Clinical trial NCT02907177
Conditions: Multiple Sclerosis
Sponsor: Actelion
Start date: 2017-03-30; Completion date: 2020-03-26
Enrollment: 136 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This clinical study compares the efficacy, safety, and tolerability of therapy with ponesimod vs placebo in subjects with active RMS who are treated with DMF (Tecfidera®).

Detailed description:
The study will assess the efficacy, safety, and tolerability of add-on therapy with ponesimod 20 mg vs placebo in adult participants with active relapsing multiple sclerosis (RMS) who are treated with dimethyl fumarate (DMF). Approximately 600 participants who have been receiving DMF for at least 6 months will be randomized in a 1:1 ratio to ponesimod 20 mg or placebo. The study consists of the following study periods: Pre-randomization period; Treatment period; Post-treatment observation period. The study includes one ponesimod treatment arm at the maintenance dose of 20 mg o.d. corresponding to the optimal dose when used as monotherapy based on the Phase 2 dose-finding trial and its ongoing extension. The study includes a placebo comparator arm, but all patients will remain on DMF background therapy throughout the study. Moreover, participants who experience a confirmed relapse or an event of 24-week confirmed disability accumulation (DMF) while on study drug will have the option to switch to an alternative treatment. The treatment period has a variable duration from a minimum of 60 weeks (for the last subject randomized) to a maximum of 156 weeks for the first subjects randomized in the trial and includes a gradual up-titration of ponesimod from a 2 mg starting dose to a 20 mg maintenance dose over a period of 14 days. The total duration of the study will be approximately up to 167 weeks.

Arms: arm 1: Ponesimod arm 2: Placebo
Interventions: intervention 1: Ponesimod intervention 2: Placebo
Intervention descriptions: intervention 1: One tablet of ponesimod 20 mg administered orally once daily in the morning from Day 15 to EOT. To reduce the first-dose effect of ponesimod, an uptitration scheme will be implemented from Day 1 to Day 14 (with dose strength increasing from 2 mg to 20 mg). intervention 2: One tablet of matching placebo administered orally once daily in the morning

Protocol documents:
Prot_000.pdf: 
TPL-000052_v10
Ponesimod / ACT-128800
Relapsing Multiple Sclerosis
Protocol AC-058B302
POINT: POnesImod aNd Tecfidera
Multicenter, randomized, double-blind, parallel-group, add-on, superiority study to 
compare the efficacy and safety of ponesimod to placebo in subjects with active 
relapsing multiple sclerosis who are treated with dimethyl fumarate (Tecfidera®)
Study Phase:
3
EudraCT Number:
2012-000541-12
Status and version:
Final Version 6
Date:
21 December 2017
Actelion document number 
(Doc No.):
D-17.622
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.
NCT02907177


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SPONSOR CONTACT DETAILS
SPONSOR
ACTELION Pharmaceuticals Ltd
Gewerbestrasse 16
CH-4123 Allschwil
Switzerland

+41 61 565 65 65
Clinical Trial Physician 
Contact details of the Clinical Trial Physician can 
be found in the Investigator Site File
MEDICAL HOTLINE
Toll phone number: [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 Trial Scientist
, MSc
Clinical Project Scientist
 PhD
Clinical Science Program Head
, MD, PhD
Clinical Trial Statistician
. (FH)
Clinical Project Statistician
, MSc
Clinical Trial Physician
Ewa Lindenstrøm, MD, PhD
Clinical Trial Pharmacologist
Drug Safety Physician
, MD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Relapsing multiple sclerosis
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CONTRACT RESEARCH ORGANIZATIONS INFORMATION
CENTRAL LABORATORY
Covance, Inc.
8211 SciCor Drive
Indianapolis, IN USA 46214
Covance, Inc.
7 rue Marcinhes
Geneva Meyrin Switzerland 1217
Covance, Inc.
1 International Business Park
#01-01 The Synergy
Singapore 609917
CENTRAL 
PK 
ANALYSIS 
LABORATORY
PRA Health Sciences - Early Development Services
Bioanalytical Laboratory
Amerikaweg 18
9407 TK Assen, The Netherlands
CENTRAL 
RANDOMIZATION
Almac Clinical Technologies
25 Fretz Road
Souderton
PA 18964
USA
CENTRAL MRI READING 
MIAC Corporation
c/o University Hospital Basel
Mittlere-Strasse 83
CH 4031 Basel, Switzerland
CENTRAL ECGs READING
eResearch Technology GmbH
Sieboldstr. 3
97230 Estenfeld, Germany
ELECTRONIC DIARY
eResearch technology GmBH
Sieboldstr. 3
97230 Estenfeld, Germany
A list of site-specific contact details for Contract Research Organizations (CROs) can be 
found in the Investigator Site File.


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Relapsing multiple sclerosis
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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-058B302, POINT, Multicenter, randomized, double-blind, parallel-group, add-on, 
superiority study to compare the efficacy and safety of ponesimod to placebo in subjects 
with active relapsing multiple sclerosis who are treated with dimethyl fumarate 
(Tecfidera®)
I approve the design of this study.
TITLE
NAME
DATE
SIGNATURE
Clinical Trial 
Physician
Ewa Lindenstrøm, 
MD, PhD
Clinica
Project
Statistician
,
PPD
P
PPD
PPD
PPD
PPD
PPD


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INVESTIGATOR SIGNATURE PAGE
Treatment name / number
Ponesimod / ACT-128800
Indication
Relapsing multiple sclerosis
Protocol number, study acronym, study title
AC-058B302, POINT, Multicenter, randomized, double-blind, parallel-group, add-on, superiority 
study to compare the efficacy and safety of ponesimod to placebo in subjects with active 
relapsing multiple sclerosis who are treated with dimethyl fumarate (Tecfidera®)
I agree to the terms and conditions relating to this study as defined in this protocol, the electronic 
Case Report Form (CRF), 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 for 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
Principal 
Investigator


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TABLE OF CONTENTS
ACTELION CONTRIBUTORS TO THE PROTOCOL.....................................................2
CONTRACT RESEARCH ORGANIZATIONS INFORMATION ...................................3
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................17
SUBSTANTIAL GLOBAL AMENDMENT 5.................................................................22
PROTOCOL SYNOPSIS AC-058B302............................................................................32
1
BACKGROUND.........................................................................................................60
1.1
Multiple sclerosis..........................................................................................60
1.1.1
Pathogenesis......................................................................................60
1.1.2
Clinical course ..................................................................................60
1.1.3
Epidemiology....................................................................................62
1.1.4
Treatment of MS...............................................................................62
1.1.4.1
Injectable disease-modifying therapies ...................................63
1.1.4.2
Orally administered disease-modifying therapies ...................63
1.1.4.3
Unmet need in relapsing multiple sclerosis.............................63
1.2
Sphingosine-1-phosphate receptors..............................................................64
1.3
Ponesimod ....................................................................................................65
1.3.1
Nonclinical studies............................................................................65
1.3.1.1
Efficacy of combined dimethyl fumarate and ponesimod 
in rats .......................................................................................66
1.3.1.2
Combination toxicity study of combined dimethyl 
fumarate and ponesimod in beagle dogs .................................67
1.3.2
Clinical studies..................................................................................67
1.3.2.1
Clinical pharmacology ............................................................68
1.3.2.2
Pharmacodynamics in humans ................................................68
1.3.2.3
Efficacy in humans..................................................................69
1.3.2.4
Safety and tolerability .............................................................70
1.3.3
Background treatment.......................................................................71
1.4
Purpose and rationale of the study................................................................71
1.5
Summary of known and potential risks and benefits....................................72
2
STUDY OBJECTIVES...............................................................................................75
2.1
Primary objective..........................................................................................75
2.2
Secondary objectives ....................................................................................75


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OVERALL STUDY DESIGN AND PLAN ...............................................................75
3.1
Study design .................................................................................................75
3.2
Study design rationale ..................................................................................76
3.3
Dose rationale...............................................................................................77
3.4
Risk mitigation strategy................................................................................78
3.4.1
Lymphopenia ....................................................................................78
3.4.2
Opportunistic infections....................................................................79
3.5
Study periods ................................................................................................80
3.5.1
Pre-randomization period .................................................................80
3.5.2
Treatment period...............................................................................80
3.5.2.1
Modification of treatment........................................................80
3.5.3
Post-treatment period and End-of-Study ..........................................81
3.5.3.1
Post-treatment safety follow-up period ...................................81
3.5.3.2
Post-treatment observation period...........................................81
3.5.3.3
End-of-Study ...........................................................................82
3.5.4
Study duration...................................................................................83
3.5.5
Study closure.....................................................................................84
3.6
Sub-studies....................................................................................................84
3.6.1
Lymphocyte subset ...........................................................................84
3.6.2
Vaccination.......................................................................................84
3.7
Site staff and their roles................................................................................85
3.7.1
Principal investigator ........................................................................85
3.7.2
Treating neurologist..........................................................................86
3.7.3
Efficacy assessor...............................................................................87
3.7.4
First-dose administrator ....................................................................87
3.7.5
Clinical coordinator / study nurse.....................................................89
3.7.6
MRI staff...........................................................................................90
3.7.7
Local radiologist or neurologist with MRI expertise........................90
3.7.8
Ophthalmologist................................................................................91
3.7.9
Pulmonary function laboratory technician or expert ........................91
3.7.10
Dermatologist....................................................................................91
3.8
Study committees .........................................................................................92
3.8.1
Independent Data Monitoring Committee........................................92
3.8.2
Ophthalmology Safety Board ...........................................................92
3.8.3
MRI safety board ..............................................................................92
3.8.4
Major adverse cardiovascular events adjudication board.................93
4
SUBJECT POPULATION..........................................................................................93
4.1
Subject population description .....................................................................93
4.2
Rationale for the selection of the study population ......................................94


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4.3
Inclusion criteria...........................................................................................95
4.4
Exclusion criteria..........................................................................................96
4.5
Women of childbearing potential ...............................................................100
4.5.1
Definition of childbearing potential................................................100
4.5.2
Acceptable methods of contraception.............................................100
4.6
Medical history...........................................................................................101
4.6.1
General Medical History.................................................................101
4.6.2
MS history.......................................................................................101
5
TREATMENTS ........................................................................................................102
5.1
Study treatment...........................................................................................102
5.1.1
Investigational treatment and matching placebo: description 
and rationale....................................................................................102
5.1.2
Study treatment administration.......................................................103
5.1.2.1
Titration.................................................................................103
5.1.2.2
Maintenance ..........................................................................104
5.1.3
Treatment assignment.....................................................................104
5.1.4
Blinding ..........................................................................................105
5.1.4.1
Study drug material related blinding.....................................105
5.1.4.2
Functional blinding................................................................105
5.1.5
Unblinding ......................................................................................107
5.1.5.1
Unblinding for final analyses ................................................107
5.1.5.2
Unblinding for IDMC review................................................107
5.1.5.3
Unblinding for suspected unexpected serious adverse 
reactions.................................................................................107
5.1.5.4
Emergency procedure for unblinding....................................107
5.1.6
Study treatment supply ...................................................................108
5.1.6.1
Study treatment packaging and labeling ...............................108
5.1.6.2
Study treatment distribution and storage...............................108
5.1.6.3
Study treatment dispensing ...................................................108
5.1.6.4
Study treatment return and destruction .................................109
5.1.7
Study treatment accountability and compliance .............................109
5.1.7.1
Drug accountability...............................................................109
5.1.7.2
Drug compliance ...................................................................109
5.1.8
Study treatment dose adjustments and interruptions ......................109
5.1.9
Guidance for re-initiation of study treatment in the event of 
study treatment interruption............................................................110
5.1.10
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 ...................................................112


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5.1.11
Premature discontinuation of study treatment ................................113
5.1.12
Study-specific criteria for interruption / premature 
discontinuation of study treatment..................................................114
5.1.12.1
Cardiovascular.......................................................................114
5.1.12.2
Hematological abnormalities.................................................115
5.1.12.3
General guidance for monitoring of subjects for 
opportunistic infections during treatment..............................115
5.1.12.4
Respiratory system ................................................................120
5.1.12.5
Pregnancy..............................................................................121
5.1.12.6
Liver abnormalities................................................................121
5.1.12.7
Ocular abnormalities .............................................................122
5.1.12.8
Discontinuation of DMF background therapy.......................123
5.2
Previous and concomitant therapy..............................................................123
5.2.1
Definitions ......................................................................................123
5.2.2
Reporting of previous/concomitant therapy in the eCRF...............124
5.2.2.1
Study-concomitant therapies .................................................124
5.2.2.2
Previous MS therapies...........................................................124
5.2.2.3
Other previous therapies........................................................125
5.2.3
Concomitant background therapy...................................................125
5.2.4
Recommended concomitant therapy...............................................125
5.2.5
Allowed concomitant therapy.........................................................125
5.2.6
Forbidden concomitant therapy ......................................................126
6
STUDY ENDPOINTS ..............................................................................................127
6.1
Efficacy endpoints ......................................................................................127
6.1.1
Primary efficacy endpoint...............................................................127
6.1.2
Secondary efficacy endpoints .........................................................128
6.1.3
Other efficacy endpoints.................................................................129
6.2
Safety endpoints .........................................................................................130
6.3
Quality of life endpoints.............................................................................131
6.4
Pharmacoeconomic endpoints....................................................................131
6.5
Pharmacokinetic and pharmacodynamic endpoints ...................................131
6.5.1
Pharmacokinetic evaluations ..........................................................131
6.5.2
Pharmacodynamic evaluations .......................................................131
6.5.3
PK/PD relationship .........................................................................132
7
STUDY ASSESSMENTS.........................................................................................132
7.1
Screening/baseline assessments..................................................................132
7.1.1
Informed consent (Visit 1 [Screening]) ..........................................132
7.1.2
Baseline demographics and disease characteristics........................133


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7.1.3
Study-concomitant therapies...........................................................133
7.1.4
Previous MS therapies ....................................................................133
7.2
Efficacy assessments ..................................................................................134
7.2.1
Neurological evaluation..................................................................134
7.2.2
Detection and evaluation of relapses ..............................................134
7.2.3
MRI evaluations..............................................................................138
7.2.4
Multiple Sclerosis Functional Composite score .............................139
7.2.5
Symbol Digit Modalities Test.........................................................140
7.2.6
Fatigue Symptom and Impacts Questionnaire-RMS ......................141
7.3
Safety assessments......................................................................................142
7.3.1
12-lead electrocardiogram ..............................................................142
7.3.2
Blood pressure ................................................................................144
7.3.3
Spirometry ......................................................................................145
7.3.4
Chest X-ray.....................................................................................147
7.3.5
Test for tuberculosis........................................................................147
7.3.6
Ophthalmologic assessments..........................................................148
7.3.7
Optical coherence tomography.......................................................149
7.3.8
Weight and height...........................................................................149
7.3.9
Physical examination......................................................................149
7.3.10
Body temperature............................................................................150
7.3.11
Pulse rate.........................................................................................150
7.3.12
Dermatological examination...........................................................151
7.3.13
Laboratory assessments ..................................................................152
7.3.13.1
Type of laboratory.................................................................152
7.3.13.2
Laboratory tests .....................................................................153
7.4
Electronic self-rated version of the Columbia-Suicide Severity Rating 
Scale............................................................................................................156
7.5
Quality of life assessments .........................................................................157
7.5.1
36-Item Short Form Health Survey v2 (SF-36v2™)......................157
7.6
Pharmacoeconomic assessments ................................................................157
7.6.1
Work Productivity and Activity Impairment Questionnaire: 
Multiple Sclerosis V2.0 ..................................................................157
7.6.2
Health care resource utilization ......................................................158
7.7
Pharmacokinetic and pharmacodynamic assessments................................158
7.7.1
Pharmacokinetic assessments .........................................................158
7.7.2
Pharmacodynamic assessments ......................................................159
7.7.2.1
Total lymphocytes .................................................................159
7.7.2.2
Blood lymphocyte subsets.....................................................159
7.8
Total blood volume.....................................................................................160
8
SCHEDULE OF VISITS ..........................................................................................161


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8.1
Pre-randomization period ...........................................................................162
8.1.1
Visit 1 (Screening)..........................................................................163
8.1.2
Visit 2 (Baseline) ............................................................................164
8.1.3
Visit 3 – Day 1 – pre-dose assessments..........................................166
8.2
Treatment period.........................................................................................167
8.2.1
Visit 3 – Randomization Day 1 – Randomization and post-dose 
assessments .....................................................................................167
8.2.2
Four-weekly lymphocyte counts.....................................................168
8.2.3
Visit 4 – Day 15..............................................................................168
8.2.4
Visit 5 – Week 4 .............................................................................169
8.2.5
In-between-visit telephone calls until Week 156 (Weeks 18, 
30, 42, 54, 66, 78, 90, 102, 114, 126, 138, and 150) ......................169
8.2.6
Visits 6 and 7 – Weeks 12 and 24...................................................170
8.2.7
Visits 8, 10, 12, 14, and 16 – Weeks 36, 60, 84, 108, 132 .............171
8.2.8
Visits 11 and 15 – Weeks 72 and 120.............................................172
8.2.9
Visits 9, 13, 17 – Weeks 48, 96, and 144 .......................................173
8.2.10
Visit 18 – EOT................................................................................174
8.3
Post-treatment period..................................................................................176
8.3.1
Post-treatment safety follow-up period...........................................176
8.3.1.1
Visit 19 – FU7d .....................................................................176
8.3.1.2
Visit 20 – FU.........................................................................176
8.3.2
Post-treatment observation period ..................................................177
8.3.2.1
Visits 6A, 7A, 8A, 10A, 12A, 14A, and 16A – Weeks 
12, 24, 36, 60, 84, 108, and 132 ............................................177
8.3.2.2
Visits 11A – Week 72 and Visit 15A – Week 120................178
8.3.2.3
Visits 9A, 13A, 17A, and 18A – Weeks 48, 96, 144, and 
156.........................................................................................178
8.4
Unscheduled visits......................................................................................179
8.4.1
Unscheduled visits for relapses (Visits R1, R2, etc.)......................179
8.4.2
Additional unscheduled visits for re-initiation of study drug 
(I1, I2, etc.) .....................................................................................181
8.4.3
Unscheduled visits (any other assessment;U1, U2, U3, etc.) .........182
9
STUDY COMPLETION AND POST-STUDY TREATMENT/MEDICAL 
CARE ........................................................................................................................183
9.1
Study completion........................................................................................183
9.2
Premature withdrawal from study ..............................................................183
9.3
Premature termination or suspension of the study......................................184
9.4
Medical care of subjects after study completion / withdrawal from 
study............................................................................................................185


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10 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS.........................185
10.1
Adverse events............................................................................................185
10.1.1
Definitions of adverse events..........................................................185
10.1.2
Intensity of adverse events..............................................................186
10.1.3
Relationship to study treatment ......................................................187
10.1.4
Adverse events associated to study design or protocol-
mandated procedures ......................................................................187
10.1.5
Reporting of adverse events............................................................187
10.1.6
Reporting of MS relapse.................................................................188
10.1.7
Follow-up of adverse events...........................................................188
10.2
Serious adverse events................................................................................189
10.2.1
Definitions of serious adverse events .............................................189
10.2.1.1
Serious adverse events...........................................................189
10.2.1.2
Serious adverse events associated with the study design 
or protocol-mandated procedures..........................................189
10.2.2
Reporting of serious adverse events ...............................................190
10.2.3
Follow-up of serious adverse events...............................................190
10.2.4
After the 30-day follow-up period..................................................190
10.2.4.1
During the PTOP period (if applicable) ................................190
10.2.4.2
After the PTOP period...........................................................190
10.2.5
Reporting procedures......................................................................190
10.3
Pregnancy ...................................................................................................191
10.3.1
Reporting of pregnancy ..................................................................191
10.3.2
Follow-up of pregnancy..................................................................191
10.4
Study safety monitoring..............................................................................191
11 STATISTICAL METHODS .....................................................................................192
11.1
Analysis sets ...............................................................................................193
11.1.1
Screened analysis set ......................................................................193
11.1.2
Full analysis set...............................................................................193
11.1.3
All-randomized set..........................................................................193
11.1.4
Per-protocol set...............................................................................193
11.1.5
Safety set.........................................................................................194
11.1.6
Other analysis sets ..........................................................................194
11.1.7
Usage of the analysis sets ...............................................................194
11.2
Variables.....................................................................................................194
11.2.1
Primary efficacy endpoint variable.................................................194
11.2.2
Secondary efficacy endpoint variables ...........................................195
11.2.2.1
Time to 12-week CDA from baseline up to EOS..................195
11.2.2.2
Time to first confirmed relapse up to EOS............................195


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11.2.2.3
Mean number of CUALs per subject per post-baseline 
MRI scan up to EOS..............................................................196
11.2.2.4
Longitudinal change over time in fatigue-related 
symptoms as measured by the symptoms domain of the 
FSIQ-RMS from baseline up to EOS....................................196
11.2.2.5
Longitudinal percent change over time in brain volume 
(PCBV) from baseline up to EOS .........................................196
11.3
Description of statistical analyses...............................................................196
11.3.1
Overall testing strategy...................................................................196
11.3.2
Analysis of the primary efficacy variable.......................................196
11.3.2.1
Hypotheses and statistical model ..........................................196
11.3.2.2
Handling of missing data.......................................................197
11.3.2.3
Main analysis.........................................................................198
11.3.2.4
Supportive/sensitivity analyses .............................................198
11.3.2.5
Subgroup analyses.................................................................199
11.3.3
Analysis of the secondary efficacy variables..................................199
11.3.3.1
Time to 12-week CDA from baseline up to EOS..................200
11.3.3.2
Time to first confirmed relapse up to EOS............................200
11.3.3.3
Mean number of CUALs per subject per post-baseline 
scan from baseline up to EOS ...............................................201
11.3.3.4
Longitudinal change over time in the fatigue related 
symptoms domain of the FSIQ-RMS from baseline up to 
EOS .......................................................................................202
11.3.3.5
Longitudinal percent change from baseline over time in 
brain volume from baseline up to EOS .................................203
11.3.4
Analysis of the other efficacy variables..........................................203
11.3.4.1
Mean number of Gd+ T1, CUAL and new or enlarging 
T2 lesions by visit..................................................................203
11.3.4.2
Change in volume of T2 lesions, volume of T1 
hypointense lesions and EDSS from baseline to each 
visit........................................................................................203
11.3.4.3
Absence of Gd+ T1 lesions, absence of new or enlarging 
T2 lesions, absence of new T1 hypointense lesions and 
subjects relapse-free ..............................................................204
11.3.4.4
Time to first 24-week CDA from baseline to EOS ...............204
11.3.4.5
NEDA status at EOS .............................................................204
11.3.4.6
Change of MSFC Z-score and SDMT score from 
baseline to EOS by visit ........................................................204
11.3.4.7
Change of FSIQ-RMS fatigue-related impacts from 
baseline to EOS by visit ........................................................204


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11.3.5
Analysis of the safety variables ......................................................204
11.3.5.1
Adverse events ......................................................................205
11.3.5.2
Cardiac safety........................................................................206
11.3.5.3
Pulmonary safety...................................................................206
11.3.5.4
Vital signs..............................................................................207
11.3.5.5
Laboratory endpoints.............................................................207
11.3.6
eC-SSRS .........................................................................................207
11.3.7
Analysis of other variable(s)...........................................................208
11.3.7.1
PK..........................................................................................208
11.3.7.2
PD..........................................................................................208
11.3.7.3
Quality of Life Questionnaire (SF-36v2TM) ..........................208
11.3.7.4
WPAI:MS Questionnaire ......................................................208
11.3.7.5
Health care resource utilization.............................................208
11.4
Interim analyses..........................................................................................208
11.5
Sample size.................................................................................................208
11.5.1
Primary endpoint.............................................................................208
11.5.2
Secondary endpoints.......................................................................209
11.5.3
Sample size sensitivity....................................................................209
11.5.4
Sample size re-estimation...............................................................209
12 DATA HANDLING..................................................................................................209
12.1
Data collection............................................................................................209
12.2
Maintenance of data confidentiality ...........................................................210
12.3
Database management and quality control.................................................210
13 PROCEDURES AND GOOD CLINICAL PRACTICE...........................................211
13.1
Ethics and Good Clinical Practice..............................................................211
13.2
Independent Ethics Committee / Institutional Review Board ....................211
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..................................................................................................214
13.9
Investigator site file ....................................................................................215
13.10
Audit ...........................................................................................................216
13.11
Inspections..................................................................................................216
13.12
Reporting of study results and publication.................................................216
14 REFERENCES..........................................................................................................218


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15 APPENDICES...........................................................................................................225
LIST OF TABLES
Table 1
Visit and assessment schedule (Part 1) ......................................................52
Table 2
Visit and assessment schedule (Part 2) ......................................................55
Table 3
Visit and assessment schedule (Part 3) ......................................................58
Table 4
Dosing scheme .........................................................................................104
Table 5
Guidance for subject monitoring and discontinuation for PFT 
decrease and persistent respiratory AEs...................................................120
Table 6
Guidance for subject monitoring and discontinuation for liver 
enzyme abnormalities...............................................................................121
Table 7
Total blood volume to be drawn per subject............................................160
LIST OF FIGURES
Figure 1
AC-058B302 study design .........................................................................83
Figure 2
Algorithm for management of treatment..................................................112
Figure 3
Flow diagram for the detection and evaluation of relapses......................137
LIST OF APPENDICES
Appendix 1
Neurostatus® scoring sheet.......................................................................225
Appendix 2
Diagnostic criteria for MS (2010 Revised McDonald Criteria)...............227
Appendix 3
Prohibited anti-arrhythmic and HR-lowering drugs.................................229
Appendix 4
Guidance for concomitant treatment with QT-prolonging drugs with 
known risk of Torsades de Pointes...........................................................230
Appendix 5
Adverse events of special interest............................................................232
Appendix 6
Abnormalities for ECG, BP and laboratory variables..............................233
Appendix 7
Multiple Sclerosis Functional Composite ................................................237
Appendix 8
Symbol Digit Modalities Test ..................................................................242
Appendix 9
Fatigue Symptoms and Impacts Questionnaire – Relapsing Multiple 
Sclerosis ...................................................................................................243
Appendix 10 SF-36v2™................................................................................................252


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Appendix 11 Work Productivity and Activity Impairment Questionnaire: Multiple 
Sclerosis ...................................................................................................262
Appendix 12 Relapse assessment questionnaire............................................................264
Appendix 13 Relapse symptom form.............................................................................268
Appendix 14 Electronic self-rated version of the Columbia-Suicide Severity 
Rating Scale..............................................................................................272
Appendix 15 Guidance for re-screening ........................................................................329


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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 
ANOVA
Analysis of variance
ARR
Annualized relapse rate
ARS
All randomized set
AST
Aspartate aminotransferase / serum glutamic oxaloacetic 
transaminase 
ATS
American Thoracic Society
AV
Atrioventricular 
b.i.d.
Twice daily
BP
Blood pressure
bpm
Beats per minute
CDA
Confirmed disability accumulation
CI
Confidence interval
CIS
Clinically isolated syndrome
CNS
Central nervous system
CRO
Contract Research Organization
CSF
Cerebrospinal fluid
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
DLCO
Diffusing capacity for the lungs measured using carbon monoxide
DMF
Dimethyl fumarate
DMT
Disease-modifying therapy
DWI
Diffusion-weighted imaging


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ECG
Electrocardiogram
eCRF
Electronic case report form
eC-SSRS
Electronic self-rated version of the Columbia-Suicide Severity 
Rating Scale
ECTRIMS
European Committee for Treatment and Research in Multiple 
Sclerosis
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
FLAIR
Fluid-attenuated inversion recovery
FS
Functional system
FSIQ-RMS
Fatigue Symptom and Impacts Questionnaire-Relapsing Multiple 
Sclerosis
FU7d
FU visit approximately 7 days after the last dose of study drug
FU
Follow-up
FVC
Forced vital capacity
GCP
Good Clinical Practice
Gd
Gadolinium
Gd
Gadolinium-enhancing
Hb
Hemoglobin
HIV
Human immunodeficiency virus
HR
Heart rate
i.m.
Intramuscular


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i.v.
Intravenous
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
ICU
Intensive care unit
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IFN
Interferon
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISAC
Independent Statistical Analysis Center
ISF
Investigator site file
JCV
John Cunningham Virus
MACE
Major adverse cardiovascular events
MedDRA
Medical Dictionary for Regulatory Activities
MIAC
Medical Image Analysis Center
MRI
Magnetic resonance imaging
MS
Multiple sclerosis
MSFC
Multiple Sclerosis Functional Composite
NEDA
No evidence of disease activity
NK
Natural killer
NMSS
US National Multiple Sclerosis Society
NOAEL
No-observed-adverse-effect level
NYHA
New York Heart Association
o.d.
Once a day
OCT
Optical coherence tomography
OSB
Ophthalmology Safety Board
PASAT
Paced Auditory Serial Addition Test
PCBV
Percent change in brain volume
PCR
Polymerase chain reaction


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PD
Pharmacodynamic(s)
PEF
Peak expiratory flow
PFT
Pulmonary function test
PK
Pharmacokinetic(s)
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
RBC
Red blood cell
RMS
Relapsing multiple sclerosis
RR
Relapsing-remitting
RRMS 
Relapsing-remitting multiple sclerosis
s.c.
Subcutaneous
S1P
Sphingosine-1-phosphate
SAE
Serious adverse event
SAF
Safety set
SAP
Statistical Analysis Plan
SBP
Systolic blood pressure
SCR
Screened analysis set
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 Normalisation, of Atrophy
SIV
Site initiation visit


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SmPC
Summary of Product Characteristics
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
USPI
United States Package Insert
WBC
White blood cell(s)
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 5
Amendment rationale
This amendment rationale applies to global protocol AC-058B302 Version 5, dated 
8 December 2016. The resulting amended global protocol is Version 6, dated 
21 December 2017.
The main reasons for this amendment are to make the following changes to inclusion 
criterion #6:

To include the presence of at least one new or one unequivocally enlarging T2 
lesion on magnetic resonance imaging (MRI) of the brain or spinal cord as an 
alternative criterion of disease activity. In order to assess this alternative criterion, 
two MRI scans have to be compared; the first MRI scan must be performed within 
15 months prior to Visit 1 (Screening) and after at least 3 months of dimethyl 
fumarate (DMF) treatment; the second MRI scan must be performed prior to 
randomization (i.e., MRI performed at Visit 2 [Baseline] may be used). The 
presence of at least one new or one unequivocally enlarging MRI T2 lesion has to 
be confirmed by the central MRI reading facility prior to randomization of the 
subject.
New or enlarging MRI T2 lesions are commonly accepted as a sign of multiple 
sclerosis (MS) disease activity [Lublin 2014] and as such are part of international
and national MS treatment guidelines [ICER Report 2017, Goodin 2002, 
Montalban 2017, Torkildsen 2016]. T2 lesions are considered a predictor of MS 
clinical activity such as relapses [Sormani 2009] and disability progression 
[Sormani 2013]. This modification takes into account the “re-baseline” MRI 
performed after at least 3 months on DMF, and the window of 15 months reflects 
the anticipated visit window for yearly MRI scans (i.e., 12 + 3 months) at sites 
where yearly MRI monitoring is standard of care.

To include the presence of MRI T1 gadolinium-enhancing (Gd+) lesions observed 
on the pre-randomization MRI scan of the brain as an alternative criterion of 
disease activity.
The presence of at least one T1 Gd+ lesion was already included in the definition 
of disease activity; however, sites could only use an MRI prior to Visit 1 
(screening) and not the pre-randomization MRI to qualify a subject for the study. 
With this modification, sites will have the possibility to detect radiological signs 
of disease activity at the pre-randomization MRI, which is in line with allowing 
pre-randomization T2 lesions to be part of inclusion criterion #6.


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Adding T2 lesions to disease-activity criteria and allowing a pre-randomization 
MRI to be a qualifying MRI will not change the study population, which will still 
consist of subjects with active relapsing MS (RMS) while on Tecfidera® with 
disease activity criteria based on relapses and active MRI lesions; the change is 
pertaining solely to the method and the timing of detecting the active MRI lesions.
Additional modifications are being made to the study protocol as follows:

The recommendation for treatment of relapses provided in Section 5.2.4 is being
modified to include a standardized dose of oral corticosteroids. High-dose oral 
corticosteroids are frequently used for treatment of relapses and have been proven
to be as effective as intravenous oral prednisolone [Burton 2009, Le Page 2015]
while less burdensome for the patients.

The text related to modification of treatment due to confirmed relapses and 
re-consenting is amended to ensure alignment within the different protocol
sections. According to Sections 5.1.1, 7.1.1, 7.2.2 and 13.3, after each confirmed 
relapse, the subjects must be made aware of the potential risks and benefits of 
continuing in the study as well as alternative treatment options available and then 
provide re-consent if they wish to continue on study treatment. 
Re-consenting subjects after each confirmed relapse is a more conservative 
approach than re-consenting only after two confirmed relapses or after 48 weeks 
of treatment and at least one confirmed relapse. Since the subjects have to be 
re-consented after each confirmed relapse, the requirement for re-consenting after 
two confirmed relapses or after 48 weeks of treatment with at least one confirmed 
relapse [originally mentioned in Sections 3.2, 3.5.2.1 and 5.1.1] is removed since 
it is redundant.

In accordance with the recent update of sections 4.4 and 4.8 of the Tecfidera®
Summary of Product Characteristics [Tecfidera USPI], in which it is now stated 
that drug-induced liver injury cases have been reported in post-marketing 
experience following Tecfidera® administration, the liver was introduced as a 
target organ of potential toxicity of dimethyl fumarate (Tecfidera®) in protocol 
Section 1.4. This modification does not warrant any change to the current 
monitoring of the liver functions, as the frequency of the tests is deemed to be 
sufficient.

To alleviate the burden on subjects and sites in case of re-screening, sites do not 
have to repeat all the pre-randomization assessments that were performed for the 
first screening attempt, as described in the guidance for re-screening in 
Appendix 15.


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
Prior to re-screening, a re-consent has to be obtained (i.e., a new Informed 
Consent Form has to be signed by the subject and by the investigator). The
pre-randomization period will then start from the date of this re-consent [see 
Sections 8, 13.3 and Appendix 15]. 

As the results from the lymphocyte subsets sub-study carry an unblinding 
potential, it is clarified in Sections 3.6.1 and 7.7.2.2 that the results from this
sub-study will be blinded to site staff and the sponsor until study closure.

In case of a temporary interruption of study treatment that lasts more than 30 days 
and leads to a permanent treatment discontinuation, the safety FU visits can be 
combined with the End-of-Treatment (EOT) visit [see Sections 8.2.10, 8.3.1.1 and 
8.3.1.2].

Section 1.3.2.3 is updated with results from an interim analysis of studies 
AC-058B201/B202 with cut-off date of 1 September 2016, which were presented 
as a poster at the European Committee for Treatment and Research in Multiple 
Sclerosis (ECTRIMS) congress in 2017.

It is now permitted to omit gadolinium administration prior to MRI T1 sequences 
in case of medical contraindication during the study; consequently allergy to 
gadolinium is being removed from exclusion criterion #19. This is justified 
because gadolinium sequences are not used for the evaluation of the primary or 
secondary endpoints of the study.

Clarification regarding the need to perform a new dermatological examination in 
case the subject was re-screened following an excision of a pre-cancerous skin 
lesion or a basocellular carcinoma is added to the section on dermatological 
examination [Section 7.3.12]. In this case, the dermatological examination 
performed at re-screening will ensure that the lesions were successfully excised.

Clarification on the time windows for the conduct of assessments and visits:
−
In-between visit telephone calls: As per Section 8.2.5, the calls are scheduled 
at Weeks 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138 and 150 (± 7 days; 
with Day 1 as a reference). However, in the same section it was stated “The 
site will contact the subject 6 weeks (± 7 days) after each of the 12-weekly 
visits (e.g., Visit 6 – Week 12, Visit 7 – Week 24, …). The window for these 
telephone calls is ± 7 days.” Thus, the change in Sections 7.2.2 and 8.2.5
provides clarification that the time window to conduct the in-between 
telephone calls may be either Weeks 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 
138 and 150 (± 7 days), or 6 weeks after the last 12-weekly visit (± 7 days).


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−
Hourly electrocardiograms (ECGs), blood pressure (BP), and pharmacokinetic 
(PK) assessments: Cardiac monitoring consisting of hourly ECG and BP 
assessments must be conducted after first dosing on Day 1 or on the first day 
of re-initiation of study drug when post-dose monitoring is required. In 
addition, PK samples are to be drawn 3 hours post-dose at Visits 3 and 6 (Day 
1 and Week 12). At Visit 6 (Week 12), an ECG must also be conducted 
3 hours post-dose. The time windows for the above-mentioned assessments
have not been specified in the study protocol. A time window of ± 15 minutes 
around the scheduled time seems reasonable for the collection of the data 
pertaining to the data time point. Thus, the study protocol is amended in order 
to provide a recommendation to perform the hourly ECG, BP, and PK within 
15 minutes from the scheduled time.
−
Home urine pregnancy tests: The time windows for the 4-weekly urine 
pregnancy tests conducted at home during the treatment period have not been 
specified in the study protocol. This test should be conducted at home within 
4 days from the scheduled time point.

Active or latent tuberculosis can be assessed by chest X-ray (CXR) or interferon
(IFN) Gamma release assay. As defined in Section 7.3.5 of the study protocol, only 
subjects with a negative IFN gamma release assay (QuantiFERON-TB-Gold®) test at 
Visit 1 (Screening) and without CXR findings at Visit 1 (Screening) or within 
90 days suggestive of active or latent tuberculosis can be included in the study. Thus,
exclusion criterion #15 is amended to clarify that subjects with active or latent 
tuberculosis as assessed by CXR or IFN gamma release assay test are excluded from 
the study. 

In order not to repeat an MRI so soon after a previous assessment, it is clarified in 
Section 7.2.3 that, in case of premature study treatment discontinuation, the MRI 
assessment at EOT does not need to be performed if the EOT visit occurs within 
4 weeks after the latest scheduled MRI assessment.

Since the ECG assessment will inform about heart rate, it is clarified in Section 7.3.11
that pulse rate assessment may be omitted in case a visit for relapse corresponds to a 
visit when 12-lead ECG is performed.

Correction is made in Sections 8.3.2.1, 8.3.2.2 and 8.3.2.3 to clarify that 
post-treatment observation visits are not recorded in the Interactive Response 
Technology system.

Clarification on the conduct of physical examination: The required examinations as 
part of the physical examination at pre-randomization and at subsequent visits are
clarified in Section 7.3.9. It is the responsibility of the principal investigator or 


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treating neurologist to perform other exams if indicated, based on medical history 
and/or symptoms.

As stated in Section 7.2.5, the Symbol Digit Modalities Test (SDMT) is administered 
along with the Multiple Sclerosis Functional Composite (MSFC) test. Since, 
depending on the site setting, the efficacy assessor may be in charge of administering 
the MSFC test, clarification is provided in Section 3.7.3 that the efficacy assessor 
may also administer the SDMT.

Section 3.5.5 is added to the study protocol in order to provide clarifications on the 
visits and assessments that will have to be performed after the study closure 
announcement by the sponsor and the time frame for these.

Sections 5.2.5 and 5.2.6 are amended to further clarify that short-term treatment with 
low dose of corticosteroids and inhaled corticosteroids for pulmonary conditions are 
allowed.

Clarification is provided in Sections 7.3.13.1 and 7.3.13.2 that an additional blood 
sample may need to be collected if deemed necessary by the investigator in case of a 
lost or deteriorated sample.

Adjustments are made to align Section 1.1.4 with recent changes in available 
therapies for MS.

The definition of 24-week CDA was not present in the study protocol and is now 
added to Section 6.1.3.

Text has been added to allow physician assistants and nurse practitioners to assume 
the role of efficacy assessor if adequately trained and certified [Section 3.7.3].
Physician assistants and nurse practitioners are trained in autonomous healthcare 
decision-making. The performing of examinations such as Expanded Disability Status 
Scale / Functional system (EDSS/FS) scoring is typically delegated to efficacy 
assessors by physicians. Any person acting as the efficacy assessor in this study will 
be trained and certified in EDSS scoring as defined in the study protocol.
Qualification and certification of the person assigned to this role will be reviewed by 
the sponsor before she/he is allowed to make an efficacy assessment.

Text has been added to allow physician assistants, nurse practitioners as well as any 
trained and qualified person as per local regulations to assume the role of 
dermatologist and first-dose administrator [Sections 3.7.10 and 3.7.4, respectively]. 
Physician assistants and nurse practitioners are trained in autonomous healthcare 
decision-making. Any person acting as the dermatologist or first-dose administrator 
in this study will have to be trained and qualified, as per local regulations, to assume 


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this role. For non-physicians the role of a dermatologist or first-dose administrator 
must be within the scope of the national and/or local authorization. The qualifications 
of non-physicians performing dermatological examinations or acting as first-dose 
administrator will need to be assessed by the sponsor prior to assignment.

Clarity has been added in Section 5.1.12.7 that the decision to permanently 
discontinue a subject due to a macular edema is based on the confirmation of macular 
edema by the local ophthalmologist.

In Sections 6.2 and 11.3.5.5.1, a safety endpoint has been added on John Cunningham 
Virus serology change from baseline up to End-of-Study.

Text has been added to allow replacement of dilated funduscopy by funduscopy with 
ultra widefield imaging when pupil dilation is medically contraindicated [Section 
7.3.6].
Finally, some inconsistencies between sections in the protocol were corrected as follows:

Table 2 and Section 7.3.4 currently state that, in case of premature study treatment 
discontinuation, the chest X-ray at Visit 18 (EOT) does not need to be performed if 
the EOT visit occurs within 48 weeks of the pre-randomization chest X-ray. This 
requirement is made consistent in Section 8.2.10.

At the unscheduled visit for relapses, the principal investigator / treating neurologist 
will need to perform a physical examination and vital signs including pulse rate and 
body temperature to exclude potential other reasons for the symptom(s) observed. In 
this event, systolic blood pressure (SBP) / diastolic blood pressure (DBP) assessment 
is not mandated. SBP/DBP assessment is therefore removed from the table of 
assessment and Section 8.4.1.

Section 3.8.3 currently defines the process for review and evaluation of brain MRIs 
by the MRI safety board in case of a suspected opportunistic infection in the central 
nervous system (CNS). Therefore, the text in Section 5.1.12.3.1 is made consistent 
with Section 3.8.3.

Section 4.5.2 currently states that if a hormonal method of contraception is chosen, 
then it must be initiated at least 30 days prior to randomization. Inclusion criterion #3 
is modified to refer to Section 4.5.2 in which the time window for each acceptable 
method of contraception is described.

Figure 2 is updated to align the definition of maintenance period with Section 5.1.9.

Spirometry and physical examination are added to the list of assessments to be 
performed at Visit 6A (Week 12) and Visit 7A (Week 24), respectively, Sections 


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8.3.2.1 and Table 3, to have the same frequency for these two assessments in the post-
treatment observation period than during the treatment period.
Changes to the protocol
Two versions of the amended protocol will be prepared: 1) a clean version and 2) a Word 
comparison document, showing deletions and insertions in comparison to the previous 
protocol version.
Amended protocol sections
The 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:
1.1.4
Treatment of MS
1.1.4.1
Injectable disease-modifying therapies
1.1.4.2
Orally administered disease-modifying therapies
1.3.2.3
Efficacy in humans
1.4
Purpose and rationale of the study
1.5
Summary of known and potential risks and benefits
3.4.1
Lymphopenia
3.5.2.1
Modification of treatment
3.5.3.2
Post-treatment observation period
Figure 1
AC-058B302 study design
3.5.5
Study closure
3.6.1
Lymphocyte subset
3.7.3
Efficacy assessor
3.7.4
First-dose administrator
3.7.7
Local radiologist or neurologist with MRI expertise
3.7.10
Dermatologist
3.8.4
Major adverse cardiovascular events adjudication board


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4.1
Subject population description
4.3
Inclusion criteria
4.4
Exclusion criteria
4.5.2
Acceptable methods of contraception
5.1.1
Investigational treatment and matching placebo: description and rationale
5.1.4.2
Functional blinding
Figure 2
Algorithm for management of treatment 
5.1.10
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
5.1.12.3.1
Guidance for screening, exclusion and on-treatment monitoring of subjects 
for progressive multifocal leukoencephalopathy / other opportunistic CNS 
infections
5.1.12.7
Ocular abnormalities
5.2.2.2
Previous MS therapies
5.2.4
Recommended concomitant therapy
5.2.5
Allowed concomitant therapy
5.2.6
Forbidden concomitant therapy
6.1.2
Secondary efficacy endpoints
6.1.3
Other efficacy endpoints
6.2
Safety endpoints
7.1.4
Previous MS therapies
7.2.2
Detection and evaluation of relapses
7.2.3
MRI evaluations
7.3.1
12-lead electrocardiogram
7.3.2
Blood pressure
7.3.6 
Ophthalmologic assessments


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7.3.9
Physical examination
7.3.11
Pulse rate
7.3.12
Dermatological examination
7.3.13.1
Type of laboratory
7.3.13.2
Laboratory tests
7.7.1
Pharmacokinetic assessments
7.7.2.2
Blood lymphocyte subsets
Table 7
Total blood volume to be drawn per subject
8
SCHEDULE OF VISITS
Figure 4
Timing of the pre-randomization assessments
8.2.1
Visit 3 – Randomization Day 1 – Randomization and post-dose 
assessments
8.2.5
In-between-visit telephone calls until Week 156 (Weeks 18, 30, 42, 54, 66, 
78, 90, 102, 114, 126, 138, and 150)
8.2.6
Visits 6 and 7 – Weeks 12 and 24 
8.2.7
Visits 8, 10, 12, 14, and 16 – Weeks 36, 60, 84, 108, 132
8.2.8
Visits 11 and 15 – Weeks 72 and 120
8.2.9
Visits 9, 13, 17 – Weeks 48, 96, and 144
8.2.10
Visit 18 – EOT
8.3.1.1
Visit 19 – FU7d
8.3.1.2
Visit 20 – FU
8.3.2.1
Visits 6A, 7A, 8A, 10A, 12A, 14A, and 16A – Weeks 12, 24, 36, 60, 84, 
108, and 132
8.3.2.2
Visits 11A – Week 72 and Visit 15A – Week 120 
8.3.2.3
Visits 9A, 13A, 17A, and 18A – Weeks 48, 96, 144, and 156 
8.4.1
Unscheduled visits for relapses (Visits R1, R2, etc.)


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8.4.2
Additional unscheduled visits for re-initiation of study drug (I1, I2, etc.)
11.3.5.5.1
Laboratory tests
13.3
Informed consent
13.12
Reporting of study results and publication 
14
REFERENCES 
Appendix 5
Adverse events of special interest
Appendix 6
Abnormalities for ECG, BP and laboratory variables
Appendix 15
Guidance for re-screening
Summary of previous amendments
Global 
Amendment
Date
Main reason(s)
1
4 December
2015
Addressing comments received during the special 
protocol assessment (SPA) review by the US FDA.
2
9 March 
2016
Addressing comments received after the US FDA’s 
review of the SPA.
3
17 June 2016
Addressing comments received during the Voluntary 
Harmonization Procedure review for this Clinical Trial 
Application in the EU.
4
8 December 
2016
Clarifying that study subjects will be re-consented to 
continue receiving study drug (rather than re-consenting 
to participate in the study) if they meet one of the 
following conditions:

The subject has completed at least 48 weeks of 
treatment in the study AND has had at least one 
confirmed relapse that occurred after 12 weeks or 
more of treatment;

The subject has experienced two confirmed relapses 
while on study treatment;

The subject has experienced an event of 24-week 
confirmed disability accumulation while on study 
treatment.


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PROTOCOL SYNOPSIS AC-058B302
TITLE
Multicenter, randomized, double-blind, parallel-group, add-on, 
superiority study to compare the efficacy and safety of 
ponesimod to placebo in subjects with active relapsing multiple 
sclerosis who are treated with dimethyl fumarate (Tecfidera®)
ACRONYM
POINT: POnesImod aNd Tecfidera
OBJECTIVES
Primary objective
The primary objective of the study is to determine whether 
add-on therapy with ponesimod reduces relapse frequency as 
compared to placebo in subjects with active relapsing multiple 
sclerosis (RMS) who are treated with dimethyl fumarate (DMF; 
Tecfidera®).
Secondary objectives

To assess the effect of add-on therapy with ponesimod vs 
placebo on disability accumulation and on other aspects of 
multiple sclerosis (MS) disease control in subjects with 
RMS who are treated with DMF (Tecfidera®);

To assess the safety and tolerability of add-on therapy with 
ponesimod vs placebo in subjects with RMS who are treated 
with DMF (Tecfidera®).
DESIGN
This is a prospective, multicenter, randomized, double-blind, 
parallel group, add-on, placebo-controlled, Phase 3, superiority 
study. The study is designed to compare the efficacy, safety, 
and tolerability of add-on therapy with ponesimod 20 mg vs 
placebo in adult subjects with active RMS who are treated with 
DMF (Tecfidera®).
PERIODS
Pre-randomization period 
This period commences up to 45 days before randomization at 
the time of the signature of the Informed Consent Form (ICF) 
and ends with subject randomization. It includes Visit 1 
(Screening), Visit 2 (Baseline) and the pre-dose assessments of 
Visit 3 (Day 1). 
Treatment period 
This period consists of a double-blind treatment period, which 
starts after randomization with the first dose of study treatment 


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during Visit 3 (Day 1 of study).
The double-blind treatment period has a variable duration from 
a minimum of 60 weeks (for the last subject randomized) to a 
maximum of 156 weeks (3 years) for the first subjects
randomized in the trial. Average duration is expected to be 
approximately 2 years. It includes a randomization visit, visits 
at 2, 4, and 12 weeks after randomization, and 12-weekly visits 
thereafter until 60 weeks after the randomization of the last 
subject or 156 weeks of treatment (whichever occurs first). 
For an individual subject, this period starts on the day of the 
first study treatment intake and continues until the premature 
discontinuation of study treatment, Week 156 or until 60 weeks 
after the randomization of the last subject (whichever occurs 
first).
End-of-Treatment (EOT) visit: The EOT visit at an individual 
level should preferably take place 1 day after the last dose of 
study treatment, but no later than 7 days after the last dose of 
study treatment.
Modification of treatment
If a subject meets one of the following conditions:

The subject has experienced a confirmed relapse while on 
study treatment;

The subject has experienced an event of 24-week confirmed 
disability accumulation (CDA) while on study treatment;
Then, the principal investigator / treating neurologist should 
consider and propose the following options to this subject:

Subject remains on study treatment. In this case, the subject 
will be asked to re-consent to continue receiving study 
treatment.

Subject prematurely discontinues study treatment and DMF 
background therapy, and begins treatment with an approved 
MS therapy at the discretion of the treating neurologist in 
accordance with local practices. In this case, the subject will 
enter the post-treatment observation period (PTOP) of the 
study.


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Subjects who prematurely discontinue study treatment for 
reasons other than lack of efficacy (e.g., safety or tolerability) 
will also enter the PTOP of the study. Treating neurologists
may choose to continue DMF therapy or may begin treatment 
with an approved MS therapy at the discretion of the treating 
neurologist in accordance with local practices. Discontinuation 
of DMF treatment should be considered in accordance with 
prescribing information
at the discretion of the treating 
neurologist and in accordance with local practices.
Subjects who permanently discontinue DMF background 
therapy will discontinue study treatment and may begin 
treatment with an approved MS therapy in accordance to local 
practices. In this case, the subject will enter the PTOP of the 
study.
Post-treatment period and End-of-Study
This period starts immediately after the last dose of study 
treatment and ends when End-of-Study (EOS) visit has been 
completed. It comprises the post-treatment safety follow-up 
(FU) period and if applicable, is followed by the PTOP.
Post-treatment safety follow-up period
All subjects will enter the safety FU period which lasts for at 
least 30 days after the last dose of study treatment and includes 
a safety FU visit approximately 30 days after the last dose of 
study treatment. Subjects participating in the lymphocyte subset 
sub-study will have an additional FU visit approximately 7 days 
after the last dose of study drug.
Post-treatment observation period
Subjects who prematurely discontinue study drug and complete 
the 30-day safety follow-up including FU visit, will enter the 
PTOP which lasts until 60 weeks after randomization of the last 
subject (i.e., planned EOT visit) irrespective of treatment 
completion. It consists of an abbreviated schedule of 
assessments at the time of the originally scheduled 12-weekly 
visits.
End-of-Study
The study level EOS will occur after all subjects have 
completed the safety FU period or the last visit of the PTOP.
For an individual subject, EOS is reached when treatment, post-


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treatment safety FU, and, if applicable, PTOP have been 
completed: 

For subjects who complete the treatment period, and for 
subjects who prematurely discontinue study treatment and 
do not enter the PTOP, the EOS visit corresponds to the 
30-day FU visit.

For subjects who prematurely discontinue study treatment 
and enter the PTOP period, the EOS visit corresponds to the 
last visit of the PTOP.
The study closure will be communicated by the sponsor 
60 weeks after the randomization of the last subject.
PLANNED DURATION
Assuming a subject recruitment time of 104 weeks (including 
the period from first subject, first visit (FSFV) to last subject, 
first visit (LSFV) and a 45-day pre-randomization period for the 
last randomized subject), the overall duration of the study from
FSFV to last subject, last visit (LSLV) will consist of 
104 weeks recruitment, followed by the minimum treatment 
time of 60 weeks, and 30 days post-treatment safety follow-up. 
This results in an anticipated study duration of approximately 
168 weeks (3.3 years). The actual overall study duration or 
subject recruitment period may vary.
For an individual subject, the maximum duration time will 
consist of a 45-day pre-randomization period followed by a 
maximal 
156-week 
treatment 
period 
and 
a 
30-day 
post-treatment safety follow-up. This results in a maximal total 
participation time of approximately 167 weeks (3.3 years).
SITE(S)
/ COUNTRY(IES)
100 sites in 15 countries (planned).
SUBJECTS / GROUPS
Approximately 600 subjects who have been receiving DMF
twice daily (b.i.d.) for at least 6 months will be randomized in a 
1:1 ratio to ponesimod 20 mg or placebo (approximately 
300 subjects per arm). Randomization will be stratified by 
baseline Expanded Disability Status Scale (EDSS) score (EDSS 
≤3.5, EDSS > 3.5).


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INCLUSION CRITERIA
1. Signed informed consent prior to initiation of any 
study-mandated procedure.
2. Males and females aged 18 to 55 years (inclusive). 
3. A woman of childbearing potential (WOCBP) is eligible 
only if the following applies:

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 monthly urine pregnancy tests 
during the study and up to 30 days after study treatment 
discontinuation;

must use reliable methods of contraception until 30 days 
after study treatment discontinuation as described in 
protocol Section 4.5.2;
4. Presenting with a diagnosis of MS as defined by the revised 
(2010) McDonald Diagnostic Criteria for MS [see 
Appendix 2] with relapsing course from onset (i.e., 
relapsing-remitting multiple sclerosis (RRMS), or secondary 
progressive multiple sclerosis (SPMS) with superimposed 
relapses).
5. Ongoing treatment with DMF for at least 6 months prior to 
Visit 1 (Screening);
6. Active disease after at least 3 months of DMF treatment 
defined by at least one of the following features:

At least one MS attack supported by objective 
neurological examination with onset within 12 months to 
1 month prior to baseline EDSS assessment;

At least one gadolinium-enhancing (Gd+) lesion on an 
MRI of the brain or spinal cord, performed within 
12 months prior to Visit 1 (Screening) or during the 
pre-randomization period (MRI assessed at Visit 2 
[Baseline] may be the qualifying scan);

Presence of at least one new or one unequivocally 
enlarging T2 lesion on an MRI of the brain or spinal 
cord, assessed by comparing two MRI scans: the first 
MRI scan must be performed within 15 months prior to 
Visit 1 (Screening) and after at least 3 months of DMF 
treatment; the second MRI scan must be performed prior
to randomization (MRI assessed at Visit 2 [Baseline] 
may be used). The presence of at least one new or one 


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unequivocally enlarging T2 lesion has to be confirmed 
by 
the 
central 
MRI 
reading 
facility
prior 
to 
randomization.
7. Ambulatory and with an EDSS score between 0 and 6.0
(inclusive) at Visit 1 (Screening) and Visit 2 (Baseline).
8. For subject with ongoing treatment with DMF ≥12 months 
prior to screening:

Lymphocyte count ≥0.8 × 109/L (≥800/mm3) at Visit 1 
(Screening) and Visit 2 (Baseline) (assessed at least 
3 weeks apart) with the lymphocyte count at Visit 2 
(Baseline) > 0.5-fold and < 2.0-fold of the count at Visit 
1 (Screening).
For subject with ongoing treatment with DMF ≥6 months 
(but < 12 months) prior to screening:

Lymphocyte count ≥0.9 × 109/L (≥900/mm3) at Visit 1 
(Screening) and Visit 2 (Baseline) (assessed at least 
3 weeks apart) with the lymphocyte count at Visit 2 
(Baseline) > 0.5-fold and < 2.0-fold of the count at Visit 
1 (Screening).
EXCLUSION CRITERIA
Pregnancy and Breastfeeding
1. Lactating or pregnant women and women intending to 
become pregnant during the study.
MS disease
2. Presenting with a diagnosis of MS with progressive course 
from onset (i.e., primary progressive MS or progressive 
relapsing MS).
3. Evidence of a relapse of MS with onset within 30 days prior 
to baseline EDSS assessment or between baseline EDSS 
assessment and randomization.
Treatments
4. Treatment with the following medications:

Within 15 days prior to randomization:
o
-blockers, diltiazem, verapamil, digoxin or any 
other anti-arrhythmic or heart rate (HR) lowering
systemic therapy [non-exhaustive list of drugs 
provided in Appendix 3]

Within 30 days prior to randomization: 
o
Adrenocorticotropic hormone (ACTH) or systemic 
corticosteroids (for any reason)


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o
Vaccination with live vaccines

Within 90 days prior to randomization:
o
Plasmapheresis, cytapheresis
o
Intravenous (i.v.) immunoglobulin
o
Treatment with an investigational drug (within 
90 days or five half-lives of the drug, whichever is 
longer), except biological agents (see below)

Within 180 days prior to randomization:
o
IFN β-1a, IFN β-1b, glatiramer acetate, or 
daclizumab
o
Systemic 
immunosuppressive 
treatment 
(e.g., cyclosporine, sirolimus, mycophenolic acid, 
azathioprine, methotrexate or cyclophosphamide)
o
Fingolimod (Note: prior treatment with fingolimod 
anytime is an exclusion criterion if discontinuation
was due to an adverse event (AE) or poor 
tolerability)

Within 12 months prior to randomization:
o
Natalizumab
o
Non-lymphocyte-depleting experimental biological 
agents

Within 24 months prior to randomization:
o
Lymphocyte-depleting biological agents such as 
rituximab or ocrelizumab
o
Cladribine

Any time prior to randomization:
o
Alemtuzumab 
o
Mitoxantrone
o
Ponesimod
o
Other investigational S1P modulators
o
Stem cell transplantation
o
Leflunomide or teriflunomide unless adequate and 
successful wash-out is documented.
Infection and Infection Risk
5. Ongoing known bacterial, viral or fungal infection (with the 
exception 
of 
onychomycosis 
and 
dermatomycosis), 
confirmed 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 


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the initial test has been negative) or hepatitis C antibody 
tests at Visit 1 (Screening).
6. Congenital or acquired severe immunodeficiency or known 
human immunodeficiency virus (HIV) infection or positive 
HIV testing at Visit 1 (Screening).
7. Negative antibody test for varicella-zoster virus at Visit 1 
(Screening).
8. 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
9. 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.
10. 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
11. Presence of macular edema.
Cardiovascular
12. 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 current unstable ischemic heart 
disease;

Cardiac failure (NYHA 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 significant symptoms or 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 atrioventricular (AV) block 


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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), 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 investigator judgment.
Metabolic
13. Type 1 or 2 diabetes which is poorly controlled according to 
investigator judgment or diabetes complicated with organ 
involvement such as diabetic nephropathy or retinopathy.
Pulmonary
14. Subjects with a clinically significant pulmonary condition 
including: 

Asthma which is insufficiently controlled according to 
investigator judgment, or any hospitalization due to 
asthma exacerbation within 6 months prior to 
randomization; 

Abnormal pulmonary function tests (PFTs): forced 
expiratory volume in 1 second (FEV1) or forced vital 
capacity (FVC) < 70% of the predicted normal value at 
Visit 2 (Baseline).
15. Active or latent tuberculosis (TB), as assessed by chest 
X-ray performed at Visit 1 (Screening) or within 90 days 
prior to Visit 1 (Screening), or interferon 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
16. Any of the following abnormal laboratory values at Visit 1 
(Screening) or Visit 2 (Baseline):

Hemoglobin (Hb) < 100 g/L

White 
blood 
cells 
(WBC) 
count 
< 3.5 × 109/L 
(< 3500/mm3)

Neutrophil count < 1.5 × 109/L (< 1500/mm3)

Platelet count < 100 × 109/L (< 100,000/ mm3)


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Hepatic
17. Known and documented moderate or severe hepatic 
impairment.
18. Any of the following abnormal laboratory values at Visit 1 
(Screening) or Visit 2 (Baseline):

Alanine aminotransferase (ALT/SGPT) > 3 × the upper 
limit of normal (ULN) 

Aspartate aminotransferase (AST/SGOT) > 3 × ULN

Total bilirubin > 1.5 × ULN (unless in the context of 
known Gilbert’s Syndrome)
Other categories
19. Contraindications for MRI such as:

Pacemaker, certain 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;

Severe renal insufficiency defined as a calculated
creatinine clearance < 30 mL/min (Cockroft-Gault);

Claustrophobia if its nature or severity is prohibitive for 
performing MRI according to the
investigator’s 
judgment.
20. History of clinically significant drug or alcohol abuse.
21. Known allergy to any of the ponesimod formulation 
excipients. 
22. 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.
23. Subjects 
unlikely 
to 
comply 
with 
protocol, 
e.g., 
uncooperative attitude, inability to return for follow-up 
visits, or known likelihood of not completing the study 
including mental condition rendering the subject unable to 
understand the nature, scope, and possible consequences of 
the study.


