Conditions: Multiple Sclerosis
Keywords: relapsing multiple sclerosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1133
Healthy volunteers: no

Brief summary:
International clinical trial to compare ponesimod and teriflunomide in relapsing multiple sclerosis

Detailed description:

Arms:
arm 1: Subjects to receive 20 mg ponesimod arm 2: Subjects to receive 14 mg teriflunomide

Interventions: intervention 1: ponesimod intervention 2: teriflunomide
Intervention descriptions: intervention 1: film-coated tablet with 20 mg ponesimod, administered orally once daily in the morning intervention 2: film-coated tablet with 14 mg teriflunomide, administered orally once daily in the morning

Protocol document:
Prot_000.pdf: 
TPL-000052_v09 
Ponesimod / ACT-128800 
Relapsing Multiple Sclerosis 
Protocol AC-058B301 
OPTIMUM: Oral Ponesimod versus Teriflunomide In relapsing MUltiple sclerosis 
Multicenter, randomized, double-blind, parallel-group, active-controlled, 
superiority study to compare the efficacy and safety of ponesimod to teriflunomide 
in subjects with relapsing multiple sclerosis 
Study Phase: 
3 confirmatory 
EudraCT Number: 
2012-000540-10 
Status and version: 
Final Version 7 
Date: 
5 December 2018 
Actelion document number 
(Doc No.): 
D-18.388
Confidentiality statement 
The information contained in this document, especially unpublished data, is the property of the sponsor of 
this study, Actelion Pharmaceuticals Ltd. It is therefore provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an Ethics Committee or Institutional 
Review Board. It is understood that this information will not be disclosed to others without written 
authorization from Actelion Pharmaceuticals Ltd, except to the extent necessary to obtain informed consent 
from those persons to whom the study treatment may be administered. 
NCT02425644


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 2/376 
Confidential 
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Doc No D-18.388 
 
SPONSOR CONTACT DETAILS 
SPONSOR  
 
ACTELION Pharmaceuticals Ltd 
Gewerbestrasse 16 
CH-4123 Allschwil 
Switzerland 
 
+
 
Clinical Trial Physician  
 
Contact details of the Clinical Trial Physician can 
be found in the Investigator Site File 
MEDICAL HOTLINE 
Toll phone number: +
 
 
 
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 Project Scientist 
 PhD 
 
Clinical Trial Scientist 
 PhD 
 
Clinical Science Program Head 
 
, MD 
Clinical Trial Physician 
Magdalena Pirozek-Lawniczek, MD 
 
Clinical Trial Statistician 
Hilke Kracker, PhD 
 
Clinical Project Statistician 
, MSc 
 
Clinical Trial Pharmacologist 
, PhD 
 
Drug Safety Physician 
, MD 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 3/376 
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Doc No D-18.388 
 
CONTRACT RESEARCH ORGANIZATIONS INFORMATION 
 
CENTRAL LABORATORY 
ACM Global Central Laboratory Limited 
23 Hospital Fields Road 
York YO10 4DZ, UK 
CENTRAL 
PK 
ANALYSIS 
LABORATORY 
Idorsia Pharmaceuticals Ltd 
Hegenheimermattweg 91 
CH-4123 Allschwil, 
Switzerland 
CENTRAL 
RANDOMIZATION 
Almac Clinical Technologies 
25 Fretz Road 
Souderton 
PA 18964 
USA  
CENTRAL MRI READING  
MIAC AG 
Marktgasse 8 
CH-4051 Basel,Switzerland  
CENTRAL ECGs READING 
eResearch Technology GmbH 
Sieboldstr. 3  
97230 Estenfeld, Germany  
CENTRAL PFTs 
OVERREADING 
eResearch Technology GmbH, 
Sieboldstr. 3  
97230 Estenfeld, Germany  
ELECTRONIC DIARY 
PHT CORPORATION  
500 Rutherford Avenue  
Charlestown, MA 02129, USA 
A list of site-specific contact details for CROs can be found in the Investigator Site 
File. 
 
 
 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
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SIGNATURE PAGE FOR ACTELION PHARMACEUTICALS LTD 
Hereinafter called Actelion 
 
Treatment name / number 
Ponesimod / ACT-128800 
Indication 
Relapsing Multiple Sclerosis 
Protocol number, study acronym, study title  
AC-058B301, OPTIMUM, Multicenter, randomized, double-blind, parallel-group, 
active-controlled, superiority study to compare the efficacy and safety of ponesimod to 
teriflunomide in subjects with relapsing multiple sclerosis 
 
I approve the design of this study. 
 
 
 
 
 
 
 
PPD
PPD


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 5/376 
Confidential 
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Doc No D-18.388 
 
INVESTIGATOR SIGNATURE PAGE 
Treatment name / number 
Ponesimod / ACT-128800 
Indication 
Relapsing Multiple Sclerosis 
Protocol number, study acronym, study title 
AC-058B301, OPTIMUM, Multicenter, randomized, double-blind, parallel-group, 
active-controlled, superiority study to compare the efficacy and safety of ponesimod to 
teriflunomide in subjects with relapsing multiple sclerosis. 
I agree to the terms and conditions relating to this study as defined in this protocol, the 
electronic Case Report Form (eCRF), and any other protocol-related documents. I fully 
understand that any changes instituted by the investigator(s) without previous agreement 
with the sponsor would constitute a protocol deviation, including any ancillary studies or 
procedures performed on study subjects (other than those procedures necessary for the 
wellbeing of the subjects). 
I agree to conduct this study in accordance with the Declaration of Helsinki principles, 
International Council on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, 
and applicable regulations and laws. I will obtain approval by an Institutional Review 
Board or Independent Ethics Committee (IRB/IEC) prior to study start and signed informed 
consent from all subjects included in this study. If an amendment to the protocol is 
necessary, I will obtain approval by an IRB/IEC and ensure approval by regulatory 
authorities (if applicable) have been obtained before the implementation of changes 
described in the amendment. I will allow direct access to source documents and study 
facilities to sponsor representative(s), particularly monitor(s) and auditor(s), and agree to 
inspection by regulatory authorities or IRB/IEC representative. I will ensure that the study 
treatment(s) supplied by the sponsor are being used only as described in this protocol. I 
will ensure that all subjects or legally designated representatives have understood the 
nature, objectives, benefits, implications, risks and inconveniences for participating in this 
study. During the conduct of the study, I will constantly monitor the risk/benefit balance 
for an individual subject. I confirm herewith that the sponsor is allowed to enter and utilize 
my professional contact details and function in an electronic database for internal purposes 
and for submission to Health Authorities worldwide. 
 
Country 
Site 
number 
Town 
Date 
 
Signature 
Site Principal 
Investigator 
 
 
 
 
 
 


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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 
LIST OF ABBREVIATIONS AND ACRONYMS .......................................................... 17 
SUBSTANTIAL GLOBAL AMENDMENT 6 ................................................................. 22 
PROTOCOL SYNOPSIS AC-058B301 ............................................................................ 31 
1 
BACKGROUND ......................................................................................................... 53 
1.1 
Multiple sclerosis ..........................................................................................53 
1.1.1 
Pathogenesis ......................................................................................53 
1.1.2 
Clinical course ..................................................................................53 
1.1.3 
Epidemiology ....................................................................................55 
1.1.4 
Treatment of MS ...............................................................................55 
1.1.4.1 
Injectable disease-modifying therapies ................................... 56 
1.1.4.2 
Orally administered disease-modifying therapies ................... 56 
1.2 
Sphingosine-1-phosphate receptors ..............................................................56 
1.3 
Ponesimod ....................................................................................................57 
1.3.1 
Nonclinical studies ............................................................................57 
1.3.2 
Clinical studies ..................................................................................58 
1.3.2.1 
Clinical pharmacology ............................................................ 58 
1.3.2.2 
Pharmacodynamics in humans ................................................ 59 
1.3.2.3 
Efficacy in humans .................................................................. 59 
1.3.2.4 
Safety and tolerability ............................................................. 60 
1.3.3 
Comparator drug ...............................................................................61 
1.4 
Purpose and rationale of the study ................................................................63 
2 
STUDY OBJECTIVES ............................................................................................... 63 
2.1 
Primary objective(s) .....................................................................................63 
2.2 
Secondary objectives ....................................................................................63 
3 
OVERALL STUDY DESIGN AND PLAN ............................................................... 64 
3.1 
Study periods ................................................................................................64 


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3.1.1 
Pre-randomization period .................................................................64 
3.1.2 
Treatment period ...............................................................................65 
3.1.3 
Post-treatment period and End-of-Study ..........................................65 
3.1.3.1 
Post-treatment safety follow-up period ................................... 65 
3.1.3.2 
Post-treatment observation period ........................................... 66 
3.1.4 
End-of-Study .....................................................................................66 
3.1.5 
Study duration ...................................................................................67 
3.1.6 
Sub-studies ........................................................................................67 
3.1.6.1 
Pulmonary function monitoring (DLCO) .................................. 68 
3.1.6.2 
Non-conventional MRI techniques ......................................... 68 
3.1.6.3 
Patient Preferences .................................................................. 68 
3.1.6.4 
Vaccination .............................................................................. 69 
3.1.7 
Extension study AC-058B303 (separate protocol) ...........................69 
3.2 
Study design rationale ..................................................................................69 
3.3 
Site personnel and their roles ........................................................................70 
3.3.1 
Principal investigator ........................................................................70 
3.3.2 
Treating neurologist ..........................................................................70 
3.3.3 
Efficacy assessor ...............................................................................72 
3.3.4 
First-dose administrator ....................................................................72 
3.3.5 
Clinical coordinator / study nurse .....................................................74 
3.3.6 
MRI staff ...........................................................................................75 
3.3.7 
Local neuroradiologist/radiologist ....................................................75 
3.3.8 
Ophthalmologist ................................................................................76 
3.3.9 
Pulmonary function laboratory technician or expert ........................76 
3.3.10 
Pulmonologist ...................................................................................76 
3.3.11 
Dermatologist ....................................................................................76 
3.4 
Study committees .........................................................................................77 
3.4.1 
Independent Data Monitoring Committee ........................................77 
3.4.2 
Statistical Analysis Center ................................................................77 
3.4.3 
Ophthalmology Safety Board ...........................................................77 
3.4.4 
Major adverse cardiovascular events adjudication board .................77 
4 
SUBJECT POPULATION .......................................................................................... 78 
4.1 
Subject population description .....................................................................78 
4.2 
Rationale for the selection of the study population ......................................78 
4.3 
Inclusion criteria ...........................................................................................79 
4.4 
Exclusion criteria ..........................................................................................80 
4.5 
Subjects of reproductive potential ................................................................84 
4.5.1 
Women of childbearing potential .....................................................84 
4.5.2 
Fertile male subject ...........................................................................85 


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4.6 
Medical history .............................................................................................85 
5 
TREATMENTS .......................................................................................................... 86 
5.1 
Study treatment .............................................................................................86 
5.1.1 
Investigational treatment: description and rationale .........................87 
5.1.2 
Comparator and matching placebo: description and rationale ..........88 
5.1.3 
Study treatment administration .........................................................88 
5.1.3.1 
Titration ................................................................................... 88 
5.1.3.2 
Maintenance ............................................................................ 89 
5.1.4 
Treatment assignment .......................................................................90 
5.1.5 
Blinding ............................................................................................90 
5.1.5.1 
Study drug material related blinding ....................................... 90 
5.1.5.2 
Functional blinding .................................................................. 90 
5.1.6 
Unblinding ........................................................................................93 
5.1.6.1 
Unblinding for final analyses .................................................. 93 
5.1.6.2 
Unblinding for IDMC .............................................................. 93 
5.1.6.3 
Unblinding for suspected unexpected serious adverse reactions
 ................................................................................................. 93 
5.1.6.4 
Emergency procedure for unblinding ...................................... 93 
5.1.7 
Study treatment supply .....................................................................94 
5.1.7.1 
Study treatment packaging and labeling ................................. 94 
5.1.7.2 
Study treatment distribution and storage ................................. 94 
5.1.7.3 
Study treatment dispensing ..................................................... 94 
5.1.7.4 
Study treatment return and destruction ................................... 95 
5.1.8 
Drug accountability and compliance ................................................95 
5.1.8.1 
Drug accountability ................................................................. 95 
5.1.8.2 
Drug compliance ..................................................................... 95 
5.1.9 
Study treatment dose adjustments and interruptions ........................96 
5.1.10 
Guidance for re-initiation of study treatment in the event of 
study treatment interruption ..............................................................96 
5.1.11 
Criteria for discharge from cardiac monitoring on Day 1, and 
on the first day of re-initiation of the investigational study drug 
following treatment interruptions .....................................................98 
5.1.12 
Premature discontinuation of study treatment ..................................99 
5.1.13 
Study-specific criteria for interruption / premature 
discontinuation of study treatment and management of 
clinically relevant events ................................................................100 
5.1.13.1 
Cardiovascular ....................................................................... 100 
5.1.13.2 
Hematological abnormalities and infections ......................... 101 
5.1.13.3 
Respiratory system ................................................................ 107 


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5.1.13.4 
Pregnancy .............................................................................. 108 
5.1.13.5 
Liver abnormalities ................................................................ 108 
5.1.13.6 
Renal function ....................................................................... 110 
5.1.13.7 
Ocular abnormalities ............................................................. 110 
5.1.13.8 
Skin reactions ........................................................................ 111 
5.1.13.9 
Peripheral neuropathy ............................................................ 111 
5.1.14 
Elimination of teriflunomide ..........................................................112 
5.1.14.1 
Accelerated elimination procedure for teriflunomide ........... 112 
5.1.14.2 
Compliance with accelerated elimination procedure ............ 112 
5.1.14.3 
Accountability of accelerated elimination procedure treatment
 ............................................................................................... 113 
5.1.14.4 
Duration of continued contraception after EOT .................... 113 
5.2 
Previous and concomitant therapy ..............................................................114 
5.2.1 
Definitions ......................................................................................114 
5.2.2 
Reporting of previous/concomitant therapy in the eCRF ...............114 
5.2.3 
Recommended concomitant therapy ...............................................115 
5.2.4 
Allowed concomitant therapy .........................................................115 
5.2.5 
Forbidden study-treatment-concomitant therapy ............................116 
6 
STUDY ENDPOINTS .............................................................................................. 117 
6.1 
Efficacy endpoints ......................................................................................117 
6.1.1 
Primary efficacy endpoint(s) ..........................................................117 
6.1.2 
Secondary efficacy endpoints .........................................................118 
6.1.3 
Other efficacy endpoints .................................................................119 
6.2 
Safety endpoints .........................................................................................120 
6.3 
Quality of life endpoints .............................................................................122 
6.4 
Pharmacoeconomic endpoints ....................................................................122 
6.5 
Pharmacokinetic and pharmacodynamic endpoints ....................................122 
6.5.1 
Pharmacokinetic endpoints .............................................................122 
6.5.2 
Pharmacodynamic endpoints ..........................................................122 
7 
STUDY ASSESSMENTS ......................................................................................... 122 
7.1 
Baseline assessments, including demographics ..........................................123 
7.1.1 
Informed consent Visit 1 (Screening) .............................................123 
7.1.2 
Baseline demographics and disease characteristics ........................124 
7.1.3 
Study-concomitant therapies ...........................................................124 
7.2 
Efficacy assessments ..................................................................................124 
7.2.1 
Neurological evaluation ..................................................................124 
7.2.2 
Detection and evaluation of relapses ..............................................125 
7.2.3 
MRI evaluations ..............................................................................128 


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7.2.4 
Supplementary non-conventional MRI sub-study ..........................129 
7.2.5 
MSFC ..............................................................................................129 
7.2.6 
Symbol Digit Modalities Test .........................................................130 
7.2.7 
FSIQ-RMS ......................................................................................130 
7.2.8 
Patient preferences ..........................................................................132 
7.2.9 
Patient’s Global Impression of Severity of Fatigue ........................132 
7.2.10 
Clinician’s Global Impression of Change of patient’s relapsing 
multiple sclerosis ............................................................................133 
7.3 
Safety assessments ......................................................................................133 
7.3.1 
12-lead electrocardiogram ..............................................................133 
7.3.2 
Blood pressure ................................................................................135 
7.3.3 
Body temperature ............................................................................136 
7.3.4 
Pulse rate .........................................................................................136 
7.3.5 
Spirometry ......................................................................................136 
7.3.6 
DLCO sub-study ...............................................................................138 
7.3.7 
Chest X-ray .....................................................................................140 
7.3.8 
Test for tuberculosis ........................................................................141 
7.3.9 
Ophthalmologic assessments ..........................................................141 
7.3.10 
Optical Coherence Tomography .....................................................142 
7.3.11 
Weight and height ...........................................................................143 
7.3.12 
Physical examination ......................................................................143 
7.3.13 
Dermatological examination ...........................................................143 
7.3.14 
Laboratory assessments ..................................................................144 
7.3.14.1 
Type of laboratory ................................................................. 144 
7.3.14.2 
Laboratory tests ..................................................................... 146 
7.4 
Electronic self-rated version of the Columbia-Suicide Severity Rating 
Scale (eC-SSRS) .........................................................................................149 
7.5 
Quality of life assessments .........................................................................150 
7.5.1 
36-Item Short Form Health Survey v2 (SF-36v2™) ......................150 
7.6 
Pharmacoeconomic assessments ................................................................150 
7.6.1 
Work Productivity and Activity Impairment Questionnaire: 
Multiple Sclerosis V2.0 ..................................................................150 
7.6.2 
Health care resource utilization ......................................................151 
7.7 
Pharmacokinetic and pharmacodynamic assessments ................................151 
7.7.1 
Pharmacokinetic assessments .........................................................151 
7.7.1.1 
Timing for sampling .............................................................. 151 
7.7.1.2 
Procedures for sampling ........................................................ 152 
7.7.1.3 
Labeling ................................................................................. 152 
7.7.1.4 
Bioanalysis ............................................................................ 152 
7.7.2 
Pharmacodynamic assessments ......................................................153 


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7.8 
Total blood volume .....................................................................................153 
8 
SCHEDULE OF VISITS .......................................................................................... 153 
8.1 
Pre-randomization period ...........................................................................155 
8.1.1 
Visit 1 (Screening) ..........................................................................155 
8.1.2 
Visit 2 (Baseline) ............................................................................156 
8.2 
Treatment period .........................................................................................158 
8.2.1 
Visit 3 – Randomization Day 1 .......................................................158 
8.2.1.1 
Visit 3 – Day 1 – pre-dose assessment .................................. 158 
8.2.1.2 
Visit 3 – Day 1 – Randomization and post-dose assessment 159 
8.2.2 
Additional safety laboratory tests until Week 24 (Week 6, 8, 
10, 14, 16, 18, 20, and 22) ..............................................................160 
8.2.3 
Visit 4 – Day 15 ..............................................................................160 
8.2.4 
Visit 5 – Week 4 .............................................................................161 
8.2.5 
Visit 6 – Week 12 and Visit 7 – Week 24 ......................................162 
8.2.6 
In-between-visit telephone calls until Weeks 108 (Weeks 18, 
30, 42, 54, 66, 78, 90, and 102) ......................................................163 
8.2.7 
Visits 8, 9, 11, and 13 – Weeks 36, 48, 72, and 96 .........................163 
8.2.8 
Visit 10 – Week 60 .........................................................................164 
8.2.9 
Visit 12 – Week 84 .........................................................................166 
8.2.10 
Visit 14 – EOT Visit .......................................................................167 
8.3 
Post-treatment period ..................................................................................169 
8.3.1 
Post-treatment safety follow-up period ...........................................169 
8.3.1.1 
Visit 15 – FU1 ....................................................................... 169 
8.3.1.2 
Visit 16 – FU 2 ...................................................................... 170 
8.3.2 
Post-treatment observation period ..................................................171 
8.4 
Unscheduled visits ......................................................................................173 
8.4.1 
Unscheduled visits for relapses (Visits R1, R2, etc.) ......................173 
8.4.2 
Additional unscheduled visits for re-initiation of study drug 
(I1, I2, etc.) .....................................................................................175 
8.5 
Unscheduled visits (any other assessment; U1, U2, U3, etc.) ....................176 
8.6 
Four-weekly pregnancy tests after EOS .....................................................177 
9 
STUDY COMPLETION AND POST-STUDY TREATMENT / MEDICAL CARE
 ................................................................................................................................... 177 
9.1 
Study completion ........................................................................................177 
9.2 
Premature withdrawal from study ..............................................................177 
9.3 
Premature termination or suspension of the study ......................................178 
9.4 
Medical care of subjects after study completion / withdrawal from 
study ............................................................................................................179 


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10 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ......................... 179 
10.1 
Adverse events ............................................................................................179 
10.1.1 
Definitions of adverse events ..........................................................179 
10.1.2 
Intensity of adverse events ..............................................................180 
10.1.3 
Relationship to study treatment ......................................................181 
10.1.4 
Adverse events associated to study design or protocol-
mandated procedures ......................................................................181 
10.1.5 
Reporting of adverse events ............................................................181 
10.1.6 
Reporting of MS relapse .................................................................182 
10.1.7 
Follow-up of adverse events ...........................................................182 
10.2 
Serious adverse events ................................................................................182 
10.2.1 
Definitions of serious adverse events .............................................182 
10.2.1.1 
Serious adverse events ........................................................... 182 
10.2.1.2 
Serious adverse events associated with the study design or 
protocol-mandated procedures .............................................. 183 
10.2.2 
Reporting of serious adverse events ...............................................183 
10.2.2.1 
During pre-randomization period .......................................... 183 
10.2.2.2 
During treatment period ........................................................ 184 
10.2.2.3 
During 30-day follow-up period ............................................ 184 
10.2.3 
Follow-up of serious adverse events ...............................................184 
10.2.4 
After the 30-day follow-up period ..................................................184 
10.2.4.1 
During the PTOP period (if applicable) ................................ 184 
10.2.4.2 
After the PTOP period ........................................................... 184 
10.2.5 
Reporting procedures ......................................................................184 
10.3 
Pregnancy ...................................................................................................185 
10.3.1 
Reporting of pregnancy ..................................................................185 
10.3.2 
Follow-up of pregnancy ..................................................................186 
10.4 
Study safety monitoring ..............................................................................186 
11 STATISTICAL METHODS ..................................................................................... 186 
11.1 
Analysis Sets ...............................................................................................187 
11.1.1 
Screened Analysis Set .....................................................................187 
11.1.2 
Full Analysis Set .............................................................................187 
11.1.3 
Per-Protocol Set ..............................................................................187 
11.1.4 
Safety Set ........................................................................................188 
11.1.5 
FSIQ-RMS Measurement Set .........................................................188 
11.1.6 
Other analysis sets ..........................................................................188 
11.1.7 
Usage of the analysis sets ...............................................................188 
11.2 
Variables .....................................................................................................189 
11.2.1 
Primary efficacy variable ................................................................189 


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11.2.2 
Secondary efficacy variables ..........................................................189 
11.2.2.1 
Fatigue Symptoms and Impact Questionnaire (FSIQ-RMS) 189 
11.2.2.2 
Cumulative number of CUAL from baseline to Week 108 ... 189 
11.2.2.3 
Time to 12-week CDA .......................................................... 189 
11.2.2.4 
Time to 24-week CDA .......................................................... 190 
11.2.3 
Other efficacy variables ..................................................................190 
11.2.3.1 
Exploratory efficacy variables ............................................... 190 
11.2.4 
Safety variables ...............................................................................192 
11.2.5 
Other variables ................................................................................192 
11.3 
Description of statistical analyses ...............................................................193 
11.3.1 
Overall testing strategy ...................................................................193 
11.3.2 
Analysis of the primary efficacy variable .......................................194 
11.3.2.1 
Hypotheses and statistical model .......................................... 194 
11.3.2.2 
Handling of missing data ....................................................... 195 
11.3.2.3 
Main analysis ......................................................................... 196 
11.3.2.4 
Supportive/sensitivity analyses ............................................. 196 
11.3.2.5 
Subgroup analyses ................................................................. 197 
11.3.3 
Analysis of the secondary efficacy variables ..................................198 
11.3.3.1 
Absolute change in FSIQ-RMS from baseline to Week 108 198 
11.3.3.2 
Cumulative number of combined unique active lesions ....... 198 
11.3.3.3 
Time to 12-week CDA .......................................................... 199 
11.3.3.4 
Time to 24-week CDA .......................................................... 200 
11.3.4 
Analysis of the other efficacy variables ..........................................201 
11.3.4.1 
Percent change in brain volume from baseline to Week 108 201 
11.3.4.2 
Number of Gd+ T1 lesions at Week 60 and Week 108 ......... 201 
11.3.4.3 
Change in volume of T2 lesions, T1 hypointense lesions, 
EDSS, 
 
from baseline to Week 60 and Week 108 .............................. 201 
11.3.4.4 
Absence of Gd+ T1 lesions, and new or enlarging T2 lesions 
and subjects relapse-free at Week 60 and Week 108 ............ 201 
11.3.4.5 
Other MRI endpoints ............................................................. 201 
11.3.4.6 
Time to first confirmed relapse ............................................. 202 
11.3.4.7 
NEDA status up to EOS ........................................................ 202 
11.3.4.8 
Change of MSFC Z-score and SDMT score from baseline to 
Week 108 ............................................................................... 202 
11.3.4.9 
Change of FSIQ-RMS and sub-scores from baseline to each 
visit (total score and impact score) ........................................ 202 
11.3.5 
Analysis of the safety variables ......................................................202 
11.3.5.1 
Adverse events ...................................................................... 203 
11.3.5.2 
Cardiac safety ........................................................................ 204 
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11.3.5.3 
Pulmonary safety ................................................................... 204 
11.3.5.4 
Vital signs .............................................................................. 205 
11.3.5.5 
Laboratory endpoints ............................................................. 205 
11.3.5.6 
Ocular safety .......................................................................... 206 
11.3.5.7 
Vaccine-specific antibody titers ............................................ 206 
11.3.5.8 
eC-SSRS ................................................................................ 206 
11.3.5.9 
Analysis of other variable(s) ................................................. 206 
11.4 
Interim analyses ..........................................................................................207 
11.5 
Sample size .................................................................................................208 
11.5.1 
Primary endpoint .............................................................................208 
11.5.2 
Secondary endpoints .......................................................................208 
11.5.2.1 
Cumulative number of CUAL ............................................... 208 
11.5.2.2 
Time to 12-week CDA .......................................................... 208 
11.5.3 
Sample size sensitivity ....................................................................209 
11.5.4 
Sample size re-estimation ...............................................................209 
11.5.5 
Other sample size considerations ....................................................209 
12 DATA HANDLING .................................................................................................. 210 
12.1 
Data collection ............................................................................................210 
12.2 
Maintenance of data confidentiality ...........................................................211 
12.3 
Database management and quality control .................................................211 
13 PROCEDURES AND GOOD CLINICAL PRACTICE ........................................... 212 
13.1 
Ethics and Good Clinical Practice ..............................................................212 
13.2 
Independent Ethics Committee / Institutional Review Board ....................212 
13.3 
Informed consent ........................................................................................212 
13.4 
Compensation to subjects and investigators ...............................................213 
13.5 
Protocol adherence/compliance ..................................................................213 
13.6 
Protocol amendments .................................................................................213 
13.7 
Essential documents and retention of documents .......................................213 
13.8 
Monitoring ..................................................................................................215 
13.9 
Investigator site file ....................................................................................216 
13.10 
Audit ...........................................................................................................216 
13.11 
Inspections ..................................................................................................216 
13.12 
Reporting of study results and publication .................................................217 
14 REFERENCES .......................................................................................................... 218 
 
 


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LIST OF TABLES 
Table 1 
Visit and assessment schedule (Part 1) ...................................................... 45 
Table 2 
Visit and assessment schedule (Part 2) ...................................................... 48 
Table 3 
Visit and assessment schedule (Part 3) ...................................................... 51 
Table 4 
Dosing scheme ........................................................................................... 89 
Table 5 
Guidance for subject monitoring and discontinuation for PFT decrease and 
persistent respiratory AEs ........................................................................ 107 
Table 6 
Guidance for subject monitoring and discontinuation for liver enzyme 
abnormalities ............................................................................................ 109 
Table 7 
Total blood volume to be drawn per subject ............................................ 153 
Table 8 
Thresholds for marked laboratory abnormalities ..................................... 232 
 
LIST OF FIGURES 
Figure 1 
Subjects who enter the extension study ...................................................... 65 
Figure 2 
Subjects who complete the 108-week treatment but do not enter the 
extension study ........................................................................................... 66 
Figure 3 
Subjects who prematurely discontinue study drug and enter the PTOP .... 66 
Figure 4 
AC-058B301 Study design ......................................................................... 67 
Figure 5 
Algorithm for management of treatment interruptions .............................. 98 
Figure 6 
Clinical assessment for potential PML ..................................................... 104 
Figure 7 
Flow diagram for the detection and evaluation of relapses ...................... 127 
Figure 8 
Overall testing strategy ............................................................................. 194 
 
 
 


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LIST OF APPENDICES 
Appendix 1 
Diagnostic criteria for MS (2010 Revised McDonald Criteria) ............... 223 
Appendix 2 
Neurostatus® scoring sheet ....................................................................... 225 
Appendix 3 
Guidance for concomitant treatment with QT-prolonging drugs with 
known risk of Torsades de Pointes ........................................................... 227 
Appendix 4 
Prohibited anti-arrhythmic and HR-lowering drugs ................................. 229 
Appendix 5 
Adverse events of special interest ............................................................ 230 
Appendix 6 
Abnormalities for ECG, BP and laboratory variables .............................. 231 
Appendix 7 
Multiple Sclerosis Functional Composite ................................................ 235 
Appendix 8 
Symbol Digit Modalities Test .................................................................. 239 
Appendix 9 
Fatigue Symptoms and Impacts Questionnaire – Relapsing Multiple 
Sclerosis (FSIQ-RMS) ............................................................................. 240 
Appendix 10 Work Productivity and Activity Impairment Questionnaire: Multiple 
Sclerosis ................................................................................................... 249 
Appendix 11 SF-36v2™ ................................................................................................ 251 
Appendix 12 Patient’s Global Impression of Severity (PGI-S) of Fatigue .................... 264 
Appendix 13 Clinician’s Global Impression of Change (CGI-C) .................................. 265 
Appendix 14 MS Patient Preference Questionnaire ...................................................... 266 
Appendix 15 Child Pugh Classification ......................................................................... 313 
Appendix 16 Electronic self-rated version of the Columbia-Suicide Severity Rating 
Scale (eC-SSRS) ...................................................................................... 314 
Appendix 17 Relapse assessment questionnaire ............................................................ 369 
Appendix 18 Relapse symptom form ............................................................................. 373 
 
 
 
 


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LIST OF ABBREVIATIONS AND ACRONYMS 
9-HPT  
9-Hole Peg Test 
ACTH  
Adrenocorticotropic hormone 
AE  
Adverse event 
ALT  
Alanine aminotransferase / serum glutamic pyruvic transaminase  
ANCOVA  
Analysis of covariance 
AP  
Alkaline phosphatase 
ARR  
Annualized Relapse Rate 
AST  
Aspartate aminotransferase / serum glutamic oxaloacetic 
transaminase  
ATS  
American Thoracic Society 
AV  
Atrioventricular  
BCRP  
Breast cancer resistant protein 
BP  
Blood pressure 
Bpm  
Beats per minute 
CDA  
Confirmed disability accumulation 
CGI-C  
Clinician’s Global Impression of Change 
CHMP  
Committee for Medicinal Products for Human Use 
CI  
Confidence interval 
CID  
Clinically Important Differences 
CNS  
Central nervous system 
CRO  
Contract Research Organization 
CSF  
Cerebrospinal fluid 
CTCAE  
Common terminology criteria for adverse events 
CTT  
Clinical trial team 
CUAL  
Combined unique active lesion 
CXR  
Chest X-ray 
CYP  
Cytochrome P450 
DBP  
Diastolic blood pressure 
DDI  
Drug-drug interaction 
DILI  
Drug-induced liver injury 


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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 
eC-SSRS  
Electronic self-rated version of the Columbia-Suicide Severity 
Rating Scale 
EDSS  
Expanded Disability Status Scale 
EMA  
European Medicines Agency 
EOS  
End-of-Study 
EOT  
End-of-Treatment 
ePRO  
Electronic PRO 
ERS  
European Respiratory Society 
ETDRS  
Early Treatment Diabetic Retinopathy Study 
FA  
Fluorescence angiography 
FAS  
Full Analysis Set 
FDA  
Food and Drug Administration 
FEF  
Forced expiratory flow 
FEV1  
Forced expiratory volume in 1 second 
FMS  
FSIQ-RMS Measurement Set 
FS  
Functional system 
FSIQ-RMS  
Fatigue Symptom and Impact Questionnaire-Relapsing Multiple 
Sclerosis 
FU  
Follow-up 
FVC  
Forced vital capacity 
GCP  
Good Clinical Practice 
Gd  
Gadolinium 
Gd+  
Gadolinium-enhancing 
Hb  
Hemoglobin 
HIV  
Human immunodeficiency virus 
HMG-CoA   
3-hydroxy-3-methylglutaryl coenzyme A 


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HR  
Heart rate 
i.m.  
Intramuscular 
i.v.  
Intravenous 
IB  
Investigator’s Brochure 
ICF  
Informed Consent Form 
ICH  
International Council on Harmonisation 
ICU  
Intensive care unit 
IDMC  
Independent Data Monitoring Committee 
IEC  
Independent Ethics Committee 
IFN  
Interferon 
IMP  
Investigational Medicinal Product 
INR  
International Normalized Ratio 
IRB  
Institutional Review Board 
IRT  
Interactive response technology 
ISF  
Investigator site file 
JCV  
John Cunningham Virus 
MACE  
Major Adverse Cardiovascular Events 
MedDRA  
Medical Dictionary for Regulatory Activities 
MIAC  
Medical Image Analysis Center 
MID  
Minimally Important Differences 
MRI  
Magnetic resonance imaging 
MS  
Multiple sclerosis 
MSFC  
Multiple Sclerosis Functional Composite 
MTR  
Magnetization transfer ratio 
NAWM  
Normal appearing white matter 
NEDA  
No evidence of disease activity 
NK  
Natural killer 
NMSS  
US National Multiple Sclerosis Society 
o.d.  
Once a day 
OAT  
Organic anion transporter 
OCT  
Optical coherence tomography 


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OSB  
Ophthalmology Safety Board 
PASAT  
Paced Auditory Serial Addition Test 
PBH  
Persistent black holes 
PCBV  
Percent change in brain volume 
PCR  
Polymerase chain reaction 
PD  
Pharmacodynamic 
PFT  
Pulmonary function test 
PGI-S  
Patient’s Global Impression of Severity 
PK  
Pharmacokinetic 
PML  
Progressive multifocal leukoencephalopathy 
PP  
Primary progressive 
PPMS  
Primary progressive multiple sclerosis 
PPS  
Per-Protocol Set 
PRMS  
Progressive relapsing multiple-sclerosis 
PRN  
As needed 
PRO  
Patient-reported outcome 
PTOP  
Post-treatment observation period 
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 
RMS  
Relapsing Multiple sclerosis 
RNA  
Ribonucleic acid 
RR  
Relapsing-remitting 
RRMS   
Relapsing-remitting multiple sclerosis 
s.c.  
Subcutaneous 
S1P  
Sphingosine-1-phosphate 
SAC  
Statistical Analysis Center 
SAE  
Serious adverse event 
SAF  
Safety Set 
SAP  
Statistical Analysis Plan 
SBP  
Systolic blood pressure 


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SDMT  
Symbol Digit Modalities Test 
SF-36v2™  
36-Item Short Form Health Survey Version 2 
SI  
International system of units 
SIENA  
Structural Image Evaluation, using Normalization, of Atrophy 
SIV  
Site initiation visit 
SOC  
System organ class 
SOP  
Standard operating procedure 
SPMS  
Secondary progressive multiple sclerosis 
SUSAR  
Suspected unexpected serious adverse reaction 
TB  
Tuberculosis 
ULN  
Upper limit of the normal range 
WBC  
White blood cell 
WHO  
World Health Organization 
WOCBP  
Woman of childbearing potential 
WPAI:MS  
Work Productivity and Activity Impairment: Multiple Sclerosis 


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SUBSTANTIAL GLOBAL AMENDMENT 6 
Amendment rationale 
This amendment rationale applies to global protocol AC-058B301 Version 6, dated 
30 August 2017. The resulting amended global protocol is Version 7, dated 5 December 
2018. 
The main reason for this amendment is to revise the secondary endpoints multiple testing 
strategy as explained further below. This revision is not based on information collected in 
the OPTIMUM study and no analysis has been performed on the OPTIMUM data to 
develop this proposal. All data collected remain fully blinded to the sponsor: 
i. 
Reduce the number of secondary endpoints in the OPTIMUM study from five to 
four to reduce the complexity of the testing strategy by including only the 
following: 
o Change from baseline to Week 108 in fatigue-related symptoms as 
measured by the symptoms domain of the Fatigue Symptom and Impact 
Questionnaire-Relapsing Multiple Sclerosis (FSIQ–RMS) 
o Cumulative number of Combined Unique Active lesions (CUAL) from 
baseline to Week 108 
o Time to 12-week Confirmed disability accumulation (CDA) from baseline 
to End of Study (EOS) 
o Time to 24-week CDA from baseline to EOS 
The “Time to 24-week CDA from baseline to EOS” endpoint will be moved from 
the exploratory endpoints to the category of secondary endpoints and the endpoints 
“Time to first confirmed relapse” and “Percent change in brain volume (PCBV) 
from baseline to Week 108” will be moved from the secondary endpoints list to the 
category of exploratory endpoints. 
The “Guideline on clinical investigation of medicinal products for the treatment of 
Multiple Sclerosis” [EMA 2015], dated 26 March 2015, recommends confirmation 
of disability accumulation based on a confirmatory Expanded Disability Status 
Scale (EDSS) at least 6 months apart as a relevant endpoint. From a regulatory point 
of view and as per EMA feedback to the sponsor, the “Time to 24-week CDA from 
baseline to EOS” endpoint would be relevant to be included as a secondary 
endpoint.  
The endpoints “Time to first confirmed relapse” and “PCBV from baseline to Week 
108” do not add substantial information on clinically important effects of the study 
drug on MS disease for the following reasons: 


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o The endpoint “Time to first confirmed relapse“ is highly correlated to the 
primary endpoint of ARR. Thus, although this endpoint may provide some 
additional insight into the drug’s effect on relapse activity, it is not expected 
to add relevant information to what is already available through the primary 
endpoint of ARR.  
o The clinical significance of brain volume loss in MS and the relevance of 
the endpoint “PCBV from baseline to Week 108” remains unclear as the 
degree of change in whole brain volume measurement that results in a 
clinically meaningful benefit is not well defined due to several 
methodological limitations in brain volume measurements. 
 
ii. 
Modify the multiple testing strategy for the control of the type I error by testing the 
secondary endpoints according to a fallback type method. As compared to the 
previously planned fixed-sequence hierarchical method, this will provide some 
opportunity to test an endpoint later in the sequence even if an endpoint tested 
earlier in the sequence has failed to show statistical significance. If statistical 
superiority of an endpoint tested earlier in the sequence can be shown the 
corresponding alpha can be passed on to endpoints later in the sequence. As a 
consequence, endpoints tested late in a fallback sequence are given a higher weight 
as compared to endpoints at the beginning of the sequence. This is in contrast to the 
previous planned hierarchical fixed sequence approach where endpoints at the 
beginning of the sequence receive a higher weight. To maintain the same weight 
ranking of the secondary endpoints it is proposed to change the order in the 
sequence. 
The hypothesis for the primary endpoint of ARR is first tested with the full alpha. 
If the primary endpoint null hypothesis is rejected, the alpha will be split evenly 
(1/3 of alpha) between the following three secondary endpoints using the fallback 
procedure, allowing for passing on alpha as per the following sequence: 
o Change from baseline to Week 108 in fatigue-related symptoms as 
measured by the symptoms domain of the FSIQ–RMS [Fatigue] 
o Cumulative number of CUAL from baseline to Week 108 [CUALs] 
o Time to 12-week CDA from baseline to EOS [12-week CDA]  
 
If a secondary endpoint listed as part of the fallback procedure above is successful, 
the preserved alpha is passed along to the next secondary endpoint in the sequence 
and the summed alpha is used for testing that endpoint. Thus, as sequential tests are 
successful, the alpha accumulates for the endpoints later in the sequence; these 
endpoints are then potentially tested with a progressively larger alpha, but always 
with at least 1/3 of the alpha. 


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In a last step, the secondary endpoint  
o Time to 24-week CDA from baseline to EOS [24-week CDA] 
 
is tested in a subsequent stage following Time to 12-week CDA with the remaining 
alpha.  
A graphical description of this testing strategy for the primary and secondary 
endpoints following the approach from Bretz, et al. [Bretz 2009] is provided in 
Figure 8 Overall testing strategy. 
Figure 8 
Overall testing strategy 
 
Based on the latest published information from recent MS trials, the disability 
accumulation rate is expected to be lower than assumed in earlier protocol versions 
[Cohen 2018, Comi 2018]. This results in a lower than anticipated probability of 
the study providing a robust evaluation of the effect of ponesimod on disability 
accumulation and, consequently, would have limited the ability to assess the other 
secondary endpoints with the previously planned hierarchical multiple testing 
strategy. The sponsor considers that the introduced fallback type multiple testing 
strategy optimizes the ability of the trial to obtain conclusive results on key disease 
parameters.  
Analyses for secondary endpoints will be conducted at an overall two-sided 5% 
alpha level, with multiplicity adjustment as per the above testing strategy. 95% 
confidence intervals will be presented. The statistical analyses sections and sample 
size calculations for the secondary endpoints have been updated accordingly.  


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Additional minor changes and clarifications were made to the protocol as follows: 
• Cladribine was added to the list of orally administered disease-modifying therapies. 
• It was clarified that oral taper of corticosteroids should not be administered in order 
to harmonize the treatment of relapses in the study and to minimize the risk of 
combined immunosuppression.  
• It was clarified that No evidence of disease activity (NEDA) status will be 
considered up to EOS. 
• It was corrected that health care utilization will be not be displayed by visit.  
• The possibility of using a chiral assay for the analysis of selected plasma PK 
samples was added to the protocol. Rationale: Metabolism of ponesimod may 
hypothetically result in chiral inversion of the parent compound to its S-enantiomer 
(ACT-128818). In plasma samples from rat and dog it was confirmed that this 
inversion did not occur in measurable quantities, using a chiral bioanalytical assay 
[ponesimod IB] but chiral inversion was never tested in humans. The validated 
bioanalytical assay that is currently being used in the study for the quantification of 
ponesimod is a non-chiral assay, not able to separate the enantiomers. 
• Wording was added to allow the analysis of biomarkers in the serum sample taken 
at Visit 2 (Baseline). 
• The definition of confirmed relapses was clarified. 
• It was clarified that the relapse assessment questionnaire may be completed during 
the additional safety blood draws (if applicable). 
• It was clarified that specific assessments collected at the end of treatment visit may 
be conducted up to 7 days prior to the last intake of study drug. 
• The definition of which EDSS assessment can qualify as confirmatory for 12- and 
24-week CDA was clarified in order to maximally use data provided by the 
investigator and minimize the impact of short-term relapse-related disability. 
Furthermore, some inconsistencies between sections in the protocol were corrected or 
clarified as follows: 
• The threshold for HHH grading for lymphocytes in Appendix 6 was aligned to the 
specifications in Sections 7.3.14.1 and 5.1.5.2. 
• The criteria leading to exclusion from the per-protocol set were aligned with the 
overall definition of the per protocol set regarding deviations that impact the 


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assessment of the primary or secondary endpoint leading to exclusion: Subjects 
developing discontinuation criteria that were not discontinued are not removed 
from per protocol analysis as these deviations are not considered to impact the 
assessment of the primary or secondary endpoint.  
In the statistical analysis section the following minor updates were made: 
• It was clarified that separate SAPs and reports will be prepared for the final analyses 
of PK data, the MRI sub-study and the Patient Preference sub-study.  
• Definition of highly active relapsing multiple sclerosis has been aligned with the 
updated therapeutic indications of Gilenya® in EMA [Gilenya® SmPC].  
• Treatment-emergent QTc > 450 ms, > 480 ms, > 500 ms are reported irrespective 
of gender to align with standard reporting. 
• For PFT reporting the provided thresholds are clarified to include subjects with a 
decrease of = 200 mL or = 12% in FEV1 or FVC.  
• The number of supportive / sensitivity statistical analyses was reduced to focus on 
the analyses required for the regulatory submission. 
• For the secondary endpoint change from baseline in FSIQ-RMS symptoms score to 
Week 108 reference to last observation carried forward has been removed and a 
repeated measurements ANCOVA using data from all scheduled visits (instead of 
an ANCOVA using only change from baseline to Week 108 data) will be applied 
to make use of all data collected at scheduled visits and make use of them in the 
analysis. 
• For the secondary and exploratory efficacy endpoints statistical models have been 
updated to adjust for the baseline result (where available) instead of the number of 
relapses in the year prior to study entry to increase statistical rigor and align with 
health authority recommendations. 
• For analyses of safety variables 95% CLs (not 99% CLs) are provided as they are 
considered descriptive analyses. 
• For analyses of AEs of special interest, and MACE, reference to logistic regression 
has been removed to align with analysis of specific safety events described in the 
introduction of Section 11.3.5.  
Finally, edits were done to correct typographical errors. 


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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: 
CONTRACT RESEARCH ORGANIZATIONS INFORMATION 
1.1.4.2  
Orally administered disease-modifying therapies 
5.2.3  
Recommended concomitant therapy 
6.1.1  
Primary efficacy endpoint(s) 
6.1.2  
Secondary efficacy endpoints 
6.1.3  
Other efficacy endpoints 
6.2 
 
Safety endpoints 
6.4 
 
Pharmacoeconomic endpoints 
7.2.2  
Detection and evaluation of relapses 
7.3.14.2 
Laboratory tests 
7.7.1.4   
Bioanalysis 
8.2.10  
Visit 14 – EOT Visit 
11 
 
Statistical Methods 
11.1.3  
Per-Protocol Set  
11.2.2  
Secondary efficacy variables 
11.2.2.1 
Fatigue Symptoms and Impact Questionnaire (FSIQ-RMS) 
11.2.2.2 
Cumulative number of CUAL from baseline to Week 108 
11.2.2.3 
Time to 12-week CDA 
11.2.2.4 
Time to 24-week CDA 
11.2.3.1 
Exploratory efficacy variables 
11.2.4  
Safety variables 


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11.3.1  
Overall testing strategy 
11.3.2.1 
Hypotheses and statistical model 
11.3.2.4 
Supportive/sensitivity analyses 
11.3.2.5 
Subgroup analyses 
11.3.3  
Analysis of the secondary efficacy variables 
11.3.3.1.1 
Hypothesis 
11.3.3.1.2 
Main Analysis 
11.3.3.1.3 
Supportive analyses 
11.3.3.2.1 
Hypothesis 
11.3.3.2.2 
Main Analysis 
11.3.3.2.3  
Supportive analyses 
11.3.3.3.1 
Hypothesis  
11.3.3.3.2 
Main Analysis 
11.3.3.3.3 
Supportive analyses 
11.3.3.4.1 
Hypothesis 
11.3.3.4.2 
Main Analysis 
11.3.3.4.3 
Supportive analyses 
11.3.4  
Analysis of the other efficacy variables 
11.3.4.1 
Percent change in brain volume from baseline to Week 108 
11.3.4.3 
Change in volume of T2 lesions, T1 hypointense lesions, EDSS, 
 
from baseline to Week 
60 and Week 108 
11.3.4.4 
Absence of Gd+ T1 lesions, and new or enlarging T2 lesions and 
subjects relapse-free at Week 60 and Week 108 
11.3.4.6 
Time to first confirmed relapse 
11.3.4.7 
NEDA status up to EOS 
11.3.4.9 
Change of FSIQ-RMS and sub-scores from baseline to each visit (total 
score and impact score) 
11.3.5 
Analysis of the safety variables 
CCI


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11.3.5.1.2 
AEs of special interest and MACE 
11.3.5.2.2 
Cardiac safety events 
11.3.5.3.1 
Pulmonary functional testing 
11.5.2.1 
Time to 12-week CDA 
11.5.2.2 
Cumulative number of CUAL 
13.12  
Reporting of study results and presentations 
Appendix 6 
Abnormalities for ECG, BP and laboratory variables 
 
 


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Summary of previous amendments 
Amendment 
Date 
Main reason(s) 
1 
29 April 2015 
Addition 
of 
a 
sub-study 
assessing 
patient 
preferences for different outcomes in the treatment 
of multiple sclerosis using an electronic Multiple 
Sclerosis Patient Preference Questionnaire. 
2 
16 July 2015 
Addressing the comments received after Voluntary 
Harmonization Procedure review for this Clinical 
Trial Application in the EU. 
3 
5 February 2016 
Addressing a comment received from the US FDA 
regarding the assessments of relapses. For this 
purpose, a standardized step-wise procedure for the 
confirmation and reporting of relapses has been 
introduced. 
4 
14 November 2016 
Modify the procedure for teriflunomide plasma 
concentration 
testing 
after 
the 
subject’s 
discontinuation from study treatment. 
5 
30 August 2017 
Allow 
the 
testing of 
teriflunomide 
plasma 
concentration in any subject who has discontinued 
study drug if deemed necessary for the subject’s 
safety, at the discretion of the investigator. 
 
 
 


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PROTOCOL SYNOPSIS AC-058B301 
TITLE 
Multicenter, 
randomized, 
double-blind, 
parallel-group, 
active-controlled, superiority study to compare the efficacy and 
safety of ponesimod to teriflunomide in subjects with relapsing 
multiple sclerosis (RMS) 
ACRONYM 
OPTIMUM: Oral Ponesimod vs Teriflunomide In relapsing 
MUltiple sclerosis  
OBJECTIVES 
Primary objective 
To determine whether ponesimod is more efficacious than 
teriflunomide in terms of reducing relapses in subjects with 
RMS. 
Secondary objectives 
1. To assess the effect of ponesimod on disability 
accumulation and on other aspects of multiple sclerosis 
(MS) disease control  
2. To assess the safety and tolerability of ponesimod in 
subjects with RMS. 
DESIGN 
Prospective, 
multicenter, 
randomized, 
double-blind, 
parallel-group, active-controlled, Phase 3, superiority study. 
PERIODS 
Pre-randomization period 
Up to 45 days before randomization. 
Treatment period 
The double-blind treatment period will last for 108 weeks. 
It will consist of a randomization visit, visits at two, four, and 
12 weeks after randomization, and 12-weekly visits thereafter.  
End-of-Treatment (EOT) 
• 
The EOT visit will take place at Week 108 (or earlier in 
case of premature discontinuation of study drug). In all 
cases, the EOT visit should take place one day after the last 
dose of study drug but no later than 7 days after the last 
dose of study drug.  
• 
Subjects who have completed treatment until Week 108 
will be proposed to enroll in an extension study conducted 
under a separate protocol. Subjects who discontinue study 
drug prematurely for any reason will not be eligible for the 
extension study. 


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• 
Subjects who prematurely discontinue study drug treatment 
should be subsequently treated according to local standard 
of care at the investigator’s discretion and will be followed 
in the post-treatment observation period. 
Post-treatment safety follow-up (FU) period:  
Teriflunomide is eliminated slowly from plasma. An 
accelerated elimination procedure must be used by all subjects 
after the last dose of study drug [see Section 5.1.14]. A safety 
FU after the last dose of study drug is mandated.  
All subjects will enter the safety FU period: 
• 
For subjects who enter the extension study, the FU period 
starts after the last dose of study drug and ends with a safety 
FU visit (FU1) 14–22 days after the last dose of study drug 
or with an abbreviated FU2 23–37 days after the last dose 
of study drug (if compliance to the teriflunomide 
accelerated elimination procedure was assessed as not 
sufficient at FU1).  
• 
For subjects who do not enter the extension study, the 
safety FU period lasts for 30 days after the last dose of 
study drug and includes two safety FU visits (FU1, FU2) at 
14–22 and 30–37 days after the last dose of study drug, 
respectively. 
Post-treatment observation period (PTOP): 
Subjects who prematurely discontinue study treatment will 
enter the PTOP which lasts until 108 weeks after randomization 
(i.e., planned EOT period). It consists of an abbreviated 
schedule of assessments at the time of the originally scheduled 
12-weekly visits.  
End-of-Study (EOS) 
• 
EOS is reached when treatment, safety FU, and, if 
applicable, PTOP have been completed. 
• 
For subjects who completed the 108-week treatment period 
and enter the extension study, the EOS visit corresponds to 
the FU visit (FU1) conducted 14–22 days after the last 
study drug dose or to the abbreviated FU2 visit conducted 
23–37 days after the last study drug dose (if needed for 
compliance reasons with the teriflunomide accelerated 
elimination procedure).  


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• For all other subjects, the EOS visit corresponds to the 
30-day FU visit (FU2) or to the last visit of PTOP (i.e., 
Week 108 Visit of the PTOP), whichever is last.  
PLANNED DURATION 
Approximately 171 weeks (3.3 years) from first subject first 
visit to last subject last visit. 
For an individual subject, the maximum duration of the study 
will be approximately 118 weeks (2.2 years). 
SITE(S) 
/ COUNTRY(IES) 
Approximately 200 sites in 25 countries in North America, 
South America, Eastern and Western Europe, Pacific (planned). 
SUBJECTS / GROUPS 
Approximately 1100 subjects will be randomized in 2 groups in 
a 1:1 ratio to receive ponesimod 20 mg (approximately 
550 subjects) 
or 
teriflunomide 
14 
mg 
(approximately 
550 subjects). 
Randomization will be stratified by prior use of MS 
disease-modifying treatment in the last two years prior to 
randomization (yes, no) and by baseline Expanded Disability 
Status Scale (EDSS) score (EDSS ≤ 3.5, EDSS > 3.5). 
INCLUSION CRITERIA 
This study will enroll adult male and female subjects aged 18 to 
55 years with established diagnosis of MS, as defined by the 
2010 revision of McDonald Diagnostic Criteria [Polman 2011], 
with relapsing course from onset (i.e., relapsing-remitting 
multiple sclerosis and secondary progressive multiple sclerosis 
[SPMS] with superimposed relapses). The trial will include up 
to a maximum 15% of subjects with SPMS with superimposed 
relapses.  
Subjects must have active disease evidenced by one or more MS 
attacks with onset within the period of 12 to 1 months prior to 
baseline EDSS assessment, or by two or more MS attacks with 
onset within the 24 to 1 months prior to baseline EDSS 
assessment, or with one or more gadolinium-enhancing (Gd+) 
lesion(s) of the brain on an MRI performed within 6 months 
prior to baseline EDSS assessment. Enrolled subjects must be 
ambulatory with an EDSS score of up to 5.5 inclusive. The 
subjects may be treatment-naïve (i.e., no MS disease-modifying 
therapy received at any time in the past) or previously treated 


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with interferon (IFN) β-1a, IFN β-1b, glatiramer acetate, 
dimethyl fumarate, or natalizumab. 
Women of childbearing potential (WOCBP) must have a 
negative pregnancy test during pre-randomization and must 
agree to use reliable methods of contraception from Visit 1 
(Screening) until 6 weeks after the first of two tests showing 
teriflunomide level < 0.02 mg/L. Fertile male subjects 
participating in the study who are sexually active with WOCBP 
must agree to use a condom during the treatment period and for 
an additional 6 weeks after the first of two tests showing 
teriflunomide level < 0.02 mg/L.  
Eligible subjects must be able and willing to give informed 
consent for participation in the clinical study. 
For the complete list of inclusion criteria, please see Section 4.3. 
EXCLUSION 
CRITERIA 
Subjects with significant medical conditions or therapies for 
such 
conditions 
(e.g., 
cardiovascular, 
pulmonary, 
immunological, hepatic, ophthalmological, ocular) or lactating 
or pregnant women are not eligible to enter the study. 
Subjects with contraindications to MRI or with clinically 
relevant medical or surgical conditions that, in the opinion of 
the investigator, would put the subject at risk by participating in 
the study are not eligible to enter the study. 
Finally, subjects unlikely to comply with protocol are not 
eligible to enter the study.  
For the complete list of exclusion criteria, please see 
Section 4.4. 
STUDY TREATMENTS 
 
 
 
 
 
 
One capsule of ponesimod 20 mg, or teriflunomide 14 mg, 
administered orally once daily preferably in the morning from 
Day 15 to EOT. 
To reduce the first-dose effect of ponesimod, an up-titration 
scheme will be implemented from Day 1 to Day 14: 
 
Ponesimod Group 
Days 1 and 2 
2 mg 
Days 3 and 4 
3 mg 
Days 5 and 6 
4 mg 
Day 7 
5 mg 


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Day 8 
6 mg 
Day 9 
7 mg 
Day 10 
8 mg 
Day 11 
9 mg 
Days 12, 13, and 14 
10 mg 
Day 15 until EOT 
20 mg 
 
CONCOMITANT 
THERAPY 
Treatment of relapses 
• 
If a relapse requires treatment with corticosteroids, 
methylprednisolone 1 g intravenous (i.v.) daily for 3 to 
5 days is recommended (without an oral taper). Treatment 
with other corticosteroids or another dose, or other routes 
of administration, or adrenocorticotropic hormone (ACTH) 
is not recommended, unless deemed absolutely necessary 
by the investigator who will document the rationale. 
• 
Treatment 
of 
relapses 
with 
plasma 
exchange 
(i.e., plasmapheresis, cytapheresis) is prohibited. 
Allowed concomitant therapy 
• 
Dalfampridine (synonymous with fampridine) on a stable 
dose for at least 90 days prior to randomization and during 
double-blind treatment. Dalfampridine therapy must not be 
started or increased in dose during the study. Stopping or 
decreasing the dose of dalfampridine during the study 
should only take place if deemed absolutely necessary by 
the investigator. 
• 
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 drug 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. 
• 
Vaccination with non-live vaccines. Subjects receiving 
non-live vaccination while on study treatment will have 
5 mL of blood drawn prior to and ≥ 3 weeks after 
vaccination in order to assess changes in vaccine-specific 


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antibody titers from pre- to post-vaccination. Samples will 
be analyzed at the end of the study. 
• 
The following medication should be administered with 
caution and carefully monitored due to potential 
interactions with teriflunomide: medications metabolized 
by cytochrome P450 (CYP)2C8 and CYP1A2, potent CYP 
and transporters inducers, medications with a low 
therapeutic index such as warfarin, substrates of organic 
anion transporter 3 (OAT3), breast cancer resistant protein 
(BCRP) and the organic anion transporter polypeptide 
(OATP) family (especially 3-hydroxy-3-methylglutaryl 
coenzyme A reductase inhibitors).  
• 
Other treatments considered necessary for the subject’s 
wellbeing and not categorized as prohibited concomitant 
medications. 
Prohibited concomitant therapy  
• 
Systemic corticosteroids and ACTH, except for the 
treatment of MS relapses and for short-term treatment with 
low dose or inhaled corticosteroids for pulmonary 
conditions; 
• 
Disease-modifying drugs for MS other than prescribed as 
per protocol; 
• 
Immunosuppressive treatment; 
• 
i.v. immunoglobulin; 
• 
Plasmapheresis, cytapheresis, or total lymphoid irradiation; 
• 
Vaccination with live vaccines; 
• 
β-blockers, diltiazem, verapamil, digoxin, or any other 
anti-arrhythmic or heart rate (HR)-lowering systemic 
therapy; 
• 
Cholestyramine or activated charcoal unless needed for an 
accelerated elimination procedure [see Section 5.1.14]; 
• 
Any other investigational drug;  
• 
Any investigational therapeutic procedure for MS 
(e.g., stent 
placement 
or 
angioplasty 
for 
chronic 
cerebrospinal 
venous 
insufficiency, 
stem 
cell 
transplantation). 


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ENDPOINTS 
Primary efficacy endpoint 
• 
Annualized relapse rate (ARR) defined as the number of 
confirmed relapses per subject-year.  
Secondary efficacy endpoints 
• 
Change from baseline to Week 108 in fatigue-related 
symptoms as measured by the symptoms domain of the 
Fatigue Symptoms and Impact Questionnaire – Relapsing 
Multiple Sclerosis (FSIQ–RMS);  
• 
Cumulative number of combined unique active lesions 
(CUAL; defined as new Gd+ T1 lesions plus new or 
enlarging T2 lesions [without double-counting of lesions]) 
from baseline to Week 108; 
• 
Time to 12-week confirmed disability accumulation (CDA) 
from baseline to EOS; 
• 
Time to 24-week CDA from baseline to EOS; 
Exploratory endpoints 
MRI-based exploratory endpoints: 
• 
Percent change in brain volume (PCBV) from baseline to 
Week 108; 
• 
Number of MRI lesions (Gd+ T1 lesions) at Week 60 and 
Week 108; 
• 
Cumulative number of new or enlarging T2 lesions from 
baseline to Week 108; 
• 
Change from baseline to Week 60 and Week 108 in the 
volume of MRI lesions (T2 lesions, T1 hypointense 
lesions); 
• 
Absence of MRI lesions (Gd+ T1 lesions, new or enlarging 
T2 lesions) at Week 60 and Week 108; 
• 
Proportion of Gd+ lesions at baseline evolving to persistent 
black holes (PBHs) by Week 108 (axonal loss); 
• 
Change of 
 
 
• 
Change in 
 
 
• 
Cumulative number of 
 
 
 
CCI
CCI
CCI


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Clinical exploratory endpoints (disease activity, relapses, 
disability accumulation): 
• 
Time to first confirmed relapse; 
• 
Absence of relapses from baseline to Week 60 and 
Week 108; 
• 
Change from baseline by visit up to Week 108 in EDSS; 
• 
No evidence of disease activity status at Week 108 (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 EOS, and 
completing treatment as planned). 
Other exploratory endpoints: 
• 
Change in Multiple Sclerosis Functional Composite 
(MSFC) Z-score from baseline by visit up to Week 108; 
• 
Change in the Symbol Digit Modalities Test (SDMT) score 
from baseline by visit up to Week 108; 
• 
Proportion of responders at Week 108 in fatigue-related 
symptoms as measured by the Fatigue Symptom and 
Impact 
Questionnaire-Relapsing 
Multiple 
Sclerosis 
(FSIQ-RMS); 
• 
Change from baseline by visit up to Week 108 in 
fatigue-related impacts as measured by the impact sub-
scales of the FSIQ–RMS. 
• 
Change from baseline in Patient’s Global Impression of 
Severity of Fatigue by visit up to Week 108;  
• 
Change from baseline in Clinician’s Global Impression of 
Change of the patient’s relapsing MS by visit up to 
Week 108; 
• 
Preferences for several treatment outcomes from MS 
subjects using the Measuring Attractiveness by a 
Categorical Based Evaluation Technique (MACBETH; 
sub-study, at selected sites only). 
Safety endpoints: 
• 
Treatment-emergent adverse events (AEs), serious adverse 
events, AEs of special interest, and major adverse 
cardiovascular events (MACE); 


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• 
AEs leading to premature discontinuation of study 
treatment; 
• 
Treatment-emergent 
morphological 
electrocardiogram 
(ECG) abnormalities (as defined by the ECG provider); 
• 
Change in 12-lead ECG variables (HR, PR, QRS, QT, 
QTcB, and QTcF) from pre-dose to selected post-doses 
assessments (1 h, 2 h, 3 h, 4 h) on Day 1 and on day of re-
initiation of study drug; 
• 
Notable 
abnormalities 
for 
selected 
12-lead 
ECG 
parameters (HR, PR, QT, QTcF) at 3-h post-dose 
assessment on Day 1, Week 12 and at the re-initiation of 
study drug when post-dose monitoring is required.  
• 
Treatment-emergent decrease of forced expiratory volume 
in 1 second (FEV1) or forced vital capacity (FVC) > 20% 
from baseline values; 
• 
Treatment-emergent decrease of percent predicted FEV1 or 
FVC > 20 percentage points from baseline values; 
• 
Change in FEV1 or FVC from baseline, absolute and % of 
absolute change to all timepoints up to EOS; 
• 
Change from baseline to EOS vs change from baseline to 
EOT in FEV1 or FVC (absolute and % of predicted); 
• 
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 and < 12% in FEV1 or FVC from 
baseline to last available FU; 
• 
Change in lung diffusion capacity as assessed by the 
diffusing capacity of the lung for carbon monoxide (DLCO; 
at selected sites only), expressed in absolute change and 
% of predicted value from baseline to all timepoints up to 
EOS; 
• 
Change from baseline to EOS vs change from baseline to 
EOT in DLCO (absolute and % of predicted) (at selected 
sites only); 
• 
Treatment-emergent notable blood pressure abnormalities; 
• 
Treatment-emergent notable laboratory abnormalities;  
• 
Change in body weight from baseline to EOS; 


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• 
Treatment-emergent electronic Columbia-Suicide Severity 
Rating Scale (eC-SSRS) suicidal ideation score of 4 or 
above, or a “yes” response on the eC-SSRS suicidal 
behavior item. 
Quality of life endpoints 
• 
Change from baseline by visit up to Week 108 in 
SF-36v2™ Health Survey domain and component scores. 
Pharmacoeconomic endpoints 
• 
Change from baseline by visit up to Week 108 in work 
productivity and activity impairment in MS (WPAI:MS) 
scores. 
• 
Health care resource utilization from baseline up to 
Week 108 (number of hospitalizations, length of stay, 
number of intensive care admissions for MS relapse and 
visits to an emergency medical services facility for MS). 
Pharmacokinetic (PK) endpoints 
• 
Plasma concentrations of ponesimod pre-dose at Week 12, 
Week 60 and Week 108 and 3 h post-dose on Day 1 and at 
Week 12. 
Pharmacodynamic (PD) endpoints 
• 
Peripheral blood lymphocyte counts pre-dose (absolute and 
change from baseline counts) by visit up to Week 108; 
• 
Change from baseline to EOS vs change from baseline to 
EOT in lymphocyte counts (absolute and % change); 
• 
Post-treatment lymphocyte recovery at 15 days and 30 days 
after study drug discontinuation. 
ASSESSMENTS 
See schedule of assessments in Table 1, Table 2, Table 3. 
STATISTICAL 
METHODOLOGY 
The Full Analysis Set (FAS) includes all randomized subjects. 
In order to adhere to the intention-to-treat principle as much as 
possible, subjects will be evaluated according to the treatment 
they have been randomized to.  
The Per-Protocol Set (PPS) comprises data from all subjects 
included in the FAS without major protocol deviations as 
categorized in Section 11.1.3.  


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The Safety Set (SAF) includes all randomized subjects who 
received at least one dose of study treatment. Subjects will be 
analyzed based on actual treatment taken, not randomized 
treatment. 
Statistical model and hypotheses for primary efficacy 
endpoint 
A generalized linear model with negative binomial distribution 
will be fitted for the primary efficacy endpoint ARR. Two-sided 
hypotheses are expressed in terms of the model parameters 
µP20mg and µT14mg. The primary null hypothesis is that the ARR 
(µ) does not differ between ponesimod 20 mg and teriflunomide 
14 mg. The alternative hypothesis is that the ARR differs 
between ponesimod 20 mg and teriflunomide 14 mg. 
H0, ARR: µP20mg - µT14mg = 0 
vs 
H1, ARR: µP20mg - µT14mg ≠ 0 
The null hypothesis will be tested by a two-sided Wald test 
within the negative binomial regression model with a two-sided 
significance level of 0.01 for conclusive evidence and 0.05 for 
a positive study. Two-sided 99% and 95% Wald confidence 
intervals will be calculated for the relative reduction in mean 
ARR for ponesimod 20 mg compared to teriflunomide 14 mg. 
The primary statistical analysis of the ARR endpoint will be 
performed on the FAS using a negative binomial model for 
confirmed relapses, with the stratification variables prior use of 
disease-modifying therapies (DMTs) and EDSS category as 
well as the number of relapses in the year prior to study entry, 
included in the model and time in the study as an offset variable. 
Sensitivity analyses will be performed on the PPS and also 
based on different subgroups derived from baseline variables. 
The secondary efficacy endpoints will be tested if the primary 
analysis on ARR has led to the rejection of the null hypothesis 
in favor of ponesimod 20 mg at an overall two-sided 
significance level of 0.05. A fallback method will be used for 
testing the family of hypotheses related to the following three 
secondary endpoints: 


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• Absolute change of FSIQ-RMS from baseline to Week 108. 
• Cumulative number of CUAL from baseline to Week 108; 
• Time to 12-week CDA from baseline up to EOS; 
This is followed in a hierarchical manner by testing  
• Time to 24-week CDA from baseline up to EOS; 
at the remaining alpha.  
The endpoints will be analyzed using the FAS population. All 
secondary endpoints will also be analyzed using the PPS 
population. 
The sample size was calculated based on the primary endpoint, 
and power calculations are provided for the secondary 
endpoints. 
Sample size for the primary endpoint 
The sample size for the study was determined by a simulation 
using the negative binomial distribution. A sample size of 
1100 subjects (550 per treatment group) would provide a power 
of approximately 90% for a significance level of 0.01, under the 
assumption that ARR is 0.320 for teriflunomide 14 mg 
and 0.215 for ponesimod 20 mg (which corresponds to a risk 
reduction of 33%) and using a dispersion = 0.9. An annual 
dropout rate of approximately 15% for the first year and 
7.5% for the second year has been assumed. 
The adjusted risk reduction for teriflunomide 14 mg in the fixed 
2-year duration TEMSO study was 31.5%, and in the variable 
duration TOWER study it was 36%. An integrated analysis 
showed a pooled 34% reduction compared to placebo. A 33% 
reduction for ponesimod 20 mg compared to teriflunomide 
14 mg gives a relative 55% reduction compared to placebo, 
which is similar to that observed in the fingolimod Phase 3 
trials. The dispersion from the ponesimod Phase 2 study was 
1.0, the calculated dispersion from the TEMSO study is 0.8; the 
chosen dispersion is the mean of the two. 
Exploratory efficacy endpoints 
No multiplicity adjustments will be made on exploratory 
efficacy endpoints. Any two-sided p-value < 0.05 will be 


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identified as statistically significant but will only be considered 
as an exploratory result. 
Safety endpoints 
Safety endpoints will mainly be analyzed descriptively by 
treatment group on the SAF. 
STUDY COMMITTEES 
An Independent Data Monitoring Committee (IDMC) 
composed of physicians with relevant medical expertise 
(including a neurologist, a neurovirologist, a neurologist with 
MRI expertise or a neuroradiologist, a cardiologist, a 
pulmonologist) and a statistician will review unblinded subject 
safety and efficacy data on an ongoing basis and is empowered 
to recommend modifications to the protocol (to enhance subject 
safety) or to recommend early termination of the study. The 
composition and operation of the IDMC are described in the 
IDMC charter. 
A statistical analysis center (a Contract Research Organization 
not otherwise involved with study conduct or statistical 
analysis) will generate unblinded analysis reports, exclusively 
for review by the IDMC throughout the trial period. 
An Ophthalmology Safety Board (OSB) composed of two 
independent ophthalmologists will review and evaluate − in a 
blinded fashion − any new or suspected cases of macular edema. 
The composition and operation of the OSB are described in the 
OSB charter. 
A MACE adjudication board will review and evaluate in a 
blinded fashion 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 the event 
belongs or not 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. 


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SUB-STUDIES 
Pulmonary function monitoring 
A sub-study assessing DLCO will be conducted in approximately 
400 subjects recruited at approximately 80 selected sites with 
appropriate equipment and experience. With the 1:1 
randomization (20 mg ponesimod or 14 mg teriflunomide), this 
will represent approximately 200 subjects per treatment group.  
Non-conventional MRI techniques 
MTR has better histological specificity than conventional 
T2-weighted MRI. MTR is sensitive to change over time and to 
treatment effects on NAWM and on focal lesions. DIR is a 
method that allows better visualization of grey matter lesions 
than conventional T2-weighted imaging. Both methods can be 
applied in multicenter settings. 
A sub-study using these non-conventional MRI techniques will 
be implemented in approximately 300 subjects recruited at 
selected sites with appropriate equipment and experience.  
Patient preferences 
A sub-study assessing patient preferences in approximately 
360 subjects recruited at selected sites will be conducted using 
an electronic questionnaire. The Multiple Sclerosis Patient 
Preference Questionnaire will be completed at home twice 
during the pre-randomization period (after Visits 1 and 
2 [Screening, Baseline]), and once during the follow-up period 
(Visit 15, FU1). 
Vaccination 
Changes in vaccine-specific antibody titers from pre- to 
post- vaccination will be assessed at the end of the study for 
subjects having received non-live vaccination while on study 
treatment.  
STUDY EXTENSION  
 
Extension study AC-058B303 (separate protocol) 
Subjects who complete the 108-week treatment will be 
proposed to enroll in a non-comparative extension study 
conducted under a separate protocol. 
 


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Table 1 
Visit and assessment schedule (Part 1) 
Periods 
Name 
PRE-RANDOMIZATION 
(1) 
TREATMENT PERIOD 
Duration 
Up to 45 Days 
108 Weeks 
Visits 
Number 
1 
2 
3 
4 
5 
6 
7 
8−9 
10 
Name 
Screening 
Baseline 
Rand 
W2 
W4 
W12 
W24 
W36 − 48 
W60 
Time 
Day −45 to −1 
Day 1 
Day 15 
Week 4 
Week 12 
Week 24 
Week 36 − 48 
Week 60 
Visit window 
 
 
 
± 1 day 
± 3 days 
± 7 days 
± 7 days 
± 7 days 
± 7 days 
Informed consent* 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria* 
X 
X 
X 
 
 
 
 
 
 
Demographics* 
X 
 
 
 
 
 
 
 
 
Medical history / smoking status* 
X 
X 
 
 
 
 
 
 
 
MS history & treatment* 
X 
 
 
 
 
 
 
 
 
McDonald criteria (revision 2010) 
X 
 
 
 
 
 
 
 
 
EDSS/FS* 
X 
X 
 
 
 
X 
X 
X 
X 
Relapse* (2) 
 
X 
X (2) <-----------------------------------------------------------------------------------------------------------------------> X (2) 
MSFC*, SDMT *  
X(3) 
X(3) 
X(3) 
 
 
X 
X 
 
X 
FSIQ-RMS** (4), PGI-S**, CGI-C*  
 
X(5) 
 
 
 
X 
X 
 
X 
SF-36v2** 
 
X 
 
 
 
X 
X 
 
X 
Health care resource utilization* (6) 
 
 
 
X 
X 
X 
X 
X 
X 
WPAI:MS** 
 
X 
 
 
 
X 
X 
 
X 
Patient preference questionnaire** (7) 
X 
X 
 
 
 
 
 
 
 
Chest X-ray* (8) 
X 
 
 
 
 
 
 
 
 
eC-SSRS** 
 
X 
 
 
 
 
 
 
X 
MRI** (9) 
 
X 
 
 
 
 
 
 
X 
Concomitant medications* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination*  
X 
X 
 
 
X 
X 
X 
 
X 
Dermatological examination* (10) 
 
X 
 
 
 
 
 
 
X 
Body weight and height* (11) 
X 
 
 
 
 
 
 
 
X 
Body temperature* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SBP/DBP* 
X 
X 
X(12) 
X 
X 
X 
X 
X 
X 
12-lead ECG** (13) 
X 
X 
X(14) 
X 
X 
X(15) 
X 
X 
X 
Ophthalmological examination* / OCT* (16) 
X 
 
 
 
 
X 
X 
 
X 
PFT** (17) 
 
X 
 
 
X 
X 
 
 
X 
Hematology/Chemistry** (fasted) 
X 
X 
 
X 
             X (18)  <------------> X (18)  
X 
X 
Urinalysis 
X 
 
 
 
X 
X 
X 
 
X 
Tuberculosis test / Viral serology ** 
X 
 
 
 
 
 
 
 
 
Additional serum sample for viral serology 
 
X 
 
 
 
 
 
 
 
Pregnancy test*/** 
X (19) 
X 
 
X 
X 
X 
X 
X 
X 
PK sampling for ponesimod* (20) 
 
 
X  
 
 
X 
 
 
X 
Study drug dispensing & accountability 
(21)*/** 
 
 
X 
X 
X 
X 
X 
X 
X 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 46/376 
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Doc No D-18.388 
 
Study drug swallowing test (optional) 
 
X 
 
 
 
 
 
 
 
AEs*/SAEs(22) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*Data collected in the eCRF 
**Data electronically transferred to sponsor. 
Day 1 (date of randomization visit) is to be used as the reference date for the purpose of calculating the subsequent visit dates (and time windows). 
(1) All pre-randomization assessments performed at Visit 1 (Screening) and Visit 2 (Baseline) may be conducted on days differing from the actual Visit 1 (Screening) 
date defined as the start of screening activities (i.e., signature of the informed consent form) and Visit 2 (Baseline)date defined as the date of baseline EDSS 
assessment. However, all pre-randomization assessments performed at Visit 1 and repeated at Visit 2 (Baseline; e.g., hematology, blood chemistry, urinalysis, 
physical examination, central laboratory, 12-lead ECGs, and SBP/DBP) must be performed at least 7 days after the Visit 1 (Screening) assessments. For women 
of childbearing potential, the serum pregnancy test at Visit 1 (Screening) must be performed at least 3 weeks before the urine pregnancy test performed pre-
randomization at Visit 2.The blood draw at Visit 2 (Baseline) should happen early enough in order obtain the results from the central laboratory and confirm 
the eligibility prior to randomization. 
(2) 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 in between the 12-weekly visits  
(e.g., Visit 6–Week 12, Visit 7–Week 24,…) in order to proactively inquire about any new or worsened neurological symptoms. These telephone calls will be 
conducted either at Weeks 18, 30, 42, 54, 66, 78, 90, and 102 (+/− 7 days), or 6 weeks after the last 12-weekly visit (+/− 7 days). 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 17]. 
(3) During pre-randomization, two practice tests and a third test serving as baseline assessment will be performed. Ideally, the three tests should be performed 
≥ 5 days apart (i.e., second test practice ≥ 5 days from first practice test and third test serving as baseline ≥ 5 days from second practice test). The first test 
practice may be done at Visit 1 (Screening), the second test practice may be done at Visit 2 (Baseline) and the third test serving as baseline may be performed 
pre-dose at Visit 3 (Randomization). 
(4) The symptoms scale (with a 24-h recall) will be completed for 7 consecutive days (the day of the visit and the 6 days after the visit). During pre-randomization, 
subjects during Visit 1 (Screening) will be provided with the FSIQ-RMS and will be instructed to complete the symptoms domain  
(i.e., section 1) of the FSIQ-RMS on 7 consecutive days prior to randomization at home (provided no other assessment performed in the meantime exclude the 
subject). Once the results from the laboratory tests confirm the subject’s eligibility, the site coordinator will contact the subject to instruct him/her to start the 
completion of the symptoms domain of the FSIQ-RMS at latest 7 days before the randomization. 
(5) No CGI-C assessment at Baseline. 
(6) Health care resource utilization data, including number of intensive care unit admission for MS relapses and emergency medical services facility visits for MS 
(7) Only for subjects participating in the patient preference substudy. The Multiple Sclerosis Patient Preference Questionnaire will be completed at home twice 
during pre-randomization (after Visits 1 and 2 [Screening and Baseline]). 
(8) Any CXR that has been performed within 90 days prior to screening can be used (in this case, no need to repeat CXR at Screening). In case of re-screening, 
CXR does not need to be repeated if CXR was performed within 90 days prior to the date of re-screening.  
(9) Brain MRI to be performed at any time an opportunistic infection in the central nervous system is suspected. In addition, non-conventional MRI techniques 
(MTR and DIR) will be performed at selected sites only.  
(10) Dermatological examination to be performed by a dermatologist. In case of re-screening, skin examination does not need to be repeated if skin examination 
from initial screening was performed within 90 days prior to the date of re-screening 
(11) Height only at Visit 1 (Screening). 
(12) SBP/DBP: Pre-dose and hourly (+/− 15 min) for at least 4 h post-dose and up to 12 h. 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 47/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
(13) Only pre-dose ECGs at all visits except Day 1 and Week 12. 
(14) Pre-dose and hourly (+/− 15 min) for at least 4 h post-dose and up to 12 h.  
(15) Pre-dose and 3-h (+/− 15 min) post-dose ECGs. 
(16) OCT and/or ophthalmological examination to be performed at any visit in the presence of visual symptoms or findings suggestive of macular edema or active 
uveitis [see Section 5.1.13.7].  
(17) Pulmonary function tests include spirometry to be performed pre-dose in all subjects and DLCO to be performed in a subset of approximately 400 subjects at 
selected sites only.  
(18) In addition, liver tests (ALT, AST, INR, alkaline phosphatase and total bilirubin) at Weeks 6, 8, 10, 14, 16, 18, 20, and, 22 will be collected, sent to, and 
analyzed at the central laboratory. Furthermore, total white blood cell and total lymphocyte counts will be assessed at Weeks 8, 16, and 20. The test window is 
± 3 days. Note: No relapse assessment questionnaire is needed when blood sample is drawn. 
(19) Serum pregnancy test at Screening, urine pregnancy test at all subsequent visits. Urine pregnancy tests (performed at home) on a 4-weekly (+/− 4 days) basis 
between the visits during the study (results to be communicated by telephone call to the principal investigator / treating neurologist). At all visits and telephone 
calls, the methods of contraception will be reviewed and the contraceptive method form entered in the eCRF must be updated as applicable. 
(20) Pharmacokinetic sampling pre-dose at Weeks 12, 60 and 108, and 3 h (+/− 15 min) post-dose on Day 1 and Week 12.  
(21) Scheduled study medication dispensing/return procedures may be adapted according to the site practice. 
(22) All AEs and SAEs that occur after signing the Informed Consent Form and up to 30 days after study treatment discontinuation must be reported. 
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CGI-C = Clinician’s Global Impression of Change of the patient’s relapsing 
MS; CXR = chest X-ray; DBP = diastolic blood pressure; DIR = double inversion recovery; 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; eCRF = electronic case report form; 
EDSS = Expanded Disability Status Scale; FS = functional system; FSIQ-RMS = Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis; INR 
= International Normalized Ratio; MRI = magnetic resonance imaging; MS = multiple sclerosis; MSFC = Multiple Sclerosis Functional Composite; MTR = 
magnetization transfer ratio; OCT = optical coherence tomography; PFT = pulmonary function test; PGI-S = Patient’s Global Impression of Severity of Fatigue; PI 
= principal investigator; PK = pharmacokinetics; SAE = serious adverse event; SBP = systolic blood pressure; SDMT = Symbol Digit Modalities Test; WPAI:MS 
= Work Productivity and Activity Impairment Index: Multiple Sclerosis. 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 48/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
Table 2 
Visit and assessment schedule (Part 2) 
Periods 
Name 
TREATMENT PERIOD 
FOLLOW-UP 
UNSCHEDULED 
Duration 
108 Weeks 
30 Days 
Visits 
Number 
11 
12 
13 
14 
15 
16 
R1, R2, … 
U1, U2, … 
I1, I2, … 
d1 
d15 
Name 
W72 
W84 
W96 
EOT 
FU1 
FU2 
Relapse 
Unscheduled 
(19) 
Re-initiation 
Day 1 of re-
initiation 
Day 15 after 
re-initiation 
Time 
Week 72 Week 84 Week 96 Week 108 or earlier 
in case of premature 
discontinuation (18) 
Last study 
drug intake 
+15 days 
Last study 
drug intake 
+30 days 
Any day between Day 1 and EOS 
Visit window 
± 7 days ± 7 days 
± 7 days 
± 7 days 
−1 day, 
+7days 
+7 days 
(22) 
+7 days 
NA 
NA 
± 1 day 
EDSS/FS* 
X 
X 
X 
X 
 
X 
X 
X 
 
 
Relapse* (1) 
X(1)<------------------------------------------------------>X(1) 
X 
X 
X 
X (21) 
 
 
MSFC*, SDMT* 
 
X 
 
X 
 
 
 
 
 
 
FSIQ-RMS** (2), PGI-S**, CGI-C * 
 
X 
 
X 
 
 
X 
X 
 
 
SF-36v2** 
 
X 
 
X 
 
 
X 
 
 
 
Health care resource utilization* (3) 
X 
X 
X 
X 
 
 
X 
 
 
 
WPAI:MS** 
 
X 
 
X 
 
 
 
 
 
 
Patient preference questionnaire** (4) 
 
 
 
 
X 
 
 
 
 
 
Chest X-ray* (5) 
 
 
 
X 
 
 
 
 
 
 
MRI** (6) 
 
 
 
X 
 
 
 
X 
 
 
eC-SSRS** 
 
 
 
X 
 
 
 
 
 
 
Concomitant medications* 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Physical examination*  
 
X 
 
X  
 
 
X 
X 
 
 
Dermatological examination* (7) 
 
 
 
X 
 
 
 
X 
 
 
Body weight* 
 
 
 
X 
 
 
 
X 
 
 
Body temperature* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SBP/DBP* 
X 
X 
X 
X 
X 
X 
 
X 
X(8) 
X 
12-lead ECG** (9) 
X 
X 
X 
X 
X 
X 
 
X 
X(9) 
X  
Pulse rate* 
 
 
 
 
 
 
X 
X(20) 
 
 
Ophthalmological examination / OCT* 
(10) 
 
 
 
X 
 
 
 
X 
 
 
Pulmonary function tests** (11) 
 
 
 
X 
X 
X 
 
X 
 
 
Hematology/Chemistry**(fasted) 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Urinalysis 
 
X 
 
X 
X 
 
 
X 
 
 
Viral serology 
 
 
 
 
 
 
 
X 
 
 
Pregnancy test*/** (12) 
X 
X 
X 
X 
X 
X (12) 
 
X 
 
 
Serum sample vaccination* (13) 
 
 
 
 
 
 
 
X 
 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 49/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
PK sampling for ponesimod* 
 
 
 
X 
 
 
 
X (14) 
 
 
Teriflunomide plasma concentration 
 
 
 
 
 
 
 
X (23) 
 
 
Accelerated elimination procedure  
 
 
 
X 
X (15) 
 
 
 
 
 
Accelerated elimination procedure 
compliance review 
 
 
 
 
X 
X (24) 
 
 
 
 
Study drug dispensing/accountability (16) 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
AEs/SAEs* (17) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*Data collected in the eCRF 
**Electronically transferred to sponsor. 
Day 1 (date of randomization visit) is to be used as the reference date for the purpose of calculating the subsequent visit dates (and time windows). 
 
