Conditions: Multiple Sclerosis Relapsing Multiple Sclerosis Advancing Multiple Sclerosis
Keywords: Multiple sclerosis Relapsing multiple sclerosis Advancing multiple sclerosis conversion siponimod adult BAF312 disease modifying therapies cognitive assessment open-label
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 185
Healthy volunteers: no

Brief summary:
To assess safety and tolerability of patients converting from approved Relapsing Multiple Sclerosis (RMS) Disease Modifying Therapies (DMTs) to siponimod.

Detailed description:
This is a 6-month, open-label, multi-center, single arm design, including advancing RMS patients, evaluating the overall safety and tolerability profile of converting from oral, injectable or infusion RMS DMTs to oral siponimod.

Arms:
arm 1: Participants will receive titrated doses of siponimod tablets, orally, once daily of 0.25 mg on Day 2, 0.5 mg on Day 3, 0.75 mg on Day 4, 1.25 mg on Day 5, and maintenance dose of siponimod 2.0 mg tablets, orally, once daily from Day 6 up to 6 months.

As of protocol amendment 3, participants entering the trial converting from fingolimod will start directly with 2 mg dose of siponimod.

Interventions: intervention 1: Siponimod
Intervention descriptions: intervention 1: Siponimod 2mg tablets taken once daily

Protocol document:
Prot_000.pdf: 
Novartis Research and Development 
BAF312A/Siponimod/Mayzent® 
Clinical Trial Protocol CBAF312AUS02 / NCT03623243
Exploring the safety and tolerability of conversion from 
oral, injectable or infusion disease modifying therapies to 
dose-titrated Oral Siponimod (Mayzent®) in patients with 
advancing forms of relapsing multiple sclerosis: A 6-month 
open label, multi-center Phase IIIb study (EXCHANGE) 
Document type: 
Amendment Protocol Version 
EUDRACT number: 
N/A 
Version number: 
v05 clean 
Clinical Trial Phase: 
IIIb 
Release date: 
27-Jul-2021 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 1.0 (01-Dec-2017) 


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Table of contents 
Table of contents .................................................................................................................. 2 
List of tables......................................................................................................................... 6 
List of figures ....................................................................................................................... 7 
List of abbreviations ............................................................................................................ 8 
Glossary of terms ............................................................................................................... 11 
Amendment 05 ................................................................................................................... 13 
Amendment 04 ................................................................................................................... 14 
Amendment 03 ................................................................................................................... 16 
Amendment 02 ................................................................................................................... 20 
Amendment 01 ................................................................................................................... 22 
Protocol summary .............................................................................................................. 24 
1 
Introduction ........................................................................................................................ 32 
1.1 
Background .......................................................................................................... 32 
1.2 
Purpose ................................................................................................................. 35 
2 
Objectives and endpoints ................................................................................................... 35 
3 
Study design ....................................................................................................................... 37 
 
 38 
4 
Rationale ............................................................................................................................ 39 
4.1 
Rationale for study design.................................................................................... 39 
 
 40 
4.2 
Rationale for dose/regimen and duration of treatment ........................................ 41 
4.3 
Rationale for choice of control drugs .................................................................. 42 
4.4 
Purpose and timing of interim analyses/design adaptations ................................ 42 
4.5 
Risks and benefits ................................................................................................ 42 
4.6 
Rationale for public health emergency mitigation procedures ............................ 43 
5 
Population .......................................................................................................................... 43 
5.1 
Inclusion criteria .................................................................................................. 43 
5.2 
Exclusion criteria ................................................................................................. 44 
6 
Treatment ........................................................................................................................... 48 
6.1 
Study treatment .................................................................................................... 48 
6.1.1 
Investigational and control drugs .......................................................... 48 
6.1.2 
Additional study treatments ................................................................... 49 
6.1.3 
Treatment arms/group ............................................................................ 49 
6.1.4 
Treatment duration ................................................................................ 49 
6.2 
Other treatment(s) ................................................................................................ 49 
6.2.1 
Concomitant therapy.............................................................................. 49 


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6.2.2 
Prohibited medication ............................................................................ 50 
6.3 
Treating the patient .............................................................................................. 50 
6.3.1 
Patient numbering .................................................................................. 50 
6.3.2 
Treatment assignment ............................................................................ 51 
6.4 
Treatment blinding ............................................................................................... 51 
6.5 
Dose escalation and dose modification ................................................................ 51 
6.6 
Additional treatment guidance ............................................................................. 51 
6.6.1 
Treatment compliance ........................................................................... 51 
6.6.2 
Emergency breaking of assigned treatment code .................................. 51 
6.7 
Preparation and dispensation ................................................................................ 51 
6.7.1 
Handling of study treatment and additional treatment .......................... 52 
6.7.2 
Instruction for prescribing and taking study treatment .......................... 52 
7 
Informed consent procedures ............................................................................................. 53 
8 
Visit schedule and assessments .......................................................................................... 54 
8.1 
Screening.............................................................................................................. 62 
8.1.1 
Information to be collected on screening failures .................................. 62 
8.2 
Patient demographics/other baseline characteristics ............................................ 63 
8.3 
Efficacy/Pharmacodynamics ................................................................................ 63 
 
 63 
8.4 
Safety/Tolerability ................................................................................................ 63 
8.4.1 
Laboratory evaluations .......................................................................... 64 
8.4.2 
Electrocardiogram (ECG)...................................................................... 66 
8.4.3 
Optical Coherence Tomography (OCT) ................................................ 66 
8.4.4 
Pregnancy and assessments of infertility ............................................... 67 
8.4.5 
Other safety evaluations ........................................................................ 67 
8.5 
Additional assessments ........................................................................................ 69 
8.5.1 
Clinical Outcome Assessments (COAs) ................................................ 69 
 
 69 
8.5.3 
Other Assessments ................................................................................. 70 
9 
Study discontinuation and completion ............................................................................... 70 
9.1 
Discontinuation .................................................................................................... 70 
9.1.1 
Discontinuation of study treatment ....................................................... 70 
9.1.2 
Withdrawal of informed consent ........................................................... 71 
9.1.3 
Lost to follow-up ................................................................................... 71 
9.1.4 
Early study termination by sponsor ....................................................... 71 
9.2 
Study completion and post study treatment ......................................................... 71 
10 Safety monitoring and reporting ........................................................................................ 72 


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10.1 
Definition of adverse events and reporting requirements .................................... 72 
10.1.1 
Adverse events....................................................................................... 72 
10.1.2 
Serious adverse events ........................................................................... 73 
10.1.3 
SAE reporting ........................................................................................ 74 
10.1.4 
Pregnancy reporting ............................................................................... 74 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................. 75 
10.2 
Additional Safety Monitoring .............................................................................. 75 
10.2.1 
Liver safety monitoring ......................................................................... 75 
10.2.2 
Prospective suicidality assessment ........................................................ 76 
10.2.3 
Bradycardia ............................................................................................ 77 
11 Data Collection and Database management ....................................................................... 77 
11.1 
Data collection ..................................................................................................... 77 
11.2 
Database management and quality control .......................................................... 77 
11.3 
Site monitoring..................................................................................................... 78 
11.4 
Virtual patient cohort ........................................................................................... 78 
12 Data analysis and statistical methods ................................................................................. 79 
12.1 
Analysis sets ......................................................................................................... 79 
12.2 
Patient demographics and other baseline characteristics ..................................... 80 
12.3 
Treatments ............................................................................................................ 80 
12.4 
Analysis of the primary endpoint(s) ..................................................................... 80 
12.4.1 
Definition of primary endpoint(s).......................................................... 80 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 80 
12.4.3 
Handling of missing values/censoring/discontinuations ........................ 81 
12.4.4 
Sensitivity and Supportive analyses ...................................................... 81 
12.5 
Analysis of secondary endpoints.......................................................................... 81 
12.5.1 
Safety endpoints .................................................................................... 81 
12.5.2 
Patient report outcomes ......................................................................... 82 
 
