4.3.2.1.4.
Pulse rate .......................................................................................................................... 64
5.4.3.2.2.
Analysis of Vital Signs.......................................................................................................... 64
5.4.3.3.
Electrocardiogram ................................................................................................................... 65


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5.4.3.3.1.
Definition of ECG variables.................................................................................................. 65
5.4.3.3.1.1.
ECG parameter measurements ........................................................................................ 65
5.4.3.3.1.2.
Morphological ECG findings ............................................................................................. 66
5.4.3.3.2.
Analysis of ECG ................................................................................................................... 67
5.4.3.4.
Spirometry and DLCO ............................................................................................................... 68
5.4.3.4.1.
Definition of Spirometry and DLCO........................................................................................ 68
5.4.3.4.2.
Analysis of Spirometry and DLCO ....................................................................................... 70
5.4.3.5.
Dermatological Examination.................................................................................................... 71
5.4.3.6.
Optical coherence tomography................................................................................................ 71
5.4.3.7.
Ophthalmological Examination................................................................................................ 71
5.4.3.8.
Physical examination............................................................................................................... 71
5.4.3.9.
Electronic self-rated version of the Columbia-Suicide Severity Rating Scale (eC-
SSRS)...................................................................................................................................... 71
5.4.3.9.1.
Definition of eC-SSRS variables .......................................................................................... 71
5.4.3.9.2.
Analysis of Columbia Suicide ideation or behavior.............................................................. 75
5.5.
Other Analyses............................................................................................................................... 75
5.5.1.
Pharmacokinetics ....................................................................................................................... 75
5.5.2.
Immunogenicity........................................................................................................................... 75
5.5.3.
Pharmacodynamics .................................................................................................................... 75
5.5.4.
Quality of life variables................................................................................................................ 76
5.5.4.1.
Change from baseline by visit up to Extension EOS in SF-36v2™ Health Survey 
domain and component scores ............................................................................................... 76
5.5.4.2.
Analysis of SF-36v2™ Health Survey ..................................................................................... 77
5.5.5.
Biomarkers.................................................................................................................................. 77
5.5.6.
Subgroups analysis .................................................................................................................... 77
5.5.7.
Interim Analyses ......................................................................................................................... 77
5.5.8.
Data Monitoring Committee (DMC) or Other Review Board ...................................................... 78
5.5.9.
Covid-19 Impact Analyses.......................................................................................................... 78
5.5.10.
Regional Crisis Impact Analyses ................................................................................................ 78
6.
SUPPORTING DOCUMENTATION .................................................................................................. 79
6.1.
Appendix 1 List of Abbreviations.................................................................................................... 79
6.2.
Appendix 2 Changes to Protocol-Planned Analyses ..................................................................... 81
6.2.1.
Changes to the analyses planned in the study protocol............................................................. 81
6.2.2.
Clarifications concerning endpoint definitions and related variables or statistical 
methods ...................................................................................................................................... 82
6.3.
Appendix 3 Demographics and Baseline Characteristics.............................................................. 83
6.3.1.
Definition of demographic variables and baseline characteristics.............................................. 83
6.3.1.1.
Demographics.......................................................................................................................... 83
6.3.1.2.
Baseline disease characteristics ............................................................................................. 83
6.3.2.
Analysis of demographic and baseline characteristics............................................................... 84
6.3.2.1.
Demographic characteristics ................................................................................................... 84
6.3.2.2.
Baseline characteristics........................................................................................................... 85
6.4.
Appendix 4 Protocol Deviations ..................................................................................................... 86
6.5.
Appendix 5 Prior and Concomitant Medications............................................................................ 87
6.5.1.
Definition of prior and concomitant medications......................................................................... 87
6.5.1.1.
Previous therapies................................................................................................................... 87
6.5.1.2.
Treatment-concomitant therapies: taken between treatment start and EOT .......................... 87
6.5.1.3.
Therapies starting after EOT ................................................................................................... 88
6.5.1.4.
Disease modifying therapies for MS (DMTs)........................................................................... 88
6.5.2.
Analysis of prior and concomitant medications .......................................................................... 88
6.5.2.1.
Disease modifying therapies (DMTs) for MS........................................................................... 89
6.6.
Appendix 6 Medical History ........................................................................................................... 90
6.6.1.
Definition of medical history........................................................................................................ 90
6.6.1.1.
General medical history........................................................................................................... 90
6.6.1.2.
Specific MS medical history..................................................................................................... 90
6.6.2.
Analysis of medical history ......................................................................................................... 90
6.7.
Appendix 7 Intervention Compliance ............................................................................................. 92


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6.8.
Appendix 8 Adverse Events of Special Interest............................................................................. 93
6.9.
Appendix 9 Medications of Special Interest................................................................................... 95
6.10.
Appendix 10 Thresholds for marked laboratory abnormalities ...................................................... 96
6.11.
Appendix 11 Covid-19.................................................................................................................... 98
6.11.1.
Immunogenicity Variables........................................................................................................... 98
6.11.2.
Analysis of Immunogenicity Related to Covid-19 Vaccination: .................................................. 98
6.11.2.1.
Analysis related definitions:..................................................................................................... 98
6.11.2.2.
Analysis of Immunogenicity Related to Covid-19 Vaccination .............................................. 100
6.11.3.
Analysis of Adverse Events Related to Covid-19 Vaccination ................................................. 101
6.12.
Appendix 12 Study visit and assessment schedule..................................................................... 102
6.13.
Appendix 13 Handling of missing/incomplete date and the time fields........................................ 107
6.13.1.
Previous / Concomitant therapies............................................................................................. 107
6.13.2.
Relapse Start Date ................................................................................................................... 108
6.13.3.
Adverse events ......................................................................................................................... 109
6.13.3.1.
Treatment-emergent AEs ...................................................................................................... 109
6.13.4.
Study treatment start and EOT date......................................................................................... 110
6.13.5.
Treatment exposure.................................................................................................................. 111
6.14.
Appendix 14 PRO and other composite assessment scoring and handling of missing data ...... 112
6.14.1.
MSFC........................................................................................................................................ 112
6.14.2.
SF-36 analysis .......................................................................................................................... 113
6.14.2.1.
SF-36 scoring ........................................................................................................................ 113
6.14.2.2.
ADaM domain generation...................................................................................................... 114
6.14.2.3.
Handling of duplicate entries on Questionnaire form for SF-36 scoring ............................... 114
6.14.2.4.
Selection of subset population for dry-run SF-36 scoring ..................................................... 115
7.
REFERENCES................................................................................................................................. 116


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VERSION HISTORY
Table 1 SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
1
04-March-2024
Not Applicable
Initial release


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1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis populations, derived variables, 
and statistical methods for the analysis of efficacy and safety for the extension study 67896153AC-
058B303, following the unblinding of the core study AC-058B301 (OPTIMUM), as planned in 
the AC-058B303 protocol.
The SAP consists of selected efficacy and safety analyses. Data from the extension study are 
pooled with that of the corresponding core study AC 058B301 (OPTIMUM). Statistical analysis 
will be descriptive unless otherwise stated. A database lock for final analysis will occur after all 
enrolled subjects in the extension study have completed the end of study visit or prematurely 
discontinue the study.
This document is based on the AC-058B303 protocol Final Version 6, dated 15 March 2022, and 
Version 6.UKR.A dated 04 August 2022.
1.1.
Objectives and Endpoints
The study has the following objectives:
1.1.1.
Safety objectives and endpoints

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.
Table 2 details the endpoints that will be analyzed for the Extension Analysis Period and for the 
Combined Analysis Period. See Section 5.1.5 for further details regarding the analysis strategy for 
safety. 
Table 2:
Safety endpoints
Endpoints
Combined 
Analysis 
Period
Extension 
Analysis 
Period
Adverse events

Treatment-emergent AEs, SAEs, and AESIs #
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 of re-initiation 
of study treatment
N
Y
Pulmonary safety


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Table 2:
Safety endpoints
Endpoints
Combined 
Analysis 
Period
Extension 
Analysis 
Period

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

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
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) at all assessments
Y
Y

Treatment-emergent notable laboratory abnormalities
Y*
Y
* Cumulative safety data, e.g., 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 is based on the anticipated risks of treatment with ponesimod
AE = adverse event; AESI-adverse event of special interest; DBP = diastolic blood pressure; ECG = electrocardiogram; 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.
Analyses on the Combined Analysis Period use the core baseline as a reference, while analyses on the Extension Analysis Period 
use the extension baseline as a refence. 
1.1.2.
Efficacy objectives and endpoints

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.
The tables below detail which endpoints will be analyzed for the Extension Analysis Period and 
for the Combined Analysis Period. See Section 5.1.1 for definitions of the Analysis Periods, and 
Section 5.1.5 for further details regarding the analysis strategy. 


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1.1.2.1.
Main clinical endpoints
The main clinical endpoints are those relating to disease activity, i.e., relapses and disability accumulation. 
Table 3:
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

Absence of relapses
Y
Y

Time from core baseline to 12-week CDA
Y
N

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 decrease ≥0.4% from baseline to all 
assessments)
Y
N
ARR = Annualized Relapse Rate; CDA = confirmed disability accumulation; EDSS = Expanded Disability Status Scale.
Analyses on the Combined Analysis Period use the core baseline as a reference, while analyses on the Extension Analysis Period use the extension baseline as a reference.
1.1.2.2.
MRI-based endpoints
Table 4:
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
N

Number of Gd+ T1 lesions at all assessments
Y
Y

Cumulative number of new or enlarging T2 lesions (relative to baseline) at all assessment
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.


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1.1.2.3.
Other endpoints
Table 5:
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.


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1.2.
Study Design and treatment period
Study AC-058B303 (the “extension study”) is a prospective, multi-center, open-label, non-
comparative, long-term extension of the Phase 3 confirmatory AC-058B301 (the “core study”). 
Details of the AC 058B301 study can be found in the study Protocol Final Version 7, dated 5 
December 2018.
Subjects who have completed the 108-week treatment period in the core study will be enrolled as 
one group treated with ponesimod 20 mg once daily in the extension study, independent of previous 
treatment allocation.
The extension study consists of a pre-treatment period, a treatment period, and a safety follow-up.
1.2.1.
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
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.
1.2.2.
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. 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).
1.2.3.
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.
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. Treatment will 
stop before 240 weeks if ponesimod becomes commercially available for the treatment of multiple 
sclerosis in the subject’s country (Treatment may also stop before 240 weeks for subjects
prematurely discontinued study treatment due to efficacy or safety or other reasons). 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 visit. The treatment 
period may include a study treatment interruption period of variable duration. 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 may follow the planned visit schedule off-
treatment with the corresponding assessments with exceptions of assessments that are contra-


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indicated due to the subject’s condition (e.g., in the event of pregnancy, scheduled MRI assessments 
will not be performed).
1.2.3.1.
End-of-treatment visit
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 visit may take place in case:

of premature discontinuation of study treatment for subjects meeting the study specific
criteria for permanent discontinuation of study treatment;

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, subjects participating in the AC-058B303 
study can continue to receive ponesimod until ponesimod is available in their respective country, or 
for a maximum of 240 weeks. Subjects 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 subjects 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 subjects, 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.
*except for subjects in Ukraine where the maximum treatment duration will be 288 weeks (or not later than 
preplanned global Last Subject Last End of Treatment in Q4 2023)
1.2.4.
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 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.


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The overall AC-058B303 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 treatment. 
1.3.
Procedures for Randomization and Stratification
This extension study is open-label, and all subjects receive ponesimod 20 mg. No randomization 
or stratification procedures were performed.
1.4.
Blinding
This extension study is open-label, and all subjects receive ponesimod 20 mg. The study treatment 
groups in the core study will remain blinded until the randomization list is revealed for the core 
study after core database lock.
2.
STATISTICAL HYPOTHESES
As the present study is an open label long-term extension of the confirmatory Phase 3 core study, 
no hypotheses are pre-specified. All analyses conducted will be exploratory. No multiplicity
adjustments will be made for the efficacy endpoints.
3.
SAMPLE SIZE DETERMINATION
As the extension study is an extension of the confirmatory Phase 3 core study, there are no sample
size statistical considerations. The sample size is pragmatically determined by how many of the 
1133 subjects randomized in the core study enroll into the extension study. Based on anticipated 
discontinuation rates in the core study, the sample size was estimated to be approximately 875 
subjects. At this final analysis, there are in total 877 subjects enrolled in the extension study.


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4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
4.1.
Definitions of analysis sets
4.1.1.
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 medication in the extension study.
4.1.2.
DLCO sub-study extension set (DLCO EXTS)
The DLCO sub-study extension set includes all subjects in the extension set who have consented to 
participate in the DLCO sub-study during the extension study (‘DLco sub-study’ ticked on 
‘Informed Consent’ extension study eCRF). Subjects are summarized in the same study treatment 
group as in the extension set.
4.1.3.
Full analysis set (FAS)
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.
4.1.4.
Safety set (SAF)
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.
4.1.5.
DLCO sub-study safety set (DLCO SAF)
The DLCO safety set includes all subjects in the safety set who have consented to participate in 
the DLCO sub-study during the core study (‘DLCO sub-study’ ticked on ‘Informed Consent’ core 
study eCRF). Subjects are summarized in the same study treatment group as in the safety set.
4.2.
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. The 
DLCO SAF and the DLCO EXTS will be used for analyses of the DLCO sub-study endpoints on 
the Combined Analysis Period and in the Extension Analysis Period respectively. Table 6 below 
provides an overview of analysis set in use for efficacy and safety endpoints. More details are 
depicted in the respective section.


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Table 6:
Use of analysis set
Endpoint 
category
Endpoint
Combine period
Extension period
FAS
EXTS
SAF
DLCO 
SAF
EXTS
DLCO 
EXTS
Efficacy
ARR
Y
Y
Y
Time 
from 
core 
study 
randomization 
to 
first 
confirmed relapse
Y
Y
Duration of relapse
Y
Y
Absence  of relapse
Y
Y
Time from core baseline to 
12-week CDA
Y
Y
Time from core baseline to 
24-week CDA
Y
Y
Change from baseline in 
EDSS
Y
Y
Gd+ T1 lesions by visit
Y
Y
New or enlarging T2 lesions 
by visit
Y
Y
Cumulative new or enlarging 
T2
Y
Y
CUAL by visit
Y
Y
Cumulative CUAL
Y
Y
Y
Total 
Volume 
of 
T1 
hypointense lesions and the 
change from baseline
Y
Y
Total volume of T2 lesions 
and the change from baseline
Y
Y
Proportion of T1 Gd+ lesions 
at baseline evolving to PBHs 
(persistent black holes) at all 
assessments
Y
Y
Percentage change in Brain 
volume from baseline
Y
Y
Y
NEDA 
status 
at 
EOS 
according to NEDA 3
Y
NEDA 
status 
at 
EOS 
according to NEDA 4
Y
Change from baseline in 
MSFC Z-score
Y
Y
Change from baseline in the 
SDMT score
Y
Y
Change from baseline in SF-
36v2™ 
Health 
Survey 
Y
Y


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Table 6:
Use of analysis set
Endpoint 
category
Endpoint
Combine period
Extension period
FAS
EXTS
SAF
DLCO 
SAF
EXTS
DLCO 
EXTS
domain 
and 
component 
scores
Safety
Exposure
Y
Y
Adverse Event
Y
Y
Laboratory test and the 
associated abnormal findings
Y
Y
Vital 
signs 
and 
the 
associated abnormal findings
Y
Y
ECG and the abnormal 
findings
Y
Y
Pulmonary safety and the 
associated abnormal findings 
(except 
lung 
diffusing 
capacity)
Y
Y
Diffusing capacity
Y
Y
eC-SSRS
Y
Demographic
Demographic
Y
Disposition
Disposition
Y
Y
5.
STATISTICAL ANALYSES
5.1.
General Considerations
5.1.1.
Analysis Periods
5.1.1.1.
Extension Analysis Period
This period includes all available data collected on or after the date of first intake of ponesimod 
treatment in the extension study, through the extension EOS for efficacy variables, or the last 
treatment date in the extension study + 15 days for safety variables.
5.1.1.2.
Combined Analysis Period
For efficacy, this period includes all available data from randomization in the core study up to 
extension EOS for subjects entering the extension, or until 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 in 
the core study up to the last treatment date in the extension study + 15 days for subjects entering 
the extension, or until the last treatment date in the core study + 15 days for subjects not entering 
the extension.


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5.1.1.3.
Core Analysis Period
This period is defined for efficacy only. It includes all available data from randomization in the 
core study up to the core EOS date.
5.1.1.4.
Post-treatment analysis Period
This period is defined for post-treatment analyses for certain safety variables. It includes all 
available data from extension EOT date (defined in Section 5.1.9.3) + 16 days (inclusive) in the 
extension study up to the extension EOS.
5.1.2.
Labels for treatment group
The following labels are used to indicate the subject's core / extension treatment allocations:

Ponesimod 20 mg / Ponesimod 20 mg

Teriflunomide 14 mg / Ponesimod 20 mg

Total
If not otherwise specified, disposition demographic and efficacy analyses will be presented by 
treatment groups and total using labels “Ponesimod 20 mg / Ponesimod 20 mg”, “Teriflunomide 
14 mg / Ponesimod 20 mg” and “Total”. Safety analyses will be presented by treatment groups 
and total using labels “Ponesimod 20 mg / Ponesimod 20 mg”, “Teriflunomide 14 mg / Ponesimod 
20 mg” and “Total”, except the analyses for exposure, treatment-emergent event incidence and 
adverse events during combined period, that is only presented by “Ponesimod 20 mg / Ponesimod 
20 mg” on SAF.
5.1.3.
Baseline and change-from-baseline
5.1.3.1.
Extension Baseline
The extension baseline value for efficacy and safety is the last valid non-missing assessment that 
is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension 
study. Records meeting these criteria in both core or the extension database are considered for 
extension baseline. Consequently, the extension baseline value may be the pre-dose assessment on 
Day 1 of the extension study, but it may also be the value at any visit from EOT visit of the core 
study (EOT/FU1/FU2 or unscheduled visits). In particular, laboratory parameters are not 
scheduled to be assessed on Day 1 of the extension study, and so (unless there is an eligible 
unscheduled assessment) the extension baseline for laboratory parameters will be the last value as 
above observed in the core study. 
Specifically, for MRI and PFT variables only, in case of available assessments on extension Day 
1, these should be considered as valid assessments for the extension baseline derivation, even if 
taken after first dose of treatment on Day 1. 
In case of multiple ECG or vital signs assessments (for the same subject, visit, parameter) in the 
core study visits (EOT/FU1/FU2 or unscheduled visits) that should be considered for the purpose 
of the baseline value derivation, the average of the results should be taken for use as baseline 
record. 


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The derived “extension baseline” value is considered a visit and is displayed in the Combined 
Analysis Period by visit tables, with corresponding change from core baseline to “extension 
baseline”. 
5.1.3.2.
Core Baseline
The core baseline value for efficacy is defined as the last non-missing value recorded before or 
on 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.
These variables are used as derived in the core study and are not re-derived for the extension 
analysis.
On days where study drug is initiated or re-initiated, the pre-dose assessment for that day is defined 
as the last non-missing assessment prior to the study drug intake on that day. The pre-dose 
assessment on Day 1 of the Analysis Period (if available) is identical to the corresponding baseline
for that Analysis Period. In case of (partially) missing assessment dates/times, or for assessments 
reported on Day 1 (or day of re-initiation) with recorded assessment time contradicting the time 
point label (e.g., pre-dose, 2 hours post-dose), the nominal visit and time point labels will be used 
to determine whether an assessment is considered for baseline (e.g., a blood pressure measurement 
with an assessment date on Day 1 but with a missing assessment time or an assessment time prior 
to the reported time of first study drug intake will not be considered for baseline if reported under 
the time point “2 hours post-dose” in the eCRF; however, it will be considered if reported as “Pre-
dose” in the eCRF).
Analysis over the Extension Analysis Period will use the extension study baseline, while analysis 
over the Combined Analysis Period will use the core study baseline.
Absolute change from baseline is defined as post-baseline value minus baseline value, i.e., a 
positive sign indicates an increase compared to baseline. A percentage change from baseline is 
defined as the absolute change from baseline divided by the baseline value (if the baseline value 
is > 0) and then multiplied by 100. Absolute and percent change from both core and extension 
baseline is calculated and stored for all continuous safety data.
5.1.4.
Visit Windows
For the extension visits, visit based assessments are generally summarized according to the 
nominal visit, except for subjects prematurely discontinuing study treatment, which are re-assigned 
following the visit windowing described in Section 5.1.10. Scheduled nominal visits, e.g., Week 
XX, are identified based on the eCRF recorded nominal visit label. Note that the eCRF allows for 
considering a visit under multiple visit labels, e.g., a Follow-up 1 or a Relapse visit can be 
considered in addition a Week XX visit. This second visit label is collected on the Visit Summary 
eCRF under ‘Corresponding visit’. In selecting results for a nominal scheduled visit both visit 
labels are considered. Priority is given to the first visit label, then to the second visit label. If no 
result is available at a scheduled nominal visit, premature EOT remapping is applied 
[Section 5.1.10]. 


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In addition, to incorporate the extended 288-week treatment period for Ukraine subjects impacted 
by regional crisis, additional visits (Extension Visit 24, Visit 25, Visit 26, Visit 27) will be added. 
The Extension Visit 23-Week 240 contains data from regional crisis-impacted Ukraine subjects 
who attend this visit, as well as the Extension EOT visit data of other non-impacted subjects who 
complete study treatment until week 240. The Extension EOT visit contains Visit 27- Week 288 
visit data from regional crisis-impacted Ukraine subjects, as well as the Extension EOT visit data 
of other non-impacted subjects (including subjects who completed study treatment at Week 240 
and subjects who switched to commercial ponesimod at early weeks and subjects who discontinued 
study treatment prematurely at earlier weeks).
Extension Analysis Period
Summaries by visit are presented by extension baseline (derived), and further scheduled nominal 
visits up to Week 240 (or up to Week 288 for Ukraine subjects). Generally, by-visit tables tabulate 
the extension baseline and nominal and derived visits as follows:

Extension baseline (Note: This is not a nominal visit but the derived baseline [see 
Section 5.1.3.1])

Extension Visit 2 - Week 2

Extension Visit 3 - Week 4

Extension Visit 4 - Week 12

Extension Visit 5 - Week 24

Extension Visit 6 - Week 36

Extension Visit 7 - Week 48

Extension Visit 8 - Week 60

Extension Visit 9 - Week 72

Extension Visit 10 - Week 84

Extension Visit 11 - Week 96

Extension Visit 12 - Week 108

Extension Visit 13 - Week 120

Extension Visit 14 - Week 132

Extension Visit 15 - Week 144

Extension Visit 16 - Week 156

Extension Visit 17 - Week 168

Extension Visit 18 - Week 180

Extension Visit 19 - Week 192

Extension Visit 20 - Week 204

Extension Visit 21 - Week 216

Extension Visit 22 - Week 228

Extension Visit 23 - Week 240

Extension Visit 24 – Week 252 (This is applicable for Ukraine subjects only)

Extension Visit 25 – Week 264 (This is applicable for Ukraine subjects only)

Extension Visit 26 – Week 276 (This is applicable for Ukraine subjects only)

Extension Visit 27 – Week 288 (This is applicable for Ukraine subjects only)

Extension EOT Visit

Extension EOS Visit 


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Premature EOT visits and EOT visits from subjects who switched to commercial ponesimod are 
mapped to and summarized within a scheduled visit, following the window approach described in 
Section 5.1.10; they will not be summarized as “Visit 23 - Week 240” (or “Visit 27 – Week 288, 
for impacted Ukraine subjects) unless they are mapped to this visit using the approach described 
in Section 5.1.10. 
Combined Analysis Period
Summaries by visit are presented by Core Baseline (derived), and further scheduled nominal core 
visits up to Core Week 108, derived Follow-up visits (FU1, FU2), Extension Baseline and further 
scheduled nominal extension visits up to Extension Week 240 (or Extension Week 288, for 
impacted Ukraine subjects). Generally, by visit tables tabulate the baselines and nominal and 
derived visits as follows:

Core Baseline (Note: This is not a nominal visit but the derived baseline, see Section 5.5.1 of 
the core CSR SAP)

Core Visit 4 - Week 2

Core Visit 5 - Week 4

Core Visit 6 - Week 12

Core Visit 7 - Week 24

Core Visit 8 - Week 36

Core Visit 9 - Week 48

Core Visit 10 - Week 60

Core Visit 11 - Week 72

Core Visit 12 - Week 84

Core Visit 13 - Week 96

Core Visit 14 - Week 108

Core Day-15 follow-up (derived)

Core Day-30 follow-up (derived)

Extension baseline (Note: This is not a nominal visit but the derived baseline for the extension 
study [see Section 5.1.3.1])

Extension Visit 2 - Week 2

Extension Visit 3 - Week 4

Extension Visit 4 - Week 12

Extension Visit 5 - Week 24

Extension Visit 6 - Week 36

Extension Visit 7 - Week 48

Extension Visit 8 - Week 60

Extension Visit 9 - Week 72

Extension Visit 10 - Week 84

Extension Visit 11 - Week 96

Extension Visit 12 - Week 108

Extension Visit 13 - Week 120

Extension Visit 14 - Week 132

Extension Visit 15 - Week 144

Extension Visit 16 - Week 156

Extension Visit 17 - Week 168


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
Extension Visit 18 - Week 180

Extension Visit 19 - Week 192

Extension Visit 20 - Week 204

Extension Visit 21 - Week 216

Extension Visit 22 - Week 228

Extension Visit 23 - Week 240

Extension Visit 24 – Week 252 (This is applicable for Ukraine subjects only)

Extension Visit 25 – Week 264 (This is applicable for Ukraine subjects only)

Extension Visit 26 – Week 276 (This is applicable for Ukraine subjects only)

Extension Visit 27 – Week 288 (This is applicable for Ukraine subjects only)

Extension EOT Visit

Extension EOS Visit.
5.1.5.
Analysis Strategy
5.1.5.1.
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
(the randomized treatment variable from the core study ADaMs will be used). 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. With this limitation acknowledged, specific 
efficacy endpoints will be analyzed only for the extension study, split by core study randomized 
treatment and overall. Section 4.2 details which efficacy endpoints will be analyzed for the 
combined core and extension studies, which additionally will be analyzed for the extension study, 
and which will be analyzed for the core study.
5.1.5.2.
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. Subjects will be analyzed according to the actual treatment they 
received in the core study (as derived in the core study ADaMs and not re-derived for the extension 
study analysis). 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 core study 
treatment group and by visit from core baseline up to last treatment + 15 days plus the EOS visit.
In addition, all safety data collected in the extension study will be analyzed for the extension study 
only and will summarize both overall and split by the core study treatment group. For this analysis, 
the extension study baseline is used as the reference. 