(1) 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 in between the 12-weekly visits  
(e.g., Visit 6–Week 12, Visit 7–Week 24,…) in order to proactively inquire about any new or worsened neurological symptoms. These telephone calls will be 
conducted either at Weeks 18, 30, 42, 54, 66, 78, 90, and 102 (+/− 7 days), or 6 weeks after the last 12-weekly visit (+/− 7 days). 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 17]. 
(2) The symptoms scale (with a 24-h recall) will be completed for 7 consecutive days (the day of the visit and the 6 days after the visit).  
(3) Health care resource utilization data, number of intensive care unit admission for MS relapses and emergency medical services facility visits for MS. 
(4) Only for subjects-participating in the patient preference sub-study. The Multiple Sclerosis Patient Preference Questionnaire will be completed at home during 
follow-up period (before Visit 15 [FU1]). 
(5) In case of premature study drug discontinuation, the chest X-ray at EOT does not need to be performed if the EOT visit occurs within less than 24 weeks of the 
pre-randomization chest X-ray. 
(6) Brain MRI to be performed at any time an opportunistic infection in the CNS is suspected. In addition, non-conventional MRI techniques (MTR and DIR) will 
be performed at selected sites only. Note: in case of premature study treatment discontinuation, the MRI assessment at EOT does not need to be performed if 
the EOT visit occurs within less than 4 weeks of the MRI assessment at Visit 10 (Week 60). 
(7) Dermatological examination to be performed by a dermatologist.  
(8) SBP/DBP: Pre-dose and hourly (+/− 15 min) for at least 4 h post-dose and up to 12 h. 
(9) Pre-dose ECGs at all visits (when applicable) except re-initiation visits. At re-initiation, pre-dose and hourly (+/− 15 min) for at least 4 h post-dose ECGs and 
up to 12 h. 
(10) OCT and/or ophthalmological examination to be performed at any visit in the presence of visual symptoms suggestive of macular edema or active uveitis [see 
Section 5.1.13.7].  
(11) PFTs include spirometry to be performed pre-dose in all subjects and DLCO to be performed in a subset of approximately 400 subjects at selected sites only. 
(12) Serum pregnancy test at FU2. Urine pregnancy test at all other visits. Urine pregnancy tests (performed at home) on a 4-weekly basis between the visits during 
the study and continued after last study drug intake on a 4-weekly basis (+/− 4 days) (performed at home) until 6 weeks after the first of two tests showing 
teriflunomide plasma level < 0.02 mg/L (results of the pregnancy tests to be communicated by telephone call to the principal investigator / treating neurologist). 
At all visits and telephone calls, the methods of contraception will be reviewed and the contraceptive method form entered in the eCRF must be updated as 
applicable. 
(13) Pre- and post-vaccination sampling for vaccine-specific antibody titers for subjects having received non-live vaccination while on study treatment (sub-study) 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 50/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
(14) When possible, collect PK sample upon experiencing SAE. Preferably, sample will be collected pre-dose, as early as possible after SAE onset, and no later 
than 7 days after the last dose of study drug. 
(15) If the subject was not compliant with the accelerated elimination procedure, the procedure must be repeated or missing intakes completed. 
(16) Scheduled study medication dispensing/return procedures may be adapted according to the site practice.  
(17) All AEs and SAEs that occur after signing the Informed Consent Form and up to 30 days after study treatment discontinuation must be reported. 
(18) The EOT visit will take place at Week 108 (or earlier in case of premature discontinuation of study drug). In all cases, the EOT visit should take place 1 day 
after the last dose of study drug but no later than 7 days after the last dose of study drug. 
(19) Unscheduled visits may be performed at any time during the study and may include all or some of the indicated assessments, based on the judgment of the 
investigator. 
(20) Only if no 12-lead ECG is performed at this visit. 
(21) Only at unscheduled visits when the subject meets with the treating neurologist (but not at other unscheduled visits (e.g., conducted for repeat ALT or AST 
testing, repeat PFT testing,…). 
(22) For subjects not continuing in the AC-058B303 extension study, FU2 will be performed 30 to 37 days after last study drug intake. For subjects continuing in 
the AC-058B303 extension study, an abbreviated FU2 will be performed 23 to 37days after last study drug intake, if needed for compliance reasons. 
The abbreviated FU2 should include: Accelerated elimination procedure compliance review, AEs/SAEs, relapse, concomitant medications 
(23) The testing of teriflunomide plasma concentration may be conducted for women of childbearing potential and fertile male subjects, if needed to confirm that 
contraception may be discontinued. Teriflunomide plasma concentration can also be assessed for any subjects not entering the extension study if deemed 
necessary for the subject’s safety, at the investigator’s discretion. Testing must not be conducted earlier than i) 20 weeks after last drug intake if the subject’s 
compliance with the accelerated elimination procedure has been assessed as sufficient [see Section 5.1.14.2]; ii) 35 weeks (i.e., 8 months) after last drug intake 
or EOS, whichever is last, if the subject’s compliance with the accelerated elimination procedure has not been assessed as sufficient. 
(24) Only if the accelerated elimination procedure has been repeated or missing intake was completed after FU1. 
AE = adverse event; ALT = Alanine aminotransferase; AST = aspartate aminotransferase; CGI-C = Clinician’s Global Impression of Change of patient’s relapsing 
MS; CNS = central nervous system; DBP = diastolic blood pressure; DLCO = diffusing capacity for the lungs measured using carbon monoxide;  
DIR = double inversion recovery; eC-SSRS = electronic self-rated version of the Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram;  
eCRF = electronic case report form; EDSS = Expanded Disability Status Scale; EOS = End-of-Study; EOT = End-of-Treatment; FS = functional system;  
FSIQ-RMS = Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis; FU1 = follow-up visit 1; FU2 = follow-up visit 2; MRI = magnetic 
resonance imaging; MS = multiple sclerosis; MSFC = Multiple Sclerosis Functional Composite; MTR = magnetization transfer ratio; OCT = optical coherence 
tomography; PFT = pulmonary function test; PGI-S = Patient’s Global Impression of Severity of Fatigue; PI = principal investigator; PK = pharmacokinetics; SAE 
= serious adverse event; SBP = systolic blood pressure; SDMT = Symbol Digit Modalities Test; WPAI:MS = Work Productivity and Activity Impairment Index: 
Multiple Sclerosis. 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 51/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
Table 3 
Visit and assessment schedule (Part 3) 
Periods 
Name 
POST-TREATMENT OBSERVATION PERIOD (PTOP) 
(to be performed after EOT) 
Duration 
Up to 108 Weeks 
Visits 
Number 
6A, 8A, 9A, 
11A,13A  
7A, 12A 
10A, 14A 
Name 
W12A, W36A, 
W48A, W72A, 
W96A 
W24A, W84A 
W60A, W108A 
Time 
Week 12-36-48-
72-96 
Week 24 and 84 
Week 60 and 108 
Visit window 
±7 days 
±7 days 
±7 days 
EDSS/ FS* 
X 
X 
X 
Relapse*(1) 
X(1)<---------------------------------------------------------------------------------------------------------------------------------->X(1) 
MRI*  
 
 
X 
FSIQ-RMS** (2), PGI-S**, CGI-C * 
X (only Week12) 
X 
X 
Concomitant medications* 
X 
X 
X 
Physical examination*  
 
 
X 
Dermatological examination* (3) 
 
 
X 
SBP/DBP* 
X 
X 
X 
12-lead ECG ** 
 
 
X 
Body temperature* 
X 
X 
X 
Pulmonary function tests** (4) 
 
 
X (Week 108 only) 
Hematology/Chemistry** (fasted) 
 
X 
X 
Urinalysis* 
 
X 
X 
Pregnancy test*/** (5) 
X 
X 
X 
AEs/SAEs * 
X 
X 
X 
 
*Data collected in the eCRF 
**Electronically transferred to sponsor. 
Day 1 (date of randomization visit) is to be used as the reference date for the purpose of calculating the subsequent visit dates (and time windows). If the first PTOP 
visit windows overlaps with FU1 or FU2 visits, visits and assessments can be combined. 
(1) 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 of the 12-weekly visits 
(e.g., Visit 6A-Week 12, Visit 7A-Week 24,…) 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 17]. 
(2) The symptoms scale (with a 24-h recall) will be completed for 7 consecutive days (the day of the visit and the 6 days after the visit, except for Visit 14A, 
see Section 8.3.2). 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 52/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
(3) Dermatological examination to be performed by a dermatologist. 
(4) PFTs include spirometry to be performed in all subjects and DLCO to be performed in a subset of approximately 400 subjects at selected sites only.  
(5) Urine pregnancy test at all visits and performed at home on a 4-weekly basis between the visits until 6 weeks after the first of two tests showing teriflunomide 
plasma level < 0.02 mg/L (results of the pregnancy tests to be communicated by telephone call to the principal investigator / treating neurologist).  
AE = adverse event; DBP = diastolic blood pressure; DLCO = diffusing capacity for the lungs measured using carbon monoxide; ECG = electrocardiogram;  
eCRF = electronic case report form; EDSS = Expanded Disability Status Scale; EOT = End-of-Treatment; FS = Functional system; FU = follow-up;  
MRI = Magnetic resonance imaging; PI = principal investigator; PTOP = post-treatment observation period; SAE = serious adverse event; SBP = systolic blood 
pressure. 
 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 53/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
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 MRI. The 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 
[Confavreux 2014a, 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 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
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Version 7 
5 December 2018, page 54/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
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 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 to define 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 2005]. 


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Historically, the term clinically isolated syndrome has been 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, clinically isolated syndrome 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). 
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 [Confavreux 2014a]. 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 have to 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 
10 disease-modifying therapies (DMTs) approved in at least one country for the treatment 
of MS. 


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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 subcutaneously 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®)  
Additional injectable drugs are currently in late-stage development for the treatment of 
RMS, including ocrelizumab, daclizumab, and AIN457 (secukinumab).  
1.1.4.2 Orally administered disease-modifying therapies 
Several oral drugs have been approved for MS: 
• Fingolimod 0.5 mg orally 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 40 to 100 mg orally per treatment week (Mavenclad®) 
Oral drugs currently in late-stage development for the treatment of RRMS include 
laquinimod [Comi 2012], and a sphingosine 1-phosphate (S1P) receptor modulator, 
RCP1063/ozanimod. Siponimod, another S1P1 receptor modulator, is currently being 
developed for the treatment of SPMS. 
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 


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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].  
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. 


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• 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 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. 
• 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 4 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]. 
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 two-fold accumulation of the drug with 
repeated daily oral dosing, and steady state is achieved within 4−5 days. There is a good 


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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 h 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.  
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 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 10, 20, and 40 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% (p < 0.0001), 83% (p < 0.0001) and 43% 
(p < 0.05) in the 40, 20, and 10 mg groups, respectively vs placebo. 


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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 10, 20, and 
40 mg/day 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 results from an interim analysis of study AC-058B201/B202 with cut-off date of 
31 October 2014 have shown sustained low rates of MRI and clinical disease activity with 
dose-dependent effects on relapse rate and disability accumulation. The model-adjusted 
ARR observed with ponesimod 20 mg was approximately 0.170, a rate similar to that 
observed with the 1.25 mg dose of fingolimod after 5 years in the Phase 2 extension study 
[Izquierdo 2013]. There was also a dose-dependent effect of ponesimod on disability 
accumulation, with a decreasing risk of 6-month confirmed disability accumulation (CDA) 
and lower rates of EDSS worsening observed with increasing doses of ponesimod.  
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 h 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 desensitization. To minimize the 
first-dose effects on HR and AV conduction, a dose up-titration regimen was successfully 
tested and is implemented in current clinical trials.  


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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 h 
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. Data from an interim analysis of the long-term 
extension study AC-058B201/B202 with a cut-off date of 31 October 2013 showed that 
dose-dependent decrease in FEV1 remained stable in patients treated with ponesimod for a 
median of more than 3 years and remains reversible over the long term. 
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. 
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 a clinical study and for at least 30 days after study drug 
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]. 
1.3.3 Comparator drug 
Teriflunomide has been chosen as the active comparator. Teriflunomide is indicated for the 
treatment of patients with relapsing forms of MS [Aubagio® USPI, Aubagio® SmPC].  
Teriflunomide is a selective and reversible inhibitor of mitochondrial dihydroorotate 
dehydrogenase, an enzyme that is necessary for pyrimidine synthesis. The inhibition of 
pyrimidine synthesis results in a cytostatic effect on peripheral T- and B-lymphocytes, 
decreasing the number of activated lymphocytes that enter the CNS, thus decreasing the 
inflammatory response known to be present in the CNS in patients with MS. Teriflunomide 
is the active metabolite of leflunomide, marketed as ARAVA® for the treatment of 
rheumatoid arthritis since 1998.  
Teriflunomide is administered orally o.d. at the doses of 7 and 14 mg in the USA and 14 mg 
in EU and other countries such as Australia. The plasma levels of teriflunomide circulating 


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at the dose of teriflunomide of 14 mg/day are comparable to the circulating levels of 
teriflunomide when leflunomide is given at the recommended dose of 20 mg/day. 
Efficacy of Aubagio® was established in two pivotal placebo-controlled trials that enrolled 
2257 patients with RMS (TOWER and TEMSO) [Confavreux 2014b, O’Connor 2011]. In 
the TEMSO study, teriflunomide reduced the ARR (0.54 for placebo vs 0.37 for 
teriflunomide at either 7 or 14 mg), with relative risk reductions of 31.2% and 31.5%, 
respectively (p < 0.001 for both comparisons with placebo). Consistent results were 
obtained in the TOWER study. Compared to placebo, only teriflunomide at the dose of 14 
mg significantly reduced the risk of confirmed accumulation of disability in TEMSO (HR 
0.70 [95% CI (0.51–0.97)]) and in TOWER (HR 0.68 [95% CI (0.47-1.00)]). Both doses 
were also shown consistently superior to placebo on a range of MRI endpoints in the 
TEMSO study. 
In the clinical studies with teriflunomide in patients with RRMS, the incidence of serious 
adverse events (SAEs) was similar among the teriflunomide group and placebo-treated 
patients. The most common adverse events (AEs) associated with teriflunomide in RRMS 
patients included increased ALT levels, alopecia, diarrhea, influenza, nausea and 
paresthesia. Severe liver injury including fatal liver failure has been reported in patients 
treated with leflunomide. As a similar risk would be expected for teriflunomide, it is 
recommended to monitor ALT levels at least bi-weekly for 6 months after starting 
treatment; teriflunomide is contraindicated in patients with severe hepatic impairment and 
patients with pre-existing acute or chronic liver disease should not be treated with 
teriflunomide.  
Based on animal data, teriflunomide may cause major birth defects if used during 
pregnancy. Pregnancy must be excluded before starting treatment with teriflunomide, and 
teriflunomide is contraindicated in pregnant women or WOCB who are not using reliable 
methods of contraception.  
Teriflunomide is eliminated slowly from the plasma. Without an accelerated elimination 
procedure, it takes on average 8 months from discontinuing the drug to reach plasma 
concentrations less than 0.02 mg/L, although because of individual variations in drug 
clearance it may take as long as 2 years. An accelerated elimination procedure must be 
used after study drug discontinuation [see Section 5.1.14]. 
More detailed information can be found in the prescribing information [Aubagio® USPI, 
Aubagio® SmPC].  
Demonstration of superiority over teriflunomide in terms of ARR is clinically relevant, as 
it would provide evidence of significant benefit of the new investigational drug compared 
to a world-wide approved, effective, first-line oral therapy. 


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1.4 Purpose and rationale of the study 
The central role of S1P in lymphocyte trafficking and the ability of an S1P receptor 
modulator to reduce the availability of circulating lymphocytes is a promising therapeutic 
approach for autoimmune diseases [see Section 1.2]. The non-selective S1P receptor 
modulator fingolimod has been proven effective in the treatment of MS, leading to an 
approval for the treatment of RMS. 
The Phase 2 dose-finding study AC-058B201 demonstrated dose-dependent effects of the 
selective and orally active S1P1 receptor modulator ponesimod on relevant MRI variables, 
and on the lymphocyte count reduction [see Section 1.3.2.2]. Altogether, the above 
elements support further development of ponesimod for the treatment of RMS and suggest, 
if this profile is confirmed in this study, that ponesimod may offer a new type of selective 
immunomodulation for the treatment of RMS. 
This Phase 3 study is considered pivotal for the registration of ponesimod in the indication 
of relapsing forms of MS. The purpose of this study is to confirm the efficacy seen in the 
Phase 2 studies and to further evaluate the safety and tolerability of ponesimod in subjects 
with RMS. Ponesimod will be compared to the active comparator teriflunomide for its 
ability to reduce relapse rate, slow disability accumulation and reduce brain volume loss as 
detected by MRI during an overall treatment period of 108 weeks.  
The present study was designed in accordance with the 2006 CHMP guidance for product 
development in MS [EMA 2006] and its draft revision, adopted by the CHMP for release 
for public consultation [EMA 2012].  
2 
STUDY OBJECTIVES 
2.1 Primary objective(s) 
The primary objective of the study is to determine whether ponesimod is more efficacious 
than teriflunomide in terms of reducing relapses in subjects with RMS. 
2.2 Secondary objectives 
• To assess the effect of ponesimod on disability accumulation and on other aspects of 
MS disease control;  
• To assess the safety and tolerability of ponesimod in subjects with RMS. 


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3 
OVERALL STUDY DESIGN AND PLAN 
This is a prospective, multicenter, randomized, double-blind, active-controlled, 
parallel-group, Phase 3, superiority study. The study is designed to compare the efficacy, 
safety, and tolerability of ponesimod 20 mg vs teriflunomide 14 mg in adult subjects with 
relapsing forms of MS. 
Approximately 1100 subjects will be randomized in two groups in a 1:1 ratio to receive 
ponesimod 20 mg (approximately 550 subjects) or teriflunomide 14 mg (approximately 
550 subjects). Randomization will be stratified by use of MS disease-modifying treatment 
in the last two years prior to randomization (yes, no) and by baseline EDSS score  
(EDSS ≤ 3.5, EDSS > 3.5). 
The study will be conducted at approximately 200 sites in 25 countries in North America, 
South America, Eastern and Western Europe, and Pacific. Randomization will proceed 
until the required number of subjects has been reached. Any eligible subject in screening 
at the time of randomization of the 1100th subject will be recruited. It will be competitive 
across participating sites. The trial will include up to a maximum of 15% of subjects with 
SPMS. Screening of the subjects with SPMS will be permitted until a maximum of 
165 subjects with SPMS have been randomized. Any eligible subject with SPMS in 
screening at the time of randomization of the 165th subject with SPMS will be recruited. It 
is permitted to re-screen subjects once [see Section 8]. Actelion may wish to replace sites 
with no subject enrollment. 
Subjects who have completed treatment until Week 108 will be proposed to enroll in an 
extension study with ponesimod, conducted under a separate protocol. Those who 
discontinue study drug prematurely will not be eligible for the extension study. 
3.1 Study periods 
The organization of the different study periods is shown in Figure 1, Figure 2, and Figure 3. 
The study consists of the following periods: 
3.1.1 Pre-randomization period  
This period starts up to 45 days before randomization at the time of the signature of the 
Informed Consent Form (ICF) and ends with subject’s randomization. It includes Visit 1 
(Screening) and Visit 2 (Baseline). 


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3.1.2 Treatment period 
This period consists of a double-blind treatment period from Day 1 to Week 108. This 
period starts on the day of randomization immediately after the 1st dose of study drug intake 
(Visit 3−Day 1 of the study) and continues until the premature discontinuation of study 
drug or the scheduled End-of-Treatment (EOT) at Week 108.  
EOT visit: The EOT visit will take place at Week 108 or earlier in case of premature 
discontinuation of study drug. In all cases, the EOT visit should preferably take place 1 day, 
and not later than 7 days, after the last dose of study drug.  
3.1.3 Post-treatment period and End-of-Study 
This period starts immediately after the last dose of study drug and ends when 
End-of-Study (EOS) visit has been completed. It comprises the post-treatment safety 
follow-up (FU) period and if applicable, the post-treatment observation period (PTOP). 
3.1.3.1 Post-treatment safety follow-up period 
All subjects will enter the safety FU period: 
• For subjects who enter the extension study, the safety FU period lasts for 14–37 days 
after the last dose of study drug and includes a safety FU visit (FU1) 14–22 days after 
the last dose of study drug. If compliance to the teriflunomide accelerated elimination 
procedure is confirmed at FU1, the subjects will then be enrolled in the extension study. 
However, if compliance to the teriflunomide accelerated elimination procedure is not 
confirmed at FU1, the procedure may be repeated or missing intakes completed. In such 
cases an abbreviated FU2 will be conducted 23–37 days after the last dose of study 
drug. Provided sufficient compliance with the accelerated elimination procedure of 
teriflunomide [see Section 5.1.14.2] is documented, subjects will then be enrolled in 
the extension study. 
Figure 1 
Subjects who enter the extension study 
 
• For subjects who do not enter the extension study, the safety FU period lasts for 30 days 
after the last dose of study drug and includes two safety FU visits (FU1, FU2) at 14–
22 and 30–37 days after the last dose of study drug, respectively. 


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Figure 2 
Subjects who complete the 108-week treatment but do not enter the 
extension study  
 
3.1.3.2 Post-treatment observation period  
Subjects who prematurely discontinue study treatment will enter the PTOP, which lasts 
from the last dose of study drug until 108 weeks after randomization (i.e., planned EOT 
period). The PTOP includes an abbreviated schedule of assessments at the time of the 
originally scheduled 12-weekly visits. The safety FU period lasts for 30 days after the last 
dose of study drug and includes two safety FU visits (FU1, FU2). 
Figure 3 
Subjects who prematurely discontinue study drug and enter the 
PTOP 
 
 
3.1.4 End-of-Study  
For an individual subject, EOS is reached when treatment, safety FU, and, if applicable, 
PTOP have been completed:  
• For subjects who completed the 108-week treatment period and enter the extension 
study, the EOS visit corresponds to FU visit (FU1) conducted 14–22 days after the last 
study drug dose or to the abbreviated FU2 visit conducted 23–37 days after the last 
study drug dose.  
• For all other subjects, the EOS visit corresponds to the 30-day FU visit (FU2) or to the 
last visit of PTOP (i.e., Week 108 Visit of the PTOP), whichever is last. 


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EOS at study level occurs at the time all subjects have completed their EOS visits, as 
described above and schematically presented in Figure 1, Figure 2, and Figure 3. 
3.1.5 Study duration  
For an individual subject, the maximum duration of the study will be approximately 
118 weeks (2.2 years).  
The overall duration of the study is expected to be 171 weeks (3.3 years). The actual overall 
study duration or subjects’ recruitment period may vary.  
The overall study design is shown in Figure 4. 
Figure 4 
AC-058B301 Study design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
EOT 
 
EOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ponesimod 20 mg o.d. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Teriflunomide 14 mg o.d. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
          (Liver tests every 2 weeks) 
   (every 12 weeks visits) 
 
 
 
 
 
 
 
 
 
 
 
(telephone calls every 12 weeks*) 
 
 
 
 
  V1         V2  V3  V4  V5                               V6                                 V7               V8 to V12             V13                       V14      FU1    FU2 
                     D1 D15 W4                              W12                           W24       W36-48-60-72-84       W96                     W108  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-
randomiz
ation 
Period 
Up to 45 
days 
 
Treatment 
Period 
108 Weeks 
 
 
 
Follow-up 
30 days 
*Telephone calls in-between Visits 6 and Visit 14 (at Weeks 18, 30, 42, 54, 66, 78, 90, and 102). See Section 
8.2.6. D = day; EOS = End-of-Study; EOT = End-of-Treatment; FU = follow-up; M = month;  
V = visit; W = week. 
3.1.6 Sub-studies  
Several sub-studies designed to evaluate specific safety and/or efficacy parameters will be 
conducted in a subset of sites and subjects. 


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3.1.6.1 Pulmonary function monitoring (DLCO) 
A sub-study assessing the diffusing capacity of the lungs, measured using carbon monoxide 
(DLCO), will be conducted in approximately 400 subjects at selected sites with appropriate 
equipment and experience. All subjects recruited at the selected sites will be proposed to 
participate in the sub-study. 
3.1.6.2 Non-conventional MRI techniques 
Magnetization transfer ratio (MTR) has better histological specificity than conventional 
T2-weighted MRI. MTR seems to be sensitive to disease-related changes over time and to 
treatment effects on normal appearing white matter (NAWM) and on focal lesions. Double 
inversion recovery (DIR) is a method that allows better visualization of grey matter lesions 
than conventional T2-weighted imaging. Both methods can be applied to multicenter 
settings. 
A sub-study using these non-conventional MRI techniques will be implemented in 
approximately 300 subjects recruited at selected sites with appropriate equipment and 
experience. All subjects recruited at the selected sites will be proposed to participate in the 
sub-study.  
3.1.6.3 Patient Preferences 
The overall purpose of this sub-study is to capture patient preferences for selected treatment 
outcomes for use as an additional input to healthcare decisions. An increased understanding 
of individual values and preferences is the basis for shared decision-making, which in turn 
encourages patient compliance and health outcomes [Bowling 2001, Coyle 2001]. Patient 
preferences will be captured using a multi-criteria analysis model, Measuring 
Attractiveness by a Categorical Based Evaluation Technique (MACBETH). MACBETH 
uses a non-numerical questioning procedure to collect preference data. The responses are 
converted, by mathematical programming, to quantitative scores, thus allowing the 
construction of value function curves and the calculation of weights [Bana E Costa 1999, 
Fasolo 2014]. 
The sub-study will include a subgroup of approximately 360 patients who will be asked to 
complete the MS Patient Preference Questionnaire developed by Actelion [Appendix 14] 
at three different timepoints (twice during pre-randomization period [after Visits 1 and 2 
(Screening, Baseline)], and once during the follow-up period [Visit 15, FU1]). The 
questionnaire will be administered in electronic format and will assess the patient 
preferences for nine outcomes including frequency of relapses, worsening of disability and 
specific adverse outcomes.  
This sub-study has the following objectives: 1) To describe the value judgments of MS 
subjects within a clinical trial using the MACBETH methodology; 2) To assess the stability 
of MS subjects’ value judgments over two timepoints; 3) To describe the impact of 


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treatment on the preferences of MS subjects; 4) To describe the relationship between 
demographics, disease characteristics, previous medical history and elicited preferences 
among MS subjects at all timepoints; 5) To construct a treatment-decision model using the 
elicited preference data; and 6) To assess the comprehension and ease of use of the 
preference elicitation instrument. 
3.1.6.4 Vaccination 
Changes in vaccine-specific antibody titers from pre- to post-vaccination will be assessed 
at the end of the study for subjects having received non-live vaccination while on study 
treatment. 
3.1.7 Extension study AC-058B303 (separate protocol) 
Subjects who complete the 108-week treatment period will be proposed to enroll in a non-
comparative extension study with ponesimod treatment conducted under a separate 
protocol.  
3.2 Study design rationale 
This Phase 3 study is intended as pivotal for the registration of ponesimod for the treatment 
of relapsing forms of MS. This study is designed to assess superiority of ponesimod vs 
teriflunomide in reducing ARR in subjects with RMS. The design of this active-controlled 
study meets the requirements laid out by the relevant CHMP guideline [EMA 2006]. 
During the study, several decisions and assessments will have to be performed. In order to 
limit the considerable risk of bias, a double-blind design is warranted.  
With the availability of efficacious disease-modifying treatments, long-term 
placebo-controlled trials have become increasingly difficult to conduct in RMS. In order 
to evaluate the benefit/risk ratio of a new treatment, active-control parallel-group trials 
comparing the new treatment to an already approved treatment are recommended. In this 
context, a superiority trial remains the most reliable means of efficacy demonstration.  
Given the low ARR observed in RMS, a trial involving a large number of subjects treated 
for a 108-week duration is considered a minimum condition to observe a sufficient 
proportion of subjects experiencing relapses and allow for the demonstration of efficacy 
on ARR. 
The size and scope of the resulting safety database for all subjects treated with ponesimod 
at the time of marketing authorization application is anticipated to meet the requirements 
of the ICH [ICH E1A 1995] and CHMP guidelines [EMA 2006; EMA 2012]. 


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3.3 Site personnel and their roles 
In order to maintain the blind [see Section 5.1.5] throughout the study and 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. 
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 case of absence of any of the staff listed below. 
For each site, the study staff will consist of:  
• A principal investigator 
• A treating neurologist (who may be the principal investigator)# 
• An efficacy assessor#  
• A first-dose administrator# 
• A clinical coordinator/study nurse (if required) 
• MRI staff 
• A radiologist/neuroradiologist 
• An ophthalmologist 
• A pulmonary function laboratory technician or expert 
• A pulmonologist (only at sites participating in the DLCO sub-study)  
• A dermatologist. 
# The roles of treating neurologist, efficacy assessor and first-dose administrator are 
irreconcilable and must be assumed by three distinct physicians.  
3.3.1 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. 
3.3.2 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 drug administration, 


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assessing and reporting MS relapses on the specific MS relapses pages of the electronic 
case report form (eCRF) [see Section 7.2.2 and Section 10.1.6], monitoring of safety 
including recording and treating of AEs (with the exception of AEs with onset after study 
drug intake and resolution prior to discharge from cardiac monitoring on Day 1 or on the 
first day of re-initiation of study drug when post-dose monitoring is required, which will 
be recorded by the first-dose administrator), physical examination, routine laboratory 
results (with the exception of WBC and lymphocyte counts), concomitant medications, 
blood pressure (BP), and ECGs (with the exception of BP and ECG on Visit 3 [Day 1] or 
on first day of re-initiation of study drug when post-dose monitoring is required, which 
will be performed by the first-dose administrator). Depending on the site setting, all BP and 
ECG assessments required by the protocol during the study may be conducted by the first-
dose administrator [see Section 3.3.4]. The treating neurologist will not perform EDSS / 
FS assessment and will not alter the EDSS or FS scores obtained by the efficacy assessor. 
The treating neurologist will not have access to MRI throughout the study, unless necessary 
for safety reasons.  
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 4.5].  
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. 


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3.3.3 Efficacy assessor 
The efficacy assessor is a physician 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 / Functional system (FS) scores using the “Neurostatus” scoring 
documents [see Appendix 2] according to the protocol schedule, as well as EDSS/FS scores 
at every unscheduled visit for confirmation of relapse. If other trained and certified 
personnel participate in EDSS/FS scoring, they must not be involved in the clinical care 
and management of the study subject.  
Throughout the study, the efficacy assessor must remain unaware of AEs, concomitant 
medications, BP, ECG measurements, MRI and laboratory results, and any other data that 
have the potential to reveal the treatment assignment, in order to avoid potential bias due 
to unblinding. For that reason, all other members of the study staff, as well as the study 
subjects, must be instructed not to discuss clinical findings or safety issues with the efficacy 
assessor.  
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 2 years thereafter. 
The same physician should preferably maintain the role of efficacy assessor for a given 
subject throughout the study. 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 MSFC test.  
3.3.4 First-dose administrator 
The first-dose administrator must be a physician who is experienced in making health care 
decisions based on ECG interpretation reports provided in a timely manner by the central 
ECG laboratory, and experienced in the evaluation of BP and signs or symptoms. If the 
first-dose administrator is adequately trained and experienced in cardiology, she/he will 
make health care decisions solely based on her/his own interpretation of the ECG (i.e., in 
the case where the reading of the ECGs by the central ECG laboratory is not provided to 
the first-dose administrator in a timely manner).  


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She/he is responsible for conducting all BP and ECG assessments requested by the protocol 
at Visit 3 (Day 1) and at visits for re-initiation of study drug when post-dose monitoring 
will be required. This includes the close monitoring of the subject during the first 4 h and 
up to 12 h following study drug intake. 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. She/he will independently assess eligibility for discharge or continued subject 
management on Visit 3 and on visits for re-initiation of study drug when post-dose 
monitoring will be required [see Sections 5.1.9, 5.1.10, and 5.1.11]. 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. Depending on the 
setting at the site, the study drug administration at Visit 3 (Day 1) or at visits for 
re-initiation of study drug when post-dose monitoring is required, may be performed under 
the supervision of the treating neurologist. In this instance, the subject must rapidly be 
transferred under first-dose administrator supervision for close post-dose monitoring. 
On Day 1 and on the first day of re-initiation of study drug when post-dose monitoring is 
required, significant findings, which in view of the first-dose administrator meet the 
definition of AE, have an onset after the study drug intake, and are resolved at the time of 
discharge of the subject from the cardiac monitoring, must be recorded directly on the 
Adverse Event page of the separate eCRF by the first-dose administrator/delegate. These 
AEs will not be visible to any of the blinded study personnel at the study site. All other 
significant findings on Day 1 and on the first day of re-initiation of study drug when 
post-dose monitoring is required that are not resolved at the time of discharge of the subject 
from the cardiac monitoring or with an onset on any other day, which in view of the 
first-dose administrator meet the definition of AEs, must be reported to the principal 
investigator / treating neurologist, who will record these events on the AE page of the 
eCRF.  
The 3-h PK sample on Day 1 or on the first day of re-initiation of study drug when 
post-dose monitoring is required should be taken by the first-dose administrator, the 
first-dose administrator nurse or another person not involved in the clinical care and 
management of the study subject. 
Any cardiac events of potential clinical concern on Day 1 and on the first day of 
re-initiation of study drug when post-dose monitoring is required must be assessed by the 
first-dose administrator for seriousness. 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. In case of acute cardiac events, and if the 
first-dose administrator is not adequately trained and experienced in cardiology and is not 


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equipped to provide emergency treatment, she/he will refer the subject to a cardiologist to 
receive emergency care and treatment. 
Any AEs with onset on Day 1 or on the first day of study drug re-initiation of study drug 
when post-dose monitoring is required leading to the premature discontinuation of study 
drug must be reported by the first-dose administrator to the principal investigator / treating 
neurologist. Similarly, any SAEs with onset on Day 1 or on the first day of study drug re-
initiation of study drug when post-dose monitoring is required must be reported by the 
first-dose administrator to the principal investigator / treating neurologist.  
The first-dose administrator must ensure that blinded study personnel at the study site, such 
as the treating neurologist and the efficacy assessor, clinical coordinator / study nurse, and 
other personnel involved in the clinical care and management of study subject, do not have 
access to Day 1 or day of re-initiation of study drug post-dose BP assessment, or ECG 
interpretation reports or to AEs with onset after the study drug intake on Day 1 or on the 
first day of re-initiation of study drug when post-dose monitoring is required, and resolved 
at the time of discharge of the subject from the cardiac monitoring on that same day. When 
the exams themselves are performed by a delegate (e.g., a study nurse), this delegate must 
not be involved in the clinical care and management of the study subject (i.e., cannot be 
the clinical coordinator / study nurse of the study [see Section 3.3.5]).  
In case the first-dose administrator is responsible for conducting all BP and ECG 
assessments requested by the protocol during the study, he/she will report to the principal 
investigator / treating neurologist any significant findings in BP or ECGs which in his/her 
view meet the definition of an AE (with the exception of BP and ECG on Visit 3 [Day 1] 
or on first day of re-initiation of study drug when post-dose monitoring is required, which 
will be reported by the first-dose administrator as explained above). These must then be 
reported and recorded on the AE page of the eCRF by the principal investigator / treating 
neurologist. 
3.3.5 Clinical coordinator / study nurse 
Depending on the organization of the investigational site, a clinical coordinator / study 
nurse may be required to assist the principal investigator / treating neurologist in all aspects 
of subject’s management. She/he will be responsible for scheduling visits and assessments 
as planned in the study protocol, recording concomitant medications, maintaining source 
documentation, and transcription of data into the eCRF. She/he will instruct the subjects 
on study drug administration, and collect, process, and send all blood and urine samples to 
the central laboratory. Additionally, she/he may be responsible for coordinating the 
conduct of: 
• MRI 
• PFTs 


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• Ophthalmological and cardiac examination (except cardiac assessment on Day 1 and 
on day of re-initiation of study drug when post-dose monitoring is required [see Section 
3.3.4]) 
• MS Functional Composite (MSFC) score 
• Symbol Digit Modalities Test (SDMT) 
• Patient-Reported Outcome (PRO) instruments 
• Fatigue Symptom and Impact Questionnaire-RMS (FSIQ-RMS) 
• 36-Item Short Form Health Survey version 2 (SF-36v2™) 
• MS Patient Preference Questionnaire (if applicable) 
• Patient’s Global Impression of Severity (PGI-S) of Fatigue 
• Work Productivity and Activity Impairment: MS (WPAI:MS). 
In the absence of a clinical coordinator / study nurse, the above tasks will be performed by 
the principal investigator or a co-investigator. 
3.3.6 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 Medical 
Image Analysis Center (MIAC), c/o University Hospital Basel, Switzerland, and primary 
data will be stored at the study site.  
3.3.7 Local neuroradiologist/radiologist 
The local neuroradiologist will review the MRI images for safety purposes and will inform 
the principal investigator / treating neurologist of any findings of concern for the subjects’ 
safety, including non-MS related findings detected on the MRI scan. She/he will not 
communicate any efficacy-related MRI results (e.g., lesion counts) to study staff or to the 
subject, unless deemed necessary for maintaining safety of the subject. 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. She/he may support the principal investigator in making a decision on eligibility 
of the subject prior to randomization by reviewing historical MRI used to assess the 
eligibility of the subject in the study (i.e., active disease evidenced by one or more Gd+ 
lesion[s] of the brain on an MRI performed within 6 months prior to randomization). 
The local radiologist will review the chest X-ray (CXR) images. At Visit 1 (Screening), 
the local radiologist will assess CXRs in order to exclude any subject with findings 
suggestive of active or latent tuberculosis (TB); any CXR that had been performed within 
90 days prior to screening can be used; if available, there is no need to repeat CXR at 


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Screening). At EOT, the local radiologist will assess CXRs in order to characterize any 
pulmonary structural changes that could have occurred during treatment. She/he will 
inform the principal investigator / treating neurologist of any findings of concern for the 
subjects’ safety. Significant findings, which, in view of the local radiologist, meet the 
definition of an AE, must be reported to the principal investigator / treating neurologist and 
recorded on the AE page of the eCRF.  
Depending on site setting, the same local radiologist may review MRI images and CXR 
images or a local radiologist may review MRI images and another local radiologist may 
review CXR images. 
3.3.8 Ophthalmologist 
The ophthalmologist will review and interpret the ophthalmological examinations and 
optical coherence tomography (OCT) assessments as scheduled in the study protocol 
[see Section 7.3.9 and 7.3.10]. In the event of suspected clinically significant findings (e.g., 
macular edema), an unscheduled OCT examination should be performed by the 
ophthalmologist, and the principal investigator / treating neurologist will be notified for 
reporting of an AE. In the event of findings observed at any visit during the study, the 
ophthalmologist will conduct further examination, as per local standard practice, to rule 
out or confirm the diagnosis. 
3.3.9 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 (ATS) / European Respiratory 
Society (ERS) guidelines [Miller 2005a].  
3.3.10 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 drug 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. 
3.3.11 Dermatologist 
A dermatologist will perform complete skin examination as scheduled in the study protocol 
[see Section 7.3.13].  


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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 examination, as per local standard practice, to rule out 
or confirm the diagnosis. 
3.4 Study committees  
3.4.1 Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) has overall responsibility for 
safeguarding the interests of subjects by reviewing unblinded safety and efficacy data 
obtained in the study and making appropriate recommendations based on the reported data, 
thus ensuring that the study is being conducted with the highest scientific and ethical 
standards. The IDMC is also responsible for reviewing the data generated and for 
recommending on subsequent actions to be taken. These actions may include: 
• Recommending modifications to the study protocol to enhance subject’s safety.  
• Recommending the termination of the study at any time if major concerns arise 
regarding the safety of ponesimod. 
The IDMC is composed of physicians with relevant medical expertise (including a 
neurologist, a neurovirologist, a neurologist with MRI expertise or a neuroradiologist, a 
cardiologist, a pulmonologist), and a statistician and will be fully operational prior to 
enrolment of the first subject into the study. The composition and operation of the IDMC 
are described in the IDMC charter. 
3.4.2 Statistical Analysis Center 
A Statistical Analysis Center (SAC), a Contract Research Organization (CRO) not 
otherwise involved in study conduct or statistical analysis, will generate all unblinded 
analysis reports, throughout the trial period, exclusively for review by the IDMC. The 
unblinded reports will be generated from blinded efficacy and safety data periodically 
transferred to the SAC.  
3.4.3 Ophthalmology Safety Board 
An Ophthalmology Safety Board (OSB) composed of two independent ophthalmologists 
will review and evaluate in a blinded fashion any new or suspected cases of macular edema. 
The composition and operation of the OSB are described in the OSB charter. 
3.4.4 Major adverse cardiovascular events adjudication board 
A major adverse cardiovascular events (MACE) adjudication board will review and 
evaluate in a blinded fashion 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 


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MACE adjudication board will determine whether the event belongs or not to one of the 
pre-specified categories including cardiovascular death, myocardial infarction, and 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 aged 18 to 55 years with 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). The trial will include up to 15% of subjects with SPMS with 
superimposed relapses, but no forced randomization is planned.  
Subjects must have active disease evidenced by one or more MS attacks within the period 
of 12 to 1 months prior to baseline EDSS assessment, or by two or more MS attacks within 
the 24 to 1 months prior to baseline EDSS assessment, or with one or more Gd+ lesion(s) 
of the brain on an MRI performed within 6 months prior to baseline EDSS assessment. The 
MRI assessed at Visit 2 (Baseline) may be serving as the qualifying scan. Enrolled subjects 
must be ambulatory with an EDSS score of up to 5.5 inclusive. The subjects may be 
treatment-naïve (i.e., no MS disease-modifying therapy received at any time in the past) or 
previously treated with IFN β-1a, IFN β-1b, glatiramer acetate, dimethyl fumarate, or 
natalizumab.  
Subjects with significant medical conditions or therapies for such conditions 
(e.g., cardiovascular, pulmonary, immunological, hepatic, ophthalmological) are not 
eligible to enter the study.  
Eligible subjects must be able and willing to give informed consent for participation in the 
clinical study. 
4.2 Rationale for the selection of the study population 
RMS is the most frequent presentation of MS. Despite multiple therapies available, many 
subjects continue to experience relapses and accumulate disability.  
Subjects with SPMS represent a significant unmet medical need for new therapeutic 
options. These subjects have generally been less studied and have often not been included 
in pivotal trials of medications approved for treatment of RMS. For these reasons, it is 
important to also evaluate the benefit/risk profile of ponesimod in subjects with SPMS with 
superimposed relapses.  


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The clinical relevance of McDonald 2010 Diagnostic Criteria, including subjects with only 
one attack, in the presence of supplementary clinical and/or MRI criteria as well as the 
value of early treatment in MS are widely recognized. 
The study will enroll subjects with recent evidence of active disease as determined by 
clinical or imaging criteria, as these are prognostic factors that identify a patient population 
in whom effective disease-modifying treatment is particularly indicated. 
The study will recruit adult subjects, restricted to subjects between 18 and 55 years of age, 
as non-MS-specific MRI lesions can appear more frequently in older age. Such lesions and 
other CNS changes due to aging make the assessment of MS more difficult and may affect 
the response to treatment, which could result in inconclusive trial results. The age range of 
the study population will be representative of the general RMS population.  
Subjects with an EDSS score 0−5.5 may have developed mild to moderate impairment but 
are still ambulatory. The clinical care and management of these subjects is compatible with 
their inclusion in clinical trials. Outcomes measured in this study require ambulatory 
subjects (e.g., MSFC). The subjects with EDSS above 5.5 will often have SPMS with 
declining disease activity and would therefore make the study population too 
heterogeneous for testing a disease-modifying potential of a new MS compound. 
Subjects with significant cardiovascular, pulmonary, immunological, hepatic, or 
ophthalmological 
medical 
conditions 
or 
therapies 
are 
excluded 
since 
such 
conditions/therapies have the potential to put the subject at increased risk of adverse drug 
reactions, and/or interfere with the treatment effect, study assessment and interpretation of 
study results.  
4.3 Inclusion criteria 
For inclusion in the study, all of the following inclusion criteria must be fulfilled. It is not 
permitted to waive any of the criteria for any subject: 
1. Signed informed consent prior to initiation of any study-mandated procedure. 
2. Males and females aged 18 to 55 years (inclusive).  
3. Subjects of reproductive potential are eligible only if the following applies: 
• WOCBP: 
− 
must have a negative serum pregnancy test at Visit 1 (Screening) and a negative 
urine pregnancy test at Visit 2 (Baseline); 
− 
must agree to undertake 4-weekly urine pregnancy tests during the study and 
up to 6 weeks after the first of two tests showing teriflunomide plasma level 
< 0.02 mg/L; 


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− 
must agree to use reliable methods of contraception from Visit 1 (Screening; 
see Section 4.5.1) until 6 weeks after the first of two tests showing teriflunomide 
level < 0.02 mg/L. 
• Fertile male subjects participating in the study who are sexually active with 
WOCBP: 
− 
 must agree to use a condom during the treatment period and for an additional 
6 weeks after the first of two tests showing teriflunomide level < 0.02 mg/L.  
• Definition of WOCBP, fertile male subjects and the reliable methods of 
contraception for this study are described in Section 4.5. 
4. Presenting with a diagnosis of MS as defined by the revised (2010) McDonald 
Diagnostic Criteria for MS [see Appendix 1], with relapsing course from onset 
(i.e., RRMS, or SPMS with superimposed relapses).  
5. Having experienced one or more documented MS attacks with onset within the period 
of 12 to 1 months prior to baseline EDSS assessment, or two or more documented MS 
attacks with onset within the period of 24 to 1 months prior to baseline EDSS 
assessment, or having one or more Gd+ lesion(s) of the brain on an MRI performed 
within 6 months prior to baseline EDSS assessment (MRI assessed at Visit 2 [Baseline] 
may be the qualifying scan). 
6. Treatment-naïve or previously treated with IFN β-1a, IFN β-1b, glatiramer acetate, 
natalizumab, or dimethyl fumarate.  
7. Ambulatory and with an EDSS score between 0 and 5.5 (inclusive) at Visit 1 
(Screening) and Visit 2 (Baseline). 
8. Agreeing to use an accelerated elimination procedure for teriflunomide after the last 
dose of study drug [see Section 5.1.14 for the description of the accelerated elimination 
procedure]. 
4.4 Exclusion criteria 
Subjects must not fulfill any of the following exclusion criteria. It is not permitted to waive 
any of the criteria for any subject: 
Pregnancy and Breastfeeding 
1. Lactating or pregnant women. 
2. Subjects wishing to parent a child during the study. 
MS disease 
3. Evidence of a relapse of MS with onset within 30 days prior to baseline EDSS 
assessment 
or 
between 
baseline 
EDSS 
assessment 
and 
randomization 
[see Section 6.1.1]. 
4. Presenting with a diagnosis of MS with progressive course from onset (i.e., primary 
progressive MS or progressive relapsing MS). 


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Treatments 
5. Treatment with the following medications within 7 days prior to randomization: 
• 
IFN β-1a, IFN β-1b, or glatiramer acetate 
6. Treatment with the following medications within 15 days prior to randomization: 
• β-blockers, diltiazem, verapamil, digoxin or any other anti-arrhythmic or HR 
lowering systemic therapy [non-exhaustive list of drugs provided in Appendix 4] 
• 
Cholestyramine or activated charcoal  
7. Treatment with the following medications within 30 days prior to randomization: 
• Adrenocorticotropic hormone (ACTH) or systemic corticosteroids (for any reason) 
• 
Dimethyl fumarate 
• 
Vaccination with live vaccines 
8. Treatment with the following medications within 90 days prior to randomization: 
• 
Plasmapheresis, cytapheresis 
• 
i.v. immunoglobulin 
• Treatment with an investigational drug (within 90 days or five half-lives of the drug, 
whichever is longer), except biological agents (see below) 
9. Treatment with the following medications within 180 days prior to randomization: 
• 
Azathioprine, methotrexate, or cyclophosphamide 
• 
Natalizumab 
• 
Other systemic immunosuppressive treatment (e.g., cyclosporine, sirolimus, 
mycophenolic acid) 
• 
Non-lymphocyte-depleting experimental biological agents (e.g., daclizumab) 
10. Treatment with the following medications within 24 months prior to randomization: 
• 
Lymphocyte-depleting biological agents such as rituximab or ocrelizumab 
• 
Cladribine 
11. Treatment with the following medications at any time prior to randomization: 
• 
Alemtuzumab  
• 
Mitoxantrone, leflunomide, or teriflunomide 
• 
Fingolimod 
• 
Ponesimod 
• 
Other investigational S1P modulators 
• 
Stem-cell transplantation 
Infection and Infection Risk 
12. Ongoing known bacterial, viral or fungal infection (with the exception of 
onychomycosis and dermatomycosis), positive hepatitis B surface antigen test at 
Visit 1 (Screening) (unless hepatitis B vaccination has occurred within 4 weeks prior 
to a positive screening test and a repeat hepatitis B surface antigen test performed 
≥ 2 weeks after the initial test has been negative) or hepatitis C antibody tests at Visit 1 
(Screening). 


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13. Congenital or acquired severe immunodeficiency or known human immunodeficiency 
virus (HIV) infection or positive HIV testing at Visit 1 (Screening). 
14.  Negative antibody test for varicella-zoster virus at Visit 1 (Screening). 
36. Known Progressive Multifocal Leukoencephalopathy (PML) infection or evidence of 
new neurological symptoms or MRI signs within 6 months prior to randomization 
which are compatible with a diagnosis of PML infection  
Malignancy  
15. History or presence of malignancy (except for surgically excised basal or squamous 
cell skin lesions), lymphoproliferative disease, or history of total lymphoid irradiation 
or bone marrow transplantation. 
16. Presence of pre-cancerous (e.g., actinic keratosis, atypical moles) or cancerous skin 
lesions (e.g., basal cell carcinoma, squamous cell carcinoma) at Visit 2 (Baseline). 
Ophthalmologic 
17. Presence of macular edema. 
Cardiovascular 
18. Any of the following cardiovascular conditions: 
• Resting HR < 50 bpm as measured by the pre-randomization 12-lead ECG on 
Day 1 
• Myocardial infarction within 6 months prior to randomization or ongoing unstable 
ischemic heart disease 
• Cardiac failure (New York Heart Association class III or IV) or any severe cardiac 
disease at the time of Visit 1 (Screening) or randomization 
• History or presence of valvular heart disease associated with symptoms or 
significant hemodynamic change according to investigator judgment 
• History or presence of cardiac rhythm disorders (e.g., sino-atrial heart block, 
symptomatic bradycardia, atrial flutter or atrial fibrillation, ventricular arrhythmias, 
cardiac arrest) 
• Presence of second-degree AV block Mobitz Type II or third-degree AV block, or 
a QTcF interval > 470 ms (females), > 450 ms (males) as measured by 12-lead 
ECG at Visit 1(Screening) or Visit 2 (Baseline) or by the pre-dose ECG at Visit 3 
(Randomization / Day 1) 
• History of syncope associated with cardiac disorders 
• Systemic arterial hypertension not controlled by medication according to the 
investigator’s judgment 
Metabolic 
19. Type 1 or 2 diabetes that is poorly controlled according to the investigator’s judgment, 
or diabetes complicated with organ involvement such as nephropathy or retinopathy. 


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Pulmonary 
20. Subjects with a clinically significant pulmonary condition including:  
• Asthma that is insufficiently controlled according to the investigator’s judgment, 
or any hospitalization due to asthma exacerbation within 6 months prior to 
randomization 
• Abnormal PFTs: FEV1 or forced vital capacity (FVC) < 70% of the predicted 
normal value at Visit 2 (Baseline) 
21. Active or latent TB, as assessed by CXR performed at Visit 1 (Screening) or within 
90 days prior to Visit 1 (Screening), or IFN gamma release assay 
(QuantiFERON-TB-Gold®) at Visit 1 (Screening), except if there is documentation 
that the subject has received adequate treatment for latent TB infection or TB disease 
previously 
Hematology 
22. Any of the following abnormal laboratory values at Visit 1 (Screening) or Visit 2 
(Baseline): 
• 
Hemoglobin (Hb) < 100 g/L 
• 
White blood cell (WBC) count < 3.5 × 109/L (< 3500/mm3) 
• 
Neutrophil count < 1.5 × 109/L (< 1500/mm3) 
• 
Lymphocyte count < 0.8 × 109/L (< 800/mm3)  
• 
Platelet count < 100 × 109/L (< 100,000/mm3) 
Hepatic 
23. Known history of active hepatitis B or C any time prior to randomization or known 
history of active hepatitis A within 3 years prior to randomization.  
24. Presence of chronic liver or biliary disease. 
25. Moderate or severe hepatic impairment defined as Child Pugh Score B or C, 
respectively, based on measurement of total bilirubin, serum albumin, International 
Normalized Ratio (INR) and as well as on presence/absence and severity of ascites and 
hepatic encephalopathy [Appendix 15].  
26. Any of the following abnormal laboratory values at Visit 1 (Screening) or Visit 2 
(Baseline): 
• 
ALT/SGPT > 2 × the upper limit of normal (ULN)  
• 
AST/SGOT > 2 × ULN 
• 
Total bilirubin > 1.5 × ULN (unless in the context of known Gilbert’s Syndrome). 
Renal 
27. Hypoproteinemia (e.g., in case of severe liver disease or nephrotic syndrome) with 
serum albumin < 3.0 g/dL. 
28. Severe renal insufficiency defined as a calculated creatinine clearance < 30 mL/min 
(Cockroft-Gault) at Visit 1 (Screening) or Visit 2 (Baseline). 


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Other categories 
29. Known history of clinically significant drug or alcohol abuse. 
30. Known allergy to any of the ponesimod formulation excipients.  
31. Known allergy to any of the Aubagio® formulation excipients.  
32. Known hereditary problems of galactose intolerance (e.g., Lapp lactase deficiency, 
glucose-galactose malabsorption). 
33. 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. 
34. Contraindications for MRI such as: 
• Pacemaker, any metallic implants such as artificial heart valves, aneurysm/vessel 
clips and any metallic material in high-risk areas which are contraindicated for MRI 
according to the local procedures 
• Known allergy to any gadolinium (Gd)-containing contrast agent 
• Claustrophobia if its nature or severity is prohibitive for performing MRI according 
to the investigator’s judgment 
35. Subjects unlikely to comply with protocol, e.g., uncooperative attitude, inability to 
return for FU 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. 
4.5 Subjects of reproductive potential 
WOCBP and fertile male subjects participating in the study must agree that they will take 
means to reduce reproductive risk as defined in the following sections. 
4.5.1 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 agree to use one of the following reliable methods 
of contraception from the Visit 1 (Screening) until 6 weeks after the first of two consecutive 
tests showing teriflunomide plasma level < 0.02 mg/L: 
• 
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, 


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it must be taken for at least 30 days prior to randomization. Non hormonal 
methods of contraception (e.g., intrauterine device) should be in place no later 
than Visit 2 (Baseline). 
− Group 2: Female or male condoms, diaphragm or cervical cap. 
OR 
• 
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 
Visit 1 [Screening]). 
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. At all visits and 4-weekly telephone calls the methods of 
contraception will be reviewed and the contraceptive method form entered in the eCRF 
must be updated as applicable. 
4.5.2 Fertile male subject 
A fertile male is defined as physiologically capable of conceiving an offspring. 
Since teriflunomide is detected in semen [Aubagio® USPI, Aubagio® SmPC], fertile male 
subjects participating in the study who are sexually active with WOCBP must agree to use 
a condom during the treatment period and for up to 6 weeks after the first of two tests 
showing teriflunomide plasma level < 0.02 mg/L and agree not to father a child during this 
period. The female partners of the fertile male subjects, if WOCBP, will need to use 
effective methods of contraception [Aubagio® USPI, Aubagio® SmPC], as assessed by the 
investigator during the same period. 
4.6 Medical history 
Relevant medical history, as defined below, must be recorded in the eCRF: 
• 
Significant chronic medical conditions at any time prior to the study (in the opinion of 
the investigator) 
• 
Cardiac, cardiovascular, pulmonary, liver, renal, eye disorder, and skin conditions, 
peripheral edema, serious infections leading to hospitalization, and malignant tumors 
at any time prior to the study 


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• 
Medically significant new acute medical conditions in the past 24 months prior to the 
study (in the opinion of the investigator) 
• 
Smoking status at the time of entry in the study. 
Previous and concomitant therapies at Baseline, as defined in Section 5.2, will be recorded 
in the eCRF. 
MS disease characteristics, evidenced by documentation in the patient charts, as defined 
below, will be recorded on the MS history page of the eCRF: 
• 
Date of first MS symptoms  
• 
Date of MS diagnosis 
• 
MS type (e.g., RRMS, SPMS) 
• 
Complication or symptoms associated with MS (e.g., optic neuritis, numbness, 
spasticity, tremor, fatigue, dizziness, dysfunctional bladder, cognitive problems, etc.) 
within the last 24 months prior to the study 
• 
Number of documented MS relapses within the last 12 months and between 12 and 
24 months prior to the study. The onset and resolution date, and treatment of these 
relapses (corticosteroids, ACTH, plasmapheresis etc.) will also be reported. 
• 
Number of documented Gd+ lesions per scan and number of documented 
T2 hyperintense lesions per scan on any MRI scan performed within 24 months prior 
to the study. Additionally, the condition of the MRI scan will be collected 
(e.g., scanner type, manufacturer and strength, the type of T1 sequence and number of 
slices used to detect Gd+, contrast agent used [Gd type], dose of contrast agent and 
time of injection, time of T1 sequence, the type of T2 sequence and number of slices 
used to detect T2 hyperintense lesions). 
• 
Previous MS disease-modifying treatments received at any time in the past. The start 
date, end date, dose, route, frequency, and reason for discontinuation will be recorded 
in the eCRF. 
5 
TREATMENTS 
5.1 Study treatment 
The treatment period consists of an up-titration period (from Day 1 to 14) and a 
maintenance period (Day 15 until EOT).  
During an initial phase of the study, the study drugs in the up-titration period will be 
administered in a double-dummy fashion. Ponesimod (or matching placebo) will be 
presented as tablet, and teriflunomide 14 mg (or matching placebo) will be presented as 
capsule (i.e., daily administration of one tablet and one capsule). At a later phase, the 


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double-dummy material (tablet and capsule) will be replaced by the daily administration 
of one capsule containing either ponesimod or teriflunomide.  
In the maintenance period, the study treatment consists of the daily administration of one 
capsule containing ponesimod 20 mg or teriflunomide 14 mg.  
If the subject expresses any concern regarding her/his ability to swallow the medicine, 
she/he will be shown an example of a capsule to be used in the study and will be given the 
option to perform a swallowing test with a placebo capsule at Visit 2 (Baseline) in order to 
test future compliance with study drug intake requirements. The test is to be done under 
the supervision of the site personnel. 
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. The 20-mg tablet is over-encapsulated. During an 
initial phase of the study, one tablet of ponesimod 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg (or matching 
placebo) will be taken orally o.d. during the up-titration period (Day 1 to 14). The matching 
placebos for the doses of 2, 3, 4, 5, 6, 7, 8, 9, and 10 mg are supplied as identical tablets, 
formulated with the same excipients but without the active ingredient, ponesimod. At a 
later phase, once the development of the over-encapsulated forms of the ponesimod tablets 
for the up-titration is completed, one capsule of 2, 3, 4, 5, 6, 7, 8, 9, and 10 mg ponesimod 
(or matching teriflunomide 14 mg) will be taken orally o.d. during the up-titration period. 
During the maintenance period, one capsule of ponesimod 20 mg (or matching 
teriflunomide 14 mg) will be taken orally o.d. 
Based on the available data and considering the currently available therapeutic options, 
ponesimod 20 mg displays the optimal benefit-risk balance for further development in 
RMS.  
Lower doses of ponesimod are unlikely to provide an adequate level of disease control and 
do not offer a relevantly improved safety profile. Consistent with a lower effect on 
lymphocytes, 10 mg ponesimod was unable to suppress MRI brain inflammatory activity 
to the level achieved with 20 mg and continued to show higher levels of clinical disease 
activity with more relapses and accumulation of disability after 3 years of treatment. While 
less efficacious, 10 mg showed similar rates of AEs and discontinuations when compared 
to 20 mg [see Sections 1.3.2.3 and 1.3.2.4].  
Doses higher than 20 mg were associated with decreased tolerability; there were increased 
discontinuation rates with 40 mg mainly due to higher pulmonary function effects and 
increased incidence of liver enzyme elevations. By contrast, there was a similar or small 
incremental effect of 40 mg compared to 20 mg on lymphocytes, MRI brain inflammatory 
activity, and clinical disease activity [see Sections 1.3.2.3 and 1.3.2.4]. 


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5.1.2 Comparator and matching placebo: description and rationale 
Teriflunomide is supplied for this study as film-coated tablets as the commercially 
available Aubagio® tablets. Each tablet contains 14 mg of teriflunomide and excipients. 
Teriflunomide tablets are over-encapsulated. The study treatments of the up-titration 
period are administered in a double-dummy fashion, one capsule of teriflunomide or 
matching placebo will be taken orally o.d. during up-titration (Days 1 to 14). Matching 
placebo capsules will contain only a filling excipient.  
In the maintenance period, study treatment always consists of the daily oral administration 
of one capsule containing teriflunomide or ponesimod (i.e., no double-dummy). The dose 
and regimen of teriflunomide are in accordance with the product labeling of Aubagio® 
[Aubagio® USPI, Aubagio® SmPC]. Aubagio® is manufactured by Sanofi. 
Two dosage forms of Aubagio®, 7 mg and 14 mg, have been approved in US, while only 
14 mg has been approved in the EU and other countries such as Australia. The reduction 
in relapse rates observed in the Phase 3 studies were comparable between the two doses, 
but the 7 mg dose has failed to demonstrate an effect on accumulation of disability. 
Teriflunomide 14 mg appears to be an appropriate comparator for ponesimod 20 mg. 
Demonstration of superiority over teriflunomide 14 mg in terms of ARR is clinically 
relevant, as it would provide evidence of significant benefit of the new investigational drug 
compared to a world-wide approved, effective, first-line oral therapy that has been shown 
to reduce relapse rate and accumulation of disability. 
5.1.3 Study treatment administration 
5.1.3.1 Titration 
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 more 
than 3 days [see Section 5.1.9].  
In order to keep the blind of the study, subjects randomized to teriflunomide will undergo 
a mock up-titration. 


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Table 4 
Dosing scheme 
Treatment 
period 
Duration 
Dose regimen in the 
ponesimod group 
Dose level 
Titration 
Days 1 and 2 
2 mg 
1 and 2 
Titration 
Days 3 and 4 
3 mg 
3 and 4 
Titration 
Days 5 and 6 
4 mg 
5 and 6 
Titration 
Day 7 
5 mg 
7 
Titration 
Day 8 
6 mg 
8 
Titration 
Day 9 
7 mg 
9 
Titration 
Day 10 
8 mg 
10 
Titration 
Day 11 
9 mg 
11 
Titration 
Days 12 to 14* 
10 mg 
12 to 14 
Maintenance 
Day 15 until EOT 
20 mg 
NA 
* = Visit 4 is to take place at Day 15 ± 1 day. The titration kit will therefore include an additional capsule and tablet (if 
applicable) for treatment on Day 15 (i.e., dose regimen in the ponesimod group = 10 mg). 
EOT = End-of-Treatment; NA = not applicable.  
Study drug up-titration, other than described above, is prohibited. Study drug 
down-titration is not foreseen in any situation and is prohibited. 
One tablet and one capsule (during the double-dummy phase) or one capsule will be taken 
orally o.d., in the morning, either with breakfast or before or after breakfast, preferably at 
approximately the same time each day. The capsule and tablet will be swallowed as a 
whole. When applicable, the tablet and the capsule (during double-dummy phase) will be 
taken in the shortest time from each other with no predefined order (tablet or capsule can 
be taken first). The last administration date and time of study drug (tablets and capsules) 
prior to the study visits and the administration date and time of study drug (tablets and 
capsules) on the days of visits will be recorded in the eCRF.  
5.1.3.2 Maintenance 
One capsule of ponesimod or teriflunomide will be taken orally o.d., preferably in the 
morning, either with breakfast or before or after breakfast. It is preferable that the capsule 
be taken each day at approximately the same time. The capsule will be swallowed as a 
whole. The last administration date and time of study drug (capsule) prior to the study visits 
and the administration date and time of study drug (capsule) on the days of visits will be 
recorded in the eCRF. 
On the day of the study visits, study drug must be administered only after the completion 
of the pre-dose safety assessments (diastolic blood pressure [DBP], systolic blood pressure 
[SBP], ECGs, PFTs, laboratory tests) and PK sampling (if scheduled).  


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5.1.4 Treatment assignment 
A total of 1100 eligible subjects will be randomized in a 1:1 ratio to ponesimod 20 mg or 
teriflunomide 14 mg, stratified by prior use of MS disease-modifying treatment in the last 
two years prior to randomization (yes, no) and by baseline EDSS score (EDSS ≤ 3.5, EDSS 
> 3.5). 
Each of the study sites will be assigned a unique site number, and every subject will receive 
a unique screening number (= subject number), which identifies the subject throughout the 
study. After having confirmed the eligibility of the subject and prior to the start of study 
treatment, the investigator/delegate contacts the interactive response technology (IRT) at 
Visit 3 to randomize the subject. The IRT assigns a randomization number to the subject 
and assigns the treatment kit number, which matches the treatment arm assigned by the 
randomization list to the randomization number of each subject. 
The randomization list is generated by an independent CRO (ALMAC Clinical 
technologies−see contact details in the IRT manual) and kept strictly confidential. 
5.1.5 Blinding 
5.1.5.1 Study drug material related blinding 
This study will be performed in a double-blind fashion. The investigator and study staff, 
the subjects, the monitors, all Clinical Trial Team (CTT) members at Actelion and CROs 
involved in the conduct of the study will remain blinded to the treatment until study closure. 
Actelion staff responsible for clinical trial supply distribution will need to be unblinded to 
ensure adequate study oversight. These persons will be clearly identified, their unblinding 
will be documented in the trial master file and they will not take part in any CTT meeting 
after study set-up has been completed.  
Until the time of unblinding for final data analysis, the randomization list is kept strictly 
confidential and accessible only to authorized persons who are not involved in the conduct 
of the study.  
The investigational treatment and active comparator, and their respective matching 
placebos (if applicable, during the initial stage when the up-titration study drug treatments 
are administered in a double-dummy fashion) are indistinguishable, and all subject’s kits 
will be packaged in the same way. 
5.1.5.2 Functional blinding 
First-dose effects on HR and AV conduction, lymphocyte counts reduction, and 
teriflunomide plasma concentration have been identified as potentially unblinding 
information. Access to this information by the site’s staff and sponsor’s study team will be 
restricted. The following measures will be taken to ensure that the efficacy assessments 


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(i.e., EDSS/FS) are done independently and that cardiac safety assessments, lymphocyte 
count and teriflunomide plasma concentration assessment are performed and reviewed 
without potential to introduce a bias: 
• The primary endpoint (ARR) and the second key secondary endpoint (disability 
accumulation) are based on the evaluations of the EDSS and FSs, assessed by an 
efficacy assessor, not involved in any other aspects of patient care and management 
throughout the study. 
• The subject will be instructed not to discuss AEs (other than those required for EDSS 
assessments), HR, pulmonary function and/or concomitant medications with the 
efficacy assessor.  
• The principal investigator / treating neurologist and first-dose administrator evaluating 
cardiac safety assessments must not discuss any issues related to patient care and 
management unless mandated for reasons of subject safety. On Day 1 and on the first 
day of re-initiation of study drug when post-dose monitoring is required, significant 
findings, which in view of the first-dose administrator meet the definition of an AE, 
have an onset after the study drug intake, and are resolved at the time of discharge of 
the subject, must be recorded directly on the AE page of the eCRF by the first-dose 
administrator/delegate. These AEs, the ECG interpretation reports and BP data 
collected on these days will not be visible to any of the blinded study personnel at the 
study site. At the sponsor’s level, these events and ECGs and BP data will be entered 
into a separate eCRF and will only be visible to the site monitor and to the first-dose 
monitor. The site monitor will not reveal any potentially unblinding information to the 
rest of the site team or to the sponsor study team and will only discuss any of these data 
with the first-dose administrator or the first-dose monitor. The first-dose monitor is a 
role created by the sponsor for the purpose of keeping the rest of the sponsor’s team 
blinded and assigned to (a) specific individual(s). The first-dose monitor will not reveal 
any potentially unblinding information to the site team or to the rest of the sponsor 
study team and her/his access to potentially unblinding information will be documented 
in the trial master file. 
• Results of the total WBC count and total lymphocyte count will not be communicated 
to the sites, sponsor, and CRO unless one of the below applies: 
− A total lymphocyte count < 0.2 × 109/L is recorded by the central laboratory. In 
this event, an alert containing the total lymphocyte count result will be sent to 
the principal investigator and the sponsor. FU monitoring must be provided as 
described in Sections 5.1.13 and 7.3.14. 


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− A WBC count > 20 × 109/L or a lymphocyte count > 8.0 × 109/L is recorded by 
the central laboratory [see Appendix 6]. In this event, an alert containing the 
total WBC or lymphocyte count result (as applicable) will be sent to the 
principal investigator and the sponsor.  
− WBC and total lymphocyte counts measured at Visit 1 (Screening), 
2 (Baseline), and any of the visits in the PTOP (if applicable) will be visible to 
the treating neurologist. Upon discontinuation of ponesimod, lymphocytes 
counts return to within normal ranges within one week. Lymphocytes counts 
are therefore expected to have returned to normal range during the 30 days 
safety follow up period preceding the start of PTOP. 
• Teriflunomide plasma concentration will be assessed after study treatment 
discontinuation for women of childbearing potential and fertile male subjects not 
entering the extension study and willing to discontinue contraception [see Section 4.5]. 
Teriflunomide plasma concentration can also be assessed for any subjects not entering 
the extension study if deemed necessary for the subject’s safety, at the investigator’s 
discretion. The following rules will apply: 
− For subjects entering the AC-058B303 extension study, no teriflunomide 
plasma testing will be conducted as part of the AC-058B301 study. The timing 
of teriflunomide plasma concentration testing and procedures are described in 
the AC-058B303 study protocol (separate protocol). 
− For subjects not entering the AC-058B303 extension study, teriflunomide 
plasma concentration testing should not occur before: 
o 20 weeks after last drug intake, if the subject’s compliance with the 
accelerated elimination procedure has been assessed as sufficient 
[see Section 5.1.14.2]. 
o 35 weeks (i.e., 8 months) after last drug intake or EOS, whichever is 
last, if the subject’s compliance with the accelerated elimination 
procedure has not been assessed as sufficient [see Sections 5.1.14.1 and 
5.1.14.4]. 
− In all cases, the results will not be communicated to the sponsor (except site 
monitor). Sites will receive the following notifications: 
o if plasma concentration was < 0.02 mg/L: notification that the 
teriflunomide test was successfully performed 


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o if plasma concentration was ≥ 0.02 mg/L: full test results and 
notification that the subject should either repeat the accelerated 
elimination procedure [see Section 5.1.14] or wait an additional time 
period before another test may be performed. 
• All MRI scans collected for the assessment of efficacy endpoints are evaluated by a 
central lab (MIAC) also in a fully blinded fashion. 
Under no circumstances should potentially unblinding information be shared with the 
efficacy assessor. 
5.1.6 Unblinding 
5.1.6.1 Unblinding for final analyses 
Full randomization information will be made available for data analysis only after database 
closure in accordance with Actelion standard operating procedures (SOPs). 
5.1.6.2 Unblinding for IDMC 
A SAC, not otherwise involved in the design, conduct and analysis of the study, will have 
access to the randomization code in order to prepare unblinded reports for review by the 
IDMC (for IDMC review meetings during the course of the trial). The randomization code 
will be made available to the SAC in accordance with the sponsor’s SOPs. 
5.1.6.3 Unblinding for suspected unexpected serious adverse reactions 
When a suspected unexpected serious adverse reaction (SUSAR) occurs for a subject 
participating in the study, Actelion Global Drug Safety will request the unblinding of the 
treatment assignment. The randomization code will not be communicated to the site staff 
or to the Actelion study team; unblinded SUSAR information will be anonymized and 
provided to Actelion Global Drug Safety, respective health authorities and Institutional 
Review Boards (IRBs) / Independent Ethics Committees (IECs) only. SUSARs will be 
reported to investigators in a blinded fashion. 
5.1.6.4 Emergency procedure for unblinding 
The investigator, study staff and sponsor staff must remain blinded to the subject’s 
treatment assignment. The identity of the study treatment may be revealed only if the 
subject experiences a medical event, the management of which would require knowledge 
of the blinded treatment assignment. In this case, the investigator can receive the unblinded 
randomization code for study treatment allocation through the IRT. In these situations, the 
decision to unblind resides solely with the investigator. Whenever it is possible and if it 
does not interfere with (or does not delay) any decision in the best interest of the subject, 
the investigator is invited to discuss the intended code break with Actelion. 


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The occurrence of any code break during the study must be clearly justified and explained 
by the investigator. The investigator must not disclose the unblinded treatment in the eCRF 
or to the sponsor or its delegates. In all cases, Actelion must be informed as soon as possible 
before or after the code break. 
The circumstances leading to the code break must be documented in the site study file and 
eCRF. 
Refer to the IRT guidelines for complete information regarding the IRT procedures for 
randomization, study drug assignment, and unblinding. 
5.1.7 Study treatment supply 
Manufacture, labeling, packaging and supply of study treatments will be conducted 
according to Good Manufacturing Practice, Good Clinical Practice (GCP) and any local or 
national regulatory requirements. 
All treatment supplies are to be used only in accordance with this protocol and not for any 
other purpose. 
5.1.7.1 Study treatment packaging and labeling 
5.1.7.1.1 Study treatment packaging 
Study treatment is provided as capsules and tablets and supplied in childproof blister packs. 
5.1.7.1.2 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.  
5.1.7.2 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. The study drug must be stored below 25 °C. 
The study drug must not be refrigerated.  
5.1.7.3 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 quantity). Subjects are asked to return all used, partially used and unused study 
treatment blister packs 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 tablet/capsules from the 
remaining study treatment and to bring it at the next visit. 


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An accurate record of the date and amount of study treatment dispensed to each subject 
must be available for inspection at any time.  
5.1.7.4 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, which will be sent to the warehouse, where Actelion or a deputy will 
check treatment reconciliation. 
5.1.8 Drug accountability and compliance 
5.1.8.1 Drug accountability 
Records of study drug dispensed and returned, dosages administered, and intervals between 
visits are kept during the study. Study treatment accountability must be performed by the 
study staff on the day of the visit and before providing further study treatment, in order to 
ensure that the subject is compliant with study requirements. Study treatment 
accountability is checked by the monitor during site visits and at EOS.  
5.1.8.2 Drug compliance 
Subjects’ compliance with study drug intake will be recorded using an electronic diary. On 
each day, the subjects will be asked to enter the date, time, number of capsules (and tablets, 
if applicable) taken, and the unique blister-card identifying number from which the 
capsules (and tablets, if applicable) are (were) taken from. In addition, during the 
up-titration, the position of the well on the blister card will be recorded in order to check 
that capsules and tablets (if applicable) were taken in the correct sequence [see gradual up-
titration in Section 5.1.3.1].  
The electronic diary will give feed-back and instruct the subject to contact the investigator 
as soon as possible before taking next dose, whenever one of the following is observed: 
• Dose is taken in an incorrect sequence during the up-titration (e.g., capsule at position 
6 taken before capsule at position 4 on the blister card);  
• 1 or more dose(s) (capsule and/or tablet if applicable) are missed during the up-titration; 
• 4 or more doses are missed during the maintenance.  
Additionally, feedback will be given to the subject whenever 1 to 3 dose(s) are missed 
during the maintenance. 
At each visit, the site personnel will crosscheck the subject’s compliance as indicated in 
the electronic diary against the study drug accountability [see Section 5.1.8.1]. Subjects 
will be asked to explain the observed discrepancies. Interruptions with known dates will 
be recorded accordingly in the study drug log [see Section 5.1.9]. Study drug intake 
requirements will be re-explained to the subject each time an interruption is observed.  


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5.1.9 Study treatment dose adjustments and interruptions 
Study drug up-titration, other than described in Section 5.1.3, is prohibited. Study drug 
down-titration is not foreseen in any situation and is prohibited. 
Study drug 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, or for administrative reasons. 
Study-specific criteria for interruption of study treatment are described in Section 5.1.13. 
The duration of an interruption is determined by the investigator and is not limited in time. 
At maximum, it will last until the investigator deems the subject necessary to require 
another MS treatment. In this event, it is recommended performing an accelerated 
elimination procedure [see Section 5.1.14] before a new immunomodulatory treatment for 
MS is started.  
Detailed guidance on how to re-initiate study drug in the event of drug interruption is 
provided in Section 5.1.10. 
Study treatment dose adjustments/interruptions must be recorded in the eCRF. 
5.1.10 Guidance for re-initiation of study treatment in the event of study treatment 
interruption 
If study drug intake 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 drug after 
study drug interruptions. 
A schematic overview of the re-initiation algorithm is given below in Figure 5.  
Depending on the day, time, and duration of study drug 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 continued with the morning dose on the following day. 
• If the subject missed taking the dose for one or more days during treatment up-titration 
(from 1 to 14 days after the first-dose of initiation/re-initiation of the study drug): 


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− The original up-titration scheme needs to be re-applied, with the initial dose and 
gradual up-titration steps for 14 days after the first-dose of re-initiation of the study 
drug. 
− On the day of the re-initiation of investigational study drug, the subject must be 
monitored for at least 4 h post-dose by the first-dose administrator, following the 
cardiac assessment schedule and applying the discharge criteria as described for 
Day 1 [see Section 5.1.11]. 
• If the subject missed taking the dose for up to three consecutive days during treatment 
maintenance (from 14 days after the first dose of initiation/re-initiation of the study 
drug onwards): 
− Dosing should be continued in the morning following the last day without 
investigational study drug intake, with the same dose taken prior to study drug 
interruption. 
− Study drug intake may be re-initiated by the subject at home. 
− 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 for four or more consecutive days during treatment 
maintenance (from 14 days after the first dose of initiation/re-initiation of the study 
drug onwards):  
− The original up-titration scheme for the investigational study drug needs to be 
re-applied. 
− On the day of the re-initiation of treatment, the subject must be monitored for at 
least 4 h post-dose by the first-dose administrator, following the cardiac assessment 
schedule and applying the discharge criteria as described for Day 1 [see Section 
5.1.11]. 
Whenever the investigator / treating neurologist becomes aware that the subject did not 
report having missed the study drug 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, need to re-initiate treatment, or should permanently discontinue treatment. 


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Figure 5 
Algorithm for management of treatment interruptions  
 
5.1.11 Criteria for discharge from cardiac monitoring on Day 1, and on the first day 
of re-initiation of the investigational study drug 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 h post-dose have been obtained) on Day 1, and 
on the first day of re-initiation of study drug 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 < 60ms; 


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• 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 h post-dose, the 
subject should be carefully monitored for an additional period, and a 12-lead ECG and a 
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 h post-
dose, she/he must be permanently discontinued from study drug. Subjects who are 
permanently discontinued should not be discharged from cardiac monitoring before vital 
signs return to near baseline values 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. 
5.1.12 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 
108 weeks. The decision to prematurely discontinue study treatment may be made by the 
subject, the investigator or Actelion. 
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 case 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. 
Premature discontinuation of study treatment may also result from a decision by Actelion, 
e.g., in case of premature termination or suspension of the study [see Section 9.3]. 
The main reason and whether discontinuation of study treatment is the decision of the 
subject, the investigator, or Actelion must be documented in the eCRF. 
A subject who prematurely discontinues study treatment is NOT considered as withdrawn 
from the study and will be followed up until Week 108 in the PTOP or until the end of the 
safety FU period (30 days after study drug discontinuation), whichever comes last [see 


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Section 3.1.3], provided that the subject’s consent for this limited participation in the study 
has not been withdrawn. 
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 permanent discontinuation from study drug 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. Initiation of 
immunomodulatory therapies is best avoided during the FU period of 15 days and until an 
accelerated elimination procedure for teriflunomide has been conducted to minimize the 
risk of immunosuppression.  
5.1.13 Study-specific criteria for interruption / premature discontinuation of study 
treatment and management of clinically relevant events 
An accelerated elimination procedure must be used by all subjects permanently 
discontinued, after the last dose of study drug [see Section 5.1.14]. 
5.1.13.1 Cardiovascular 
Subjects must be permanently discontinued from study drug 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 h 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 drug following drug interruptions after 12 h 
post-dose monitoring, or 
• The subject needs to receive systemic chronic treatment with β-blockers, diltiazem, 
verapamil, digoxin, or any other anti-arrhythmic or HR lowering therapy 
[non-exhaustive list of drugs provided in Appendix 4].  


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FU monitoring will have to be provided until the event resolves, the condition is stable, or 
the change is regarded as no longer clinically relevant. 
Continuous ECG monitoring is recommended for subjects who meet study drug 
discontinuation criteria related to bradycardia or other arrhythmia. Subjects who are 
permanently discontinued should not be discharged from the monitored setting before vital 
signs return to near baseline values and until there is no persisting ECG abnormality (e.g., 
QT prolongation, AV block second degree or higher) or ongoing AE requiring (continued) 
cardiac monitoring, or until medically indicated. Any clinically relevant finding meeting 
the definition of an AE will be recorded accordingly in the respective eCRF. 
In case of any signs and 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. In case a cardiac origin is suspected, permanent 
discontinuation of study drug should be considered. 
In case subjects experience sustained de novo or worsening of pre-existing hypertension 
during the course of the treatment with the study drug which, in the opinion of the 
investigator, cannot be adequately controlled by medications, study drug should be 
permanently discontinued. 
5.1.13.2 Hematological abnormalities and infections 
Subjects must be permanently discontinued from study drug at any time throughout the 
study in the event of: 
• Confirmed neutrophil count < 1.0 × 109/L (< 1000 cells/mm3)  
• Confirmed platelet count < 50 × 109/L (< 50 000 cells/mm3) 
• Confirmed total lymphocyte count < 0.2 × 109/L (< 200 cells/mm3) 
Confirmation will be done as follows: 
Whenever a neutrophil count < 1.0 × 109/L, a platelet count < 50 × 109/L, or 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 within 48 h at the latest to repeat 
the test at trough level (pre-dose) by the central laboratory (unless the clinical situation 
mandates immediate local testing). If the repeat test confirms a neutrophil count  
< 1.0 × 109/L, a platelet count < 50 × 109/L, or a total lymphocyte count < 0.2 × 109/L the 
study drug must be discontinued. Neutrophil, platelet, or lymphocyte counts must be 
monitored at least once a week by the central laboratory until the neutrophils or platelets 
have returned to ≥ 80% of the baseline value or the lymphocyte count has returned to  


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≥ 0.8 × 109/L or ≥ 80% of the baseline value. Any clinically relevant finding meeting the 
definition of an AE will be recorded accordingly in the eCRF. 
In the event of a decrease of neutrophil or platelet not reaching the above alert levels, test 
at trough level (pre-dose) may be repeated. Upon confirmation of the decline over time of 
neutrophil or platelet counts, study drug may be interrupted at the discretion of the 
investigator. Possible causes for this decline including signs and symptoms suggestive of 
an infection should be assessed.  
In the event of a suspected opportunistic infection of the CNS, the study drug must be 
interrupted and the subject referred to an expert in infectious diseases for further 
examination and treatment. For any other infection the subject should be treated as 
clinically indicated and study drug may be interrupted or permanently discontinued at the 
discretion of the investigator. In case of study drug 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 drug may be re-
initiated at the discretion of the investigator. 
In the event of permanent discontinuation from study drug due to infection, adequate 
treatment needs to be provided and the subject must be monitored until complete resolution 
of the infection.  
A guidance for screening and monitoring of subjects for opportunistic infection is provided 
in Sections 5.1.13.2.1 and 5.1.13.2.2. Subjects must be advised to be proactive and alert in 
reporting any unusual neurological symptom 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.  
5.1.13.2.1 Guidance for screening, 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, 


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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., cyclosporine, tacrolimus, 
sirolimus, and mycophenolate), and therapeutic monoclonal antibodies (e.g., rituximab, 
infliximab, etanercept, basiliximab, daclizumab, efalizumab, alemtuzumab, and 
muromonab-CD3) [Kappos 2011]. 
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. 
In order to facilitate the recognition of potential PML infection in MS subjects and to 
minimize the risk of enrolling subjects with undiagnosed or unrecognized PML infection 
in the clinical study of ponesimod, the following guidance is provided. The proposed 
algorithm is based on the updated experts’ panel recommendation for monitoring subjects 
who receive treatment with natalizumab [Kappos 2011].  
Subjects with known PML infection or evidence of new neurological symptoms or MRI 
signs within 6 months prior to randomization that are compatible with a diagnosis of PML 
infection are not be eligible for the study. The proposed algorithm should be applied for all 
subjects with evidence of new neurological symptoms or MRI signs compatible with PML 
within 6 months prior to randomization [Figure 6]. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 6 
Clinical assessment for potential PML 
Are features typical of MS relapse? 
Clinical features indicative of MS relapse are:  
•
Acute onset 
•
Occurs over several hours to days, reaches 
usually stable phase, and resolves 
spontaneously, even without treatment 
•
Clinical presentation includes diplopia, optic 
neuritis, and myelopathy (e.g., paraparesis, 
discrete sensory level) 
Features suggestive of pathology other 
than MS? 
Clinical features indicative of PML are: 
•
Subacute onset 
•
Occurs over several weeks and is progressive 
•
Clinical presentation includes aphasia, 
behavioural and neurophysiological 
alteration, retrochiasmal visual deficits, 
hemiparesis, and seizures
Clinical presentation 
Subject presented with or reported new neurological symptoms or MRI signs compatible with PML 
within 6 months prior to planned randomization 
Investigator is able to rule out PML 
History and examination 
Subject is eligible to enter study  
Investigator is NOT able to rule out PML 
Investigator should consider: 
•
Performing MRI and lumbar puncture for JC 
virus DNA 
•
Other non-MS pathology in addition to PML, 
especially opportunistic infections 
Subject is NOT eligible to enter study 
Investigator is still NOT able to rule out 
PML  
Investigator is able to rule out PML  
•
No suspicious signs of PML or other opportunistic infections on MRI  
•
Lumbar puncture is negative for JC virus DNA 
•
Clinical signs and symptoms no longer suspicious of PML or opportunistic 
infection 


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For subjects who have been enrolled in the 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 (especially 
in case of prior exposure to natalizumab or other immunosuppressive agents) and, in case 
of clinical features indicative of these conditions, the following diagnostic procedures are 
recommended: 
• Perform MRI including T1 sequences with Gd (and additional MRI sequences if 
needed) and include comparison with the previous MRI images in the interpretation of 
the MRI results; 
• Interrupt study drug until PML or other opportunistic CNS infection has been excluded 
with confidence; 
• 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 of PML. 
In case 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 of the study drug 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 drug should be permanently discontinued, the case should be reported 


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to the sponsor as an SAE and the subject should be managed according to the local standard 
of care. 
In case the MRI at scheduled visit 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 drug should be interrupted and should not be re-introduced until this 
suspicion has been ruled out. 
5.1.13.2.2 General 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 infection, the subject must be referred to an expert in infectious diseases 
for further examination and treatment. The study drug must be permanently discontinued 
in case of opportunistic CNS infections. For any other opportunistic infections, the study 
drug 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 with neurological symptoms primarily. 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 drug 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]. 


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5.1.13.3 Respiratory system 
In case of abnormal spirometry results or persistent respiratory symptoms (e.g., dyspnea), 
the subject will be closely observed, spirometry will be repeated, and study drug 
discontinuation should be considered, according to the guidance provided in Table 5.  
Table 5 
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 drug 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.  
AE = adverse event; FEV1 = forced expiratory volume in 1 second; FU = follow-up; FVC = forced vital vapacity;  
PFT = pulmonary function test. 
If clinically significant, persistent respiratory AEs (e.g., dyspnea) are reported, PFTs must 
be performed and study drug may be interrupted at the discretion of the investigator. In 
case of study drug 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 drug interruption, if PFTs normalize and lung toxicity is unlikely, study 
drug may be re-initiated at the discretion of the investigator. 
The decision to permanently discontinue study drug will be made after evaluation of all 
available information concerning concomitant medications, other potential causes of 
respiratory AEs, and the clinical status of the subject. Further diagnostic work-up and 


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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 drug may be prescribed short-acting β2 agonist (to 
be used on ‘as needed’ basis / ‘PRN’ 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 drug discontinuation 
should be considered at the discretion of the investigator. 
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. 
5.1.13.4 Pregnancy 
If a subject becomes pregnant while on study drug, study drug 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. If the subject wishes to continue 
pregnancy, Actelion Global Drug Safety will request the unblinding of the treatment 
assignment and only the subject allocated to teriflunomide will perform an accelerated 
elimination procedure [see Section 5.1.14].  
If a female partner to a male study participant becomes pregnant while the study participant 
is on study drug, the study drug in the male subject must be permanently discontinued. 
Actelion Global Drug Safety will request the unblinding of the treatment assignment. In 
case the male subject has been on teriflunomide, the investigator must counsel the subject 
and discuss the risks of continuing with the pregnancy and the possible effects on the fetus. 
If the subject was on ponesimod, there is no risk for the female partner to continue 
pregnancy. The accelerated elimination procedure will be performed in the male subject 
only if the subject was on teriflunomide. 
Male and female subjects participating in the study and wishing to father a child or wishing 
to become pregnant during the study must discontinue study drug, perform an accelerated 
elimination procedure, and continue contraception as indicated per protocol until 6 weeks 
after the first of two tests indicating serum teriflunomide level < 0.02 mg/L. 
5.1.13.5 Liver abnormalities 
In case 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 
drug discontinuation should be considered according to the guidance provided in Table 6.  


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Table 6 
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 > 1.5 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 h, permanently 
discontinue study drug, 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 drug, 
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 > 1.5 × ULN 
• 
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 drug, 
and perform FU. 
 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; FU = follow-up; INR = International Normalized 
Ratio; ULN = upper limit of normal range. 
Whenever AST or ALT ≥ 3 × 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 


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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 6. Further diagnostic 
work-up 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 case of study drug interruption, the subject will be closely observed and FU liver tests 
will be performed. Following study drug interruption, if liver tests normalize and 
drug-related hepatotoxicity is unlikely, study drug may be re-initiated at the discretion of 
the investigator. Re-initiation following interruption according to the above criteria can 
only be done once during the study. The decision to permanently discontinue study drug 
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 drug should be 
permanently discontinued according to Table 6. In all cases of permanent study drug 
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. 
5.1.13.6 Renal function 
Subjects must be permanently discontinued from study drug at any time throughout the 
study in the event of a rapid serum creatinine increase to > 150 µmol/L or rapid decrease 
in calculated creatinine clearance to < 30 mL/min (Cockroft-Gault) that cannot be rapidly 
reversed (by volume repletion or relief of urinary tract obstruction [according to etiology]). 
Any clinically relevant finding meeting the definition of an AE will be recorded 
accordingly in the eCRF. 
5.1.13.7 Ocular abnormalities 
In the event of suspected clinically significant findings (e.g., macular edema), 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 drug and will be managed and followed up until resolution. The OSB will 
receive all information related to suspected cases of macular edema and will perform 
central review of OCT results and subject data. 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 drug 
but will require additional ophthalmologic assessments as detailed below: 


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5.1.13.7.1 Guidance for monitoring and management of subjects with uveitis 
In case of suspicion of active uveitis (ocular pain, floaters, blurred vision, increased 
intraocular pressure) at Screening or during a scheduled ophthalmological assessment, 
fluorescence angiography (FA) should be performed (unless contra-indicated according to 
the ophthalmologist) in addition to the scheduled ophthalmological assessment and OCT, 
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 contraindicated) as soon 
as possible. If active uveitis can be confirmed and macular edema can be ruled out, the 
subject may continue in the study without interrupting the study drug. Such subjects will 
need to be controlled by the ophthalmologist after 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 ocular pressure, preferably with Goldmann applanation tonometry, 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 has to be discontinued. 
If uveitis is progressing in spite of treatment, the investigator may consider interrupting or 
permanently discontinuing the study drug. 
5.1.13.8 Skin reactions 
Subjects must be permanently discontinued from study drug at any time throughout the 
study in the event of Stevens-Johnson syndrome or toxic epidermal necrolysis or drug 
reaction with eosinophilia and systemic symptoms. Subjects will be managed and 
followed-up until resolution. 
5.1.13.9 Peripheral neuropathy 
In case of development of symptoms suggestive of peripheral neuropathy such as bilateral 
numbness or tingling of hands or feet, the investigator should evaluate the subject and 
decide whether the diagnosis of peripheral neuropathy is likely. Such evaluation may 
include further clinical and/or neurophysiological diagnostic work-up for peripheral 
neuropathy according to the local practice. If, as a result of such evaluation, diagnosis of 
peripheral neuropathy is likely according to the investigator, the subject must 
be permanently discontinued from study drug, managed and followed up until resolution. 
Any clinically relevant finding meeting the definition of an AE will be recorded 
accordingly in the eCRF.  