 82 
12.7 
Interim analyses ................................................................................................... 83 
12.8 
Sample size calculation ........................................................................................ 83 
12.8.1 
Primary endpoint(s) ............................................................................... 83 
 
 84 
13 Ethical considerations and administrative procedures ....................................................... 84 
13.1 
Regulatory and ethical compliance ...................................................................... 84 
13.2 
Responsibilities of the investigator and IRB/IEC ................................................ 84 
13.3 
Publication of study protocol and results ............................................................. 84 
13.4 
Quality Control and Quality Assurance ............................................................... 85 


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14 Protocol adherence ............................................................................................................. 85 
14.1 
Protocol Amendments .......................................................................................... 85 
15 References .......................................................................................................................... 86 
16 Appendices ......................................................................................................................... 89 
16.1 
Appendix 1: Vital signs ....................................................................................... 89 
16.2 
Appendix 2: Liver event definition and follow up requirements ......................... 90 
16.3 
Appendix 3: Specific Renal Alert Criteria and Actions and Event Follow-up .... 92 
16.4 
Appendix 4: List of generic names of potent inhibitors/inducers of 
CYP2C9/CYP3A4 ............................................................................................... 94 
16.5 
Appendix 5: Assessing Immunity to Varicella .................................................... 97 
16.6 
Appendix 6: Teriflunomide Accelerated Elimination Program (for patients 
treated with teriflunomide at screening or within 8 months prior to 
screening) ............................................................................................................. 97 
16.7 
Appendix 7: Recommendations for the management of bradycardia ................. 98 
16.8 
Appendix 8: Guidelines for Ophthalmic examination and management of 
Macular Edema .................................................................................................... 99 


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List of tables 
Table 2-1 
Objectives and related endpoints ........................................................... 35 
Table 6-1 
Core Treatment Period .......................................................................... 49 
Table 6-2 
Prohibited medication ............................................................................ 50 
Table 6-3 
Dose and treatment schedule ................................................................. 52 
Table 8-1 
Assessment Schedule ............................................................................. 57 
 
 61 
Table 8-3 
Physical Assessments ............................................................................ 64 
Table 8-4 
Laboratory Assessments ........................................................................ 64 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse .......................................................................................... 75 
Table 16-1 
Liver Event and Laboratory Trigger Definitions ................................... 90 
Table 16-2 
Follow Up Requirements for Liver Events and Laboratory Triggers .... 90 
Table 16-3 
Dual moderate CYP2C9/strong or moderate CYP3A4 inhibitors ......... 94 
Table 16-4 
Moderate CYP2C9 inhibitors ................................................................ 94 
Table 16-5 
Strong CYP3A4 inhibitors..................................................................... 94 
Table 16-6 
Moderate CYP3A4 inhibitors ................................................................ 95 
Table 16-7 
Dual moderate CYP2C9/moderate or strong CYP3A4 inducers ........... 95 
Table 16-8 
Moderate CYP2C9 inducers .................................................................. 95 
Table 16-9 
Strong CYP3A4 inducers ...................................................................... 96 
Table 16-10 
Moderate CYP3A4 inducers .................................................................. 96 


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List of figures 
Figure 3-1 
Siponimod Target Daily Dose ............................................................... 38 
Figure 3-2 
Exchange Study Design ......................................................................... 38 


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List of abbreviations 
 
AE 
Adverse Event 
AESI 
ALT 
Adverse Events of Special Interest 
Alanine Aminotransferase 
ALP 
Alkaline Phosphatase 
ANCOVA 
Analysis of covariance 
ARR 
Annualized Relapse Rate 
AST 
Aspartate Aminotransferase 
AV 
Atrioventricular 
BAF312 
Siponimod 
BBB 
Blood Brain Barrier 
BID 
Twice a day 
BMI 
Body Mass Index 
BLRM 
Bayesian Logistic Regression Model 
BRACE 
Betaseron, Rebif, Avonex, Copaxone, Extavia and other interferons 
and glatiramer acetate 
BUN 
Blood Urea Nitrogen 
CDP 
Clinical Development Plan 
CDS 
Core Data Sheet 
CK 
Creatinine Kinase 
ClinRO 
Clinician Reported Outcomes 
COA 
Clinical Outcome Assessment 
CO2 
carbon dioxide 
CRF 
Case Report/Record Form (paper or electronic) 
CO 
Country Organization 
CQA 
Clinical Quality Assurance 
CRO 
Contract Research Organization 
CDSGs 
The Clinical Development Safety Guidelines 
COPD 
Chronic Obstructive Pulmonary Disease 
CSR 
Clinical study report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTC 
Common Terminology Criteria 
CMO&PS 
Chief Medical Office and Patient Safety 
CV 
coefficient of variation 
DIN 
Drug Inducted Nephrotoxicity 
DLT 
Dose Limiting Toxicity 
DMC 
Data Monitoring Committee 
DMT 
Disease Modifying Therapy 
DS&E 
Drug Safety and Epidemiology 
ECG 
Electrocardiogram 
eCOA 
Electronic Clinical Outcome Assessment 
e-C-SSRS 
Electronic Columbia-Suicide Severity Rating Scale 
EDC 
Electronic Data Capture 
EDSS 
Expanded Disability Status Scale 


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ELISA 
Enzyme-linked immunosorbent assay 
EOI 
End of Infusion 
EOS 
End of Study 
EOT/S 
End of Treatment/Study 
eSource 
Electronic Source 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
H 
Hour 
HbsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
hCG 
Human Chorionic Gonadotropin 
HCP 
Healthcare Professional 
HCV 
Hepatitis C virus 
HEOR 
Health Economics & Outcomes Research 
HIV 
Human immunodeficiency virus 
HRQoL 
Health-Related Quality of Life 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
IMP 
Investigational Medicinal Product 
ICH 
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
i.v. 
intravenous 
 
 
LFT 
Liver function test 
LDH 
lactate dehydrogenase 
LLOQ 
lower limit of quantification 
LLN 
lower limit of normal 
MAP 
Manage Access Program 
MedDRA 
Medical dictionary for regulatory activities 
mg 
milligram(s) 
ml 
milliliter(s) 
MS 
Multiple Sclerosis 
MTD 
Maximum Tolerated Dose 
Nab 
Neutralizing antibody 
 
 
ObsRO 
Observer Reported Outcomes 
Q.D. 
once a day 
OCT 
PA 
Optical Coherence Tomography 
posteroanterior 


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PC 
Personal Computer 
PD 
Pharmacodynamic(s) 
 
 
PerfO 
Performance Outcomes 
PK 
Pharmacokinetic(s) 
p.o. 
oral(ly) 
PRO 
Patient Reported Outcomes 
 
 
QRS 
Quantron Resonance System 
QTcF 
QT interval corrected by Fridericia’s formula 
PT 
prothrombin time 
RAP/SAP 
The Report and Analysis Plan (RAP) is a regulatory document which 
documents preplanned statistical analyses 
RBC 
red blood cell(s) 
RDE 
Recommended dose for expansion 
REB 
Research Ethics Board 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RMS 
Relapsing Multiple Sclerosis 
RRMS 
Relapsing-Remitting Multiple Sclerosis 
RP2D 
Recommended phase two dose 
RU 
Resource Utilization 
R Value 
ALT/ALP x ULN 
SAE 
Serious Adverse Event 
s.c. 
subcutaneous 
sCR 
serum creatinine 
SD 
standard deviation 
SDMT 
Single Digit Modality Test 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic-Pyruvic Transaminase 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TD 
Study Treatment Discontinuation 
TQSM-9 
Treatment Satisfaction Questionnaire for Medication 
ULN 
upper limit of normal 
ULQ 
upper limit of quantification 
WBC 
white blood cell(s) 
WHO 
World Health Organization 
WoC 
Withdrawal of Consent 