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5.1.6.
Definition of treatment-emergent
A safety assessment (ECG, vital signs, laboratory, etc.) is considered treatment-emergent relative 
to the Analysis Period, and a safety event (AE, serious adverse event [SAE], Death, etc.) is 
considered treatment-emergent relative to the Analysis Period, if the assessment date is on or after 
the study treatment start date in the Analysis Period and prior to or on the study treatment end date 
+ 15 days (inclusive). In case of planned pregnancy interruption, a safety assessment is considered 
treatment emergent relative to the Analysis Period if one of the following conditions is met:
-
the assessment date is on or after the study treatment start date in the Analysis Period and 
prior to or on the last study drug intake date prior to pregnancy interruption + 15 days 
(inclusive)
-
the assessment date is on or after the re-initiation date of study treatment after planned 
pregnancy and prior to or on the End of Treatment (EOT) date + 15 days (inclusive). 
In case of multiple planned pregnancies interruptions, the above definition will be adapted, that 
any assessment in the following interval is not considered as treatment emergent: date between the 
last study drug intake date prior to each pregnancy interruption + 15 days (inclusive) and the re-
initiation date of study treatment after each planned pregnancy (excluded). 
If both the assessment date/time and the date/time of study treatment start (or of re initiation after 
planned pregnancy) are available, only events with date/time on or after the date/time of study 
treatment start (or of re initiation after planned pregnancy) are considered to be treatment 
emergent. In case of (partially) missing assessment dates/times, or for assessments on treatment 
Day 1 with reported assessment time contradicting the time point label, the nominal visit and 
time point labels will be used to determine whether an assessment is considered as
treatment-emergent or not. For example, a blood pressure measurement with an assessment date 
on Day 1 but a missing assessment time or an assessment time after the time of first study drug 
intake, will not be considered treatment emergent if reported under the time point “Pre-dose” in 
the eCRF, however it will be considered treatment-emergent if reported as “2 hours post-dose” in 
the eCRF.
Missing or partially missing onset or occurrence dates are imputed as described in Section 6.13. If 
both the onset/occurrence date/time and the date/time of study treatment start are available, only 
events with date/time on or after the date/time of study treatment start are considered to be 
treatment emergent.
For subjects who are currently on an interruption for planned pregnancy on the database lock date, 
study treatment end date for the above definitions is taken as the date associated with the study 
drug record on the “Maintenance” eCRF page of the extension study, where reason for treatment 
end = “Temporarily interrupted due to planned pregnancy as defined in the protocol”.
5.1.7.
Study Day
5.1.7.1.
Extension Study Day
For all data analyses on the Extension Analysis Period described in this SAP, the first day of study 
drug intake in the extension study is defined as Extension study Day 1. The day prior to study drug 
start date in the extension study is defined as Extension study Day minus1; therefore there is no 
study Day 0. Study days of dates prior to Extension Day 1 are calculated as ‘date minus extension 


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study drug start date’, and study days of date after Extension Day 1 are calculated as ‘date minus 
extension study drug start date 1’.
5.1.7.2.
Combined Study Day
For all data analyses on the Combined Analysis Period Study, Day refers to the number of days 
elapsed since randomization date plus 1 (e.g., Combined Study Day 1 is the day of randomization). 
For dates prior to randomization, the combined study day is the negative number of days elapsed 
between the date under consideration and the day of randomization. Therefore, there is no study 
Day 0.
5.1.8.
Coding
The following coding dictionaries will be used: 

AEs will be coded using MedDRA version 26.0;

Medications (previous and concomitant) will be coded using the WHO-Drug Dictionary 
version March 2023 B3G .
5.1.9.
Dates
The following variables for the core study are used as derived in the core study, and are not re-
derived for the extension analysis:

Core study treatment start date;

Core EOT / study treatment end date;

Core EOS date;

Core screening date;

Core Study Day;

Core Treatment Day.
5.1.9.1.
Extension enrollment date
The extension enrollment date is the date when the subject signed the Informed Consent Form and 
is taken directly from RAVE.
5.1.9.2.
First study drug intake date/time in extension study
The first study drug intake date/time in the extension study is taken as the earliest intake 
documented in any of the following eCRF sections: ‘Study Drug Administration - Day 1 / Re-
Initiation’, ‘Study Drug Administration’, Study drug administration - Re-initiation after planned 
pregnancy’, ‘Up-titration Summary’, ‘Up-titration Ponesimod’, or ‘Maintenance Ponesimod’. This 
is derived in the SDTM.DM dataset as the ‘Date/Time of first study treatment’ (RFXSTDTC).
5.1.9.3.
Extension End-of-Treatment (EOT) date
If a subject is considered to have prematurely discontinued treatment in the extension study, the 
date of last study drug intake in the extension study corresponds the end of treatment date, derived 
as:

The maximum of [End date up-titration on eCRF page ‘Up-titration Summary’, Treatment end 
date on eCRF page ‘Up-titration Ponesimod’; Treatment end date on eCRF page ‘Maintenance 


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Ponesimod’]; this is derived in the SDTM.DM dataset as the ‘Date/Time of last study 
treatment’ (RFXENDTC);

If missing based on the above, then the treatment termination date as recorded on the RAVE 
primary form is taken. This is derived in the SDTM.DS dataset as ‘Start Date/Time of 
Disposition Event’ (DSSTDTC) where the ‘Subcategory for Disposition Event’ (DSSCAT) is 
‘TREATMENT TERMINATION’ and the ‘Standardized Disposition Term’ (DSDECOD) is 
not ‘COMPLETED’.
If a subject is considered to have completed treatment as per protocol, the date of last extension 
study drug intake corresponds to the minimum of:

Treatment end date on extension study eCRF page ‘Maintenance Ponesimod’ corresponding 
to the record “Completed as per protocol”; this is derived in the SDTM.DM dataset as the 
‘Date/Time of last study treatment’ (RFXENDTC);

If missing based on the above, then the treatment termination date as recorded on the RAVE 
primary form is taken. This is derived in the SDTM.DS dataset as ‘Start Date/Time of 
Disposition Event’ (DSSTDTC) where the ‘Subcategory for Disposition Event’ (DSSCAT) is 
‘TREATMENT TERMINATION’ and the ‘Standardized Disposition Term’ (DSDECOD) is 
‘COMPLETED’;
5.1.9.4.
Extension End-of-Study (EOS) date
If a subject is considered to have completed the extension study per protocol, the extension End-
of-Study (EOS) date is defined as the date on the end of extension study eCRF page. This is derived 
in the SDTM.DM dataset as the ‘Subject Reference End Date/Time’ (RFENDTC). If this date is 
missing, the last recorded visit on the eCRF is considered as the extension EOS date. If this date 
is also missing, the date of last contact during the extension study is taken, derived in the 
SDTM.DS dataset as ‘Start Date/Time of Disposition Event’ (DSSTDTC) where the ‘Standardized 
Disposition Term’ (DSDECOD) is not ‘LOST TO FOLLOW-UP’.
5.1.10.
Re-assignment of EOT visits / visit windowing
For core study, analysis visits are used as derived in the core study and are not re-derived for the 
extension analysis.
Extension study
If a subject discontinued study drug prematurely, as defined in Section 5.4.1.1.5, the EOT visit 
will be considered as the premature EOT visit. This rule also applies to subjects who are treatment 
completers but switched to commercial ponesimod prior to Week 240.
For all parameters unless stated below: For subjects who discontinued study drug prematurely 
with available premature EOT visit and subjects who switched to commercial ponesimod, the visit 
may be re-assigned to a scheduled visit as follows:

If a result is missing for a scheduled visit, it can be replaced with a result from a premature 
EOT visit available in the respective visit window [see Table 7].


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Table 7:
Premature End-of-Treatment remapping
Visit window
Nominal value
Day
Lower limit for
Day
Upper limit for
Day
Week 2
15
2
22
Week 4 (Except LB)
29
23
70
Week 12 (Except LB)
85
71
126
Week 4* (For LB only)
29
23
42
Week 8* (For LB only)
57
43
70
Week 12* (For LB only)
85
71
98
Week 16* (For LB only)
113
99
126
Week 20* (For LB only)
141
127
154
Week 24* (For LB only)
169
155
210
Week 24 (Except LB)
169
127
210
Week 36
253
211
294
Week 48
337
295
378
Week 60
421
379
462
Week 72
505
463
546
Week 84
589
547
630
Week 96
673
631
714
Week 108
757
715
798
Week 120
841
799
882
Week 132
925
883
966
Week 144
1009
967
1050
Week 156
1093
1051
1134
Week 168
1177
1135
1218
Week 180
1261
1219
1302
Week 192
1345
1303
1386
Week 204
1429
1387
1470
Week 216
1513
1471
1554
Week 228
1597
1555
1638
Week 240
1681
1639
Open end** / 1722***
Week 252***
Week 264***
Week 276***
Week 288***
1765
1849
1933
2017
1723
1807
1891
1975
1806
1890
1974
Open end
Day refers to treatment day, i.e., days from extension study treatment start. 
* These analysis windows applied for Laboratory (LB) assessments only, as described
** This applied for subjects not impacted by regional crisis
*** This applied for Ukraine subjects with extended treatment period and additional visits
MRI and C-SSRS: For MRI and C-SSRS measurements visit windowing of premature EOT visits 
is conducted using ± 3 months around the target day (Week 48: Day 246 to Day 428; Week 96: 
Day 582 to Day 764; Week 144: Day 918 to Day 1100; Week 192: Day 1254 to Day 1436; Week 
240: ≥ Day 1590 for subjects who are not impacted by extended study duration, or Day 1590 to 
1772 for Ukraine subjects with extended study duration; Week 288: ≥ Day 1926 (this applies for 
Ukraine subjects with extended study duration due to regional crisis) Note: as planned pregnancy 
visits are considered scheduled MRIs for analysis, they are also re-mapped using the same rules.


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MSFC and SDMT: For premature EOT visits which occurred before day 245, the remapping rules 
follow the same in Table 7. For premature EOT visits and the EOT visits from patients who 
switched to commercial ponesimod, the remapping of EOT visits follows the same rule as in MRI 
and C-SSRS.
SF-36: For SF-36 questionnaires collected via an electronic device visit windowing is applied as 
a general process. To ensure a more precise visit labels, questionnaires based on dates will be 
assigned to the visits as following. If multiple questionnaires are available, the one closest to target 
is selected. The visit windowing will also be applied to premature EOT assessments.
Week 24 -- Target: Day 169; Range: Day 1 to Day 252; 
Week 48 -- Target: Day 337, Range: Day 253 to Day 504; 
Week 96 -- Target: Day 673, Range: Day 505 to Day 840;
Week 144 -- Target: Day 1009, Range: Day 841 to Day 1176; 
Week 192 -- Target: Day 1345, Range: Day 1177 to Day 1512; 
Week 240 -- Target: Day 1681, Range: ≥ Day 1513 for subjects who are not impacted by extended 
study duration, or Day 1513 to 1848 for Ukraine subjects with extended study duration; 
Week 288 -- Target: Day 2017, Range: ≥ Day 1849 (this applies for Ukraine subjects with extended 
study duration due to regional crisis).
5.2.
Subject Dispositions
All disposition summaries will be in a n (%) format, i.e. a frequency count with accompanying 
percentage. 
5.2.1.
Definition of disposition variables
For all disposition variable definitions for the core study (such as subjects randomized, subjects 
treated, subjects discontinued treatment/study, etc.), refer to the core study SAP. These variables 
will be used as derived in the core. 
5.2.1.1.
Enrolled subjects in the extension study
Subjects enrolled are those subjects who have signed the Informed Consent Form for the extension 
study (per the ‘Informed Consent’ eCRF module).
5.2.1.2.
Treated subjects in the extension study
A subject is considered treated if they received at least one dose of ponesimod in the extension 
study and signed the informed consent form for the extension study.
5.2.1.3.
Subjects completing the core treatment and study as per protocol 
and not entering the extension 
A subject is considered to meet these criteria if they completed treatment and study in the core per 
protocol (according to the corresponding definition included in the core study SAP) and did not 
subsequently enter the extension study.


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5.2.1.4.
Subjects prematurely discontinued from treatment in the extension 
See definition in Section 5.4.1.1.
5.2.1.5.
Subjects completed study in the extension as per protocol
See definition in Section 5.4.1.1.
5.2.1.6.
Subjects prematurely discontinued from study in the extension 
A subject is considered to have prematurely discontinued from study in the extension if a reason 
for study stopped and a date of discontinuation (‘Date of last successful contact’) is reported in the 
eCRF page “Study Discontinuation”. See also Section 5.4.1.1.8 for more details.
5.2.1.7.
Subjects prematurely discontinued from treatment or study in the 
extension 
Subjects are considered to have prematurely discontinued from treatment or study in the extension 
if they prematurely discontinued from treatment in the extension, or they prematurely discontinued 
from study in the extension , or both.
5.2.1.8.
Subjects interrupted treatment for planned pregnancy in the 
extension 
Subjects who interrupted treatment for planned pregnancy in the extension have a record in the 
extension eCRF labeled ‘Maintenance Ponesimod’ form with reason for treatment end given as 
‘Temporarily interrupted due to planned pregnancy as defined in the protocol’ and without first 
study drug intake date in the extension eCRF ‘Study drug administration- Re-initiation after 
planned Pregnancy’ form. The duration of treatment interruption due to planned pregnancy is 
defined as [min (EOS date, end date of pregnancy interruption) – Start date of pregnancy 
interruption + 1]. Duration of treatment interruption due to planned pregnancy is excluded from 
all definitions of exposure durations and compliance with study treatment.
5.2.1.9.
Last study drug intake date prior to pregnancy interruption date
The last study drug intake date prior to pregnancy interruption is taken as the date associated 
with the study drug record on the ‘Maintenance Ponesimod’ eCRF page of the extension study, 
where reason for treatment end = ‘Temporarily interrupted due to planned pregnancy as defined 
in the protocol’.
5.2.1.10.
Time in study
The following variables are defined for time in study during the Extension Analysis Period: 
Time in extension study (months) is defined as the time elapsed between (extension enrollment 
date and the date of extension EOS visit +1) × 12 / 365.25.
In addition, the duration of time in the extension study for each subject is categorized as follows:

≤ 6 months;

> 6 months and ≤ 12 months;

> 12 months and ≤ 18 months;


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
> 18 months and ≤ 24 months;

> 24 months and ≤30 months;

> 30 months and ≤36 months;

> 36 months and ≤42 months;

> 42 months and ≤48 months;

> 48 months and ≤54 months;

> 54 months and ≤ 60 months;

> 60 months
The following variables are defined for time in the combined studies during the Combined 
Analysis Period: 
Time in combined core/extension studies (months) is defined as the time elapsed between date
of randomization in the core study and the core EOS visit (for subjects who did not enter the 
extension study) or extension EOS visit date (for subjects who entered the extension study) + 1) × 
12 / 365.25.
The potential interruption between the core study and the extension study is ignored for the 
duration on combined studies variable derivation.
In addition, the time in combined core/extension studies for each subject is categorized as follows:

≤ 6 months;

> 6 months and ≤ 12 months;

> 12 months and ≤ 18 months;

> 18 months and ≤ 24 months;

> 24 months and ≤30 months;

> 30 months and ≤36 months;

> 36 months and ≤42 months;

> 42 months and ≤48 months;

> 48 months and ≤54 months;

> 54 months and ≤ 60 months;

> 60 months and ≤ 66 months;

> 66 months and ≤ 72 months;

> 72 months and ≤ 78 months;

> 78 months and ≤ 84 months;

> 84 months
5.2.2.
Analysis of subject disposition
5.2.2.1.
Subject disposition
Frequency counts and percentages for all the following variables will be presented in a summary 
table by core treatment group and overall based on the FAS: 
Core study:

Subjects randomized in the core study;

Subjects treated in the core study;

Subjects prematurely discontinued treatment in the core study; 


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
Subjects completed treatment in the core study;

Subjects prematurely discontinued from the core study; 

Subjects completed the core study per protocol;

Subjects completed the core treatment and study per protocol;

Subjects completed the core treatment and study as protocol and did not enroll in the extension 
study.
Extension study:

Subjects enrolled in the extension study; 

Subjects treated in the extension study;

Subjects prematurely discontinued treatment in the extension study;

Subjects interrupted treatment for planned pregnancy;

Subjects completed treatment in extension study (further split into: “Completed as per 
protocol” or “Approved Drug Available For Indication”);

Subjects prematurely discontinued from the extension study; 

Subjects completed the extension study;

Subjects completed the extension treatment and study per protocol;

Subjects prematurely discontinued from treatment or study in the extension study.
The denominator for percentages for core study variables above will be based on the number of 
randomized subjects in the core study. The denominator for percentages for the extension study 
variables above will be based on the number of enrolled subjects in the extension study (except for 
the percentage of ‘enrolled in the extension study’, which will be based on the number of 
randomized subjects in the core study).
A subject disposition flow-chart will be produced including all the disposition information listed 
above.
The number and percent of subjects in the EXTS are summarized by country and site, by core 
study treatment group, and overall.
All subject disposition variables will be presented in a dedicated listing.
5.2.2.2.
Study treatment and study discontinuation 
Frequency counts and percentages for all subjects who discontinued treatment, all subjects who 
discontinued study, reasons for discontinuation of treatment, and reasons for discontinuation of 
study, will be presented in a summary table which will be stratified by core study treatment and 
overall, for the Extension Analysis Period using the EXTS. 
A KM plot for time to premature treatment discontinuation will be produced for the Extension 
Analysis Period on the EXTS. Subjects that complete the study treatment will be censored at the 
date of study treatment completion.
Reasons for treatment discontinuation in the extension and reasons for extension study
discontinuation will be presented in separate listings. 


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5.2.3.
Analysis sets
The number and percentage of subjects in each analysis set are summarized in a table, by core 
treatment group, and overall. Percentages are based on the FAS.
A listing of subject membership in the different analysis sets will be created.
5.2.4.
Time in study 
Time in study will be analyzed, by core treatment group and overall, separately for each of the 
following Analysis Periods:

Extension Analysis Period (using EXTS);

Combined Analysis Period (using EXTS).
Time on study will be summarized descriptively, separately for Combined and Extension Analysis 
Period as follows:

Time in study (months): descriptive statistics;

Time in study (months) by category (cumulative): frequency counts and percentages.
A KM plot for time to end of extension study will be produced for the Extension Analysis Period 
on the EXTS. Subjects complete study will be censored at the date of study completion.
Time on study information will be included in subject disposition listing(s).
5.3.
Analysis of efficacy variables
5.3.1.
Definition of Endpoint(s)
5.3.1.1.
Relapse-related variables
5.3.1.1.1.
Annualized Relapse Rate (ARR)
The ARR is defined as the number of relapses per subject-year. 
The ARR will be calculated for both confirmed relapses and for all relapses, for both the Combined 
and the Extension Analysis Periods.
To evaluate the ARR for both the Combined and the Extension Analysis Periods, the following 
variables will be derived per subject and Analysis Period:

Number of all relapses (confirmed and unconfirmed) from start date of the Analysis Period up 
to the end of Analysis Period;

Number of confirmed relapses from start date of the Analysis Period up to end of analysis;

Length of observation expressed in years, defined as: (Analysis Period end date −Analysis 
Period start date of 1) in days, divided by 365.25.

Logarithm of the length of observation during Analysis Period as derived above.


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Additionally, for the Core Analysis Period, the following ARR related variables from the core 
study will be included in the ADaM dataset as derived in the core study: 

Number of confirmed relapses from date of randomization in the core up to core EOS;

Length of observation during the core study expressed in years, defined as: [core EOS date − 
date of randomization in the core 1] in days, divided by 365.25;
Additionally, the number of confirmed relapses and length of observation time will be derived per 
24-week time period, separately for the Core and the Extension Analysis Periods, for the following 
time periods: 
Core Analysis Period

Core Week 0-24: ≥ Core Day 1 ≤ Core Day 168;

Core Week 24-48: > Core Day 168 ≤ Core Day 336; 

Core Week 48-72: > Core Day 336 ≤ Core Day 504; 

Core Week 72-96: > Core Day 504 ≤ Core Day 672; 

Core Week 96-EOS: > Core Day 672 ≤ Core EOS; 
Extension Analysis Period 

Extension Week 0-24: ≥ Extension Day 1 ≤ Extension Day 168;

Extension Week 24-48: > Extension Day 168 ≤ Extension Day 336; 

Extension Week 48-72: > Extension Day 336 ≤ Extension Day 504; 

Extension Week 72-96: > Extension Day 504 ≤ Extension Day 672; 


Extension Week 96-120: > Extension Day 672 ≤ Extension Day 840;

Extension Week 120-144: > Extension Day 840 ≤ Extension Day 1008;

Extension Week 144-168: > Extension Day 1008 ≤ Extension Day 1176;


Extension Week 168-192: > Extension Day 1176 ≤ Extension Day 1344;

Extension Week 192-216: > Extension Day 1344 ≤ Extension Day 1512;

Extension Week 216-Extension EOS: > Extension Day 1512 ≤ Extension EOS;
Core Day 1 is the date of randomization in the core study.  Extension Day 1 is the date of first 
ponesimod administration in the extension study. In the event that a subject has their core EOS 
visit date recorded after their extension treatment start date, the extension treatment start date will 
be considered to be Extension Day 1 and the core EOS will be considered to be the extension 
treatment start date minus 1 day. 
For both the core and extension studies, the number of relapses is derived according to the number 
of relapses entered on the eCRF module ‘Relapse Summary’. Whether a relapse is confirmed is 
according to the treating neurologist / principal investigator, i.e., according to the question 
‘Relapse meeting the criteria for a confirmed relapse?’ on eCRF module ‘Relapse Summary’.
Also based on the eCRF module ‘Relapse Summary’, each reported relapse episode is assessed as 
being treated with corticosteroids (as per eCRF question ‘Treatment of relapse with 
corticosteroids?’) and as leading to hospitalization (as per eCRF question ‘Did the MS relapse 
require hospitalization for reasons other than administration of IV corticosteroids?’). These relapse 


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qualifiers are solely derived from eCRF module ‘Relapse Summary’, i.e., irrespective of 
corresponding documentation in eCRF module ‘Corticosteroids for Treatment of Relapse’. 
5.3.1.1.2.
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 study + 1 in days.
Time to first (confirmed) relapse is calculated over the Combined Analysis Period only. The 
following censoring rules are applied:

Subjects who entered the extension study and remained free of relapses will be censored at 
the extension EOS date;

Subjects who prematurely discontinued from extension study and remained free of relapses 
will be censored at the date of last contact.

Subjects who did not enter the extension and ended the core study free of relapses will be 
censored at the core study EOS date;

Subjects who prematurely discontinued from core study and remained free of relapses will 
be censored at the date of last contact.
For censored subjects, the time is defined as EOS − date of randomization + 1 in days.
5.3.1.1.3.
Duration of (confirmed) relapse
Duration of (confirmed) relapse (days) is derived as (confirmed) relapse end date − relapse start 
date + 1 day. Duration of (confirmed) relapse will be set to be missing if either start date or end 
date is missing or incomplete. 
5.3.1.2.
MRI-related variables
MRI data are read centrally by Medical Image Analysis Center (MIAC) and provided to the 
sponsor. The derivation of the MRI endpoints is according to the visit identification in the MIAC 
database. 
In the core study, MRI scans are scheduled at Baseline, at the Week 60 Visit, and the Week 108 
(EOT) Visit. For subjects prematurely discontinuing treatment, an additional premature EOT visit 
MRI is scheduled. In addition, unscheduled MRI scans may be conducted any time. MRI scans are 
used as mapped in the core study, as described in the core study SAP. 
In the extension study, MRI scans are scheduled at Week 48, Week 96, Week 144, and Week 192 
Visits, and at the Week 240 EOT (for Ukraine subjects in addition at Week 288 EOT) Visit. In 
addition, unscheduled MRI scans may be conducted any time including at planned pregnancy 
interruption and re-initiation visits. 
MRI variables are based on the result from the corresponding nominal visit (or from a re-mapped 
premature EOT or pre-planned pregnancy visit. 