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5.1.14 Elimination of teriflunomide 
5.1.14.1 Accelerated elimination procedure for teriflunomide 
Teriflunomide is eliminated slowly from plasma. Without an accelerated elimination 
procedure, it takes on average 8 months to reach plasma concentrations less than 
0.02 mg/L, although because of individual variations in drug clearance it may take as long 
as 2 years.  
At EOT, all subjects will have to undergo an accelerated elimination procedure consisting 
of either of the following procedures: 
• Administration of cholestyramine 8 g three times a day (i.e., every 8 h) for 11 days. If 
cholestyramine 8 g three times a day is not well tolerated, cholestyramine 4 g three 
times a day can be used.  
• Administration of 50 g oral activated charcoal two times a day (i.e., every 12 h) for 11 
days.  
If either elimination procedure is poorly tolerated, treatment days do not need to be 
consecutive unless there is a need to lower teriflunomide plasma concentration rapidly. It 
is permissible to switch from cholestyramine to activated charcoal (or vice versa) for 
reasons of tolerability.  
5.1.14.2 Compliance with accelerated elimination procedure 
Subjects’ compliance with the elimination procedure will be reviewed and assessed after 
each elimination procedure. The recommended compliance should include intake of 
33 doses of cholestyramine (8 g or 4 g) or 22 doses of activated charcoal (50 g). Plasma 
concentration of teriflunomide should not serve to assess compliance. Please refer to 
Sections 5.1.5.2 and 5.1.14.4 for timing of teriflunomide testing after EOT. 
Note: At FU1 and (abbreviated) FU2, plasma concentration of teriflunomide will not be 
measured. The testing should occur as described in Section 5.1.14.4. 
For subjects not entering the AC-058B303 extension study, subjects compliance will be 
reviewed at FU1. If the compliance has been assessed by the investigator as not sufficient 
at FU1, the subject will be asked to complete missing intakes or repeat the procedure. 
In such a case a new compliance assessment will be performed at FU2. If the compliance 
has been assessed as not sufficient at FU2, washout may be obtained through additional 
elimination procedures or by waiting for several months of natural elimination according 
to the subject’s preferences. Duration of continued contraception and timing of 
teriflunomide testing are described in Section 5.1.14.4. 
For subjects entering the AC-058B303 extension study, compliance will be reviewed at 
FU1. If the compliance has been assessed as not sufficient at FU1, the investigator will 


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decide if the elimination procedure should be repeated or missing intakes completed. In 
such a case a new compliance assessment will be performed at an abbreviated FU2. The 
abbreviated FU2 should be scheduled to allow enough time for completing the elimination 
procedure. The subject will only be eligible to enter the extension study AC-058B303 if 
the compliance was assessed as sufficient at FU1 or abbreviated FU2. Duration of 
continued contraception and timing of teriflunomide testing are described in the AC-
058B303 extension study protocol. If the compliance has been assessed as not sufficient at 
abbreviated FU2, the subject will not be eligible to enter the extension study AC-058B303. 
In such a case, teriflunomide washout may be obtained through additional elimination 
procedures or by waiting for several months of natural elimination according to the 
subject’s preferences. Duration of continued contraception and timing of teriflunomide 
testing are described in Section 5.1.14.4. 
5.1.14.3 Accountability of accelerated elimination procedure treatment 
At FU1 and FU2 (if accelerated elimination procedure was repeated after FU1), the number 
of bottles (activated charcoal) or sachets (cholestyramine) dispensed and returned, and the 
dosages administered are recorded on the non-IMP accountability log by the site staff. The 
accelerated elimination procedure treatment accountability is checked by the monitor at 
EOS. If the accountability cannot be performed (e.g., subject doesn’t return bottles or 
sachets), compliance will be evaluated based on discussions with the subject. 
5.1.14.4 Duration of continued contraception after EOT 
Contraception measures as described in Section 4.5, must be continued until at least 
6 weeks after the first of two consecutive tests showing a teriflunomide concentration 
< 0.02 mg/L. The testing of teriflunomide plasma concentration may be conducted for 
WOCBP and fertile male subjects, if needed, to confirm that contraception can be 
discontinued.  
For subjects not participating in the AC-058B303 extension study, plasma concentration 
of teriflunomide must not be measured earlier than 20 weeks after the last study drug intake, 
and provided the subject has been compliant with the accelerated elimination procedure of 
teriflunomide [see Section 5.1.14.2]. If the subject has not been compliant with the 
accelerated elimination procedure, testing for teriflunomide must not be done before 35 
weeks (i.e., 8 months) after last dose of study drug or EOS, whichever comes last.  
• If teriflunomide plasma concentration is as anticipated less than 0.02 mg/L, the site will 
receive notification that the test was successfully performed and that teriflunomide 
concentration is < 0.02 mg/L (actual concentration will not be displayed). A second test 
will be performed approximately 15 days after the first test to confirm the result. 
• If plasma teriflunomide concentration is more than 0.02 mg/L, site will receive 
notification that teriflunomide plasma level is ≥ 0.02 mg/L and the actual concentration 
will be displayed on the report. In such a case, the accelerated elimination procedure 


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may be repeated at the discretion of the investigator and the subject will be instructed 
to continue contraception until at least 6 weeks after the first of two consecutive tests 
that show teriflunomide plasma concentration level below 0.02 mg/L. 
For subjects continuing into the extension study AC-058B303 the applicable procedures 
for teriflunomide tests/retests and for continuation of contraception will be described in the 
AC-058B303 study protocol (separate protocol). 
The duration of contraception after EOT should follow the following rules: 
• For subjects continuing in the extension study AC-058B303 (separate protocol): 
the duration of contraception will be described in the AC-058B303 study protocol. 
• For subjects not continuing in the extension study AC-058B303 (both males and 
females): the duration of contraception should always be until at least 6 weeks after the 
first of two consecutive tests that show teriflunomide plasma concentration level below 
0.02 mg/L. Subjects who leave the study before achieving this should be instructed to 
follow this requirement outside the study.  
5.2 Previous and concomitant therapy 
5.2.1 Definitions 
A previous therapy is any treatment for which the end date is prior to the start of study (i.e., 
signing of informed consent). 
All therapy that is study concomitant (i.e., ongoing or initiated after signing of informed 
consent, and initiated before EOS visit) must be captured in the eCRF.  
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. 
5.2.2 Reporting of previous/concomitant therapy in the eCRF 
The use of all study-concomitant therapy (including contraceptives or traditional and 
alternative medicines, i.e., plant-, animal-, or mineral-based medicines) will be recorded in 
the eCRF. The generic name, start/end dates of administration (as well as whether it was 
ongoing at start of treatment and/or EOS), route, dose, and indication will be recorded in 
the eCRF. 
Any previous administration of disease-modifying treatment for MS (IFN beta 1a [Rebif® 
- Avonex®, Plegridy®], IFN beta 1b [Betaseron®], glatiramer acetate [Copaxone®, 
Glatopa®], fingolimod [Gilenya®], dimethyl fumarate/BG-12 [Tecfidera®], natalizumab 
[Tysabri®], alemtuzumab [Lemtrada®]) at any time prior to screening will be recorded in 


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the previous MS treatment form of the eCRF. The start date, end date, dose, route, 
frequency, and reason for discontinuation will be recorded in the eCRF.  
The therapies used for the treatment of relapses experienced by the subject in the past 
24 months will be recorded in the previous MS treatment form of the eCRF 
(e.g., corticosteroids, ACTH). For each therapy, the start date, end date, reason for 
discontinuation, dose, route, and frequency of administration will be recorded in the eCRF. 
Any previous relevant therapy as per principal investigator / treating neurologist judgment 
(e.g., therapies listed in exclusion criteria, therapies for relevant medical history) will be 
recorded in the previous therapy form of the eCRF. 
5.2.3 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 ACTH is not recommended unless deemed absolutely 
necessary and must be documented in the patient charts by the investigator. Oral taper 
with corticosteroids should not be administered in any case. 
• Treatment of relapses with plasma exchange (i.e., plasmapheresis, cytapheresis) is 
prohibited. 
5.2.4 Allowed concomitant therapy 
• Dalfampridine (synonymous with fampridine) on a stable dose for at least 90 days prior 
to randomization and during double-blind treatment. Dalfampridine therapy must not 
be started or increased in dose during the study. Stopping or decreasing the dose of 
dalfampridine during the study should only take place if deemed absolutely necessary 
and must be documented in the patient charts by the investigator; 
• 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 drug 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 3]; 
• Vaccination with non-live vaccines. Subjects receiving non-live vaccination while on 
study treatment will have 5 mL of blood drawn prior to and ≥ 3 weeks after vaccination 
in order to assess changes in vaccine-specific antibody titers from pre- to 
post-vaccination. Samples will be analyzed at the end of the study [see Section 3.1.6.4]. 


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• The following medications should be administered with caution due to potential 
interaction with teriflunomide:  
− Teriflunomide is an inhibitor of cytochrome P450 (CYP)2C8 in vivo: CYP2C8 
substrates such as repaglinide, paclitaxel, pioglitazone, or rosiglitazone should 
be carefully monitored when co-administered with study drug treatment as they 
may have higher exposure; 
− Teriflunomide may be a weak inducer of CYP1A2 in vivo: medicinal products 
metabolized by CYP1A2 such as duloxetin, alosetron, theophylline and 
tizanidine should be used with caution during study drug treatment, as reduction 
of the efficacy of these products may be observed; 
− A 25% decrease in peak INR was observed when teriflunomide was 
co-administered with warfarin as compared with warfarin alone. Therefore, 
when warfarin is co-administered with study drug treatment, close INR FU and 
monitoring is recommended;  
− Teriflunomide is an inhibitor of organic anion transporter (OAT)3 in vivo: when 
study drug treatment is co-administered with substrates of OAT3, such as 
cefaclor, benzylpenicillin, ciprofloxacin, indometacin, ketoprofen, furosemide, 
cimetidine, zidovudine, caution is recommended; 
− Co-administration 
of 
substrates 
of 
breast 
cancer 
resistant 
protein 
(e.g., topotecan, sulfasalazine, daunorubicin, doxorubicin) and the OAT 
polypeptide family (e.g., nateglinide, repaglinide, rifampicin) and especially 
HMG-CoA reductase inhibitors (e.g., rosuvastatin, simvastatin, atorvastatin, 
pravastatin) with the study drug treatment should be undertaken with caution. 
Subjects should be closely monitored for signs and symptoms of excessive 
exposure to these medicinal products, and reduction of the dose of these 
medicinal products should be considered; 
− Rifampicin and other known potent CYP and transporter inducers such as 
carbamazepine, phenobarbital, phenytoin and St John’s Wort may result in a 
decrease in teriflunomide exposure. Co-administration of these drugs with 
study drug treatment should be used with caution.  
• Other treatments considered necessary for the subject’s wellbeing and not categorized 
as prohibited concomitant medications. 
5.2.5 Forbidden study-treatment-concomitant therapy 
• 
Systemic corticosteroids and ACTH, except for the treatment of MS relapses [see 
Section 5.2.3] 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 8 weeks during the 


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whole study duration) 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; 
• 
Immunosuppressive treatment (e.g., cladribine, mitoxantrone or other systemic 
immunosuppressive treatments such as azathioprine, cyclophosphamide, cyclosporine 
or methotrexate); 
• 
i.v. immunoglobulin; 
• 
Plasmapheresis, cytapheresis, or total lymphoid irradiation; 
• 
Vaccination with live vaccines; 
• 
β-blockers, diltiazem, verapamil, digoxin, or any other anti-arrhythmic or 
HR-lowering systemic therapy [non-exhaustive list of drugs provided in  
Appendix 4]; 
• 
Cholestyramine or activated charcoal unless needed for an accelerated elimination 
procedure;  
• 
Any other investigational drug; 
• 
Any investigational therapeutic procedure for MS (e.g., stent placement or angioplasty 
for chronic cerebrospinal venous insufficiency, stem-cell transplantation). 
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 
For each of the study endpoints, baseline is defined as the last value recorded prior to 
randomization (the actual visit used as baseline might be different across endpoints). 
6.1 Efficacy endpoints 
6.1.1 Primary efficacy endpoint(s) 
The primary endpoint is ARR. This endpoint is based on the number of confirmed relapses 
per subject-year. 
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 h, 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 


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as a relapse [see Section 7.2.2]. 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).  
6.1.2 Secondary efficacy endpoints 
There are four secondary efficacy endpoints, which will be analyzed as per the statistical 
testing strategy outlined in Section 11.3.1:  
• 
Change from baseline to Week 108 in fatigue-related symptoms as measured by 
the symptoms domain of the FSIQ–RMS 
 
• 
Cumulative number of combined unique active lesions (CUAL) from baseline to 
Week 108 
Definition: CUAL are new Gd+ T1 lesions plus new or enlarging T2 lesions (without 
double-counting of lesions). 
• 
Time to 12-week CDA from baseline to EOS 
Definition: A 12-week CDA is an increase of at least 1.5 in EDSS for subjects with a 
baseline EDSS score of 0.0 or an increase of at least 1.0 in EDSS for subjects with a 
baseline EDSS score of 1.0 to 5.0, or an increase of at least 0.5 in EDSS for subjects with 
a baseline EDSS score ≥ 5.5 which is to be confirmed after 12 weeks.  
Baseline EDSS is defined as the last EDSS score recorded prior to randomization. The 
initial EDSS increase, meeting the above criteria, is defined as the onset of disability 
accumulation.  
All EDSS measurements (with or without relapse, at a scheduled or unscheduled visit) will 
be used to determine the onset of disability accumulation. However, EDSS scores used for 
confirmation of disability accumulation must be obtained at a scheduled visit 
(i.e., unscheduled visits cannot be used as confirmatory visits) outside any ongoing relapse. 
In this context, relapse duration is defined as period between start and end dates if available 


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and limited to 90 days from onset if end date is not available or duration is longer than 90 
days.  
In order to confirm that the EDSS increase is persistent, all EDSS measurements between 
the onset and the 12-week EDSS confirmation (minus 7-day visit time-window) need to 
show an increase in EDSS, meeting the criteria for accumulation of disability as defined 
above.  
• 
Time to 24-week CDA from baseline to EOS 
Definition: A 24-week CDA is an increase of at least 1.5 in EDSS for subjects with a 
baseline EDSS score of 0.0 or an increase of at least 1.0 in EDSS for subjects with a 
baseline EDSS score of 1.0 to 5.0, or an increase of at least 0.5 in EDSS for subjects with 
a baseline EDSS score ≥ 5.5 which is to be confirmed after 24 weeks.  
Baseline EDSS is defined as the last EDSS score recorded prior to randomization. The 
initial EDSS increase, meeting the above criteria, is defined as the onset of disability 
accumulation.  
All EDSS measurements (with or without relapse, at a scheduled or unscheduled visit) will 
be used to determine the onset of disability accumulation. However, EDSS scores used for 
confirmation of disability accumulation must be obtained at a scheduled visit (i.e., 
unscheduled visits cannot be used as confirmatory visits) outside any ongoing relapse. In 
this context, relapse duration is defined as period between start and end dates if available 
and limited to 90 days from onset if end date is not available or duration is longer than 90 
days.  
In order to confirm that the EDSS increase is persistent, all EDSS measurements between 
the onset and the 24-week EDSS confirmation (minus 7-day visit time-window) need to 
show an increase in EDSS, meeting the criteria for accumulation of disability as defined 
above. 
6.1.3 Other efficacy endpoints 
MRI-based exploratory endpoints: 
• 
Percent change in brain volume (PCBV) from baseline to Week 108 
Definition: Longitudinal brain volume measurements are derived from MRI scans by using 
Structural Image Evaluation, using Normalization, of Atrophy methodology (SIENA) 
[Smith 2001, Smith 2002]. 
• 
Number of MRI lesions (Gd+ T1 lesions) at Week 60 and Week 108 
• 
Cumulative number of new or enlarging T2 lesions from baseline to Week 108 
• 
Change from baseline to Week 60 and Week 108 in the volume of MRI lesions 
(T2 lesions, T1 hypointense lesions) 


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• 
Absence of MRI lesions (Gd+ T1 lesions, new or enlarging T2 lesions) at Week 60 
and Week 108 
• 
Proportion of Gd+ lesions at baseline evolving to persistent black holes (PBHs) by 
Week 108 (axonal loss) 
• 
Change of 
 
• 
Change in
 
  
• 
Cumulative number of
 
 
Clinical exploratory endpoints (disease activity, relapses, disability progression): 
• 
Time to first confirmed relapse 
Definition: Time from randomization to first confirmed relapse. Relapse definition is 
given in Section 6.1.1. Date of the first confirmed relapse is defined as the onset date 
of the first confirmed relapse.  
• 
Absence of confirmed relapses from baseline to Weeks 60 and 108 
• 
Change from baseline by visit up to Week 108 in EDSS 
• 
No evidence of disease activity (NEDA) status up to EOS (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 EOS and completing treatment 
as planned)  
Other exploratory endpoints: 
• 
Change in MSFC Z-score from baseline by visit up to Week 108  
• 
Change in the SDMT score from baseline by visit up to Week 108  
• 
FSIQ-RMS patient improvement response (clinically important difference, defined as 
a reduction in the FSIQ-RMS score ≥ a threshold value anchored on the PGI-S of 
Fatigue scale, which will be determined by a blinded analysis of the data, as described 
in Section 11.4); 
• 
Change from baseline by visit up to Week 108 in fatigue-related impacts as measured 
by the impact sub-scales of the FSIQ–RMS  
• 
Change from baseline in PGI-S of Fatigue by visit up to Week 108;  
• 
Change from baseline in Clinician’s Global Impression of Change (CGI-C) of 
patient’s relapsing MS by visit up to Week 108; 
• 
Preferences for several treatment outcomes from MS subjects using the MACBETH 
methodology (sub-study, at selected sites only). 
6.2 Safety endpoints 
Treatment-emergent period is defined as the time from first study drug intake up to 15 days 
(inclusive) after last study drug intake. The following safety endpoints will be analyzed: 
• 
Treatment-emergent AEs, SAEs, AEs of special interest#, and MACE 
CCI
CCI
CCI


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• 
AEs leading to premature discontinuation of study treatment 
• 
Treatment-emergent morphological ECGs abnormalities (as defined by the ECG 
provider) 
• 
Change in 12-lead ECG variables (HR, PR, QRS, QT, QTcB, QTcF) from pre-dose to 
selected post-dose assessments (1h, 2h, 3h, 4h) on Day 1 and on day of re-initiation of 
study drug 
• 
Notable abnormalities* for selected 12-lead ECG variables (HR, PR, QT, QTcF) at 
3-hpost-dose assessment on Day 1, Week 12, and at the re-initiation of study drug 
when post-dose monitoring is required  
• 
Treatment-emergent decrease of FEV1 or FVC > 20% from baseline values  
• 
Treatment-emergent decrease of percent predicted FEV1 or FVC > 20 percentage 
points from baseline values 
• 
Change in FEV1 or FVC from baseline, absolute and % of absolute change to all 
timepoints up to EOS 
• 
Change from baseline to EOS vs change from baseline to EOT in FEV1 or FVC 
(absolute and % of predicted) 
• 
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 and < 12% in FEV1 or FVC 
from baseline to last available FU 
• 
Change in lung diffusion capacity as assessed by DLCO (at selected sites only), 
expressed in absolute change and % of predicted value from baseline to all timepoints 
up to EOS 
• 
Change from baseline to EOS vs change from baseline to EOT in DLCO (absolute and 
% of predicted; at selected sites only) 
• 
Treatment-emergent notable BP abnormalities* 
• 
Treatment-emergent notable laboratory abnormalities* 
• 
Change in body weight from baseline to EOS 
• 
Treatment-emergent electronic self-rated version of the Columbia-Suicide Severity 
Rating Scale (eC-SSRS) suicidal ideation score of 4 or above, or a “yes” response on 
the eC-SSRS suicidal behavior item 
# The selection of AEs of special interest is based on the anticipated risks of treatment with ponesimod or 
teriflunomide (e.g., liver enzyme abnormalities) and on the events that may be related to MS comorbidities 
(e.g., seizures or stroke) as described in Appendix 5; the final list of AEs of special interest will be defined 
in the Statistical Analysis Plan (SAP). 
* The selection of notable abnormalities considered for the analyses is based on standard definitions and the 
anticipated risks of treatment with ponesimod or teriflunomide as described in Appendix 6; the final list of 
abnormalities will be defined in the SAP. 


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6.3 Quality of life endpoints 
• Change from baseline by visit up to Week 108 in SF-36v2™ Health Survey domain 
and component scores. 
6.4 Pharmacoeconomic endpoints 
• Change from baseline by visit up to Week 108 in WPAI:MS scores 
• Health care resource utilization from baseline up to Week 108 (number of 
hospitalizations, length of stay, number of intensive care admissions for MS relapse 
and visits to an emergency medical services facility for MS) 
6.5 Pharmacokinetic and pharmacodynamic endpoints 
6.5.1 Pharmacokinetic endpoints 
• Plasma concentrations of ponesimod pre-dose at Weeks 12, 60, and 108 and 3 h 
post-dose on Day 1 and at Week 12. 
6.5.2 Pharmacodynamic endpoints 
• Peripheral blood lymphocyte counts pre-dose (absolute and change from baseline 
counts) by visit up to Week 108 
• Change from baseline to EOS vs change from baseline to EOT in lymphocyte counts 
(absolute and % change) 
• Post-treatment lymphocyte recovery at 15 days and 30 days after study drug 
discontinuation 
7 
STUDY ASSESSMENTS 
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 Actelion 
to whom these tasks are delegated. The set-up and oversight will be agreed upon with 
Actelion. The supervision of any external facilities remains under the responsibility of the 
principal investigator. 
Calibration certificates for the following devices used to perform study assessments must 
be available prior to the randomization of the first subject:  
• Temperature measurement devices for study medication storage area and lab sample 
storage (e.g., freezer). 


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• Spirometer; in addition, a copy of the calibrations check (syringe check) of the day of 
measurement must be stored and a log of calibration check results must be maintained 
at the site [see Section 7.3.5]. 
• DLCO gas analyzer (if applicable); in addition, a copy of the 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 7.3.6].  
• ECGs. 
• BP monitoring device. 
• MRI; in addition, prior to the start of the study, each MRI site must be qualified by 
MIAC [see Section 7.2.3]. 
7.1 Baseline assessments, including demographics 
7.1.1 Informed consent Visit 1 (Screening) 
Prior to performing any study-specific procedures or assessments, the subject must provide 
written informed consent to participate in the study. If the signing of informed consent and 
performance of the first study-specific procedures or assessments take place on the same 
day, it must be clear from the source documents that informed consent was obtained prior 
to any study-specific procedures being performed. If a study-specific procedure or 
assessment has been performed as part of routine assessments and the results are available 
prior to the subject’s signing of informed consent, such procedure or assessment may be 
used to assess eligibility and does not have to be repeated (CXR [see Section 7.3.7]). 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 (ISF). The language used in the oral and written 
information about the trial, and including the ICF, will be provided in a language that is 
fully understandable to the subject. 
Separate informed consent must be obtained from those subjects participating in the DLCO, 
non-conventional MRI, and patient preference sub-studies. 
For subjects who provide informed consent but are subsequently not randomized into the 
study, the reasons for not being randomized will be recorded in eCRF. 


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7.1.2 Baseline demographics and disease characteristics 
Baseline demographics (sex, age, race, body weight, and height) are to be recorded in the 
eCRF at Visit 1 (Screening). Complete, clinically relevant medical history and current 
conditions, as well as smoking status and MS disease characteristics [see Section 4.6] are 
to be documented in the eCRF. 
7.1.3 Study-concomitant therapies 
All study-concomitant therapy (including contraceptives and traditional and alternative 
medicines, i.e., plant-, animal-, or mineral-based medicines) taken by the subject from the 
signing of informed consent 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. 
7.2 Efficacy assessments 
7.2.1 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. 
EDSS and FS assessments will be performed at Visits 1 (Screening), 2 (Baseline), 6 to 
13 (Week 12 and every 12 weeks thereafter), 14 (EOT), 16 (FU2), and at any unscheduled 
visit in the event of relapses (R1, R2, etc.) or other unscheduled visits (U1, U2, etc.). If 
applicable, EDSS and FS will also be assessed at the corresponding visits in the PTOP 
(Visits 6A to 14A). 
EDSS and FS assessments will only be performed by the efficacy assessor who should 
preferably maintain this role for a given subject throughout the study [see Section 3.3.3]. 
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 2] 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.  


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7.2.2 Detection and evaluation of relapses 
Detection and evaluation of relapses will be done as follows [Figure 7]: 
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 in between the 
12-weekly visits (e.g., Visit 6–Week 12, Visit 7–Week 24,…) even after possible 
premature discontinuation from the study treatment (e.g., Visit 6A–Week 12 in the PTOP, 
Visit 7A–Week 24 in the PTOP,…) in order to proactively inquire about any new or 
worsened neurological symptoms. These telephone calls will be conducted either at Weeks 
18, 30, 42, 54, 66, 78, 90, and 102 (+/− 7 days), or 6 weeks after the last 12-weekly visit 
(+/− 7 days). If applicable, the contacts 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 17]. 
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 scheduled and unscheduled visit (limited to unscheduled visits when the 
subject will meet with the principal investigator / treating neurologist, but not at other 
unscheduled visits conducted for repeat testing (e.g., ALT or AST PFT …), the principal 
investigator / treating neurologist will interview the subject to determine whether or not a 
relapse may have occurred since last visit using a dedicated relapse assessment 
questionnaire [see Appendix 17] and the relapse symptom form [see Appendix 18]. 
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 in Section 6.1.1 have been verified and, 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. (Note: At scheduled visits the EDSS assessment planned for this 
visit will be used). The completed questionnaire [see Appendix 12] and the outcome of the 
examination [see Appendix 13] will be collected in the eCRF. 
Step 3: ‘The efficacy assessor will perform the EDSS/FS assessment within 7 days from 
the onset of new or worsening neurological symptom(s) [see Section 7.2.1].  


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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 5.2.3], treatment should be initiated as early as recommended 
by local clinical practice. The blinded 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., an 
increase of the magnitude described in Section 6.1.1 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 6.1.1]. 
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 3 outcomes: no relapse, unconfirmed relapse, or confirmed relapse. 
New or worsened neurological symptoms reported by the subject and for which there is 
another, 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 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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Figure 7 
Flow diagram for the detection and evaluation of relapses 
 


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7.2.3 MRI evaluations 
MRI scans will be performed at Visits 2 (Baseline), 10 (Week 60), and 14 (EOT) and at 
any unscheduled visit (U1, U2, etc.). If applicable, MRI scans will also be performed at the 
corresponding visits in the PTOP (Visits 10A and 14A). Testing at all visits may be 
performed up to 7 days prior to or after the visit date. In case of premature study treatment 
discontinuation, the MRI at EOT does not need to be performed if the EOT visit occurs 
within less than 4 weeks of the MRI assessment at Visit 10 (Week 60). 
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 PD-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.). 
All MRI data will be analyzed by the MIAC, c/o University Hospital Basel, Switzerland. 
MRI scans which are of unacceptable quality for central reading evaluation will be 
repeated.  
Prior to the start of the study, each MRI site must be qualified by MIAC. To be qualified, 
each MRI site will perform a dummy scan according to the parameter settings defined in 
the study MRI manual (separate document) and submit the image data to the MIAC who 
will assess the image quality, the quality of the data transfer, and the compatibility with the 
electronic data processing and will qualify the site accordingly. The dummy scan will not 
use contrast agent and will be performed on a volunteer or patient, having signed a specific 
informed consent for this MRI assessment. Once qualified, each MRI site must maintain 
all the study-specific parameter settings unchanged throughout the study. 
Detailed instructions on procedures, standardization, qualification, recording, and transfer 
of data, etc., will be provided in the study MRI manual (separate document).  
Lesion count of MRI performed within 24 months prior to the study will be recorded on 
the MS history page of the eCRF. These scans will not be analyzed by the MIAC.  
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 be informed of any findings of concern 
for the subject’s safety including non-MS-related findings detected on the MRI scan, but 
efficacy-related MRI results (e.g., lesion counts) will not be communicated to study staff 
or to the subject, unless deemed necessary for maintaining safety of the subject. Study 
participants with clinically relevant findings on MRI will be followed up until establishing 


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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 in the Medical History or as AE, as applicable. 
7.2.4 Supplementary non-conventional MRI sub-study 
Supplementary non-conventional MRI scans assessing MTR and DIR will be performed at 
selected sites with adequate equipment and expertise at the same timepoints as the 
conventional MRI scan described above. Only subjects who consent under a separate 
informed consent for non-conventional MRI will participate in the sub-study. It is 
anticipated that up to 300 subjects will participate to the sub-study. 
Similarly to the conventional MRI scans, data will be interpreted by MIAC. 
Detailed instructions on procedures, standardization, qualification, recording, and transfer 
of data, etc., will be provided in the study MRI manual (separate document). 
7.2.5 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 pre-randomization and at Visits 6, 7, 10, 12 (Weeks 12, 24, 60, 
and 84), and 14 (EOT).  
During the pre-randomization Period, two practice tests and a third test serving as baseline 
assessment will be performed. Ideally, the three tests should be performed  
≥ 5 days apart (i.e., second test practice ≥ 5 days from first practice test and third test 
serving as baseline ≥ 5 days from second practice test). The first test practice may be done 
at Visit 1 (Screening), the second test practice may be done at Visit 2 (Baseline) and the 
third test, serving as baseline, may be performed pre-dose at Visit 3 (Randomization). 
MSFC will be administered in combination with SDMT [see Section 7.2.6] in the following 
sequence: 
1. Timed 25-Foot Walk (7.62 meter)  
2. 9-HPT 
3. PASAT 
4. SDMT 


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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 administrator will be trained 
on the test administration before the initiation of the site. The test will only be administered 
by a trained administrator.  
A more comprehensive description of the test and its administration is provided in 
Appendix 7. 
7.2.6 Symbol Digit Modalities Test 
The SDMT [Smith 1982, Benedict 2006] measures attention and processing speed much 
like the PASAT. It will be administered along with the MSFC at pre-randomization and at 
Visits 6, 7, 10, 12 (Weeks 12, 24, 60, 84), and 14 (EOT).  
During the pre-randomization Period, two practice tests and a third test serving as baseline 
assessment will be performed. Ideally, the three tests should be performed  
≥ 5 days apart (i.e., second test practice ≥ 5 days from first practice test and third test 
serving as baseline ≥ 5 days from second practice test). The first test practice may be done 
at Visit 1 (Screening), the second test practice may be done at Visit 2 (Baseline) and the 
third test serving as baseline may be performed pre-dose at Visit 3 (Randomization). 
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.  
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 as Appendix 8. The rater will record the subject’s 
responses on a validated paper form that will be collected and transcribed in the eCRF. 
Actelion Pharmaceuticals 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 translations. 
7.2.7 FSIQ-RMS 
The FSIQ-RMS is a 20-item PRO measure that was developed by Actelion to evaluate 
fatigue-related symptoms and the impacts of those symptoms on the lives of people with 
RMS. The development of FSIQ-RMS is in accordance with the requirements set forth in 
the Final Guidance to the Industry on Subject Reported Outcomes: Use in Medical Product 
Development to Support Label Claims [FDA 2009a]. The questionnaire will be 
administered in an electronic format and consists of two separate domains: 


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• The FSIQ-RMS symptom domain (FSIQ-RMS-S) consists of seven items assessing 
fatigue-related symptoms with a recall period of 24 h measured on an 11-point numeric 
rating scale; the symptom domain score ranges from 0 to 77 with a higher score 
indicating greater fatigue. This domain (i.e., section 1 of the questionnaire) will be 
completed on 7 consecutive days. 
• The FSIQ-RMS impact domain (FSIQ-RMS-I) consists of 13 items assessing 
impacts of fatigue-related symptoms with a recall period of 7 days measured on a 
5-point Likert scale, ranging from no impact to extreme impact; the impact domain 
score ranges from 0 to 65 with a higher score indicating greater impact. As the impact 
domain of the FSIQ-RMS (i.e., section 2 of the questionnaire) has a 7-day recall period, 
it will only be completed on the last day (i.e., seventh day) of completion of section 1.  
FSIQ-RMS will be completed during the pre-randomization period, at Visits 6, 7, 10, and 
12 (Weeks 12, 24, 60, 84), 14 (EOT), and at unscheduled visits due to relapses (R1, R2, 
etc.) or other unscheduled visits (U1, U2, etc.) as described below. If applicable, 
FSIQ-RMS will also be performed at the corresponding visits in the PTOP. 
The completion of the FSIQ-RMS during the pre-randomization period will be done as 
follows: At Visit 1 (Screening), subjects who appear eligible based on the assessments 
made during this visit (but prior to the results from the laboratory assessments are received) 
will be provided with the electronic device containing the FSIQ-RMS.  
Once the results from the laboratory assessments confirm the subject’s eligibility, and 
provided no other assessment performed in the meantime excludes the subject, the site 
coordinator will contact and ask the subject to start the completion of the FSIQ-RMS. 
At home, the subject will complete the symptom domain of the FSIQ-RMS for 7 days 
(i.e., section 1 of the questionnaire). On the seventh day, the subject will also complete the 
impact domain of the FSIQ-RMS (i.e., section 2 of the questionnaire). The information 
captured from this assessment will be used as the baseline data for the FSIQ-RMS. Ideally, 
the FSIQ-RMS will be completed during the 7 consecutive days preceding the 
randomization.  
After randomization, the symptoms domain of the FSIQ-RMS (i.e., section 1 of the 
questionnaire) will be completed by the subject at home on a daily basis, starting in the 
evening of the day of a visit when the FSIQ-RMS is administered (Day 1 of questionnaire 
administration cycle) and during the 6 subsequent days (i.e., over 7 days in total). Subjects 
will return the completed FSIQ-RMS diary at the next scheduled visit. On the seventh day, 
the subject will also complete the impact domain of the FSIQ-RMS (i.e., section 2 of the 
questionnaire). If applicable, at the end of the PTOP, the FSIQ-RMS will be completed 
prior to Visit 14A (Week 108), ideally, during the 7 consecutive days preceding the visit. 


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The data from the electronic device will be collected by the vendor who will send the results 
to Actelion. The individual questionnaires will be completed only in countries for which 
validated translations are available. 
A sample of the FSIQ-RMS is provided as Appendix 9. 
7.2.8 Patient preferences 
Patient preferences for several treatment outcomes will be assessed in a subset of 
approximately 360 subjects using an electronic questionnaire developed by Actelion. 
Subjects will be recruited at selected sites in countries for which translations are available. 
Only subjects who consent under a separate informed consent for MS Patient Preference 
Questionnaire will participate in the sub-study. The MS Patient Preference Questionnaire 
will be completed at home twice during the pre-randomization period (after Visits 1 and 2 
[Screening, Baseline]), and during the follow-up period (before Visit 15, FU1) using an 
electronic device. All questionnaire responses will be electronically transferred to the 
Actelion database. Support for navigating the questionnaire will be provided as a tutorial 
within the electronic device. No guidance as to the content of the responses will be provided 
to the subject. 
A sample of the MS Patient Preference Questionnaire is provided as Appendix 14. 
7.2.9 Patient’s Global Impression of Severity of Fatigue 
The PGI-S of Fatigue assesses the subject’s fatigue severity on a given day. The scale is 
scored by the subject on an 11-point numeric rating scale ranging from 0 to 10, anchored 
at 0 = “Not severe at all” and 10 = “Very severe”. The questionnaire will be administered 
in an electronic format. 
PGI-S of Fatigue will be completed during the pre-randomization period at Visit 2 
(Baseline), at Visits 6, 7, 10, and 12 (Weeks 12, 24, 60, 84), 14 (EOT), and at unscheduled 
visits due to relapses (R1, R2, etc.) or other unscheduled visits (U1, U2, etc.). If applicable, 
PGI-S will also be performed at the corresponding visits in the PTOP. 
The individual questionnaires will be completed only in countries for which validated 
translations are available. 
It is recommended that the PGI-S of Fatigue is completed prior to any clinical assessments 
and before study drug exposure on the day of the visit. Preferably, subjects would complete 
the PGI-S of Fatigue while waiting for their appointment before any interaction with health 
care providers to avoid any potential bias or impact of interventions in their responses. 
A sample of the PGI-S of Fatigue is provided as Appendix 12. 


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7.2.10 Clinician’s Global Impression of Change of patient’s relapsing multiple 
sclerosis 
The CGI-C of patient’s relapsing MS requires the clinician to assess the change in subject’s 
relapsing MS severity compared to Baseline (Visit 2). The question is scored by the 
investigator on a 7-point Likert scale ranging from 1 to 7, anchored at 1 = “Very much 
improved” and 7 = “Very much worse”. The questionnaire will be completed on a paper 
form and subsequently transcribed in the eCRF. 
CGI-C of patient’s relapsing MS will be completed at Visits 6, 7, 10, and 12 (Weeks 12, 
24, 60, 84), 14 (EOT), and at unscheduled visits due to relapses (R1, R2, etc.) or other 
unscheduled visits (U1, U2, etc.). If applicable, CGI-S will also be performed at the 
corresponding visits in the PTOP. 
A sample of the CGI-C of patient’s relapsing MS is provided as Appendix 13.  
7.3 Safety assessments 
The definitions, reporting and FU of AEs, SAEs and potential pregnancies are described in 
Section 10. 
7.3.1 12-lead electrocardiogram 
A standard 12-lead ECG will be recorded at all scheduled study visits with the subject in a 
fully rested supine position after the subject has been allowed to rest for a minimum of 5 
min prior to the measurement. Pre-dose ECG may also be performed at unscheduled visits 
(U1, U2, etc.).  
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 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. In addition, at all sites where the first-dose administrator is not 
adequately experienced in interpreting ECGs, at Visit 3 (Day 1) and on the day of 
re-initiation of study drug when post-dose monitoring will be required, the pre-dose and 
post-dose ECGs required for evaluation of discharge criteria will be transmitted to the 
central ECG laboratory for expedite evaluation, and the ECG report will be returned to the 
site within approximately 1–2 h from transmittal.  
Details will be provided in the ECG laboratory manual. 
At Visit 3 (Day 1) and visits for re-initiation of study drug when post-dose monitoring will 
be required, the 12-lead ECG monitoring will be performed under the responsibility of the 
first-dose administrator. At all other visits, it will be performed under the responsibility of 
the treating neurologist or the first-dose administrator, depending on the site setting [see 


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Section 3.3.2 and Section 3.3.4]. The first-dose administrator will ensure that blinded study 
personnel at the study site, such as the treating and evaluating neurologists, clinical 
coordinator / study nurse, and other personnel involved in the clinical care and 
management of study subject, do not have access to post-dose ECG interpretation reports 
at Visit 3 (Day 1) and at visits for re-initiation of study drug when post-dose monitoring 
will be required (Visits I1, I2, etc.).  
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). 
At Visit 3 pre-dose (Day 1), the first-dose administrator must provide the ECG results and 
interpretation to the principal investigator / treating neurologist and support her/him, if 
requested, to make a final decision on the subject’s eligibility according to the 
inclusion/exclusion criteria. At Visit 3 (Day 1), the pre-dose ECG must be performed prior 
to 
randomization 
and 
the 
applicable 
points 
from 
exclusion 
criterion 
#18 
(e.g., HR < 50 bpm, presence of second-degree AV block Mobitz Type II or third-degree 
AV block, or a QTcF interval > 470 ms (females), > 450 ms (males), see Section 4.4) must 
be ruled out. 
During the treatment period ECGs must be performed at pre-dose. Additionally, at Visit 6 
(Week 12) during the treatment period, ECGs must also be performed at 3 h post-dose. In 
case of need of concomitant treatment with a QT-prolonging drug with known risk of 
Torsades de Pointes, additional ECGs will be performed according to the guidance 
provided in Appendix 3. 
At Visit 3 (Day 1) and on the day of re-initiation of study drug when post-dose monitoring 
is required [see Section 5.1.10], ECGs must be performed at pre-dose, and hourly (+/− 15 
min) thereafter for a minimum of 4 h and up to 12 h post-dose. Subjects may be discharged 
from the cardiac monitoring if they meet the discharge criteria before 12 h post-dose but 
no sooner than the (report of) ECG at 4 h post-dose has been evaluated by the first-dose 
administrator [see Section 5.1.11]. If the subject does not meet the defined discharge 
criteria at 12 h post-dose, the subject will be permanently discontinued from the study drug 
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 5.1.11], or until medically indicated. 
On Day 1 and on the first day of re-initiation of study drug when post-dose monitoring is 
required, significant findings, which in view of the first-dose administrator meet the 
definition of a (non-serious) AE, have an onset after the study drug intake, and are resolved 
at the time of discharge of the subject from cardiac monitoring, must be recorded directly 
on the AE page of the eCRF by the first-dose administrator. These AEs will not be visible 


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to any of the blinded study personnel at the study site. All other significant findings on Day 
1 or on the first day of re-initiation of study drug when post-dose monitoring is required 
that are serious or unresolved at the time of discharge of the subject from cardiac 
monitoring or with an onset on any other day, which in her/his view meet the definition of 
an AE, must be reported to the principal investigator / treating neurologist who will record 
these events on the AE page of the eCRF. 
7.3.2 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 in a fully rested supine position after the subject has been 
allowed to rest for a minimum of 5 min prior to the measurement. At all assessments 
(except post-dose assessments after first dose on Day 1 or at re-initiation), 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 calculated by the eCRF. Post-dose assessments at 
Visit 3 (Day 1) and at visits for re-initiation of study drug when post-dose monitoring is 
required 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 drug when post-dose monitoring is required.  
At Visit 3 (Day 1) and at visits for re-initiation of study drug when post-dose monitoring 
will be required, the assessment of vital signs will be performed under the responsibility of 
the first-dose administrator who will also evaluate and interpret these assessments. At all 
other visits, it will be performed under the responsibility of the treating neurologist or the 
first-dose administrator, depending on the site setting [see Section 3.3.2 and Section 3.3.4].  
On Day 1 and on the first day of re-initiation of study drug when post-dose monitoring is 
required, significant findings, which in view of the first-dose administrator meet the 
definition of an AE, have an onset after the study drug intake, and are resolved at the time 
of discharge of the subject, must be recorded directly on the AE page of the eCRF by the 
first-dose administrator. These AEs will not be visible to any of the blinded study personnel 
at the study site. All other significant findings on Day 1 or on the first day of re-initiation 
of study drug when post-dose monitoring is required that are unresolved at the time of 
discharge of the subject from cardiac monitoring or with an onset on any other day which 
in her/his view meet the definition of an AEs must be reported to the principal investigator 
/ treating neurologist who will record these events on the AE page of the eCRF. 
BP measurements will be performed at all scheduled study visits. In addition, unscheduled 
BP measurements may be performed at any time during the study (Visits U1, U2, etc.). At 


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Visit 3 (Day 1) and on days of re-initiation of study drug when post-dose monitoring is 
required, [see Section 5.1.10], SBP and DBP will be measured at pre-dose and hourly (+/− 
15 min) thereafter for a minimum of 4 h and up to 12 h post-dose. Subjects may be 
discharged from cardiac monitoring if they meet the discharge criteria before 12 h post-
dose but no sooner than 4 h post-dose [see Section 5.1.11]. If the subject does not meet the 
defined discharge criteria at 12 h post-dose, the subject will be permanently discontinued 
from the study drug but will continue the cardiac monitoring, and additional BP 
measurements will be performed until changes are no longer clinically relevant [i.e., 
discharge criteria are met; see Section 5.1.11], or until medically indicated. 
7.3.3 Body temperature 
Body temperature will be assessed at all scheduled study visits. Body temperature will also 
be assessed at unscheduled visits for relapses (Visits R1, R2, etc.). In addition, body 
temperature measurements may be performed at any time during the study, as part of 
unscheduled visits (Visits U1, U2, etc.). 
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. 
7.3.4 Pulse rate 
Pulse rate will be assessed at unscheduled visits for relapses (Visits R1, R2, etc.). If the 
visit for relapse corresponds to a visit when 12-lead ECG is performed, pulse rate 
assessment may be omitted. Pulse rate may also be assessed at any time during the study, 
as part of unscheduled visits (Visits U1, U2, etc.) 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. 
7.3.5 Spirometry 
Spirometry tests will be performed at Visits 2, 5, 6, 10, 14, 15, and 16 (Baseline, Week 4, 
Week 12, Week 60, EOT, FU1 and FU2). If applicable, spirometry tests will also be 
performed at Visit 14A in the PTOP. In addition, unscheduled spirometry will have to be 
conducted in the event of persistent respiratory symptoms (e.g., dyspnea). 


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Prior to randomization, spirometry can be performed at Visit 2 or at any time during the 
pre-randomization period. Spirometry at Visits 5, 6, 10, 15, and 16 (Week 4, 12, 60, FU1, 
and FU2) may be performed up to 7 days prior to or after the visit date. At Visit 14 (EOT), 
spirometry may be performed up to 7 days prior to the visit date but no later than 7 days 
after the discontinuation of study drug. It is highly recommended that all spirometry 
assessments are performed in the morning, preferably between 06:00 and 10:00, at 
approximately the same time to avoid diurnal variation. When applicable, it is also highly 
recommended that all spirometry assessments are performed prior to study drug intake. 
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 will be conducted according to the ATS / ERS guidelines [Miller 2005a, 
Miller 2005b]. A central vendor will provide equipment and detailed instructions for use, 
calibration and validation of spirometers. The provided spirometer must fulfill the technical 
requirements and recommendations for range and accuracy for forced expiratory 
maneuvers from the ATS/ERS guidelines [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. A copy of the calibrations of the day of 
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.  
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. All PFT technicians or other 
experienced persons participating in the studies will be trained on the specific requirements 
for the studies and have refreshment on ATS/ERS recommendations before study start and 
when compliance issues are identified. In addition, a specific PFT manual will describe the 
procedures to be implemented by the pulmonary function facility at each investigational 
site, in order to maintain high quality standards and in order to ensure the validity of the 
data collected.  
Subjects must refrain from taking short-acting-beta-agonists (e.g., salbutamol) for 6 h and 
long-acting-beta-agonists for 24 h prior to spirometry testing. If taken, the test should be 


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rescheduled. To perform the spirometry test, subjects will be rested for a minimum of 5 min 
prior to start. Sufficient forced expiratory maneuvers (up to a maximum of eight) will be 
performed to produce a minimum of three technically acceptable and repeatable traces 
(according to ATS/ERS guideline criteria; see PFT manual). The best (largest) FEV1 and 
FVC values from the three acceptable and repeatable tests will serve for the calculation of 
% of predicted values and used for the endpoint derivations. These values may come from 
separate maneuvers. The FEV1 and FVC measures obtained at Visit 2 (Baseline) and 
selected as described above will be used as the study baseline. 
All recorded spirometry values will be transmitted to the centralized reader, and will be 
reviewed by independent readers. Quality of the assessments will be evaluated for 
compliance with ATS/ERS criteria, and queries may be sent to the sites for clarification. If 
quality issues are identified, additional training will be provided. PFT values that trigger 
study drug discontinuation will be flagged. 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. Assessments may need 
to be repeated if results are of poor quality and/or inconclusive as per central reading. 
Predicted normal values for FVC and FEV1 will be used to determine exclusion criteria. 
Predicted normal values will be adjusted for subjects from ethnic groups other than 
white/Caucasian. The formulas for the calculation of the predicted normal values for FEV1 
and FVC and the ethnic group adjustments used in this study are those of the European 
Community for Coal and Steel [Quanjer 1993] (see details in PFTs manual). 
Spirometry conduct, documentation, performance, training details (of the responsible PFT 
site personnel), and quality control procedures are described in the PFT manual. 
7.3.6 DLCO sub-study 
DLCO will be assessed in a subset of approximately 400 subjects at selected sites with 
appropriate and established PFT expertise. Only subjects who consent under a separate 
informed consent for DLCO will participate in the sub-study. The assessment will be 
conducted at Visits 2, 5, 6, 10, 14, 15, and 16 (Baseline, Week 4, Week 12, Week 60, EOT, 
FU1, and FU2). If applicable, DLCO tests will also be performed at Visit 14A in the PTOP. 
In addition, unscheduled DLCO tests may be performed at any time during the study (Visits 
U1, U2, etc.).  
Prior to randomization, DLCO can be performed at Visit 2 or at any time during the 
pre-randomization period. DLCO at Visit 5, 6, 10, 15, and 16 (Week 4, 12, 60, FU1, and 
FU2) may be performed up to 7 days prior to or after the visit date. At Visit 14 (EOT), 
DLCO may be performed up to 7 days prior to the visit date but no later than 7 days after 
the discontinuation of study drug. 


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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. All PFT technicians or other experienced participating persons will be 
trained on the specific requirements and have refreshment on ATS/ERS recommendations 
before starting on the study and will receive additional training when non-compliance 
issues are identified.  
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; see DLCO manual). There must be a minimal 
interval of at least 4 min between each effort performed. Data from all DLCO efforts 
collected during a session will be captured in the eCRF.  
All recorded DLCO values will be transmitted to a centralized reader and will be reviewed 
by independent readers. Quality of the assessments will be evaluated for compliance with 
ATS/ERS criteria and will be reported in the eCRF; queries may be sent to the sites for 
clarification. If quality issues are identified, additional training will be provided to the site. 
Assessments may need to be repeated if results are of poor quality and/or inconclusive as 
per central reading facility. The selection of the DLCO values to be used for the main 
endpoint derivations will be validated by the independent readers. The mean of two best 
within-session DLCO efforts that meet the acceptability criteria according to the 
independent reader assessment 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 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 (see details in 
PFT manual). 


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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 drug 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 specific PFT manual will describe the procedures to be implemented by the pulmonary 
function facility at each investigational site in order to maintain high quality standards and 
to ensure validity of the data collected. To the extent logistically feasible, all within-subject 
DLCO should preferably be done by the same tester. 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. 
7.3.7 Chest X-ray 
CXR will be performed at Visit 1 (Screening) or at any time during the pre-randomization 
period and assessed by the local radiologist in order to exclude any subject with findings 
suggestive of active or latent TB. Any CXR performed within 90 days prior to screening 
can be used; if available, there is no need to repeat CXR at Screening. In case of 
re-screening, CXR does not need to be repeated if it was performed within 90 days prior to 
the date of re-screening.  
CXR will be repeated at the EOT visit in all subjects to characterize any pulmonary 
structural changes occurring during treatment. In case of premature discontinuation, the 
CXR at EOT does not need to be performed if the EOT visit occurs within less than 
24 weeks of the pre-randomization CXR. All examinations will be documented in the 
source documents of the subject. Examinations 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. Study participants, who experience clinically significant changes in 
CXR 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.  


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7.3.8 Test for tuberculosis 
An IFN gamma release assay (QuantiFERON-TB-Gold®) will be performed at Visit 1 
(Screening) to screen for active or latent TB. The test will be analyzed and interpreted at 
the central laboratory [see Section 7.3.14], and transferred to the eCRF database.  
Only subjects with a negative test at Screening and without CXR findings [see 
Section 7.3.7] at Screening or within the previous 90 days suggestive of active or latent 
tuberculosis can be included in the study. If the test result is positive, subjects must not be 
included in the study, except if there is documentation that the subject has received 
adequate treatment for TB previously. If the test result is inconclusive (invalid, 
indeterminate, or borderline), the test may be repeated once and a negative result must be 
obtained prior to randomization in order to include the subject. If the result of the repeated 
test is again inconclusive (invalid, indeterminate, or borderline), subjects must not be 
included in the study. 
Details on the performance of the test for TB will be provided in the specific central 
laboratory manual. 
7.3.9 Ophthalmologic assessments 
Ophthalmologic assessments will be performed by an ophthalmologist at Visits 1 
(Screening), 6 (Week 12), 7 (Week 24), 10 (Week 60), and 14 (EOT). Testing at Visit 1 
can be performed at any time during the pre-randomization period. Testing at Visits 6, 7, 
10 (Weeks 12, 24, and 60) may be performed up to 7 days prior to or after the visit date. 
At Visit 14 (EOT), testing may be performed up to 7 days prior to the visit date but no later 
than 7 days after the discontinuation of study drug. In addition, unscheduled 
ophthalmological examination will be done in the event of visual symptoms or findings 
suggestive of active uveitis [see Section 5.1.13.7].  
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 in case of 
suspicion of active uveitis at Screening or during a scheduled ophthalmological assessment 
(unless contra-indicated according to the ophthalmologist) [see Section 5.1.13.7]. While 
the visual acuity and ocular pressure measurement themselves may be performed by a 
delegate (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 


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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.  
The purpose of the assessment prior to randomization is to exclude subjects with macular 
edema or diabetic retinopathy from the study, and to document a baseline assessment. 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. 
7.3.10 Optical Coherence Tomography 
OCT will be assessed at Visits 1 (Screening), 6 (Week 12), 7 (Week 24), 10 (Week 60), 
and 14 (EOT). Testing at Visit 1 can be performed at any time during the 
pre-randomization period. Testing at Visits 6 and 10 (Week 12 and 60) may be performed 
up to 7 days prior to or after the visit date. At Visit 14 (EOT), testing may be performed up 
to 7 days prior to the visit date but no later than 7 days after the discontinuation of study 
drug. In addition, unscheduled OCT examination will have to be assessed in the event of 
visual symptoms or findings suggestive of macular edema according to the 
ophthalmologist’s decision, or in case of active uveitis diagnosed during the study 
[see Section 5.1.13.7]. While the OCT exam may be performed by a delegate 
(e.g., technician, optometrician), the review and interpretation must be performed by the 
ophthalmologist.  
The purpose of the assessment prior to randomization is to exclude subjects with macular 
edema or diabetic retinopathy from the study, and to document a baseline assessment. The 
site will use the OCT device available locally and must ensure it is working properly. To 
the extent that is logistically feasible, the same OCT machine is to be used for each 
individual subject throughout the study.  
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. 
The OSB will receive all information related to suspected cases of macular edema and will 
perform a central, blinded review of OCT results and subject data of suspected cases of 
macular edema. 


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7.3.11 Weight and height 
Body weight will be measured at Visits 1 (Screening), 10 (Week 60) and 14 (EOT). 
In addition, unscheduled body weight measurement may be performed at any time during 
the study (Visits U1, U2, etc.). Body height is only measured at Visit 1 (Screening). Data 
will be collected in the eCRF. 
7.3.12 Physical examination 
Physical examination is performed by the principal investigator or treating neurologist at 
Visits 1 (Screening), 2 (Baseline), 5, 6, 7, 10, and 12 (Weeks 4, 12, 24, 60, and 84), 
14 (EOT), and at unscheduled visits due to relapses (R1, R2, etc.). If applicable, physical 
examination will also be performed at Visits 10A and 14A in the PTOP. In addition, 
unscheduled physical examination may be performed at any time during the study (Visits 
U1, U2, etc.) if deemed necessary by the investigator.  
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. 
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 7.2.1] does not obviate the requirement for the examination 
of the neurological function as part of the physical examination by the treating neurologist. 
7.3.13 Dermatological examination 
A complete skin examination will be performed by a dermatologist at Visits 2 (Baseline), 
10 (Week 60), and 14 (EOT). If applicable, dermatological examination will also be 
performed at Visits 10A and 14A in the PTOP. In addition, unscheduled complete skin 
examination may be performed by the dermatologist at any time during the study 
(Visits U1, U2, etc.). The purpose of the skin examination prior to randomization is to 
record the pre-existing lesions, exclude subjects with suspicious skin lesions 
(pre-cancerous, cancerous) from the study, and to document a baseline assessment. In case 
of re-screening, skin examination does not need to be repeated if skin examination from 
initial screening was performed within 90 days prior to the date of re-screening.  


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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.  
7.3.14 Laboratory assessments 
7.3.14.1 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 Actelion’s clinical 
database. 
Under specific circumstances (e.g., subject lives far away from the site and cannot return 
every 2 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. 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 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. In all cases, testing of total lymphocytes count 
at a local laboratory is not to be assessed and collected unless deemed absolutely necessary 
by the investigator for maintaining safety of the subject. 
If a central laboratory sample is lost, has deteriorated or cannot be analyzed for whatever 
reason, the investigator may collect an additional sample as soon as possible for retest 
analysis if still clinically relevant. 


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The central laboratory will provide all laboratory results by fax or normal mail to the site 
with the exception of the results of the total WBC count, total lymphocyte count, and 
teriflunomide plasma concentration.  
• Total WBC count and total lymphocyte count: WBC and lymphocyte count results 
during treatment period will not be communicated to the site unless a total lymphocyte 
count < 0.2 × 109/L is recorded by the central laboratory. In this event, an alert 
containing the total lymphocyte count result will be sent to the principal investigator / 
treating neurologist and the sponsor [see Section 5.1.13].  
• Teriflunomide plasma concentration:  
− For subjects not entering the AC-058B303 extension study: Teriflunomide 
plasma concentration may be assessed if needed to determine if contraception 
can be discontinued [see Section 5.1.14.4]. Teriflunomide plasma concentration 
can also be assessed for any subjects not entering the extension study if deemed 
necessary for the subject’s safety, at the investigator’s discretion. Sites will 
receive notification if teriflunomide plasma level is < 0.02 mg/L. Sites will also 
receive notification if teriflunomide plasma level is ≥ 0.02 mg/L; In this event, 
the principal investigator / treating neurologist will decide whether the 
accelerated elimination procedure should be repeated (e.g., if rapid elimination 
is needed, such as a wish to become pregnant or father a child 
[see Section 5.1.14] or whether physiological elimination alone is warranted). 
− For subjects who enter the AC-058B303 extension study: The timing of 
teriflunomide test and procedures are described in the AC-058B303 study 
protocol (separate protocol).  
• A WBC count > 20 × 109/L or a lymphocyte count > 8.0 × 109/L is recorded by the 
central laboratory [see Appendix 6]. In this event, an alert containing the total WBC or 
lymphocyte count result (as applicable) will be sent to the principal investigator and 
the sponsor. 
• WBC and total lymphocyte counts measured at Visit 1 (Screening), 2 (Baseline), and 
any of the visits in the PTOP (if applicable) will be visible to the treating neurologist. 
All laboratory reports must be signed and dated by the principal investigator or delegate 
within 5 calendar 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 


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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. 
7.3.14.2 Laboratory tests 
Blood samples will be drawn preferably in a fasted condition and, when applicable, before 
the morning administration of study medication at Visit 1 (Screening), Visit 2 (Baseline), 
Visits 4 to 13 (Week 2, 4, 12 and every 12 weeks thereafter), Visit 14 (EOT), Visit 15 
(FU1), and Visit 16 (FU2) and, if applicable, at the corresponding visits in the PTOP (Visits 
7A, 10A, 12A, and 14A). In addition, ALT, AST, INR, alkaline phosphatase (AP), and 
total bilirubin will be assessed on a bi-weekly basis until Week 24 (i.e., at Week 6, 8, 
10, 14, 16, 18, 20, and 22). Furthermore, total WBC and total lymphocyte counts will 
be assessed on a 4-weekly basis until Week 24 (i.e., at Week 8, 16, and 20). Unscheduled 
laboratory tests may be performed at any time during the study (Visits U1, U2, etc.). 
Urinalysis will be assessed using dipsticks at Visit 1 (Screening), Visits 5, 6, 7, 10, and 12 
(Week 4, 12, 24, 60, and 84), Visit 14 (EOT), and Visit 15 (FU1) and, if applicable, at the 
corresponding visits in the PTOP (Visits 7A, 10A, 12A, and 14A). In addition, unscheduled 
urinalysis may be performed at any time during the study (Visits U1, U2, etc.). 
Laboratory assessments at Visit 1 must be performed a minimum of 7 days before the 
laboratory assessment at Visit 2. 
If a laboratory sample cannot be evaluated (e.g., is lost or deteriorated), an additional 
sample may need to be taken if deemed necessary by the investigator. 
Hematology 
• Red blood cell count 
• Total and differential WBC counts (basophils, eosinophils, lymphocytes, monocytes, 
neutrophils, band forms) 
• Platelet count 
• Hb 
• Hematocrit 
Clinical chemistry 
• Fasting glucose 
• ALT, AST, AP, total bilirubin, lactate dehydrogenase  
• INR 
• Creatinine 
• Calculated creatinine clearance (Cockroft-Gault) 


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• Urea 
• Uric acid 
• Total cholesterol 
• Triglycerides 
• Sodium, potassium, chloride, calcium 
• Total protein, albumin 
• C-reactive protein 
Virus serology 
• Hepatitis B surface antigen, Hepatitis C antibodies*, HIV1 and HIV2 antibodies, 
varicella-zoster virus antibodies at Visit 1 (Screening). 
*In the event of a positive Hepatitis C antibody test, site can draw an additional 
confirmatory blood sample for testing of Hepatitis C viral RNA. 
Biomarkers and additional analyses in the event of infections  
• A serum sample will be taken at Visit 2 (Baseline) 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 or for analysis of biomarkers. 
Additional analyses in the event of a vaccination with non-live vaccines 
• Subjects receiving non-live vaccination while on study treatment will have 5 mL of 
blood drawn prior to and ≥ 3 weeks after vaccination in order to explore changes in 
vaccine-specific antibody titers from pre- to post-vaccination. Samples are to be stored 
at the central laboratory to be analyzed at the end of the study. 
Test for TB 
• An IFN gamma release assay will be performed at Visit 1 (Screening) to screen for 
active or latent TB [see Section 7.3.8]. 
Pregnancy test 
A serum pregnancy test for WOCBP will be performed at Visit 1 (Screening) and at 
Visit 16 (FU2) and if pregnancy is suspected during the study. Urine pregnancy tests will 
be performed at Visit 2 (Baseline), Visits 4 to 12 (Weeks 2, 4, 12, and every 12 weeks 
thereafter), Visit 14 (EOT), and Visit 15 (FU1). Additionally, urine pregnancy tests will be 
performed at home every 4 weeks (+/− 4 days) between the visits. Subjects will 


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communicate the result (telephone call) of the tests to the principal investigator / treating 
neurologist. Urine pregnancy testing, performed at home every 4 weeks, will be continued 
after last study drug intake on a 4-weekly basis until 6 weeks after the first of two tests 
showing teriflunomide plasma level < 0.02 mg/L (results to be communicated by telephone 
call to the principal investigator / treating neurologist). 
In order for WOCBP to be randomized in the study, they must have a confirmed negative 
serum pregnancy test at Visit 1 and a second confirmed negative urine pregnancy test prior 
to randomization. The two tests must be performed a minimum of 3 weeks apart.  
Serum pregnancy testing results will be automatically transferred from the central 
laboratory database to Actelion’s clinical database. Urine pregnancy testing results will be 
recorded in the eCRF. In case 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. 
Evaluation of teriflunomide elimination:  
The testing of teriflunomide plasma concentration may only be conducted for women of 
childbearing potential and fertile male subjects, if needed, to confirm that contraception 
can be discontinued.  
For subjects not entering the AC-058B303 study, teriflunomide plasma levels will be 
determined by the central laboratory if necessary to determine if contraception can be 
discontinued. Teriflunomide plasma concentration can also be assessed for any subjects 
not entering the extension study if deemed necessary for the subject’s safety, at the 
investigator’s discretion. The testing should not occur before 20 weeks after last drug 


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intake (if accelerated elimination procedure has been completed) or not before 35 weeks 
(i.e., 8 months) after last drug intake or EOS, whichever is last (if accelerated elimination 
procedure has not been completed) [see Sections 5.1.14.1 and 5.1.14.4] by a previously 
described 
high-performance 
liquid 
chromatography 
method 
[Sobhani 
2010]. 
The possibility to test teriflunomide by the central laboratory after EOS will be offered. In 
this case, the results will only be communicated to the site.  
For subjects who enter the AC-058B303 extension study: the timing of teriflunomide tests 
is described in the separate AC-058B303 study protocol. 
7.4 Electronic self-rated version of the Columbia-Suicide Severity Rating 
Scale (eC-SSRS) 
The electronic self-rated version of the eC-SSRS is used to reliably and consistently 
monitor subjects for suicidal ideation and behavior during the study.  
The eC-SSRS assesses lifetime suicidality during an initial baseline evaluation  
(Visit 2-Baseline), and then prospectively monitors ideations and behaviors at subsequent 
follow-up assessments (Visit 10-Week 60 and Visit 14-EOT). At each visit, 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 computer 
administration. Subjects will be asked to respond to standardized clinical questions aiming 
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, after 
the PGI-S of Fatigue, WPAI:MS and SF-36v2™ have been completed. Preferably, subjects 
would complete the eC-SSRS while waiting for their appointment before any interaction 
with health care providers. 
A sample of the eC-SSRS (in English) is provided as Appendix 16. The scale will be 
administered using a telephone-based system. The clinical site will provide a telephone to 
be used during above mentioned visits and the subject will respond to the questions with 
the telephone keypad. The data will be collected by the vendor who will send the results to 
Actelion. 
Actelion has been granted a license agreement for the use of the eC-SSRS.  


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7.5 Quality of life assessments 
7.5.1 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 Visit 2 (Baseline), at Visits 6, 7, 
10, 12 (Weeks 12, 24, 60, and 84), and 14 (EOT) and at unscheduled visits due to relapses 
(R1, R2,etc.). 
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 determine the physical and mental component 
summary scores as described in the SF-36v2™ manual [Maruish 2011]. 
It is recommended that the SF-36v2™ Questionnaire is completed prior to any clinical 
assessments, after the PGI-S of Fatigue and WPAI:MS have been completed. Preferably, 
subjects would complete the SF-36v2™ while waiting for their appointment before any 
interaction with health care providers to avoid any potential bias in their responses. 
The SF-36v2™ with a 4-week recall period will be used. A sample of the SF-36v2™ 
(in English) is provided as Appendix 11. The questionnaire will be administered in an 
electronic format. The data from the electronic device will be collected by the vendor who 
will send the results to Actelion. 
Actelion has been granted a license agreement for the use of the SF-36v2™ questionnaire. 
The individual questionnaires will be completed only in countries for which validated 
translations are available. 
7.6 Pharmacoeconomic assessments 
7.6.1 Work Productivity and Activity Impairment Questionnaire: Multiple 
Sclerosis V2.0 
The WPAI:MS is a 6 question patient-reported quantitative assessment of the amount of 
absenteeism, presenteeism, work productivity loss and activity impairment attributable to 
MS during the previous 7 days.  
Actelion has adapted the specific health version of the WPAI version 2, which was 
developed by Reilly Associates for MS.  
The WPAI:MS will be completed by the subject at Visit 2 (Baseline), at Visits 6, 7, 10, 12 
(Weeks 12, 24, 60, and 84), and 14 (EOT).  


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WPAI:MS outcomes are expressed as impairment percentages, with higher numbers 
indicating greater impairment and less productivity, i.e., worse outcomes. 
It is recommended that the WPAI:MS Questionnaire is completed prior to any clinical 
assessments, after the PGI-S of Fatigue has been completed. Preferably, subjects would 
complete the WPAI:MS while waiting for their appointment before any interaction with 
health care providers to avoid any potential bias or impact of interventions in their 
responses. 
A sample of the WPAI:MS (in English) is provided as Appendix 10. The questionnaire 
will be administered in an electronic format. The data from the electronic device will be 
collected by the vendor who will send the results to Actelion. 
Actelion Pharmaceuticals has notified the developer about the use of the instrument in this 
study. No license is required for the administration of the instrument. The individual 
questionnaires will be completed only in countries for which validated translations are 
available. 
7.6.2 Health care resource utilization 
Health care resource utilization data, including number of intensive care unit (ICU) 
admissions for MS relapses and emergency medical facility visits for MS will be collected 
at Visits 4 to 13 (Weeks 2, 4, 12, 24, 36, 48, 60, 72, 84, and 96), and 14 (EOT) as well as 
at unscheduled visits due to relapse (R1, R2,…).  
Subjects will be asked to report any visits to emergency medical services facilities due to 
MS since the last study visit, and the dates will be captured in the eCRF. Hospitalization 
due to MS relapses will be captured in the eCRF including the length of stay and any 
admissions to ICU. 
7.7 Pharmacokinetic and pharmacodynamic assessments 
These assessments are done to investigate PD and PK effects of ponesimod. 
7.7.1 Pharmacokinetic assessments 
7.7.1.1 Timing for sampling 
PK samples will be collected during this study for all subjects, in order to provide 
information about study drug exposure in the target population. Blood samples will be 
collected pre-dose at Visits 6, 10 and 14 (EOT; Week 12, 60 and 108). Additionally, at 
Visits 3 and 6 (Day 1 and Week 12), PK samples will be drawn 3 h (+/− 15 min) post-dose.  
When possible, a PK sample will be collected for all subjects experiencing SAEs. In this 
event, the sample should be collected pre-dose, as early as possible after SAE onset, and 
no later than 7 days after the last dose of study drug. 


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7.7.1.2 Procedures for sampling 
Up to 3 mL of blood must be collected in tubes containing ethylenediaminetetraacetic acid. 
Immediately following collection of the required blood volume, the tubes must be slowly 
tilted backwards and forwards (no shaking) to bring the anti-coagulant into solution, and 
immediately cooled on ice. Within 30 min of collection, the tubes must be centrifuged at 
approximately 1500 g for 10 min at 2 to 8 °C. When a centrifuge that can be cooled is not 
available, the blood samples and the bucket of the centrifuge must be cooled on ice prior 
to centrifugation. The plasma must be transferred into one labeled opaque polypropylene 
tube to avoid carry-over of erythrocytes. All samples must be stored in an upright position 
≤ −20 °C (Freezer settings: intended temperature −25 °C; upper limit −20 °C). The exact 
time of collection of the blood sample must be entered in the eCRF, as well as the status of 
the subject (fed or fasted), and the time of last previous study drug intake. Blood samples 
for PK analysis must be drawn prior to study drug intake on the day of the visit (except at 
Visits 3 and 6, when a sample will be drawn 3 h post-dose).  
To prevent degradation of ponesimod in the plasma samples, exposure to light should be 
minimized. After centrifugation, plasma samples should be kept in the dark. 
Note: 
The 3-h PK sample on Day 1 or on the first day of re-initiation of study drug when 
post-dose monitoring is required should be taken by the first-dose administrator, the 
first-dose administrator nurse or another person not involved in the clinical care and 
management of the study subject. 
7.7.1.3 Labeling 
Details of the collection and shipment of the samples can be found in the laboratory manual 
provided to the investigator. The tubes and labels for the samples will be provided to the 
investigator and/or staff by the central laboratory. 
7.7.1.4 Bioanalysis 
The concentration of ponesimod in plasma will be determined by a validated liquid 
chromatography-tandem mass spectrometry assay by Idorsia PK analyses services. The 
lower limit of quantification is 1 ng/mL. 
Concentrations will be calculated by interpolation from a calibration curve. Quality control 
samples will be analyzed throughout the study. Their measured concentrations will be used 
to determine between-run and overall precision and accuracy of the analyses. 
If required, a selection of plasma PK samples may be analyzed by, or under the supervision 
of, the sponsor to assess the chiral inversion of ponesimod, and/or document the presence 
of circulating metabolites using a qualified research method. 


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The samples will be destroyed upon signature of the Clinical Study Report. 
7.7.2 Pharmacodynamic assessments 
The PD marker is total lymphocyte counts, which will be measured as part of the 
hematology tests [see Section 7.3.14].  
7.8 Total blood volume 
The total blood volume to be drawn per subject during the entire course of the study is 
described in Table 7. 
Table 7 
Total blood volume to be drawn per subject 
Test 
Number 
of tests 
Volume 
per test 
Total volume per test 
throughout the study 
Viral serology at Screening6 
1 
 5 mL 
5 mL 
Interferon gamma release assay for tuberculosis at 
Screening 
1 
3 x 1 mL 
 3 mL 
Serum sample at Baseline1 
1 
 5 mL 
 5 mL 
Hematology2 
18 
3 mL 
54 mL 
Blood chemistry3 
23 
7.5 mL 
172.5 mL 
INR 
23 
3 mL 
69 mL 
Ponesimod PK 
5 
3 mL 
15 mL 
Teriflunomide plasma concentration 
2 
5 mL 
10 mL 
Vaccine specific Antibody titres4 
2 
5 mL 
10 mL 
Total blood volume drawn throughout the study: 343.5 mL5, 6 
1. To be stored at the central laboratory for potential retrospective analyses of viral serology titers in the event of 
infections. 
2. Additional samples may be needed in the event of lymphocytes < 200 cells/μ L. 
3. Includes serum pregnancy test at Screening, if needed. 
4. Additional samples may be taken in the event of a vaccination with a non-live vaccine. 
5. If the blood sample cannot be evaluated (e.g., is lost or deteriorated) additional samples may need to be taken if 
deemed necessary by the investigator. 
6. In the event of a positive Hepatitis C antibody test, site can draw an additional confirmatory blood sample (6 mL) for 
testing of Hepatitis C viral RNA. INR = International Normalized Ratio; PK = pharmacokinetics. 
No genomic testing will be performed on any blood sample collected during this study. 
8 
SCHEDULE OF VISITS 
A tabulated summary of all visits and assessments described in the following sections is 
provided in Table 1, Table 2, and Table 3. The schedule of visit dates should be established 
at the time of screening. To the extent possible, subjects will be expected to adhere to the 
established visit schedule. 
The timepoint for every visit is defined taking as a reference Day 1 (Visit 3), which is the 
day of randomization.  
When scheduling the different assessments for a subject visit, the following should be taken 
in account: 


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• The subject must come to the clinic in a fasted condition for all visits and, when 
applicable, before the morning administration of study drug.  
• At Visit 3 (Day 1) and on the days of re-initiation of study drug when post-dose 
monitoring is required (if applicable), the assessments during the visits will be divided 
into two parts: before (pre-dose) and after (post-dose) the administration of the study 
drug, which will be taken at the site 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.  
• When applicable, PK sampling is to be done pre-dose with an additional sample drawn 
3 h post-dose at Visits 3 (Day 1) and 6 (Week 12). On these visits, post-dose sampling 
must be drawn on the same day as pre-and post-dose ECGs and SBP/DBP are 
performed. 
• 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.  
• Preferably, questionnaires will be completed by the subject in the morning prior to any 
other protocol mandated assessment and prior to any other discussion with the 
investigator or treating neurologist. Subjects will provide responses to the 
questionnaires while waiting for their appointment. Questionnaires should be 
completed in the following order: 
− PGI-S of Fatigue 
− WPAI:MS 
− SF-36v2™ 
− eC-SSRS 
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. 


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It is permitted to re-screen subjects once if the reason for non-eligibility was transient (e.g., 
abnormal laboratory test, insufficient wash-out period of a forbidden medication), provided 
that documented authorization has been received from Actelion. Subjects who were not 
eligible because of a negative test for varicella-zoster antibodies may also be re-screened 
once after having been vaccinated. All pre-randomization assessments should then be 
repeated at the time of re-screening (with the exception of CXR and dermatological 
examination if performed within 90 days prior to the date of re-screening). 
Unscheduled visits may be performed at any time during the study. Depending on the 
reason for the unscheduled visit (e.g., relapse, AE, central laboratory re-test), 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 Pre-randomization period 
The pre-randomization period must take place within 45 days prior to randomization and 
include the Visit 1 (Screening), Visit 2 (Baseline) and the pre-dose assessments of Visit 3 
(Day 1).  
The start of screening occurs on the day the first screening assessment was performed (i.e., 
signature of informed consent). 
8.1.1 Visit 1 (Screening) 
Visit 1 will be performed from 45 to 11 days prior to randomization. The Visit 1 date is 
defined as the date of start of pre-randomization period (i.e., signature of the ICF). During 
this visit, subject informed consent will be obtained, and the assessments required for the 
determination of subject eligibility will be performed. These assessments may generally be 
performed on separate days within the pre-randomization period.  
Visit 1 includes: 
• After discussing the study with the investigator and after agreeing to study participation 
by signing the ICF, subjects will be assigned a subject number by the IRT provider. It 
is the responsibility of the investigator to obtain written informed consent prior to any 
screening assessment. The subject number will identify the subject throughout the 
study. In case of re-screening [see Section 8], the subject number assigned during the 
first screening procedure will be retained. 
• Review of MS diagnosis and McDonald 2010 criteria 
• Recording of demographics, medical history, smoking status, and disease 
characteristics 
• Recording of previous and concomitant medications [see Section 5.2]. 
• EDSS/FS (performed by the efficacy assessor) 


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• SBP/DBP  
• Body weight and height 
• Body temperature 
• Physical examination  
• Ophthalmological examination (under the responsibility of the ophthalmologist) 
• OCT (under the responsibility of the ophthalmologist) 
• Hematology, blood chemistry, and serum pregnancy test for WOCBP 
• TB test 
• Viral serology 
• Urinalysis 
• 12-lead ECG  
• MSFC and SDMT (first test practice) 
• FSIQ-RMS (subjects who appear eligible based on the assessments made during this 
visit will be provided with the FSIQ-RMS and will be instructed to complete the 
symptoms domain of the FSIQ-RMS at home, provided no other assessment performed 
in the meantime excludes the subject). Once the results from the laboratory assessments 
confirm the subject’s eligibility, the site coordinator will contact the subject to instruct 
him/her to start the completion of the FSIQ-RMS [see Section 7.2.7]. 
• Patient Preference Questionnaire (sub-study at selected site only; subjects who appear 
eligible based on the assessments made during this visit will be provided with the 
Patient Preference Questionnaire and will be instructed to complete the questionnaire 
at home, before coming to site for Visit 2). 
• CXR (Any CXR performed within 90 days prior to screening can be used). In case of 
re-screening, CXR does not need to be repeated if it was performed within 90 days 
prior to the date of re-screening. 
• Recording of AEs/SAEs: all AEs/SAEs occurring after signing of the ICF are to be 
reported in the eCRF and on an SAE form, if applicable. 
The principal investigator / treating neurologist must check inclusion/exclusion criteria. 
The next visit (Visit 2) will only be scheduled if the subject meets all the eligibility criteria. 
Date of screen failure will be collected in the IRT system and in the eCRF; additionally, 
the reasons for screening failure are documented in the eCRF (screening information is 
collected for all screen failure subjects). 
8.1.2 Visit 2 (Baseline)  
Visit 2 will be performed anytime within the pre-randomization period. The date of EDSS 
assessment defines the date of the visit. During this visit, the inclusion and exclusion 
criteria will be confirmed, and baseline assessments will be performed and recorded. While 


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the assessments may generally be performed anytime during the pre-randomization period, 
the following points should be considered: 
• All Visit 1 assessments repeated at Visit 2 (Baseline; i.e., hematology, blood chemistry, 
12-lead ECGs, physical examination, and SBP/DBP) must be performed at least 7 days 
after the Visit 1 assessments.  
• MSFC performed at Visit 2 (Baseline) must be performed at least 5 days after the 
assessment at Visit 1 (Screening) and at least 5 days before the assessment at Visit 3 
(Randomization). 
• For WOCBP, the urine pregnancy test at Visit 2 must be performed at least 3 weeks 
after the serum pregnancy test performed at Visit 1. 
• PGI-S of Fatigue (subject completes the questionnaire prior to any clinical assessments 
or interaction with health care providers, preferably while waiting for their 
appointment) 
• WPAI:MS (subject completes the questionnaire after PGI-S of Fatigue, prior to any 
clinical assessments or interaction with health care providers, preferably while waiting 
for their appointment) 
• SF-36v2TM (subject completes the questionnaire after PGI-S of Fatigue and WPAI:MS, 
prior to any clinical assessments or interaction with health care providers, preferably 
while waiting for their appointment) 
• eC-SSRS (subject completes the questionnaire after PGI-S of Fatigue, WPAI:MS, and 
SF-36v2TM prior to any clinical assessments or interaction with health care providers, 
preferably while waiting for their appointment) 
• Recording of change in previous and concomitant medications since Visit 1 
[see Section 5.2] 
• EDSS/FS (performed by the efficacy assessor) 
• MS relapse 
• SBP/DBP  
• 12-lead ECG  
• Physical examination 
• Body temperature 
• Skin examination (performed by the dermatologist). In case of re-screening, skin 
examination does not need to be repeated if skin examination from initial screening 
was performed within 90 days prior to the date of re-screening. 
• Hematology, blood chemistry  
• Urine pregnancy test for WOCBP  
• Additional serum sample for potential retrospective analysis of viral serology titers 
• Spirometry 


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• DLCO (if applicable; under the responsibility of the pulmonologist) 
• MRI 
• MSFC and SDMT (second practice test) 
• Recording of AEs/SAEs: all AEs/SAEs occurring after signing of the ICF are to be 
reported in the eCRF and on the SAE form, if applicable. 
• Patient Preference Questionnaire (sub-study at selected site only; subjects who appear 
eligible based on the assessments made during this visit will be instructed to complete 
the questionnaire at home before coming to site for Visit 3). 
• If the subject expresses any concern regarding her/his ability to swallow the medicine, 
she/he will be shown an example of a capsule to be used in the study and will be given 
the option to perform a swallowing test with a placebo capsule in order to test future 
compliance with study drug intake requirements. The test is to be done under the 
supervision of the site personnel. 
The principal investigator / treating neurologist must check all inclusion/exclusion criteria. 
The next visit (Visit 3) will only be scheduled if the subject meets all the eligibility criteria 
assessed at this time. Date of screen failure will be collected in the IRT system and in the 
eCRF; additionally, the reasons for screening failure are documented in the eCRF 
(screening information is collected for all screen failure subjects). 
8.2 Treatment period 
The treatment period consists of Visits 3 to 14 (Randomization Day 1, Week 2, 4, 12, and 
every 12 weeks thereafter until EOT/Week 108).  
8.2.1 Visit 3 – Randomization Day 1 
Visit 3 corresponds to the start of the treatment period and the date of randomization in the 
IRT system (Day 1 of the study). The ECGs (pre- and post-dose), BP (pre- and post-dose), 
and first-dose administration must be performed on the same day and define the date of the 
visit. The assessments during this visit will be divided into two parts: before (pre-dose) and 
after (post-dose) the administration of the study drug. 
8.2.1.1 Visit 3 – Day 1 – pre-dose assessment 
The principal investigator / treating neurologist must check all inclusion/exclusion criteria. 
Pre-dose assessments include: 
• Recording of change in previous and concomitant medications since Visit 1 
[see Section 5.2] 
• MS relapse 
• Body temperature 
• MSFC and SDMT (third test serving as baseline assessment) 
• SBP/DBP (under the responsibility of the first-dose administrator) 


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• 12-lead ECG (under the responsibility of the first-dose administrator) 
• Recording of methods of contraception (for WOCBP and fertile men only) 
• Recording of AEs/SAEs: all AEs/SAEs occurring after signing of the ICF are to be 
reported in the eCRF and on an SAE form, if applicable. 
8.2.1.2 Visit 3 – Day 1 – Randomization and post-dose assessment 
If eligible, the subject should be randomized in the study, and take the first dose of study 
drug. The subject must be monitored for up to 12 h post-dose. Starting at 4 h post-dose, the 
first-dose administrator must check whether the subject fulfills the discharge criteria from 
cardiac monitoring [see Section 5.1.11]. Subjects may be discharged from cardiac 
monitoring if they meet the discharge criteria before 12 h post-dose but no sooner than the 
(report of) 4 h post-dose ECG has been evaluated by the first-dose administrator 
[see Section 5.1.11]. 
Visit 3 randomization and post-dose assessment includes: 
• After confirmation of eligibility (i.e., verification of all entry criteria) by the 
investigator: 
− Randomization via IRT to obtain randomization and study treatment kit number 
− Dispensing of study treatment 
• SBP/DBP hourly (+/− 15 min) for up to 12 h post-dose with a minimum of 4 h post-
dose (under the responsibility of the first-dose administrator) 
• 12-lead ECG hourly (+/− 15 min) until the evaluation of the ECG performed at 4 h 
post-dose is available. For subjects not meeting the discharge criteria at 4 h post-dose, 
further ECGs will be performed every hour for up to 12 h post-dose until the discharge 
criteria are met (under the responsibility of the first-dose administrator) 
• PK sampling at 3 (+/− 15 min) h post-dose 
• Recording of AEs and SAEs (Note: On Day 1, significant findings that, in view of the 
first-dose administrator, meet the definition of an AE, have an onset after the study 
drug intake, and are resolved at the time of discharge of the subject from cardiac 
monitoring, must be recorded directly on the AE page of the eCRF by the first-dose 
administrator/delegate. These AEs will not be visible to any of the blinded study 
personnel at the study site.)  
• Remind WOCBP and fertile men to use the methods of contraception defined for this 
study. The reminders must be documented in the hospital chart. 
• Schedule an appointment for next visit and instruct subject to: 
− bring back all blister packs (used, partially used and unused blister packs) 
− come fasted to the site 
− not take study treatment on the day of study visit prior to coming to the site  


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− 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 assigned to the ponesimod arm will need to gradually up-titrate from 2 mg to 
10 mg during Day 1 to 14. To maintain the blinding of the study, subjects assigned to the 
teriflunomide arm will mock up-titrate. As there is no site visit planned until Day 15, 
subjects will be instructed on how to perform the gradual up-titration / mock up-titration 
during Visit 3.  
The subject will be instructed to contact the site if she/he has any questions or problems. 
8.2.2 Additional safety laboratory tests until Week 24 (Week 6, 8, 10, 14, 16, 18, 20, 
and 22) 
The test window is ± 3 days. Under specific circumstances (e.g., subject lives far away 
from the site and cannot return every 2 weeks during the first 24 weeks), laboratory samples 
could be drawn in a local laboratory close to where the subject lives, and analyzed at central 
laboratory [see Section 7.3.14.1]. 
At Week 6, 10, 14, 18, and 22: 
• Laboratory tests including AST, ALT, INR, AP and total bilirubin 
At Week 8, 16, and 20: 
• Laboratory tests including:  
− AST, ALT, INR, AP and total bilirubin 
− Total WBC counts 
− Total lymphocyte counts. 
8.2.3 Visit 4 – Day 15  
The visit window for this visit is ± 1 day. 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: 
• 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) 
• 12-lead ECG (pre-dose) 
• MS relapse 


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• Health care resource utilization since the last visit  
• Hematology, blood chemistry  
• Urine pregnancy test for WOCBP  
• Recording of AEs and SAEs 
• Study medication accountability and compliance review 
• IRT call and study drug dispensing 
• Remind WOCBP and fertile men to use the methods of contraception defined for this 
study. The reminders must be documented in the hospital chart. 
• Schedule an appointment for next visit and instruct subject to: 
− bring back all blister packs (used, partially used and unused blister packs) 
− come fasted to the site  
− 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. 
8.2.4 Visit 5 – Week 4  
The visit window for these visits is ± 3 days. The ECG assessment 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: 
• Recording of changes in concomitant medications 
• Assessment and recording in the eCRF of methods of contraception (for WOCBP only) 
• SBP/DBP (pre-dose) 
• 12-lead ECG (pre-dose) 
• Body temperature 
• MS relapse 
• Health care resource utilization since the last visit  
• Physical examination  
• Spirometry (pre-dose) 
• DLCO (if applicable; pre-dose, under the responsibility of the pulmonologist) 
• Hematology, blood chemistry  
• Urinalysis  
• Urine pregnancy test for WOCBP  
• Recording of AEs and SAEs 
• Study medication accountability and compliance review 


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• Dispense one urine pregnancy test for WOCBP, remind to test for pregnancy on a 
4-weekly basis (+/− 4 days) and to communicate the results to the principal investigator 
/ treating neurologist (by telephone) 
• Remind WOCBP and fertile men to use the methods of contraception defined for this 
study. The reminders must be documented in the hospital chart. 
• Schedule an appointment for next visit and instruct subject to: 
− bring back all blister packs (used, partially used and unused blister packs) 
− come fasted to the site 
− 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. 
8.2.5 Visit 6 – Week 12 and Visit 7 – Week 24  
The visit window for these visits is ± 7 days. The EDSS must be assessed during this visit 
window (i.e., ± 7 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 7 days prior to or after this visit date. The visits 
include: 
• PGI-S of Fatigue (subject completes the questionnaire prior to any clinical assessments 
or interaction with health care providers, preferably while waiting for their 
appointment) 
• WPAI:MS (subject completes the questionnaire after PGI-S of Fatigue, prior to any 
clinical assessments or interaction with health care providers, preferably while waiting 
for their appointment) 
• SF-36v2TM (subject completes the questionnaire after PGI-S of Fatigue and WPAI:MS, 
prior to any clinical assessments or interaction with health care providers, preferably 
while waiting for their appointment) 
• Recording of changes in concomitant medications 
• Assessment and recording in the eCRF of methods of contraception (for WOCBP only) 
• SBP/DBP (pre-dose) 
• 12-lead ECG (pre-dose and 3 h (+/− 15 min) post-dose; Visit 6 only) 
• MS relapse 
• EDSS/FS (performed by the efficacy assessor) 
• Health care resource utilization since the last visit  
• MSFC/SDMT  
• CGI-C 
• Physical examination  


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• Body temperature 
• Spirometry (pre-dose; Visit 6 only) 
• DLCO (if applicable; pre-dose; Visit 6 only; under the responsibility of the 
pulmonologist) 
• OCT (under the responsibility of the ophthalmologist) 
• Ophthalmological examination (under the responsibility of the ophthalmologist) 
• Hematology, blood chemistry  
• PK sampling (pre-dose and 3 h (+/− 15 min) post-dose; Visit 6 only) 
• Urinalysis  
• Urine pregnancy test for WOCBP  
• Recording of AEs and SAEs 
• Study medication accountability and compliance review 
• IRT call and study drug dispensing 
• Dispense two urine pregnancy tests for WOCBP, remind to test for pregnancy on a 
4-weekly basis (+/− 4 days) and to communicate the results to the principal investigator 
/ treating neurologist (by telephone) 
• Remind WOCBP and fertile men to use the methods of contraception defined for this 
study. The reminders must be documented in the hospital chart 
• Schedule an appointment for next visit and instruct subject to: 
− bring back all blister packs (used, partially used and unused blister packs) 
− come fasted to the site 
− 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 
• Give instructions for completion of FSIQ-RMS [see Section 7.2.7]. 
8.2.6 In-between-visit telephone calls until Weeks 108 (Weeks 18, 30, 42, 54, 66, 78, 
90, and 102) 
The site will contact the subject in between the 12-weekly visits (e.g., Visit 6–Week 12, 
Visit 7–Week 24,…) even after possible premature discontinuation from the study 
treatment (e.g., Visit 6A–Week 12 in the PTOP, Visit 7A–Week 24 in the PTOP,…). These 
telephone calls will be conducted either at Weeks 18, 30, 42, 54, 66, 78, 90, and 102  
(+/− 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. 
8.2.7 Visits 8, 9, 11, and 13 – Weeks 36, 48, 72, and 96  
The visit window for these visits is ± 7 days. The EDSS must be assessed during this visit 
window (i.e., ± 7 days). The date of drug dispensing, preferably corresponding to the date 