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Glossary of terms 
Additional treatment 
Medicinal products that may be used during the clinical trial as described 
in the protocol, but not as an investigational medicinal product (e.g. any 
background therapy) 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), 
saliva, tissue, urine, stool, etc. taken from a study patient 
Cohort 
A specific group of patients fulfilling certain criteria and generally treated 
at the same time 
Control drug 
A study drug (active or placebo) used as a comparator to reduce 
assessment bias, preserve blinding of investigational drug, assess 
internal study validity, and/or evaluate comparative effects of the 
investigational drug 
Cycles 
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g., q28 days) 
Dosage 
Dose of the study treatment given to the patient in a time unit (e.g. 100 
mg once a day, 75 mg twice a day) 
Electronic Data Capture 
(EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical 
study data using data collection systems, such as Web-based 
applications, interactive voice response systems and clinical laboratory 
interfaces. EDC includes the use of Electronic Case Report Forms 
(eCRFs) which are used to capture data transcribed from paper source 
forms used at the point of care. 
End of the clinical trial 
The end of the clinical trial is defined as the last visit of the last patient or 
at a later point in time as defined by the protocol. 
Enrollment 
Point/time of patient entry into the study at which informed consent must 
be obtained 
eSource (DDE) 
eSource Direct Data Entry (DDE) refers to the capture of clinical study 
data electronically, at the point of care. eSource Platform/Applications 
reduce the use of paper capture source data during clinical visits. 
eSource combines source documents and case report forms (eCRFs) 
into one application, allowing for the real time collection of clinical trial 
information to Novartis and other oversight authorities, as appropriate. 
Healthy volunteer 
A person with no known significant health problems who volunteers to be 
a study participant 
Investigational 
drug/treatment 
The drug whose properties are being tested in the study 
Medication number 
A unique identifier on the label of medication kits 
Mis-randomized 
patients 
Mis-randomized patients are those who were not qualified for 
randomization and who did not take study treatment, but have been 
inadvertently randomized into the study 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study 
(concomitant or rescue therapy) 
Part 
A sub-division of a study used to evaluate specific objectives or contain 
different populations. For example, one study could contain a single dose 
part and a multiple dose part, or a part in patients with established 
disease and in those with newly-diagnosed disease. 


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Patient 
An individual with the condition of interest for the study- 
Note: use “patient” in population section only, use “patient” in the rest of 
the document 
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, and 
Follow-up) which are described in the Protocol. Periods define the study 
phases and will be used in clinical trial database setup and eventually in 
analysis 
Perpetrator drug 
A drug which affects the pharmacokinetics of the other drug 
Premature patient 
withdrawal 
Point/time when the patient exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this 
time all study drug administration is discontinued and no further 
assessments are planned 
Randomization number 
A unique identifier assigned to each randomized patient 
Run-in Failure 
A patient who is screened but not randomized/treated after the run-in 
period (where run-in period requires adjustment to patient’s intervention 
or treatment) 
Screen Failure 
A patient who did not meet one or more criteria that were required for 
participation in the study 
Source Data/Document 
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource. 
Stage in cancer 
The extent of a cancer in the body. Staging is usually based on the size 
of the tumor, whether lymph nodes contain cancer, and whether the 
cancer has spread from the original site to other parts of the body 
Start of the clinical trial 
The start of the clinical trial is defined as the signature of the informed 
consent by the first patient. 
Study treatment 
Any single drug or combination of drugs or intervention administered to 
the patient as part of the required study procedures. 
Study treatment 
discontinuation 
When the patient permanently stops taking any of the study drug(s) prior 
to the defined study treatment completion date (if any) for any reason; 
may or may not also be the point/time of study discontinuation 
Patient 
A trial participant (can be a healthy volunteer or a patient) 
Patient number 
A unique number assigned to each patient upon signing the informed 
consent. This number is the definitive, unique identifier for the patient and 
should be used to identify the patient throughout the study for all data 
collected, sample labels, etc. 
Treatment arm/group 
A treatment arm/group defines the dose and regimen or the combination, 
and may consist of 1 or more cohorts. 
Variable 
A measured value or assessed response that is determined from specific 
assessments and used in data analysis to evaluate the drug being tested 
in the study 
Victim drug 
The drug that is affected by the drug-drug interaction 
Withdrawal of study 
consent 
Withdrawal of consent is defined as when a patient does not want to 
participate in the study any longer, and does not want any further visits or 
assessments, and does not want any further study related contact, and 
does not allow analysis of already collected biologic material. 


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Amendment 05 
 
Rationale for Amendment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Amendment 04 
Rationale for Amendment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Added Section 4.6 to address public health emergency mitigation procedures 
• Section 6.7.2 to enable IMP home delivery of oral medication directly to a trial 
participant’s home rather than dispensed as part of an on-site study visit. 
• Updated Section 7 to enable remote consent 
• Updated Section 8 (including sections 8.4 and 8.5) to enable virtual or phone efficacy and 
safety assessments or visits to the participant´s home, if possible, in the study, as well as 
remote COA data collection. 
• Updated Section 11.4 Virtual Patient Cohort to include language on mitigation 
procedures for closure of the virtual patient cohort at discretion of the sponsor. 
Amendment 4 removes the enrollment cap for Strata 1, referenced in the Amendment 3 rationale 
section, and allows patients with prior oral DMT (fumarates and teriflunomide) to continue to 
enroll. Real-world evidence indicates that the majority of siponimod patients transitioning from 
a prior DMT were most frequently taking another oral DMT (Shah et al, 2020). By lifting the 
enrollment cap for Strata 1, the amendment ensures that EXCHANGE generates clinical 
evidence that reflects real-world treatment paradigms and supports patients and providers. 


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Additional interim analyses may be conducted at additional time points based on study 
enrollment under Amendment 4 to evaluate continued efficacy and safety data (for example, 
50% enrollment). These interim analyses will allow for an evaluation of the infusion strata, 
which was incorporated with Amendment 3. 
Additional changes are listed below: 
• Addition of Vumerity® (diroximel fumarate) and generic forms of dimethyl fumarate 
changed in Inclusion Criteria and throughout 
• Added interim analysis description to Protocol Summary, Section 4.4, and Section 
12.7 
• Added language for clarity on ongoing virtual and traditional cohorts to Protocol 
Summary, Section 3, and Section 4.1 
• Protocol Summary: 
• Correction made to Month 6 corresponding Visit number (Visit 5) for first 
interim analysis 
• Updated Study Design language in Section 11.4 
• Table 8-1: Updated table as Hepatitis screen is only required at Screening 
• Table 8-1: Correction made to footnote #8 to reflect correct reference section in 
protocol 
• Section 4.4 and Section 12.7: Added language for conducting additional interim 
analyses 
• Section 8.4.4: Updated language for guidance on pregnancy testing 
 
 
• Revised Inclusion Criteria: 
• #6: Addition of Vumerity® (diroximel fumarate) and generic forms of dimethyl 
fumarate 
• #7 removed from Protocol Summary, as this was not reflected and consistent 
with the main protocol 
• Revised Exclusion Criteria: 
• #14: Added clarifying language to described history of or current significant 
cardiac disease 