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STUDY TREATMENTS
Investigational treatment
One
tablet
of ponesimod 20 mg or matching placebo, 
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:
Duration
Dose regimen in the 
ponesimod group
Day 1 and 2
2 mg
Day 3 and 4
3 mg
Day 5 and 6
4 mg
Day 7
5 mg
Day 8
6 mg
Day 9
7 mg
Day 10
8 mg
Day 11
9 mg
Day 12 to 14
10 mg
Day 15 until EOT
20 mg
CONCOMITANT 
THERAPY
Concomitant background therapy
In order to be eligible for this study, subjects must have been 
treated with DMF (Tecfidera®) for at least 6 months prior to 
Visit 1 (Screening). Subjects should be treated with DMF as per 
prescribing information [Tecfidera USPI,
Tecfidera SmPC] 
throughout the course of the study [see Section 3.5.2.1].
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 2-agonists for respiratory symptoms and/or 
reduced pulmonary function during study treatment (please 
refer to Sections 5.1.12.4 and 7.3.3 for guidance);


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
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 4];

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 will 
be analyzed at the end of the study;

Low dose corticosteroid (up to 10 mg prednisone equivalent 
daily), given as 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 whole 
study duration);

Inhaled corticosteroids for pulmonary conditions;

Other treatments considered necessary for the subject’s 
benefit and not categorized as prohibited concomitant 
medications.
Forbidden concomitant therapy
The below list of forbidden concomitant therapies is applicable 
to all subjects receiving study treatment, but not to the subjects 
who prematurely discontinued study treatment and participate 
in the PTOP.

Systemic corticosteroids and ACTH, except for:
the 
treatment of MS relapses (see Recommended therapy
below);
short-term treatment with a low dose of 
corticosteroid; and inhaled corticosteroids for pulmonary 
conditions (see Allowed concomitant therapy above);

Disease-modifying drugs for MS other than prescribed as 
per protocol (e.g., interferon beta, glatiramer acetate, 
fingolimod, 
teriflunomide, 
natalizumab,
or 
other 
monoclonal antibody therapy);

Immunosuppressive 
treatment 
(e.g., cladribine, 
mitoxantrone 
or 
other 
systemic 
immunosuppressive 
treatments 
such 
as 
azathioprine, 
cyclophosphamide, 
cyclosporine, methotrexate, or leflunomide);

Intravenous immunoglobulin;

Plasmapheresis, cytapheresis, or total lymphoid irradiation;


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
Vaccination with live vaccines;

-blockers, diltiazem, verapamil, digoxin, or any other 
anti-arrhythmic or heart rate lowering systemic therapy 
[non-exhaustive list of drugs provided in Appendix 3];

Any other investigational drug; 

Any 
investigational 
therapeutic 
procedure 
for 
MS 
(e.g., stent 
placement 
or 
angioplasty 
for 
chronic 
cerebrospinal venous insufficiency (CCSVI), 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.
Recommended therapy – treatment of relapses

If a relapse requires treatment with corticosteroids, 
methylprednisolone 1 g i.v., oral methylprednisolone in the 
dose range of 1 g to 1.25 g or equivalent doses of oral 
prednisone or prednisolone daily for 3 to 5 days is 
recommended (without an oral taper). Treatment with other 
corticosteroids, another dose, other routes of administration, 
or ACTH is not recommended unless deemed necessary and 
must be documented in the patient charts by the 
investigator.

Treatment 
of 
relapses 
with 
plasma 
exchange 
(i.e., plasmapheresis, cytapheresis) is prohibited.
ENDPOINTS
Primary efficacy endpoint

Annualized relapse rate (ARR) defined as the number of 
confirmed relapses from randomization up to EOS, per 
subject-year.
Secondary efficacy endpoints

Time to 12-week CDA from baseline up to EOS;

Time to first confirmed relapse up to EOS;

Mean number of combined unique active lesions (CUALs) 
per post-baseline scan up to EOS;

Longitudinal change over time in fatigue-related symptoms 
as measured by the symptom domain of the FSIQ–RMS
from baseline up to EOS; 


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
Longitudinal percent change over time in brain volume from 
baseline up to EOS.
Other efficacy endpoints
MRI-based exploratory endpoints:

Percent change in brain volume (PCBV) from baseline to 
Week 48, 96, 144, EOT, and EOS;

Mean number of CUALs per subject per scan from baseline 
up to Week 48, 96, 144, EOT, and EOS;

Mean number of Gd+ T1 lesions per subject per scan from 
baseline up to Week 48, 96, 144, EOT, and EOS;

Mean number of new or enlarging T2 lesions per subject per 
scan from baseline to Week 48, 96,144, EOT, and EOS;

Change from baseline to Week 48, 96, 144, EOT, and EOS 
in the volume of MRI lesions (T2 lesions, T1 hypointense 
lesions);

Absence of MRI lesions (Gd+ T1 lesions, new or enlarging 
T2 lesions, new T1 hypointense lesions) from baseline to 
Week 48, 96, 144, EOT, and EOS.
Clinical exploratory endpoints (disease activity, relapses, 
disability progression):

Absence of confirmed relapses from baseline up to EOS;

Time to first 24-week CDA from baseline up to EOS;

Change in EDSS from baseline by visit to EOS;

No evidence of disease activity (NEDA) status at EOS
(defined by the absence of confirmed relapse, Gd+ T1 
lesions, new or enlarging T2 lesions, 12-week CDA, as well 
as absence of annual brain volume decrease ≥0.4% from 
baseline to EOS and completing treatment as planned).
Other clinical exploratory endpoints:

Change in Multiple Sclerosis Functional Composite 
(MSFC) Z-score from baseline by visit up to EOS;

Change in the Symbol Digit Modalities Test (SDMT) score 
from baseline by visit up to EOS;

Change from baseline by visit up to EOS in fatigue-related 
impacts as measured by the impact sub-scales of the 
FSIQ-RMS.


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Safety endpoints

Treatment-emergent AEs, serious adverse events, AEs of 
special interest#,
major adverse cardiovascular
events 
(MACE), and 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, QT 
corrected for HR on the basis of Bazett’s formula [QTcB], 
QT corrected for heart rate on the basis of Fridericia’s 
formula [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 treatment when post-dose monitoring 
is required;

Notable abnormalities* for selected 12-lead ECG variables 
(HR, PR, QT, QTc) at 3-hour post dose assessment on Day 
1, Week 12 and at the re-initiation of study treatment when 
post-dose monitoring is required;

Treatment-emergent decrease of FEV1 or FVC > 20% from 
baseline values or 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 versus 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 post-EOT follow-up

Treatment-emergent notable blood pressure abnormalities*;

Treatment-emergent notable laboratory abnormalities*;

Change in body weight from baseline to EOS;

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.

Change in John Cunningham Virus serology from baseline 
up to EOS.
# # The selection of AEs of special interest is based on the anticipated risks of 
treatment with ponesimod and on the events that may be related to MS 


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co-morbidities (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 as described in Appendix 6; the final list of abnormalities will 
be defined in the SAP.
Quality of life endpoints

Change from baseline by visit up to EOT in SF-36v2™ 
Health Survey domain and component scores.
Pharmacoeconomic endpoints

Change from baseline by visit up to EOT in work 
productivity and activity impairment in MS (WPAI:MS) 
scores.

Health care resource utilization from baseline by visit up to 
EOT on-treatment visit (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) evaluations

Plasma concentrations of ponesimod pre-dose at Week 12, 
Week 24, Week 48, Week 96, Week 144, EOT and FU, and
3 hours post-dose on Day 1 and at Week 12.
Pharmacodynamic (PD) evaluations

Absolute 
and 
percent 
change 
in 
peripheral 
blood 
lymphocyte counts pre-dose by visit up to EOS.

Absolute and percent change in lymphocytes subsets by 
visit up to EOS (Sub-study).
PK/PD relationship

Correlation of selected efficacy and safety variables with 
absolute lymphocyte counts and magnitude of reduction of 
lymphocyte counts may be analyzed.
ASSESSMENTS
Refer to the schedule of assessments in Table 1, Table 2, and 
Table 3.
STATISTICAL 
METHODOLOGY
The Statistical Analysis Plan (SAP) will be finalized prior to 
database lock for the final analyses. The SAP provides the full 
details of all analyses, data displays, and algorithms to be used 


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for data derivations.
Screened analysis set
The screened analysis set (SCR) includes all subjects who were 
screened and received a subject number.
Full analysis set
The full analysis set (FAS) includes all randomized subjects
who were treated with at least one dose of study treatment and 
have at least one post-baseline efficacy assessment. 
All primary statistical analyses of efficacy endpoints will be 
based on the FAS. 
All-randomized set
The all-randomized set includes all randomized subjects. 
Per-protocol set
The per-protocol set (PPS) comprises all subjects included in 
the FAS without any major protocol deviations. 
Safety set
The safety set (SAF) includes all subjects who received at least 
one dose of study treatment. Subjects will be analyzed based on 
actual treatment taken.
Primary endpoint variable
The primary endpoint is the ARR defined as the number of 
confirmed relapses per subject-year. All confirmed relapses up 
to the EOS will be included in the analysis.
Secondary endpoint variables
There are five secondary efficacy endpoints, which will be 
analyzed in a hierarchical manner:

Time to 12-week CDA from baseline up to EOS;

Time to first confirmed relapse up to EOS;

Mean number of CUALs per subject per post-baseline MRI 
scan from baseline up to EOS;

Longitudinal absolute change over time in fatigue-related 
symptoms as measured by the symptom domain of the 
FSIQ-RMS from baseline up to EOS;

Longitudinal percent change over time in brain volume from 
baseline up to EOS;


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Primary endpoint hypotheses
Two-sided hypotheses are expressed in terms of the model 
parameters µPonesimod and µPlacebo. The primary null hypothesis is 
that the ARR (µ) does not differ between ponesimod and 
placebo. The alternative hypothesis is that the ARR differs 
between ponesimod and placebo.
H0, ARR: µPonesimod - µPlacebo = 0
vs
H1, ARR: µPonesimod - µPlacebo ≠ 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 0.05. Two-sided 95% Wald confidence 
intervals (CIs) will be calculated for the relative reduction in 
mean ARR for ponesimod compared to placebo.
Primary endpoint main analysis
The primary statistical analysis will be performed on the FAS 
using a negative binomial model for confirmed relapses, with 
the stratification variable EDSS category included as covariate 
in the model and the logarithm of the time on treatment up to 
EOS as an offset variable. 
Secondary endpoint analysis 
The secondary efficacy endpoints will be tested in a hierarchical 
manner in the order listed above on the FAS if the primary 
analysis on ARR has led to the rejection of the null hypothesis 
in favor of ponesimod. The hierarchical testing procedure starts 
from the top, and it stops when a null hypothesis cannot be 
rejected.
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 30 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 


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which there is a specific clinical interest in connection with 
ponesimod. 
Sample size
The sample size for the study was determined by a simulation 
using the negative binomial distribution. A sample size of 
600 subjects (300 per treatment group) will provide a power of 
approximately 90% for a significance level of 0.05, under the 
assumption that the ARR (for confirmed relapses up to EOS) is 
0.50 for placebo and 0.325 for ponesimod (which corresponds 
to a risk reduction of 35%), and using a dispersion k = 1.3 
(where the variance is = µ + k µ2). A mean subject follow-up of 
1.9 years is assumed with 3.3 years maximum follow-up. 
STUDY COMMITTEES
Independent Data Monitoring Committee
An 
Independent 
Data 
Monitoring 
Committee 
(IDMC) 
composed of physicians with relevant medical expertise in 
neurology, cardiology, infectious diseases, immunology and/or
hematology, pulmonology, and a statistician, will review 
unblinded subject safety and efficacy data on an ongoing basis 
and is empowered to recommend modifications to the protocol.
The composition and operation of the IDMC are described in 
the IDMC charter.
Ophthalmology Safety Board
An Ophthalmology Safety Board (OSB) composed of two 
independent ophthalmologists will review and evaluate in a 
blinded fashion any new or suspected cases of macular edema. 
Important findings will be communicated to the IDMC. The 
composition and operation of the OSB are described in the OSB 
charter.
MRI safety board
A MRI safety board composed of radiologists and/or 
neurologists with relevant MRI expertise will review and 
evaluate in a blinded fashion the brain MRIs selected by the 
local radiologists or neurologists with MRI expertise and 
exported to the Medical Image Analysis Center (MIAC) in 
cases of a suspected opportunistic infection in the central 
nervous system. The MRI safety board will communicate the 
results of the review to the site and important findings will be
communicated to the IDMC. The composition and operation of 
the MRI safety board are described in the MRI safety board 


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charter. 
MACE adjudication board
A MACE adjudication board will review and evaluate in a 
blinded fashion the MACE reported in the study. The 
composition and operations of MACE adjudication board will 
be described in the MACE adjudication board charter.
SUB-STUDIES
Lymphocyte subsets
A sub-study assessing lymphocyte subsets will be conducted in 
approximately 200 subjects [see Section 7.7.2.2]. Participation 
in the sub-study will be mandatory for all subjects until at least
the first 200 subjects are randomized to the main study. T cell, 
B cell, and NK cell counts as well as T cell subsets (e.g., CD4+
naïve, CD4+ effector memory, CD4+ central memory, CD8+
naïve, CD8+ effector memory, CD8+ central memory, CD8+
terminally differentiated effector memory, Th17 cells, Treg 
cells, and Th1 cells) will be analyzed at the central laboratory 
by fluorescence activated flow cytometry using a combination 
of cell surface markers. Other lymphocyte subsets may also be 
analyzed. Selected lymphocyte subsets may also be analyzed 
functionally ex vivo. Results will be provided regularly to the 
IDMC. Results from the lymphocyte subsets sub-study will be 
blinded to site staff and the sponsor until study closure.
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 a non-live vaccination while on study 
treatment.


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Table 1
Visit and assessment schedule (Part 1)
Periods
Name
PRE-RANDOMIZATION (1)
TREATMENT PERIOD
Duration
Up to 45 Days
Up to 60 weeks after the randomization of the last subject
Visits
Number
1
2
3
4
5
6
7
8,10, 12, 14, 16
11, 15
Name
Screening (1)
Baseline (1)
Rand
W2
W4
W12
W24
W36,W60, W84, 
W108, W132
W72, W120
Time
Day −45 to −1
Day 1
Day 15
Day 28
Week 12
Week 24
Week 36, 60, 84, 
108, 132
Week 72, 120
Visit window
± 1 day
± 5 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
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)
X
X
X
X
SF-36v2**
X
X
X
X
Health care resource utilization* (5)
X
X
X
X
X
X
X
WPAI:MS**
X
X
X
X
Chest X-ray* (6)
X
eC-SSRS**
X
MRI**
X
X
X
Concomitant medications*
X
X
X
X
X
X
X
X
X
Physical examination* 
X
X
X
X
Body temperature*
X
X
X
X
X
X
X
X
X
Dermatological examination* (7)
X
Body weight and height* (8)
X
X
Systolic/diastolic blood pressure*
X
X
X (9)
X
X
X
X
X
X
12-lead ECG** (10)
X
X
X (11)
X
X
X (11)
X
X
X
Ophthalmological examination*(12)
X
X
X
OCT*(12)
X
X
X
Spirometry*
X
X
Hematology/chemistry**
X
X
X
X
X
X
X
X


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Urinalysis*
X
X
X
X
Lymphocytes** (13) 
X
X
X
X (13)
X (13)
X
X
Lymphocyte subsets** (14)
X
X
X
Tuberculosis test**
X
Viral serology**
X
JCV serology**
X
Additional serum sample for viral serology
X
Pregnancy test*/**
X (15)
X
X
X
X
X
X
X
PK sampling (pre dose, except Visit 3)*
X (16)
X (16)
X
Study treatment dispensing & accountability 
(17)
X
X
X
X
X
X
X
AE*/SAE* (18)
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) 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 (Screening) that are repeated at Visit 2 (Baseline; e.g., physical 
examination, 12-lead ECGs, SBP/DBP) with the exception of hematology and blood chemistry laboratory assessments must be performed at least 7 days after 
the Visit 1 (Screening) assessments. Blood chemistry and hematology assessments at Visit 2 (Baseline) must be performed at least 21 days after the 
hematology and blood chemistry laboratory assessments performed at Visit 1 (Screening) [see Section 4.3]. Similarly, for women of childbearing potential, 
the serum pregnancy test at Visit 1 (Screening) must be performed at least 21 days before the urine pregnancy test performed at Visit 2 (Baseline). All 
baseline assessments, including the ECG and blood pressure performed pre-dose on first day of dosing at Visit 3 (Day 1) must be performed before 
randomization. The blood draw at Visit 2 (Baseline) should happen early enough in order to 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, 102, 114, 126, 138 and 150 (± 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 telephone questionnaire for relapse assessment [see Appendix 12]. After the occurrence of each 
confirmed relapse, subjects will be asked to re-consent to continue receiving study treatment [see Section 13.3].
(3) During pre-randomization, two practice tests and a third test serving as baseline assessment will be performed. Ideally, the 3 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 practice 
test may be done at Visit 1 (Screening), the second practice test 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-hour recall) will be completed for 7 consecutive days (the day of the visit and the 6 days after the visit) with an average score 
being taken across these 7 days. The completion of the FSIQ-RMS during the pre-randomization period will be done as follows: At Visit 1 (Screening), 


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subjects who appear eligible based on the assessments made during this visit will be provided with the FSIQ-RMS. Once the results from the laboratory tests 
confirm the subject’s eligibility, and provided no other assessment performed in the meantime excludes the subject, the site coordinator will contact the 
subject to instruct him/her 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 7th day, the subject will also complete the impacts domain of the FSIQ-RMS (i.e., section 2 of the questionnaire). 
(5) Healthcare resource utilization data, including number of hospital visits, length of stay, number of Intensive care unit admissions for MS relapses and 
emergency medical services facility visits for MS.
(6) Any CXR that has been performed within 90 days prior to Visit 1 (Screening) can be used (in this case, no need to repeat CXR at Visit 1 [Screening]). 
(7) Dermatological examination to be performed by a dermatologist [see Section 7.3.12]. 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.
(8) Height only at Visit 1 (Screening).
(9) SBP/DBP: Pre-dose and hourly (± 15 minutes) for at least 4 hours post-dose and up to 12 hours.
(10) Only pre-dose ECGs at all visits except Visit 3 (Day 1), and Visit 6 (Week 12). 
(11) Pre-dose and hourly (± 15 minutes) for at least 4 hours post-dose ECGs and up to 12 hours on Day 1. Pre-dose and 3 hour (± 15 minutes) post-dose at Week 
12. 
(12) OCT and/or ophthalmological examination to be performed at any visit in the presence of visual symptoms suggestive of macular edema or active uveitis.
(13) Total lymphocyte counts will be tested every 4 weeks (± 3 days) up to Week 24 (i.e., additional lymphocyte tests will be performed at Week 8, Week 16, and 
Week 20) and every 12 weeks thereafter. 
(14) Lymphocyte subset analysis will be performed on a subset of at least 200 subjects randomized to the main study.
(15) Serum pregnancy test at Visit 1 (Screening), urine pregnancy test at all subsequent visits. Urine pregnancy tests (performed at home) on a 4-weekly basis 
(± 4 days) between the visits during the study (results of the pregnancy test to be communicated by telephone call to the principal investigator / treating 
neurologist).
(16) Three hours (± 15 minutes) post-dose at Visit 3 (Day 1); pre-dose and 3 hours (± 15 minutes) post-dose at Visit 6 (Week 12).
(17) Scheduled study medication dispensing/return procedures may be adapted according to the site practice.
(18) 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; CXR = chest X-ray; DBP= diastolic blood pressure; eCRF = electronic case report form; eC-SSRS = electronic self-rated version of the 
Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; EDSS = expanded disability status scale; FS = functional system; FSIQ-RMS = fatigue 
symptoms and impacts questionnaire – relapsing multiple sclerosis; JCV = John Cunningham Virus; MRI = magnetic resonance imaging; MS = multiple 
sclerosis; MSFC = multiple sclerosis functional composite; OCT = optical coherence tomography; PK = pharmacokinetics, SAE = serious adverse event; 
SBP = systolic blood pressure; SDMT = symbol digit modalities test; SF-36v2 = 36-Item Short Form Health Survey Version 2; WPAI:MS = work productivity 
and activity impairment in MS.


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Table 2
Visit and assessment schedule (Part 2)
Periods
Name
TREATMENT PERIOD
FOLLOW-UP
UNSCHEDULED
Duration
Up to 60 weeks after randomization of 
the last subject
30 Days
Visits
Number
9, 13, 17
18
19
20
I1, I2, …
R1, R2, …
U1, U2, …
d1
d15
Name
W48, W96, 
W144
EOT
FU7d 
(16)
FU
(17)
Re-initiation
Relapse
Unscheduled 
(15)
Day 1 of re-
initiation
Day 15 after 
re-initiation
Time
Week 48, 96, 
144
Up to Week 156 or 
earlier in case of 
premature 
discontinuation
Last study 
treatment 
intake
+ 7 days
Last study 
treatment 
intake
+ 30 days
Any day between Day 1 and 
EOT
Any day between Day 1 and 
EOS
Visit window
± 7 days
+ 7 days
± 2 days
+ 7 days
NA
± 1 day
+ 7 days
NA
EDSS/FS*
X
X
X
X
X
Relapse* (1)
       X (1)                                                                              X (1)
X
MSFC, SDMT*
X
X
FSIQ-RMS** (2)
X
X
X
X
X
SF-36v2**
X
X
X
Health care resource utilization* (3)
X
X
X
WPAI:MS**
X
X
Chest X-ray* (4)
X
eC-SSRS**
X
X
MRI** 
X
X
X
Concomitant medications*
X
X
X
X
X
Physical examination* 
X
X 
X
X
Body temperature*
X
X
X
X
X
X
X
Pulse rate*
X
X (18)
Dermatological examination* (5)
X
X
X
Body weight*
X
X
X
Systolic/diastolic blood pressure*
X
X
X
X (6)
X
X
12-lead ECG** (7)
X
X
X
X (7)
X
X
Ophthalmological examination* (8)
X
X
X
X
OCT* (8)
X
X
X
Spirometry* 
X
X
X
X
Hematology/chemistry**
X
X
X
X
Urinalysis*
X
X
X
X
Lymphocytes**
X
X
X
X


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Relapsing multiple sclerosis
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Doc No D-17.622
Lymphocyte subsets** (9)
X
X
X
X
JCV serology**
X
X
Pregnancy test*/** (10)
X
X
X
X
Serum sample vaccination* (11)
X
PK sampling pre dose*
X
X
X
X(12)
Study treatment dispensing & accountability (13)
X
X
X
X
X
AE*/SAE * (14)
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 worsened 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, 102, 114, 126, 138 and 150 (± 7 days), or 6 weeks after the last 12-weekly visit (± 7 days). Whenever between visits a 
subject experiences any new or worsened 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 telephone questionnaire for relapse assessment [see Appendix 12]. After the occurrence of each 
confirmed relapse, subjects will be asked to re-consent to continue receiving study treatment [see Section 13.3].
(2) The symptoms scale (with a 24-hour recall) will be completed for 7 consecutive days (the day of the visit and the 6 days after the visit) with an average score 
being taken across these 7 days. At Visit 20 (FU), the FSIQ-RMS will be completed at home prior to the visit, ideally, during the 7 consecutive days 
preceding the visit.
(3) Healthcare resource utilization data, including number of hospital visits, length of stay, number of Intensive care unit admissions for MS relapses and 
emergency medical services facility visits for MS.
(4) In case of premature study treatment discontinuation, the chest X-ray at EOT does not need to be performed if the EOT visit occurs within 48 weeks of the 
pre-randomization chest X-ray.
(5) Dermatological examination to be performed by a dermatologist [see Section 7.3.12].
(6) SBP/DBP: Pre-dose and hourly (± 15 minutes) for at least 4 hours post-dose and up to 12 hours.
(7) Only pre-dose ECGs at all visits (if applicable) except EOT and re-initiation visits. At re-initiation, pre-dose and hourly (± 15 minutes) for at least 4 hours 
post-dose ECGs and up to 12 hours.
(8) OCT and/or ophthalmological examination to be performed at any visit in the presence of visual symptoms suggestive of macular edema or active uveitis. 
(9) Lymphocyte subset analysis will be performed on a subset of at least 200 subjects randomized to the main study.
(10) Serum pregnancy test at FU. Urine pregnancy tests at all other visits. Urine pregnancy tests (performed at home) on a 4-weekly basis (± 4 days) between the 
visits until 4 weeks after last study treatment intake (results of the pregnancy test to be communicated by telephone call to the principal investigator / treating 
neurologist).
(11) Pre and post-vaccination sampling for vaccine-specific antibody titers for subjects having received non-live vaccines while on study treatment (sub-study).
(12) When possible, collect PK sample upon experiencing a SAE. Preferably, sample will be collected pre-dose, as early as possible after SAE onset, and within 
7 days after the last dose of study treatment.
(13) Scheduled study medication dispensing/return procedures may be adapted according to the site practice. 
(14) All AEs and SAEs that occur after signing the Informed Consent Form and up to 30 days after study treatment discontinuation must be reported.


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(15) 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.
(16) Visit performed only for subject participating in the lymphocyte subset sub-study
(17) If a total lymphocyte count 0.5 × 109/L is observed at FU an alert will be sent to the principal investigator and the sponsor. Discontinuation of DMF 
treatment should be considered in accordance with prescribing information [Tecfidera USPI, Tecfidera SmPC].
(18) Pulse rate to be assessed only if no 12-lead ECG is performed at this visit.
AE = adverse event; DBP= diastolic blood pressure; DMF = dimethyl fumarate; eCRF = electronic case report form; eC-SSRS = electronic self-rated version of 
the Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; EDSS = expanded disability status scale; EOT = end-of-treatment; FU7d = FU visit 
approximately 7 days after the last dose of study drug; FS = functional system; FSIQ-RMS = fatigue symptoms and impacts questionnaire – relapsing multiple 
sclerosis; 
FU 
= 
follow-up; 
JCV 
= 
John 
Cunningham 
Virus; 
MRI = magnetic resonance imaging; MS = multiple sclerosis; MSFC = multiple sclerosis functional composite; OCT = optical coherence tomography; 
PK = pharmacokinetics, SAE = serious adverse event; SBP = systolic blood pressure; SDMT = symbol digit modalities test; SF-36v2 = 36-Item Short Form 
Health Survey Version 2; SmPC = Summary of Product Characteristics; USPI = United States Prescribing Information; WPAI-MS = work productivity and 
activity impairment in MS.


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Table 3
Visit and assessment schedule (Part 3)
Periods
Name
Post-Treatment observation period (PTOP)
(to be performed after EOT, and FU)
Duration
Up to 60 weeks after randomization of the last subject
Visits
Number
6A, 7A, 8A, 10A, 12A, 14A, 16A 
11A, 15A
9A, 13A, 17A, 18A
Name
W12A, W24A, W36A, W60A, W84A, W108A, W132A
W72A, W120A
W48A - W96A - W144A -
W156A
Time
Weeks 12, 24, 36, 60, 84, 108, 132
Weeks 72, 120
Weeks 48, 96, 144, 156
Visit window
± 7 days
± 7 days
± 7 days
EDSS/FS*
X
X
X
Relapse* (1)
                           X (1)                                                                                                                        X (1)
MRI** 
X (Week 24 only)
X
X
FSIQ-RMS** (2)
X (only Weeks 12 and 24)
X
X
Concomitant medications*
X
X
X
Physical examination* 
X (Week 24 only)
X
X
Body temperature*
X
X
X
Dermatological examination* (3)
X
Systolic/diastolic blood pressure*
X
X
X
12-lead ECG **
X
Spirometry*
X (Week 12 only)
X
Hematology/chemistry**
X
X
X
Urinalysis*
X
X
X
Lymphocytes**
X
X
X
Lymphocyte subsets**
X (only Weeks 12 and 24)
X
JCV serology**
X
Adverse events (AE)*
X
X
X
Serious adverse events (SAE)*
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 worsened neurological symptoms. In addition, the site will contact the subject in-between 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. These telephone calls will be conducted 
either at Weeks 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138 and 150 (± 7 days), or 6 weeks after the last 12-weekly visit (± 7 days). Whenever between visits 
a subject experiences any new or worsened 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 telephone questionnaire for relapse assessment [see Appendix 12].


Ponesimod / ACT-128800
Relapsing multiple sclerosis
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(2) The symptoms scale (with a 24-hour recall) will be completed for 7 consecutive days (the day of the visit and the 6 days after the visit) with an average score 
being taken across these 7 days. At Visit 18A (Week 156), the FSIQ-RMS will be completed at home prior to the visit, ideally, during the 7 consecutive days 
preceding the visit.
(3) Dermatological examination to be performed by a dermatologist [see Section 7.3.12]. 
ECG = electrocardiogram; EDSS = expanded disability status scale; EOT = End-of-Treatment; FS = functional system; FSIQ-RMS = fatigue symptoms and 
impacts questionnaire – relapsing multiple sclerosis; FU = Follow up; JCV = John Cunningham Virus; MRI = magnetic resonance imaging.


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PROTOCOL
1
BACKGROUND
1.1
Multiple sclerosis
Multiple sclerosis (MS) is an inflammatory autoimmune disorder of the central nervous 
system (CNS) and the most common cause of progressive neurological disability in 
young adults [Compston 2008]. This chronic demyelinating disease is characterized by 
heterogeneous clinical expression, an unpredictable course and a variable prognosis. In 
MS, the frequent and major neurological disability has important personal, social, and 
financial consequences for patients, their families, and health care systems.
1.1.1
Pathogenesis
Although the etiology of MS is still unknown it is widely accepted that it is an 
immune-mediated, demyelinating process precipitated by unknown environmental factors 
in genetically susceptible people. 
MS results from a cascade of events involving activation of the immune system, acute 
focal inflammatory demyelination, and axonal loss with limited remyelination, 
culminating in chronic multifocal sclerotic plaques in the brain and spinal cord.
1.1.2
Clinical course
The two main clinical features of MS are exacerbations (also called attacks or relapses) 
and progressive loss of neurological function. Relapses are considered the clinical 
expression of acute, inflammatory, focal lesions of the brain or spinal cord, 
corresponding to axonal demyelination, which leads to the slowing or blockade of axonal 
conduction at diverse affected sites of the brain and spinal cord. This inflammatory 
disease activity may translate to a large variety of clinical symptoms and signs and/or 
acute lesions visualized on magnetic resonance imaging (MRI). 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 2014, 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). 


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Approximately 6570% of RRMS patients experience gradual accumulation of disability 
and fewer relapses later in their disease, which evolves into a secondary progressive 
MS (SPMS) stage characterized by less inflammatory and more pronounced 
neurodegenerative features. The median time for patients with RRMS to progress into 
SPMS is about 10 years [Noseworthy 2000, Compston 2008]. In primary progressive MS 
(PPMS), patients experience progression of 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]. In 2011, the NMSS Advisory Committee proposed 
to redefine the MS course by taking into account disease activity and progression and 
eliminate the progressive relapsing MS (PRMS) category [Lublin 2014]. A patient with 
RRMS who has a 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, no Gdactivity, or no new or 
unequivocally enlarging T2 lesions during the assessment period. 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) 

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 independently 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 (CIS) applied to those patients who 
have experienced a single clinical event, who have had other possible diagnoses 
excluded, and who did not fulfill the Diagnostic Criteria for MS [Polman 2005]. With the 
2010 revision of McDonald’s Diagnostic Criteria, CIS patients with clinical and/or MRI 
signs of dissemination in space and MRI signs of dissemination in time are now 
diagnosed with relapsing MS (RMS).
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 2014]. 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 
15 disease-modifying therapies (DMTs) approved in at least one country for the treatment 
of MS. Disease-modifying treatments for MS are ususally administered as monotherapy. 
If the disease continues to be active (relapses and/or inflammatory MRI lesions) in spite 
of the given treatment, a shift to a more effective compound (treatment escalation) is 
usually considered, however, the criteria for such treatment escalation vary between 
countries and physicians. At the top of the escalation hierarchy are the two monoclonal 
antibodies, natalizumab and alemtuzumab, and, in some cases, mitoxantrone, all of which 


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require i.v. infusion. An oral option with comparable or better risk-benefit profile is 
currently not available.
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 g i.m. once weekly (Avonex®)

IFN β-1a 22 or 44 g s.c. 3 times weekly (Rebif®)

IFN β-1b 250 g s.c. every other day (Betaferon®, Betaseron®, Extavia®)

Pegylated IFN β-1a 125 g s.c. every 14 days (Plegridy®)

Glatiramer acetate 20 mg s.c. once a day (o.d.) or 40 mg three times a week 
(Copaxone®)

Glatiramer acetate 20 mg s.c. once a day (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®)

Daclizumab 150 mg s.c. once a month (Zinbryta®)

Ocrelizumab 600 mg i.v. every 6 months (Ocrevus®). 
Additional injectable drugs are currently in late-stage development for the treatment of 
RMS, including 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®). NB: only 14 mg dose is approved in the 
EU

Dimethyl fumarate (DMF, BG-12) gastro-resistant hard capsules 120/240 mg twice 
daily (b.i.d.) (Tecfidera®)

Cladribine 3.5 mg/kg body weight over 2 years (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. Siponimod, another S1P1 receptor modulator, is currently being developed for 
the treatment of MS with relapsing onset.
1.1.4.3
Unmet need in relapsing multiple sclerosis
Despite multiple disease modifying therapies recently becoming available for the 
treatment of relapsing MS, a significant unmet need remains. Existing therapies are only 


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partly effective in reducing ongoing inflammatory tissue damage and clinical attacks and 
disability progression.
In recently completed Phase 3 trials with the most effective injectable (alemtuzumab) or 
oral therapies (fingolimod, DMF), up to one-third of MS patients experience an MS 
relapse, 10-20% experience a progression of their disability, and approximately 50% 
have either clinical or MRI manifestations of active disease over a 2-year treatment 
course [Kappos 2010, Gold 2012, Fox 2012, Cohen 2012, Coles 2012]. With availability 
of several first-line (e.g., IFN β, glatiramer acetate) and second-line (e.g., natalizumab, 
alemtuzumab) therapies, the choice of initial MS therapy and the switch from one therapy 
to another has become individualized and based on considerations of efficacy, safety, 
tolerability, and convenience of treatment administration. However, given the complexity 
of MS pathogenesis and heterogeneity among patients, combination therapy strategies 
that target distinct disease mechanisms might be more effective than medications used as 
monotherapy. Combination of two oral disease modifying therapies showing high 
efficacy and a favorable risk-benefit profile may represent an attractive alternative to 
currently available treatment escalation options which carry significant safety concerns 
for opportunistic infections and autoimmunity (e.g., natalizumab, alemtuzumab) and 
tolerability burden due to i.v. administration. 
1.2
Sphingosine-1-phosphate receptors 
S1P plays a central role in lymphocyte trafficking [Cyster 2005, Brinkmann 2007, 
Brinkmann 2010, Schwab 2007, and references therein]. S1P is synthesized and secreted 
by many cell types, including platelets, erythrocytes, and mast cells, and elicits a variety 
of physiological responses [Cyster 2005, Alvarez 2007]. Among other effects, 
lymphocyte egress from primary and secondary lymphoid organs is dependent on the 
S1P1 receptor. S1P1 receptor modulators block lymphocyte migration out of lymphoid 
tissue into the lymphatic and vascular circulation, thereby reducing peripheral 
lymphocyte counts and preventing lymphocyte recruitment to sites of inflammation. 
Following withdrawal of an S1P1 receptor agonist, the functional lymphocytes return to 
the circulation from their sites of sequestration. Other functions that do not rely on 
homing mechanisms, such as antibody generation by B lymphocytes, first-line 
immunological protection by granulocytes and monocytes, and antigen-dependent T cell 
activation and expansion, are not affected by this mechanism [Pinschewer 2000]. 
S1P itself induces pleiotropic effects, which are mediated by a family of 
five G protein-coupled receptors, S1P1-S1P5, located on endothelial cells, vascular and 
cardiac smooth muscle cells, and cardiac myocytes [Alvarez 2007, Brinkmann 2007, 
Brinkmann 2010]. The first S1P receptor modulator, fingolimod (FTY720, Gilenya®), 
which has been approved by the FDA and the EMA for the treatment of MS, is not 
selective for the S1P1 receptor but interacts with all five S1P receptors [Brinkmann 2007, 


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Brinkmann 2010]. S1P1 selectivity is expected to maintain the therapeutic effects 
mediated via this receptor subtype while avoiding unwanted effects mediated by other 
receptor subtypes [Sobel 2013].
1.3
Ponesimod 
Ponesimod, an iminothiazolidinone derivative, is an orally active, selective modulator of 
the S1P1 receptor that induces a rapid, dose-dependent, and reversible reduction in 
peripheral blood lymphocyte count by blocking the egress of lymphocytes from lymphoid 
organs. T and B cells are most sensitive to ponesimod mediated sequestration. In contrast, 
monocyte, natural killer (NK) cell and neutrophil counts are not reduced by ponesimod. 
The effect of ponesimod on circulating effector T cells represents a promising therapeutic 
approach for diseases in which activated T cells play a critical role. 
More detailed information can be found in the Investigator’s Brochure (IB) 
[Ponesimod IB].
1.3.1
Nonclinical studies
The main findings in the nonclinical studies conducted with ponesimod are:

Ponesimod causes a rapid and substantial reduction in circulating lymphocytes in rats 
and dogs, which is also rapidly and fully reversible. The effect correlates well with 
the plasma concentration of ponesimod.

Studies with ponesimod in animal models of T cell-mediated diseases, such as MS, 
rheumatoid arthritis, type 1 diabetes and skin hypersensitivity, consistently indicated 
a therapeutic potential of ponesimod at oral doses that lower peripheral blood 
lymphocyte counts. 

Ponesimod shows an oral bioavailability of 3574%, low clearance, and a tissue 
distribution greater than total body water in rats and dogs. Plasma protein binding is 
high (≥98.9%) in rats, dogs, and humans.

The metabolism of ponesimod is comparable in rats, dogs, and humans. The main 
metabolite, ACT-338375 (M13), is present in plasma of mice, rats, and dogs at levels 
similar to or higher than steady-state exposures in humans at 40 mg/day.

Based on available nonclinical data, the potential for drug-drug interactions (DDIs) is 
limited. The metabolite M13 has no liability for causing DDIs via inhibition of 
cytochrome P450 (CYP) enzymes or transport proteins. M13 is not a time-dependent 
inhibitor of CYP3A4, CYP2D6 or CYP2C9. Neither ponesimod nor the M13 
metabolite approach plasma concentrations expected to inhibit CYP2C9 or CYP2C19 
after daily doses of 20 mg at steady-state.

The following main target organs for ponesimod-related toxicity were identified: lung 
(mouse, rat, dog), heart (dog), nervous system (clinical signs, dog), skin (dog), the red 


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blood cell (RBC) compartment (dog, rat), liver (all species), and adrenals (rat). The 
observed findings were in general dose-related in terms of incidence and/or degree of 
severity. Full or partial reversibility was seen for the majority of findings after 
4 weeks of treatment followed by a 4-week recovery period and after 26 and 
52 weeks of treatment followed by a 13-week recovery period. In the dog, the heart 
findings observed in the 26-week study were still observed after the 13-week 
recovery period. No-observed-(adverse)-effect levels (NO[A]ELs) were established at 
2 mg/kg/day in rats and 0.4 mg/kg/day in dogs in the 4-week toxicity studies, at 
30 mg/kg/day in rats and 2 mg/kg/day in dogs in the 26-week toxicity studies, and at 
3 mg/kg/day in dogs in the 52-week study. In mice treated for 13 weeks, the NOAEL 
was established at 90 mg/kg/day.

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].
1.3.1.1
Efficacy of combined dimethyl fumarate and ponesimod in rats
Dimethyl fumarate is the active principle of the commonly prescribed psoriasis drug 
Fumaderm™and the MS drug Tecfidera®. 
Both neuroprotective and anti-inflammatory effects are induced by DMF through 
activation of the Nrf-2 pathway and disruption of the NF-κB pathway that is involved in 
the regulation of cytokines and lymphocyte apoptosis [Scannevin 2012]. In an 
experimental autoimmune encephalomyelitis (EAE) disease model of MS in mice, DMF 
dose-dependently inhibited disease symptoms, demyelination, neurodegeneration and 
inflammation [Linker 2011, Schilling 2006]. 
Ponesimod has been demonstrated to be beneficial in EAE mostly by inhibiting 
lymphocyte infiltration [Gergely 2012, Papadopoulos 2010, Gonzalez-Cabrera 2012,
Kataoka 2005, Webb 2004]. Inhibitory effects on NF-κB and activation of Nrf-2 have not 
been described for S1P1 modulators. By combining DMF with ponesimod, multiple 
different pathways (inhibition of NF-κB activation, activation of Nrf-2, and inhibition of 
lymphocyte infiltration) may result in increased efficacy such as preservation of 
neuromuscular function and prevention of disability progression in MS.
The combined administration of DMF and ponesimod was compared to DMF alone in a 
rat model of relapsing-remitting EAE. Sensory-motor deficits were assessed throughout 
the observation-time of 40 days. In contrast to DMF alone (40 mg/kg or 80 mg/kg orally, 
daily), the combination of DMF with ponesimod (100 mg/kg orally, daily) showed a 
reduction of clinical scores throughout the whole treatment-phase. This suggests that the 


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combination of DMF with ponesimod is more efficacious in this model of relapsing-
remitting EAE as compared to DMF alone [Ponesimod IB].
1.3.1.2
Combination toxicity study of combined dimethyl fumarate and ponesimod in 
beagle dogs
The combined toxicity and systemic exposure of ponesimod and DMF was studied in 
beagle dogs who received oral administrations for 13 consecutive weeks as follows:

ponesimod 3, 10, and 40 mg/kg/day (n = 4/sex/dose group) 

DMF 5, 25, and 50 mg/kg/day (n = 4/sex/dose group) 

ponesimod + DMF: 3+5, 10+25 and 40+50 mg/kg/day (n = 4/sex/dose group) 

a vehicle control group with (n = 4/sex)
Systemic exposure was evaluated after 1 week and 13 weeks. The toxicological 
assessment included clinical signs, food consumption, body weight, blood pressure, ECG, 
ophthalmology, hematology, clinical chemistry, urinalysis, organ weights, and 
macroscopic/microscopic evaluation. Possible effects on the immune system were 
assessed by immunophenotyping, histology of primary and secondary lymphoid organs 
and T cell dependent antigen response.
The safety profile of ponesimod treated dogs was in line with findings previously seen 
such as reduced white blood cell counts and lymphocytes, reduced protein and increased 
cholesterol. Histopathologically, arterial lesion in the heart was observed at the mid and 
high ponesimod dose. DMF treatment led mainly to the expected reduction in food 
consumption, body weight and creatinine at the mid and high dose. 
The combination of ponesimod with DMF induced effects comparable with each 
compound alone; there was no evidence for new or synergistic toxicity. A NOAEL could 
be established at the low doses of 3 mg/kg/day ponesimod alone or combined with 
5 mg/kg/day DMF and at 5 mg/kg/day for DMF alone. The ponesimod NOAEL of 
3 mg/kg/day is in line with previous studies. At this dose level the exposure to ponesimod
was 10400/21800 h·ng/mL (males/females) when given alone and 11500/13100 
(males/females) when given in combination with DMF [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 5 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 


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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 is also being
investigated in subjects suffering from chronic graft versus host disease.
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 correlation between the plasma concentration of ponesimod and the peripheral 
blood total lymphocyte count. Food, age, race or sex do not appear to relevantly affect the 
PK and PD of ponesimod. The PK DDI potential of ponesimod is judged to be low based 
on current nonclinical and clinical data. 
More detailed information can be found in the IB [Ponesimod IB].
1.3.2.2
Pharmacodynamics in humans
Oral administration of ponesimod dose-dependently reduces the circulating lymphocyte 
count in humans. The maximum reduction from baseline of approximately 65–80% is 
achieved after a single dose of ≥50 mg, or 40 mg o.d. at steady-state. The nadir in 
lymphocyte count is attained within 610 hours following a given single dose. There is 
no evidence of tachyphylaxis on lymphocyte count. Peripheral blood counts of both T 
and B cells are reduced by ponesimod, while NK cells and neutrophils are not reduced. 
Food, race and sex 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 
one week following ponesimod treatment discontinuation.
More detailed information can be found in the IB [Ponesimod IB].


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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.
The study was not powered to detect a significant effect of ponesimod on clinical 
endpoints such as annualized relapse rate (ARR) or time to first confirmed relapse. 
Treatment with ponesimod was associated with a reduction in the 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 a delay 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 an ongoing 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 the same dose of 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. After at least 48 weeks and up to 96 weeks of treatment in the extension 
study, subjects who were receiving 40 mg ponesimod daily were randomized in a 
1:1 ratio to 10 or 20 mg ponesimod daily for continuation in the study.
The results from an interim analysis of study AC-058B201/B202 with cut-off date of 
1 September 2016 [Havrdova 2017] (median treatment exposure > 5.5 years) have shown 
sustained low numbers of brain inflammatory lesions on MRI and low clinical disease 
activity with dose-dependent effects on relapse rate and disability accumulation. The 
model-adjusted ARR observed with ponesimod 20 mg was 0.153, a rate similar to that 
observed with the 1.25 mg dose of fingolimod after 5 years in the Phase 2 extension 


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study [Izquierdo 2013]. There was also a dose-dependent effect of ponesimod on 
disability accumulation, with a 49% (p = 0.024) relative risk reduction in the ponesimod 
20 mg arm compared to the ponesimod 10 mg arm. The incidence of overall adverse 
event (AEs), serious adverse events (SAEs) and AEs leading to discontinuation over 
6 years was similar in patients treated with ponesimod 20 mg compared to those treated 
with ponesimod 10 mg.
More detailed information can be found in the IB [Ponesimod IB].
1.3.2.4
Safety and tolerability
Clinical studies to date have identified transient changes in heart rate (HR) and 
atrioventricular (AV) conduction as the most prominent safety-related signal with 
ponesimod. Oral doses of ponesimod resulted in dose-dependent sinus rate reductions in 
all treated subjects; the changes were transient and resolved largely within 610 hours 
after dosing. In some subjects, these HR reductions were accompanied by a transient 
effect on AV conduction with prolongation of the PR interval on the electrocardiogram 
(ECG) and, occasionally, second degree AV-block. The effects on HR and AV 
conduction 
diminish 
with 
repeated 
administration 
of 
ponesimod, 
indicating 
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. 
Breathing difficulties and pulmonary function test (PFT) changes have also been detected 
in humans. Mild transient dyspnea/cough was noted frequently 26 hours after an oral 
dose of 40 mg or higher, and was associated with a clinically relevant forced expiratory 
volume in 1 second (FEV1) decrease from baseline. Symptoms resolved spontaneously 
upon discontinuation of treatment with ponesimod, and PFTs returned to baseline upon 
drug discontinuation. In study AC-058B201, dyspnea AEs were reported in 6.1% of
patients in the ponesimod 20 mg group as compared to 3.3% in the placebo group. 
Accordingly 13.5% of patients in the ponesimod 20 mg group had FEV1 < 80% of their 
baseline measurements at least once during the treatment period compared to 3.3% in the 
placebo group. However, none of the patients in the 20 mg group discontinued treatment 
due to a respiratory AE. Doses higher than 20 mg were associated with decreased 
tolerability; there were increased discontinuation rates with 40 mg mainly due to more 
pronounced pulmonary function effects and an increased incidence of liver enzyme 
elevations. 
Data from an interim analysis of the long-term extension study AC-058B201/B202 with a 
cut-off date of 31 October 2014 showed that dose-dependent decrease in FEV1 remained 
stable in patients treated with ponesimod for up to approximately 4 years and were 
reversible after treatment discontinuation.


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Elevations of aspartate transaminase (AST) and/or alanine aminotransferase (ALT) 
without any substantial bilirubin increase (i.e., total bilirubin > 2 times upper limit of 
normal [ULN]) have been noted with ponesimod; they have been reversible with or 
without 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
Background treatment
Dimethyl fumarate (Tecfidera®) was approved by the FDA in 2013 for the treatment of 
patients with RMS and it was approved by EMA in January 2014 for the treatment of 
RRMS. In the two Phase 3 placebo-controlled 2-year studies DEFINE and CONFIRM, 
DMF reduced the ARR by 53% and 44% respectively, as compared to placebo at the 
approved dose of 240 mg b.i.d. [Gold 2012, Fox 2012]. Efficacy on disability progression 
has not been consistently demonstrated: in the DEFINE study, DMF reduced the risk of 
3-month sustained disability progression as compared to placebo (hazard ratio = 0.62, 
95% CI: 0.44, 0.87). In the CONFIRM study, the difference between the placebo group 
and the DMF treatment group on this endpoint was not statistically significant. The main 
side effects associated with DMF are abdominal pain, diarrhea, nausea, flushing, and 
lymphopenia.
1.4
Purpose and rationale of the study
None of the disease modifying therapies currently available for relapsing MS can fully 
suppress inflammatory activity in the CNS and halt clinical attacks or disability 
progression of the disease. 
Patients who have active disease despite being treated with first line treatments for MS 
such as IFNs, glatiramer acetate, teriflunomide or DMF may need treatment escalation to 
more efficacious agents. The currently existing alternatives include monoclonal 
antibodies natalizumab or alemtuzumab, subject to availability in a given country. These 
agents provide high efficacy but require i.v. infusions, and are associated with potentially 


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serious and life threatening adverse reactions. In particular, the occurrence of 
opportunistic infections such as progressive multifocal leukoencephalopathy (PML) in 
patients treated with natalizumab, and autoimmune disorders in those treated with 
alemtuzumab have raised concern. 
Ponesimod may represent a safer oral alternative for treatment escalation in RMS. A 
Phase 3 study (AC-058B301) is currently ongoing to assess the efficacy and safety of 
ponesimod monotherapy in patients with RMS.
Study AC-058B302 aims to expand the clinical utility of ponesimod by assessing the 
efficacy and safety of add-on treatment with ponesimod in patients whose RMS is not 
sufficiently controlled by DMF (Tecfidera®).
Tecfidera® is a recently approved first-line treatment of RMS which is already widely 
used across North America and Europe. Based on Phase 3 clinical trial results, during 
2 years of treatment with DMF almost one-third of patients had a relapse and 
approximately 50% had ongoing radiological or clinical signs of disease activity, thus 
disease is not sufficiently controlled in many patients on DMF [Fox 2012, Gold 2012]. 
Both ponesimod and DMF have effects on the immune system, but neither compound has 
shown a profound immunosuppression. The target organs of potential toxicity of DMF do 
not generally overlap with those of ponesimod, with the exception of the immune system
and liver. Although via different mechanisms, both compounds lead to a reduction of
lymphocyte counts in peripheral blood, which are routinely monitored and can be used to 
guide treatment decisions in the clinical trial and in clinical practice. Thus, adding 
ponesimod to DMF might represent a safer treatment escalation with the added value of 
an oral administration when compared to current options for treatment escalation. 
Nonclinical studies of this combination indicate improved efficacy of the combination 
when compared to DMF alone without new safety findings of concern [Sections 1.3.1.1
and 1.3.1.2]. These observations support the clinical testing of ponesimod add-on to DMF 
in patients with RMS. Nevertheless, as the addition of ponesimod to DMF has not yet 
being tested in humans, specific safety measures have been designed and will be 
implemented in this study as described in Section 3.4. Assuming high efficacy and 
acceptable safety are shown in humans, the add-on of ponesimod to DMF (Tecfidera®) 
may display a favorable benefit/risk balance and represent a valuable treatment option for 
RMS patients insufficiently controlled by DMF monotherapy. 
1.5
Summary of known and potential risks and benefits
DMF (Tecfidera®) is an oral fumaric acid ester approved for the treatment of RMS. Phase 
3 clinical studies with DMF have shown a significant reduction of a brain inflammatory 


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activity and relapse rate compared with placebo in patients with RMS [Gold 2012, 
Fox 2012].
Subjects treated with DMF with recent evidence of active disease may still benefit from 
continuation of DMF treatment in the proposed study, even if they are randomized to 
placebo for the following reasons:

MS is a clinically heterogeneous disease with an underlying complex pathology and 
unpredictable course. At an individual subject level, disease activity and response to 
treatment may vary with time. Therefore, continuation of DMF treatment may still be 
beneficial even if subjects had recent evidence of active disease prior to entering the 
study and are randomized to placebo add-on therapy.

Several lines of evidence indicate that the annualized relapse rate (ARR) for subjects
assigned to the placebo arm in RMS clinical trials decreases substantially when 
compared to the pre-trial ARR [Steinvorth 2013]. Among other reasons, careful 
patient management and increased adherence to treatment may explain these findings 
and provide justification for a positive benefit/risk balance for subjects receiving
placebo add-on therapy in the study.
Ponesimod is an oral, selective, and reversible modulator of the S1P1 receptor under 
investigation for the treatment of RMS. In a large Phase 2 study performed in patients 
with RRMS, ponesimod has been shown to reduce the number of inflammatory lesions in 
the brain and the number of relapses compared with placebo [Olsson 2014]. Furthermore, 
in a long-term extension of the Phase 2 study (ongoing, blinded), there was also a trend 
towards a dose-dependent decrease in disability accumulation and in brain volume loss 
with ponesimod [Pozzilli 2013]. Ponesimod has therefore the potential to benefit patients 
with MS with residual disease activity by reducing relapses.
The mechanisms of action of DMF and ponesimod appear to be complementary and 
suggest potential additive or synergistic efficacy when combined. Indeed, both drugs 
have immunomodulatory and neuroprotective properties but they act on distinct 
molecular and cellular targets. While DMF decreases lymphocyte proliferation and 
inhibits pro-inflammatory cytokines, ponesimod inhibits migration and egress of T and B 
cells from secondary lymphoid organs. Similarly, while DMF may increase neural cell 
survival by reducing oxidative stress, ponesimod may activate astrocytes and 
oligodendrocytes promoting re-myelination. In a rat model of relapsing-remitting EAE, 
the combination of DMF with ponesimod showed a marked reduction of clinical scores 
throughout the whole treatment-phase [Ponesimod IB]. In summary, the combination of 
ponesimod with DMF may reduce inflammation and prevent disability accumulation,
resulting in additive or synergistic efficacy in MS. Hence, this study has the ambitious 
aim to reduce disease activity to a level which is not achievable with monotherapy.


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Additionally, subjects enrolled in the study may receive improved medical care for their 
RMS. Subjects who prematurely discontinue study treatment will enter the Post-treatment 
observation period (PTOP) in which they will be allowed to receive other approved MS 
therapies and will continue to receive improved medical care as part of the study. Their 
participation in the study will also allow collection and analysis of information that may 
help patients obtain better care in the future.
When considering combinations of different drugs, it is important to minimize risk of 
overlapping or increased toxicity. Side effects of ponesimod do not substantially overlap 
with those of DMF. The main side effects associated with DMF are abdominal pain, 
diarrhea, nausea, flushing and lymphopenia [Tecfidera SmPC, Tecfidera USPI]. A few 
cases of PML have also been reported after long-term treatment with DMF, the majority 
in association with sustained lymphopenia [see Section 3.4.2]. Clinical studies conducted 
to date with ponesimod in MS patients have identified first-dose effects on HR and AV 
conduction, blood pressure, pulmonary function effects, macular edema, and liver 
enzyme elevations as potential risks [see Section 1.3.2.4]. Both DMF and ponesimod can 
reduce lymphocyte counts, but the mechanisms and modalities of lymphocyte-lowering 
effects of the two drugs are different and are not expected to lead to a profound 
immune-suppression. In a 13-week treatment duration study in dogs [Ponesimod IB], the 
combination of ponesimod with DMF induced effects comparable to those observed with 
each drug alone with no evidence of new or increased toxicities.
The study includes several safety measures for monitoring and minimizing the potential 
risks of combining ponesimod with DMF. These include:

Specific study inclusion and exclusion criteria to reduce the risk of high grade 
lymphopenia during the course of the study and select subjects without enhanced risk 
of opportunistic infections [see Section 4.3];

Protocol-specific procedures, including criteria for interruption and premature 
discontinuation for minimizing and managing the risk of lymphopenia and 
opportunistic infection [see Sections 5.1.12.2 and 5.1.12.3];

Criteria for premature discontinuation in the event of lack of efficacy during the 
study, allowing
subjects
to receive other treatments (rescue therapy) [see 
Section 3.5.2.1];

An overview surveillance by two independent safety committees (i.e., an MRI safety 
board and an Independent Data Monitoring Committee (IDMC) [see Sections 3.8.1
and 3.8.3]).
During the study, MRI scanning will be performed every 6 months. These MRI scans will 
require the injection of a gadolinium (Gd)-containing contrast agent which may, in rare 


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cases, lead to serious allergic reactions. Gd administration may be omitted if medically 
contraindicated. In addition, chest X-rays will be performed at Visits 1 (Screening) and 
18 (End-of-Treatment [EOT]) (i.e., at least 63 weeks apart, or 48 weeks in the event of 
premature discontinuation), thus exposing subjects to a limited quantity of radiation.
The above listed considerations, related to the known and potential risks, together with 
the risk mitigation measures planned for the study, and the expected improved efficacy of 
the ponesimod add-on therapy as compared to DMF alone, provide a rationale for a
positive benefit/risk for subjects participating in the study.
It is the investigator’s responsibility to monitor the risk-benefit ratio of study treatment 
administration, as well as the degree of distress caused by study procedures on an
individual subject level, and to discontinue study treatment or the study if, on balance, 
he/she believes that continuation would be detrimental to the subjects’ well-being.
2
STUDY OBJECTIVES
2.1
Primary objective
The primary objective of the study is to determine whether add-on therapy with 
ponesimod reduces relapse frequency as compared to placebo in subjects with active 
RMS who are treated with DMF (Tecfidera®).
2.2
Secondary objectives

To assess the effect of add-on therapy with ponesimod vs placebo on disability 
accumulation and on other aspects of MS disease control in subjects with RMS who 
are treated with DMF (Tecfidera®); 

To assess the safety and tolerability of add-on therapy with ponesimod vs placebo in 
subjects with RMS who are treated with DMF (Tecfidera®).
3
OVERALL STUDY DESIGN AND PLAN
3.1
Study design
This is a prospective, multicenter, randomized, double-blind, parallel-group, add-on,
placebo-controlled, Phase 3, superiority study. The study is designed to compare the 
efficacy, safety, and tolerability of add-on therapy with ponesimod 20 mg vs placebo in 
adult subjects with active RMS who are treated with DMF (Tecfidera®).
Approximately 600 subjects who have been receiving DMF b.i.d. for at least 6 months 
will be randomized in a 1:1 ratio to ponesimod 20 mg or placebo (approximately 
300 subjects per arm). Randomization will be stratified by baseline Expanded Disability 
Status Scale (EDSS) score (EDSS ≤ 3.5, EDSS > 3.5).