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5.3.1.2.1.
T1 Gd+ lesions
The following variables are derived at each scheduled visit during the Combined Analysis Period:

Total number of T1 Gd+ lesions, derived as:
Number of new T1 Gd+ lesions (T1GdNewR) + number of persisting T1 Gd+ lesions 
(T1GdR);

Total number of T1 Gd+ lesions, categorized (0, 1, 2, 3, 4, 5, 6-10, 11+). 
In addition, the following analyses will be conducted:

The cumulative number of Gd+ T1 lesions from core baseline to extension EOS and 
corresponding number of scans included will be used as derived.

Absence of Gd+ T1 lesions at each visit: ‘Gd+ T1 lesions at each visit’ are considered 
‘absent’, if the number of Gd+ T1 lesions at each visit is zero. If > 0 they are considered 
‘present’. This applies to nominal visit collected in the CRF.

Absence of Gd+ T1 lesions from Core baseline until extension EOS: Absence of new 
Gd+ T1 lesions from Core baseline to extension EOT (including all unscheduled scans) is 
defined ‘absent’ if the ‘number of new Gd+ T1 lesions’ at all post-baseline MRI scans up 
to the extension EOS is zero. This includes all scheduled and all unscheduled visits. If > 0 
at any visit it is considered ‘present’. The corresponding ‘Number of MRI scans’ and time 
to last MRI scan are derived. If no MRI result at the visit is available (based on visit 
window), the information is considered missing (for lesion free subjects).  

Total volume of T1 hypointense lesions and the change from baseline: Total volume of 
T1 hypointense lesions (mm3) (variable T1BHVOL) is recorded by the central reader at 
each visit. The change from Core baseline is derived as the change from total volume of 
T1 hypointense lesions at Core study Visit 2-Baseline. The change from Extension baseline 
is derived as the change from last available record of total of T1 hypointense lesions prior 
to Extension Baseline.

Proportion of Gd+ T1 lesions at Core Baseline evolving to persistent black holes 
(PBHs): It is the proportion (%) of ‘Number of T1 hypointense lesions (persistent black 
holes) evolved from T1 Gad.-enhancing lesion at V2 - Baseline core study’ (variable 
T1BHV2C) at each scan visit out of the ‘Number of Gd+ T1 lesions at Core baseline’.
Note: Gd+ T1 lesions are assumed to not enhance for more than 12 weeks. This requires handling 
of data as follows:

If at a visit, number of persisting T1 Gd+ lesions are not recorded, the number of Gd+T1 
lesions is the number of new T1 Gd+ lesions. Rationale: As per central reader processes 
persisting T1 Gd+ lesions are not assessed for subjects with scheduled MRIs scheduled more 
than 12 weeks apart. 

If at an MRI scan which is >12 weeks (84 days) since the last previous scheduled MRI scan a 
persisting lesion count > 0 is recorded, these persisting lesions are considered implausible 
and therefore not to be considered in derivations of total Gd+ T1 counts. 


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5.3.1.2.2.
New or enlarging T2 lesions
The following variables will be evaluated at each visit:

Total number of new or enlarging T2 lesions (relative to previous visit), derived as:
Number of new or enlarging T2 lesions without gadolinium-enhancement (T2new_R) + new 
or enlarging T2 lesions with gadolinium-enhancement (T2newGd_R);

Total number of new or enlarging T2 lesions (relative to previous visit) categorized (0, 1–
5, 6–10, 11+);

Cumulative new or enlarging T2 lesions from core baseline up to each visit up to extension 
EOS. Cumulative new or enlarging T2 lesions will not be derived if any post-baseline record 
is missing with a reason of “Dependent evaluation missing: Reference required for evaluation 
is not available (missing or rejected)” in the SDTM variable MO.MOREASND.
Where “new” refers to last prior available scheduled visit (note: planned pregnancy visits are 
considered scheduled MRIs for analysis), and specifically for evaluations at extension study Visit 
7, results are compared to Visit 14 EOT from the core study.
In addition, the follow cumulative variables are derived:
The cumulative number of new or enlarging T2 lesions from core baseline to extension EOS
is derived as the sum of number of the sum of total number of new or enlarging T2 lesions (as 
derived above) at all post-baseline MRI at all post-core baseline MRI scans up to the extension 
EOT MRI visit. This includes premature EOT scans if available, and unscheduled scans only if it 
is the last available scan for the subject. 
The time up to the last MRI (years) included in the above is derived as = Date of last MRI 
considered in derivation − core randomization date + 1 divided by 365.25 days. 
Similarly, the cumulative number of new or enlarging T2 lesions from extension baseline to 
extension EOS is derived as described above, together with the time, where time is relative to 
enrollment in the extension study.
If the baseline MRI is missing, new or enlarging T2 lesions as compared to baseline cannot be 
assessed and consequently the endpoint is considered missing. The baseline MRI is considered 
missing if presence of T1 Gd+ lesions at baseline is missing. The following analyses will be 
conducted as well:

Absence of new or enlarging T2 lesions at each visit: ‘New or enlarging T2 lesions’ are 
considered ‘absent’, if the number of New or enlarging T2 lesions at each visit is zero. If 
> 0 they are considered ‘present’. This applies to nominal visit collected in the CRF. 

Absence of new or enlarging T2 lesions from Core baseline until extension EOS:
Absence of new or enlarging T2 lesions from Core baseline to extension EOT (including 
all unscheduled scans) is defined ‘absent’ if the ‘number of new or enlarging T2 lesions’ 
at all post-baseline MRI scans up to the extension EOS is zero. This includes all scheduled 
and all unscheduled visits. If > 0 at any visit it is considered ‘present’. The corresponding 
‘Number of MRI scans’ and time to last MRI scan are derived. If no MRI result at the visit 
is available (based on visit window), the information is considered missing (for lesion free 
subjects).  


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
Total volume of T2 lesions and the change from baseline: Total volume of T2 lesions 
(mm3) (variable T2VOL) is recorded by the central reader at each visit. The change from 
Core baseline is derived as the change from total volume of T2 lesions at Core study Visit 
2-Baseline. The change from Extension baseline is derived as the change from last 
available record of total volume of T2 lesions prior to Extension Baseline.
5.3.1.2.3.
Combined unique active lesions (CUAL) and cumulative CUAL
The number of combined unique active lesions (CUAL) at each scan visit is defined as the sum of 
new T1 Gd+ lesions (T1GdNew_R) and new or enlarging T2 lesions without gadolinium-
enhancement (T2New_R) at each scan visit. Categorization of CUAL at each visit is (0, 1–5, 6–
10, 11-15, 16-20, 21-25, 26+).
The cumulative number of CUAL from core baseline to extension EOS is defined as the sum of 
new T1 Gd+ lesions (T1GdNew_R) and new or enlarging T2 lesions without gadolinium-
enhancement (T2New_R) (i.e., without double-counting the lesions) at all post-baseline MRI visits 
up to the extension EOS. This includes premature EOT scans, if available, and unscheduled scans 
only if it is the last available scan for the subject. Categorization of cumulative CUAL at each visit 
is (0, 1–5, 6–10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41+).
The cumulative number of CUAL from extension baseline to extension EOS is also derived as 
described above. 
The time up to the last MRI (years) included in the above is derived as = Date of last MRI 
considered in derivation – core randomization date / extension enrollment date + 1 divided by 
365.25 days. 
Note that CUAL will be calculated at each visit only if baseline Gd+ T1 lesions is available and 
“New or enlarging T2 lesions” is not missing at that visit. Otherwise the CUAL is set to be missing.
5.3.1.2.4.
Percent Change of Brain Volume from Baseline
Brain volume is recorded by the central reader as normalized brain volume at the baseline visit 
and at subsequent visits as a percent change relative to the value at the baseline visit. Percent 
change of brain volume from baseline to subsequent visits is not manually derived but taken 
directly from the central reader variable at the corresponding scheduled visit.
The following types of percent change of brain volume are assessed in the extension study: 
-
Percentage change of Brain Volume from Core Baseline 
-
Percentage change of Brain Volume from Extension Baseline, i.e. from Core study EOT
-
Annual percentage change of Brain Volume from Core Baseline to Core study week 108,
defined as: percentage change of MRI brain volume assessment at core study week 108 
relative to Core baseline / years-of-follow-up. Here the years-of-follow-up is: (Date of MRI 
brain volume assessment at core study week 108 – randomization date in core study +1 ) / 
365.25
-
Annual percentage change of Brain Volume from Core Baseline to extension EOS, defined 
as: percentage change of last MRI brain volume assessment relative to Core baseline / 
years-of-follow-up. Here the years-of-follow-up is: (Date of last MRI brain volume 
assessment in extension study – randomization date in core study +1 ) / 365.25.


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-
Annual percentage change of Brain Volume at any assessment by visit from Core Baseline 
to extension EOS, defined as: percentage change of last MRI brain volume assessment by 
visit relative to Core baseline / years-of-follow-up. Here the years-of-follow-up is: (Date 
of last MRI brain volume assessment of the visit in extension study – randomization date 
in core study +1 ) / 365.25.
5.3.1.3.
Neurological variables
5.3.1.3.1.
CDA: 12/24-week confirmed disability accumulation
A 12/24-week confirmed disability accumulation (CDA) is defined as a 12/24-week sustained 
increase from the core baseline EDSS score, according to the definitions described below, which 
is confirmed at a scheduled visit after 12/24 weeks. 12/24-week CDA is defined for the Combined 
Analysis Period only. 
Every EDSS score obtained (scheduled or unscheduled) within a 12/24-week window after the 
first progression should also meet the progression criteria, in order to count a subject as having 
12/24-week CDA. The 12/24-Week CDA progression starts on the day of the first sustained 
increase of EDSS after core baseline. 
Core baseline EDSS is defined as the last available EDSS score prior to or on the date of 
randomization.
In the core study, disability as measured by EDSS is assessed in all subjects at Screening, Baseline, 
and thereafter at scheduled visits every 12 weeks until the end of study. Additional EDSS 
assessments for individual subjects may have been conducted between scheduled visits (i.e., during 
an MS relapse).
In the extension study, disability as measured by EDSS is assessed in all subjects at enrollment 
and thereafter at scheduled visits every 12 weeks until the end of study, as well as at unscheduled 
visits (during an MS relapse or at any time during the study based on the judgment of the 
investigator).
CDA is defined as:

Sustained increase of at least 1.5 in EDSS for subjects with a core baseline EDSS score of 0,

Sustained increase of at least 1.0 in EDSS for subjects with a core baseline EDSS score of 1.0 
to 5.0,

Sustained increase of at least 0.5 in EDSS for subjects with a core baseline EDSS score ≥5.5,
confirmed after 12 or 24 weeks.
Disability progression can only be confirmed at a scheduled visit, where the EOT and EOS visits 
count as scheduled visits and can only be confirmed in the absence of a relapse.
Steps to determine 12/24-week CDA
1. All valid post-baseline EDSS assessments (scheduled or unscheduled) will be compared to 
baseline to assess if the absolute change from baseline meets the CDA criteria, described 
above. Take the first absolute change from core baseline that meets the criteria for EDSS 
increase. Onset date of the corresponding potential 12/24-week CDA is the EDSS assessment 
date.
2. Confirmation of the 12/24-week CDA: 


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a.
The CDA is confirmed ≥ 70/154 days, respectively for 12/24-week CDA, from the onset 
date of the progression (based on 84 days between assessments and ± 7 days of visit 
windows for 12-week CDA, so 84 days - two times 7-day visit time window, and based on 
168 days between assessments - two times 7-day visit time window for 24-week CDA);
b. The EDSS assessments conducted during a relapse, i.e. from relapse start date (inclusive) 
to minimum of relapse end date and relapse start date + 90 days (exclusive) are not 
considered for confirmation;
c.
Every EDSS score available (scheduled or unscheduled) between the CDA onset and the 
confirmation visit will be checked. If all EDSS scores meet the CDA criteria, the subject 
will be considered to have a 12/24-week CDA. If any EDSS within this period does not 
meet the CDA criteria, the CDA cannot be confirmed;
d. If a subject dies due to MS during the study, he/she will be considered as having a 12/24-
week CDA with onset date being date of death. Deaths of subjects that are not study related 
will be censored, as described below.
3. The algorithm should check all possible onsets of a 12/24-week CDA for each subject, starting 
with the first possible onset, by date, up to the last possible onset. If at some time point a 12/24-
week CDA is confirmed, the algorithm can stop and proceed with the next subject. If at none 
of the assessments a 12/24-week CDA could be confirmed, the subject is considered as not 
having 12/24-Week CDA. This subject will be censored according to the below rules. Subjects 
with a 12/24-Week CDA will be considered as having an event (‘0’), censored subjects as 
having no event (‘1’).
Handling of missing dates 
Missing dates for EDSS assessments will be imputed as follows:

Partial date: Maximum of ‘lower limit’, ‘previous scheduled EDSS assessment according to 
the visit label’ + 1 day (if available), and ‘randomization date’

Missing date: do not impute and exclude from analysis/
See Section 6.13 for further details on handling missing dates.
Missing dates for relapse start and end dates will be handled as follows:

Partial or missing relapse end date with available relapse start date: use relapse start date + 90 
days or upper limit of partial end date if earlier.

Partial relapse start date: If only day is missing, consider the relapse has started on the last day 
of the month (or on relapse end date − 1 day if earlier) and ended 60 days later or at (upper 
limit of a partial) relapse end date, if earlier. If the month or year are missing the relapse does 
not lead to non-consideration of an EDSS assessment.

Missing relapse start date: Corresponding relapse does not lead to non-consideration of an 
EDSS assessment. Do not consider imputed relapse start dates.


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5.3.1.3.2.
Time to first 12 or 24-week CDA
Time to first 12- or 24-week CDA is defined as start date of the first 12- or 24-week CDA −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 without an EDSS increase for subjects without a CDA (as 
defined above) −date of randomization in the core study + 1.
Subjects without post baseline assessment (without EDSS increase) are censored on randomization 
date. For subjects without baseline EDSS score missing values are assigned.
5.3.1.3.3.
Change from baseline in EDSS 
Absolute change from baseline in EDSS score by visit is derived, based on the overall EDSS score 
as reported by the investigator in the eCRF. 

The change from baseline in EDSS score will be calculated both for the Combined and the 
Extension Analysis Periods, using the core baseline for the Combined Analysis Period and the 
extension baseline for the Extension Analysis Period. 
5.3.1.4.
Other efficacy variables
5.3.1.4.1.
NEDA-3 status up to extension EOS
No evidence of disease activity (NEDA)-3 up to extension EOS is defined by the absence of 
confirmed relapse, Gd+ T1 lesions, new or enlarging T2 lesions, and 12-week CDA. If at least one 
of the criteria is not fulfilled or the subject discontinues treatment prematurely, the subject is not 
considered to have achieved NEDA-3.
Derivation details
A subject is considered as having evidence of disease activity if at least one of the following 
applies:

Any confirmed relapse up to extension EOS.  

Presence of Gd+ T1 lesions during the course of study until extension EOS.

Presence of new or enlarging T2 lesions during the course of study until extension EOS. 

Any 12-week CDA up to extension EOS.
Subjects that discontinue treatment prematurely are considered as showing evidence of disease 
activity, irrespective of what the reason for treatment discontinuation is.   
Subjects without evidence of disease activity as defined above, who have missing outcome for any 
component (absence of confirmed relapse up to extension EOS, absence of new Gd+ T1 lesions 
from Core baseline to Extension EOS, absence of new or enlarging T2 lesions from Core baseline 
to Extension EOS) are considered to have missing outcome for NEDA-3.   
5.3.1.4.2.
NEDA-4 status up to extension EOS
No evidence of disease activity (NEDA)-4 up to EOS is defined by the absence of confirmed 
relapse, Gd+ T1 lesions, new or enlarging T2 lesions, 12-week CDA until EOS, and absence of 


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annual brain volume decrease ≥ 0.4% at all assessments from Core Baseline up to Extension EOS. 
If at least one of the criteria is not fulfilled or the subject discontinues treatment prematurely, the 
subject is not considered to have achieved NEDA-4.
Derivation is as for NEDA-3, but in addition a subject is considered as having evidence of disease 
activity if the following applies:

Annual brain volume at any assessment from core baseline to extension EOS decrease ≥ 
0.4%. The annual brain volume change is defined in Section 5.3.1.2.4. If at any visit the 
percentage change is <= -0.4% then the criteria “Annual brain volume decrease ≥ 0.4%” is 
met
5.3.1.4.3.
Change in Multiple Sclerosis Functional Composite (MSFC) Z-score 
from baseline by visit up to Extension EOS
The Multiple Sclerosis Functional Composite (MSFC) score consists of 3 clinical examinations: 
Timed 25-Foot Walk, 9-Hole Peg Test (9-HPT), and Paced Auditory Serial Addition Test 
(PASAT-3” version). 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 pre-randomization (3 tests conducted on 3 days apart, where the first 
2 are considered practice tests) and at post-baseline Visits as scheduled in the protocol.
For each assessment, the MSFC score will be calculated as the mean of the Z-scores of the 
3 components: 
(1) Timed 25-Foot Walk (T25FW) score (s)
(2) 9-Hole Peg Test (9-HPT) score (s)
(3) Paced Auditory Serial Addition Test (PASAT-3) score (Number correct).
Details for generating the MSFC Z-score and how to handle missing data are given in 
Section 6.14.1.
For analysis, baseline and nominal post-baseline visits are considered. See Section 5.1.10 for 
remapping of premature end of treatment or unscheduled visits (includes unscheduled visits due 
to relapse). 
Baseline is defined as the last available MSFC score prior to or on randomization date. While this 
should usually present the subject’s 3rd test, if that is missing, results from the practice test may be 
used. A flag is added indicating the number of tests conducted up to the baseline test inclusive. 
5.3.1.4.4.
Change in the symbol digit modalities test (SDMT) score from 
baseline by visit up to Extension EOS
The symbol digit modalities test (SDMT) measures attention and processing speed much like the 
PASAT. It is administered along with the MSFC at pre-randomization (3 tests, where the first 2 are 
considered practice tests) and at post-baseline visits as scheduled.


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For analysis, baseline and nominal post-baseline visits are considered. See Section 5.1.9 for 
remapping of premature end of treatment or unscheduled visits. 
Baseline is defined as the last available SDMT score prior to or on randomization date. While this 
should usually present the subject’s 3rd test, if that is missing results from the practice test may be 
used. A flag is added indicating the number of tests conducted up to the baseline test inclusive.
5.3.2.
Analysis Methods
5.3.2.1.
Statistical methodology 
5.3.2.1.1.
Statistical methodology for count data
Count data will be analyzed assuming data is negative binomially (NB) distributed. 
A generalized linear model with NB distribution will be assumed.
tj
denotes the length of observation (time in study) for subject j.
Yj
denotes the number of relapses for subject j during tj.
µj 
denotes the mean of the NB distribution of Yj.
The mean for the distribution of the ARR for subject j, denoted by µj /tj, will be modeled by the 
following equation: 


θ
x j
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.
The SAS code for the NB model is as follows:
proc genmod data=ADREL;
     model relnum_r = / dist=negbin link=log offset = log(Time);
run;
If the model does not converge the Poisson distribution will be used instead of the negative 
binomial distribution.
5.3.2.1.2.
Statistical methodology for time to event data
The analysis of time-to-event data are conducted using Kaplan-Meier (KM) estimates of events 
over time. Estimates of the event rate are obtained for each study treatment group using the KM 
method as implemented in SAS proc lifetest. The reference time is the study day, i.e., days elapsed 
since first treatment. The KM estimates at different time points are plotted together with the 95% 
two-sided confidence limits (CLs), calculated using Greenwood’s formula for the estimate of the 
standard error. Intervals will be displayed by 24 weeks up to last available time point.
The SAS code for the KM analysis is as follows:
proc lifetest data= method=KM; 
   time survtime*censor(1);
run;


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5.3.2.2.
Analysis of relapse-related variables
5.3.2.2.1.
Main analysis of ARR
The main statistical analysis will be performed on the FAS and EXTS using all data in the 
Combined Analysis Period. The model described in Section 5.3.2.1 for confirmed relapses will be 
used, with core study treatment as a factor and the logarithm of time in study (in years) from 
randomization up to the end of the Combined Analysis Period as an offset variable. ARR will be 
summarized descriptively by core treatment group in a table for confirmed relapses as follows:

Number of confirmed relapses per subject: descriptive statistics;

Number of confirmed relapses per subject: frequency counts and percentages for categories 0, 
1, 2, 3, 4, 5-10 and 11+;

Total number of confirmed relapses: frequency count:

Total time in study (subject years): sum;

Raw ARR: total number of confirmed relapses / total time in study.
Mean model-based estimates of the ARR (for confirmed relapses), by core study treatment group, 
as well as 95% CIs will be presented. A rate ratio comparing ponesimod with teriflunomide 14 mg 
will be derived from the model including 95% CIs. 
The fit of the model will be assessed and other distributions such as the Poisson distribution will 
be considered in case of a lack of fit.
5.3.2.2.2.
Additional analyses of ARR
All relapses will be analyzed for the Combined Analysis Period on the FAS and EXTS as described 
in Section 5.3.2.1.1, i.e., including the first summary table described (and adding the ARR estimate 
and 95% CI from a NB model). 
This approach will also be used to analyze confirmed relapses on:the Extension Analysis Period 
using the EXTS and the EXTS and for all relapses on:

the Extension Analysis Period using the EXTS; 
with the logarithm of the appropriate observation time during the related period as an offset 
variable. 
Additionally, for confirmed relapses, the ARR estimate and 95% CI from a Poisson model (as the 
NB model is not expected to converge for all time periods) will be determined by 24-week period 
(as defined in Section 5.3.1) using FAS and EXTS as follows. The log of observational time during 
each interval will be used as offset.

Core Analysis Period (core weeks 0-24, 24-48, 48-72, 72-96, 96-core EOS);

Extension Analysis Period (extension weeks 0-24, 24-48, 48-72, 72-96, 96-120, 120-144, 144-
168, 168-192, 192-216, 216-Extension EOS).
A line plot will be created to present the ARR estimate and the corresponding 95% CI by 24 weeks 
period.


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Relapse characteristics will be summarized using descriptive statistics for the Combined Analysis 
Period on the FAS and for the Extension Analysis Period on the EXTS. This includes the 
following: 

Number (%) of subjects with at least one: relapse, relapse requiring hospitalization, relapse 
treated with corticosteroids; for all relapses up to EOS/cut-off and for confirmed relapses up 
to EOS/cut-off. 

Number (%) of relapses (out of total number of relapses) requiring hospitalization, treated with 
corticosteroids and descriptive statistics for continuous data for relapse duration (days); for all 
relapses up to EOS as well as for confirmed relapses up to EOS. 
Full details of all relapses will be presented in a listing.
5.3.2.2.3.
Time to first (confirmed) relapse
The analysis of time from randomization in the core study to first confirmed relapse during the 
Combined Analysis Period (up to EOS/cut-off for subjects entering the extension study or up to 
core EOS for subjects not entering the extension study) will be performed on the FAS and EXTS
using KM methods. 
Time to first confirmed relapse will be summarized on the FAS in a table including, the number 
of subjects with event / censored, KM estimates and corresponding CI (anticipated time points of 
24-week intervals: 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264 and 288 weeks), and median 
(as well as 25th and 75th percentiles) of the survival function together with CIs. A graphical display 
presenting a KM plot going upward is presented, including CIs at specific time points. Intervals 
will be displayed 24 weeks up to the last time point.
Censoring rules are defined in Section 5.3.1.1.2. The analysis will be repeated for time to first 
relapse including all relapses. 
Time to first relapse and time to first confirmed relapse data will be listed using the FAS.
5.3.2.3.
Analysis of MRI-related variables
5.3.2.3.1.
T1 Gd+ lesions
The total number of Gd+ T1 lesions per visit will be summarized descriptively as continuous data 
and in categories (anticipated categories: 0, 1, 2, 3, 4, 5, 6-10, 10+), for the Combined Analysis 
Period on the EXTS. 
Descriptive statistics on absence of Gd+ T1 lesions (frequency and percentages of subjects with 
lesions absent, present) will be presented by visit, and cumulative for absence of Gd+ T1 lesions 
from Core baseline up to extension EOT will be tabulated. This analysis will be done for combined 
period using EXTS.
The total number of Gd+ T1 lesions will be analyzed by visit for the Combined Analysis Period 
on the EXTS using a negative binomial regression model: the response variable is the number of 
lesions at the respective visit, with core study treatment as a factor and no offset. Mean model-
based estimates and corresponding 95% CIs will be presented. The corresponding plots will also 
be presented.