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Amendment 03 
Rationale for amendment 
Amendment 3 broadens the pre-treatment groups to include natalizumab (an α4-integrin 
antagonist, humanized monoclonal antibody) and ocrelizumab (a humanized monoclonal 
antibody that targets the CD20 marker on B-lymphocytes) infusion therapies in order to 
characterize the short term safety profile after conversion. The generation of this data is 
important as it is expected that patients who are currently treated with natalizumab and/or 
ocrelizumab may convert to siponimod for reasons of safety, tolerability, effectiveness or access. 
There are no known safety or tolerability concerns with the co-administration of siponimod 
with natalizumab or ocrelizumab. The purpose of broadening the pre-treatment groups is to 
further understand this relationship (Leurs et al., 2018); (Kappos et al., 2015). 
Sustained fingolimod induced receptor internalization of S1P receptors has been demonstrated 
in a number of separate studies (Jo et al., 2005); (Oo et al., 2007); (Mullershausen et al., 2009); 
(Snelder et al., 2016). Both siponimod and fingolimod are sphingospine 1-phosphate (S1P) 
receptor agonists causing complete internalization and down‐regulation of the S1P1 receptor 
(Matloubian et al., 2004); (Chiba et al., 2006); (O’Sullivan et al., 2016); (Chun et al., 2010); 
(Subei and Cohen, 2015). It is postulated that the known immunomodulatory effect on 
lymphocytes and transient nature of the heart rate (HR) is most likely related to receptor 
internalization and degradation (Mullershausen et al., 2009)). This downregulation renders 
lymphocytes unresponsive to the normal S1P gradient, and deprives them of the obligatory 
signal that would ordinarily allow them to egress from lymphoid tissues and recirculate to the 
periphery (Chun et al., 2010). Long-term suppression of receptors and minimized transient 
effects on HR are maintained by subsequent regular dosing ( Brown et al., 2019 ). Therefore, 
HR and atrioventricular (AV) conduction effects are not expected in patients 
converting from fingolimod therapy. Thus, Amendment 3 will omit the need for 
siponimod titration regimen for patients converting from fingolimod therapy in order to enhance 
understanding of the role of titration, or lack of, when converting between the two S1P receptor 
modulators. All study patients are dosed under the care of a healthcare practitioner. Fingolimod 
patients will receive an additional telephone call from site staff at the end of day 1 as part of 
additional safety measures. 
In order to ensure each pre-treatment strata in this study has a sufficient and balanced number 
of subjects to assert a clinically meaningful outcome, a balanced stratification of 50 patients per 
strata will be adopted, and therefore increasing the enrollment number to a maximum of 400 
patients. 
Lastly, in an attempt to help 1) remove ambiguity, 2) clarify the protocol language for principal 
investigators, 3) be consistent with siponimod label and or 4) account for the aforementioned 
changes, revisions to the exclusion criteria (including adding time or scenario qualifiers), study 
design graphic and other applicable supporting areas, were warranted. Each revised section is 
supported by applicable rationale as outlined in the details below. 
The purpose for Amendment 03 is to: 
• Broaden pre-treatment groups to include infusion disease modifying therapies, 
specifically, natalizumab and ocrelizumab. 
• Removal of titration regimen for patients converting from fingolimod treatment 


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• Expand study n to 300-400 patients 
• Revise inclusion criteria: 
• #6: Include natalizumab and ocrelizumab to conversion options 
• Revise exclusion criteria: 
• #4 & #5: Move post-menopausal women description from standalone exclusion and 
merge with existing pregnancy and contraception exclusion. The prior exclusion #5 
was merely a description of women who are considered post-menopausal and not of 
child bearing potential and not a separate exclusionary criteria different from the 
pregnancy exclusion. 
• #12: Delete natalizumab, daclizumab and ocrelizumab from prohibited list. 
Natalizumab and ocrelizumab will be added to pre-treatment groups for inclusion; 
daclizumab is no longer commercially available. 
• #12: Added sub-criteria “more than 24 months prior treatment exposure to 
natalizumab”. Based on critical assessment of the limited data available, combined 
with the opinion of steering committee members, it is suggested that patients with 
more than 24 months of prior natalizumab exposure may be at high risk for PML. 
Therefore, to minimize patient safety risks, added sub-bullet to exclusion #12. 
• #14: Added time qualifier to history of cardiovascular disease consistent with label 
“within last 6 months.” 
• #14: Added therapeutic disease qualifier to patients receiving treatment with beta- 
blockers “for cardiac disease/comorbidities” 
• #17: Added exception to WBC count to include “while on injectable or oral DMT’s 
at screening, except fingolimod” to reflect appropriate drop in WBC clinical lab 
values. Exception for fingolimod added given the direct effect on peripheral 
lymphocyte subpopulations including WBCs. 
• #17: Added new sub-bullet “for patients previously exposed to natalizumab, anti- 
JCV antibody positive and index > 1.5.” Based on critical assessment of the limited 
data available, combined with the opinion of steering committee members, it is 
suggested that patients with an anti-JCV antibody index >1.5 are considered high risk 
for PML and therefore should be excluded if no MRI monitoring is part of the study 
design to help minimize risk of serious immunodeficiency. 
• Updated study design figure 3-2. 
• Clarify: 
• Section 1.2: Added identification of clinical gap and lack of data for conversion 
between S1P receptor modulators. 
• Section 1.2: Added rationale for broadening pre-treatment groups to include 
natalizumab and ocrelizumab. 
• Section 2: Added infusion to treatment options described in primary objective. 
• Section 3: Added definition of “immediate conversion” to be “cessation of existing 
DMT and initiation of siponimod within 24 hours, followed by subsequent 5-day dose 
titration.” Additionally clarified teriflunomide treatment group will undergo 
accelerated elimination prior to initiating siponimod. 


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• Section 3: Added clarification that patients converting from fingolimod will not 
undergo titration period and instead immediately start 2mg dose, upon completion of 
required screening tests, including genotyping CYP2C9*1*1, as part of the 
inclusion/exclusion criteria. 
• Section 3: Added clarification that patients converting from natalizumab will 
undergo at least 4 week washout period at time of consent prior to converting to dose- 
titrated siponimod. 
• Section 3: Added clarification that patients converting from ocrelizumab will 
undergo at least 14 week washout period at time of consent prior to converting to 
dose-titrated siponimod. 
• Section 3, Figure 3-2: Updated study design figure to reflect changes in section 3. 
• Section 4.2: Added rationale for removal of titration regimen for patients converting 
from S1P receptor modulator, fingolimod. 
• Section 5: Clarified functional definition of advancing RMS for purposes of this 
study. 
• Section 5.1: Revised inclusion criteria to include infusion therapy, natalizumab and 
ocrelizumab. 
• Section 5.2: Revised exclusion criteria as described above. 
• Section 6.1.3: Clarifying titration language to include all patients except fingolimod 
group. 
• Section 6.2.1.1: Clarifying language for patients treated with beta-blockers for non- 
cardiac treatment purposes. 
• Section 6.2 Table: Removal of prohibited medication criteria “any other 
immunomodulatory of disease modifying MS treatment, including but not limited to, 
fingolimod, interferon beta, glatiramer acetate or systemic corticosteroids.” This 
statement is incorrect because we are allowing fingolimod, interferon beta and 
glatiramer acetate in this study. Added removal of systemic corticosteroids as there is 
no implication of this medication on patients in this study. Prohibition of steroids is 
only required when conducting MRI to minimize confounding of post-lesion repair 
mechanisms. 
• Section 6.3.2: Clarification around titration regimen for all patients except those 
converting from fingolimod. 
• Section 6.7.2: Clarification around titration regimen for all patients except those 
converting from fingolimod. 
• Section 6.3 Table 6-3: Revised table header to “Treatment Schedule for All Pre- 
Treatment groups except Fingolimod” and added separate dose and treatment 
schedule for fingolimod patients. 
• Section 8: Added disease modifying therapy washout regimen table and language for 
interferon-beta, dimethyl fumarate; accelerated elimination for teriflunomide; 
fingolimod; natalizumab and; ocrelizumab. Clarification language regarding pre-dose 
ECG, pre-dose HR, and post-dose HR collection methods. 
• Section 8 Table 8-1: Added CD19+ B-cell titer at Screening only to support B-cell 
regeneration kinetic insights during conversion to siponimod. Added footnote 


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reflecting this is only needed for patients converting from ocrelizumab as that is the 
only B-cell therapy being introduced in this study. 
• Section 8.4.1 Table 8-3: Added CD19+ titers to “additional tests” subsection. 
• Section 8.4.3: Added clarifying language that the OCT test can be performed by 
referred ophthalmologist or clinically trained neurologist with expertise in assessing 
structural measurement of retinal nerve fiber layer thickness, optic nerve head and 
macular anatomy and is in possession of appropriate OCT equipment in-office. 
• Section 12.4: Added clarifying language related to the primary objective. 
• Section 12.8.1: Added revised language regarding sample size, precision estimates 
and infusion therapy n. in order to achieve balanced stratification. 
• Appendix 16.6: Added clarifying guidance around accelerated elimination program 
for patients converting from teriflunomide. 
• Appendix 16.8: Corrected Visit 3 to Visit 4 and added clarifying language regarding 
OCT as described in section 8.4.3. 
• Additional changes are listed below: 
• Correction of “Siponimod” to lower case “siponimod throughout protocol. 
• Ensure CYP2C9 is marked in full form and not abbreviated. 
• Replacement of investigational compound name BAF312 to brand-name, Mayzent ® 
throughout protocol. 
• Minor clarifications to background introduction. 