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The study will be conducted at approximately 100 sites in 15 countries. Randomization 
will proceed until the required number of subjects has been reached. Any eligible subject 
in screening at the time of randomization of the 600th subject will be recruited. Subject
enrollment will be competitive across participating sites. 
It is permitted to re-screen subjects once [see Section 8]. Actelion may wish to replace 
sites with no subject enrollment.
3.2
Study design rationale
The present study was designed to assess whether ponesimod as add-on therapy to DMF
(Tecfidera®) is superior to add-on placebo to DMF (Tecfidera®) in reducing relapses in 
subjects with active RMS. Eligible subjects entering the study will have received DMF 
therapy for at least 6 months prior to study entry with clinical and/or MRI-documented 
disease activity after at least 3 months on DMF. The requirement for 6 months of DMF 
treatment prior to study entry aims to ensure a relatively stable effect of DMF on 
lymphocytes as well as better adherence to treatment during the study as most of flushing 
and gastrointestinal AEs occur during the initial months following initiation of DMF 
treatment. According to expert opinion, at least 6 months of DMF treatment would be 
necessary before the response to DMF can be considered insufficient and additional 
treatment justified. 
The requirement for evidence of active MS disease after at least 3 months of DMF 
treatment is based on data from Phase 2 and Phase 3 clinical studies showing increased 
therapeutic efficacy of DMF after at least 3 months of treatment. 
The requirements set in this study are considered to represent the earliest timepoints at 
which the treating neurologist would consider escalating the therapy if disease activity 
persists, avoiding the risk of a too early change in treatment. 
The study includes a placebo comparator arm, but all subjects will remain on DMF 
background therapy throughout the treatment period. Moreover, during the study subjects
who experience a confirmed relapse or an event of 24-week confirmed disability 
accumulation (CDA) will have the option to switch to an alternative treatment. During 
the study, several decisions and assessments including subjective judgment will have to 
be performed. In order to limit the considerable risk of bias, a double-blind design is 
warranted. 
The study includes only one ponesimod treatment arm at the maintenance dose of 20 mg 
o.d. corresponding to the optimal dose when used as monotherapy based on the Phase 2 
dose-finding trial and its ongoing extension [see also dose rationale Section 3.3].
No ponesimod monotherapy treatment arm has been included in the present study.
Importantly, the clinical efficacy of ponesimod (20 mg o.d.) monotherapy is already 


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being evaluated against teriflunomide (14 mg o.d., Aubagio®) in the ongoing pivotal 
Phase 3 AC-058B301 study. The objective of this study is to assess ponesimod as add-on 
therapy in patients with active disease on DMF, with the ambitious aim at suppressing 
disease activity to a level which is not achieved with available therapies. Add-on studies 
can assess the superiority of active treatment over placebo on a background medication. 
The proposed add-on design without testing the add-on arm against each monotherapy is 
quite common in other therapeutic areas (e.g., in rheumatology in studies testing add-on 
design to disease modifying antirheumatic drugs [DMARD], in oncology, etc.) and has 
been also used in MS. The SENTINEL study tested natalizumab as add-on to IFN β-1a 
versus placebo add-on to IFN β-1a [Rudick 2006]. Two Phase 2 studies tested 
teriflunomide as add-on to either IFN β-1a or glatiramer acetate in comparison to placebo 
add-on and the Phase 3 study TERACLES was planned to confirm the benefit of add-on 
teriflunomide to IFN β-1a in comparison to placebo [Freedman 2012].
In order to evaluate the ARR over an estimated mean treatment duration of 
approximately 2 years, a study design with variable treatment duration was chosen. The 
minimum treatment time will be of at least 60 weeks. However, based on a projected
recruitment time of approximately 2 years, prolonged study treatment exposure time of 
up to 3.3 years will be available for efficacy and safety analysis.
3.3
Dose rationale
Based on the available Phase 2 data, ponesimod 20 mg o.d. displayed the optimal 
benefit/risk balance and this dose was selected for Phase 3 studies.
Lower doses of ponesimod did not provide an adequate level of disease control and did 
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 4 years of treatment. 
While more efficacious, 20 mg showed similar rates of AEs and discontinuations when 
compared to 10 mg; the pulmonary function effects were lower with 10 mg but the 
difference was not clinically relevant. Ponesimod 40 mg was associated with decreased 
tolerability, leading to increased discontinuation rates, mainly due to pulmonary function 
effects and liver enzyme elevations. By contrast, there was a similar or only small 
incremental effect of 40 mg compared to 20 mg on lymphocytes, MRI brain 
inflammatory activity, and clinical disease activity.
Ponesimod will be added to DMF in patients who have active disease while on DMF 
therapy, thus it is expected that the full efficacy of ponesimod, as achieved with 20 mg, 
will be required to adequately control disease activity. Furthermore, given that the AE 
profiles of the two drugs are different, it is reasonable to expect that the safety profile of 


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the 20 mg dose will not substantially change and will also be acceptable when added-on 
to DMF.
3.4
Risk mitigation strategy 
To minimize, assess, and manage potential risks to patients who will receive ponesimod 
and DMF or DMF alone, a risk mitigation strategy consisting of several components has
been implemented in this study. These include: i) specific study inclusion and exclusion 
criteria to ensure that patients who have underlying characteristics that increase their risk 
for an adverse outcome are excluded; ii) protocol specific procedures, including criteria 
for interruption and premature discontinuation [see Section 5.1.12] for minimizing and 
managing certain AEs with particular emphasis on lymphopenia and opportunistic 
infections [see Sections 3.4.1 and 3.4.2], iii) an overview surveillance by two 
independent safety committees (i.e., an MRI safety board, and an IDMC, see Sections
3.8.1 and 3.8.3). 
3.4.1
Lymphopenia
Both ponesimod and DMF have lymphocyte-lowering effects. Low lymphocyte counts 
can potentially increase the risk of infections including opportunistic infections, and need 
to be monitored. The mechanism and modality of lymphocyte count reduction by the two 
drugs are very different. DMF treatment slowly reduces lymphocyte counts by inducing 
apoptosis of lymphocytes with a nadir after one year of treatment. By contrast, 
ponesimod treatment induces lymphocyte count reduction within one week by reversible 
sequestration of lymphocytes in secondary lymphoid tissues. Discontinuation of DMF 
treatment is followed by a slow increase of lymphocyte counts over several weeks, while 
discontinuation of ponesimod is followed by recovery of lymphocyte counts within one 
week. In a 13-week treatment duration study in dogs, the combination of ponesimod with 
DMF induced effects on lymphocyte counts comparable to those observed with each drug 
alone. The effect on lymphocytes by adding ponesimod to DMF has not been investigated
in humans. All these aspects represent important safety concerns that have been taken 
into account when designing appropriate safety measures as follows:

To reduce the risk of high grade lymphopenia during the course of the study, only 
subjects with lymphocyte counts 0.8 × 109/L (800/mm3) after at least 12 months 
of DMF treatment or subjects with lymphocyte counts ≥ 0.9 109/L (≥ 900/mm3) 
after at least 6 months of DMF treatment (but < 12 months) will be enrolled [see 
inclusion criterion #8 in Section 4.3].

To ensure a relatively stable effect of DMF on lymphocyte has been reached prior to 
study entry, subjects with large excursions in lymphocyte counts between screening 
and baseline assessments (at least 3 weeks apart) will not be included [see inclusion 
criterion #8 in Section 4.3].


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
To ensure a prompt detection of high grade lymphopenia or unstable declining 
lymphocyte counts while on DMF or after adding ponesimod to DMF, lymphocyte 
counts will be monitored every 4 weeks (± 3 days) during the initial 24 weeks, and 
then every 12 weeks for the remainder of the study.

To facilitate management of potential lymphopenia for patients who discontinue 
study treatment and enter the PTOP, lymphocyte counts will be made readily 
available to the treating neurologists. Upon discontinuation of ponesimod, 
lymphocytes generally return to within the normal range within one week. 
Lymphocyte counts are therefore expected to have returned to normal range during 
the 30-day follow up period preceeding the start of PTOP, unless the lymphopenia 
was due to DMF background treatment. Thus, there is no risk of unblinding to 
ponesimod treatment when providing lymphocyte count values during the PTOP. 

To ensure that any unexpected effect on lymphocytes by adding ponesimod to DMF 
is properly assessed in due time, the IDMC will perform a review of lymphocyte 
count data on an ongoing basis, starting with a cut-off corresponding to 12 weeks 
after randomization of the 20th subject in the study. Furthermore, the IDMC will 
continue to review lymphocyte count and other data at regular intervals 
approximately every 4 months during the study [see also Section 3.8.1].
3.4.2
Opportunistic infections
Both ponesimod and DMF have immune-modulating properties which may increase the 
risk of opportunistic infections. Opportunistic infections of the CNS require particular 
vigilance due to the risk of invalidating or fatal outcome. Although no cases of PML have 
been reported with ponesimod, single cases of this disease were reported in patients 
treated with fingolimod, another S1P receptor modulator, without previous treatment with 
natalizumab or immunosuppressants. Cases of PML with DMF (Tecfidera®) have also 
been reported, the majority in association with sustained lymphopenia. Add-on of
ponesimod to DMF may potentially increase the risk of such infections. Therefore, 
several measures will be in place to select subjects without enhanced risk of such 
infections and to detect signs of infections as early as possible during the course of the 
study [see Section 5.1.12.3. Previous treatments with potential delayed risk of infection 
will be prohibited anytime prior to the study (i.e., alemtuzumab, mitoxantrone) or will be 
allowed only after appropriate wash-out period (e.g., natalizumab, rituximab, 
azathioprine, methotrexate). An MRI safety board will perform centralized expert 
evaluation of MRI images selected by the local radiologists or neurologists with MRI 
expertise in case of suspected opportunistic CNS infections including PML. 
The risk of opportunistic infections should be seen in the perspective of expected benefit 
of ponesimod added-on to DMF and of the currently accepted benefit/risk profile of 
natalizumab where the approximate risk of PML is in the range of 1/10,000–1/100 and 


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varies 
with 
John 
Cunningham 
Virus 
(JCV)-specific 
antibody 
status, 
prior 
immunosuppression and duration of treatment [Calabrese 2015]. The overall incidence of 
PML in
natalizumab-treated patients was 3.78/1000 as of 3 December 2014
[Kornek 2015]. The currently known risk of PML with fingolimod and DMF is
substantially lower and it remains unclear whether it is significantly elevated compared to 
the general population [Van Schependom 2015]. These considerations, together with the 
risk mitigation measures planned for the study, and in light of expected improved 
efficacy of the ponesimod add-on
therapy
as compared to
DMF
alone [see 
Section 11.5.1] provide a rationale for an acceptable benefit/risk ratio for the trial.
3.5
Study periods
The study consists of the following study periods:
3.5.1
Pre-randomization period 
This period commences 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), Visit 2 (Baseline) and the pre-dose assessments of Visit 3 (Day 1). 
3.5.2
Treatment period 
This period consists of a double-blind treatment period, which starts after randomization 
with the first dose of study treatment during Visit 3 (Day 1 of study).
The double-blind treatment period has a variable duration from a minimum of 60 weeks 
(for the last subject randomized) to a maximum of 156 weeks (3 years) for the first 
subjects randomized in the trial. Average duration is expected to be approximately 
2 years. It includes a randomization visit, visits at 2, 4 and 12 weeks after randomization, 
and 12-weekly visits thereafter until 60 weeks after the randomization of the last subject
or 156 weeks of treatment (whichever occurs first). 
For an individual subject, this period starts on the day of the first study treatment intake 
and continues until the premature discontinuation of study treatment, Week 156, or until 
60 weeks after the randomization of the last subject (whichever occurs first).
EOT visit: The EOT visit at an individual level should preferably take place 1 day after 
the last dose of study treatment, but no later than 7 days after the last dose of study 
treatment.
3.5.2.1
Modification of treatment
If a subject meets one of the following conditions:

The subject has experienced a confirmed relapse while on study treatment;

The subject has experienced an event of 24-week CDA while on study treatment;


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Then, the principal investigator / treating neurologist should consider and propose the 
following options to this subject:

Subject remains on study treatment. In this case, the subject will be asked to 
re-consent to continue receiving study treatment [see Section 13.3].

Subject prematurely discontinues study treatment and DMF background therapy, and 
begins treatment with an approved MS therapy at the discretion of the treating 
neurologist in accordance with local practices. In this case, the subject will enter the 
post-treatment observation period (PTOP) of the study [see Section 3.5.3.2].
Subjects who prematurely discontinue study treatment for reasons other than lack of 
efficacy (e.g., safety or tolerability) will also enter the PTOP of the study [see 
Section 3.5.3.2]. Treating neurologists may choose to continue DMF therapy or may 
begin treatment with an approved MS therapy at the discretion of the treating neurologist 
in accordance with local practices. Discontinuation of DMF treatment should be 
considered 
in 
accordance 
with 
prescribing 
information
[Tecfidera USPI,
Tecfidera SmPC] at the discretion of the treating neurologist and in accordance with local 
practices.
Subjects who permanently discontinue DMF background therapy will discontinue study 
treatment [see Section 5.1.12.8] and may begin treatment with an approved MS therapy 
in accordance with local practices. In this case, the subject will enter the PTOP of the 
study [see Section 3.5.3.2].
3.5.3
Post-treatment period and End-of-Study
This period starts immediately after the last dose of study treatment and ends when 
End-of-Study (EOS) visit has been completed. It comprises the post-treatment safety 
follow-up (FU) period and if applicable, is followed by the PTOP.
3.5.3.1
Post-treatment safety follow-up period
All subjects will enter the safety FU period which lasts for at least 30 days after the last 
dose of study treatment and includes a safety FU visit approximately 30 days after the 
last dose of study treatment. Subjects participating in the lymphocyte subset sub-study 
will have an additional FU visit approximately 7 days after the last dose of study drug 
(FU7d) [see Section 3.6.1].
3.5.3.2
Post-treatment observation period 
Subjects who prematurely discontinue study drug and complete the 30-day safety 
follow-up including the FU visit, will enter the PTOP which lasts until 60 weeks after 
randomization of the last subject or until Week 156, whichever is first (i.e., planned EOT
visit) irrespective of treatment completion. It consists of an abbreviated schedule of 
assessments at the time of the originally scheduled 12-weekly visits. The aim is to 


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follow-up with the subjects after discontinuation of study treatment and to collect 
long-term data while the subject possibly receives other approved MS therapies. 
While participating in the PTOP, subjects may not be enrolled in another clinical trial. 
They may, however, withdraw their consent to participate to this study at any time [see 
Section 9.2].
3.5.3.3
End-of-Study
The study level EOS will occur after all subjects have completed the safety FU period or 
the last visit of the PTOP.
For an individual subject, EOS is reached when treatment, post-treatment safety FU, and 
if applicable, the PTOPs have been completed: 

For subjects who complete the treatment period, and for subjects who prematurely 
discontinue study treatment and do not enter the PTOP, the EOS visit corresponds to 
the 30-day FU visit (FU). 

For subjects who prematurely discontinue study treatment and enter the PTOP period, 
the EOS visit corresponds to the last visit of the PTOP.
The overall study design is shown in Figure 1.


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Figure 1
AC-058B302 study design
D = day; DMF = dimethyl fumarate; EOS = End-of-Study; EOT = End-of-Treatment; FU = follow-up; V = visit; 
W = week; *Lymphocyte tests every 4 weeks (± 3 days) until Week 24; ** Subjects participating in the lymphocyte 
subset sub-study will have an additional FU visit approximately 7 days after the last dose of study drug (FU7d). 
3.5.4
Study duration
Assuming a subject recruitment time of 104 weeks (including the period from first 
subject, first visit [FSFV]
to last subject, first visit [LSFV]
and a 45-day 
pre-randomization period for the last randomized subject), the overall duration of the 
study from FSFV to last subject, last visit (LSLV) will consist of 104 weeks recruitment, 
followed by the minimum treatment time of 60 weeks, and 30 days post-treatment safety 
follow-up. This results in an anticipated study duration of approximately 168 weeks 
(3.3 years). The actual overall study duration or subject’s recruitment period may vary.
For an individual subject, the maximum duration time will consist of a 45-day 
pre-randomization period followed by a maximal 156-week treatment period and a 
30-day post-treatment safety follow-up. This results in a maximal total participation time 
of approximately 167 weeks (3.3 years).


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3.5.5
Study closure
The study closure will be communicated by the sponsor 60 weeks after the randomization 
of the last subject.
All subjects on study drug should perform the Visit 18 (EOT) assessments within 
4 weeks after study closure is communicated by the sponsor, and then the post-treatment 
safety follow-up (i.e., Visit 19 [FU7d], if applicable, and Visit 20 [FU]). For these 
subjects, the EOS visit corresponds to Visit 20 (FU).
All subjects who prematurely discontinued from the study treatment and entered the 
PTOP should perform the Visit 18A (Week 156) assessments within 4 weeks after study 
closure is communicated by the sponsor. For these subjects, the EOS visit corresponds to
Visit 18A (Week 156).
3.6
Sub-studies
Two sub-studies designed to evaluate specific safety variables will be conducted in a 
subset of sites and subjects.
3.6.1
Lymphocyte subset
Ponesimod decreases total lymphocyte counts but some lymphocyte subsets are more 
sensitive to this effect than others. DMF and other fumaric acid esters may also decrease 
total lymphocyte counts but the effect on lymphocyte subsets is not well understood. The 
effect of ponesimod add-on to DMF on lymphocyte subsets is not known. Analysis of 
blood lymphocyte subsets may provide a better understanding of the immunomodulatory 
effect of ponesimod when added on to DMF in subjects with RMS.
A sub-study assessing lymphocyte subsets will be conducted in approximately 
200 subjects [see Section 7.7.2.2]. Participation in the sub-study will be mandatory for all 
subjects until at least the first 200 subjects are randomized to the main study. T cell, B 
cell, and NK cell counts as well as T cell subsets (e.g., CD4+ naïve, CD4+ effector 
memory, CD4+ central memory, CD8+ naïve, CD8+ effector memory, CD8+ central 
memory, CD8+ terminally differentiated effector memory, Th17 cells, Treg cells, and 
Th1cells) will be analyzed at the central laboratory by fluorescence activated flow 
cytometry using a combination of cell surface markers. Other lymphocyte subsets may 
also be analyzed. Selected lymphocyte subsets may also be analyzed functionally ex vivo. 
Results will be provided regularly to the IDMC. Results from the lymphocyte subsets 
sub-study will be blinded to site staff and the sponsor until study closure.
3.6.2
Vaccination
In order to characterize the immune response in subjects receiving ponesimod add-on to 
DMF therapy, changes in vaccine-specific antibody titers from pre- to post-vaccination 


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will be assessed at the end of the study for subjects having received a non-live 
vaccination while on study treatment.
3.7
Site staff and their roles
In order to maintain the blind [see Section 5.1.4] 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 dermatologist
# The roles of treating neurologist, efficacy assessor and first-dose administrator are 
irreconcilable and must be assumed by three distinct persons. 
3.7.1
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 


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oversees the accrual of appropriate subjects, the conduct of the study according to the 
trial protocol, and the collection of the required data.
3.7.2
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, 
assessing and reporting MS relapses on the specific MS relapses pages of the electronic 
case report form [eCRF; see Sections 7.2.2 and 10.1.6], monitoring of safety, including 
recording and treating of AEs (with the exception of non-serious 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 post-dose 
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 3.7.4].
The treating neurologist will not perform EDSS / FS assessment and will not alter the 
EDSS or FS scores obtained by the efficacy assessor [see Section 7.2.2]. The treating 
neurologist will not have access to MRI data 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 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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3.7.3
Efficacy assessor
The efficacy assessor is a physician, physician assistant, or nurse practitioner who will
perform the detailed neurological examination for obtaining the EDSS / Functional 
System (FS) scores using the “Neurostatus” scoring forms [see Appendix 1] 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 forms 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 person 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 of ensuring consistency in EDSS/FS scoring with the primary efficacy
assessor. 
Depending on the site setting, the efficacy assessor may be in charge of administering the 
Multiple Sclerosis Functional Composite (MSFC) test and the Symbol Digit Modalities 
Test (SDMT).
3.7.4
First-dose administrator
The first-dose administrator must be a physician, physician assistant, nurse practitioner, 
or any trained and qualified person as per local regulations capable of making healthcare 
decisions based on ECG interpretation reports provided in a timely manner by the central 
ECG laboratory, and experienced in the evaluation of BP and clinical signs or symptoms. 
For non-physicians the role of first-dose administrator must be within the scope of the 
national and/or local authorization. If the first-dose administrator is adequately trained 


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and experienced in cardiology, she/he will make healthcare decisions solely based on 
her/his own interpretation of the ECG (in which case expedited central reading of the 
ECGs by the central ECG laboratory will not be required). 
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 is required. This includes the close monitoring of the subject during the first 
4 hours and up to 12 hours 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 first-dose administrator. She/he will independently assess eligibility for 
discharge from cardiac monitoring or continued subject management on Visit 3 and on 
visits for re-initiation of study drug when post-dose monitoring is required [see Sections 
5.1.8, 5.1.9, and 5.1.10]. 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 ECGs assessments requested by the 
protocol during the study. Depending on the setting at the site, study drug administration 
at Visit 3 (Day 1), or at visits for re-initiation of study drug following a temporary 
cessation of treatment when post-dose monitoring is required, may be performed under 
the supervision of the treating neurologist. In this case, the subject must be rapidly 
transferred to the first-dose administrator, who will supervise the 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 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. During the study, all 
clinical records related to first-dose data (e.g., 12-lead ECG printouts, BP results, AEs, 
etc.) must be filed in a separate medical chart only visible to the first-dose administrator.
All other AEs (i.e., those with an onset prior to study drug intake or which are not 
resolved at the time of discharge from the cardiac monitoring or with an onset after 
discharge from the cardiac monitoring), as well as all SAEs and all AEs requiring study 
drug discontinuation must be reported to the principal investigator / treating neurologist, 
who will record these events on the AE page of the eCRF.
The 3-hour 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.


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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 case of such 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 equipped to provide emergency treatment, she/he will refer the 
subject to a cardiologist to receive emergency care and treatment.
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 
subjects, 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 3.7.5]). 
In case the first-dose administrator is responsible for conducting all BP and ECGs 
assessments requested by the protocol during the study, he/she will report to the principal 
investigator / treating neurologist any significant findings on 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.
3.7.5
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


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
PFTs

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 3.7.4])

MSFC score

SDMT

Patient-Reported Outcome (PRO) instruments:
o
Fatigue Symptom and Impacts Questionnaire-RMS (FSIQ-RMS)
o
36-Item Short Form Health Survey version 2 (SF-36v2™)
o
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.
3.7.6
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. 
3.7.7
Local radiologist or neurologist with MRI expertise
The local radiologist or neurologist with MRI expertise 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 radiologist or 
neurologist with MRI expertise, 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 radiologist or 
neurologist with MRI expertise will conduct further examination, as per local standard 
practice, to rule out or confirm the diagnosis. In case of suspicion of PML, the local 
radiologist or neurologist with MRI expertise should perform MRI as described in the 
Section 7.2.3. She/he may support the principal investigator in making a decision on 
eligibility of the subject prior to randomization by reviewing MRIs performed up to 
15 months prior to screening used to assess the eligibility of the subject in the study.
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 


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suggestive of active or latent tuberculosis (TB; any CXR that had been performed within 
90 days prior to Visit 1 (Screening) can be used; if available, there is no need to repeat 
CXR at Visit 1 [Screening]). At Visit 18 (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 or neurologist with MRI expertise may review MRI images 
and another local radiologist may review CXR images.
3.7.8
Ophthalmologist
The ophthalmologist will review and interpret the ophthalmological examinations and 
optical coherence tomography (OCT) assessments as scheduled in the study protocol [see 
Sections 7.3.6 and 7.3.7]. 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.
3.7.9
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]. 
3.7.10 Dermatologist
A dermatologist is a physician, physician assistant, nurse practitioner, or any trained and 
qualified person per local regulations who will perform complete skin examinations as 
scheduled in the study protocol [see Section 7.3.12]. For non-physicians the role of a 
dermatologist must be within the scope of the national and/or local authorization.
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 
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3.8
Study committees
3.8.1
Independent Data Monitoring Committee
An 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 in accordance with the International Council for Harmonisation (ICH) -
Good Clinical Practice (GCP) guidelines. 
The IDMC is composed of physicians with relevant medical expertise in neurology, 
cardiology, infectious diseases, immunology and/or hematology, pulmonology, 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.
The IDMC will perform a review of all available data including lymphocyte counts on an 
ongoing basis, starting with a cut-off corresponding to 12 weeks after randomization of 
the 20th subject in the study. The IDMC will continue to review data at regular intervals 
(approximately every 4 months) during the study. The IDMC will be responsible for 
recommending actions which may include:

continuation of the study as per protocol,

modifications to the study protocol to preserve subject’s safety and/or data integrity,

termination of the study at any time if major concerns arise regarding the safety of the 
study subjects.
No interim analysis is planned for the study. An Independent Statistical Analysis Center 
(ISAC), 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 ISAC.
3.8.2
Ophthalmology Safety Board
An Ophthalmology Safety Board (OSB) composed of two independent ophthalmologists 
will review and evaluate in a blinded fashion any new or suspected cases of macular 
edema. Important findings will be communicated to the IDMC. The composition and 
operation of the OSB are described in the OSB charter.
3.8.3
MRI safety board
An MRI safety board composed of radiologists and/or neurologists with relevant MRI 
expertise will review and evaluate in a blinded fashion the brain MRIs selected by the 
local radiologists or neurologists with MRI expertise and exported to the MIAC in cases 
of a suspected opportunistic infection in the CNS. The MRI safety board will 


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communicate the results of the review to the site and important findings will be 
communicated to the IDMC. The composition and operation of the MRI safety board are 
described in the MRI safety board charter. 
3.8.4
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 adverse 
events that will be sent for adjudication will be based on a pre-defined list of preferred 
terms belonging to relevant Standardized MedDRA Queries related to cardiovascular and 
stroke and recorded as serious in the eCRF. For each AE sent for MACE adjudication,
the MACE adjudication board will determine whether the event does or does not belong
to one of the pre-specified categories including, but not limited to, 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). 
Subjects must have been treated with DMF for at least 6 months and have active disease 
after at least 3 months of DMF treatment, defined by at least one of the following 
features: 

At least one MS attack with onset within 12 months to 1 month prior to baseline 
EDSS assessment;

At least one Gd+ lesion on an MRI of the brain or spinal cord, performed either 
within 12 months prior to Visit 1 (Screening) or during the pre-randomization
period (MRI assessed at Visit 2 [Baseline] may be the qualifying scan);

Presence of at least one new or one unequivocally enlarging T2 lesion on an MRI 
of the brain or spinal cord, assessed by comparing two MRI scans: the firstMRI 
scan must be performed within 15 months prior to Visit 1 (Screening) and after at 
least 3 months of DMF treatment; the second MRI scan must be performed prior 
to randomization (MRI assessed at Visit 2 [Baseline] may be used). The presence 
of at least one new or unequivocally enlarging T2 lesion has to be confirmed by 
the MRI central reading facility prior to randomization.


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Enrolled subjects must be ambulatory with an EDSS score of up to 6.0 inclusive. The 
subjects may have been previously treated with other MS disease modifying therapies 
including IFN -1a, IFN -1b, glatiramer acetate, leflunomide, teriflunomide, 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. According to the US label [Tecfidera USPI], these subjects can also be treated 
with Tecfidera®, but they have generally been less studied and have often not been 
included in pivotal trials of medications approved for the treatment of RMS. For these 
reasons, it is important to also evaluate the benefit/risk profile of ponesimod in subjects 
who are treated with Tecfidera® and have SPMS with superimposed relapses. 
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 is widely recognized.
The study will enroll subjects treated with DMF with recent evidence of active disease as 
determined by clinical or imaging criteria. Inclusion criteria for active disease consist of 
prognostic factors that identify patients not responding satisfactorily to treatment, and 
thus require more efficacious therapies. The requirement for at least 6 months of DMF 
treatment prior to study entry aims to ensure: 

A better adherence to treatment during the study as most of flushing and 
gastrointestinal AEs which lead usually to treatment discontinuation occur during the 
initial months following DMF treatment,

the evaluation of patient’s response to DMF treatment occurs at an appropriate time 
to avoid delaying additional treatment or a change in treatment,

most of the effect of DMF on lymphocyte counts is established.
Furthermore, the requirement for imaging or clinical signs of disease activity after at least 
3 months of DMF treatment is to ensure additional treatment is justified [see Section 3.2]. 


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The study will recruit adult subjects, restricted to subjects between 18 and 55 years of 
age, which is the age range used in most contemporary clinical trials in MS. In older MS 
subjects presence of non-MS-specific white matter lesions on MRI can make patient 
selection and evaluation of disease activity during the study more difficult. In addition, 
the treatment effect is expected to be less pronounced in older MS patients and other 
co-morbidities, which appear in older age, may make the MS assessment difficult. The 
age range of the study population will be representative of the general RMS population. 
Subjects with an EDSS score 0–6.0 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 performance). The subjects with EDSS above 6.0 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 underlying characteristics that increase their risk for an adverse outcome
will be excluded from this study. In particular, subjects with low or unstable lymphocyte 
counts while on DMF, subjects who have been previously treated or have only recently 
discontinued certain immunosuppressive or lymphocyte-depleting drugs, and subjects 
with ongoing infections or immunodeficiency will be excluded from the study.
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. A woman of childbearing potential (WOCBP) is eligible only if the following applies:

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 monthly urine pregnancy tests during the study and up to 
30 days after study treatment discontinuation;

must use reliable methods of contraception until 30 days after study treatment 
discontinuation as described in Section 4.5.2;
Definition of WOCBP and the acceptable methods of contraception for this study are
described in Section 4.5.


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4. Presenting with a diagnosis of MS as defined by the revised (2010) McDonald 
Diagnostic Criteria for MS [see Appendix 2] with relapsing course from onset 
(i.e., RRMS, or SPMS with superimposed relapses).
5. Ongoing treatment with DMF for at least 6 months prior to Visit 1 (Screening).
6. Active disease after at least 3 months of DMF treatment defined by at least one of the 
following features:

At least one MS attack supported by objective neurological examination with 
onset within 12 months to 1 month prior to baseline EDSS assessment;

At least one Gd+ lesion on an MRI of the brain or spinal cord, performed either 
within 12 months prior to Visit 1 (Screening) or during the pre-randomization 
period (MRI assessed at Visit 2 [Baseline] may be the qualifying scan);

Presence of at least one new or one unequivocally enlarging T2 lesion on an MRI 
of the brain or spinal cord, assessed by comparing two MRI scans: the first MRI 
scan must be performed within 15 months prior to Visit 1 (Screening) and after at 
least 3 months of DMF treatment; the second MRI scan must be performed prior 
to randomization (MRI assessed at Visit 2 [Baseline] may be used). The presence 
of at least one new or one unequivocally enlarging T2 lesion has to be confirmed 
by the MRI central reading facility prior to randomization.
7. Ambulatory and with an EDSS score between 0 and 6.0 (inclusive) at Visit 1 
(Screening) and Visit 2 (Baseline).
8. For subjects with ongoing treatment with DMF ≥12 months prior to screening:

Lymphocyte count ≥0.8 × 109/L (≥800/mm3) at Visit 1 (Screening) and Visit 2 
(Baseline) (assessed at least 3 weeks apart) with the lymphocyte count at Visit 2 
(Baseline) > 0.5-fold and < 2.0-fold of the count at Visit 1 (Screening).
For subjects with ongoing treatment with DMF ≥6 months (but < 12 months) prior to 
screening:

Lymphocyte count ≥ 0.9 109/L (≥ 900/mm3) at Visit 1 (Screening) and Visit 2 
(Baseline) (assessed at least 3 weeks apart) with the lymphocyte count at Visit 2 
(Baseline) > 0.5-fold and < 2.0-fold of the count at Visit 1 (Screening).
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 and women intending to become pregnant during the 
study.
MS disease
2. Presenting with a diagnosis of MS with progressive course from onset (i.e., PPMS or 
PRMS).


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3. Evidence of a relapse of MS with onset within 30 days prior to baseline EDSS 
assessment or between baseline EDSS assessment and randomization.
Treatments
4. Treatment with the following medications:

Within 15 days prior to randomization:
o
-blockers, diltiazem, verapamil, digoxin or any other anti-arrhythmic or HR 
lowering systemic therapy [non-exhaustive list of drugs provided in
Appendix 3]

Within 30 days prior to randomization: 
o
Adrenocorticotropic hormone (ACTH) or systemic corticosteroids (for any 
reason)
o
Vaccination with live vaccines

Within 90 days prior to randomization:
o
Plasmapheresis, cytapheresis
o
Intravenous immunoglobulin
o
Treatment with an investigational drug (within 90 days or five half-lives of the 
drug, whichever is longer), except biological agents (see below)

Within 180 days prior to randomization:
o
IFN β-1a, IFN β-1b, glatiramer acetate, or daclizumab
o
Other systemic immunosuppressive treatment (e.g., cyclosporine, sirolimus, 
azathioprine, methotrexate, mycophenolic acid, or cyclophosphamide)
o
Fingolimod (Note: prior treatment with fingolimod at any time is an exclusion
criterion if discontinuation was due to an adverse event (AE) or poor 
tolerability)

Within 12 months prior to randomization:
o
Natalizumab
o
Non-lymphocyte-depleting experimental biological agents

Within 24 months prior to randomization:
o
Lymphocyte-depleting biological agents such as rituximab or ocrelizumab
o
Cladribine

Any time prior to randomization:
o
Alemtuzumab
o
Mitoxantrone
o
Ponesimod
o
Other investigational S1P modulators
o
Stem cell transplantation
o
Leflunomide or teriflunomide unless adequate and successful wash-out is 
documented.


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Infection and Infection Risk
5. Ongoing known bacterial, viral or fungal infection (with the exception of 
onychomycosis and dermatomycosis), confirmed 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).
6. Congenital or acquired severe immunodeficiency or known human immunodeficiency 
virus (HIV) infection or positive HIV testing at Visit 1 (Screening).
7. Negative antibody test for varicella-zoster virus at Visit 1 (Screening).
8. Known 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
9. 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.
10. 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
11. Presence of macular edema.
Cardiovascular
12. 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 current unstable 
ischemic heart disease;

Cardiac failure (NYHA 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 significant 
symptoms or 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 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), Visit 2 (Baseline) or by the pre-dose ECG at Visit 3 
(Randomization / Day 1);


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
History of syncope associated with cardiac disorders;

Systemic arterial hypertension not controlled by medication according to 
investigator judgment.
Metabolic
13. Type 1 or 2 diabetes which is poorly controlled according to investigator judgment or 
diabetes complicated with organ involvement such as diabetic nephropathy or 
retinopathy.
Pulmonary
14. Subjects with a clinically significant pulmonary condition including: 

Asthma which is insufficiently controlled according to investigator 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).
15. 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
16. Any of the following abnormal laboratory values at Visit 1 (Screening) or Visit 2 
(Baseline):

Hemoglobin (Hb) < 100 g/L

White blood cells (WBC) count < 3.5 × 109/L (< 3500/mm3)

Neutrophil count < 1.5 × 109/L (< 1500/mm3)

Platelet count < 100 × 109/L (< 100,000/mm3)
Hepatic
17. Known and documented moderate or severe hepatic impairment.
18. Any of the following abnormal laboratory values at Visit 1 (Screening) or Visit 2 
(Baseline):

ALT/SGPT > 3 × ULN 

AST/SGOT > 3 × ULN

Total bilirubin > 1.5 × ULN (unless in the context of known Gilbert’s Syndrome)
Other categories
19. Contraindications for MRI such as:


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
Pacemaker, certain 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;

Severe renal insufficiency defined as a calculated creatinine clearance 
< 30 mL/min (Cockroft-Gault);

Claustrophobia if its nature or severity is prohibitive for performing MRI 
according to the investigator’s judgment.
20. History of clinically significant drug or alcohol abuse.
21. Known allergy to any of the ponesimod formulation excipients. 
22. 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.
23. Subjects unlikely to comply with protocol, e.g., uncooperative attitude, inability to 
return for follow-up visits, or known likelihood of not completing the study including 
mental condition rendering the subject unable to understand the nature, scope, and 
possible consequences of the study.
4.5
Women of childbearing potential
4.5.1
Definition of childbearing potential
A woman is considered to be of childbearing potential unless she meets at least one of the 
following criteria:

Previous bilateral salpingectomy, bilateral salpingo-oophorectomy or hysterectomy.

Premature ovarian failure confirmed by a specialist.

XY genotype, Turner syndrome, uterine agenesis.

Post-menopausal, defined as 12 consecutive months with no menses without an 
alternative medical cause (ICH M3 definition).
4.5.2
Acceptable methods of contraception
WOCBP [definition see Section 4.5.1] must follow the below contraception scheme up to 
at least 30 days after study treatment discontinuation:

Two methods of contraception, one from Group 1 and one from Group 2, defined as 
follows:
o
Group 1: Oral, implantable, transdermal or injectable hormonal contraceptives,
which are associated with inhibition of ovulation, or intrauterine devices. 
Methods of contraception from Group 1 must be taken for at least 30 days prior 
to randomization.
o
Group 2: Female or male condoms, diaphragm or cervical cap.
OR


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
True abstinence from intercourse with a male partner only when this is in line with 
the preferred lifestyle of the subject. If true abstinence from intercourse with a male 
partner is chosen, then it must be started at latest at Visit 1 (Screening).
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 (prior 
to randomization) of the absence of sperm in the ejaculate.
Rhythm methods or the use of a condom by a male partner alone are not considered 
acceptable methods of contraception for this study. 
The methods of contraception used (including non-pharmacological methods) must be 
recorded in the eCRF.
4.6
Medical history
4.6.1
General 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);

Significant (in the opinion of the investigator) cardiovascular, pulmonary, liver, renal, 
eye disorder, and skin conditions, serious infections leading to hospitalization, and 
malignant tumors at any time prior to the study;

Medically significant new acute medical conditions in the past 12 months prior to the 
study (in the opinion of the investigator);

Smoking status at the time of entry in the study;

Episodes of anaphylaxis, angioedema, flushing in the past 12 months.
Previous and concomitant therapies at pre-randomization, as defined in Section 5.2, will 
be recorded in the previous/concomitant medication page of the eCRF.
4.6.2
MS history
MS disease characteristics, as defined below and evidenced by documentation in the 
patient charts, will be recorded on the MS history page of the eCRF:

Date of first known MS symptoms;

Date of MS diagnosis;

MS type (e.g., RRMS, SPMS);


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
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 date and the duration of the relapse when 
available, and treatment of these relapses (corticosteroids, ACTH, plasmapheresis 
etc.) will 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. For 
treatments received in the last 24 months prior to the study, start date, end date, dose, 
route, frequency,
and reason for discontinuation will be recorded in the 
previous/concomitant medication page of the eCRF [see Section 5.2.2]. 
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). 
In the maintenance period, the study treatment consists of the daily administration of one 
tablet containing ponesimod 20 mg [see Section 5.1.8] (or matching placebo).
5.1.1
Investigational treatment and matching placebo: 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. 
During the up-titration period (Day 1 to 14) and the maintenance period, one tablet of 
ponesimod 2, 3, 4, 5, 6, 7, 8, 9, 10, or 20 mg (or matching placebo) will be taken orally 
o.d. The matching placebos for the doses of 2, 3, 4, 5, 6, 7, 8, 9, 10, and 20 mg are 
supplied as identical tablets, formulated with the same excipients but without the active 
ingredient, ponesimod. The 20 mg tablets and their matching placebo dispensed during 
the treatment maintenance are identical and indistinguishable and will be packaged in the 
same way.
The proposed add-on design will assess the superiority of ponesimod over placebo on a 
background of DMF therapy, an approved disease modifying therapy for the treatment of 


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RMS. The use of a placebo comparator is additionally justified by the provision of the 
option to switch to an alternative treatment or to remain on study treatment for subjects 
who meet at least one of the following conditions:

Subjects have experienced a confirmed relapse;

Subjects have experienced an event of 24-week CDA.
In any of the above cases, the subject will be asked to re-consent to continue receiving 
study treatment [see Section 13.3].
5.1.2
Study treatment administration
One tablet of ponesimod (or matching placebo) will be taken orally o.d. During the 
titration, the tablet will be taken in the morning, either with breakfast or before or after 
breakfast. During maintenance, the tablet will preferably be taken in the morning (either 
with breakfast or before or after breakfast). Overall, it is preferable that the tablet is taken 
each day at approximately the same time. The tablet will be swallowed as a whole. The 
last administration date and time of study treatment prior to the study visits and the 
administration date and time of study treatment on the days of visits will be recorded in 
the eCRF.
5.1.2.1
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 on HR 
and AV conduction. 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].


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Table 4
Dosing scheme
Treatment period
Duration
Dose regimen in the 
ponesimod group
Titration
Day 1 and 2
2 mg
Titration
Day 3 and 4
3 mg
Titration
Day 5 and 6
4 mg
Titration
Day 7
5 mg
Titration
Day 8
6 mg
Titration
Day 9
7 mg
Titration
Day 10
8 mg
Titration
Day 11
9 mg
Titration
Day 12 to 14*
10 mg
Maintenance
Day 15 until EOT
20 mg
* 
Visit 4 is to take place at Day 15 1 day. 
EOT = End-of-Treatment; NA = not applicable.
Study treatment up-titration, other than described above, is prohibited. Study treatment 
down-titration is not foreseen in any situation and is prohibited.
5.1.2.2
Maintenance
On the day of the study visits, study treatment must be administered only after the 
completion of the pre-dose safety assessments (diastolic BP [DBP], systolic BP [SBP], 
ECGs, PFTs, laboratory tests) and PK sampling (if scheduled).
5.1.3
Treatment assignment
A total of 600 eligible subjects will be randomized in a 1:1 ratio to ponesimod 20 mg or 
placebo, stratified 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 informed 
consent has been signed, the investigator/delegate contacts the Interactive Response 
Technology system (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.
The randomization list is generated by an independent Contract Research Organization 
(CRO) and kept strictly confidential.


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5.1.4
Blinding
5.1.4.1
Study drug material related blinding
This study will be performed in a double-blind fashion. The investigator and study staff, 
the subjects, the monitors, Actelion staff, and CROs involved in the conduct of the study 
will remain blinded to the study treatment until study closure. Actelion staff responsible 
for clinical trial supply distribution may need to be unblinded to ensure adequate 
distribution of study treatment. These persons will be clearly identified, their unblinding 
will be documented in the trial master file and they will not take part in any Clinical Trial 
Team meetings after the IRT is activated.
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 its matching placebo are indistinguishable and all 
subject’s kits will be packaged in the same way.
5.1.4.2
Functional blinding
First-dose effects on HR and AV conduction, and lymphocyte count reduction have been 
identified as potentially unblinding information. Access to this information by the site’s 
staff and sponsor’s study team will be restricted. The following measures will be taken to 
ensure that the efficacy assessments (i.e., EDSS/FS) are done independently and that 
cardiac safety assessments, and lymphocyte count assessments are performed and 
reviewed without potential to introduce a bias:

The primary endpoint (ARR) and the first secondary endpoint (disability 
accumulation) are based on the evaluations of the EDSS and FS scores, 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 and any other 
medical event that have the potential of revealing the treatment allocation 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 separate 
eCRF by the first-dose administrator / delegate. These AEs, the ECGs interpretation 


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reports and BP data collected on these days will not be visible to any of the blinded 
study personnel at the study site. During the study, all clinical records related to first 
dose data (e.g., 12-lead ECG printouts, BP results, AEs, etc.) must be filed in a 
separate medical chart only visible to the first-dose administrator. 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 medical and scientific review of the BP and 12-lead ECG data assessed 
during cardiac monitoring after first dosing or after re-initiation. In order to keep the 
rest of the sponsor’s team blinded 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 will be clearly identified. 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 assessed during the 
double blind treatment period will not be communicated to the sites, sponsor, and 
CRO involved in the conduct of the study 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 / treating neurologist and the sponsor. FU 
monitoring must be provided as described in Sections 5.1.12.2 and 7.3.13. 
−
A WBC count > 20 109/L or a lymphocyte count > 8.0 109/L is recorded 
by the central laboratory. In this event, an alert containing the total WBC or 
lymphocyte count result (as applicable) will be sent to the principal 
investigator / treating neurologist and the sponsor.
−
A total lymphocyte count decrease of > 50% from the value recorded at Visit 
5 (Week 4) associated with a total lymphocyte count < 0.5 109/L (< 500 
cells/mm3) is recorded at 2 consecutive scheduled visits after Visit 5 (Week 
4). In this event, an alert containing the lymphocyte count result will be sent to 
the principal investigator / treating neurologist and the sponsor.
−
A total lymphocyte count < 0.5 × 109/L is observed at FU. In this event, an 
alert containing the total lymphocyte count result will be sent to the principal 
investigator / treating neurologist. Discontinuation of DMF treatment should 
be considered in accordance with prescribing information [Tecfidera USPI, 
Tecfidera SmPC].
−
WBC and total lymphocyte counts measured at any of the visits in the PTOP. 
For subjects who have entered PTOP following study drug discontinuation, 


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lymphocyte count values recorded after entering the PTOP will be visible to 
the principal investigator / treating neurologist.

All MRI scans collected for the assessment of efficacy endpoints are evaluated by a 
central reading center (MIAC) also in a fully blinded fashion.
Under no circumstances should potentially unblinding information be shared with the 
efficacy assessor.
5.1.5
Unblinding
5.1.5.1
Unblinding for final analyses
Full randomization information will be made available for data analysis only after 
database closure in accordance with Actelion standard operating procedures (SOPs).
5.1.5.2
Unblinding for IDMC review
An ISAC, not otherwise involved in the design, conduct and analysis of the study, will 
have access to the randomization code in order to prepare 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 ISAC in accordance with the sponsor’s SOPs.
5.1.5.3
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.
5.1.5.4
Emergency procedure for unblinding
The investigator, study staff and sponsor staff must remain blinded to the subject’s study 
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 unblinding with 
Actelion.


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The occurrence of any unblinding during the study must be clearly justified and 
explained by the investigator. In all cases, Actelion must be informed as soon as possible 
before or after the unblinding.
The circumstances leading to unblinding must be documented in the Investigator Site File 
(ISF) and eCRF.
5.1.6
Study treatment supply
Manufacture, labeling, packaging, and supply of study treatment will be conducted 
according to Good Manufacturing Practice (GMP), GCP, and any local or national 
regulatory requirements.
All study treatment supplies are to be used only in accordance with this protocol, and not 
for any other purpose.
5.1.6.1
Study treatment packaging and labeling
5.1.6.1.1 Study treatment packaging
Study treatment is provided as tablets and supplied in childproof blister packs.
5.1.6.1.2 Study treatment labeling
Study treatment is labeled to comply with the applicable laws and regulations of the 
countries in which the study sites are located.
5.1.6.2
Study treatment distribution and storage
Study treatment supplies must be kept in an appropriate, secure area and stored according 
to the conditions specified on the label. 
5.1.6.3
Study treatment dispensing
The subjects will receive sufficient study treatment to cover the period up to the next 
scheduled visit. Alternatively, scheduled study medication dispensing/return procedures 
may be adapted according to the site practice (i.e., if the subject comes to the 
investigational site more frequently than the scheduled visits, it is then possible to 
dispense medication in smaller quantities). Subjects are asked to return all used, partially 
used and unused study treatment blister packs and unused tablets 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 from the remaining study treatment and to bring it at the 
next visit.
An accurate record of the date and amount of study treatment dispensed to each subject 
must be available for inspection at any time.


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5.1.6.4
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 and tablets, which will be sent to the warehouse where Actelion or a 
deputy will check treatment reconciliation. 
5.1.7
Study treatment accountability and compliance
5.1.7.1
Drug accountability
Records of study treatment 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. 
5.1.7.2
Drug compliance
Subjects’ compliance with study treatment intake will be recorded using an electronic 
diary. On each day, the subjects will be asked to enter the date, time, number of tablets 
taken, and the unique blister-card identifying number from which the tablets were taken. 
In addition, during the up-titration, the position of the well on the blister card will be 
recorded in order to check that tablets were taken in the correct sequence [see gradual 
up-titration in Section 5.1.2.1].
The electronic diary will give feedback 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., tablet at position 
6 taken before tablet at position 4 on the blister card); 

1 or more tablets 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 treatment accountability [see Section 5.1.7.1]. 
Subjects will be asked to explain the observed discrepancies. Interruptions with known 
dates will be recorded accordingly in the study treatment log of the eCRF [see 
Section 5.1.8]. Study treatment intake requirements will be re-explained to the subject 
each time an interruption is observed.
5.1.8
Study treatment dose adjustments and interruptions
Study treatment up-titration, other than described in Section 5.1.2.1, is prohibited. Study 
treatment down-titration is not foreseen in any situation and is prohibited.


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Study treatment interruption should be avoided. If study treatment intake is interrupted by 
the subject for any reason, she/he must immediately inform the investigator / treating 
neurologist.
Study treatment may be temporarily interrupted (i.e., re-start of the study treatment is 
possible) 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 5.1.12. The duration of a temporary interruption 
is determined by the investigator and is not limited in time. At maximum, it will last until 
the investigator deems necessary to require another MS treatment for the subject, which 
would end the temporary interruption and trigger permanent discontinuation of the study 
treatment. 
Detailed guidance on how to re-initiate study treatment in the event of drug interruption 
is provided in Section 5.1.9.
Study treatment dose adjustments/interruptions must be recorded in the eCRF.
5.1.9
Guidance for re-initiation of study treatment in the event of study treatment
interruption
If study 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 in Figure 2. 
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 resumed 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):
−
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 hours post-dose by the first-dose administrator, 


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following the cardiac assessment schedule and applying the discharge criteria 
as described for Day 1 [see Section 5.1.10].

If the subject missed taking the dose for up to three consecutive days during treatment 
maintenance (from Day 15 onwards after the first dose of initiation/re-initiation of the 
study drug):
−
Dosing should be resumed in the morning, 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 Day 15 onwards after the first dose of initiation/
re-initiation of the study drug): 
−
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 hours post-dose by the first-dose administrator, following the cardiac 
assessment schedule and applying the discharge criteria as described for Day 
1 [see Section 5.1.10].
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 patient can continue 
regular dosing, needs to re-initiate treatment, or should permanently discontinue 
treatment.


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Figure 2
Algorithm for management of treatment
5.1.10 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
Discharge from cardiac monitoring on Day 1, and on the first day of re-initiation of study 
drug following drug interruptions, can occur at the earliest when the evaluation of the 
pre-dose and all the hourly (± 15 minutes) post-dose ECGs until 4 hours post-dose have 
been obtained, provided the following criteria have been met:

ECG-derived resting HR 45 bpm, and if HR 50 bpm it must not be the lowest 
value post-dose;

SBP 90 mmHg;

QT corrected for heart rate on the basis of Fridericia’s formula (QTcF) 500 ms and 
QTcF increase from pre-dose 60 ms;
Investigational study drug interruption for one or more days
Investigational study drug 
interruption for up to 
3 consecutive days during 
maintenance period
(from Day 15 onwards)
Investigational study drug 
interruption for more than 
3 consecutive days at any 
time during the study
Investigational study drug 
interruption for at least one 
day during up-titration
period (Day 1–14)
Continue dosing in the 
morning of the following 
day, with the same dose 
taken prior to 
interruption.
Study drug may be 
re-initiated by the patients at 
home
Restart up-titration at study site and monitor                     
for up to 12 h post-dose


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
No persisting significant ECG abnormality (e.g., AV-block second or third degree) or 
ongoing AE requiring continued hospitalization or prohibiting study continuation as 
an out-patient.
If the subject does not meet the discharge criteria (as described above) at 4-hour 
post-dose, the subject should be carefully monitored for an additional period of up to 
8 hours, 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 hours 
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.
5.1.11 Premature discontinuation of study treatment
The decision to prematurely discontinue study drug may be made by the subject, the 
investigator, or Actelion. The main reason and whether discontinuation of study drug is 
the decision of the subject, the investigator, or Actelion, must be documented in the 
eCRF.
A subject has the right to prematurely discontinue study drug at any time by withdrawal 
from study drug only or by withdrawal from any further participation in the study
(i.e., premature withdrawal from the study, see Section 9.3).
The investigator should discontinue study drug for a given subject if the risks outweigh 
the potential benefits.
Study drug may be discontinued in response to an AE, lack of efficacy (including disease 
progression, treatment failure, worsening of subject’s condition), a protocol deviation 
(including eligibility failure, non-compliance with study requirements), a diagnostic or 
therapeutic procedure, a laboratory abnormality, or for administrative reasons.
Study-specific criteria for discontinuation of study drug are described in Section 5.1.12.
A subject who prematurely discontinues study drug is NOT considered as withdrawn 
from the study and will be followed in the PTOP until up to 60 weeks after the 
randomization of the last subject, provided that the subject’s consent for this limited 
participation in the study has not been withdrawn.
Subjects will be asked to return for an EOT visit preferably 1 day after last dose of study 
drug, but no later than 7 days after last dose of study drug. Subjects will be asked to 
attend FU visit (FU) 30 days after last dose of study drug. Subjects participating in the 


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lymphocyte subset sub-study will have an additional FU visit approximately 7 days after 
the last dose of study drug (FU7d). Then, subjects will attend 12-weekly visits as part of 
the PTOP until EOS. The assessments that are performed at each visit are described in the 
‘Abbreviated visit and assessment schedule for subjects who prematurely discontinued 
study treatment’ [Table 3].
A subject who prematurely discontinues study treatment and withdraws consent to 
participate in any further study assessments is considered as withdrawn from the study. 
Subjects who die or are lost to follow-up [see Section 9.2] are also considered as 
withdrawn from the study. Withdrawal from the study and follow-up medical care of 
subjects withdrawn from the study is described in Sections 9.2 and 9.4, respectively.
5.1.12 Study-specific criteria for interruption / premature discontinuation of study 
treatment
5.1.12.1 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 hour and is associated with symptoms 
of bradycardia (e.g., syncope, dizziness, or vertigo), or

QTcF > 500 ms is observed at any time throughout the study, as documented by 
12-lead ECG, or

the subject does not meet the criteria for discharge from cardiac monitoring on Day 1, 
or on the first day of re-initiation of study drug following drug interruptions after 
12 hours post-dose monitoring, or

the subject needs to receive systemic chronic treatment with -blockers, diltiazem, 
verapamil, digoxin, or any other anti-arrhythmic or
HR lowering therapy 
[non-exhaustive list of drugs provided in Appendix 3]. 
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 


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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.
5.1.12.2 Hematological abnormalities
Subjects must be permanently discontinued from study drug at any time throughout the 
study if one of the following occurs:

Confirmed total lymphocyte count decrease of > 50% from the value recorded at Visit 
5 (Week 4) associated with a total lymphocyte count < 0.5 109/L (< 500 cells/mm3) 
at 2 consecutive scheduled visits after Visit 5 (Week 4)

Confirmed total lymphocyte count 0.2 × 109/L (< 200 cells/mm3)
Confirmation will be done as follows:
Whenever one of the above conditions is met, an alert will be sent by the central 
laboratory to the principal investigator and the sponsor. The principal investigator will 
immediately contact the subject and ask her/him to return to the site either within 2 weeks 
if the total lymphocyte count is < 0.5 109/L but ≥ 0.2 109/L or within 48 hours at the 
latest if the total lymphocyte count is < 0.2 109/L 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 that one of the above conditions is met, then the 
study drug must be discontinued.
Lymphocyte counts must be monitored at least once a week by the central laboratory 
until the lymphocyte count has returned to ≥ 0.8 × 109/L or ≥ 80% of the value recorded 
at Visit 2 (Baseline). Any clinically relevant finding meeting the definition of an AE will 
be recorded accordingly in the eCRF.
5.1.12.3 General guidance for monitoring of subjects for opportunistic infections 
during treatment
Heightened vigilance is required for opportunistic infections caused by virus, fungi and 
bacteria. In the event of an opportunistic infection, the subject must permanently 


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discontinue the study drug and must be referred to an expert in infectious diseases for 
further examination and treatment. Early antiviral treatment will be considered.
Opportunistic infections caused by the reactivation of human herpes viruses (herpes 
simplex viruses, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus) may be 
primarily associated with neurological symptoms. The neurotropic herpes viruses (herpes 
simplex and varicella-zoster) are frequent human pathogens and their reactivation can 
cause serious infections of the CNS such as encephalitis and meningitis. The most 
frequent characteristics of these infections are an acute onset, associated with fever, 
headache, confusion, personality changes, and disorientation. Any suspicion of these 
infections must lead to immediate interruption of study drug treatment and to early 
initiation of antiviral treatment [Steiner 2007].
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].
The diagnostic workup and management of subjects with suspicion of opportunistic 
infection accompanied by CNS symptoms is described in Section 5.1.12.3.1.
5.1.12.3.1 Guidance for screening, exclusion and on-treatment monitoring of subjects for 
progressive multifocal leukoencephalopathy / other opportunistic CNS 
infections
Subjects with known 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, will not be eligible for the study. Subjects in whom suspicion of PML or 
other opportunistic CNS infections has been raised after randomization by new or 
worsening neurological symptoms combined with results of objective neurological exam 
or by MRI findings will have the study drug and DMF interrupted, and will be referred to 
the local MRI department to perform MRI as described in Section 7.2.3 which will be 
reviewed by the MRI safety board [see Section 3.8.3]. The suspicion of PML or other 
opportunistic CNS infections will be raised if the subjective and objective findings cannot 
readily be explained by the subject’s MS (e.g., a relapse) or another known condition 
(e.g., abnormal speech due to a dental intervention or limb weakness due to a trauma) not 
corresponding to exclusion criteria or if signs of PML / other opportunistic CNS infection 
are present on MRI. The additional diagnostic workup may include lumbar puncture for 
cerebrospinal fluid (CSF) analysis including test for JCV in CSF. If, based on the results 


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of the MRI safety board review, other diagnostic tests and clinical symptoms and signs,
the suspicion of PML or other opportunistic CNS infections can be ruled out, the 
investigator will consider re-start of the study drug if the risk/benefit is still considered 
positive for the subject and if criteria for permanent discontinuation of the study drug 
have not been met. NB: In subjects with suspicion of acute CNS infection, early lumbar 
puncture and antiviral treatment should be considered.
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 
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. People 
with autoimmune rheumatic diseases, especially systemic lupus erythematosus, are also 
at higher risk of PML [Kappos 2011].
As mentioned in Section 3.4.2, MS subjects treated with natalizumab are at increased risk 
of developing PML. In addition to natalizumab, cases of PML have been reported in 
subjects treated with various drugs, usually in combination with corticosteroids, including 
alkylating agents (e.g., cyclophosphamide, carmustine, and dacarbazine), purine 
analogues (e.g., fludarabine, cladribine, and azathioprine), immunosuppressants 
(e.g., cyclosporin, 
tacrolimus, 
sirolimus, 
and 
mycophenolate), 
and 
therapeutic 
monoclonal antibodies (e.g., rituximab, infliximab, etanercept, basiliximab, daclizumab, 
efalizumab, alemtuzumab, and muromonab-CD3) [Kappos 2011]. Sporadic cases of PML 
have occurred in patients treated with DMF [FDA 2015] and with fingolimod
[Gilenya USPI]. The diagnosis of PML is based on a combination of clinical, imaging 
and laboratory findings according to the consensus statement from the American 
Academy of Neurology published in 2013 [Berger 2013]. Among the common clinical 
findings are motor weakness, gait abnormalities, visual field deficits, speech and 
language disturbances, and incoordination. Sensory loss, seizures, headache, and diplopia 
occur less frequently. Although all these symptoms can be due to MS relapse, the time 
course often helps to distinguish PML from MS. While MS relapses tend to occur over 
hours to days, normally stabilize, and can resolve without treatment, PML tends to be 
progressive over days to weeks [Chalkley 2013].
In a retrospective study of MRI scans in 40 patients with MS treated with natalizumab 
and PML [Yousry 2012] the characteristic pattern of early PML lesions included:

Subcortical localization

MRI signal: T2- and DW-hyperintense and T1-hypointense lesions;

Lesion border: sharp toward the grey matter and ill-defined toward the white matter.