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of registration of the visit in the IRT system 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:  
• Recording of changes in concomitant medications 
• Assessment and recording in the eCRF of methods of contraception (for WOCBP only) 
• SBP/DBP (pre-dose) 
• 12-lead ECG (pre-dose) 
• Body temperature 
• MS relapse 
• EDSS/FS (performed by the efficacy assessor) 
• Health care resource utilization since the last visit  
• Hematology, blood chemistry  
• Urine pregnancy test for WOCBP 
• Recording of AEs and SAEs 
• Study medication accountability and compliance review 
• IRT call and study drug dispensing 
• Dispense two urine pregnancy tests for WOCBP, remind to test for pregnancy on a 
4-weekly basis (+/−4 days) and to communicate the results to the principal investigator 
/ treating neurologist (by telephone) 
• Remind WOCBP and fertile men to use the methods of contraception defined for this 
study. The reminders must be documented in the hospital chart. 
• Schedule an appointment for next visit and instruct subject to: 
− bring back all blister packs (used, partially used and unused blister packs) 
− come fasted to the site  
− 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. 
8.2.8 Visit 10 – Week 60 
The visit window for this visit is ± 7 days. The EDSS must be assessed during this visit 
window (i.e., ± 7 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 7 days prior to or after this visit date. The visit 
includes: 
• PGI-S of Fatigue (subject completes the questionnaire prior to any clinical assessments 
or interaction with health care providers, preferably while waiting for their 
appointment) 


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• WPAI:MS (subject completes the questionnaire after PGI-S of Fatigue, prior to any 
clinical assessments or interaction with health care providers, preferably while waiting 
for their appointment) 
• SF-36v2TM (subject completes the questionnaire, after PGI-S of Fatigue and WPAI:MS 
prior to any clinical assessments or interaction with health care providers, preferably 
while waiting for their appointment) 
• eC-SSRS (subject completes the questionnaire after PGI-S of Fatigue, WPAI:MS, and 
SF-36v2TM prior to any clinical assessments or interaction with health care providers, 
preferably while waiting for their appointment) 
• Recording of changes in concomitant medications 
• Assessment and recording in the eCRF of methods of contraception (for WOCBP only) 
• SBP/DBP (pre-dose) 
• 12-lead ECG (pre-dose) 
• MS relapse 
• EDSS/FS (performed by the efficacy assessor) 
• MRI  
• Health care resource utilization since the last visit  
• MSFC/SDMT 
• CGI-C 
• Body weight  
• Physical examination  
• Body temperature 
• Skin examination (skin examination performed by the dermatologist) 
• Spirometry (pre-dose) 
• DLCO (if applicable; pre-dose; under the responsibility of the pulmonologist) 
• OCT (under the responsibility of the ophthalmologist) 
• Ophthalmological examination (under the responsibility of the ophthalmologist) 
• Hematology, blood chemistry  
• PK sampling (pre-dose) 
• Urinalysis  
• Urine pregnancy test for WOCBP  
• Recording of AEs and SAEs 
• Study medication accountability and compliance review 
• IRT call and study drug dispensing 
• Dispense two urine pregnancy tests for WOCBP, remind to test for pregnancy on a 
4-weekly basis (+/−4 days) and to communicate the results to the principal investigator 
/ treating neurologist (by telephone) 


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• Remind WOCBP and fertile men to use the methods of contraception defined for this 
study. The reminders must be documented in the hospital chart. 
• Schedule an appointment for next visit and instruct subject to: 
− bring back all blister packs (used, partially used and unused blister packs) 
− come fasted to the site  
− 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 
• Give instructions for completion of FSIQ-RMS [see Section 7.2.7]. 
8.2.9 Visit 12 – Week 84 
The visit window for this visit is ± 7 days. The EDSS must be assessed during this visit 
window (i.e., ± 7 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 7 days prior to or after this visit date. The visit 
includes: 
• PGI-S of Fatigue (subject completes the questionnaire prior to any clinical assessments 
or interaction with health care providers, preferably while waiting for their 
appointment) 
• WPAI:MS (subject completes the questionnaire after PGI-S of Fatigue, prior to any 
clinical assessments or interaction with health care providers, preferably while waiting 
for their appointment) 
• SF-36v2TM (subject completes the questionnaire, after PGI-S of Fatigue and 
WPAI:MS, prior to any clinical assessments or interaction with health care providers, 
preferably while waiting for their appointment) 
• Recording of changes in concomitant medications 
• Assessment and recording in the eCRF of methods of contraception (for WOCBP only) 
• SBP/DBP (pre-dose) 
• 12-lead ECG (Pre-dose) 
• MS relapse 
• EDSS/FS (performed by the efficacy assessor) 
• Health care resource utilization since the last visit  
• MSFC/SDMT 
• CGI-C 
• Physical examination  
• Body temperature 
• Hematology, blood chemistry  


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• Urinalysis  
• Urine pregnancy test for WOCBP 
• Recording of AEs and SAEs 
• Study medication accountability and compliance review 
• IRT call and study drug dispensing 
• Dispense two urine pregnancy tests for WOCBP; remind to test for pregnancy on a 
4-weekly basis (+/−4 days) and to communicate the results to the principal investigator 
/ treating neurologist (by telephone) 
• Remind WOCBP and fertile men to use the methods of contraception defined for this 
study. The reminders must be documented in the hospital chart 
• Schedule an appointment for next visit and instruct subject to: 
− bring back all blister packs (used, partially used and unused blister packs) 
− come fasted to the site  
− 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 
• Give instruction for completion of FSIQ-RMS [see Section 7.2.7]. 
8.2.10 Visit 14 – EOT Visit  
The EOT visit will take place at Week 108 (± 7 days) or earlier in case of premature 
discontinuation of study drug. In all cases, the EOT visit must take place after the last dose 
of study drug. Preferably, the visit and all assessments will take place 1 day after the last 
dose of study drug, but no later than 7 days after the last dose. Specific assessments (i.e., 
MRI, skin examination, CXR, spirometry, DLCO, OCT / Ophthalmological examination, 
hematology, blood chemistry, PK) may be conducted up to 7 days prior to last intake of 
study drug. If a study treatment interruption is transformed into a permanent premature 
discontinuation, the EOT visit should be done as soon as possible, but no later than 7 days 
after the decision to discontinue was made. The date of EDSS assessment, preferably 
corresponding to the date of registration of the visit in the IRT system, defines the date of 
the visit. The visit includes: 
• PGI-S of Fatigue (subject completes the questionnaire prior to any clinical assessments 
or interaction with health care providers, preferably while waiting for their 
appointment) 
• WPAI:MS (subject completes the questionnaire after PGI-S of Fatigue, prior to any 
clinical assessments or interaction with health care providers, preferably while waiting 
for their appointment) 


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• SF-36v2TM a second time (subject completes the questionnaire, after PGI-S of Fatigue 
and WPAI:MS, prior to any clinical assessments or interaction with health care 
providers, preferably while waiting for their appointment) 
• eC-SSRS (subject completes the questionnaire after PGI-S of Fatigue, WPAI:MS, and 
SF-36v2TM prior to any clinical assessments or interaction with health care providers, 
preferably while waiting for their appointment) 
• Recording of changes in concomitant medications 
• Assessment and recording in the eCRF of methods of contraception (for WOCBP only) 
• SBP/DBP  
• 12-lead ECG  
• MS relapse 
• EDSS/FS (performed by the efficacy assessor) 
• MRI (in case of premature study treatment discontinuation, the MRI at EOT does not 
need to be performed if the EOT visit occurs within less than 4 weeks of the MRI 
assessment at Visit 10 [Week 60]; may be conducted up to 7 days before last intake of 
study drug) 
• Health care resource utilization since the last visit  
• MSFC/SDMT  
• CGI-C 
• Body weight 
• Physical examination  
• Body temperature 
• Skin examination (performed by the dermatologist, may be conducted up to 7 days 
before last intake of study drug) 
• CXR (in case of premature study treatment discontinuation, the CXR at EOT does not 
need to be performed if the EOT visit occurs within less than 24 weeks of the 
pre-randomization CXR) (may be conducted up to 7 days before last intake of study 
drug) 
• Spirometry (may be conducted up to 7 days before last intake of study drug)  
• DLCO (if applicable; under the responsibility of the pulmonologist; may be conducted 
up to 7 days before last intake of study drug) 
• OCT (under the responsibility of the ophthalmologist; may be conducted up to 7 days 
before last intake of study drug) 
• Ophthalmological examination (under the responsibility of the ophthalmologist) 
• Hematology, blood chemistry (may be conducted up to 7 days before last intake of 
study drug)  
• PK sampling (pre-dose) (may be conducted up to 7 days before last intake of study 
drug)  
• Urinalysis  


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• Urine pregnancy test for WOCBP  
• Recording of AEs and SAEs 
• Study medication accountability and compliance review 
• IRT call 
• Remind WOCBP and fertile men to use the methods of contraception defined for this 
study. The reminders must be documented in the hospital chart 
• Dispense cholestyramine or activated charcoal 
• Patient Preference Questionnaire (if applicable; subjects will be instructed to complete 
the questionnaire at home before coming to FU1 visit) 
• Schedule an appointment for next visit and instruct subject to: 
− come fasted 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 
• Give instruction for completion of FSIQ-RMS [see Section 7.2.7].  
8.3 Post-treatment period 
8.3.1 Post-treatment safety follow-up period 
The safety FU period includes Visits 15 and 16 (FU1 and FU2). 
• For subjects who enter the extension study, the safety FU period lasts for 14 to 37 days 
after the last dose of study drug and consists of a safety FU visit (FU1) at 15 days 
(−1 day, +7 days) after the last dose of study drug, and for subjects who need to 
repeat/complete the accelerated elimination procedure of teriflunomide after FU1, there 
is also an abbreviated safety FU2 visit (at 23–37 days after the last dose of study drug). 
For subjects who transition to the AC-058B303 study without FU2 visit, the FU1 visit 
corresponds to the EOS visit. 
• For subjects who do not enter the extension study, the safety FU period lasts for 30 days 
after the last dose of study drug and includes two safety FU visits (FU1, FU2) at  
14–22 and 30–37 days after the last dose of study drug, respectively. For these subjects, 
the EOS visit corresponds to the 30-day FU visit (FU2) or to the last visit of PTOP 
(i.e., Visit 14A [Week 108] of the PTOP), whichever is last. 
8.3.1.1 Visit 15 – FU1 
The FU1 visit will take place 14–22 days after the last dose of study drug. For subjects 
continuing in the AC-058B303 extension study, it is preferable to schedule the visit after 
the planned completion of the accelerated elimination procedure for teriflunomide. The 
visit includes: 


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• Recording of changes in concomitant medications 
• Assessment and recording in the eCRF of methods of contraception (for WOCBP only) 
• SBP/DBP 
• 12-lead ECG  
• Body temperature 
• MS relapse 
• Spirometry  
• DLCO (if applicable; under the responsibility of the pulmonologist) 
• Hematology, blood chemistry  
• Accelerated elimination procedure compliance review 
− If compliance is not confirmed: restart or complete missing intake for the 
accelerated elimination procedure  
• Urinalysis  
• Urine pregnancy test for WOCBP  
• Recording of AEs and SAEs 
• Remind WOCBP and fertile men to use the methods of contraception defined for this 
study. The reminders must be documented in the hospital chart 
• If applicable, schedule an appointment for next visit and instruct subject to: 
− come fasted 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. 
8.3.1.2 Visit 16 – FU 2 
For subjects not continuing in the AC-058B303 extension study, the FU2 visit will take 
place between 30 and 37 days after the last dose of study drug.  
• Recording of changes in concomitant medications 
• Assessment and recording in the eCRF of methods of contraception (for WOCBP only) 
• SBP/DBP  
• 12-lead ECG  
• Body temperature 
• MS relapse 
• EDSS/FS (performed by the efficacy assessor) 
• Spirometry  
• DLCO (if applicable; under the responsibility of the pulmonologist) 
• Hematology, blood chemistry  
• Accelerated elimination procedure compliance review (if applicable) 


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− If compliance is not confirmed: decide whether to restart or complete the 
accelerated elimination procedure  
• Serum pregnancy test for WOCBP  
• Recording of AEs and SAEs 
• Dispense urine pregnancy tests for WOCBP, remind to test for pregnancy on a 
4-weekly basis (+/−4 days – until the first of two tests showing teriflunomide plasma 
level < 0.02 mg/L [see Section 5.1.14]) and to communicate the results to the principal 
investigator / treating neurologist [by phone]) 
• Remind WOCBP and fertile men to use the methods of contraception defined for this 
study (until the first of two tests showing teriflunomide plasma level < 0.02 mg/L 
[see Section 5.1.14]. The reminders must be documented in the hospital chart 
• If applicable, schedule an appointment for next visit and instruct subject to: 
− come fasted to the site at the next visit  
− 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 
For subjects continuing in the AC-058B303 extension study and in whom compliance with 
teriflunomide elimination procedure was assessed as not sufficient at FU1 visit, an 
abbreviated FU2 will take place between 23 and 37 days after the last dose of study drug. 
The abbreviated FU2 visit includes: 
• Accelerated elimination procedure compliance review 
• Recording of AEs/SAEs,  
• MS relapse  
• Recording of changes in concomitant medications 
If the teriflunomide accelerated procedure is still assessed as not sufficient at abbreviated 
FU2 visit, the subject will be not eligible to enter the extension study and will need to 
perform the remaining assessments scheduled for a full FU2 visit. 
8.3.2 Post-treatment observation period 
Subjects who prematurely discontinue study treatment will perform the EOT and safety 
FU visits (FU1, FU2) and will enter the PTOP which lasts until 108 weeks after 
randomization (i.e., planned EOT period). It consists of an abbreviated schedule of 
assessments at the time of the originally scheduled 12-weekly visits. The timepoints and 
visit windows are the same as the corresponding visits during the treatment period but the 
number of assessments is reduced [see Section 3.1.3.2 and Table 3]. After FU2 has been 
performed, the study visits must continue according to the original visit and assessment 
schedule. If the first PTOP visit window overlaps with FU1 or FU2 visits, visits and 
assessments can be combined.  


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The PTOP consists of visits 6A, 7A, 8A, 9A, 10A, 11A, 12A, 13A and 14A conducted at 
Weeks 12, 24, 36, 48, 60, 72, 84, 96, and 108. The visit window for these visits is ± 7 days. 
The EDSS must be assessed during this visit window (i.e., ± 7 days). The date of EDSS 
assessment 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: 
• Recording of changes in concomitant medications 
• Assessment and recording in the eCRF of methods of contraception (for males and 
WOCB; until 6 weeks after the first of two tests showing teriflunomide plasma level 
< 0.02 mg/L) 
• SBP/DBP 
• 12-lead ECG (Visits 10A and 14A only) 
• Body temperature 
• MS relapse 
• Physical examination (Visits 10A, and 14A only) 
• Skin examination (Visits 10A and 14A only; performed by the dermatologist) 
• EDSS/FS (performed by the efficacy assessor) 
• MRI (Visits 10A and 14A only) 
• Spirometry (Visit 14A only) 
• DLCO (if applicable; under the responsibility of the pulmonologist; Visit 14A only) 
• Hematology, blood chemistry (Visit 7A, 10A, 12A, and 14A only) 
• Urinalysis (Visits 7A, 10A, 12A, and 14A only) 
• Recording of AEs and SAEs 
• Dispense two urine pregnancy tests for WOCBP, remind to test for pregnancy on a 
4-weekly basis (+/−4 days – until the first of two tests showing teriflunomide plasma 
level < 0.02 mg/L [see Section 5.1.14]) and to communicate the results to the principal 
investigator / treating neurologist [by telephone]) 
• Remind WOCBP and fertile men to use the methods of contraception defined for this 
study (until 6 weeks after the first of two tests showing teriflunomide plasma level 
< 0.02 mg/L [see Section 5.1.14]). The reminders must be documented in the hospital 
chart 
• Give instruction for completion of FSIQ-RMS at Visit 6A–Week 12,  
Visit 
7A–Week 
24, 
Visit 
10A–Week 
60, 
Visit 
12A–Week 
84, 
and  
Visit 14A–Week 108 only). At Visit 14A (Week 108), the FSIQ-RMS will be 
completed prior to the visit, ideally, during the 7 consecutive days preceding the visit 
• PGI-S of Fatigue (at Visit 6A–Week 12, Visit 7A–Week 24, Visit 10A–Week 60, Visit 
12A–Week 84, and Visit 14A–Week 108 only; subject completes the questionnaire 
prior to any clinical assessments or interaction with health care providers, preferably 
while waiting for their appointment).  


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• If applicable, schedule an appointment for the next visit and instruct subject to: 
− come fasted 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. 
8.4 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. These visits include (but are 
not limited to) those performed due to safety (e.g., occurrence of an AE, laboratory 
abnormalities), administration of study drug (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. 
8.4.1 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 17] and the relapse 
symptoms form [see Appendix 18] 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: 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 


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patient 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 blinded 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: 
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: 
• PGI-S of Fatigue (subject completes the questionnaire prior to any clinical assessments 
or interaction with health care providers, preferably while waiting for their 
appointment) 
• SF-36v2TM (subject completes the questionnaire after PGI-S of Fatigue, prior to any 
clinical assessments or interaction with health care providers, preferably while waiting 
for their appointment) 
• Recording of changes in concomitant medications 
• MS relapse 
• EDSS/FS (performed by the efficacy assessor) 
• CGI-C 
• Health care resource utilization since the last visit  
• Recording of AEs and SAEs 
• Schedule an appointment for next visit and instruct subject to: 
− come fasted 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 
• Give instruction for completion of FSIQ-RMS [see Section 7.2.7].  
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. 


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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 are the ones of this regular visit. 
8.4.2 Additional unscheduled visits for re-initiation of study drug (I1, I2, etc.) 
As described in detail in Section 5.1.10, subjects may need to be monitored at the study 
site when re-initiating study drug following a study drug treatment interruption. 
In such cases, there will be two visits; one visit on the day of re-initiation (d1) and an 
additional visit 14 days (+/− 1 day) after the day of re-initiation (d15).  
The following assessments/procedures must be done during the visit on the day of 
re-initiation (d1): 
• 12-lead ECG pre-dose and hourly (+/− 15 min) for up to 12 h post-dose (under the 
responsibility of the first-dose administrator)  
• SBP/DBP pre-dose and hourly (+/− 15 min) for up to 12 h post-dose (under the 
responsibility of the first-dose administrator) 
• Recording of AEs and SAEs 
• IRT call and study drug dispensing 
• 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 h 
post-dose but no sooner than 4 h post-dose [see Section 5.1.11]. 
The following assessments need to be done during the visit 14 days after the day of 
re-initiation: 
• SBP/DBP (pre-dose) 
• 12-lead ECG (pre-dose) 
• Recording of AEs and SAEs 
• IRT call – Return of study drug blisters and unused medication, and dispensing of new 
blisters, if appropriate. 
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 drug when post-dose monitoring is required.  
These visits for the cardiac monitoring of the subjects for re-initiating study drug when 
post-dose monitoring is required are additional unscheduled visits. The regular scheduled 
study visits must be resumed according to the original visit and assessment schedule. If the 
visit occurs at the same time as a regular visit, all assessments of the regular visit have to 
be performed in addition. 


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8.5 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: 
• PGI-S of Fatigue (subject completes the questionnaire prior to any clinical assessments 
or interaction with health care providers, preferably while waiting for their 
appointment) 
• Assessment of concomitant medications 
• Assessment of methods of contraception (for WOCBP only) 
• PFTs 
• SBP/DBP 
• 12-lead ECGs (e.g., in case of need of concomitant treatment with a QT-prolonging 
drug with known risk of Torsades de Pointes [see Appendix 3]) 
• Ophthalmological examination (e.g., presence of visual symptoms suggestive of active 
uveitis [see Section 5.1.13.7]) 
• OCT (e.g., presence of visual symptoms suggestive of macular edema or active uveitis 
[see Section 5.1.13.7]) 
• MRI 
• EDSS/FS 
• FSIQ-RMS 
• CGI-C 
• Physical examination 
• Body temperature 
• Pulse rate (to be assessed only if no 12-lead ECG is performed)  
• Skin examination 
• Measurement of vital signs and/or body weight 
• Complete laboratory tests including: hematology, blood chemistry, viral serology, 
urinalysis, or serum pregnancy test (for WOCBP only) 
• Assessment of AEs and SAEs 
• IRT call – Return of study drug blisters and unused medication, and dispensing of new 
blisters, if appropriate 
• PK – When possible, a PK sample will be collected for all subjects experiencing SAEs. 
In this event, a sample will preferably be collected pre-dose, as early as possible after 
SAE onset, and no later than 7 days after the last dose of study drug. 
Additional unscheduled spirometry will have to be conducted in the event of respiratory 
symptoms (e.g., dyspnea) during the course of the study. Administration of inhaled 


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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 7.3.14.2 needs 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 7.3.14]. 
8.6 Four-weekly pregnancy tests after EOS 
WOCBP [see Section 4.5.1] must have additional urine pregnancy tests on a 4-weekly basis 
until 6 weeks after the first of two tests showing teriflunomide plasma level < 0.02 mg/L 
[see Section 5.1.14]. The visit window for these tests is +/− 4 days. 
These tests can be done by the subject at home. The principal investigator / treating 
neurologist must be informed about the results of this test via phone, and must report it in 
the source data. 
9 
STUDY COMPLETION AND POST-STUDY TREATMENT / 
MEDICAL CARE 
9.1 Study completion  
For an individual subject, EOS is reached when treatment, safety FU and, if applicable, 
PTOP periods have been completed:  
• For subjects who completed the 108-week treatment period and enter the extension 
study, the EOS visit corresponds to the FU visit (FU1) conducted 14–22 days after the 
last dose of study drug, or to the abbreviated FU2 visit conducted 23–37 days after the 
last study drug.  
• For all the other subjects, the EOS visit corresponds to the FU visit (FU2) 30–37 days 
after the last dose of study drug or to the last visit of PTOP (i.e., Visit 14A (Week 108) 
of the PTOP), whichever is latest.  
The reason(s) for discontinuing the study along with who made the decision, if applicable 
(i.e., subject, investigator or Actelion) must be recorded in the eCRF.  
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. 


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The investigator may withdraw a subject from the study (without regard to the subject’s 
consent) if, on balance, they believe that continued participation in the study would be 
contrary to the best interests of the subject. Withdrawal from the study may also result from 
a decision by Actelion for any reason, including premature termination or suspension of 
the study [see Section 9.3]. 
A subject who prematurely discontinues study drug is not considered as withdrawn from 
the study and will enter the PTOP period consisting of an abbreviated schedule of 
assessment, at the time of the originally scheduled 12-weekly visits. 
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 in case the subject cannot 
be reached). If the subject cannot be reached, the site must make a reasonable effort to 
contact the subject, document all attempts and enter the loss of 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 Actelion) 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 drug and discuss FU medical care, including 
undergoing the accelerated elimination procedure for teriflunomide. 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 
Actelion reserves the right to terminate the study at any time globally or locally. 
Investigators can terminate the participation of their site in the study at any time. 


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If a study is suspended or prematurely terminated, Actelion will promptly inform the 
investigators, the IRBs/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 Actelion 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 a study without prior agreement from 
Actelion, the investigator must promptly inform Actelion and the IRB/IEC, and provide 
both with a detailed written explanation of the termination or suspension. 
If the IRB/IEC suspends or terminates its approval/favorable opinion of a study, the 
investigator must promptly notify Actelion and provide a detailed written explanation of 
the termination or suspension. 
Any suspension or premature termination of the study must be discussed with the IDMC. 
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.  
An extension study with ponesimod treatment, conducted under a separate protocol, will 
be considered for subjects who complete the 108-week treatment as scheduled.  
10 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
10.1 Adverse events 
10.1.1 Definitions of adverse events 
An AE is any adverse change, i.e., any unfavorable and unintended sign, including an 
abnormal laboratory finding, symptom or disease that occurs in a subject during the course 
of the study, 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. 
AEs include: 
• Exacerbation of a pre-existing disease with the exception of MS relapse and associated 
symptoms [see Section 10.1.6]. 


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• Increase in frequency or intensity of a pre-existing episodic disease or medical 
condition. 
• Disease or medical condition detected or diagnosed during the course of the study even 
though it may have been present prior to the start of the study. 
• Continuous persistent disease or symptoms present at study start that worsen following 
the start of the study.  
• Abnormal assessments, e.g., change on physical examination, ECG findings, if they 
represent a clinically significant finding that was not present at study start or worsened 
during the course of the study. 
• Laboratory test abnormalities if they represent a clinically significant finding, 
symptomatic or not, that 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.  
Overdose, misuse and abuse of the study treatment should be reported as an AE and, in 
addition, study treatment errors must be documented in the study drug log of the eCRF. 
10.1.2 Intensity of adverse events 
The intensity of clinical AEs is graded on a three-point scale – mild, moderate, severe – 
and is reported on specific AE pages of the eCRF.  
If the intensity of an AE worsens during study treatment administration, only the worst 
intensity should be reported on the AE page. If the AE lessens in intensity, no change in 
the severity is required. 
If the intensity of an AE with an onset date between informed consent signature and start 
of study treatment and which is ongoing at the start of treatment worsens after the start of 
study treatment, a new AE page must be completed. The onset date of this new AE 
corresponds to the date of worsening in intensity. 
The three categories of intensity are defined as follows: 
 Mild 
The event may be noticeable to the subject. It does not influence daily activities and does 
not usually 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 reported as either related or 
unrelated. The determination of the likelihood that the study drug caused the AE will be 
provided by an investigator who is a qualified physician. 
10.1.4 Adverse events associated to study design or protocol-mandated procedures 
An AE is defined as related to study design or protocol-mandated procedures if it appears 
to have a reasonable possibility of a causal relationship to either the study design or to 
protocol-mandated procedures. Examples include discontinuation of a subject’s previous 
treatment during a washout period leading to exacerbation of underlying disease. 
10.1.5 Reporting of adverse events 
All AEs occurring after study start (i.e., signing of informed consent) and up to 30 days 
after study treatment discontinuation or up to initiation of study treatment in the extension 
study or up to the last visit of PTOP (i.e., Week 108 visit of the PTOP) (whichever is latest; 
extension study conducted under a separate protocol) must be recorded on specific AE 
pages of the eCRF. Actelion may contact the investigator to obtain further information.  
Cardiac events 
The first-dose administrator [see Section 3.3.4] must ensure that blinded study personnel 
at the study site, such as the treating neurologists, efficacy assessor, clinical coordinator / 
study nurse, and other personnel involved in the clinical care and management of the 
subject, do not have access to Day 1 and day of re-initiation of study drug post-dose BP 
assessment or ECG interpretation reports, or to AEs with onset on Day 1 or on the first day 
of re-initiation of study drug which have an onset after study drug intake and are resolved 
at the time of discharge from cardiac monitoring.  
However, significant findings (e.g., new ECG abnormalities, bradycardia) that meet the 
definition of an AE must be recorded on the AE page of the eCRF. 


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On Day 1 and on the first day of re-initiation of study drug when post-dose monitoring is 
required, significant findings that, in view of the first-dose administrator, meet the 
definition of an AE, have an onset after the study drug intake, and are resolved at the time 
of discharge of the subject from cardiac monitoring, must be reported directly on the AE 
page of the separate eCRF by the first-dose administrator/delegate. These AEs will not be 
visible to any of the blinded study personnel at the study site. All other significant findings 
on Day 1 and on the first day of re-initiation of study drug when post-dose monitoring is 
required but unresolved at the time of discharge from cardiac monitoring of the subject, 
which in her/his view meet the definition of an AE, must be reported to the principal 
investigator / treating neurologist who will record these events on the AE page of the eCRF. 
Similarly, any AEs with onset on Day 1 or on the first day of study drug re-initiation when 
post-dose monitoring is required leading to the premature discontinuation of study drug 
must be reported by the first-dose administrator to the principal investigator / treating 
neurologist who will record these events on the AE page of the eCRF. 
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).  
10.1.7 Follow-up of adverse events 
AEs still ongoing more than 30 days after study treatment discontinuation must be followed 
up until they are no longer considered clinically relevant, or until the event outcome is 
provided. 
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 ICH guidelines as any AE fulfilling at least one of the following 
criteria: 
• Fatal. 


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• Life-threatening: refers to an event in which the subject was at risk of death at the time 
of the event. It does not refer to an event that hypothetically might have caused death 
had it been more severe. 
• Requiring inpatient hospitalization or prolongation of existing hospitalization. 
• Resulting in persistent or significant disability or incapacity. 
• Congenital anomaly or birth defect. 
• Medically significant: refers to important medical events that may not immediately 
result in death, be life-threatening, or require hospitalization but may be considered to 
be SAEs when, based upon appropriate medical judgment, they may jeopardize the 
subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in the definitions above.  
The following reasons for hospitalization are 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 (e.g., if a 
complication prolongs hospitalization). 
10.2.1.2 Serious adverse events associated with the study design or protocol-mandated 
procedures  
An SAE is defined as related to study design or protocol-mandated procedures if it appears 
to have a reasonable possibility of a causal relationship to either the study design or to 
protocol-mandated procedures. Examples include discontinuation of a subject’s previous 
treatment during a washout period leading to exacerbation of underlying disease or a 
complication of an invasive procedure that is specifically required by the protocol. 
10.2.2 Reporting of serious adverse events  
10.2.2.1 During pre-randomization period  
All SAEs that occur after study start (i.e., signing of informed consent) must be reported 
(whether considered associated or not associated with study design or study-mandated 
procedures).  
These SAEs must be reported on an SAE form and also in the eCRF.  


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10.2.2.2 During treatment period 
All SAEs, regardless of investigator-attributed causal relationship, must be reported. 
These SAEs must be reported on an SAE form and also on the AE pages in the eCRF. 
10.2.2.3 During 30-day follow-up period 
All SAEs, regardless of investigator-attributed causal relationship, that occur up to 30 days 
after study treatment discontinuation, must be reported on AE pages in the eCRF and on 
an SAE form.  
10.2.3 Follow-up of serious adverse events  
SAEs 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  
10.2.4.1 During the PTOP period (if applicable) 
All SAEs, regardless of investigator-attributed causal relationship, that occur during the 
PTOP period must be reported on AE pages in the eCRF and on an SAE form. 
10.2.4.2 After the PTOP period 
New SAEs occurring after the 30-day FU period, or after the last visit of PTOP (whichever 
applies and is last) must be reported to the Actelion drug safety department within 24 h of 
the investigator’s knowledge of the event, only if considered causally related to previous 
exposure to the study treatment by the investigator.  
10.2.5 Reporting procedures 
All SAEs must be reported by the investigator to the Actelion drug safety department 
within 24 h of the investigator’s first knowledge of the event. 
MS relapses and associated symptoms are exempted from being reported on an SAE 
form by the investigator to the Actelion drug safety department with the exceptions 
described in Section 10.1.6.  
All SAEs must be recorded on an SAE form, irrespective of the study treatment received 
by the subject, and whether or not this event is considered by the investigator to be related 
to study treatment.  
The SAE forms must be faxed to the Actelion drug safety department (contact details are 
provided on the SAE form). The investigator must complete the SAE form in English, and 
must assess the causal relationship of the event to study treatment. 


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FU information about a previously reported SAE must also be reported within 24 h of 
receiving it. The Actelion drug safety department may contact the investigator to obtain 
further information.  
If the subject is hospitalized in a hospital other than the study site, it is the investigator’s 
responsibility to contact this hospital to obtain all SAE relevant information and 
documentation. 
The reference safety documents to assess expectedness of a suspect serious adverse 
reaction and reported by the sponsor to health authorities, IRBs/IECs and investigators are 
the reference safety information section of the IB [Ponesimod IB] and reference safety 
information of the Aubagio® Summary of Product Characteristics.  
MS relapses and associated symptoms are commonly seen with the underlying disease and 
are therefore expected to occur in this subject population. The MS relapses and associated 
symptoms reported as serious (unless fatal) are waived and will be treated as expected and 
will therefore not require systematic unblinding or expedited reporting to health authorities, 
IRBs/IECs, and investigators. However, all MS relapses (irrespective of seriousness) will 
be collected on the specific relapse pages of the eCRF in the clinical trial database and 
monitored during the study by the sponsor and by the IDMC. 
10.3 Pregnancy 
If a woman becomes pregnant while on study treatment, study treatment must be 
discontinued. The investigator must counsel the subject and discuss the risks of continuing 
with the pregnancy and the possible effects on the fetus. If the woman wishes to continue 
pregnancy, Actelion Global Drug Safety will request the unblinding of the treatment 
assignment and only the subject allocated to teriflunomide will have to perform an 
accelerated elimination procedure. 
10.3.1 Reporting of pregnancy 
Irrespective of the treatment received by the subject, any pregnancy occurring during the 
study including during the 30 days following study treatment discontinuation and the entire 
duration for continued contraception after EOT, as mandated by the protocol 
[see Section 5.1.14], must be reported within 24 h of the investigator’s knowledge of the 
event.  
Pregnancies must be reported on the Actelion Pregnancy form, which is faxed to the 
Actelion drug safety department (see contact details provided on the Actelion Pregnancy 
form), and on the AE page in the eCRF. 
Any pregnancy diagnosed in the female partner of a male subject during treatment with the 
investigational product must be reported to Actelion within 24 h of the investigator’s 


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knowledge of the event. A Pregnant partner information release form will be provided to 
the pregnant partner prior to collecting any information on the pregnancy and its outcome. 
10.3.2 Follow-up of pregnancy  
Any pregnancy must be followed to its conclusion and its outcome must be reported to the 
Actelion drug safety department. 
Any AE associated with the pregnancy occurring during the FU period after study drug 
discontinuation must be reported on separate AE pages in the eCRF. Any SAE occurring 
during the pregnancy must be reported on an SAE form as described in Section 10.2.2. 
10.4 Study safety monitoring 
Clinical study safety information (AEs, SAEs, laboratory values, ECGs, vital signs, and 
project-specific labs/examinations as required) is monitored and reviewed on a continuous 
basis by the Actelion clinical team (in charge of ensuring subjects’ safety as well as data 
quality) by periodically monitoring clinical study activities from protocol conception to 
database closure. In addition, an IDMC is monitoring safety data [see Section 3.4]. 
11 STATISTICAL METHODS 
All statistical analyses will be conducted by Actelion or by designated CROs supervised 
by Actelion. 
The SAP(s) for the final analyses will be approved prior to database lock. The SAP for the 
clinical study report will provide the full details of all analyses, data displays, and 
algorithms to be used for data derivations. Separate SAPs and reports are planned for the 
final analyses of PK data, the MRI sub-study, and the Patient Preference sub-study.  
A separate SAP for the blinded interim analysis to determine the FSIQ-RMS response 
thresholds will be finalized shortly after the first subject is enrolled into the study.  
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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Absolute changes from baseline are defined as post-baseline value minus baseline value, 
i.e., a positive sign indicates an increase as compared to baseline. 
A percentage (relative) change from baseline is defined as the absolute change from 
baseline divided by the baseline value (if the baseline value does not equal 0) multiplied 
by 100. 
The baseline value for efficacy is defined as the last non-missing value recorded prior to 
randomization for each endpoint and each subject individually. The baseline value for 
safety is defined as the last non-missing value recorded prior to first study drug intake for 
each endpoint and each subject individually unless stated otherwise in the SAP.  
The EOS is defined as the date on the End-of-Study eCRF page. If this date is missing the 
last recorded visit on the eCRF is considered as the EOS date.  
The EOT date is defined as the date of the last dose of study treatment intake.  
11.1 Analysis Sets 
11.1.1 Screened Analysis Set 
The screened analysis set (SCR) includes all subjects who were screened and received a 
subject number. 
11.1.2 Full Analysis Set 
The Full Analysis Set (FAS) includes all randomized subjects.  
All primary statistical analyses of efficacy endpoints will be based on the FAS. In order to 
adhere to the intention-to-treat principle as much as possible:  
• In order to preserve the randomization subjects will be evaluated according to the 
treatment they have been randomized to (which may be different to the treatment they 
have received) and stratum information used for randomization as recorded in the 
Interactive Voice Response System (which may be different to the information 
available on the eCRF after data validation); 
• Unless otherwise stated, all available efficacy data up to the EOS date will be included, 
irrespective of whether a subject has stopped study treatment earlier or has received 
any MS treatment other than that to which the subject was randomized to. 
11.1.3 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 primary/secondary endpoints, 
occurring prior to or at randomization. Due to the nature of the primary endpoint which is 
assessed over the entire study period rather than at a fixed timepoint, only the data accrued 


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after occurence of a major protocol deviation will be excluded for the PPS analysis for a 
given subject.  
All reportable protocol deviations will be evaluated before unblinding and classified into 
the four categories below.  
Subjects will be excluded from the PPS if: 
• Subject is randomized and did not satisfy certain eligibility criteria; 
Data will be excluded for subjects after the occurrence of one of the following criteria: 
• Subject received the wrong study treatment or incorrect dose;  
• Subject took an unauthorized concomitant medication;  
• Occurrence of major protocol deviation that could confound the interpretation of 
analysis conducted on the FAS.  
Additional details regarding the definition of the reasons for subject/data exclusion from 
the PPS will be defined in the final SAP. 
11.1.4 Safety Set 
The safety set (SAF) includes all randomized subjects who received at least one dose of 
study treatment. Subjects will be analyzed based on actual treatment taken. 
11.1.5 FSIQ-RMS Measurement Set 
An FSIQ-RMS measurement set (FMS) includes the first 291 randomized subjects who 
received at least one dose of study treatment [see Section 11.5.5 for sample size 
justification]. 
11.1.6 Other analysis sets 
Other analysis datasets are defined in the corresponding SAPs, e.g., PK populations, 
sub-study populations, and subgroups of (special) interest. 
11.1.7 Usage of the analysis sets 
The FAS and the PPS are used for the analysis of the primary and the secondary endpoints. 
Results for the primary and secondary efficacy endpoints based on the PPS will supplement 
those based on the FAS and assess the robustness of treatment effects. 
MRI, clinical exploratory endpoints and other clinical exploratory endpoints will be 
analyzed using the FAS. 
The FMS will be used for the confirmation of the threshold values for the minimal level of 
change required to identify FSIQ-RMS responders. 
All safety data will be analyzed using the SAF. 


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11.2 Variables 
11.2.1 Primary efficacy variable  
The primary endpoint is the ARR defined as the number of confirmed relapses per 
subject-year. All relapses up to EOS (including the FU period and PTOP) will be included 
in the analysis. For the statistical analysis of the ARR, the following variables will be used:  
• 
The Subject’s number of confirmed relapses up to EOS;  
• 
Length of observation expressed in years, defined as: [EOS date minus date of 
randomization + 1] divided by 365.25  
For the definition of relapse and confirmed relapse, see Section 6.1.1. 
11.2.2 Secondary efficacy variables 
There are four secondary efficacy endpoints, which will be analyzed as per the statistical 
testing strategy outlines in Section 11.3.1: 
• Change from baseline to Week 108 in fatigue-related symptoms as measured by the 
symptoms domain of the FSIQ-RMS;  
• Cumulative number of CUAL from baseline to Week 108; 
• Time to 12-week CDA from baseline to EOS;  
• Time to 24-week CDA from baseline to EOS. 
11.2.2.1 Fatigue Symptoms and Impact Questionnaire (FSIQ-RMS) 
The endpoint is defined as the absolute change in the FSIQ–RMS (weekly) symptoms score 
from baseline to Week 108. Additional details will be provided in the SAP. 
11.2.2.2 Cumulative number of CUAL from baseline to Week 108 
Cumulative number of CUAL [defined in Section 6.1.2] from baseline to Week 108 is 
calculated as the sum of lesions at all post-baseline MRI visits up to Week 108. 
11.2.2.3 Time to 12-week CDA 
Time to 12-week CDA from baseline to EOS is defined as: 
• 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 weeks, see detailed definition in Section 6.1.2.  


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Time to first 12-week CDA is defined as start date of the first 12-week CDA minus date of 
randomization +1 in days.  
For a subject without a 12-week CDA, the censored time to 12-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 + 1.  
This will constitute a right-censored observation. 
Further details of the derivation of this variable will be provided in the SAP. 
11.2.2.4 Time to 24-week CDA 
Time to 24-week CDA from baseline to EOS is defined as EDSS increase described in 
Section 6.1.2 confirmed after 24 weeks.  
Time to first 24-week CDA is defined as start date of the first 24-week CDA minus date of 
randomization +1 in days.  
For a subject without a 24-week CDA, the censored time to 24-week CDA is defined as: 
• [date of last EDSS assessment without an EDSS increase (as defined above)] minus 
date of randomization + 1.  
This will constitute a right-censored observation. Further details of the derivation of this 
variable will be provided in the SAP. 
11.2.3 Other efficacy variables 
11.2.3.1 Exploratory efficacy variables 
MRI-based exploratory variables: 
• 
Percent change in brain volume from baseline to Week 108; 
• 
Number of Gd+ T1 lesions at Week 60 and Week 108; 
• 
Cumulative number of new or enlarging T2 lesions from baseline to Week 108, 
calculated as the sum of lesions at all post-baseline MRI visits up to Week 108; 
• 
Change from baseline to Week 60 in the volume of T2 lesions, calculated as the value 
at Week 60 minus the value at Baseline; 
• 
Change from baseline to Week 108 in the volume of T2 lesions, calculated as the value 
at Week 108 minus the value at Baseline; 
• 
Change from baseline to Week 60 in the volume of T1 hypointense lesions, calculated 
as the value at Week 60 minus the value at Baseline; 
• 
Change from baseline to Week 108 in the volume of T1 hypointense lesions, calculated 
as the value at Week 108 minus the value at Baseline; 
• 
Absence of Gd+ T1 lesions at Week 60 and Week 108; 


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• 
Absence of new or enlarging T2 lesions at Week 60 and Week 108; 
• 
Proportion of Gd+ lesions at Baseline evolving to PBHs by Week 108 (axonal loss); 
• 
Change of
 
 
• 
Change in 
 
;  
• 
Cumulative number of
 
. 
Clinical exploratory variables (disease activity, relapses, disability progression): 
• 
Time to first confirmed relapse up to EOS; 
Defined as: Date of first confirmed relapse minus date of randomization date + 1 in 
days. Subjects without any relapse will be censored at the EOS date, and the time is 
defined as EOS date minus date of randomization + 1 in days. 
• 
Absence of confirmed relapses from baseline to Weeks 60 and 108; 
• 
Time to 24-week CDA from baseline to EOS defined similarly to 12-week CDA; 
• 
Change in EDSS from baseline up to Week 108, by visit; 
• 
NEDA status up to EOS (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 EOS). If at least one of the four criteria is not fulfilled or the subject 
discontinues treatment prematurely, the subject is not considered to have achieved 
NEDA.  
Other exploratory variables: 
• 
Change from baseline up to Week 108 in MSFC Z-score; 
• 
Change from baseline up to Week 108 in the SDMT score; 
• 
FSIQ-RMS Patient Improvement Response (minimally important difference) is 
defined as a reduction in the FSIQ-RMS weekly symptom score ≥ a threshold value 
anchored on the PGI-S of Fatigue scale, which will be determined by a blinded analysis 
of the data as described in Section 11.4. 
• 
FSIQ-RMS Clinical Improvement Response (clinically important difference) is 
defined as a reduction in the FSIQ-RMS weekly symptom score ≥ a threshold value 
anchored on the CGI-C scale, which will be determined by a blinded analysis of the 
data as described in Section 11.4. 
• 
Change from baseline up to Week 108 in fatigue-related impact sub-domain scores 
(Physical, Cognitive / Emotional, Coping) as measured by FSIQ-RMS. 
• 
Change from baseline in PGI-S of Fatigue by visit up to Week 108;  
• 
Change from baseline in CGI-C by visit up to Week 108; 
Detailed information on the analyses of these endpoints will be provided in the SAP. 
Additional exploratory endpoints and/or analyses may be defined in the SAP. 
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11.2.4 Safety variables 
The following safety endpoints/variables will be analyzed. The SAP will summarize these 
variables in more detail. 
• 
Treatment-emergent AEs, SAEs, AEs of special interest, and MACE; 
• 
AEs leading to premature discontinuation of study treatment; 
• 
Treatment-emergent morphological ECG abnormalities (as defined by the ECG 
provider); 
• 
Change in 12-lead ECG variables (HR, PR, QRS, 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 drug; 
• 
Notable abnormalities for selected 12-lead ECG variables (HR, PR, QT, QTc) at 3 h 
post-dose assessment on Day 1 and Week 12 and at the re-initiation of study drug 
when post-dose monitoring is required;  
• 
Treatment-emergent decrease of FEV1 or FVC > 20% from baseline values;  
• 
Treatment-emergent decrease of percent predicted FEV1 or FVC > 20 percentage 
points from baseline values; 
• 
Change in FEV1 or FVC from baseline, absolute and % of absolute change to all 
timepoints up to EOS; 
• 
Change from baseline to EOS vs change from baseline to EOT in FEV1 or FVC 
(absolute and % of predicted); 
• 
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 last available FU visit; 
• 
Change in lung diffusion capacity as assessed by DLCO expressed in absolute change 
and % of predicted value from baseline to all timepoints up to EOS; 
• 
Change from baseline to EOS vs change from baseline to EOT in DLCO (absolute and 
% of predicted); 
• 
Treatment-emergent notable BP abnormalities; 
• 
Treatment-emergent notable laboratory abnormalities;  
• 
Change in body weight from baseline to EOS; 
• 
Treatment-emergent eC-SSRS suicidal ideation score of 4 or above, or a “yes” 
response on the eC-SSRS suicidal behavior item. 
11.2.5 Other variables  
• Change from baseline by visit up to Week 108 in SF-36v2™ Health Survey domain 
and component scores; 
• Change from baseline by visit up to Week 108 in WPAI:MS scores; 


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• Health care resource utilization from baseline by visit up to Week 108 (number of 
hospitalizations, length of stay, number of ICU admissions for MS relapse and visits to 
an emergency medical services facility for MS); 
• Plasma concentrations of ponesimod pre-dose at Day 15; Weeks 12, 60, and 108; and 
3 h post-dose on Day 1 and Week 12; 
• Peripheral blood lymphocyte counts pre-dose by visit (absolute count and change from 
baseline) up to Week 108; 
• Change from baseline to EOS vs change from baseline to EOT in lymphocyte counts 
(absolute and % change); 
• Post-treatment lymphocyte recovery at 15 days and 30 days after study drug 
discontinuation. 
11.3 Description of statistical analyses 
11.3.1 Overall testing strategy 
The primary endpoint (ARR using confirmed relapses) will be tested using a negative 
binomial regression model, comparing the investigational treatment (ponesimod 20 mg) 
with the comparator (teriflunomide 14 mg) at full alpha.  
If the primary endpoint null hypothesis is rejected, the alpha will be split evenly (1/3 of 
alpha) between the following three secondary endpoints using the fallback procedure, 
allowing for passing on alpha within the fallback procedure as per the following sequence: 
• Change from baseline to Week 108 in fatigue-related symptoms as measured by the 
symptoms domain of the FSIQ–RMS [Fatigue] 
• Cumulative number of CUAL from baseline to Week 108 [CUALs] 
• Time to 12-week CDA from baseline to EOS [12-week CDA]  
If a secondary endpoint listed as part of the fallback procedure above is successful, the 
preserved alpha in the sequence is passed along to the next secondary endpoint in the 
sequence and the summed alpha is used for testing that endpoint. Thus, as sequential tests 
are successful, the alpha accumulates for the endpoints later in the sequence; these 
endpoints are then potentially tested with a progressively larger alpha, but always with at 
least 1/3 of the alpha. 
In a last step, the secondary endpoint  
• Time to 24-week CDA from baseline to EOS [24-week CDA] 
is tested in a subsequent stage following Time to 12-week CDA with the remaining alpha.  
A graphical description of this testing strategy for the primary and secondary endpoints 
following the approach of Bretz, et al. [Bretz 2009] is provided in Figure 8. 


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Figure 8 
Overall testing strategy 
 
The primary null hypothesis will be tested at a two-sided 1% alpha level, and if this is 
rejected the study will be declared to show conclusive evidence of efficacy. If the primary 
null hypothesis can only be rejected at the two-sided 5% alpha level, the study will be 
declared positive.  
Analyses for secondary endpoints will be conducted at an overall two-sided 5% alpha level, 
with multiplicity adjustment as per the testing strategy outlined in Figure 8. 
11.3.2 Analysis of the primary efficacy variable 
11.3.2.1 Hypotheses and 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 
Yj 
denotes the number of relapses for subject j during tj 
µj  
denotes the mean of the negative binomial 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
′
=
µ
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. 


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Two-sided hypotheses are expressed in terms of the model parameters µP20mg and µT14mg. 
The primary null hypothesis is that the ARR (µ) does not differ between ponesimod 20 mg 
and teriflunomide 14 mg. The alternative hypothesis is that the ARR differs between 
ponesimod 20 mg and Teriflunomide 14 mg. 
H0, ARR: µP20mg - µT14mg = 0  
vs 
H1, ARR: µP20mg - µT14mg ≠ 0  
The null hypothesis will be tested by a two-sided Wald test within the negative binomial 
regression model [see Section 11.3.2.3], with a two-sided significance level of 0.01 for 
conclusive evidence and 0.05 for a positive study. Two-sided 95% and 99% Wald CIs will 
be calculated for the relative reduction in mean ARR for ponesimod 20 mg compared to 
teriflunomide 14 mg. 
11.3.2.2 Handling of missing data 
11.3.2.2.1 Main analysis of the primary endpoint 
All confirmed relapses from randomization up to the EOS visit for subjects in the FAS will 
be used in the main analysis of the primary endpoint regardless of study drug compliance; 
therefore no data will be excluded from the analysis.  
Every effort will be made to collect as complete relapse information 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 primary efficacy analysis, unless it is clear that they have 
occurred prior to randomization. No other missing data imputation is used for the main 
analysis of the primary endpoint.  
11.3.2.2.2 Sensitivity analyses of the primary endpoint 
Missing data will be assessed in a number of ways to test the robustness of the primary 
endpoint results and to ensure that selection bias/informative drop-outs have not had an 
influence on the results.  
New or Worsening Neurological Symptoms Considered as relapses: 
New or worsening neurological symptoms are reported via a telephone interview or at the 
site in a face-to-face interview and at both these times a decision must be taken by the 
treating neurologist to refer the subject to the efficacy assessor. Once referred to the 
efficacy assessor the symptom is considered a relapse and is assessed for confirmation. To 
ensure there is no bias in the selection of symptoms considered as relapses between 
treatments, an analysis will compare the proportion of these new or worsening neurological 


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symptoms that are considered as relapses and as confirmed relapses. If there is an 
imbalance in the selection between treatments, this will be explored further.  
Early Study Withdrawal: 
To assess the impact of subjects withdrawing from the study prior to Week 108 (+ FU 
period) a number of sensitivity analyses will be performed. These include the imputation 
of confirmed relapses using various assumptions for the period with missing data. The 
proportion of missing data will be calculated as:  
1-  
Cumulative time between randomization and EOS
Cumulative time between randomization and theoretical Week 108 
A worst case imputation will impute the observed ARR for ponesimod subjects up to EOS 
during the period EOS up to Week 108 and impute zero relapses for the teriflunomide 
subjects during this period. A second approach will impute the observed teriflunomide 
ARR up to EOS for the period EOS up to Week 108 for both treatments, using simulations 
and bootstrapping techniques to calculate the 95% and 99% CIs. A third and more 
conservative approach will impute the observed individual treatment ARR up to EOS for 
the period EOS up to Week 108. 
11.3.2.3 Main analysis 
The primary statistical analysis will be performed on the FAS population using the model 
described in Section 11.3.2.1 for confirmed relapses, with the stratification variables (prior 
use of DMTs and EDSS category), as well as the number of relapses in the year prior to 
study entry and the logarithm of time on treatment up to EOS as an offset variable, included 
in the model.  
11.3.2.4 Supportive/sensitivity analyses 
The following supportive analyses (based on the FAS, if not otherwise stated) are planned 
using the model described in Section 11.3.2.1: 
• ARR only counting confirmed relapses occurring up to EOT + 7 days; 
• Analysis with treatment as the only covariate in the model for all confirmed relapses up 
to EOS; 
• Analysis adjusting for the stratification covariate using the actual EDSS at baseline and 
prior use of DMTs as recorded on the eCRF for all confirmed relapses up to EOS and 
up to EOT + 7 days; 
• Analysis counting only confirmed relapses up to starting alternative MS treatments or 
EOS for subjects not switching; 
• Analyses using different methods of relapse imputation between EOT + 7 days and EOS 
(PTOP) to further assess the impact of treatment discontinuation and/or switching to 
alternative MS treatments;  


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• Analyses based on the PPS population counting confirmed relapses up to EOS; 
• Analysis using all relapses (confirmed or unconfirmed) up to EOS; 
• A descriptive summary of the amount of data collected under protocol version 3 or 
earlier versions, compared to protocol version 4 will be considered in the SAP. Further 
additional inferential analysis will be described if deemed necessary.  
Further analyses will be described in the SAP. 
11.3.2.5 Subgroup analyses 
The ARR within each level of each subgroup will be analyzed using an unadjusted negative 
binomial model. Subgroups of interest (including the stratification factors) are: 
• Baseline EDSS (≤ 3.5, > 3.5); 
• Geographical region (North America, Latin America, Western Europe, Eastern Europe, 
Rest of the World); 
• Gender (male, female); 
• Age (< 40, ≥ 40); 
• MS subtype (relapsing remitting, secondary progressive with superimposed relapses); 
• Prior MS treatment (yes, no); 
• Relapse in the year prior to study entry (≤ 1, ≥ 2); 
• Gd+ T1 lesions at Baseline (absent, present); 
• Highly active disease (yes, no). A subject is considered to have highly active disease if 
one or both of the following conditions are met: 
 Any MS disease modifying therapy received in the 12 months prior to study 
and one or both of the following conditions are met: 
 ≥ 1 relapse within the last 12 months prior to study and baseline MRI 
shows either ≥ 1 Gd+ T1 lesion and/or ≥ 9 T2lesions  
 ≥ 1 relapse within the last 24 months prior to study and number of 
relapses in the 12 months prior to study ≥ number of relapses between 
24 and 12 months prior to study. 
 ≥ 2 relapses within the last 12 months prior to study and baseline EDSS > 2 and 
≥ 1 Gd+ T1 lesion on baseline MRI. 
Further subgroup analyses might be performed using other baseline characteristics and 
other variables. The analyses including interaction tests will be specified in more detail in 
the SAP. 


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11.3.3 Analysis of the secondary efficacy variables 
The secondary efficacy endpoints will be tested as outlined in Section 11.3.1 if the primary 
analysis on ARR has led to the rejection of the null hypothesis in favor of ponesimod 
20 mg.  
The endpoints will be analyzed using the FAS. All secondary endpoints will also be 
analyzed using the PPS. 
11.3.3.1 Absolute change in FSIQ-RMS from baseline to Week 108 
11.3.3.1.1 Hypothesis 
The FSIQ-RMS weekly symptoms score ranges from 0 to 90 with a higher score indicating 
more pronounced fatigue. A repeated measurement ANCOVA will be used to compare the 
change from baseline to Week 108 across both treatment groups. The underlying 
hypotheses are expressed as two means, assuming the outcomes of the endpoint for both 
treatments are normally distributed: 
H0, FSIQ: µP20mg - µT14mg = 0  
  
vs 
H1, FSIQ: µP20mg - µT14mg ≠ 0  
 
Each null hypothesis will be tested by an F-test by comparing the resulting p-value to the 
local alpha as per the overall testing strategy, see Section 11.3.1. 
11.3.3.1.2 Main Analysis  
The main analysis for this variable will be performed on the FAS comparing ponesimod 
20 mg to teriflunomide 14 mg using a repeated measurements ANCOVA model with 
baseline, prior use of DMTs, EDSS category and the FSIQ symptoms score at baseline as 
covariates. 
11.3.3.1.3 Supportive analyses 
The following supportive analyses (based on the FAS if not otherwise stated) are planned: 
• Analysis with treatment as the only factor within subgroups levels; 
• Analysis based on the PPS. 
11.3.3.2 Cumulative number of combined unique active lesions 
11.3.3.2.1 Hypothesis 
Two-sided hypotheses are expressed in terms of the model parameters µP20mg and µT14mg. 
The primary null hypothesis is that the CUAL (µ) does not differ between ponesimod 


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20 mg and teriflunomide 14 mg. The alternative hypothesis is that the CUAL differs 
between ponesimod 20 mg and teriflunomide 14 mg. 
H0, CUAL: µP20mg - µT14mg = 0  
vs 
H1, CUAL: µP20mg - µT14mg ≠ 0  
The null hypothesis will be tested by a two-sided Wald test within the negative binomial 
regression model [see Section 11.3.1], by comparing the resulting p-value to the local alpha 
as per the overall testing strategy, see Section 11.3.1. Two-sided 95% Wald CIs will be 
calculated for the relative reduction in mean CUAL for ponesimod 20 mg compared to 
teriflunomide 14 mg. 
11.3.3.2.2 Main Analysis 
The main statistical analysis will be performed on the FAS using a similar model as 
described in Section 11.3.2.1 for confirmed relapses, with the stratification variables, prior 
use of DMTs and EDSS category, as well as the presence of T1 Gd+ lesions at baseline, 
included in the model.  
11.3.3.2.3 Supportive analyses 
The following supportive analyses (based on the FAS if not otherwise stated) are planned 
using the same type of model, but: 
• based on the PPS; 
• subgroup analyses with subgroups defined by baseline characteristics. 
11.3.3.3 Time to 12-week CDA 
11.3.3.3.1 Hypothesis 
Hypotheses are formulated in terms of “survival” functions S(t), i.e., the probability that 
time to 12-week CDA is ≥ t for a day t relative to the date of randomization. Two-sided 
hypotheses are expressed in terms of the survival functions SP20mg (t) and ST14mg (t). 
H0,CDA: SP20mg (t) = ST14mg (t) for all t ≥ 0  
vs 
H1,CDA: SP20mg (t) ≠ ST14mg (t) for all t ≥ 0 
The null hypothesis will be tested using a two-sided stratified log-rank test by comparing 
the resulting p-value to the local alpha as per the overall testing strategy, see Section 11.3.1.  


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11.3.3.3.2 Main Analysis  
The main analysis will be performed on the FAS by a two-sided stratified log-rank test 
with stratification factors (prior use of DMTs and EDSS category). Kaplan-Meier estimates 
for the survival functions will be provided. 
11.3.3.3.3 Supportive analyses 
The following supportive analyses (based on the FAS if not otherwise stated) are planned: 
• Unstratified log-rank test; 
• Adjusted (for same variables as primary analysis) and unadjusted Cox’s proportional 
hazards model;  
• Unadjusted Cox’s proportional hazards model within subgroups levels; 
• Stratified and unstratified log-rank test based on the PPS; 
• Adjusted and unadjusted Cox’s proportional hazards model based on the PPS; 
• Worst case analysis where all unconfirmed disability accumulations at Week 108 (these 
events cannot be confirmed due to Week 108 being the last scheduled on-treatment 
visit) are considered as confirmed. 
11.3.3.4 Time to 24-week CDA 
11.3.3.4.1 Hypothesis 
Hypotheses are formulated in terms of “survival” functions S(t), i.e., the probability that 
time to 24-week CDA is ≥ t for a day t relative to the date of randomization. Two-sided 
hypotheses are expressed in terms of the survival functions SP20mg (t) and ST14mg (t). 
H0,CDA24: SP20mg (t) = ST14mg (t) for all t ≥ 0  
vs 
H1,CDA24: SP20mg (t) ≠ ST14mg (t) for all t ≥ 0 
The null hypothesis will be tested using a two-sided stratified log-rank test by comparing 
the resulting p-value to the local alpha as per the overall testing strategy, see Section 11.3.1.  
11.3.3.4.2 Main Analysis  
The main analysis will be performed on the FAS by a two-sided stratified log-rank test 
with stratification factors (prior use of DMTs and EDSS category). Kaplan-Meier estimates 
for the survival functions will be provided. 
11.3.3.4.3 Supportive analyses 
Supportive analyses as described in Section 11.3.3.3.3 for the Time to 12-week CDA 
endpoint are planned.  


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11.3.4 Analysis of the other efficacy variables 
The analyses of all exploratory variables will be based on the FAS and described in detail 
in the SAP. If required, exploratory variables will also be analyzed by subgroups or by 
other baseline variables. Details will be provided in the SAP. All statistical models used 
will be stratified by prior use of DMTs and EDSS category. Adjustment for further 
covariates, e.g., baseline value when modeling change from baseline variables, will be 
detailed in the SAP. All subjects will be included in the analysis even if subjects are off 
study treatment. Missing data imputation rules will be described in the SAP.  
11.3.4.1 Percent change in brain volume from baseline to Week 108 
The percent change in brain volume from baseline to Week 108 will be performed on the 
FAS using an ANCOVA with treatment as a factor and the randomization stratification 
factors (prior use of DMTs and EDSS category), as well as brain volume at baseline as 
covariates. 
11.3.4.2 Number of Gd+ T1 lesions at Week 60 and Week 108 
The number of Gd+ T1 lesions at each visit will be analyzed using a negative binomial 
regression model similar to that described in Section 11.3.2.1. 
11.3.4.3 Change in volume of T2 lesions, T1 hypointense lesions, EDSS, 
 
from baseline to Week 60 and Week 
108 
All variables related to change in lesion volume, change in EDSS, change in 
 
 at Week 60 and Week 108 will be 
analyzed using an ANCOVA with treatment, including stratification variablesand baseline 
values as covariates. Changes to other visits will be summarized descriptively.  
11.3.4.4 Absence of Gd+ T1 lesions, and new or enlarging T2 lesions and subjects 
relapse-free at Week 60 and Week 108 
Absence of Gd+ T1 lesions, and new or enlarging T2 lesions, and subjects that are relapse-
free at Weeks 60 and 108 will be analyzed using a logistic regression with treatment as a 
factor, including stratification variables and baseline value as covariates.  
11.3.4.5 Other MRI endpoints 
Cumulative number of new or enlarging T2 lesions from baseline to Week 108 and 
cumulative number of 
 
 will be analyzed in a similar manner to cumulative 
CUAL. Proportion of Gd+ lesions at Baseline evolving to PBHs by Week 108 (axonal loss) 
will be summarized descriptively. 
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11.3.4.6 Time to first confirmed relapse  
The analysis for this variable will be performed on the FAS using a two-sided stratified 
log-rank test with stratification variables (prior use of DMTs, EDSS category) and number 
of relapses in the year prior to study entry. Kaplan-Meier estimates for the survival 
functions will be plotted using Kaplan-Meier curves and will be tabulated by 12-week 
intervals. 
11.3.4.7 NEDA status up to EOS 
NEDA is analyzed using a logistic regression model with treatment as a factor and 
stratification variables and number of relapses in the year prior to study entry included in 
the model.  
11.3.4.8 Change of MSFC Z-score and SDMT score from baseline to Week 108 
The changes from baseline to the Week 108 assessment of both scores are analyzed using 
an ANCOVA, similar to the analyses described for brain volume changes in 
Section 11.3.4.1. 
11.3.4.9 Change of FSIQ-RMS and sub-scores from baseline to each visit (total score 
and impact score) 
The absolute change from baseline FSIQ-RMS weekly symptoms score and impact 
sub-domain scores is analyzed over time using a repeated measurement ANCOVA, as for 
the analysis for change in FSIQ-RMS symptoms score to Week 108. Estimates and 
two-sided 95% CI will be calculated for the effects of ponesimod relative to teriflunomide 
at each visit.  
11.3.5 Analysis of the safety variables 
The SAF will be used to perform all safety analyses.  
If not otherwise stated, only treatment-emergent safety data (observations up to 15 days 
after study drug discontinuation) will be considered in tables and figures. All safety data 
will be included in listings, with flags for safety data not considered to be 
treatment-emergent. 
Specific safety events (AEs, laboratory tests, ECG findings, etc.) will be considered. In 
general, they consist of one or more well-defined safety events which are similar in nature 
and for which there is a specific clinical interest in connection with ponesimod 20 mg or 
teriflunomide 14 mg.  
For each specific safety event of interest, the number and percentage of subjects with at 
least one event will be reported. Point estimates and 95% CIs for safety event incidences 
and the relative risk ratio relative to teriflunomide 14 mg will be provided without 
adjustment for multiplicity. 


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Time to first onset of safety events of interest may be displayed by Kaplan-Meier estimates. 
Subjects not experiencing the safety event will be censored at the minimum of the EOS 
date and 15 days after last dose of study drug. Where applicable, study treatment will be 
compared by hazard ratios and corresponding 95% CIs from a Cox’s regression model. For 
specific safety events where recurrence and/or duration are of interest, appropriate event 
history analysis such as an Andersen-Gill model for recurrent events will be described in 
the SAP.  
11.3.5.1 Adverse events 
All AEs will be coded using the latest version of MedDRA available at the time of database 
closure. 
11.3.5.1.1 Treatment-emergent AEs and SAEs  
Treatment-emergent AEs and SAEs will be tabulated by study treatment, system organ 
class (SOC) and preferred terms within each SOC: the number and percentage of subjects 
who experienced at least one (S)AE, at least one (S)AE within each SOC and at least one 
S(AE) within each preferred term will be displayed. (S)AEs will also be summarized by 
decreasing frequency of preferred term. (S)AEs will also be tabulated by maximum 
intensity and relationship to ponesimod 20 mg or teriflunomide 14 mg.  
11.3.5.1.2 AEs of special interest and MACE 
AEs of special interest and MACE will be summarized in the same way as stated in the 
previous section and compared between treatments. The definition of the AEs of special 
interest is provided in Appendix 5. 
11.3.5.1.3 AEs leading to premature discontinuation of study drug 
(S)AEs leading to premature discontinuation of study drug will be summarized in a similar 
manner as that described in Section 11.3.5.1.1. 
11.3.5.1.4 Post-treatment AEs and SAEs 
Post-treatment (S)AEs occurring over 15 days after treatment discontinuation will be 
summarized in a similar manner as described in Section 11.3.5.1.1. 
11.3.5.1.5 Deaths 
Fatal SAEs occurring any time after the start of treatment will be summarized in a similar 
manner as described in Section 11.3.5.1.1.  


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11.3.5.2 Cardiac safety 
11.3.5.2.1 12-lead ECG assessments 
Descriptive summary statistics by visit and study treatment will be provided for observed 
treatment-emergent values and absolute changes from baseline in numeric 12-lead ECG 
values (HR, PR, QRS, QT, QTcB, and QTcF). Data will be summarized from pre-dose to 
the post-dose assessments at 1 h, 2 h, 3 h, and 4 h on Day 1 and also at the re-initiation of 
study drug. 
Notable abnormalities for selected 12-lead ECG variables (HR, PR, QT, QTcF) will be 
summarized for all data of the 3-h post-dose assessments on Day 1, Week 12 and also at 
the re-initiation of study drug.  
In addition, treatment-emergent morphological ECG abnormalities will be summarized 
(using data from the ECG provider).  
11.3.5.2.2 Cardiac safety events 
Cardiac safety events will include:  
• Treatment-emergent QTc > 450 ms, > 480 ms, > 500 ms 
• Treatment-emergent QTc increase from baseline > 30 ms, > 60 ms 
• Other treatment-emergent abnormalities observed by 12-lead ECG 
• Treatment-emergent (serious) cardiac AEs of special interest. 
11.3.5.3 Pulmonary safety 
11.3.5.3.1 Pulmonary functional testing 
Descriptive summary statistics by visit and study treatment will be provided for observed 
treatment-emergent values and changes from baseline by visit in FEV1, FVC and 
FEV1/FVC ratio (all expressed in absolute change, % change and % of predicted value).  
The number and proportion of treatment-emergent decreases of percent predicted FEV1 or 
FVC > 20 percentage points from baseline at any time up to EOT will be summarized by 
treatment. 
The trend effect of treatment on the percent predicted FEV1 over time will be analyzed by 
treatment using a regression analysis with time as the independent variable and FEV1 
adjusted for age at the time of the assessment as the dependent variable. Assessments 
during up-titration and after the subject discontinues treatment will not be included in this 
analysis. 
The mean (and 95% CIs) change from baseline to EOS and from baseline to EOT in FEV1 
or FVC (absolute and % predicted) will be plotted by treatment. A scatter plot will display 


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the change from baseline to EOS vs the change from baseline to EOT on an individual 
subject level by study treatment. 
For the subset of subjects with a decrease of ≥ 200 mL or ≥ 12% in FEV1 or FVC from 
baseline at EOT, the number and percentage of subjects with a decrease of ≤ 200 mL and 
≤ 12% from baseline to last available FU in FEV1 or FVC will be summarized by treatment. 
11.3.5.3.2 Lung diffusion capacity 
Descriptive summary statistics and changes from baseline by visit and study treatment will 
be provided for observed treatment-emergent values and changes from baseline (expressed 
in absolute change and % of predicted value) in DLCO. 
11.3.5.3.3 Pulmonary safety events 
Pulmonary safety events will include:  
• Treatment-emergent decrease of FEV1 or FVC to < 80% of baseline values 
• (Serious) pulmonary AEs of special interest  
• Withdrawal due to pulmonary reasons / AE 
11.3.5.4 Vital signs 
Descriptive summary statistics by visit and study treatment will be provided for observed 
treatment-emergent values and absolute changes from baseline in HR, BP, and body 
weight. 
Treatment-emergent notable BP abnormalities will also be summarized. The definition for 
notable abnormalities is provided in Appendix 6. 
11.3.5.5 Laboratory endpoints 
11.3.5.5.1 Laboratory tests 
Descriptive summary statistics by visit and study treatment will be provided for observed 
treatment-emergent values and absolute changes from baseline for laboratory tests 
(hematology, blood chemistry, urinalysis). Data will be displayed in SI units whenever 
possible and graphical approaches will be applied. 
11.3.5.5.2 Laboratory safety events 
Laboratory safety events will 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 6]  
• Treatment-emergent laboratory test abnormalities based on FDA guidance for DILI 
[FDA 2009b] (for ALT / AST / total bilirubin) 


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• Lymphocyte count reversibility after EOT, expressed in absolute change and percent 
change from baseline 
The definition for notable abnormalities is provided in Appendix 6. 
11.3.5.6 Ocular safety 
Ocular safety events will include: 
• Treatment-emergent ocular AEs of specific interest 
11.3.5.7  Vaccine-specific antibody titers 
For subjects receiving non-live vaccination while on study treatment, descriptive summary 
statistics by study treatment will be provided for observed values and absolute changes in 
vaccine-specific antibody titers from pre- to post-vaccination. 
11.3.5.8 eC-SSRS 
The number of subjects (including percentages) 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 treatment arm.  
11.3.5.9  Analysis of other variable(s) 
11.3.5.9.1 PK  
Trough level (pre-dose) plasma concentrations of ponesimod at Weeks 12, 60 and 108 and 
plasma concentrations of ponesimod at 3 h post-dose at Day 1 and Week 12 will be 
analyzed by descriptive statistics, including arithmetic mean, standard deviation, 
minimum, maximum, and median. 
11.3.5.9.2 PD 
Total lymphocyte counts at each visit assessment will be analyzed by descriptive statistics, 
including arithmetic mean, standard deviation, minimum, maximum, and median. 
The relationship between ponesimod concentration and total lymphocyte counts will be 
investigated by modeling and simulation. 
11.3.5.9.3 Quality of Life Questionnaire (SF36v2TM) 
Data in the health survey domain and component scores will be summarized descriptively 
by visit and study treatment up to Week 108 in the FAS. 
11.3.5.9.4 WPAI:MS Questionnaire 
Data in the pharmacoeconomic WPAI:MS Questionnaire will be summarized descriptively 
by visit and study treatment, up to Week 108 in the FAS. 


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11.3.5.9.5 Health care resource utilization  
Data on health care resource utilization will be summarized descriptively by visit and study 
treatment, up to Week 108 in the FAS. 
11.3.5.9.6 Patient preferences 
Data on patient preferences will be summarized descriptively by visit and study treatment, 
up to 15 days after last dose of study drug in the FAS (sub-study). 
11.4 Interim analyses 
No unblinded interim analysis is planned for the study; however, a blinded interim analysis 
based on the first 291 randomized subjects will be performed in order to confirm the 
definition of FSIQ responders. 
In order to understand and interpret change in the FSIQ-RMS Fatigue Symptoms endpoint 
within this clinical population, it is important to anchor this change to a meaningful 
threshold of change from the clinician and patient perceptions. The first threshold, the 
Minimally Important Differences (MID), is computed as the smallest difference in scores 
between groups in the domain of interest that patients perceive as beneficial. Similarly, the 
Clinically Important Differences (CID) is computed as another threshold in which the 
clinician perceives the change as beneficial. There are multiple methods to compute 
Minimally Clinically Important Differences, which include: patient perspective, clinician 
perspective, and data-driven approaches (anchor- and distribution-based). Comparison of 
these methods allows for the approximation of MID and CID responder thresholds.  
Within this study, two anchors have been selected for evaluating change on the FSIQ-RMS 
Fatigue Symptom score: the PGI-S of Fatigue for patient-reported change in fatigue 
severity and the CGI-C for the clinician’s global impression of the patient’s MS severity. 
Each will be collected simultaneously to the FSIQ-RMS measures. 
For the blinded FSIQ responder definition analysis, the MID as assessed by subjects will 
be measured using a common distribution-based method: ½ standard deviation change 
from baseline of the FSIQ-RMS Fatigue Symptom score based on the FMS. Anchor-based 
estimates for the MID will group subjects based on change on the PGI-S of Fatigue from 
baseline to each subsequent visit. Anchor-based methods for the CID calculation as 
assessed by clinician’s grouped improvement categories on the CGI-C from weekly 
baseline and subsequent visit scores. Effect size estimates for each group of subjects will 
be calculated as the mean score difference between weekly baseline and subsequent visit 
scores, divided by the pooled baseline standard deviation. Cohen’s thresholds for 
interpreting the magnitude of an effect size suggests the following: 0.2 (small), 0.5 
(moderate), and 0.8 (large). As such, the expectation for interpreting the MID and CID are 
effect-size estimates greater than 0.2, which is considered the minimal amount of change 
necessary for detecting meaningful improvement. 


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11.5 Sample size 
The sample size is calculated based on the primary endpoint, and the power is calculated 
for the secondary endpoints. For the secondary endpoint FSIQ-RMS, no sample size 
calculations were carried out as valid assumptions are difficult to make due to the recent 
release of the endpoint.  
11.5.1 Primary endpoint 
The sample size for the study was determined by a simulation using the negative binomial 
distribution. A sample size of 1100 subjects (550 per treatment group) will provide a power 
of approximately 90% for a significance level of 0.01, under the assumption that ARR is 
0.320 for teriflunomide 14 mg and 0.215 for ponesimod 20 mg (which corresponds to a 
risk reduction of 33%), and using a dispersion = 0.9. An annual dropout rate of 
approximately 15% has been assumed for the first year and 7.5% for the second year. 
The adjusted risk reduction for teriflunomide 14 mg vs placebo in the fixed two-year 
duration TEMSO study was 31.5%, and 36% in the variable duration TOWER study. An 
integrated analysis showed a pooled 34% reduction compared to placebo. A 33% reduction 
for ponesimod 20 mg compared to teriflunomide 14 mg gives a relative 55% reduction 
compared to placebo, similar to that observed in the fingolimod Phase 3 trials. The 
dispersion from the ponesimod Phase 2 study was 1.0; the calculated dispersion from the 
TEMSO study is 0.8, so the chosen dispersion is the mean of the two. 
11.5.2 Secondary endpoints 
Keeping the sample size fixed at 550 subjects per treatment group, the power to detect 
clinically meaningful treatment effects for the secondary endpoints is shown below. 
No power was calculated for FSIQ-RMS or Time to 24-week CDA. 
11.5.2.1 Cumulative number of CUAL 
Assuming 1.5 CUAL per year for teriflunomide, a reduction of 33% for ponesimod and a 
dispersion of 3.65 will give an approximate power of 80% for a two-sided local 
significance level of 0.05/3. If, within the fallback procedure, alpha can be passed on to the 
hypothesis on CUAL a local two-sided significance level of 0.05/3*2, results in a power 
of 86%. Dropout rates as for the primary endpoint have been assumed. 
11.5.2.2 Time to 12-week CDA 
Assuming a 12-week CDA rate at 2 years for teriflunomide 14 mg of 16% and a hazard 
ratio of 0.67 (i.e., 2-year progression of 11% for ponesimod 20 mg), this gives with a 
sample size of 1100 an approximate power of 45% for a two-sided local significance level 
of 0.05/3. If, within the fallback procedure, alpha can be passed on to Time to 12-week 
CDA a local two-sided significance level of 0.05/3*2 (~0.033) or 0.05 can be used resulting 


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in a power of approximately 56% or 62%, respectively. Dropout rates as for the primary 
endpoint have been assumed.  
11.5.3 Sample size sensitivity 
Increasing the ARR for ponesimod to 0.223 (which corresponds to a risk reduction of 30%) 
decreases the power to approximately 80%. If the ARR is 10% lower than assumed in both 
ponesimod 20 mg (ARR = 0.194) and teriflunomide 14 mg (ARR = 0.288), the power 
reduces to approximately 87%.  
11.5.4 Sample size re-estimation 
There is no sample-size re-estimation planned. 
11.5.5 Other sample size considerations 
The sample size necessary for the confirmation of minimal change thresholds for 
identifying responders on the FSIQ-RMS symptom scale is based on psychometric 
analyses, which will be performed using data from the FMS. 
For confirmation, as a preliminary analysis, these thresholds will be evaluated using 
blinded data collected within the Phase 3 clinical trial (AC-058B301) on a subset of 
subjects with available data on the FSIQ-RMS, the PGI-S of Fatigue and the CGI-C 
(in MS) between baseline and Week 108. 
Using data collected within a non-interventional observational study, preliminary 
thresholds were calculated using two anchors: 1) patient-reported severity of fatigue as 
measured by the PGI-S of Fatigue with a mean improvement level of 6.19 and 2) clinician-
reported severity of MS as measured by the CGI-C with a mean improvement level of 
11.68. Given the consideration of these thresholds, it is necessary to identify the number 
of subjects required to detect the same level of change within the confirmatory Phase 3 
clinical trial. As the data will be blinded for this psychometric confirmatory analysis, power 
calculation based upon a paired t-test for mean difference between baseline and Week 108 
was conducted. 
Results from a statistical power analysis suggest that, in order to detect a −6.19 change 
from baseline in FSIQ-RMS Symptoms score (assumed baseline standard deviation  
= 24.1), an N of approximately 98 subjects demonstrating change would be necessary to 
obtain statistical power at a recommended 0.90 level. For the −11.68 change from baseline 
in FSIQ-RMS Symptoms score (assumed baseline standard deviation = 24.1), an N of 
approximately 29 subjects demonstrating change would be necessary to obtain statistical 
power at a recommended 0.90 level.  
In an observational study with MS patients over 13 weeks where the FSIQ-RMS was 
administered, 27% of the patients indicated no change in their fatigue level, 43% improved 
in a meaningful way on the PGI-S of Fatigue, and the remaining 30% worsened. If this 


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information is applied to the power calculation for the blinded analysis set, the sample size 
needs to be increased to 228 subjects (98 would demonstrate an improvement, 130 subjects 
would not change or deteriorate and could therefore not be used for the analysis). 
Furthermore, adjusting for a drop-out rate of 15% and 7.5% for Year 1 and Year 2, 
respectively, leads to a sample size of 291 subjects for the blinded responder threshold 
analysis. 
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 (refer to 
21 CFR Part 11). In addition to the main eCRF, a separate eCRF will be used to collect 
data with unblinding potential generated on Day 1 and on the first day of re-initiation of 
study drug when post-dose monitoring is required. This data will only be visible to the site 
monitor, the first-dose monitor and to an Independent Data Management Team 
[see Sections 5.1.5.2 and 10.1.5]. 
Entries recorded by the subject in the electronic device (FSIQ-RMS, PGI-S of Fatigue, 
SF-36v2TM, MS Patient Preference Questionnaire, and WPAI:MS) and the eC-SSRS are 
considered source data. The site staff will review and ensure completeness and readability 
(if applicable) of the subject’s entries. 
Subject screening and enrollment data will be completed for all subjects (i.e., eligible and 
non-eligible) through the IRT system and eCRF. 
For each subject enrolled, regardless of study treatment initiation, an eCRF must be 
completed and signed by the investigator/delegate. This also applies to those subjects who 
fail to complete the study. If a subject withdraws from the study, the reason must be noted 
on the eCRF.  


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12.2 Maintenance of data confidentiality 
The investigator/delegate must ensure that data confidentiality is maintained. On CRFs or 
other documents submitted to Actelion, subjects must be identified only by number and 
never 
by 
name 
or 
initials, 
hospital 
numbers 
or 
any 
other 
identifier. 
The investigator/delegate must keep a subject identification code list at the site, showing 
the randomization number, the subject’s name, date of birth and address or any other 
locally accepted identifiers. Documents identifying the subjects (e.g., signed ICFs) must 
not be sent to Actelion, and must be kept in strict confidence by the investigator/delegate. 
12.3 Database management and quality control 
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 Actelion 
on an ongoing basis to look for unexpected patterns in data and study monitoring. If 
discrepant data are detected, a query specifying the problem and requesting clarification 
will be issued and visible to the investigator/delegate via the eCRF. All electronic queries 
visible in the system either require a data correction (when applicable) and a response from 
the investigator/delegate to clarify the queried data directly in the eCRF, or simply a data 
correction in the eCRF. The investigator/delegate must, on request, supply Actelion with 
any required background data from the study documentation or clinical records. This is 
particularly important when errors in data transcription are suspected. In the case of health 
authority queries, it is also necessary to have access to the complete study records, provided 
that subject confidentiality is protected. 
This process will continue until database closure. 
Laboratory samples, ECGs, spirometry, eDiary, PGI-S of Fatigue, MS Patient Preference 
Questionnaire, SF-36v2TM, FSIQ-RMS, eC-SSRS, and WPAI:MS assessments will be 
processed centrally through their respective central laboratory/provider, and the results will 
be sent electronically to Actelion. If local laboratory data is obtained as may be required 
per protocol in certain instances, it must be entered in the eCRF by the site.  
After the database has been declared complete and accurate, the database will be closed. 
Any changes to the database after that time may only be made as described in the 
appropriate SOP. After database closure, the investigator will receive the eCRF of the 
subjects of her/his site (including all data changes made) on electronic media or as a paper 
copy. 


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13 PROCEDURES AND GOOD CLINICAL PRACTICE 
13.1 Ethics and Good Clinical Practice 
Actelion and the investigators will ensure that the study is conducted in full compliance 
with ICH-GCP guidelines, the principles of the “Declaration of Helsinki” and with the laws 
and regulations of the country in which the research is conducted.  
13.2 Independent Ethics Committee / Institutional Review Board 
The investigator will submit this protocol and any related document provided to the subject 
(such as Subject Information Leaflet used to obtain informed consent) to an IRB or IEC. 
Approval from the committee must be obtained before starting the study, and must be 
documented in a dated letter to the investigator, clearly identifying the study, the 
documents reviewed, and the date of approval.  
Modifications made to the protocol after receipt of the approval must also be submitted as 
amendments by the investigator to the IRB/IEC in accordance with local procedures and 
regulations [see Section 13.6]. 
A list of members participating in the IRB/IEC meetings must be provided, including the 
names, qualifications and functions of these members. If that is not possible, the attempts 
made to obtain this information along with an explanation as to why it cannot be obtained 
or disclosed must be documented in the study documentation. If a study staff member was 
present during a meeting, it must be clear that this person did not vote. 
13.3 Informed consent 
It is the responsibility of the investigator/delegate to obtain informed consent according to 
ICH-GCP guidelines and local regulations from each individual participating in this study 
and/or legal representative. The investigator/delegate must explain to subjects that they are 
completely free to refuse to enter the study or to withdraw from it at any time for any 
reason. 
The ICF will be provided in the country local language(s). 
Site staff authorized to participate in the consent process and/or to obtain consent from the 
subject and/or legal representative will be listed on an Actelion Delegation of Authority 
form. A study physician must always be involved in the consent process.  
The subject and/or legal representative must sign, personally date and time (if appropriate) 
the ICF before any study-related procedures (i.e., any procedures required by the protocol) 
begin. The ICF must also be signed, personally dated and timed (if the first study-mandated 
procedure was performed on the same day informed consent was obtained) by the 
authorized site staff listed on the Actelion Delegation of Authority form. 


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A copy of the signed and dated ICF is given to the subject and/or legal representative; the 
original is filed in the site documentation.  
The informed consent process must be fully documented in the subject’s medical records, 
including study reference, subject number, date/time (if applicable) when the subject was 
first introduced to Actelion clinical study, date/time (if applicable) of consent, who 
participated in the consent discussion, who consented the subject and any additional person 
present during the consent process (e.g., subject family member), copy of the signed ICF 
given to the subject / legal representative. 
13.4 Compensation to subjects and investigators 
Actelion provides insurance in order to indemnify (with both legal and financial coverage) 
the investigator/site against claims arising from the study, except for claims that arise from 
malpractice and/or negligence. 
The compensation of the subject in the event of study-related injuries will comply with 
applicable regulations. 
13.5 Protocol adherence/compliance 
The investigator must conduct the study in compliance with the approved version of the 
protocol and must not implement any deviation/change from the protocol, except when 
deviation is necessary to eliminate an immediate hazard to the subject.  
If a protocol deviation occurs, the investigator/delegate will inform Actelion or its 
representative, in a timely manner. The investigator/delegate must document and explain 
any deviation from the approved protocol. IRB/IEC and regulatory authorities must be 
informed, according to their requirements, but no later than 15 calendar days after the 
event. 
13.6 Protocol amendments 
Any change to the protocol can only be made through a written protocol amendment. 
A protocol amendment must be submitted to an 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’s 
file, and subject clinical source documents.  
These records must be kept by the investigator for as long as is necessary to comply with 
Actelion’s requirements (e.g., as specified in the clinical study agreement), and national 
and/or international regulations, whichever would be the longest period. If the investigator 
cannot guarantee this archiving requirement at the investigational site for any or all of the 
documents, special arrangements respecting the data confidentiality must be made between 
the investigator and Actelion to store these documents outside the site, so that they can be 
retrieved in case of a regulatory inspection. No study document should be destroyed 
without prior written approval from Actelion. Should the investigator wish to assign the 
study records to another party or move them to another location Actelion must be notified 
in advance.  
If the site is using an electronic/computerized system to store subject medical records, it 
can be used for the purpose of the clinical study if it is validated (as per 21 CFR Part 11 or 
equivalent standard) and if the 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 of source data needed 
for verification by the monitor. The print-outs must be numbered, stapled together with a 
cover sheet, signed and dated by the investigator/delegate to confirm that these certified 
copies are exact copies having 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 Actelion’s instructions. If it were not possible for the 
monitor to observe this process, it would not be possible to rely on the site’s certified copies 
and therefore the site cannot be selected for the clinical study. The printouts should be filed 
either with the subject medical records or with the subject’s eCRF. 


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13.8 Monitoring 
Prior to study start, a site initiation visit (SIV) will be performed after the required essential 
study documents are approved by Actelion. The study treatment will be shipped to the site 
upon approval of the required essential documents.  
The principal investigator must ensure that all site personnel involved in the study will be 
present during the SIV and will dedicate enough time to it. Site information technology 
support should also be available during the initiation visit.  
The SIV must be completed before the site can start the screening of study subjects. 
Following the SIV, a copy of the completed initiation visit report and FU letter will be 
provided to the principal investigator and filed in the ISF. 
During the study, the monitor will contact and visit the investigational site regularly, and 
on request must be permitted to have access to trial facilities and all source documents 
needed to verify adherence to the protocol and the completeness, consistency and accuracy 
of the data being entered in the CRFs and other protocol-related documents. Actelion 
monitoring standards require full verification that informed consent has been provided, and 
verification of adherence to the inclusion/exclusion criteria, documentation of SAEs, and 
the recording of the main efficacy, safety and tolerability endpoints. Additional checks of 
the consistency of the source data with the CRFs 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 and first-dose administrator must ensure that the eCRF is 
completed after a subject’s visit to the site, and that all requested subject files (e.g., ICFs, 
medical notes/charts, other documentation verifying the activities conducted for the study) 
are available for review by the 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 and when there are no more active 
subjects and after all study data have been accepted by medical review and all FU issues 
have been resolved. In case a site does not enroll any subjects, the close-out visit may be 
performed prior to study database closure at the discretion of Actelion. 


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13.9 Investigator site file 
Each site will be provided with an ISF prior to the initiation visit. It will contain all the 
essential documents that are required to always be up-to-date and filed at site as per ICH 
GCP section 8. 
The ISF will include a table of contents listing the essential documents. All study related 
documentation must be maintained in the ISF. 
In some cases, exceptions can be discussed with the 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. 
The ISF must be stored in a secure and access-restricted area during and after the study. 
It must be kept by the site for as long as needed to comply with any applicable rules and 
regulations, ICH-GCP as well as instructions from Actelion. If the site needs to transfer the 
ISF to another location and/or if the site facility can no longer store the ISF, the principal 
investigator must inform Actelion immediately.  
If the principal investigator will change, or if the site will relocate, the monitor must be 
notified as soon as possible.  
13.10 Audit 
Actelion’s Global Quality Management representatives may audit the investigator site 
(during the study or after its completion). The purpose of this visit will be to determine the 
investigator’s adherence to ICH-GCP, the protocol, and applicable regulations; adherence 
to Actelion’s requirements (e.g., SOPs) will also be verified. Prior to initiating this audit, 
the investigator will be contacted by Actelion to arrange a time for the audit.  
The investigator and staff must cooperate with the auditor(s) and allow access to all study 
documentation (e.g., subject records) and facilities. 
13.11 Inspections 
Health authorities and/or IRBs/IECs may also wish to conduct an inspection of Actelion’s 
clinical study (during the study or after its completion).  
Should an inspection be requested by a health authority and/or IRB/IEC, the investigator 
must inform Actelion 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. 