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Amendment 02 
Rationale for amendment 
The purpose for Amendment 02 is to: 
• Revised exclusion criteria #22 to also exclude CYP2C9*2/*3 and CYP2C9*1/*3 patients: 
• Genetic polymorphisms of the CYP2C9 enzyme are a major determinant of the inter- 
individual variability in the dosage requirements of siponimod. Per the Mayzent 
approved US Package Insert, Mayzent® is contraindicated in patients who have a 
CYP2C9*3/*3 genotype because of substantially elevated siponimod plasma levels. 
MAYZENT dosage adjustment to 1 mg is recommended in patients with 
CYP2C9*1/*3 or *2/*3 genotype because of an increase in exposure to siponimod. 
However, due to the current unavailability of a 1mg dosage form for Mayzent, 
patients with the CYP2C9*1/*3 and *2/*3 genotypes are dosed using the 0.25mg 
tablets (4 x 0.25mg = 1mg). Novartis will exclude the CYP2C9*3/*3, CYP2C9*2/*3, 
and CYP*1/*3 patients from the CBAF312AUS02 study and will only enroll patients 
who after titration, will take the 2mg recommended maintenance dose (CYP2C9 
Genotypes *1/*1, *1/*2, or *2/*2). 
• Revised ECG interval values to reflect PR interval: >200 msec; QRS duration ≥120 msec; 
QTcF >430 msec (males); QTcF >450 msec (females) 
• Revised Exclusion #23: Concomitant use of MAYZENT and drugs that cause moderate 
CYP2C9 and moderate or strong CYP3A4 inhibition (Appendix 4). 
• Added exclusion #24: Concomitant use of MAYZENT and drugs that cause moderate 
CYP2C9 and strong CYP3A4 induction (Appendix 4). 
• Added exclusion #25: Use of cannabinoid or cannabidiol products 30 days prior to 
screening. 
a. At this time, there is no evidence of combination treatment with cannabinoid or 
cannabidiol products and siponimod. Thus, for patients’ safety, the concomitant use 
of these products will be excluded from the study. 
• Removed Visit 2/Day 7 (in office/home visit) 
a. In line with the approved US package insert for Mayzent, Novartis removes the Day 7 
pre-dose ECG. 
• Under Figure 3-1: Removed the managed access program and updated language for 
patient services hub for post-trial. 
 
Additional changes are listed below: 
• Exclusion criteria Note 2: Updated to reflect that each patient may be rescreened no more 
than 1 time. 
• Section 4.4 and Section12.7: Update visit number from Visit 3 (Day 28) to Month 6 (Visit 
5/Day 168). 
• Section 8 Table 8-1 Assessment Schedule: Grayed out Visit 2 (Day 7) not to be 
performed. 
• Removed footnote #4 (12 Hour fasted food samples). 


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• Added language to footnote # 
• Section 8, Table 8-3 physical examination and neurological exam language was updated. 
• Section 8.4.1 Laboratory Evaluations under CYP2CP testing language was updated. 
• Section 8.4.2 Electrocardiogram language was updated. 
• Sections 8, 10.2.2 and 16.7 (Appendix 7): Revision of pre-dose (< 55bpm) and post-dose 
(<45 bpm) bradycardia definition to be consistent throughout protocol. 
• Section 15: Added references. 
• Section 16.4: Updated Appendix 4. 
 
All relevant section(s) of the protocol are updated to reflect the update in the exclusion criteria 
and removal of Day 7 pre-dose ECG. 


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Amendment 01 
Rationale for amendment 
 
The purpose for Amendment 01 is to update all relevant section(s) of the protocol related to: 
• Drug supply, reflecting the details of how the drug is supplied and will be provided in a 
pharmacy manual. 
• Additional cardiac monitoring for Day 1 and Day 7 prior to treatment 
• The addition of ophthalmic assessment (optical coherence tomography; OCT) at Day 1 
(baseline) and Day 84 for incidences of macular edema. 
 
Additional changes are listed below: 
• Table 2-1: Removed CSSRS from exploratory objectives. 
• Section 5.2 – Updated Exclusion criteria #15 to be aligned with definition of high-risk 
cardiac patients in the CBAF312A2304 study. 
• Section 6.1.1: 
a. Added a requirement of restarting titration, if a day or more of the 5-day titration is 
missed. 
b. Added that a pharmacy manual will be provided, with specific instructions, regarding 
study drug, titration and maintenance dose. 
c. Added sentence: “If the patient has missed greater than 30 consecutive days of 
treatment, using his/her best medical judgement, the PI should consider terminating 
the patient from the study.” 
• Section 6.5: Added “Siponimod dose adjustments are not permitted.” 
• Section 6.7: Added that supply of siponimod will be described in pharmacy manual. 
• Section 6.7.2: Added that sites should refer to pharmacy manual for specific instructions 
on preparation and dispensation of study treatment. 
• Section 8: Updated language in first bullet regarding assessment of vitals and heart rate at 
Visit 1 (Day 1). 
• Table 8-1: 
a. Added visit windows (±days) for each clinical visit 
b. Updated visit names and numbering, as well as added heart rate assessment (pre-dose) 
at baseline visit. 
c. Updated height assessment, from being performed at every visit, to just done at 
screening and EOT/S visits. 
d. Included OCT assessment at Day 1 (baseline) and Day 84. 
e. Included ECG assessments at screening, Day 1 (baseline) pre-dose, and Day 7 pre- 
dose. 
• Section 8.4.2: provided detailed direction on when to obtain ECG assessment (Day 1 and 
Day 7; pre-dose). Further, provided instructions should the patient be at cardiac risk. 


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• Section 8.4.5: We included the use of OCT as part of ophthalmologic assessments at 
baseline prior to siponimod treatment and on Day 84 (3 months post initial treatment with 
siponimod. The purpose of this assessment is to monitor incidences of macular edema in 
patients treated with siponimod. This inclusion can be found in the Table of Assessment 
(Table 8-1; Section 8.4.5 and Appendix 8) 
• Section 10.2.2: Updated C-SSRS language including clarification regarding the method in 
which it will be administered. 
• Section10.2.2: Added bradycardia as an adverse event of special interest 
• Added Section 11.4: Potential Remote Patient Cohort. (These are patients who would 
potentially be allowed to participate, in the study, remotely, via online technology and 
telemedicine). 
• Section 12.5.1: Added language that change in heart rate (and other vitals), from baseline 
to 6-hours post dose, may be summarized in secondary endpoint analysis. 
• Section 12.7: Updated language to state that: an interim analysis on the safety data will be 
conducted at the time of approximately 50 patients completing Visit 3 (Day 28). 
• Section 12.8.1: Updated language to state that: A sample size of 300 patients will provide 
us the precision (half-width of 95% confidence interval) of 5.6%. 
• Section 16.7: Included treatment management for bradycardia. 
• Section 16.8: Include guidelines for ophthalmic examination and management of macular 
edema 