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In all but one patient the discrimination between new PML lesions and MS lesions could 
be done without problems.
The most useful laboratory finding for PML is demonstrating the presence of JCV in CSF 
using polymerase chain reaction (PCR). The sensitivity of the newer ultrasensitive 
techniques is 95% and the method is highly specific. However, a negative JCV PCR 
result should not exclude a possible diagnosis of PML.
Based on these three criteria (clinical, MRI and CSF), the diagnostic certainty of PML 
can be categorized into definite (all three criteria positive), probable (two out of three
criteria positive), possible (one out of three criteria positive) and not PML (all criteria 
negative). Subjects with probable PML should be managed as those with definite PML.
Case 1: At Visit 1 (Screening).
The subjects in whom the suspicion of PML / other opportunistic CNS infection has been 
raised by the investigator based on evidence of new neurological symptoms or MRI signs 
within 6 months prior to Visit 1 (Screening), which are compatible with a diagnosis of
PML infection, will have MRI performed as described in Section 7.2.3, and reviewed by 
the MRI safety board. Based on the relevant clinical findings, results of MRI review, and, 
if justified and indicated, CSF analyses, the investigator will determine the probability of 
PML. Only subjects in whom PML/other opportunistic CNS infection can be ruled out 
will be eligible for the study. Subjects with possible PML at Visit 1 (Screening) in whom 
this diagnosis has been later ruled out will be eligible for a single re-screening.
Case 2: Subject randomized in the study, coming to scheduled visits.
The subjects in whom the suspicion of PML/other opportunistic CNS infection has been 
raised by the investigator as described above, will have the study drug and DMF 
interrupted and will have MRI performed as described in Section 7.2.3, and the site can 
ask for a review of the MRI by the MRI safety board [see Section 3.8.3]. Further 
diagnostic workup (such as lumbar puncture for JCV) will be performed at investigator’s 
discretion. Based on the relevant clinical and nonclinical findings, including the MRI 
evaluation by the MRI safety board if applicable, the investigator will determine the 
probability of PML/other opportunistic CNS infection. Subjects in whom PML/other 
opportunistic CNS infection can be ruled out will be eligible for re-start of the study 
medication. Subjects with definite or probable PML or diagnosis of other opportunistic 
CNS infection will have the study drug and DMF permanently discontinued and will be 
managed according to the local practice (e.g., immune reconstitution and high dose 
corticoids). Subjects with possible PML/other opportunistic CNS infection will be 
observed off-study drug and assessed with repeated clinical, imaging and/or laboratory 
exams at the investigator’s discretion until the PML/other opportunistic CNS infection 


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has been ruled out or confirmed. The study drug may be re-started if PML / other 
opportunistic CNS infection has been ruled out at a later time point. 
Case 3: Subject randomized in the study, reporting new or worsening neurological 
symptoms outside the scheduled visits.
In case a subject contacts the investigator because of new or worsening neurological 
symptoms, the investigator should see the subject at an unscheduled visit as soon as 
possible and perform a full neurological exam in order to decide if the symptoms can be 
explained by a relapse or can be otherwise explained, or if suspicion of PML/other 
opportunistic CNS infection should be raised. If the findings indicate a relapse, the 
subject will be referred to the efficacy assessor for EDSS assessment. If the findings raise 
suspicion of PML/ other opportunistic CNS infection, the subject will have the study drug
and DMF interrupted and will have MRI performed as described in Section 7.2.3, and the 
site can ask for a review of the MRI by the MRI safety board. Further diagnostic workup 
(such as lumbar puncture for JCV) will be performed at investigator’s discretion. The 
further process will be the same as for Case 2 above. 
Case 4: MRI from a scheduled visit shows findings not typical for MS.
In case the MRI at a scheduled visit shows signs atypical for MS, detected by the 
neuroradiologist or during the central review by the MIAC, the site and the sponsor will 
be alerted and the site can ask for a review of the MRI by the MRI safety board. The 
subject will be invited for an unscheduled visit at which the investigator will interview 
the subject for neurological signs and symptoms and perform a full neurological exam. In 
the event of suspicion of PML, the study drug will be interrupted. Based on the full 
evaluation of the subject, relevant clinical findings and results of any additional 
investigations, such as lumbar puncture for JCV, the investigator will determine the 
probability of PML/other opportunistic CNS infection. Subjects in whom PML/other 
opportunistic CNS infection can be ruled out will be eligible for re-start of the study 
medication. Subjects with definite or probable PML or diagnosis of other opportunistic 
CNS infection will have the study drug and DMF permanently discontinued and will be 
managed according to the local practice (e.g., immune reconstitution and high dose 
corticoids). Subjects with possible PML/other opportunistic CNS infection will be 
observed off-study drug and assessed with repeated clinical, imaging and/or laboratory 
exams at the investigator’s discretion until the PML/other opportunistic CNS infection 
has been ruled out or confirmed. The study drug may be re-started if PML / other 
opportunistic CNS infection has been ruled out at a later time point.


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5.1.12.4 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 capacity; 
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 
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 2 agonist 
(to be used on an ‘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 


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(e.g., high-resolution computerized tomography, diffusing capacity for the lungs 
measured using carbon monoxide [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.
5.1.12.5 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.
5.1.12.6 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. 
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 
hours, 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
Permanently discontinue study drug, and 
perform FU.


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Item
Laboratory parameter
Guidance
ALT or AST ≥3 × ULN and TBL ≥2 × ULN or 
INR 1.5
ALT or AST ≥3 × ULN with the appearance of 
fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or 
eosinophilia (5%)
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 
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 study treatment 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.
5.1.12.7 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. Any clinically 
relevant finding meeting the definition of an AE will be recorded accordingly in the 


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eCRF. The OSB will receive all information related to suspected cases of macular edema 
and will perform central review of OCT results and subject data.
Subjects with active uveitis but without macular edema may continue on the study drug 
but will require additional ophthalmologic assessments as detailed below.
5.1.12.7.1 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 Visit 1 (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.
5.1.12.8 Discontinuation of DMF background therapy
Subjects who permanently discontinue DMF background therapy must permanently 
discontinue study treatment and may begin treatment with an approved MS therapy in 
accordance to local practices.
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).


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A study-concomitant therapy is any therapy which is ongoing or initiated after signing of 
informed consent, and initiated before EOS visit. All study-concomitant therapies must 
be captured in the eCRF [see Section 5.2.2.1]. 
Study concomitant therapies include study treatment-concomitant therapies, which is any 
therapy either ongoing at the start of study treatment or 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
5.2.2.1
Study-concomitant therapies
The use of all study-concomitant therapy (including traditional and alternative medicines, 
i.e., plant-, animal-, or mineral-based medicines; see definition in Section 5.2.1) will be 
recorded in the Concomitant Medications form of the eCRF. Contraceptives will be 
recorded in a specific Contraceptive Methods form of the eCRF. The generic name, 
start/end dates of administration (as well as whether it was ongoing at start of treatment 
and/or EOS), route, dose, frequency, and indication will be recorded in the corresponding 
forms of the eCRF. DMF intake (i.e., the background concomitant therapy) will be 
recorded on a specific log of the eCRF [see Section 5.2.2.3]). 
5.2.2.2
Previous MS therapies
Any previous administration of disease-modifying treatment for MS (e.g., IFN β-1a 
[Rebif® - Avonex®, Plegridy®], IFN β-1b [Betaferon®, Extavia®], glatiramer acetate 
[Copaxone®, Glatopa®], natalizumab [Tysabri®], teriflunomide [Aubagio®], mitoxantrone 
[Novantrone®], alemtuzumab [Lemtrada®], daclizumab [Zynbryta®], ocrelizumab 
[Ocrevus®], cladribine [Mavenclad®]), at any time prior to Visit 1 (Screening) will be 
recorded in the previous MS treatment form of the eCRF [see Section 1.1.4]. For 
treatments received in the last 24 months prior to the study, start date, end date and 
reason for discontinuation will be recorded in the eCRF. In addition, dose, route, and 
frequency should be recorded in the eCRF, if available. For treatments stopped before the 
last 24 months prior to the study, start date, end date, and reason for discontinuation may 
be reported only if known and evidenced in the source documents. 
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.


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5.2.2.3
Other previous therapies
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 Medications form of the eCRF.
5.2.3
Concomitant background therapy
In order to be eligible for this study, subjects must have been treated with DMF
(Tecfidera®) for at least 6 months prior to Visit 1 (Screening). Subjects should be treated 
with DMF as per prescribing information [Tecfidera USPI, Tecfidera SmPC] throughout 
the course of the study [see Section 3.5.2.1].
Any previous administration including, if applicable, the last initiation of DMF
(Tecfidera®) prior to Visit 1 (Screening) as well as intake (start date, end date, dose 
change, and reason for interruption and/or discontinuation) during the study must be 
recorded in the DMF-specific log of the eCRF. 
5.2.4
Recommended concomitant therapy
Treatment of relapses:

If a relapse requires treatment with corticosteroids, methylprednisolone 1 g i.v., oral 
methylprednisolone in the dose range of 1 g to 1.25 g or equivalent doses of oral 
prednisone or prednisolone daily for 3 to 5 days is recommended (without an oral 
taper). These administrations will be reported in the eCRF. Treatment with other 
corticosteroids, another dose, other routes of administration, or ACTH is not 
recommended unless deemed necessary and must be documented in the patient charts 
by the investigator.

Treatment of relapses with plasma exchange (i.e., plasmapheresis, cytapheresis) is 
prohibited. The effect of plasmapheresis on relapse recovery is not sufficiently well 
documented to justify its inclusion as part of the protocol. Allowing plasmapheresis 
as per investigator discretion would lead to inhomogeneous treatment of relapses 
which could affect the study outcome in an unpredictable direction.
5.2.5
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;


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
Short-acting 2-agonists for respiratory symptoms and/or reduced pulmonary 
function during study treatment (please refer to Sections 5.1.12.4 and 7.3.3 for 
guidance);

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 4);

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 will be analyzed at the end of the study;

Low dose of corticosteroids (up to 10 mg of prednisone equivalent daily), given as 
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 whole study duration) 

Inhaled corticosteroids for pulmonary conditions;

Other treatments considered necessary for the subject’s benefit and not categorized as 
prohibited concomitant medications.
5.2.6
Forbidden concomitant therapy
The below list of forbidden concomitant therapies is applicable to all subjects receiving 
study treatment, but not to the subjects who prematurely discontinued study treatment 
and participate in the PTOP.

Systemic corticosteroids and ACTH, except for: the treatment of MS relapses [see 
Section 5.2.4]; short-term treatment with a low dose of corticosteroid; and inhaled 
corticosteroids for pulmonary conditions [see Section 5.2.5];

Disease-modifying drugs for MS other than prescribed as per protocol (e.g., IFN , 
glatiramer acetate, fingolimod, teriflunomide, natalizumab or other monoclonal 
antibody therapy);

Immunosuppressive treatment (e.g., cladribine, mitoxantrone or other systemic 
immunosuppressive 
treatments 
such 
as 
azathioprine, 
cyclophosphamide, 
cyclosporine, methotrexate, or leflunomide);

Intravenous immunoglobulin;

Plasmapheresis, cytapheresis, or total lymphoid irradiation;

Vaccination with live vaccines;

-blockers, diltiazem, verapamil, digoxin, or any other anti-arrhythmic or HR
lowering systemic therapy [non-exhaustive list of drugs provided in Appendix 3];

Any other investigational drug; 


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
Any investigational therapeutic procedure for MS (e.g., stent placement or 
angioplasty for chronic cerebrospinal venous insufficiency (CCSVI), 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
6.1
Efficacy endpoints
For each of the study efficacy endpoints, baseline is defined as the last value recorded 
prior to randomization (the actual visit used as baseline might be different across 
endpoints).
6.1.1
Primary efficacy endpoint
The primary endpoint is ARR. This endpoint is defined as the number of confirmed 
relapses from randomization up to EOS, 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 hours, in 
the absence of fever or infection. 

The new, worsening or recurrent neurological symptoms are to be evaluated by the 
treating neurologist and, if all the elements of the above definition have been verified,
in the absence of another, better explanation of the subject’s symptoms, the event is 
considered 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 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 point; unless EDSS = 0, then an increase of 
at least 1.0 point 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).


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6.1.2
Secondary efficacy endpoints
There are five secondary efficacy endpoints, which will be analyzed in a hierarchical 
manner: 

Time to 12-week CDA from baseline up 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,
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 during pre-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, for the purpose of confirmation, only EDSS measured more than 30 days after 
the onset of a confirmed relapse will be used. This is to avoid a confirmation of disability 
accumulation caused by a relapse. In order to confirm that the EDSS increase is 
persistent, all EDSS measurements between the onset and the 12-week EDSS 
confirmation (minus visit time-window) need to show an increase in EDSS, meeting the 
criteria for accumulation of disability as defined above.

Time to first confirmed relapse up to EOS.
Definition: 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.

Mean number of combined unique active lesions (CUALs) per subject per
post-baseline MRI scan up to EOS.
Definition: CUALs are new GdT1 lesions plus new or enlarging T2 lesions (without 
double-counting of lesions).


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
Longitudinal change over time in fatigue-related symptoms as measured by the 
symptoms domain of the FSIQ–RMS from baseline up to EOS.

Longitudinal percent change over time in brain volume from baseline up to EOS.
Definition: Longitudinal brain volume measurements are derived from MRI scans by 
using Structural Image Evaluation, using Normalisation, of Atrophy methodology 
(SIENA) [Smith 2001, Smith 2002].
6.1.3
Other efficacy endpoints
MRI-based exploratory endpoints:

Percent change in brain volume (PCBV) from baseline to Weeks 48, 96, 144, EOT,
and EOS;

Mean number of CUALs per subject per scan from baseline up to Weeks 48, 96, 144, 
EOT, and EOS;

Mean number of Gd+T1 lesions per subject per scan from baseline up to Weeks 48, 
96, 144, EOT, and EOS;

Mean number of new or enlarging T2 lesions per subject per scan from baseline to
Weeks 48, 96,144, EOT and EOS;

Change in the volume of MRI lesions (T2 lesions, T1 hypointense lesions) from 
baseline to Weeks 48, 96, 144, EOT, and EOS;

Absence of MRI lesions (Gd+ T1 lesions, new or enlarging T2 lesions, new T1 
hypointense lesions) from baseline to Weeks 48, 96, 144, EOT, and EOS.
Clinical exploratory endpoints (disease activity, relapses, disability progression):

Absence of confirmed relapses from baseline up to EOS;

Time to first 24-week CDA from baseline up 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, 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 during pre-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. 


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However, for the purpose of confirmation, only EDSS measured more than 30 days after 
the onset of a confirmed relapse will be used. This is to avoid a confirmation of disability 
accumulation caused by a relapse. In order to confirm that the EDSS increase is 
persistent, all EDSS measurements between the onset and the 24-week EDSS 
confirmation (minus visit time-window) need to show an increase in EDSS, meeting the 
criteria for accumulation of disability as defined above.

Change in EDSS from baseline by visit up to EOS;

No evidence of disease activity (NEDA) status at EOS (defined by the absence of 
confirmed relapse, Gd+ T1 lesions, new or enlarging T2 lesions, 12-week CDA, as 
well as absence of annual brain volume decrease ≥ 0.4% from baseline to EOS and 
completing treatment as planned).
Other clinical exploratory endpoints:

Change in MSFC Z-score from baseline by visit up to EOS;

Change in the SDMT score from baseline by visit up to EOS;

Change from baseline by visit up to EOS in fatigue-related impacts as measured by 
the impact sub-scales of the FSIQ–RMS.
6.2
Safety endpoints
The treatment-emergent period is defined as the time from first study drug intake up to 
30 days (inclusive) after last study drug intake. The following safety endpoints will be 
analyzed:

Treatment-emergent AEs, SAEs, AEs of special interest#, MACE, and 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, QT corrected for HR on the 
basis of Bazett’s formula [QTcB], Fridericia’s formula [QTcF]) from pre-dose to 
selected post-dose assessments (1 h, 2 h, 3 h, 4 h) on Day 1 and on day of re-initiation 
of study treatment when post-dose monitoring is required;

Notable abnormalities* for selected 12-lead ECG variables (HR, PR, QT, QTc) at 
3-hour post-dose assessment on Day 1, Week 12 and at the re-initiation of study 
treatment when post-dose monitoring is required;

Treatment-emergent decrease of FEV1 or FVC > 20% from baseline values or 
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 
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
Change from baseline to EOS versus 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 post EOT follow-up;

Treatment-emergent notable blood pressure 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;

Change in JCV serology from baseline up to EOS.
# The selection of AEs of special interest is based on the anticipated risks of treatment with ponesimod and 
on the events that may be related to MS co-morbidities (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 as described in Appendix 6; the final list of abnormalities 
will be defined in the SAP.
6.3
Quality of life endpoints

Change from baseline by visit up to EOT in SF-36v2™ Health Survey domain and 
component scores.
6.4
Pharmacoeconomic endpoints

Change from baseline by visit up to EOT in WPAI:MS scores.

Health care resource utilization from baseline by visit up to EOT on-treatment visit
(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 evaluations

Plasma concentrations of ponesimod pre-dose at Week 12, Week 24, Week 48, 
Week 96, Week 144, EOT and FU, and 3 hours post-dose on Day 1 and at Week 12.
6.5.2
Pharmacodynamic evaluations

Absolute and percent change in peripheral blood lymphocyte counts pre-dose by visit 
up to EOS.

Absolute and percent changes in lymphocytes subsets by visit up to EOS [sub-study; 
see Section 3.6.1].


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6.5.3
PK/PD relationship

Correlation of selected efficacy and safety variables with absolute lymphocyte counts 
and magnitude of reduction of lymphocyte counts may be analyzed.
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).

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 7.3.3].

ECG recorder.

BP monitoring device.

MRI; in addition, prior to the start of the study, each MRI site must be qualified by 
the MIAC [see Section 7.2.3].
7.1
Screening/baseline assessments
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 (e.g., CXR 
[see Section 7.3.4]). 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 


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is the responsibility of the principal investigator / treating neurologist to explain the study 
in all its aspects to the subject and obtain her/his informed consent. The informed consent 
process will be documented in the investigator site file. The oral and written information 
about the trial, as well as the ICF, will be provided in a language that is fully 
understandable to the subject.
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.
In order to ensure subjects are made aware of potential risks and benefits of continuing in 
the study as well as alternative treatment options available, subjects who continue study 
treatment and DMF background therapy upon experiencing a confirmed relapse or a 
24-week CDA while on study drug will be asked to re-consent to continue receiving 
study treatment.
7.1.2
Baseline demographics and disease characteristics
Baseline demographics (sex, age, race, ethnicity, body weight, height, and childbearing 
potential [if applicable]) 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 their respective forms (i.e., Concomitant Medications form or 
Contraceptive Methods form) 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 [see Section 5.2.2.1].
7.1.4
Previous MS therapies
Any previous administration of disease-modifying treatment for MS (e.g., IFN β-1a 
[Rebif® - Avonex®, Plegridy®], IFN β-1b [Betaseron®, Betaferon®, Extavia®], glatiramer 
acetate [Copaxone®, Glatopa®], natalizumab [Tysabri®], teriflunomide [Aubagio®],
fingolimod [Gilenya®],
mitoxantrone [Novantrone®], alemtuzumab [Lemtrada®], 
daclizumab [Zynbryta®], ocrelizumab [Ocrevus®], cladribine [Mavenclad®]), at any time 
prior to Visit 1 (Screening) will be recorded in the previous MS treatment form of the 
eCRF [see Sections 1.1.4 and 5.2.2.2].


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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 Visit 1 (Screening), Visit 2 (Baseline), 
Visit 6 (Week 12) and every 12 weeks thereafter until Visit 18 (EOT), Visit 20 (FU), 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 18A).
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 3.7.3].
The efficacy assessor must not consult prior EDSS/FS scores when performing the 
current EDSS/FS assessment. In no case will the treating neurologist alter the EDSS/FS 
score obtained by the efficacy assessor. The examination will be based on the modified 
neurological examination ‘Neurostatus’ [Appendix 1] using the corresponding scoring 
documents. The EDSS/FS scoring will be recorded in the eCRF. NB: Fatigue, which is 
an optional part of the ‘Neurostatus’ assessment will not contribute to the Cerebral FS 
score. 
7.2.2
Detection and evaluation of relapses
Detection and evaluation of relapses will be done as follows [see Figure 3]:
Step 1: At every study visit, subjects are reminded to contact their principal investigator / 
treating neurologist immediately in the event of the appearance of any new or worsening
neurological symptoms. In addition, the site will contact the subject 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, 102, 114, 126, 138 and 150 (± 7 days), or 6 weeks 
after the last 12-weekly visit (± 7 days).


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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 telephone 
questionnaire for relapse assessment [see Appendix 12]. 
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., spirometry, liver enzymes), the 
principal investigator / treating neurologist will interview and examine the subject to 
determine whether or not a relapse may have occurred since last visit using a dedicated 
relapse assessment questionnaire [see Appendix 12] and the relapse symptom form [see 
Appendix 13].
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, in the absence of another, better 
explanation of the subject’s symptoms). If so, 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 after 
the onset of new or worsening neurological symptom(s) [see Section 7.2.1]. Important 
note: EDSS and FS assessments will be performed only by the efficacy assessor. The 
efficacy assessor must not consult prior EDSS/FS scores when performing the current 
EDSS/FS assessment. In no case will the treating neurologist alter the EDSS/FS score 
obtained by the efficacy assessor. If the relapse requires treatment with corticosteroids 
[see Section 5.2.4], 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., 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 


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neurologist will decide if the relapse is confirmed or not, according to the protocol 
definition of confirmed relapse [see Section 6.1.1]. After the occurrence of each 
confirmed relapse, subjects will be asked to re-consent to continue receiving study 
treatment [see Section 13.3].
Once step 1 of the relapse detection has been initiated (whether by subject calling the site, 
by interview of the subject at scheduled visit, or by scheduled calls from the site to the 
subject), the final result of the relapse detection and confirmation process will be 
captured as one of the following three outcomes: no relapse, unconfirmed relapse, or 
confirmed relapse. New or worsened neurological symptoms reported by the subject and 
for which there is another better explanation for the subject’s current symptoms than an 
MS relapse will be captured on an AE page.
All MS relapses, whether or not confirmed, must be reported on specific relapse pages of 
the eCRF. MS relapses and associated symptoms are not to be entered on the AE page of 
the eCRF with the following exceptions:

MS relapses with fatal outcome (these must always be recorded as an AE on the AE 
page in addition to being reported as SAEs).

MS relapses that, in the view of the investigator, warrant specific notice due to 
unusual frequency, severity or remarkable clinical manifestations (these should be 
reported as an AE on the AE page of the eCRF and, if applicable, on the SAE form).


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Figure 3
Flow diagram for the detection and evaluation of relapses


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7.2.3
MRI evaluations
MRI scans will be performed at Visit 2 (Baseline), Visit 7 (Week 24), Visit 9 (Week 48)
and every 24 weeks thereafter up to Visit 17 (Week 144) and at Visit 18 (EOT). In 
addition, MRI scans may be performed at any unscheduled visit (U1, U2, etc.) if deemed 
necessary for the subject safety. If applicable, MRI scans will also be performed at the 
corresponding 24 weekly visits in the PTOP. In case of premature study treatment 
discontinuation, the MRI at EOT does not need to be performed if the EOT visit occurs 
within 4 weeks after the latest scheduled MRI assessment.
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.
Fluid-attenuated inversion recovery (FLAIR), diffusion-weighted imaging (DWI), 
T1-weighted imaging before and after i.v. administration of 0.1 mmol/kg body weight 
(= 0.2 mL/kg) of Gd as well as T2-weighted imaging will be performed. Gd may cause 
nausea and vomiting and in very rare cases allergic reactions that could require 
immediate anti-anaphylactic therapy (such as steroids, epinephrine/adrenaline, etc.). Gd 
administration may be omitted if medically contraindicated.
MRI data will be analyzed by the MIAC, c/o University Hospital Basel, Switzerland for 
MRI efficacy outcomes (i.e., T1-weighted images before and after Gd administration, and 
T2-weighted images). All FLAIR and DWI MRI scans will be exported to the MIAC. 
The MIAC will only analyze the images selected by the local radiologist or neurologist 
with MRI expertise upon notification for review by the site (i.e., in the event of a 
suspected opportunistic infection) [see Section 3.8.3]. 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 the 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).


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Lesion counts of MRIs 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, except 
when the MIAC’s opinion is needed for T2-based eligibility criterion (i.e., when the 
inclusion criterion 6 is fulfilled only by potential presence of at least one new or one 
unequivocally enlarging T2 lesion based on historical MRI scans). 
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 radiologist or 
neurologist with MRI expertise. 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 the safety of the subject. Study participants with clinically relevant findings 
on MRI will be followed up until establishing the final diagnosis and managed as per 
local medical practice. Other diagnostic procedures may be performed as a FU 
assessment according to local standard procedures when considered necessary by the 
investigator. Incidental clinically relevant findings on MRI will be reported in the 
Medical History or as AE, as applicable.
7.2.4
Multiple Sclerosis Functional Composite score
The MSFC score consists of three 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 (see details below) and at Visit 6 (Week 12), 
Visit 7 (Week 24), Visit 9 (Week 48), and every 24 weeks thereafter until Visit 17
(Week 144), and at Visit 18 (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 practice test ≥5 days from first practice test and third test 
serving as baseline ≥5 days from second practice test). The first practice test may be 
done at Visit 1 (Screening), the second practice test may be done at Visit 2 (Baseline) and 
the third test, serving as baseline, may be performed pre-dose at Visit 3 (Randomization).
The MSFC results will be entered by the rater on a specific form which will serve as a 
source document and the relevant data will be transferred by the site to the eCRF.


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MSFC will be administered in combination with the SDMT [see Section 7.2.5] in the 
following sequence:
1. Timed 25-Foot Walk (7.62 meter) 
2. 9-HPT
3. PASAT
4. SDMT
A full description of the administration of the scale, sequence of tests and scoring will be 
given in a separate document provided to each site. The test 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.
7.2.5
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 (see 
details below) and at Visit 6 (Week 12), Visit 7 (Week 24), Visit 9 (Week 48), and every 
24 weeks thereafter until Visit 17 (Week 144), and at Visit 18 (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 practice test ≥5 days from first practice test and third test 
serving as baseline ≥5 days from second practice test). The first practice test may be 
done at Visit 1 (Screening), the second practice test 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.


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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.
7.2.6
Fatigue Symptom and Impacts Questionnaire-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:

The FSIQ-RMS symptom domain (FSIQ-RMS-S) consists of seven items 
assessing fatigue-related symptoms with a recall period of 24 hours measured on 
an 11-point numeric rating scale; the symptom domain score ranges from 0 to 
70 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 impacts 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 scale, ranging from no impact to extreme impact; the impacts domain 
score ranges from 0 to 52 with a higher score indicating greater impact. As the 
impacts 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., 7th day) of completion 
of section 1.
FSIQ-RMS will be completed during the pre-randomization period, at Visit 6 (Week 12), 
Visit 7 (Week 24), Visit 9 (Week 48), and every 24 weeks thereafter until Visit 18
(EOT), Visit 20 (FU), 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 being 
received) will be provided with 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 7th day, the subject will also complete the impacts


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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 symptom 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). On the 
7th day, the subject will also complete the impacts domain of the FSIQ-RMS (i.e., section 
2 of the questionnaire). Subjects will return the completed FSIQ-RMS diary at the next 
scheduled visit. If applicable, the FSIQ-RMS will also be completed at home prior to 
Visit 20 (FU) and Visit 18A (Week 156), ideally during the 7 consecutive days preceding 
these visits.
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. 
7.3
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 minutes. 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 is required, the pre-dose and 
post-dose ECGs required for evaluation of discharge criteria will be transmitted to the 
central ECG laboratory for expedited evaluation, and the ECG report will be returned to 
the site within approximately 1–2 hours from transmittal. 


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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 is
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 
Sections 3.7.2 and 3.7.4]. 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 subjects, do not have access to post-dose ECGs at Visit 3 (Day 1) 
and at visits for re-initiation of study drug when post-dose monitoring is required 
(Visits I1, I2, etc.; see Section 8.4.2). 
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 (Day 1), the pre-dose ECG must be performed prior to randomization and the 
applicable point from exclusion criterion #12 (e.g., HR < 50 bpm, presence of 
second-degree AV block or third degree AV block, or a QTcF interval > 470 ms 
[females], > 450 ms [males]; see Section 4.4) must be ruled out. 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. 
During the treatment period ECGs must be performed at pre-dose. Additionally, at Visit 6 
(Week 12), an ECG must also be performed at 3 hours post-dose. In case concomitant 
treatment with a QT-prolonging drug with known risk of Torsades de Pointes is needed, 
additional ECGs will be performed according to the guidance provided in Appendix 4.
At Visit 3 (Day 1) and on the day of re-initiation of study drug when post-dose 
monitoring is required [see Section 5.1.9], ECGs must be performed at pre-dose, and 
hourly (± 15 minutes) thereafter for a minimum of 4 hours and up to 12 hours post-dose. 
Subjects may be discharged from the cardiac monitoring if they meet the discharge 
criteria before 12 hours post-dose but no sooner than the (report of) ECG at 4 hours post-
dose has been evaluated by the first-dose administrator [see Section 5.1.10]. If the subject 
does not meet the defined discharge criteria at 12 hours post-dose, the subject will be 
permanently discontinued from the study 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 5.1.10), or until 
medically indicated.


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At Visit 3 (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 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 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
Blood pressure measurements, including SBP and DBP, 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 Visit 3 (Day 1), the pre-dose BP 
measurement must be performed prior to randomization. At Visit 3 (Day 1) and on days 
of re-initiation of study drug when post-dose monitoring is required [see Section 5.1.9], 
SBP and DBP will be measured at pre-dose and hourly (± 15 minutes) thereafter for a 
minimum of 4 hours and up to 12 hours post-dose. Subjects may be discharged from 
cardiac monitoring if they meet the discharge criteria before 12 hours post-dose but no 
sooner than 4 hours post-dose [see Section 5.1.10]. If the subject does not meet the 
defined discharge criteria at 12 hours post-dose, the subject will be permanently 
discontinued from the study 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 5.1.10), or until medically indicated.
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 minutes. 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 be 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 days of re-initiation of study 
drug when post-dose monitoring is required. 


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At Visit 3 (Day 1) and at visits for re-initiation of study drug when post-dose monitoring 
is 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 Sections 3.7.2 and 3.7.4]. 
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 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 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.
7.3.3
Spirometry
Spirometry tests to assess pulmonary function will be performed at Visit 2 (Baseline), 
Visit 6 (Week 12), Visit 9 (Week 48) and every 48 weeks thereafter until Visit 17
(Week 144), Visit 18 (EOT), Visit 20 (FU), and at unscheduled visits (U1, U2, etc.) if 
clinically indicated. If applicable, spirometry tests will also be performed at the 
corresponding visits in the PTOP. In addition, unscheduled spirometry will have to be 
conducted in the event of persistent respiratory symptoms (e.g., dyspnea).
Prior to randomization, spirometry can be performed at Visit 2 (Baseline) or at any time 
during the pre-randomization period. It is highly recommended that all spirometry 
assessments are performed in the morning, and prior to study drug intake.
Subjects must refrain from taking short-acting beta-agonists (e.g., salbutamol) for 6 hours 
and long-acting beta-agonists for 24 hours prior to spirometry testing. If taken, the test 
should be rescheduled. To perform the spirometry test, subjects will be rested for a 
minimum of 5 minutes prior to start. 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 American Thoracic Society (ATS) /
European Respiratory Society (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.


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Spirometry testing will consist of FVC and FEV1 assessments. 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 assessed at each 
timepoint: FEV1; FVC; and the peak expiratory flow (PEF). An anonymized copy of 
these results, including all tracings (i.e., all flow volume curves, volume time curves (if 
available) and numeric values from every performed effort as additional parameters and 
quality check documents routinely collected by the PFTs site (i.e., calibration results and 
log) may be collected by the sponsor for quality control purposes.
The best (largest) FEV1, FVC and PEF values from the three acceptable and repeatable 
tests will be recorded in the eCRF as absolute volume in liters and as flow in liters/second 
(rounded to two decimal places). These values may come from separate maneuvers. The 
FEV1/FVC ratio will be derived from the FVC and FEV1 values recorded in the eCRF.
Spirometry tests will be conducted according to the ATS/ERS guidelines [Miller 2005a, 
Miller 2005b]. 
The 
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 testing laboratory will 
ensure that the spirometer is functioning properly and is calibrated according to 
manufacturer instruction and ATS/ERS guidelines. A copy of the calibrations from 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. For each test, the name of the tester must be stored as 
source documents in the patient charts. 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 study will be trained on the 
specific requirements for the study and be reminded of 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. 
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.


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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.
7.3.4
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 Visit 1 (Screening) can be used; if available, there is no need to repeat 
CXR at Visit 1 (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 Visit 18 (EOT) 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 48 weeks of 
the pre-randomization CXR. All examinations will be documented in the source 
documents of the subject. 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. 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. 
7.3.5
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 7.3.13], and transferred to the eCRF database. 
Only subjects with a negative test at Visit 1 (Screening) and without CXR findings [see 
Section 7.3.4] at Visit 1 (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 


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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.
7.3.6
Ophthalmologic assessments
Ophthalmologic assessments will be performed by an ophthalmologist at Visit 1 
(Screening), Visit 6 (Week 12), Visit 7 (Week 24), Visit 9 (Week 48), and every 
48 weeks thereafter until Visit 17 (Week 144), Visit 18 (EOT), Visit 20 (FU) and at 
unscheduled visits. 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.
Testing at Visit 1 (Screening) can be performed at any time during the pre-randomization 
period. At Visit 18 (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, an 
unscheduled ophthalmological examination will be done in the event of visual symptoms 
or findings suggestive of active uveitis [see Section 5.1.12.7]. 
The safety ophthalmological assessment includes previous eye history and ophthalmic 
conditions, 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.
In cases where pupil dilatation is medically contraindicated then dilated funduscopy can 
be replaced by funduscopy with ultra widefield imaging. Additionally, the safety 
ophthalmological assessment will include FA in case of suspicion of active uveitis at 
Visit 1 (Screening) or during a scheduled ophthalmological assessment (unless 
contra-indicated according to the ophthalmologist) [see Section 5.1.12.7]. While the 
visual acuity and ocular pressure measurement themselves may be performed by a 
delegate (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. FA (if applicable) 
may be performed by a delegate (e.g., technician, optometrician) but always in the 
presence of the ophthalmologist who will review and interpret the results. 
All ophthalmological examinations will be documented in the source documents of the 
subject. All variables 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 variable, it should be specified on the corresponding eCRF page. Clinically 


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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.
7.3.7
Optical coherence tomography
OCT will be assessed at Visit 2 (Baseline), Visit 6 (Week 12), Visit 7 (Week 24), Visit 9 
(Week 48), and every 48 weeks until Visit 17 (Week 144), and at Visit 18 (EOT). OCT 
may also be performed at unscheduled visits (U1, U2, U3, etc.). Testing at Visit 2
(Baseline) can be performed at any time during the pre-randomization period. 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.
At Visit 18 (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 
examinations 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 5.1.12.7]. While the OCT exam 
may be performed by a delegate (e.g., technician, optometrician), the review and 
interpretation must be performed by the ophthalmologist. 
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 10.1.1], 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.
7.3.8
Weight and height
Body weight will be measured at Visit 1 (Screening), Visit 2 (Baseline), Visit 9 
(Week 48), and every 48 weeks until Visit 17 (Week 144), and at Visit 18 (EOT). Height 
is only measured at Visit 1 (Screening). Data will be collected in the eCRF.
7.3.9
Physical examination
Physical examination is performed by the principal investigator or treating neurologist at 
Visit 1 (Screening), Visit 2 (Baseline), Visit 7 (Week 24), and every 24 weeks thereafter 
until Visit 17 (Week 144), at Visit 18 (EOT), and at unscheduled visits due to relapses 


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(R1, R2, etc.). If applicable, physical examination will also be performed at 
corresponding visits 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.
7.3.10 Body temperature
Body temperature will be measured at all scheduled study visits. Body temperature will 
also be measured at unscheduled visits for relapses (Visits R1, R2, etc.). In addition, 
unscheduled body temperature measurements may be performed at any time during the 
study (Visits U1, U2, etc.).
All body temperature assessments will be documented in the source documents of the 
subject. All body temperature assessments 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.
7.3.11 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, 


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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 on any of the assessed variables, 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.
7.3.12 Dermatological examination
A complete skin examination will be performed by a dermatologist at Visit 2 (Baseline), 
Visit 9 (Week 48), and every 48 weeks thereafter until Visit 17 (Week 144), and at 
Visit 18 (EOT). If applicable, dermatological examination will also be performed at 
corresponding visits 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 unless the screen failure was due to a skin 
lesion. If the screen failure was due to a pre-cancerous skin lesion or basocellular 
carcinoma that was then completely excised, the subject may be re-screened, in which 
case a new dermatological examination with focus on the excised skin lesion(s) has to be 
performed during pre-randomization. 
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.


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7.3.13 Laboratory assessments
7.3.13.1 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., if the subject lives far from the site and cannot return 
every 4 weeks (± 3 days) for the lymphocyte count assessments), laboratory samples may 
be collected at a laboratory close to where the subject lives (satellite laboratory), and sent 
to the central laboratory for analysis. In such a case, the satellite laboratory must be 
provided with the central laboratory sampling 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.
In exceptional cases (e.g., subject is hospitalized in a different hospital from the study 
center due to a medical emergency, or missing central laboratory values) local laboratory 
results (with the corresponding normal ranges) will be entered into the clinical database 
via dedicated CRF pages. 
If a central laboratory sample is lost or cannot be analyzed for whatever reason, the 
investigator may collect an additional sample as soon as possible for retest analysis, 
unless a local laboratory sample was collected within the same time-window and these 
test results are available.
The central laboratory will provide all laboratory results by fax or email to the site with 
the exception of the results of the total WBC count and total lymphocyte count. The
lymphocyte count results obtained during treatment period will be communicated to the 
site only if 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 / treating neurologist and the sponsor [see Section 5.1.12.2].

A WBC count > 20 109/L or a lymphocyte count > 8.0 109/L is recorded by the 
central laboratory. In this event, an alert containing the total WBC or lymphocyte 
count result (as applicable) will be sent to the principal investigator / treating 
neurologist and the sponsor.

A total lymphocyte count decrease of > 50% from the value recorded at Visit 5 
(Week 4) associated with a total lymphocyte count < 0.5 109/L (< 500 cells/mm3) is 


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recorded at 2 consecutive scheduled visits after Visit 5 (Week 4). In this event, an 
alert containing the lymphocyte count result will be sent to the principal investigator / 
treating neurologist and the sponsor.

A total lymphocyte count < 0.5 × 109/L is observed at FU. In this event, an alert 
containing the total lymphocyte count result will be sent to the principal investigator / 
treating neurologist. Discontinuation of DMF treatment should be considered in 
accordance with prescribing information [Tecfidera USPI, Tecfidera SmPC].

WBC and total lymphocyte counts measured at any of the visits in the PTOP. For 
subjects who have entered the PTOP following study drug discontinuation, 
lymphocyte count values recorded after entering the PTOP will be visible to the 
principal investigator / 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 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.
7.3.13.2 Laboratory tests
When applicable, blood samples will be drawn before the morning administration of 
study medication at Visit 1 (Screening), Visit 2 (Baseline), Visit 4 (Week 2), Visit 5 
(Week 4), Visit 6 (Week 12) and every 12 weeks thereafter up to Visit 18 (EOT), and at 
Visit 20 (FU) and, if applicable, at all corresponding visits in the PTOP (see anticipated 
total blood volume in Table 7). Unscheduled laboratory tests may be performed at any 
time during the study (Visits U1, U2, U3, etc.).
Additional lymphocyte count measurements will be performed every 4 weeks (± 3 days) 
up to Week 24. 
During the pre-randomization period, hematology and clinical chemistry laboratory 
assessments at Visit 1 (Screening) must be performed a minimum of 21 days before the 
laboratory assessment at Visit 2 (Baseline).
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.


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Hematology

RBC count

Total and differential WBC counts (basophils, eosinophils, lymphocytes, monocytes, 
neutrophils, band forms)

Platelet count

Hb

Hematocrit
Clinical chemistry

Glucose

ALT, AST, alkaline phosphatase (AP), total bilirubin, lactate dehydrogenase

INR

Creatinine

Calculated creatinine clearance (Cockroft-Gault)

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).
JCV serology testing

JCV antibodies at Visit 2 (Baseline) and every 48 weeks up to Visit 18 (EOT), and, if 
applicable, at all corresponding visits in the PTOP. Aggregate data from this analysis 
will be reviewed by the IDMC and the sponsor, but will not be communicated to the 
sites until database closure unless deemed necessary for safety reasons (i.e., signs or
symptoms raising suspicion of PML). In case of screening failure, the sample 
collected at Visit 2 (Baseline) will not be analyzed.
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.


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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 7.3.5].
Pregnancy test
A serum pregnancy test for WOCBP will be performed at Visit 1 (Screening), Visit 20 
(FU), and if pregnancy is suspected during the study. Urine pregnancy tests will be 
performed at Visit 2 (Baseline), Visit 4 (Week 2), Visit 5 (Week 4), Visit 6 (Week 12), 
and every 12 weeks thereafter up to Visit 17 (Week 144), and at Visit 18 (EOT).
Additionally, urine pregnancy tests will be performed at home every 4 weeks (± 4 days)
between the visits. Subjects will communicate the result (telephone call) of the tests 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 (Screening) and a second confirmed negative urine 
pregnancy test at Visit 2 (Baseline) prior to randomization. The two tests must be 
performed a minimum of 21 days 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
Urinalysis will be assessed using dipsticks at Visit 1 (Screening), Visit 6 (Week 12), 
Visit 7 (Week 24), and every 24 weeks thereafter up to Visit 17 (Week 144), Visit 18
(EOT), and Visit 20 (FU). If applicable, urinalysis will also be performed at all 


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corresponding visits in the PTOP. In addition, unscheduled urinalysis may be performed 
at any time during the study (Visits U1, U2, etc.).
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 variable 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.
7.4
Electronic self-rated version of the Columbia-Suicide Severity Rating 
Scale
The electronic self-rated version of the C-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 9 [Week 48], Visit 13 [Week 96], Visit 17 [Week 144] and 
Visit 18 [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 electronic administration. Subjects will be asked to 
respond to standardized clinical questions aimed at measuring the severity of suicidal 
ideation (rated on a 5-point ordinal scale), the levels of suicidal behavior, and the 
category self-injurious behavior without suicidal intent. Any subject 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 WPAI:MS and SF-36v2™ have been completed. Preferably, subjects would complete 
the eC-SSRS while waiting for their appointment before any interaction with healthcare 
providers. It is recommended that the subject stays at site until the report has been 
reviewed by the PI / treating neurologist.
A sample of the eC-SSRS (in English) is provided as Appendix 14. The data will be 
collected via electronic data capture and processed centrally by a 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 Visit 6
(Week 12), Visit 7 (Week 24), Visit 9 (Week 48), and every 24 weeks thereafter up to 
Visit 17 (Week 144), and at Visit 18 (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 preferable that the SF-36v2™ Questionnaire is completed prior to any clinical 
assessments, after the 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 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 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 six-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. 


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The WPAI:MS will be completed by the subject at Visit 2 (Baseline), at Visit 6 
(Week 12), Visit 7 (Week 24), Visit 9 (Week 48), and every 24 weeks thereafter up to 
Visit 17 (Week 144), and at Visit 18 (EOT).
WPAI:MS outcomes are expressed as impairment percentages, with higher numbers 
indicating greater impairment and less productivity, i.e., worse outcomes.
It is preferable that the WPAI:MS Questionnaire is completed prior to any clinical 
assessments. 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 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 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 Visit 2 (Baseline), Visit 4 (Day 15) and at every visit thereafter up to Visit 18
(EOT) as well as at unscheduled visits due to relapse (R1, R2, etc.). 
Subjects will be asked to report any hospital visit, length of stay, any visits to emergency 
medical services facilities due to MS since the last study visit, 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
7.7.1
Pharmacokinetic assessments
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 Visit 6 (Week 12), Visit 7 (Week 24), Visit 9 (Week 48), Visit 13 
(Week 96), Visit 17 (Week 144), Visit 18 (EOT) and at Visit 20 (FU). Additionally, at 
Visits 3 and 6 (Day 1 and Week 12), PK samples will be drawn 3 hours (± 15 minutes) 
post-dose. 


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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.
Details of the collection and shipment of the samples will be described in the laboratory 
manual. The tubes and labels for the sampling will be provided by the central laboratory.
The date and the time of blood sample collection will be entered in the eCRF, as well as 
the status of the patient (fed or fasted). The date and time of the last study treatment 
dosing before blood draw will be entered in the eCRF.
The concentration of ponesimod in plasma will be determined by a validated liquid 
chromatography-tandem mass spectrometry assay by PRA Health Sciences – Early 
Development Sciences, bioanalytical laboratory. The lower limit of quantification is 
1 ng/mL.
Note: 
The 3-hour PK sample collected 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.
7.7.2
Pharmacodynamic assessments
7.7.2.1
Total lymphocytes
The main PD marker is total lymphocyte count, which will be measured as part of the 
hematology tests [see Section 7.3.13.2].
7.7.2.2
Blood lymphocyte subsets
Blood samples for lymphocyte subset analysis will be taken from approximately 
200 subjects at Visit 2 (Baseline), Visit 6 (Week 12), Visit 7 (Week 24), Visit 9
(Week 48), Visit 13 (Week 96), Visit 17 (Week 144), Visit 18 (EOT), Visit 19 (FU7d),
and at Visit 20 (FU). Participation in the sub-study will be mandatory for all subjects 
until at least the first 200 subjects are randomized [see Section 3.6.1] to the main study. If 
applicable, lymphocyte subsets will also be assessed at the corresponding visits in the 
PTOP (Visits 6A, 7A, 9A, 13A, 17A, and 18A).
The site staff will ship the blood samples to the central laboratory for analysis. T cell, 
B cell, and NK cell counts will be analyzed as well as T cell subsets (e.g., CD4+ naïve, 
CD4+ effector memory, CD4+ central memory, CD8+ naïve, CD8+ effector memory, 
CD8+ central memory, CD8+ terminally differentiated effector memory, Th17 cells, Treg 
cells, and Th1 cells), will be analyzed by fluorescence activated flow cytometry using a 
combination of cell surface markers. Other lymphocyte subsets may also be analyzed. 


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Selected lymphocyte subsets may also be analyzed functionally ex vivo (e.g., production 
of cytokines). Results from the lymphocyte subsets sub-study will be blinded to site staff
and the sponsor until study closure.
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
Main study
Test
Number 
of tests
Volume 
per test
Total volume per test 
throughout the study
Viral serology at Visit 1 (Screening)
1
7.5 mL
7.5 mL
Interferon gamma release assay for tuberculosis at Visit 1 
(Screening)
1
3 × 1 mL
3 mL
Serum sample at Visit 2 (Baseline)1
1
5 mL
5 mL
Hematology2
19
2 mL
38 mL
Blood chemistry3
19
2.5 mL
47.5 mL
Lymphocytes4
3
2 mL
6 mL
INR
19
1.8 mL
34.2 mL
Ponesimod PK
9
3 mL
27 mL
Vaccine specific Antibody titers5
2
5 mL
10 mL
JCV serology
5
5 mL
25 mL
Total blood volume drawn throughout the main study: 203.2 mL6,7
Lymphocyte subsets sub-study (approximately 200 subjects)
Test
Number 
of tests
Volume 
per test
Total volume per test 
throughout the study
Lymphocyte subsets
9
6 mL
54 mL
Additional blood volume drawn for the sub- study: 54 mL
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/L.
3. Includes serum pregnancy test at Visit 1 (Screening), if needed.
4. Blood samples for lymphocyte counts are required to obtain 4-weekly (± 3 days) lymphocyte counts up to Week 24. 
5. Additional samples may be taken in the event of a vaccination with a non-live vaccine.


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6. 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. 
7. In the event of a positive Hepatitis C antibody test, site can draw an additional confirmatory blood sample (2.5 mL) 
for testing of Hep 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 Visit 1 (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 into account:

When applicable, the subject must come to the clinic 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. At Visit 3 (Day 1) PK 
sampling is to be drawn 3 hours post-dose. At Visit 6 (Week 12) PK 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 discussion with the 


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investigator or treating neurologist. Subjects will provide responses to the 
questionnaires while waiting for their appointment. Questionnaires should preferably 
be completed in the following order:
−
WPAI:MS
−
SF-36v2™
−
eC-SSRS
To ensure compliance, at each visit the study personnel must remind WOCBP to use the 
methods of contraception defined for this study. The reminders must be documented in 
the hospital chart.
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. Re-screening 
requires re-consenting i.e., a new ICF must be signed by the subject and by the 
investigator. All pre-randomization assessments do not need to be repeated at the time of 
re-screening if they were performed within 90 days or within 37 days for laboratory (i.e., 
hematology, blood chemistry, and pregnancy test). The guidance  indicating which test 
needs to be repeated at the time of the re-screening authorization is provided in 
Appendix 15.
The randomization must occur within 45 days from the date of Visit 1 (Screening; i.e.,
date of signature of the informed consent) or, in case of re-screening, within 45 days from
the date of re-screening (i.e., date of signature of the new informed consent).
Unscheduled visits may be performed at any time during the study. Depending on the 
reason for the unscheduled visit (e.g., AE), appropriate assessments will be performed 
based on the judgment of the investigator and the results will be recorded in the CRF.
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 pre-dose assessments of Visit 3 
(Day 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) and 
Visit 2 (Baseline) dates. All baseline assessments, including the ECG and blood pressure 
performed pre-dose on first day of dosing at Visit 3 (Day 1) must be performed before 
randomization [see Figure 4].


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The start of screening occurs on the day the first screening assessment was performed 
(i.e., signature of informed consent).
Figure 4
Timing of the pre-randomization assessments
8.1.1
Visit 1 (Screening)
Visit 1 (Screening) will be performed at maximum 45 days prior to randomization. The 
Visit 1 (Screening) date is defined as the date of start of pre-randomization period (i.e., 
signature of the informed consent). 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 (Screening) 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.


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
Recording of demographics, medical history, smoking status, and disease 
characteristics.

Recording of previous and concomitant medications [see Section 5.2.2].

EDSS/FS (performed by the efficacy assessor).

SBP/DBP.

Body weight and height.

Physical examination.

Body temperature.

Ophthalmological examination (under the responsibility of the ophthalmologist).

Hematology (including lymphocytes), 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. 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 the 
subject to instruct him/her to start the completion of the FSIQ-RMS [see 
Section 7.2.6].

CXR (any CXR performed within 90 days prior to Visit 1 [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 the inclusion/exclusion 
criteria. The next visit (Visit 2 [Baseline]) will only be scheduled if the subject meets all 
the eligibility criteria. If applicable, the date of screening failure will be collected in the 
IRT system and in the eCRF; additionally, the reasons for screening failure will be 
documented in the eCRF (screening information is collected for all screening failure 
subjects).
8.1.2
Visit 2 (Baseline) 
Visit 2 (Baseline) 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 


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recorded. While the assessments may generally be performed anytime during the 
pre-randomization period [see Figure 4], the following points should be considered:

All Visit 1 (Screening) assessments repeated at Visit 2 (Baseline) with the exception 
of hematology and blood chemistry laboratory assessments (e.g., 12-lead ECGs, 
physical examination, SBP/DBP) must be performed at least 7 days after the Visit 1 
(Screening) assessments. 

Hematology and blood chemistry laboratory assessments at Visit 2 (Baseline) must be 
performed at least 21 days after the hematology and blood chemistry laboratory 
assessments performed at Visit 1 [Screening; see Section 4.3]. 

Similarly, for WOCBP, the urine pregnancy test at Visit 2 (Baseline) must be 
performed at least 21 days after the serum pregnancy test performed at Visit 1
(Screening).

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).
Visit 2 (Baseline) includes:

WPAI:MS (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 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 WPAI:MS and SF-36v2™ 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 
[Screening; see Section 5.2].

EDSS/FS (performed by the efficacy assessor).

MS relapse.

Health care resource utilization

SBP/DBP.

12-lead ECG.

Physical examination.

Body temperature.

Body weight.

OCT (under the responsibility of the ophthalmologist).


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
Dermatological examination (performed by the dermatologist). In case of 
re-screening, dermatological
examination does not need to be repeated if 
dermatological examination from initial screening was performed within 90 days 
prior to the date of re-screening.

Hematology (including lymphocytes), blood chemistry.

Lymphocyte subsets (only at sites participating in sub-study).

JCV serology.

Urine pregnancy test for WOCBP.

Additional serum sample for potential retrospective analysis of viral serology titers.

Spirometry.

MRI.

MSFC and SDMT (second practice test).

FSIQ-RMS.

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.
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 screening failure subjects).
8.1.3
Visit 3 – Day 1 – pre-dose assessments
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 assessments during Visit 3 will be divided into 
two parts: before (pre-dose) and after (post-dose) the administration of the first study 
drug dose [see Section 8.2.1]. 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 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 
[Screening; 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).

12-lead ECG (under the responsibility of the first-dose administrator).

Recording of methods of contraception (for WOCBP).


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
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
Treatment period
The treatment period consists of the post-dose assessments at Visit 3 to Visit 18 
(Randomization Day 1, Weeks 2, 4, 12, and every 12 weeks thereafter until EOT). 
8.2.1
Visit 3 – Randomization Day 1 – Randomization and post-dose assessments
The treatment period starts with first dose taken during Visit 3 (Day 1 of the study). 
The randomization must occur within 45 days from the date of Visit 1 (Screening; i.e., 
date of signature of the informed consent) or, in case of re-screening, within 45 days from 
the date of re-screening (i.e., date of the first assessment performed as part of the 
re-screening).
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 hours post-dose. Starting at 4 hours 
post-dose, the first-dose administrator must check whether the subject fulfills the 
discharge criteria from cardiac monitoring [see Section 5.1.10]. Subjects may be 
discharged from cardiac monitoring if they meet the discharge criteria before 12 hours 
post-dose but no sooner than the (report of) 4 hours post-dose ECG has been evaluated by 
the first-dose administrator [see Section 5.1.10].
Visit 3 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 minutes) for up to 12 hours post-dose with a minimum of 
4 hours post-dose (under the responsibility of the first-dose administrator).

12-lead ECG hourly (± 15 minutes) for up to 12 hours post-dose with a minimum of 
4 hours post-dose (under the responsibility of the first-dose administrator).

PK sampling at 3 hours (± 15 minutes) post-dose (NB: this should be performed after 
the corresponding hourly 12-lead ECG and SBP/DBP measurement).

Recording of AEs and SAEs (NB: 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 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.).


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
Remind WOCBP 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:
−
not take study treatment on the day of study visit prior to coming to the site.
−
contact their principal investigator / treating neurologist at the clinical site 
immediately in the event of the appearance of any symptoms suggestive of an MS 
exacerbation.
Subjects assigned to the ponesimod arm will need to gradually up-titrate from 2 mg to 
10 mg during Day 1 to 14. As there is no site visit planned until Day 15, subjects will be 
instructed 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
Four-weekly lymphocyte counts
Lymphocyte counts will be assessed every 4 weeks up to Week 24 (i.e., additional 
lymphocyte tests will be performed at Week 8, Week 16, and Week 20). (Thereafter, 
lymphocyte counts will be assessed every 12 weeks up to EOT.)
The test window is ± 3 days. Under specific circumstances (e.g., subject lives far away 
from the site and cannot return every 4 weeks), laboratory samples could be drawn in a 
local laboratory close to where the subject lives, and analyzed at the central laboratory 
[see Section 7.3.13].
8.2.3
Visit 4 – Day 15 
The visit window for this visit is ± 1 day. The visit includes:

MS relapse.

Health care resource utilization since the last visit.

Recording of changes in concomitant medications.

Body temperature.

SBP/DBP (pre-dose).

12-lead ECG (pre-dose).

Hematology (including lymphocytes), blood chemistry.

Assessment and recording in the eCRF of methods of contraception (for WOCBP 
only).

Urine pregnancy test for WOCBP.

Recording of AEs and SAEs.

Study treatment accountability and compliance review.

IRT call and study treatment dispensing.

Remind WOCBP to use the methods of contraception defined for this study. The 
reminders must be documented in the hospital chart.


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
Schedule an appointment for next visit and instruct subject to:
−
bring back any blister packs (used, partially used and unused blister packs) and 
any unused tablets.
−
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 ± 5 days. 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).

MS relapse.

Health care resource utilization since the last visit. 

Body temperature.

Hematology (including lymphocytes), blood chemistry.

Urine pregnancy test for WOCBP.

Recording of AEs and SAEs.

Study treatment accountability and compliance review.

IRT call and study treatment dispensing.

Remind WOCBP 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 any blister packs (used, partially used and unused blister packs) and 
any unused tablets.
−
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
In-between-visit telephone calls until Week 156 (Weeks 18, 30, 42, 54, 66, 78, 
90, 102, 114, 126, 138, and 150)
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, 102, 


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114, 126, 138 and 150 (± 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.
8.2.6
Visits 6 and 7 – Weeks 12 and 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:

WPAI:MS (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 the WPAI:MS, prior to any 
clinical assessments or interaction with health care providers, preferably while 
waiting for their appointment).

EDSS/FS (performed by the efficacy assessor).

MS relapse.

MSFC/SDMT.

Health care resource utilization since the last visit.

MRI (Visit 7 only).

Recording of changes in concomitant medications.

Assessment and recording in the eCRF of methods of contraception (for WOCBP 
only).

Physical examination (Visit 7 only).

Body temperature.

SBP/DBP (pre-dose).

12-lead ECG pre-dose (and 3 hours (± 15 minutes) post-dose at Visit 6 only).

OCT (under the responsibility of the ophthalmologist).

Ophthalmological examination (under the responsibility of the ophthalmologist).

Spirometry (pre-dose; Visit 6 only).

Hematology (including lymphocytes), blood chemistry.

Urinalysis.

Lymphocyte subsets (only at sites participating in sub-study).