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13.12 Reporting of study results and publication  
Study results will be documented in a clinical study report that will be signed by Actelion 
representatives and the coordinating investigator (or principal investigator for single-center 
studies). 
Separate reports are planned for the final analyses of PK data, the MRI sub-study, and the 
Patient Preference sub-study.  
The coordinating investigator and the steering committee / advisory board, if any, will have 
the opportunity to review the analysis of the data and to discuss the interpretation of the 
study results with Actelion prior to publication. 
Actelion will post results from its clinical studies on Actelion’s clinical trial disclosure 
system and on external/national registries, as required by law. 
Actelion’s policy on disclosure of clinical research information can be found at:  
http://www.actelion.com/documents/corporate/policies-charters/policy-clinical-research-
information.pdf 
In accordance with the Good Publication Practices and ethical practice, the results of the 
study will be submitted for publication in a peer-reviewed journal. Study results can be 
submitted for presentation at a congress before publication in a peer-reviewed journal. 
Authorship will be determined in accordance with the International Committee of Journal 
Editors criteria, and be based on: 
• Substantial contributions to: the conception or design of the study, or the acquisition, 
analysis or interpretation of data; and 
• Drafting of the publication or critical review for important intellectual content; and  
• Providing final approval of the version to be published; and 
• Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately investigated 
and resolved.  
The list of authors of any publication of study results may include representatives of 
Actelion and will be determined by mutual agreement. 
Any study-related publication written independently by investigators must be submitted to 
Actelion for review at least 30 days prior to submission for publication or presentation. 
Upon review, Actelion may provide comments and may also request alterations and/or 
deletions for the sole purpose of protecting its confidential information and/or patent rights. 
Neither the institution nor the investigator should permit publication during such a review 
period. 


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Appendix 1 
Diagnostic criteria for MS (2010 Revised McDonald Criteria) 
Clinical Presentation 
Additional Data Needed for MS Diagnosis 
≥ 2 attacksa; objective 
clinical evidence of ≥ 2 
lesions or objective clinical 
evidence of 1 lesion with 
reasonable historical 
evidence of a prior attackb 
Nonec 
≥ 2 attacksa; objective 
clinical evidence of 1 lesion 
Dissemination in space, demonstrated by:  
≥ 1 T2 lesion in at least 2 of 4 MS-typical regions of the CNS (periventricular, 
juxtacortical, infratentorial, or spinal cord)d; or 
Await a further clinical attacka implicating a different CNS site 
1 attacka; objective clinical 
evidence of ≥ 2 lesions 
Dissemination in time, demonstrated by: 
Simultaneous presence of asymptomatic gadolinium-enhancing and non-
enhancing lesions at any time; or 
A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, 
irrespective of its timing with reference to a baseline scan; or  
Await a second clinical attacka 
1 attacka; objective clinical 
evidence of 1 lesion 
(clinically isolated 
syndrome) 
Dissemination in space and time, demonstrated by: 
For dissemination in space (DIS): 
≥ 1 T2 lesion in at least 2 of 4 MS-typical regions of the CNS (periventricular, 
juxtacortical, infratentorial, or spinal cord); or 
Await a second clinical attacka implicating a different CNS site; and 
For dissemination in time (DIT): 
Simultaneous presence of asymptomatic gadolinium-enhancing and non-
enhancing lesions at any time; or  
A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, 
irrespective of its timing with reference to a baseline scan; or  
Await a second clinical attacka 
Insidious neurological 
progression suggestive of 
MS (PPMS) 
1 year of disease progression (retrospectively or prospectively 
determined) plus 2 of 3 of the following criteriad: 
1. Evidence for DIS in the brain based on ≥ 1 T2 lesions in the 
MS-characteristic (periventricular, juxtacortical, or infratentorial) regions 
2. Evidence for DIS in the spinal cord based on ≥ 2 T2 lesions in the cord 
3. Positive CSF (isoelectric focusing evidence of oligoclonal bands and/or 
elevated IgG index) 
If the criteria are fulfilled and there is no better explanation for the clinical presentation, 
the diagnosis is ‘‘MS’’; if suspicious, but the Criteria are not completely met, the diagnosis 
is ‘‘possible MS’’; if another diagnosis arises during the evaluation that better explains the 
clinical presentation, then the diagnosis is ‘‘not MS.’’ 
aAn attack (relapse; exacerbation) is defined as patient-reported or objectively observed 
events typical of an acute inflammatory demyelinating event in the CNS, current or 


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historical, with duration of at least 24 hours, in the absence of fever or infection. It should 
be documented by contemporaneous neurological examination, but some historical events 
with symptoms and evolution characteristic for MS, for which no objective neurological 
findings are documented, can provide reasonable evidence of a prior demyelinating event. 
Reports of paroxysmal symptoms (historical or current) should, however, consist of 
multiple episodes occurring over not less than 24 hours. Before a definite diagnosis of MS 
can be made, at least 1 attack must be corroborated by findings on neurological 
examination, visual evoked potential response in subjects reporting prior visual 
disturbance, or MRI consistent with demyelination in the area of the CNS implicated in the 
historical report of neurological symptoms. 
bClinical diagnosis based on objective clinical findings for 2 attacks is most secure. 
Reasonable historical evidence for 1 past attack, in the absence of documented objective 
neurological findings, can include historical events with symptoms and evolution 
characteristics for a prior inflammatory demyelinating event; at least 1 attack, however, 
must be supported by objective findings. 
cNo additional tests are required. However, it is desirable that any diagnosis of MS be made 
with access to imaging based on these criteria. If imaging or other tests (for instance, CSF) 
are undertaken and are negative, extreme caution needs to be taken before making a 
diagnosis of MS, and alternative diagnoses must be considered. There must be no better 
explanation for the clinical presentation, and objective evidence must be present to support 
a diagnosis of MS. 
dGadolinium-enhancing lesions are not required; symptomatic lesions are excluded from 
consideration in subjects with brainstem or spinal cord syndromes. 
MS = multiple sclerosis; CNS = central nervous system; MRI = magnetic resonance 
imaging; DIS = dissemination in space; DIT = dissemination in time; PPMS = primary 
progressive multiple sclerosis; CSF = cerebrospinal fluid; IgG = immunoglobulin G. 
 
[Polman 2011] 


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Appendix 2 
Neurostatus® scoring sheet 
 


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Appendix 3 
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 hypokalaemia when considering 
treatment with a QT-prolonging drug. If treatment with such drugs is considered necessary, 
the principal investigator / treating neurologist should always discuss with the first-dose 
administrator and/or a cardiologist the appropriateness of combining such drugs with the 
study drug and may interrupt or permanently discontinue study drug. If the principal 
investigator determines in the best interest of the subject to concomitantly administer a QT-
prolonging drug with known risk of Torsades de Pointes the following recommendations 
must be adhered to:  
a) For a need to start treatment or to increase the dose of a QT-prolonging drug with known 
risk of Torsades de Pointes during the up-titration, treatment with study drug must be 
interrupted.  
• Study drug can only be re-initiated [see Section 5.1.10] after the QT-prolonging drug 
has been stopped or once the QT-prolonging drug has reached the steady state  
o Once the QT-prolonging drug has reached the steady state and prior to 
re-initiation of study drug, the QTcF interval obtained pre-dose on the day of 
the planned re-initiation must be ≤ 450 ms for males or ≤ 470 ms for females 
o Following re-initiation of study drug, at next visit (scheduled or unscheduled 
occurring after completion of the up-titration), perform ECG measurements 
pre-dose.  
b) For a need to start treatment or to increase the dose of a QT-prolonging drug with known 
risk of Torsades de Pointes during the study excluding the up-titration (i.e., after 2 weeks 
of study drug initiation or re-initiation).  
• At visit (scheduled or unscheduled) prior to initiation or dose increase of 
QT-prolonging drug with known risk of Torsades de Pointes, perform ECGs 
measurements pre-dose.  
o If prior to initiation or dose increase of QT-prolonging drug with known risk of 
Torsades de Pointes, the QTcF interval is > 450 ms for males or > 470 ms for 
females, treatment with study drug must be interrupted. 


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• At next visit (scheduled or unscheduled occurring once the QT-prolonging drug has 
reached the steadystate [approximately after 5 half-lives of the QT-prolonging drug]) 
following initiation or dose increase of QT-prolonging drug with known risk of 
Torsades de Pointes, perform ECGs measurements pre-dose. 


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Appendix 4 
Prohibited anti-arrhythmic and HR-lowering drugs 
The following anti-arrhythmic and HR-lowering drugs (systemic administration) are 
prohibited during the study [see Section 5.2.5]: 
• Adenosine 
• Lidocaine 
• Acebutolol 
• Lorajmine 
• Ajmaline 
• Lorcainide 
• Amiodarone 
• Metoprolol 
• Aprinidine 
• Mexiletine 
• Atenolol 
• Morcizine 
• Azimilide 
• Nadolol 
• Bepridil 
• Phenytoin 
• Betaxolol 
• Pilocarpine 
• Bisoprolol 
• Prajmaline 
• Bretylium 
• Procainamide 
• Bunaftine 
• Propafenone 
• Carvedilol 
• Propranolol 
• Cibenzoline 
• Quinidine 
• Disopyramide 
• Sotalol 
• Dofetilide 
• Sparteine 
• Dronedarone 
• Tedisamil 
• Encainide 
• Timolol 
• Esmolol 
• Tocainide 
• Flecainide 
• Vernakalant 
• Ibutilide 
 
• Ivabradine 
 
 
If, in the judgment of the investigator, it is in the best interests of the subject to receive any 
of the drugs listed above, study drug must be permanently discontinued. This list is not 
exhaustive, other anti-arrhythmic or HR-lowering drugs are also prohibited. In case of 
doubt, please discuss with the sponsor the use of any potential anti-arrhythmic or 
HR-lowering drug. 


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Appendix 5 
Adverse events of special interest 
AEs of special interest will include the anticipated risks of treatment with ponesimod, 
teriflunomide (e.g., liver enzyme abnormalities) and the events that may be related to MS 
comorbitities (e.g., seizures or stroke), and will address the following safety areas:  
 
• Effect on HR and rhythm related AEs 
• Hepatobiliary disorders / Liver enzyme abnormality related AEs 
• Pulmonary related AEs  
• Eye disorders related AEs 
• Infection related AEs 
• Skin malignancy related AEs 
• Non-skin malignancy related AEs 
• Cardiovascular related AEs 
• Hypertension related AEs 
• Stroke related AEs 
• Seizure related AEs 
A list of AEs of special interest (MedDRA preferred terms) will be defined in the SAP. 


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Appendix 6 
Abnormalities for ECG, BP and laboratory variables 
 
Notable abnormalities for ECG and BP that are related to the potential effects of ponesimod 
or teriflunomide 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 drugs (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 drug) and should not be confused with the term “call alert” used by 
the central laboratory for laboratory results, which will be communicated to the 
investigator. Not all ALERTS listed in this table will be “call alerts” from the central 
laboratory and vice versa. 
PLEASE NOTE: Thresholds for abnormality of level L or H are not provided in this 
appendix but will be provided in the central laboratory manual. Parameters for which no 
threshold is defined in Table 8 below may be defined in the central laboratory manual.  


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Table 8 
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 (if baseline is 
above ULN) 
Increase in > 40 g/L 
above ULN or above 
baseline (if baseline is 
above 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 
ALERT:  
< 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 
ALERT:  
< 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 
≥ 5 ULN 
ALERT:  
≥ 5 ULN 
≥ 8 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 or 
> 1.5 times above 
baseline if on 
anticoagulation 
ALERT:  
> 1.5 combined with 
ALT or AST ≥ 3 ULN 
> 2.5 ULN or 
> 2.5 times above 
baseline if on 
anticoagulation 
 
 
Lactate deshydrogenase 
ND 
ND 
ND 
ND 
Creatinine (umol/L)* 
ND 
ND 
>1.5 ULN or >1.5 x 
baseline  
> 3 ULN or >3 x baseline 
ALERT:  
> 150 
Creatinine clearance (mL/min) 
< 60  
< 30  
ALERT:  
< 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  


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Parameter (SI unit) 
LL 
LLL 
HH 
HHH 
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:  
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]. 
ALERT = study-specific alerts that trigger specific actions by the investigator [see Sections 5.1.13 and 5.1.14]; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; ND = not defined; may be complemented by definitions provided by the central laboratory (see central laboratory manual); ULN = upper limit 
of normal. 
 
 
 
 
 


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Appendix 7 
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 


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3. Trial 1, Dominant Hand, 9-HPT 
4. Trial 2, Dominant Hand, 9-HPT 
5. Trial 1, Non-Dominant Hand, 9-HPT 
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) that can be used to detect 
change over time in a group of MS subjects. This is done by creating Z-scores for each 
component of the MSFC. 
MSFC Score = {Zarm, average + Zleg, average + Zcognitive} / 3.0 
Where Zxxx =Z-score 


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Appendix 8 
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 9 
Fatigue Symptoms and Impacts Questionnaire – Relapsing Multiple 
Sclerosis (FSIQ-RMS) 
INSTRUCTIONS 
This questionnaire asks about your experience with your Relapsing Multiple 
Sclerosis (relapsing MS).    
 
• This section of the questionnaire asks about your fatigue-related 
symptoms of relapsing MS over the past 24 hours.   
Please select the response that best describes your experience. Please answer 
all of the questions and do not skip any. There are no right or wrong answers to 
any of the questions. 


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Section 1 
 
Instructions:  
Please select the response that best describes your experience with relapsing MS symptoms in 
the past 24 hours while doing routine daily activities (e.g. housework, yard work, shopping, 
working). 
 
1.  In the past 24 hours, while doing routine daily activities, how physically tired did you feel? 
Not physically tired at 
all 
 
Extremely physically 
tired 
▼ 
 
▼ 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.  In the past 24 hours, while doing routine daily activities, how mentally tired did you feel? 
Not mentally tired at 
all 
 
Extremely mentally 
tired 
▼ 
 
▼ 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.  In the past 24 hours, while doing routine daily activities, how physically weak did you feel? 
Not weak at all 
 
Extremely weak 
▼ 
 
▼ 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.  In the past 24 hours, how would you rate your energy while doing routine daily activities?  
A lot of energy 
 
No energy at all 
▼ 
 
▼ 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.  In the past 24 hours, while doing routine daily activities, how worn out did you feel? 
Not worn out at all 
 
Extremely worn out 
▼ 
 
▼ 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.  In the past 24 hours, while doing routine daily activities, how sleepy did you feel? 
Not sleepy at all  
 
Extremely sleepy 
▼ 
 
▼ 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Instructions:  
Please select the response that best describes your experience with relapsing MS symptoms in 
the past 24 hours while at rest (e.g. reading a book, watching TV). 
 
7.  In the past 24 hours, how worn out did you feel while at rest? 
Not worn out at all 
 
Extremely worn out 
▼ 
 
▼ 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Section 2 
INSTRUCTIONS 
This questionnaire asks about your experience with your Relapsing Multiple 
Sclerosis (relapsing MS). 
This section of the questionnaire asks about how your life was affected by 
fatigue-related symptoms of relapsing MS in the past 7 days. 
Please select the response that best describes your experience. Please answer 
all of the questions and do not skip any. There are no right or wrong answers to 
any of the questions. 
Instructions:  
Please read and answer each of the following questions by selecting the response that best 
describes your experience in the past 7 days. 
 
1. 
Thinking about your fatigue-related symptoms over the past 7 days, how much difficulty 
did you have running errands (such as grocery shopping or going to the bank or ATM)? 
0 
No difficulty 
1 
A little difficulty 
2 
Moderate difficulty 
3 
Quite a bit of difficulty 
4 
Extreme difficulty 
 
2. 
Thinking about your fatigue-related symptoms over the past 7 days, how much difficulty 
did you have communicating clearly? 
0 
No difficulty 
1 
A little difficulty 
2 
Moderate difficulty 
3 
Quite a bit of difficulty 
4 
Extreme difficulty 
 
3. 
Thinking about your fatigue-related symptoms over the past 7 days, how much difficulty 
did you have thinking clearly? 


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0 
No difficulty 
1 
A little difficulty 
2 
Moderate difficulty 
3 
Quite a bit of difficulty 
4 
Extreme difficulty 
 
4. 
Thinking about your fatigue-related symptoms over the past 7 days, how difficult was it 
for you to motivate yourself to do routine daily activities? 
0 
Not difficult 
1 
A little difficult 
2 
Moderately difficult 
3 
Quite difficult 
4 
Extremely difficult 
 
5. 
Thinking about your fatigue-related symptoms over the past 7 days, how much difficulty 
did you have doing indoor household chores? 
0 
No difficulty 
1 
A little difficulty 
2 
Moderate difficulty 
3 
Quite a bit of difficulty 
4 
Extreme difficulty 
 
6. 
Thinking about your fatigue-related symptoms over the past 7 days, how much difficulty 
did you have walking? 


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0 
No difficulty 
1 
A little difficulty 
2 
Moderate difficulty 
3 
Quite a bit of difficulty 
4 
Extreme difficulty 
 
7. 
Thinking about your fatigue-related symptoms over the past 7 days, how much difficulty 
did you have maintaining relationships with people you are close to? 
0 
No difficulty 
1 
A little difficulty 
2 
Moderate difficulty 
3 
Quite a bit of difficulty 
4 
Extreme difficulty 
 
8. 
Thinking about your fatigue-related symptoms over the past 7 days, how much difficulty 
did you have taking part in social activities (such as going to the movies or going out to 
eat)? 
0 
No difficulty 
1 
A little difficulty 
2 
Moderate difficulty 
3 
Quite a bit of difficulty 
4 
Extreme difficulty 
 
9. 
Thinking about your fatigue-related symptoms over the past 7 days, how frustrated 
were you? 


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0 
Not at all 
1 
A little bit 
2 
Somewhat 
3 
Quite a bit  
4 
Extremely 
 
10. 
Thinking about your fatigue-related symptoms over the past 7 days, how often were 
you forgetful?  
0 
Never 
1 
Rarely 
2 
Some of the time 
3 
Most of the time 
4 
Almost all of the time 
 
11. 
Thinking about your fatigue-related symptoms over the past 7 days, how often did you 
have to take a nap? 
0 
Never 
1 
Rarely 
2 
Some of the time 
3 
Most of the time 
4 
Almost all of the time 
 


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12. 
Thinking about your fatigue-related symptoms over the past 7 days, how often did you 
have to take a break? 
0 
Never 
1 
Rarely 
2 
Some of the time 
3 
Most of the time 
4 
Almost all of the time 
 
13. 
Thinking about your fatigue-related symptoms over the past 7 days, how often did you 
have to rearrange your plans? 
0 
Never 
1 
Rarely 
2 
Some of the time 
3 
Most of the time 
4 
Almost all of the time  
 
 
 


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Appendix 10 Work Productivity and Activity Impairment Questionnaire: Multiple 
Sclerosis 
 
 
 
 
 


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Appendix 11 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)) 
 
Your Health and Well-Being 
 
This survey asks for your views about your health. This information will help 
keep track of how you feel and how well you are able to do your usual 
activities.  Thank you for completing this survey! 
 
For each of the following questions, please select the one box that best 
describes your answer. 
 
In general, would you say your health is: 
 
Excellent 
Very good 
Good 
Fair 
Poor 


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Compared to one year ago, how would you rate your health in general now? 
 
Much better now than one year ago 
Somewhat better now than one year ago 
About the same as one year ago 
Somewhat worse now than one year ago 
Much worse now than one year ago 
 
 
 
The following question is about activities you might do during a typical day. 
 
Does your health now limit you in vigorous activities, such as running, lifting 
heavy objects, participating in strenuous sports?  If so, how much? 
 
Yes, limited a lot 
Yes, limited a little 
No, not limited at all 
 
The following question is about activities you might do during a typical day. 
 
Does your health now limit you in moderate activities, such as moving a table, 
pushing a vacuum cleaner, bowling, or playing golf?  If so, how much? 
 
Yes, limited a lot 
Yes, limited a little 
No, not limited at all 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 253/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
The following question is about activities you might do during a typical day. 
 
Does your health now limit you in lifting or carrying groceries?  If so, how 
much? 
 
Yes, limited a lot 
Yes, limited a little 
No, not limited at all 
 
The following question is about activities you might do during a typical day. 
 
Does your health now limit you in climbing several flights of stairs?  If so, how 
much? 
 
Yes, limited a lot 
Yes, limited a little 
No, not limited at all 
 
The following question is about activities you might do during a typical day. 
 
Does your health now limit you in climbing one flight of stairs?  If so, how 
much? 
 
Yes, limited a lot 
Yes, limited a little 
No, not limited at all 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 254/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
The following question is about activities you might do during a typical day. 
 
Does your health now limit you in bending, kneeling, or stooping?  If so, how 
much? 
 
Yes, limited a lot 
Yes, limited a little 
No, not limited at all 
The following question is about activities you might do during a typical day. 
 
Does your health now limit you in walking more than a mile?  If so, how much? 
 
Yes, limited a lot 
Yes, limited a little 
No, not limited at all 
 
The following question is about activities you might do during a typical day. 
 
Does your health now limit you in walking several hundred yards?  If so, how 
much? 
 
Yes, limited a lot 
Yes, limited a little 
No, not limited at all 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 255/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
The following question is about activities you might do during a typical day. 
 
 
Does your health now limit you in walking one hundred yards?  If so, how 
much? 
 
Yes, limited a lot 
Yes, limited a little 
No, not limited at all 
 
The following question is about activities you might do during a typical day. 
 
Does your health now limit you in bathing or dressing yourself?  If so, how 
much? 
 
Yes, limited a lot 
Yes, limited a little 
No, not limited at all 
 
During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities? 
 
Cut down on the amount of time you spent on work or other activities as a 
result of your physical health 
 
All of the time 
Most of the time 
Some of the time 
A little of the time 
None of the time 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 256/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities? 
 
Accomplished less than you would like as a result of your physical health 
 
All of the time 
Most of the time 
Some of the time 
A little of the time 
None of the time 
 
During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities? 
 
Were limited in the kind of work or other activities as a result of your physical 
health 
 
All of the time 
Most of the time 
Some of the time 
A little of the time 
None of the time 
 
During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities? 
 
Had difficulty performing the work or other activities as a result of your physical 
health (for example, it took extra effort) 
 
All of the time 
Most of the time 
Some of the time 
A little of the time 
None of the time 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 257/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities? 
 
Cut down on the amount of  time you spent on work or other activities as a 
result of any emotional problems (such as feeling depressed or anxious) 
 
All of the time 
Most of the time 
Some of the time 
A little of the time 
None of the time 
 
During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities? 
 
Accomplished less than you would like as a result of any emotional problems 
(such as feeling depressed or anxious) 
 
All of the time 
Most of the time 
Some of the time 
A little of the time 
None of the time 
 
During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities? 
 
Did work or other activities less carefully than usual as a result of any 
emotional problems (such as feeling depressed or anxious) 
 
All of the time 
Most of the time 
Some of the time 
A little of the time 
None of the time 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 258/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
During the past 4 weeks, to what extent has your physical health or emotional 
problems interfered with your normal social activities with family, friends, 
neighbors, or groups? 
 
Not at all 
Slightly 
Moderately 
Quite a bit 
Extremely 
 
How much bodily pain have you had during the past 4 weeks? 
 
None 
Very mild 
Mild 
Moderate 
Severe 
Very Severe 
 
During the past 4 weeks, how much did pain interfere with your normal work 
(including both work outside the home and housework)? 
 
Not at all 
A little bit 
Moderately 
Quite a bit 
Extremely 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 259/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
This question is about how you feel and how things have been with you during 
the past 4 weeks.  Please give the one answer that comes closest to the way 
you have been feeling.   
 
How much of the time during the past 4 weeks did you feel full of life? 
 
All of the time 
Most of the time 
Some of the time 
A little of the time 
None of the time 
This question is about how you feel and how things have been with you during 
the past 4 weeks.  Please give the one answer that comes closest to the way 
you have been feeling.   
 
How much of the time during the past 4 weeks have you been very nervous? 
 
All of the time 
Most of the time 
Some of the time 
A little of the time 
None of the time 
 
This question is about how you feel and how things have been with you during 
the past 4 weeks.  Please give the one answer that comes closest to the way 
you have been feeling.   
 
How much of the time during the past 4 weeks have you felt so down in the 
dumps that nothing could cheer you up? 
 
All of the time 
Most of the time 
Some of the time 
A little of the time 
None of the time 
This question is about how you feel and how things have been with you during 
the past 4 weeks.  Please give the one answer that comes closest to the way 
you have been feeling.   
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 260/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
How much of the time during the past 4 weeks have you felt calm and 
peaceful? 
 
All of the time 
Most of the time 
Some of the time 
A little of the time 
None of the time 
 
This question is about how you feel and how things have been with you during 
the past 4 weeks.  Please give the one answer that comes closest to the way 
you have been feeling.   
 
How much of the time during the past 4 weeks did you have a lot of energy? 
 
All of the time 
Most of the time 
Some of the time 
A little of the time 
None of the time 
 
This question is about how you feel and how things have been with you during 
the past 4 weeks.  Please give the one answer that comes closest to the way 
you have been feeling.   
 
How much of the time during the past 4 weeks have you felt downhearted and 
depressed? 
 
All of the time 
Most of the time 
Some of the time 
A little of the time 
None of the time 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 261/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
This question is about how you feel and how things have been with you during 
the past 4 weeks.  Please give the one answer that comes closest to the way 
you have been feeling.   
 
How much of the time during the past 4 weeks did you feel worn out? 
 
All of the time 
Most of the time 
Some of the time 
A little of the time 
None of the time 
 
 
This question is about how you feel and how things have been with you during 
the past 4 weeks.  Please give the one answer that comes closest to the way 
you have been feeling.   
 
How much of the time during the past 4 weeks have you been happy? 
 
All of the time 
Most of the time 
Some of the time 
A little of the time 
None of the time 
 
This question is about how you feel and how things have been with you during 
the past 4 weeks.  Please give the one answer that comes closest to the way 
you have been feeling.   
 
How much of the time during the past 4 weeks did you feel tired? 
 
All of the time 
Most of the time 
Some of the time 
A little of the time 
None of the time 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 262/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
During the past 4 weeks, how much of the time has your physical health or 
emotional problems interfered with your social activities (like visiting with 
friends, relatives, etc.)? 
 
All of the time 
Most of the time 
Some of the time 
A little of the time 
None of the time 
 
 
How TRUE or FALSE is the following statement for you? 
 
I seem to get sick a little easier than other people. 
 
Definitely true 
Mostly true 
Don’t know 
Mostly false 
Definitely false 
 
How TRUE or FALSE is the following statement for you?   
 
I am as healthy as anybody I know. 
 
Definitely true 
Mostly true 
Don’t know 
Mostly false 
Definitely false 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 263/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
How TRUE or FALSE is the following statement for you?   
 
I expect my health to get worse. 
 
Definitely true 
Mostly true 
Don’t know 
Mostly false 
Definitely false 
 
How TRUE or FALSE is the following statement for you?   
 
My health is excellent. 
 
Definitely true 
Mostly true 
Don’t know 
Mostly false 
Definitely false 
 
 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 264/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
Appendix 12 Patient’s Global Impression of Severity (PGI-S) of Fatigue  
 
Patient’s Global Impression of Severity of Fatigue 
 
Please select the response which best describes the severity of your fatigue today 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 265/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
Appendix 13 Clinician’s Global Impression of Change (CGI-C) 
 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 266/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
Appendix 14 MS Patient Preference Questionnaire 
Questionnaire 
[Benefits of MS treatments] 
Patients with multiple sclerosis are prescribed medication to prevent new relapses, to 
increase the time until their MS gets worse, and to reduce the chance of disability due to 
disease progression. The following sections focus on your preferences for the benefits 
associated with some MS treatments.  
 
[Screen 1 - Number of Relapses] 
Relapsing MS (RMS), is the most common type of MS. Relapses are signs or symptoms 
from the central nervous system, (which consists of the brain, spinal cord and optic nerves) 
such as muscle weakness, tingling, double vision or dizziness, and are due to changes in 
the central nervous system due to inflammation which occurs in MS.  
Please use the ‘i’ button to see more information on relapses in MS. 
 
[Screen 2] 
Imagine a treatment where patients could experience: 
 
0 
or 
4 
relapses in the next 2 years 
 
[Screen 3] 
For you, how much more preferable is: 
 
0 
compared to 
4 
relapses in the next 2 years 
 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 267/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 4] 
Imagine a treatment where patients could experience: 
 
1 
or 
4 
relapses in the next 2 years 
 
 
[Screen 5] 
For you, how much more preferable is: 
 
1 
compared to 
4 
relapses in the next 2 years 
 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
 
[Screen 6] 
Imagine a treatment where patients could experience: 
 
0 
or 
1 
relapses in the next 2 years 
 
 
[Screen 7] 
For you, how much more preferable is: 
 
0 
compared to 
1 
relapses in the next 2 years 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 268/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
 
[Screen 8] 
Imagine a treatment where patients could experience: 
 
2 
or 
4 
relapses in the next 2 years 
 
[Screen 9] 
For you, how much more preferable is: 
 
2 
compared to 
4 
relapses in the next 2 years 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
 
[Screen 10] 
Imagine a treatment where patients could experience: 
 
1 
or 
2 
relapses in the next 2 years 
 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 269/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 11] 
For you, how much more preferable is: 
 
1 
compared to 
2 
relapses in the next 2 years 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
 
[Screen 12] 
Imagine a treatment where patients could experience: 
 
3 
or 
4 
relapses in the next 2 years 
 
 
[Screen 13] 
For you, how much more preferable is: 
 
3 
compared to 
4 
relapses in the next 2 years 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 270/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 14] 
Imagine a treatment where patients could experience: 
 
2 
or 
3 
relapses in the next 2 years 
 
 
[Screen 15] 
For you, how much more preferable is: 
 
2 
compared to 
3 
relapses in the next 2 years 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
Thank you. You have provided all the required responses. You can check and change your 
responses by selecting Back. Select OK and then Next when ready to save your responses. 
 
 
Time until your MS gets worse 
 
[Screen 1] 
In patients with MS, the disease usually gets worse although it cannot be predicted in an 
individual case how much worse MS will become and how long it will take for MS to 
become worse. 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 271/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 2] 
Please select the situation that is closest to your current functioning level related to MS. 
Before answering, please use the ‘i’ button to see the descriptions of the levels of 
disability used in this questionnaire. 
 
□ Situation 1: You have no disability or mild disability. If your MS gets worse, you 
will move to a stage of moderate disability.  
 
□ Situation 2: You have moderate disability. If your MS gets worse, you will move to 
a stage of relatively severe disability  
 
□ Situation 3: You have relatively severe disability. If your MS gets worse, you will 
move to a stage of severe disability. 
 
□ Situation 4: You have severe disability. If your MS gets worse, you will move to a 
stage of very severe disability 
 
 
[Screen 3] 
Imagine a treatment where patients could experience: 
8 
or 
2 
years until MS got worse 
 
 
[Screen 4] 
For you, how much more preferable is: 
8 
compared to 
2 
years until your MS gets worse 
 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 272/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 5] 
Imagine a treatment where patients could experience: 
 
6 
or 
2 
years until MS got worse 
 
 
[Screen 6] 
For you, how much more preferable is: 
6 
compared to 
2 
years until your MS gets worse 
 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
[Screen 7] 
Imagine a treatment where patients could experience: 
8 
or 
6 
years until MS got worse 
 
[Screen 8] 
For you, how much more preferable is: 
8 
compared to 
6 
years until your MS gets worse 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 273/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
[Screen 9] 
Imagine a treatment where patients could experience: 
 
4 
or 
2 
years until MS got worse 
 
 
[Screen 10] 
For you, how much more preferable is: 
 
4 
compared to 
2 
years until your MS gets worse 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
 
[Screen 11] 
Imagine a treatment where patients could experience: 
6 
or 
4 
years until MS got worse 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 274/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 12] 
For you, how much more preferable is: 
 
6 
compared to 
4 
years until your MS gets worse 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
Thank you. You have provided all the required responses. You can check and change 
your responses by selecting Back. Select OK and then Next when ready to save your 
responses. 
 
 
 
[Screen 0 - Disability due to disease progression]  
The treatments in MS aim to reduce the progression from your current level of functioning 
to the next level of disability. The questions in this section relate to preventing a transition 
from one MS-related disability level to the next level (“worsening of MS”). Please tell us 
your preferences, independent of your current MS functioning level.  
Before answering, please use the ‘i’ button to see the descriptions of the levels of 
disability used in this questionnaire. 
 
[Screen 1] 
Imagine a treatment where patients could experience: 
No or Mild 
or 
Very Severe 
disability  
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 275/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 2] 
For you, how much more preferable is: 
 
No or 
Mild 
compared to 
 Very 
Severe 
disability 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
[Screen 3] 
Imagine a treatment where patients could experience: 
Moderate 
or 
Very Severe 
disability 
 
 
[Screen 4] 
For you, how much more preferable is: 
Moderate 
compared to 
Very 
Severe 
disability 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 276/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 5] 
Imagine a treatment where patients could experience: 
No or Mild 
or 
Moderate 
disability 
 
[Screen 6] 
For you, how much more preferable is: 
No or 
Mild 
compared to 
Moderate 
disability 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
[Screen 7] 
Imagine a treatment where patients could experience: 
Relatively 
Severe 
or 
Very 
Severe 
disability 
 
[Screen 8] 
For you, how much more preferable is: 
 
Relatively 
Severe 
compared to 
Very 
Severe 
disability 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 277/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
Weakly preferable 
Very weakly preferable 
 
 
[Screen 9] 
Imagine a treatment where patients could experience: 
Moderate 
or 
Relatively 
Severe 
disability 
 
[Screen 10] 
For you, how much more preferable is: 
 
Moderate 
compared to 
Relatively 
Severe 
disability 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
[Screen 11] 
Imagine a treatment where patients could experience: 
Severe 
or 
Very 
Severe 
disability 
[Screen 12] 
For you, how much more preferable is: 
Severe 
compared to 
Very 
Severe 
disability 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 278/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
[Screen 13] 
Imagine a treatment where patients could experience: 
Relatively 
Severe 
or 
 
Severe 
disability 
[Screen 14] 
For you, how much more preferable is: 
Relatively 
Severe 
compared to 
Severe 
disability 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
Thank you. You have provided all the required responses. You can check and change your 
responses by selecting Back. Select OK and then Next when ready to save your responses. 
 
[Risks of MS treatments] 
Patients with multiple sclerosis are treated with drugs that may be associated with liver 
failure, serious infections or increased risk for cancer. For some of the MS drugs, increased 
monitoring in the hospital may be necessary after the first dose of the drug to ensure that 
quick medical help is available in case of important side effects. The following sections 
focus on your preferences for the risks associated with some MS treatments.  
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 279/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 1 - Liver Failure] 
Drugs for MS may interfere with the functioning of your liver and in rare cases lead to liver 
failure. The next section will ask you about the chance of liver failure (serious enough to 
require hospitalization or interruption of the MS treatment) within 10 years of treatment. 
Please use the ‘i’ button to see more information on liver failure related to MS treatment. 
 
[Screen 2] 
Imagine a treatment where: 
0 
or 
8 
out of 100 patients could experience 
liver failure within 10 years of 
treatment 
 
[Screen 3] 
For you, how much more preferable is: 
0 
compared to 
8 
out of 100 patients having liver 
failure within 10 years of treatment 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 280/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 4] 
Imagine a treatment where: 
2 
or 
8 
out of 100 patients could experience 
liver failure within 10 years of 
treatment 
 
[Screen 5] 
For you, how much more preferable is: 
2 
compared to 
8 
out of 100 patients having liver 
failure within 10 years of treatment 
 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
 
[Screen 6] 
Imagine a treatment where: 
0 
or 
2 
out of 100 patients could experience 
liver failure within 10 years of 
treatment 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 281/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 7] 
For you, how much more preferable is: 
0 
compared to 
2 
out of 100 patients having liver 
failure within 10 years of treatment 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
 
[Screen 8] 
Imagine a treatment where: 
4 
or 
8 
out of 100 patients could experience 
liver failure within 10 years of 
treatment 
 
[Screen 9] 
For you, how much more preferable is: 
4 
compared to 
8 
out of 100 patients having liver 
failure within 10 years of treatment 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
 
[Screen 10] 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 282/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
Imagine a treatment where: 
 
2 
or 
4 
out of 100 patients could experience 
liver failure within 10 years of 
treatment 
 
[Screen 11] 
For you, how much more preferable is: 
 
2 
compared to 
4 
out of 100 patients having liver 
failure within 10 years of treatment 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
 
[Screen 12] 
Imagine a treatment where: 
 
6 
or 
8 
out of 100 patients could experience 
liver failure within 10 years of 
treatment 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 283/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 13] 
For you, how much more preferable is: 
 
6 
compared to 
8 
out of 100 patients having liver 
failure within 10 years of treatment 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
 
 
 
[Screen 14] 
Imagine a treatment where: 
 
4 
or 
6 
out of 100 patients could experience 
liver failure within 10 years of 
treatment 
 
[Screen 15] 
For you, how much more preferable is: 
 
4 
compared to 
6 
out of 100 patients having liver 
failure within 10 years of treatment 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 284/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
Thank you. You have provided all the required responses. You can check and change your 
responses by selecting Back. Select OK and then Next when ready to save your responses. 
 
 
[Screen 1 - Serious Infection leading to disability] 
Some of the treatments for MS may lead to a weakened immune system and some patients 
may develop serious infections. The following questions are related to the chance 
(probability) of developing a severe infection leading to a disability within 10 years of 
treatment. 
 
Please use the ‘i’ button to see more information on serious infection leading to 
disability.  
 
 
[Screen 2] 
Imagine a treatment where: 
5 out of 100,000 
or 
5 out of 100 
patients could experience a serious 
infection leading to disability within 
10 years of treatment  
 
[Screen 3] 
For you, how much more preferable is: 
 
5 out of 
100,000 
compared to 
5 out of 
100 
patients having a serious infection 
leading to disability within 10 years 
of treatment 
 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
[Screen 4] 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 285/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
Imagine a treatment where: 
 
5 out of 
10,000 
or 
5 out of 
100 
patients could experience a serious 
infection leading to disability within 
10 years of treatment 
 
 
[Screen 5] 
For you, how much more preferable is: 
 
5 out of 
10,000 
compared to 
5 out of 
100 
patients having a serious infection 
leading to disability within 10 years 
of treatment 
 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
 
[Screen 6] 
Imagine a treatment where: 
5 out of 
100,000 
or 
5 out of 
10,000 
patients could experience a serious 
infection leading to disability within 
10 years of treatment 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 286/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 7] 
For you, how much more preferable is: 
5 out of 
100,000 
compared to 
5 out of 
10,000 
patients having a serious infection 
leading to disability within 10 years 
of treatment 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
[Screen 8] 
Imagine a treatment where: 
5 out of 
1,000 
or 
5 out of 
100 
patients could experience a serious 
infection leading to disability within 
10 years of treatment 
 
[Screen 9] 
For you, how much more preferable is: 
5 out of 
1,000 
compared to 
5 out of 
100 
patients having a serious infection 
leading to disability within 10 years 
of treatment 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 287/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 10] 
Imagine a treatment where: 
 
5 out of 
10,000 
or 
5 out of 
100 
patients could experience a serious 
infection leading to disability within 
10 years of treatment 
 
 
[Screen 11] 
For you, how much more preferable is: 
5 out of 
10,000 
compared to 
5 out of 
100 
patients having a serious infection 
leading to disability within 10 years 
of treatment 
 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
 
Thank you. You have provided all the required responses. You can check and change your 
responses by selecting Back. Select OK and then Next when ready to save your responses. 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 288/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 1 - Cancer] 
Some MS drugs acting through the immune system may increase the risk of getting a 
malignant tumor (cancer). This can be a skin cancer, blood cancer or any other type of 
cancer. There is currently no evidence supporting such risk for the MS drugs used in this 
study but patients are being observed for development of cancer.  
Please use the ‘i’ button for more information on the risk of cancer in MS. 
 
 
[Screen 2] 
Imagine a treatment where: 
0 
or 
150 
out of 1,000 patients could develop 
cancer within 10 years of treatment 
 
 
[Screen 3] 
For you, how much more preferable is: 
0 
compared to 
150 
out of 1,000 patients developing 
cancer within 10 years of treatment 
 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 289/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 4] 
Imagine a treatment: 
 
50 
or 
150 
out of 1,000 patients could develop 
cancer within 10 years of treatment 
 
 
[Screen 5] 
For you, how much more preferable is: 
50 
compared to 
150 
out of 1,000 patients developing 
cancer within 10 years of treatment 
 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
 
[Screen 6] 
Imagine a treatment: 
 
 
0 
or 
50 
out of 1,000 patients could develop 
cancer within 10 years of treatment 
 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 290/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 7] 
For you, how much more preferable is: 
0 
compared to 
50 
out of 1,000 patients developing 
cancer within 10 years of treatment 
 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
 
[Screen 8] 
Imagine a treatment where: 
 
100 
or 
150 
out of 1,000 patients could develop 
cancer within 10 years of treatment 
 
[Screen 9] 
For you, how much more preferable is: 
 
100 
compared to 
150 
out of 1,000 patients developing 
cancer within 10 years of treatment 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
 
 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 291/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 10] 
Imagine a treatment where: 
 
50 
or 
100 
out of 1,000 patients could develop 
cancer within 10 years of treatment 
 
 
[Screen 11] 
For you, how much more preferable is: 
 
50 
compared to 
100 
out of 1,000 patients developing 
cancer within 10 years of treatment 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
 
Thank you. You have provided all the required responses. You can check and change your 
responses by selecting Back. Select OK and then Next when ready to save your responses. 
 
 
[Screen 1 - Monitoring of the heart] 
With some treatments for MS it is necessary to monitor the heart on the day of the first 
dose of the drug or when re-starting the drug after an interruption of more than 3 days.  
Please use the ‘i’ button to see more information on monitoring of the heart in MS. 
 
 
[Screen 2] 
Imagine a treatment where patients could experience: 
0 
or 
24 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 292/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
hours spent in the hospital for 
monitoring of the heart 
 
 
[Screen 3] 
For you, how much more preferable is: 
 
0 
compared to 
24 
hours spent in the hospital for 
monitoring of the heart 
 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
 
[Screen 4] 
Imagine a treatment where patients could experience: 
 
6 
or 
24 
hours spent in the hospital for 
monitoring of the heart 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 293/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 5] 
For you, how much more preferable is: 
 
 
6 
compared to 
24 
hours spent in the hospital for 
monitoring of the heart 
 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
 
[Screen 6] 
Imagine a treatment where patients could experience: 
0 
or 
6 
hours spent in the hospital for 
monitoring of the heart 
 
 
[Screen 7] 
For you, how much more preferable is: 
0 
compared to 
6 
hours spent in the hospital for 
monitoring of the heart 
 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 294/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 8] 
Imagine a treatment where patients could experience: 
12 
or 
24 
Hours spent in the hospital for 
monitoring of the heart 
 
 
[Screen 9] 
For you, how much more preferable is: 
12 
compared to 
24 
hours spent in the hospital for 
monitoring of the heart 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
 
[Screen 10] 
Imagine a treatment where patients could experience: 
6 
or 
12 
hours spent in the hospital for 
monitoring of the heart 
 
 
[Screen 11] 
For you, how much more preferable is: 
6 
compared to 
12 
hours spent in the hospital for 
monitoring of the heart 
 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 295/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
 
[Screen 12] 
Imagine a treatment where patients could experience: 
18 
or 
24 
hours spent in the hospital for 
monitoring of the heart 
 
 
[Screen 13] 
For you, how much more preferable is: 
18 
compared to 
24 
hours spent in the hospital for 
monitoring of the heart 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
 
[Screen 14] 
Imagine a treatment where patients could experience: 
12 
or 
18 
hours spent in the hospital for 
monitoring of the heart 
 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 296/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 15] 
For you, how much more preferable is: 
 
12 
compared to 
18 
hours spent in the hospital for 
monitoring of the heart 
 
Extremely preferable 
Very strongly preferable 
Strongly preferable 
Moderately preferable 
Weakly preferable 
Very weakly preferable 
 
Thank you. You have provided all the required responses. You can check and change your 
responses by selecting Back. Select OK and then Next when ready to save your responses. 
 
[Screen 1 - Weights] 
The following section will show you all the treatment outcomes you have previously seen 
and we will ask you several questions about which treatment outcome is the most important 
(for you) and how you judge moving from the worst possible outcome to the best outcome. 
Once you have identified the most important outcome it will be removed from the list and 
then you will be asked to indicate your next most important outcome until all questions are 
completed. 
Please use the ‘i’ button to see more information on the weighting questions. 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 297/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 2] 
Which of the following improvements is most important? (Please select one) 
 
Worse 
 
Best 
 
Number of relapses 
4 relapses 
 
0 relapses 
 
Time until your MS 
gets worse 
2 years 
 
8 years 
Disease progression 
 
Very severe disability 
 
No or Mild disability 
 
Liver Failure 
8 out of 100 patients 
 
No patients 
 
Serious infection 
leading to disability 
5 out of 100 patients 
 
5 out of 100,000 patients 
 
Cancer 
150 out of 1,000 
patients 
 
No patients 
 
Monitoring of the 
heart 
24 hours in hospital 
 
No time spent in hospital 
 
 
[Screen 3] 
How important is this improvement? 
 
Worse 
 
Best 
Treatment outcome 1 
selected 
outcome level 
 
outcome level 
 
 
 
 
 
 
 
 
 
Extremely important 
Very strongly important  
Strongly important  
Moderately important  
Weakly important 
Very weakly important  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 298/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 4] 
Which of the following improvements is the next most important? (Please select one) 
 
Worse 
 
Best 
Treatment outcome 1 
 
outcome level 
 
outcome level 
Treatment outcome 2 
 
outcome level 
 
outcome level 
Treatment outcome 3 
 
outcome level 
 
outcome level 
Treatment outcome 4 
 
outcome level 
 
outcome level 
Treatment outcome 5 
 
outcome level 
 
outcome level 
Treatment outcome 6 
 
outcome level 
 
outcome level 
Treatment outcome 7 
 
outcome level 
 
outcome level 
 
 
[Screen 5] 
How important is this improvement? 
 
Worse 
 
Best 
Treatment outcome 2 
selected 
outcome level 
 
outcome level 
 
 
 
 
 
 
 
 
 
Extremely important 
 Very strongly important  
Strongly important  
Moderately important  
Weakly important 
Very weakly important  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 299/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 6] 
How much more important is the improvement at the top compared to the improvement 
at the bottom? 
 
Worse 
 
Best 
Treatment outcome 1 
selected 
outcome level 
 
outcome level 
 
 
Worse 
 
Best 
Treatment outcome 2 
selected 
outcome level 
 
outcome level 
 
 
 
 
 
 
 
 
 
 
Extremely important 
Very strongly important  
Strongly important  
Moderately important  
Weakly important 
Very weakly important  
Indifferent 
  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 300/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 7] 
Which of the following improvements is the next most important? (Please select one) 
 
Worse 
 
Best 
 
Treatment outcome 1 
outcome level 
 
outcome level 
 
Treatment outcome 2 
outcome level 
 
outcome level 
Treatment outcome 3 
 
outcome level 
 
outcome level 
Treatment outcome 4 
 
outcome level 
 
outcome level 
Treatment outcome 5 
 
outcome level 
 
outcome level 
Treatment outcome 6 
 
outcome level 
 
outcome level 
Treatment outcome 7 
 
outcome level 
 
outcome level 
 
 
[Screen 8] 
How important is this improvement? 
 
Worse 
 
Best 
Treatment outcome 3 
selected 
outcome level 
 
outcome level 
 
 
 
 
 
 
 
 
Extremely important 
 Very strongly important  
Strongly important  
Moderately important  
Weakly important 
Very weakly important  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 301/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 9] 
How much more important is the improvement at the top compared to the improvement 
at the bottom? 
 
Worse 
 
Best 
Treatment outcome 2 
selected 
outcome level 
 
outcome level 
 
 
Worse 
 
Best 
Treatment outcome 3 
selected 
outcome level 
 
outcome level 
 
 
 
 
 
 
 
 
 
 
Extremely important 
 Very strongly important  
Strongly important  
Moderately important  
Weakly important 
Very weakly important  
Indifferent 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 302/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 10 ] 
Which of the following improvements is the next most important? (Please select one) 
 
Worse 
 
Best 
 
Treatment outcome 1 
outcome level 
 
outcome level 
 
Treatment outcome 2 
outcome level 
 
outcome level 
 
Treatment outcome 3 
outcome level 
 
outcome level 
Treatment outcome 4 
 
outcome level 
 
outcome level 
Treatment outcome 5 
 
outcome level 
 
outcome level 
Treatment outcome 6 
 
outcome level 
 
outcome level 
Treatment outcome 7 
 
outcome level 
 
outcome level 
 
 
[Screen 11] 
How important is this improvement? 
 
Worse 
 
Best 
Treatment outcome 4 
selected 
outcome level 
 
outcome level 
 
 
 
 
 
 
 
 
 
 
 
 
Extremely important 
 Very strongly important  
Strongly important  
Moderately important  
Weakly important 
Very weakly important  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 303/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 12] 
How much more important is the improvement at the top compared to the improvement 
at the bottom? 
 
Worse 
 
Best 
Treatment outcome 3 
selected 
outcome level 
 
outcome level 
 
 
Worse 
 
Best 
Treatment outcome 4 
selected 
outcome level 
 
outcome level 
 
 
 
 
 
 
 
 
 
 
Extremely important 
 Very strongly important  
Strongly important  
Moderately important  
Weakly important 
Very weakly important  
Indifferent  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 304/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 13] 
Which of the following improvements is the next most important? (Please select one) 
 
Worse 
 
Best 
 
Treatment outcome 1 
outcome level 
 
outcome level 
 
Treatment outcome 2 
outcome level 
 
outcome level 
 
Treatment outcome 3 
outcome level 
 
outcome level 
 
Treatment outcome 4 
outcome level 
 
outcome level 
Treatment outcome 5 
 
outcome level 
 
outcome level 
Treatment outcome 6 
 
outcome level 
 
outcome level 
Treatment outcome 7 
 
outcome level 
 
outcome level 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 305/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 14] 
How important is this improvement? 
 
Worse 
 
Best 
Treatment outcome 5 
selected 
outcome level 
 
outcome level 
 
 
 
 
 
 
 
 
 
[Screen 15] 
How much more important is the improvement at the top compared to the improvement 
at the bottom? 
 
Worse 
 
Best 
Treatment outcome 4 
selected 
outcome level 
 
outcome level 
 
 
Worse 
 
Best 
Treatment outcome 5 
selected 
outcome level 
 
outcome level 
 
 
 
 
 
 
 
 
Extremely important 
 Very strongly important  
Strongly important  
Moderately important  
Weakly important 
Very weakly important  
Extremely important 
 Very strongly important  
Strongly important  
Moderately important  
Weakly important 
Very weakly important  
Indifferent  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 306/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 16] 
Which of the following improvements is the next most important? (Please select one) 
 
Worse 
 
Best 
 
Treatment outcome 1 
outcome level 
 
outcome level 
 
Treatment outcome 2 
outcome level 
 
outcome level 
 
Treatment outcome 3 
outcome level 
 
outcome level 
 
Treatment outcome 4 
outcome level 
 
outcome level 
 
Treatment outcome 5 
outcome level 
 
outcome level 
Treatment outcome 6 
 
outcome level 
 
outcome level 
Treatment outcome 7 
 
outcome level 
 
outcome level 
 
 
[Screen 17] 
How important is this improvement? 
 
Worse 
 
Best 
Treatment outcome 6 
selected 
outcome level 
 
outcome level 
 
 
 
 
 
 
 
 
Extremely important 
 Very strongly important  
Strongly important  
Moderately important  
Weakly important 
Very weakly important  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 307/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 18] 
How much more important is the improvement at the top compared to the improvement 
at the bottom? 
 
Worse 
 
Best 
Treatment outcome 5 
selected 
outcome level 
 
outcome level 
 
 
Worse 
 
Best 
Treatment outcome 6 
selected 
outcome level 
 
outcome level 
 
 
 
 
 
 
 
 
 
 
Extremely important 
 Very strongly important  
Strongly important  
Moderately important  
Weakly important 
Very weakly important  
Indifferent  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 308/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 19] 
Which of the following improvements is the next most important? (Please select one) 
 
Worse 
 
Best 
 
Treatment outcome 1 
outcome level 
 
outcome level 
 
Treatment outcome 2 
outcome level 
 
outcome level 
 
Treatment outcome 3 
outcome level 
 
outcome level 
 
Treatment outcome 4 
outcome level 
 
outcome level 
 
Treatment outcome 5 
outcome level 
 
outcome level 
 
Treatment outcome 6 
outcome level 
 
outcome level 
Treatment outcome 7 
 
outcome level 
 
outcome level 
 
 
 
[Screen 20] 
How important is this improvement? 
 
Worse 
 
Best 
Treatment outcome 7 
selected 
outcome level 
 
outcome level 
 
 
 
 
 
 
 
 
Extremely important 
 Very strongly important  
Strongly important  
Moderately important  
Weakly important 
Very weakly important  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 309/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 21] 
How much more important is the improvement at the top compared to the improvement at 
the bottom? 
 
Worse 
 
Best 
Treatment outcome 6 
selected 
outcome level 
 
outcome level 
 
 
Worse 
 
Best 
Treatment outcome 7 
selected 
outcome level 
 
outcome level 
 
 
 
 
 
 
 
 
 
 
Thank you. You have provided all the required responses. You can check and change your 
responses by selecting Back. Select OK and then Next when ready to save your responses. 
 
 
[Screen 1 - Numeracy] 
The questions in the next section are about your numeracy. Please read the questions 
carefully and try to give the correct answer. 
Please use the ‘i’ button to see more information on numeracy. 
[Screen 2] 
Imagine that we roll a fair, six-sided die 1,000 times. Out of 1,000 rolls, how many times 
do you think the die would come up with even (2, 4, or 6)? 
__________________________________ 
[Screen 3] 
Extremely important 
 Very strongly important  
Strongly important  
Moderately important  
Weakly important 
Very weakly important  
Indifferent  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 310/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
In the BIG BUCKS LOTTERY, the chance of winning a £10,000 prize is 1%. What is your 
best guess about how many people would win a £10,000 prize if 1,000 people each buy a 
single ticket to BIG BUCKS? 
____________________________________ 
 
[Screen 4] 
In the ACME PUBLISHING SWEEPSTAKES, the chance of winning a car is 1 in 1,000. 
What percent of tickets of ACME PUBLISHING SWEEPSTAKES win a car? 
__.__% 
 
Thank you. You have provided all the required responses. You can check and change your 
responses by selecting Back. Select OK and then Next when ready to save your responses.


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 311/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 1 - Comprehension/Ease of use] 
Thank you for participating in this study. In the next screens please tell us about your 
experience with completing the questionnaire.  
[Screen 2] 
On a scale of 1 to 7, where 1 = not at all easy and 7 = very easy, how easy was it to 
understand the questions in the questionnaire? 
__________ 
 
[Screen 3] 
Was enough information provided to help you understand the purpose of the 
questionnaire? 
 
Yes 
 
No 
o If yes, where did you receive the best information to help with this 
questionnaire? 
 From the clinic 
 From the help pages in the questionnaire 
 Other 
 
 
 
 
[Screen 4] 
 
 
 
 
o If no, what additional information would have been helpful?  
 
 
 
 
 
 
 
 
  
Please state other 
 
 
 
 
 
200 characters 
200 characters 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 312/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
[Screen 5] 
What was the most challenging aspect of completing this questionnaire? 
 
 
 
 
 
 
 
 
[Screen 6] 
Please use the box below to provide any other general comments on your experience with 
this questionnaire. 
 
 
 
 
 
 
 
 
 
 
 
Thank you. You have provided all the required responses. You can check and change your 
responses by selecting Back. Select OK and then Next when ready to save your responses. 
 
 
 
 
 
 
 
400 characters 
400 characters 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 313/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
Appendix 15 Child Pugh Classification 
 
Parameter 
Points scored for observed findings 
1 
2 
3 
Ascites 
Absent  
Slight 
Moderate 
Hepatic 
encephalopathy 
grade* 
None 
1 or 2 
3 or 4 
Bilirubin 
micromol/L 
(mg/dL) 
 
< 34.2 
< 2 
 
34.2 − 51.3 
2 − 3 
 
> 51.3 
> 3 
Albumin g/L (g/dL) 
> 3.5 
2.8 − 3.5 
< 2.8 
INR 
< 1.7 
1.7 − 2.3 
> 2.3 
Child Pugh 
classification: 
A: score 5−6 
B: score 7−9 
C: score 10−15 
 
 
 
 
*Hepatic encephalopathy classification: 
Grade 0: normal consciousness, personality, neurological examination, 
electroencephalogram 
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps 
waves 
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves 
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower 
waves 
Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2−3 cps delta 
activity 
 
Sources: 
Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data 
Analysis, and Impact on Dosing and Labeling. FDA, May 2003 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc
es/ucm072123.pdf (Accessed 13 March 2015) 
 
BMJ Best practice website, http://bestpractice.bmj.com/best-
practice/monograph/278/diagnosis/criteria.html (Accessed 13 March 2015) 


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Appendix 16 Electronic self-rated version of the Columbia-Suicide Severity Rating 
Scale (eC-SSRS) 
eC-SSRS 2.0 Call Script – Lifetime (Corresponding to Visit 2 - baseline assessment) 
Core Language: US English 
Introduction 
NRT01 
In this interview, I am going to ask questions about thoughts you may have had and 
actions you may have done related to wanting to be dead or killing yourself. First I will 
ask about thoughts regarding wanting to be dead or killing yourself that you have not 
actually acted on. Later I will ask about any actions you may have actually done or 
preparations you have made. I will let you know when we switch from thoughts to 
actions.  
  
Passive Suicide Ideation  
Q01 
At any time in your life, 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 
  
Active Suicide Ideation  
Q02 
Have you actually had any thoughts of killing yourself, at any time?  
  
If Yes, press 1  
If No, press 2  
  
Ideation Level = 2 
  
Q03 
Have you thought about how you might do this?  
  


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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 
At any time, have you ever 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  
  
Ideation Level = 4 
  
Q05 
At any time, have you ever started to work out, or actually worked out, the specific 
details of how to kill yourself?  
  
If Yes, press 1  
If No, press 2  
  
Q05q 
Did you actually intend to carry out the details of your plan?  
  


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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 you, at some point, 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.  
  
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?  
  


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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  
  
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?  
  
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.  
  


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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  
  
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 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.  
  


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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?  
  
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  
  


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Version 7 
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Doc No D-18.388 
 
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.  
  
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?  
  


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Version 7 
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Doc No D-18.388 
 
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 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.  
  
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?  
  


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Doc No D-18.388 
 
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  
  
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  


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Version 7 
5 December 2018, page 323/376 
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Doc No D-18.388 
 
  
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  
  
Q04aNRT 
You indicated before that you had 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.  
  
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?  
  


Ponesimod / ACT-128800 
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Version 7 
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Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
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?  
  
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.  
  


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Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 325/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
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  
  
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 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.  
  
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?  


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Version 7 
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Confidential 
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Doc No D-18.388 
 
  
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  
  
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? 


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Version 7 
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Doc No D-18.388 
 
  
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.  
  
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  
  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
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EudraCT 2012-000540-10 
Doc No D-18.388 
 
If Recent Ideation is required, go to Recent Ideation Section 
  
Recent Ideation  
Level 1 Ideation 
You indicated that at some time in your life you have wished you were dead or that 
you could go to sleep and not wake up. Have you had any thoughts like that in the past: 
I months? 
  
Have you wished you were dead or that you could go to sleep and not wake up in the 
past: I months? 
  
If Yes, press 1  
If No, press 2  
  
Level 2 Ideation 
You indicated that there has been a time in your life when you had thought of killing 
yourself. Have you had any thoughts like that in the past: I months? 
  
Have you had any thoughts of killing yourself in the past: I months? 
  
If Yes, press 1  
If No, press 2  
  
Level 3 Ideation 
You indicated that there has been a time in your life when you thought about how you 
might kill yourself. Have you thought about how you might kill yourself in the past: I 
months? 
  
Have you thought about how you might kill yourself in the past: I months, even though 
you didn’t intend to act on the thoughts? 
  
If Yes, press 1  
If No, press 2  
  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
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EudraCT 2012-000540-10 
Doc No D-18.388 
 
Level 4 Ideation 
You indicated that there has been a time in your life when you thought about how you 
might kill yourself and that you had some intention of acting on those thoughts. Have 
you had any intentions of acting on thoughts about killing yourself in the past: I 
months? 
  
Have you had any intentions of acting on a method to kill yourself in the past: I 
months? 
  
If Yes, press 1  
If No, press 2  
  
Level 5 Ideation 
You indicated that there was a time in your life when you worked on a plan or had 
worked out details for killing yourself and that you had some intention to carry out the 
plan. Have you made specific plans or worked out the details for killing yourself with 
the intention of carrying them out in the past: I months? 
  
If Yes, press 1  
If No, press 2  
  
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.  
  
Suicidal Behavior  
Q06a 
At any time in your life, have you made a suicide attempt?  
  
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.  


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Doc No D-18.388 
 
  
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 
Did you think it was possible that you could have died from what you did? 
  
If Yes, press 1  
If No, press 2  
  


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Doc No D-18.388 
 
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 
Have you ever 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. 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? 
  
If Yes, press 1  
If No, press 2  
  
Q07e 
Did you think it was possible that you could have died from what you did? 


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Doc No D-18.388 
 
  
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 
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.  
  
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 …  
  
If loop > 1 
Consider the time you did something dangerous before that …  
  
Q08c_1 
Were you trying to harm yourself when you did this?  
  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 333/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
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, 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, were you injured more 
seriously than surface scratches or mild nausea?  
  
If Yes, press 1  
If No, press 2  
  
Q09RB 
Did this occur within the past: I months? 
  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 334/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
If Yes, press 1  
If No, press 2  
  
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  
  
Q09.1NRT 
Earlier, you indicated that there were two times when you intended to kill yourself or 
thought you could have died from what you did. I want to know if you suffered any 
physical injuries.  
  
Q09.1 
If Q06a = YES 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 335/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
As a result of your most recent attempt, 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 recent time you tried to hurt yourself, were you injured more 
seriously than surface scratches or mild nausea?  
  
If Yes, press 1  
If No, press 2  
  
Q09.1RB 
Did this occur within the past: I months? 
  
If Yes, press 1  
If No, press 2  
  
Q09.1a 
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  
  
Q09.1b 
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?  
  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 336/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
If Yes, press 1  
If No, press 2  
  
Q09.1c 
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  
  
Q09.2 
If Q06a = YES 
As a result of your first attempt, 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 first time you tried to hurt yourself, were you injured more seriously 
than surface scratches or mild nausea?  
  
If Yes, press 1  
If No, press 2  
  
Q09.2RB 
Did this occur within the past: I months? 
  
If Yes, press 1  
If No, press 2  
  
Q09.2a 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 337/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
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  
  
Q09.2b 
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  
  
Q09.2c 
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  
  
Q09.4NRT 
Earlier, you indicated that there were three or more times you intended to kill yourself 
or thought you could have died from what you did. Now I want to know if you suffered 
any physical injuries each time. 
  
Q09.4 
If Q06a = YES 
As a result of your most recent attempt, 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-058B301, OPTIMUM 
Version 7 
5 December 2018, page 338/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
  
If Q06a = NO 
As a result of the most recent time you tried to hurt yourself, were you injured more 
seriously than surface scratches or mild nausea?  
  
If Yes, press 1  
If No, press 2  
  
Q09.4RB 
Did this occur within the past: I months? 
  
If Yes, press 1  
If No, press 2  
  
Q09.4a 
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  
  
Q09.4b 
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  
  
Q09.4c 
Did your injury cause you to be extremely drowsy, or result in broken bones, or severe 
bleeding?  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 339/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
  
If Yes, press 1  
If No, press 2  
  
Q09.5 
If Q06a = YES 
As a result of your first attempt, 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 first time you tried to hurt yourself, were you injured more seriously 
than surface scratches or mild nausea?  
  
If Yes, press 1  
If No, press 2  
  
Q09.5a 
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  
  
Q09.5b 
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?  
  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 340/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
If Yes, press 1  
If No, press 2  
  
Q09.5c 
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  
  
Q09.6 
If Q06a = YES 
As a result of your most serious attempt, 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, were you injured more 
seriously than surface scratches or mild nausea?  
  
If Yes, press 1  
If No, press 2  
  
Q09.6a 
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  
  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 341/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
Q09.6b 
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  
  
Q09.6c 
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  
  
Q09.8RB 
Did this occur within the past: I months? 
  
If Yes, press 1  
If No, press 2  
  
Q09.8 
Although you were not injured most recently, 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  
  
Q09.9 
Although you were not injured the first time, how serious could your injuries have 
been?  
  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 342/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
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  
  
Q09.10RB 
Did this occur within the past: I months? 
  
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  
  
Interrupted Attempts 
Q10 
Has there ever been 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?  
  
Please enter the number using your touch tone phone.  
  
Q10RB 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 343/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
Was the last time you were stopped from trying to end your life by someone or 
something in the past: I months? 
  
If Yes, press 1  
If No, press 2  
  
Aborted Attempts 
Q11 
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?  
  
Please enter the number using your touch tone phone.  
  
Q11RB 
Was the last time you stopped yourself from trying to end your life in the past: I 
months? 
  
If Yes, press 1  
If No, press 2  
  
Preparatory Acts or Behaviors 
Q12NRT 
Asses prior responses and present introduction: 
Other than the times you have already told me about 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,  
  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 344/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
Other than the times you have already told me about 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 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 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 when you did things intending to 
kill yourself or thought you might have died, 
  
Other than the times you have already told me about 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 when you started to do something 
to end your life but stopped yourself,  
  
Q12 
Have you ever 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?  
  
Please enter the number using your touch tone phone.  
  
Q12RB 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 345/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
Was the last time you took steps toward making a suicide attempt or preparing to kill 
yourself in the past: I months? 
  
If Yes, press 1  
If No, press 2  
  
Exit 
Thank you and Good bye. 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 346/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
eC-SSRS 2.0 Call Script – Since Last Call (Corresponding to Week 60 and 
Week 108 assessments) 
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 
  
Active Suicide Ideation  
Q02 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 347/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
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  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 348/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
  
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. 
  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 349/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
If days SLC > 120 
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?  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 350/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
  
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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Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 351/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
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?  
  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 352/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
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.  
  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 353/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
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 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 354/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
questions, I want you to think about the time you were feeling the most suicidal since 
your last call.  
  
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? 
  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 355/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
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  
  
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?  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 356/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
  
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  
  
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? 
  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 357/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
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? 
  
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.  
  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 358/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
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  
  
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. 
  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 359/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
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  
  
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?  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 360/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
  
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.  
  
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 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 361/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
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? 
  
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 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 362/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
  
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 
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?  
  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 363/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
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? 
  
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.  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 364/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
  
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 
  
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? 
  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 365/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
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  
  
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  
  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 366/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
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  
  
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? 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 367/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
  
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 
Asses prior responses and present introduction: 
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, 
  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 368/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
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? 
  
Please enter the number using your touch tone phone.  
  
Exit 
Thank you and Good bye. 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 369/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
Appendix 17 Relapse assessment questionnaire 
 
TO BE FILLED OUT BY THE TREATING NEUROLOGIST AND/OR STUDY NURSE 
When applicable, for each of the Questions 1 to 5 below, complete either the phone 
interview or visit interview questions. 
Phone interview 
 
Visit interview  
During a visit at the study site  
(scheduled or unscheduled) 
 Subject calling the site to report 
new/worsened symptoms  
 
 Scheduled call from the site to the 
subject for relapse detection 
 
Date of phone interview  
 
_ _ . _ _ _ . _ _ 
dd   mmm   yy 
Date of visit 
 
_ _ . _ _ _ . _ _ 
dd   mmm   yy 
1. Is / was the subject having new neurological symptom(s) or an acute 
worsening of pre-existing neurological symptom(s)? 
 
Visit 
 Yes → Go to Question 2 
 Yes  → Go to Question 2 
 No → STOP Relapse 
investigation 
 No → STOP Relapse investigation 
2. Are / were symptoms suggestive of a relapse (e.g. rapid onset, typically 
hours or days as opposed to weeks/months, symptom type)?  
 
Visit 
 Yes/possibly → Go to Question 3 
 Yes/possibly → Go to Question 3 
 Definitely not → STOP Relapse 
investigation and enter subject’s 
symptoms or diagnosis on the 
eCRF AE page 
 Definitely not → STOP Relapse 
investigation and enter subject’s 
symptoms or diagnosis on the AE 
eCRF page 
3. Did the symptoms last > 24 hours? 
 
Visit 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 370/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
 Yes/possibly → Go to Question 5 
and complete date and time of 
start of symptoms  
 Yes/possibly → Go to Question 5 
and complete date and time of start 
of symptoms 
 No → Go to Question 4 and 
complete date and time of start of 
symptoms 
 No → Go to Question 4 and 
complete date and time of start of 
symptoms 
Date of start of symptoms  
 
_ _ . _ _ _ . _ _ 
dd   mmm   yy 
Date of start of symptoms  
 
_ _ . _ _ _ . _ _ 
dd   mmm   yy 
Time of start of symptoms 
 
_ _ . _ _ 
hh   mm  
Time of start of symptoms 
  
_ _ . _ _ 
hh   mm 
4. Have the symptoms started within the last 24 hours? 
(To be answered only if answer to question 3 was “No”) 
 
Visit 
 Yes → Go to Question 5 
 Yes → Go to Question 5 
 No → STOP Relapse 
investigation and enter subject’s 
symptoms or diagnosis on the 
AE eCRF page 
 No → STOP Relapse investigation 
and enter subject’s symptoms or 
diagnosis on the AE eCRF page 
5. Does / did the subject have concomitant fever or an infection and, if yes, 
are/were the symptoms more likely due to fever/infection than to a 
relapse? 
 
Visit 
 Yes→ STOP Relapse 
investigation and enter subject’s 
symptoms or diagnosis on the 
AE eCRF page 
 Yes → STOP Relapse investigation 
and enter subject’s symptoms or 
diagnosis on the AE eCRF page 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 371/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
 No / not sure → Invite the subject 
to an unscheduled visit as soon 
as possible but at least 24 hours 
after the onset of symptom(s).  
→ Go to Question 7 but if answer 
to question 4 was “Yes”, answer 
additionally question 6 at the visit 
performed at least 24 hours after 
symptom onset  
 No / not sure → If this visit occurs 
< 24 hours from symptom onset, 
invite the subject to an unscheduled 
visit as soon as possible but at least 
24 hours after the onset of 
symptom(s) 
→ Go to Question 7, but if question 
answer to question 4 was “Yes”, 
answer additionally question 6 at the 
visit performed at least 24 hours 
after symptom onset 
 
Question 6 - 8 can only be asked during a visit at the study site (scheduled or 
unscheduled) which occurs at least 24 hours after the symptoms onset. 
Visit interview  
during a visit at the study site (scheduled or unscheduled) 
Date of visit  
(complete only if different from the one reported for question 1 to 5) 
 
_ _ . _ _ _ . _ _ 
dd   mmm   yy 
6. Did the symptoms last > 24 hours? 
(To be answered only at a visit performed at least 24 hours after onset of symptoms and if answer to question 4 was “Yes” 
during an earlier interview (i.e. an interview conducted within 24 hours from symptom onset)): 
 Yes / possibly  → Go to Question 7 
 Definitely not  → STOP Relapse investigation and enter subject’s symptoms or 
diagnosis on the AE eCRF page 
7. Prior to the onset of this event, were the MS symptom(s) stable or 
improving over the last 30 days? 
 Yes / possibly  → Go to Question 8 
 No → Choose 1 below option 
 The previous symptoms corresponded to a relapse, which is recorded in the 
eCRF 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 372/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
→ STOP the relapse investigation for the new episode and enter the 
symptoms on the AE eCRF page unless the current symptoms are 
considered as part of the most recent relapse. Note: New or recurrent 
symptoms that occur less than 30 days following onset of a protocol-
defined relapse should be considered part of the same relapse. 
 The previous symptoms were not due to a relapse 
→ Go to Question 8 and make sure that those previous symptoms are 
recorded on the AE eCRF page 
8. Is there another and better explanation for the subject’s current 
symptoms than an MS relapse? 
 Yes → STOP Relapse investigation and enter subject’s symptoms or diagnosis 
on the AE page 
 No  → Enter symptoms in the “Relapse symptom form “.  
→ The subject should undergo EDSS assessment by the efficacy assessor 
within 7 days from the relapse onset (Note: no referral is needed at scheduled 
visits where EDSS/FS score is assessed as part of the scheduled assessment 
for this visit - in this event, the EDSS assessment planned for this visit will be 
used as part of the relapse assessment) 
 
 
 
 
 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 373/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
Appendix 18 
Relapse symptom form 
TO BE FILLED OUT BY THE TREATING NEUROLOGIST 
Relapse symptom Form 
Visual (optic) functions  
Did the subject report any new or worsening symptoms 
belonging to the visual functions? 
 Yes 
 
If yes, complete the 
below 
 No 
 
 
 Decreased vision 
 Changed vision (excl. double vision) e.g. blurred vision 
 Decreased visual field 
 Scotoma 
 Ocular pain 
 Other 
If other, please specify: 
Brainstem functions  
Did the subject report any new or worsening symptoms 
belonging to the brain stem functions? 
 Yes 
 
If yes, complete the 
below 
 No 
 
 
 Double vision 
 Sudden hearing decrease or loss 
 Oscillopsia 
 Numbness in the face 
 Symptoms of facial nerve weakness (e.g. problems with eye or mouth 
closure, facial asymmetry) 
 Dysarthria 
 Dysphagia 
 Vertigo 
 Other 
If other, please specify: 
Pyramidal functions  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 374/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
Did the subject report any new or worsening symptoms 
belonging to the pyramidal functions? 
 Yes 
 
If yes, complete the 
below 
 No 
 
 
 Weakness in any extremity 
 Muscle stiffness/spasticity 
 Impaired walking or hopping 
 Other 
If other, please specify: 
Cerebellar functions  
Did the subject report any new or worsening symptoms 
belonging to the cerebellar functions? 
 Yes 
 
If yes, complete the 
below 
 No 
 
 
 Difficulties keeping balance while sitting, standing or walking 
 Tremor 
 Vertigo 
 Clumsy movements 
 Other 
If other, please specify: 
Sensory functions  
Did the subject report any new or worsening symptoms 
belonging to the sensory functions? 
 Yes 
 
If yes, complete the 
below 
 No 
 
 
 Any abnormal sensation 
 Tingling 
 Central pain syndrome 
 Other 
If other, please specify: 
Bowel and Bladder functions  


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 375/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
Did the subject report any new or worsening symptoms 
belonging to the bowel and bladder functions? 
 Yes 
 
If yes, complete the 
below 
 No 
 
 
 Urinary retention 
 Urinary urgency 
 Urinary incontinence 
 Constipation 
 Bowel incontinence 
 Other 
If other, please specify: 
Cerebral functions 
Did the subject report any new or worsening symptoms 
belonging to the Cerebral functions? 
 Yes 
 
If yes, complete the 
below 
 No 
 
 
 Problems with cognition (e.g. memory, concentration) 
 Fatigue 
 Mood disorders 
 Other 
If other, please specify: 
Ambulation  
Did the subject report any new or worsening symptoms 
belonging to the ambulation? 
 Yes 
 
If yes, complete the 
below 
 No 
 
 
 Reduced walking distance 
 Need for increased/new assistance (e.g. from no assistance to unilateral 
assistance) 
 Reduced walking speed 


Ponesimod / ACT-128800 
Relapsing multiple sclerosis 
Protocol AC-058B301, OPTIMUM 
Version 7 
5 December 2018, page 376/376 
Confidential 
EudraCT 2012-000540-10 
Doc No D-18.388 
 
 Other 
If other, please specify: 
Other new or worsening symptoms attributed to relapse but difficult to classify into 
functional systems  
Did the subject report any other symptoms attributable 
to a relapse? 
 Yes 
 No 
• 
If yes, please specify: 
 
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT 
AC-058B301
Multicenter, randomized, double-blind, parallel-group, active-controlled, 
superiority study to compare the efficacy and safety of ponesimod to teriflunomide 
in subjects with relapsing multiple sclerosis
Purpose of Analysis
Clinical Study Report
Investigational Drug
Ponesimod (ACT-128800)
Protocol Number
AC-058B301 / OPTIMUM
Actelion Document Number
D-19.178
Document Status/Version Number
Final Version 2.0
Date
20 June 2019
Author
 Statistician
Author
 Statistician
Reviewer
 Project Statistician
Reviewer
Clinical Project Physician
Reviewer
, Clinical Project Scientist
Reviewer
, Safety Project Physician
Reviewer
, Clinical Trial 
Physician
Reviewer
, Clinical Trial Scientist
Reviewer
, Medical Writer
Reviewer
, Statistical Programmer
Confidential
Property of Actelion Pharmaceuticals Ltd. May not be used, divulged, published or 
otherwise disclosed without the consent of Actelion Pharmaceuticals Ltd.
NCT02425644


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TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................12
1
INTRODUCTION.......................................................................................................16
2
STUDY DESIGN AND FLOW..................................................................................16
2.1
Study design .................................................................................................16
2.1.1
Periods ..............................................................................................17
2.1.2
Blinding ............................................................................................19
2.2
Study visit and assessment schedule ............................................................19
3
OBJECTIVES .............................................................................................................23
3.1
Primary objective(s) .....................................................................................23
3.2
Secondary objectives ....................................................................................23
4
CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN THE 
STUDY PROTOCOL .................................................................................................23
4.1
Changes to the analyses planned in the study protocol ................................23
4.2
Changes in the conduct of the study / data collection ..................................24
4.3
Clarifications concerning endpoint definitions and related variables or 
statistical methods.........................................................................................25
5
DEFINITIONS OF VARIABLES ..............................................................................25
5.1
Subject disposition........................................................................................25
5.1.1
Screened subjects..............................................................................25
5.1.2
Screening failures .............................................................................26
5.1.3
Subjects randomized.........................................................................26
5.1.4
Subjects treated.................................................................................26
5.1.5
Subject study treatment completion status........................................26
5.1.6
Subject study completion status........................................................27
5.1.7
Time in study and time on treatment ................................................28
5.1.8
Disposition by protocol version........................................................28
5.2
Subject characteristics ..................................................................................29
5.2.1
Demographics ...................................................................................29
5.2.2
Baseline disease characteristics ........................................................29
5.2.3
Other baseline characteristics ...........................................................33
5.2.4
Medical history .................................................................................33
5.2.5
Previous and concomitant therapies .................................................33
5.2.5.1
Previous therapies....................................................................33


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5.2.5.2
Study concomitant therapies: taken between study treatment 
start and EOS...........................................................................34
5.2.5.3
Treatment concomitant therapies: taken between study 
treatment start and EOT ..........................................................34
5.2.5.4
Therapies starting after EOT ...................................................34
5.2.5.5
Disease modifying therapies for MS (DMTs).........................34
5.2.5.6
Corticosteroids for Treatment of Relapse ...............................35
5.2.5.7
Beta blocking agents ...............................................................36
5.2.5.8
Therapies used for accelerated elimination.............................36
5.2.6
Other subject characteristics.............................................................36
5.2.6.1
Chest X-Ray ............................................................................36
5.2.6.2
Reproductive system findings .................................................36
5.3
Study treatment exposure and compliance ...................................................37
5.3.1
Exposure ...........................................................................................37
5.3.2
Compliance with study treatment .....................................................38
5.3.2.1
Compliance as percentage of days on study drug ...................38
5.3.2.2
Other compliance variables.....................................................39
5.3.3
Study treatment adjustments or interruptions ...................................40
5.4
Efficacy variables .........................................................................................40
5.4.1
Primary efficacy variable(s): ARR up to EOS..................................40
5.4.1.1
General derivation details for relapses ....................................41
5.4.1.2
Variables for supplementary analyses of primary endpoint....42
5.4.2
Secondary efficacy variables ............................................................45
5.4.2.1
Change from baseline to Week 108 in fatigue-related 
symptoms as measured by the FSIQ–RMS symptoms score..45
5.4.2.2
Cumulative number of combined unique active lesions 
(CUAL) from baseline to Week 108 .......................................46
5.4.2.3
Time to 12-week Confirmed Disability Accumulation (CDA) 
up to EOS ................................................................................48
5.4.2.4
Time to 24-week CDA ............................................................51
5.4.3
Exploratory MRI efficacy variables .................................................52
5.4.3.1
Number of 
53
5.4.3.2
Cumulative number of 
 
Cumulative number of 
 
55
5.4.3.4
Percent Change of 
5.4.3.5
Change from baseline in the 
 
56
5.4.3.6
Change from baseline in the 
......................................................56
5.4.3.7
Absence of 
56


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5.4.3.8
Absence of 
 
...........................................................................................57
5.4.3.9
Proportion of
 
......................57
5.4.4
Other clinical efficacy variables .......................................................57
5.4.4.1
...............................................57
5.4.4.2
Absence of
 
58
5.4.4.3
Change in 
58
5.4.4.4
.......................................................58
5.4.4.5
.......................................................59
5.4.4.6
Change in 
 
60
5.4.4.7
Change in the
 
61
5.4.4.8
.........................................61
5.4.4.9
Change from baseline by visit up to
 
..............................................................................61
5.4.4.10
Change from baseline in 
 
..............62
5.4.4.11
Change from baseline in 
 
 
..........................................................................................62
5.5
Safety variables.............................................................................................62
5.5.1
Definition of treatment-emergency, baseline and change-from-
baseline, last on treatment, follow-up assessments for safety 
variables............................................................................................62
5.5.2
Adverse events..................................................................................64
5.5.2.1
Frequency and prevalence of adverse events ..........................64
5.5.2.2
Intensity of adverse events ......................................................64
5.5.2.3
Relationship of adverse events................................................64
5.5.2.4
Fatal adverse events.................................................................64
5.5.3
Deaths ...............................................................................................64
5.5.4
Serious adverse events......................................................................65
5.5.5
Adverse events leading to discontinuation of study treatment .........65
5.5.6
Adverse events leading to temporary interruption of study 
treatment ...........................................................................................65
5.5.7
Adverse events leading to hospitalization ........................................65
5.5.8
Adverse events on Day 1 and Day 1 of re-initiation of study 
treatment ...........................................................................................65
5.5.9
Other significant adverse events.......................................................65


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5.5.9.1
Adverse events of special interest ...........................................65
5.5.9.2
Major adverse cardiovascular events (MACE) .......................66
5.5.10
Vital signs and body weight..............................................................66
5.5.10.1
Blood pressure.........................................................................66
5.5.10.2
Height and Weight...................................................................67
5.5.10.3
Body Temperature...................................................................68
5.5.10.4
Pulse rate .................................................................................68
5.5.11
12-Lead Electrocardiogram (ECG)...................................................68
5.5.11.1
Quantitative ECG variables.....................................................68
5.5.11.2
Qualitative ECG variables.......................................................69
5.5.12
Laboratory.........................................................................................70
5.5.12.1
Derivations ..............................................................................71
5.5.13
Other safety variables .......................................................................71
5.5.13.1
Pulmonary function tests - Spirometry....................................71
5.5.13.2
Pulmonary function tests - DLCO.............................................73
5.5.13.3
Dermatological Examination...................................................75
5.5.13.4
Optical coherence tomography................................................75
5.5.13.5
Ophthalmological Examination...............................................75
5.5.13.6
Physical examination...............................................................75
5.5.13.7
Suicidal ideation......................................................................75
5.6
Quality of life variables ................................................................................77
5.6.1
Change from baseline by visit up to Week 108 in SF-36v2™ 
Health Survey domain and component scores..................................77
5.7
Pharmacoeconomic variables .......................................................................78
5.7.1
Change from baseline by visit up to Week 108 in Work 
productivity and activity impairment (WPAI:MS) scores................78
5.7.2
Health care resource utilization from baseline up to Week 108.......78
5.8
Pharmacodynamic variables.........................................................................79
6
DEFINITION OF PROTOCOL DEVIATIONS.........................................................79
7
ANALYSIS SETS.......................................................................................................80
7.1
Definitions of analysis sets...........................................................................80
7.1.1
Screened analysis set ........................................................................80
7.1.2
Full analysis set.................................................................................80
7.1.3
Per-protocol analysis set / Per-protocol analysis ..............................80
7.1.4
Safety analysis set.............................................................................82
7.1.5
Other analysis sets ............................................................................83
7.1.5.1
Non-conventional MRI sub-study full analysis set .................83
7.1.5.2
Patient preference sub-study full analysis set..........................83
7.1.5.3
DLCO sub-study safety analysis set..........................................83
7.1.5.4
Post-treatment observation period analysis set (PTOP Set)....83


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7.1.5.5
Post-treatment safety analysis set............................................83
7.2
Usage of the analysis sets .............................................................................83
8
DEFINITION OF SUBGROUPS................................................................................84
9
STATISTICAL ANALYSES......................................................................................85
9.1
Overall testing strategy.................................................................................85
9.1.1
Overall testing strategy.....................................................................85
9.2
General rules for data presentations .............................................................87
9.3
Display of subject disposition, protocol deviations and analysis sets ..........88
9.3.1
Subject disposition............................................................................88
9.3.2
Protocol deviations ...........................................................................89
9.3.3
Analysis sets .....................................................................................89
9.4
Analyses of subject characteristics...............................................................90
9.4.1
Demographics ...................................................................................90
9.4.2
Baseline disease characteristics ........................................................90
9.4.3
Other baseline characteristics ...........................................................90
9.4.4
Medical history .................................................................................90
9.4.5
Previous and concomitant therapies .................................................90
9.4.5.1
Disease modifying therapies (DMTs) for MS.........................91
9.4.5.2
Concomitant steroid for treatment of relapses.........................91
9.4.5.3
Beta blocking agents ...............................................................91
9.4.5.4
Therapies used for accelerated elimination.............................92
9.4.6
Other subject characteristics.............................................................92
9.5
Analysis of study treatment exposure and compliance.................................92
9.5.1
Exposure ...........................................................................................92
9.5.2
Compliance with study treatment .....................................................92
9.6
Analysis of the primary efficacy variable.....................................................92
9.6.1
Primary estimand..............................................................................92
9.6.2
Hypothesis and statistical model.......................................................93
9.6.3
Main analysis ....................................................................................93
9.6.4
Sensitivity analyses to main analysis................................................94
9.6.4.1
ARR based on confirmed relapses up to EOS on the FAS -
unadjusted analysis..................................................................94
9.6.4.2
ARR based on confirmed relapses up to EOS including derived 
stratification variable...............................................................94
9.6.4.3
ARR imputation analysis for subjects withdrawing from the 
study prematurely (imputation from EOS to theoretical Week 
108)..........................................................................................95
9.6.5
Supplementary analyses....................................................................96
9.6.5.1
ARR up to EOT + 7 days for confirmed relapses ...................96


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9.6.5.2
ARR based on confirmed relapses up to EOS - Per protocol 
analysis ....................................................................................97
9.6.5.3
ARR based on all relapses up to EOS on the FAS..................97
9.6.5.4
ARR based on confirmed relapses up to start of new DMT for 
MS on the FAS........................................................................98
9.6.5.5
ARR up to EOS for imputed confirmed relapses....................98
9.6.5.6
ARR post EOT + 7 days following premature treatment 
discontinuation ........................................................................98
9.6.5.7
ARR by time period ................................................................98
9.6.5.8
Forest plot of primary efficacy analysis and main sensitivity / 
supplementary analyses...........................................................98
9.6.6
Other analyses related to the primary endpoint ................................99
9.6.6.1
Relapse characteristics and relapse symptoms........................99
9.6.6.2
Number of new or worsening neurological symptoms up to 
EOS .......................................................................................100
9.6.6.3
Change in the collection of the primary endpoint introduced by 
protocol amendment 3...........................................................100
9.6.7
Subgroup analyses ..........................................................................100
9.7
Analysis of the secondary efficacy variables .............................................101
9.7.1
Analysis of change from baseline in FSIQ-RMS weekly 
symptoms score (Fatigue) to Week 108 .........................................101
9.7.1.1
Hypothesis and statistical model ...........................................101
9.7.1.2
Statistical Analysis ................................................................101
9.7.1.3
Supportive / Sensitivity analyses...........................................102
9.7.1.4
Descriptive analyses..............................................................103
9.7.1.5
Subgroup analyses.................................................................103
9.7.2
Analysis of cumulative unique active lesions from baseline up 
to Week 108 (CUAL) .....................................................................104
9.7.2.1
Hypothesis and statistical model ...........................................104
9.7.2.2
Statistical analysis .................................................................104
9.7.2.3
Supportive/sensitivity analyses .............................................105
9.7.2.4
Subgroup analyses.................................................................106
9.7.3
Analysis of Time to 12-week CDA ................................................106
9.7.3.1
Hypothesis and statistical model ...........................................106
9.7.3.2
Statistical analysis .................................................................107
9.7.3.3
Supportive / sensitivity analyses ...........................................107
9.7.3.4
Subgroup analyses.................................................................108
9.7.1
Analysis of Time to 24-week CDA ................................................108
9.7.1.1
Hypothesis and statistical model ...........................................108
9.7.1.2
Handling of missing data.......................................................109
9.7.1.3
Statistical analysis .................................................................109
9.7.1.4
Supportive/sensitivity analyses .............................................109


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9.7.1.5
Subgroup analyses.................................................................110
9.8
Analysis of exploratory MRI efficacy variables.........................................110
9.8.1
Number of 
110
9.8.2
Cumulative number of 
 
111
9.8.3
Percent change of 
 
........................................................................................111
9.8.4
Change from baseline in the 
 
............................................................................112
9.8.5
Change from baseline in the 
 
112
9.8.6
Absence of 
.................112
9.8.7
Absence of 
 
..................................................................................................113
9.8.8
Proportion of
.........................................................................................113
9.9
Analysis of other clinical efficacy variables...............................................113
9.9.1
Time to 
.......................................................113
9.9.2
Absence of
 
114
9.9.3
Change in 
...............114
9.9.4
..............................................................114
9.9.5
..............................................................114
9.9.6
Change in 
 
..................................................................................................115
9.9.7
Change in the 
 
..................................................................................................115
9.9.8
.................................................115
9.9.9
Change from baseline by visit up to
 
....................................................................................115
9.9.10
Change from baseline in 
 
..................................................................................................116
9.9.11
Change from baseline in
 
 
.................................................................................................116
9.10
Analysis of safety variables........................................................................116
9.10.1
Adverse events................................................................................116
9.10.2
Deaths, other serious adverse events ..............................................117
9.10.2.1
Death .....................................................................................117


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9.10.2.2
Serious adverse events (SAEs)..............................................118
9.10.2.3
Treatment-emergent adverse events leading to study treatment 
discontinuation ......................................................................118
9.10.2.4
Other significant adverse events............................................119
9.10.3
Electrocardiography (ECG) ............................................................120
9.10.4
Vital signs and body weight............................................................121
9.10.5
Laboratory tests...............................................................................122
9.10.6
Pulmonary function tests - Spirometry...........................................123
9.10.7
Pulmonary function tests - DLCO....................................................124
9.10.8
Analysis of other safety variables...................................................125
9.10.8.1
Columbia Suicide ideation or behavior.................................125
9.11
Analysis of quality of life variables............................................................126
9.11.1
Change from baseline by visit up to Week 108 in SF-36v2™ 
Health Survey domain and component scores................................126
9.12
Analysis of pharmacoeconomic variables ..................................................126
9.12.1
Change from baseline by visit up to Week 108 in WPAI:MS 
scores ..............................................................................................126
9.12.2
Health care resource utilization ......................................................126
9.13
Analysis of pharmacodynamic variables....................................................126
9.14
Analysis of pharmacokinetic variables.......................................................127
10 GENERAL STATISTICAL METHODOLOGY......................................................127
10.1
Statistical methodology for count data .......................................................127
10.1.1
Imputation methods for count data.................................................128
10.2
Statistical methods for binary data .............................................................130
10.2.1
Logistic regression..........................................................................130
10.3
Statistical methods for continuous data......................................................130
10.3.1
ANOVA / ANCOVA model...........................................................130
10.3.2
Mixed effects repeated measurements model.................................131
10.3.3
Rank ANCOVA..............................................................................132
10.4
Statistical methods for time-to-event data..................................................133
10.4.1
Time to Event and log-rank test......................................................133
10.4.2
Cox proportional hazard model ......................................................134
11 GENERAL DEFINITIONS AND DERIVATIONS.................................................134
11.1
Dates, times and days .................................................................................134
11.2
Analysis period definitions.........................................................................135
11.2.1
Efficacy study periods ....................................................................135
11.3
Re-assignment of premature EOT visits / Visit windowing.......................135
11.4
Summaries by visit .....................................................................................137
11.4.1
LOCF imputation............................................................................139


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11.5
Listings of safety data for subjects with deviations from study 
treatment schedule ......................................................................................139
12 HANDLING OF MISSING/INCOMPLETE DATE AND TIME FIELDS .............139
12.1
Previous / Concomitant therapies...............................................................140
12.1.1
Previous / Concomitant therapies date imputation .........................141
12.2
Relapse........................................................................................................141
12.3
Adverse event onset and death dates ..........................................................141
12.4
Study treatment start and EOT ...................................................................143
13 LIST OF SUMMARY TABLES, LISTINGS AND FIGURES ...............................143
14 REFERENCES..........................................................................................................144
15 ATTACHMENTS .....................................................................................................146
16 APPENDICES...........................................................................................................171


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LIST OF TABLES
Table 1
Dosing scheme................................................................................................18
Table 2
Visit and assessment schedule (Part 1) ...........................................................20
Table 3
Visit and assessment schedule (Part 2) ...........................................................21
Table 4
Visit and assessment schedule (Part 3) ...........................................................22
Table 5
Disease modifying therapies for MS...............................................................35
Table 6
Conversion into prednisone-equivalent dose..................................................36
Table 7
Overview of the different main analysis sets and their usage.........................84
Table 8
Example scenarios secondary endpoint alpha allocation................................87
Table 9
Premature end of treatment remapping.........................................................136
Table 10
Visit windowing for questionnaire and psychometric assessment data........137
Table 11
Handling of missing or partial start and end dates for previous/concomitant 
therapies ........................................................................................................140
Table 12
Scoring and transforming scales ...................................................................178
Table 13
Thresholds for marked laboratory abnormalities..........................................182
LIST OF FIGURES
Figure 1
Study Design...................................................................................................17
Figure 2
Overall testing strategy ...................................................................................86
LIST OF APPENDICES
A.
Adverse Events of special interest ................................................................171
B.
Protocol Deviation code list..........................................................................172
C.
PRO and other composite assessment scoring and handling of missing 
data................................................................................................................173
C.1.
.......................................................................................................173
C.2.
FSIQ-RMS Symptoms score ...................................................................174
C.3.
FSIQ-RMS impacts domain.....................................................................175
C.4.
SF-36 scoring...........................................................................................175
C.5.
WPAI:MS scoring....................................................................................180
D.
Laboratory marked abnormalities.................................................................182
E.
Document history..........................................................................................183


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LIST OF ABBREVIATIONS AND ACRONYMS
%FEV1
FEV1 expressed as % of predicted normal value
%FVC
FVC expressed as % of predicted normal value
9 HPT
9-Hole Peg Test
AE
Adverse event
AESI
Adverse event of special interest
ALP
Alkaline phosphatase 
ALT
Alanine aminotransferase 
ARR
Annualized relapse rate
AST
Aspartate aminotransferase
BMI
Body mass index
BP
Blood pressure
bpm
Beats per minute
CDA
Confirmed disability accumulation
CFR
(US) Code of Federal Regulations
CI
Confidence interval
CL
Confidence limit(s)
CRF
Case report form
CRO
Contract research organization
CSR
Clinical study report
CUAL
Cumulative number of combined unique active lesions
DBP
Diastolic blood pressure
DLCO
Diffusing capacity of the lung for carbon monoxide
DMTs
Disease modifying therapies for MS
ECG
Electrocardiogram
eCRF
Electronic case report form
eC-SSRS
Columbia-Suicide Severity Rating Scale (electronic self-rated 


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version)
EDSS
Expanded Disability Status Scale
EMA
European Medicines Agency
EOS
End-of-study
EOT
End-of-treatment
EU
European Union
FAS
Full analysis set
FDA
(US) Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
FSFV
First subject first visit
FSIQ-RMS
Fatigue Symptom and Impact Questionnaire-Relapsing Multiple 
Sclerosis
FU
Follow-up
FVC
Forced vital capacity
GCP
Good Clinical Practice
Gd+
Gadolinium enhancing
ICF
Informed Consent Form
ICH
International Council on Harmonisation
ICU
Intensive care unit
IDMC
Independent Data Monitoring Committee
INR
International normalized ratio
IRT
Interactive response technology
KM
Kaplan-Meier
LOCF
Last observation carried forward
LSLV
Last subject last visit
MACE
Major adverse cardiovascular events
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple imputation
MMRM
Mixed effect model repeated measures
MRI
Magnetic resonance imaging


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MS
Multiple Sclerosis
MSFC
Multiple Sclerosis Functional Composite
NAP
Not applicable
NCI
(US) National Cancer Institute
OCT
Optical coherence tomography
PASAT-3
Paced Auditory Serial Addition Test
PBH
Persistent black hole
PD
Pharmacodynamic
PFT
Pulmonary function test
PK
Pharmacokinetic
PPS
Per-protocol analysis set
PTOP
Post treatment observation period
QOL
Quality of life
QTC
Corrected QT interval
QTCB
QT interval corrected for heart rate using Bazett’s formula
QTCF
QT interval corrected for heart rate using Fridericia’s formula
RMS
Relapsing multiple sclerosis
RRMS
Relapsing-remitting multiple sclerosis
SAF
Safety analysis set
SAP
Statistical analysis plan
SAS
Statistical analysis system
SBP
Systolic blood pressure
SCR
Screened analysis set
SD
Standard deviation
SDMT
Symbol digit modalities test
SDTM
Study Data Tabulation Model 
SE
Standard error
SI
Standard international


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SOC
System organ class
SOP
Standard operating procedure
SPMS
Secondary progressive multiple sclerosis with superimposed 
relapses 
T25W
Timed 25 Foot Walk
TBIL
Total bilirubin
ULN
Upper limit of the normal range
WHO
World Health Organization
WHODRUG
WHO drug dictionary
WPAI:MS
Work Productivity Activity Impairment: Multiple Sclerosis


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1
INTRODUCTION
This Statistical Analysis Plan (SAP) describes the analyses and presentation of the 
primary, secondary and exploratory efficacy endpoints as well as all safety, quality of life 
(QOL), pharmacoeconomic and pharmacodynamic (PD) endpoints for the clinical study 
report (CSR) of the AC-058B301 study (OPTIMUM).
Separate SAPs (not described here) are developed for analyses on: 

Pharmacokinetic (PK) endpoints

Patient preference questionnaire

MRI sub-study endpoints
Source data for the analyses are provided as Statistical Analysis Software (SAS®) data 
sets according to Clinical Data Interchange Standards Consortium (CDISC) Study Data 
Tabulation Model (SDTM).
2
STUDY DESIGN AND FLOW
The study is a prospective, multicenter, randomized, double-blind, active-controlled, 
parallel-group, Phase 3, superiority study in adult subjects with relapsing forms of MS.
1133 subjects are randomized in two groups: ponesimod 20 mg or teriflunomide 14 mg, 
using a 1:1 ratio, stratified by use of multiple sclerosis (MS) disease-modifying treatment 
in the last two years prior to randomization (yes, no) and by baseline Expanded Disability 
Status Scale (EDSS) score (EDSS ≤ 3.5, EDSS > 3.5).
The study is conducted at approximately 161 sites (randomized subjects) in 28 countries 
in North America, Eastern and Western Europe, and Pacific region.
2.1
Study design
The overall design of the two-arm study is shown in Figure 1. 
Subjects who have completed treatment up to Week 108 can be enrolled in a long-term
open-label extension study with ponesimod, protocol AC-058B303 (OPTIMUM-LT).
Data from the extension study will not be included in the analyses described in this SAP.
Subjects who prematurely discontinue treatment can remain in the study up to Week 108, 
in a post-treatment observation period (PTOP). 