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Protocol summary 
 
 
Protocol number 
CBAF312AUS02 
Full Title 
Exploring the safety and tolerability of conversion from oral 
injectable or infusion disease modifying therapies to dose- 
titrated Oral Siponimod in patients with advancing forms of 
relapsing multiple sclerosis: A 6-month open label, multi- 
center Phase IIIb study (EXCHANGE) 
Brief title 
Study of the safety and tolerability dose-titrated Oral 
Siponimod in patients with relapsing forms of multiple 
sclerosis. 
Sponsor and Clinical Phase 
Novartis 
Clinical Phase IIIb 
Investigation type 
Drug 
Study type 
Interventional, Open-label 
Purpose and rationale 
The purpose of this study is to assess early phase safety and 
tolerability of converting patients from approved oral, 
injectable or infusion RMS DMTs to siponimod. The results of 
this study will guide clinically relevant decisions related to the 
transition from frequently used RMS DMTs to siponimod and 
provide clinically relevant data on safety and tolerability for 
healthcare providers who are considering converting patients 
from currently approved RMS DMT to siponimod. 
Primary Objective(s) 
The primary objective is to evaluate overall safety and 
tolerability profile of siponimod in advancing RMS patients 
(including a broader population that had not been previously 
studied with siponimod who are converting from currently 
approved oral, injectable or infusion RMS DMT). 
Secondary Objectives 
• 
Objective 1: To evaluate treatment satisfaction outcomes 
using the Treatment Satisfaction Questionnaire for 
Medication (TSQM-9) with siponimod in advancing RMS 
patients. 
• 
Objective 2: To evaluate cardiac safety, in the overall 
population during siponimod treatment initiation 
• 
Objective 3: To evaluate treatment adherence with 
siponimod. 
Study design 
This is a 6-month, open-label, multi-center, single treatment 
arm design, including 300-400 advancing RMS patients, 
evaluating overall safety and tolerability profile when acutely 
converting to siponimod from oral, injectable or infusion RMS 
DMT. This study consists of two parts: The Screening Period 
and Core Treatment Period, plus a 30-day follow-up telephone 
call. 
 
 
 
 
 


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Population 
The study population will consist of out-patient, male and 
female patients, ≥18-65 years of age, with an EDSS score > 
2.0-6.5 with advancing RMS with or without progressive 
features. Approximately 300-400 patients will be enrolled in 
this study from up to 80 study sites in the USA. The study 
plans to screen approximately 570 patients. 
 
 
 
Key Inclusion criteria 
Patients eligible for inclusion in this study must meet all of the 
following criteria: 
1. Signed informed consent must be obtained prior to 
participation in the study. 
2. Male or female aged 18 to 65 years (inclusive) at 
screening 
3. Patients with advancing RMS as defined by the principal 
investigator 
4. Prior history of relapsing MS (RMS), with or without 
progressive features, according to the 2010 Revised 
McDonald or Lublin criteria (Lublin et al, 2013) 
5. Disability status at screening with an EDSS score of >2.0 
to 6.5 (inclusive) 
6. Having been continuously treated with beta-interferons, 
glatiramer acetate, fingolimod, fumarates, teriflunomide, 
natalizumab or ocrelizumab for at least 3 months at the 
time of consent 
7. Patients desiring to start treatment with a DMT 
investigated in advancing stages of multiple sclerosis. 
Key Exclusion criteria 
Patients meeting any of the following criteria are not eligible for 
inclusion in this study. No additional exclusions may be applied 
by the investigator in order to ensure that the study population 
will be representative of all eligible patients: 
1. Patients with an active chronic disease (or stable but 
treated with immune therapy) of the immune system other 
than MS (e.g., rheumatoid arthritis, scleroderma, 
Sjogren’s syndrome, Crohn’s disease, ulcerative colitis, 
etc.) or with a known immunodeficiency syndrome (AIDS, 
hereditary immune deficiency, drug-induced immune 
deficiency). 
2. Pregnant or nursing (lactating) women, where pregnancy 
is defined as the state of a female after conception and 
until the termination of gestation, confirmed by a positive 
hCG laboratory test. 
3. Women of child-bearing potential, defined as all women 
physiologically capable of becoming pregnant, unless 


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they are using highly effective methods of contraception 
while taking study treatment and for 30 days (30 = 5 times 
the terminal half-life of siponimod) after stopping study 
treatment. Highly effective contraception methods include: 
• 
Total abstinence (when this is in line with the 
preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not 
acceptable methods of contraception 
• 
Female sterilization (have had surgical bilateral 
oophorectomy with or without hysterectomy), total 
hysterectomy, or tubal ligation at least six weeks 
before taking study treatment. In case of 
oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up 
hormone level assessment 
• 
Male sterilization (at least 6 months prior to 
screening). For female patients on the study, the 
vasectomized male partner should be the sole 
partner for that patient 
• 
Use of oral, (estrogen and progesterone), injected or 
implanted hormonal methods of contraception or 
placement of an intrauterine device (IUD) or 
intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure 
rate <1%), for example hormone vaginal ring or 
transdermal hormone contraception. 
In case of use of oral contraception women should 
have been stable on the same pill for a minimum of 3 
months before taking study treatment. 
• 
Women are considered post-menopausal and not of 
child bearing potential if they have had 12 months of 
natural (spontaneous) amenorrhea with an 
appropriate clinical profile (e.g. age appropriate 
history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy), 
total hysterectomy or tubal ligation at least six weeks 
ago. In the case of oophorectomy alone, only when 
the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is 
she considered not of child bearing potential. 
4. Sexually active males unwilling to use a condom during 
intercourse while taking study treatment and for 30 days 
(30 days = 5 times the terminal half-life of siponimod) after 
stopping study treatment. A condom is required for all 
sexually active male participants to prevent them from 
fathering a child AND to prevent delivery of study 
treatment via seminal fluid to their partner. In addition, 
male participants must not donate sperm for the time 
period specified above. 
If local regulations deviate from the contraception 
methods listed above to prevent pregnancy, local 
regulations apply and will be described in the ICF. 


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5. History of malignancy of any organ system (other than 
localized basal cell carcinoma of the skin), treated or 
untreated, within the past 5 years, regardless of whether 
there is evidence of local recurrence or metastases. 
6. Diabetes mellitus, unless well controlled and without 
known organ complications including but not limited to 
heart disease, reduced renal function, significant retinal 
pathology or neuropathy. 
7. Diagnosis of macular edema 1 year prior to screening. 
8. Patients with active systemic bacterial, viral, or fungal 
infections or known to have AIDS or have positive HIV 
antibody. 
9. Positive results of screening period testing for serological 
markers for hepatitis A, B, C and E, indicating acute or 
chronic infection: 
• 
anti-HAV IgM 
• 
HBs Ag and/or anti-HBc IgM 
• 
anti-HEV IgM (if positive IgG and/or IgM, perform 
HEV-RNA PCR and if negative, patient can be 
included). 
Note: If the treating physician suspects false positive hepatitis 
serology results, such as an antibody pattern indicating acute 
hepatitis infection but no corresponding elevated liver enzymes 
and no signs or symptoms of liver disease, a HEV-RNA PCR 
will be performed and will be the deciding factor to determine 
whether the patient has hepatitis A, B, C, or E. If negative, the 
treating physician may document (in source data and in a eCRF 
comment) that the serology results are considered false 
positive and consider including the patient. 
10. Negative for varicella-zoster virus IgG antibodies at 
Screening unless there is other evidence of immunity to 
VZV based on the CDC criteria 
(https://www.cdc.gov/chickenpox/hcp/immunity.html; see 
Appendix 1) 
11. Have received any live or live-attenuated vaccines 
(including for varicella-zoster virus or measles) within 2 
months of screening. 
12. Have been treated with any of the medications listed 
below: 
• 
Intravenous immunoglobulin within 2 months prior to 
screening 
• 
Immunosuppressive/chemotherapeutic medications 
(e.g., azathioprine, methotrexate) within 6 months 
prior to screening 
• 
Cyclophosphamide within 2 years prior to screening 
• 
More than 24 months prior treatment exposure to 
natalizumab 
• 
Rituximab, ofatumumab, ublituximab or cladribine 
within 2 years prior to randomization 
• 
Alemtuzumab at any time 