PK sampling pre-dose (and 3 hours (± 15 minutes) post-dose at Visit 6 only; NB: this 
should be performed after the corresponding hour 12-lead ECG and SBP/DBP 
measurement).

Urine pregnancy test for WOCBP.

Recording of AEs and SAEs.


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
Study medication accountability and compliance review.

IRT call and study treatment 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 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 any blister packs (used, partially used and unused blister packs) and 
any unused tablets.
−
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.

Dispense the FSIQ-RMS and give instructions for completion.
8.2.7
Visits 8, 10, 12, 14, and 16 – Weeks 36, 60, 84, 108, 132
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: 

MS relapse.

EDSS/FS (performed by the efficacy assessor).

Health care resource utilization since the last visit.

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).

Hematology (including lymphocytes), blood chemistry.

Urine pregnancy test for WOCBP.

Recording of AEs and SAEs.

Study treatment accountability and compliance review.

IRT call and study treatment 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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Relapsing multiple sclerosis
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Version 6
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Doc No D-17.622

Remind WOCBP 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 any blister packs (used, partially used and unused blister packs) and 
any unused tablets.
−
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
Visits 11 and 15 – Weeks 72 and 120
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: 

WPAI:MS (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 WPAI:MS, prior to any clinical 
assessments or interaction with health care providers, preferably while waiting for 
their appointment).

EDSS/FS (performed by the efficacy assessor).

MS relapse.

MSFC/SDMT.

Health care resource utilization since the last visit.

Recording of changes in concomitant medications.

MRI.

Assessment and recording in the eCRF of methods of contraception (for WOCBP 
only).

Physical examination.

Body temperature.

SBP/DBP (pre-dose).

12-lead ECG (pre-dose).

Hematology (including lymphocytes), blood chemistry.

Urinalysis.

Urine pregnancy test for WOCBP.

Recording of AEs and SAEs.

Study treatment accountability and compliance review.


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
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Confidential
EudraCT 2012-000541-12
Doc No D-17.622

IRT call and study treatment 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 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 any blister packs (used, partially used and unused blister packs) and 
any unused tablets.
−
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.

Dispense the FSIQ-RMS and give instructions for completion.
8.2.9
Visits 9, 13, 17 – Weeks 48, 96, and 144
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: 

WPAI:MS.

SF-36v2TM.

eC-SSRS.

EDSS/FS.

MS Relapse.

MSFC, SDMT.

Health care resource utilization.

MRI.

Recording of changes in concomitant medications.

Assessment and recording in the eCRF of methods of contraception (for WOCBP 
only).

Physical examination.

Body temperature.

Dermatological examination.

Body weight.

SBP/DBP (pre-dose).

12-lead ECG (pre-dose).

OCT (under the responsibility of the ophthalmologist).


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
Ophthalmological examination.

Spirometry.

Hematology (including lymphocytes), blood chemistry.

Urinalysis.

Lymphocyte subsets (only at sites participating in sub-study).

PK sampling.

JCV serology.

Urine pregnancy test for WOCBP.

Recording of AEs and SAEs.

Study treatment accountability and compliance review.

IRT call and study treatment 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 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 any blister packs (used, partially used and unused blister packs) and 
any unused tablets.
−
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.

Dispense the FSIQ-RMS and give instructions for completion.
8.2.10 Visit 18 – EOT
This visit will be conducted after at least 60 weeks of treatment and up to Week 156 or 
earlier in case of premature discontinuation of study treatment (+ 7 days). When study 
closure is communicated by the sponsor, all subjects on study drug should perform the 
Visit 18 (EOT) assessments for this study within 4 weeks [see Section 3.5.5].
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 of study drug. If a study treatment temporary interruption leads 
to 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. If the study 
treatment interruption leading to the permanent premature discontinuation lasts more than 
30 days, then Visit 19 (FU7d), if applicable, and Visit 20 (FU) can be combined with 
Visit 18 (EOT). 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:


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
WPAI:MS.

SF-36v2.

eC-SSRS.

EDSS/FS.

MS Relapse.

MSFC, SDMT.

Health care resource utilization.

CXR (in case of premature study treatment discontinuation, the CXR at EOT does not 
need to be performed if the EOT visit occurs within 48 weeks of the 
pre-randomization CXR).

MRI.

Recording of changes in concomitant medications.

Assessment and recording in the eCRF of methods of contraception (for WOCBP 
only).

Physical examination.

Body temperature.

SBP/DBP.

Dermatological examination.

Body weight.

12-lead ECG.

Ophthalmological examination.

OCT (under the responsibility of the ophthalmologist).

Spirometry.

Hematology (including lymphocytes), blood chemistry.

Urinalysis.

Lymphocyte subsets (only at sites participating in sub-study).

PK sampling.

JCV serology.

Urine pregnancy test for WOCBP.

Recording of AEs and SAEs.

Study treatment accountability and compliance review.

IRT call.

Remind WOCBP 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 any blister packs (used, partially used and unused blister packs) and 
any unused tablets.


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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.

Dispense the FSIQ-RMS and give instructions for completion.
8.3
Post-treatment period
8.3.1
Post-treatment safety follow-up period

The safety FU period lasts 30 days and includes Visit 19 (FU7d; only for subjects
participating in the lymphocyte sub-study), and Visit 20 (FU).
8.3.1.1
Visit 19 – FU7d
If a temporary interruption of study treatment lasts more than 30 days and leads to
permanent premature discontinuation, Visit 19 (FU7d) can be combined with the EOT 
visit. 
The FU7d visit will take place 7 days after the last dose of study treatment (± 2 days). 
Only subjects participating in the lymphocyte subset sub-study will have this additional 
FU visit. The visit includes:

Lymphocyte subsets (only at sites participating in sub-study).

Recording of AEs and SAEs.
8.3.1.2
Visit 20 – FU
If a temporary interruption of study treatment lasts more than 30 days and leads to
permanent premature discontinuation, Visit 20 (FU) can be combined with the EOT visit. 
The FU visit will take place at least 30 days after the last dose of study treatment, but no 
later than 37 days after last dose of study treatment. The visit includes:

EDSS/FS.

MS Relapse.

FSIQ-RMS. At Visit 20 (FU), the FSIQ-RMS will be completed at home prior to the 
visit, ideally, during the 7 consecutive days preceding the visit.

Recording of changes in concomitant medications.

Body temperature.

SBP/DBP.

12-lead ECG.

Ophthalmological examination.

Spirometry.

Urinalysis.

Hematology (including lymphocytes*), blood chemistry.

PK sampling.


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
Lymphocyte subsets (only at sites participating in sub-study).

Serum pregnancy test for WOCBP.

Recording of AEs and SAEs.
* If a total lymphocyte count < 0.5 × 109/L is observed at FU, an alert will be sent to the 
principal investigator and the sponsor [see Section 7.3.13.1]. Discontinuation of DMF 
treatment should be considered in accordance with prescribing information 
[Tecfidera USPI, Tecfidera SmPC].
8.3.2
Post-treatment observation period
Subjects who prematurely discontinue study treatment will perform the EOT and safety 
FU visits (FU7d [if applicable], FU) and will enter the PTOP which lasts until 60 weeks 
after randomization of the last subject (i.e., scheduled 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 3.5.3.2]. After 
FU has been performed, the study visits must continue according to the original visit and 
assessment schedule. If the first PTOP visit window overlaps with FU7d (if applicable) or 
FU visits, visits and assessments can be combined. 
8.3.2.1
Visits 6A, 7A, 8A, 10A, 12A, 14A, and 16A – Weeks 12, 24, 36, 60, 84, 108, 
and 132
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:

EDSS/FS.

MS relapse.

MRI (Visit 7A – Week 24 – only).

Recording of changes in concomitant medications.

Physical examination (Visit 7A – Week 24 – only).

Body temperature.

SBP/DBP.

Spirometry (Visit 6A – Week 12 – only).

Hematology (including lymphocytes), blood chemistry.

Urinalysis.

Lymphocyte subsets (only at sites participating in sub-study; Visits 6A and 7A –
Weeks 12 and 24 only).

Recording of AEs and SAEs.


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
Dispense the FSIQ-RMS and give instructions for completion (Visit 6A – Week 12 
and Visit 7A – Week 24 only).
8.3.2.2
Visits 11A – Week 72 and Visit 15A – Week 120 
The visit window for these visits is ± 7 days. The EDSS must be assessed during this visit 
window (i.e., ± 7 days). The 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:

EDSS/FS.

MS relapse.

MRI.

Recording of changes in concomitant medications.

Physical examination.

Body temperature.

SDP/DBP.

Hematology (including lymphocytes), blood chemistry.

Urinalysis.

Recording of AEs and SAEs.

Dispense the FSIQ-RMS and give instructions for completion.
8.3.2.3
Visits 9A, 13A, 17A, and 18A – Weeks 48, 96, 144, and 156
When study closure is communicated by the sponsor, all subjects who prematurely 
discontinued from the study treatment and entered the PTOP should perform the 
Visit 18A (Week 156) assessments within 4 weeks [see Section 3.5.5].
The visit window for these visits is ± 7 days. The EDSS must be assessed during this visit 
window (i.e., ± 7 days). The 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:

EDSS/FS.

Relapse.

MRI.

Recording of changes in concomitant medications.

Physical examination.

Body temperature.

Dermatological examination.

SBP/DBP.

12-lead ECG.

Spirometry.


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
Hematology (including lymphocytes), blood chemistry.

Urinalysis.

Lymphocyte subsets (only at sites participating in the sub-study).

JCV serology.

Recording of AEs and SAEs.

Dispense the FSIQ-RMS and give instructions for completion. At Visit 18A 
(Week 156), the FSIQ-RMS will be completed at home prior to the visit, ideally, 
during the 7 consecutive days preceding the visit.
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 treatment (e.g., re-initiation, return of unused 
study medication, need to initiate treatment with a QT-prolonging drug), and/or MS 
related issues (e.g., relapses).
The date of the visit and the reason for such visits as well as any data related to study 
assessments performed at unscheduled visits will be recorded in the eCRF.
8.4.1
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 12] and the relapse 
symptoms form [see Appendix 13] 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 after onset or worsening of the symptom(s). The 
decision regarding whether the new or worsened neurological symptoms are 


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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 patient and the presence or absence of a qualifying increase in the 
EDSS/FS (i.e., 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 an AE on the AE 
page in addition to being reported as SAEs).

MS relapses that, in the view of the investigator, warrant specific notice due to 
unusual frequency, severity or remarkable clinical manifestations (these should be 
reported as an AE on the AE page of the eCRF and, if applicable, on the SAE form).
Additionally, the following assessments must be done during those visits:

EDSS/FS (performed by the efficacy assessor).

MS relapse.

Health care resource utilization since the last visit.

SF-36v2TM (subject completes the questionnaire prior to any clinical assessments or 
interaction with health care providers, preferably while waiting for their 
appointment).

Recording of changes in concomitant medications.

Recording of AEs and SAEs.

Schedule an appointment for next visit and instruct subject to:
−
bring back any blister packs (used, partially used and unused blister packs) and 
any unused tablets.
−
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.

Dispense the FSIQ-RMS and give instruction for completion.
If a relapse visit is within 5 days prior to the date of a regular visit where MRI is 
assessed, efforts should be made to perform the MRI assessments prior to the start of 
treatment with i.v. corticosteroids. However, if this is not possible, then the MRI should 
be delayed until at least 14 days after the last dose of corticosteroids.
These visits for relapses are additional unscheduled visits. The regular scheduled study 
visits must be resumed according to the original visit and assessment schedule. If the visit 


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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 5.1.9, 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):

Body temperature.

12-lead ECG pre-dose and hourly (± 15 minutes) for up to 12 hours post-dose (under 
the responsibility of the first-dose administrator).

SBP/DBP pre-dose and hourly (± 15 minutes) for up to 12 hours 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 hours post-dose but 
no sooner than 4 hours post-dose [see Section 5.1.10].
The following assessments need to be done during the visit 14 days after the day of 
re-initiation:

Body temperature.

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 perfomed in addition.


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8.4.3
Unscheduled visits (any other assessment;U1, U2, U3, etc.)
An unscheduled site visit may be performed at any time during the study (between 
scheduled visits), as necessary, at the investigator’s discretion. The date of the visit and 
the reason for such visits as well as any data related to study assessments performed at 
unscheduled visits will be recorded in the eCRF. During such visits, any of the following 
assessments may be performed at the investigator’s discretion:

EDSS/FS.

FSIQ-RMS.

MRI.

Assessment of concomitant medications.

Physical examination.

Body temperature.

Pulse rate (to be assessed only if no 12-lead ECG is performed at this visit)

SBP/DBP.

12-lead ECGs (e.g., in case concomitant treatment with a QT-prolonging drug with 
known risk of Torsades de Pointes is needed [see Appendix 4]). 

Ophthalmological examination (e.g., presence of visual symptoms suggestive of 
active uveitis [see Section 5.1.12.7]).

OCT (e.g., presence of visual symptoms suggestive of macular edema or active 
uveitis [see Section 5.1.12.7]).

Spirometry.

Complete laboratory tests including: hematology including lymphocytes, blood 
chemistry, viral serology, urinalysis, or serum pregnancy test (for WOCBP only).

Assessment of AEs and SAEs.

Dermatological examination.

Assessment of methods of contraception (for WOCBP only).

Measurement of body weight.

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 (trough), 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. An inhaled short-acting β2 
agonist (e.g., albuterol/salbutamol) for symptom relief may be administered at the 
discretion of the investigator. Administration of any short-acting β2 agonist will be 
recorded in the eCRF.


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If any of the laboratory variables listed in Section 7.3.13.2 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 7.3.13].
9
STUDY COMPLETION AND POST-STUDY TREATMENT/MEDICAL 
CARE
9.1
Study completion 
For an individual subject, EOS is reached when treatment, safety FU period and, if 
applicable, the PTOP period have been completed: 

For subjects who remained under study treatment as defined per protocol 
(i.e., Week 156 or 60 weeks after randomization of the last subject [whichever occurs 
first]) and for subjects who prematurely discontinue study treatment and do not enter 
the PTOP, the EOS visit corresponds to Visit 20 (FU) 30 days after the last dose of 
study treatment. 

For subjects who prematurely discontinued study treatment (for whatever reason) and 
entered the PTOP, the EOS corresponds to the last PTOP visit performed.
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 safety FU 
period and, if applicable, PTOP period 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 (i.e., withdrawal of consent), die or are lost to FU for any other 
reason. If a subject withdraws consent, no further data will be collected in the eCRF from 
the date of withdrawal onward. The investigator may withdraw a subject from the study 
(without regard to the subject’s consent) if, on balance, they believe that continued 
participation in the study would be contrary to the best interests of the subject. 
Withdrawal from the study may also result from a decision by 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 
assessments, 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 


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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. Data obtained during this last appointment / telephone call will be recorded in the 
subjects’ medical records. No data will be collected in the eCRF, except the vital status, if 
the subject agrees. 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.
If the 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 the study without prior agreement 
from Actelion, the investigator must promptly inform Actelion and the IRB/IEC, and 
provide both with a detailed written explanation of the termination or suspension.


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If the IRB/IEC suspends or terminates its approval/favorable opinion of the 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. 
In making choices for treatment after withdrawal from the study or the study completion, 
the investigator should consider that subjects may have been treated with two 
immunomodulators concomitantly (i.e., DMF and ponesimod) for variable periods of 
time. This 
is 
particularly 
relevant when 
switching 
treatment to 
powerful 
immunosuppressive drugs such as natalizumab. Particular attention should be given to 
monitoring immune system function (e.g., lymphocyte counts, vaccination responses) and 
occurrence of opportunistic infections in these patients as the risk may potentially be 
increased. 
Open label ponesimod (alone or as add-on to Tecfidera) may be offered to the subjects 
after study withdrawal/completion as compassionate treatment when allowed by local 
regulations.
The initial treatment allocation should remain blinded until after database closure [see 
Section 5.1.4] unless emergency unblinding is required [see Section 5.1.5.4].
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 30 days after study treatment 
discontinuation), whether or not considered by the investigator as related to study 
treatment.


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AEs include:

Exacerbation of a pre-existing disease with the exception of MS relapse and 
associated symptoms [see Section 10.1.6].

Increase in frequency or intensity of a pre-existing episodic disease or medical 
condition.

Disease or medical condition detected or diagnosed during the course of the study 
even though it may have been present prior to the start of the study.

Continuous persistent disease or symptoms present at study start that worsen 
following the start of the study. 

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.


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
Moderate
The event may make the subject uncomfortable. Performance of daily activities may be 
influenced, and intervention may be needed.

Severe
The event may cause noticeable discomfort and usually interferes with daily activities. 
The subject may not be able to continue in the study, and treatment or intervention is 
usually needed.
A mild, moderate, or severe AE may or may not be serious [see Section 10.2]. These 
terms are used to describe the intensity of a specific event. Medical judgment should be 
used on a case-by-case basis. 
Seriousness, rather than severity assessment, determines the regulatory reporting 
obligations.
10.1.3 Relationship to study treatment 
Each AE must be assessed by the investigator as to whether or not there is a reasonable 
possibility of causal relationship to the study treatment, and reported as either related or 
unrelated. The determination of the likelihood that the study drug caused the AE will be 
provided by an investigator who is a qualified physician.
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 the last visit of the PTOP (i.e., Week 156 
visit of the PTOP) (whichever is latest) 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 3.7.4] must ensure that blinded study personnel 
at the study site, such as the treating neurologist, 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 
assessments or ECGs 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 and which are resolved at 
the time of discharge. 


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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.
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 an AE on the AE 
page in addition to being reported as SAEs).

MS relapses that, in the view of the investigator, warrant specific notice due to 
unusual frequency, severity or remarkable clinical manifestations (these should be 
reported as an AE on the AE page of the eCRF and, if applicable, on the SAE form).
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.


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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.

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.


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10.2.2 Reporting of serious adverse events 
All SAEs occurring after study start (i.e., signing of informed consent) up to 30 days after 
study treatment discontinuation must be reported on AE pages in the eCRF and on SAE 
forms, regardless of the investigator-attributed causal relationship with study treatment or 
study-mandated procedures.
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 SAE forms.
10.2.4.2 After the PTOP period
New SAEs occurring after the 30-day FU period, or after the last visit of the PTOP 
(whichever applies and is the latest) must be reported to the Actelion drug safety 
department within 24 hours of the investigator’s knowledge of the event, only if 
considered causally related to previous exposure to the study treatment by the 
investigator. 
10.2.5 Reporting procedures
All SAEs must be reported by the investigator to the Actelion drug safety department 
within 24 hours of the investigator’s first knowledge of the event.
The MS relapses and associated symptoms are exempt 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.
FU information about a previously reported SAE must also be reported within 24 hours 
of receiving it. The Actelion drug safety department may contact the investigator to 
obtain further information. 


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If the subject is hospitalized in a hospital other than the study site, it is the investigator’s 
responsibility to contact this hospital to obtain all SAE relevant information and 
documentation.
The reference safety document to assess expectedness of a suspect serious adverse 
reaction and reported by the sponsor to health authorities, IRBs/IECs and investigators, is 
the reference safety information section of the IB [Ponesimod IB]. 
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. 
10.3.1 Reporting of pregnancy
Irrespective of the treatment received by the subject, any pregnancy occurring during the 
study including during 30 days following study treatment discontinuation must be 
reported within 24 hours 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.
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 


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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 3.8.1].
11 STATISTICAL METHODS
All statistical analyses will be conducted by Actelion or by designated CROs supervised 
by Actelion.
The Statistical Analysis Plan (SAP) will be approved prior to database lock for the final 
analyses. The SAP provides the full details of all analyses, data displays, and algorithms 
to be used for data derivations. 
All data will be listed and endpoints will be summarized by appropriate descriptive 
statistics (tables or figures), typically including:

Number of non-missing observations, number of missing observations, mean, 
standard deviation, median, Q1, Q3, minimum and maximum for continuous 
endpoints;

Number of non-missing observations, number of missing observations and frequency 
with percentage per category (percentages based on the number of non-missing 
observations) for categorical endpoints;

Number of subjects at risk, cumulative number of events, cumulative number of 
censored observations and Kaplan-Meier estimates of the survival function for 
time-to-event endpoints.
Absolute change from baseline is defined as post-baseline value minus baseline value, 
i.e., a positive sign indicates an increase as compared to baseline.
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 = 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.
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. 


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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 who were treated with at 
least one dose of study treatment and have at least one post-baseline efficacy assessment. 

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 
IVRS system (which may be different to the information available on the eCRF after 
data validation);

Unless otherwise stated, all available efficacy data for the primary and secondary 
endpoints up to the EOS visit will be included in the analysis, regardless of study 
treatment discontinuation and/or switches to alternative MS treatments.
11.1.3 All-randomized set
The all-randomized set (ARS) includes all subjects that were randomized.
11.1.4 Per-protocol set
The per-protocol set (PPS) comprises all subjects included in the FAS without any major 
protocol deviations that impact the assessment of the 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 for a 
subject collected after a major protocol deviation for subjects developing protocol 
deviations during the study will be excluded for the PPS analysis. 
All reportable protocol deviations will be evaluated before unblinding and classified into 
the five 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 developed treatment discontinuation criteria during the study but was not 
discontinued;

Subject received the wrong study treatment or incorrect dose; 

Subject took an unauthorized concomitant medication; 


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
Key study procedures missed or performed out of window (e.g., Randomization code 
was broken). 
Additional details regarding the definition of the reasons for subject/data exclusion from 
the PPS will be defined in the final SAP.
11.1.5 Safety set
The safety set (SAF) includes all subjects who received at least one dose of study 
treatment. Subjects will be analyzed based on actual treatment taken.
11.1.6 Other analysis sets
Other analysis datasets will be defined in the SAP (or corresponding SAPs), e.g., PK set, 
PD set, sub-study sets, and subgroups of interest.
11.1.7 Usage of the analysis sets
The FAS, ARS, 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 
and ARS will supplement those based on the FAS and assess the robustness of treatment 
effects.
Other MRI, clinical exploratory endpoints and other exploratory endpoints will be 
analyzed using the FAS.
All safety data will be analyzed using the SAF.
The usage of other analysis sets will be described in the SAP. 
11.2 Variables
Variables are defined only for the primary and secondary endpoints. Variables for 
exploratory and other endpoints will be defined in the SAP.
11.2.1 Primary efficacy endpoint variable
The primary endpoint is the ARR defined as the number of confirmed relapses per 
subject-year. All confirmed relapses from randomization up to EOS 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 relapses and confirmed relapses, see Section 6.1.1.


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11.2.2 Secondary efficacy endpoint variables
There are five secondary efficacy endpoints, which will be analyzed in a hierarchical 
manner:

Time to 12-week CDA from baseline up to EOS;

Time to first confirmed relapse from baseline up to EOS;

Mean number of CUALs per subject per post-baseline MRI scan up to EOS;

Longitudinal change over time in fatigue-related symptoms as measured by the 
symptoms domain of the FSIQ-RMS from baseline up to EOS;

Longitudinal percent change over time in brain volume from baseline up to EOS.
11.2.2.1 Time to 12-week CDA from baseline up to EOS
Time to 12-week CDA from baseline up to EOS is defined as an:

Increase of at least 1.5 in EDSS for subjects with a baseline EDSS score of 0; or

Increase of at least 1.0 in EDSS for subjects with a baseline EDSS score of 1.0 to 5.0;
or

Increase of at least 0.5 in EDSS for subjects with a baseline EDSS score ≥5.5;
confirmed after 12 weeks. 
Time to first 12-week CDA is defined as the 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 up to EOS 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.
11.2.2.2 Time to first confirmed relapse up to EOS
The time to first confirmed relapse is defined as:

Date of first confirmed relapse minus date of randomization + 1 in days.
Subjects without any relapses will be censored at the EOS date, and the time is defined as 
EOS date minus date of randomization + 1 in days.


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11.2.2.3 Mean number of CUALs per subject per post-baseline MRI scan up to EOS
The mean number of CUALs [defined in Section 6.1.3] per subject per post-baseline MRI 
scan up to EOS is calculated per subject as the sum of the lesions at all post-baseline MRI 
scans up to EOS divided by the number of MRI scans.
11.2.2.4 Longitudinal change over time in fatigue-related symptoms as measured by 
the symptoms domain of the FSIQ-RMS from baseline up to EOS
The variables required for this endpoint are the visit identifier and the absolute change in 
the FSIQ–RMS fatigue-related symptoms at each visit defined as the value at each visit 
up to EOS minus the value at baseline. Additional details for dealing with missing data 
will be provided in the SAP.
11.2.2.5 Longitudinal percent change over time in brain volume (PCBV) from baseline 
up to EOS
PCBV will be calculated at each visit using the skull as scaling constraint by performing 
halfway registration between images from the MRI assessments from baseline up to EOS:

Percent change from the mean brain surface displacement between the MRI scans 
(SIENA method).
Further details of the derivation of this variable will be provided in the SAP.
11.3 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 ponesimod with placebo. The five secondary 
endpoints will be tested, in order as listed in Section 11.2.2, using a hierarchical testing 
approach. The primary null hypotheses will be tested at a two-sided 5% alpha level, and 
if this is rejected, the study will be declared to show conclusive evidence of efficacy.
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.


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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.
Two-sided hypotheses are expressed in terms of the model parameters Ponesimod and 
µPlacebo. The primary null hypothesis is that the ARR (µ) does not differ between 
ponesimod and placebo. The alternative hypothesis is that the ARR differs between 
ponesimod and placebo.
H0, ARR: µPonesimod - µPlacebo = 0
vs
H1, ARR: µPonesimod - µPlacebo ≠ 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 0.05. 
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. No missing data 
imputation is used for the main analysis of the primary 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.
11.3.2.2.2 Sensitivity analysis 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 stages a decision must be taken by the 


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treating neurologist to refer the subject to the efficacy assessor. Only at this point is the 
symptom considered a relapse and is assessed for confirmation. To ensure 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 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 the Study Closure 
(60 weeks after the last subject is randomized or Week 156) 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 Study Closure or Week 156
A worst case imputation will impute the observed ARR for ponesimod subjects up to 
EOS during the period EOS up to Study Closure and impute 0 relapses for placebo 
subjects during this period. A second imputation method will impute the observed 
placebo ARR up to EOS for the period EOS up to SC for both treatments, using 
simulations and bootstrapping techniques to calculate the 95% CI. A third more 
conservative approach will impute the observed individual treatment ARR up to EOS for 
the period EOS up to SC in a similar manner.
11.3.2.3 Main analysis
The primary statistical analysis will be performed on the FAS using the model described 
in Section 11.3.2.1 for confirmed relapses, with the stratification variable EDSS category
included as covariate in the model and the logarithm of time on treatment up to EOS as 
an offset variable. The effect size will be measured by the relative reduction in the model 
estimated mean ARR for ponesimod compared to placebo including two-sided 95% Wald 
CIs.
11.3.2.4 Supportive/sensitivity analyses
The main supportive analysis will count all confirmed relapses up to EOT + 30 days
using the FAS. In addition to the missing data sensitivity analysis described in 
Section 11.3.2.2, the following sensitivity analyses (based on the FAS, if not otherwise 
stated) are planned using the model described in Section 11.3.2.1:

Analysis with treatment as the only covariate in the model for all confirmed relapses 
up to EOS and up to EOT +30 days;

Analysis adjusting for the stratification covariate using the actual EDSS recorded at 
baseline on the eCRF up to EOS and up to EOT + 30 days;


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
Analysis adjusting for additional baseline characteristics up to EOS and EOT 
+ 30 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 + 30 days and 
EOS (PTOP) to further assess the impact of switching to alternative MS treatments; 

Analyses based on the PPS counting confirmed relapses up to EOS;

Analysis using all relapses (confirmed or unconfirmed) up to EOS and EOT 
+ 30 days;
Further sensitivity 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 factor) are:

Baseline EDSS (≤ 3.5, 3.5);

MS subtype (relapsing remitting, secondary progressive);

Gender (male, female);

Age (40, ≥ 40);

Prior MS treatment other than DMF (yes, no);

Relapse in the previous 6 month prior to study entry while on treatment with DMF 
(≤1, ≥ 2);

Gd+ T1 lesions at baseline (absent, present);
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.
11.3.3 Analysis of the secondary efficacy variables
The secondary efficacy endpoints will be tested in a hierarchical manner if the primary 
analysis on ARR has led to the rejection of the null hypothesis in favor of ponesimod. 
The hierarchical testing procedure starts from the top, and it stops when a null hypothesis 
cannot be rejected. The order of testing is as follows:

Time to 12-week CDA from baseline up to EOS;

Time to first confirmed relapse up to EOS;

Mean number of CUALs per subject per post-baseline MRI scan up to EOS;

Longitudinal change over time in fatigue-related symptoms as measured by the 
symptoms domain of the FSIQ-RMS from baseline up to EOS.

Longitudinal percent change over time in brain volume from baseline up to EOS.


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All hypotheses need to be rejected at a two-sided alpha-level of 0.05. The endpoints will 
be analyzed using the FAS. All secondary endpoints will also be analyzed using the PPS.
11.3.3.1 Time to 12-week CDA from baseline up to EOS
11.3.3.1.1 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 SPonesimod (t) and SPlacebo (t).
H0,CDA: SPonesimod (t) = SPlacebo (t) for all t ≥ 0
vs
H1,CDA: SPonesimod (t) ≠ SPlacebo (t) for all t ≥ 0
The null hypothesis will be tested using a two-sided stratified log-rank test.
11.3.3.1.2 Analyses 
The primary analysis of Time to 12-week CDA will be performed on the FAS using a 
two-sided stratified log-rank test with stratification factor EDSS category. Kaplan-Meier 
estimates for the survival functions will be plotted using Kaplan-Meier curves and will be 
tabulated by 12-week intervals. The treatment effect will be measured by means of a 
hazard ratio calculated using a Cox’s proportional hazard model with treatment, and 
baseline EDSS category as covariates. 
11.3.3.1.3 Supportive analyses
Supportive analyses will include an unstratified log-rank test, adjusted and unadjusted 
Cox’s proportional hazards models, analyses based on the PPS and analyses up to EOT + 
30 days. A worst case analysis where all unconfirmed disability accumulations at EOS
are considered as confirmed will also be performed.
11.3.3.2 Time to first confirmed relapse up to EOS
11.3.3.2.1 Hypothesis
The two-sided hypothesis is expressed in terms of “survival functions” SPonesimod (t) and 
SPlacebo (t).
H0,TTFR: SPonesimod (t) = SPlacebo (t) for all t ≥ 0
vs
H1,TTFR: SPonesimod (t) ≠ SPlacebo (t) for all t ≥ 0
The null hypothesis will be tested using a two-sided stratified log-rank test.


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11.3.3.2.2 Analyses 
The primary analysis for this variable will be performed on the FAS using a two-sided 
stratified log-rank test, stratified by baseline EDSS category. Kaplan-Meier estimates for 
the survival functions will be plotted using Kaplan-Meier curves and will be tabulated by 
12-week intervals. The treatment effect will be measured by means of a hazard ratio 
calculated using a Cox’s proportional hazard model with treatment, baseline EDSS 
category as covariates.
11.3.3.2.3 Supportive analyses
Supportive/sensitivity analyses will include an unstratified log-rank test, adjusted and 
unadjusted Cox’s proportional hazards models, analyses based on the PPS and analyses 
counting all confirmed relapses up to EOT + 30 days. An analysis using all relapses
(confirmed and unconfirmed) will also be included. Missing data will be assessed using 
different censoring rules based on each subject’s status at EOT + 30 days and EOS.
11.3.3.3 Mean number of CUALs per subject per post-baseline scan from baseline up 
to EOS
11.3.3.3.1 Hypothesis
Two-sided hypotheses are expressed in terms of the model parameters µPonesimod and 
µPlacebo similar to the primary endpoint. The null hypothesis is that the mean CUALs (µ) 
per subject per scan does not differ between ponesimod and placebo. The alternative 
hypothesis is that the mean CUALs per subject per scan differ between the two 
treatments.
H0, CUAL: µPonesimod - µPlacebo = 0
vs
H1, CUAL: µPonesimod - µPlacebo ≠ 0
The null hypothesis will be tested by a two-sided Wald test within the negative binomial 
regression model at a two-sided alpha of 0.05 [see Section 11.3.2.1].
11.3.3.3.2 Analyses 
The primary analysis of the mean number of CUALs per scan will be performed on the 
FAS using a similar model as described in Section 11.3.2.1 for the primary endpoint, with 
the baseline EDSS category included in the model. The log of the number of scans will 
be used as an offset variable so that estimates will be displayed as mean CUALs per scan. 
Two-sided 95% Wald CIs will be calculated for the relative reduction in mean CUALs
per scan for ponesimod compared to placebo.


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11.3.3.3.3 Supportive analyses
Supportive/sensitivity analyses will include a model with no adjustment for any baseline 
characteristics, models adjusting for additional baseline characteristics, subgroup 
analyses, analysis excluding MRI scans performed within 30 days after treatment with 
corticosteroids and analyses based on the PPS. Different methods of imputation for 
subjects with missing lesion counts will be considered in the SAP.
11.3.3.4 Longitudinal change over time in the fatigue related symptoms domain of the 
FSIQ-RMS from baseline up to EOS
11.3.3.4.1 Hypothesis
FSIQ-RMS-S is a score ranging from 0 to 70 with a higher score indicating more 
pronounced fatigue. This endpoint will be analyzed using a generalized linear mixed 
model to account for repeated measures, to compare the overall absolute change in the 
fatigue score between the two treatment groups. The hypotheses are expressed as a linear 
combination of the fixed-effects and are tested at a two-sided significance level of 0.05:
H0, FSIQ: µPonesimod - µPlacebo = 0
Vs
H1, FSIQ: µPonesimod - µPlacebo ≠ 0
The null-hypothesis will be tested by an F-test.
11.3.3.4.2 Analyses 
The primary analysis of change over time in FSIQ-RMS will be performed on the FAS 
using an adjusted generalized linear mixed model with treatment, time, baseline EDSS 
category as fixed effect and subject as a random effect. An F-test will be used to compare 
the overall mean percent change over time in ponesimod compared to placebo. The 
difference in treatment means and a two-sided 95% CI will also be used to measure the 
overall treatment effect. The differences at each visit, the effect of time and the 
interaction between treatment and time will be assessed within the same model. The 
compound symmetry covariance matrix will be used in the model, however the suitability 
of this structure will be assessed visually and also compared to an unstructured or 
autoregressive covariance matrix by assessing the Akaike’s information criteria.
11.3.3.4.3 Supportive analyses
Supportive analysis will include an unadjusted model excluding the baseline stratification 
variable, an adjusted model including additional baseline covariates, model based on the 
PPS. Missing data imputation will be discussed in the SAP.


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11.3.3.5 Longitudinal percent change from baseline over time in brain volume from 
baseline up to EOS
11.3.3.5.1 Hypothesis
The secondary endpoint percent change from baseline over time in brain volume up to 
EOS will be analyzed using a generalized linear mixed model to account for repeated 
measures, to compare the overall percent change in brain volume between the two 
treatment groups. The hypotheses are expressed as a linear combination of the fixed-
effects and are tested at a two-sided significance level of 0.05:
H0, PCBV: µPonesimod - µPlacebo = 0
vs
H1, PCBV: µPonesimod - µPlacebo ≠ 0
11.3.3.5.2 Analyses 
The primary analysis of percent change from baseline in brain volume will be performed 
on the FAS using an adjusted generalized linear mixed model using the same approach as 
for the FSIQ-RMS secondary endpoint above [Section 11.3.3.4.2].
11.3.3.5.3 Supportive analyses
Supportive analyses will be similar to those described in Section 11.3.3.4.3 for 
FSIQ-RMS.
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. Each 
null hypothesis will be tested with a two-sided significance level set to 0.05 in an 
exploratory manner. All statistical models used will be stratified by baseline EDSS 
category. For analyses by visit, the observed data will be used as primary analysis and a 
supportive analysis will use last observation carried forward (LOCF) or other imputation 
methods where appropriate.
11.3.4.1 Mean number of Gd+ T1, CUAL and new or enlarging T2 lesions by visit
The mean number of Gd+ T1, CUAL and new or enlarging T2 lesions per subject per 
scan up to Week 48, Week 96, Week 144, EOT and EOS will be analyzed using a 
negative binomial regression model similar to that described in Section 11.3.3.4.
11.3.4.2 Change in volume of T2 lesions, volume of T1 hypointense lesions and EDSS 
from baseline to each visit
All variables related to change in lesion volume and change in EDSS at Week 48, 
Week 96, Week 144, EOT and EOS will be analyzed using an analysis of variance


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(ANOVA) with treatment, baseline EDSS category as covariate. Changes to other visits 
will be summarized descriptively. 
11.3.4.3 Absence of Gd+ T1 lesions, absence of new or enlarging T2 lesions, absence 
of new T1 hypointense lesions and subjects relapse-free 
Absence of Gd+ T1 lesions, new T1 hypointense and new or enlarging T2 lesions at 
Week 48, Week 96, Week 144, EOT and EOS will be analyzed using a logistic regression 
model with treatment as a factor, including baseline EDSS category as covariate. Subjects 
that are relapse-free at EOT + 30 days will be analyzed in a similar manner. 
11.3.4.4 Time to first 24-week CDA from baseline to EOS
The analysis for this variable follows the same approach as described in Section 11.3.3.2.
11.3.4.5 NEDA status at EOS
NEDA status at EOS is defined by the absence of confirmed relapses, Gd+ T1 lesions, 
new or enlarging T2 lesions, 12-week CDA, and an annual brain volume decrease of 
≤0.4% from baseline to EOS. If at least one of the five criteria is not fulfilled or the 
subject discontinues treatment prematurely, the subject is not considered to have achieved 
NEDA. NEDA will be analyzed using a logistic regression model with treatment as a 
factor and baseline EDSS category included in the model. 
11.3.4.6 Change of MSFC Z-score and SDMT score from baseline to EOS by visit
The changes from baseline by visit up to the EOS assessment of both scores are analyzed 
using an ANOVA, similar to the analyses described in Section 11.3.4.2.
11.3.4.7 Change of FSIQ-RMS fatigue-related impacts from baseline to EOS by visit 
The changes from baseline by visit up to the EOS assessment of fatigue-related impacts 
as measured by the impact sub-scales of the FSIQ–RMS will be analyzed similarly to 
fatigue-related symptoms in Section 11.3.3.4.
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 30 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. 


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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 or placebo. 
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 using logistic regression. The 
definition of those AEs is provided in Appendix 5.
AEs of special interest and MACE will also be summarized with point estimates and 95% 
CIs for event incidences adjusted for time on treatment and the relative risk ratio of 
ponesimod compared to placebo will be provided without adjustment for multiplicity.
In some cases, time to first onset of AEs of special interest or MACE will be displayed by 
Kaplan-Meier estimates. Subjects not experiencing the safety event will be censored at 
the minimum of the EOS date and 30 days after last dose of study drug. Where 
applicable, ponesimod will be compared to placebo using 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. 
11.3.5.1.3 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 30 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
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 and QTc) will be 
summarized for all data of the 3-hour 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
that were not present before first study drug intake (using data from the ECG provider). 
Cardiac safety events will be summarized as categorical variables. 
11.3.5.3 Pulmonary safety
Descriptive summary statistics by visit and study treatment will be provided for observed 
treatment-emergent values and changes from baseline by visit in FEV1 and FVC (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% from baseline at any time up to EOT + 30 will be summarized by 
treatment.
The trend effect of treatment of the percent predicted FEV1 over time will be analyzed by 
treatment using a regression analysis with time as the independent variable and % 
predicted FEV1 calculated with the 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 and % change from baseline to EOS and from baseline 
to EOT in FEV1 or FVC (absolute and % of predicted) will be plotted by treatment. A 
scatter plot will display the change from baseline to EOS versus 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.
Pulmonary safety events will be summarized as categorical variables. 


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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 descriptively. 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 and percentage changes from baseline for 
laboratory tests (hematology, blood chemistry, urinalysis). Data will be displayed in SI 
units whenever possible and graphical approaches will be applied for certain variables.
The lymphocyte count reversibility after EOT will be summarized by plotting the mean 
(and 95% CIs) change from baseline to EOT and change from baseline to EOS by 
treatment. A scatter plot will display the change from baseline to EOS versus the change 
from baseline to EOT on an individual subject level by study treatment.
Change in JCV serology from baseline up to EOS will be summarized descriptively.
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];

Treatment-emergent laboratory test abnormalities based on FDA guidance for DILI 
[FDA 2009b] (for ALT / AST / total bilirubin).
Laboratory safety events will be summarized as categorical variables. The definition for 
notable abnormalities is provided in Appendix 6.
11.3.6 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.


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11.3.7 Analysis of other variable(s)
11.3.7.1 PK 
Trough level (pre-dose) plasma concentrations of ponesimod at each visit and at EOT, 
and plasma concentrations of ponesimod at 3 hours post-dose at Day 1 and Week 12 will 
be analyzed by descriptive statistics, including arithmetic mean, standard deviation, 
minimum, maximum, and median.
11.3.7.2 PD
The relationship between ponesimod concentration and total lymphocyte counts will be 
investigated by modeling and simulation.
11.3.7.3 Quality of Life Questionnaire (SF-36v2TM)
Data in the health survey domain and component scores will be summarized descriptively 
by visit and study treatment up to EOS in the FAS.
11.3.7.4 WPAI:MS Questionnaire
Data in the pharmacoeconomic WPAI:MS Questionnaire will be summarized 
descriptively by visit and study treatment, up to EOS in the FAS.
11.3.7.5 Health care resource utilization 
Data on health care resource utilization will be summarized descriptively by visit and 
study treatment, up to EOT in the FAS.
11.4 Interim analyses
No interim analysis is planned for the study.
11.5 Sample size
The sample size is calculated based on the primary endpoint, and the power is calculated 
for the time to 12-week CDA secondary 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 600 subjects (300 per treatment group) will 
provide a power of approximately 90% for a significance level of 0.05, under the 
assumption that the ARR (for confirmed relapses up to EOS) is 0.50 for placebo and 
0.325 for ponesimod (which corresponds to a risk reduction of 35%), and using a 
dispersion k = 1.3 (where the variance is = µ + k µ2). A mean subject follow-up of 
1.9 years is assumed with 3.3 years maximum follow-up. 
The dispersion from the ponesimod Phase 2 study was 1.0; a higher dispersion is 
assumed here due to the potentially higher disease activity in this subject population.


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11.5.2 Secondary endpoints 
Assuming 12-week CDA rate at 2 years for placebo of 0.3 and a hazard ratio of 
0.55 (i.e., 2-year progression of 0.165 for ponesimod), a maximum number of 120 events 
are required to attain an approximate power of 90% for a two-sided significance level of 
0.05. 
11.5.3 Sample size sensitivity
The power for varying different assumptions of placebo ARR, % reduction, dispersion 
and mean follow-up time is presented in the table below. 
Annualized Relapse Rate
% 
Reduction
Dispersion
Mean FU 
Time
Power
Placebo
Ponesimod
Varying Placebo ARR up to EOS
0.400
0.260
35.0%
1.3
1.9
86.5%
0.600
0.390
35.0%
1.3
1.9
92.5%
Varying % Reduction
0.500
0.375
25.0%
1.3
1.9
60.1%
0.500
0.350
30.0%
1.3
1.9
77.7%
0.500
0.288
42.5%
1.3
1.9
98.4%
Varying Dispersion
0.500
0.325
35.0%
0.5
1.9
97.3%
0.500
0.325
35.0%
2.0
1.9
82.3%
Varying Follow-Up Time
0.500
0.325
35.0%
1.3
1.4
84.9%
0.500
0.325
35.0%
1.3
2.5
93.4%
11.5.4 Sample size re-estimation
There is no sample-size re-estimation planned.
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.
Electronic CRF data will be captured via electronic data capture (using the Rave system 
provided by Medidata Solutions, Inc., a web-based tool). The investigator and site staff 
will be trained to enter and edit the data via a secure network, with secure access features 


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(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 5.1.4.2 and 10.1.5].
Entries recorded by the subject in the electronic diary (FSIQ-RMS, SF-36v2TM, 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, a eCRF must be 
completed and signed by the investigator/delegate. This also applies to those subjects 
who fail to complete the study. If a subject withdraws from the study, the reason must be 
noted on the eCRF. 
12.2 Maintenance of data confidentiality
The investigator/delegate must ensure that data confidentiality is maintained. On 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 


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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, eDiary, 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 date 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.
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 


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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’s local language(s) and will be translated to the 
subject’s preferred language if requested by the subject due to difficulties understanding 
the local language.
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.
A copy of the signed and dated ICF is given to the subject and/or legal representative; the 
original is filed in the site documentation. 
The informed consent process must be fully documented in the subject’s medical records, 
including study reference, subject number, date/time (if applicable) when the subject was 
first introduced to the Actelion clinical study, date/time (if applicable) of consent, who 
participated in the consent discussion, who consented the subject and any additional 
person present during the consent process (e.g., subject family member), copy of the 
signed ICF given to the subject / legal representative.
Re-screening requires re-consenting i.e., a new ICF must be signed by the subject and the 
investigator.
Re-consent
In order to ensure subjects are made aware of potential risks and benefits of continuing in 
the study as well as alternative treatment options available, subjects who continue study 
treatment and DMF background therapy upon experiencing a confirmed relapse or a 
24-week CDA while on study drug will be asked to re-consent to continue receiving 
study treatment. 


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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.
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 


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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.
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.


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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.
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 


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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.
13.12 Reporting of study results and publication 
Study results will be documented in a clinical study report that will be signed by Actelion 
representatives and the coordinating investigator (or principal investigator for 
single-center studies).
The coordinating investigator 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 Clinical Trial Register (VICTOR) 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


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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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2006;354(9):911-23.
[Scannevin 2012] Scannevin RH, Chollate S, Jung MY, Shackett M, Patel H, Bista P, et 
al. Fumarates promote cytoprotection of central nervous system cells against 
oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway. 
J Pharmacol Exp Ther 2012;341(1):274-84.
[Schilling 2006] Schilling S, Goelz S, Linker R, Luehder F, Gold R. Fumaric acid esters 
are effective in chronic experimental autoimmune encephalomyelitis and suppress 
macrophage infiltration. Clin Exp Immunol 2006;145(1):101-7.
[Schwab 2007] Schwab JM, Cyster JG. Finding a way out: lymphocyte egress from 
lymphoid organs. Nat Immunol 2007;8:1295–301.
[Smith 1982] Smith A. Symbol digit modalities test: Manual, (Western Psychological 
Services, Los Angeles, 1982).
[Smith 2001] Smith SM, De Stefano N, Jenkinson M, et al. Normalised accurate 
measurement of longitudinal brain change. J Comput Assist Tomogr 
2001;25(3):466–475.
[Smith 2002] Smith SM, Zhang Y, Jenkinson M, et al. Accurate, robust and automated 
longitudinal 
and 
cross-sectional 
brain 
change 
analysis. 
Neuroimage 
2002;17(1):479–489.
[Sobel 2013] Sobel K, Menyhart K, Killer N, Renault B, Bauer Y, Studer R, et al. 
Sphingosine 1-phosphate (S1P) receptor agonists mediate pro-fibrotic responses in 
normal human lung fibroblasts via S1P2 and S1P3 receptors and Smad-independent 
signaling. J Biol Chem 2013;288(21):14839-51. 
[Sormani 2009] Sormani MP , Bonzano L, Roccatagliata L, Cutter GR, Mancardi GL, 
Bruzzi P. Magnetic resonance imaging as a potential surrogate for relapses in 
multiple sclerosis: a meta-analytic approach. Ann Neurol 2009;65:268–275;
[Sormani 2013] Sormani MP, Bruzzi P. MRI lesions as a surrogate for relapses in 
multiple sclerosis: a meta-analysis of randomised trials. Lancet Neurol. 2013 Jul; 
12(7):669-76.
[Steiner 2007] Steiner I, Kennedy PG, Pachner AR. The neurotropic herpes viruses: 
herpes simplex and varicella-zoster. Lancet Neurol 2007;6:1015–28.
[Steinvorth 2013] Steinvorth SM, Röver Christian, Schneider S, et al. Explaining 
temporal trends in annualized relapse rates in placebo groups of randomized 


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controlled trials in 
relapsing multiple sclerosis: 
systemic review and 
metaregression. MSJ 2103;19:1580–6.
[Tecfidera USPI] Tecfidera® (dimethyl fumarate) oral tablets – Full prescribing 
information. Available from:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204063lbl.pdf
[Tecfidera SmPC] Tecfidera® Summary of product characteristics. European Medicines 
Agency Tecfidera® product information. Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/002601/WC500162069.pdf
[Torkildsen 2016] Torkildsen Ø, Myhr KM, Bø L. Disease-modifying treatments for 
multiple sclerosis - a review of approved medications. Eur J Neurol. 2016 Jan; 23 
Suppl 1:18-27.
[Van Schependom 2015] 
Van 
Schependom 
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print]
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[WHO 2008] Thompson AJ, Rompani P, Dua T, et al. WHO/MSIF: Atlas of MS: 
multiple sclerosis resources across the world. Mult Scler 2008; S153.
[Yousry 2012] Yousry TA1, Pelletier D, Cadavid D, Gass A, Richert ND, Radue EW, 
Filippi M. Magnetic resonance imaging pattern in natalizumab-associated 
progressive multifocal leukoencephalopathy. Ann Neurol. 2012 Nov;72(5):779-87.


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15 APPENDICES
Appendix 1
Neurostatus® scoring sheet


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PPD


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Appendix 2
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 if 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 3
Prohibited anti-arrhythmic and HR-lowering drugs
The following anti-arrhythmic and HR-lowering drugs (systemic administration) are 
prohibited during the study [see Section 5.2.6]:
       Adenosine
       Lidocaine
       Acebutolol
       Lorajmine
       Ajmaline
       Lorcainide
       Amiodarone
       Metoprolol
       Aprinidine
       Mexiletine
       Atenolol
       Moracizine
       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 4
Guidance for concomitant treatment with QT-prolonging drugs with 
known risk of Torsades de Pointes
QT-prolonging medications with known risk of Torsades de Pointes (e.g., azithromycin, 
citalopram, clarithromycin, erythromycin, escitalopram, moxifloxacin, etc.) should be 
administered with caution since ponesimod may potentially enhance their effect on QT 
interval. A list of QT-prolonging medications with known risk of TdP is published by 
AZCERT [University of Arizona CERT http://crediblemeds.org/]. The investigator 
should also take into account other relevant risk factors such as hypokalemia 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 5.1.9] after the QT-prolonging drug 
has been stopped or once the QT-prolonging drug has reached the steady-state.
−
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.
−
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. 
−
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 steady-state [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 5
Adverse events of special interest
Adverse events of special interest (AESIs) will include the anticipated risks of treatment
with ponesimod and the events that may be related to MS comorbitities (e.g., seizures or 
stroke), and will address the following safety areas: 

Effect on heart rate and rhythm AESIs (including hypotension) 

Hepatobiliary disorders / Liver enzyme abnormality AESIs

Pulmonary AESIs 

Macular edema AESIs

Infection AESIs

Herpetic infection AESIs

Skin malignancy AESIs

Non-skin malignancy related AESIs

Cardiovascular AESIs

Hypertension AESIs

Stroke AESIs

Seizure AESIs
A list of AESIs (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 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 the table below may be defined in the central laboratory manual. 


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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
> 600
> 999
RBC count (1012 /L)
ND
ND
ND
ND
WBC count (109 /L)
NA
< 1.9
> 20.0
ALERT:
> 20.0
> 100.0
Lymphocyte (109 /L)
ND
< 0.2
ALERT:
< 0.2
Decrease of > 50 % 
from the value of 
total lymphocyte 
count recorded at 
Visit 5 (Week 4) 
associated with a 
total lymphocyte 
count < 0.5 109/L 
recorded at two 
consecutive visits 
after Visit 5 
(Week 4)
> 4.0
≥ 8
Neutrophils (109 /L) 
< 1.5 
< 1.0
ND
ND


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Parameter (SI unit)
LL
LLL
HH
HHH
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
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
Creatinine clearance (mL/min)
< 60 
< 30 
ND
ND
Urea (mmol/L)
ND
ND
> 2.5 ULN
> 5 ULN


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Parameter (SI unit)
LL
LLL
HH
HHH
Albumin (g/L)
< 30 
< 20
ND
ND
Protein total (g/L)
ND
ND
ND
ND
C-reactive protein (mg/L)
ND
ND
ND
ND
Glucose (mmol/L)
< 3.0
< 2.2
> 8.9
>13.9
Potassium (mmol/L)
< 3.2
< 3.0
> 5.5
> 6.0
Sodium (mmol/L)
ND
< 130
> 150 
> 155 
Calcium (mmol/L)
< 2.0 
< 1.75
> 2.9
> 3.1
Chloride (mmol/L)
ND
ND
ND
ND
Triglyceride (mmol/L)
ND
ND
> 3.42
> 11.4
Cholesterol (mmol/L)
ND
ND
> 7.75
> 12.92
Serum pregnancy test
ND
ND
ND
Positive
ALERT: 
Positive
* HH and HHH based on CTCAE 2010 v4.03 [CTCAE 2010]. An ALERT wil 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 Section 7.3.13.1]; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; NA = not applicable; INR = International Normalized Ratio; MCH = mean corpuscular hemoglobin; MCV = mean corpuscular volume;
ND = not defined; may be complemented by definitions provided by the central laboratory (see central laboratory manual); RBC = red blood count; 
SI = international system of units; ULN = upper limit of normal; WBC = white blood cell.


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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 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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Doc No D-17.622


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 241/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 242/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
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.


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 243/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Appendix 9
Fatigue Symptoms and Impacts Questionnaire – Relapsing Multiple 
Sclerosis
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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Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 244/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Section 1
Please enter today’s date: DD/MM/YYYY
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


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 245/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
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


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 246/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
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


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 247/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
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


Ponesimod / ACT-128800
Relapsing multiple sclerosis
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Version 6
21 December 2017, page 248/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
3.
Thinking about your fatigue-related symptoms over the past 7 days, how much difficulty 
did you have thinking clearly?
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


Ponesimod / ACT-128800
Relapsing multiple sclerosis
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Version 6
21 December 2017, page 249/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
6.
Thinking about your fatigue-related symptoms over the past 7 days, how much difficulty 
did you have walking?
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


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 250/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
9.
Thinking about your fatigue-related symptoms over the past 7 days, how frustrated
were you?
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


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 251/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
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 


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 252/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Appendix 10
SF-36v2™
SF-36v2® Health Survey © 1992, 2000, 2009 
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 response that best 
describes your answer.
In general, would you say your health is:
Excellent
Very good
Good
Fair
Poor
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


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 253/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
The following questions are about activities you might do during a typical day.  
Does your health now limit you in these activities? If so, how much?
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
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
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
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
Does your health now limit you in climbing one flight of stairs? If so, how much?


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 254/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Yes, limited a lot
Yes, limited a little
No, not limited at all
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
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
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
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
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


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 255/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
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 as a result of your 
physical health?
During the past 4 weeks, how much of the time have you 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
During the past 4 weeks, how much of the time have you 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 were you 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 difficulty


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Relapsing multiple sclerosis
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Version 6
21 December 2017, page 256/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
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
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 as a result of any 
emotional problems (such as feeling depressed or anxious)?
During the past 4 weeks, how much of the time have you 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 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 done work or other 
activities less carefully than usual as a result of any emotional problems (such as 
feeling depressed or anxious)?


Ponesimod / ACT-128800
Relapsing multiple sclerosis
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Version 6
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Confidential
EudraCT 2012-000541-12
Doc No D-17.622
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, 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
These questions are about how you feel and how things have been with you 
during the past 4 weeks. For each question, please give the one answer that 


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Relapsing multiple sclerosis
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Version 6
21 December 2017, page 258/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
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
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
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
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


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Relapsing multiple sclerosis
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Version 6
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Confidential
EudraCT 2012-000541-12
Doc No D-17.622
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
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
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
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
How much of the time during the past 4 weeks did you feel tired?
All of the time


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Relapsing multiple sclerosis
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Version 6
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Confidential
EudraCT 2012-000541-12
Doc No D-17.622
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 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 each of the following statements for you?
I seem to get sick a little easier than other people.
Definitely true
Mostly true
Don’t know
Mostly false
Definitely false
I am as healthy as anybody I know.
Definitely true
Mostly true
Don’t know
Mostly false
Definitely false
I expect my health to get worse.
Definitely true


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 261/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Mostly true
Don’t know
Mostly false
Definitely false
My health is excellent.
Definitely true
Mostly true
Don’t know
Mostly false
Definitely false


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 262/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Appendix 11
Work Productivity and Activity Impairment Questionnaire: Multiple 
Sclerosis


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 263/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622


Ponesimod / ACT-128800
Relapsing multiple sclerosis
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Version 6
21 December 2017, page 264/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Appendix 12
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


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Confidential
EudraCT 2012-000541-12
Doc No D-17.622

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


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Confidential
EudraCT 2012-000541-12
Doc No D-17.622

No / not sure → Invite the subject 
to an unscheduled relapse 
assessment 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 relapse assessment 
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
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 one option below

The previous symptoms corresponded to a relapse, which is recorded in 
the eCRF


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Version 6
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EudraCT 2012-000541-12
Doc No D-17.622
→ 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 other and better explanation for the patient’s current symptoms 
than an MS relapse?

Yes → STOP Relapse investigation and enter patient’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)


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Version 6
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EudraCT 2012-000541-12
Doc No D-17.622
Appendix 13
Relapse symptom form
TO BE FILLED OUT BY THE TREATING NEUROLOGIST
Relapse symptom Form
Visual (optic) functions
Did the patient 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 patient 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


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Relapsing multiple sclerosis
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Version 6
21 December 2017, page 269/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Did the patient 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 patient 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 patient 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-058B302, POINT
Version 6
21 December 2017, page 270/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Did the patient 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 patient 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 patient 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-058B302, POINT
Version 6
21 December 2017, page 271/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622

Other
If other, please specify:
Other new or worsening symptoms attributed to relapse but difficult to classify into 
functional systems 
Did the patient report any other symptoms attributable to 
a relapse?

Yes

No

If yes, please specify:


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 272/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Appendix 14
Electronic self-rated version of the Columbia-Suicide Severity Rating 
Scale 
eC-SSRS 2.0 Web Script – Lifetime (Corresponding to Visit 2 [Baseline] assessment)
Core Language:  US-English Web
Introduction
NRT01
In this interview, we are 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.  
<br><br><b>First</b> we will ask about <b>thoughts</b> regarding <b>wanting to be 
dead</b> or killing yourself that you have <b>not actually</b> acted on. 
<br><br><b>Later</b> we will ask about any actions you may have <b>actually done or 
preparations you have made.</b>  We 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? 
Yes
No
Ideation Level = 1
Active Suicide Ideation 
Q02
Have you actually had any thoughts of killing yourself, at any time? 
Yes
No
Ideation Level = 2
Q03
Have you thought about how you might do this? 