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Total volume of T1 hypointense lesions and the change from core baseline per visit is summarized 
descriptively based on observed data, for combine analysis period using the EXTS. In addition, 
total volume of T1 hypointense lesions and the change from extension baseline per visit is 
summarized descriptively for extension period using EXTS. The total volume of T1 hypointense
lesion data will be listed using FAS.
Descriptive statistics of the proportions of Gd+ T1 lesions at core baseline evolving to persistent 
black holes will be presented by visit in the subset of subjects with Gd+ T1 lesions present at 
baseline using the EXTS for combined period. Same analysis in relative to extension baseline (i.e. 
Core study EOT) will be repeated using EXTS during extension period. A listing will be prepared 
using the FAS. 
Gd+ T1 lesions data will be listed on the FAS. 
5.3.2.3.2.
New or enlarging T2 lesions
The total number of new or enlarging T2 lesions per visit will be summarized descriptively as 
continuous and in categories (anticipated categories: 0, 1, 2, 3, 4, 5, 6-10, 11+), for the Combined 
Analysis Period on the EXTS. 
The cumulative number of new or enlarging T2 lesions from core baseline up to extension EOS
(Combined Analysis Period) (i.e. from baseline up to extension EOS) will be analyzed on the 
EXTS using a negative binomial regression model with core study treatment as a factor and the 
log of time up to last MRI (in years) considered for analysis as an offset variable. Mean 
model-based estimates and corresponding 95% CIs will be presented. The same model is applied 
for extension period on the EXTS.
Descriptive summary statistics for the cumulative number of new or enlarging T2 lesions from 
core baseline up to extension EOS on the EXTS will be presented by treatment group for 
continuous data and frequency per categories (anticipated: 0, 1–5, 6–10, 11-20, 20+), total counts 
and total cumulative observation time (time up to the last MRI scan in years) summed for all 
subjects, raw yearly rate (total count / total cumulative observation time). Descriptive summary 
statistics for the cumulative number of new or enlarging T2 lesions from extension baseline up to 
extension EOS on the EXTS will be presented in the same way.
Descriptive statistics on absence of new or enlarging T2 lesions by visit (frequency and 
percentages of subjects with lesions absent, present) will be presented by visit, and cumulative for 
absence of new or enlarging T2 lesions from Core baseline up to extension EOS will be tabulated.
This analysis will be done for combined period using EXTS. 
The total number of new or enlarging T2 lesions will be analyzed by visit for the Combined 
Analysis Period on the EXTS, using the negative binomial model, as described in Section 5.3.2.3.1, 
for the total number Gd+ T1 lesions per visit. The corresponding plots will also be presented.
Total volume of T2 lesions and change from baseline per visit is summarized descriptively based 
on observed data, for combine analysis period using the EXTS. Same analysis will be repeated 
using EXTS relative to Extension baseline during Extension period. The total volume of T2 lesion 
data will be listed using FAS.
T2 lesion data will be listed on the FAS.


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5.3.2.3.3.
Combined unique active lesions (CUAL)
The total number of CUAL lesions at Week 60 and at Week 108 of the core study, and Week 48, 
Week 96, Week 144, Week 192, Week 240, Week 288 and EOT of the extension study, will be 
analyzed by visit for the Combined Analysis Period on the FAS and EXTS, using the negative 
binomial model: the response variable is the number of CUAL at respective visit, with study 
treatment at core baseline as a factor and no offset. Model based estimates and the corresponding 
95% CI will be tabulated. The corresponding plots will also be presented.
The total number of CUAL per visit will be summarized descriptively as continuous and in 
categories (anticipated categories: 0, 1–5, 6–10, 11-15, 16-20, 21-25, 26+), for the Combined 
Analysis Period on the FAS and EXTS.
The cumulative number of CUAL will be analyzed using a negative binomial regression model,
similar as described in Section 5.3.2.3.2 for the cumulative number of new or enlarging T2 lesions, 
but using log of the total years from core baseline to last MRI scan as offset variable. CUAL will 
be analyzed from:

Core baseline up to extension EOS (Combined Analysis Period) using EXTS;

Extension baseline up to extension EOS (Extension Analysis Period) on the EXTS;
Descriptive summary statistics of the number of CUALs from core baseline up to extension EOS
(Combined Analysis Period) using EXTS will be presented for continuous data and in categories 
(0, 1–2, 3–5, 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41+). The total number of CUALs 
as well as the total cumulative time up to the last MRI scan (summed for all subjects) will also be 
displayed. From the total number of CUALs and the total cumulative time up to the last MRI scan 
the raw number of CUALs per year will be calculated and summarized. Descriptive summary 
statistics for the number of CUALs from extension baseline up to extension EOS (Extension 
Analysis Period) on the EXTS will be presented in the same way.
In addition, the cumulative CUAL up to each visit during combined analysis period will be 
analyzed on FAS and EXTS using a negative binomial regression model, similar as described in 
Section 5.3.2.3.2 for the cumulative number of new or enlarging T2 lesions, but using log of  the 
total years from core baseline to last MRI scan as offset variable. Model based estimates and the 
corresponding 95% CI will be tabulated.  The corresponding plots will also be presented.
A listing of CUAL data will be presented using FAS.
5.3.2.3.4.
Percent Change of Brain Volume from Baseline
PCBV from Core Baseline to Extension EOT will be summarized using descriptive statistics by 
visit based on observed data and listed using the FAS and EXTS.
PCBV from Core study EOT to Extension EOT will be summarized using descriptive statistics by 
visit based on observed data and listed using the EXTS.
Number and percentage of subjects with annual change from Core Baseline to Extension EOT in 
PCBV <= -0.4% will be summarized by visit using EXTS.
Number and percentage of subjects with annual change from Core study EOT to to Extension EOT 
in PCBV <= -0.4% will be summarized by visit using EXTS.


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5.3.2.4.
Analysis of neurological variables
5.3.2.4.1.
Analysis of disability progression (12/24-week CDA)
The analysis of time from core study baseline to confirmed first 12- and 24-week CDA will be 
summarized in a similar manner to the time to first relapse variable, for the Combined Analysis 
Period, using FAS and EXTS.
A listing with 12/24-week CDA results will be produced.
5.3.2.4.2.
Change in EDSS from baseline by visit up to EOS
The EDSS score and change from baseline in EDSS score by visit and core study treatment group 
will be summarized using descriptive statistics on the EXTS for the Combined Analysis Period as 
well as on the EXTS for the Extension Analysis Period. Mean changes from core baseline in EDSS
score are also presented graphically with their standard error over time (plots starting with zero 
change at baseline), for the Combined Analysis Period on the EXTS.
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.
A listing(s) of EDSS / functional system (FS) scores will be produced. 
5.3.2.5.
Analysis of other efficacy variables
5.3.2.5.1.
NEDA-3 status up to EOS 
Descriptive statistics of NEDA-3 status (Yes, No, Missing) up to Extension EOS including its 
components ([i] Presence of confirmed relapse, [ii] Presence of Gd+ T1 lesions, [iii] Presence of 
new or enlarging T2 lesions, [iv] 12-week CDA event, or [v] premature treatment discontinuation) 
will be presented using the EXTS. A listing will be prepared. 
5.3.2.5.2.
NEDA-4 status up to EOS 
NEDA-4 status up to Extension EOS will be analyzed in the same way as NEDA-3 status on the 
EXTS.
5.3.2.5.3.
Change in MSFC Z-score from baseline by visit up to Extension EOS 
MSFC Z-score as well as its subcomponents scores and changes from core baseline will be 
descriptively summarized for each treatment group by visit on the EXTS. Mean change (± SE) 
over time will be graphically presented by treatment group. Same analysis relative to extension 
baseline will be done on the EXTS during extension period. A listing will be prepared. 
5.3.2.5.4.
Change in the SDMT score from baseline by visit up to Extension 
EOS 
SDMT scores and change from baseline will be descriptively summarized for each treatment group 
by visit on the EXTS. Mean change (± SE) over time will be graphically presented by treatment 
group. Same analysis relative to extension baseline will be done on the EXTS during extension 
period. A listing will be prepared. 


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5.4.
Safety Analyses
All safety analyses will be based on the safety analysis set based on actual intervention received.
Safety summaries for each analysis period will be based on the safety analysis sets described in 
Section 4, unless otherwise specified.
For all continuous safety variables, descriptive statistics by intervention group will include the N, 
mean, standard deviation, median, minimum, and maximum. To convey the uncertainty associated 
with the summary statistics, the line plots will incorporate standard error (defined as sample 
standard deviation divided by the square root of sample size) for continuous variables. Categorical 
variables will be summarized by intervention group using frequency counts and percentages.
5.4.1.
Extent of Exposure
5.4.1.1.
Definition of extent of exposure
5.4.1.1.1.
Exposure (Time on treatment)
The following variables are defined for exposure during the Extension Analysis Period: 
Duration of exposure to ponesimod in the extension (months) excluding interruptions is 
defined as the time elapsed between (the date of first study drug intake in the extension study and
date of last study drug intake in the extension study + 1) × 12 / 365.25, excluding any temporary 
treatment interruptions. 
Duration of exposure to ponesimod in the extension (months) is defined as the time elapsed 
between (the date of first study drug intake in the extension study and  the date of last study drug 
intake in the extension study + 1) × 12 / 365.25, independent of any treatment interruptions (except 
for treatment interruption due to planned pregnancy).
In addition, the duration of exposure as derived above for each subject is categorized as follows:

≥ 1 day and ≤ 6 months;

> 6 months and ≤ 12 months;

> 12 months and ≤ 18 months;

> 18 months and ≤ 24 months;

> 24 months and ≤ 30 months;

> 30 months and ≤ 36 months;

> 36 months and ≤ 42 months;

> 42 months and ≤ 48 months;

> 48 months and ≤ 54 months;

> 54 months and ≤ 60 months;

> 60 months.
The following variables are defined for exposure to ponesimod treatment during the Combined 
Analysis Period, for subjects randomized to ponesimod in the core study only: 
Combined duration of exposure to ponesimod (months) excluding interruptions is defined as 
the time elapsed between [the date of first ponesimod intake in the core study and the date of last 


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ponesimod intake in the extension study + 1 (in days)] × 12 / 365.25, excluding any temporary 
treatment interruptions. 
Combined duration of exposure to ponesimod (months) is defined as the time elapsed between 
[the date of first ponesimod intake in the core study and the date of last ponesimod intake in the 
extension study + 1 (in days)] × 12 / 365.25, independent of any treatment interruptions (except 
for treatment interruption due to planned pregnancy).
In addition, the combined duration of exposure for each subject is categorized as follows:

≥ 1 day and ≤ 6 months;

> 6 months and ≤ 12 months;

> 12months and ≤ 18 months;

> 18 months and ≤ 24 months;

> 24 months and ≤ 30 months;

> 30 months and ≤ 36 months;

> 36 months and ≤ 42 months;

> 42 months and ≤ 48 months;

> 48 months and ≤ 54 months;

> 54 months and ≤ 60 months;

> 60 months and ≤ 66 months;

> 66 months and ≤ 72 months;

> 72 months and ≤ 78 months;

> 78 months and ≤ 84 months

> 84 months
5.4.1.1.2.
Compliance with study treatment
Compliance is calculated as a percentage as:
Ponesimod exposure during the Analysis Period excluding interruptions / Ponesimod exposure 
during the Analysis Period independent of interruptions (except for treatment interruption due to 
planned pregnancy as defined above) × 100.
Compliance as derived above is categorized as < 80%, ≥ 80 – < 90 %, ≥ 90 – < 95 %, ≥95- <100%, 
100% and >100%.
5.4.1.1.3.
Treatment duration (days with intake documented) during up-titration 
period (extension study)
The number of days with intake documented is based on entries on the eCRF ‘Up-titration 
Summary’ and/or ‘Up-titration Ponesimod’.
For subjects where the investigator confirmed the up-titration has been conducted as planned, the 
‘Up-titration Summary’ eCRF is filled out, collecting only start and end date of the entire titration 
period without collecting ‘number of tablets taken’. In that case the ‘Number of days with intake 
documented’ is derived and considered to be ‘titration end date - titration start date + 1 day’.
For all other subjects, information is collected on the ‘Up-titration Ponesimod’ eCRF, ‘Intake date’
resulting in potentially multiple records of up-titration drug intake (collecting in addition ‘number 


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of tablets taken’). In that case, ‘Number of days with intake documented’ for each record is derived 
in the same way as during the maintenance period.
5.4.1.1.4.
Treatment duration (days with intake documented) during 
maintenance period (extension study)
Per protocol, one tablet of study drug is to be taken per day. On the ‘Maintenance Ponesimod’
eCRF log form, each record collects ‘Treatment start date’, ‘Treatment end date’, ‘Daily Dose’
(Default value 20 mg – Maintenance), and ‘Total number of tablets taken’. If, for a record, the 
‘Number of tablets taken’ is ≤ ‘Treatment end date’ −‘Treatment start date’ + 1, it is assumed that 
the ‘Number of tablets taken’ represents the ‘Number of days with intake documented’ during that 
record’s period of study drug intake. If, for a record, the ‘Number of tablets taken’ is > ‘Treatment 
end date’ −‘Treatment start date’ + 1, ‘Number of days with intake documented’ is set to 
‘Treatment end date’ −‘Treatment start date’ + 1. These subjects are flagged as having taken > 1 
capsule per day on at least one occasion.
5.4.1.1.5.
Study treatment completion/discontinuation 
Discontinuation from study treatment in the core study is used as derived in the core study. See 
the core study SAP for details. 
Study treatment discontinuations in the extension study are collected on the extension eCRF page 
‘Premature Discontinuation of Study Treatment’.
A premature permanent treatment discontinuation in the extension study is defined as permanently 
stopping treatment prior to the extension EOT visit (Week 240/Week 288 for those Ukraine 
subjects, or at the time ponesimod is commercially available for treatment of MS in the subject’s 
country, whichever occurs first). 
Reasons for premature treatment discontinuation in the extension study are as follows:

Death;

Lost to follow-up;

Pre-specified study treatment discontinuation criteria;

Subject decision (further split into: Adverse event, Lack of efficacy, No reason provided,
Other);

Physician decision (further split into: Adverse event, Lack of efficacy, Other);

Sponsor decision (further split into: Study termination, Other).
Study treatment completion records are collected on the extension eCRF page “Maintenance 
Ponesimod” where fields “Completed as per protocol” or “Approved Drug Available For
Indication” are entered. 
5.4.1.1.6.
Study treatment interruptions
Study treatment interruptions in the core study is used as derived in the core study.
Temporary treatment interruptions refer to any period of time between a temporary study treatment 
end date and subsequent study treatment start date during which the subject did not receive study 
treatment. When considering the Combined Analysis Period, the time between end of treatment in 
the core study and start of treatment in the extension study is also a treatment interruption. The 
cumulative duration of all such treatment interruptions is derived for each subject. 


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In addition, for each subject, the number of interruptions > 3 days is counted. 
5.4.1.1.7.
Re-initiation of ponesimod
Re-initiations during the extension study are defined as any up-titration in the study drug log with 
a treatment gap of > 3 days before the start of new up-titration regimen. In case of an interrupted 
up-titration during a re-initiation, followed by another re-initiation, the subject is considered as 
having two re-initiations. Interruptions of > 3 days without new up-titration regimen are not 
counted as re-initiations, but will be flagged in the data. All relevant re-initiation information will 
be included in the exposure (ADEX) domains.
Re-initiations during the core study are used as derived in the core study ADaMs and not re-
derived. 
The first administration of ponesimod at the start of the extension study is not considered to be a 
re-initiation.
5.4.1.1.8.
Study completion/discontinuation
Study discontinuation/completion in the core study is used as derived in the core study. See the 
core study SAP for details.
For an individual subject, extension EOS is reached when treatment has been 
completed/discontinued and safety follow-up (FU) has been completed. Thus, a subject is 
considered to have completed the study per protocol if they perform the EOS visit as scheduled 
(30–44 days after the permanent discontinuation of study treatment), even if they prematurely 
discontinued from study treatment. However, study withdrawal can happen at any time between 
premature treatment discontinuation/completion and the EOS/FU assessment. Such subjects are 
considered to have discontinued from the study, even if they completed treatment. Reasons for and 
date of study discontinuation are captured on the eCRF page “Study Discontinuation”.
Possible reasons for study withdrawal are as follows:

Death;

Lost to follow-up;

Subject decision/ withdrawal of consent (further split into: Adverse event, Lack of efficacy, 
No reason provided, Other);

Physician decision (further split into: Adverse event, Lack of efficacy, Other);

Sponsor decision (further split into: Study termination, Other).
5.4.1.2.
Analysis of extent of exposure
5.4.1.2.1.
Exposure
Exposure to ponesimod treatment will be summarized descriptively, both for the Combined 
Analysis Period using the FAS (only for subjects included in the SAF who were initially treated 
with ponesimod 20 mg in the core study) and for the Extension Analysis Period by core study 
treatment group and overall, using the EXTS, as follows:

Treatment exposure (months): descriptive statistics;

Treatment exposure (months) by category (cumulative): frequency counts and percentages;

Total subject years exposure


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
Treatment exposure (months) excluding interruptions: descriptive statistics;

Cumulative duration of interruptions: descriptive statistics; 

Number of treatment interruptions > 3 days: frequency;

Number of subjects with at least 1 treatment interruption > 3 days: frequency counts and 
percentages;

Number of subjects with at least 1 treatment re-initiation: frequency counts and percentages;

Number of subjects with at least 2 treatment re-initiation: frequency counts and percentages;
5.4.1.2.2.
Compliance with study treatment
Compliance with ponesimod treatment is summarized using descriptive statistics for continuous 
and categorical data both for the Combined Analysis Period using the FAS (only for subjects 
included in the SAF who were initially treated with ponesimod 20 mg in the core study) and for 
the Extension Analysis Period by core study treatment and overall, using the EXTS. Exposure and 
compliance are also presented in a subject data listing.
5.4.2.
Adverse Events
5.4.2.1.
General consideration in adverse events
An AE is any event reported by the investigator on the Adverse Event eCRF. 
AEs that started in the core study and were still ongoing on Day 1 of the extension study are 
reported in the ‘Ongoing Adverse Events from AC-058B301’ extension eCRF form. If the event 
worsened in intensity/seriousness after start of study treatment in the extension study, such an 
event was reported in the usual Adverse Event eCRF Form.
All AEs are coded using the MedDRA dictionary (version 26.0).
For the summaries on the Combined Analysis Period, AEs from core and extension study 
(specifically AEs included in the extension eCRF as ‘ongoing’ from the core study and the original 
AEs included in the core eCRF) will be merged using a dedicated ID linking variable included in 
the related SDTM datasets. The following rules will be used by merging the SDTM datasets:

If information regarding the seriousness of an ongoing AE is inconsistent between the two 
databases, the AE is conservatively considered to be serious;

The outcome as entered in extension study will be used for the analysis;

If the action taken for an ongoing AE is given as temporarily interrupted in the core study 
database, and the action taken is missing, none, not applicable, or unknown in the extension
study database, then the value from the core will be retained. For all the other cases the action 
taken as entered in extension study will be used for the analysis;

If an event entered on the form “Ongoing adverse events from AC-058B301” eCRF page in 
the extension, this AE will not be considered as treatment-emergent with respect to the 
Extension Analysis Period, and no dates or other variables will be imputed if missing or partial. 
Such events will appear in listings only. 
For the Combined Analysis Period, cumulative data such as AEs and SAEs will only be 
summarized for subjects initially treated with ponesimod 20 mg in the core study.


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5.4.2.2.
Analysis variables in AE
5.4.2.2.1.
Frequency of adverse events and AEs per 100 subject-years
AEs are summarized according to both frequency (number of subjects and percentages) and AEs 
per 100 subject-years (number of events and rate) and based on various grouping terms (for 
example MedDRA preferred term, or MedDRA primary system organ class). 
For frequency of subjects experiencing an AE, AEs reported more than once for a subject within 
the Analysis Period (based on grouping term) are counted only once per subject. 
AEs per 100 subject-years = Total cumulative number of events during the Analysis Period / 
Cumulative observation time in the treatment-emergent period over all subjects (100 years) per 
grouping term.
For total cumulative number of events, multiple records of the same MedDRA preferred term in 
the AE dataset for the same subject count as individual events (episodes of the same type of event) 
unless they have the same start date and, if available, time. 
The observation time (in days) per subject for summaries of treatment-emergent AEs is calculated 
as: 

minimum (extension EOT + 15, extension EOS) - ponesimod start date in the extension study 
+ 1, for the Extension Analysis Period;

minimum (extension EOT + 15, extension EOS) – ponesimod treatment start date in the core 
study +1, for subjects in the Combined Analysis Period who had entered extension study. 

minimum (core EOT + 15, core EOS) – ponesimod treatment start date in the core study +1, 
for subjects in the Combined Analysis Period who did not enter extension study. 
5.4.2.2.2.
Treatment-emergent adverse events
Treatment-emergent adverse events (TEAEs) are defined as AEs occurring from start of treatment 
up to treatment end date + 15 days.
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.
AEs with completely missing start date will be considered treatment-emergent. If it is not clear 
whether the event is treatment-emergent or not (in case of partial dates), the event will be 
considered treatment-emergent (e.g., start date of AE is documented in the database as May 2016 
and treatment start date 23 May 2016, see definition of handling of missing data in Section 6.13.3).
Extension study day of onset
Study day of onset (relative to the start of the extension study) is derived for all TEAEs in the 
Extension Analysis Period. 
TEAEs on Day 1 of re-initiation of ponesimod treatment are those AEs that start at or after the 
time of the first administration of ponesimod on Day 1 of the re-initiation after study drug 
interruption, and before the following calendar date. Day of onset relative to the start of a re-


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initiation is derived for all treatment-emergent adverse events in the Extension Analysis Period in 
the same way as described above for extension study day of onset. 
AE duration (days)
AE duration in days is derived for all treatment-emergent adverse events with complete start and 
end dates only as AE end date − AE start date + 1. Furthermore, duration of AE is derived only if 
both start date and end date are complete.
5.4.2.2.3.
Serious adverse events
An AE is considered to be an SAE if the field “Serious?” is answered “Yes” in the eCRF module 
‘Adverse Event’, in case information on seriousness is missing, the AE is conservatively 
considered to be serious.
5.4.2.2.4.
Adverse events leading to permanent discontinuation of study 
treatment
An AE is considered to be an AE leading to discontinuation if the field “Action taken with study 
drug” is answered “Permanently discontinued” in the eCRF module ‘Adverse Event’.
5.4.2.2.5.
Adverse events leading to temporary interruption of study treatment
An AE is considered to be an AE leading to discontinuation if the field “Action taken with study 
drug” is answered “Temporarily interrupted” in the eCRF module ‘Adverse Event’.
5.4.2.2.6.
Adverse events leading to hospitalization
AEs leading to hospitalization are those where the eCRF question ‘Did the Adverse Event require 
subject hospitalization?’ is recorded as ‘Yes’ on the Adverse Event eCRF.
5.4.2.2.7.
Fatal adverse events
Fatal AEs are those with ‘Fatal’ reported as outcome.
5.4.2.2.8.
Deaths
Death information (date of death and primary cause) is taken from the Death eCRF. 
5.4.2.2.9.
Post-treatment AEs and SAEs
Post-treatment (S)AEs are (S)AEs occurring after the last treatment administration + 15 days up 
to extension EOS.
5.4.2.2.10.
Adverse events of special interest (AESI)
AESIs include the anticipated risks of treatment with study drug and events that may be related to 
MS comorbidities. The following safety areas are addressed by the pre-defined AESIs; detailed 
definition is given in Appendix 8:

Bradyarrhythmia occurring post-first dose

Macular edema

Bronchoconstriction

Severe liver injury

Serious opportunistic infections including PML


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
Skin cancer

Non-skin malignancy

Convulsions

Unexpected neurological or psychiatric symptoms/signs (PRES, ADEM, atypical MS 
relapses)
5.4.2.2.11.
Major adverse cardiovascular events (MACE) 
Based on a pre-defined list of preferred terms belonging to relevant Standardized Medical 
Dictionary for Regulatory Activities Queries (SMQs), AEs are selected for the major adverse 
cardiovascular event (MACE) adjudication board evaluation. For each case sent for MACE 
adjudication, the board members individually assess whether the case is a myocardial infarction, a 
stroke, or another AE. For fatal cases, each member determines whether the death is considered of 
cardiovascular, non-cardiovascular, or undetermined cause. If not all individual assessments 
concur, the case is classified into the above listed categories based on a consensus meeting. For 
data analysis, each case is assigned to one of the following categories: 

cardiovascular death (if a death case is classified as cardiovascular);

non-fatal myocardial infarction (if the case is classified as myocardial infarction but not as 
cardiovascular death);

non-fatal stroke (if the case is classified as stroke but not as cardiovascular death);

no MACE (if the case is classified as other adverse event, but not as cardiovascular death).
The onset date and treatment-emergent status of a MACE is determined by the onset date and 
treatment-emergent status of the corresponding AE. In case more than one AE is linked to the same 
MACE case, the earliest treatment-emergent AE onset date determines the MACE onset date; if 
none of the linked AEs are considered treatment-emergent, the earliest AE onset date determines 
the MACE onset date. This may lead to cardiovascular death MACE with an onset date prior to 
the date of death. 
5.4.2.2.12.
Intensity of adverse events
AE intensity is entered into the database as ‘Mild’, ‘Moderate’, or ‘Severe’. For AEs reported more 
than once for a subject, only the worst outcome is considered. AEs with missing severity 
assessment are imputed to be of ‘severe’ intensity.
5.4.2.2.13.
Relationship of adverse events
Relationship to study treatment is entered into the database as ‘related’ or ‘not related’. For AEs 
reported more than once for a subject, only the worst relationship is considered. AEs with missing 
relationship are considered to be related.
5.4.2.3.
Analysis of 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 will be included in tables and figures. 
Additionally, non-treatment-emergent data at Core Day-15 follow-up, Core Day-30 follow-up and
extension EOS visits may also be included in certain tables and figures. All safety data will be 
included in listings, with flags for safety data considered to be treatment-emergent to a specific 
Analysis Period.