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Figure 1
Study Design
Randomization
EOT
EOS
Ponesimod 20 mg o.d.
Teriflunomide 14 mg o.d.
          (Liver tests every 2 weeks)
   (every 12 weeks visits)
  V1         V2  V3  V4  V5                               V6                                 V7               V8 to V12             V13                       V14      FU1    FU2
                     D1 D15 W4                              W12                             W24       W36-48-60-72-84       W96                     W108
Pre-
randomiz
ation
Period
Up to 45
days
Treatment
Period
108 Weeks
Follow-up
30 days
D = day; EOS = End-of-Study; EOT = End-of-Treatment; FU = follow-up; M = month; o.d. = once daily; 
V = visit; W = week.
2.1.1
Periods
The study consists of the following protocol defined periods:

Pre-randomization period starts with signature of the Informed Consent Form (ICF) 
and ends with subject’s randomization and lasts up to 45 days (per screening attempt). 
Subjects can be re-screened once. 

Treatment period starts on the day of randomization immediately after the 1st dose 
of study drug intake (Visit 3Day 1 of the study) and continues until the premature 
discontinuation of study drug or the scheduled End-of-Treatment (EOT) visit at Week 
108. Subjects receive double-blind treatment throughout the treatment period. The 
treatment period consists of a titration and a maintenance phase. 
–
A 2-week titration scheme is implemented on Day 1 (or at re-initiation following 
a treatment interruption of more than 3 days) to reduce the first-dose effect of 
ponesimod [see Table 1]. 
–
The titration phase is followed by the maintenance phase with one capsule of 
ponesimod 20 mg or teriflunomide 14 mg administered orally once daily in the 
morning (from Day 15 to End-of-Treatment [EOT]).


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
Post-treatment period starts immediately after the last dose of study drug and ends 
with the End-of-Study visit. It comprises the post-treatment safety follow-up (FU) 
period and if applicable, the PTOP. During the post-treatment period, all subjects 
undergo the accelerated elimination procedure of teriflunomide lasting for 11 days 
with administration of cholestyramine (8 mg three times daily, or if not tolerated 4
mg three times daily) or activated charcoal (50 g two times daily), see protocol for 
details.
–
Post-treatment safety follow-up period
For subjects who enter the extension study AC-058B303, the safety FU period 
ends with the FU1 visit (scheduled 14–22 days after last dose of study drug). If 
they have not complied with the teriflunomide accelerated elimination procedure 
at the time of FU1, it ends with the abbreviated FU2 visit (scheduled 23–37 days 
after the last dose of study drug).
For subjects who do not enter the extension study, the safety FU period ends with 
FU2 visit (scheduled 30–37 days after last dose of study drug). 
–
Post-treatment observation period 
Subjects who prematurely discontinue study treatment enter the PTOP period. It 
lasts from last dose of study drug until 108 weeks after randomization (i.e., end of 
planned treatment period) with 12-weekly visits as per the original visit schedule. 
Safety follow-up visits are conducted in addition, following the post-treatment 
safety follow-up period schedule. 
Table 1
Dosing scheme
Treatment period
Duration
Dose regimen in the 
ponesimod group
Dose regimen in the 
teriflunomide group
Titration
Day 1 and 2
2 mg
14 mg
Titration
Day 3 and 4
3 mg
14 mg
Titration
Day 5 and 6
4 mg
14 mg
Titration
Day 7
5 mg
14 mg
Titration
Day 8
6 mg
14 mg
Titration
Day 9
7 mg
14 mg
Titration
Day 10
8 mg
14 mg
Titration
Day 11
9 mg
14 mg
Titration
Day 12 to 14
10 mg
14 mg
Maintenance
Day 15 until EOT*
20 mg
14 mg
*Visit 4 is to take place at Day 15 1 day. The titration kit will therefore include an additional capsule and tablet (if 
applicable) for treatment on Day 15 (i.e., dose regimen in the ponesimod group = 10 mg). Dosing scheme during re-
initiation following treatment interruption of > 3 days follows the same titration dosing scheme. 
EOT = End-of-Treatment. 


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2.1.2
Blinding
This study is performed in a double-blind fashion. Refer to the protocol for aspects 
related to study drug material related blinding and functional blinding. To maintain 
functional blinding data are collected in two databases, i.e., a main database and a 
database with data considered to possibly lead to unblinding of treatment allocation 
(database of unblinding potential). During the conduct of the study, the Actelion trial 
team only has access to the main database. The main database will contain all data except 
data collected on the day of the first dose or on the day of re-initiation until discharge of 
the subject for: adverse events, hourly vital signs and electrocardiogram (ECG) 
measurements, and will exclude all post-baseline data for the lymphocytes and white-
blood-cell laboratory parameters. Spirometry data will not be available to Actelion 
Biostatistics. Final analyses for the CSR described in this SAP will be presented from 
both main and first-dose databases combined.  
2.2
Study visit and assessment schedule
Table 2–Table 3 show a schematic representation of the assessments during the study.
Table 4 shows a schematic representation of the assessments during the PTOP. 


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Table 2
Visit and assessment schedule (Part 1)
Periods
Name
PRE-RANDOMIZATION
TREATMENT PERIOD
Duration
Up to 45 Days
108 Weeks
Visits
Number
1
2
3
4
5
6
7
89
10
Name
Screening
Baseline
Rand
W2
W4
W12
W24
W36 48
W60
Time
Day 45 to 1
Day 1
Day 15
Week 4
Week 12
Week 24
Week 36 48
Visit window
± 1 day
± 3 days
± 7 days
± 7 days
± 7 days
± 7 days
Informed consent*
X
Inclusion/exclusion criteria*
X
X
X
Demographics*, MS history & treatment*, McDonald 
criteria (revision 2010), Chest X-ray*, Tuberculosis test / 
Viral serology **
X
Additional serum sample for viral serology
X
Medical history / smoking status*
X
X
EDSS/FS*
X
X
X
X
X
X
Relapse*
X
           X <---------------------------------------------------------------------------------------------------------------------------> X
* 
X
X
X
X
X
X
FSIQ-RMS** (1), 
 SF-36v2**, 
WPAI:MS**
X
X
X
X
Health care resource utilization* 
X
X
X
X
X
X
Patient preference questionnaire** (Sub-study)
X
X
eC-SSRS**
X
X
MRI** (3)
X
X
Physical examination* 
X
X
X
X
X
X
Dermatological examination* 
X
X
Body weight and height* (4)
X
X
Body temperature*
X
X
X
X
X
X
X
X
X
SBP/DBP*
X
X
X(5)
X
X
X
X
X
X
12-lead ECG** 
X
X
X(5)
X
X
X(6)
X
X
X
Ophthalmological examination* / OCT* 
X
X
X
X
PFT incl. spirometry (All) and DLCO (sub-study)** 
X
X
X
X
Hematology/Chemistry** (fasted)
X
X
X
               X (7)  <------------> X (7) 
X
X
Urinalysis
X
X
X
X
X
Pregnancy test*/**
X 
X
X
X
X
X
X
X
PK sampling for ponesimod* (8)
X 
X
X
Study drug dispensing & accountability */**
X
X
X
X
X
X
X
Study drug swallowing test (optional)
X
AEs*/SAEs, Concomitant medications*
X
X
X
X
X
X
X
X
X
*Data collected in the eCRF, **Data electronically transferred to sponsor, Day 1 (date of randomization visit).
(1) FSIQ-RMS symptoms scale will be completed for 7 consecutive days. (2) No 
 assessment at Baseline. (3) Non-conventional 
) at selected
sites only. (4) Height only at Visit 1 (Screening). (5) Pre-dose and hourly for at least 4 h post-dose and up to 12 h. (6) Pre-dose and 3 h post-dose. (7) In addition, ALT, AST, 
INR, alkaline phosphatase and total bilirubin at Weeks 6, 8, 10, 14, 16, 18, 20, and, 22; total white blood cell and total lymphocyte counts at Weeks 8, 16, and 20. 
(8) Pharmacokinetic sampling pre-dose at Weeks 12, 60 and 108, and 3 h post-dose on Day 1 and Week 12. 


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Table 3
Visit and assessment schedule (Part 2)
Periods
Name
TREATMENT PERIOD
FOLLOW-UP
UNSCHEDULED
Duration
108 Weeks
30 Days
Visits
Number
11
12
13
14
15
16
R1, R2, …
U1, U2, …
I1, I2, …
d1
d15
Name
W72
W84
W96
EOT
FU1
FU2
Relapse
Unscheduled (1)
Re-initiation
Day Re-1
Day Re-15
Time
Week 72
Week 
84
Week 
96
Week 108 or at premature 
discontinuation 
Last study drug 
intake 15 days
Last study drug 
intake 30 days
Any day between Day 1 and EOS
Visit window
± 7 days ± 7 days± 7 days
± 7 days
−1 day, +7days
+7 days (22)
7 days
NA
NA
± 1 day
EDSS/FS*
X
X
X
X
X
X
X
Relapse*
X<------------------------------------------------------>X
X
X
X
X
FSIQ-RMS**,
X
X
X
X
SF-36v2**
X
X
X
Health care resource utilization*
X
X
X
X
X
WPAI:MS**
X
X
 (Sub-study)
X
Chest X-ray*
X
MRI** (2)
X
X
eC-SSRS**
X
Physical examination* 
X
X 
X
X
Dermatological examination*, Body weight *
X
X
SBP/DBP*, 12-lead ECG**
X
X
X
X
X
X
X
X(3)
X
Pulse rate*
X
X(4)
Ophthalmological examination / OCT* 
X
X
PFT incl. spirometry (All) and DLCO (sub-study)** 
X
X
X
X
Hematology/Chemistry**(fasted)
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
Viral serology, Serum sample vaccination*
X
Pregnancy test*/**
X
X
X
X
X
X
X
PK sampling for ponesimod*
X
X (5)
Teriflunomide plasma concentration
X (4)
Accelerated elimination procedure 
X
X (4)
Accelerated elimination procedure compliance 
X
X (4)
Study drug dispensing/accountability
X
X
X
X
X
X
X
X
AEs*/SAEs, Concomitant medications*, Body 
temperature*
X
X
X
X
X
X
X
X
X
X
*Data collected in the eCRF, **Electronically transferred to sponsor, Day 1 = date of randomization visit, 
(1) Unscheduled visits may include all or some of the indicated assessments. (2) Brain MRI to be performed at any time an opportunistic infection in the CNS is suspected. 
Non-conventional 
 at selected sites only. Note: MRI assessment at EOT does not need to be performed if the EOT visit occurs within < 4 weeks of 
the MRI assessment at Visit 10. (3) Pre-dose and hourly for at least 4 h post-dose and up to 12 h. (4) If needed (see protocol for details). (5) When possible, collect PK sample upon 
experiencing SAE.


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Table 4
Visit and assessment schedule (Part 3)
Periods
Name
POST-TREATMENT OBSERVATION PERIOD (PTOP)
(to be performed after EOT)
Duration
Up to 108 Weeks
Visits
Number
6A, 8A, 9A, 
11A,13A 
7A, 12A
10A, 14A
Name
W12A, W36A, 
W48A, W72A, 
W96A
W24A, W84A
W60A, W108A
Time
Week 12-36-
48-72-96
Week 24 and 
84
Week 60 and 108
Visit window
±7 days
±7 days
±7 days
EDSS/FS*
X
X
X
Relapse*
X<---------------------------------------------------------------------------------------------------------------------------------->X
MRI* 
X
FSIQ-RMS** (1), 
**, 
 *
X (only Week12)
X
X
Concomitant medications*
X
X
X
Physical examination* 
X
Dermatological examination* 
X
SBP/DBP*
X
X
X
12-lead ECG **
X
Body temperature*
X
X
X
PFT incl. spirometry (All) and DLCO (sub-study)** 
X (Week 108 only)
Hematology/Chemistry** (fasted)
X
X
Urinalysis*
X
X
Pregnancy test*/** 
X
X
X
AEs/SAEs *
X
X
X
*Data collected in the eCRF, **Electronically transferred to sponsor, Day 1 = randomization visit. If the first PTOP visit windows overlaps with FU1 or FU2
visits, visits and assessments can be combined.
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
; CNS = 
central nervous system; d = day(s); DBP = diastolic blood pressure; DLco = Diffusing capacity for carbon monoxide; 
 ECG = 
electrocardiogram; eCRF = electronic case report form; eC-SSRS = Columbia Suicide Severity Rating Scale (electronic self-rated version); EDSS = Expanded 
Disability Status Scale; EOS = End of Study; EOT = End of Trial; FS = functional system; FSIQ-RMS = Fatigue Symptom and Impact Questionnaire-Relapsing 
Multiple Sclerosis; FU = Follow-up; h = hour(s); INR = international normalized ratio; MRI = magnetic resonance imaging; MS = multiple sclerosis; 
MTR = magnetization transfer ratio; OCT = Optical coherence tomography; PFT = pulmonary function test; 
 
severity; PK = pharmacokinetic(s); SAE = serious adverse event; SBP = systolic blood pressure;
 test; W = week(s);
WPAI:MS = Work Productivity Activity Impairment: Multiple Sclerosis.


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3
OBJECTIVES
3.1
Primary objective(s)
The primary objective of the study is to determine whether ponesimod is more 
efficacious than teriflunomide in terms of reducing relapses in subjects with Relapsing 
Multiple Sclerosis (RMS).
3.2
Secondary objectives

To assess the effect of ponesimod on disability accumulation and on other aspects of 
MS disease control; 

To assess the safety and tolerability of ponesimod in subjects with RMS.
4
CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN 
THE STUDY PROTOCOL 
4.1
Changes to the analyses planned in the study protocol
Sensitivity analyses of the primary endpoints related to early study withdrawal as 
specified in section 11.3.2.2.2 of the protocol have been updated to account for recent 
advancements in statistical methodology by
applying multiple imputation (MI) 
techniques for negative binomial count data [see Section 9.6.4.3]. 
The assumptions for the multiple imputation approaches for imputation of relapses 
between EOS and Week 108 following premature study withdrawal are generally in line 
with those specified in the protocol.  
An overview of the newly introduced multiple imputation approaches is provided below: 
Protocol approach 
SAP approach
Impute with the observed individual 
treatment ARR
‘Missing at Random’ approach: ARR after withdrawal for each 
treatment arm is assumed to be the ARR in the respective arm before 
withdrawal. 
Equivalent to protocol specified approach.  
Impute 
with 
the 
observed 
teriflunomide 
ARR 
for 
both 
treatment arms
Reference-based MI approaches: The rate in the reference 
(teriflunomide) arm is used for imputation in both the ponesimod and 
teriflunomide arms. 
Two different approaches, ‘Copy reference’ and ‘Jump to reference’, 
are applied, see Section 9.6.4.3 for details. Similar to protocol specified 
approach.


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Impute with the observed ARR for 
ponesimod and impute zero relapses 
for teriflunomide
‘Delta adjustment’ MI approach: A range of deltas (deviation from 
the MAR assumption based on multiplicative factors δ for ARR) 
covering plausible to extreme and unlikely scenarios are considered 
for both treatment arms.
The scenario with δ = 0.1 for teriflunomide (impute based on 0.1 ×
teriflunomide ARR under MAR) and δ = 1 for ponesimod (impute 
based on ponesimod ARR under MAR) represents a scenario that is 
similar, but slightly less extreme than the protocol specified approach. 
The equivalent delta adjustment scenario to the protocol approach (δ
= 0 for teriflunomide) is not considered to avoid numerical 
instabilities of the multiple imputation algorithm. 
For the imputation analyses after EOT + 7 days (see sensitivity analyses in 
Section 9.6.5.1) the period for imputing relapses is from EOT + 7 days to Week 108 in 
the SAP instead of from EOT + 7 days to EOS as specified in section 11.3.2.4 of the 
protocol. Rationale for the change is to align with the per protocol planned period for 
observing relapses at least up to Week 108 and to handle intercurrent events of premature 
treatment discontinuation irrespective of subsequent study withdrawal. Purpose of the 
analysis remains to assess the impact of treatment discontinuation and/or switching to 
alternative MS treatments as specified in the protocol. 
4.2
Changes in the conduct of the study / data collection
A total of 6 protocol amendments were conducted. The main reasons are described 
below.
Protocol version 2, 29 April 2015: Addition of a sub-study assessing patient preferences 
for different outcomes in the treatment of multiple sclerosis.
Protocol version 3, 16 July 2015: Among other changes, the following updates were 
made to address comments received after Voluntary Harmonization Procedure review for 
this Clinical Trial Application in the EU: Introduction of the electronic self-rated version 
of the Columbia-Suicide Severity Rating Scale (eC-SSRS), total white blood cell and 
total lymphocyte count monitoring every four weeks up to Week 24; Reducing the time 
window for the EDSS assessments to ensure that EDSS assessments of two subsequent 
visits are at least 10 weeks and no more than 14 weeks apart. 
Protocol version 4, 5 February 2016: Addressing a comment received from the US 
FDA regarding the assessment of relapses. For this purpose, a standardized step-wise 
procedure for the early detection, confirmation and reporting of relapses has been 
introduced. This included incorporating a relapse assessment questionnaire into the study 
(based on telephone calls and visits). 


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Protocol version 5, 14 November 2016 Main reason for the amendment was to modify 
the procedure for teriflunomide plasma concentration testing after the subject’s 
discontinuation from study treatment. Further small clarifications and updates were made. 
Protocol version 6, 30 August 2017 Main reason for the amendment was to allow for 
testing of teriflunomide plasma concentration in any subject who has discontinued study 
drug if deemed necessary for the subject’s safety, at the discretion of the investigator. 
Timing of the testing of teriflunomide plasma concentration remains dependent on study 
drug discontinuation and compliance with the accelerated elimination procedure. Further 
small clarifications and updates were made.
Protocol version 7, 5 Dec 2018 Changes include updating the testing strategy for the 
secondary endpoints from a hierarchical testing strategy to the described fallback type 
strategy. 
 are 
demoted from secondary to exploratory endpoints. Time to 24-week disability has been 
added as a secondary endpoint following CHMP feedback.
4.3
Clarifications concerning endpoint definitions and related variables or 
statistical methods
The protocol endpoints ‘Change from baseline to EOS vs change from baseline to EOT’
for lymphocyte counts, pulmonary function tests (PFTs) and DLCO parameters analyses 
for assessing reversibility are clarified as follows: ‘Change from baseline to EOS’ is 
clarified to not include assessments from the post-treatment observation period, but only 
from the safety follow-up period (up to EOT + 37 days). Consequently, in this SAP the 
terminology ‘change from baseline to last follow-up assessment’ instead of ‘change from 
baseline to EOS’ is used. The rationale for this is to allow the assessment of the 
reversibility of the effects on these endpoints prior to the initiation of other DMTs in the 
PTOP.
5
DEFINITIONS OF VARIABLES
This section provides the definitions and sources for all variables used in the analyses, 
including specifications for the derivations.
General recurrent definitions (e.g., study treatment start date, baseline, and EOS date) or 
unit conversions are described in Section 11.
5.1
Subject disposition
5.1.1
Screened subjects
A subject is considered screened if the subject has signed any informed consent (for the 
main study or any of the sub-studies) and is assigned a subject number by the interactive 
response technology (IRT) provider. A screened subject is considered re-screened if a 
second screening visit date is documented in the electronic Case Report Form (eCRF).


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5.1.2
Screening failures
A subject is considered a screening failure, if screened but not randomized into the study 
(as per the recording in the IRT system). Subjects screened more than once and 
subsequently randomized are not counted as screening failures.
The reason for not being randomized is documented on the randomization eCRF:

Failure to meet randomization criteria (“Subject eligible as per inclusion/exclusion 
criteria?” answered “No”)
OR

“Subject withdrew consent” or “Other” (Reason provided following “Was the subject 
randomized?” answered with “No”)
If a subject at a screening attempt is not randomized but no reason for not being 
randomized is reported, the reason is categorized as ‘Unknown’. Two variables are 
derived to hold reason(s) for not being randomized:

Reason for not being randomized at first attempt (not applicable [NAP], if subject 
randomized at first attempt; reason derived from first attempt, irrespective of 
existence and outcome of a second attempt)

Reason for screening failure (NAP, if subject randomized; reason derived from first 
attempt if no second attempt, or from second attempt otherwise)
5.1.3
Subjects randomized 
A subject is considered randomized if a randomization date and number are recorded in 
the IRT system.
5.1.4
Subjects treated 
A subject is considered treated if they received as least one dose of study drug as 
documented in any study drug log eCRFs (see Section 5.3.1 for eCRFs involved).
5.1.5
Subject study treatment completion status
Subjects who complete study treatment as per protocol are those with a record in the 
eCRF ‘Maintenance Ponesimod/Teriflunomide’ form with reason for treatment end given 
as ‘Completed as per protocol’.
A subject is considered to have prematurely discontinued from the study treatment if:

at least one reason (‘Study treatment stopped due to’) is reported on the eCRF form 
‘Premature Discontinuation of Study Treatment’ and/or

the
reason for treatment end is documented as ‘Premature Permanent 
Discontinuation’ on the eCRF ‘Up-titration Ponesimod/Placebo’, ‘Up-titration 
Teriflunomide/Placebo’ or ‘Maintenance Ponesimod/Teriflunomide’


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The date of treatment discontinuation is the last date study drug was taken [defined in 
Section 5.3.1]. In case of a (partially) missing discontinuation date, the date is imputed 
with the EOS date as defined in Section 5.1.6, or with the upper limit of the partial date if 
prior to EOS.
Reasons for premature discontinuation from study treatment are documented on the 
‘Premature Discontinuation of Study Treatment’ eCRF with the following possible 
answers: ‘Death’, ‘Lost to follow-up’, ‘Pre-specified study treatment discontinuation 
criteria’, ‘Subject decision’ (further split into ‘Tolerability related’, ‘Efficacy related’, 
‘Other’, or ‘Not known’), ‘Physician decision’ (further split into ‘Adverse event’, ‘Lack 
of efficacy / Treatment failure’ or ‘Other’) or ‘Sponsor decision’ (further split into ‘Study 
termination by sponsor’ or ‘Other’). Whenever ‘Other’ is selected, free text can be 
provided in addition. Both recorded levels for treatment discontinuation (e.g., ‘Subject 
decision’ as well as ‘Tolerability related’), if pre-specified, are to be included in analyses, 
while any free text is not to be reported in tables, only listed. An additional category 
called ‘Reason not provided’ is defined for subjects where the reason is missing.
Subjects who have prematurely discontinued treatment are considered to have stayed in 
the study beyond safety follow-up if their EOS date is after EOT + 30 days. These 
subjects will be considered to have entered the PTOP beyond the safety follow-up period.
5.1.6
Subject study completion status
A subject is considered to have completed the study as per the corresponding entry on the 
‘End of Study’ eCRF (“Did the subject complete the study?” answered with “Yes”). All 
subjects not completing the study are considered to have prematurely discontinued the 
study. 
Note: A subject who prematurely discontinued study treatment but completed the PTOP 
is considered to have completed the study according to the protocol.
The End-of-Study (EOS) date is defined as the ‘Date of End of Study’ collected on the 
end of study eCRF, unless a subject is lost to follow-up or dies, in which case ‘Date of 
Last Contact’ from the end-of-study eCRF or ‘Date of Death’ from Death eCRF are used. 
If missing, the last recorded visit date (i.e., the latest assessment date within any visit) is 
considered as the EOS date. 
For subjects completing the 108 weeks of treatment and entering the extension study, the 
EOS visit should occur at the FU1 visit (scheduled 14–22 days after last drug intake), or
at the abbreviated FU2 visit if available (scheduled 23–37 days after last drug intake). For
subjects completing the 108 weeks of treatment and not entering the extension study, the 
EOS visit corresponds to the FU2 visit (scheduled 30–37 days after last drug intake). For 
subjects prematurely discontinuing study treatment, EOS is scheduled to be the Week 
108 visit (Visit 14A – W108A – Week 108).


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For subjects prematurely discontinuing the study, reasons for premature discontinuation 
from study are: ‘Death’, ‘Lost to follow-up’, ‘Subject decision’ (further split into 
‘Withdrawal of consent’, ‘Tolerability related’, ‘Efficacy related’, and ‘Other’), 
‘Physician decision’ (further split into ‘Adverse event’ and ‘Other’) or ‘Sponsor decision’
(further split into ‘Study terminated’ and ‘Other’). Whenever ‘Other’ is selected, free text 
can be provided in addition. An additional category ‘Reason not provided’ is defined for 
subjects where the reason is missing.
5.1.7
Time in study and time on treatment
Time in study (years) is derived as (EOS date −randomization date + 1 day) / 365.25.
Time in study separated into prior and after protocol version 4 is derived as:

Time in study after protocol version 4 (years) = (EOS date −maximum of 
(randomization date, start date under protocol version 4) + 1 day) / 365.25

Time in study prior to protocol version 4 (years) = Time on study (years) −Time on 
study after protocol version 4 (years). It is zero for subjects with no data collected 
under protocol version < 4. 
Time on treatment is derived as (EOT date −study treatment start date + 1 day) / 365.25.
5.1.8
Disposition by protocol version
As part of protocol version 4, systematic relapse assessment questionnaires at phone 
interviews and visits have been introduced, which may affect data collection of the 
primary endpoint. For each subject, it is therefore established whether they were 
randomized or had data collected under protocol version 1-3 or under protocol version 4 
or higher.  

Randomized under protocol version (1–3, ≥4). A subject is considered randomized 
under protocol version ≥4 if randomized on or after the start date under protocol 
version ≥4, otherwise they are considered randomized under protocol version 1–3. 
The start date under protocol version 4 is the earliest date of informed consent for 
the main study on any protocol version > 3 (as documented on the ‘Informed 
Consent’ eCRF). 

Data collected under protocol version 1–3 (yes/no). A subject has data collected 
under protocol version 1–3 if they have been randomized under protocol version 1–3. 

Data collected under protocol version ≥4 (yes/no). A subject has data collected 
under protocol version ≥4 if their EOS date is after their start date under protocol 
version ≥4. 
Note: Subjects can have data collected under multiple versions and can have data 
collected according to both definitions above. 


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5.2
Subject characteristics
5.2.1
Demographics
The following demographic variables are derived:

Sex, from the ‘Demographics’ eCRF (Male, Female)

Age (years), from the ‘Demographics’ eCRF; if available, ‘Age at re-screening’
overwrites the initially entered ‘Age’

Age categories derived from the above as follows: < 18, 18–30, 31–40, 41–55, and 
≥56 years. Age high-level categories: < 40, and ≥ 40. Age categories as per EudraCT
requirement: < 12, 12–17, 18–64, 65–84, and ≥85

Height (cm), from the ‘Height & Body Weight’ eCRF

Weight (kg), from the ‘Height & Body Weight’ or from the ‘Body Weight’ eCRF:
The latest measurement available prior to study treatment start date is selected. If first 
intake is not documented, use the latest measurement available prior to 
randomization. If neither date is available (for screen failures), the latest weight 
assessment available is used.

BMI (kg/m2) derived as Weight (kg) / (Height (cm) / 100)2

BMI categories: < 18.5, ≥18.5 – < 25, ≥25 – < 30, and ≥30

Race, from the ‘Demographics’ eCRF (Black or African American, American Indian 
or Alaska Native, Asian, Native Hawaiian or Other Pacific Islander, White, Other,
and Not applicable)

Ethnicity, from the ‘Demographics’ eCRF (Hispanic or Latino, Not Hispanic or 
Latino, and Unknown)

Country based on site mapping performed on SDTM level

Geographical region of site, countries are assigned to the following regions:
–
European Union (EU): Bulgaria, Croatia, Czech Republic, Finland, France, 
Germany, Greece, Hungary, Italy, Latvia, Lithuania, Poland, Portugal, Romania, 
Spain, Sweden, United Kingdom
–
Europe Non-EU + Russia: Belarus, Bosnia and Herzegovina, Georgia, Russian 
Federation, Serbia, Ukraine 
–
North America: Canada, United States 
–
Rest of World: Israel, Mexico, Turkey
5.2.2
Baseline disease characteristics
Baseline characteristics variables are defined as follows:


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Stratification variables from IRT

Baseline expanded disability status scale (EDSS) (from IRT) (≤ 3.5, 3.5) from 
the IRT system

MS disease modifying treatment within 2 years prior to randomization (from 
IRT) (Yes/No), from IRT system
Baseline disease characteristics variables from eCRF / non-IRT external data

Baseline EDSS score, defined as the latest available EDSS score as entered in the 
EDSS/FS eCRF (i.e., not re-derived based on sub-scores) prior to or on the date of 
randomization

Baseline EDSS (from eCRF), categorized as (≤ 3.5, 3.5), derived from the baseline 
EDSS score

MS disease modifying treatment within 2 years prior to randomization (from 
eCRF) (Yes/No), each documented Disease modifying therapies for MS (DMTs), as 
specified in Section 5.2.5.4, will be flagged as follows: 
‘Taken in previous 2 years’, if:

Medication end date* is after/on randomization date – 730 days and prior 
to randomization date; or

Medication end date* is after/on randomization date – 730 days and start 
date* is not after date of randomization; or

Medication start date* is after/on randomization date – 730 days and prior 
to randomization date; or

Ongoing at end of study? is ticked “Yes” and start date* is available and 
not after date of randomization; or

Ongoing at start of Treatment? is ticked “Yes”, unless end date* is prior to 
randomization date – 730 days.
‘Not taken in previous 2 years’, if 

Medication end date* is prior to randomization date – 730 days; or

Medication start date* of the medication is after the randomization date.
‘Undetermined whether taken in previous 2 years’, if 

Medication end date is partial and only part of its range^ is within the 
period between randomization date – 730 days and randomization date; or

Medication end date is missing but question “Ongoing at start of 
Treatment?” is not ticked “Yes” and either start date* is prior to 
randomization date – 730 days, or start date is missing.
*Or in case of partial dates if the entire range^ of possible dates (both lower and 
upper limit) falls within the specified period. 


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^ Range of partial dates is the time interval defined by lower and upper limit of 
the partial date. 
A subject is considered as having had MS disease modifying treatment within 2 
years prior to randomization (from eCRF), if they either have at least one DMT
flagged ‘Taken in previous 2 years’, or if they have any DMT flagged as 
‘Undetermined whether taken in previous 2 years’ and the site classified the subject 
for ‘MS treatment within 2 years (from IRT)’ as ‘Yes’. All other subjects are not 
considered to have had DMT in the last two years prior to randomization. 
Any prior MS disease modifying treatment (Yes/No), any DMT prior to 
randomization, i.e., classified as previous, or ongoing at study treatment start (
derived as specified in Section 5.2.5, or ongoing at randomization for non-treated 
randomized subjects), unless the start date is between randomization date + 1 and 
study treatment start date. 

Time since first symptoms (years), defined as [Date of randomization Date of first 
MS symptoms + 1] in days / 365.25. Taken from ‘MS History Disease 
Characteristics’ 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 (years), defined as: [Date of randomization Date of 
initial diagnosis + 1] in days / 365.25. Taken from ‘MS History Disease 
Characteristics’ 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.

MS subtype (RRMS / SPMS), relapsing-remitting multiple sclerosis [RRMS], 
secondary progressive multiple sclerosis [SPMS] with superimposed relapses). Taken 
from ‘MS History Disease Characteristics’ eCRF at screening; subtype at re-
screening overwrites the initially entered subtype.

Time since most recent relapse (months) at screening, defined as [Date of 
screening Onset date of latest MS relapse prior to screening + 1] in days / 30.4375. 
From eCRF form ‘MS History - Relapse’ at screening. Take the most recent “Onset 
date of previous relapse” among all previous relapses entered on the ‘MS History -
Relapse’ eCRF. Partial onset dates 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). Data 
collected at re-screening overwrites the initially entered data.


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
Number of relapses in the year prior to study entry, as reported in the 
corresponding question on the ‘MS History - Relapse’ eCRF (i.e., not based on 
recorded onset dates of previous relapses). Data collected at re-screening overwrites 
the initially entered data.

Number of relapses in the 2 years prior to study entry as reported in the 
corresponding question on the ‘MS History - Relapse’ eCRF (i.e., not based on 
recorded onset dates of previous relapses). Data collected at re-screening overwrites 
the initially entered data.

Presence of Gd+ T1 lesions (yes/no) on baseline MRI scan as provided by the MRI 
central reading.

Number of documented Gd+ T1 lesions on baseline MRI scan as provided by the 
MRI central reading.

Volume of T2 lesions on baseline MRI scan as provided by the MRI central reading.

Number of T2 lesions on baseline MRI scan as provided by the MRI central reading, 
categorized into < 9 and ≥9.

Highly active disease (yes, no). A subject is considered to have highly active disease 
if one or both of the following conditions are met:   
Any disease modifying therapy for MS as specified in Section 5.2.5.4 received 
during the year* before randomization and one or both of the following
conditions are met:

≥1 relapse within 1 year prior to study entry and the baseline MRI 
read centrally shows either ≥1 Gd+ T1 lesion and/or ≥9 T2 lesions

Number of relapses within 1 year prior to study entry ≥number of 
relapses between 2 and 1 year prior to study entry, for subjects with at 
least one relapse within 2 years prior to study entry.
≥2 relapses within the 1 year prior to study entry and baseline EDSS score 
> 2 and baseline MRI read centrally shows ≥1 Gd+ T1 lesion.
* i.e., any intake documented between randomization date – 365 days and 
randomization date; (partially) missing medication start and stop dates are 
imputed as described in Section 12.1.
A subject is considered not to have a highly active disease if either condition stated 
above is not met unless either condition cannot be assessed due to missing data. 

Smoking status (Current smoker, Former smoker, Never smoked), taken from 
‘Smoking status’ eCRF.


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Note: For re-screened subjects, information for baseline characteristics ‘at screening’ is 
taken from the last Re-screening Visit, if available, instead of the Screening Visit.
Handling of missing/partial dates: In case of partial dates for required dates (MS 
symptoms, initial diagnosis, latest MS relapse prior to Screening), the lower limit is used 
in derivations. Missing dates are not replaced; the corresponding variable is considered 
missing. 
5.2.3
Other baseline characteristics
Other baseline characteristics are not derived but reported as recorded on the eCRF in 
listings. It includes information collected on:

‘Smoking status’ eCRF (Number of cigarettes a day, Number of years smoked, Year 
quit, in addition to smoking status baseline characteristics)
5.2.4
Medical history
Medical history includes previous and/or concomitant diseases or diagnoses recorded in 
the Medical History eCRF. Reported terms are coded using MedDRA (version 21.0).
Previous medical history are those diseases or diagnoses with an end date before or equal 
to the study treatment start date. In the event of a partial end date that overlaps with first 
dose (e.g., May 2013 and first dose occurred on 23 May 2013) or if an end date is 
missing, the medical history is considered as previous if ongoing is ticked ‘No’. All other 
medical history terms are considered concomitant. For subjects randomized but not 
treated the randomization date is used instead of the study treatment start date.
Data originating from the eCRF ‘MS History - Complication or Symptoms Associated 
with MS’ are flagged to be summarized separately. No start and stop dates are collected 
on this page, however, an ongoing (no/yes) at (re-)screening flag is available. If this flag 
is missing, the complication/symptoms is considered concomitant.
5.2.5
Previous and concomitant therapies
Therapies are collected in the following CRF
pages: ‘Previous Medications’, 
‘Concomitant Medications’, ‘MS Specific Treatment History’ (List of pre-specified MS 
specific treatments if ticked as ‘Yes’) automatically leading to a corresponding record on 
‘MS Specific Treatment History Log’, ‘Study-treatment-concomitant Therapy - Disease-
modifying Treatment for MS’, ‘Corticosteroids for Treatment of Relapse’.
Terms are coded using the WHO drug code dictionary and the anatomic therapeutic 
chemical (ATC) class code (version dated 1 March 2018 or later).
Handling of partial or missing start and end dates is detailed in Section 12.1. 
5.2.5.1
Previous therapies
Previous therapies are therapies that were started and stopped prior to study treatment 
start date.  


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5.2.5.2
Study concomitant therapies: taken between study treatment start and EOS
Includes all therapies that have been taken after study treatment start date up to EOS.
This includes therapies ongoing at study start, as well as therapies starting after study 
treatment start date, or after study treatment end date. 
5.2.5.3
Treatment concomitant therapies: taken between study treatment start and 
EOT
Includes all therapies that have been taken after study treatment start date up to EOT (last 
drug intake). This includes therapies ongoing at study start, as well as therapies starting 
after study treatment start date. 
In addition, the following are flagged in the datasets:

Therapies starting during study treatment administration: Derived as treatment 
concomitant therapies starting on or after study treatment start. 

Therapies ongoing at study treatment start: Includes all treatment concomitant 
therapies that started prior to study treatment start, i.e. have not been started during
study treatment administration.

Therapies taken between study treatment start and EOT + 15 days: Includes all study 
concomitant therapies with start date prior to EOT + 15 days. It reflects the therapies 
taken during the period defining treatment-emergent used for safety reporting. 
Handling of partial or missing start and end dates is detailed in Section 12.1. 
5.2.5.4
Therapies starting after EOT
Includes all study concomitant therapies that have been started after EOT (last drug 
intake). This includes therapies with start date from EOT + 1 day onwards. 
Handling of partial or missing start and end dates is detailed in Section 12.1. Therapies 
with missing start date will be considered to have started on treatment.
5.2.5.5
Disease modifying therapies for MS (DMTs)
Disease modifying therapies 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. For thisstatistical analyses, DMTs 
will be identified on an ingredient level if containing any of the text indicated in Table 5
below. Medications in ATC class S (sensory organs, i.e., ophthalmologicals and/or 
otologicals) will not be considered. 
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’ or 
‘MS Specific Treatment History Log’ eCRF) will also be taken into account.


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Table 5
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
ETRASIMOD
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. 
Start of alternative DMTs for MS (required for efficacy analysis): 
For each subject receiving study concomitant DMTs the start date is defined as the first 
start date of any study concomitant DMT. 
Imputation of partial start date is detailed in Section 12.1.1. Missing start dates will not 
be imputed, consequently therapies with missing start date will not be considered in 
efficacy analyses up to start of alternative DMTs for MS. 
Note on previous DMTs: Occurrence of previous DMTs (stopped prior to ICF consent) is 
assessed systematically (Yes/No tick boxes) in the ‘MS Specific Treatment History’
eCRF for selected medications. However, for reporting purposes, medications are 
identified via coding as specified above. On the ‘MS Specific Treatment History Log’ the 
‘reason for discontinuation’ (free text) is collected and will be included in listings of MS 
specific therapies. 
5.2.5.6
Corticosteroids for Treatment of Relapse
Corticosteroids for treatment of relapses are medications with preferred drug name from 
Table 6* recorded on the corresponding eCRF. 
Doses of corticosteroids will be converted to prednisone equivalent doses in mg/day and 
are calculated as described in Table 6 with cumulative dose derived.


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Accumulated steroid dose (prednisone equivalent doses in mg) for treatment of relapse 
from study treatment start (i) up to EOS, and (ii) up to EOT + 7 days are derived for each 
subject. It is the sum of cumulative steroid dose (mg) across all medications taken in the 
respective period. Cumulative steroid dose mg per medication is derived as 
dose mg/day × duration (days). Subjects without steroid use for treatment of relapses 
have an accumulated dose of 0 mg. 
Table 6
Conversion into prednisone-equivalent dose
Corticosteroid
Dose equivalent to
1 mg prednisone
Conversion factor into 
prednisone equivalent
Prednisone
1 mg
1/1
Cortisone
5 mg
1/5
Hydrocortisone
4 mg
1/4
Prednisolone
1 mg
1/1
Triamcinolone
0.8 mg
1/0.8
Methylprednisolone
0.8 mg
1/0.8
Dexamethasone
0.15 mg
1/0.15
Betamethasone
0.12 mg
1/0.12
*Corresponding salts, i.e., preferred drug name starting with the listed terms are considered as well and corresponding 
dose is converted in the same way. 
Source: GlobalRPh.
5.2.5.7
Beta blocking agents
Beta blocking agents are defined as medications with WHO Drug ATC level 2 code C07: 
“BETA BLOCKING AGENTS”. It presents a sub-class of ATC class C ‘cardiovascular 
system’. 
5.2.5.8
Therapies used for accelerated elimination
Defined as medications to be used for the protocol mandated accelerated elimination 
procedure for teriflunomide following treatment discontinuation, i.e., preferred drug 
names “COLESTYRAMINE” or “CHARCOAL, ACTIVATED”. 
5.2.6
Other subject characteristics
5.2.6.1
Chest X-Ray
Collected at screening and EOT visit in the Chest X-Ray eCRF. No definitions and 
derivations (other than treatment day of assessment) necessary. Any resulting findings are 
recorded as adverse event (or medical history).
5.2.6.2
Reproductive system findings
Data will be taken from the eCRF. No definitions and derivations (other than treatment 
day of assessment) necessary. 


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Includes all information mapped to RP SDTM domain (reproductive system findings) 
including Childbearing potential / Fertility from Demographics eCRF. 
5.3
Study treatment exposure and compliance
Exposure and compliance information will be taken from the Study Drug Log eCRFs:

Up-titration Summary eCRF (collects information on up-titrations conducted as 
planned as per protocol, recording start and end date of up-titration);

Up-titration Ponesimod/Placebo eCRF (collects information on up-titration if not 
conducted as planned as per protocol, separately for up-titration tablets on daily 
basis);

Up-titration Teriflunomide/Placebo eCRF (collects information on up-titration if 
not conducted as planned as per protocol, separately for up-titration capsules on daily 
basis);

Maintenance 
Ponesimod/Teriflunomide
eCRF
(collects 
information 
on 
maintenance study drug intake based on maintenance capsules).
To derive the study treatment start date and time, in addition information collected on 
Study drug administration eCRFs (‘Study Drug Administration - Randomization/Day 1’, 
‘Study Drug Administration’, ‘Study Drug Administration - Re- Initiation’ eCRF) is 
considered. 
In addition, subjects filled an electronic study treatment diary (eDiary). Sites were 
instructed to review the entries in the subject study treatment diary versus the 
protocol-mandated drug intake regimen and versus the number of tablets and capsules
dispensed and returned. Any discrepancy was to be clarified during the site visits, and 
actual drug intake was to be recorded in the eCRF, hence the information from the eCRF 
is considered to be the most reliable, and all exposure derivations including derivation of 
EOT date are only based on eCRF data.
5.3.1
Exposure
Study treatment start date is defined as the earliest study drug start date documented in 
the study drug administration or study drug log eCRF pages, as listed above.
The time of study treatment start (time of first exposure to treatment) is taken from the 
study drug administration eCRF, where the date is equal to the study treatment start date, 
if available.
The EOT date is defined as the latest study treatment end date, as recorded on the Study 
Drug Log (SDL) eCRFs listed above.
The following exposure variables are derived:


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Duration of Study Treatment (days) = EOT date - Study treatment start date + 1 day. 
Duration of Study Treatment is also derived in weeks (days divided by 7), months (days 
divided by 30.4375), and years (days divided by 365.25).
Duration of Study Treatment is categorized as follows: ≤24 weeks (168 days), > 24 
weeks to ≤60 weeks (420 days), > 60 weeks to ≤84 weeks (588 days), > 84 weeks to
≤108 weeks (756 days), > 108 weeks (756 days).
‘Study treatment exposure, interruptions excluded’ equals the ‘Number of days with 
intake documented’ for a subject overall as defined as part of the compliance derivations 
described in Section 5.3.2.1.
5.3.2
Compliance with study treatment
5.3.2.1
Compliance as percentage of days on study drug
Compliance is assessed as the percentage of days from the date of first intake until EOT 
with study drug intake documented in the eCRF:
no.  of days with intake documented
(date of EOT-study treatment start date ) + 1 day × 100
Note: Compliance below 100% must not be indicative of a deviation from the protocol 
since the protocol mandates dose interruptions for certain very specific safety scenarios 
as well as based on investigator’s judgment.
For reporting, the calculated compliance is categorized as follows: 100%, 90% – < 100%,
80% –< 90%, 50% – < 80%, > 0% – < 50%, 0%.
The number of days with study drug intake documented is derived as follows:
During up-titration period
The number of days with intake documented is based on entries on the eCRF ‘Up-
titration 
Summary’
and/or 
‘Up-titration 
Ponesimod/Placebo’
or
‘Up-titration 
Teriflunomide/ Placebo’, with separate entries for tablets (Ponesimod/Placebo) and 
capsules (Teriflunomide/ Placebo). 
Only the intake of the dose form with active drug is considered.
For subjects where the investigator confirmed the up-titration has been conducted as 
planned, the ‘Up-titration Summary’ eCRF is filled, collecting only start and end date of 
the entire titration period without collecting ‘number of capsules taken’ or ‘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/Placebo’ or 
‘Up-titration Teriflunomide/Placebo’ eCRF, ‘Treatment start date’ resulting in potentially 


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multiple records of up-titration drug intake (collecting in addition ‘number of capsules
taken’ or ‘number 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
but based on the dose form with active drug only. 
During maintenance period
As per protocol, one capsule of study drug is to be taken per day. On the ‘Maintenance 
Ponesimod/Teriflunomide’ eCRF log form, each record collects ‘Treatment start date’, 
‘Treatment end date’, and ‘Number of capsules taken’.  If, for a record, the ‘Number of 
capsules taken’ is ≤ ‘Treatment end date’ −‘Treatment start date’ + 1, it is assumed that 
the ‘Number of capsules 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 capsules 
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 for the 
compliance calculation. These subjects are flagged as having taken > 1 capsule per day 
on at least one occasion.
The ‘Number of days with intake documented’ for a subject overall is derived as the sum 
across all study drug log records (sum across up-titration, or maintenance records; 
multiple periods of study drug intake during up-titration or maintenance are possible, e.g.,
due to interruptions, or detailed up-titration eCRF filled). 
5.3.2.2
Other compliance variables 
Compliance to up-titration regimen based on eCRF 
For each episode of up-titration, a subject is considered as not having complied with the 
up-titration scheme if either of the following is documented in the study drug log eCRFs 
for the kit containing active drug:

Premature permanent study drug discontinuation (documented as reason for treatment 
end in at least one instance in the up-titration eCRF drug log);

Capsule or Tablet (whatever corresponds to the active drug) is taken in an incorrect 
sequence during the up-titration (documented as reason for treatment end ‘Up-
titration scheme not followed (other than interruption)’ in at least one instance in the 
up-titration eCRF drug log); 

1 or more tablets or capsules are missed during the up-titration (‘temporarily 
interrupted’ documented as reason for treatment end at least one instance in the up-
titration eCRF drug log);

More than one tablet or capsule taken on any day during the up-titration;

Up-titration lasted < 13 days based on duration of up-titration period (see definition 
below);

Up-titration lasted > 15 days based on duration of up-titration period (see definition 
below).


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Duration of up-titration is derived as last titration end date - first titration start date for 
each up-titration period.
Other compliance variables during maintenance period
The following deviations from the protocol-intended study drug maintenance are 
identified from the ‘Maintenance Ponesimod/Teriflunomide’ eCRF log form and flagged 
on a subject basis:

More than 1 capsule of study drug taken per day on at least one occasion (derivation 
see above);

At least one occasion of treatment interruption of more than 3 days documented, but 
maintenance treatment resumed or started without up-titration. This includes 
occasions when maintenance treatment started more than 4 days after the day up-
titrations stopped.
5.3.3
Study treatment adjustments or interruptions
Study-specific criteria for interruption and discontinuation of study treatment were pre-
specified in the protocol [section 5.1.13]. The protocol did not allow any study treatment 
dose adjustments. 
Study treatment interruptions are assessed via the compliance variables described in 
Section 5.3.2 and the assessment adverse events leading to changes in study treatment as 
described in Section 5.5.5. 
Subjects with at least one interruption: Derived as subjects with ‘Study treatment 
exposure, interruptions excluded’ < ‘Duration of Study Treatment’, based on the 
definitions in Section 5.3.1. 
Total duration of interruption(s)
(days)
is derived as ‘Duration of Study 
Treatment’−’Study treatment exposure, interruptions excluded’. 
Interruptions with reported reason are those where the reported reason for treatment end 
in the study drug log is ‘Temporarily interrupted due to an AE’, or ‘Temporarily 
interrupted not due to an AE’. 
5.4
Efficacy variables
5.4.1
Primary efficacy variable(s): ARR up to EOS
The primary endpoint is the Annualized Relapse Rate (ARR) up to EOS, based on 
confirmed relapses according to the treating neurologist / principal investigator. ARR is
defined as the number of confirmed relapses per subject-year.
For subjects completing the study as planned the EOS is scheduled to occur at least 
108 weeks (± 7 days) after randomization. 


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More precisely, for subjects prematurely discontinuing treatment the EOS is scheduled to 
occur 108 weeks (± 7 days) after randomization. For subjects completing the 108-week 
treatment period the EOS is scheduled to occur prior to entry into the open-label 
extension (14–22 days after EOT, or 23–37 days after EOT in exceptional cases) or after 
the safety follow-up period for subjects not entering the open-label extension (30–37 days 
after EOT). 
A confirmed relapse is defined as a record with ‘Relapse meeting the criteria for a 
confirmed relapse?’ answered ‘Yes’ on the ‘Relapse Summary’ eCRF. All confirmed 
relapses from randomization up to EOS will be included in the analysis. 
For the statistical analysis of ARR, the following data will be used: 

Number of confirmed relapses from date of randomization up to EOS date;

Length of observation expressed in years, defined as: [EOS date −date of 
randomization 1] in days, divided by 365.25.
The logarithm of the length of observation up to EOS will be used as an offset variable in 
the primary efficacy and sensitivity analyses.
Confirmed relapses ‘from date of randomization up to EOS date’ includes all confirmed 
relapses unless starting prior to randomization.
5.4.1.1
General derivation details for relapses
A relapse (confirmed or unconfirmed) is identified from the ‘Relapse Summary’ eCRF 
with ‘Did the subject experience a relapse’ ticked as ‘Yes’. For each relapse the 
corresponding start and end date/time, as well as outcome, treatment with corticosteroids, 
action taken with study drug and need for hospitalization, and whether an EDSS was 
completed are recorded. For relapses with completed EDSS it is collected whether it 
qualifies as a confirmed relapse (see definition details for primary efficacy variable 
above). A relapse which is not a confirmed relapse is considered an ‘unconfirmed 
relapse’. 
Relapses ‘from date of randomization up to EOS date’ include all relapses unless starting 
prior to randomization. Additional flags will be added for relapses from date of 
randomization up to EOT + 7 days (relapse start date in respective period), relapses after 
EOT + 7 days (start date from EOT + 8 days). 
Note: Relapses with missing start date are considered to have started on randomization 
date for analysis. Relapses with partial start date are considered to have started at the 
lower limit (but earliest on randomization date).


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5.4.1.2
Variables for supplementary analyses of primary endpoint
According to the protocol, several supportive/sensitivity analyses are planned for the 
primary efficacy endpoint, including the ARR analysis from randomization up to 
EOT + 7 days, with EOT date defined as date of last drug intake [see Section 11.1]. 
Those and other additional variables are defined below. Analyses that do not require 
additional variable derivations will not be mentioned in this section but will be described 
in the ‘Statistical Analysis’ section, e.g., the ARR up to EOS analysis with treatment as 
the only covariate uses the same variable as the primary efficacy analysis. 
5.4.1.2.1
ARR up to EOT+7 days for confirmed relapses
The variable considers confirmed relapses up to EOT + 7:

The subject’s number of confirmed relapses from date of randomization up to date of 
EOT + 7 days;

Length of observation up to EOT + 7 expressed in years, defined as: [Min (EOT date 
+ 7 days, EOS date) date of randomization 1] in days, divided by 365.25.
5.4.1.2.2
ARR up to EOS for all relapses
The variable considers all relapses (confirmed and unconfirmed) up to EOS:

The subject’s number of all relapses from date of randomization up to date of EOS;

Length of observation expressed in years, defined as: [EOS date −date of 
randomization 1] in days, divided by 365.25.
5.4.1.2.3
ARR up to EOT+7 days for all relapses
The variable considers all relapses up to EOT + 7:

The subject’s number of all relapses from date of randomization up to date of
EOT + 7 days

Length of observation up to EOT + 7 days, see above. 
5.4.1.2.4
ARR up to EOS or per protocol exclusion for confirmed relapses
ARR up to EOS for the per protocol analysis is derived in the same way as the variable 
for the main analysis but including only confirmed relapses prior to first occurrence of a 
deviation leading to exclusion from per protocol [see Section 7.1.3]. The considered 
observation time is derived as for the main analysis but replacing EOS date with the per 
protocol exclusion date, if available. 
Similar variables are derived for ARR up to EOT + 7 days for the per protocol analysis.
5.4.1.2.5
ARR up to the start of alternative DMTs for MS
This variable considers confirmed relapses up to the point where an alternative disease 
modifying treatments (DMT) for MS is started as follows:


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
The subject’s number of confirmed relapses from date of randomization up to the day 
before the start of new DMT for MS or up to EOS date for subjects not starting a new 
DMT;

Length of observation expressed in years, defined as: [Min (Day before start date of 
new DMT for MS, date of EOS) −date of randomization 1] in days, divided by 
365.25.
Start of alternative DMTs for MS is defined in Section 5.2.5.4 and based on study 
concomitant MS specific therapies. Variables will be derived separately for confirmed 
and all relapses.
5.4.1.2.6
ARR up to EOS for imputed confirmed relapses
Defined in the same way as number of confirmed relapses for the primary analysis unless 
the confirmation status is missing (e.g., due to the EDSS not being completed). Relapses 
with missing confirmation status are imputed as confirmed relapses. The length of 
observation is defined as for the primary analysis. 
5.4.1.2.7
ARR post EOT + 7 days following premature treatment discontinuation
Defined for subjects prematurely discontinuing treatment with EOS date after 
EOT + 7 days:

The subject’s number of confirmed relapses from EOT + 8 days to EOS;

Length of observation expressed in years, defined as: [(EOS date −EOT date 
+ 8) + 1] in days, divided by 365.25.
5.4.1.2.8
ARR by period
ARR is derived per period. Variables are defined separately for confirmed relapses and 
for all relapses. The following periods are considered:
ARR up to Week 60
Derived in the same way as for the ARR up to EOS but including only confirmed/all 
relapses with onset date from randomization date up to Day 420. Observation time is the 
time from randomization until earliest of Day 420 or EOS. 
ARR after Week 60
Derived in the same way as for the ARR up to EOS but excluding confirmed/all relapses 
with onset date prior to or on Day 420. 
ARR by 12-week periods
Similarly, ARR for approximately 3-month intervals are defined: Baseline to Week 12 
(Day 1–84), Week 13 to Week 24 (Day 85–168), Week 25 to Week 36 (Day 169–252), 
Week 37 to Week 48 (Day 253–336), Week 49 to Week 60 (Day 337–420), Week 61 to 


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Week 72 (Day 421–504), Week 73 to Week 84 (Day 505–588), Week 85 to Week 96 
(Day 589–672), after Week 96 (≥ Day 673).
Note: Relapses with missing start date are considered to have started on randomization 
date for period assignation. Relapses with partial start date are considered to have started 
at the lower limit (but earliest on randomization date).
5.4.1.2.9
Number of new or worsening neurological symptoms up to EOS
The variable is defined as the number of new or worsening neurological symptoms 
reported on the relapse assessment questionnaire (‘Is/was the subject having new 
neurological symptom(s) or an acute worsening of pre-existing neurological 
symptom(s)?’ answered with ‘Yes’) from randomization up to EOS. 
Each new or worsening neurological symptom is further sub-classified into the following 
categories: confirmed relapse, unconfirmed relapse, and symptoms not considered a 
relapse. 
Derivation details
Information is taken from the relapse assessment questionnaire eCRF pages (‘Phone 
interview’, or ‘Relapse Assessment Questionnaire’
either ‘Visit Interview’
or 
‘Unscheduled Visit Interview’), which have been introduced with protocol version 4.
A new or worsening neurological symptom is linked to a relapse via the onset date (‘Date 
of start of symptoms’ corresponding to the new or worsening neurological symptom is 
identical to the relapse onset date of a relapse reported on the Relapse Summary eCRF). 
If a symptom cannot be linked to a relapse it is classified as ‘Symptoms not considered a 
relapse’. Symptoms linked to a relapse are further categorized into confirmed and 
unconfirmed relapses, as per Section 5.4.1.1.
Note that for subjects randomized under protocol versions 1–3 neurological symptoms 
are only expected to be recorded from the start date of protocol version 4 onwards.  
5.4.1.2.10 Variables for further analyses related to relapses
Duration of relapse (days) is derived as relapse end date −relapse start date + 1 days. 
Relapse symptoms linked to a relapse. The following categories of symptoms are 
considered: Visual (optic) functions, Brainstem functions, Pyramidal functions, 
Cerebellar functions, Sensory functions, Bowel and Bladder functions, Cerebral 
functions, Ambulation, Other relapse symptom taken from the relapse symptoms eCRF. 
The number of functional systems affected (number of categories, see above) per 
relapse is derived. 


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5.4.2
Secondary efficacy variables
5.4.2.1
Change from baseline to Week 108 in fatigue-related symptoms as measured by 
the FSIQ–RMS symptoms score
The Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-
RMS) is a validated patient reported outcome instrument from which a fatigue symptoms 
score and sub-domain impact scores can be obtained, where higher scores indicate greater 
fatigue or impact [Protocol appendix 9]. The questionnaire consists of 2 parts: section 1 is 
a daily diary and is answered during 7 consecutive days. Section 2 is a weekly diary and 
is answered on the 7th day of the 7 consecutive days where the daily diaries were filled in. 
The questionnaire is completed using an electronic device that automatically tracks the 
completion date. Data are transferred electronically to the sponsor.  
FSIQ-RMS is completed during the pre-randomization period (i.e., at Visit 2: 7 
consecutive days preceding the randomization [Baseline visit]), and during the post-
randomization period, i.e., at scheduled Visits 6, 7, 10, and 12 (Weeks 12, 24, 60, 84, 
respectively), 14 (Week 108), as well at premature EOT visit and at unscheduled visits 
(due to relapses or other unscheduled visits). If applicable, it is also completed at the 
corresponding visits in the PTOP. For more details refer to Table 2–Table 4.
FSIQ-RMS symptoms domain (FSIQ-RMS-S) consists of 7-items assessing fatigue 
related symptoms collected as a daily diary (section 1) on an 11-point numeric rating 
scale (0–10) with a 24-hour recall period.
The FSIQ-RMS-S score may be computed as a daily or weekly 0 to 100 score (higher
score implies greater fatigue). To be able to compute a daily symptoms score, at least 4 
items of the symptoms diary must be non-missing; otherwise the score is considered 
“missing”. For each 7-day weekly score, at least 4 reported diaries with at least 4 items 
completed on each diary day are needed to calculate the FSIQ-RMS-S weekly score. If 
fewer than 4 diaries with data on at least 4 items are available within the 7-day period, 
then the weekly score is considered as “missing”. Details of the scoring rules to calculate 
FSIQ-RMS-S daily and weekly scores as well as rules to define baseline and post 
baseline FSIQ-RMS-S weekly scores are given in the Appendix C.2.
Change from baseline in FSIQ-RMS symptoms score is defined as the absolute change 
from baseline to each time point. 
5.4.2.1.1
Variables for supplementary analysis
For supplementary analyses change from baseline for the following weekly scores will be 
considered in addition separately:

Up to EOT + 7 days

Per protocol - for subjects in the PPS data up to the first protocol deviation leading to 
exclusion from the per protocol analysis


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
LOCF by visit weekly scores by visit based on last observation carried forward 
(LOCF) will be derived. Baseline data will not be carried forward. 
5.4.2.2
Cumulative number of combined unique active lesions (CUAL) from baseline 
to Week 108
CUAL from baseline to Week 108 is calculated as the sum of new T1 Gadolinium-
enhanced (Gd+) lesions and new or enlarging T2 lesions without Gd enhancement on T1 
at all post-baseline MRI visits up to the Week 108 MRI visit (if the Week 108 visit is 
missing, consider all post-baseline scans up to EOS).  
MRI scans are scheduled at Baseline, at the Week 60 Visit, and the Week 108 Visit. For 
subjects who prematurely discontinue treatment, an additional premature EOT visit MRI 
is scheduled. Unscheduled MRI scans may be conducted in addition. 
MRI data are read centrally and provided to the sponsor.
To account for varying observation time, e.g. in case of premature study withdrawal or 
missing MRI assessments, the analysis will be adjusted by: Time up to the last MRI 
(years) = (Date of last MRI considered in derivation of CUAL −Randomization date + 1)
/ 365.25 days. 
Rationale: Due to the fact that yearly MRI scans are scheduled, the CUAL count is 
expected to be mainly driven by new T2 lesions. The number of T2 lesions is expected to 
increase with observation time. In contrast, in studies where MRI scans are scheduled 
more regularly, the CUAL count is mainly driven by new T1 Gd+ lesions which are 
expected to increase with the ‘Number of MRI scans’ conducted. Also, in this study, 
there is an additional MRI following premature treatment discontinuation which can 
occur at any time, therefore the ‘number of MRI scans’ is not necessarily expected to be a 
good approximation of the observation time. 
5.4.2.2.1
Derivations details
The central reader provides the ‘Number of new T1 Gd+ enhancing lesions’ (variable 
T1GdNew_R) and ‘Number of new T2 lesions without Gd enhancement’ (variable 
T2New_R) at a visit as compared to the last scheduled MRI scan (with premature EOT 
visit being considered a scheduled MRI). At the first scheduled post-baseline visit 
comparison is made to baseline (with baseline defined as the Baseline Visit 2, or Visit 2 -
2nd attempt if available [see Section 5.4.3] for details and a rationale). 
CUAL from baseline to Week 108 is derived as the sum of ‘Number of new T1 Gd+ 
enhancing lesions’ and ‘Number of new T2 lesions without Gd enhancement on T1’
across all post-baseline MRI visits up to the Week 108 MRI visit (if missing up to EOS) 
irrespectively if a visit is conducted during PTOP or not.
For subjects without unscheduled MRI visits this includes MRIs from the Week 60 Visit, 
Week 108 Visit, and if applicable premature EOT visit.


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As only the number of new lesions as compared to the last scheduled visit is recorded by 
the central reader, lesions are not expected to be double counted when summing over 
scheduled visits. 
In the rare event that the Baseline MRI visit is conducted after randomization date, the 
variable is derived in the same way, i.e., based on the nominal visit. Note that effectively 
the derived variable then covers a period starting slightly after randomization. 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.
For subjects with at least one unscheduled post-baseline MRI scan, care needs to be taken 
in the derivation to avoid double counting of lesions and the following algorithm applies:
–
If a subject has an unscheduled MRI which is the last available MRI in the time 
period considered (i.e., if Week 108 MRI visit is missing, last MRI result up to EOS): 
Include that last unscheduled MRI when deriving CUAL in the same way as for 
scheduled visits.  
–
If a subject has an unscheduled MRI which is not the last available MRI for the 
subject: Do not include that unscheduled MRI. Rationale: New / enlarging lesions at 
the unscheduled MRI as well as at the later scheduled MRI are reported in reference 
to the previous scheduled visit. Including both may result in double counting. 
5.4.2.2.2
Variables for supplementary Analysis
CUAL up to EOT + 7 days
Defined as the cumulative number of combined unique active lesions from baseline to 
EOT + 7 days. Includes only MRI scans conducted after randomization and prior to 
EOT + 7 days (last drug intake + 7 days). All other derivations follow the same approach 
as for CUAL from baseline to Week 108, in Section 5.4.2.2. Note that unscheduled MRI 
assessments previously not included may now be included in the derivation, if they 
become the last MRI assessment in the newly considered period. The time up to the last 
MRI scan used in the derivation is calculated. 
Subjects completing treatment with complete MRI information will be flagged 
(completing treatment, with baseline MRI scan available, and all post-baseline scheduled 
MRI scan results [Week 60 and Week 108] available and conducted up to EOT + 7 days). 
This will allow for a complete-case analysis, if needed.  
CUAL up to EOS or per protocol exclusion
Defined for subjects in the PPS as the cumulative number of combined unique active 
lesions from baseline to first deviation leading to exclusion from the per protocol 
analysis. Includes only MRI scans conducted after randomization and prior to per 
protocol exclusion date. All other derivations follow the same approach as for CUAL 


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from baseline to Week 108, in Section 5.4.2.2. The time up to the last MRI scan used in 
the derivation is calculated. 
5.4.2.3
Time to 12-week Confirmed Disability Accumulation (CDA) up to EOS
5.4.2.3.1
Main analysis of secondary endpoint
Time to first 12-week CDA is defined as the time from start date of the first onset of 12-
week CDA minus date of randomization + 1 in days. Subjects without 12-week CDA are 
censored, following the rules below. It is assessed from baseline up to EOS.
Assessing disability by EDSS
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 patients may be conducted between scheduled visits (i.e.,
during an MS relapse). The EDSS is a disability scale that ranges from 0 (normal) to 10.0 
(death) in 0.5-point steps (1-point step from 0 to 1). It is based on standard neurological 
examination in conjunction with observations concerning ambulation. For analysis the 
overall EDSS score as reported by the investigator from the eCRF is considered (Field: 
‘Expanded disability status scale’).
EDSS increase criteria for disability accumulation
The following criteria for an increase in EDSS in derivation of disability accumulation 
apply:

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;
where baseline EDSS is defined as the last available EDSS score prior to or on the date of 
randomization.
12-week CDA
A 12-week CDA is an increase in EDSS as compared to baseline according to the criteria 
above which is confirmed at a scheduled visit after 12 weeks. The increase needs to be 
persistent at all EDSS assessments (scheduled or unscheduled) between onset (first EDSS 
increase in the considered period) and confirmation. 12-week CDA is assessed 
sequentially up to the last available EDSS assessment for a subject in the study following 
the algorithm detailed below.
Disability progression can only be confirmed at a scheduled visit, where the EOT (Visit 
Week 108 or premature EOT visit), and FU visits count as scheduled visits, outside of an 
ongoing relapse. In this context, relapse duration is defined as period between start date 
(inclusive) and end date (exclusive) if available and limited to 90 days from onset if end 
date is not available or duration is longer than 90 days.


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Algorithm for deriving 12-week CDA
1. For all post-baseline EDSS assessments (scheduled or unscheduled) assess if the 
absolute change from baseline meets the EDSS increase criteria for disability 
accumulation, described above. Start with the first EDSS assessment that meets the 
criteria for EDSS increase. Onset date of the corresponding potential 12-week CDA is 
the EDSS assessment date.
2. Confirmation of EDSS increase: 
a.
An EDSS increase of a potential 12-week CDA has to be confirmed by an EDSS 
increase at a scheduled visit, at least 70 days*, from the onset date of the potential 
12-week CDA.
* Note: As visits are scheduled every 12 weeks with a time window of ± 7 days 
for conducting the EDSS assessment, the minimum per-protocol allowed time 
difference between two EDSS assessments scheduled 12 weeks apart is 70 days 
(12 weeks = 84 days minus a 7-day visit time window for each of the 2 visits, i.e.,
84 days −14 days = 70 days). 
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. 
If an EDSS increase cannot be confirmed due to no available EDSS assessment, 
but the subjects dies due to MS (experiences a relapse with outcome death, or 
death with reason ‘Multiple sclerosis’) the CDA is also considered confirmed, 
with confirmation date being the death date and onset date the initial EDSS 
increase. 
b. A confirmed EDSS increase as per (a) is considered persistent if every EDSS 
score available (scheduled or unscheduled) between the onset and the 
confirmation date of a potential 12-week CDA meets the EDSS increase criteria. 
The initial EDSS increase is considered a 12-week CDA. 
If any EDSS from onset to confirmation does not meet the EDSS increase criteria, 
the increase is not persistent and the initial EDSS increase is not considered a 
12-week CDA.
3. Repeat step 2 for all EDSS assessments with an EDSS increase as per the criteria 
above for disability accumulation, starting with the first possible onset, by date, up to 
the last possible onset. Once a 12-week CDA is identified the algorithm can stop. 
4. If at none of the assessments a 12-week CDA is identified, but the subject dies due to 
MS (experiences a relapse with outcome death) the subject is considered to have a 
12-week CDA with onset date being the death date. 


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5. If no 12-week CDA is identified, the subject is considered censored with the 
censoring date derived according to the rules below.
Censoring
Censoring date is defined as: Date of last EDSS assessment without an EDSS increase. 
Time to censoring is defined as censoring date minus date of randomization 1.
Subjects without post-baseline assessment are censored on randomization date. Similar, 
subjects without CDA who have only EDSS assessments with an EDSS increase that 
cannot be confirmed, are censored on randomization date. For subjects without baseline 
EDSS score, missing values are assigned.
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
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.
5.4.2.3.2
Variables for supplementary analyses
5.4.2.3.2.1 Time to 12-week CDA up to EOS or per protocol exclusion
Time to 12-week CDA for the per protocol analysis is derived in the same way as for the 
variable for the main analysis, but only based on EDDS assessments (for onset and 
confirmation) conducted prior to first occurrence of a deviation leading to exclusion from 
per protocol [see Section 7.1.3]. Also, deaths due to MS are only considered up to that 
date. Subjects not experiencing a 12-week CDA event based on their per protocol data 
are censored at the last EDSS prior to per protocol exclusion without possible onset as for 
the main analysis. 
5.4.2.3.2.2 Time to 12-week CDA up to EOT + 7
The variable for the main analysis described above will be repeated for 12-week CDAs
up to EOT + 7 days. The onset date of the 12-week CDA must be up to EOT + 7 days; 
the confirmation of the 12-week CDA can be on-treatment or based on post-treatment 


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data. Otherwise the same rules as described in Section 5.4.2.3.1 apply. Subjects that are 
considered not to have 12-week on-treatment CDA are censored on the last EDSS 
assessment up to EOT + 7 days, following the same rules as described in the previous 
section.
5.4.2.3.2.3 Time to potential 12-week CDA up to EOS
12-week CDA requires confirmation of an EDSS increase by a scheduled EDSS 
assessment 12 weeks after progression onset. A potential onset at the end of the study 
may not be confirmed due to end of follow-up within the study. For time to potential 12-
week CDA up to EOS all subjects censored in the main analysis with an EDSS increase
at the last EDSS assessment in the study are considered as having a potential 12-week 
CDA, although the confirmation is missing. The onset date of the event for these subjects 
is the first EDSS increase after the last EDSS assessment without increase. Otherwise the 
same approach for derivation as described in Section 5.4.2.3.1 is followed.
5.4.2.3.2.4 Time to potential 12-week CDA up to EOS or per protocol exclusion
The time to potential 12-week CDA analysis is repeated for time to 12-week CDA up to 
EOS or per protocol exclusion. 
5.4.2.3.2.5 Time to 12-week CDA up to EOS – alternative censoring 
12-week CDA events and corresponding time to event are derived as above for the main 
analysis [see Section 5.4.2.3.1]. 
Subjects without 12-week CDA event are censored at their last scheduled EDSS 
assessment −12 weeks (84 days). 
This alternative censoring algorithm is applied (a) to ensure independence of censoring 
from the EDSS outcome and consequently avoid informative censoring and (b) to reflect 
that onset of 12-week CDA events can only occur 12 weeks prior to the last scheduled 
assessment. 
5.4.2.4
Time to 24-week CDA
5.4.2.4.1
Main analysis of secondary endpoint
The derivation of the variables for Time to 24-week CDA up to EOS follows the same 
approach as described in Section 5.4.2.3.1, but onset of progression is to be confirmed 
after 24 weeks (≥154 days, i.e., 168 days −two times 7-day visit time window) instead 
of after 12 weeks. The progression has to be persistent between onset and confirmation.
5.4.2.4.2
Variables for supplementary analyses
5.4.2.4.2.1 Time to 24-week CDA up to EOS or per protocol exclusion 
Time to 24-week CDA for the per protocol analysis is derived in the same way as for the 
variable for the main analysis, but only based on EDDS assessments conducted prior to 
first occurrence of a deviation leading to exclusion from per protocol [see Section 7.1.3]. 


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Also, deaths due to MS are only considered up to that date. Subjects not experiencing an 
event based on their per protocol data are censored at the last EDSS prior to per protocol 
exclusion without an EDSS increase as for the main analysis. 
5.4.2.4.2.2 Time to 24-week CDA up to EOT + 7
The variable for the main analysis described above will be repeated for 24-week CDAs
up to EOT + 7. The onset date of the 24-week CDA must be up to EOT + 7 days; the 
confirmation of the 24-week CDA can be on-treatment or based on post-treatment data. 
Otherwise exactly the same rules as described in Section 5.4.2.3.1 apply. Subjects that are 
considered not to have 24-week CDA up to EOT + 7 are censored on the last EDSS 
assessment without an EDSS increase up to EOT + 7 days, following the same rules as 
described in the previous section.
5.4.2.4.2.3 Time to potential 24-week CDA
24-week CDA requires confirmation of an EDSS increase by a scheduled EDSS 
assessment 24 weeks after progression onset. A potential onset at the end of the study 
may not be confirmed due to end of follow-up within the study. For time to potential 24-
week CDA up to EOS all subjects censored in the main analysis with an EDSS increase 
at the last EDSS assessment in the study are considered as having a potential 24-week 
CDA, although the confirmation is missing. The onset date of the event for these subjects 
is the first EDSS increase after the last EDSS assessment without increase. Otherwise the 
same approach for derivation as described in Section 5.4.2.3.1 is followed.
5.4.2.4.2.4 Time to potential 24-week CDA up to EOS or per protocol exclusion 
The time to potential 24-week CDA analysis is repeated for time to 24-week CDA up to
EOS or per protocol exclusion.
5.4.2.4.2.5 Time to 24-week CDA up to EOS – alternative censoring 
24-week CDA events and corresponding time to event are derived as above for the main 
analysis [see Section 5.4.2.3.1]. 
Subjects without 24-week CDA event are censored at their last scheduled EDSS 
assessment −24 weeks (168 days). 
This alternative censoring algorithm is applied (a) to ensure independence of censoring 
from the EDSS outcome and consequently avoid informative censoring and (b) to reflect 
that onset of 24-week CDA events can only occur 24 weeks prior to the last scheduled 
assessment. 
5.4.3
Exploratory MRI efficacy variables
MRI data are provided from a central reader.


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Baseline
The central reader defines the result from ‘Visit 2 - Baseline’ as baseline (or ‘Visit 2a -
Baseline 2nd attempt’ if available) and uses that Baseline visit as a reference in 
derivations of various variables (e.g. new or enlarging T2 lesions). 
For analysis, baseline for MRI variables is defined in the same way, i.e., Visit 2 unless 
Visit 2a is available. In the unexpected case a Visit 2 scan is conducted after 
randomization, it is still considered as baseline. 
MRI at 
 or at
visit windowing
MRI variables at 
 or 
 are based on the result from the corresponding 
nominal visit (or from a re-mapped premature EOT visit [see Section 11.3]). In case of 
missing results, MRI results from an unscheduled visit can be re-mapped to a scheduled 
visit if conducted during the time window specified in Section 11.3. Care needs to be 
taken however in derivation of cumulative variables where occasionally unscheduled 
MRIs are not included, as per the respective derivation details.   
Handling of missing MRI results at 
 at 
If MRI at 
 or 
 is missing, a last observation carried forward (LOCF) 
approach is implemented. The last MRI scan up to the visit window upper limit as 
specified in Section 11.3 is considered. Baseline information is not carried forward.
5.4.3.1
Number of 
 at 
 and 
The 
 per visit is derived as the sum of 
 
 
 
at that visit. 
Handling of missing MRI results at 
 or 
 follows the general rules for 
MRI data described in Section 5.4.3 above. 
 LOCF and 
 LOCF 
variables are also derived.
The 
 to 
is derived 
as the sum of 
 
 This includes
 scans if 
available. It may include 
if it is the 
, following 
selection of 
 To account 
for a potentially varying number of scans contributing to the variable, the analysis will be 
adjusted by the ‘Number of MRI scans’ included in the derivation. Similarly, the 
 to 
 is derived. 
The 
 
 All other derivations follow the same approach as 


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above for lesions up to 
 To account for a potentially varying number of scans 
contributing to the variable, the analysis will be adjusted by the ‘Number of 
 
is derived.
Note: The number of 
 
 
At baseline 
 are not available, thus no 
corresponding record is expected. 
Note: 
 are assumed to not enhance for more than 12 weeks. This requires 
handling of data as follows:

If at a visit, number of 
 are not recorded, the number of 
 Rationale: As per 
 
 
 
t 
 and 
 

If at a 
 
 is recorded, these 
 are considered 
implausible and therefore not to be considered in derivations of 
.
5.4.3.2
Cumulative number of 
 
 
Cumulative number of 
 
is
calculated as the sum of 
 
 
 
 as compared to the previous scheduled visit are recorded by 
the 
 in two distinct categories: 
 
 and 
 
at a visit as compared to the 
previous scheduled visit. The sum of both is the 
’
at that visit compared to the previous scheduled visit. For subjects with missing baseline 
MRI, the number of 
 from baseline cannot be assessed and 
the endpoint is considered missing.
The cumulative number of 
 is
derived as the sum of the ‘
’ at all scheduled 
post-baseline MRI visits:
 
and premature EOT visit if applicable
(irrespectively if a visit is conducted during PTOP or not), for subjects with only 
scheduled post-baseline MRI scans. 
For subjects with at least one unscheduled post-baseline MRI scan, care needs to be taken 
in the derivation to avoid double counting of 
 and the following algorithm applies:


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–
If a subject has an unscheduled MRI which is the last available MRI in the time 
period considered: Include that last unscheduled MRI when summing over ‘number 
of new or 
’ in the same way as the scheduled visits.
–
If a subject has an unscheduled MRI which is not the last available MRI for the 
subject in the time period considered: Do not include that unscheduled MRI. 
Rationale: New / 
 at the unscheduled MRI as well as at the later 
scheduled MRI are reported in reference to the previous scheduled visit. Including 
both would result in double counting. 
To account for varying observation time the analysis will be adjusted by: Time up to the 
last MRI (years) = Date of last MRI considered in derivation −Randomization date + 1
divided by 365.25 days. 
Rationale: The number of 
 is expected to increase with observation time, not 
solely by the ‘
’. Therefore, adjustment by observation time is 
conducted. As in this study an additional MRI following premature treatment 
discontinuation is scheduled, the ‘number of MRI scans’ is not necessarily expected to be 
a good approximation of the observation time.
Similarly, the cumulative number of 
 
 
 is derived. All post-baseline MRI visits up to the 
 visit (or if missing 
) are considered. 
Cumulative number of 
Cumulative number of 
 on treatment is derived in the same 
way as above but only considering MRI scans recorded between study treatment start and 
. The time up to last MRI scans included in the derivation of the variable is 
calculated and used for adjustment in the analysis.
5.4.3.3
Cumulative number of 
 
Derived in the same way as for 
 
[see Section 5.4.2.2], 
but only including MRI scans up to the 
 
 (if missing, up to 
  
Note that if an unscheduled MRI becomes the last available MRI in the considered time 
period it is to be included in deriving the sum of lesions.
5.4.3.4
Percent Change of 
 
 
Percent change of 
 
 is not manually derived, but
taken directly from the 
 at the corresponding 
scheduled 
 visit (irrespectively if during PTOP or not). Percent change from 
baseline to 
 is defined in a similar way. 