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• 
Any mitoxantrone during previous 2 years prior to 
randomization or evidence of cardiotoxicity following 
mitoxantrone or a cumulative life-time dose of more 
than 60 mg/m2 
• 
If patients treated with teriflunomide cannot or will not 
undergo the accelerated elimination process 
(Appendix 6) 
• 
Stem cell transplantation 
• 
Lymphoid irradiation, bone marrow transplantation or 
other immunosuppressive treatments with effects 
potentially lasting over 6 months, at any time. 
13. Patients with any medically unstable condition as 
determine by the investigator. 
14. Any of the following conditions or treatments that may 
affect cardiovascular function within last 6 months: 
• 
Heart rate < 55 bpm at screening 
• 
Cardiac conduction disorders such as incomplete left 
bundle branch block or second degree AV block 
Mobitz type I (Mobitz I) (either history or observed at 
screening) 
• 
Minor ECG findings at screening PR interval: >200 
msec; QRS duration ≥120 msec; QTcF >430 msec 
(males); QTcF >450 msec (females) 
• 
History of or current significant cardiac disease 
including cardiac failure (NYHA functional class II-IV), 
myocarditis, cardiomyopathy, angina pectoris or 
myocardial infarction (within 6 months), unstable 
angina (within 6 months), stroke (within 6 months), 
TIA (within 6 months), decompensated heart failure 
requiring hospitalization (within 6 months) or 
uncontrolled arterial hypertension 
• 
Patients receiving treatment with beta-blockers for 
cardiac disease/comorbidities. 
• 
Any other condition which, in the opinion of the 
investigator, has a potential for AV conduction 
suppression and/or other risk factors that may require 
expanded cardiac monitoring 
• 
Patients diagnosed with right bundle branch block, 
either at the screening visit for entry of the study or 
during the conduct of the study 
15. Any of the following pulmonary conditions: 
• 
History of or active severe respiratory disease, 
including COPD, or pulmonary fibrosis, 
• 
Tuberculosis, except for history of successfully 
treated tuberculosis or a history of prophylactic 
treatment after positive PPD skin reaction 
• 
Patient with severe asthma or asthma requiring 
regular treatment with oral steroids 


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16. Patients with any of the following hepatic conditions prior 
to screening: 
• 
history of alcohol abuse, chronic liver or biliary 
disease 
• 
total or conjugated bilirubin greater than 1.5 times 
ULN range, unless in the context of Gilbert’s 
syndrome 
• 
alkaline phosphatase (AP) greater than 1.5 times the 
ULN range 
• 
AST (SCOT), ALT (SGPT) or Gamma-glutamyl- 
transferase (GGT) greater than 3 times the ULN 
range within the last 6 months 
17. Any of the following abnormal laboratory values prior to 
screening: 
• 
Serum creatinine > 1.7 mg/dL (150 umol/L) 
• 
White blood cells (WBC) count <3,500/mm3 (<3.5 x 
10(9)/L), while on injectable or oral DMT’s at 
screening, except fingolimod 
• 
Lymphocyte count <500/mm3 (<0.5 x 10(9)/L) while 
on all DMT’s at screening except fingolimod 
• 
Serum potassium > ULN 
• 
Or other clinically significant laboratory assessment 
(i.e. hypomagnesemia or hypokalemia) 
• 
For patients previously exposed to natalizumab, anti- 
JCV antibody positive and index > 1.5 
18. Patients with the following neurological/psychiatric 
disorders prior to screening: 
• 
History of substance abuse (drug or alcohol) or any 
other factor (i.e. serious psychiatric condition) that 
may interfere with the patient’s ability to cooperate 
and comply with the study protocol 
• 
Progressive neurological disorder, other than MS, 
which may affect participation in the study or require 
the use of medications not allowed by the protocol 
19. Use of other investigational drugs at the time of enrollment 
or within prior 30 days; or five elimination half-lives, or 
until the expected pharmacodynamics effect has returned 
to baseline, whichever is longer. 
20. History of hypersensitivity to the study drug or to drugs of 
similar chemical classes. 
21. Homozygosity for CYP2C9*3/*3 or heterozygous for 
CYP2C9*2/*3 or CYP2C9*1/*3 (to be tested at 
screening) or refusal to test for CYP2C9 variants. 
22. Concomitant use of MAYZENT and drugs that cause 
moderate CYP2C9 and moderate or strong CYP3A4 
inhibition (Appendix 4). 


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23. Concomitant use of MAYZENT and drugs that cause 
moderate CYP2C9 and strong CYP3A4 induction 
(Appendix 4). 
24. Use of cannabinoid or cannabidiol products 30 days prior 
to screening. 
25. Any other disease or condition, which could interfere with 
participation in the study according to the study protocol, 
or with the ability of the patients to cooperate and comply 
with the study procedures. 
Note 1: If a patient fails on one or more laboratory (or other) 
assessment criteria, as part of the screening process, the 
assessment (s) may be repeated at the discretion of the 
investigator and the patient may be included if criteria are then 
met, provided the assessments are completed within the 
screening period. 
Note 2: In certain cases rescreening of patients that were 
previously determined ineligible may be permitted. When a 
patient is re-screened, a new patient identification number will 
be assigned and all screening assessments must be repeated. 
Each patient may be rescreened no more than one time. 
No additional exclusions may be applied by the investigator, in 
order to ensure that the study population will be representative 
of all eligible patients. 
Study treatment 
All eligible patients will receive oral siponimod (Mayzent ®). 
The study treatment will be provided for the duration of the 
trial from baseline (Day 1) through last day of the treatment 
period. 
Efficacy assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Key safety assessments 
Physical examinations 
Monitoring of laboratory markers in blood (plasma/serum) 
Monitoring of macular edema through the use of OCT 
Electrocardiogram (ECG) 
Adverse event monitoring 


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Other assessments 
An assessment of Patient reported outcomes is planned in this 
trial using 
 Patient reported 
outcomes (PRO) 
Data analysis 
The primary aim of this study is to evaluate the overall safety 
and tolerability profile of siponimod 2 mg in patients with 
relapsing forms of MS. 
The number (and percentage) of patients with treatment 
emergent adverse events suspected to be related to study 
medication will be summarized by primary system organ class 
and preferred term. The 95% confidence interval for the 
overall rate of adverse event suspected to be related to study 
medication will be calculated. 
A patient with multiple adverse events within a category 
(overall, primary system organ class, or preferred term) is only 
counted once towards the total of that category. 
The above analyses will be conducted on the Safety Set. For 
the purpose of earlier dissemination, an interim analysis on 
the safety data will be conducted at the time of approximately 
50 patients will complete their Month 6 (visit 5). Additional 
interim analyses may be conducted at additional time points 
based on study enrollment in order to evaluate continued 
efficacy and safety data (for example, 50% enrollment). 
These interim analyses will also allow for an evaluation of the 
infusion strata. 
 
 
 
 
Key words 
Siponimod, Disease Modifying Therapy , Multiple Sclerosis, 
Relapsing Multiple Sclerosis, Relapsing-Remitting Multiple 
Sclerosis, Secondary Progressive MS 