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Relapsing multiple sclerosis
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Version 6
21 December 2017, page 273/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Yes
No
Ideation Level = 3
Q03.1
What way of killing yourself did you think of most often? 
with medication 
by hanging 
by jumping 
with a gun 
by some other method 
Q04
At any time, have you ever had any intention of acting on these thoughts of killing 
yourself?  <br><br>As opposed to, you have the thoughts, but you definitely would not 
act on them? 
Yes
No
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? 
Yes
No
Q05q
Did you actually intend to carry out the details of your plan? 
Yes


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Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 274/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
No
Ideation Level = 5
Q05r
How did you intend to kill yourself? 
with medication 
by hanging 
by jumping 
with a gun 
by some other method 
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.  We want to ask you a few more questions about that.  
<br><br>When responding to these questions, we 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? 
less than once a week 
about once a week 
2 to 5 times a week
daily or almost daily
many times a day
Q01b
How long did the thoughts last? 
fleeting\\, lasting seconds to minutes 
less than an hour 


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Relapsing multiple sclerosis
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Version 6
21 December 2017, page 275/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
between 1 and 4 hours 
between 4 and 8 hours 
more than 8 hours 
Q01c
Did you make any attempt to <b>try</b> 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? 
Yes
No
Q01d
How easily could you control or stop these thoughts? 
easily controlled these thoughts 
with a little difficulty 
with some difficulty 
with a lot of difficulty 
unable to control these thoughts 
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? 
Yes
No
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. 
something definitely stopped you 


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Relapsing multiple sclerosis
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Version 6
21 December 2017, page 276/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
something probably stopped you 
you are uncertain whether something stopped you 
something most likely did not stop you 
something definitely did not stop you 
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? 
Yes
No
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?  <br><br>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? 
it was completely to get attention\\, revenge or a reaction from others 
it was mostly to get attention\\, revenge or a reaction from others 
equally to get attention\\, revenge or a reaction from others and to end or stop the pain
mostly to end or stop the pain \\(that is\\, you could not go on living with the pain or how 
you were feeling\\)
completely to end or stop the pain 
Q02aNRT
You indicated before that you had thought of killing yourself.  We want to ask you a few 
more questions about that.  <br><br>When responding to these questions, we want you 
to think about the time you were feeling most suicidal. 


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Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 277/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Q02a
When you were feeling most suicidal, how often did you think of killing yourself? 
less than once a week 
about once a week 
2 to 5 times a week
daily or almost daily
many times a day
Q02b
How long did these thoughts of killing yourself last? 
fleeting\\, lasting seconds to minutes 
less than an hour 
between 1 and 4 hours 
between 4 and 8 hours 
more than 8 hours 
Q02c
Did you make any attempt to <b>try</b> to control or stop these thoughts, whether you 
were successful in controlling them or not? 
Yes
No
Q02d
How easily could you control or stop thinking about killing yourself? 
easily controlled these thoughts 
with a little difficulty 
with some difficulty 
with a lot of difficulty 
unable to control these thoughts 


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Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 278/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Q02e.1
Did you think about things like family, religion, or fear of pain or death that might affect 
your decision about killing yourself? 
Yes
No
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. 
something definitely stopped you 
something probably stopped you 
you are uncertain whether something stopped you 
something most likely did not stop you 
something definitely did not stop you 
Q02f.1
When you thought about killing yourself, did you have a reason in mind like ending your 
pain or getting attention or revenge? 
Yes
No
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?  <br><br>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? 
it was completely to get attention\\, revenge or a reaction from others 


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 279/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
it was mostly to get attention\\, revenge or a reaction from others 
equally to get attention\\, revenge or a reaction from others and to end or stop the pain 
mostly to end or stop the pain \\(that is\\, you could not go on living with the pain or how 
you were feeling\\)
completely to end or stop the pain 
Q03aNRT
You indicated before that you had thought about how you might kill yourself.  We want to 
ask you a few more questions about that.  <br><br>When responding to these questions, 
we 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? 
less than once a week 
about once a week 
2 to 5 times a week
daily or almost daily
many times a day
Q03b
When you had these thoughts, how long did they last? 
fleeting\\, lasting seconds to minutes 
less than an hour 
between 1 and 4 hours 
between 4 and 8 hours 
more than 8 hours 


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Relapsing multiple sclerosis
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Version 6
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Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Q03c
Did you make any attempt to <b>try</b> to control or stop these thoughts, whether you 
were successful in controlling them or not? 
Yes
No
Q03d
How easily could you control or stop thinking about how you might kill yourself? 
easily controlled these thoughts 
with a little difficulty 
with some difficulty 
with a lot of difficulty 
unable to control these thoughts 
Q03e.1
Did you think about things like family, religion, or fear of pain or death that might affect 
your decision about killing yourself? 
Yes
No
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. 
something definitely stopped you 
something probably stopped you 
you are uncertain whether something stopped you 
something most likely did not stop you 
something definitely did not stop you 


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 281/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Q03f.1
When you thought about killing yourself, did you have a reason in mind like ending your 
pain or getting attention or revenge? 
Yes
No
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?  <br><br>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? 
it was completely to get attention\\, revenge or a reaction from others 
it was mostly to get attention\\, revenge or a reaction from others 
equally to get attention\\, revenge or a reaction from others and to end or stop the pain 
mostly to end or stop the pain \\(that is\\, you could not go on living with the pain or how 
you were feeling\\)
completely to end or stop the pain 
Q04aNRT
You indicated before that you had thought about killing yourself and that you had some 
intention of acting on these thoughts.  We want to ask you a few more questions about 
that.  <br><br>When responding to these questions, we 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? 


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 282/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
less than once a week 
about once a week 
2 to 5 times a week
daily or almost daily
many times a day
Q04b
How long did the thoughts last? 
fleeting\\, lasting seconds to minutes 
less than an hour 
between 1 and 4 hours 
between 4 and 8 hours 
more than 8 hours 
Q04c
Did you make any attempt to <b>try</b> to control or stop these thoughts about actually 
killing yourself, whether you were successful in controlling them or not? 
Yes
No
Q04d
How easily could you control or stop thinking about killing yourself? 
easily controlled these thoughts 
with a little difficulty 
with some difficulty 
with a lot of difficulty 
unable to control these thoughts 
Q04e.1
Did you think about things like family, religion, or fear of pain or death that might affect 
your decision about killing yourself? 


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 283/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Yes
No
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. 
something definitely stopped you 
something probably stopped you 
you are uncertain whether something stopped you 
something most likely did not stop you 
something definitely did not stop you 
Q04f.1
When you thought about killing yourself, did you have a reason in mind like ending your 
pain or getting attention or revenge? 
Yes
No
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?  <br><br>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? 
it was completely to get attention\\, revenge or a reaction from others 
it was mostly to get attention\\, revenge or a reaction from others 
equally to get attention\\, revenge or a reaction from others and to end or stop the pain 


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 284/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
mostly to end or stop the pain \\(that is\\, you could not go on living with the pain or how 
you were feeling\\)
completely to end or stop the pain 
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.  We want to ask 
you a few more questions about that.  <br><br>When responding to these questions, we 
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? 
less than once a week 
about once a week 
2 to 5 times a week
daily or almost daily
many times a day
Q05b
How long did the thoughts last? 
fleeting\\, lasting seconds to minutes 
less than an hour 
between 1 and 4 hours 
between 4 and 8 hours 
more than 8 hours 
Q05c
Did you make any attempt to <b>try</b> to control or stop these thoughts about actually 
killing yourself, whether you were successful in controlling them or not? 
Yes


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 285/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
No
Q05d
How easily could you control or stop thinking about killing yourself? 
easily controlled these thoughts 
with a little difficulty 
with some difficulty 
with a lot of difficulty 
unable to control these thoughts 
Q05e.1
Did you think about things like family, religion, or fear of pain or death that might affect 
your decision about killing yourself? 
Yes
No
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. 
something definitely stopped you 
something probably stopped you 
you are uncertain whether something stopped you 
something most likely did not stop you 
something definitely did not stop you 
Q05f.1
When you thought about killing yourself, did you have a reason in mind like ending your 
pain or getting attention or revenge? 
Yes
No


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 286/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
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?  <br><br>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? 
it was completely to get attention\\, revenge or a reaction from others 
it was mostly to get attention\\, revenge or a reaction from others 
equally to get attention\\, revenge or a reaction from others and to end or stop the pain 
mostly to end or stop the pain \\(that is\\, you could not go on living with the pain or how 
you were feeling\\)
completely to end or stop the pain 
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.  <br><br>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? 
Yes
No


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 287/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Level 2 Ideation
You indicated that there has been a time in your life when you had thought of killing 
yourself.  <br><br>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? 
Yes
No
Level 3 Ideation
You indicated that there has been a time in your life when you thought about how you 
might kill yourself.  <br><br>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 did not intend to act on the thoughts?
Yes
No
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.  
<br><br>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? 
Yes
No


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 288/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
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.  <br><br>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? 
Yes
No
Midpoint Transition  (NRT02)
We are almost finished.  <br><br>So far we have been asking about thoughts and feelings 
you may have had.  <br><br>Now we 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? 
Yes
No
Q06b
Use the number keys to enter the number of suicide attempts you have made. 
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-058B302, POINT
Version 6
21 December 2017, page 289/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Q06c
If loop = 1
When you made your most recent attempt, were you trying to end your life? 
Yes
No
If loop = 2
When you made your first attempt, were you trying to end your life? 
Yes
No
If loop = 3
When you made your most serious attempt, were you trying to end your life? 
Yes
No
Q06e
Did you think it was possible that you could have died from what you did? 
Yes
No
Q06d
So then
you wanted to die\\, even a little\\, when you did this
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


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 290/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Q07a
Have you ever done anything to intentionally hurt or harm yourself? 
Yes
No
Q07b
Use the number keys 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?
Yes
No
Q07e
Did you think it was possible that you could have died from what you did? 


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 291/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Yes
No
Q07d
So then
you wanted to die\\, even a little\\, when you did this
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
Q08a
Have you done anything dangerous where you could have died? 
Yes
No
Q08b
Use the number keys 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


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 292/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Q08c_1
Were you trying to harm yourself when you did this? 
Yes
No
Q08c
Were you trying to end your life?
Yes
No
Q08d
So then
you wanted to die\\, even a little\\, when you did this
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
Lethality
Q09
If Q06a = YES
As a result of your <b>most serious</b> attempt, were you injured more seriously than 
surface scratches or mild nausea? 
Yes
No
If Q06a = NO
As a result of the <b>most serious</b> time you tried to hurt yourself, were you injured 
more seriously than surface scratches or mild nausea? 
Yes


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Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 293/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
No
Q09RB
Did this occur within the past  B  months? 
Yes
No
Q09a
Were you hospitalized for <b>medical</b> treatment of the physical injury you suffered?  
<br><br>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?  
<br><br>If you were hospitalized for psychiatric evaluation, but not for medical treatment 
of a severe physical injury, answer No. 
Yes
No
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? 
Yes
No
Q09c
Did your injury cause you to be extremely drowsy, or result in broken bones, or severe 
bleeding? 
Yes
No


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Version 6
21 December 2017, page 294/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
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. <br><br>We want to know if you 
suffered any physical injuries. 
Q09.1
If Q06a = YES
As a result of your <b>most recent</b> attempt, were you injured more seriously than 
surface scratches or mild nausea?  
Yes
No
If Q06a = NO
As a result of the <b>most recent</b> time you tried to hurt yourself, were you injured 
more seriously than surface scratches or mild nausea? 
Yes
No
Q09.1RB
Did this occur within the past  B  months? 
Yes
No
Q09.1a
Were you hospitalized for <b>medical</b> treatment of the physical injury you suffered?  
<br><br>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?  
<br><br>If you were hospitalized for psychiatric evaluation, but not for medical treatment 
of a severe physical injury, answer No. 


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Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 295/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Yes
No
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? 
Yes
No
Q09.1c
Did your injury cause you to be extremely drowsy, or result in broken bones, or severe 
bleeding? 
Yes
No
Q09.2
If Q06a = YES
As a result of your <b>first</b> attempt, were you injured more seriously than surface 
scratches or mild nausea?
Yes
No
If Q06a = NO
As a result of the <b>first</b> time you tried to hurt yourself, were you injured more 
seriously than surface scratches or mild nausea? 
Yes
No


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Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 296/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Q09.2RB
Did this occur within the past  B  months? 
Yes
No
Q09.2a
Were you hospitalized for <b>medical</b> treatment of the physical injury you suffered?  
<br><br>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?  
<br><br>If you were hospitalized for psychiatric evaluation, but not for medical treatment 
of a severe physical injury, answer No. 
Yes
No
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? 
Yes
No
Q09.2c
Did your injury cause you to be extremely drowsy, or result in broken bones, or severe 
bleeding? 
Yes
No


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Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 297/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
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. <br><br>Now we want to know if you 
suffered any physical injuries each time. 
Q09.4
If Q06a = YES
As a result of your <b>most recent</b> attempt, were you injured more seriously than 
surface scratches or mild nausea?  
Yes
No
If Q06a = NO
As a result of the <b>most recent</b> time you tried to hurt yourself, were you injured 
more seriously than surface scratches or mild nausea? 
Yes
No
Q09.4RB
Did this occur within the past  B  months? 
Yes
No
Q09.4a
Were you hospitalized for <b>medical</b> treatment of the physical injury you suffered?  
<br><br>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?  
<br><br>If you were hospitalized for psychiatric evaluation, but not for medical treatment 
of a severe physical injury, answer No. 


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Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 298/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Yes
No
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? 
Yes
No
Q09.4c
Did your injury cause you to be extremely drowsy, or result in broken bones, or severe 
bleeding? 
Yes
No
Q09.5
If Q06a = YES
As a result of your <b>first</b> attempt, were you injured more seriously than surface 
scratches or mild nausea?
Yes
No
If Q06a = NO
As a result of the <b>first</b> time you tried to hurt yourself, were you injured more 
seriously than surface scratches or mild nausea? 
Yes
No


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Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 299/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Q09.5a
Were you hospitalized for <b>medical</b> treatment of the physical injury you suffered?  
<br><br>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?  
<br><br>If you were hospitalized for psychiatric evaluation, but not for medical treatment 
of a severe physical injury, answer No. 
Yes
No
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? 
Yes
No
Q09.5c
Did your injury cause you to be extremely drowsy, or result in broken bones, or severe 
bleeding? 
Yes
No
Q09.6
If Q06a = YES
As a result of your <b>most serious</b> attempt, were you injured more seriously than 
surface scratches or mild nausea? 
Yes
No


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Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 300/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
If Q06a = NO
As a result of the <b>most serious</b> time you tried to hurt yourself, were you injured 
more seriously than surface scratches or mild nausea? 
Yes
No
Q09.6a
Were you hospitalized for <b>medical</b> treatment of the physical injury you suffered?  
<br><br>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?  
<br><br>If you were hospitalized for psychiatric evaluation, but not for medical treatment 
of a severe physical injury, answer No. 
Yes
No
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? 
Yes
No
Q09.6c
Did your injury cause you to be extremely drowsy, or result in broken bones, or severe 
bleeding? 
Yes
No
Q09.8RB
Did this occur within the past  B  months? 


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Relapsing multiple sclerosis
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Version 6
21 December 2017, page 301/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Yes
No
Q09.8
Although you were not injured <b>most recently</b>, how serious could your injuries 
have been? 
what you did was not likely to cause injury 
what you did was likely to cause physical injury\\, but probably not death 
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 
Q09.9
Although you were not injured the <b>first</b> time, how serious could your injuries 
have been? 
what you did was not likely to cause injury 
what you did was likely to cause physical injury, but probably not death 
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 
Q09.10RB
Did this occur within the past  B  months? 
Yes
No
Q09.10
Although you were not injured during the <b>most serious</b> time, how serious could 
your injuries have been? 


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Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 302/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
what you did was not likely to cause injury 
what you did was likely to cause physical injury\\, but probably not death 
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 
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?
Yes
No
Q10a
About how many times have you been stopped from ending your life by someone or 
something? 
Please enter the number.
Q10RB
Was the last time you were stopped from trying to end your life by someone or 
something in the past  B  months? 
Yes
No
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? 
Yes


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Relapsing multiple sclerosis
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Version 6
21 December 2017, page 303/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
No
Q11a
About how many times have you stopped yourself from ending your life? 
Please enter the number.
Q11RB
Was the last time you stopped yourself from trying to end your life in the past  B  
months? 
Yes
No
Preparatory Acts or Behaviors
Q12NRT
Asses prior responses and present introduction:
<b>Other</b> than the times you have already told us 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, 
<b>Other</b> than the times you have already told us 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,
<b>Other</b> than the times you have already told us 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,
<b>Other</b> than the times you have already told us 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,


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Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 304/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
<b>Other</b> than the times you have already told us about when you did things 
intending to kill yourself or thought you might have died, 
<b>Other</b> than the times you have already told us about when you started to do 
something to end your life but someone or something stopped you,
<b>Other</b> than the times you have already told us 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?
Yes
No
Q12a
About how many times?
Please enter the number.
Q12RB
Was the last time you took steps toward making a suicide attempt or preparing to kill 
yourself in the past B  months? 
Yes
No
Exit
You have completed your interview.  Thank you and Good bye.


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Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 305/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
eC-SSRS Web Script – Since Last Call (Corresponding to Visit 9 [Week 48], Visit 13 
[Week 96], Visit 17 [Week 144] and Visit 18 [EOT] 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 Web
Introduction
NRT01
The last time you were interviewed about thoughts or actions related to wanting to be 
dead or killing yourself was  [day] [date].  That was [num] days ago.  <br><br>During 
<b>this</b> interview we want you to <b>only</b> consider thoughts or actions that 
have occurred since that date.  <br><br>In answering the following questions, only 
report your thoughts and actions over the past  [num] days or since [day] [date].
If days SLC > 120
The last time you were interviewed about thoughts or actions related to wanting to be 
dead or killing yourself was  [day] [date].  <br><br>During <b>this</b> interview we 
want you to <b>only</b> consider thoughts or actions that have occurred since that 
date.  <br><br>In answering the following questions, only report your thoughts and 
actions since  [day] [date].
Passive Suicide Ideation 
Q01
Since your last interview, have you wished you were dead or wished you could go to 
sleep and not wake up?
Yes
No
Ideation Level = 1


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21 December 2017, page 306/330
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EudraCT 2012-000541-12
Doc No D-17.622
Active Suicide Ideation 
Q02
Since your last interview on [day] [date], [num] days ago have you actually had any 
thoughts of killing yourself?
If days SLC > 120
Since your last interview on [day] [date], have you actually had any thoughts of killing 
yourself?
Yes
No
Ideation Level = 2
Q03
Have you thought about how you might do this? 
Yes
No
Ideation Level = 3
Q03.1
What way of killing yourself did you think of most often?
with medication 
by hanging 
by jumping 
with a gun 
by some other method 


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Relapsing multiple sclerosis
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Version 6
21 December 2017, page 307/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Q04
Since your last interview, have you had any intention of acting on these thoughts of 
killing yourself?  <br><br>As opposed to, you have the thoughts, but you definitely 
would not act on them?
Yes
No
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 interview? 
Yes
No
Q05q
Did you actually intend to carry out the details of your plan?
Yes
No
Ideation Level = 5
Q05r
How did you intend to kill yourself?
with medication 
by hanging 
by jumping 
with a gun 
by some other method 


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Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 308/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Ideation Probing 
Q01aNRT
You just indicated that since your last interview, you had wished you were dead or 
wished that you could go to sleep and not wake up.  We want to ask you a few more 
questions about that.  <br><br>When responding to these questions, we want you to 
think about the time when these thoughts were most severe in the past  [num] days.
If days SLC > 120
You just indicated that since your last interview, you had wished you were dead or 
wished that you could go to sleep and not wake up.  We want to ask you a few more 
questions about that.  <br><br>When responding to these questions, we want you to 
think about the time when these thoughts were most severe since your last interview.
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? 
less than once a week 
about once a week 
2 to 5 times a week 
daily or almost daily
many times a day 
Q01b
How long did the thoughts last?
fleeting\\, lasting seconds to minutes 
less than an hour 
between 1 and 4 hours 
between 4 and 8 hours 
more than 8 hours 


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Version 6
21 December 2017, page 309/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Q01c
Did you make any attempt to <b>try</b> 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?
Yes
No
Q01d
How easily could you control or stop these thoughts? 
easily controlled these thoughts 
with a little difficulty 
with some difficulty 
with a lot of difficulty 
unable to control these thoughts 
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? 
Yes
No
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. 
something definitely stopped you 
something probably stopped you 
you are uncertain whether something stopped you 
something most likely did not stop you 
something definitely did not stop you 


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Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 310/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
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? 
Yes
No
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?  <br><br>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? 
it was completely to get attention\\, revenge or a reaction from others 
it was mostly to get attention\\, revenge or a reaction from others 
equally to get attention\\, revenge or a reaction from others and to end or stop the pain
mostly to end or stop the pain \\(that is\\, you could not go on living with the pain or 
how you were feeling\\) 
completely to end or stop the pain 
Q02aNRT
You indicated before that since your last interview you had thought of killing yourself. 
We want to ask you a few more questions about that. <br><br>When responding to 
these questions, we 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 interview you had thought of killing yourself. 
We want to ask you a few more questions about that. <br><br>When responding to 
these questions, we want you to think about the time you were feeling most suicidal 
since your last interview.


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 311/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Q02a
When you were feeling most suicidal, how often did you think of killing yourself? 
less than once a week 
about once a week 
2 to 5 times a week 
daily or almost daily
many times a day 
Q02b
How long did these thoughts of killing yourself last? 
fleeting\\, lasting seconds to minutes 
less than an hour 
between 1 and 4 hours 
between 4 and 8 hours 
more than 8 hours 
Q02c
Did you make any attempt to <b>try</b> to control or stop these thoughts, whether you 
were successful in controlling them or not? 
Yes
No
Q02d
How easily could you control or stop thinking about killing yourself? 
easily controlled these thoughts 
with a little difficulty 
with some difficulty 
with a lot of difficulty 
unable to control these thoughts 


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Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 312/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Q02e.1
Did you think about things like family, religion, or fear of pain or death that might affect 
your decision about killing yourself? 
Yes
No
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. 
something definitely stopped you 
something probably stopped you 
you are uncertain whether something stopped you 
something most likely did not stop you 
something definitely did not stop you 
Q02f.1
When you thought about killing yourself, did you have a reason in mind like ending your 
pain or getting attention or revenge? 
Yes
No
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?  <br><br>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? 
it was completely to get attention\\, revenge or a reaction from others 
it was mostly to get attention\\, revenge or a reaction from others 
equally to get attention\\, revenge or a reaction from others and to end or stop the pain 


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 313/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
mostly to end or stop the pain \\(that is\\, you could not go on living with the pain or 
how you were feeling\\) 
completely to end or stop the pain 
Q03aNRT
You indicated before that since your last interview you had thought about how you 
might kill yourself. We want to ask you a few more questions about that. <br><br>When 
responding to these questions, we 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 interview you had thought about how you 
might kill yourself. We want to ask you a few more questions about that. <br><br>When 
responding to these questions, we want you to think about the time you were feeling 
the most suicidal since your last interview.
Q03a
When you were feeling most suicidal, how often did you think about how you might kill 
yourself? 
less than once a week 
about once a week 
2 to 5 times a week 
daily or almost daily
many times a day 
Q03b
When you had these thoughts, how long did they last? 
fleeting\\, lasting seconds to minutes 
less than an hour 
between 1 and 4 hours 
between 4 and 8 hours 
more than 8 hours 


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Relapsing multiple sclerosis
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Version 6
21 December 2017, page 314/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Q03c
Did you make any attempt to <b>try</b> to control or stop these thoughts, whether you 
were successful in controlling them or not? 
Yes
No
Q03d
How easily could you control or stop thinking about how you might kill yourself?
easily controlled these thoughts 
with a little difficulty 
with some difficulty 
with a lot of difficulty 
unable to control these thoughts 
Q03e.1
Did you think about things like family, religion, or fear of pain or death that might affect 
your decision about killing yourself? 
Yes
No
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. 
something definitely stopped you 
something probably stopped you 
you are uncertain whether something stopped you 
something most likely did not stop you 
something definitely did not stop you 


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 315/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
Q03f.1
When you thought about killing yourself, did you have a reason in mind like ending your 
pain or getting attention or revenge? 
Yes
No
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?  <br><br>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? 
it was completely to get attention\\, revenge or a reaction from others 
it was mostly to get attention\\, revenge or a reaction from others 
equally to get attention\\, revenge or a reaction from others and to end or stop the pain 
mostly to end or stop the pain \\(that is\\, you could not go on living with the pain or 
how you were feeling\\) 
completely to end or stop the pain 
Q04aNRT
You indicated before that since your last interview you thought about killing yourself 
and that you had some intention of acting on these thoughts.  We want to ask you a few 
more questions about that.  <br><br>When responding to these questions, we 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 interview you thought about killing yourself 
and that you had some intention of acting on these thoughts.  We want to ask you a few 
more questions about that.  <br><br>When responding to these questions, we want you 
to think about the time you were feeling the most suicidal since your last interview.


Ponesimod / ACT-128800
Relapsing multiple sclerosis
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Version 6
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Confidential
EudraCT 2012-000541-12
Doc No D-17.622
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? 
less than once a week 
about once a week 
2 to 5 times a week 
daily or almost daily
many times a day 
Q04b
How long did the thoughts last?
fleeting\\, lasting seconds to minutes 
less than an hour 
between 1 and 4 hours 
between 4 and 8 hours 
more than 8 hours 
Q04c
Did you make any attempt to <b>try</b> to control or stop these thoughts about 
actually killing yourself, whether you were successful in controlling them or not?
Yes
No
Q04d
How easily could you control or stop thinking about killing yourself? 
easily controlled these thoughts 
with a little difficulty 
with some difficulty 
with a lot of difficulty 


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Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 317/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
unable to control these thoughts 
Q04e.1
Did you think about things like family, religion, or fear of pain or death that might affect 
your decision about killing yourself? 
Yes
No
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. 
something definitely stopped you 
something probably stopped you 
you are uncertain whether something stopped you 
something most likely did not stop you 
something definitely did not stop you 
Q04f.1
When you thought about killing yourself, did you have a reason in mind like ending your 
pain or getting attention or revenge? 
Yes
No
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?  <br><br>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? 
it was completely to get attention\\, revenge or a reaction from others 
it was mostly to get attention\\, revenge or a reaction from others 


Ponesimod / ACT-128800
Relapsing multiple sclerosis
Protocol AC-058B302, POINT
Version 6
21 December 2017, page 318/330
Confidential
EudraCT 2012-000541-12
Doc No D-17.622
equally to get attention\\, revenge or a reaction from others and to end or stop the pain 
mostly to end or stop the pain \\(that is\\, you could not go on living with the pain or 
how you were feeling\\) 
completely to end or stop the pain 
Q05aNRT
You indicated before that since your last interview 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. We want to ask you a few more questions about that. <br><br>When 
responding to these questions, we 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 interview 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. We want to ask you a few more questions about that. <br><br>When 
responding to these questions, we want you to think about the time you were feeling 
the most suicidal since your last interview.
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?
less than once a week 
about once a week 
2 to 5 times a week 
daily or almost daily
many times a day 
Q05b
How long did the thoughts last?
fleeting\\, lasting seconds to minutes 


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less than an hour 
between 1 and 4 hours 
between 4 and 8 hours 
more than 8 hours 
Q05c
Did you make any attempt to <b>try</b> to control or stop these thoughts about 
actually killing yourself, whether you were successful in controlling them or not?
Yes
No
Q05d
How easily could you control or stop thinking about killing yourself? 
easily controlled these thoughts 
with a little difficulty 
with some difficulty 
with a lot of difficulty 
unable to control these thoughts 
Q05e.1
Did you think about things like family, religion, or fear of pain or death that might affect 
your decision about killing yourself? 
Yes
No
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. 
something definitely stopped you 
something probably stopped you 


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Doc No D-17.622
you are uncertain whether something stopped you 
something most likely did not stop you 
something definitely did not stop you 
Q05f.1
When you thought about killing yourself, did you have a reason in mind like ending your 
pain or getting attention or revenge? 
Yes
No
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?  <br><br>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? 
it was completely to get attention\\, revenge or a reaction from others 
it was mostly to get attention\\, revenge or a reaction from others 
equally to get attention\\, revenge or a reaction from others and to end or stop the pain 
mostly to end or stop the pain \\(that is\\, you could not go on living with the pain or 
how you were feeling\\) 
completely to end or stop the pain 
Midpoint Transition  (NRT02)
We are almost finished.  <br><br>So far we have been asking about thoughts and 
feelings you may have had.  <br><br>Now we would like to know about things you may 
have done to try to hurt yourself since your last interview.
Suicidal Behavior 
Q06a
Since your last interview on [day] [date] have you made a suicide attempt?


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Doc No D-17.622
Yes
No
Q06b
Use the number keys to enter the number of suicide attempts you have made since your 
last interview. 
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?
Yes
No
If loop = 2
When you made your first attempt, were you trying to end your life?
Yes
No
If loop = 3
When you made your most serious attempt, were you trying to end your life?
Yes
No


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Doc No D-17.622
Q06e
Did you think it was possible that you could have died from what you did?
Yes
No
Q06d
So then
you wanted to die\\, even a little\\, when you did this
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
Q07a
Since your last interview, have you done anything to intentionally hurt or harm 
yourself?
Yes
No
Q07b
Use the number keys to enter the number of times you have intentionally hurt or 
harmed yourself since your last interview. 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. 


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Doc No D-17.622
If loop > 1
Consider the time you hurt or harmed yourself before that
Q07c
Were you trying to end your life?
Yes
No
Q07e
Did you think it was possible that you could have died from what you did?
Yes
No
Q07d
So then
you wanted to die\\, even a little\\, when you did this
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
Q08a
Since your last interview, have you done anything dangerous where you could have 
died?
Yes
No
Q08b
Use the number keys to enter the number of times you have done dangerous activities 
where you could have died in the past [num] days.


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Doc No D-17.622
If days SLC > 120
Use the number keys to enter the number of times you have done dangerous activities 
where you could have died since your last interview.
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?
Yes
No
Q08c
Were you trying to end your life?
Yes
No
Q08d
So then
you wanted to die\\, even a little\\, when you did this


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Protocol AC-058B302, POINT
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EudraCT 2012-000541-12
Doc No D-17.622
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
Lethality
Q09
If Q06a = YES
As a result of your <b>most serious</b> attempt since your last interview, were you 
injured more seriously than surface scratches or mild nausea?
Yes
No
If Q06a = NO
As a result of the <b>most serious</b> time you tried to hurt yourself  since your last 
interview, were you injured more seriously than surface scratches or mild nausea?
Yes
No
Q09a
Were you hospitalized for <b>medical</b> treatment of the physical injury you 
suffered?  <br><br>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?  <br><br>If you were hospitalized for psychiatric evaluation, but not for 
medical treatment of a severe physical injury, answer No.
Yes
No
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?


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Doc No D-17.622
Yes
No
Q09c
Did your injury cause you to be extremely drowsy, or result in broken bones, or severe 
bleeding?
Yes
No
Q09.10
Although you were not injured during the <b>most serious</b> time, how serious could 
your injuries have been?
what you did was not likely to cause injury 
what you did was likely to cause physical injury\\, but probably not death 
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 
Interrupted Attempts
Q10
Since your last interview, 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?
Yes
No
Q10a
About how many times have you been stopped from ending your life by someone or 
something since your last interview?  
Please enter the number.


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Doc No D-17.622
Aborted Attempts
Q11
Since your last interview, 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?
Yes
No
Q11a
About how many times have you stopped yourself from ending your life in the last  
[num] days, since your last interview? 
If days SLC > 120
About how many times have you stopped yourself from ending your life since your last 
interview? 
Please enter the number.
Preparatory Acts or Behaviors
Q12NRT
Asses prior responses and present introduction:
<b>Other</b> than the times you have already told us about since your last interview 
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,
<b>Other</b> than the times you have already told us about since your last interview 
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,
<b>Other</b> than the times you have already told us about since your last interview 
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


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Version 6
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EudraCT 2012-000541-12
Doc No D-17.622
<b>Other</b> than the times you have already told us about since your last interview 
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,
<b>Other</b> than the times you have already told us about since your last interview 
when you did things intending to kill yourself or thought you might have died,
<b>Other</b> than the times you have already told us about since your last interview 
when you started to do something to end your life but someone or something stopped 
you,
<b>Other</b> than the times you have already told us about since your last interview 
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?
Yes
No
Q12a
About how many times?
Please enter the number.
Exit
You have completed your interview.  Thank you and Good bye.


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Doc No D-17.622
Appendix 15
Guidance for re-screening
It is permitted to re-screen subjects once if the reason for non-eligibility was transient 
(e.g., abnormal laboratory test, insufficient wash-out period of a forbidden medication), 
provided that documented authorization has been received from Actelion. Re-screening 
requires re-consenting i.e., a new Informed Consent Form must be signed by the subject
and the PI.

If the screening failure was due to a laboratory result (i.e., one or more 
hematology variables and/or one or more biochemistry variables were out of 
eligibility range) from Visit 1 (Screening):
o
All hematology and/or blood chemistry assessments from Visit 1 
(Screening) need to be repeated and will then be used for assessing 
eligibility.
o
Other pre-randomization assessments do not need to be repeated if 
performed within 90 days (with the exception of 12-lead ECG and 
pregnancy test which should be performed within 37 days) prior to the 
date of re-screening and if their outcome was not exclusionary.

If the screening failure was due to a laboratory result from Visit 2 (Baseline):
o
Laboratory assessments from Visit 2 (Baseline) must be repeated.
o
Laboratory assessments from Visit 1 (Screening) must be repeated unless
performed within 37 days prior to the re-screening. In this case, laboratory 
assessments at Visits 1 and 2 (re-screening) must be performed at least 
21 days apart.
o
Other pre-randomization assessments do not need to be repeated if 
performed within 90 days (with the exception of 12-lead ECG and 
pregnancy test which should be performed within 37 days) prior to the 
date of re-screening and if their outcome was not exclusionary.

If the reason for screening failure was due to an assessment other than laboratory 
tests:
o
The assessment leading to the screening failure has to be repeated.
o
Other pre-randomization assessments do not need to be repeated if 
performed within 90 days prior to the date of re-screening (with the 
exception of 12-lead ECG, hematology, blood chemistry and pregnancy 
test which should be performed within 37 days) and if the outcome was 
not exclusionary.


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Doc No D-17.622

If the screening failure wais due to more than one assessment (e.g., laboratory and 
dermatological assessments) and the re-screening was authorized by Actelion:
o
All pre-randomization assessments have to be repeated.

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT 
AC-058B302 
POINT: POnesImod aNd Tecfidera
Multicenter, randomized, double-blind, parallel-group, add-on, superiority study to 
compare the efficacy and safety of ponesimod to placebo in subjects with active relapsing 
multiple sclerosis who are treated with dimethyl fumarate (Tecfidera®)
Purpose of Analysis
Synoptic Clinical Study Report
Investigational Drug
Ponesimod (ACT-128800)
Protocol Number
AC-058B302 / POINT
Actelion Document Number
D-20.202
Document Status/Version Number
Final Version 2.0
Date
16 June 2020
Author
, Trial Statistician
Co-Author
, CROS NT Trial Statistician
Reviewer
, Clinical Statistical Leader
Reviewer
, Clinical Leader
Reviewer
, Scientific Leader
Reviewer
 Medical Safety Physician
Reviewer
 Clinical Trial Physician
Reviewer
, Senior Clinical Scientist
Confidential
Property of Actelion, a Janssen Pharmaceutical Company of Johnson and Johnson
May not be used, divulged, published or otherwise disclosed without the consent of Actelion 
NCT02907177
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Statistical Analysis Plan
For Clinical Study Report
Doc No D-20.202
TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND ACRONYMS ....................................................................... 8
1
INTRODUCTION.................................................................................................................. 11
2
STUDY DESIGN AND FLOW............................................................................................. 11
2.1
Study design ............................................................................................................ 12
2.1.1
Periods ......................................................................................................... 13
2.1.2
Blinding ....................................................................................................... 14
2.1.3
Sub-studies................................................................................................... 15
2.1.3.1
Lymphocyte subset............................................................................. 15
2.2
Study visit and assessment schedule ....................................................................... 15
3
OBJECTIVES ........................................................................................................................ 24
3.1
Primary objective(s) ................................................................................................ 24
3.2
Secondary objectives ............................................................................................... 24
4
CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN THE STUDY 
PROTOCOL........................................................................................................................... 24
4.1
Changes to the analyses planned in the study protocol ........................................... 24
4.2
Changes in the conduct of the study / data collection ............................................. 25
4.3
Clarifications concerning endpoint definitions and related variables or 
statistical methods.................................................................................................... 26
5
DEFINITIONS OF VARIABLES ......................................................................................... 26
5.1
Subject disposition................................................................................................... 26
5.1.1
Screened subjects......................................................................................... 26
5.1.2
Screening failures ........................................................................................ 26
5.1.3
Subjects randomized.................................................................................... 27
5.1.4
Subjects treated............................................................................................ 27
5.1.5
Subject study treatment completion status................................................... 27
5.1.6
Subject study completion status................................................................... 28
5.1.7
Time in study ............................................................................................... 28
5.2
Subject characteristics ............................................................................................. 29
5.2.1
Demographics .............................................................................................. 29
5.2.2
Baseline disease characteristics ................................................................... 29
5.2.3
Previous and concomitant therapies ............................................................ 31
5.2.3.1
Previous therapies............................................................................... 32
5.2.3.2
Treatment concomitant therapies ....................................................... 32
5.2.3.3
Therapies starting after EOT .............................................................. 32
5.3
Exposure and compliance........................................................................................ 32


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Statistical Analysis Plan
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5.3.1
Study treatment exposure and compliance .................................................. 32
5.3.1.1
Study treatment exposure ................................................................... 33
5.3.1.2
Compliance with study treatment....................................................... 33
5.3.2
Study treatment adjustments or interruptions .............................................. 34
5.3.3
DMF exposure and compliance ................................................................... 35
5.3.3.1
DMF exposure during study treatment............................................... 35
5.3.3.2
Compliance with DMF treatment during study treatment.................. 36
5.4
Efficacy variables .................................................................................................... 36
5.4.1
Primary efficacy variable(s): ARR up to EOS............................................. 36
5.4.1.1
General derivation details for relapses ............................................... 37
5.4.1.2
Variables for supplementary analyses of primary endpoint............... 37
5.4.2
Secondary efficacy variables ....................................................................... 37
5.4.2.1
Time to 12-week confirmed disability accumulation (CDA) up to 
EOS .................................................................................................... 37
5.4.2.2
Time to first confirmed relapse .......................................................... 40
5.4.2.3
Number of combined unique active lesions (CUAL) up to EOS....... 40
5.4.3
Exploratory MRI efficacy variables ............................................................ 41
5.4.3.1
Number of CUALs ............................................................................. 42
5.4.3.2
Number of T1 Gd+ lesions................................................................. 42
5.4.3.3
Number of new or enlarging T2 lesions............................................. 43
5.4.4
Other clinical efficacy variables .................................................................. 44
5.4.4.1
Time to 24-week CDA ....................................................................... 44
5.4.4.2
Change in EDSS from baseline by visit up to EOS ........................... 44
5.5
Safety variables........................................................................................................ 44
5.5.1
Definition of treatment-emergent, baseline and change-from-baseline, 
last on treatment, follow-up assessments for safety variables..................... 44
5.5.2
Adverse events............................................................................................. 45
5.5.2.1
Frequency and prevalence of adverse events ..................................... 45
5.5.2.2
Intensity of adverse events ................................................................. 46
5.5.2.3
Relationship of adverse events to study treatment ............................. 46
5.5.2.4
Relationship of adverse events to DMF ............................................. 46
5.5.2.5
Fatal adverse events............................................................................ 46
5.5.3
Deaths .......................................................................................................... 46
5.5.4
Serious adverse events................................................................................. 46
5.5.5
Adverse events leading to discontinuation of study treatment .................... 46
5.5.6
Adverse events leading to temporary interruption of study treatment......... 46
5.5.7
Adverse events leading to hospitalization ................................................... 46
5.5.8
Adverse events on Day 1 and Day 1 of re-initiation of study treatment ..... 47
5.5.9
Other significant adverse events.................................................................. 47
5.5.9.1
Adverse events of special interest ...................................................... 47
5.5.9.2
Major adverse cardiovascular events.................................................. 47
5.5.10
Vital signs and body weight......................................................................... 48


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5.5.10.1
Blood pressure.................................................................................... 48
5.5.10.2
Height and Weight.............................................................................. 49
5.5.10.3
Body Temperature.............................................................................. 49
5.5.10.4
Pulse rate ............................................................................................ 49
5.5.11
12-Lead Electrocardiogram ......................................................................... 49
5.5.11.1
Quantitative ECG variables................................................................ 49
5.5.11.2
Qualitative ECG variables.................................................................. 50
5.5.12
Laboratory.................................................................................................... 51
5.5.12.1
Derivations ......................................................................................... 52
5.5.13
Other safety variables .................................................................................. 53
5.5.13.1
Pulmonary function tests - Spirometry............................................... 53
5.5.13.2
Suicidal ideation................................................................................. 54
5.6
Pharmacodynamic variables.................................................................................... 55
5.6.1
Total lymphocyte counts.............................................................................. 55
5.6.2
Lymphocyte subsets..................................................................................... 56
6
DEFINITION OF PROTOCOL DEVIATIONS.................................................................... 57
7
ANALYSIS SETS.................................................................................................................. 57
7.1
Definitions of analysis sets...................................................................................... 57
7.1.1
Screened analysis set ................................................................................... 57
7.1.2
Full analysis set............................................................................................ 57
7.1.3
Safety analysis set........................................................................................ 57
7.1.4
Other analysis sets ....................................................................................... 58
7.1.4.1
Post-treatment safety analysis set....................................................... 58
7.1.4.2
Lymphocyte T cell subset analysis set ............................................... 58
7.1.4.3
Lymphocyte B cell subset analysis set............................................... 58
7.2
Usage of the analysis sets ........................................................................................ 58
8
DEFINITION OF SUBGROUPS........................................................................................... 58
9
STATISTICAL ANALYSES................................................................................................. 59
9.1
Overall testing strategy............................................................................................ 59
9.1.1
Overall testing strategy................................................................................ 59
9.2
General rules for data presentations ........................................................................ 59
9.3
Display of subject disposition, protocol deviations and analysis sets ..................... 60
9.3.1
Subject disposition....................................................................................... 60
9.3.2
Protocol deviations ...................................................................................... 60
9.3.3
Analysis sets ................................................................................................ 60
9.4
Analyses of subject characteristics.......................................................................... 60
9.4.1
Demographics .............................................................................................. 60
9.4.2
Baseline disease characteristics ................................................................... 61


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9.4.3
Previous and concomitant therapies ............................................................ 61
9.5
Analysis of study treatment exposure and compliance............................................ 61
9.5.1
Study treatment exposure and compliance .................................................. 61
9.5.1.1
Study treatment exposure ................................................................... 61
9.5.1.2
Compliance with study treatment....................................................... 61
9.5.2
DMF exposure and compliance ................................................................... 62
9.5.2.1
DMF exposure during study treatment............................................... 62
9.5.2.2
Compliance with DMF during study treatment.................................. 62
9.6
Analysis of the primary efficacy variable................................................................ 62
9.6.1
Hypothesis and statistical model.................................................................. 62
9.6.2
Main analysis ............................................................................................... 62
9.6.3
Sensitivity analyses to main analysis........................................................... 63
9.6.4
Supplementary analyses............................................................................... 63
9.6.4.1
ARR based on all relapses up to EOS on the FAS............................. 63
9.6.5
Subgroup analyses ....................................................................................... 63
9.7
Analysis of the secondary efficacy variables .......................................................... 63
9.7.1
Analysis of time to 12-week CDA............................................................... 63
9.7.2
Time to first confirmed relapse.................................................................... 63
9.7.3
Analysis of cumulative unique active lesions (CUAL) from baseline up to 
EOS.............................................................................................................. 64
9.8
Analysis of exploratory MRI efficacy variables...................................................... 64
9.8.1
Number of CUALs....................................................................................... 64
9.8.2
Number of T1 Gd+ lesions .......................................................................... 65
9.8.3
Number of new or enlarging T2 lesions ...................................................... 65
9.8.1
Analysis of time to 24-week CDA............................................................... 65
9.8.2
Change in EDSS from baseline by visit up to EOS..................................... 66
9.9
Analysis of safety variables..................................................................................... 66
9.9.1
Adverse events............................................................................................. 66
9.9.2
Deaths, other serious adverse events ........................................................... 67
9.9.2.1
Death .................................................................................................. 67
9.9.2.2
Serious adverse events........................................................................ 67
9.9.2.3
Treatment-emergent adverse events leading to study treatment 
discontinuation ................................................................................... 67
9.9.2.4
Other significant adverse events......................................................... 67
9.9.3
Electrocardiography (ECG) ......................................................................... 67
9.9.4
Vital signs and body weight......................................................................... 68
9.9.5
Laboratory tests............................................................................................ 69
9.9.6
Pulmonary function tests - Spirometry........................................................ 70
9.9.7
Columbia Suicide ideation or behavior ....................................................... 70
9.10
Analysis of pharmacodynamic variables................................................................. 70
9.10.1
Total lymphocyte counts.............................................................................. 70
9.10.2
Lymphocyte subsets..................................................................................... 71


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10 GENERAL STATISTICAL METHODOLOGY................................................................... 71
10.1
Statistical methodology for count data .................................................................... 71
10.2
Statistical methods for time-to-event data............................................................... 72
10.2.1
Time to event ............................................................................................... 73
11 GENERAL DEFINITIONS AND DERIVATIONS.............................................................. 73
11.1
Dates, times and days .............................................................................................. 73
11.2
Analysis period definitions...................................................................................... 74
11.2.1
Efficacy study periods ................................................................................. 74
11.3
Re-assignment of premature EOT visits / Visit windowing.................................... 74
11.4
Summaries by visit .................................................................................................. 75
12 HANDLING OF MISSING/INCOMPLETE DATE AND TIME FIELDS .......................... 77
12.1
Previous / concomitant therapies............................................................................. 77
12.1.1
Previous / concomitant therapies date imputation....................................... 79
12.2
Relapse..................................................................................................................... 79
12.3
Adverse event onset and death dates ....................................................................... 79
12.4
Study treatment start and EOT ................................................................................ 80
13 LIST OF SUMMARY TABLES, LISTINGS AND FIGURES ............................................ 81
14 REFERENCES....................................................................................................................... 81
15 ATTACHMENTS .................................................................................................................. 82
1
PROTOCOL DEVIATIONS BEFORE RANDOMIZATION .............................................. 83
1.1
Informed consent and patient rights ........................................................................ 83
1.2
General Eligibility ................................................................................................... 84
1.3
Inclusion Criteria ..................................................................................................... 86
1.4
Exclusion Criteria.................................................................................................... 87
1.5
Pregnancy and Contraception.................................................................................. 91
1.6
Other ........................................................................................................................ 91
2
PROTOCOL DEVIATIONS AFTER RANDOMIZATION................................................. 92
2.1
Informed consent and subject rights........................................................................ 92
2.2
Safety....................................................................................................................... 92
2.3
Contraception and Pregnancies ............................................................................... 99
2.4
Efficacy / Endpoint................................................................................................ 100
2.5
Blinding ................................................................................................................. 101
2.6
Study drug.............................................................................................................. 103
2.7
Other ...................................................................................................................... 105


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3
PROTOCOL DEVIATIONS AFTER END OF TREATMENT ......................................... 106
3.1
Safety..................................................................................................................... 106
3.2
Efficacy / Endpoint................................................................................................ 106
4
PROTOCOL DEVIATIONS AT ANYTIME DURING THE STUDY .............................. 107
4.1
Safety and Pregnancy ............................................................................................ 107
4.2
Efficacy / Endpoint................................................................................................ 109
4.3
Other ...................................................................................................................... 110
16 APPENDICES
     112
LIST OF TABLES
Table 1
Dosing scheme
14
Table 2
Visit and assessment schedule (Part 1)
16
Table 3
Visit and assessment schedule (Part 2)
19
Table 4
Visit and assessment schedule (Part 3)
22
Table 5
Overview of the different main analysis sets and their usage
58
Table 6
Premature end of treatment remapping (except MRI)
74
Table 7
Premature end of treatment remapping (MRI)
75
Table 8
Handling of missing or partial start and end dates for previous/concomitant 
therapies
78
Table 9
Thresholds for marked laboratory abnormalities                                                      114
LIST OF FIGURES
Figure 1
Study Design
12
LIST OF APPENDICES
A.
Adverse Events of Special Interest                                                                           112
B.
Protocol deviation code list                                                                                       113
C.
Laboratory marked abnormalities                                                                             114
D.
Document history                                                                                                      116


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LIST OF ABBREVIATIONS AND ACRONYMS
%predFEV1
FEV1 expressed as % of predicted normal value
%predFVC
FVC expressed as % of predicted normal value
ACTH
Adrenocorticotropic hormone
ADaM
Analysis Data Model
AE
Adverse event
AESI
Adverse event of special interest
ALP
Alkaline phosphatase 
ALT
Alanine aminotransferase 
AP
Alkaline phosphatase
ARR
Annualized relapse rate
AST
Aspartate aminotransferase
ATC
Anatomic therapeutic chemical
BMI
Body mass index
bpm
Beats per minute
CDA
Confirmed disability accumulation
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence interval
CRA
Clinical Research Associate
CRF
Case report form
CSR
Clinical study report
CUAL
Combined unique active lesions
DBP
Diastolic blood pressure
DMF
Dimethyl fumarate
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


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EOT
End-of-Treatment
EU
European Union
FAS
Full analysis set
FDA
(US) Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
FS
Functional system
FVC
Forced vital capacity
GCP
Good Clinical Practice
Gd+
Gadolinium enhancing
HR
Heart rate
ICF
Informed Consent Form
IDMC
Independent Data Monitoring Committee
INR
International normalized ratio
IRT
Interactive response technology
IVRS
Interactive voice response
JCV
John Cunningham virus
KM
Kaplan-Meier
LLOQ
Lower limit of quantification
MACE
Major adverse cardiovascular events
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
MS
Multiple Sclerosis
NAP
Not applicable
NB
Negative binomial
PCS
Physical component summary
PD
Pharmacodynamic
PEF
Peak expiratory flow
PFT
Pulmonary function test
PI
Principal Investigator


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PML
Progressive multifocal leukoencephalopathy
PT
Preferred term
PTOP
Post treatment observation period
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
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical analysis plan
SBP
Systolic blood pressure
SCR
Screened analysis set
SD
Standard deviation
SDTM
Study Data Tabulation Model 
SE
Standard error
SI
Standard international
SMQs
Standardized MedDRA Queries
SOC
System organ class
SPA
Special Protocol Assessment
SPMS
Secondary progressive multiple sclerosis with superimposed relapses 
STS
Study treatment start
TBIL
Total bilirubin
ULN
Upper limit of the normal range
WBC
White blood cell
WHO
World Health Organization
WHODRUG
WHO drug dictionary


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1
INTRODUCTION
This Statistical Analysis Plan (SAP) describes the analyses and presentation of the key efficacy, 
safety and pharmacodynamic (PD) endpoints for the synoptic clinical study report (CSR) of the 
AC-058B302 study (POINT).
Separate SAPs (not described here) are developed for analyses on: 

Vaccination specific antibody titers. 
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).
On 26 November 2019 it was decided to prematurely terminate the study. 
This decision was made following the recommendation from the Independent Data Monitoring 
Committee (IDMC) at the IDMC meeting on 10 September 2019 to further evaluate the feasibility 
of the AC-058B302/POINT study. The study started enrolling subjects in March 2017, and after 
2.5 years of recruitment had enrolled 136 subjects (22% of the targeted population). The IDMC 
recommendation was as follows:

The IDMC recognized the Sponsor’s efforts to increase enrolment but these were not 
successful. Therefore, the IDMC members are concerned that the study will not be finished in 
an adequate timeframe which will impair a proper assessment of safety, efficacy, and 
feasibility.

With the current recruitment rate the IDMC members regard the study as futile.

IDMC members request arguments against futility from the sponsor to continue the study as 
per protocol.
As a result of this evaluation, the Sponsor concluded that the current study design with the required 
sample size is unlikely to achieve the study objectives, and therefore prematurely terminated the 
study.
Following the decision to prematurely terminate the study, it was decided also to produce a 
synoptic CSR of the key efficacy and safety data only. 
2
STUDY DESIGN AND FLOW
This is a prospective, multicenter, randomized, double-blind, parallel-group, add-on, 
placebo-controlled, Phase 3, superiority study. The study is designed to compare the efficacy, 
safety, and tolerability of add-on therapy with ponesimod 20 mg vs placebo in adult subjects with 
active relapsing multiple sclerosis (RMS) who are treated with dimethyl fumarate (DMF; 
Tecfidera®).
It was planned to randomize approximately 600 subjects who had been receiving DMF twice daily
for at least 6 months in a 1:1 ratio to ponesimod 20 mg or placebo (approximately 300 subjects per 


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arm). Randomization is stratified by baseline Expanded Disability Status Scale (EDSS) score 
(EDSS ≤ 3.5, EDSS > 3.5).
At the time of the decision to terminate the study, a total of 136 subjects had been randomized at 
54 sites (randomized subjects) in 17 countries in North America, and Eastern and Western Europe
regions.
Following the decision to terminate the study:

Subjects in screening at the time of the announcement were required to be screen failed;

Subjects on study treatment were required to perform the End-of-Treatment (EOT) visit within 
8 weeks and the follow-up visits;

Subjects in the post treatment observation period (PTOP) were required to perform the Visit 
18A within 4 weeks.
2.1
Study design
The overall design of the two-arm study is shown in Figure 1. 
Subjects who prematurely discontinue study drug and complete the 30-day safety follow-up 
including the FU visit, can enter the PTOP which lasts until 60 weeks after randomization of the 
last subject or until Week 156, whichever is first (i.e., planned EOT visit) irrespective of treatment 
completion. 
Figure 1
Study Design
D = day; DMF = dimethyl fumarate; EOS = End-of-Study; EOT = End-of-Treatment; FU = follow-up; V = visit; W = week; 
*Lymphocyte tests every 4 weeks (± 3 days) until Week 24; ** Subjects participating in the lymphocyte subset sub-study will 
have an additional FU visit approximately 7 days after the last dose of study drug (FU7d). 


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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 the subject’s randomization and lasts up to 45 days (per screening attempt). Subjects can 
be re-screened once. It includes Visit 1 (Screening), Visit 2 (Baseline) and the pre-dose 
assessments of Visit 3 (Day 1).

Treatment period starts on the day of randomization immediately after the first dose of study 
drug intake (Visit 3Day 1 of the study). The double-blind treatment period has a variable 
duration from a minimum of 60 weeks (for the last subject randomized) to a maximum of 
156 weeks (3 years) for the first subjects randomized in the trial. Average duration is expected 
to be approximately 2 years. It includes a randomization visit, visits at 2, 4, and 12 weeks after 
randomization, and 12-weekly visits thereafter until 60 weeks after the randomization of the 
last subject or 156 weeks of treatment (whichever occurs first). 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 effects of ponesimod 
[see Table 1]. During the up-titration period, one tablet of ponesimod 2, 3, 4, 5, 6, 7, 8, 9,
or 10 mg (or matching placebo) will be taken orally once daily.
–
The titration phase is followed by the maintenance phase with one tablet of ponesimod 
20 mg (or matching placebo) administered orally once daily in the morning (from Day 15 
to EOT). 

Post-treatment period starts immediately after the last dose of study treatment and ends when 
End-of-Study (EOS) visit has been completed. It comprises the post-treatment safety follow-up 
period and if applicable, is followed by the PTOP.
–
Post-treatment safety follow-up period
All subjects will enter the safety follow-up period which lasts for at least 30 days after the last 
dose of study treatment and includes a safety follow-up visit approximately 30 days after the 
last dose of study treatment (FU visit). Subjects participating in the lymphocyte subset sub-
study will have an additional follow-up visit approximately 7 days after the last dose of study 
drug (FU7d visit).
–
Post-treatment observation period 
Subjects who prematurely discontinue study drug and complete the 30-day safety follow-up 
including the FU visit, will enter the PTOP which lasts until 60 weeks after randomization of 
the last subject or until Week 156, whichever is first (i.e., planned EOT visit) irrespective of 
treatment completion. The PTOP consists of an abbreviated schedule of assessments at the 
time of the originally scheduled 12-weekly visits (i.e., not all assessments are performed, see 
visit schedule). Safety follow-up visits are conducted in addition, following the post-treatment 
safety follow-up period schedule. 


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
End-of-study: the study level EOS occurs after all subjects have completed the safety follow-
up period or the last visit of the PTOP. For an individual subject, EOS is reached when 
treatment, post-treatment safety follow-up, and if applicable, the PTOPs have been completed: 
-
For subjects who complete the treatment period, and for subjects who prematurely 
discontinue study treatment and do not enter the PTOP, the EOS visit corresponds to the 
30-day follow-up visit (FU visit). 
-
For subjects who prematurely discontinue study treatment and enter the PTOP period, the 
EOS visit corresponds to the last visit of the PTOP.
Table 1
Dosing scheme
Treatment period
Duration
Dose regimen in the ponesimod 
group
Titration
Day 1 and 2
2 mg
Titration
Day 3 and 4
3 mg
Titration
Day 5 and 6
4 mg
Titration
Day 7
5 mg
Titration
Day 8
6 mg
Titration
Day 9
7 mg
Titration
Day 10
8 mg
Titration
Day 11
9 mg
Titration
Day 12 to 14*
10 mg
Maintenance
Day 15 until EOT
20 mg
-
* Visit 4 is to take place at Day 15 1 day. 
-
EOT = End-of-Treatment.
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, a main database and a first dose database. During the conduct of the 
study, the Actelion trial team (with the exception of the Clinical Research Associate (CRA) / Site 
manager) does not have access to the first dose database. The main database contains 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 (AEs), hourly vital signs and electrocardiogram (ECG) 
measurements, and will exclude all treatment-emergent data for the lymphocytes and white blood
cell (WBC) laboratory parameters. In addition, spirometry data will not be available to Actelion 
Biostatistics until after database lock. Final analyses for the CSR described in this SAP will be
presented from both main and first-dose databases combined.  