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Handling of missing MRI results follows the general rules for MRI data described in 
Section 5.4.3 above, with 
 and 
 LOCF variables also derived. 
Variables for supplementary analysis
For analysis using a repeated measurements model all post-baseline MRI scans will be 
included (
 
 
) with time (days from 
randomization to each MRI scan) as continuous covariate. Percent change of 
 
 from baseline will be taken from the corresponding central reader variable, and 
the time up to each MRI scan (in days) from randomization is derived as Date of MRI 
scan −Date of randomization + 1.
5.4.3.5
Change from baseline in the 
 
 and to 
 
 is recorded by the central reader at each visit (
 
).
Change from baseline in the 
 at a visit is calculated as the value at a 
post-baseline visit minus the value at Baseline visit. It is derived for 
 and 
 
from the corresponding visit (irrespectively if conducted during PTOP or not). 
Handling of missing MRI results follows the general rules for MRI data described in 
Section 5.4.3 above, with 
 LOCF and 
 LOCF variables also derived. 
5.4.3.6
Change from baseline in the 
to 
 
 and 
 
 
Handling of missing MRI results follows the general rules for MRI data described in 
Section 5.4.3 above, with 
 
 and 
 
 variables also derived. 
5.4.3.7
Absence of 
 
 and 
 
 at 
 and 
are considered ‘absent’, if the number of 
 at 
 and at 
 is zero. If > 0 they are considered ‘present’. 
See Section 5.4.3.1 for derivation of ‘
 at 
and 
 at 
If no MRI result at the visit is available, the 
information is considered missing.
Similarly, ‘
 to 
(including all 
unscheduled scans)’ (required for derivation of 
 in Sections 5.4.4.4– 5.4.4.5) is 
defined ‘absent’ if the ‘number of new Gd+ T1 lesions’ at all post-baseline 
 up 
to the 
 MRI visit (if missing, up to 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 is derived. If no MRI result at the visit 


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is available (based on visit window), the information is considered missing (for lesion 
free subjects).  
5.4.3.8
Absence of 
 at 
 and 
 
 
 as compared to baseline are considered 
‘absent’, if the number of 
 
 is zero at all scheduled and 
unscheduled visits up to 
 If it is > 0 at any visit it is considered ‘present’. 
 at 
 as compared to baseline are considered ‘absent’, 
if the number of 
 is zero at all scheduled and unscheduled 
visit up to 
 (or if the 
 visit is missing but the subject has absence of 
lesions up to 
 If it is > 0 at any visit up to 
 (or if the 
 visit is 
missing up to 
 it is considered ‘present’. 
If no MRI result at the respective visit is available (based on visit window) or no baseline 
MRI is available, the information is considered missing (for lesion free subjects). 
5.4.3.9
Proportion of 
 
 
 
Only defined for subjects with 
 present at baseline. 
It is the proportion (%) of 
 
 
Results from the 
 visit are considered 
irrespectively if conducted during PTOP or not. In addition, it is derived at the 
 
visit. Number of 
 by visit (at 
 
and at 
is considered as separate variable.
The number of 
) by visit is taken from the 
central reader (variable 
. For 
’
[see Section 5.4.3.1].
Handling of missing MRI results follows the general rules for MRI data described in 
Section 5.4.3 above. In addition, a variable with LOCF imputation at 
 and 
 
 is derived. For subjects with missing results (either at baseline or post-baseline), the 
proportion is considered missing.
5.4.4
Other clinical efficacy variables
5.4.4.1
Time to 
The time to first confirmed relapse (in days) is defined as [Date of 
 
−Date of randomization + 1] in days.
Subjects without any 
 will be censored at the EOS date, and the time is 
defined as [Date of EOS −Date of randomization + 1] in days.


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Derivation of 
 from randomization up to EOS is detailed in 
Section 5.4.1. Among these 
, the earliest 
 start date is the ‘Date 
of 
. For analysis the variable is displayed in weeks: variables in 
days divided by 7. 
5.4.4.2
Absence of 
 to
 and 
(
For the derivation of this variable 
and their corresponding onset dates,
as defined in Section 5.4.1, are considered. 
Absence of 
 to 
 outcomes are derived as:
‘Yes’ at 
Subjects are considered not 
 at 
 if any confirmed 
 starting between randomization date and 
 is recorded. 
‘No’ at 
Subjects are considered 
 at 
 if no 
 
 starting between randomization date and 
is recorded, and they were still 
on study on 
 (EOS date on or after 
). 
‘Missing’ at 
 Subjects without 
, but no longer on study on 
Day 420, are considered missing.
Absence of 
 from baseline to EOS (
is derived in the same 
way as above but replacing 
 with EOS day. Relapse free subjects with premature 
study withdrawal prior to 
 (
 will be considered to have ‘Missing’
outcome. 
5.4.4.3
Change in 
 to 
Absolute changes 
 by visit are derived, based on the overall 
 as reported by the investigator in the eCRF [see Section 5.4.2.3.1]. For 
subjects prematurely discontinuing treatment, results collected during PTOP are 
considered at the corresponding nominal visit in the same way as for subjects completing 
treatment at 
 as planned (e.g. by visit analysis at 
 considers both 
‘
and ‘PTOP 
visits). Baseline 
 is defined as in Section 5.4.2.3.1.    
On-treatment 
 will be flagged, i.e.,
 
 performed after 
study treatment start (date/time) and prior to EOT + 7 days. 
5.4.4.4
 
. If at 
least one of the criteria is not fulfilled or the subject discontinues treatment prematurely, 
the subject is not considered to have achieved 


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Derivation details
A subject is considered as having 
 activity if at least one of the 
following applies:

 derived as 
detailed in Section 5.4.1.  

 
 
present [see Section 5.4.3.7]. 

 
o 
 present [see Section 5.4.3.8]. 

; see Section 5.4.2.3.1 for event derivation and event 
date.
Subjects that discontinue treatment prematurely are considered as showing 
 
, irrespective of what the reason for treatment discontinuation is.   
Subjects 
 as defined above, who have missing 
outcome for any component (absence of 
 (
 
 
 a
 
) are considered to have missing outcome for 
   
 to 
Derived in same way as above but replacing always EOS (or 
 with 
 
Subjects that discontinue treatment prematurely but after 
 (
) are 
considered to have achieved 
 at 
 unless any other condition is met. 
Subjects 
 with missing outcome for any component at 
 are considered missing.  
5.4.4.5
No 
is defined by the 
 
 
 If at least one of the 
criteria is not fulfilled or the subject discontinues treatment prematurely, the subject is not 
considered to have achieved 
Derivation is as for 
, but in addition a subject is considered as having 
 
if the following applies:

 
[see Section 5.4.3.4].  
 
Derived in same way as above but replacing always EOS (or 
 with 
Subjects who discontinue treatment prematurely but after 
 
 are 


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considered to have achieved 
-
at 
 unless any other condition is met. 
Threshold for percent change of brain volume at 
 is ≤−0.4%.
5.4.4.6
Change in 
 
 
The 
 
 
 
 
 
 will be assessed at pre-randomization 
 
) and at 
 
 
 and at unscheduled visits due to 
 
or other unscheduled visits (
etc.) and if applicable, at the corresponding visits in 
the PTOP. The outcome is recorded in the eCRF.
For each assessment, the 
 score will be calculated as the mean of the Z-scores of 
the 
Details for generating the 
 Z-score and how to handle missing data are given in 
Appendix C.1.
For analysis, baseline and nominal post-baseline visits are considered. See Section 11.3
for remapping of premature end of treatment or unscheduled visits (includes unscheduled 
visits due to relapse). 
Baseline is defined as the last available 
 score prior to or on randomization date. 
While this should usually present the subjects 
 the 
 may be used. A flag is added indicating the 
 conducted up to 
the 
inclusive. 
Furthermore, to address premature study discontinuation an additional variable based on 
last observation carried forward (LOCF) is derived. 


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5.4.4.7
Change in the 
 
 
The 
 
 It is administered along with the 
 at pre-randomization (3 tests, 
where the first 2 are considered practice tests) and at 
 
, 
 and if applicable, at the corresponding visits in the 
PTOP and at unscheduled visits (due to 
 or other unscheduled visits) and its 
outcome the 
 score is recorded in the eCRF.
For analysis, baseline and nominal post-baseline visits are considered. See Section 11.3
for remapping of premature end of treatment or unscheduled visits. 
Baseline is defined as the last available 
 score prior to or on randomization date. 
While this should usually present the subjects 
 
A flag is added indicating the
 conducted up to 
the 
. 
Furthermore, in order to address premature study discontinuation an additional variable 
based on last observation carried forward (LOCF) is derived. 
5.4.4.8
 
 
as a binary variable and defined as:

 
 
he threshold has been derived based on a blinded interim analysis anchored on 
the 
5.4.4.9
Change from baseline by visit up to 
 
 
 
The
For each of these 
 (higher 
score implies greater 
) are calculated from the scores of the items in the 


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respective sub-domains. A total score will not be computed for the 
 as 
the research interest, currently, is on the 
. See Appendix C.3 for 
details on the scoring.
It is derived for the following time points: Baseline, 
 
 
 Change from baseline is defined 
as absolute change from baseline. 
5.4.4.10 Change from baseline in 
 
 
 
Th
 
 
 The questionnaire will be administered in an electronic format.
PGI-S of Fatigue is completed during the pre-randomization period at 
 
 
 and at 
unscheduled visits (due to 
 or other unscheduled visits). If applicable, 
 will 
also be performed at the corresponding visits in the PTOP. For analysis, visits are 
assigned based time windowing as detailed in Section 11.3.
Absolute change from baseline is derived with baseline defined as last available score up 
to and including randomization date.
5.4.4.11 Change from baseline in
 
 
 
The 
 
 
 
The questionnaire will be completed on a 
paper form and subsequently transcribed in the eCRF.
will be completed at 
 
 
 and at unscheduled visits (due to 
 or other 
unscheduled visits). If applicable, CGI-C will also be performed at the corresponding 
visits in the PTOP. For analysis, nominal visits are considered. See Section 11.3 for 
remapping of premature end of treatment or unscheduled visits.  
5.5
Safety variables
5.5.1
Definition of treatment-emergency, baseline and change-from-baseline, last 
on treatment, follow-up assessments for safety variables
For all safety data analyses described in this SAP, baseline is considered to be the last 
valid assessment prior to first study drug intake. 


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For each individual safety variable, baseline is defined to be the last valid measurement 
available before the date and time of first dose intake of study treatment, unless otherwise 
specified. 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 (if available) is identical to baseline;
however, missing pre-dose data on Day 1 is not imputed with baseline. 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 (for example 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).
Absolute changes from baseline are 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 baseline is calculated and stored for all continuous 
safety data.
In addition, the following assessments are flagged or derived per parameter:

Last on-treatment assessment: Last assessment prior to or on EOT date +1 day)

Day-15 follow-up, between EOT + 8 days and EOT + 22 days [see Section 11.4]

Day-30 follow-up, between EOT + 23 days and EOT + 37 days [see Section 11.4]

Last follow-up assessment: Last assessment between EOT + 8 and EOT + 37 days
A safety assessment (ECG, vital signs, laboratory) is considered treatment-emergent, if 
the assessment date is on or after the study treatment start date and prior to or on the 
study treatment end date + 15 days (inclusive). If both, the assessment 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. 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 if reported as “2 hours post-dose”
in the eCRF.


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A safety event (AE, SAE, Death) is considered treatment-emergent if the onset date/date 
of occurrence is on or after the study treatment start date and prior to or on the EOT date 
+ 15 days (inclusive). Missing or partially missing onset or occurrence dates are imputed 
as described in Section 12.3. 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.
5.5.2
Adverse events
An adverse event (AE) is any event reported by the investigator on the Adverse Event 
eCRF of the main database or the database of unblinding potential. All AEs are coded 
using MedDRA dictionary (version 21.0).
5.5.2.1
Frequency and prevalence of adverse events
AEs are summarized according to both frequency and prevalence 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
(based on grouping term) are counted only once per subject. 
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 (EOT + 15, EOS) −study treatment start date + 1. 
5.5.2.2
Intensity of adverse events
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.
5.5.2.3
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. 
Adverse events with missing relationship are considered to be related.
5.5.2.4
Fatal adverse events
Fatal adverse events are those with ‘Death’ reported as outcome.
5.5.3
Deaths
Death information (date of death and primary cause) is taken from the Death eCRF. 


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5.5.4
Serious adverse events
An AE is considered serious if the question ‘Serious?’ on the Adverse Event eCRF is 
answered with ‘Yes’. AEs with seriousness criteria missing are considered to be serious 
AEs.
5.5.5
Adverse events leading to discontinuation of study treatment
Adverse events leading to discontinuation of study treatment are those with ‘Action taken 
with study drug’ reported as ‘Permanently discontinued’.
5.5.6
Adverse events leading to temporary interruption of study treatment
Adverse events leading to temporary interruption of study treatment are those with 
‘Action taken with study drug’ reported as ‘Temporarily interrupted’.
5.5.7
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.
5.5.8
Adverse events on Day 1 and Day 1 of re-initiation of study treatment
Treatment-emergent AEs on Day 1 of study treatment are those AEs that start on or after 
study treatment start (on Day 1), by time and date, and before the following calendar 
date. 
Treatment-emergent AEs on Day 1 of re-initiation of study treatment are those AEs that 
start on the date of a study treatment re-initiation. 
Note: AEs in the first dose database with a different onset date than the first study drug 
intake or Day 1 of re-initiation of study treatment are not considered as ‘Day 1’ / ‘Day 1 
of re-initiation of study treatment’ events.
5.5.9
Other significant adverse events
5.5.9.1
Adverse events of special interest 
Adverse events of special interest (AESI) 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 adverse events of special interest, detailed 
definition is given in Appendix A:

Effect on heart rate and rhythm AESI (including hypotension) 

Hypertension AESI

Hepatobiliary disorders / Liver enzyme abnormality AESI

Pulmonary AESI

Macular edema AESI

Infection AESI

Herpetic infection AESI


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
Skin malignancy AESI

Non-skin malignancy AESI

Seizure AESI
5.5.9.2
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 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 adverse event. 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 AE is 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. 
5.5.10 Vital signs and body weight
Blood pressure data are collected in the eCRFs for both the main database and the 
database of unblinding potential. Weight and height are collected in the eCRF of the main 
database only.
5.5.10.1 Blood pressure
Systolic (SBP) and diastolic blood pressure (DBP) are measured twice (i.e., two SBP 
measurements and two DBP measurements) at all assessments (except the hourly post-
dose assessments after first dose on Day 1 and on study drug re-initiation). For all data 
analyses, for derivation of baseline, last on-treatment, Day-15 follow-up, Day-30 follow-
up, last follow-up assessment, and for flagging of high or low values, the average of the 
first and second measurements are considered. The average calculated in the eCRF 
irrespective of position of the subject (supine, standing, sitting) or arm (right, left) is 


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used. If only one measurement is available, this is used for all further derivations and 
summary statistics.
Baseline is flagged and absolute and percent changes from baseline are calculated for 
each post-baseline value, as described in Section 5.5.1. In the same manner, pre-dose 
values are flagged and absolute and percent change from pre-dose are calculated for the 
hourly post-dose assessments after first dose on Day 1 or at re-initiation. 
Assessments meeting the following conditions 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
For all hourly post-dose assessments after first dose on Day 1 or at re-initiation 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
5.5.10.2 Height and Weight
Height (cm) will only be summarized in the baseline characteristics and thus no 
derivations (other than treatment day of assessment) are required. Absolute and percent 


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change from baseline is calculated for each post-baseline weight (kg) value, as described 
in Section 5.5.1.  
5.5.10.3 Body Temperature
Collected at all visits in the Body Temperature eCRF as ‘normal’ or ‘abnormal’. No 
definitions and derivations (other than treatment day of assessment) necessary.
5.5.10.4 Pulse rate
Collected at unscheduled visits in the Pulse Rate eCRF as ‘normal’ or ‘abnormal’. No 
definitions and derivations (other than treatment day of assessment) necessary.
5.5.11 12-Lead Electrocardiogram (ECG)
Only the visit, date and time information of the ECG data is collected on the eCRF for
both the main database and the database of unblinding potential. ECG measurement data 
is collected using vendor machines from ERT. Data is automatically submitted to ERT by 
the machine, centrally read, and transferred from ERT to Actelion. 
5.5.11.1 Quantitative ECG variables
Central reader ECG data contains the following quantitative measurements and derived 
variables: Heart rate (HR) (bpm), PR interval (ms), QRS duration (ms), RR interval (ms), 
QT interval (ms), QTCB (ms) and QTCF (ms). Heart rate is labeled “Mean heart rate” in 
the data transferred, however for consistency with earlier studies and to avoid 
misinterpretation as value coming from Holter monitoring, the label used in the CSR is 
“Heart rate”. Baseline is flagged and absolute and percent changes from baseline are
calculated for each post-baseline value as described in Section 5.5.1. 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 Day 1 or at re-
initiation. 
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/timepoint is 
used in case of multiple data available for a visit or visit/timepoint.  
All assessments meeting the following conditions 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 prolongations of > 500 ms 

QTcF/QTcB prolongations of > 480 ms

QTcF/QTcB prolongations of > 450 ms 

QTcF/QTcB increase from baseline > 30 ms


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
QTcF/QTcB increase from baseline > 60 ms

QTcF/QTcB prolongations of > 500 ms and increase from baseline > 30 ms

QTcF/QTcB prolongations of > 500 ms and increase from baseline > 60 ms

QTcF/QTcB prolongations of > 450 ms and increase from baseline > 30 ms

QTcF/QTcB prolongations of > 450 ms and increase from baseline > 60 ms
In addition, similar notable abnormality flags are derived in relation to the pre-dose 
measurements for the post-dose assessments on Day 1 and start of study drug re-
initiation, and for the 3-hours post-dose measurement at Week 12 visit:

PR interval > 200 ms and increase of > 20 ms compared to pre-dose assessment  

QTcF/QTcB increase from pre-dose assessment of > 30 ms

QTcF/QTcB increase from pre-dose assessment of > 60 ms
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 a
visit or visit/timepoint.  
5.5.11.2 Qualitative ECG variables
Morphological ECG findings are reported by the central reader, and mapped to CDISC 
standard (codelist C71150, with high level categories from codelist C71152) in the 
SDTM. 
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 pre-treatment 
assessment (i.e. at any ECG assessed prior to the study treatment start) or “Pre-existing”
if present at any pre-treatment assessment. In case of missing or non-evaluable pre-


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treatment ECG assessment, it is conservatively assumed that any treatment-emergent 
morphological ECG finding is “New”. 
For presentation of these findings in by-visit and by-hour tables, all reported 
abnormalities are considered in case of multiple assessments available at a visit or 
visit/timepoint.
5.5.12 Laboratory
Safety laboratory samples are centrally analyzed by ACM and the results are 
electronically transferred to Actelion. 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, see protocol). Quantitative results from local laboratories are not summarized (i.e. 
not included in summary statistics or graphical representations). 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 hematology, clinical chemistry and urinalysis comprise the following 
parameters planned as per protocol:
Hematology: Red blood cell count, Total and differential WBC counts 
(basophils, eosinophils, lymphocytes, monocytes, neutrophils, band forms), 
Platelet count, Hemoglobin, Hematocrit.
Liver function tests and coagulation: INR, ALT, AST, AP, total bilirubin.
Clinical chemistry (excl. liver tests): Lactate dehydrogenase, Creatinine, 
creatinine clearance (calculated by the central laboratory using Cockroft-Gault),
Blood Urea Nitrogen, Urate, Glucose, Total cholesterol, Triglycerides, Sodium, 
potassium, chloride, calcium, Total protein, albumin, C-reactive protein
Urinalysis (dipstick provided by central laboratory): pH (5.0, 6.0, 6.5, 7.0, 7.5, 
8.0, 8.5), Glucose (Negative, Trace, +, ++, +++, ++++), Proteins (Negative, 
Trace, +, ++, +++, ++++), Occult Blood (Negative, Trace, +, ++, +++), 
Leukocytes (Negative, Trace, +, ++, +++), Bilirubin (Negative, +, ++, +++), 
Urobilinogen (3.2, 16, 33, 66, ≥131). Also, for each of those parameters it is 
collected whether the result is normal or abnormal, and - if abnormal - whether 
clinically significant (no/yes).
For the above protocol planned parameters for hematology, liver tests, and clinical 
chemistry, the derivations detailed in Section 5.5.12.1 will be performed. 
Derivations (other than treatment day of assessment) are not performed for any other 
laboratory parameters, and only the raw information and treatment day of assessment are


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listed. This includes any laboratory parameters that were not planned to be collected per
the protocol, and the following protocol planned parameters: 
Hepatitis B Virus Surface Antigen, Varicella Zoster Virus IgG Antibody, HIV-1/2 
Antibody, Hepatitis C Virus Antibody, M. tuberculosis IFN Gamma Response, 
pregnancy tests (Choriogonadotropin Beta, serum / urine), Teriflunomide plasma
concentration.
5.5.12.1 Derivations
Numerical results are converted into both conventional and SI units as 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, baseline, last on-treatment, Day-15 follow-up, Day-30 follow-up, 
last follow-up assessment is flagged and absolute change from baseline and percent 
changes from baseline are calculated for each post-baseline value, as described in 
Section 5.5.1.
Flags are derived according to project specific ranges for marked laboratory 
abnormalities as documented in the protocol [see Appendix D]. 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 parameter 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):

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 > 1.5 combined with ALT or AST ≥ 3 ULN (at the same sample date).
5.5.13 Other safety variables
5.5.13.1 Pulmonary function tests - Spirometry
Spirometry measurement data are collected using vendor machines from ERT. Data is 
automatically submitted to ERT by the machine. Prior to database lock and unblinding, 
Spirometry data are not transferred to any member of Actelion biostatistics as these data 


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are considered to carry a moderate risk of potential unblinding. The following parameters
are provided:

Forced Vital Capacity [FEV1] (L), 

Forced Expiratory Volume in 1 Second [FVC] (L), 

FEV1/FVC (%), 

Predicted FEV1 (L), 

Percent Predicted FEV1 [%FEV1] (%), 

Predicted FVC (L), 

Percent Predicted Forced Vital Capacity [%FVC] (%), 

Peak Expiratory Flow (L/s),

Forced Expiratory Flow 25–75% (L/s),

Forced Expiratory Flow 25% (L/s),

Forced Expiratory Flow 50% (L/s),

Forced Expiratory Flow 75% (L/s)
Several efforts per visit per subject may be recorded in the database (usually 8 efforts), 
and potentially even two or more sets of efforts per subject per visit (e.g., 2 × 8 efforts). 
For each set of efforts the best effort at a visit per parameter (e.g., FEV1, FVC) is 
identified by the spirometry over read at ERT (variable XPSPID = “0”). The central 
reader grades the best effort as ‘acceptable’, ‘borderline’, or ‘unacceptable’ (variable 
‘BTR Grade Code’). 
Analyses are based on best efforts. If two or more sets of efforts are available at the same 
visit the following algorithm applies for the selection of the effort at that visit. Only one 
best effort per subject per visit will be selected. FEV1/FVC (%) is rederived from the 
FEV1 best effort and FVC best efforts. The selection of the records is defined as follows:
Step 1: Only select ‘best effort’ records.
Step 2:
a. If at least one ‘acceptable’ or ‘borderline’ rated test is available at a visit, chose the 
highest parameter value amongst all available ‘acceptable’ or ‘borderline’ rated test at 
that visit (per parameter).
b. If no ‘acceptable’ or ‘borderline’ rated test is available, but at least one ‘unacceptable’
rated test is available, chose the highest parameter value amongst all available 
‘unacceptable’ rated tests at that visit (per parameter).
Note: if only one value is present at a visit then this is the highest value and it is selected.
Step 3:
For baseline choose the highest value prior to study treatment start. 


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Note: For deriving baseline apply the algorithm from above on all available records that 
could qualify for baseline (e.g., if two sets of efforts are available on two different days
prior to study treatment start, derive BL as the highest best effort).
Note: To favor selection of re-screening records for re-screened subjects, records 
qualifying for baseline are selected in a two-step approach: (i) Derive baseline based on 
all records collected in a 45-day window prior to study treatment start. If no such record 
is available, then (ii) derive baseline based on all records prior to study treatment start.  
Baseline is flagged and absolute and percent changes from baseline are calculated for 
each post-baseline value, and last on-treatment and follow-up assessments are derived as 
described in Section 5.5.1.  
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 %FEV1: < −20 %, < −30%

Absolute change from baseline in %FVC: < −20 %, < −30%

FEV1/FVC < 70%

Absolute change from baseline in FEV1 ≤ −200 mL or percent change from baseline 
in FEV1 ≤ −12 % 

Absolute change from baseline in FVC ≤ −200 mL or percent change from baseline in 
FVC ≤ −12 % 

Absolute change from baseline in FEV1 > −200 mL and percent change from 
baseline in FEV1 > −12 % 

Absolute change from baseline in FVC > −200 mL and percent change from baseline 
in FVC > −12 % 
In the subset of subjects experiencing a decrease of ≥200 mL or ≥12% in FEV1 (or 
FVC) from baseline to the last assessment on treatment, the condition is considered
Reversible, if no decrease of ≥200 mL and ≥12% in FEV1 (or FVC) from baseline is 
present at the last follow-up assessment. If the last follow-up assessment is not fulfilling 
the above described reversibility criteria, the condition is considered Not reversible. If 
no follow-up assessment is available, reversibility cannot be assessed due to missing data.  
5.5.13.2 Pulmonary function tests - DLCO
DLCO will be assessed in a subset of 333 subjects at selected sites with appropriate and 
established PFT expertise. DLCO test results are reviewed by a centralized independent 
reader. 
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 


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DLCO measurements 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.  
In addition, DLco based on acceptable results only is derived, for sensitivity analyses. A 
maneuver is considered acceptable if ERT’s overall statement is entered as “OK”, i.e.,
only assessments reported as “acceptable DLCO data received” or “borderline acceptable 
DLCO data received” are considered for analysis. The mean value of the two highest 
acceptable DLCO measurements is derived. If only one acceptable DLCO measurements is 
available at an assessment, that measurement is used.  
Only these derived assessment-level values are used for any further derivation, the term 
‘DLCO at visit’ will refer to this value derived from the individual maneuver
measurements. 
The following derivations are performed (for DLCO from all measurements and DLCO
from acceptable measurements separately):

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:
o
DLCO Hb corrected = DLCO × (10.22 + Hb [g/dL]) / (1.7 × Hb [g/dL]) for male 
subjects older than 14 years;
o
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:
o
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;
o
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


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Baseline is flagged and absolute and percent changes from baseline are calculated for 
each post-baseline value, and last on-treatment and follow-up assessments are derived, as 
described in Section 5.5.1.  
Assessments meeting the following conditions are flagged in the ADaM dataset:

Percent change from baseline in DLCO: < −20 %

Percent change from baseline in hemoglobin corrected DLCO : < −20 %

Absolute change from baseline in percent predicted DLCO: < −20 %
5.5.13.3 Dermatological Examination
Collected at baseline, Week 60, and EOT visit in the Dermatological Examination eCRF. 
No definitions and derivations necessary. Any resulting findings are recorded as adverse 
event (or medical history).
5.5.13.4 Optical coherence tomography
Collected at screening, Week 12, Week 24, Week 60, and EOT visit 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).
5.5.13.5 Ophthalmological Examination
Collected at screening, Week 12, Week 24, Week 60, and EOT visit. 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).
5.5.13.6 Physical examination 
Collected at screening, baseline, Week 4, Week 12, Week 24, Week 60, Week 84, EOT 
and FUP visit eCRFs. No definitions and derivations necessary. Any resulting findings 
are recorded as adverse event (or medical history or relapse).
5.5.13.7 Suicidal ideation
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 Visit 2-Baseline), and then prospectively monitors ideations and behaviors
at subsequent follow-up assessments since the last call (scheduled at Visit 10-Week 60 
and Visit 14-Week 108).
The eC-SSRS outcome categories are provided below. Each category has a binary 
response (yes/no) and are numbered and ordered below for convenience. 
1 – Wish to be Dead 
2 – Non-specific Active Suicidal Thoughts 


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3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
5 – Active Suicidal Ideation with Specific Plan and Intent 
6 – Preparatory Acts or Behavior 
7 – Aborted Attempt 
8 – Interrupted Attempt 
9 – Actual Attempt (non-fatal) 
10 – Completed Suicide 
Furthermore, self-injurious behavior without suicidal intent is also an eC-SSRS 
outcome (although not suicide-related) and has a binary response (yes/no). (Q07a)
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. 
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.
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).
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 EOT + 15 days*, for pre-treatment lifetime, and for pre-treatment recent history. 
Shifts from baseline (worst outcome from pre-treatment recent history) to the worst 
outcome up to EOT + 15 days will be derived using the following categories: No ideation 


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(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’
(i.e., not from a lifetime) questionnaire are considered for the analysis. Note: The 
questionnaire was introduced while the study was ongoing. Approximately 15% subjects 
are therefore expected to have their lifetime questionnaire completed during a post-
baseline visit. 
Baseline is defined as last available recent history result (maximum score) up to study 
treatment start date, i.e., pre-treatment recent history result. 
Lifetime (pre-treatment) is defined as any event (worst outcome) in recent history and 
lifetime evaluation(s) up to study treatment start date. 
5.6
Quality of life variables
5.6.1
Change from baseline by visit up to Week 108 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).
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. Details 
for generating these domain scores and aggregate component scores, handle missing data 
items and duplicated item entries are given in Appendix C.4. 
The SF-36v2™ is completed by the subject on an electronic device at Visit 2 (Baseline), 
at Visits 6, 7, 10, 12 (Weeks 12, 24, 60, and 84), and 14 (W108) and at unscheduled visits 
due to relapses (R1, R2, etc.). 


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For analysis, visits are assigned based on time windowing, as detailed in Section 11.3. 
Baseline is defined as last available score up to or on randomization date. A variable with 
LOCF imputation by visit is derived for the domain and aggregated scores. 
5.7
Pharmacoeconomic variables 
5.7.1
Change from baseline by visit up to Week 108 in Work productivity and 
activity impairment (WPAI:MS) scores 
The WPAI:MS V2.0 assesses work productivity and activity impairment. It has a recall 
period of 7 days. The following variables are considered:

Current paid employment status (Y/N)
Four WPAI:MS outcome scores are considered that are expressed as impairment 
percentages, with higher numbers indicating greater impairment and less productivity:

Percentage of work time missed due to MS (absenteeism),

Percentage of impairment while working due to MS (presenteeism), 

Percentage of overall work impairment due to MS,

Percentage of activity impairment due to MS. 
The first three of these outcomes will be calculated only for those subjects who are 
working for pay, and the last outcome will be calculated for all subjects. See 
Appendix C.5 for details on the scoring. 
WPAI is completed by the subject on an electronic device at Visit 2 (Baseline), and at 
Visits 6, 7, 10, and 12 (Weeks 12, 24, 60, 84, respectively), 14 (Week 108). For analysis, 
visits are assigned based on time windowing, as detailed in Section 11.3.
Absolute change from baseline is derived with baseline defined as last available score up 
to and including randomization date.
5.7.2
Health care resource utilization from baseline up to Week 108 
Health care resource utilization data is taken from the following CRF pages: 
Hospitalization as recorded on the Adverse events, and ‘Relapse summary’ forms. 
Intensive care unit admissions for MS relapses are taken from ‘Intensive Care Unit 
Admissions for MS Relapses’ form. Emergency room visits for MS are taken from the 
‘Emergency medical facility visits for MS’ form. 
The following health care resource utilization variables will be derived:

Number of admissions / visits from baseline to Week 108 (Frequency of health care 
resource utilizations)

Length of stay (days) from baseline to Week 108 (Duration of health care resource 
utilizations) 


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The variables above are derived for the following categories

Any hospitalization: Derived from the Adverse event, Relapse summary and 
‘Intensive Care Unit Admissions for MS Relapses eCRFs.

Hospitalizations due to AEs: Derived from the AE page

Hospitalizations due to relapses: Derived from the Relapse summary eCRF

Intensive Care Unit (ICU) admissions for MS Relapses: Derived from the ‘Intensive 
Care Unit Admissions for MS Relapses’ form and includes all admissions 
(irrespectively if due to MS relapse or due to MS)

Emergency room visits for MS relapses: Derived from the ‘Intensive Care Unit 
Admissions for MS Relapses’ form and includes visits due to MS relapse and due to 
MS. Note that emergency room visits are not considered hospitalizations.
The length of stay (in days) per admission is defined as: Length of hospitalization = End 
date of hospitalization −Start date of hospitalization + 1 (in days).
The length of stay (in days) from baseline to Week 108 per category taking into account 
multiple encounters is derived as the sum of length of stay across all admissions / visits 
only considering days from baseline (randomization date) to Week 108 (Day 756). In 
case of overlapping hospitalizations, each day is counted only once. 
The number of admissions / visits from baseline to Week 108 is defined as a count 
variable per category. Two hospitalizations with identical admission date will be counted 
as one hospitalization.
5.8
Pharmacodynamic variables
Peripheral blood lymphocyte counts from central laboratory (absolute and change from 
baseline counts) are derived, as described in Section 5.5.12. 
Lymphocyte counts are further categorized into the following categories:

< 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.
Lymphocyte counts from central laboratory are flagged for analysis according to their
sample dates as ‘Baseline’, ‘Last on treatment’, ‘Day-15 follow-up’, ‘Day-30 follow-up’, 
and ‘Last follow-up assessment’ following the rules described in Sections 5.5.1 and 11.4.
6
DEFINITION OF PROTOCOL DEVIATIONS
This section refers to all protocol deviations as recorded in the database following the 
specifications provided in the protocol deviation code list.


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Protocol deviation ‘Study drug taken from non-allocated kit’ (PD_MM.058) will be 
classified at unblinding into the following two sub-protocol deviations: ‘Study drug taken 
from non-allocated kit: non-assigned treatment received’ (PD_MM.0581) or ‘Study drug 
taken from non-allocated kit: assigned treatment received’ at unblinding (PD_MM.0582). 
Protocol deviations are categorized while being entered into the database into the 
following categories: 

Important protocol deviations (Yes/No)

Timing (before Randomization / after Randomization / after end of treatment/ 
anytime during the study) 
In addition, protocol deviations are categorized by high-level topic in line with the 
Protocol Deviation code list [see Appendix B].
7
ANALYSIS SETS
7.1
Definitions of analysis sets
7.1.1
Screened analysis set
The Screened Analysis Set (SCR) includes all subjects who were screened and received a 
subject number.
7.1.2
Full analysis set 
The Full Analysis Set (FAS) includes all randomized subjects.
In order to preserve the randomization, subjects will be evaluated according to the 
treatment they have been randomized to. 
The main analyses of the primary and all secondary endpoints will be based on the FAS.
For the efficacy analyses on the FAS, unless otherwise stated, all available efficacy data 
up to the EOS will be included.
7.1.3
Per-protocol analysis set / Per-protocol analysis
The Per-Protocol analysis (PP analysis) will be based on data from all subjects in the 
FAS not affected by major protocol deviations. Major protocol deviations are defined as 
protocol deviations that impact the assessment of the primary/secondary endpoints.
The Per-protocol Set (PPS) comprises all subjects included in the FAS without any major 
protocol deviations occurring prior to or at randomization. Due to the nature of the 
primary endpoint which is assessed over the entire study period rather than at a fixed time 
point, for subjects developing major protocol deviations during the study, only data 
collected after a major protocol deviation will be excluded from the PP analysis. 


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Subjects will be excluded from the PPS if:

Subject is randomized and did not satisfy certain eligibility criteria:
–
Subject presenting no diagnosis of MS as defined by the revised (2010) 
McDonald Diagnostic Criteria for MS or with no relapsing course from onset (no 
diagnosis of RRMS or SPMS with superimposed relapses) [PD_PP.013];
–
No active disease as required per study protocol inclusion criterion 5 
[PD_PP.014];
–
Diagnosis of MS with progressive course from onset (i.e., diagnosis of primary 
progressive MS or progressive relapsing MS) [PD_PP.047];
–
Treatment within 90 days prior to randomization with medication listed in study 
protocol exclusion criterion 8 [PD_PP.024], medications: Plasmapheresis, 
cytapheresis, i.v. immunoglobulin, Treatment with an investigational drug (within 
90 days or five half-lives of the drug, whichever is longer), except biological 
agents;
–
Treatment within 180 days prior to randomization with medication listed in study 
protocol exclusion criterion 9 [PD_PP.025], medications: Azathioprine, 
methotrexate, 
or 
cyclophosphamide, 
Natalizumab, 
Other 
systemic 
immunosuppressive treatment (e.g., cyclosporine, sirolimus, mycophenolic acid), 
Non-lymphocyte-depleting experimental biological agents (e.g., daclizumab);
–
Treatment within 24 months prior to randomization with lymphocyte-depleting 
biological agents (e.g. rituximab or ocrelizumab) or cladribine [PD_PP.026];
–
Treatment at any time prior to randomization with alemtuzumab, mitoxantrone, 
leflunomide, teriflunomide, fingolimod, ponesimod or other investigational S1P 
modulators, stem-cell transplantation [PD_PP.027];

Subject received no treatment or did not comply with treatment:
–
No treatment taken: Any randomized subject who never received study drug 
[PD_MM.175] is excluded from the Per Protocol Set; 
–
Compliance < 80 %, as per compliance based on days on study drug, derived from 
the eCRF, as described in Section 5.3.2.1, is excluded from the Per Protocol Set
Data will be excluded from the per protocol analysis for subjects after the occurrence 
of one of the following criteria:

Subject received wrong study treatment or incorrect dose:
–
Wrong study treatment taken for > 14 days (> 2 consecutive kits as one kit 
contains 7 doses): Derived as protocol deviation ‘Study drug taken from a non-
allocated kit’ [PD_MM.058] and only applies if at least 2 non-allocated kits
containing wrong treatment (derived at unblinding: PD_MM.0581) have been 
taken, exclusion from first intake start date + 14 days onwards. Note: Wrong study 


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treatment taken for ≤14 days is not expected to affect efficacy considerably based 
on pharmacodynamic profile of the study treatment.
–
Premature treatment discontinuation: Any randomized subject with premature 
treatment discontinuation, derived from the eCRF, as described in Section 5.1.5, 
exclusion from EOT + 7 days onwards.

Subject took an unauthorized concomitant medication:
–
Treatment with systemic corticosteroids and ACTH during treatment, except for 
MS relapses and short-term treatments with low dose/inhaled corticosteroids for 
pulmonary conditions defined in study protocol [PD_MM.087], from date of 
protocol deviation onwards;
–
Any administration of disease modifying therapy for MS during the treatment 
period [PD_MM.088, PD_MM.093], exclusion from medication start date 
onwards;
–
During treatment period, any investigational procedure for MS [PD_MM.096], 
from date of procedure onwards;

Occurrence of major protocol deviation that could confound the interpretation 
of analysis conducted on the FAS;
–
EDSS assessments not conducted for more than 6 months, exclusion from ‘last 
EDSS date prior to 6-month gap + 6 months’ onward; derived from eCRF: time 
between two consecutive EDSS assessments (or last EDSS assessment and EOS 
date) is > 6 months (182 days).
–
Subject’s randomized treatment allocation was unblinded. Treatment code broken 
before unblinding of the study (for a reason not related to management of a 
clinical event [PD_MM.054], or any other unblinding documented in the IRT/
eCRF), exclusion from date of unblinding onwards.
7.1.4
Safety analysis set 
The safety analysis set (SAF) includes all subjects who received at least one dose of 
study treatment. Irrespective of the randomized treatment group, subjects are summarized 
grouped:

by actual treatment received, if the same kind of study treatment (teriflunomide or 
ponesimod) was taken throughout the study.

within the treatment group they were exposed to for the majority of time on study 
treatment in case both study treatments (teriflunomide and ponesimod) were taken by 
a subject at some point during the study. If a subject received teriflunomide and 
ponesimod for exactly the same number of days, they are summarized within the 
treatment they are assigned to by randomization.


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Some analyses are conducted based on the following safety set subsets:

Subset of subjects with at least one re-initiation (based on eCRF Study Drug 
Administration - Re-Initiation)

Subset excluding subjects from centers in Canada, the United States, and Mexico. 
Subset is used to address differences in assessment schedule of laboratory 
assessments in local protocol versions as compared to the global protocol version.  

Subset of subjects who received non-randomized study drug during the study (derived 
from protocol deviation PD_MM.058.1)

Subset of subjects who resumed ponesimod maintenance treatment without 
up-titration after an interruption of >3 days [see Section 5.3.2.2]

Subset of subjects who deviated from planned up-titration regimen [see 
Section 5.3.2.2]
7.1.5
Other analysis sets
The following other analysis sets are defined:
7.1.5.1
Non-conventional MRI sub-study full analysis set 
Includes all subjects in the full analysis set who have consented to participate in the non-
conventional MRI techniques sub-study (‘Non-conventional MRI techniques sub-study’
ticked on ‘Informed Consent’ eCRF).  
7.1.5.2
Patient preference sub-study full analysis set
Includes all subjects in the full analysis set who have consented to participate in the 
Patient Preference sub-study (‘Patient Preference Questionnaire’ ticked on ‘Informed 
Consent’ eCRF).  
7.1.5.3
DLCO sub-study safety analysis set 
Includes all subjects in the safety set who have consented to participate in the DLCO sub-
study (‘DLCO sub-study’ ticked on ‘Informed Consent’ eCRF). Subjects are summarized 
in the same treatment group as in the safety analysis set.
7.1.5.4
Post-treatment observation period analysis set (PTOP Set)
Includes all subjects in the full analysis set who prematurely discontinued treatment (see 
definition in Section 5.1.5), with EOS date after EOT + 7 days. 
7.1.5.5
Post-treatment safety analysis set
Includes all subjects in the safety analysis set who have an EOS date > EOT + 15 days.
Subjects are summarized in the same treatment group as in the safety analysis set. 
7.2
Usage of the analysis sets
Table 7 provides an overview of the analysis set usage for the main variables of the 
study.


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Table 7
Overview of the different main analysis sets and their usage
Analyses/Data Displays
Screened 
analysis set
Full analysis set 
Safety analysis 
set 
Per protocol 
analysis set
Inclusion/exclusion criteria

Demographic characteristics


Baseline characteristics


Medical history

Previous and concomitant 
medications

Treatment exposure

Efficacy: Primary endpoint


Efficacy: Secondary 
endpoints


Efficacy: Exploratory 
endpoints

Safety endpoints

All subject listings

Main analysis of the primary efficacy endpoint is based on the Full analysis set, selected listings will be prepared on the 
Screened analysis set.
8
DEFINITION OF SUBGROUPS
The below described subgroups are considered in selected efficacy analyses. If 
applicable, the category in bold type is the reference category used in the statistical 
analysis of these subgroups.

Prior use of MS disease-modifying treatment in the last two years prior to 
randomization (yes, no) as documented by the IRT system and used as randomization 
strata.

Baseline Expanded Disability Status Scale score (EDSS ≤ 3.5, EDSS > 3.5) as 
documented by the IRT system and used as randomization strata.

Prior use of MS disease-modifying treatment in the last two years prior to 
randomization (yes, no) as derived based on medications entered in the eCRF [see 
Section 5.2.2].

Any prior treatment for MS (yes, no).

Baseline Expanded Disability Status Scale score (EDSS ≤ 3.5, EDSS > 3.5) as 
documented in the eCRF.

Geographical region of site (Europe Non-EU + Russia, European Union (EU) + UK, 
North America, Rest of World), as defined in Section 5.2.1;

Sex (male, female);

Age at screening (< 40 years, ≥ 40 years);

MS subtype (relapsing remitting, secondary progressive with superimposed 
relapses)


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
Number of documented MS relapses within the last 12 months prior to screening (≤ 1, 
≥ 2), as defined in Section 5.2.2;

Gd+ T1 lesions at baseline, on MRI scan as provided by the central reader (absent, 
present);

Highly active disease (yes, no), as defined in Section 5.2.2;

Protocol version at randomization:
–
Randomized pre-PV4: Subjects who have consented originally to protocol 
versions 1 to 3; these subjects can have data collected under protocol versions 1 to 
3 only or under protocol versions 1 to 4.
–
Randomized post-PV4: Subjects who have consented to PV4 only; data of these 
subjects is only being collected under PV4.
derived as described in Section 5.1.8. 
In case of missing information, the corresponding subject is not considered for the 
respective subgroup analysis. 
9
STATISTICAL ANALYSES
9.1
Overall testing strategy
9.1.1
Overall testing strategy
A multiple testing strategy is applied for the primary and secondary endpoints. The 
testing strategy starts with testing the primary endpoint at full alpha, followed 
hierarchically by a fallback type procedure for the secondary endpoints. 
The multiple testing strategy starts with testing the primary endpoint (ARR using 
confirmed relapses), comparing the investigational treatment (ponesimod 20 mg) with the 
comparator (teriflunomide 14 mg) at full alpha. 
If the primary endpoint null hypothesis is rejected, the alpha will be split evenly (1/3 of 
alpha) between the following three secondary endpoints using the fallback procedure, 
allowing for passing on alpha within the fallback procedure as per the following 
sequence:

Change from baseline to Week 108 in fatigue-related symptoms as measured by the 
symptoms domain of the FSIQ–RMS [Fatigue]

Cumulative number of unique active lesions from baseline to Week 108 [CUALs]

Time to 12-week CDA from baseline to EOS [12-week CDA] 
If a secondary endpoint listed as part of the fallback procedure above is successful, the 
preserved alpha in the sequence is passed along to the next secondary endpoint in the 
sequence and the summed alpha is used for testing that endpoint. Thus, as sequential tests 
are successful, the alpha accumulates for the endpoints later in the sequence; these 
endpoints are then potentially tested with a progressively larger alpha, but always with at 
least 1/3 of the alpha.


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In a last step, the secondary endpoint 

Time to 24-week CDA from baseline to EOS [24-week CDA]
is tested in a subsequent stage following Time to 12-week CDA with the remaining 
alpha.  
A graphical description of this testing strategy for the primary and secondary endpoints 
following the approach of Bretz et al. [Bretz 2009] is provided in Figure 2. 
Figure 2
Overall testing strategy
ARR = Annualized relapse rate; CDA = Confirmed disability accumulation; CUAL = Cumulative number of combined 
unique active lesions; H = Hypothesis. 
The primary null hypothesis will be tested at a two-sided 1% alpha level, and if rejected 
the study will be declared to show conclusive evidence of efficacy on the primary 
endpoint. If the primary null hypothesis can only be rejected at the two-sided 5% alpha 
level, the study will be declared positive.
The alpha level for the overall testing strategy across primary and secondary endpoints is 
set at 5%. Multiplicity adjustment as per the testing strategy outlined above will be
performed. If the null hypothesis for the primary endpoint is rejected at two-sided alpha 
of 5% this leads to the example scenarios for alpha allocation for the secondary endpoints 
detailed as in Table 8.
Any further conducted tests will be considered exploratory. 


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Table 8
Example scenarios secondary endpoint alpha allocation
Scenario
Endpoint
Proportion of α
p-value for test
Statistically 
significant
1
Fatigue
CUALs
12-week CDA
24-week CDA
1/3
2/3
1
1
< 1/3 α
< 2/3 α
< α
< α
Yes
Yes
Yes
Yes
2
Fatigue
CUALs
12-week CDA
24-week CDA
1/3
1/3
2/3
2/3
> 1/3 α
< 1/3 α
< 2/3 α
< 2/3 α
No
Yes
Yes
Yes
3
Fatigue
CUALs
12-week CDA
24-week CDA
1/3
2/3
1/3
1/3
< 1/3 α
> 2/3 α
< 1/3 α
< 1/3 α
Yes
No
Yes
Yes
4
Fatigue
CUALs
12-week CDA
24-week CDA
1/3
2/3
1
0
< 1/3 α
< 2/3 α
< α
Yes
Yes
No
5
Fatigue
CUALs
12-week CDA
24-week CDA
1/3
1/3
1/3
1/3
> 1/3 α
> 1/3 α
< 1/3 α
< 1/3 α
No
No
Yes
Yes
6
Fatigue
CUALs
12-week CDA
24-week CDA
1/3
1/3
1/3
0
>1/3 α
>1/3 α
>1/3 α
No
No
No
Scenarios for secondary endpoint alpha allocation are conditional on rejecting the primary null hypothesis. 
CDA = Confirmed disability accumulation; CUAL = Cumulative number of combined unique active lesions. 
9.2
General rules for data presentations
This section describes the general rules applied for all data displays, unless otherwise 
specified in each corresponding section. Standard Guiding Rules and Principles and 
standard outputs are followed where applicable.
SAS version 9.4 is used for the preparation of all tables, listings and figures. Listings are 
sorted by treatment group, subject number (includes sorting by country and center) and 
timing (dates and/or visits as applicable). For analyses performed on multiple analysis 
sets, only one listing containing all analyzed subjects is presented. Names of outputs have 
a suffix that indicates the analysis set (e.g., _SAF for Safety set).


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Data are listed and summarized using appropriate descriptive statistics:

Number of non-missing observations, number of missing observations, mean, 
standard deviation, minimum, Q1, median, Q3, and maximum for continuous 
variables;

Number of non-missing observations, and frequency with percentage per category 
(percentages based on the number of non-missing observations) for categorical 
endpoints;

Some continuous variables obtained at scheduled visits are graphically presented 
utilizing box plots, on a time axis scaled by the target days of nominal visits. The box 
indicates the interquartile range, a horizontal line within the box indicates the median, 
and a diamond shape indicates the mean. Whiskers denote minimum and maximum 
values within the boundary of +/- 1.5 times the size of the interquartile range. Circles 
indicate outliers from +/- 1.5 times the size of the interquartile range.

Some continuous variables are graphically presented based on mean change +/- SE on 
a time axis scaled to the target days of the corresponding visit. The standard error SE 
is derived as SD/√!.
Example table layouts:
ACT-128800/JNJ-67896153              Protocol: AC-058B301<TITLE>
Analysis set: <Set>
—————————————————————————————————————————————————————————————————
           Ponesimod        Teriflunomide      Total
             20 mg              14 mg   
           N = XX              N = XX         N = xx
—————————————————————————————————————————————————————————————————
<XXX>     XX              XX                XX             
—————————————————————————————————————————————————————————————————
Treatment groups are displayed in the order (left to right) of Ponesimod 20 mg, 
Teriflunomide 14 mg, Total (if applicable). For figures, ponesimod is displayed in red 
with solid line style and teriflunomide is displayed in black with dashed line style.
9.3
Display of subject disposition, protocol deviations and analysis sets
9.3.1
Subject disposition
The number and percent of subjects in the FAS is summarized by country and site.
The number and percent of subjects screened and re-screened (incl. reasons for screening 
failure), subjects randomized, subjects completing study as per protocol, subjects treated, 
and subjects completed treatment per protocol, as well as subjects completing both 
treatment and study as per protocol are summarized for the SCR. For subjects that failed
screening more than once, only the reason of the last failure is reported in the summary 
table. 


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All reasons for screening failures are included in the listing. The listing also includes the 
date of screening / re-screening, an indicator variable (‘Yes’, ‘No’) for failed screening 
attempts, the randomization date, and the number of days from successful screening to 
randomization.
The number and percent of subjects by reason for premature discontinuation from study
is tabulated for the FAS. The number and percent of subjects by reason for premature 
discontinuation from study treatment is tabulated for the SAF.
Time in study and Time on treatment is presented with an inverse cumulative distribution 
function by treatment arm, descriptive statistics with cumulative time are displayed on 
the FAS.
Based on the FAS, the number and percent of subjects randomized under protocol 
versions 1–3 and 4 or higher are summarized by randomized treatment group. Based on 
the FAS, the number of subjects with data collected and the time on study (from 
randomization up to EOS) under protocol version 1–3 and under version 4 or higher are
summarized by randomized treatment group by using descriptive statistics for continuous
variables, overall and by time on study prior to protocol version 4 and time under study 
protocol version 4 or higher. Cumulative time on study (from randomization up to EOS) 
is presented overall, and cumulative time on study (from randomization up to EOS) is 
presented by time relative to version 4 along with percentage of overall time on study 
(from randomization up to EOS).
All subjects with unmet eligibility criteria are listed. For subjects re-screened unmet 
criteria from the initial screening visit are flagged. Subjects randomized with unmet 
criteria in their last screening attempt are flagged in the listing.
9.3.2
Protocol deviations
All protocol deviations as well as important protocol deviations are summarized by 
category (first timing, then high-level topic), per treatment group and overall on the FAS. 
A listing of all protocol deviations (coded term, reported term) is provided on the SCR.
9.3.3
Analysis sets
The number and percentage of subjects in each analysis set and subjects included in the 
Per protocol analysis with data up to EOS are summarized in a table, per treatment group 
and overall. 
Reasons for excluding subjects from the PPS, as well as reasons for excluding data from 
the Per protocol analysis are listed and summarized in a table. The time in study up to per 
protocol exclusion is summarized descriptively on the FAS. 


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9.4
Analyses of subject characteristics
9.4.1
Demographics
Demographic characteristics [defined in Section 5.2.1] are summarized using descriptive 
statistics for continuous and categorical data using the FAS, PPS and DLCO safety set. 
Tables are presented by treatment group and overall. Demographic characteristics on the 
FAS will also be summarized by geographical region. All variables are also presented in 
a subject data listing based on the SCR.
9.4.2
Baseline disease characteristics
Baseline disease characteristics [defined in Section 5.2.2] are summarized using 
descriptive statistics for continuous and categorical data using the FAS and PPS. Tables 
are presented by treatment group and overall. Baseline disease characteristics on the FAS 
will also be summarized by geographical region. All variables are also presented in 
subject data listings based on the SCR.
9.4.3
Other baseline characteristics
Other baseline disease characteristics [defined in Section 5.2.3] are listed based on the
SCR. 
9.4.4
Medical history
Previous and concomitant medical histories [defined in Section 5.2.4] are summarized 
separately, by treatment group and overall, by tabulating 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) using the FAS. SOCs are sorted by descending 
order of frequency. If the frequencies of SOCs are the same, alphabetical order is used. 
The same rule applies for preferred terms within SOC.
Complication or Symptoms Associated with MS within the last 24 months prior to the 
study [defined in Section 5.2.4] are summarized, by treatment group and overall, by 
tabulating the number and percentages of subjects who had/have at least one event and 
had/have each complication/symptom (by predefined term sorted by descending order of 
frequency) separately for previous conditions (not ongoing at screening) and conditions 
ongoing at screening using the FAS.
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 based 
on the SCR.
9.4.5
Previous and concomitant therapies
Number and percentages of subjects having taken at least one treatment are presented by 
at least one therapy, 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, for the FAS, by treatment group and overall. ATC classes


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are sorted by descending order of frequency. 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.
The above described frequencies are summarized by treatment group and overall for the 
following therapies:

Previous therapies (stopped prior to study treatment start)

Study concomitant therapies (taken between study treatment start and EOS)

Treatment concomitant therapies (taken between study treatment start and EOT)

Therapies taken between study treatment start and EOT + 15 days
All therapies taken are reported in one subject listing with all information collected on the 
eCRF presented, using flags to mark previous, study concomitant, treatment concomitant 
as well as ongoing at study treatment start using the screened set. 
9.4.5.1
Disease modifying therapies (DMTs) for MS
The following therapies are summarized in the same way as for the previous / 
concomitant therapies above by treatment group and overall on the FAS: 

Previous DMTs for MS 

Study concomitant DMTs for MS

Treatment concomitant DMTs for MS

DMTs for MS started after EOT + 7 days
All DMTs for MS taken are reported in one subject listing using flags to mark previous, 
study concomitant, treatment concomitant as well as ongoing at study treatment start
using the FAS.
9.4.5.2
Concomitant steroid for treatment of relapses
Study concomitant steroids (taken between study treatment start and EOS) are 
summarized in the same way as concomitant therapies by treatment on the FAS. 
Accumulated steroid dose for treatment of relapse (i) up to EOS, and (ii) up to 
EOT + 7 days is summarized using descriptive statistics by treatment group on the FAS. 
A listing of corticosteroids for treatment of relapses on the FAS is prepared.
9.4.5.3
Beta blocking agents
Treatment concomitant beta blocking agents (taken between study treatment start and 
EOT) are summarized in the same way as for treatment concomitant therapies on the 
FAS. A listing of beta blocking agents on the FAS is prepared. 


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9.4.5.4
Therapies used for accelerated elimination
Therapies used for accelerated elimination started between EOT and EOT + 15 days are 
summarized in the same way as for treatment concomitant therapies on the FAS. A listing 
of therapies used for accelerated elimination on the FAS is prepared. 
9.4.6
Other subject characteristics
Other subject characteristics will be listed. This comprises the Chest X-Ray and 
Reproductive system findings. 
9.5
Analysis of study treatment exposure and compliance
9.5.1
Exposure
Exposure to study drug [defined in Section 5.3.1] is summarized using descriptive 
statistics for continuous and categorical data using the SAF. In addition, this table 
displays the overall subject year exposure (sum over all subjects’ exposure). Tables are 
presented by treatment group. All variables are also presented in subject data listings 
based on the SAF.
Subjects with at least one interruption, duration of interruptions as well as subjects with 
interruptions with reported reason will be summarized by treatment group on the SAF.   
9.5.2
Compliance with study treatment
Compliance with study treatment variables [defined in Section 5.3.2] are summarized 
using descriptive statistics for continuous and categorical data using the SAF. Tables are 
presented by treatment group. All variables are also presented in subject data listings 
based on the FAS.
9.6
Analysis of the primary efficacy variable
9.6.1
Primary estimand
The primary estimand, the target for estimation in this study, is defined by the following 
components:
Population: Subjects with relapsing multiple sclerosis (RMS), as defined by the 
inclusion/exclusion criteria from the study.
Variable: ARR (number of confirmed relapses per subject-year) up to EOS, with EOS 
being at least 108 weeks after randomization [see Section 5.4.1].
Intercurrent events with corresponding strategies:

Treatment discontinuation: Treatment Policy Strategy; including all confirmed 
relapses regardless of treatment discontinuation.


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
Start of alternative DMTs for MS: Treatment Policy Strategy; including all 
confirmed relapses, regardless of start of alternative DMTs. Note: As per protocol 
alternative DMTs for MS are only allowed to be started after treatment 
discontinuation, therefore this intercurrent event is not expected to occur prior to or
independent from treatment discontinuation. 

Study discontinuation: Hypothetical Strategy; effect if all subjects remained on 
study as planned per protocol. The assumptions for handling study discontinuation are 
detailed for the main analysis in Section 9.6.3 and for the sensitivity analyses on 
premature study withdrawal in Section 9.6.4.3. 
Summary Measure: Rate ratio of ponesimod versus teriflunomide.
The primary analysis will be based on the Full Analysis set [see Section 7.1.2]. 
9.6.2
Hypothesis and statistical model
A generalized linear model with negative binomial distribution for the number of 
confirmed relapses will be assumed as described in Section 10.1.
Two-sided hypotheses are expressed in terms of the model parameters µP20mg and µT14mg. 
The primary null hypothesis is that the ARR (and consequently the model parameter µ) 
does not differ between ponesimod 20 mg and teriflunomide 14 mg. The alternative 
hypothesis is that the ARR differs between ponesimod 20 mg and teriflunomide 14 mg. 
H0, ARR: µP20mg - µT14mg = 0 
versus
H1, ARR: µP20mg - µT14mg ≠ 0 
The null hypothesis will be tested by a two-sided Wald test within the NB regression 
model, with a two-sided significance level of 0.01 for conclusive evidence and 0.05 for a 
positive study. Two-sided 99% and 95% Wald CIs and the associated p-value will be 
calculated for the relative reduction in mean ARR for ponesimod 20 mg compared to 
teriflunomide 14 mg.
9.6.3
Main analysis
The primary statistical analysis will be performed up to EOS on the FAS using an NB 
regression model for confirmed relapses, with treatment as a factor and the binary 
stratification variables (EDSS ≤3.5 versus EDSS > 3.5; DMT within last 2 years prior to 
randomization [Yes/No]) and the number of relapses in the year prior to study entry
(categories ≤1 [or missing, in order to avoid excluding subjects from the analysis] and 
≥2) included in the model. The model also includes an offset variable defined as the log 
of time on study (in years) from randomization up to EOS. The primary null hypothesis 
will be tested with a two-sided alpha level of 1% for conclusive evidence and 5% for a 
positive study.


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Mean model-based estimates of the ARR (for confirmed relapses), by treatment arm, as 
well as 99% CIs and 95% CIs are presented. A rate ratio comparing ponesimod 20 mg 
with teriflunomide 14 mg will be derived from the model including 99% CIs, 95% CIs
and the corresponding p-value. The dispersion parameter will also be displayed.
Descriptive summary statistics of the number of confirmed relapses as a continuous 
variable and the number of confirmed relapses in categories (0, 1, 2, 3, 4, ≥ 5), by 
treatment arm will be presented. The total cumulative number of confirmed relapses, as 
well as the total cumulative time on study (summed for all subjects) will also be 
displayed. From the total number of confirmed relapses and the total time on study the 
raw unadjusted ARR, by treatment arm, will be calculated and summarized.
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. The treatment-by-covariate
interactions will also be assessed in separate models; if the interaction p-value is < 0.01 it 
will be investigated further to determine the nature of the interaction (quantitative or 
qualitative).
Handling of study discontinuation
For the main analysis it is assumed that follow-up time after study discontinuation is 
missing at random: a hypothetical scenario is considered assuming that subjects who 
discontinued the study would have similar efficacy as the subjects from the same 
treatment group who did not discontinue the study. 
Sensitivity analyses on this assumption are described in Section 9.6.4.
9.6.4
Sensitivity analyses to main analysis
9.6.4.1
ARR based on confirmed relapses up to EOS on the FAS - unadjusted 
analysis
Same analysis as for the main analysis, but with treatment as the only factor in the model, 
i.e., not adjusting for covariates including stratification variables. This analysis is 
conducted to assess the effect of adjusting for covariates in the primary analysis. 
9.6.4.2
ARR based on confirmed relapses up to EOS including derived stratification 
variable
Same analysis as for the main analysis, but instead of adjusting for the stratification 
variables from the IRT adjust for eCRF-derived stratification variables. 
This analysis was requested by the FDA for the SPA review of study AC-058B302 and is 
performed to ensure that the results are consistent with the primary analysis, which are 
adjusted for the IRT stratification variables and – after eCRF data cleaning – might not 
match. 


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9.6.4.3
ARR imputation analysis for subjects withdrawing from the study prematurely 
(imputation from EOS to theoretical Week 108)
To assess the impact of subjects withdrawing from the study prior to Week 108,
sensitivity analyses will be performed. These include the imputation of confirmed 
relapses using various assumptions for the period with missing data.
The proportion of missing data, i.e., missing observation time, will be calculated as
1 Cumulative time between randomization and EOS (or theoretical Week 108,if earlier)
Cumulative time between randomization and theoretical Week 108
and will be summarized descriptively. Time up to EOS (i.e., time in study) will be 
presented based on an inverse cumulative distribution function [see Section 9.3.1].
Multiple imputation (MI) methods for count data are applied, following the approach 
from Keene 2014; see Section 10.1.1 for details. 
Number of relapses between EOS and theoretical Week 108 will be imputed for subjects 
who have prematurely discontinued from the study.  
Several approaches will be used for the imputation of events:

Missing at random (MAR) MI approach: Under this approach, the rate after 
withdrawal for each treatment arm is assumed to be the rate in the respective arm 
before withdrawal.

Reference-based MI approaches: The rate in the reference (teriflunomide 14 mg) 
arm is used for imputation in both the ponesimod 20 mg and teriflunomide 14 mg
arms. While the post-withdrawal events in the teriflunomide 14 mg arm are imputed 
under the MAR assumption for that arm, two different approaches are applied for the 
imputation of the post-withdrawal events in the ponesimod arm:
a. Copy reference MI approach: Impute based on the reference arm; For a subject 
in the ponesimod arm, if the event rate prior to withdrawal is better than would be 
expected on the reference arm, under this approach, their imputed event rate after 
withdrawal will also be better than the expected event rate on the reference arm.
The copy reference imputation is expected to be less favorable for ponesimod 
20 mg as compared to MAR approach as it is relative to the rate in the reference 
arm, but not as extreme as the jump to reference approach described below. 
b. Jump to reference MI approach: Impute based on the reference arm; For a 
subject in the ponesimod arm, if the event rate prior to withdrawal is worse than 
would be expected on the ponesimod arm, under this approach, their imputed 
event rate after withdrawal will be worse than the expected event rate on the 
reference arm. This approach assumes that withdrawn subjects on the ponesimod 


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20 mg treatment will quickly lose any positive effect of their treatment (relative to 
the reference arm) when it is stopped.
The resulting rate ratio and corresponding 99% and 95% CIs will be reported and 
presented in tables and graphically.
A delta-adjustment MI method [Keene 2014] will also be applied to further assess 
deviations from the MAR assumption:

Delta adjustment MI approach: Starting with the MAR assumption for both 
treatment arms, a 2-way delta adjustment is applied. 
Ponesimod 20 mg arm: The rate after withdrawal is multiplied by δP, ranging from 
1 (MAR, i.e. same rate as prior to withdrawal) to 3.1 (~Tripling of relapse rate) in
steps of 0.3. 
Teriflunomide 14 mg arm: The rate after withdrawal is multiplied by δT, ranging from 
0.1 (relapse rate reduced by 90%) over 1 (MAR, i.e. same rate as prior to withdrawal) 
to 3.1 (~tripling of relapse rate) in steps of 0.3.
For each imputed dataset the same negative binomial regression model as for the primary 
analysis will be fit and results will be combined using Rubin’s rule [see Section 10.1.1]. 
The resulting rate ratios and corresponding 99% CIs and p-values will be reported and 
presented in tables and graphically.
9.6.5
Supplementary analyses
Supplementary analyses are conducted for other quantities of interest. 
9.6.5.1
ARR up to EOT + 7 days for confirmed relapses
The primary efficacy model will be repeated only including confirmed relapses up to 
EOT + 7 days as a response variable, treatment as a factor, the stratification variables and 
the number of relapses in the year prior to study entry (≤1 [or missing] and ≥2) as 
covariates based on the FAS. The model is offset by the log of number of days from 
randomization up to EOT + 7 days. 
The following sensitivity analyses related to confirmed relapses up to EOT + 7 days are
conducted:

ARR based on confirmed relapses up to EOT + 7 days on the FAS – unadjusted 
analysis:


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Same analysis as for the main analysis, but with number of confirmed relapses up to 
EOT + 7 days as a response variable, and treatment as the only factor in the model, 
i.e., not adjusting for covariates, including stratification variables. The analysis is 
conducted to assess the effect of adjusting for covariates. 

ARR based on confirmed relapses up to EOT + 7 days on the FAS – multiple 
imputation between EOT + 7 days and theoretical Week 108:
Furthermore, sensitivity analyses based on multiple imputation are conducted based on 
different assumptions following treatment discontinuation to assess the hypothetical 
effect if subjects would have stayed on treatment up to Week 108. Multiple imputation 
methods for count data are applied as for the sensitivity analyses related to the primary 
analysis [Section 9.6.4.3 and Section 10.1.1]. For subjects who have prematurely 
discontinued treatment post-treatment events, i.e., the number of relapses between 
EOT + 7 and theoretical Week 108, will be imputed.   
Imputation of events is conducted with the following MI approaches: Missing at Random 
(MAR), Copy reference, Jump to reference. The corresponding interpretations are 
detailed in Section 9.6.4.3, only that imputation is now conducted post EOT + 7 days 
instead of post-study withdrawal.
The resulting rate ratio and corresponding 99% and 95% CIs will be reported and 
presented in tables and graphically.
9.6.5.2
ARR based on confirmed relapses up to EOS - Per protocol analysis
Same analysis as for the main analysis, but with number of confirmed relapses up to EOS
(per-protocol) as a response variable and the logarithm of time (in years) between 
randomization and EOS (or up to per protocol exclusion date) as an offset variable based 
on the PPS. Conducted to check the consistency of the treatment effect in the per protocol 
analysis with the effect in the main analysis. This analysis will evaluate whether a bias in 
evaluating the treatment effect has been introduced in the FAS due to major protocol 
deviations.
9.6.5.3
ARR based on all relapses up to EOS on the FAS
Same analysis as for the main analysis, but with number of all relapses up to EOS as a 
response variable. All other aspects of the model are as per the main analysis. This 
analysis is described to check the consistency of the treatment effect on all relapses and 
that no bias was introduced in the confirmation of relapses. 
The following sensitivity analysis is conducted 

ARR based on all relapses up to EOS including derived stratification variable: Same 
analysis as for the main analysis, but instead of adjusting for the stratification 
variables from IRT adjust for eCRF-derived stratification variables. 


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9.6.5.4
ARR based on confirmed relapses up to start of new DMT for MS on the FAS
Same analysis as for the main analysis, but with number of confirmed relapses up to the 
minimum of EOS date, or the start of a new DMT for MS as a response variable, and the 
logarithm of time (in years) between randomization and the Min (EOS date, start of a 
new DMT for MS) as an offset variable. By checking the consistency of the treatment 
effect in this analysis with the effect observed in the main analysis, we evaluate whether a 
bias in evaluating the treatment effect has been introduced in the FAS analysis due to the 
decision to start a DMT.
9.6.5.5
ARR up to EOS for imputed confirmed relapses
Same analysis as for the main analysis, but with number of imputed confirmed relapses 
up to EOS as a response variable (relapses with missing confirmation status imputed as 
confirmed relapses). All other aspects of the model are as per the main analysis. This 
analysis is conducted to assess that no bias was introduced by missing confirmation status 
(e.g., due to EDSS not completed). 
9.6.5.6
ARR post EOT + 7 days following premature treatment discontinuation
This analysis is similar to the analysis described for the primary efficacy variable, using a 
model with the number of confirmed relapses in the PTOP as a response variable, 
treatment, stratification variables and the number of relapses in the year prior to study 
(≤1 [or missing] and ≥ 2) entry as factors and the logarithm of time between 
EOT + 8 days and EOS (in years) as an offset variable. The analysis is based on the 
Post-treatment observation period analysis set (FAS subjects prematurely discontinuing 
treatment with EOS date after EOT + 7 days).
9.6.5.7
ARR by time period
Confirmed relapses are analyzed by time period (up to Week 60, post Week 60, and in 
12 week periods). The analysis is conducted separately for each period using descriptive 
statistics and fitting a model as for the primary efficacy variable (adjusting for the same 
covariates), with logarithm of observation time in the respective period (in years) as an 
offset variable. The following are displayed for each period: ARR with 95% CI per 
treatment arm, Rate ratio with 95% CI together with number of subjects included in the 
analysis. 
9.6.5.8
Forest plot of primary efficacy analysis and main sensitivity / supplementary 
analyses
Results of the analyses will be summarized in forest plots containing: ARR including 
99% CIs, by treatment (as text); Number of subjects by treatment (as text); Rate ratio 
including 99% CIs (as graphic); Dotted reference line at rate ratio = 1; Solid reference 
line for the primary analysis rate ratio; Indicators to the right and to the left of the 
reference line favoring ponesimod 20 mg or teriflunomide 14 mg; Treatment effect p-
value (as text). The plot will be repeated presenting 95% CIs.


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The following sensitivity analyses for the primary estimand will be displayed in one 
forest plot:

Primary efficacy analysis for all confirmed relapses up to EOS, adjusted for the 
stratification variables (IRT) and the number of relapses in the year prior to study 
entry based on the FAS (as a reference);

Sensitivity analysis for all confirmed relapses up to EOS, unadjusted based on the 
FAS;

Sensitivity analysis for all confirmed relapses up to EOS, adjusted for derived 
stratification variables and the number of relapses in the year prior to study entry on 
the FAS;
Sensitivity analyses on the FAS for the primary estimand on handling missing data 
[see Section 9.6.4.3] will be displayed in a forest plot as well. It will contain the primary 
efficacy analysis, the MAR, Copy reference, and Jump to reference as well as a subset of 
results from the delta adjustment method.
The main supplementary analyses to the primary estimand will be displayed in a second 
forest plot:

Primary efficacy analysis for all confirmed relapses up to EOS, adjusted for the 
stratification variables (IRT) and the number of relapses in the year prior to study 
entry based on the FAS (as a reference);

Supportive analysis of all confirmed relapses up to EOT + 7 days, adjusted for the 
stratification variables (IRT) and the number of relapses in the year prior to study 
entry based on the FAS;

Supportive analysis for all confirmed relapses up to EOS collected per-protocol, 
adjusted for the stratification variables (IRT) and the number of relapses in the year 
prior to study entry based on the PPS;

Supportive analysis for all relapses up to EOS, adjusted for the stratification variables 
(IRT) and the number of relapses in the year prior to study entry based on the FAS.

Supportive analysis for all relapses up to start of new disease modifying therapy 
(DMT) for MS, adjusted for the stratification variables (IRT) and the number of 
relapses in the year prior to study entry based on the FAS.

Supportive analysis for ARR up to EOS for imputed confirmed relapses.
9.6.6
Other analyses related to the primary endpoint
9.6.6.1
Relapse characteristics and relapse symptoms
Relapse characteristics will be summarized using descriptive statistics on the FAS. This 
includes the following: 


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Number (%) of subjects with at least one: relapse, relapse requiring hospitalization, 
relapse treated with corticosteroids; for all relapses up to EOS, confirmed relapses up to 
EOS, all relapses up to EOT + 7 days, confirmed relapses up to EOT + 7 days. 
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, 
all relapses up to EOT + 7 days, confirmed relapses up to EOT+7 days. Number (%) of 
relapses (out of total number of relapses) per relapse symptom category, as well as 
number of functional systems affected per relapse (out of total number of relapses) is 
summarized descriptively per category by treatment arm. It is conducted for all relapses 
up to EOS as well as for confirmed relapses up to EOS, all relapses up to EOT + 7 days, 
confirmed relapses up to EOT + 7 days.
9.6.6.2
Number of new or worsening neurological symptoms up to EOS
New or worsening neurological symptoms up to EOS are summarized overall and by 
sub-categories (confirmed relapse, non-confirmed relapse, symptoms not considered a 
relapse) using descriptive statistics by treatment arm. Percentages for sub-categories are 
presented out of the total number of new or worsening neurological symptoms. 
New or worsening neurological symptoms are reported via a telephone interview or at the 
site in a face-to-face interview and at both these times a decision must be taken by the 
treating neurologist to refer the subject to the efficacy assessor. Once referred to the 
efficacy assessor the symptom is considered a relapse and is assessed for confirmation. 
To ensure there is no bias in the selection of symptoms considered as relapses between 
treatments, an analysis will compare the proportion of these new or worsening 
neurological symptoms that are considered as relapses or as confirmed relapses. If there 
is an imbalance in the selection between treatments, this will be explored further. 
9.6.6.3
Change in the collection of the primary endpoint introduced by protocol 
amendment 3
To investigate the impact of protocol amendment 3, the cumulative time in the study with 
data collected under protocol version 3 or earlier (prior to switching to PV4) as a 
proportion of the total cumulative time in the study will be calculated. Depending on the 
proportion of data collected under each protocol, further supportive analysis will be 
introduced to assess the impact of the change in the method of the primary endpoint 
collection. The analysis is detailed in Section 9.3.1.
9.6.7
Subgroup analyses
Subgroup analyses for confirmed relapses up to EOS will be conducted on the subgroup 
variables listed in Section 8 using the FAS and will be repeated for a Per Protocol 
analysis. The analysis is conducted to assess consistency of the overall treatment effect 
across subgroup variables. 


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A separate NB model will be fitted within each subgroup level for confirmed relapses up 
to EOS, with treatment as the only covariate and the log of the time (in years) from 
randomization up to EOS as an offset variable. Estimates of ARR by treatment arm, rate 
ratio with 99% CIs within each subgroup level will be presented, accompanied by the 
number of subjects per category. The analysis is repeated presenting 95% CIs within each 
subgroup level.
The treatment-by-subgroup interaction p-value is estimated for each subgroup variable 
from a separate model including treatment, the subgroup and the treatment-by-subgroup 
interaction term(s) using a Likelihood ratio test. Interactions with a p-value < 0.01 will be 
investigated further to determine the nature of the interaction (quantitative or qualitative) 
and the association with other subgroups.
Results are presented in a summary table and in a forest plot. The forest plot will include 
the ‘overall’ treatment effect, based on the primary efficacy analysis as a reference line. 
Point estimates are presented within the forest plot with its size proportional to the 
number of subjects in the subgroup.
9.7
Analysis of the secondary efficacy variables
9.7.1
Analysis of change from baseline in FSIQ-RMS weekly symptoms score 
(Fatigue) to Week 108
9.7.1.1
Hypothesis and statistical model 
Change from baseline in FSIQ-RMS weekly score is analyzed using a repeated 
measurements ANOVA model to compare the change from baseline to Week 108 across 
both treatment groups. The underlying hypotheses are expressed as two means, assuming 
the endpoint follows a normal distribution: 
H0, FSIQ: μP20mg, W108 - μT14mg, W108 = 0 vs. 
H1, FSIQ: μP20mg, W108 - μT14mg, W108 ≠0. 
The hypotheses are assessed at a statistical significance level of 1/3 α = 0.05/3 as per the 
overall testing strategy [see Section 9.1.1] based on a t-test for contrasts of mean 
estimates, once the null hypothesis for the primary endpoint has been rejected. 
9.7.1.2
Statistical Analysis 
The main analysis will be based on the FAS. A mixed effect model repeated measures 
(MMRM) which includes baseline (FSIQ-RMS SWSc Base) and the two stratification 
factors, i.e., prior use of DMT (Yes/No), baseline EDSS category (EDSS ≤3.5, 
EDSS > 3.5) as covariates, treatment (fixed effects), visit, treatment by visit interaction, 
and baseline (FSIQ-RMS SWSc Base) by visit interaction is applied. An unstructured 
co-variance structure shared across treatment groups will be used to model within patient 
errors. The Kenwood Roger approximation will be used to estimate denominator degree 
of freedom and adjusted standard errors. This model assumes that missing data follow the 


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missing at random assumption. Subjects with at least one available score at a post-
baseline visit and at the baseline visit are included in the analysis.
Treatment effects per visit are derived based on (difference in) least-square means with 
corresponding 95% CIs and p-values derived using the t-distribution. They will be 
presented in tabular and graphical form. 
The main comparison for this secondary endpoint is conducted on the difference in least-
square means at Week 108. The corresponding p-value is compared to the local 
significance level of 1/3 α = 0.05/3. 
The SAS code for this model is as follows (considered “draft” until fully validated at 
analysis stage):
proc mixed data=;
    class subject treatment visit DMT EDSS;
    model Chg = Base  DMT  EDSS  treatment visit treatment*visit Base*visit/ noint 
ddfm=kr;
    repeated visit /
sub = subject type = un;
    lsmeans Treatment*Visit / pdiff CL OM;
run;
If the normality assumptions seems grossly violated the analysis will be conducted based 
on a rank ANCOVA of change from baseline to Week 108 using a stratified test [see 
Section 10.3.3]. 
9.7.1.3
Supportive / Sensitivity analyses 
Further supportive and sensitivity analyses will be carried out as indicated below. Results 
in terms of treatment difference (95% CI) at Week 108 will be tabulated and forest plots 
will be provided. 
9.7.1.3.1
Change from baseline in FSIQ-RMS weekly symptom score to Week 108 -
delta worsening adjustment in ponesimod 
To evaluate the robustness of the main analysis to deviations from the missing at random 
assumption a delta worsening multiple imputation analysis is conducted. Starting with a 
MAR multiple imputation approach the mean effect following drop-out (last score 
available) is assumed to worsen in the ponesimod 20 mg arm by delta, δP, using a 
marginal approach. δP is increased by small increments until the outcome of the analysis 
shifts from significance to non-significance. An increment size of 0.5 is applied (clinical 
meaningful threshold for change / 10). For the teriflunomide 14 mg arm a MAR multiple 
imputation is performed, i.e., without adding any worsening (δT = 0 for all analyses). 
Analysis for the imputed datasets follows the main analysis and a pooled treatment 
difference estimate, 95% CI and p-value are obtained for each delta. Results are 
displayed graphically versus delta. 


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The analysis is only conducted if the main analysis is significant. 
Non-monotone missing data (in-between missing data points) are imputed based on 
MCMC methods using Proc MI in SAS in a first step of the multiple imputation 
procedure. The covariates baseline FSIQ score, prior use of DMT, and baseline EDSS 
category are considered in the imputation model.
9.7.1.3.2
Change from baseline in FSIQ-RMS weekly symptom score to Week 108 
(LOCF) - ANCOVA
An ANCOVA of change from baseline to Week 108 based on LOCF is conducted, 
adjusting for the same covariates as in the main analysis (baseline value and stratification 
variables). Mean, mean difference and 95% CIs are presented. 
9.7.1.3.3
Change from baseline in FSIQ-RMS weekly symptom score to Week 108 -
based on on-treatment data (up to EOT + 7 days)
The above MMRM for the main analysis will be repeated fitting the model only to data 
collected up to EOT + 7 days. A treatment comparison at Week 108 is conducted.
9.7.1.3.4
Change from baseline in FSIQ-RMS weekly symptom score to Week 108 - Per 
protocol analysis 
A per-protocol analysis will be conducted as supportive. This analysis will be based on 
subjects in the PPS and will only include data in the analysis that were collected prior to a 
protocol deviation leading to exclusion from the per protocol analysis. A model as for the 
primary analysis is applied on the reduced data and a treatment comparison at Week 108 
is conducted. 
9.7.1.4
Descriptive analyses
Daily responses to FSIQ-RMS symptoms items 1, 2, 3, 4, 5, 6, and 7, FSIQ-RMS 
Symptoms Daily Scores will be listed, as well as the FSIQ-RMS weekly symptoms score. 
For each treatment group, by visit, Symptoms Weekly Scores based on observed data and 
LOCF, and change from baseline of these scores will be summarized using descriptive 
statistics. Change from baseline by visit is in addition presented graphically using mean 
(± SE). A separate by visit summary displaying only change from baseline up to 
EOT + 7 days will be provided.
Frequency and percentages of subjects with an available score will be summarized by 
visit. 
9.7.1.5
Subgroup analyses
Subgroup analyses for change from baseline to Week 108 in FSIQ-RMS symptoms score 
will be conducted on the subgroup variables listed in Section 8, apart from recruitment 
period, using the FAS. The analysis is conducted to assess consistency of the overall 
treatment effect across subgroup variables. 


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The above main MMRM analysis will be repeated within subgroup levels using a model 
as for the main analysis without adjustments for stratification factors. Estimates of mean 
at Week 108 by treatment arm, difference in means with 95% CIs within each subgroup 
level will be presented, accompanied by the number of subjects per category. 
The treatment-by-subgroup interaction p-value is estimated for each subgroup variable 
from a separate model including treatment, the subgroup and the treatment-by-subgroup 
interaction term(s). Interactions with a p-value < 0.01 will be investigated further to 
determine the nature of the interaction (quantitative or qualitative) and the association 
with other subgroups.
Results are presented in a summary table and in a forest plot. The forest plot will include 
the ‘overall’ treatment effect, based on the main efficacy analysis as a reference line. 
Point estimates are presented within the forest plot with its size proportional to the 
number of subjects in the subgroup.
9.7.2
Analysis of cumulative unique active lesions from baseline up to Week 108 
(CUAL)
9.7.2.1
Hypothesis and statistical model 
A generalized linear model with negative binomial distribution as described in Section 
10.1 will be assumed for the number of cumulative unique active lesions from baseline to 
Week 108.
Two-sided hypotheses are expressed in terms of the model parameters µP20mg and µT14mg
from the negative binomial regression model. The null hypothesis is that the CUAL (µ) 
does not differ between ponesimod 20 mg and teriflunomide 14 mg. The alternative 
hypothesis is that the CUAL differs between ponesimod 20 mg and teriflunomide 14 mg.
H0, CUAL: µP20mg -  µT14mg  = 0  
                   vs
H1, CUAL: µP20mg -  µT14mg  ≠ 0  
The treatment effect will be evaluated based on the relative reduction in mean CUAL for 
ponesimod 20 mg compared to teriflunomide 14 mg, with corresponding 95% Wald CI. 
The null hypothesis will be tested by a two-sided Wald test, comparing the p-value to the 
local significance level as per the overall testing strategy [see Section 9.1].
9.7.2.2
Statistical analysis
The main analysis of the secondary endpoint CUAL will be performed on the FAS using 
a negative binomial regression model with treatment as a factor and the binary 
stratification variables (EDSS ≤3.5 versus EDSS > 3.5; DMT within last 2 years prior to 
randomization [Yes/No]) and Gd+ T1 lesions at baseline (absent or present) included in 


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the model. The model also includes an offset variable defined as the log of the time up to 
last MRI (in years) considered for analysis. 
Mean model-based estimates of the number of CUALs per year will be provided by 
treatment group, as well as 95% Wald CIs. A rate ratio comparing ponesimod 20 mg with 
teriflunomide 14 mg will be derived from the model including 95% Wald CIs and the 
corresponding p-value. The dispersion parameter will also be displayed.
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. 
Descriptive summary statistics of the number of CUALs up to Week 108 continuous and 
in categories (0, 1–5, 6–10, 11+) will be presented. 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. 
A listing of CUAL data will be presented.
9.7.2.2.1
Handling of missing data
CUAL is derived based on all available MRI scans up to the Week 108 visit (or EOS if 
missing) [see Section 5.4.2.2]. To account for missing MRI scans and consequently 
varying follow-up time, the log-transformed time up to the last post-baseline MRI is used
as an offset in the model. Subjects with no post-baseline MRI result will be excluded 
from the analysis. 
9.7.2.3
Supportive/sensitivity analyses
9.7.2.3.1
Analysis of CUALs from baseline to EOS - Missing data sensitivity: 
Imputation from last MRI scan to Week 108 
To assess the impact of missing data on CUAL, i.e., last MRI scan conducted prior to 
Week 108, sensitivity analyses will be performed. These include the imputation of 
CUALs between last MRI scan and the theoretical Week 108 using different assumptions 
for the period with missing data on the FAS.
Time up to the last MRI scan is presented with a cumulative distribution function by 
treatment arm.
Sensitivity analyses for the main analysis will be conducted based on the MI method for 
negative binomial count data [see Section 10.1.1].
For subjects with missing Week 108 MRI scan the number of CUALs from last MRI scan 
up to the theoretical Week 108 will be imputed under different assumptions. 


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For all MI methods, subjects without a post-baseline MRI scan will be imputed based on 
baseline covariates; they will not be excluded from the analyses. No imputation is 
performed for subjects with missing baseline MRI; they are excluded from the analyses.
Imputation of events is conducted under the following assumptions: Missing at Random 
(MAR), Copy reference, Jump to reference. The corresponding interpretations are 
detailed in Section 9.6.4.3, only that imputation is now conducted post last MRI scan 
instead of post study-withdrawal. 
For each imputed dataset the analysis is adjusted for the same covariates as for the main 
analysis, i.e., the binary stratification variables (EDSS ≤3.5 versus EDSS > 3.5; DMT 
within last 2 years prior to randomization [Yes/No]) and Gd+ T1 lesions at baseline
(absent or present).
The rate ratio estimates with corresponding 95% CIs will be computed for each method.
9.7.2.3.2
Analysis of CUAL - per protocol analysis
The main analysis will be repeated using a per protocol analysis approach, i.e., on the 
PPS and considering MRI scans up to the first deviation leading to exclusion from the per 
protocol analysis. The number of CUALs (per protocol) is used as a response variable 
and the log of the time to the last MRI scan (years) considered in the per-protocol 
analysis as an offset variable [see Section 5.4.2.2]. Covariate adjustment as for the main 
analysis will be applied. 
9.7.2.3.3
Analysis of CUALs from baseline to EOT + 7 days
The main analysis will be repeated using the number of CUALs up to EOT + 7 days as a 
response variable, and the log of the time to the last MRI scan (years) considered in this 
analysis as an offset variable [see Section 10.1], using the FAS. Covariate adjustment as 
for the main analysis will be applied.
9.7.2.4
Subgroup analyses
Subgroup analyses for CUAL from baseline to Week 108 will be conducted on the 
subgroup variables listed in Section 8, apart from recruitment period, using the FAS. The 
analysis is conducted to assess consistency of the overall treatment effect across subgroup 
variables. 
From a methodological point of view subgroup analyses as for the primary endpoint will 
be applied, with results presented in a table and a forest plot. 
9.7.3
Analysis of Time to 12-week CDA
9.7.3.1
Hypothesis and statistical model 
Hypotheses are formulated in terms of survival functions S(t), i.e., the probability that 
time to 12-week CDA is ≥ t for a day t relative to the date of randomization. Two-sided 
hypotheses are expressed in terms of the survival functions SP20mg (t) and ST14mg (t).


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H0,CDA: SP20mg (t) = ST14mg (t) for all t ≥ 0 
    vs.
H1,CDA: SP20mg (t) ≠ ST14mg (t) for all t ≥ 0
The null hypothesis will be tested using a two-sided stratified log-rank test. The p-value 
will be compared to the local significance level as per the overall testing strategy [see 
Section 9.1]. 
9.7.3.2
Statistical analysis
The main analysis on ‘Time to 12-Week CDA up to EOS’ will be performed on the FAS 
by a two-sided stratified log-rank test with stratification factors (EDSS ≤3.5 versus 
EDSS > 3.5; DMT within last 2 years prior to randomization [Yes/No]) as stratification 
variables. 
In addition, hazard ratio and 95% CI based on a stratified Cox regression will be 
provided. The model will include treatment as factor, and the same covariates as for the
log-rank analysis as stratification variables.
Data are summarized in a table including, number of subjects with event / censored, 
Kaplan-Meier estimates (unstratified) and corresponding CI (anticipated time points: 12, 
24, …, 108 weeks), and median (as well as 25th and 75th percentiles) of the survival 
function together with CIs. A graphical display presenting a Kaplan-Meier plot 
(unstratified) going upward is presented including CIs at specific time points as well as 
the log-rank p-value, hazard ratio and CI from the main analysis. 
A listing of 12-week CDA data will be prepared.
9.7.3.2.1
Handling of missing data
See variable derivation in Section 5.4.2.3.1.
9.7.3.3
Supportive / sensitivity analyses
To explore the effect of the stratification variables included in the primary analysis log-
rank test and Cox regression the main analysis will be repeated by adding each 
stratification variable separately at a time, as well as performing equivalent un-stratified 
analyses (only treatment as factor). 
9.7.3.3.1
Time to 12-Week CDA up to EOS - Per Protocol analysis.
The same analyses as for the main analysis will be repeated based on the Time to 
12-Week CDA up to EOS or per protocol exclusion using the PPS, see variable from 
Section 5.4.2.3.2.1.