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Generally, safety data are 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 Period using 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, unless 
otherwise specified.
5.4.2.3.1.
Adverse events
Unless otherwise specified, all the AE summaries described below are produced for the Combined 
Analysis Period (only for subjects included in the SAF who were initially treated with ponesimod 
20 mg in the core study) and for the Extension Analysis Period by core study treatment and overall, 
using the EXTS. 
An overview of TEAEs is presented, per study treatment group, as the number and percentage of 
subjects having any AE, any severe AE, any drug-related AE, any AE leading to study drug 
discontinuation, any SAE, any drug-related SAE, or any fatal SAE. Similarly, an overview of 
TEAEs per 100 subject-years is also presented.
The following summary tables will be created to present the frequency and percentage of subjects 
with any AE, an AE in each primary SOC, and each individual AE (preferred term). SOCs are 
sorted by descending order of frequency in the ponesimod arm. If the frequencies of SOCs are the 
same, alphabetical order is used. The same rule applies for preferred terms within SOC:

All AEs;

TEAEs;

TEAEs per 100 subject-years;TEAEs with onset on Day 1 of a re-initiation (all re-initiations 
summarized together, for subjects with at least one re-initiation), Extension Analysis Period 
only;

TEAEs leading to permanent discontinuation of study treatment;

TEAEs considered to be related to study drug;

Severe TEAEs;

Post-treatment AEs (subjects that entered the period between EOT date + 16 and EOS ), 
Extension Analysis Period only.
The following summary tables will also be produced, presenting the frequency and percentage of 
subjects with any AE, and each individual AE (preferred term) by descending frequency:

TEAEs;

TEAEs per 100 subject-years;

TEAEs leading to permanent discontinuation of study treatment;


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
TEAEs reported in ≥ 5% of subjects in any group (after rounding into the 1st decimal in 
percentage, e.g. an event occurring in 4.955% of subjects will be rounded to be 5.0% and 
therefore be included in this summary table ).
The following summary tables will also be produced, presenting the frequency and percentage of 
subjects with any AE, and each individual AE (preferred term) by maximum intensity:

TEAEs.
AEs (preferred terms) reported more than once in a subject during the period summarized are 
counted once in frequency tables. Percentages are based on the SAF (ponesimod subjects) or on 
the EXTS as applicable.
5.4.2.3.2.
Deaths
The number and percentage of subjects who died during the extension study are summarized per 
core study treatment group, including the reported primary cause of death.
A separate listing including all deaths will be provided; treatment-emergent deaths will be flagged 
as such in that listing. 
5.4.2.3.3.
Serious adverse events (SAEs)
SAEs are summarized by SOC and preferred term. The following summaries are presented:

Treatment-emergent SAEs;

Treatment-emergent SAEs per 100 subject-years;

Treatment-emergent SAEs with onset on Day 1 of a re-initiation (for subjects with at least one 
re-initiation), Extension Analysis Period only;

Treatment-emergent SAEs leading to permanent discontinuation of study treatment

Treatment emergent SAEs with fatal outcome; (this will be tabulated only if there are more 
than 5 SAE-caused fatal events)
In addition, the following summary tables will also be produced, presenting the frequency and 
percentage of subjects with any SAE, and each individual SAE (preferred term) by descending 
frequency:

Treatment-emergent SAEs;

Treatment-emergent SAEs leading to premature discontinuation of study drug, Extension 
Analysis Period only.
SAEs, SAEs leading to hospitalization, and fatal SAEs will be presented in dedicated listings.
5.4.2.3.4.
Treatment-emergent adverse events leading to study treatment 
discontinuation
AEs and SAEs leading to premature discontinuation of study drug are summarized by SOC and 
preferred term as listed above.
A listing for AEs leading to premature discontinuation of study drug will be presented.


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5.4.2.3.5.
Adverse events of special interest (AESIs) 
For each of the AESI categories described in Section 5.4.2.2, the number and percentage of 
subjects with each AESI is summarized by core treatment group and preferred term for treatment-
emergent AESIs. In addition, the number and percentage of subjects having any event of that 
category, having any serious event, any fatal event or any event leading to premature 
discontinuation of study drug is presented. Similarly, treatment-emergent AESIs per 100 subject-
years are summarized per AESI category.
AESI are presented in dedicated listings (one for each AESI category).
5.4.2.3.6.
Major adverse cardiovascular events (MACE) 
A summary table will be produced for the Combined Analysis Period on the FAS and for the 
Extension Analysis Period on the EXTS presenting the frequency and percentage of subjects with 
any treatment-emergent MACE and having an event of the MACE subcategories (cardiovascular 
death, non-fatal myocardial infarction, non-fatal stroke) per core treatment group.
MACE are also presented in a dedicated listing.
5.4.3.
Additional Safety Assessments
5.4.3.1.
Clinical Laboratory Tests
5.4.3.1.1.
Laboratory Test variables
Safety laboratory samples are centrally analyzed by ACM and the results are electronically 
transferred to sponsor’s database. In exceptional cases, the protocol allows the utilization of local 
laboratories. Local laboratory analysis results are entered in the eCRF with some exceptions for 
blinding reasons (e.g., lymphocytes are not entered in the eCRF). Qualitative results like (marked) 
abnormality categorization, liver test elevation categories, etc., are derived from local laboratory 
data and summarized together with qualitative results derived from central laboratory data.
Safety laboratory assessments are conducted per schedule in section 6.12. Additional safety 
laboratory tests were allowed as per protocol at week 8, 16 and 20 and these assessments will also 
be tabulated.
Numerical results are converted into both conventional and SI units per QS document OTH-
000005 (Definition of Marked Abnormalities in Laboratory Data). Results reported as below the 
lower limit of quantification (LLOQ) are set to the LLOQ value. Results reported as >XX are set 
to XX for calculation of summary statistics. For all quantitative safety laboratory data, 
core/extension baseline is flagged and absolute change from core/extension baseline and percent 
changes from core/extension baseline are calculated for each post-baseline value, as described in 
Section 5.1.6. 
The Estimated Creatinine Clearance (eCLCr) is derived for analysis at each assessment (values 
based on Cockroft-Gault formula):
eCLCr (mL/min) = (140 − Age) × baseline Weight (in kg) × constant / serum creatinine (in 
μmol/L), where constant is 1.23 for men and 1.04 for women
Or
eCLCr (mL/min) = (140 − Age) × baseline Weight (in kg) × constant / (72 × serum creatinine (in 
mg/dL) where constant is 1 for men, 0.85 for women


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If the assessment comes from the core study (excluding the ones used as baseline value for the 
Extension Analysis Period):

Age is re-calculated at each assessment as follows:
Age at core screening (or re-screening) + 0.5 + (Date of laboratory assessment − Date of 
core screening (or re-screening))/365.25. 

Baseline weight is the weight collected at core screening.
If the assessment comes from the core study but it is used as baseline for the Extension Analysis 
Period, or if the assessment comes from the extension study:

Age is re-calculated at each assessment as follows:
Age at start of extension + 0.5 + (Date of laboratory assessment – Extension enrollment 
date)/365.25. 

Baseline weight is the weight collected at start of extension.
Flags are derived according to project specific ranges for marked laboratory abnormalities, as 
documented in Appendix 10. Marked laboratory abnormalities are labeled to indicate the 
increasing severity of abnormally low (“LL”, “LLL”), or high values (“HH”, and “HHH”) for each 
of the laboratory parameters listed. For INR, the general range specified in the protocol is applied 
to all subjects irrespective of concomitant treatment with anticoagulants.
The following flags
will be derived for Alanine aminotransferase
(ALT), Aspartate 
aminotransferase (AST), Total bilirubin (TBIL), and Alkaline phosphatase (ALP) at the 
subject/assessment level:

ALT: ≥ 1 × ULN, ≥ 3 × ULN, ≥ 5 × ULN, ≥ 8 × ULN, ≥ 10 × ULN, ≥20 × ULN

AST: ≥ 1 × ULN, ≥ 3 × ULN, ≥ 5 × ULN, ≥ 8 × ULN, ≥ 10 × ULN, ≥ 20 × ULN

ALT or AST: ≥ 3 × ULN, ≥ 5 × ULN, ≥ 8 × ULN, ≥ 10 × ULN, ≥ 20 × ULN

TBIL ≥ 2 × ULN

ALT or AST ≥ 3 × ULN and TBIL ≥ 2 × ULN (at the same sample date)

ALT or AST ≥ 3 × ULN and TBIL ≥ 2 × ULN + AP < 2 × ULN (at the same sample date)

INR value (ratio) > 1.5 combined with ALT or AST ≥ 3 ULN (at the same sample date).
In addition, the following treatment-emergent alerts regarding lymphocyte counts will be flagged:

< 0.2 10^9/L;

≥ 0.2 × 10^9/L – < 0.5 × 10^9/L;

≥ 0.5 × 10^9/L – < 0.8 × 10^9/L;

≥ 0.8 × 10^9/L – < 1.0 × 10^9/L;

≥ 1.0 × 10^9/L.
The following laboratory test will be presented in table and figure summaries. Other laboratory 
tests with abnormal findings will be presented in listings only.
Laboratory tests in standard unit
Erythrocytes (10^12/L)
Leukocytes (10^9/L)
Basophils (10^9/L)


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Basophils/Leukocytes (%)
Eosinophils (10^9/L)
Eosinophils/Leukocytes (%)
Lymphocytes (10^9/L)
Lymphocytes/Leukocytes (%)
Monocytes (10^9/L)
Monocytes/Leukocytes (%)
Neutrophils (10^9/L)
Neutrophils/Leukocytes (%)
Platelets (10^9/L)
Hemoglobin (g/L)
Hematocrit (L/L)
Lactate Dehydrogenase (U/L)
Creatinine (umol/L)
Creatinine Clearance (mL/min)
Estimated Creatinine Clearance (mL/min)
Urea Nitrogen (mmol/L)
Urea (mmol/L)
Urate (umol/L)
Glucose (mmol/L)
Cholesterol (mmol/L)
Triglycerides (mmol/L)
Sodium (mmol/L)
Potassium (mmol/L)
Chloride (mmol/L)
Calcium (mmol/L)
Protein (g/L)
Albumin (g/L)
C Reactive Protein (mg/L)
Alanine Aminotransferase (U/L)
Aspartate Aminotransferase (U/L)
Alkaline Phosphatase (U/L)
Bilirubin (umol/L)
Prothrombin Intl. Normalized Ratio
5.4.3.1.2.
Analysis of Laboratory Tests
The following tables will be produced for laboratory tests, both for the Combined Analysis Period, 
by core study treatment, using SAF (the summaries marked with § will include only the subjects 
who were initially treated with ponesimod 20 mg in the core study), and for the Extension Analysis 
Period, by core study treatment and overall, using the EXTS. 

Summary of absolute and absolute change from baseline values for laboratory tests 
(hematology, blood chemistry [excluding liver tests], liver tests): descriptive statistics by visit;

Summary of percent change from baseline values for lymphocyte counts: descriptive statistics 
by visit;


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
Incidence of marked laboratory abnormalities (LL, LLL, HH, HHH) as defined in Section 6.10: 
frequency counts and percentages, where percentages are based on the number of subjects with 
at least one post-baseline value in the Analysis Period (i.e., number of subjects at risk);§

Incidence of special laboratory abnormalities for ALT, AST, Bilirubin, and ALP: frequency 
counts and percentages, where percentages are based on the number of subjects with at least 
one post-baseline value (i.e., number of subjects at risk);§

Incidence of marked treatment-emergent laboratory abnormalities for lymphocyte counts: 
frequency counts and percentages, where percentages are based on the number of subjects with 
at least one post-baseline value (i.e., number of subjects at risk)§.

A plot to evaluate Drug-Induced Serious Hepatotoxicity (eDISH plot) based on the highest 
observed treatment-emergent ALT and total bilirubin values will be provided for safety 
analysis set during combined period, as well as for extension period by treatment group. 
Individual subject’s values expressed as × ULN are plotted on a log-log scatter plot (ALT on 
the horizontal axis, total bilirubin on the vertical axis); reference lines are drawn at Hy’s law 
thresholds, i.e., at 3 × ULN for ALT and at 2 × ULN for total bilirubin.
For abnormalities, the worst case in each direction is considered and summarized in all 
applicable categories, i.e., a subject counted in LLL is also counted in LL for a given parameter; 
also, a subject maybe counted in both the high and the low category for a given parameter. 
Unscheduled assessments that meet the pre-defined high/low criteria will be flagged and may be 
included in the corresponding incidence tables.
In general, local laboratory results with missing visits labels are not included in any summary 
tables. However, due to regional crisis or other reasons, Central lab testing was not available for 
some patients and the laboratory tests were performed only locally. Therefore, data from local 
laboratory might also be considered for summary tables. Below is the hierarchy of assigning 
laboratory data for a definite nominal visit.
1. For nominal laboratory visit listed in section 6.12 (as well as the additional safety visit at 
week 8, week 16 and week 20), if there is scheduled central laboratory data, the results 
from the central laboratory data at this nominal visit will be used.
2. If there is no available scheduled central laboratory data at this nominal visit, data from 
centrally assessed unscheduled laboratory data attached to this nominal visit will be 
considered.
3. If there is no available central laboratory data attach to this nominal visit (neither scheduled 
nor unscheduled assessments), data from the following sources will be considered, within 
the time window of the nominal visit (see Table 7 for the visit window).
a.
Locally assessed laboratory data within the designated visit window;
b. Remapped premature EOT at this designated visit window.
In case there are multiple data within the same visit window, the record closest to the scheduled 
target day will be selected for summary statistics. In case there are two records with equal distance 
to schedule target day, the one occurs after target day will be used.


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Figure 2:
Flowchart of selecting laboratory data for nominal visit


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In addition, the following figures will be produced for lymphocyte counts, both for the Combined 
Analysis Period, by core study treatment, using SAF, and for the Extension Analysis Period, using 
the EXTS:

Summary of mean percent change from baseline values (and their standard error) for 
lymphocyte counts by visit: mean plot starting with zero change at baseline.
The specified abnormal findings (i.e. any laboratory test result of exceeding/not meeting the 
thresholds for marked laboratory abnormality in Section 6.10) in safety laboratory hematology,
clinical chemistry and other laboratory parameters planned per protocol are also presented in 
subject data listings, for Extension Analysis Period only.
A listing will be created for all lymphocyte counts at each visit. The marked abnormality findings 
in lymphocyte count will be flagged in the listing.
For urinalysis no definitions and derivations necessary. Any resulting findings are recorded as 
adverse event (or medical history or relapse).
In addition, the following analysis will be performed for teriflunomide concentration which was 
measured at extension study day 1 for treatment group “Teriflunomide 14 mg / Ponesimod 20 mg”. 

Number of subjects with teriflunomide concentration assessed.

Number of subjects with non-detectable teriflunomide concentration 

Descriptive summary (N, arithmetic mean, SD, geometric mean, coefficient of variation 
[CV%], median, range,  and IQ range) of the teriflunomide concentration in subjects whose 
sample were detectable. 
A listing will be provided  for all subjects with assessable teriflunomide concentration on extension 
study day 1.
5.4.3.2.
Vital Signs 
5.4.3.2.1.
Definition of Vital Signs variables
5.4.3.2.1.1.
Blood Pressure
Per protocol, blood pressure measurements, including systolic (SBP) and diastolic (DBP) blood 
pressure will be performed at all scheduled study visits, both during the core and the extension 
study. 
Data is stored along with nominal visit and time point labels that will be used for the analysis. Data 
from both studies (core and extension) will be pooled for the analysis.
At all assessments (except the hourly post-dose assessments after first dose on Day 1 at re-
initiation), blood pressure will be measured twice (i.e., two SBP measurements and two DBP 
measurements) and recorded in the eCRF. The average of the two values will be calculated on the 
eCRF and recorded as “Mean SBP” and “Mean DBP”. For all data analysis, baselines, and for 
flagging of high or low values, these mean values will be used. If only one measurement is 
available, this is used for all further derivations and summary statistics.
Extension / core baseline is flagged and absolute and percent changes from extension/core baseline 
are calculated for each post-baseline value. In the same manner, pre-dose values are flagged and 


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absolute and percent change from pre-dose are calculated for the hourly post-dose assessments 
after first dose on extension study Day 1 at re-initiation. 
For by-visit and by-hour tables presenting summary statistics of quantitative vital signs results, the 
latest (by date/time) transmitted measurement per nominal subject-visit / time point is used in case 
of multiple data available at that visit or visit / time point.
Assessments meeting the following conditions for notable abnormalities are flagged in the
ADaM dataset:

SBP ≤90 mmHg or ≥ 20 mmHg decrease from baseline;

SBP ≤90 mmHg;

≥20 mmHg decrease from baseline in SBP;

SBP ≥ 160 mmHg or ≥ 20 mmHg increase from baseline;

SBP ≥ 160 mmHg;

SBP ≥140 mmHg;

≥20 mmHg increase from baseline SBP;

DBP ≤50 mmHg or ≥15 mmHg decrease from baseline;

DBP ≤50 mmHg;

≥15 mmHg decrease from baseline in DBP;

DBP ≥ 100 mmHg or ≥ 15 mmHg increase from baseline;

DBP ≥ 100 mmHg;

DBP ≥ 90 mmHg;

≥15 mmHg increase from baseline in DBP.
The above flags are derived for the Extension Analysis Period using extension baseline as a 
reference, and additionally for the Combined Analysis Period using the core baseline value as a 
reference. 
For all hourly post-dose assessments after first dose on extension study Day 1 at re-initiations 
during the extension, flags are set for the following conditions:

SBP ≤90 mmHg or ≥20 mmHg decrease from pre-dose;

≥20 mmHg decrease from pre-dose in SBP;

DBP ≤50 mmHg or ≥15 mmHg decrease from pre-dose;

≥ 15 mmHg decrease from pre-dose in DBP.
For details of the vital signs abnormality flags derived during the core study, see the core SAP
[D-19.178]. These variables are used as derived in the core study, and are not re-derived for the 
extension analysis.
5.4.3.2.1.2.
Weight
Weight is collected in the eCRF of the core study at Screening, Visit 10 (Week 60), EOT Visit 
(Week 108), and at unscheduled visits; and in the eCRF of the extension study at Visits 7, 11, 15, 
19, and EOT (Weeks 48, 96, 144, 192, and 240), and at unscheduled visits.
Data is stored along with nominal visit and time point labels that will be used for the analysis.
Absolute and percent change from core/extension baseline is calculated for each post-baseline 
weight (kg) value. 


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5.4.3.2.1.3.
Body Temperature
Body temperature is collected at all visits in the Body Temperature eCRF as ‘normal’ or 
‘abnormal’ both for the core and the extension studies. 
No definitions and derivations (other than treatment day of assessment) are necessary.
5.4.3.2.1.4.
Pulse rate
Pulse rate is collected as ‘normal’ or ‘abnormal’ at unscheduled visits in the Pulse Rate eCRF of 
the core and extension studies, and additionally at visits where no 12-lead ECG is performed during 
the extension study (as indicated in Protocol Table 12 and Table 13). 
No definitions and derivations (other than treatment day of assessment) are necessary.
5.4.3.2.2.
Analysis of Vital Signs
The following outputs will be produced for blood pressure (SBP and DBP) and body weight, both 
for the Combined Analysis Period, by core study treatment, using SAF (the summaries marked 
with § will include only the subjects who were initially treated with ponesimod 20 mg in the core 
study), and for the Extension Analysis Period, by core study treatment and overall using the EXTS: 

Summary of absolute values for blood pressure parameters and body weight: descriptive 
statistics by visit;

Summary of absolute and absolute change from baseline values for blood pressure parameters 
and body weight: descriptive statistics by visit; mean changes from baseline in blood pressure 
are also presented graphically with their standard error over time (plots starting with zero 
change at baseline);

Number and percentage of subjects with any treatment-emergent blood pressure result meeting 
the criteria defined in Section 5.4.3.2.1 Percentages are based on the number of subjects with 
at least one treatment-emergent result available for the corresponding parameter.§
The following outputs will be produced for blood pressure (SBP and DBP), for the Extension 
Analysis Period only, by core study treatment and overall using the EXTS:

Summary of pre- and post-dose values for vital signs parameters on Day 1 of first reinitiation: 
descriptive statistics time point. Note: data from re-initiations beyond the first are listed only; 
Strictly speaking the Day 1 of extension study is also counted as “Day 1 of first re-initiation” 
as subjects had experienced study treatment interruption between end of core study and start 
of extension study. Nevertheless in this context the “Day 1 of first re-initiation” applies for re-
initiation after a study drug interruption during extension period.

Summary of absolute and absolute change from pre-dose to post-dose values for vital signs 
parameters on Day 1 of first re-initiation: descriptive statistics by time point. Note: data from 
re-initiations beyond the first are listed only;

Number and percentage of subjects with any post-dose blood pressure result meeting the 
criteria defined in Section 5.4.3.2.1 on Day 1 of (any) re-initiation. Percentages are based on 
the number of subjects with at least one post-dose blood pressure result available for the 
corresponding parameter.
Unscheduled visits are not presented in summary tables by visit. Unscheduled assessments that 
meet the pre-defined high/low criteria will be flagged and included in the corresponding incidence 
tables.


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The outputs summarizing high and low blood pressure will only use treatment-emergent data. 
All notable abnormality in blood pressure (as specified above) are listed by core study treatment 
group and visit.
5.4.3.3.
Electrocardiogram
5.4.3.3.1.
Definition of ECG variables
5.4.3.3.1.1.
ECG parameter measurements
The following variables are collected: Heart Rate (HR) (bpm), PR interval (ms), QRS (ms), QT 
(ms). Corrected QT values QTcF (ms) and QTcB (ms) (based on Fridericia’s and Bazett’s 
formulae) are provided by the central vendor and will not be recalculated.
Data are stored along with nominal visit and time point labels that will be used for the analysis. 
Extension/core baseline is flagged and absolute and percent changes from baseline are calculated 
for each post-baseline value. In the same manner, pre-dose values are flagged and absolute and 
percent changes from pre-dose are calculated for the hourly post-dose assessments after first dose 
on extension study Day 1 at re-initiations during the extension study.
For by-visit and by-hour tables presenting summary statistics of quantitative ECG results, the latest 
(by date/time) transmitted measurement per nominal subject-visit / time point is used in case of 
multiple data available at that visit or visit / time point.
Assessments meeting the following conditions for notable abnormalities are flagged in the 
ADaM dataset:

Heart rate ≤ 50 bpm;

Heart rate ≤ 45 bpm;

Heart rate ≤40 bpm;

PR interval > 200 ms and increase of > 20 ms compared to baseline assessment;

QTcF/QTcB prolongation of > 500 ms;

QTcF/QTcB prolongation of > 480 ms;

QTcF/QTcB prolongation of > 450 ms;

QTcF/QTcB increase from baseline of > 30 ms;

QTcF/QTcB increase from baseline of > 60 ms;

QTcF/QTcB prolongations of > 500 ms and increase from baseline of > 30 ms;

QTcF/QTcB prolongations of > 500 ms and increase from baseline of > 60 ms;

QTcF/QTcB prolongations of > 450 ms and increase from baseline of > 30 ms;

QTcF/QTcB prolongations of > 450 ms and increase from baseline of > 60 ms.
Notable abnormalities are derived for the Extension Analysis Period using extension baseline as a 
reference, and additionally for the Combined Analysis Period using the core baseline as a 
reference. 
In addition, assessments meeting the following conditions for notable abnormalities on Day 1 of 
re-initiation during the Extension Analysis Period are flagged in the ADaM dataset:

PR interval > 200 ms and increase of > 20 ms compared to pre-dose assessment;

QTcF/QTcB increase from pre-dose of > 30 ms;


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
QTcF/QTcB increase from pre-dose of > 60 ms.
For details of the ECG notable abnormality flags derived during the core study. These variables 
are used as derived in the core study and are not re-derived for the extension analysis.
For presentation of these outliers in by-visit and by-hour tables, the most extreme (i.e., lowest heart 
rate and highest interval) is considered in case of multiple data available at that visit or visit / time 
point. 
5.4.3.3.1.2.
Morphological ECG findings
Morphological ECG findings are reported by the central reader, and mapped to CDISC standard 
(codelist C71153, with high level categories from codelist C71152) in the SDTM. 
For details of the morphological ECG findings variables collected during the core study, see the 
core SAP [D-19.178]. These variables are used as derived in the core study, and are not re-derived 
for the extension analysis.
For analyses in tables the following categories are anticipated: 

Atrioventricular Conduction

Axis and Voltage

Chamber Hypertrophy or Enlargement

Conduction

Ectopy

Intraventricular-Intraatrial Conduction

Rhythm Not Otherwise Specified

ST Segment, T wave, and U wave

Sinus Node Rhythms and Arrhythmias

Supraventricular Arrhythmias

Supraventricular Tachyarrhythmias

Ventricular Arrhythmias
Findings related to interpretation or technical issues are only included in listings. 
Morphological ECG findings are flagged as “New” if not present at any assessment prior to first 
treatment in the Analysis Period, or “Pre-existing” if present at such assessment. For the Combined 
Analysis Period, in case of missing or non-evaluable pre-treatment ECG assessment, it is 
conservatively assumed that any treatment-emergent morphological ECG finding is “New”.
Morphological ECG findings on Day 1 of (any) re-initiation
Morphological ECG findings on Day 1 of a re-initiation are those findings that start at or after the 
time of the ponesimod administration on Day 1 of a re-initiation, and before the following calendar 
date. 
Morphological ECG findings with onset on Day 1 of re-initiation are considered with respect to 
any re-initiation of ponesimod during the Extension Analysis Period. Morphological ECG findings 
on Day 1 of a re-initiation are considered to be “New” if they were not present at any pre-dose 
assessment on the day of re-initiation, or if no pre-dose assessment on day of re-initiation was 
performed.