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2.1.3
Sub-studies
Two sub-studies were designed to evaluate specific safety variables and are conducted in a subset 
of sites and subjects.
2.1.3.1
Lymphocyte subset
A sub-study assessing lymphocyte subsets was conducted and it was planned to include 
approximately 200 subjects. Participation in the sub-study was mandatory for all subjects until at 
least the first 200 subjects were randomized to the main study. Due to the early termination of the 
study with 136 randomized subjects, it is expected that all are also participating in the lymphocyte 
sub-study. T cell, B cell, and NK cell counts as well as T cell subsets (e.g., CD4+ naïve, CD4+
effector memory, CD4+ central memory, CD8+ naïve, CD8+ effector memory, CD8+ central 
memory, CD8+ terminally differentiated effector memory, Th17 cells, Treg cells, and Th1 cells) 
will be analyzed at the central laboratory. All subjects were to be analyzed for T cell subsets. In 
addition, approximately 50 subjects were to be analyzed for B cell subsets. Other lymphocyte 
subsets may also be analyzed. Selected lymphocyte subsets may also be analyzed functionally 
ex vivo. Results from the lymphocyte subsets sub-study will be blinded to site staff and the sponsor
until study closure (i.e., database lock and unblinding).
2.2
Study visit and assessment schedule
Table 2 and 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 (1)
TREATMENT PERIOD
Duration
Up to 45 Days
Up to 60 weeks after the randomization of the last subject
Visits
Number
1
2
3
4
5
6
7
8,10, 12, 14, 16
11, 15
Name
Screening (1)
Baseline (1)
Rand
W2
W4
W12
W24
W36,W60, W84, W108, W132
W72, W120
Time
Day −45 to −1
Day 1
Day 15
Day 28
Week 
12
Week 
24
Week 36, 60, 84, 108, 132
Week 72, 120
Visit window
± 1 day
± 5 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
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)
X
X
X
X
SF-36v2**
X
X
X
X
Health care resource utilization* (5)
X
X
X
X
X
X
X
WPAI:MS**
X
X
X
X
Chest X-ray* (6)
X
eC-SSRS**
X
MRI**
X
X
X
Concomitant medications*
X
X
X
X
X
X
X
X
X
Physical examination* 
X
X
X
X
Body temperature*
X
X
X
X
X
X
X
X
X
Dermatological examination* (7)
X
Body weight and height* (8)
X
X
Systolic/diastolic blood pressure*
X
X
X (9)
X
X
X
X
X
X
12-lead ECG** (10)
X
X
X (11)
X
X
X (11)
X
X
X
Ophthalmological examination*(12)
X
X
X
OCT*(12)
X
X
X
Spirometry*
X
X
Hematology/chemistry**
X
X
X
X
X
X
X
X
Urinalysis*
X
X
X
X


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Lymphocytes** (13) 
X
X
X
X (13)
X (13)
X
X
Lymphocyte subsets** (14)
X
X
X
Tuberculosis test**
X
Viral serology**
X
JCV serology**
X
Additional serum sample for viral serology
X
Pregnancy test*/**
X (15)
X
X
X
X
X
X
X
PK sampling (pre dose, except Visit 3)*
X (16)
X (16)
X
Study treatment dispensing & accountability (17)
X
X
X
X
X
X
X
AE*/SAE* (18)
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 worsened 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, 102, 114, 126, 138 
and 150 (± 7 days), or 6 weeks after the last 12-weekly visit (± 7 days). Whenever between visits a subject experiences any new or worsened 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 telephone questionnaire for relapse
assessment [see Appendix 12]. After the occurrence of each confirmed relapse, subjects will be asked to re-consent to continue receiving study treatment [see Protocol Section 
13.3].
(2) The symptoms scale (with a 24-hour recall) will be completed for 7 consecutive days (the day of the visit and the 6 days after the visit) with an average score being taken across 
these 7 days. At Visit 20 (FU), the FSIQ-RMS will be completed at home prior to the visit, ideally, during the 7 consecutive days preceding the visit.
(3) Healthcare resource utilization data, including number of hospital visits, length of stay, number of Intensive care unit admissions for MS relapses and emergency medical services 
facility visits for MS.
(4) In case of premature study treatment discontinuation, the chest X-ray at EOT does not need to be performed if the EOT visit occurs within 48 weeks of the pre-randomization
chest X-ray.
(5) Dermatological examination to be performed by a dermatologist [see Protocol Section 7.3.12].
(6) SBP/DBP: Pre-dose and hourly (± 15 minutes) for at least 4 hours post-dose and up to 12 hours.
(7) Only pre-dose ECGs at all visits (if applicable) except EOT and re-initiation visits. At re-initiation, pre-dose and hourly (± 15 minutes) for at least 4 hours post-dose ECGs and 
up to 12 hours.
(8) OCT and/or ophthalmological examination to be performed at any visit in the presence of visual symptoms suggestive of macular edema or active uveitis. 
(9) Lymphocyte subset analysis will be performed on a subset of at least 200 subjects randomized to the main study.
(10) Serum pregnancy test at FU. Urine pregnancy tests at all other visits. Urine pregnancy tests (performed at home) on a 4-weekly basis (± 4 days) between the visits until 4 weeks 
after last study treatment intake (results of the pregnancy test to be communicated by telephone call to the principal investigator / treating neurologist).
(11) Pre and post-vaccination sampling for vaccine-specific antibody titers for subjects having received non-live vaccines while on study treatment (sub-study).
(12) When possible, collect PK sample upon experiencing a SAE. Preferably, sample will be collected pre-dose, as early as possible after SAE onset, and within 7 days after the last 
dose of study treatment.
(13) Scheduled study medication dispensing/return procedures may be adapted according to the site practice. 
(14) All AEs and SAEs that occur after signing the Informed Consent Form and up to 30 days after study treatment discontinuation must be reported.
(15) 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.
(16) Visit performed only for subject participating in the lymphocyte subset sub-study


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(17) If a total lymphocyte count 0.5 × 109/L is observed at FU an alert will be sent to the principal investigator and the sponsor. Discontinuation of DMF treatment should be 
considered in accordance with prescribing information [Tecfidera USPI, Tecfidera SmPC].
(18) Pulse rate to be assessed only if no 12-lead ECG is performed at this visit.
AE = adverse event; DBP= diastolic blood pressure; DMF = dimethyl fumarate; eCRF = electronic case report form; eC-SSRS = electronic self-rated version of the Columbia-
Suicide Severity Rating Scale; ECG = electrocardiogram; EDSS = expanded disability status scale; EOT = end-of-treatment; FU7d = FU visit approximately 7 days after the last 
dose of study drug; FS = functional system; FSIQ-RMS = fatigue symptoms and impacts questionnaire – relapsing multiple sclerosis; FU = follow-up; JCV = John Cunningham 
Virus; MRI = magnetic resonance imaging; MS = multiple sclerosis; MSFC = multiple sclerosis functional composite; OCT = optical coherence tomography; 
PK = pharmacokinetics, SAE = serious adverse event; SBP = systolic blood pressure; SDMT = symbol digit modalities test; SF-36v2 = 36-Item Short Form Health Survey Version 
2; SmPC = Summary of Product Characteristics; USPI = United States Prescribing Information; WPAI-MS = work productivity and activity impairment in MS.


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Table 3
Visit and assessment schedule (Part 2)
Periods
Name
TREATMENT PERIOD
FOLLOW-UP
UNSCHEDULED
Duration
Up to 60 weeks after 
randomization of the last subject
30 Days
Visits
Number
9, 13, 17
18
19
20
I1, I2, …
R1, R2, 
…
U1, U2, …
d1
d15
Name
W48, W96, 
W144
EOT
FU7d 
(16)
FU
(17)
Re-initiation
Relapse
Unscheduled 
(15)
Day 1 of re-
initiation
Day 15 after 
re-initiation
Time
Week 48, 96, 
144
Up to Week 156 
or earlier in case 
of premature 
discontinuation
Last study treatment 
intake + 7 days
Last study treatment 
intake + 30 days
Any day between Day 1 and 
EOT
Any day between Day 1 and 
EOS
Visit window
± 7 days
+ 7 days
± 2 days
+ 7 days
NA
± 1 day
+ 7 days
NA
EDSS/FS*
X
X
X
X
X
Relapse* (1)
       X (1)                                                                              X (1)
X
MSFC, SDMT*
X
X
FSIQ-RMS** (2)
X
X
X
X
X
SF-36v2**
X
X
X
Health care resource utilization* (3)
X
X
X
WPAI:MS**
X
X
Chest X-ray* (4)
X
eC-SSRS**
X
X
MRI** 
X
X
X
Concomitant medications*
X
X
X
X
X
Physical examination* 
X
X 
X
X
Body temperature*
X
X
X
X
X
X
X
Pulse rate*
X
X (18)
Dermatological examination* (5)
X
X
X
Body weight*
X
X
X
Systolic/diastolic blood pressure*
X
X
X
X (6)
X
X
12-lead ECG** (7)
X
X
X
X (7)
X
X
Ophthalmological examination* (8)
X
X
X
X
OCT* (8)
X
X
X
Spirometry* 
X
X
X
X
Hematology/chemistry**
X
X
X
X
Urinalysis*
X
X
X
X
Lymphocytes**
X
X
X
X
Lymphocyte subsets** (9)
X
X
X
X
JCV serology**
X
X


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Pregnancy test*/** (10)
X
X
X
X
Serum sample vaccination* (11)
X
PK sampling pre dose*
X
X
X
X(12)
Study treatment dispensing & 
accountability (13)
X
X
X
X
X
AE*/SAE * (14)
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 worsened 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, 102, 114, 126, 138 
and 150 (± 7 days), or 6 weeks after the last 12-weekly visit (± 7 days). Whenever between visits a subject experiences any new or worsened 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 telephone questionnaire for relapse 
assessment [see Appendix 12]. After the occurrence of each confirmed relapse, subjects will be asked to re-consent to continue receiving study treatment [see Protocol Section 
13.3].
(2) The symptoms scale (with a 24-hour recall) will be completed for 7 consecutive days (the day of the visit and the 6 days after the visit) with an average score being taken across 
these 7 days. At Visit 20 (FU), the FSIQ-RMS will be completed at home prior to the visit, ideally, during the 7 consecutive days preceding the visit.
(3) Healthcare resource utilization data, including number of hospital visits, length of stay, number of Intensive care unit admissions for MS relapses and emergency medical services 
facility visits for MS.
(4) In case of premature study treatment discontinuation, the chest X-ray at EOT does not need to be performed if the EOT visit occurs within 48 weeks of the pre-randomization 
chest X-ray.
(5) Dermatological examination to be performed by a dermatologist [see Protocol Section 7.3.12].
(6) SBP/DBP: Pre-dose and hourly (± 15 minutes) for at least 4 hours post-dose and up to 12 hours.
(7) Only pre-dose ECGs at all visits (if applicable) except EOT and re-initiation visits. At re-initiation, pre-dose and hourly (± 15 minutes) for at least 4 hours post-dose ECGs and 
up to 12 hours.
(8) OCT and/or ophthalmological examination to be performed at any visit in the presence of visual symptoms suggestive of macular edema or active uveitis. 
(9) Lymphocyte subset analysis will be performed on a subset of at least 200 subjects randomized to the main study.
(10) Serum pregnancy test at FU. Urine pregnancy tests at all other visits. Urine pregnancy tests (performed at home) on a 4-weekly basis (± 4 days) between the visits until 4 weeks 
after last study treatment intake (results of the pregnancy test to be communicated by telephone call to the principal investigator / treating neurologist).
(11) Pre and post-vaccination sampling for vaccine-specific antibody titers for subjects having received non-live vaccines while on study treatment (sub-study).
(12) When possible, collect PK sample upon experiencing a SAE. Preferably, sample will be collected pre-dose, as early as possible after SAE onset, and within 7 days after the last 
dose of study treatment.
(13) Scheduled study medication dispensing/return procedures may be adapted according to the site practice. 
(14) All AEs and SAEs that occur after signing the Informed Consent Form and up to 30 days after study treatment discontinuation must be reported.
(15) 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.
(16) Visit performed only for subject participating in the lymphocyte subset sub-study
(17) If a total lymphocyte count 0.5 × 109/L is observed at FU an alert will be sent to the principal investigator and the sponsor. Discontinuation of DMF treatment should be 
considered in accordance with prescribing information [Tecfidera USPI, Tecfidera SmPC].
(18) Pulse rate to be assessed only if no 12-lead ECG is performed at this visit.


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AE = adverse event; DBP= diastolic blood pressure; DMF = dimethyl fumarate; eCRF = electronic case report form; eC-SSRS = electronic self-rated version of the Columbia-
Suicide Severity Rating Scale; ECG = electrocardiogram; EDSS = expanded disability status scale; EOT = end-of-treatment; FU7d = FU visit approximately 7 days after the last 
dose of study drug; FS = functional system; FSIQ-RMS = fatigue symptoms and impacts questionnaire – relapsing multiple sclerosis; FU = follow-up; JCV = John Cunningham 
Virus; MRI = magnetic resonance imaging; MS = multiple sclerosis; MSFC = multiple sclerosis functional composite; OCT = optical coherence tomography; 
PK = pharmacokinetics, SAE = serious adverse event; SBP = systolic blood pressure; SDMT = symbol digit modalities test; SF-36v2 = 36-Item Short Form Health Survey Version 
2; SmPC = Summary of Product Characteristics; USPI = United States Prescribing Information; WPAI-MS = work productivity and activity impairment in MS.


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Table 4
Visit and assessment schedule (Part 3)
Periods
Name
Post-Treatment observation period (PTOP)
(to be performed after EOT, and FU)
Duration
Up to 60 weeks after randomization of the last subject
Visits
Number
6A, 7A, 8A, 10A, 12A, 14A, 16A 
11A, 15A
9A, 13A, 17A, 18A
Name
W12A, W24A, W36A, W60A, W84A, W108A, W132A
W72A, W120A
W48A - W96A - W144A -
W156A
Time
Weeks 12, 24, 36, 60, 84, 108, 132
Weeks 72, 120
Weeks 48, 96, 144, 156
Visit window
± 7 days
± 7 days
± 7 days
EDSS/FS*
X
X
X
Relapse* (1)
                           X (1)                                                                                                                         X (1)
MRI** 
X (Week 24 only)
X
X
FSIQ-RMS** (2)
X (only Weeks 12 and 24)
X
X
Concomitant medications*
X
X
X
Physical examination* 
X (Week 24 only)
X
X
Body temperature*
X
X
X
Dermatological examination* (3)
X
Systolic/diastolic blood pressure*
X
X
X
12-lead ECG **
X
Spirometry*
X (Week 12 only)
X
Hematology/chemistry**
X
X
X
Urinalysis*
X
X
X
Lymphocytes**
X
X
X
Lymphocyte subsets**
X (only Weeks 12 and 24)
X
JCV serology**
X
Adverse events (AE)*
X
X
X
Serious adverse events (SAE)*
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 worsened neurological symptoms. In addition, the site will contact the subject in-between 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. These telephone calls will be conducted either at Weeks 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138 
and 150 (± 7 days), or 6 weeks after the last 12-weekly visit (± 7 days). Whenever between visits a subject experiences any new or worsened 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 telephone questionnaire for relapse 
assessment [see Appendix 12].
(2) The symptoms scale (with a 24-hour recall) will be completed for 7 consecutive days (the day of the visit and the 6 days after the visit) with an average score being taken across 
these 7 days. At Visit 18A (Week 156), the FSIQ-RMS will be completed at home prior to the visit, ideally, during the 7 consecutive days preceding the visit.
(3) Dermatological examination to be performed by a dermatologist [see Protocol Section 7.3.12]. 


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ECG = electrocardiogram; EDSS = expanded disability status scale; EOT = End-of-Treatment; FS = functional system; FSIQ-RMS = fatigue symptoms and impacts questionnaire 
– relapsing multiple sclerosis; FU = Follow up; JCV = John Cunningham Virus; MRI = magnetic resonance imaging.


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3
OBJECTIVES
3.1
Primary objective(s)
The primary objective of the study is to determine whether add-on therapy with ponesimod reduces 
relapse frequency as compared to placebo in subjects with active RMS who are treated with DMF 
(Tecfidera®).
3.2
Secondary objectives

To assess the effect of add-on therapy with ponesimod vs placebo on disability accumulation 
and on other aspects of multiple sclerosis (MS) disease control in subjects with RMS who are 
treated with DMF (Tecfidera®); 

To assess the safety and tolerability of add-on therapy with ponesimod vs placebo in subjects 
with RMS who are treated with DMF (Tecfidera®).
4
CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN THE
STUDY PROTOCOL 
4.1
Changes to the analyses planned in the study protocol
The early termination of the study has significant impact on the power of the study to detect 
differences, and some endpoints require a minimum time on study that is reached by very few 
subjects. As a synoptic CSR will be produced to report the study data, only key efficacy and safety
data will be reported.    
The following additional changes are also applied:

In the study protocol section 6.1.2 (secondary efficacy endpoints), the derivation of the time to 
12-week confirmed disability accumulation (CDA), states that “for the purpose of 
confirmation, only EDSS measured more than 30 days after the onset of a confirmed relapse 
will be used.”. Relapses with unspecified end date are considered resolved at 90 days post 
onset. SAP Section 5.4.2.1 clarifies that the cutoff used will be 90 days rather than 30 days in 
line with this definition. 

The study protocol states that the mean number of combined unique active lesions (CUALs)
and T2 lesions will be estimated per subject per scan, from negative binomial models including 
the log of the number of scans as an offset variable. However, the number of T2 lesions is 
expected to increase with observation time, and as the premature EOT magnetic resonance 
imaging (MRI) scan can occur at any time, ‘number of MRI scans’ is not necessarily expected 
to be a good approximation of the observation time for T2. This also applies to CUALs as with 
MRI scans scheduled every 24 weeks, the CUAL count is expected to be mainly driven by new 
T2 lesions. Therefore, instead, the mean number of CUALs and T2 lesions will be estimated 
per subject per year, from negative binomial models including the log of time up to last MRI 
scan as an offset variable.


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
The protocol defines the treatment-emergent period as up to 30 days following study drug 
discontinuation. This is updated in this SAP to up to 15 days following study drug 
discontinuation, in-line with the approach used for analysis across the ponesimod MS program.

The protocol states that “All safety data will be included in listings, with flags for safety data 
not considered to be treatment-emergent.”. This approach will be reversed, i.e. the flags will 
be applied to treatment-emergent data points.

The protocol states that “The lymphocyte count reversibility after EOT will be summarized by 
plotting the mean (and 95% CIs) change from baseline to EOT and change from baseline to 
EOS by treatment. A scatter plot will display the change from baseline to EOS versus the 
change from baseline to EOT on an individual subject level by study treatment.”. This analysis 
will not be performed as the change from EOT does not consider the relationship to baseline 
and can therefore be misleading. 
4.2
Changes in the conduct of the study / data collection
A total of 5 global protocol amendments were conducted. The main reasons are described below.
Protocol version 2, 4 December 2015: Main reason for the amendment was to address comments 
received after Special Protocol Assessment (SPA) review by the US FDA. The main changes were 
introduction of a standardized procedure for reporting and confirming relapses (relapse assessment 
questionnaire), clarification of the process for EDSS and functional system (FS) assessment, 
modifications and clarifications to the primary efficacy analysis and definitions associated with 
the primary endpoint, modification of the inclusion/exclusion criteria in the context of the SAP 
procedure, and clarification on the data review process by the IDMC during the study. 
Protocol version 3, 9 March 2016: Main reason for the amendment was to add further 
clarification to address the comments received during the US FDA’s review of the SPA.
Protocol version 4, 17 June 2016: Main reason for the amendment was to address the comments 
received during the Voluntary Harmonization Procedure review for this Clinical Trial Application 
in the EU. The main changes were the addition of a new section to describe the known and potential 
risks and benefits associated with the participation in the study, the introduction of the electronic 
self-rated version of the Columbia-Suicide Severity Rating Scale (eC-SSRS©) to monitor subjects 
for suicidal ideation or behavior during the study, the addition of further criteria to allow 
modification of treatment in case a subject experiences relapses/lack of efficacy during the study, 
and clarification that the hormonal methods of contraception are restricted to those which are 
associated with inhibition of ovulation. Additional changes were made to minimize the potential 
risks for subjects, to enhance subjects’ safety monitoring, and to alleviate the burden on subjects 
and sites. 
Protocol version 5, 8 December 2016: Main reason for the amendment is to clarify that subjects 
will be re-consented to continue receiving study drug if they meet one of the following conditions: 
completed at least 48 weeks of treatment in the study and has had at least one confirmed relapse 
which occurred after 12 or more weeks of treatment, experienced two confirmed relapses while on 
study treatment, or experienced an event of 24-week CDA while on study treatment.  


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Protocol version 6, 21 December 2017: Main reason for the amendment is to make changes to 
inclusion criteria 6, which is modified to include the presence of at least one new or one 
unequivocally enlarging T2 lesion on MRI on a pre-randomization scan as an alternative criterion 
of disease activity, and also to include the presence of T1 gadolinium enhancing (Gd+) lesions 
observed on the pre-randomization MRI scan as an alternative criterion of disease activity. 
Additional local amendments were also created. 
4.3
Clarifications concerning endpoint definitions and related variables or 
statistical methods
The following clarifications are applied:

Mean number of CUALs up to EOS is given in the protocol as secondary efficacy endpoint. It 
is also listed as an exploratory MRI endpoint. It is clarified here that it is considered to be a 
secondary endpoint. 

The derivation of the ‘HH’ and ‘HHH’ ranges for hemoglobin marked abnormalities were 
changed to better clarify how to derive pre-treatment assessments and post-treatment 
assessments when baseline is ≤ upper limit of normal (ULN) [see Appendix C for details].
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 the lymphocyte sub-study) 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). The same subject number is used 
in the case of re-screening. 
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 (“Is subject eligible as per inclusion/exclusion criteria?”
answered “No”)
OR


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
“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 at 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
Due to the early termination of the study, no treatment completers as per protocol are expected as 
no subjects will have completed 156 weeks of treatment / 60 weeks of treatment following 
randomization of the last subject. 
Subjects who complete study treatment up to study termination are defined as those meeting any 
of the following conditions:

a record in the eCRF ‘Maintenance Ponesimod/Placebo’ form with reason for treatment end 
given as ‘Completed as per protocol’;

reason ‘Sponsor decision’ with sub-reason ‘Study termination’ (for question ‘Study treatment 
stopped due to’) is reported on the eCRF form ‘Premature Discontinuation of Study 
Treatment’,

the reason for treatment end is documented as ‘Study Closure Announcement by Sponsor’ on 
the eCRF ‘Up-titration Ponesimod/Placebo’ or ‘Maintenance Ponesimod/ Placebo’.
A subject is considered to have prematurely discontinued from the study treatment if:

at least one reason (‘Study treatment stopped due to’) which is not ‘Sponsor decision’ with 
sub-reason ‘Study termination’ 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’ or ‘Maintenance Ponesimod/ Placebo’.


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The date of treatment discontinuation is the last date study drug was taken [defined in 
Section 5.3.1.1]. 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 ‘Adverse event’, ‘Lack of efficacy’, ‘No reason provided’, or ‘Other’), ‘Physician 
decision’ (further split into ‘Adverse event’, ‘Lack of efficacy’ or ‘Other’) or ‘Sponsor decision’
(sub-reason ‘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 ‘Adverse event’),
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.
5.1.6
Subject study completion status
A subject is considered to have completed the study up to study termination if the corresponding 
entry on the ‘Study Discontinuation’ eCRF for question ‘Study stopped due to’ is answered with 
‘Sponsor decision’ and corresponding specify field is answered with ‘Study termination’. These 
subjects are considered to have completed study up to study termination. 
All subjects not completing the study up to the early termination of the study as defined above are 
considered to have prematurely discontinued the study. 
The EOS date is defined as the ‘Date of Subject Decision’ (if reason for study discontinuation was 
‘Subject Decision/Withdrawal of consent’), ‘Date of Physician Decision’ (if reason for study 
discontinuation was ‘Physician Decision’) collected on the ‘Study Discontinuation’ eCRF, or 
‘Date of recorded last study visit / assessment’ (if reason for study discontinuation was ‘Sponsor 
Decision’), unless a subject is lost to follow-up or dies, in which case ‘Date of last successful 
contact’ from the Study Discontinuation 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 prematurely discontinuing the study, reasons for premature discontinuation from 
study are: ‘Death’, ‘Lost to follow-up’, ‘Subject decision/Withdrawal of consent’ (further split into 
‘Adverse event’, ‘Lack of efficacy’, ‘No reason provided’ and ‘Other’), ‘Physician decision’
(further split into ‘Adverse event’, ‘Lack of efficacy’ and ‘Other’) or ‘Sponsor decision’ (‘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
Time in study (years) is derived as (EOS date −randomization date + 1 day) / 365.25.
Time in study (months) is derived as (EOS date − randomization date + 1 day) / 30.4375.


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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.

Body mass index (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) + UK: Austria, Belgium, Bulgaria, Czech Republic, France, 
Germany, Greece, Hungary, Italy, Poland, Portugal, Spain, United Kingdom
–
Europe Non-EU + Russia: Russian Federation 
–
North America: Canada, United States 
–
Rest of World: Mexico
5.2.2
Baseline disease characteristics
Baseline characteristics variables are defined as follows:
Stratification variables from IRT

Baseline EDSS (from IRT) (≤ 3.5, 3.5) from the IRT system


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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

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.

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.

Prior MS treatment other than DMF (yes/no) (‘yes’ if any MS treatment recorded on then 
‘MS Specific Treatment History’ eCRF form or as prior concomitant medications on the 


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‘Study-concomitant therapy - Disease-modifying treatment for MS’ eCRF; otherwise ‘no’ if 
no such medications are recorded).

Months on DMF at screening defined as [Date of screening DMF start date] in days / 
30.4375. DMF start date is defined as the earliest DMF start date documented in the Drug Log 
– DMF eCRF. In case of partially missing DMF start date, the start date is imputed to the latest 
possible date, see Section 12.1.1 for full details.

Relapses in the previous 6 months prior to study entry while on treatment with DMF (0, 
1, ≥ 2) number of relapses recorded in the 6 months prior to date of screening based on recorded 
onset dates of previous relapses (‘MS History – Relapse’ eCRF form) and recorded start/end 
dates of DMF treatment.

Presence of T1 Gd+ lesions (yes/no) in the previous 12 months prior to study, as provided 
by sites (yes/no) - (‘MS history - MRI’ eCRF form).

Presence of T1 Gd+ lesions (yes/no) on baseline MRI scan as provided by the MRI central 
reading.

Number of documented T1 Gd+ lesions on baseline MRI scan as provided by the MRI central 
reading.

Presence of new or enlarging T2 (yes/no) in the previous 12 months prior to study, as 
provided by sites (yes/no) - (‘MS history - MRI’ eCRF form).

Volume of T2 lesions on baseline MRI scan as provided by the MRI central reading.

Smoking status (Current smoker, Former smoker, Never smoked), taken from ‘Smoking 
status’ eCRF.
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
Previous and concomitant therapies
Therapies are collected in the following CRF pages: ‘Previous Medications’, ‘Concomitant 
Medications’, ‘Interferon beta-1a history’, ‘Interferon beta-1b history’, ‘Glatiramer acetate 
history’, ‘Natalizumab history’, ‘Mitoxantrone history’, ‘Alemtuzumab concentrate history’, 
‘Teriflunomide history’, ‘Daclizumab history’, ‘Ocrelizumab history’, ‘Cladribine history’, ‘Other 
MS Specific Treatment History’, ‘Study-concomitant therapy - Disease-modifying treatment for 
MS’, ‘Corticosteroids for Treatment of Relapse’.


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Terms are coded using the World Health Organization (WHO) drug code dictionary (WHODRUG) 
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. 
5.2.3.1
Previous therapies
Previous therapies are therapies that were started and stopped prior to study treatment start date.  
5.2.3.2
Treatment concomitant therapies
Includes all therapies that have been taken after study treatment start date up to EOT (last drug 
intake) + 15 days. This includes therapies ongoing at study start, as well as therapies starting after 
study treatment start date. 
Handling of partial or missing start and end dates is detailed in Section 12.1. 
5.2.3.3
Therapies starting after EOT
Includes all 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. 
5.3
Exposure and compliance
5.3.1
Study treatment exposure and compliance
Exposure and compliance with ponesimod / placebo information will be taken from the Study 
Drug Log eCRFs:

Up-titration Summary Ponesimod/Placebo 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);

Maintenance Ponesimod/Placebo eCRF (collects information on maintenance study drug 
intake based on maintenance tablets).
To derive the study treatment start date and time, in addition information collected on Study drug 
administration eCRFs (‘Study Drug Administration - Day 1/Re-initiation’, ‘Study Drug 
Administration’) 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 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 


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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.
5.3.1.1
Study treatment 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 
eCRFs listed above.
The following exposure variables are derived:
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 ≤48
weeks (336 days), > 48 weeks to ≤72 weeks (504 days), > 72 weeks to ≤96 weeks (672 days),
> 96 weeks to ≤120 weeks (840 days), > 120 weeks to ≤144 weeks (1008 days), > 144 weeks 
(1008 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 5.3.1.2.1.
5.3.1.2
Compliance with study treatment
5.3.1.2.1
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% is not necessarily 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%, 99% – < 100%,
80% –< 99%, 50% – < 80%, > 0% – < 50%, 0%.
The number of days with study drug intake documented is derived as follows:


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During up-titration period
The number of days with intake documented is based on entries on the eCRF ‘Up-titration 
Summary Ponesimod/Placebo’ and/or ‘Up-titration Ponesimod/Placebo’. 
For subjects where the investigator confirmed the up-titration has been conducted as planned, the 
‘Up-titration Summary Ponesimod/Placebo’ eCRF is filled, collecting only start and end date of 
the entire titration period without collecting ‘number of tablets taken’. In that case the ‘Number of 
days with intake documented’ is derived and considered to be ‘titration end date − titration start 
date + 1 day’.
For all other subjects, information is collected on the ‘Up-titration Ponesimod/Placebo’ eCRF, 
‘Treatment start date’ resulting in potentially multiple records of up-titration drug intake 
(collecting in addition ‘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 tablet of study drug is to be taken per day. On the ‘Maintenance 
Ponesimod/Placebo’ eCRF log form, each record collects ‘Treatment start date’, ‘Treatment end 
date’, and ‘Number of tablets taken’. If, for a record, the ‘Number of tablets taken’ is ≤ ‘Treatment 
end date’ −‘Treatment start date’ + 1, it is assumed that the ‘Number of tablets taken’ represents 
the ‘Number of days with intake documented’ during that record’s period of study drug intake. If,
for a record, the ‘Number of tablets taken’ is > ‘Treatment end date’ −‘Treatment start date’ + 1, 
‘Number of days with intake documented’ is set to ‘Treatment end date’ −‘Treatment start date’
+ 1 for the compliance calculation. These subjects are flagged as having taken > 1 tablet 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). 
The following deviations from the protocol-intended study drug maintenance are identified from 
the ‘Maintenance Ponesimod/Placebo’ eCRF log form and flagged on a subject basis:

More than 1 tablet 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.
5.3.2
Study treatment adjustments or interruptions
Study-specific criteria for interruption and discontinuation of study treatment were pre-specified 
in the protocol section 5.1.12. The protocol did not allow any study treatment dose adjustments. 


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Study treatment interruptions are assessed via the compliance variables described in 
Section 5.3.1.2 and the assessment AEs 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 5.3.1.1. 
Total duration of interruption(s) (days) is derived as ‘Duration of Study Treatment’−’Study 
treatment exposure, interruptions excluded’. 
5.3.3
DMF exposure and compliance
Exposure and compliance with DMF information will be taken from the Drug Log - DMF 
(Tecfidera) eCRF (collects information on DMF start date, end date, dose, frequency and reason 
for treatment end). All DMF dose changes, interruptions and discontinuations are to be reported 
here. 
5.3.3.1
DMF exposure during study treatment
The on-study DMF start date is defined as:

the study treatment start date (as defined in Section 5.3.1.1) for subjects who were receiving 
DMF on study treatment start date, as documented in the Drug Log – DMF eCRF;

the earliest DMF start date documented in the Drug Log – DMF eCRF that is after the study 
treatment start date, for subjects who were not DMF on study treatment start date, as 
documented in the Drug Log – DMF eCRF.
The DMF end date is defined as latest DMF end date documented in the Drug Log – DMF eCRF.
If the end date of the DMF record with the latest start date is missing, DMF is assumed to be 
ongoing at study treatment EOT and the DMF end date is imputed with study treatment EOT.
The following exposure variables are derived:
Duration of DMF treatment on study (days) = DMF end date – on-study DMF start date + 1 
day. Duration of DMF Treatment on study is also derived in weeks (days divided by 7), months 
(days divided by 30.4375), and years (days divided by 365.25). 
Duration of DMF Treatment on study is categorized as follows: ≤24 weeks (168 days), > 24 weeks
to ≤48 weeks (336 days), > 48 weeks to ≤72 weeks (504 days), > 72 weeks to ≤96 weeks 
(672 days), > 96 weeks to ≤120 weeks (840 days), > 120 weeks to ≤144 weeks (1008 days), 
> 144 weeks (1008 days).
‘DMF treatment exposure, interruptions excluded’ equals the ‘Number of days with DMF 
intake documented’ between study treatment start date and study drug EOT for a subject overall 
as defined as part of the compliance derivations described in Section 5.3.3.2


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5.3.3.2
Compliance with DMF treatment during study treatment
Compliance is assessed as the percentage of days from the date of first study drug intake until EOT 
with DMF intake documented in the eCRF:
no.  of days with DMF intake documented
(date of EOT-study treatment start date ) + 1 day × 100
Note: Compliance below 100% is not necessarily 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%, 99% – < 100%,
80% –< 99%, 50% – < 80%, > 0% – < 50%, 0%.
The number of days with DMF intake documented is derived as follows:
On the ‘Drug Log - DMF’ eCRF log form, each record collects ‘DMF start date’, ‘DMF end date’, 
and ‘Individual dose’. If, for a record, the ‘Individual dose’ is > 0, it is assumed that the subject 
took DMF for each day covered by the record. For each record, the start date is defined to be the 
maximum of (DMF start date associated with the record, study treatment start date), and the end 
date is defined to be the minimum of (DMF end date associated with the record, EOT date).
The ‘Number of days with DMF intake documented’ for a subject overall is derived as the sum 
across all DMF drug log records. 
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.
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.


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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. 
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).
5.4.1.2
Variables for supplementary analyses of primary endpoint
5.4.1.2.1
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.
5.4.2
Secondary efficacy variables
5.4.2.1
Time to 12-week confirmed disability accumulation (CDA) up to EOS
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’). 


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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 (Up to Week 156
or earlier 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.
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. 


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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. 
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.


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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 to have 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.
5.4.2.2
Time to first confirmed relapse
The time to first confirmed relapse (in days) is defined as [Date of first confirmed relapse − Date 
of randomization + 1] in days.
Subjects without any confirmed relapses will be censored at the EOS date, and the time is defined 
as [Date of EOS − Date of randomization + 1] in days.
Derivation of confirmed relapses from randomization up to EOS is detailed in Section 5.4.1. 
Among these confirmed relapses, the earliest relapse start date is the ‘Date of first confirmed 
relapse’. For analysis the variable is displayed in weeks: variables in days divided by 7. 
5.4.2.3
Number of combined unique active lesions (CUAL) up to EOS
The cumulative number of CUAL from baseline to EOS is calculated as the sum of new T1 Gd+ 
lesions and new or enlarging T2 lesions without Gd enhancement on T1 at all post-baseline MRI 
visits up to EOS.  
MRI scans are scheduled at Baseline, and every 24 weeks thereafter, i.e., at the visits at Week 24, 
Week 48, Week 72, Week 96, Week 120, Week 144 Visit and at the EOT 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 MRI scans are scheduled every 24 weeks, 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, and which does not occur per 


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the planned schedule for any subjects and so the ‘number of MRI scans’ is not necessarily expected 
to be a good approximation of the observation time. 
5.4.2.3.1
Derivation 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). 
Cumulative CUAL from baseline to EOS 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 up to EOS irrespective of whether a visit is conducted during PTOP 
or not.
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: 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. 
5.4.3
Exploratory MRI efficacy variables
MRI data are provided from a central reader.
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). 


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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 post-baseline scheduled visits - visit windowing
MRI variables at scheduled visits 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.   
5.4.3.1
Number of CUALs 
The cumulative number of CUALs from baseline to Week 24, Week 48, Week 72, Week 96 and 
EOT is derived in the same way as for CUAL from baseline to EOS [see Section 5.4.2.3], but only 
including MRI scans up to the applicable MRI visit (if missing, up to remapped equivalent) as 
applicable.  
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.
5.4.3.2
Number of T1 Gd+ lesions 
The number of T1 Gd+ lesions per visit is derived as the sum of ‘number of new T1 Gad.-
enhancing lesions’ (T1GdNew_R) + ‘number of persisting T1 Gad.-enhancing lesions’ (T1Gd_R)
as provided by the central reader at that visit. 
Handling of missing MRI results at scheduled visits follows the general rules for MRI data 
described in Section 5.4.3 above.
The cumulative number of new T1 Gd+ lesions from baseline to Week 48 is derived as the sum 
of number of new T1 Gd+ lesions at all post-baseline MRI scans up to the Week 48 MRI visit. 
This includes premature EOT scans if available. It may include unscheduled scans if it is the last 
available scan, following selection of unscheduled MRIs as per derivation of CUAL 
[Section 5.4.2.3]. 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.
Note: The number of T1 Gd+ lesions at baseline is taken from the variable ‘Number of T1 Gad.-
enhancing lesions at V2 – Baseline/Number of persisting T1 Gad.-enhancing lesions’ (T1Gd_R).
At baseline new T1 Gd+ lesions are not available, thus no corresponding record is expected. 
Note: T1 Gd+ lesions are assumed to not enhance for more than 12 weeks. This requires handling 
of data as follows:

If at a visit, number of persisting T1 Gd+ lesions are not recorded, the number of Gd+T1 
lesions is the number of new T1 Gd+ lesions. Rationale: As per central reader processes 


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persisting T1 Gd+ lesions are not assessed for subjects with scheduled MRIs scheduled more 
than 12 weeks apart (i.e., MRIs are scheduled every 24 weeks). 

If at a MRI scan which is > 12 weeks (84 days) since the last previous scheduled MRI scan a 
persisting lesion count > 0 is recorded, these persisting lesions are considered implausible
and therefore not to be considered in derivations of total T1 Gd+ counts.
The cumulative number of new T1 Gd+ lesions from baseline will also be derived in the same way 
as described above for cumulative up to Week 48 for the following timepoints: Week 24, Week 72, 
Week 96, and EOT and EOS. 
5.4.3.3
Number of new or enlarging T2 lesions 
New or enlarging T2 lesions as compared to the previous scheduled visit are recorded by the 
external reader in two distinct categories: ‘Number of new or enlarging T2 lesions without Gad. 
enhancement on T1’ (T2New_R) and ‘Number of new or enlarging T2 lesions with Gad. 
enhancement on T1’ (T2NewGd_R) at a visit as compared to the previous scheduled visit. The 
sum of both is the ‘number of new or enlarging T2 lesions’ at that visit compared to the previous 
scheduled visit. For subjects with missing baseline MRI, the number of new or enlarging T2 lesions 
from baseline cannot be assessed and the endpoint is considered missing. The baseline MRI is 
considered missing if presence of T1 Gd+ lesions at baseline is missing.
The cumulative number of new or enlarging T2 lesions from baseline to Week 24, Week 48, Week 
72, Week 96, EOT and EOS is calculated as the sum of lesions at all post-baseline MRI visits up 
to the applicable MRI visit.
The cumulative number of new or enlarging T2 lesions from baseline up to the applicable MRI 
visit is derived as the sum of the ‘number of new or enlarging T2 lesions’ at all scheduled 
post-baseline MRI visits, including 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 lesions and the following algorithm applies:
–
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 
enlarging T2 lesions’ 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 / 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 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. 


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Rationale: The number of T2 lesions is expected to increase with observation time, not solely by 
the ‘Number of MRI scans’. 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.
5.4.4
Other clinical efficacy variables
5.4.4.1
Time to 24-week CDA
The derivation of the variables for Time to 24-week CDA up to EOS follows the same approach 
as described in Section 5.4.2.1, 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.
5.4.4.2
Change in EDSS from baseline by visit up to EOS
Absolute changes from baseline in EDSS score by visit are derived, based on the overall EDSS 
score as reported by the investigator in the eCRF. 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 as planned (e.g., by visit analysis at Week 24, 
considers both ‘Week 24’ and ‘PTOP Week 24’ visits). Baseline EDSS is defined as in 
Section 5.4.2.1.    
On-treatment EDSS assessments will be flagged, i.e., EDSS assessments performed after study 
treatment start (date/time) and prior to EOT + 7 days. 
5.5
Safety variables
5.5.1
Definition of treatment-emergent, 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. Assessments at Visit 1 (Screening) and Visit 2 
(Baseline), with date on or prior to the date of first intake of study treatment, and with no time 
collected, are considered eligible for baseline. 
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 
timepoint label (e.g., pre-dose, 2 hours post-dose), the nominal visit and timepoint 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 


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baseline if reported under the timepoint “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 (last on 
treatment may come from a scheduled or an unscheduled visit)

Day-30 follow-up, between EOT + 16 days and EOT + 37 days [see Section 11.4]
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 timepoint label, the nominal visit and timepoint 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 timepoint “Pre-dose” in the eCRF, however it will be considered if reported as “2 hours 
post-dose” in the eCRF.
A safety event (AE, serious 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 AE is any event reported by the investigator on the Adverse Event eCRF of the main database 
or the first dose database. 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 [PT], or MedDRA primary system organ 
class[SOC]).  


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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 PT 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. 
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 to study treatment
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 (i.e., ‘related’). 
AEs with missing relationship are considered to be related.
5.5.2.4
Relationship of adverse events to DMF
Relationship to DMF 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 (i.e., ‘related’). AEs with 
missing relationship are considered to be related.
5.5.2.5
Fatal adverse events
Fatal AEs 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. 
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 SAEs.
5.5.5
Adverse events leading to discontinuation of study treatment
AEs 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
AEs 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.


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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 AESI, 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

Skin malignancy AESI

Non-skin malignancy AESI

Seizure AESI
5.5.9.2
Major adverse cardiovascular events
Based on a pre-defined list of PTs belonging to relevant Standardized MedDRA Queries (SMQs), 
AEs are selected for the major adverse cardiovascular events (MACE) adjudication board
evaluation. For each case sent for MACE adjudication, the board members individually assess 
whether the case is a myocardial infarction, a stroke, or another AE. For fatal cases, each member 
determines
whether the death is considered of cardiovascular, non-cardiovascular, or 
undetermined cause. If not all individual assessments concur, the case is classified into the above 
listed categories based on a consensus meeting. For data analysis, each case is assigned to one of 
the following categories:  

cardiovascular death (if a death case is classified as cardiovascular)

non-fatal myocardial infarction (if the case is classified as myocardial infarction but not as 
cardiovascular death)

non-fatal stroke (if the case is classified as stroke but not as cardiovascular death)

no MACE (if the case is classified as other AE, but not as cardiovascular death).


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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 first dose 
database. 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-30 follow-up, and for flagging of high or low values, 
the average of the first and second measurements is considered. The average calculated in the 
eCRF irrespective of position of the subject (supine, standing, sitting) or arm (right, left) is 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. 
For by-visit and by-hour tables presenting summary statistics of quantitative vital signs results, the 
latest (by date/time) transmitted measurement per nominal subject-visit / time point is used in case 
of multiple data available at that visit or visit / time point.
Assessments meeting the following conditions 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


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
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 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
Only the visit, date and time information of the ECG data is collected on the eCRF for both the 
main database and the first dose database. ECG measurement data is collected using vendor 
machines from ERT (central ECG provider). 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), 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 with values 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.  


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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

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


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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-treatment ECG assessment, it 
is conservatively assumed that any treatment-emergent morphological ECG finding is “New”. 
5.5.12 Laboratory
Laboratory tests will be performed at Visit 1 (Screening), Visit 2 (Baseline), Visit 4 (Week 2), 
Visit 5 (Week 4), Visit 6 (Week 12) and every 12 weeks thereafter up to Visit 18 (EOT), and at 
Visit 20 (FU) and, if applicable, at all corresponding visits in the PTOP. Unscheduled laboratory 
tests may be performed at any time during the study (Visits U1, U2, U3, etc.).
Additional lymphocyte count measurements will be performed every 4 weeks up to Week 24. 
Safety laboratory samples are centrally analyzed by Covance 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: International normalized ratio (INR), alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), (alkaline phosphatase) AP, 
total bilirubin (TBIL).
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).


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John 
Cunningham 
Virus
(JCV)
serology 
testing: 
JCV 
antibodies
(positive/negative/indeterminate).
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 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).
5.5.12.1 Derivations
Numerical results are converted into both conventional and standard international (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, and Day-30 follow-up assessments are 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 C]. 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 (AP):

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).
* ULN ꞊ upper limit of the normal range.


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5.5.13 Other safety variables
5.5.13.1 Pulmonary function tests - Spirometry
Spirometry tests to assess pulmonary function will be performed at Visit 2 (Baseline), Visit 6 
(Week 12), Visit 9 (Week 48) and every 48 weeks thereafter until Visit 17 (Week 144), Visit 18 
(EOT), Visit 20 (FU), and at unscheduled visits (U1, U2, etc.) if clinically indicated. If applicable, 
spirometry tests will also be performed at the corresponding visits in the PTOP. 
Spirometry tests will be conducted at site according to the ATS/ERS guidelines [Miller 2005a, 
Miller 2005b]. The best (largest) forced expiratory volume in 1 second (FEV1), forced vital 
capacity (FVC) and peak expiratory flow (PEF) values from the three acceptable and repeatable 
tests will be recorded in the eCRF as absolute volume in liters and as flow in liters/second (rounded 
to two decimal places). These values may come from separate maneuvers. The FEV1/FVC ratio 
will be derived from the FVC and FEV1 values recorded in the eCRF.
Prior to database lock and unblinding, spirometry data are not transferred to any member of 
Actelion biostatistics as these data are considered to carry a moderate risk of potential unblinding.
The following parameters are collected on the eCRF at each visit:

FVC (L), 

FEV1 (L), 

PEF (L/s).
The following variables are derived for analysis (predicted values based on Quanjer
[Quanjer 1993]):

FEV1/FVC (%), 

Predicted normal FEV1[L] for male subjects = 4.30 × height (m) − 0.029 × age (years) at study 
enrollment − 2.49;

Predicted normal FEV1[L] for female subjects = 3.95 × height (m) − 0.025 × age (years) at 
study enrollment − 2.60;

Predicted normal FVC[L] for male subjects = 5.76 × height (m) − 0.026 × age (years) at study 
enrollment − 4.34;

Predicted normal FVC[L] for female subjects = 4.43 × height (m) − 0.026 × age (years) at 
study enrollment − 2.89. 
For the predicted normal values derivations above, age and height collected at study screening are 
used; also age is set to 25 years if age is between 18 and 25 years and a conversion factor of 0.9 
must be multiplied to the predicted normal value if subject race is other than ‘White’.

Percent of the corresponding predicted normal value is also calculated for FEV1[L] and 
FVC[L] as follows:
Percent of the predicted value (%) = [measured value] ×100 / [predicted normal value].


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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 Day-30 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 %predFEV1: < −20 %, < −30%

Absolute change from baseline in %predFVC: < −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 % 
5.5.13.2 Suicidal ideation
The 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 9-Week 48, Visit 13-Week 96, Visit 
17-Week 144 and Visit 18-EOT).
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 
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)


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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 (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. 
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
Pharmacodynamic variables
5.6.1
Total lymphocyte counts
The main PD marker is total lymphocyte count, which is measured as part of the hematology test 
from central laboratory. Absolute and change from baseline counts are derived, as described in 
Section 5.5.12. 


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Total 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.
For each subject in the SAF, the nadir (i.e., lowest) treatment-emergent lymphocyte value (up to 
EOT + 15 days) is flagged.
Subjects who have a value after Visit 5 (Week 4) (scheduled or unscheduled) which is both 
< 0.5 × 10^9/L and represents a decrease from Week 4 > 50%, and which is maintained at all visits 
(scheduled or unscheduled) for the next 24 weeks, will be flagged.  
For example, if a subject has a value of 0.9 × 10^9/L at Visit 5 (Week 4), then a value of 
0.4 × 10^9/L at Visit 6 (Week 12), a value of 0.35 × 10^9/L at Visit 7 (Week 24) and a value of 
0.4 × 10^9/L at Visit 8 (Week 36), then the subject will be flagged as meeting the above criterion. 
Subjects who have a value after Visit 5 (Week 4) (scheduled or unscheduled) which is both 
< 0.5 × 10^9/L and represents a decrease from Week 4 of > 50%, and who discontinue treatment 
within 24 weeks, will be flagged separately if this decrease is maintained at their remaining study 
scheduled visits, where EOT and FU are considered to be scheduled visits.
Total lymphocyte counts from central laboratory are flagged for analysis according to their sample 
dates as ‘Baseline’, ‘Last on treatment’ and ‘Day-30 follow-up’ following the rules described in 
Section 5.5.1 and Section 11.4.
5.6.2
Lymphocyte subsets
A sub-study assessing lymphocyte subsets will be conducted in approximately 200 subjects. 
Participation in the sub-study will be mandatory for all subjects until at least the first 200 subjects 
are randomized to the main study. T cell, B cell, and NK cell counts as well as T cell subsets 
(e.g., CD4+ naïve, CD4+ effector memory, CD4+ central memory, CD8+ naïve, CD8+ effector 
memory, CD8+ central memory, CD8+ terminally differentiated effector memory, Th17 cells, Treg 
cells, and Th1cells) will be analyzed at the central laboratory. All subjects were to be analyzed for 
T cell subsets. In addition, the approximately 50 subjects were to be analyzed for B cell subsets. 
Other lymphocyte subsets may also be analyzed. Selected lymphocyte subsets may also be 
analyzed functionally ex vivo.
Blood samples for lymphocyte subset analysis will be taken from approximately 200 subjects at 
Visit 2 (Baseline), Visit 6 (Week 12), Visit 7 (Week 24), Visit 9 (Week 48), Visit 13 (Week 96), 
Visit 17 (Week 144), Visit 18 (EOT), Visit 19 (FU7d), and at Visit 20 (FU). If applicable, 
lymphocyte subsets will also be assessed at the corresponding visits in the PTOP (Visits 6A, 7A, 
9A, 13A, 17A, and 18A).


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Absolute and change from baseline values for lymphocyte subsets are derived as described in 
Section 5.5.12. 
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.
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 who were treated with at least one 
dose of study treatment and have at least one post-baseline efficacy assessment. 

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 IVRS system (which may 
be different to the information available on the eCRF after data validation);

Unless otherwise stated, all available efficacy data for the primary and secondary endpoints up 
to the EOS visit [see Section 11.4] will be included in the analysis, regardless of study 
treatment discontinuation and/or switches to alternative MS treatments.
7.1.3
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 (ponesimod or placebo) 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 (ponesimod and placebo) were taken by a subject at some point 


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during the study. If a subject received ponesimod and placebo for exactly the same number of 
days, they are summarized within the treatment they are assigned to by randomization.
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).
7.1.4
Other analysis sets
The following other analysis sets are defined:
7.1.4.1
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. 
7.1.4.2
Lymphocyte T cell subset analysis set
Includes all subjects in the safety analysis set who have at least one evaluable baseline and at least 
one evaluable post-baseline on-treatment sample for the lymphocyte T cell subset analysis. 
7.1.4.3
Lymphocyte B cell subset analysis set
Includes all subjects in the safety analysis set who have at least one evaluable baseline and at least 
one evaluable post-baseline on-treatment sample for the lymphocyte B cell subset analysis.   
7.2
Usage of the analysis sets
Table 5 provides an overview of the analysis set usage for the main variables of the study.
Table 5
Overview of the different main analysis sets and their usage
Analyses/Data Displays
Screened analysis set
Full analysis set 
Safety analysis set 
Inclusion/exclusion criteria

Demographic characteristics

Baseline characteristics

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
Due to the low number of subjects recruited in this early terminated study, no subgroup analyses 
will be performed. 


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9
STATISTICAL ANALYSES
9.1
Overall testing strategy
9.1.1
Overall testing strategy
The primary endpoint (ARR using confirmed relapses) will be tested using a negative binomial 
regression model, comparing ponesimod with placebo. Due to the early termination of the study, 
analysis of the five secondary endpoints will be considered exploratory. No adjustment for 
multiplicity will be performed.  
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., _S for Safety set).
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 are graphically presented based on mean change +/−standard error 
(SE) on a time axis scaled to the target days of the corresponding visit. The SE is derived as 
standard deviation (SD)/√$.

All safety data will be included in listings, with flags for safety data considered to be 
treatment-emergent.
Example table layouts:
ACT-128800/JNJ-67896153              Protocol: AC-058B302<TITLE>
Analysis set: <Set>
—————————————————————————————————————————————————————————————————
           Ponesimod 20 mg       Placebo         Total
           / DMF                / DMF        
           N = XX              N = XX         N = xx
—————————————————————————————————————————————————————————————————
<XXX>     XX              XX                XX             
—————————————————————————————————————————————————————————————————


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Treatment groups are displayed in the order (left to right) of Ponesimod 20 mg / DMF, Placebo / 
DMF, Total (if applicable). For figures, ponesimod / DMF is displayed in red with solid line style 
and placebo / DMF 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.
A listing including subject disposition is also provided on the FAS.
Furthermore, a listing of study initiation and completion dates is also provided.
The number and percent of subjects screened and re-screened (incl. reasons for screening failure), 
subjects randomized, subjects completing study up to study termination, subjects treated, and 
subjects completing study treatment up to study termination, as well as subjects completing both
treatment and study up to study termination 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. 
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. Listings of subjects with premature study/treatment 
withdrawal and related reasons are also provided on FAS.
A listing of randomization scheme and codes (for randomized subjects only) as well as a listing 
with Informed Consent information are produced respectively on FAs and SCR.
9.3.2
Protocol deviations
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) by country and site is provided on 
the SCR.
9.3.3
Analysis sets
Subject membership in the different analysis sets is presented in a listing. 
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. Tables are presented by treatment group and 
overall. All variables are also presented in a subject data listing based on the SCR.


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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. Tables are presented by treatment 
group and overall. All variables are also presented in subject data listings based on the SCR.
9.4.3
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 PT within each ATC class (ATC class level 4). All 
summaries are tabulated by ATC class, and individual PTs within each ATC class, for the FAS, 
by treatment group and overall. ATC classes 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 PTs 
within ATC class. If the frequencies of ATC class are the same, alphabetical order is used. The 
same rule applies for PTs within ATC class.
The above described frequencies are summarized by treatment group and overall for the following 
therapies:

Treatment concomitant 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, treatment concomitant, and therapies starting after EOT, 
as well as ongoing at study treatment start using the screened set. 
9.5
Analysis of study treatment exposure and compliance
9.5.1
Study treatment exposure and compliance
9.5.1.1
Study treatment exposure
Exposure to study drug [defined in Section 5.3.1.1] 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, together with compliance, based on the SAF.
Subjects with at least one interruption as well as duration of interruptions will be summarized by 
treatment group on the SAF. Subject exposure to study drug is listed. Subjects with > 1 tablet taken 
on at least one day or maintenance treatment resumed without up-titration after an interruption of 
> 3 days are flagged. 
9.5.1.2
Compliance with study treatment
Compliance with study treatment variables [defined in Section 5.3.1.2] 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, together with exposure, 
based on the SAF.


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9.5.2
DMF exposure and compliance
9.5.2.1
DMF exposure during study treatment
Exposure to DMF [defined in Section 5.3.3.1] 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.
9.5.2.2
Compliance with DMF during study treatment
Compliance with DMF variables [defined in Section 5.3.3.2] 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
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 Ponesimod and µPlacebo. The 
primary null hypothesis is that the ARR (µ) does not differ between ponesimod and placebo. The 
alternative hypothesis is that the ARR differs between ponesimod and placebo.
H0, ARR: µPonesimod - µPlacebo = 0
vs
H1, ARR: µPonesimod - µPlacebo ≠ 0
The null hypothesis will be tested by a two-sided Wald test within the negative binomial regression 
model [see Section 9.6.2], with a two-sided significance level of 0.05. 
9.6.2
Main analysis
The primary statistical analysis will be performed up to EOS on the FAS using a negative binomial 
(NB) regression model for confirmed relapses, with treatment as a factor and the binary 
stratification variable for EDSS category (EDSS ≤3.5 versus EDSS > 3.5) from IRT 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 effect size will be measured by the relative reduction in the 
model estimated mean ARR for ponesimod compared to placebo including two-sided 95% Wald 
confidence interval (CIs).
Mean model-based estimates of the ARR (for confirmed relapses), by treatment arm, as well as 
95% CIs are presented. A rate ratio comparing ponesimod 20 mg with placebo will be derived 
from the model including 95% CIs and the corresponding p-value. The dispersion parameter will 
also be displayed.


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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. 
9.6.3
Sensitivity analyses to main analysis
No sensitivity analyses are planned. 
9.6.4
Supplementary analyses
9.6.4.1
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. 
A listing of relapses and a listing for number of relapses will be prepared on FAS.
9.6.5
Subgroup analyses
No subgroup analyses are planned. 
9.7
Analysis of the secondary efficacy variables
All analyses of secondary efficacy variables are considered to be exploratory. 
9.7.1
Analysis of time to 12-week CDA
Time to first confirmed 12-week CDA up to EOS will be summarized on the FAS in a table 
including, number of subjects with event / censored, Kaplan-Meier estimates (unstratified) and 
corresponding CI (anticipated timepoints: 12, 24, …, 156 weeks), and median (as well as 25th and 
75th percentiles) of the survival function together with CIs. 
A listing of 12-week CDA data will be prepared.
9.7.1.1.1
Handling of missing data
See variable derivation in Section 5.4.2.1.
9.7.2
Time to first confirmed relapse
Time to first confirmed relapse will be summarized on the FAS in a table including, number of 
subjects with event / censored, Kaplan-Meier estimates (unstratified) and corresponding CI 
(anticipated timepoints: 12, 24, …, 156 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 


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(unstratified) going upward is presented including CIs at specific timepoints.  Intervals will be 
displayed up to the time point where at least 10% of subjects are still at risk.
Time to first confirmed relapse data will be listed using the FAS.
9.7.3
Analysis of cumulative unique active lesions (CUAL) from baseline up to EOS
The main analysis of the secondary endpoint CUAL will be performed on the FAS using a negative 
binomial regression model: response variable is the cumulative number of CUALs up to EOS, with 
treatment as a factor and the IRT stratification variable for EDSS (EDSS ≤3.5 versus EDSS > 3.5) 
included in 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 subject per year will be provided by 
treatment group, as well as 95% Wald CIs. A rate ratio comparing ponesimod 20 mg with placebo
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 from baseline up to EOS will be presented 
for continuous data and frequency per categories (0, 1–5, 6–10, 11+) anticipated. 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 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.
9.8
Analysis of exploratory MRI efficacy variables
9.8.1
Number of CUALs 
The cumulative number of CUALs from baseline up to Weeks 24, 48, 72, 96 and EOT will be 
analyzed on the FAS using a negative binomial regression model: response variable is the 
cumulative number of CUALs up to each timepoint, with treatment as a factor and EDSS category
(IRT) as a covariate, and the log of the time up to last MRI scan for the timepoint (in years) as an
offset. Mean model-based estimates for the number of CUALs per subject per year, rate ratio, and 
corresponding 95% CIs will be presented.
The cumulative number of CUALs from baseline up to each timepoint will be summarized 
descriptively using the FAS. The total number of CUALs as well as the total cumulative time up 
to the last MRI scan at the timepoint (summed for all subjects) will also be displayed. From the 
total number of CUALs and the total cumulative time to the last MRI scan the raw number of 
CUALs per year will be calculated and summarized. 
CUAL data will be listed on the FAS.


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9.8.2
Number of T1 Gd+ lesions 
The cumulative number of T1 Gd+ lesions up to Weeks 24, 48, 72, 96, EOT and EOS will be 
analyzed on the FAS using a negative binomial regression model, with the cumulative number of 
T1 Gd+ lesions up to the timepoint as the response variable, treatment as a factor, EDSS 
stratification category as a covariate, and the log of the number of included scans up to the 
timepoint as an offset. Mean model-based estimates for the number of T1 Gd+ lesions per subject 
per scan, rate ratio, and corresponding 95% CIs will be presented.
The cumulative number of T1 Gd+ lesions from baseline up to each timepoint will be summarized 
descriptively using the FAS. The total number of T1 Gd+ lesions as well as the total number of 
included scans (summed for all subjects) will also be displayed. From the total number of T1 Gd+ 
lesions and the total number of included scans the raw number of T1 Gd+ lesions per scan will be 
calculated and summarized. For the number of T1 Gd+ lesions from baseline up to EOS the 
frequency per category will also be presented (anticipated categories: 0, 1, 2, 3, 4+). 
Descriptive summary statistics of the number of T1 Gd+ lesions at each scheduled visit will also 
be presented. 
T1 Gd+ lesion data will be listed on the FAS.
9.8.3
Number of new or enlarging T2 lesions 
The cumulative number of new or enlarging T2 lesions up to Weeks 24, 48, 72, 96, EOT and EOS
will be analyzed on the FAS using a negative binomial regression model as described above in 
Section 9.8.1 for number of CUALs, with the cumulative number of new or enlarging T2 lesions
up to the timepoint as the response variable.
The cumulative number of new or enlarging T2 lesions from baseline up to each timepoint will be 
summarized descriptively using the FAS. The total number of new or enlarging T2 lesions as well 
as the total cumulative time up to the last MRI scan at the timepoint (summed for all subjects) will 
also be displayed. From the total number of new or enlarging T2 lesions and the total cumulative 
time to the last MRI scan the raw number of new or enlarging T2 lesions per year will be calculated 
and summarized. For the number of new or enlarging T2 lesions from baseline up to EOS the 
frequency per category will also be presented (anticipated categories: 0, 1, 2, 3, 4+). 
Descriptive summary statistics of the number of new or enlarging T2 lesions at each scheduled 
visit will also be presented. 
T2 lesion data will be listed on the FAS.
9.8.1
Analysis of time to 24-week CDA
Analysis of time to 24-week CDA will be analyzed in the same way as analysis of time to 12-week 
CDA as described in Section 9.7.1.