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9.7.3.3.2
Time to 12-Week CDA up to EOT + 7 days
Repeat the main analysis of the secondary endpoint based on 12-Week CDA up to 
EOT + 7 days, as defined in Section 5.4.2.3.2.2, using the FAS.
9.7.3.3.3
Time to potential 12-Week CDA up to EOS
Repeat of the main analysis of this secondary endpoint based on time to potential 12-
Week CDA, as defined in Section 5.4.2.3.2.3, using the FAS. 
9.7.3.3.4
Time to potential 12-Week CDA up to EOS – Per protocol analysis
Repeat of the main analysis of this secondary endpoint based on time to potential 12-
Week CDA up to EOS or per protocol exclusion using the PPS. 
9.7.3.3.5
Time to 12-Week CDA up to EOS – alternative censoring
The same analyses as for the main analysis will be repeated based on time to 12-Week 
CDA up to EOS with alternative censoring algorithm [see Section 5.4.2.3.2.5].
9.7.3.4
Subgroup analyses
Subgroup analyses for time to 12-week CDA up to EOS on the FAS will be conducted on 
the subgroup variables listed in Section 8 (apart from ‘recruitment period’) using the 
FAS. The analysis is conducted to assess consistency of the overall treatment effect 
across subgroup variables. 
Separate Cox regression models will be fitted within each subgroup level using only 
treatment as a factor and no other covariates. The hazard ratio and 95% CI of the 
treatment effect within each subgroup level will be displayed, accompanied by number of 
subjects with events / censored. 
The treatment-by-subgroup interaction p-value is estimated for each subgroup variable 
from a separate model including treatment, the subgroup and the treatment-by-subgroup
interaction term(s). 
Results are presented in a summary table and in a forest plot. The forest plot will include 
the ‘overall’ treatment effect, based on the primary efficacy analysis as a reference line. 
Point estimates are presented within the forest plot with its size proportional to the 
number of events in the subgroup.
9.7.1
Analysis of Time to 24-week CDA
9.7.1.1
Hypothesis and statistical model 
Hypotheses are formulated in terms of survival functions S(t), i.e., the probability that 
time to 24-week CDA up to EOS is ≥ t for a day t relative to the date of randomization. 
Two-sided hypotheses are expressed in terms of the survival functions SP20mg (t) and 
ST14mg (t).
H0,CDA: SP20mg (t) = ST14mg (t) for all t ≥ 0 


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    vs.
H1,CDA: SP20mg (t) ≠ ST14mg (t) for all t ≥ 0
The null hypothesis will be tested using a two-sided stratified log-rank test.  The p-value 
will be compared to the local significance level as per the overall testing strategy [see 
Section 9.1]. 
9.7.1.2
Handling of missing data
See variable derivation in Section 5.4.2.4.1.
9.7.1.3
Statistical analysis
The main analysis on ‘Time to 24-Week CDA up to EOS’ will be performed on the FAS 
by a two-sided stratified log-rank test with stratification factors (EDSS ≤3.5 versus
EDSS > 3.5; DMT within last 2 years prior to randomization [Yes/No]) as stratification 
variables, similar to the analysis for ‘Time to 12-Week CDA up to EOS’.
Hazard ratio and 95% CI based on a stratified cox regression will be provided. The model
will include treatment as factor, and the same covariates as for the log-rank analysis as 
stratification variables.
Data are summarized in a table including, number of subjects with event / censored, 
Kaplan-Meier estimates (unstratified) and corresponding CI (anticipated time points: 12, 
24, …, 108 weeks), and median (as well as 25th and 75th percentiles) of the survival 
function together with CIs. A graphical display presenting a Kaplan-Meier plot 
(unstratified) going upward is presented including CIs at specific time points as well as 
the log-rank p-value, hazard ratio and CI from the main analysis. 
A listing of 24-week CDA data will be prepared.
9.7.1.4
Supportive/sensitivity analyses
To explore the effect of the stratification variables included in the primary analysis log-
rank test and cox regression the main analysis will be repeated by adding each 
stratification variable separately at a time, as well as performing equivalent un-stratified 
analyses (only treatment as factor). 
9.7.1.4.1
Time to 24-Week CDA - Per Protocol analysis.
The same analyses as for the main analysis will be repeated based on the Time to 
24-Week CDA up to EOS or per protocol exclusion using the PPS.
9.7.1.4.2
Time to 24-Week on treatment CDA up to EOT + 7 
Repeat of the main analysis of this secondary endpoint based on 24-Week CDA up to 
EOT + 7 days using the FAS.


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9.7.1.4.3
Time to potential 24-Week CDA up to EOS
Repeat the main analysis of this secondary endpoint based on time to potential 24-Week 
CDA using the FAS. 
9.7.1.4.4
Time to potential 24-Week CDA -Per protocol analysis
Repeat of the main analysis of this secondary endpoint based on time to potential 24-
Week CDA up to EOS or per protocol exclusion using the PPS. 
9.7.1.4.5
Time to 24-Week CDA up to EOS – alternative censoring
The same analyses as for the main analysis will be repeated based on time to 24-Week 
CDA up to EOS with alternative censoring algorithm [see Section 5.4.2.4.2.5].
9.7.1.5
Subgroup analyses
Subgroup analyses for time to 24-week CDA up to EOS on the FAS will be conducted on 
the subgroup variables listed in Section 8 (apart from ‘recruitment period’) using the FAS
using the same methods as for time to 12-week CDA up to EOS. The analysis is 
conducted to assess consistency of the overall treatment effect across subgroup variables. 
9.8
Analysis of exploratory MRI efficacy variables
9.8.1
Number of 
 at 
 and 
The number of Gd+ T1 lesions at 
 and at 
 will be analyzed by visit on 
the FAS using a negative binomial regression model: Response variable is the 
 of 
 at 
(observed, and separately for LOCF), or at 
(observed, and 
separately for LOCF) respectively, treatment as a factor and 
 
, and 
 at baseline (absent 
or present) as covariates, and no offset. Mean model-based estimates, rate ratio, and 
corresponding 95% CIs and p-value will be presented
The number of
 per visit will be summarized descriptively continuous and 
in categories (anticipated categories: 0, 1, 2, 3, 4+) based on observed data, as well as 
based on LOCF imputation, using the FAS. 
 data will be listed on the 
FAS. 
The cumulative number of 
 up to 
 per scan will be analyzed 
on the FAS using a negative binomial regression model with treatment as a factor and 
 
as covariates. The model also includes an offset 
variable defined as the log of the number of 
 considered for analysis. 
Mean model-based estimates, rate ratio, and corresponding 95% CIs and p-value will be 
presented. Descriptive statistics of cumulative number of 
 up to 
 
 and up to 
will be displayed, separately based on MRI scans up to EOS and 
up to EOT + 7 days. 


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9.8.2
Cumulative number of 
 
The cumulative number of
 
 will 
be analyzed on the FAS using a negative binomial regression model with treatment as a 
factor and 
 
and 
 at baseline (absent or present) as covariates. The model also includes 
an offset variable defined as the log of the time up to last MRI (in years) considered for 
analysis. Mean model-based estimates by treatment arm, and rate ratio
with 
corresponding 95% CIs and p-value will be presented. The analysis is repeated for 
cumulative number of 
 
 
Descriptive summary statistics for the number of 
 
 and to 
 will be presented for continuous data and 
frequency per categories (anticipated: 0, 1–5, 6–10, 11+), by treatment group, 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).
 will be listed.
9.8.3
Percent change of 
 to 
 to 
 and to 
 will be summarized using descriptive 
statistics by visit based on observed data, as well as based on 
 
 and 
listed using the FAS. 
 to 
 will be analyzed based on a linear mixed model using 
the FAS. The model is fitted on the response variable 
 from baseline using all 
available post-baseline MRI scans, and is assumed to follow a normal distribution. Time 
(days from randomization to each MRI scan) is considered as linear continuous covariate 
(a linear time effect is assumed, as supported by results seen for fingolimod 
[Radue 2012]). Fixed effects: Treatment is considered as a factor, and a treatment by time 
interaction is included, the analysis is adjusted for the following covariates: 
 
, 
 
 
 and normalized 
. Subject is 
considered as random effect (intercept) and the within subject covariance matrix is 
assumed to follow a spatial power covariance structure of time (considering time as 
continuous covariate). Mean change at 
 (
 and at 
 (
 
using least square means and difference between treatment arms based on contrasts 
(estimates, 95% CIs, corresponding p-value for treatment difference) will be provided. 
 at 
 is analyzed in addition using a repeated measurement 
ANOVA model (MMRM) with fixed effects: Treatment, Visit (
 
 as 
categorical variable and treatment by visit interaction. Covariates are considered as 
above. An unstructured covariance structure within subjects is considered. Mean change 


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by visit (
 
 and absolute differences in mean change between 
treatment arms are reported based on LS means (estimates, 95% CI, corresponding p-
value for treatment difference).
9.8.4
Change from baseline in the 
 
 and to 
 
The change from baseline in 
 at 
 and 
 will be 
analyzed on the FAS using a repeated measurements ANOVA model (MMRM), with 
treatment as factor, and time (visit) as categorical variable, a treatment by time 
interaction, and unstructured covariance matrix, assuming residuals follow a normal 
distribution. The analysis is adjusted for the following covariates: 
 
Mean change by visit (using least square means) and difference between treatment arms 
by visit using a contrast (estimates, 95% CIs, corresponding p-value for treatment 
difference) will be provided by visit. 
Change from baseline in 
 per visit (at 
 and 
 is 
summarized descriptively based on observed data, as well as based on LOCF imputation, 
using the FAS and 
 data will be listed. 
9.8.5
Change from baseline in the 
 to 
 
and to 
Analyze in the same way as for change from baseline in 
 to 
 
and to 
 
9.8.6
 at 
 and 
 (at 
 and separately at 
 will be 
analyzed on the FAS using a logistic regression model [see Section 10.1.1] with 
treatment as factor, adjusting for the following covariates: 
 
 
Odds ratio for the treatment effect with 95% Wald CIs and corresponding p-
value will be presented. Subjects with missing information are excluded from the 
analysis. A similar analysis is conducted for 
 
 from 
 to 
 and 
 
Descriptive statistics on 
 
s (
 
 will be presented by visit, and cumulative for 
 
 up to each visit. A listing will be prepared using 
the FAS. 


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9.8.7
 
 at 
 and 
 up to each visit on the FAS is analyzed in the 
same way as for 
 [see Section 9.8.6], using logistic regression 
and descriptive statistics. 
9.8.8
Proportion of
 
 will be presented by visit (nominal and 
LOCF) in the subset of subjects with 
. A 
listing will be prepared using the FAS. 
9.8.9
Cumulative number of 
 to 
 
Analyzed in the same way as the main analysis of the secondary endpoint number of 
 up to 
 using a negative binomial regression model on the FAS [see 
Section 9.7.2.2].
Descriptive summary statistics of the number of 
 up to 
 will be presented 
in the same way as for the number of 
 up to 
 but using categories 
(anticipated: 0, 1–2, 3–5, 6+). 
9.9
Analysis of other clinical efficacy variables
9.9.1
 
A two-sided stratified log-rank test with stratification variables (EDSS ≤3.5 versus
EDSS > 3.5; DMT within last 2 years prior to randomization [Yes/No]) and number of 
 in the year prior to study entry, will be performed on the FAS. Hazard ratio and 
95% CI based on a stratified cox regression will be provided. The model will include 
treatment as factor, and the same covariates as for the stratified log-rank test as 
stratification variables. In addition, an unstratified analysis is conducted using a log-rank 
test and Cox regression. 
 
 will be summarized on the FAS in a table including, 
number of subjects with event / censored, Kaplan-Meier estimates (unstratified) and 
corresponding CI (anticipated time points: 
), and median (as well as 
25th and 75th percentiles) of the survival function together with CIs. A graphical display 
presenting a Kaplan-Meier plot (unstratified) going upward is presented including CIs at 
specific time points as well as the log-rank p-value, hazard ratio and CI from the main 
analysis.
data will be listed using the FAS.


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9.9.2
Absence of 
 to 
 and 
(
Absence of 
 to 
 and to 
(
are
analyzed on the FAS as for absence of 
 by visit [see Section 9.8.6] using 
descriptive statistics and a logistic regression model adjusting for the following 
covariates: 
 
 
Subjects with missing outcome are included in the analysis and considered not meeting 
 
 
9.9.3
Change in 
 
The 
 score and change from baseline in 
 score by visit and treatment group 
will be summarized using descriptive statistics on the FAS. A separate by visit summary 
displaying only change from baseline up to EOT + 7 days will be provided. A listing of 
 / 
 scores will be produced on the FAS. 
Change from baseline in 
 score will be analyzed on the FAS using an repeated 
measurements ANOVA model (MMRM) [see Section 10.3.2], with treatment, visit, and 
visit by treatment interaction as fixed effects and adjusting for the following covariates: 
 
Least square means and 95% 
confidence intervals by visit will be presented using a graphical approach. 
9.9.4
 
at 
 as defined in Section 5.4.4.4, will be 
analyzed on the FAS using a logistic regression model [see Section 10.1.1] with 
treatment as factor, adjusting for the following covariates: 
 
 
. 
Odds ratio for the treatment effect with 95% Wald CIs and corresponding p-value will be 
presented. Subjects with missing information are excluded from the analysis. 
Descriptive statistics of 
 status 
 including its components 
 
 
ill be presented at 
 and 
 using the FAS. A listing 
will be prepared. 
9.9.5
 at 
 as defined in Section 5.4.4.5, will be 
analyzed in the same way as 
status on the FAS [see Section 9.9.4].


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9.9.6
Change in 
 to 
 
as well as its subcomponents scores and changes from baseline will be 
descriptively summarized for each treatment group by visit on the FAS (observed and 
LOCF). Mean change (± SE) over time will be graphically presented by treatment group. 
A listing will be prepared. 
A mixed effect model repeated measures (MMRM) analysis on change from baseline in 
 
 will be conducted following the same approach as for the FSIQ-RMS 
weekly symptoms score (main analysis) [see Section 9.7.1.2]. Results will be presented in 
a table and graphically by visit.
9.9.7
Change in the 
 to 
 
 scores and change from baseline will be descriptively summarized for each 
treatment group by visit on the FAS (observed and LOCF). Mean change (± SE) over 
time will be graphically presented by treatment group. A listing will be prepared. 
A mixed effect model repeated measures (MMRM) analysis on change from baseline will 
be conducted following the same approach as for the FSIQ-RMS weekly symptoms score 
(main analysis) [see Section 9.7.1.2]. Results will be presented in a table and graphically 
by visit.
9.9.8
 
 will be summarized using frequencies and 
percentages by visit on the FAS. 
at 
 will be analyzed using a logistic 
regression model adjusting for the two stratification factors. i.e., 
 
and the baseline 
 symptom score as covariates. Subjects with missing 
at 
 will 
be considered to have not responded. Subjects with missing baseline 
 
 are not included in the analysis.  
Cumulative distribution function (CDF) plots will be provided for change from baseline 
to 
 in 
 (observed and LOCF) to visualize the 
entire distribution of responses, i.e., the proportion of patients at each point along the 
scale score continuum who experience change at that level or lower, by treatment arm.
This will allow for simultaneously evaluating 
 
 
9.9.9
Change from baseline by visit up to 
 in 
 
 
 
nd change from baseline will be descriptively summarized for 


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each treatment group by visit on the FAS. Mean change (± SE) over time will be 
graphically presented by treatment group. A listing will be prepared. 
A mixed effect model repeated measures (MMRM) analysis on change from baseline will 
be conducted for each of the 
 separately following the same approach as for 
the FSIQ-RMS weekly symptoms score (main analysis) [see Section 9.7.1.2]. Results 
will be presented in a table and graphically by visit. 
9.9.10
Change from baseline in 
 to 
 
To evaluate the 
, summary statistics of the 
 (n, % per 
 as well as mean, SD, median and range for absolute values and changes 
from baseline) per visit by treatment group will be tabulated and change from baseline as 
well as % in each of the 
 will be graphically presented. 
9.9.11
Change from baseline in
 
 
 
To evaluate the 
 overtime, summary statistics of the 
 (n, % per 
 as well as mean, SD, median and range) per 
visit by treatment group will be tabulated and the change from baseline as well as % in 
each of the 
 will be graphically presented. 
9.10 Analysis of safety variables
9.10.1
Adverse events
All AEs captured (i.e., from signature of informed consent up to EOS) are reported in the 
subject listings based on the SCR, treatment-emergent events are flagged.
Unless otherwise specified, the SAF is used for all analyses of AEs. 
An overview of treatment-emergent AEs is presented, per 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 serious AE, any drug-related serious AE, or 
any fatal serious AE. 
Also, AEs are summarized by system organ class and preferred term: Presenting, per 
treatment group, the number and percentage of subjects having any AE, having an AE in 
each primary SOC, and having 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.
The following summaries are presented:

Treatment emergent AEs

Treatment emergent AEs on Day 1

Treatment emergent AEs on Day 1 of re-initiation, for subjects with at least one re-
initiation


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
Treatment emergent AEs leading to temporary interruption of study treatment

Treatment emergent AEs considered to be related to study drug

Treatment emergent AEs with fatal outcome

AEs with onset prior to first study drug intake (based on the screened analysis set)

Post-treatment AEs with onset after EOT + 15 days, for subjects in the post-treatment 
safety analysis set

Treatment emergent AEs with onset prior to or at EOT + 1 day
Also, treatment-emergent AEs, treatment-emergent AE related to study treatment, and 
treatment-emergent AE leading to premature discontinuation of study treatment are 
summarized by preferred term: presenting, per treatment group, the number and 
percentage of subjects having any AE, and having each individual AE (preferred term). 
Preferred terms are sorted by descending order of frequency in the ponesimod arm. If the 
frequencies are the same, alphabetical order is used.
In addition, one summary table of treatment-emergent AEs by preferred term sorted by 
absolute percent difference (descending) between ponesimod and teriflunomide is 
presented. 
For all treatment-emergent AEs, the number of occasions (i.e. recurrent events) and 
corresponding cumulative subject-years of observation, and – based on Poisson 
regression – the average annualized event rates are tabulated by preferred term sorted by 
descending rate ratio [see Section 10.1].
Treatment-emergent AEs by maximum intensity are summarized by presenting, per 
treatment group, the number and percentage of subjects having any AE, and having each 
individual AE (preferred term).
For the disclosure of the results to EudraCT and ClinicalTrials.gov (and inclusion in the 
clinical study report appendix), frequent treatment emergent non-serious AEs, i.e.,
preferred terms reported in ≥ 5% of subjects in at least one treatment group, are 
summarized as follows:
1) The number and percentage of subjects having any frequent non-serious AE, and 
having each individual non-serious AE (preferred term). 
2) The overall number of frequent non-serious AEs (i.e., reported episodes), and the 
number and percentage of frequent AEs (preferred term). Here the denominator is the 
overall number of frequent non-serious AEs.
9.10.2
Deaths, other serious adverse events
9.10.2.1 Death
The number and percentage of subjects who died are summarized per treatment group, 
including the reported primary cause of death. A summary table is provided for all deaths 


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overall and split by time of death (treatment-emergent and more than 15 days after end of 
study treatment).
A separate listing including all deaths is provided based on the SCR; treatment-emergent 
deaths are flagged as such in that listing. 
9.10.2.2 Serious adverse events (SAEs)
Unless otherwise specified, the SAF is used for all analyses of SAEs.
SAEs are summarized by SOC and preferred term. The following summaries are 
presented:

Treatment emergent SAEs

Treatment emergent SAEs on Day 1

Treatment emergent SAEs on Day 1 of re-initiation, for subjects with at least one re-
initiation

Treatment emergent SAEs with fatal outcome

Treatment emergent SAEs with fatal outcome considered to be related to study drug

Treatment emergent SAEs considered to be related to study drug

Treatment emergent SAEs leading to study drug interruption

SAEs with onset prior to first study drug intake (based on the screened analysis set)

Post-treatment SAEs with onset after EOT + 15 days, for subjects in the post-
treatment safety analysis set.
In addition, treatment-emergent SAEs, treatment-emergent SAE related to study 
treatment, and treatment-emergent SAE leading to premature discontinuation of study 
treatment are summarized by preferred term. 
For the disclosure of the results to EudraCT and ClinicalTrials.gov (and for inclusion in 
the clinical study report appendix), the overall number of treatment emergent SAEs (i.e., 
reported episodes), and the number and percentage SAEs (preferred term) are 
summarized. Percentages of subjects are based on the number of subjects in the safety 
analysis set and the percentages of events are based on the total number of events.
9.10.2.3 Treatment-emergent adverse events leading to study treatment discontinuation
The SAF is used for all analyses of (S)AEs leading to discontinuation. AEs and SAEs 
leading to premature discontinuation of study drug are summarized by SOC and preferred 
term. The following summaries are presented:

Treatment-emergent AEs leading to premature discontinuation of study drug

Treatment-emergent AEs leading to premature discontinuation of study drug on 
treatment day 1

Treatment-emergent AEs leading to premature discontinuation of study drug on 
Day 1 of re-initiation, for subjects with at least one re-initiation


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
Treatment-emergent SAEs leading to premature discontinuation of study drug

Treatment-emergent SAEs leading to premature discontinuation of study drug on 
treatment day 1

Treatment-emergent SAEs leading to premature discontinuation of study drug on 
Day 1 of re-initiation, for subjects with at least one re-initiation
In addition, treatment-emergent AEs leading to premature discontinuation of study drug 
are summarized by preferred term. 
9.10.2.4 Other significant adverse events
9.10.2.4.1 Adverse events of special interest (AESIs) 
For each of the AESI categories described in Section 5.5.9.1, the following information is 
presented: The number and percent of subjects with AESI is summarized by preferred 
term per treatment arm. 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, the relative risk relative to teriflunomide (incl. 
95% CI). The table will also include key estimates from a time to first event analysis 
(Kaplan-Meier estimates and hazard ratio along with 95% CI), the number of occasions 
(i.e., recurrent events) and corresponding cumulative subject-years of observation, and 
based on Poisson regression, the average annualized event rate and rate ratio with 
corresponding rate ratio incl. 95% CI. Corresponding time to first event (Kaplan-Meier)
curves (going upwards) are graphically displayed as described in Section 10.4. Separate 
listings are prepared on the FAS.
These tables and graph are presented for the following subcategories:

Treatment-emergent AESIs, based on the SAF for each AESI category separately;

Hepatobiliary disorders / Liver enzyme abnormality AESI that occurred after start of 
study drug and up to and including EOT + 1 day
In addition, treatment-emergent AESI Effect on heart rate and rhythm related AEs are 
summarized by time of onset by presenting, per treatment group, the number and 
percentage of subjects having any AE, and having each individual AE (preferred term). 
Preferred terms are sorted by descending order of frequency in the ponesimod arm. This 
analysis is done

By day of onset after study start, by groups: Day 1, Day 2, Day 3, Day 4, Day 5, 
Day 6, Day 7, Day 8, Day 9, Day 10, Day 11, Day 12, Day 13, Day 14, Day 15, Day 
16, > Day 16


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
By day of onset after any re-initiation of up-titration, for the following (daily) by 
groups: Day 1 of any re-initiation, Day 2 of any re-initiation… , Day 16 of any 
re-initiation
9.10.2.4.2
Major adverse cardiovascular events (MACE) 
Based on the SAF, treatment emergent MACEs are summarized by presenting, per 
treatment group, the number and percentage of subjects having any MACE, and having
an event of the MACE subcategories (cardiovascular death, non-fatal myocardial 
infarction, non-fatal stroke), and the relative risk relative to teriflunomide (including 95% 
CI). The table will also include key estimates from a time to first event analysis 
(Kaplan-Meier estimates and hazard ratio along with 95% CI), the number of occasions 
(i.e., recurrent events) and corresponding cumulative subject-years of observation, the 
average annualized event rate and corresponding Poisson rate ratio including 95% CI. 
Corresponding time to first event (Kaplan-Meier) curves are graphically displayed as 
described in Section 10.4. A listing is prepared. 
9.10.3
Electrocardiography (ECG)
The following summary displays are provided by treatment group, all based on the SAF:

Quantitative ECG results and absolute change from baseline, as described in 
Section 5.5.11.1,
are summarized, by parameter and visit.
Except for data 
summarized under ‘Baseline’, ‘Day-15 follow-up’ and ‘Day-30 follow-up’, only 
treatment-emergent results from nominal scheduled visits are included, premature 
EOT visit is mapped to a scheduled visit [see Section 11.3]. These are summarized 
descriptively and mean changes (with standard error) from baseline in heart rate are 
also presented graphically over time (plots starting with zero change at baseline);

Quantitative ECG results and absolute change from pre-dose on Day 1, by time point
(pre-dose, 1–12 hours post dose), are summarized descriptively and mean changes 
(with standard error) from pre-dose in heart rate are also presented graphically over 
time (plots starting with zero change at pre-dose), plots are only to include Hours 1–
4;

Descriptive summary statistics of quantitative ECG result and absolute change from 
pre-dose on Day 1 of first Re-initiation, by time point (pre-dose, 1– 12 hours post 
dose); Note: Data from re-initiations beyond the first are listed only;

Number and percentage of subjects with any treatment-emergent PR, QTcF 
prolongations and HR outliers together with 95% CIs for proportions (Clopper-
Pearson exact method) are presented overall and by visit. Percentages are based on 
the number of subjects with at least one treatment emergent result available for the 
corresponding parameter. Abnormalities are presented cumulatively, i.e., a subject 
with a treatment emergent QTcF result > 500 ms is also summarized in the category 
QTcF > 450 ms;


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
Number and percentage of subjects with any post-dose PR, QTcF prolongations and 
HR outliers on Day 1 or Day 1 of Re-initiation together with 95% CIs for proportions 
(Clopper-Pearson exact method) are presented overall post-dose hours and by 
individual time point. Percentages are based on the number of subjects with at least 
one post-dose result available for the corresponding parameter and time point. 
Abnormalities are presented cumulatively;

Number and percentage of subjects with any 3-hr post-dose PR, QTcF prolongations 
and HR outliers on Day 1, Week 12 Visit, and Day 1 of any re-initiation together with 
95% CIs for proportions (Clopper-Pearson exact method). For this analysis the ECG 
results reported as 3-hours post-dose are considered, irrespective of actual time the 
ECG was performed. Percentages are based on the number of subjects with a result 
available for the corresponding parameter at 3-hours post-dose. Abnormalities are 
presented cumulatively;

Number and percentage of subjects with prior morphological ECG findings, and 
new/pre-existing treatment-emergent morphological ECG findings (at any time 
during the respective periods, i.e., prior or treatment-emergent), by abnormality and 
group term following CDISC terminology are presented. New (as compared to any 
assessment prior to study drug start) findings are also presented by visit;

Number and percentage of subjects with prior and new/pre-existing morphological 
ECG findings on Day 1 or on Day 1 of any re-initiation, by abnormality and group 
term following CDISC terminology are presented. New (as compared to any 
assessment prior to study drug start) post-dose hourly ECG findings are also 
presented and by individual time point;

Number and percentage of subjects with prior and new/pre-existing treatment-
emergent morphological ECG findings at Visit 4 (Week 2), by abnormality and group 
term following CDISC terminology.
All ECG data including QTc parameters are listed by treatment group and subject based 
on the SCR. All marked abnormalities are flagged and morphological findings are listed.
9.10.4
Vital signs and body weight
The following summary displays are provided by treatment group, all based on the SAF:

Blood pressure and body weight including absolute change from baseline, as 
described in Section 5.5.10, are summarized, by parameter and visit. Except for 
‘Baseline’, ‘Last on treatment’, ‘Day-15 follow-up’ and ‘Day-30 follow-up’, only 
treatment-emergent results from nominal scheduled visits are included; premature 
EOT visit is mapped to a scheduled visit [see Section 11.3]. These are summarized 
descriptively and mean changes (with standard error) from baseline in blood pressure 
are also presented graphically over time (plots starting with zero change at baseline);


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
Blood pressure including absolute change from baseline on Day 1, by time point
(pre-dose, 1–12 hours post dose), are summarized descriptively and mean changes 
(with standard error) from pre-dose are also presented graphically over time (plots 
starting with zero change at pre-dose);

Descriptive summary statistics of blood pressure including absolute change from pre-
dose on Day 1 of first Re-initiation, by time point (pre-dose, 1–12 hours post dose);
Note: Data from re-initiations beyond the first are listed only;

Number and percentage of subjects with any treatment-emergent blood pressure result 
meeting the criteria defined in Section 5.5.10.1. Percentages are based on the number 
of subjects with at least one treatment-emergent result available for the corresponding 
parameter;

Number and percentage of subjects with post-dose blood pressure result on Day 1 and 
Day 1 of any re-initiation meeting the criteria defined in Section 5.5.10.1 are 
presented overall post-dose hours and by individual time point. Percentages are based 
on the number of subjects with blood pressure results available for the corresponding 
parameter and timepoint;
All blood pressure and body weight results are listed by treatment group and visit based 
on the SCR. Qualitative results (‘normal’ or ‘abnormal’) of body temperature and pulse 
rate are listed as collected in the eCRF, by treatment group and visit based on the SCR.
9.10.5
Laboratory tests
Descriptive summary statistics by visit (including protocol-mandated between visit 
assessments) and treatment group are provided for laboratory test results reported by the 
central laboratory and corresponding absolute changes from baseline, based on the SAF. 
Except for ‘Baseline’, ‘Last on treatment’, ‘Day-15 follow-up’ and ‘Day-30 follow-up’, 
only treatment-emergent results from nominal scheduled visits are included; premature 
EOT visit is mapped to a scheduled visit [see Section 11.3]. Data are displayed in SI units 
as provided by the central laboratory. In the same manner, mean absolute changes from 
baseline with their standard error are presented graphically (plots starting with zero 
change at baseline). Values from unscheduled visits are not included in by visit 
summaries but are included in the listings and in the summaries for marked abnormalities 
and liver function test abnormalities.
For lymphocyte counts, this table and plot are also provided on percent changes from 
baseline. The number of subjects with at least one treatment-emergent marked laboratory 
abnormality is summarized by treatment group, based on the SAF. 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. In addition, the number of subjects 
with treatment-emergent liver function test abnormalities is summarized by treatment 


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group. This tabulation is also repeated for abnormalities that occurred after start of study 
drug and up to and including EOT + 1 day. The denominator for percentages is the 
number of subjects with at least one post-baseline assessment.
A plot to evaluate Drug-Induced Serious Hepatotoxicity (eDISH plot) is provided based 
on the highest observed treatment-emergent ALT and total bilirubin values, considering 
both, central and local laboratory data. 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. A footnote is presenting, for each treatment group, the 
number and percentage of subjects falling in each of the 4 quadrants defined by these 
reference lines. This eDISH plot is repeated for abnormalities that occurred after start of 
study drug and up to and including EOT + 1 day.
Safety laboratory hematology, clinical chemistry, urinalysis parameters planned as per 
protocol are also presented in subject data listings based on the SCR. All abnormalities 
and marked abnormalities including those at baseline are flagged in the listings.
Other laboratory parameters are presented in a separate listing on the SCR. 
Further analyses related to lymphocytes are described in Section 9.13.
9.10.6
Pulmonary function tests - Spirometry
The following summary displays are provided by treatment group, all based on the SAF:

Treatment-emergent FEV1, FVC, FEV1/FVC, %FEV1, and %FVC including 
absolute and percent change from baseline, as described in Section 5.5.13.1, are 
summarized, by parameter and visit. Except for ‘Baseline’, ‘Last on treatment’, 
‘Day-15 follow-up’ and ‘Day-30 follow-up’, only treatment-emergent results from 
nominal scheduled visits are included; premature EOT visit is mapped to a scheduled 
visit [see Section 11.3]. These are summarized descriptively and mean changes from 
baseline are also presented graphically with their standard error over time (plots 
starting with zero change at baseline).

A scatter plot of all measured treatment-emergent %FEV1 values is provided. 
Treatment groups are color-coded and linear regression lines (with time as 
explanatory variable) are drawn per treatment group. These regression lines are to 
visualize the course over time after an initial change in pulmonary function and for 
that reason, exclude measurements taken prior to study day 26. The regression 
equation is given in a footnote.

Number and percentage of subjects with any occasion of treatment-emergent low 
spirometry values as defined in Section 5.5.13.1 are presented. Percentages are based 
on the number of subjects with at least one treatment-emergent result available for the 
corresponding parameter;


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
In the subset of subjects experiencing a decrease of ≥ 200 mL or ≥ 12% in FEV1 (or 
FVC) from baseline to the last assessment on treatment, the number and percentage of 
subjects with the condition reversed, not reversed, or missing data on reversibility at 
the last follow-up result is provided;

FEV1, FVC, FEV1/FVC, %FEV1, %FVC at the following three time points (for 
definition, see Section 5.5.1) are displayed graphically by box-and-whisker plots 
visualizing mean, median, interquartile ranges, SD, and outliers over time: Baseline, 
last assessment on treatment, and Day-15 follow-up assessment. All subjects with 
data available at all three time points are included. A corresponding table is included 
as well.

Individual absolute change from baseline to last assessment on treatment versus
absolute change from baseline to last follow-up assessment is graphically displayed
for FEV1, FVC, %FEV1, and %FVC by means of scatterplots with treatment groups 
color-coded.
All spirometry results (best effort results) are listed by treatment group and visit based on 
the SCR. 
9.10.7 Pulmonary function tests - DLCO
The following summary displays are provided by treatment group, all based on the DLCO
sub-study safety analysis set:

Treatment-emergent Hemoglobin corrected DLCO, Percent predicted DLCO, and DLCO
including absolute and percent change from baseline as described in Section 5.5.13.2, 
are presented, by parameter and visit. Except for ‘Baseline’, ‘Last on treatment’, 
‘Day-15 follow-up’ and ‘Day-30 follow-up’, only treatment-emergent results from 
nominal scheduled visits are included; premature EOT visit is mapped to a scheduled 
visit [see Section 11.3]. These are summarized descriptively and mean changes from 
baseline are also presented graphically with their standard error over time (plots 
starting with zero change at baseline). The analysis is repeated based DLCO
measurements graded acceptable.  

A scatter plot of all measured treatment-emergent Percent predicted DLCO values is 
provided. Treatment groups are color-coded, and linear regression lines are drawn per 
treatment group. This regression lines are to visualize the course over time after an 
initial change in pulmonary function and for that reason, excludes any measurements 
taken prior to study day 26. The regression equation is given in a footnote.

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 5.5.13.2 are presented. Percentages are based on the number of subjects with 


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at least one treatment-emergent result available for the corresponding parameter. The 
analysis is repeated based DLCO measurements graded acceptable.

Hemoglobin corrected DLCO, Percent predicted DLCO, and DLCO at the following 
three time points [for definition, see Section 5.5.13.2] are displayed graphically by 
box-and-whisker plots visualizing mean, median, interquartile ranges, SD, and 
outliers over time: Baseline, last assessment on treatment, and Day-15 follow-up 
assessment. All subjects with data available at all three time points are included. A 
corresponding table is included as well.

Individual absolute change from baseline to last assessment on treatment versus 
absolute change from baseline to last follow-up assessment is graphically displayed 
for Hemoglobin corrected DLCO, Percent predicted DLCO, and DLCO by means of 
scatterplots with treatment groups color-coded.
All DLCO results (derived mean values per assessment) are listed by treatment group and 
visit based on the SCR. 
9.10.8
Analysis of other safety variables
Other safety assessment results will be listed. This comprises the following assessments: 
Dermatological examination, OCT, and Ophthalmological Examination and Columbia 
Suicide Severity assessment. 
9.10.8.1 Columbia Suicide ideation or behavior
Suicidal Ideation, Suicidal Behavior or Self-Injurious Behavior without Suicidal Intent 
will be listed for each patient, at each assessment visit on the SAF. Events occurring 
during the period up to EOT + 15 days (treatment-emergent period) will be flagged.
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 and 
visit, as well as up to EOT + 15 days (worst outcome). Analyses will be based on subjects 
in the SAF who have at least one eC-SSRS measurement during the respective visit or
period available. The analysis will be repeated in the subgroup of patients with no 
baseline result available.
For subjects who have in addition a baseline eC-SSRS assessment available shifts from 
baseline (maximum score from pre-treatment recent history) to the worst reported 
outcome (the maximum score) up to EOT + 15 days will be tabulated by treatment group 
to demonstrate any changes in Suicidal Ideation and Suicidal Behavior score categories. 


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9.11 Analysis of quality of life variables
9.11.1
Change from baseline by visit up to Week 108 in SF-36v2™Health Survey 
domain and component scores 
Quality of life analysis based on the SF-36v2™will be performed on the FAS. 
The eight normative (t-scores) domain scores, PCS and MCS will be summarized 
descriptively over time (Baseline, Weeks 12, 24, 60, 84, 108) by treatment groups
(observed and LOCF). Changes overtime will be graphically presented for each of the 
domains, PCS and MCS by treatment group (mean and ±SE). The health transition item 
(#2) will be summarized separately (in categories) by visit and a shift table from baseline 
to Week 108 (observed and LOCF) will be prepared. 
9.12 Analysis of pharmacoeconomic variables
9.12.1
Change from baseline by visit up to Week 108 in WPAI:MS scores 
Analyses will be summarized and listed on the FAS. WPAI scores and number of 
subjects currently employed by visit during the main study are summarized per treatment 
group. WPAI-MS
outcome measures (absenteeism, presenteeism, overall work 
impairment and activity impairment) will be graphically presented over time using mean 
± SE. 
9.12.2
Health care resource utilization
Health care resource utilization will be summarized and listed on the FAS.
Descriptive summary statistics will be displayed for subjects with at least one and 
frequency of health care resource utilizations as well as length of stay (days) from 
baseline up to Week 108 for the following categories: all hospitalizations, 
hospitalizations due to AE, hospitalizations due to relapse, ICU admissions due to MS 
relapses, emergency room visits due to MS. 
9.13 Analysis of pharmacodynamic variables
Descriptive analyses of lymphocyte data are described in Section 9.10.5. Only 
lymphocyte counts from central laboratory, irrespective of whether obtained at a 
scheduled or unscheduled visit, are included in any of the below describe analyses.
For each subject in the SAF, the 

Nadir (i.e., lowest) treatment-emergent lymphocyte value (up to EOT + 15 days)
is identified and summarized by means of frequency counts and percentages based on the 
categories specified in Section 5.8.
Lymphocyte counts and percent change from baseline in lymphocyte counts at the 
following time points [for definition, see Section 5.8] are summarized using descriptive 


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statistics and displayed graphically by box-and-whisker plots visualizing mean, median, 
interquartile ranges, SD, and outliers over time: Baseline, Last on-treatment, Day-15 
follow-up (plus one display adding Day-30 follow-up in addition). Only subjects with 
data available at all three (four) time points are included. Corresponding descriptive data 
is tabulated. 
Individual absolute and percent change from baseline in lymphocyte counts to last 
assessment on treatment versus absolute and percent change from baseline to last 
follow-up is graphically presented by means of scatterplots with treatment groups color-
coded.
9.14 Analysis of pharmacokinetic variables
Will be detailed in a separate analysis plan. 
10 GENERAL STATISTICAL METHODOLOGY
This section describes in general terms the statistical models and methods applied.
10.1 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 for subject j.
Yj
denotes the counts of interest 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 with 99% CI is as follows (considered “draft” until fully 
validated at analysis stage):
proc genmod data=ADREL;
     class Treat Strat Covar;
     model COUNTS = Treat Strat Covar / dist=negbin link=log 
     offset = offset;
lsmeans Treat / cl exp alpha = 0.01 OM;
     estimate ‘Ponesimod - Teriflunomide’ “ Treat 1 -1 / exp alpha = 0.01; 
run;


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The offset variable used will be specified per analysis (e.g. for ARR it is the log-
transformed observation time, for total T1 lesions it is the log-transformed number of 
available MRI scans, …). 
The ‘LSMEANS’ statement will output the mean estimates for each of the treatment arms 
with 99% Wald CIs; the option OM ensures that the mean is derived for categorical 
covariates with weights as per observed marginal proportions.
The ‘ESTIMATE’ statement will output the rate ratio of the treatment effect with 99% 
Wald CIs. The direction of the estimate statement (governed by ‘1 1’ or ‘−1 1’) is 
chosen such that the rate ratio relative to teriflunomide is provided (with rate ratio < 1 
indicating ponesimod is better).
To obtain 95% CIs the option alpha = 0.05 is used in the LSMEANS and ESTIMATE 
statements. 
The number of covariates / stratification variables included in the model is different from 
analysis to analysis, and these are described in the respective analysis sections [see 
Section 9]. Interaction terms might be included in the model, depending on the analysis.
If the NB distribution is not considered to be appropriate (e.g. due to non-convergence), 
other distributions such as the Poisson and zero-inflated Poisson will be explored. For the 
Poisson distribution, a Poisson regression is conducted with model equation identical to 
the one for the negative binomial regression. The SAS code is as follows (considered 
“draft” until fully validated at analysis stage):
proc genmod data=ADREL;
     class Treat Strat Covar;
     model COUNTS = Treat Strat Covar / dist=poisson link=log 
     offset = offset;
lsmeans Treat / cl exp alpha = 0.01;
     estimate ‘Ponesimod - Teriflunomide’ “ Treat 1 -1 / exp alpha = 0.01; 
run;
10.1.1 Imputation methods for count data
Multiple imputation for count data will be applied for sensitivity analyses of the primary 
and secondary count data. 
A multiple imputation approach following Keene 2014 is followed, count data being 
assumed to follow a negative binomial distribution. Implementation will be based on a 
SAS Macro publicly available [see Roger 2017].  
The general multiple imputation is a 3-step approach:
(i) Create nimpute imputed datasets. Details are specified below in the imputation 
algorithm.


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(ii) Analyze each imputed dataset using a negative binomial model as for the 
corresponding main analysis. (Details such as response, covariates, and offset are 
specified per analysis). 
(iii) Derive multiple imputation inferential statistics by combining step (ii) results using 
Rubin’s rules. 
In step (iii) the rate ratio with corresponding CI (99% and/or 95%) will be derived.
For creation of the imputed datasets in step (i) the following imputation algorithm will be 
followed:
Imputation algorithm for negative binomial count data
1. Fit a bayesian log-linear negative binomial regression model on non-missing data,

For imputation between EOS and Week 108 fit to count data up to EOS; for 
imputation between EOT+7 and Week 108 fit to count data up to EOT + 7;

Use logarithm of time (in years) as an offset variable, treatment as a factor and 
adjust for covariates as for the main analysis;

Use non-informative priors for the model parameters (Default option for proc 
genmod with bayes statement); 
–
Generate samples for the model parameters (linear regression parameters β 
and dispersion parameter k) from the posterior distribution using MCMC
(seed = 24092010). 
The following initial MCMC specifications will be used: 1000 burn-in 
iterations (nbi = 1000), 20000 iterations after burn-in (nmc = 20000), with a 
thinning of 5 (thin = 5). This yields a total of 4000 posterior draws (nmc 
thin), which corresponds to the number of multiple imputations (nimpute =
4000). The MCMC specifications, may be adjusted based on diagnostic 
checks for the Bayesian model.
2. Impute the count data for the missing follow-up time conditional on the follow-up 
information available based on the parameter estimates samples from step 1, under 
the considered assumption (MAR, copy reference, jump to reference, or delta 
adjustment). The conditional distribution follows also a negative binomial 
distribution; see Keene 2014 for details (seed = 30112013). 
3. Derive the overall imputed count variable by adding up the observed count data (e.g.,
confirmed relapses up to EOS for imputation between EOS and Week 108) and the 
simulated count data for the missing follow-up time (from step 2). 
4. Repeat this nimpute times to obtain nimpute complete datasets.


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Imputation based on baseline covariates only
Imputation based on baseline covariates only (required for imputation of CUALs from 
baseline to Week 108 for subjects without any post-baseline MRI scan) can be 
implemented with the above algorithm as follows: Subjects with missing information are 
included in the input dataset with count variable of zero and time variable of zero. 
Interpretation is that no events (e.g., CUALs) have been observed since baseline for zero
follow-up time. The imputation algorithm steps 2–3 will impute the counts for the entire 
time period from randomization to Week 108 which is the missing follow-up time in this 
case. The conditional distribution simplifies in this case to the marginal distribution and 
thus imputation will be based on baseline covariates only [see Keene 2014]. Note that in 
step 1 of the imputation algorithm, these zero follow-up time records will be ignored 
when fitting the Bayesian negative binomial regression model as the offset (log of the 
follow-up time) does not exist.  
10.2 Statistical methods for binary data
10.2.1 Logistic regression
A logistic regression model is considered for binary response variables separately by 
visit. The model is applied, e.g., to absence of Gd+ T1 lesions by visit. The model 
includes treatment as factor and covariates as specified in the respective analysis section. 
Specifically, the model with the structure below is used: 
+,-./(0)~ 23 + 24TREAT + 27 COVAR
Odds ratio estimates of the treatment effect (ponesimod vs teriflunomide) and 95% Wald 
CIs as well as the corresponding p-value are derived. The SAS code for this model is as 
follows (considered “draft” until fully validated at analysis stage):
proc logistic data=;
     class Treat Strat Covar;
     model BINARY_RESPONSE = Treat Strat Covar;
     oddsratio Treat /cl=wald;
     ods output OddsRatiosWald = oddsr;
     lsmeans trt / ilink cl oddsratio OM;
run;
10.3 Statistical methods for continuous data
10.3.1 ANOVA / ANCOVA model
An analysis of variance (ANOVA) model is considered for continuous responses that are 
expected to be approximately normally distributed. Treatment is included as a factor. 
Adjustment for additional covariates, as well as interaction terms might be included, 
depending on the analysis, in which case it is usually referred to as analysis of covariance 
(ANCOVA) model.


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The SAS code for this model is as follows (considered “draft” until fully validated at 
analysis stage):
proc glm data= ;
     class Treat Strat Covar;
     model Response = Treat Strat Covar ;
     lsmeans Treat / cl alpha = 0.05 OM;
run;
10.3.2 Mixed effects repeated measurements model
A general mixed model for repeated measurements (linear mixed effects model) is 
considered for continuous responses that are expected to be approximately normally 
distributed and measured at scheduled visits over the course of the study. 
Mixed effect repeated measurement model (MMRM) by visit data
The model includes fixed effects for treatment, visit as categorical covariate, the 
stratification variables as well as other categorical covariates and the interaction between 
treatment and visit. Additional covariates may be added. An unstructured covariance 
matrix for within-subject errors is applied. Treatment effect at a specific time point 
inferential statistics are derived based on contrasts and t-distribution, overall fixed effect 
treatment effect is assessed based on Type III effects.
The SAS code for this model is as follows (considered “draft” until fully validated at 
analysis stage):
Proc mixed data=; 
   class subject Treat Visit Strat Covar;
   model Response = Treat Visit Treat*Visit Strat Covar / noint DDFM = KR solution;
   repeated Visit /subject=subject type=un;
   lsmeans Treat*Visit / pdiff CL OM;
run;
Mixed effect model with time as continuous variable
A mixed model for repeated measurements similar to the model above but considering 
time as a continuous variable and assuming a linear time effect is considered. Fixed 
effects are treatment, time (continuous) and treatment by time interaction. Further 
covariates can be added to the model. Subject is considered as random effect with spatial 
power correlation function (generalization of the autoregressive order one structure for 
unequally spaced data) of time (continuous) for the within-subject errors. This model can 
be applied using the following SAS code:


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Proc mixed data=; 
   class subject Treat Strat;
   model Response = Treat Time Treat*Time Strat Covar / noint DDFM = KR solution;
   random Int / subject = subject type = un;
   repeated / subject=subject type= SP(POW)(Time);
   lsmeans Treat / cl diff at time = 108 OM; *Time presented in Weeks;
run;
10.3.3 Rank ANCOVA
A rank analysis of covariance will be considered for continuous responses that are not 
approximately normally distributed.
The non-parametric ANCOVA procedure 
incorporates three steps:
1. Transformation of baseline and post-baseline change values for all patients 
(regardless of treatment groups) to standardized ranks (i.e., ranks divided by the 
number of patients ranked plus 1, mean ranks in case of ties). For a stratified 
approach standardized ranks are obtained in each stratum separately. 
2. Fit linear regression of post-baseline standardized ranks (by stratum for stratified 
analysis) on baseline standardized ranks and determine residuals. 
3. Application of the Wilcoxon-Mann-Whitney test to these residuals (or van Elteren 
test for a stratified analysis) to test null hypothesis of no difference in location 
between treatment arms against the alternative of a difference in location. 


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SAS code for the analysis:
PROC RANK DATA=dataset TIES=MEAN NPLUS1 OUT=stdrank;
BY strata; *optional for stratified analysis;
VAR base outcome;
RUN;
PROC GLM DATA=stdrank;
BY strata; *optional for stratified analysis;
MODEL outcome = base / PREDICTED;
ODS OUTPUT PredictedValues = pred;
ID treat;
RUN;
* Step 3 for unstratified analysis;
PROC NPAR1WAY DATA=pred WILCOXON;
CLASS treat;
VAR residual;
RUN;
* Step 3 for stratified analysis;
PROC FREQ DATA=pred SCORES=MODRIDIT;
TABLES strata*treat*residual / CMH2;
RUN;
* base represents the Baseline value of the endpoint;
* outcome represents the post-Baseline endpoint;
* strata represents the stratification variable(s);
* treat represents the treatment group;
10.4 Statistical methods for time-to-event data
The analysis of time-to-event data are conducted using Kaplan-Meier estimates of events 
over time (including graphical representation), stratified log-rank test and Cox 
proportional hazard model.
10.4.1 Time to Event and log-rank test
Estimates of the event rate are obtained for each treatment group using the Kaplan-Meier 
method as implemented in SAS Proc Lifetest. The graphical representation follows the 
recommendations from Pocock [Pocock 2002]. Two-sided CIs at specific time points are 
constructed, with confidence limits calculated using Greenwood’s formula for the 
estimate of the standard error. Median time to event (as well as 25th and 75th percentiles) 
for each group are provided with the corresponding two-sided CIs calculated using the 
method of Brookmeyer [Brookmeyer 1982].
The stratified log-rank test is conducted with SAS Proc Lifetest where the STRATA 
statement includes the specified stratification variables and the GROUP option includes 
the treatment variable (treat). The TIME statement includes a variable with times to event 


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(time) and an indicator variable for right censoring (censor) with 1 representing 
censoring.
Proc lifetest data= method=KM; 
   time survtime*censor(1);
   strata STRAT COVAR / group=treat diff=control(‘Teriflunomide’);
run;
10.4.2 Cox proportional hazard model
SAS Proc Phreg is used to estimate the hazard ratio, the p-value associated with the 
treatment effect hazard ratio and the CI of the hazard ratio (using Wald-based methods). 
The Cox regression model can be implemented using the following code: 
Proc phreg data =;
  class treat (ref=‘Teriflunomide’) 
        Strat;
  model TimeTo*censor(1)= treat /risklimits ties=exact;
  strata Strat;
run;
An investigation into the assumption of proportional hazards for treatment is performed 
informally using a plot of the complementary log-log of the survival against the log of 
time (for each group). If the hazards are proportional, the lines should be approximately 
parallel. A plot of the Schoenfeld residuals against time and log(time) is also constructed, 
including a Loess curve [Collett 1994]. Departure from a horizontal line indicates 
violations of the proportional hazard assumption. A test of a non-zero slope is also 
derived based on traditional linear regression model. Since certain types of 
non-proportionality are not detected by the test, both the test and the plot are used to 
assess the non-proportionality assumption.
11 GENERAL DEFINITIONS AND DERIVATIONS
11.1 Dates, times and days
Study treatment start date see definition in Section 5.3.1.
End-of-Treatment (EOT) / Study treatment end date, defined as the latest study 
treatment end date as recorded on the Study Drug Log (SDL) eCRFs [see Section 5.3.1].
End-of-Study (EOS) date defined as the ‘Date of End of Study’ collected on the end of 
study eCRF, unless a subject is lost to follow-up or dies, in which case ‘Date of Last 
Contact’ or ‘Date of Death’ from Death eCRF are used [see Section 5.1.6].
Screening date defined as the visit date of the last available screening visit, i.e., date of 
Visit 1A for re-screened subjects, date of Visit 1 for all others.  
Study Day refers to the number of days elapsed since randomization date plus 1 (e.g., 
Study Day 1 is the day of randomization). For dates prior to randomization, study day is 


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the negative number of days elapsed between the date under consideration and the day of 
randomization. Therefore, the study day is always different from 0.
For efficacy analyses also referred to as ‘Day’. 
Treatment Day refers to the number of days elapsed since study treatment start date plus 
1 (e.g., Treatment Day 1 is the day of study treatment start). For dates prior to study 
treatment start, treatment day is the negative number of days elapsed between the date 
under consideration and the day of study treatment start. Therefore, it is always different 
from 0.
For safety analyses also referred to as ‘Day’. 
11.2 Analysis period definitions
11.2.1
Efficacy study periods
The ‘Efficacy Study Period’ of primary interest in this study is the period from 
randomization up to the EOS date, defined as: [Randomization; EOS].
For sensitivity efficacy analyses an ‘Efficacy Treatment Period’ is defined as:
[Randomization; EOT + 7 days].
11.3 Re-assignment of premature EOT visits / Visit windowing
For all parameters unless stated below: For subjects who discontinued study drug 
prematurely with available premature EOT visit, 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 9].


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Table 9
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
29
23
70
Week 12
85
71
126
Week 24
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
Open end
Day refers to treatment day, i.e., days from study treatment start. 
MRI: For MRI measurements visit windowing of premature EOT visits is conducted 
using ± 3 months around the target day (Week 60: Day 330 to Day 512; Week 108: 
≥Day 665) to account for the less frequent assessment schedule.
Patient reported outcomes collected on electronic device: For patient reported 
outcome data collected via an electronic device visit windowing is applied as a general 
process. Rationale is that incorrect visit labels are not corrected via a query process
whereas the questionnaire date is tracked automatically by the device therefore, the latter
is considered to provide most reliable information. Questionnaires based on dates will be 
assigned to the visits based on Table 10. If multiple questionnaires are available, the one 
closest to target is selected. 
Physician reported questionnaire and other composite assessment data
 
 
 Nominal visits are considered. If missing at the nominal visit, data from 
a premature end of treatment visit (if not available or appropriate then from an 
unscheduled visit) is assigned to the visits based on Table 10. If multiple unscheduled
assessments qualify the one closest to target is selected. 


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Table 10
Visit windowing for questionnaire and psychometric assessment data
Visit window
Nominal value
Day
Lower limit for
Day (Week)
Upper limit for
Day (Week)
Baseline
-1
Open end
1
Week 12
85
2 (W0+)
126 (W18)
Week 24
169
127 (W18+)
294 (W42)
Week 60
421
295 (W42+)
504 (W72)
Week 84
589
505 (W72+)
672 (W96)
Week 108
757
673 (W96+)
Open end
Day refers to study day, i.e., days from randomization date. Wx+ = after week x.
11.4 Summaries by visit
Visit based safety and PD assessments are generally summarized according to the 
nominal visit. Except for Visit 14 (EOT/Week 108) in subjects prematurely discontinuing 
study treatment, Visit 15 (FU1, Day-15 follow-up assessment), and Visit 16 (FU2, Day-
30 follow-up assessment). Those are derived following the rules below:

Premature EOT visits are re-assigned following the visit windowing described in 
Section 11.3

Day-15 follow-up assessment: Any assessment within EOT date + 8 days and EOT 
date + 22 days. If multiple assessments fall into that period, the one corresponding to 
the regular FU1 visit (Visit 15) is selected, if none of the multiple assessments 
corresponds to that visit, the one closest to EOT date +15 days is selected, if there are 
two closest assessments, the later one is selected.

Day-30 follow-up assessment: Any assessment within EOT date + 23 days and EOT 
date + 37 days. If multiple assessments fall into that period, the one corresponding to 
the regular FU2 visit (Visit 16) is selected, if none of the multiple assessments 
corresponds to that visit, the one closest to EOT date + 30 days is selected, if there are 
two closest assessments, the later one is selected. 
In addition, the ‘Last on-treatment’ assessment is flagged. This is defined to be the latest 
assessment prior to or on EOT date +1 day.    
Summaries by visit are presented by Baseline (derived), and further scheduled nominal 
visits up to Week 108 (irrespectively if conducted during PTOP or not), Last on-
treatment, and derived Follow-up visits (FU1, FU2). Generally, by visit tables are 
tabulating the baseline and nominal and derived visits as follows:

Baseline (Note: This is not a nominal visit but the derived baseline; see Section 5.5.1)

Visit 4 - Week 2


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
Visit 5 - Week 4

Visit 6 - Week 12

Visit 7 - Week 24

Visit 8 - Week 36

Visit 9 - Week 48

Visit 10 - Week 60

Visit 11 - Week 72

Visit 12 - Week 84

Visit 13 - Week 96

Visit 14 - Week 108

Last on-treatment (derived; see Section 5.5.1)

Day-15 follow-up (derived)

Day-30 follow-up (derived)
Premature EOT visits are mapped to and summarized within a scheduled visit following 
the window approach described in Section 11.3; they will not be summarized as “Visit 14 
- Week 108” unless they are mapped to this visit as per approach described in 
Section 11.3.  
As per protocol, WBC and total lymphocyte counts will be assessed every 4 weeks up to 
Week 24 (i.e., there are 3 protocol mandated between-visit assessments for those tests at 
Week 8, Week 16, and Week 20 when no regular visit is scheduled). Likewise, liver tests 
(ALT, AST, INR, alkaline phosphatase and total bilirubin) will be assessed in-between 
visits at Weeks 6, 8, 10, 14, 16, 18, 20, and 22 in all countries except Canada, the United 
States, and Mexico. In Canada, the United States, and Mexico there are only 3 protocol 
mandated between-visit assessments for the liver function tests at Week 8, Week 16, and 
Week 20.
These assessments are considered scheduled and are included in corresponding by-visit 
tabulations labeled as follows:

Additional Visit - Week 6

Additional Visit - Week 8

Additional Visit - Week 10

Additional Visit - Week 14

Additional Visit - Week 16

Additional Visit - Week 18

Additional Visit - Week 20

Additional Visit - Week 22
Visit-based efficacy, quality of life or pharmaeconomic assessments are summarized 
according to the nominal visit up to EOS, irrespective if conducted during PTOP or not:


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
Baseline (Derived)

Visit 6 - Week 12

Visit 7 - Week 24

Visit 8 - Week 36

Visit 9 - Week 48

Visit 10 - Week 60

Visit 11 - Week 72

Visit 12 - Week 84

Visit 13 - Week 96

Visit 14 - Week 108
Premature EOT visits are mapped to and summarized within a scheduled visit following 
the window approach described in Section 11.3; they will not be summarized as “Visit 14 
- Week 108” unless they are mapped to this visit as per approach described in 
Section 11.3.  
11.4.1 LOCF imputation 
LOCF imputation by visit is applied for several variables and is derived as follows: If a 
scheduled visit is missing or the result at a scheduled visit is missing, the outcome is 
imputed with the last available post-baseline result up to the upper limit of the visit 
window [see Section 11.3]. Baseline observations are not carried forward. 
11.5 Listings of safety data for subjects with deviations from study treatment 
schedule
For safety data analysis based on the safety analysis set, subjects who - in error - were 
treated with both study treatments (teriflunomide and ponesimod) are summarized under 
the treatment group the subjects were exposed to for the longest time [see Section 7.1.4]. 
In order to individually review and – as needed – discuss their safety results, safety data 
listings are repeated in this subset of subjects.  
Likewise, listings of adverse events, blood pressure and ECG results are provided for 
subjects who resumed ponesimod maintenance treatment without up-titration after an 
interruption of > 3 days and for subjects who deviated from planned up-titration regimen.  
12 HANDLING OF MISSING/INCOMPLETE DATE AND 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. 


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12.1 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 11]. 
Table 11
Handling of missing or partial start and end dates for 
previous/concomitant therapies
eCRF
page
Start date 
End date
Previous / 
Concomitant 
Prev*
Unless 
start 
date 
clearly 
after/on STS 
(Start date either: prior to STS 
date, partial with either lower 
or upper limit prior to STS 
date, or missing)
Unless end date after/on STS
(Either prior STS, partial with either lower 
or upper limit prior STS, or missing)
Previous
Con**
Unless 
start 
date 
clearly 
after/on STS (as above)
Prior to STS date; or
Partial with upper limit prior to STS date; 
Previous
Con**
Start date confirmed prior STS
(Start date either: prior to STS 
date, partial with upper limit 
prior to STS date) 
End date on STS date and ‘Ongoing at start 
of Treatment’ ticked ‘No’; or
Partial with lower limit prior to STS date 
and upper limit after/on STS date and 
‘Ongoing at start of Treatment’ ticked ‘No’; 
Previous
Any
All other cases not listed above
All other cases not listed above
Study 
concomitant
STS = Study treatment start; For subjects randomized but not treated the randomization date is used instead of the STS.
* 
Includes ‘Previous Medications’ or ‘MS Specific Treatment History Log’ eCRF: On these forms as per CRF 
completion guidelines only medications that stopped prior to signature of informed consent are to be recorded. 
** Includes all forms collecting therapies apart from ‘Previous Medications’ or ‘MS Specific Treatment History Log 
eCRF.
To derive treatment concomitant therapies in case of missing or partial start dates for a 
study concomitant therapy the following rules apply: 

Start date is available and after EOT, or start date is partial with lower limit after 
EOT: not considered treatment concomitant irrespective of end date

Start date is available and prior or on EOT, start date is partial with lower limit prior 
or on EOT, or start date is missing: considered treatment concomitant irrespective of 
end date

Subjects randomized but not treated are not considered to have any treatment 
concomitant medications
To further flag study concomitant therapies as ‘ongoing at study treatment start’ or 
‘started during study drug administration’ medications the following rules apply: 

Study concomitant therapies with missing start date or partial start dates potentially 
falling into the treatment period (i.e., lower limit prior or on EOT) are considered to 


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have been started during study drug administration unless ‘Ongoing at start of 
Treatment’ ticked ‘Yes’ then it is considered ongoing at study treatment start.
12.1.1 Previous / Concomitant therapies date imputation
The following imputation of partial dates is made: 
Previous therapies: Impute partial start date with lower limit, and partial end date with 
minimum of upper limit and study treatment start date −1. Missing dates are not 
imputed. 
Study concomitant therapies ongoing at study treatment start: Impute partial start date 
with lower limit and partial end date with upper limit. Missing dates are not imputed. 
Study concomitant therapies not ongoing at study treatment start: Impute partial start date 
with maximum of lower limit and study treatment start date, impute partial end date with 
upper limit. Missing dates are not imputed. 
12.2 Relapse
Type of date/time 
Date/time is incomplete
Date/time is missing
Relapse start date (collected on 
‘Relapse Summary’ eCRF)
Maximum of lower limit and 
randomization date
Unless upper limit is prior to 
randomization date, then upper 
limit
Randomization date
eCRF = electronic case report form. 
12.3 Adverse event onset and death dates
The following imputation rules are applied for (partially missing) AE onset dates and 
(partially missing) dates of death:

Onset day missing: If month and year is clearly on or after study treatment start 
(short: STS, the date of first study drug intake) month and year, and clearly before or 
on the month and year of last intake date + 15 days, consider the event as treatment-
emergent. With regard to the date imputation, the following rules are applied:
–
If the record’s origin is the First-Dose eCRF and month and year correspond to 
month and year of STS, impute onset date and time as the date and time of the 
first study drug intake. 
–
If the record’s origin is the First-Dose eCRF and month and year are clearly after 
STS month and year, but a date of re-initiation with corresponding month and 
year is documented, impute onset date and time as the date and time of this re-
initiation study drug intake (in case more than one study drug re-initiations are 


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documented in this month and year, impute with the date and time of the earliest 
of those).
–
If the record’s origin is the First-Dose eCRF and month and year are clearly after 
STS month and year, but no date of re-initiation with corresponding month and 
year is documented, the onset date is imputed to the 1st day of the month and year 
given and time to 00:00.
–
If the record’s origin is the main CRF and month and year is clearly on or after 
STS month and year, the onset date is imputed as the maximum of (date of 
Treatment day 2, 1st day of the month and year given) and time is imputed to 
00:00.
–
If event onset month and year is clearly prior to the STS month and year, the 
onset date is imputed to the last day of the given month (i.e., 28th, 29th, 30th, or 
31st depending on month) and year and time is imputed to 00:00. This imputation 
is done irrespective of eCRF origin (First-Dose or Main).

Onset day and month missing: If the year is the same year as the year of STS or later, 
and if the year is prior to or in the same year as the last intake date + 15 days, 
consider AE as treatment-emergent. With regard to the date imputation, the following 
rules are applied:
–
If the record’s origin is the First-Dose eCRF and the year corresponds to the year 
of STS, impute onset date and time as the date and time of the STS.
–
If the record’s origin is the First-Dose eCRF and the year is clearly after the year 
of STS, 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 (in 
case 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 record’s origin is the First-Dose eCRF and the year is clearly after the year 
of STS, but no date of re-initiation with corresponding year is documented, the 
onset date is imputed to January 1st of the given year and time to 00:00.
–
If the record’s origin is the main CRF and year is clearly on or after the year of 
STS, the onset date is imputed as date of maximum of (Treatment day 2, January 
1st of the given year) and time is imputed to 00:00.
–
If the event onset year is clearly prior to the year of STS, the onset date is imputed 
to 31-December of the given year and time is imputed to 00:00. This imputation is 
done irrespective of eCRF origin (First-Dose or Main).

Missing onset time is imputed to
–
the time of the STS, if the onset date equals the STS.
–
the time of the study drug intake at re-initiation, if the onset date equals the date 
of a documented study drug re-initiation. 
–
00:00, for any other onset date.


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
Onset date is completely missing: Consider as treatment-emergent. 
The onset date and time is imputed as date and time of the STS (if death date or if AE 
onset date with record’s origin is the First-Dose eCRF), if AE onset date with record 
origin in the main CRF, the onset date is imputed as Study Day 2.
12.4 Study treatment start and EOT
The following imputations of study treatment start and EOT are considered for assigning 
safety events and assessments to the treatment-emergent period and used for deriving 
efficacy variables with definitions requiring EOT date. It is not considered for derivation 
of exposure variables. Details for assigning safety events and assessments to the 
treatment-emergence period, as described in Section 5.5.1, apply.
Type of date/time 
Date/time is incomplete
Date/time is missing
Study treatment 
start date
Maximum of lower limit and 
randomization date. 
Randomization date
Study treatment 
start time
See missing.
0:00 or randomization time if study 
treatment start date (after imputation) is 
equal to randomization date.
EOT 
Earliest between treatment start 
date + 756 days (108 weeks), the 
upper limit, EOS date, and Death 
date.
Earliest between treatment start date + 756
days (108 weeks), EOS date and Death 
date.
EOS = End of Study; EOT = End of Trial. 
13 LIST OF SUMMARY TABLES, LISTINGS AND FIGURES
The list of summary tables, listings, and figures is stored in a separate document in Excel
format.


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14 REFERENCES
[Bretz 2009] Bretz F, Maurer W, Brannath W, et al. A graphical approach to sequentially 
rejective multiple test procedures. Statist Med. 2009;28(4):586-604.
[Brookmeyer 1982] Brookmeyer R, Crowley JA. CI for the median survival time. 
Biometrics. 1982;38:29-41.
[Collett 1994] Collett D. Modelling survival data in medical research. London: 
Chapman & Hall; 1994.
[Cotes 1993] Cotes JE, Chinn DJ, Quanjer PH, Roca J, Yernault JC. Standardization of 
the measurement of transfer factor (diffusing capacity). Report Working Party 
Standardization of Lung FunctionTests, European Community for Steel and Coal. 
Official Statement of the European Respiratory Society. Eur Respir J. 
1993;16(Suppl.):41-52.
[Cuzick 2005] Cuzick J. Forest plots and the interpretation of subgroups. The Lancet. 
2005;365(9467):1308.
[Dmitrienko 2010] Dmitrienko A, Tamhane AC, Bretz F. Multiple testing problems in 
pharmaceutical statistics. CRC Press; 2010.
[Keene 2014] Keene, O. N., Roger, J. H., Hartley, B. F., & Kenward, M. G. Missing data 
sensitivity analysis for recurrent event data using controlled imputation. Pharm 
Stat. 2014;13(4):258-264.
[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.
[Pocock 2002] Pocock SJ, Clayton TC, Altman DG. Survival plots of time-to-event 
outcomes in clinical trials: good practice and pitfalls. The Lancet. 2002;359:1686-9.
[Radue 2012] Radue EW, et al. “Impact of fingolimod therapy on magnetic resonance 
imaging outcomes in patients with multiple sclerosis.” Arch Neurol. 2012 
Oct;69(10):1259-1269.
[Reilly Associates 2002] WPAI coding; Coding Rules for Self-Administration. Margaret 
Reilly Associates Inc; 2002. Downloaded from http://www.reillyassociates.net/
WPAI_Coding.html on 21 Nov 2016.
[Roger 2017] Roger, J. Reference-based MI for Negative Binomial discrete data – SAS 
macros. Downloaded from https://missingdata.lshtm.ac.uk/2017/04/07/reference-
based-mi-for-negative-binomial-discrete-data/ on 15 Nov 2018. 


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[Ware 2000] Ware JE, Kosinsky M, Dewey JE. How to score version 2 of the SF-36 
Health Survey. Lincoln RI: QualiMetric Incorporated, 2000.


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15 ATTACHMENTS
Attachment 1
Protocol Deviation Code List


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16 APPENDICES
A. Adverse Events of special interest
Adverse events of special interest (AESIs) include the anticipated risks of treatment with 
ponesimod and events that may be related to MS comorbitities. 
The definitions for AESIs are based on the systematic approach using Standardized 
MedDRA Queries (SMQ). The additional relevant terms can be added to the search or 
deleted appropriately providing the rationale for the change. The proposal is based on 
MedDRA version 21.0. The following safety areas are addressed by the pre-defined 
AESIs:

Effect on heart rate and rhythm AESI (including hypotension) 
Effect on heart rate and rhythm AESI are identified by the preferred terms (PT) in the 
following SMQ: Bradyarrhythmias (including conduction defects and disorders of sinus 
node function) (SMQ) [20000053]. In addition, the following PT will be added to the 
search for AEs addressing effects on heart rate and rhythm: ‘Bradycardia’, 
‘Electrocardiogram RR interval prolonged’, ‘Heart rate decrease’, ‘Presyncope’, 
‘Syncope’, ‘Loss of consciousness’, ‘Chronotropic incompetence’, and ‘Central 
bradycardia’.  
Hypotension will be identified searching the following PT: ‘Blood pressure decreased’, 
‘Blood pressure diastolic decreased’, ‘Blood pressure orthostatic decreased’, ‘Blood 
pressure systolic decreased’, ‘Diastolic hypotension’, ‘Hypotension’, ‘Mean arterial 
pressure decreased’, ‘Orthostatic hypotension’, ‘Procedural hypotension’, ‘Circulatory 
collapse’, ‘Blood pressure fluctuation’, ‘Labile blood pressure’ and ‘Blood pressure 
ambulatory decreased’. 

Hypertension AESI
Hypertension AESI are identified by the PT in the following SMQ: Hypertension SMQ 
(narrow scope) [20000147].

Hepatobiliary disorders / Liver enzyme abnormality AESI
Hepatobiliary disorders/ Liver enzyme abnormality AESI are identified by the PT in the 
following SMQ: Drug related hepatic disorders – comprehensive (SMQ) (broad scope) 
[20000006]. This SMQ is included in the SMQ Hepatic disorder (SMQ) but only the PT 
included in Drug related hepatic disorders - comprehensive search (SMQ) are included to 
identify hepatobiliary disorders / Liver enzyme abnormality AESI.

Pulmonary AESI
These AEs are identified by the PT the in the following SMQs: Asthma/bronchospasm 
(SMQ) (broad scope) [20000025] or Interstitial lung disease (SMQ) (broad scope) 


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[20000042]. The PT ‘Dyspnoea at rest’, ‘Dyspnoea’, ‘Dyspnoea exertional’, ‘Carbon 
monoxide diffusing capacity decreased’, ‘Pulmonary function test abnormal’, ‘Pulmonary 
function test decreased’, ‘Vital capacity abnormal’, and ‘Vital capacity decreased’ are 
added to the search pre-defined by SMQs Asthma/bronchospasm or Interstitial lung 
disease.  

Macular edema AESI
Macular edema AESI are identified by the following PT: ‘Macular oedema’, ‘Macular 
hole’, ‘Macular pseudohole’, ‘Macular rupture’, ‘Macular cyst’, ‘Retinal oedema’, 
‘Diabetic 
retinal 
oedema’, 
‘Cystoid 
macular 
oedema’, 
‘Papilloedema’, 
and 
‘Pseudopapilloedema’.

Infection AESI
Infection AESI are identified by the adverse events belonging to the SOC (System Organ 
Class) Infections and Infestations (SOC), only if reported as serious or severe.

Herpetic infection AESI
Herpetic infection AESI are identified by the PT in the following high level terms: 
Herpes viral infections (HLT) and the following preferred terms will be added to the 
search for AEs addressing varicella zoster infection: ‘Encephalitis post varicella’, 
‘Herpes gestationis’, ‘Herpes simplex test positive’, ‘Human herpes virus 6 serology 
positive’, ‘Human herpes virus 8 test positive’, and ‘Herpes virus test abnormal’.  

Skin malignancy AESI
Skin malignancy AESI are identified by the PT in the following SMQs: Skin neoplasms 
malignant and unspecified (SMQ) (broad scope) [20000173].  

Non-skin malignancy AESI
Non-skin malignancy AESI are identified by the PT in the following SMQ: Malignant or 
unspecified tumours (SMQ) (broad scope) [20000091] excluding the PT which included 
in the following SMQs: Skin neoplasms, malignant and unspecified (SMQ) (broad scope) 
[20000173]. 

Seizure AESI
Seizure AESI are identified by any preferred term in the following SMQ: Convulsions 
(narrow scope) (SMQ) [20000079].
B. Protocol Deviation code list
Protocol deviations are defined as per the Protocol Deviation code list, version 4, 8 June 
2018. Protocol deviations are categorized according to the categories in the Protocol 


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Deviation code list (level 2 heading, e.g. ‘Informed Consent and Patient Rights’, ‘General 
Eligibility’, …) [Attachment 1].
C. PRO and other composite assessment scoring and handling of missing data
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
the MSFC Z-score 
 
 


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C.2. FSIQ-RMS Symptoms score
Daily Symptoms Scores:
FSIQ-RMS Symptoms Daily scores (FSIQ-RMS SDSc_Dj) will be calculated for each 
day Dj of assessment as 0 to 100 score using following equation:
FSIQ-RMS SDSc_Dj=
(Sum of non-missing items 1, 2, 3, 4, 5, 6, 7 ) at D j
RSTUIJ VW XVXYTZ[[ZXL Z\IT[ ∗^ZL_I[\ JK\ZXL (`a) ∗100,
Daily scores will be derived at each day (where day refers to study day from 
randomization) with assessment. If for a given day, more than 3 out of the 7 items are 
missing in the Diary, then the Symptoms daily score FSIQ-RMS SDSc_Dj will be set to 
missing.
Weekly Symptoms Scores:
FSIQ-RMS Symptoms Weekly Scores (FSIQ-RMS SWSc_ Wi) within a 7 consecutive 
day period (Week i) are calculated from daily scores FSIQ-RMS SDSc_Dj as follows:
FSIQ-RMS SWSc_ Wi=
Sum of the non-missing FSIQ-RMS SDSc_Dj
RSTUIJ VW XVX−TZ[[ZXL cZKJd cKd[ K\ QIIef ,
if the number of missing daily scores is < 4 (i.e. at least 4 daily scores are available). 
If more than 3 daily scores are missing (i.e., less than 4 daily scores are available), the 
weekly score FSIQ-RMS SWSc_ Wi cannot be calculated and is considered missing. 
Weekly scores are derived for the following time points Wi: Baseline (Pre-randomization 
period), Visits 6 (Week 12), 7 (Week 24), 10 (Week 60), 12 (Week 84) and 14 (Week 
108). 
Visits will be assigned based on time windowing [see Section 11.3]. The weekly score for 
a visit is derived based on the 7-day time period with non-missing weekly score.
Preference is given to 7-day time periods with (i) minimum number of missing daily 
scores and (ii) with the seventh day being closest to target. If two periods are equally 
close to target the worst score is considered. 
Baseline Symptoms Weekly Score will be derived during the closest 7-day time period 
prior to and including randomization date in which a non-missing weekly score can be 
derived. 
Change from baseline FSIQ-RMS SWSc to each assessment visit (CHN FSIQ-RMS 
SWSc Base_Wi) will be derived as: Weekly score (FSIQ-RMS SWSc Wi) −Baseline score 
(FSIQ-RMS SWSc Base).


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C.3. FSIQ-RMS impacts domain
FSIQ-RMS impact sub-domain scores are derived as a weekly 0 to 100 score. They are 
derived based on the second part of the questionnaire based on questions referring to the 
last 7 days. Weekly scores are therefore derived based on questions answered during a 
single day. 
Each sub-domain score is defined based on 5 items. If at least 3 of these 5 items are 
available, the scores can be derived. Otherwise it is considered missing. Formulae for 
derivation are provided below. 
FSIQ-RMS Physical Impacts Weekly score:
FSIQ-RMS-PIWSc Wi =
(Sum of non missing items 1, 5, 6, 8, 13 )at Weekj
Number non missing items ∗Highest rating (4)
∗100
FSIQ-RMSc Cognitive/Emotional Impacts Weekly score:
FSIQ-RMS-CEIWSc Wi=
(Sum of non missing items 2, 3, 7, 9, 10) at Weekj
Number of non missing items ∗Highest rating (4) ∗100
FSIQ-RMS Coping Impacts Weekly score:
FSIQ-RMS-CIWSc Wi =
(Sum of non missing items 4, 8, 11, 12, 13) at Weekj
Number of non missing items ∗Highest rating (4) ∗100
Scores are derived for the following time points Wi: Baseline (Pre-randomization period), 
Visits 6 (Week 12), 7 (Week 24), 10 (Week 60), 12 (Week 84) and 14 (Week 108). Visits 
will be assigned based on time windowing [see Section 11.3]. 
Baseline is defined as last available score prior to and including randomization date. 
Change from baseline is defined as absolute change from baseline. 
C.4. SF-36 scoring
Recoding items
Scores for each question response are indicated on the questionnaire. Firstly, seven of the 
questions are reverse scored, to ensure that a higher item value indicates better health 
(Items 11b & 11d, 9a & 9e, 6, 9d & 9h). Three of the questions also need to be 
recalibrated. These are question 1 and questions 7 and 8. Recalibration and reverse score 
items are as follows:


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Precoded and final values for Item 7
Response choices 
Precoded Value
Final Value
None 
1
6.0
Very mild
2
5.4
Mild
3
4.2
Moderate
4
3.1
Severe
5
2.2
Very Severe
6
1.0
Precoded and final values for item 8 where both items 7 and 8 are answered
Response choices 
Item 8 Precoded     
V l
Item 7 Precoded Value
Item 8 Final value
Not at all
1
1
6
Not at all
1
2 through 6
5
A little bit
2
1 through 6
4
Moderately
3
1 through 6
3
Quite a bit
4
1 through 6
2
Extremely
5
1 through 6
1
Precoded and final values for item 8 where item 7 is not answered
Response choices 
Item 8 Precoded 
Item 8 Final Value
Not at all 
1
6.0
A little bit
2
4.75
Moderately
3
3.5
Quite a bit
4
2.25
Extremely
5
1.0
Precoded and Final Values for Item 1
Response choices 
Precoded Value
Final Value
Excellent 
1
5.0
Very Good
2
4.4
Good
3
3.4
Fair
4
2.0
Poor
5
1.0


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Precoded and Final Values for Items 11a & 11c, and 11b & 11d
Response choices 
Precoded Item Value
Final Value Items 11a & 
11c
Final Value Items 11b & 
11d
Definitely true 
1
1
5
Mostly true
2
2
4
Don’t know
3
3
3
Mostly false
4
4
2
Definitely false
5
5
1
Precoded and Final Values for Items 9a - 9i 
Response choices 
Precoded Item Value
Final Value Items 9a, 
9d, 9e, 9h 
Final Value Items 9b, 
9c, 9f, 9g, 9i
All of the time 
1
5
1
Most of the time
2
4
2
Some of the time
3
3
3
A little of the time
4
2
4
None of the time
5
1
5
Precoded and Final Values for Item 6
Response choices 
Precoded Value
Final Value
Not at all 
1
5
Slightly
2
4
Moderately
3
3
Quite a bit
4
2
Extremely
5
1
Computing domain scores
The raw score for each domain is then calculated as the sum of the scores for the items in 
that domain, as shown in Table 12. For example the raw score for role physical is the sum 
of the scores for items 4a, 4b, 4c and 4d. The next step is to transform each raw domain 
score to a domain scale 0–100 score. This is calculated as follows:
(Actual raw score −lowest possible raw score) / Possible raw score range × 100
where the possible raw score range is the highest possible raw score for that domain 
minus the lowest possible raw score for that domain. This transformation converts the 
lowest and highest possible scores to 0 and 100, respectively. Scores between these 
values represent the percentage of the total possible score achieved. All except one of the 
36 items (Item 2 self-reported health transition) are used to score the eight SF-36 
domains. Each item is used in scoring only one domain. The table below provides the 
information necessary to apply the above formula to each domain.


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Table 12
Scoring and transforming scales
Domain
- Raw Domain scores 
(individual final item value 
range)
Lowest 
possible raw 
score
Highest 
possible raw 
score
Possible raw 
score range
Physical 
Functioning
3.a to j (1-3)
10
30
20
Role-Physical
4.a to d (1-5)
4
20
16
Bodily Pain
7# +8# (1-6)
2
12 
10
General Health
1# + 11.a + b* + c + d* (1-5)
5
25
20
Vitality
9.a* + e* + g + i (1-5)
4
20
16
Social 
Functioning
6* + 10 (1-5)
2
10
8
Role-
Emotional
5.a + b + c (1-5)
3
15
12
Mental Health
9.b + c + d* + f + h*(1-5)
5
25
20
! Sum of the final item values after recalibrating and recoding, 
* indicates items with reversed scores
# indicates items with recalibrated scores
Computing normalized domain scores
For each of the individual domain the scale 0-100 score is standardized using a z-score 
transformation. The z score is computed by subtracting the mean 0-100 general US 
population score (1998) from the computed scale 0-100 score and dividing the difference 
by the corresponding domain standard deviation from the 1998 general U.S. population 
as detailed in SF-36 Physical and Mental Health Summary Scales: How to score Version 
2 of the SF-36 Health Survey [Ware 2000].
Calculations of the Z scores using 1998 General US population Means and SD are as 
follows:
PF Z = (PF −83.29094) ÷ 23.75883
RP Z = (RP −82.50964) ÷ 25.52028
BP Z = (BP −71.32527) ÷ 23.66224
GH Z = (GH −70.84570) ÷ 20.97821
VT Z = (VT −58.31411) ÷ 20.01923
SF Z = (SF −84.30250) ÷ 22.91921
RE Z = (RE −87.39733) ÷ 21.43778
MH Z = (MH −74.98685) ÷ 17.75604


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Each of the individual domain z-score is then transformed to norm based (mean 50, 
standard deviation 10) scoring (also known as t scores) by multiplying each domain z-
score by 10 and adding the resulting product to 50.
Normative domain scores:
PFt = (PF Z × 10) + 50
RPt = (RP Z × 10) + 50
BPt = (BP Z × 10) + 50
GHt = (GH Z × 10) + 50
VTt = (VT Z × 10) + 50
SFt = (SF Z × 10) + 50
REt = (RE Z × 10) + 50
MHt = (MH Z × 10) + 50
Computing PCS and MCS measures 
Physical and Mental Component Summary measures (PCS and MCS respectively) are 
also calculated. These are aggregate scores for the physical and mental components 
which are computed by multiplying each of the individual domain z-scores (calculated as 
described above) by their respective physical/mental factor score coefficients and 
summing the eight products.
Aggregate component summaries are derived as follows: 
PCSZ = (PFZ × 0.42402) + (RPZ × 0.35119) + (BPZ × 0.31754) + (GHZ × 0.24954) + 
(VTZ × 0.02877) + (SFZ × -0.00753) + (REZ × -0.19206) + (MHZ × -0.22069)
MCSZ = (PFZ × -0.22999) + (RPZ × -0.12329) + (BPZ × -0.09731) + (GHZ × -0.01571) + 
(VTZ × 0.23534) + (SFZ × 0.26876) + (REZ × 0.43407) + (MHZ × 0.48581)
Each summary measure is then transformed to the norm-based (mean 50, standard 
deviation 10) scoring (t scores). This is accomplished by multiplying each aggregated 
score by 10 and adding the resulting product to 50.
Normative Physical Component Summary score: PCSt = (PCSZ × 10) + 50
Normative Mental Component Summary score: MCSt = (MCSZ × 10) + 50
Handling of Missing data 
Imputation for missing items in a domain
For an individual domain where 50% or more of the item questions are non-missing, the 
average of the non-missing items for that patient in that domain is calculated. This 


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average is then be used to impute the remaining missing item questions of that domain.
Note: imputation should be based on the final domain score after recalibration / reverse 
scores of pre coded scores.
However, if more than 50% of item questions are missing the domain is recorded as 
missing. 
Aggregated scores are computed after the imputation rule has been applied to the 
component domains, but are set to missing if any domain is missing. 
Handling of duplicate entries on Questionnaire form
Duplicate entries within the same day for a question item are handled as follows:

If a respondent marks two responses which are adjacent to each other, then the worst 
case (lowest value) is selected. Note this is selected based on the item score after 
recalibration / reverse scores of pre coded scores.

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
C.5. WPAI:MS scoring
The four WPAI:MS outcome scores are defined based on the outcome Q1–Q6 of 
Questions 1–6 (ref: http://www.reillyassociates.net/WPAI_Scoring.html):
Q1 = currently employed (Y/N)
Q2 = hours missed due to MS
Q3 = hours missed other reasons
Q4 = hours actually worked
Q5 = degree MS affected productivity while working
Q6 = degree MS affected regular activities
WPAI:MS outcome scores are defined as detailed below. At each assessment visit for 
those who are currently employed the following 3 scores are defined:

Absenteeism: Percent work time missed due to MS = Q2 / (Q2 + Q4) × 100

Presenteeism: Percent impairment while working due to MS = Q5 / 10 ×100

Work productivity loss: Percent overall work impairment due to MMS = {Q2 / (Q2 
+ Q4) + [(1–Q2 / (Q2 + Q4)) × (Q5 / 10)]} × 100
For all subjects irrespective of their current employment status

Activity impairment: Percent activity impairment due to MS = Q6 / 10 × 100


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Scoring: Handling of missing or inconsistent data
The following rules for handling of missing or inconsistent data within the same day are 
implemented as described in the section “Coding Rules for Self-Administration” by 
Reilly Associates [Reilly Associates 2002]. 

Employment status (Q1):
If Q1 = ‘YES’ or Q1 = ‘NO’ or ‘missing’ and hours missed (Q2) or hours worked 
(Q4) > 0, then subjects is considered employed. 
If Q1 = ‘missing’ and hours missed (Q2) and hours worked (Q4) = 0, then considered 
not employed (i.e., Q1 considered No).

Hours missed (Q2) and hours worked (Q4) 
If hours worked (Q4) = 0, then productivity while at work (Q5) is not applicable and 
considered as missing.
If subject enters a range of hours for (Q2 or Q4), use the midpoint.
If a subject is considered employed but hours missed (Q2) is missing, then impute as 
zero. 

Productivity Questions (Q5 and Q6) 
If for one question, two responses are provided, enter the midpoint and round to 
nearest integer.
Missing response after applying the above scoring
WPAI scores cannot be calculated if there is a missing response to one or more 
corresponding individual questions.


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D. Laboratory marked abnormalities
Table 13
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
> 8.0
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 
≥ 5 ULN
Alkaline Phosphatase (U/L)
ND
ND
> 2.5 ULN
> 5 ULN
INR*
ND
ND
> 1.5 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
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
Triglyceride (mmol/L)
ND
ND
> 3.42
> 11.4
Cholesterol (mmol/L)
ND
ND
> 7.75
> 12.92
* HH and HHH based on CTCAE 2010 v4.03. 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.
Source: Protocol AC-058B301, appendix 6.


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E. Document history
Version
Effective Date
Reason (main)
1.0
11 Dec 2018
New
2.0
20 June 2019
FSIQ-RMS responder threshold added based on 
results from anchor analysis
Minor update for efficacy analyses: estimates per 
treatment arm (least square means) derived based 
on observed margins
12-week and 24-week CDA: handling of relapse 
start date and end date clarified; alternative 
censoring approach added based on health 
authority feedback.
Safety analyses: Additional analyses added, small 
updates based on health authority feedback 
including presentation of AEs from Day 1 to 
Day 16 and updates to blood pressure and heart 
rate abnormality thresholds.
Editorial updates have been applied.