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For presentation of these findings in by-visit and by-hour tables, all reported abnormalities are 
considered in case of multiple assessments available at that visit or visit / time point.
5.4.3.3.2.
Analysis of ECG
The following outputs will be produced for ECG, both for the Combined Analysis Period, by core 
study treatment, using SAF (the summaries marked with § will include only the subjects who were 
initially treated with ponesimod 20 mg in the core study), and for the Extension Analysis Period, 
by core study treatment and overall, using the EXTS:

Summary of absolute values for ECG parameters (HR, PR, QRS, QT, and QTcF / QTcB): 
descriptive statistics by visit;

Summary of absolute and absolute change from baseline values for ECG parameters (HR, PR, 
QRS, QT, and QTcF / QTcB): descriptive statistics by visit. Mean changes from baseline in 
heart rate are also presented graphically with their standard error over time (plots starting with 
zero change at baseline);

Incidence of treatment-emergent notable abnormalities (PR prolongations and HR outliers as 
defined in Section 5.4.3.3.1.1): frequency counts and percentages, overall and by visit, where 
percentages are based on the number of subjects with at least one post-baseline value (i.e.,
number of subjects at risk);§

Incidence 
of 
clinically 
relevant 
morphological 
ECG 
findings
[as 
defined 
in 
Section 5.4.3.3.1.1], by abnormality and group term, overall and by visit: frequency counts and 
percentages;§
The following outputs will be produced for the Extension Analysis Period only, by core study 
treatment and overall, using the EXTS:

Summary of pre- and post-dose values for ECG parameters (HR, PR, QRS, QT, and QTcF / 
QTcB) on Day 1 of first re-initiation: descriptive statistics time point. Strictly speaking the 
Day 1 of extension study is also counted as “Day 1 of first re-initiation” as subjects had 
experienced study treatment interruption between end of core study and start of extension 
study. Nevertheless in this context the “Day 1 of first re-initiation” applies for re-initiation 
after a study drug interruption during extension period.

Summary of absolute and absolute change from pre-dose values for post-dose values of ECG 
parameters (HR, PR, QRS, QT and QTcF / QTcB) on Day 1 of first re-initiation: descriptive 
statistics by time point.

Incidence of treatment-emergent PR prolongations and HR outliers [as defined in
Section 5.4.3.3.1.1] on Day 1 of (any) re-initiation: frequency counts and percentages, overall 
post-dose and by post-dose time point, where percentages are based on the number of subjects 
with at least one post-dose value (i.e., number of subjects at risk).

Incidence of clinically relevant morphological ECG findings on Day 1 of (any) re-initiation by 
abnormality and group term, overall and by time point: frequency counts and percentages.
Only newly occurring treatment-emergent abnormalities and findings are reported, i.e. if a subject 
has a particular event/finding prior to first treatment in the Analysis Period, and the same 
event/finding occurs again during the Analysis Period, it will not be reported in the summary table. 
“Pre-existing” findings will be only flagged in datasets and reported in listing. Unscheduled visits 
are not presented in summary tables by visit. Unscheduled assessments that meet the pre-defined 
high/low criteria will be flagged and may be included in the corresponding incidence tables.


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All ECG notable abnormality data as specified above will be included in listings.
5.4.3.4.
Spirometry and DLCO
5.4.3.4.1.
Definition of Spirometry and DLCO
Spirometry tests are performed to assess pulmonary function.
In the core study, spirometry measurement data are collected using vendor machines from ERT 
and data are automatically submitted to ERT by the machine. In the extension study, spirometry 
measurement data are assessed at site and entered on the eCRF. 
The following variables are collected in the extension study: 

FEV1 (Forced Expiratory Volume in 1 Second) [L];

FVC (Forced Vital Capacity) [L];
The following variables are derived for analysis (predicted values based on Quanjer
[Quanjer 1993]):

FEV1 / FVC ratio = FEV1 [L] / FVC [L];

Predicted normal FEV1[L] for male subjects = 4.30 × height (m) − 0.029 × age (years) at 
extension study enrollment − 2.49;

Predicted normal FEV1[L] for female subjects = 3.95 × height (m) − 0.025 × age (years) at 
extension study enrollment − 2.60;

Predicted normal FVC[L] for male subjects = 5.76 × height (m) − 0.026 × age (years) at 
extension study enrollment − 4.34;

Predicted normal FVC[L] for female subjects = 4.43 × height (m) − 0.026 × age (years) at 
extension study enrollment − 2.89. 
For the predicted normal values derivations above, age as collected at study extension enrollment 
and height collected at core study screening are used; also age is set to 25 years if age is between 
18 and 25 years and a conversion factor of 0.9 must be multiplied to the predicted normal value if 
subject race is other than ‘White’.

Percent of the corresponding predicted normal value is also calculated for FEV1[L] and 
FVC[L] as follows:
Percent of the predicted value (%) = [measured value] x100 / [predicted normal value]
The percent of the predicted normal values FEV1 and FVC, as calculated by the vendor, for core 
study data will be used, and are not re-derived for the extension analysis.
For the core study assessments, analyses are based on best efforts, for details see CSR SAP for 
core study.
Core/extension baseline is flagged and absolute and percent changes from core/extension baseline 
are calculated for each post-baseline value. 
Assessments meeting the following conditions are flagged in the ADaM dataset:

Percent change from baseline in FEV1: < −20%, < −30%;

Percent change from baseline in FVC: < −20%, < −30%;

Absolute change from baseline in %PRED FEV1: < −20%, < −30%;


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
Absolute change from baseline in %PRED FVC: < −20%, < −30%;

FEV1/FVC < 70%.
For details of the same conditions for the core study, see the core SAP. These flags are used as 
derived in the core study, and are not re-derived for the extension analysis.
Spirometry - DLCO
Subjects who participated in the DLCO sub-study during the core study were asked to continue their 
participation in the DLCO sub-study during the extension study. Subjects who chose to continue 
participation provided consent under a separate informed consent for the DLCO sub-study.
The DLCO assessment is conducted at extension study Visits 3, 7, 11, 15, 19, EOT, and EOS. In 
addition, unscheduled DLCO tests may be performed at any time during the study.
An assessment usually consists of multiple maneuvers. Among multiple maneuvers (reported 
within the same visit and assessment date), the mean value of the two highest DLCO measurements 
are derived to represent the DLCO at that assessment. If only one DLCO measurement is available 
at an assessment, that measurement is used. Within the eCRF, DLCO values are converted into
‘mmol/min/kPA’, which is the unit used in reporting.
Only these derived assessment-level values are used for any further derivations, the term ‘DLCO at 
visit’ will refer to this value derived from the individual maneuvers measurements. 
The following derivations are performed for DLCO from all measurements:

DLCO adjusted for Hemoglobin (Hb) is derived based on the method of Cotes [Macintyre 2005]
using the Hb reported by the central laboratory (or from local laboratory if missing) at the same 
nominal visit based on below formulae:
–
DLCO Hb corrected = DLCO × (10.22 + Hb [g/dL]) / (1.7 × Hb [g/dL]) for male subjects older 
than 14 years;
–
DLCO Hb corrected = DLCO × (9.38 + Hb [g/dL]) / (1.7 × Hb [g/dL]) for female subject 
subjects and all subjects ≤ 14 years;
If no Hb value is available at the corresponding visit, this variable is missing.

Predicted DLCO corresponding to each assessment is derived based on Cotes [Cotes 1993] as 
follows:
–
DLCO predicted = 11.11 × Height [m] −0.066 × Age [years] −6.03, for male subjects, age is 
set to 25 years if age below 25 years;
–
DLCO predicted = 8.18 × Height [m] −0.049 × Age [years] − 2.74, for female subjects, age is 
set to 25 years if age below 25 years;
The age used in above formula is derived as follows: Age at baseline + 0.5 + (Date of 
assessment − Date of (re-)screening) / 365.25;

Percent Predicted DLCO is derived as: 
100 × DLCO Hb corrected / DLCO predicted
Assessments meeting the following conditions for notable abnormality are flagged in the ADaM 
dataset:

Percent change from baseline in DLCO: < −20%;

Percent change from baseline in hemoglobin corrected DLCO d: < −20%;

Absolute change from baseline in Percent predicted DLCO: < −20%.


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5.4.3.4.2.
Analysis of Spirometry and DLCO
Spirometry:
The following outputs will be produced for PFTs, both for the Combined Analysis Period, using 
SAF, and for the Extension Analysis Period, using the EXTS:

Summary of absolute values for PFT parameters (FEV1, FVC, FEV1/FVC ratio, %PRED 
FEV1, %PRED FVC): descriptive statistics by visit;

Summary of absolute change from baseline values for PFT parameters (FEV1, FVC, 
FEV1/FVC ratio, %PRED FEV1, %PRED FVC): descriptive statistics by visit;

Summary of percent change from baseline values for PFT parameters (FEV1, FVC, FEV1/FVC 
ratio, %PRED FEV1, %PRED FVC): descriptive statistics by visit;

Summary of absolute change from baseline values for PFT parameters (FEV1, FVC, 
FEV1/FVC ratio, %PRED FEV1, %PRED FVC): mean plot with core study treatment group 
color-coded (plot starting with zero change at baseline).

Summary of percent change from baseline values for PFT parameters (FEV1, FVC, FEV1/FVC 
ratio, %PRED FEV1, %PRED FVC): mean plot with core study treatment group color-coded 
(plot starting with zero change at baseline).
In addition, the following outputs will be produced both for the Combined Analysis Period, using 
the SAF and only for subjects who received ponesimod 20 mg in the core study, and for the 
Extension Analysis Period, using the EXTS:

Incidence of treatment-emergent spirometry outliers [as defined in Section 5.4.3.4.1]: 
frequency counts, percentages, where percentages are based on the number of subjects with at 
least one treatment-emergent result available for the corresponding parameter.
Unscheduled visits are not presented in summary tables by visit. Unscheduled assessments that 
meet the pre-defined high/low criteria will be flagged and may be included in the corresponding 
incidence tables.
All notable abnormality in spirometry results (best effort results from core study and all results 
from extension study) will be listed by study treatment group and visit.
In addition, to understand the change in PFT parameters (FEV1, FVC, FEV1/FVC ratio, %PRED 
FEV1, %PRED FVC) after EOT, the following analyses will be done for subjects who continue 
any DMT (see section 6.5.1.4 for DMT list) after EOT date versus subjects who have no DMT 
after EOT date (irrespective of the original treatment group):

Absolute values of PFT parameters over the following visits: Core baseline, Extension 
Baseline, Extension EOT, Extension EOS and the change from Core baseline using EXTS.

A line graph to present the percent change from core baseline in PFT parameters over the 
following visits: Core baseline, Extension Baseline, Extension EOT, Extension EOS.
Note that the group labels in this analysis are “Any DMT”  and “No DMT”, irrespective of the 
treatment group. Only subjects who have EOS visit and the EOS visit is at least 5 days after the 
EOT date are included in this analysis (refer to section 5.5.6 for more details).


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Spirometry (Pulmonary Function Tests) - DLCO 
The following summary displays are provided, by study treatment group, for the Combined 
Analysis Period (the summaries marked with § will include only the subjects who were initially 
treated with ponesimod 20 mg in the core study) on the DLco sub-study safety analysis set, and 
for the Extension Analysis Period on the DLco sub-study extension analysis set:

Treatment-emergent Hemoglobin corrected DLco, percent predicted DLco and DLco 
including absolute and percent change from core baseline, as described in Section 5.4.3.4.1, 
are presented, by parameter and visit. Except for ‘Baseline’, only treatment-emergent results 
from nominal scheduled visits are included; premature EOT visit is mapped to a scheduled 
visit. These are summarized descriptively and mean absolute and percentage changes from 
baseline are also presented graphically with their standard error over time (plots starting with 
zero change at baseline).

Number and percentage of subjects with any occasion of treatment-emergent low Hemoglobin 
corrected DLco, Percent predicted DLco, and DLco values as defined in Section v are 
presented. Percentages are based on the number of subjects with at least one treatment-
emergent result available for the corresponding parameter.§
All notable abnormality DLCO results (derived mean values per assessment) are listed by study 
treatment group and visit.
5.4.3.5.
Dermatological Examination
Collected in the Dermatological Examination eCRF. No definitions and derivations necessary. 
Any resulting findings are recorded as adverse event (or medical history). No additional statistical 
outputs are needed in this field.
5.4.3.6.
Optical coherence tomography
Collected in the Optical coherence tomography (OCT) eCRF. No definitions and derivations 
necessary. Any resulting findings are recorded as adverse event (or medical history or relapse). No 
additional statistical outputs are needed in this field.
5.4.3.7.
Ophthalmological Examination
Data will be taken from both Ophthalmological Examination eCRFs. No definitions and 
derivations necessary. Any resulting findings are recorded as adverse event (or medical history or 
relapse). No additional statistical outputs are needed in this field.
5.4.3.8.
Physical examination 
No definitions and derivations necessary. Any resulting findings are recorded as adverse event (or 
medical history or relapse). No additional statistical outputs are needed in this field.
5.4.3.9.
Electronic self-rated version of the Columbia-Suicide Severity Rating 
Scale (eC-SSRS)
5.4.3.9.1.
Definition of eC-SSRS variables
The electronic self-rated version of the Columbia-Suicide Severity Rating Scale (eC SSRS©) is 
an assessment instrument that evaluates suicidal ideation and behavior. During an initial 
assessment it assesses lifetime as well as the recent history suicidality (scheduled at Core study 


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Visit 2-Baseline), and then prospectively monitors ideations and behaviors at subsequent follow 
up assessments since the last call throughout Core and Extension study.
The eC-SSRS outcome categories are provided below. The categories are ordered by increasing 
seriousness. Each category has a binary response (yes/no) and are numbered and ordered below 
for convenience


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Table 8:
eC-SSRS outcome categories
Suicidal category
Question category
Label in QSTEST in QS dataset
Suicidal Ideation 
(1-5)
Category 1: Wish to be dead
“CSS01-Wish to be Dead” and “CSS02-Wish to be Dead”
Category 
2: 
Non-specific 
active 
suicidal 
thoughts
“CSS01-Non-Specific Suicidal Thought” and “CSS02-Non-Specific 
Suicidal Thought”
Category 3: Active suicidal ideation with any 
methods (not plan) without intent to act
“CSS01-Suicidal Ideation-No Intent” and “CSS02-Suicidal Ideation-
No Intent”
Category 4: Active suicidal ideation with some 
intent to act, without specific plan
“CSS01-Ideation With Intent, No Plan” and “CSS02-Ideation With 
Intent, No Plan”
Category 5: Active suicidal ideation with 
specific plan and intent
“CSS01-Ideation With
Plan/Intent” and “CSS02-Ideation With 
Plan/Intent”
Suicidal 
Behavior (6-10)
Category 6: Preparatory acts or behavior
“CSS01-Preparatory 
Acts/Behavior” 
and 
“CSS02-Preparatory 
Acts/Behavior”
Category 7: Aborted attempt
“CSS01-Aborted Attempt” and “CSS02-Aborted Attempt”
Category 8: Interrupted attempt
“CSS01-Interrupted Attempt” and “CSS02-Interrupted Attempt”
Category 9: Non-fatal suicide attempt
“CSS01-Most Lethal Attempt Damage”, “CSS01-Most Recent Attempt 
Damage”, “CSS01-Most Lethal Attempt Potential”, “CSS01-Most 
Recent Attempt Potential”, “CSS02-Most Lethal Attempt Damage”, 
“CSS02-Most Lethal Attempt Potential”
Category 10: Completed suicide


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Furthermore, self-injurious behavior without suicidal intent is also an eC-SSRS outcome 
(although not suicide-related) and has a binary response (yes/no), this will be assigned as score 11 
and to be summarized for subjects with these events.
The initial assessment has a lifetime and a recent history assessment. The recent history covers the 
last 1 month for suicidal ideation, and the last 3 months for suicidal behavior. Recent history 
questionnaire questions are only assessed for outcome categories with corresponding lifetime 
outcome question answered as yes. If the lifetime assessment for an outcome category is ‘No’, also 
the corresponding recent history outcome is considered ‘No’ for analysis. The “lifetime and a 
recent history assessment” is performed twice during the course of the study, respectively at core 
study baseline and at extension visit 7 – week 48. 
Scoring: Scores are created at each assessment as follows:

Suicidal Ideation Score: The maximum suicidal ideation category (1–5 on the eC-SSRS) 
present at the assessment. Assign a score of 0 if no ideation is present.

Suicidal Behavior Score: The maximum suicidal behavior category (6–10 on the eC-SSRS) 
present at the assessment. Assign a score of 0 if no behavior is present.
For each assessment timepoint, a subject with multiple reported outcomes for suicidal 
ideation and suicidal behavior will be summarized under the worst reported outcome (i.e., 
max[1–5] and max[6–10], respectively).
Throughout all post-baseline assessments, a subject can have multiple suicidal ideation or suicidal 
behaviors, the worst reported outcome will be considered as the post-baseline outcome.
The following definitions will be used:

Suicidal ideation: A “yes” answer to any one of the five suicidal ideation questions 
(Categories 1-5) on the eC-SSRS. Taken from the ‘Reported most severe ideation level’.  

Suicidal behavior: A “yes” answer to any one of the five suicidal behavior questions 
(Categories 6-10) on the eC-SSRS.

Suicidal ideation or suicidal behavior 

Serious suicidal ideation (score ≥ 4) or suicidal behavior
The definitions above will be defined at any time in the period from study treatment start up to 
Extension EOT + 15 days*, for pre-treatment lifetime, and for pre-treatment recent history. 
Suicidal Ideation and Suicidal Behavior score categories: Shifts from baseline (worst outcome 
from pre-treatment recent history) to the worst outcome up to Extension EOT + 15 days (inclusive)
will be derived using the following categories: No ideation (score 0), non-serious suicidal ideation 
(score 1–3), serious suicidal ideation (score 4–5), suicidal behavior (score 5–10). 
*Only post-baseline assessments after study treatment start date from a ‘since last call’ questionnaires and 
the “Recently” questionnaire assessed at B303 extension week 48 (visit 7) are considered for the analysis. 
Baseline is defined as last available recent history result (maximum score) up to study treatment 
start date at core study, i.e., pre-treatment recent history result at core baseline. This is taken from 
the answers to the “Recently” category questionnaires at core study baseline. If the lifetime 
assessment at core study baseline for an outcome category is ‘No’, also the corresponding recent 


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history outcome is considered ‘No’ for analysis. The core study baseline has already been derived 
and captured in B301 ADaM dataset and can be used directly.
5.4.3.9.2.
Analysis of Columbia Suicide ideation or behavior
Number (%) of subjects with suicidal ideation (overall and by category), suicidal behavior (overall 
and by category), suicidal ideation score ≥ 4 or suicidal behavior and/or self-injurious behavior 
without suicidal intent will be tabulated by treatment group at Core baseline visit and at Extension 
week 48. The “Lifetime” and “Recently” results will be summarized separately. In addition, the 
worst outcome of post-core-baseline assessment up to Extension EOT + 15 days (including the 
assessment at Extesion week 48) will be presented. Analyses will be based on subjects in the SAF
and EXTS who have at least one eC-SSRS measurement during Combined analysis period
available. 
For subjects who have in addition a core baseline eC-SSRS assessment available shifts from core 
baseline (maximum score from pre-treatment recent history) to the worst reported outcome (the 
maximum score) up to Extension EOT + 15 days will be tabulated by treatment group to 
demonstrate any changes in Suicidal Ideation and Suicidal Behavior score categories (i.e. No 
ideation, non-serious suicidal ideation, serious suicidal ideation , suicidal behavior).
A listing will be generated for subjects who have positive value of any Suicidal Ideation, Suicidal 
Behavior or Self-Injurious Behavior without Suicidal Intent of that visits. To be specific, if a 
subject had outcome “Y” in the Suicidal ideation category “1-Wish to be Dead” at Extension visit 
11, all suicidality scores of that visit will be listed. On the contrary, if all outcomes of suicidality 
score are negative then this visit won’t be listed.
5.5.
Other Analyses
5.5.1.
Pharmacokinetics
No Pharmacokinetics analysis is applied in this study.
5.5.2.
Immunogenicity
Details of immunogenicity analyses conducted in this study are presented in Sections 6.11 for 
Covid-19
5.5.3.
Pharmacodynamics
The pharmacodynamic (PD) marker evaluated in this study is Peripheral lymphocyte counts, which 
were measured as part of the clinical laboratory hematology tests. 
To capture the abnormality in lymphocyte counts, among the treatment-emergent-flags abnormal 
values, the lowest lymphocyte counts through all post-baseline assessments are further categorized 
into the following categories. This will be done separately for combined period and for extension 
period.

< 0.2 × 10^9/L;

≥ 0.2 × 10^9/L – < 0.5 × 10^9/L;

≥ 0.5 × 10^9/L – < 0.8 × 10^9/L;

≥ 0.8 × 10^9/L – < 1.0 × 10^9/L;

≥ 1.0 × 10^9/L.


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The following analyses will be conducted:

Peripheral lymphocyte counts and the associated percentage change from core baseline by 
visit and by treatment group during combined period using SAF, along with a line graph 
to present the percent change from core baseline in peripheral lymphocyte counts by 
treatment group over visit. Note that only the following nominal visits will be visualized 
in the plot: Core period -- Baseline, Week 2, Week 4, Week 12, Week 24, Week 48, Week 
72, Week 96, Week 108, D15 FU, D30 FU; Extension period – Baseline, Week 2, Week 
4, Week 12, Week 24, Week 48, Week 96, Week 144, Week 192, Week 240, Week 288, 
extension EOT, extension EOS.

Peripheral lymphocyte counts and the associated percentage extension change from 
baseline by visit and by treatment group during extension period using EXTS, along with 
a line graph to present the percent change from core baseline in peripheral lymphocyte 
counts by treatment group over visit.

Incidence of treatment-emergent marked abnormalities for blood lymphocyte counts for 
combined period using SAF and for extension period using EXTS.
In addition, to understand the change in lymphocyte counts after EOT, the following analyses will 
be done for subjects who continue any DMT after EOT date versus subjects who have no DMT 
after EOT date:

Peripheral lymphocyte counts over the following visits: Core baseline, Extension Baseline, 
Extension EOT, Extension EOS visit and the change from Core baseline using EXTS.

A line graph to present the percent change from core baseline in peripheral lymphocyte 
counts over the following visits: Core baseline,  Extension Baseline, Extension EOT, 
Extension EOS.
Note that the group labels in this analysis are “Any DMT”  and “No DMT”, irrespective of the 
treatment group. Only subjects who have EOS visit and the EOS visit is at least 5 days after the 
EOT date are included in this analysis(refer to section 5.5.6 for more details)..
5.5.4.
Quality of life variables
5.5.4.1.
Change from baseline by visit up to Extension EOS in SF-36v2™ 
Health Survey domain and component scores 
The SF-36v2™ instrument is a generic health related quality of life assessment provided by the 
Medical Outcomes Trust, Boston, USA.
It contains 36 items measuring health across eight areas or domains: Physical Functioning (PF, 10 
items: #3a – #3j); Social Functioning (SF, 2 items: #6 & #10); Role Limitations due to physical 
problems (RP, 4 items: #4a – #4d); Role Limitations due to emotional problems (RE, 3 items: #5a 
– #5c); Mental Health (MH, 5 items: #9b – # 9h); Vitality (VT, 4 items: #9a – #9i); Bodily Pain 
(BP, 2 items: #7 & #8) and General Health perceptions (GH, 5 items: #1, #11a – #11d) and an 
additional item on reported Health Transition to perceive changes in health status in the past 12 
months (HT, 1 item: # 2).


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In addition, Physical and Mental Component Summary (PCS and MCS) measures are calculated 
based on aggregate domain scores.
For each of the eight domains, scores will be coded, summed and transformed to generate a score 
from 0 (worst possible health state) to 100 (best possible health state). These domain scores as well 
as PCS and MCS will then be standardized to Z scores and then again will be transformed to create 
norm based scoring also known as t-scores. Scoring will be performed via licensed vendor 
QualityMetric using ProCore software. QualityMetric's 1998 US population weights will be used 
to generate norm-based scores, which is consistent with methods in core study AC 058B301 
(OPTIMUM). Weighting for norm-based score calculation is embedded in the ProCore Software.
The SF-36v2™ is completed by the subject on an electronic device at defined visits up to extension 
EOS (see Section 6.12). 
5.5.4.2.
Analysis of SF-36v2™ Health Survey
Quality of life analysis based on the SF-36v2™will be performed on the Combined period and 
Extension period using EXTS. 
The eight normative (t-scores) domain scores, PCS and MCS will be summarized descriptively 
over time. In addition, the change from core baseline as well as change from extension baseline 
will be summarized by analysis visits.
5.5.5.
Biomarkers
No biomarker analysis is applied in this study.
5.5.6.
Subgroups analysis
To understand the change in some safety profiles after EOT, the following “Post-treatment 
DMT” subgroup is defined and the analysis by subgroup will be performed.