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9.8.2
Change in EDSS from baseline by visit up to EOS
The EDSS score and change from baseline in EDSS score by visit and treatment group will be 
summarized using descriptive statistics on the FAS. A listing of EDSS / FS scores will be produced 
on the FAS. 
9.9
Analysis of safety variables
9.9.1
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 SAE, any drug-related SAE, or any fatal SAE. 
Also, AEs are summarized by SOC and PT: 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 (PT). 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 PTs 
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

Treatment-emergent AEs leading to temporary interruption of study treatment

Treatment-emergent AEs considered to be related to DMF

Treatment-emergent AEs considered to be related to study drug

Treatment-emergent AEs with fatal outcome
Also, treatment-emergent AEs are summarized by PT: presenting, per treatment group, the number 
and percentage of subjects having any AE, and having each individual AE (PT). PTs are sorted by 
descending order of frequency in the ponesimod arm. If the frequencies are the same, alphabetical 
order is used.
For the disclosure of the results to EudraCT and ClinicalTrials.gov (and inclusion in the CSR
appendix), frequent treatment-emergent non-serious AEs, i.e., PTs 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 (PT). 
2) The overall number of frequent non-serious AEs (i.e., reported episodes), and the number and 
percentage of frequent AEs (PT). Here the denominator is the overall number of frequent non-
serious AEs.


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9.9.2
Deaths, other serious adverse events
9.9.2.1
Death
A separate listing including all deaths is provided based on the SCR; treatment-emergent deaths 
are flagged as such in that listing. 
9.9.2.2
Serious adverse events
Unless otherwise specified, the SAF is used for all analyses of SAEs.
SAEs are summarized by SOC and PT. 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 considered to be related to study drug
For the disclosure of the results to EudraCT and ClinicalTrials.gov (and for inclusion in the CSR
appendix), the overall number of treatment-emergent SAEs (i.e., reported episodes), and the 
number and percentage SAEs (PT) 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.
9.9.2.3
Treatment-emergent adverse events leading to study treatment discontinuation
The SAF is used for all analyses of AEs leading to discontinuation. AEs leading to premature 
discontinuation of study drug are summarized by SOC and PT. The following summaries are 
presented:

Treatment-emergent AEs leading to premature discontinuation of study drug.
9.9.2.4
Other significant adverse events
9.9.2.4.1
Adverse events of special interest 
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 each AESI is summarized by PT 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 is presented. 
AESI are presented in a dedicated listing. 
9.9.2.4.2
Major adverse cardiovascular events 
A listing of MACE events is prepared. 
9.9.3
Electrocardiography (ECG)
The following summary displays are provided by treatment group, all based on the SAF:


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
Quantitative ECG results and absolute change from baseline, as described in Section 5.5.11.1,
are summarized descriptively, by parameter and visit. Except for data summarized under 
‘Baseline’, ‘last-on-treatment’ 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];

Quantitative ECG results and absolute change from pre-dose on Day 1, by timepoint (pre-dose, 
1–4 hours post dose), are summarized descriptively;

Number and percentage of subjects with any treatment-emergent PR, QTcF prolongations and 
HR outliers are presented overall. 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;

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. 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 new treatment-emergent morphological ECG 
findings, by abnormality and group term following CDISC terminology are presented;

Number and percentage of subjects with new treatment-emergent post-dose morphological 
ECG findings on Day 1 or on Day 1 of any re-initiation, by abnormality and group term 
following CDISC terminology are presented.
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.
9.9.4
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 descriptively, by parameter and visit. Except for ‘Baseline’,
‘Last on treatment’ 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];

Blood pressure including absolute change from baseline on Day 1, by timepoint (pre-dose, 
1–4 hours post dose), are summarized descriptively;


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
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 meeting the
criteria defined in Section 5.5.10.1 are presented overall post-dose hours. Percentages are 
based on the number of subjects with blood pressure results available for the corresponding 
parameter.
Unscheduled visits are not presented in summary tables by visit. Unscheduled assessments that 
meet the pre-defined high/low criteria will be flagged and may be included in the corresponding 
incidence tables.
All blood pressure as well as body weight, body temperature and pulse rate results are listed by 
treatment group and visit based on the SCR. A listing for blood pressure measurements in subjects 
with at least one treatment-emergent marked blood pressure abnormality will also be presented on 
SCR.
9.9.5
Laboratory tests
Descriptive summary statistics by visit 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’ 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. 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 is 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 group. The denominator for percentages is the number 
of subjects with at least one post-baseline assessment.
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.
A shift table of the frequency counts and percentages of number of subjects with positive, negative 
and indeterminate results at baseline and at EOS for JCV serology will be presented separately.
Other laboratory parameters are presented in a separate listing on the SCR. 


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Further analyses related to lymphocytes and lymphocyte subsets are described in Section 9.10.
9.9.6
Pulmonary function tests - Spirometry
The following summary displays are provided by treatment group, all based on the SAF:

Treatment-emergent FEV1, FVC, FEV1/FVC, %predFEV1, and %predFVC including 
absolute and percent change from baseline, as described in Section 5.5.13.1, are summarized
descriptively, by parameter and visit. Except for ‘Baseline’, ‘Last on treatment’ 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]. 

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;
All spirometry results are listed by treatment group and visit based on the SCR. A listing of 
spirometry data in subjects with treatment-emergent decrease >= 0.2 L or >= 12% in FEV1 (or 
FVC) is also presented.
9.9.7
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 SCR. 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 up to EOT + 15 days (worst outcome). 
Analyses will be based on subjects in the SAF who have at least one treatment-emergent 
eC-SSRS© measurement 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. 
All eC-SSRS© data will be presented in a listing on SCR.
9.10 Analysis of pharmacodynamic variables
9.10.1 Total lymphocyte counts
Descriptive analyses of lymphocyte data are described in Section 9.9.5. Only lymphocyte counts 
from central laboratory, irrespective of whether obtained at a scheduled or unscheduled visit, are 
included in any of the below described analyses.


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For each subject in the SAF, the nadir (i.e., lowest) treatment-emergent lymphocyte value (up to 
EOT + 15 days) is summarized by means of frequency counts and percentages based on the 
categories specified in Section 5.6.
Frequency counts and percentages will be presented for the number of subjects with:

Total lymphocyte counts < 0.5 × 10^9/L and > 50% decrease from baseline at Week 4, 
maintained at all visits for the next 24 weeks, where the denominator for percentages is the 
number of subjects with a total lymphocyte count at all scheduled visits for the next 24 weeks;

Total lymphocyte counts < 0.5 × 10^9/L at any visit after Week 4 and > 50% decrease from 
Week 4, maintained at all visits for the next 24 weeks, OR total lymphocyte count < 0.5 × 
10^9/L at any visit after Week 4 and > 50% decrease from Week 4, discontinuing for any 
reason within 24 weeks, with decrease maintained for remaining scheduled study visits, where 
the denominator for percentages is the number of subjects with a total lymphocyte count < 0.5 
× 10^9/L and > 50% decrease from Week 4 at any visit after Week 4.
9.10.2 Lymphocyte subsets
All collected parameters from the T cell lymphocyte subset will be presented descriptively, with 
absolute values, as well as absolute and percent change from baseline values presented, using the 
T cell lymphocyte subset analysis set. 
All collected parameters from the B cell lymphocyte subset will be summarized in the same way, 
using the B cell lymphocyte subset analysis set. 
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.


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The SAS code for the NB model with 95% 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 = 0.05 OM;
     estimate ‘Ponesimod - Placebo’ “ Treat 1 -1 / exp alpha = 0.05; 
run;
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 
95% 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 95% Wald CIs. 
The direction of the estimate statement (governed by ‘1 1’ or ‘−1 1’) is chosen such that the rate 
ratio relative to placebo is provided (with rate ratio < 1 indicating ponesimod is better).
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 = 0.05;
     estimate ‘Ponesimod - Placebo’ “ Treat 1 -1 / exp alpha = 0.05; 
run;
10.2 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).  Intervals will be displayed on plots up to the time point where 
at least 10% of subjects are still at risk.


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10.2.1 Time to event
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 timepoints 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].
11 GENERAL DEFINITIONS AND DERIVATIONS
11.1 Dates, times and days
Study treatment start date see definition in Section 5.3.1.1.
End-of-Treatment (EOT) / Study treatment end date, defined as the latest study treatment end 
date as recorded on the Study Drug Log eCRFs [see Section 5.3.1.1].
End-of-Study (EOS) date is defined as the ‘Date of Subject Decision’ (if reason for study 
discontinuation was ‘Subject Decision’), ‘Date of Physician Decision’ (if reason for study 
discontinuation was ‘Physician Decision’) collected on the ‘Study Discontinuation’ eCRF, or 
‘Date of recorded last study visit / assessment’ (if reason for study discontinuation was ‘Sponsor 
Decision’), unless a subject is lost to follow-up or dies, in which case ‘Date of last successful 
contact’ from the Study Discontinuation 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 [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 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’. 


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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].
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:

Scheduled nominal visits, e.g., Week xx, are identified based on the eCRF recorded nominal 
visit label. Note that the eCRF allows for considering a visit under multiple visit labels, e.g., a 
Follow-up 1 or a Relapse visit can be considered in addition a Week xx visit. This 2nd visit 
label is collected on the Visit Summary eCRF under ‘Corresponding visit’. In selecting results 
for a nominal scheduled visit both visit labels are considered. Priority is given to the 1st visit 
label, afterwards to the 2nd visit label. If at a scheduled nominal visit no result is available, 
premature EOT remapping is applied.

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 6 and Table 7].
Table 6
Premature end of treatment remapping (except MRI)
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
798
Week 120
841
799
882
Week 132
925
883
966
Week 144
1009
967
1050
Week 156
1093
1051
Open end
Day refers to treatment day, i.e., days from study treatment start. 


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Table 7
Premature end of treatment remapping (MRI)
Visit window
Nominal value
Day
Lower limit for
Day
Upper limit for
Day
Week 24
169
85
252
Week 48
337
253
420
Week 72
505
421
588
Week 96
673
589
756
Week 120
841
757
924
Week 144
1009
925
1050
Week 156
1093
1051
Open end
Day refers to treatment day, i.e., days from study treatment start. 
11.4 Summaries by visit
Visit based safety and PD assessments are generally summarized according to the nominal visit. 
Except for Visit 18 (EOT/Week 156) in subjects prematurely discontinuing study treatment, Visit 
19 (FU7d, Day 7 follow-up assessment for lymphocyte subset only), and Visit 20 (FU, 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-7 follow-up
assessment: Any assessment within EOT date + 6
days and 
EOT date + 15 days. If multiple assessments fall into that period, the one corresponding to the 
regular FU7d visit (Visit 19) is selected, if none of the multiple assessments corresponds to 
that visit, the one closest to EOT date + 7 days is selected, if there are two closest assessments, 
the later one is selected.

Day-30 follow-up assessment: Any assessment within EOT date + 16 days and EOT date + 37 
days. If multiple assessments fall into that period, the one corresponding to the regular FU visit 
(Visit 20) 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 (last on treatment may come from a scheduled or an 
unscheduled visit).    
Summaries by visit are presented by Baseline (derived), and further scheduled nominal visits up 
to Week 156 (irrespectively if conducted during PTOP or not), Last on-treatment, and derived
Follow-up visits (FU7d, FU). 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

Visit 15 - Week 120

Visit 16 - Week 132

Visit 17 - Week 144

Visit 18 - Week 156

Last on-treatment (derived; see Section 5.5.1)

Day-7 follow-up (derived) (lymphocyte subset only)

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 18 - Week 156”
unless they are mapped to this visit as per approach described in Section 11.3.  
As per protocol, 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). 
These assessments are considered scheduled and are included in corresponding by-visit tabulations 
labeled as follows:

Additional Visit - Week 8

Additional Visit - Week 16

Additional Visit - Week 20
Visit-based efficacy are summarized according to the nominal visit up to EOS, irrespective if 
conducted during PTOP or not:

Baseline (Derived)

Visit 4 - Week 2

Visit 6 - Week 12

Visit 7 - Week 24

Visit 9 - Week 48

Visit 11 - Week 72

Visit 13 - Week 96


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
Visit 15 - Week 120

Visit 17 - Week 144

Visit 18 - Week 156
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 18 - Week 156”
unless they are mapped to this visit as per approach described in Section 11.3.  
EOS visit is defined for efficacy endpoints and JCV:

For subjects who complete the treatment period, and for subjects who prematurely discontinue 
study treatment and do not enter the PTOP, the EOS visit corresponds to the 30 day follow-up
visit (FU) for efficacy endpoints, and for the last available visit for JCV. 

For subjects who prematurely discontinue study treatment and enter the PTOP period, the EOS 
visit corresponds to the last visit of the PTOP.
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. 
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 treatment concomitant therapies are applied [see
Table 8]. 


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Table 8
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
for which 
Start date prior to or on EOT+15 
days 
(Start date either: prior to or on 
EOT+15 days, or partial with 
lower limit prior to or on EOT+15 
days)
Any
Treatment 
concomitant
Any
All other cases not listed above 
for which 
Start date after EOT+15 days 
(Start date either: after EOT+15 
days, or partial with lower limit 
after EOT+15 days)
Any
Post-treatment
STS = Study treatment start; For subjects randomized but not treated the randomization date is used instead of the STS.
* 
Includes ‘Previous Medications’ or any of the individual MS Specific Treatment History Log eCRFs (e.g., ‘Interferon beta-1a 
history’, ‘Glatiramer acetate history’ etc): 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’ and any of the individual MS Specific Treatment 
History Log eCRFs.
Subjects randomized but not treated are not considered to have any treatment concomitant 
medications.
To further flag treatment 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 have been 
started during study drug administration unless ‘Ongoing at start of Treatment’ ticked ‘Yes’
then it is considered ongoing at study treatment start.


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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. 
Treatment 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. 
Treatment 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 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.


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–
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.

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. 


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Details for assigning safety events and assessments to the treatment-emergent 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 
+ 1092 days (156 weeks), the upper 
limit, EOS date, and Death date.
Earliest between treatment start date + 1092
days (156 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.
14 REFERENCES
[Brookmeyer 1982] Brookmeyer R, Crowley JA. CI for the median survival time. Biometrics. 
1982;38:29-41.
[Miller 2005a] Miller MR, Crapo R, Hankinson J, et al. ATS/ERS Task Force. General 
considerations for lung function testing. Eur Respir J 2005;26(1):153–61. Review.
[Miller 2005b] Miller MR, Hankinson J, Brusasco V, et al; ATS/ERS Task Force. Standardisation 
of spirometry. Eur Respir J 2005;26(2):319–38.
[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.
[Quanjer 1993] Quanjer PH, Tammeling GJ, Coates JE, Pedersen OF, Peslin R, Yernault JC. Lung 
volumes and forced ventilatory flows. Working Party Report: Standardization of Lung 
Function Tests, European Community for Steel and Coal. Official statement of the European 
Respiratory Society. Eur Resp J. 1993 March;6(Suppl 16):5-40.


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15 ATTACHMENTS
Attachment 1
Protocol Deviation Code List
Protocol deviation code list version 4.0, 16 June 2020.


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1
PROTOCOL DEVIATIONS BEFORE RANDOMIZATION
Note: Applies to first screening attempt and re-screening, unless specified otherwise.
1.1
Informed consent and patient rights
Condition
Type
Identifier
Source/Instructions
Additional 
information 
expected?
Important 
PD
No informed consent form (ICF) 
signed
M
PD_MM.200
Monitor PD
PD to be reported even if subject is 
not randomized
Yes
Informed consent form signed after 
first study procedure
P
PD_PP.201
eCRF 
[Inclusion Criterion 1]
Except subject number assignation -
not a procedure
PD to be reported even if subject is 
not randomized
Yes
No ICF signed at re-screening
M
PD_MM.202 
Monitor PD 
Yes
Informed consent form signed after 
first study procedure at re-screening
P
PD_PP.203
eCRF 
[Inclusion Criterion 1 at re-screening]
Except subject number assignation -
not a procedure
PD to be reported even if subject is 
not randomized
Yes
Informed consent procedures 
conducted by a non-qualified person
M
PD_MM.003
Monitor PD
Yes
During pre-randomization period, 
new ICF version not signed at first 
applicable visit
M
PD_MM.204
Monitor PD
Yes
Other violation of Informed consent 
procedures
M
PD_MM.205
Monitor PD
No


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e.g., wrong or draft version, wrong 
language, missing information (e.g., 
signature time…)
1.2
General Eligibility
Condition
Type
Identifier
Source/Instructions
Additional 
information 
expected?
Important 
PD
Randomization performed without 
taking into account centrally provided 
quality review (MRI)
M
PD_MM.050
eCRF
[MRI Summary]
Monitor PD
No
Randomization performed based on 
local laboratory results
M
PD_MM.051
Monitor PD
No
Any pre-randomization safety 
assessment for eligibility not 
performed prior to randomization
M
PD_MM.206
eCRF
Monitor PD
e.g., Dermatological exam, Blood 
pressure, Chest X-ray, 
Ophthalmological exam, OCT, Lab 
samples, Pregnancy tests, ECG, 
Spirometry
Includes assessments not performed 
at all and assessments performed 
after randomization
Yes
Any pre-randomization assessment 
not required for eligibility not 
performed prior to randomization
M
PD_MM.207
eCRF
Monitor PD
e.g., Weight, Physical exam, Body 
temperature, Urinalysis, eC-SSRS, 
Smoking status, JCV serology, viral 
serology sample
Includes assessments not performed 
at all and assessments performed 
after randomization
No


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Pre-randomization assessments not 
performed using centrally provided 
devices
M
PD_MM.054
Monitor PD
e.g., ECG
No
Subject re-screened without sponsor 
approval
M
PD_MM.208
Monitor PD
GCS&E input
No
Any pre-randomization safety 
assessment required for eligibility 
performed, but with at least one 
repeated assessment or test missing
M
PD_MM.209
Monitor PD / eCRF
e.g., V1 and V3 ECG confirming 
eligibility but V2 ECG not done; INR 
V1 available and V2 result 
unavailable)
No
Any pre-randomization assessment 
required for eligibility performed, but 
results not available at randomization 
(subject retrospectively not eligible)
M
PD_MM.210
Monitor PD
e.g., Lab results available after 
randomization and not confirming 
eligibility
Yes
Any pre-randomization assessment 
required for eligibility performed, but 
results not available at randomization 
(subject retrospectively eligible)
M
PD_MM.211
Monitor PD
e.g., Lab results available after 
randomization and confirming 
eligibility
No
Any pre-randomization assessment 
required for eligibility not performed 
as per study protocol and not 
covered by another PD code
M
PD_MM.212
Monitor PD / eCRF
No
Pre-randomization EDSS not 
performed according to study 
protocol or performed after 
randomization
M
PD_MM.301
Monitor PD / eCRF
[EDSS/FS forms]
Includes assessments not done
Yes
Pre-randomization MRI not 
performed according to study 
protocol or performed after 
randomization
M
PD_MM.302
Monitor PD / eCRF
[MRI Summary]
Includes assessments not done;
MRI not repeated in case of 
unacceptable quality as per central 
overread, missing sequences
Yes


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Pre-randomization FSIQ-RMS not 
performed according to study 
protocol or performed after 
randomization
M
PD_MM.303
Monitor PD / eCRF
[ePRO: FSIQ-RMS]
Includes assessments not done;
FSIQ: e.g., symptoms domain not 
completed or completed less than 4 
days, impact domain not completed; 
MRI: not repeated in case of 
unacceptable quality as per central 
over-read, missing sequences
No
1.3
Inclusion Criteria
Condition
Type
Identifier
Source/Instructions
Additional 
information 
expected?
Important 
PD
Age < 18 or > 55 at Visit 1 
(Screening)
P
PD_PP.007
eCRF
[Inclusion Criterion 2]
Yes
Woman of childbearing potential 
without a negative serum pregnancy 
test at Visit 1 (Screening) or a 
negative urine pregnancy test at Visit 
2 (Baseline)
P
PD_PP.008
eCRF
[Inclusion Criterion 3a]
Yes
Woman of childbearing potential not 
agreeing to undertake monthly urine 
pregnancy tests during the study or 
up to 30 days after study treatment 
discontinuation
P
PD_PP.213
eCRF
[Inclusion Criterion 3b]
Yes
Woman of childbearing potential not 
agreeing to use reliable methods of 
contraception until 30 days after 
study treatment discontinuation as 
described in protocol section 4.5.2
P
PD_PP.214
eCRF
[Inclusion Criterion 3c]
Yes


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Subject presenting no diagnosis of 
MS as defined by the revised (2010) 
McDonald Diagnostic Criteria for MS 
or with no relapsing course from 
onset (i.e., not RRMS or SPMS with 
superimposed relapses)
P
PD_PP.012
eCRF
[Inclusion Criterion 4]
Yes
Subject not treated with DMF for at 
least 6 months prior to Visit 1 
(Screening)
P
PD_PP.013
eCRF
[Inclusion Criterion 5]
Yes
Subject with no active disease after 
at least 3 months of DMF treatment 
as per protocol inclusion criterion 6
P
PD_PP.215
eCRF
[Inclusion Criterion 6a]
[Inclusion Criterion 6b]
[Inclusion Criterion 6c]
Yes
Subject not assessed as ambulatory 
or with EDSS > 6.0 at Visit 1 
(Screening) or Visit 2 (Baseline)
P
PD_PP.016
eCRF
[Inclusion Criterion 7]
Yes
Subject not meeting lymphocyte 
count requirements at Visit 1 
(Screening) or Visit 2 (Baseline) as 
per protocol inclusion criteria 8
P
PD_PP.017
eCRF
[Inclusion Criterion 8]
Yes
1.4
Exclusion Criteria
Condition
Type
Identifier
Source/Instructions
Additional 
information 
expected?
Important 
PD
Lactating or pregnant woman or 
woman intending to become 
pregnant during the study
P
PD_PP.018
eCRF
[Exclusion Criterion 1]
Yes
Presenting with a diagnosis of MS 
with progressive course from onset 
(i.e., PPMS or PRMS)
P
PD_PP.019
eCRF
[Exclusion Criterion 2]
Yes
Evidence of a relapse of MS within 
30 days prior to baseline EDSS 
P
PD_PP.020
eCRF
[Exclusion Criterion 3]
Yes


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assessment or between baseline 
EDSS assessment and 
randomization
Treatment with beta-blockers, 
diltiazem, verapamil, digoxin or any 
other anti-arrhythmic or HR lowering 
systemic therapy within 15 days prior 
to randomization
P
PD_PP.021
eCRF
[Exclusion Criterion 4a]
Yes
Treatment with adrenocorticotropic 
hormone (ACTH), systemic 
corticosteroids, or vaccination with 
live vaccines within 30 days prior to 
randomization
P
PD_PP.022
eCRF
[Exclusion Criterion 4b]
Yes
Treatment with plasmapheresis, 
cytapheresis, intravenous 
immunoglobulin or with an 
investigational drug as specified in 
the protocol within 90 days prior to 
randomization
P
PD_PP.023
eCRF
[Exclusion Criterion 4c]
Yes
Treatment with daclizumab 
(applicable since protocol v5), IFN 
beta-1a, IFN beta-1b, glatiramer 
acetate, other systemic 
immunosuppressive treatment, or 
fingolimod as specified in the 
protocol within 180 days prior to 
randomization
P
PD_PP.216
eCRF
[Exclusion Criterion 4d]
Yes
Treatment with natalizumab or non-
lymphocyte-depleting experimental 
biological agents within 12 months 
prior to randomization
P
PD_PP.217
eCRF
[Exclusion Criterion 4e]
Yes


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Treatment with lymphocyte-depleting 
biological agents (such as rituximab 
or ocrelizumab) or cladribine within 
24 months prior to randomization
P
PD_PP.026
eCRF
[Exclusion Criterion 4f]
Yes
Treatment with alemtuzumab, 
mitoxantrone, ponesimod, other 
investigational S1P modulators, 
stem-cell transplantation, 
leflunomide/teriflunomide (unless 
washed-out) at any time prior to 
randomization
P
PD_PP.027
eCRF
[Exclusion Criterion 4g]
Yes
Any infection or infection risk as per 
exclusion criteria 5, 6 and 7
P
PD_PP.304
eCRF
[Exclusion Criteria 5, 6, 7]
Yes
Known Progressive Multifocal 
Leukoencephalopathy (PML) 
infection / evidence of new 
neurological symptoms / MRI signs 
within 6 months prior to 
randomization compatible with a PML 
infection diagnosis
P
PD_PP.305
eCRF
[Exclusion Criterion 8]
Yes
Any malignancy or pre-cancerous 
conditions as per protocol exclusion 
criteria 9 and 10
P
PD_PP.218
eCRF
[Exclusion Criteria 9, 10]
Yes
Presence of macular edema
P
PD_PP.030
eCRF
[Exclusion Criterion 11]
Yes
Any of the cardiovascular conditions 
as per protocol exclusion criteria 12
P
PD_PP.031
eCRF
[Exclusion Criteria 12a to 12h]
Yes
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
P
PD_PP.032
eCRF
[Exclusion Criterion 13]
Yes


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Subjects with a clinically significant 
pulmonary condition as per protocol 
exclusion criteria 14
P
PD_PP.033
eCRF
[Exclusion Criteria 14a, 14b]
Yes
Active or latent TB, except if there is 
documentation that the subject has 
received adequate treatment for 
latent TB infection or TB disease 
previously as per protocol exclusion 
criteria 15
P
PD_PP.034
eCRF
[Exclusion Criterion 15]
Yes
Any of the hematology abnormal 
laboratory values at Visit 1 
(Screening) or Visit 2 (Baseline) as 
per protocol exclusion criteria 16
P
PD_PP.035
eCRF
[Exclusion Criteria 16a to 16d]
Yes
Subject with known and documented 
moderate or severe hepatic 
impairment
P
PD_PP.036
eCRF
[Exclusion Criterion 17]
Yes
Any abnormal liver laboratory values 
at Visit 1 (Screening) or Visit 2 
(Baseline) as per protocol exclusion 
criteria 18
P
PD_PP.037
eCRF
[Exclusion Criterion 18a to 18c]
Yes
Contraindications for MRI as per 
protocol exclusion criteria 19
P
PD_PP.038
eCRF
Up to protocol version 4 included: 
[Exclusion Criteria 19a to 19d]
From protocol version 6 onwards: 
[Exclusion Criteria 19a to 19c]
Yes
Subject with history of clinically 
significant drug or alcohol abuse
P
PD_PP.039
eCRF
[Exclusion Criterion 20]
Yes
Subject with known allergy to any of 
the ponesimod formulation excipients
P
PD_PP.040
eCRF
[Exclusion Criterion 21]
Yes
Subject with any other clinically 
relevant medical or surgical condition 
which, in the opinion of the 
P
PD_PP.041
eCRF
[Exclusion Criterion 22]
Yes


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investigator, would put the subject at 
risk by participating in the study
Subject unlikely to comply with 
protocol as per protocol exclusion 
criteria 23
P
PD_PP.042
eCRF
[Exclusion Criterion 23]
Yes
1.5
Pregnancy and Contraception
Condition
Type
Identifier
Source/Instructions
Additional 
information 
expected?
Important 
PD
Woman of childbearing potential with 
a negative serum pregnancy test at 
Visit 1 (Screening) and a negative 
urine pregnancy test at Visit 2 
(Baseline) performed < 21 days apart
M
PD_MM.009
Monitor PD / eCRF
[Demographics]
[Urine Pregnancy Test]
[Central Lab]
e.g., serum and urine pregnancy 
tests performed 20 days apart
No
Contraceptive methods requirements 
for WOCBP as described in protocol 
section 4.5.2 not followed by subject
M
PD_MM.219
Monitor PD / eCRF
[Contraceptive Methods]
e.g., hormonal contraceptive started 
less than 30 days prior to 
randomization
Note: To be used only if deviation 
occurred prior to randomization. If 
deviation occurred after 
randomization, use code MM.138
No
1.6
Other
Condition
Type
Identifier
Source/Instructions
Additional 
information 
expected?
Important 
PD
Pre-randomization period > 45 days
P
PD_PP.055
eCRF
[Randomization]
No


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Any repeated assessment during 
pre-randomization period visits 
performed without respecting the 
minimum interval between 
assessments as defined per study 
protocol (except pregnancy tests)
M
PD_MM.056
Monitor PD / eCRF
[Central lab]
For DM only: to be reported once
No
Missing source documents related to 
pre-randomization period
M
PD_MM.058
Monitor PD
No
Incorrect stratum factor "EDSS <= or 
> 3.5" communicated to IVRS at 
randomization
P
PD_PP.220
eCRF
Yes
2
PROTOCOL DEVIATIONS AFTER RANDOMIZATION
Note: Applies any time after randomization, unless specified otherwise (e.g., during PTOP).
2.1
Informed consent and subject rights
Condition
Type
Identifier
Source/Instructions
Additional 
information 
expected?
Important 
PD
New ICF version not signed at first 
applicable protocol scheduled visit or 
signed after procedure related to new 
protocol version was performed
M
PD_MM.221
Monitor PD
No
2.2
Safety
Condition
Type
Identifier
Source/Instructions
Additional 
information 
expected?
Important 
PD
On Day 1 or on first day of re-
initiation, any post-dose assessment 
not performed within 24 hours after 
pre-dose assessments
M
PD_MM.162
Monitor PD
To be reported in FDM database
Yes


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On Day 1 or on first day of re-
initiation of study drug (when post-
dose monitoring is required), subject 
discharged from hospital before 4 
hour post-dose or before criteria for 
discharge were met
M
PD_MM.117
Monitor PD / eCRF
[Systolic/Diastolic Blood Pressure − 
(Post-dose]
[Discharge from Hospital]
[12 Lead ECG − Post-dose]
To be reported in FDM database
Yes
On Day 1 or on first day of re-
initiation of study drug (when post-
dose monitoring is required), post-
dose monitoring not performed 
according to protocol
M
PD_MM.118
Monitor PD
To be reported in FDM database
No
During maintenance period, any 
interruption > 3 days where study 
drug was re-initiated without up-
titration or without post-dose cardiac 
monitoring
M
PD_MM.222
Monitor PD / eCRF
[Study Drug Log]
Yes
Study drug not interrupted or 
discontinued (if applicable) upon 
reaching any of the cardiovascular 
discontinuation criteria
M
PD_MM.119
Monitor PD / eCRF
[Premature Discontinuation of Study 
Treatment]
[ECG]
Refer to section 5.1.12.1 of the study 
protocol
Yes
Study drug not interrupted or 
discontinued (if applicable) upon 
reaching any of the hematological 
abnormalities discontinuation criteria
M
PD_MM.120
Monitor PD / eCRF
[Study Drug Log]
[Premature Discontinuation of Study 
Treatment]
[Local Laboratory]
[Central Lab]
Refer to section 5.1.12.2 of the study 
protocol
Yes
Study drug not interrupted or 
discontinued (if applicable) upon 
M
PD_MM.124
Monitor PD / eCRF
[Study Drug Log]
Yes


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subject experiencing an event of 
suspected opportunistic infection
[Local Laboratory]
[AE] 
[Central Lab]
Refer to section 5.1.12.3 of the study 
protocol
Subject not monitored or 
discontinued (if applicable) from 
study drug upon reaching any of the 
respiratory system (PFT decrease 
and persistent respiratory AEs) 
monitoring and discontinuation 
criteria
M
PD_MM.125
Monitor PD / eCRF
[Study Drug Log]
[Premature Discontinuation of Study 
Treatment]
[AE]
[Spirometry forms]
GCS&E input 
Refer to section 5.1.12.4 of the study 
protocol
Yes
Study drug not interrupted or 
discontinued (if applicable) upon 
pregnancy determination
M
PD_MM.126
Monitor PD / eCRF
[Study Drug Log]
[Premature Discontinuation of Study 
Treatment]
[AE]
Refer to section 5.1.12.5 of the study 
protocol
Yes
Study drug not interrupted or 
discontinued (if applicable) upon 
reaching any of the liver 
abnormalities monitoring and 
discontinuation criteria
M
PD_MM.128
Monitor PD / eCRF
[Study Drug Log]
[Premature Discontinuation of Study 
Treatment]
[Local Laboratory]
[AE]
[Central Lab]
Refer to section 5.1.12.6 of the study 
protocol
Yes
Study drug not interrupted or 
discontinued (if applicable) upon 
M
PD_MM.129
Monitor PD / eCRF
[Study Drug Log]
Yes


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reaching any of the ocular 
abnormalities discontinuation criteria
[Premature Discontinuation of Study 
Treatment]
[AE]
Refer to section 5.1.12.7 of the study 
protocol
No unscheduled OCT examination 
performed upon experiencing 
suspected clinically significant 
findings indicative of macular edema
M
PD_MM.223
Monitor PD / eCRF
[AE]
e.g., blurred vision
Yes
Subject not discontinued from study 
drug after discontinuation from DMF 
background therapy
P
PD_PP.132
eCRF
[Study Drug Log]
[Drug Log - DMF (Tecfidera)]
Refer to section 5.1.12.8 of the study 
protocol
Yes
Subject remained on study drug but 
not re-consented to continue 
participation in the study after 
experiencing a confirmed relapse or 
a 24-week confirmed disability 
accumulation
M
PD_MM.133
Monitor PD / eCRF
[Informed Consent]
Yes
Subject with active uveitis not 
monitored and managed as per 
guidance described in the study 
protocol
M
PD_MM.224
Monitor PD / eCRF
[AE]
Refer to section 5.1.12.7.1 of the 
study protocol
Yes
No follow-up monitoring provided 
until any event of clinical concern has 
resolved or until the condition has 
stabilized or until the change was 
regarded as no longer clinically 
relevant
M
PD_MM.225
Monitor PD
Yes
Treatment of relapse with ACTH or 
other corticosteroids, dose or route of 
M
PD_MM.226
Monitor PD / eCRF
[Relapse Summary]
No


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administration than recommended 
per study protocol
[Corticosteroids for Treatment of 
Relapse]
[Previous/Concomitant Medications]
Includes tapering, treatment > 5 
days, IM administration
During treatment period, any start or 
dose increase of dalfampridine
M
PD_MM.140
Monitor PD / eCRF
[Previous/Concomitant Medications]
\CM\CMSPID\\
Yes
During treatment period, any stop or 
dose decrease of dalfampridine
M
PD_MM.141
Monitor PD / eCRF
[Previous/Concomitant Medications]
[Coding]
\CM\CMSPID\\
No
During treatment period, QT-
prolonging drug with known risk of 
Torsades de pointes started or 
increased in dose without adhering to 
recommendation defined in study 
protocol
M
PD_MM.227
Monitor PD / eCRF
[Previous/Concomitant Medications]
[Study Drug Log]
[ECG]
Refer to Appendix 4 of the study 
protocol
Yes
During treatment period, treatment 
with systemic corticosteroids and 
ACTH except for MS relapses and for 
short-term treatment with low dose or 
inhaled corticosteroids for pulmonary 
conditions
M
PD_MM.143
Monitor PD / eCRF
[Relapse Summary]
[Corticosteroids for Treatment of 
Relapse]
[Previous/Concomitant Medications]
[Coding]
Yes
During treatment period, treatment 
with any disease modifying drug for 
MS other than DMF and study drug 
prescribed as per protocol
M
PD_MM.144
Monitor PD / eCRF
[Previous/Concomitant Medications]
[Coding]
\CM\CMSPID\\
Yes
During treatment period, treatment 
with immunosuppressive 
(e.g., cladribine, mitoxantrone or 
other systemic immunosuppressive: 
azathioprine, cyclophosphamide, 
M
PD_MM.145
Monitor PD / eCRF
[Previous/Concomitant Medications]
[Coding]
Refer to section 5.2.6 of the study 
protocol
Yes


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cyclosporine or methotrexate) except 
DMF
During treatment period, treatment 
with intravenous immunoglobulins
M
PD_MM.146
Monitor PD / eCRF
[Previous/Concomitant Medications]
[Coding]
Yes
During treatment period, treatment 
with plasma exchange or total 
lymphoid irradiation
M
PD_MM.147
Monitor PD / eCRF
[Previous/Concomitant Medications]
[Coding]
Yes
During treatment period, vaccination 
with live vaccines
M
PD_MM.148
Monitor PD / eCRF
[Previous/Concomitant Medications]
[Coding]
Yes
During treatment period, treatment 
with another investigational drug
M
PD_MM.228
Monitor PD / eCRF
[Previous/Concomitant Medications]
[Coding]
\CM\CMSPID\\
Yes
During treatment period, treatment 
with beta-blockers, diltiazem, 
verapamil, digoxin, or any other anti-
arrhythmic or HR-lowering systemic 
therapy
M
PD_MM.150
Monitor PD / eCRF
[Previous/Concomitant Medications]
[Coding]
Yes
During treatment period, any 
investigational therapeutic procedure 
for MS
M
PD_MM.151
Monitor PD / eCRF
[Previous/Concomitant Medications]
[Coding]
\CM\CMSPID\\
Yes
Lymphocyte repeat testing not 
performed or was performed out-of-
time window
M
PD_MM.121
Monitor PD / eCRF
[Local Laboratory]
[Central Lab]
Yes
Spirometry repeat testing not 
performed or performed out-of-time 
window
M
PD_MM.122
Monitor PD / eCRF
[Spirometry]
Yes
Liver function repeat testing not 
performed or performed out-of-time 
window
M
PD_MM.123
Monitor PD / eCRF
[Local Laboratory]
[Central Lab]
Yes


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Any spirometry assessment not 
performed as per protocol
M
PD_MM.184
Monitor PD
e.g., less than 3 technically 
acceptable and repeatable traces, 
more than 8 expiratory manoeuvers
No
Any repeated safety assessment not 
performed according to the time 
interval defined in the study protocol
M
PD_MM.171
Monitor PD / eCRF
[Systolic/Diastolic Blood Pressure; 
Systolic/Diastolic Blood Pressure − 
Pre-dose; Spirometry; 
Ophthalmological examination; OCT; 
Body Weight; 
Physical Examination; Body 
Temperature; Pulse Rate; 
Dermatological Examination]
[Central Lab]
For DM only: to be reported once
No
Two consecutive safety assessments 
not performed or performed but 
results not available and no re-test 
done
M
PD_MM.229
Monitor PD / eCRF
Vendor data
Valid for each following assessment 
if not performed as a whole:  
Spirometry, ECG, Physical exam, 
Body weight, Body temperature, 
Blood pressure, both Ophthalmology 
and OCT, Chemistry or Hematology
Yes
Single scheduled non-blood safety 
assessment missing
M
PD_MM.230
Monitor PD / eCRF
Vendor data
Valid for each following assessment 
if not performed as a whole: 
Spirometry, Urinalysis, Body 
temperature, Weight, eC-SSRS (if 
not done or if recorded on paper), 
ECG, both Ophthalmology and OCT
Not valid if PD_MM.229 is applicable
For DM only: to be reported once
No


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Any missing single blood safety 
assessment not performed or 
performed but with unavailable 
results
M
PD_MM.231
Monitor PD / eCRF
Vendor data
Valid for whole Hematology or 
Chemistry
Not valid if PD_MM.229 is applicable
For DM only: to be reported once
No
Any of the monthly total lymphocyte 
count assessments during the first 24 
weeks of treatment not performed
M
PD_MM.174
Monitor PD
Yes
2.3
Contraception and Pregnancies
Condition
Type
Identifier
Source/Instructions
Additional 
information 
expected?
Important 
PD
Contraception requirement for 
woman of childbearing potential not 
followed
M
PD_MM.138
Monitor PD / eCRF
[Contraception Log]
Yes
Any urine pregnancy test to be done 
at home or at site not performed or 
any test result not shared with study 
personnel
M
PD_MM.232
Monitor PD / eCRF
[Urine Pregnancy Test forms]
No
Study personnel did not remind 
women of childbearing potential to 
use the methods of contraception 
defined for this study
M
PD_MM.177
Monitor PD
No
Absence of appropriate follow-up of a 
subject pregnancy
M
PD_MM.127
Monitor PD / eCRF
[AE]
Refer to section 10.3.2 of the study 
protocol
Yes


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2.4
Efficacy / Endpoint
Condition
Type
Identifier
Source/Instructions
Additional 
information 
expected?
Important 
PD
Any scheduled EDSS assessment 
not done
M
PD_MM.233
Monitor PD / eCRF
No
Any EDSS assessment not 
performed as per study protocol 
(impact on validity of EDSS score)
M
PD_MM.234
Monitor PD / eCRF
Any deviation not matching to codes 
PD_MM.306, PD_MM.307, 
PD_MM.152, PD_MM.233: To be 
reviewed by GCS&E for coding to 
either PD_MM.234 or PD_MM.235.
Yes
Any EDSS assessment not 
performed as per protocol (no impact 
on EDSS score validity)
M
PD_MM.235
Monitor PD / eCRF
Any deviation not matching to codes 
PD_MM.306, PD_MM.307, 
PD_MM.152, PD_MM. 233: To be 
reviewed by GCS&E for coding to 
either PD_MM.234 or PD_MM.235
No
No EDSS assessment performed to 
confirm a relapse
M
PD_MM.152
Monitor PD / eCRF
[EDSS/FS forms]
Yes
EDSS assessment to confirm relapse 
performed after start of treatment 
with steroids
M
PD_MM.306
Monitor PD / eCRF
[EDSS/FS forms]
[Relapse Summary]
[Corticosteroids for Treatment of 
Relapse]
[Previous/Concomitant Medications]
Yes
EDSS assessment to confirm relapse 
performed >7 days after the onset of 
symptoms
P
PD_MM.307
Monitor PD / eCRF
[EDSS/FS forms]
[Relapse Summary]
No
FSIQ-RMS symptoms or impact 
domain at given visit or FSIQ-RMS 
M
PD_MM.237
Monitor PD / Vendor data
No


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impact domain not assessable at 
EOS visit
e.g., symptoms domain not 
completed or completed less than 4 
days, impact domain not completed; 
For DM only: to be reported once
Any MRI not performed as per 
protocol during treatment period or 
PTOP
M
PD_MM.308
Monitor PD / eCRF
e.g., not done or not repeated in 
case of MRI unacceptable as per 
central over-read, missing 
sequences, not as per protocol 
schedule
Yes
2.5
Blinding
Condition
Type
Identifier
Source/Instructions
Additional 
information 
expected?
Important 
PD
At least one Actelion study team 
member (except site monitor, first 
dose monitor, first dose data 
scientist) had access to data 
potentially revealing treatment 
assignment as defined in study 
protocol
M
PD_MM.105
Monitor PD
CTT PD
Except alerts as defined per protocol
Yes
PI/study nurse, or any other 
personnel involved in the clinical care 
and management of subject 
deliberately tried to find out treatment 
assignment
M
PD_MM.238
Monitor PD
e.g., local lab results of lymphocytes
Yes
Any site personnel had access to any 
post-randomization MRI report 
containing MS-related information 
without justification documented on 
the report
M
PD_MM.239
Monitor PD
Except in case of pre-defined 
threshold documented at site
No


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Treatment code broken before 
unblinding of the study for a reason 
not related to management of a 
clinical event
M
PD_MM.107
Monitor PD / eCRF
[Subject Unblinding]
Monitor to provide date of potential 
unblinding
\Date of 
Unblinding\\\
Yes
Efficacy assessor involved in clinical 
care and management or made 
aware of any data potentially 
revealing treatment assignment
M
PD_MM.240
Monitor PD
e.g., AEs, ECGs, lab results
Monitor to provide date of potential 
unblinding
\Date of potential 
unblinding\\\
Yes
PI/treating neurologist, clinical 
coordinator/study nurse or any other 
personnel involved in clinical care 
and management of subject who 
have had access to Day 1 or first day 
of SD re-initiation data
M
PD_MM.104
Monitor PD
Monitor to provide date of potential 
unblinding
\Date of potential 
unblinding\\\
No
Any site personnel made aware of 
any data with unblinding potential 
assessed as high or moderate not 
related to management of a clinical 
event (except Day 1 or first day of re-
initiation of study drug data)
M
PD_MM.309
Monitor PD
Data reviewed by at least one site 
member (except alerts as defined per 
protocol). Monitor to provide date. 
Unblinding type to be provided to 
CDDM based on “Potential 
Unblinding Event Documentation 
Form”); Type of unblinding to be 
reported for BST only for 
lymphocytes and/or WBC
\Date of potential
unblinding\ Type: 
Lymphocytes
and/or Type: WBC\\
Yes
Any site personnel made aware of 
data with unblinding potential 
assessed as low (except Day 1 or 
day of re-initiation of study drug data)
M
PD_MM.310
Monitor PD
Data received but site claiming not 
reviewing the results (except alerts 
as defined per protocol); Monitor to 
provide date. Unblinding type to be 
provided to CDDM based on 
“Potential Unblinding Event 
Documentation Form”);
\Date of potential 
unblinding\ Type: 
Lymphocytes
and/or Type: WBC\\
No


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Type of unblinding to be reported for 
BST only for lymphocytes and/or 
WBC
Any site personnel involved in clinical 
care and management of subject 
who has reviewed Day 1 or re-
initiation data
M
PD_MM.311
Monitor PD /
Monitor to provide date of unblinding
\Date of potential 
unblinding\\\
Yes
2.6
Study drug
Condition
Type
Identifier
Source/Instructions
Additional 
information 
expected?
Important 
PD
Incorrect request of kit type via IVRS 
(i.e., up-titration kit instead of 
maintenance kit or vice-versa)
M
PD_MM.111
Monitor PD
Yes
Study drug taken from non-allocated 
kit
M
PD_MM.242
Monitor PD
[Compliance from ePRO]
e.g., incorrect kit dispensed, 
accidental exchange
NB: PD to be classified after unblinding 
into the following two protocol sub-
deviations: ‘Study drug taken from non-
allocated kit: non-assigned treatment 
received’ (PD_MM.242.1) or ‘Study drug 
taken from non-allocated kit: assigned 
treatment received’ at unblinding 
(PD_MM.242.2)
Date of intake from 
incorrect kit (start 
and end date), 
incorrect kit 
number. I.e.:
\Start date\End 
date\Kit number\
Yes
Lack of compliance with study drug 
during up-titration
M
PD_MM.243
Monitor PD / Vendor data
[Compliance from ePRO]
e.g., study drug interrupted >1 day 
without restarting up-titration, drug 
not taken in the correct sequence
Yes


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For DM only: to be raised manually in 
case of temporary interruption and 
no re-initiation.
During up-titration period, at least 
one study drug dose not taken in the 
morning
M
PD_MM.244
Monitor PD
For DM only: to be reported once
No
IMP temperature excursion of any 
dispensed kit with GQM (GMP-DP) 
approval for use
M
PD_MM.245
Monitor PD
For DM only: to be reported once
No
IMP temperature excursion of any 
dispensed kit without GQM (GMP-
DP) approval for use
M
PD_MM.246
Monitor PD
For DM only: to be reported once
No
Misuse or abuse of the study 
treatment
M
PD_MM.137
Monitor PD / Vendor data / eCRF
[Study Drug Log]
>3 doses taken on the same day
Yes
Overdose of study treatment
M
PD_MM.312
eCRF / Monitor PD /
≤3 additional doses taken on the 
same day
No
Study drug accountability and 
compliance check (if eDiary data 
available) not performed at least one 
applicable visit
M
PD_MM.247
Monitor PD
For DM only: to be reported once
No
Subject did not return all used, 
partially used and unused study 
treatment blister packs at least one 
applicable visit
M
PD_MM.248
Monitor PD
For DM only: to be reported once
No
Subject took study treatment on the 
day of study visit prior to visit 
assessment(s)
M
PD_MM.115
Monitor PD
For DM only: to be reported once
No
Any missing recording of study drug 
intake in the eDiary
M
PD_MM.249
Monitor PD
e.g., no record at the time of study 
drug intake;
No


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For DM only: to be reported once
Study drug not available at site in 
due time
M
PD_MM.250
Monitor PD
Valid for late IMP delivery causing 
any interruption
No
2.7
Other
Condition
Type
Identifier
Source/Instructions
Additional 
information 
expected?
Important 
PD
Any protocol scheduled visit not done 
(except follow-up and EOT visits)
M
PD_MM.251
Monitor PD / eCRF
No
Study drug administered but 
randomization not done per IRT 
system
M
PD_MM.252
Monitor PD / eCRF
[Randomization]
[Study Drug Log]
Yes
Study drug administered but 
date/time of first dose < date/time of 
randomization
P
PD_PP.253
eCRF
Yes
Any pre-dose assessment performed 
post-dose (except pre-dose PK 
sampling)
M
PD_MM.254
Monitor PD / eCRF
For DM only: to be reported once per 
visit if all assessments done post-
dose
No
Any randomized subject who never 
received study drug
M
PD_MM.101
Monitor PD
CRA: specify reason for not 
administering the study drug
No
Any pre-dose PK sampling 
performed post-dose
M
PD_MM.255
Monitor PD / eCRF
No
Any PK sample not taken
M
PD_MM.256
Monitor PD / eCRF
No
Post-dose PK sampling performed 
out of time window
M
PD_MM.257
Monitor PD / eCRF
No
Missing source documents related to 
treatment period
M
PD_MM.179
Monitor PD
No


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Vaccine-specific antibody titers 
assessment before and/or after non-
live vaccination not performed
M
PD_MM.258
Monitor PD / eCRF
No
Any scheduled visit performed out of 
time window (except EOT and follow-
up visits)
M
PD_MM.259
Monitor PD / eCRF
[Visit Summary]
No
3
PROTOCOL DEVIATIONS AFTER END OF TREATMENT
Note: Applies any time after end of treatment unless specified otherwise.
3.1
Safety
Condition
Type
Identifier
Source/Instructions
Additional 
information 
expected?
Important 
PD
Any post-treatment safety follow-up 
not performed according to protocol
M
PD_MM.260
Monitor PD / eCRF
[Visit Summary (FU Day30)] [Visit
Summary (FU Day7)] [Study 
discontinuation]
e.g., follow-up performed out of time 
window, missing safety assessment
No
Any applicable follow-up visits not 
done
M
PD_MM.313
Monitor PD / eCRF
[Visit Summary (FU Day30)] [Visit 
Summary (FU Day7)]
Yes
3.2
Efficacy / Endpoint
Condition
Type
Identifier
Source/Instructions
Additional 
information 
expected?
Important 
PD
FSIQ-RMS symptoms domain not 
assessable at EOS visit
M
PD_MM.156
Monitor PD
e.g., not completed for at least 4 
days
No


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Visit 18 (EOT) not performed within 7 
days after study drug discontinuation 
for a subject who completed the 
treatment period as per study 
protocol
M
PD_MM.261
Monitor PD / eCRF
[Visit Summary]
e.g., EOT visit performed out of time 
window
No
Visit 18 (EOT) not performed within 7 
days after study drug discontinuation 
for a subject who prematurely 
discontinued study drug
M
PD_MM.262
Monitor PD / eCRF
[Visit Summary]
e.g., EOT visit performed out of time 
window
No
Visit 18 (EOT) not performed for a 
subject who completed the treatment 
period as per study protocol
M
PD_MM.314
Monitor PD / eCRF
e.g., EOT visit not done
Yes
Visit 18 (EOT) not performed for a 
subject who prematurely 
discontinued study drug
M
PD_MM.315
Monitor PD / eCRF
e.g., EOT visit not done
Yes
4
PROTOCOL DEVIATIONS AT ANYTIME DURING THE STUDY
4.1
Safety and Pregnancy
Condition
Type
Identifier
Source/Instructions
Additional 
information 
expected?
Important 
PD
Any SAE reporting not performed as 
per protocol (e.g., delayed)
M
PD_MM.178
Monitor PD
[AE]
Yes
Any pregnancy reporting not 
performed as per protocol
M
PD_MM.263
Monitor PD
Yes
Any MRI not reviewed by local 
radiologist or neurologist with MRI 
expertise
M
PD_MM.164
Monitor PD
Yes
Any assessment or procedure 
performed by a non-qualified or non-
M
PD_MM.264
Monitor PD
No


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trained person (except EDSS and 
MRI) or by an non-delegated person
PFT done without at least 5 minutes 
of rest prior to testing or done without 
refraining from taking SABA/LABA for 
6/24 hours prior to testing
M
PD_MM.265
Monitor PD
For DM only: to be reported once
No
Blood Pressure or ECG done without 
at least 5 minutes of rest prior to 
testing
M
PD_MM.266
Monitor PD
For DM only: to be reported once
No
Any blood pressure assessment not 
measured in supine position
P
PD_PP.165
eCRF
[Systolic/Diastolic Blood Pressure]
Visit 3 post-dose assessments: to be 
reported in FDM database
For DM only: to be reported once
No
Any Dermatology or Chest X-ray 
assessment not performed, or Chest 
X-ray: performed but results not 
available
M
PD_MM.267
Monitor PD / eCRF
No
Any lymphocyte sub-study 
assessment not performed or 
performed but with at least one test 
missing
M
PD_MM.173
Monitor PD / eCRF
[Central Lab]
For DM only: to be reported once
No
Blood pressure not measured on the 
same arm at every assessment
P
PD_PP.166
eCRF
[Systolic/Diastolic Blood Pressure]
Visit 3 post-dose assessments: to be 
reported in FDM database
For DM only: to be reported once
No
Contraceptive methods not 
documented in the source notes
M
PD_MM.268
Monitor PD
For DM only: to be reported once
No
Any safety or efficacy assessment or 
any questionnaire performed out of 
time window
M
PD_MM.172
Monitor PD / ePRO
[SF-36v2™, WPAI:MS]
For DM only: to be reported once
No


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Includes Phone Interviews
4.2
Efficacy / Endpoint
Condition
Type
Identifier
Source/Instructions
Additional 
information 
expected?
Important 
PD
Any EDSS assessment performed by 
personnel not qualified or trained and 
certified (certification consists of the 
"Neurostatus e-Test" web-based 
interactive test)
M
PD_MM.102
Monitor PD / eCRF
[EDSS/FS forms]
"Neurostatus e Test" web-based 
interactive test not passed or not re-
certified as per protocol
Yes
Any ophthalmology related EDSS 
assessment not performed by the 
efficacy assessor
M
PD_MM.269
Monitor PD
For DM only: to be reported once
No
Any relapse assessment / symptom 
questionnaire not performed as per 
protocol at any time during the study
M
PD_MM.270
Monitor PD
Includes: 
- in-between visits telephone calls for 
relapse detection not done 
- any assessment for relapse 
detection not done (i.e.. 
questionnaires (RAQ, symptoms 
form, FSIQ-RMS, SF-36), Body 
temperature, Physical exam, Pulse 
rate or ECG)
For DM only: to be reported for all 
missing relapse assessment / 
symptom questionnaire
No
SF-36 or WPAI:MS questionnaire 
not performed or performed but with 
one or more question missing
M
PD_MM.271
Monitor PD / ePRO
[SF-36v2™, WPAI:MS]
For DM only: to be reported once
No
Any MSFC/SDMT missing or not 
performed as per protocol
M
PD_MM.272
Monitor PD
No


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Includes: Two PASAT forms (i.e. 
Form A and B) not administered in a 
counterbalanced way across visits (< 
40% of one type) Incorrect sequence 
of tests or tests not timed;
For DM only: to be reported once
4.3
Other
Condition
Type
Identifier
Source/Instructions
Additional 
information 
expected?
Important 
PD
Any assessment performed not 
required by study protocol
M
PD_MM.273
Monitor PD
Except additional, repeated 
assessments or unscheduled visits 
which are required per protocol to 
follow-up on AEs or laboratory 
abnormalities
e.g., extra labs, PFTs or MRIs; 
For DM only: to be reported once
No
E-diary not used at any visit
M
PD_MM.274
Monitor PD
For DM only: to be reported once
No
Data provided by site to external 
vendors containing potential patient 
identifiers
M
PD_MM.275
Monitor PD / Vendor data
e.g., real date of birth, subject’s 
initials
No
Any central laboratory report not 
signed / dated or signed / dated more 
than 5 calendar days after receipt
M
PD_MM.276
Monitor PD
For DM only: to be reported once
No
Any applicable assessment not 
signed / dated (except central 
laboratory)
M
PD_MM.277
Monitor PD
e.g., ECG, PFT or MRI reports; 
Includes reports not signed and/or 
not dated;
For DM only: to be reported once
No


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Any performed assessment not 
conducted as per protocol 
requirements
M
PD_MM.168
Monitor PD
Valid only if not covered by another 
PD code
For DM only: to be reported once per 
deviation type
No
Any other protocol deviation
M
PD_MM.186
Monitor PD
For DM only: to be reported once per 
type of issue
No


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16 APPENDICES
A. 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 SMQs. 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 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) [20000042]. The PT 
‘Dyspnoea at rest’, ‘Dyspnoea’, ‘Dyspnoea exertional’, ‘Carbon monoxide diffusing capacity 
decreased’, ‘Pulmonary function test abnormal’, ‘Pulmonary function test decreased’, ‘Vital 


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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 AEs belonging to the SOC 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 and the following PTs 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 PT 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, 10 June 2020. 
Protocol deviations are categorized according to the categories in the Protocol Deviation code list 
(level 2 heading, e.g., ‘Informed Consent and Patient Rights’, ‘General Eligibility’, …)
[Attachment 1].


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C. Laboratory marked abnormalities
Table 9
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)
MCH (pg/Cell)
ND
ND
ND
ND
MCV (fL)
ND
ND
ND
ND
Hematocrit (L/L)
< 0.28 (female)
< 0.32 (male)
< 0.20
> 0.55 (female)
> 0.60 (male)
> 0.65
Platelet count (109 /L)
< 75 
< 50
> 600
> 999
RBC count (1012 /L)
ND
ND
ND
ND
WBC count (109 /L)
NA
< 1.9
> 20.0
ALERT:
> 20.0
> 100.0
Lymphocyte (109 /L)
ND
< 0.2
ALERT:
< 0.2
Decrease of > 
50 % from the 
value of total 
lymphocyte 
count recorded 
at Visit 5 
(Week 4) 
associated with 
a total 
lymphocyte 
count < 0.5 
109/L recorded 
at two 
consecutive 
visits after Visit 
5 (Week 4)
> 4.0
≥ 8
Neutrophils (109 /L) 
< 1.5 
< 1.0
ND
ND


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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
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
Creatinine clearance (mL/min)
< 60 
< 30 
ND
ND
Urea (mmol/L)
ND
ND
> 2.5 ULN
> 5 ULN
Albumin (g/L)
< 30 
< 20
ND
ND
Protein total (g/L)
ND
ND
ND
ND
C-reactive protein (mg/L)
ND
ND
ND
ND
Glucose (mmol/L)
< 3.0
< 2.2
> 8.9
>13.9
Potassium (mmol/L)
< 3.2
< 3.0
> 5.5
> 6.0
Sodium (mmol/L)
ND
< 130
> 150 
> 155 
Calcium (mmol/L)
< 2.0 
< 1.75
> 2.9
> 3.1
Chloride (mmol/L)
ND
ND
ND
ND
Triglyceride (mmol/L)
ND
ND
> 3.42
> 11.4
Cholesterol (mmol/L)
ND
ND
> 7.75
> 12.92
Serum pregnancy test
ND
ND
ND
Positive
ALERT: 
Positive


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* 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 Protocol Section 7.3.13.1]; ALT = alanine 
aminotransferase; AST = aspartate aminotransferase; NA = not applicable; INR = International Normalized Ratio; MCH = mean 
corpuscular hemoglobin; MCV = mean corpuscular volume; ND = not defined; may be complemented by definitions provided by 
the central laboratory (see central laboratory manual); RBC = red blood count; SI = international system of units; ULN = upper 
limit of normal; WBC = white blood cell.
Source: Protocol AC-058B302, appendix 6.
D. Document history
Version
Effective Date
Reason (main)
1.0
16 April 2020
New
2.0
16 June 2020
Reduction of scope and change to synoptic CSR