Sub-population included in the analysis: This subgroup analysis includes the subjects 
who have an EOS visit and the start date of the EOS visit is at least 5 days after the EOT 
date.

Post-treatment DMT subgroup definition: A patient in the above-defined sub-population
will be assigned to the “Any DMT” category if meeting all the following conditions:
1) There is a record in CMDECOD in SDTM.CM for any of the therapies listed in 
Section 6.5.1.4, and the medication is administered systemically via the following 
routes: Intravenous (IV), Oral, Subcutaneous (SC), Intramuscular (IM).
2) The corresponding CMSTDTC is on or after the EOT date, or CMSTDTC is before 
EOT date and CMENDTC is after the EOT date, or CMSTDTC is before EOT date 
and CMENDTC is missing indicating that the medication is ongoing at EOS.
Otherwise, the patient is assigned to the “No DMT” category.
5.5.7.
Interim Analyses
An interim analysis was conducted in 2019 with data cut-off date of 2019-11-30. Details were 
documented in the interim analysis SAP.


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5.5.8.
Data Monitoring Committee (DMC) or Other Review Board
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. 
5.5.9.
Covid-19 Impact Analyses
(i)
In order to assess the impact of the Covid-19 pandemic on the ongoing study, the 
following additional outputs will be presented: the frequency of major PDs related to 
the pandemic and  study drug compliance pre- and post-pandemic. A table of 
frequencies for major PDs related to the Covid-19 pandemic. This can be identified in 
SDTM.DV dataset by DVTERM which includes the prefix “Covid-19-related” and 
DVSCAT= “Major”. 
(ii)
A listing of major PDs related to the Covid-19 pandemic will be presented.
(iii)
A table for study drug compliance for the categories pre-Covid-19 and post-Covid-19 
will be presented, where pre/post-Covid-19 is defined as pre/post-January 1, 2020. 
Interruptions occurred pre-Covid 19 is considered in pre-Covid 19 period but excluded 
from post-Covid 19 period.
(iv)
The number of events of Covid-19 related discontinuations will be presented.
5.5.10.
Regional Crisis Impact Analyses
In order to assess the impact of the regional crisis in Ukraine and Russia on the ongoing study, the 
following additional output will be presented: 
(i)
A listing of all major PDs related to the regional crisis.
(ii)
A table for study drug compliance for categories pre-Regional Crisis and post-Regional 
Crisis will be presented for subjects from impacted countries (defined as Ukraine, 
Russia and Belarus) and for subjects from Ukraine. The pre/post-Regional Crisis is 
defined as pre/post February 24, 2022. Interruptions occurred pre-Regional Crisis is 
considered in pre-Regional Crisis period but excluded from post-Regional Crisis 
period.


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6.
SUPPORTING DOCUMENTATION
6.1.
Appendix 1 List of Abbreviations
%PRED FEV1
FEV1 expressed as % of predicted normal value
%PRED FVC
FVC expressed as % of predicted normal value
ADaM
Analysis data sets
AE
Adverse event
AESI
Adverse event of special interest
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ARR
Annualized Relapse Rate
AST
Aspartate aminotransferase
ATC
Anatomic Therapeutic Chemical
BMI
Body mass index
bpm
Beats per minute
CDA
Confirmed disability accumulation
CDDM
Clinical Development Data Management
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence interval
CL
Confidence limit
CRF
Case report form
CSR
Clinical Study Report
CUAL
Combined unique active lesions
DBP
Diastolic blood pressure
DLco
Diffusing capacity of the lungs for carbon monoxide
DMTs
Disease modifying therapies for MS
ECG
Electrocardiogram
eCRF
Electronic case report form
EDSS
Expanded Disability Status Scale
EOS
End-of-Study
EOT
End-of-Treatment
EXTS
Extension Set
FAS
Full analysis set
FDA
(US) Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
FS
Functional System
FU
Follow-up
FU
Follow-up
FVC
Forced vital capacity
Gd
Gadolinium-enhancing
Hb
Hemoglobin


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HR
Heart Rate
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
INR
International normalized ratio
KM
Kaplan-Meier
LLOQ
Lower limit of quantification
LT
Long Term
MAA
Marketing Authorization Application
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
MIAC
Medical Image Analysis Center
Min
Minimum
MRI
Magnetic resonance imaging
MS
Multiple sclerosis
MSFC
Multiple Sclerosis Functional Composite
NB
Negative binomial
NDA
New Drug Application
PD
Protocol deviation
PFT
Pulmonary function test
PPS
PCBV
Per-protocol analysis set
Percent change from baseline in brain volume
PR
Pulse Rate
PTOP
Post-treatment observation period
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
RMS
Relapsing multiple sclerosis
SAF
Safety analysis set
SAP
Statistical Analysis Plan
SAS®
Statistical Analysis Software
SBP
Systolic Blood Pressure
SD
Standard deviation
SDTM
Study Data Tabulation Model
SE
Standard error
SMQs
Standardized Medical Dictionary for Regulatory Activities
SOC
System Organ Class
STS
Study treatment start
TBIL
Total bilirubin
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
WHO
World Health Organization


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6.2.
Appendix 2 Changes to Protocol-Planned Analyses
6.2.1.
Changes to the analyses planned in the study protocol
The following changes to the analyses planned in the study protocol have been implemented in 
this SAP for the interim analysis:

Section 11.4.8.2 of the AC-058B303 protocol [D-18.056] describes the following QTcF 
prolongation flags: QTcF > 450 ms (male), > 470 ms (female), > 500 ms (male), and > 520 ms 
(female). These differ from the flags used in the core study, which are not differentiated for 
sex and are set at QTcF > 450 ms, > 480 ms, and > 500 ms. For consistency, the QTcF flags 
used in the core study will also be used in the extension study for QTcF as well as QTcB 
analyses. 

The adverse event of special interest (AESI) list was updated. The primary changes is adding 
Non-skin malignancy which was not defined in the protocol

The safety endpoint for change in lung diffusion capacity as assessed by diffusing capacity of 
the lungs (DLCO) will be analyzed for both the Combined and the Extension Analysis Periods 
(rather than only for the Combined Analysis Period, as initially planned in the protocol).

In addition to frequency of adverse events (AEs), AEs will also be summarized as rate per 100 
subject-years.

In data listings, flags for safety data considered to be treatment-emergent with specific 
reference to the related analysis period will be included (rather than flags for safety data not 
considered treatment-emergent as reported in the protocol).

DLCO sub-study safety set and DLCO sub-study extension set will be defined and used for the 
DLCO sub-study.

The derivation of the ‘HH’ and ‘HHH’ ranges for hemoglobin marked abnormalities were 
changed to better clarify how to derive pre-treatment assessments and post-treatment 
assessments when baseline is ≤ upper limit of normal (ULN).

Per protocol set removed from analysis.

The main efficacy analysis for final CSR focuses on combined period using EXTS. This is 
different from protocol Section 11.4.2.3. The argument is: given that long treatment duration 
in extension study (240 weeks) in comparison of core study (108 weeks), more focus should 
be placed in the population who have participated the extension study. The analysis using 
FAS in the combined period will still be conducted for key efficacy endpoints (see 
Section 4.2)

The change from baseline for urinalysis depicted in protocol Table 9 is removed. Any 
resulting abnormal findings are recorded as adverse event (or medical history) and therefore 
no further analysis is needed. In addition, more urinalysis parameters are assessed in 
qualitative results and hence the analysis “change from baseline” is not applicable. 

The definition of NEDA 4 in terms of change in brain volume is updated in section 5.3.1.4.2
to be “Annual brain volume from core baseline to extension EOS decrease ≥ 0.4% at all 
assessment” This corrects the typo made in protocol table 6 “annual brain volume change ≥-
0.4% from baseline to all assessments”.


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6.2.2.
Clarifications concerning endpoint definitions and related variables 
or statistical methods
The abnormality criteria for the international normalized ratio (INR) variously appears in the 
protocol as INR > 1.5 and INR ≥ 1.5 ULN. It is clarified here that the correct definition is INR > 
1.5 and this will be used for all related definitions and analyses.
A subject is considered to have completed the study if they complete the End-of-Study (EOS) and 
safety follow-up assessments. It is clarified in this SAP that this is independent of treatment 
completion, i.e., a subject can prematurely discontinue from treatment but go on to complete the 
study per protocol.


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6.3.
Appendix 3 Demographics and Baseline Characteristics
6.3.1.
Definition of demographic variables and baseline characteristics
For details of the demographic and baseline characteristics variables collected at the start of the 
core study, see the core SAP [D-19.178]. These variables are used as derived in the core study and 
are not re-derived for the extension analysis.
6.3.1.1.
Demographics
The following demographic variables are derived at the start of the extension study:

Sex, as collected on the ‘Demographics’ eCRF (Male, Female);

Age at start of extension (years), from the ‘Demographics’ eCRF; 

Age categories derived from the above as follows: 18–30, 31–40, 41–55, ≥56 years;

Weight at start of the extension study (kg), from the ‘Body Weight’ eCRF of the core study
End-of-Treatment (EOT) visit;

Body mass index (BMI) at start of the extension study (kg/m2) derived as 
Weight (kg) / (Height (cm) / 100)2;

BMI categories: < 18.5; ≥18.5 – < 25; ≥ 25 – < 30; ≥ 30.
Height, race, ethnicity, country, and region are collected at the start of the core study and are used 
as derived in the core study. 
6.3.1.2.
Baseline disease characteristics
The following baseline characteristics variables are derived at the start of the extension study:

Expanded Disability Status Scale (EDSS) score at extension baseline, defined as the latest 
available EDSS score as entered in the EDSS / FS eCRF (i.e., not re-derived based on sub-
scores) of either the core or the extension study, that is prior to or on the date of first ponesimod 
administration in the extension study;

EDSS score at extension baseline, categorized as (≤ 3.5, 3.5), derived from the EDSS score 
at extension baseline above.

Time since first symptoms at start of extension (years), defined as [Extension enrollment 
date – Date of first MS symptoms + 1] / 365.25. Date of first MS symptoms is taken from ‘MS 
History Disease Characteristics’ core eCRF at screening. Partial dates of first MS symptoms, 
are imputed to the 1st day of the month (if the day is missing) and to the 1st of January (if the 
day and month are missing). No imputation is performed if the date is completely missing.

Time since initial diagnosis at start of extension (years), defined as: [Extension enrollment 
date −Date of initial diagnosis + 1] / 365.25. Date of initial diagnosis is taken from ‘MS History 
Disease Characteristics’ core eCRF at screening. Partial dates of initial diagnosis are imputed 
to the maximum of [Date of first MS symptoms, 1st day of the month] (if the day is missing) 
and to the maximum of [Date of first MS symptoms, 1st of January] (if the day and month are 
missing). No imputation is performed if the date is completely missing.

Time since most recent relapse (months) at start of extension, defined as [Extension 
enrollment date −Start date of latest MS relapse prior to enrollment in the extension study + 
1] in days / 30.4375. 


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For most recent relapse, the following sources of relapses are considered:
1) Relapses prior to entry into the core study: from the core eCRF, form ‘MS History - Relapse’ 
at screening. The most recent “Onset date of previous relapse” among all previous relapses 
entered on the ‘MS History - Relapse’ eCRF is used as derived in the core study. 
2) Relapses occurring during the core study: from core eCRF, take the most recent “Start date 
of relapse” among all relapses entered on the ‘Relapse Summary’ eCRF form. Partial start
dates are imputed to the maximum of [Date of previous relapse documented, 1st day of the 
month] (if the day is missing) and to the maximum of [Date of previous relapse documented,
1st of January] (if the day and month are missing). Data collected at re-screening overwrites 
the initially entered data.
Take the latest date from either of the above that is prior to extension enrollment date. 

Number of documented MS relapses in the last year prior to start of extension, defined as 
the number of MS relapses entered on the ‘Relapse Summary’ of the core eCRF for which the 
start date of the relapse is prior to the extension enrollment date and after the extension 
enrollment date – 365 days. 

Number of documented MS relapses in the last 2 years prior to start of extension, defined 
as the number of MS relapses entered on the ‘Relapse Summary’ of the core eCRF for which 
the start date of the relapse is prior to the extension enrollment date [see Section 5.1.9.1] and 
after the extension enrollment date − 730 days.

Presence of Gd+ T1 lesions (yes/no) on extension baseline MRI scan as provided by the MRI 
central reading.

Number of documented Gd+ T1 lesions on extension baseline MRI scan as provided by the 
MRI central reading.

Volume of T2 lesions on extension baseline MRI scan as provided by the MRI central reading.
6.3.2.
Analysis of demographic and baseline characteristics
6.3.2.1.
Demographic characteristics
Demographic characteristics at start of the extension study will be summarized descriptively for 
subjects in the EXTS (and separately for subjects included in the DLCO EXTS) in a single table, as 
follows:

Sex: frequency counts and percentages;

Race: frequency counts and percentages;

Age at start of extension (years): descriptive statistics;

Age at start of extension (years) by category: frequency counts and percentages;

Race: frequency counts and percentages;

Ethnicity: frequency counts and percentages;

Height: descriptive statistics;

Weight at start of extension: descriptive statistics;

BMI at start of extension: descriptive statistics;

BMI at start of extension by category: frequency counts and percentages;


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
Geographical region / Country of enrolling site: frequency counts and percentages.
Height, race, ethnicity, geographical region, and country are used as derived in the core study. 
Tables are presented by core treatment group and overall. All variables are also presented in a 
subject data listing.
6.3.2.2.
Baseline characteristics
Baseline disease characteristics [defined in Section 6.3.1.2] are summarized using descriptive 
statistics for continuous and categorical data using EXTS. Tables are presented by core treatment 
group and overall. All variables are also presented in subject data listing(s) based on the EXTS.
In addition, core baseline characteristics will be summarized for the Core Analysis Period using 
EXTS.
All variables are also presented in a subject data listing.


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6.4.
Appendix 4 Protocol Deviations
This section refers to all protocol deviations as recorded in the database following the 
specifications provided in the protocol deviation code list.
Protocol deviations are categorized while being entered into the database into the following 
categories: 

Important protocol deviations (Yes/No)
In addition, protocol deviations are categorized by high-level topic in line with the Protocol 
Deviation code list.
Important protocol deviations for the extension study are summarized by category, by core 
treatment group, and overall on the EXTS. 
A listing of important protocol deviations (coded term, reported term) by country and site is 
provided.


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6.5.
Appendix 5 Prior and Concomitant Medications
6.5.1.
Definition of prior and concomitant medications
Therapies administered during the extension study are collected in the following eCRF pages: 
‘Concomitant Medications’, ‘Study-concomitant Therapy - Disease-modifying Treatment for 
MS’, ‘Corticosteroids for Treatment of Relapse’.
Therapies administered during the core study (core treatment-concomitant therapies) will be 
included as part of the concomitant therapies analysis for the Combined Analysis Period.
Terms are coded using the WHO drug code dictionary and the anatomic therapeutic chemical 
(ATC) class code (version dated  March 2023).
Handling of partial or missing start and end dates is detailed in Section 6.13.
Therapies are flagged as previous/concomitant/after treatment with respect to the relevant Analysis 
Period.
Therapies that were started during the core study and are ongoing during the extension study 
(specifically therapies included in the extension eCRF as ‘ongoing’ from the core study and the 
original therapies included in the core eCRF) will have a record in the core database and a 
corresponding record in the extension database. These records will be merged in the ADaM dataset 
using a dedicated ID linking variable included in the related SDTM dataset.
6.5.1.1.
Previous therapies
Previous therapies are therapies that were started and stopped prior to study treatment start date in 
the Analysis Period.
For the purpose of the analysis on the Extension Analysis Period, therapies reported in the core 
database that started after EOT in the core study and stopped prior to study treatment start date in 
the extension study, as well as therapies reported in the extension database that started and stopped 
prior to study treatment start date in the extension study, are flagged separately as “extension 
previous therapies”. 
6.5.1.2.
Treatment-concomitant therapies: taken between treatment start and 
EOT
Treatment-concomitant therapies are all therapies that have been taken between the study 
treatment start date in the Analysis Period and EOT date (last study drug intake) + 30 days in the 
Analysis Period, with the exception of corticosteroids for treatment of relapse, for which the EOT 
+ 7 days is used. This includes therapies ongoing at the start of the Analysis Period, as well as 
therapies starting after the start and before the end of the Analysis Period. DMT which is initiated 
on or after the study treatment start date and before the EOT date are also considered as 
concomitant. DMT which started on or after the EOT date is considered as “Post-treatment DMT” 
and not considered as treatment concomitant therapies.
Treatment-concomitant therapies that started during the core study and which were reported as 
ongoing at the start of the extension study (per the eCRF form ‘Ongoing Concomitant medication 
from AC-058B301’ with question ‘Were any medication started in AC-058B301 and still ongoing 
at the time of the ICF signature in AC-058B303?’ answered as ‘Yes’) are flagged to be summarized 
separately.


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6.5.1.3.
Therapies starting after EOT
Includes all therapies (except DMT) that have been started after the EOT (last drug intake) for the 
Extension Analysis Period only. This includes therapies with start date from EOT + 1 day onwards.
Therapies with missing start date will be considered to have started on treatment. 
6.5.1.4.
Disease modifying therapies for MS (DMTs) 
Disease modifying therapies (DMTs) are defined as therapies which can favorably alter the course 
of the disease by reducing the rate and severity of relapses or delaying disease progression by 
preventing accumulation of disability. DMTs will be identified on an ingredient level if containing 
any of the text indicated in Table 9 below. Medications in ATC class S (non-systemic 
administration) will not be considered. Only the medications which are administered systemically 
via the following routes are considered as DMT: Intravenous (IV), Oral, Subcutaneous (SC), 
Intramuscular (IM).
In addition, any other potential DMT, i.e., medications with preferred drug name 
“INVESTIGATIONAL DRUG” or “BLINDED THERAPY” for multiple sclerosis (recorded 
either on the ‘Study-treatment-concomitant therapy - Disease-modifying’ eCRF) will also be taken 
into account. 
Table 9:
Disease modifying therapies for MS
ALEMTUZUMAB
MITOXANTRONE
AZATHIOPRINE
MYCOPHENOLIC ACID
CERALIFIMOD
NATALIZUMAB
CICLOSPORIN
OCRELIZUMAB
CLADRIBINE
OFATUMUMAB
CYCLOPHOSPHAMIDE
OZANIMOD
DACLIZUMAB
PEGINTERFERON BETA-1A
DIMETHYL FUMARATE
PLOVAMER
FINGOLIMOD
PLOVAMER ACETATE
GLATIRAMER ACETATE
RITUXIMAB
INTERFERON BETA-1A
SECUKINUMAB
INTERFERON BETA-1B
TERIFLUNOMIDE
LAQUINIMOD
SIPONIMOD
METHOTREXATE
IMMUNOGLOBULINS NOS
INTERFERON ALFA
VUMERITY
PONESIMOD
ETRASIMOD
BAFIERTAM
DIROXIMEL FUMARATE
A text search in ingredients will be conducted: Include all medications containing any of the text above to ensure salts (e.g.,
“Fingolimod Hydrochloride” …) and combination therapies are included. 
6.5.2.
Analysis of prior and concomitant medications
Treatment-concomitant therapies will be summarized, both for the Combined Analysis Period 
(therapies taken during the combined period), and for the Extension Analysis Period (therapies 
taken during the extension period), by core study treatment and overall, using the EXTS.
Treatment-concomitant therapies that were originally recorded in the core study database and 
which were ongoing at extension study start will be summarized additionally on the EXTS. 


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Number and percentages of subjects having taken at least one treatment will be presented by ATC 
class and individual preferred term within each ATC class (ATC class level 4). All summaries are 
tabulated by ATC class, and individual preferred terms within each ATC class.
ATC classes are sorted by descending order of frequency overall. If the frequencies of ATC class 
are the same, alphabetical order is used. The same rule applies for preferred terms within ATC 
class. If the frequencies of ATC class are the same, alphabetical order is used. The same rule 
applies for preferred terms within ATC class.
Previous therapies (with respect to the Extension Analysis Period directlya) as well as therapies 
started after the extension EOT will be listed. 
*Previous therapies for the Extension Analysis Period include those therapies that started after 
EOT in the core study and stopped prior to study treatment start date in the extension study, as 
well as therapies that started and stopped prior to study treatment start date in the core study that 
were newly reported in the extension study database. Previous therapies that started and ended 
prior to the start of the core study, or which were concomitant in the core study (and are previous 
relative to the extension) will be reported in the core study only.
Previous therapies with respect to the Core Analysis Period (i.e. those therapies started and stopped 
prior to study treatment start date in the core study) are not reported in any analysis output (both 
on combined or extension analysis period).
All therapies taken are reported in subject listings with all information collected on the eCRF 
presented, using flags to mark previous, extension/combined Analysis Period concomitant, as well 
as ongoing at extension study treatment start.
6.5.2.1.
Disease modifying therapies (DMTs) for MS
Treatment-concomitant DMTs for MS are summarized in the same way as for the concomitant 
therapies above by study treatment group and overall, for the Combined Analysis Period using the 
EXTS and for the Extension Analysis Period using the EXTS. Post-treatment DMT will also be 
summarized using EXTS.
All DMTs taken for MS are reported in subject listings using flags to mark previous, 
extension/combined Analysis Period concomitant as well as ongoing at extension study treatment 
start.
                                                
a
Previous therapies for the Extension Analysis Period include those therapies that started after EOT in the core 
study and stopped prior to study treatment start date in the extension study, as well as therapies that started and 
stopped prior to study treatment start date in the core study that were newly reported in the extension study 
database. Previous therapies that started and ended prior to the start of the core study, or which were concomitant 
in the core study (and are previous relative to the extension), will be reported in the core study only.


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6.6.
Appendix 6 Medical History
6.6.1.
Definition of medical history
6.6.1.1.
General medical history 
The following medical history is collected on the extension study eCRF:

Ongoing Medical History (from the core study); 

Additional Medical History (not reported in the core study);
Reported terms are coded using MedDRA (version 26.0). 
The question ‘Does the subject have any clinically significant past or concomitant 
disease/diagnosis ongoing from AC-058B301?’ (Yes/No) will be used to identify medical history 
ongoing at the start of the extension study. 
The question ‘Does the subject have any additional clinically significant past or concomitant 
disease/diagnosis not already reported in AC-058B301?’ (Yes/No) will be used to identify new 
medical history reported during the extension study only.
Medical history in the extension study is not merged with the medical history collected in the core 
study. Only medical history collected in the extension study is reported as part of this SAP. 
6.6.1.2.
Specific MS medical history
Specific complications or symptoms associated with MS are recorded on a specific the eCRF pages 
‘MS History - Complication or Symptoms (AC-058B301) and ongoing at signature of Informed 
Consent in AC-058B303’ as well as ‘MS disease changes’. Complications and symptoms 
originating from these pages are flagged to be summarized separately. Only specific MS medical 
history that is ongoing at the start of the extension study will be summarized. The question 
‘Ongoing at Visit 1 – AC-058B303’ (Yes/No) will be used to identify MS medical history ongoing 
at the start of the extension study. Only records with answer “Yes” will be considered as ongoing 
at start of the extension. 
6.6.2.
Analysis of medical history
Medical history ongoing at the start of the extension study will only be summarized for the 
Extension Analysis Period, by core study treatment and overall, using the EXTS. The number and 
percentages of subjects who had/have at least one event and had/have each disease/diagnosis (by 
system organ class [SOC] and preferred term) will be tabulated. SOCs are sorted by descending 
order of frequency overall. If the frequencies of SOCs are the same, alphabetical order is used. The 
same rule applies for preferred terms within SOC. 
Any additional medical history collected in the extension (not reported in the core study) will be 
listed only.
Complications or symptoms associated with MS ongoing at the start of the extension study are 
summarized by study treatment group and overall, by tabulating the number and percentages of 
subjects who had/have each complication/symptom (by predefined term sorted by descending 
order of frequency overall). 


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MS disease changes since entry into the core study will be listed separately (these data are not 
coded).
All variables including – as applicable – the treatment day relative to study treatment start date of 
start and end date of diagnosis/disease are presented in a subject data listing.


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6.7.
Appendix 7 Intervention Compliance
Compliance calculation is not applicable for this study.


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6.8.
Appendix 8 Adverse Events of Special Interest
The definitions for AESIs are based on the systematic approach using Standardized MedDRA 
Queries (SMQ). The definitions for AESIs are based on the systematic approach using 
Standardized MedDRA Queries (SMQ) / MedDRA version 26.0.The following safety areas are 
addressed by the pre-defined AESIs:
Table 10:
AESI
AESI
SMQ
PT
Bradyarrhythmia 
occurring 
post-first dose
Bradyarrhythmias 
(including 
conduction defects and disorders 
of the sinus node function)
Blood 
pressure 
ambulatory 
decreased, 
Blood 
pressure 
decreased, 
Blood 
pressure 
decreased, 
Blood 
pressure 
diastolic 
decreased, 
Blood 
pressure 
fluctuation, 
Blood 
pressure orthostatic decreased, 
Blood 
pressure 
systolic 
decreased, Bradycardia, Central 
bradycardia., 
Chronotropic 
incompetence, 
Circulatory 
collapse, Diastolic hypotension, 
Electrocardiogram RR interval 
prolonged, Heart rate decreased, 
Hypotension, 
Labile 
blood 
pressure, Loss of consciousness, 
Mean 
arterial 
pressure 
decreased, 
Orthostatic 
hypotension, 
Presyncope, 
Procedural 
hypotension, 
Syncope
Macular edema
Cystoid 
macular 
oedema, 
Diabetic 
retinal 
oedema, 
Macular cyst, Macular hole, 
Macular 
oedema, 
Macular 
pseudohole, Macular rupture, 
Papilloedema, 
Pseudopapilloedema, 
Retinal 
oedema
Bronchoconstriction
Asthma/bronchospasm 
(narrow 
and broad)
Interstitial lung disease (narrow 
and broad)


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Table 10:
AESI
AESI
SMQ
PT
Severe liver injury
Hepatic failure, fibrosis and 
cirrhosis and other liver damage-
related conditions (narrow)
Hepatitis, 
non-infectious 
(narrow)
Serious opportunistic infections 
including PML
Opportunistic infections (narrow)
Skin cancer
Skin neoplasms malignant and 
unspecified (narrow and broad)
Non-skin malignancy
Malignant or unspecified tumours 
(narrow and broad) excluding the 
PTs included in the SMQ Skin 
neoplasms 
malignant 
and 
unspecified (narrow and broad)
Convulsions
Convulsions (narrow)
Unexpected 
neurological 
or 
psychiatric 
symptoms/signs 
(PRES, ADEM, atypical MS 
relapses)
Acute 
disseminated 
encephalomyelitis, 
Posterior 
reversible 
encephalopathy 
syndrome, Multiple sclerosis 
relapse


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6.9.
Appendix 9 Medications of Special Interest
No concomitant medications of special interest are defined.


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6.10.
Appendix 10 Thresholds for marked laboratory abnormalities
Table 11:
Thresholds for marked laboratory abnormalities
Parameter (SI unit)
LL
LLL
HH
HHH
Hemoglobin (g/L)
< 100
< 80
> 20 g/L above ULN (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)
> 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)
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
WBC count (109 /L)
NA
< 1.9
> 20.0
> 100.0
Lymphocyte (109 /L)
ND
< 0.2
> 4.0
≥ 8
Neutrophils (109 /L) 
< 1.5 
< 1.0
ND
ND
Eosinophils (109 /L) 
ND
ND
> 5.0
ND
Polymorphonuclear 
leucocyte/Band cells (%)
ND
ND
> 90%
> 95%
AST (U/L)*
ND
ND
≥ 3 ULN
≥ 5 ULN
ALT (U/L)*
ND
ND
≥ 3 ULN
≥ 5 ULN
Total bilirubin (umol/L)
ND
ND
≥ 2 ULN 
ALERT: 
≥ 2 ULN combined with 
ALT or AST ≥3 ULN
≥ 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
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
Urea Nitrogen (mmol/L)
ND
ND
> 2.5 ULN
> 5 ULN
Urate (umol/L)
ND
ND
> 1 ULN
ND
Albumin (g/L)
< 30 
< 20
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


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Parameter (SI unit)
LL
LLL
HH
HHH
Cholesterol (mmol/L)
ND
ND
> 7.75
> 12.92
Serum pregnancy test
ND
ND
ND
Positive
Teriflunomide (ng/mL)
ND
ND
ND
> 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 2009].
ALERT = study-specific alerts that trigger specific actions by the investigator [see protocol Section 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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6.11.
Appendix 11 Covid-19
This appendix describes the analyses and presentation of immunogenicity and clinical endpoints 
for objectives related to the assessment of immune response to Covid-19 vaccination in subjects 
in the AC-058B303 study. 
Specific objectives are:

To describe binding antibody concentrations to SARS-CoV-2 S protein as measured by 
ELISA

To describe binding antibody concentrations to SARS-CoV-2 N protein as measured by 
ELISA 

To describe Covid-19 infection Adverse events (AEs).
6.11.1.
Immunogenicity Variables
For Covid-19 vaccination, the following humoral immune responses are measured, including titers 
of neutralizing antibodies and S- and N-ELISA titers.
Humoral Assay
Purpose
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
6.11.2.
Analysis of Immunogenicity Related to Covid-19 Vaccination:
6.11.2.1.
Analysis related definitions:
Covid-19 vaccine analysis set: Study subjects who have a complete Covid-19 first vaccine 
regimen and at least one non-zero vaccine‑specific antibody titers assessed within a timeframe 
(defined as any timepoint prior to the start of  Covid-19 vaccine or within the 365 days after the 
1st dosing or within 365 days after any boosters).  
First Vaccine Regimen: For each subject, the 1st and 2nd doses of vaccine in the SDTM CM 
dataset are considered. Definition of 1st Vaccine Regimen for Janssen vaccine: Only the 1st dose 
is considered.
First Booster: The 1st subsequent dose of vaccine after first vaccine regimen is considered as the 
First Booster.
Second Booster: The 2nd subsequent dose of vaccine after first vaccine regimen is considered as 
the Second Booster.
Lymphocyte counts for a subject corresponding to a specific vaccination will be determined as 
the minimum of the last two available values within six months prior to the first vaccination date
of first vaccine regimen. If only one value is available within this range, this value will be used. If 
none are available in the range, the lymphocyte value corresponding to the particular vaccination 
will be considered missing. Categories of “Lymphocyte Count < 500 mm^3” and “Lymphocyte
Count >= 500 mm^3” will be used in the analysis.
Analysis based on BAU/ml: In order to calibrate across different assays, the WHO has proposed 
International Standards (WHO IS). The WHO IS assigned unit for quantifying immunoglobulins 


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is BAU/ml. Per Nexelis, the conversion of ELISA units (EU/ml) to BAU/ml is as shown below 
(see Attachment below): 
Antibodies assessment related to vaccine sequence:
Pre-vaccine antibodies assessment: for each subject, the antibodies assessment which is prior to 
and closest start date of 1st vaccine regimen, is considered as Pre-vaccine antibodies assessment. 
Antibodies assessment post 1st vaccine regimen: for each subject, the antibody assessments on or 
after start of first vaccine regimen and before 1st booster are considered as antibody assessments 
post-1st vaccine regimen. The average of all values in a time frame of 365 days after the start of 
first vaccine regimen will be used as “Antibodies assessment post-1st vaccine regimen” in the 
analysis.
Antibodies assessment post 1st booster: for each subject, the antibody assessments on or after 
start of 1st booster and before the 2nd booster are considered as antibody assessments post-1st
booster. The average of all values in a time frame of 365 days after the start of first booster will 
be used as the “Antibodies assessment post 1st booster” in the analysis.
Antibodies assessment post 2nd booster: for each subject, the antibody assessments on or after 
start of 2nd booster and before the 3rd booster are considered as antibody assessments post-2nd
booster. The average of all values in a time frame of 365 days after start of second booster will 
be used as the “Antibodies assessment post 2nd booster” in the analysis.
Antibodies assessment post 3rd booster: for each subject, the antibody assessments on or after 
start of 3rd booster and before the 4th booster are considered as antibody assessments post-3rd
booster. The average of all values in a time frame of 365 days after start of third booster will be 
used “Antibodies assessment post 3rd booster”.
Prior Covid-19 infection evidence related to vaccine sequence:
If a subject encountered one or more Covid-19 infection AEs and the start date of AE is prior to 
or on the start date of 1st vaccine regimen, the subject is considered to have Prior Covid-19 
infection evidence related to 1st vaccine regimen.
If a subject encountered one or more Covid-19 infection AEs and the start date of AE is prior to 
or on the date of 1st booster, the subject is considered to have Prior Covid-19 infection evidence 
related to 1st booster, irrespective if the start date of AE is prior to 1st vaccine regimen.


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6.11.2.2.
Analysis of Immunogenicity Related to Covid-19 Vaccination
A demographic table of study subjects who received Covid-19 vaccination will be provided
including :
- number and percentage of subjects having pre-vaccination antibody assessment
- number and percentage of subjects having post-1st vaccine regimen assessment
- number and percentage of subjects having post-1st booster assessment
- number and percentage of subjects having post-2nd booster assessment
- number and percentage of subjects having post-3rd booster assessment
- age at time of 1st vaccination
- sex
- exposure (years) to ponesimod at time of 1st vaccination
- number and percentage of subjects in different vaccine type of the 1st vaccine regimen
- number and percentage of subjects with or without evidence of Covid-19 infection prior to 1st
vaccine regimen
- number and percentage of subjects in different categories of lymphocyte count
In the above frequency tabulations, percentage is calculated based on number of subjects in Covid-
19 Vaccine Analysis Set.
For S-ELISA and N-ELISA assays, the following results will be presented: 
-
N, geometric mean and corresponding 95% CI of the actual values of pre-vaccination, post-
first vaccine regimen, post-first, post-second and post-third booster. Note that the analysis by 
timepoint will be performed only if more than 5 subjects have antibody concentration measured
at that timepoint.
-
Dot plots with dots for subject values with the corresponding geometric mean, 95% CI, 
minimum and maximum for each assay, for pre-, post- 1st vaccine regimen, post- 1st booster 
and post- 2nd booster will be presented. In the graphs, values in BAU/ml unit will be displayed 
on the log10 scale. Note that the analysis by timepoint will be performed only if more than 5 
subjects have antibody concentration measured at that timepoint.
-
The above analyses will be repeated for S-ELISA antibody concentrations for the following 
subgroups: vaccine type of the 1st vaccine regimen, evidence of Covid-19 infection prior to 1st
vaccine regimen and categories of lymphocyte count. Box plot will be generated to visualize 
S-ELISA antibody concentrations for the above-mentioned subgroups. Note that the analysis
by timepoint will be performed only if more than 5 subjects have antibody concentration 
measured at the timepoint.
Analyses of S-ELISA and N-ELISA antibody concentration will be presented in BAU/ml unit 
only. 
For the calculation of the geometric mean and its corresponding 95% CI, the arithmetic mean and
its corresponding 95% CI are calculated on the log10 transformed values. These values are back-
transformed to provide the geometric mean and its corresponding 95% CI.
A listing containing assessment date, timepoint related to each vaccination and value of S-ELISA
and N-ELISA assessment antibody concentration will be provided. 
A listing of Covid-19 vaccinations will be provided.


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6.11.3.
Analysis of Adverse Events Related to Covid-19 Vaccination
A summary table will be provided for the following Covid-19 infection AEs for the Covid-19 
Vaccine Analysis Set: 
(i)
any Covid-19 infection AEs.
(ii)
any Covid-19 infection serious AEs.
(iii)
any Covid-19 infection AEs sorted by severity (mild, moderate, severe).
(iv)
any Covid-19 infection AEs leading to treatment discontinuation. 
(v)
any Covid-19 infection AE leading to death.
For each of the above, summary tables will include overall, and the following time-points: 
(vi)
any Covid-19 infection AEs prior to 1st dose of vaccination
(vii)
any Covid-19 infection AE post 1st dose (Day 1) of vaccination
AE listing will include age at time of vaccination, days since 1st dose of vaccination, start and end 
dates, AE preferred/reported term, vaccine PT and AE severity. 


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6.12.
Appendix 12 Study visit and assessment schedule
Table 12 and Table 13 show a schematic representation of the assessments during the extension 
study


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Table 12:
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
Pregnancy test*/** (10)
X
X
X
X
X
X
X serum
X serum
Elimination procedure compliance 
X
X
Teriflunomide plasma concentration
X (11)
Additional serum sample for viral 
serology*
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


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* 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 protocol 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. 
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.
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. 
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).
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 13:
Visit and assessment schedule (Part 2)
Periods
Name
FOLLOW-UP
UNSCHEDULED
Duration
30 Days
Visits
Number
24
R1, R2, …
U1, U2, …
I1, I2, …
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 (± 5 days) 
days 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)
Ophthalmological examination/OCT* 
(3)
X
X
X
X
Pulmonary function tests* (4)
X
X
X
X
Hematology/Chemistry**
X
X
X
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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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 and hourly (± 15 min) for at least 4 hours post-dose and up to 12 hours.
2)
ECGs: Pre-dose and hourly (± 15 min) for at least 4 hours post-dose and up to 12 hours. 
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. 
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 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.
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 study treatment 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. 
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.
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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6.13.
Appendix 13 Handling of missing/incomplete date and the time fields
In the following, ‘lower limit’ and ‘upper limit’ refer to the minimum or maximum, respectively, 
of a possible date. For example, if the day is missing, the lowest limit is the first day of the given 
month and the upper limit is the last day of the given month. If the day and month are missing, the 
lower limit refers to the first day of the given year and the upper limit to the last day of the given 
year. The earliest and the latest dates refer to the first or last date, respectively, when ordered in 
sequence. 
6.13.1.
Previous / Concomitant therapies
For previous and concomitant therapies with missing or partial start and end dates the following 
rules for assignation to previous therapies and study concomitant therapies are applied [see 
Table 14].
Table 14:
Handling of missing or partial start and end dates for previous/concomitant therapies
eCRF 
page
Analysis 
Period
Start date
End date
Previous / 
Concomitant
Prev*
Combined 
Analysis Period
Unless start date clearly after/on 
core STS 
(Start date either: prior to core 
STS date, partial with either 
lower or upper limit prior to 
core STS date, or missing)
Unless end date after/on 
core STS
(Either prior core STS, 
partial with either lower 
or upper limit prior core 
STS, or missing)
Previous
Con**
Combined 
Analysis Period
Unless start date clearly after/on 
core STS (as above)
Prior to core STS date; or
Partial with upper limit 
prior to core STS date;
Previous
Con**
Combined 
Analysis Period
Start date confirmed prior core 
STS
(Start date either: prior to core 
STS date, partial with upper 
limit prior to core STS date) 
End date on core STS 
date and ‘Ongoing at 
start of Treatment’ ticked 
‘No’; or
Partial with lower limit 
prior to core STS date 
and upper limit after/on 
core 
STS 
date 
and 
‘Ongoing at start of 
Treatment’ ticked ‘No’; 
Previous
Con***
Extension 
Analysis Period
Unless start date clearly after/on 
extension STS 
(Start date either: prior to 
extension STS date, partial with 
either lower or upper limit prior 
to extension STS date, or 
missing)
Prior to extension STS 
date; or
Partial with upper limit 
prior to extension STS 
date;
Previous 
Con***
Extension 
Analysis Period
Start date confirmed prior 
extension STS
(Start date either: prior to 
extension STS date, partial with 
upper limit prior to extension 
STS date) 
End date on extension 
STS date and ‘Ongoing 
at start of Treatment’ 
ticked ‘No’; or
Partial with lower limit 
prior to extension STS 
date
and upper limit 
after/on extension STS 
date and ‘Ongoing at 
start of Treatment’ ticked 
‘No’; 
Previous






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–
Onset day and month missing: If the year is the same year as the year of first study drug 
intake in the extension study or later, and if the year is prior to or in the same year as the 
minimum of (cut-off date, last intake date + 15 days), the AE is considered to be treatment-
emergent. For pregnancy interruptions, if the year is the same year as the year of first study 
drug intake in the extension study or later, and if the year is prior to or in the same year as 
the minimum of (cut-off date, last intake date + 15 days), the AE is considered to be 
treatment-emergent.If the year corresponds to the year of first study drug intake (in the 
extension study), impute onset date and time as the date and time of the first study drug 
intake in the extension study. If first study drug intake (in the extension study) is missing, 
then use enrollment date/time.
–
If the year is clearly after the year of first study drug intake in the extension study, but a 
date of re-initiation with corresponding year is documented, impute onset date and time as 
the date and time of this re-initiation study drug intake (if more than one study drug re-
initiations are documented in this year, impute with the date and time of the earliest of 
those).
–
If the year is clearly after the year of first study drug intake in the extension study, but no 
date of re-initiation with corresponding year is documented, the onset date is imputed to 1 
January of the given year and time to 00:00.
–
If neither date of first study drug intake in the extension study nor extension enrollment 
date are available, or if the event onset year is clearly prior to the year of first study drug 
intake (or, if missing, year of enrollment), the onset date is imputed to 31 December of the 
given year and time is imputed to 00:00.

Missing onset time is imputed to:
–
the time of the first study drug intake in the extension study, if the onset date equals the 
date of first study drug intake in the extension study. 
–
the time of the study drug intake at re-initiation in the extension study, if the onset date 
equals the date of a documented study drug re-initiation. 
–
00:00, for any other onset date.

Onset 
date 
is 
completely 
missing: 
considered 
to 
be 
treatment-emergent. 
The onset date and time are imputed as date and time of the first study drug intake in the 
extension study.
AEs with missing or partial onset date may be considered to be treatment-emergent as per the 
definitions above. However, they are not considered to be “Day 1” AEs and will not appear in 
summaries of AEs on Day 1.
For AEs reported on the “Ongoing Adverse Events from AC-058301” eCRF page for the extension 
study, no dates are imputed and the events are considered to be not treatment-emergent with respect 
to the Extension Analysis Period. 
6.13.4.
Study treatment start and EOT date
The following imputations of study treatment start and extension EOT date are considered for 
assigning safety events and assessments to the treatment-emergent period and used for deriving 
efficacy variables with definitions requiring extension EOT date. It is not considered for derivation 
of exposure variables.




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6.14.
Appendix 14 PRO and other composite assessment scoring and handling 
of missing data
6.14.1.
MSFC
A more comprehensive description of the test and its administration is provided in the protocol 
appendix 6. The MSFC score will be calculated as the mean of the Z-scores of the 3 components:
(1) Timed 25-Foot Walk (T25FW) 
(2) 9-Hole Peg Test (9-HPT) 
(3) Paced Auditory Serial Addition Test (PASAT-3).
for each of the scheduled assessment visit using the following equation (MSFC administration and 
scoring manual, Fisher et al., 2001, National MS society). 
MSFC Z-scoret = Z arm, average  t – Z leg, average t + Z cognitive t 

In more details the score will be calculated as follows: 
MSFC Z-score t =
{[(Average 1/9-HPT t - Baseline Mean 1/9-HPT) / Baseline Std Dev (1/9-HPT)]
+ [- (Average T25FW t - Baseline Mean T25FW) / Baseline Std Dev T25FW ]
+ [( PASAT-3 t - Baseline Mean PASAT-3) / Baseline Std Dev PASAT-3]} / 3
Where t = time, baseline mean and SD refer to the mean and standard deviation in the study 
independent of treatment arm (FAS) at baseline.
The average (1/9-HPT) and average T25FW are derived as follows. 
Average 1/9-HPT= [1/Mean trials arm left +1/ mean trials arm right]/2
()*+,-* ./012 = mean of trials (i.e. trial 1 and trial 2) = (trial 1+ trial 2)/2
For the T25FW and 9-HPT, a higher raw score represents deterioration whereas, for the PASAT-3 
a lower raw score represents deterioration. After the transformation to Z-scores the negative values 
Z-scores of each of the components as well as the MSFC Z-score indicate deterioration in the 
neurological function.
The subcomponents are considered in addition separately. These are: Average T25FW in seconds, 
PASAT-3 score in number correct, and the Average 9-HPT in seconds. The Average 9-HPT is 
defined as Average 9-HPT = mean ( Mean trials arm left, mean trials arm right).
Handling of missing data for MSFC analysis
For assessments 9-HPT and T25FW, if only one trial is available that score is used instead of the 
mean, if more trials are available at the same visit the mean is derived based on all available trials. 
For assessments 9-HPT, if only results from one arm are available, the reciproce is used for 
Average 1/9-HPT.
For overall composite MSFC score, if any of the three components is missing at that visit, the 
MSFC score is set to be missing, no imputation is conducted. 


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6.14.2.
SF-36 analysis
6.14.2.1.
SF-36 scoring
SF-36 scoring is performed via licensed vendor QualityMetric using PRO CORE software. The 36 
questions are imported for processing and detailed process steps can be found in PRO CORE 1.4
manual. 
The original SDTM QSTESTCD need to be transformed into imported test code requested by PRO 
CORE. Below are coding rules.
QSTESTCD
QSTEST
SF-36 coding for PRO CORE
SF36201
SF-36 v2.0 Standard-Question 1
GH01
SF36202
SF-36 v2.0 Standard-Question 2
HT
SF36203A
SF-36 v2.0 Standard-Question 3a
PF01
SF36203B
SF-36 v2.0 Standard-Question 3b
PF02
SF36203C
SF-36 v2.0 Standard-Question 3c
PF03
SF36203D
SF-36 v2.0 Standard-Question 3d
PF04
SF36203E
SF-36 v2.0 Standard-Question 3e
PF05
SF36203F
SF-36 v2.0 Standard-Question 3f
PF06
SF36203G
SF-36 v2.0 Standard-Question 3g
PF07
SF36203H
SF-36 v2.0 Standard-Question 3h
PF08
SF36203I
SF-36 v2.0 Standard-Question 3i
PF09
SF36203J
SF-36 v2.0 Standard-Question 3j
PF10
SF36204A
SF-36 v2.0 Standard-Question 4a
RP01
SF36204B
SF-36 v2.0 Standard-Question 4b
RP02
SF36204C
SF-36 v2.0 Standard-Question 4c
RP03
SF36204D
SF-36 v2.0 Standard-Question 4d
RP04
SF36205A
SF-36 v2.0 Standard-Question 5a
RE01
SF36205B
SF-36 v2.0 Standard-Question 5b
RE02
SF36205C
SF-36 v2.0 Standard-Question 5c
RE03
SF36206
SF-36 v2.0 Standard-Question 6
SF01
SF36207
SF-36 v2.0 Standard-Question 7
BP01
SF36208
SF-36 v2.0 Standard-Question 8
BP02
SF36209A
SF-36 v2.0 Standard-Question 9a
VT01
SF36209B
SF-36 v2.0 Standard-Question 9b
MH01
SF36209C
SF-36 v2.0 Standard-Question 9c
MH02
SF36209D
SF-36 v2.0 Standard-Question 9d
MH03
SF36209E
SF-36 v2.0 Standard-Question 9e
VT02
SF36209F
SF-36 v2.0 Standard-Question 9f
MH04
SF36209G
SF-36 v2.0 Standard-Question 9g
VT03
SF36209H
SF-36 v2.0 Standard-Question 9h
MH05
SF36209I
SF-36 v2.0 Standard-Question 9i
VT04
SF36210
SF-36 v2.0 Standard-Question 10
SF02


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SF36211A
SF-36 v2.0 Standard-Question 11a
GH02
SF36211B
SF-36 v2.0 Standard-Question 11b
GH03
SF36211C
SF-36 v2.0 Standard-Question 11c
GH04
SF36211D
SF-36 v2.0 Standard-Question 11d
GH05
The normative score and the 0-100 scale score for individual domain, along with the normative 
score for PCS and MCS will be exported from PRO CORE. The exported code and the 
corresponding ADaM parameter code and descriptions are outlined below.
Outputed 
Parameter Code
Parameter Code in 
ADaM 
Parameter Description in ADaM
BP
BP
Bodily Pain 0-100 Score
GH
GH
General Health 0-100 Score
MH
MH
Mental Health 0-100 Score
PF
PF
Physical Functioning 0-100 Score
RE
RE
Role-Emotional 0-100 Score
RP
RP
Role-Physical 0-100 Score
SF
SF
Social Functioning 0-100 Score
VT
VT
Vitality 0-100 Score
BP_NBS
BPT
Bodily Pain Normative Score
GH_NBS
GHT
General Health Normative Score
MH_NBS
MHT
General Health Normative Score
PF_NBS
PFT
Physical Functioning Normative Score
RE_NBS
RET
Role-Emotional Normative Score
RP_NBS
RPT
Role-Physical Normative Score
SF_NBS
SFT
Social Functioning Normative Score
VT_NBS
VTT
Vitality Normative Score
MCS
MCST
Normative Mental Component Summary Score
PCS
PCST
Normative Physical Component Summary Score
Descriptive statistics will be performed based on normative scores. 
In addition, there is no transformation of item Health Transition. Analysis of Health Transition 
will be based on the original results.
6.14.2.2.
ADaM domain generation
For combined analysis, only the composite score is stored in the ADaM dataset. The original SF-
36 questionnaires will be kept in SDTM only.
6.14.2.3.
Handling of duplicate entries on Questionnaire form for SF-36 
scoring
For SF-36 scoring, unique assessment per subject per question item per day is required. In case a 
subject have duplicate entries within the same day for a question item, the following handling rules 
will be applied:


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
If a respondent marks two responses which are adjacent to each other, then the worst case
(lowest value) is selected. For questions BP01, BP02, GH01, GH03, GH05, VT01, VT02,
SF01, MH03 and MH05, the record with higher score is considered “worst case”. For other
questions the record with lower score is considered “worst case”.

If a respondent marks  two  responses which are not adjacent  to each other, then the score is
missing for that item.

If a respondent marks three or more responses then the score is missing for that item.
6.14.2.4.
Selection of subset population for dry-run SF-36 scoring
Due to limited administrations licensed at PRO CORE, a subset of data from internal SDTM data 
(dated 30Oct2023) will be selected for Dry-run. The selection rules are outlined below:
1. To select subjects who have completed the study or subjects who have reached visit “Week
240”.
2. To check SF-36 assessments for these subjects and exclude subjects with multiple
assessments within the same date.
3. To include all assessments at any visits for the selected subjects for SF-36 scoring for Dry-
run.
4. To keep subjects who have completed the study prior to 31-12-2022 or who have visit
“Week 240”.
5. In order to perform visit remapping for EOT visit of subjects who prematurely discontinue
the study. The SF-36 assessments of the first 10 subjects who had discontinued the study
are added for Dry-run analysis.
This results to approximately 1000 assessments to be included for Dry-run.


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7.
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