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1 
Introduction 
1.1 
Background 
Multiple Sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS) 
characterized by inflammation, demyelination and axonal/neuronal destruction, ultimately 
leading to severe disability. It affects approximately 2.5 million individuals worldwide and has 
distinct clinical stages including relapsing remitting MS (RRMS), secondary progressive MS 
(SPMS) and primary progressive MS (PPMS). At the time of diagnosis, approximately 85% of 
patients have recurrent, acute relapses of neurological symptoms. More than 50% of patients 
with poorly treated RRMS transition to secondary progressive disease within 15-20 years 
(Tremlett et al, 2008). In progressive stages, relapses are absent or infrequent, yet disability 
continues to gradually worsen (MS Society, accessed 2018). 
The McDonald Criteria (McDonald et al, 2001) was the first diagnostic criteria for MS to 
employ MRI measures alongside of clinical assessments. As more data and experience with 
MRI were acquired (Tintore et al. 2000; Swanton et al. 2006, 2007; Montalban et al. 2010)) the 
criteria evolved further with two subsequent revisions (Polman et al 2005, 2011). Currently, 
the 2010 revision of the McDonald Criteria is utilized to characterize the patients’ clinical stage 
and determine the patients’ eligibility to participate in the trial. 
Currently, approved disease modifying therapies (DMTs) are indicated for use in relapsing 
forms of MS (RMS) in the USA. RMS includes RRMS and SPMS patients with superimposed 
relapses. The effect of drug in these SPMS patients is presumed to have increased effect on 
inflammatory activities (relapses and gadolinium enhancing lesions), efficacy on disability 
progression has not been confirmed in secondary progressive patients. Mitoxantrone is the only 
therapy approved for reducing neurologic disability and/or the frequency of clinical relapses in 
patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing- 
remitting multiple sclerosis (i.e., patients whose neurologic status is significantly abnormal 
between relapses) in the USA. However, data demonstrating the efficacy of mitoxantrone in 
SPMS patients (Goodin et al, 2002) and the risks associated with mitoxantrone (heart failure, 
leukemia) limits its use. 
Sphingosine-1-phosphate (S1P) receptor modulators possess a unique mechanism of action in 
the treatment of relapsing and progressive MS (Gergely et al, 2012). The S1P1 and S1P5 
receptors are commonly found on the surface of astrocytes and oligodendrocytes, residing in 
the CNS, and are potentially implicated in mechanisms affecting CNS repair (O’Sullivan et al. 
2016). Siponimod (Mayzent®), approved by the US FDA in March 2019 for treatment of 
relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing 
remitting disease and active secondary progressive disease in adults, is a S1P1/S1P5-selective 
agonist. It has scientific evidence for involvement with reducing T-cell migration to the CNS, 
astrogliosis, oligodendrocyte process modulation and increased cell survival (Chiba et al, 2012); 
(Sanna et al, 2004). The mechanism of action on immune cells is similar to the first-in-class 
drug, fingolimod, with S1P1-mediated trapping of lymphocytes in the peripheral lymphatic 
tissues. Siponimod, however, has a different chemotype than fingolimod, as it is not a prodrug 
and thus does not require a phosphorylation step in vivo. It readily crosses the blood-brain- 
barrier (BBB), and preclinical studies suggest: it may prevent synaptic neurodegeneration 
(Gentile et al, 2016); increases levels of myelin basic protein; promotes remyelination; and 


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activates pERK and pAKT signaling to promote internalization of S1P1 receptors to a greater 
extent (O’Sullivan et al, 2016) than S1P itself (Gentile et al, 2016); (O’Sullivan et al, 2016). In- 
vitro studies show that by binding to these specific receptors, siponimod may prevent the 
activation of these cells, helping to reduce loss of physical and cognitive function associated 
with MS (Aslanis et al, 2012).) 
Next to its effects in lymphocyte trafficking and trapping in peripheral lymphatic tissue (similar 
to fingolimod), expression of S1P1 receptor ligands in atrial, septal and ventricular cardiac 
myocytes (as well as endothelial cells of cardiac vessels in humans) has been established and 
associated with the regulation of heart rate (HR) at treatment initiation in both healthy patients 
and in MS patients. 
The half-life of siponimod compared to fingolimod is shorter (approximately 30 h versus 200 
h), therefore drug effects cease more rapidly after discontinuation. 90% Recovery of the 
baseline lymphocyte counts after treatment withdrawal from steady state conditions should be 
achieved in one week at a daily siponimod dose of 2mg. However, residual pharmacodynamics 
effects, such as lowering effects on peripheral lymphocyte count may persist for up to 3 to 4 
weeks after the last dose. Use of immunosuppressants within this period may lead to an additive 
effect on the immune system and therefore caution should be applied 3 to 4 weeks after the last 
dose. 
The siponimod receptor selectivity and half-life has the potential to enable full efficacy in MS 
without targeting other S1P receptors (S1P3 and/or S1P4), which together with the more rapid 
washout may improve the safety profile. 
The Phase I clinical pharmacology trials, siponimod was safe and generally well tolerated. The 
study detected a dose dependent bradyarrhythmic effect within 2-3 hours after intake of first 
dose. 
A placebo-controlled Phase II study in patients (N=297) with RRMS was conducted to 
determine the dose-response curve for the MRI-based efficacy of siponimod, and to characterize 
its safety and tolerability (Selmaj et al 2013). A significant dose response relationship at Month 
3 was observed (p=0.0001, Emax model). Siponimod treatment reduced the combined unique 
active lesion (CUAL) count by up to 80% vs. placebo, with the 2mg dose providing near- 
maximal efficacy. Annualized relapse rates (ARR) were 0.61, 0.20 and 0.30 for the 0.5, 2 and 
10mg doses, respectively, vs 0.58 for placebo (p<0.05 for 2mg vs. placebo only). 
• Five transient symptomatic bradyarrhythmic events without sequelae were observed with 
the two highest doses. 
• Other safety findings included liver enzyme elevation (4.3% of patients at higher dose 
levels had transaminases >3x upper limit normal (ULN) and one case of macular edema in 
a patient with history of uveitis. 
• Serious adverse events (SAEs) included one death (27 days post study drug 
discontinuation), likely due to coronary artery disease. 
Due to the occurrence of bradyarrhythmic events during in the Phase I trial, a dose titration was 
implemented in the Phase II study, resulting in the attenuation of the earlier observed negative 
chronotropic and dromotropic effects. There were no symptomatic bradyarrhythmic events or 
asymptomatic AV-blocks of concern following the introduction of the initial-dose titration 
scheme. 


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The double-blind registration Phase III EXPAND trial, (N=1651) demonstrated unique effects 
on SPMS patients (Kappos et al, 2018). The majority of the study population had been on other 
DMTs prior to entering into the study. In patients randomized to the siponimod arm, 
approximately 69% of patients had previously been treated with either IFNβ-1a or IFNβ-1b 
while 26% of patients had been treated with glatiramer acetate. For patients on prior DMTs, 
there were specific washout requirements implemented without any monitoring during the 
washout. Given the development of additional S1P receptor modulators over the last few years, 
transition between S1P treatments has not broadly assessed. Theoretically, while both 
siponimod and fingolimod demonstrate persistent internalization and enhanced degradation of 
the S1P-receptor, there is clinical utility in understanding the role of titration, or lack of, when 
converting between the two S1P therapeutic options to ensure patients are not undertreated. 
 
Safety results from the Phase III trial demonstrated that siponimod is safe and well tolerated 
• 197 (18%) patients on siponimod and 83 (15%) on placebo had at least one serious 
adverse event. 
• Headache, nasopharyngitis, urinary tract infection, and falls were the most frequent 
adverse events, being reported in more than 10% of patients in both treatment groups 
(siponimod vs placebo) 
• Hypertension was reported in 115 patients (10%) on siponimod compared with 41 (8%) on 
placebo 
• Four deaths occurred in each treatment group. Deaths in the siponimod group were due to 
metastatic gastrointestinal melanoma within 4 months of commencing siponimod; septic 
shock in a patient with terminal colon cancer; urosepsis more than 10 weeks after 
discontinuation of siponimod and after two doses of rituximab; and suicide. 
• Cardiac effects: 1346 (82%) of 1651 patients underwent continuous mobile cardiac 
telemetry for up to 6 days. 
• During double-blind treatment initiation, the maximum reduction in mean heart rate 
• On day 1 was 5.3 bpm in the siponimod group (4 h post-dose) and 1.2 bpm in the 
placebo group (1 h post-dose) 
• On day 7, mean reductions were 3.1 bpm and 2.0 bpm, in siponimod and placebo 
treated patients, respectively (3 h post-dose) 
• For 68 patients (6%) receiving siponimod and 17 (3%) receiving placebo, bradycardia, 
decreased heart rate, or sinus bradycardia were reported as adverse events. 
• Two of these events on day 7 in the siponimod group were symptomatic, one leading 
to treatment discontinuation. 
• No cases of Mobitz type II or high degree atrioventricular block were observed during 
double-blind treatment 
To date, phase III studies have not examined the safety considerations among RRMS or SPMS 
patients who had undergone acute conversion to siponimod from other DMT treatment. As the 
disease progresses with a need to convert from one DMT to another, assessing the effects (safety 
and efficacy) of this acute conversion from existing DMTs becomes important. In order to 
address the benefits and risk needs of a patient and public health relevance across a broad MS 


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population representative of clinical practice, it is necessary to understand the implications of 
overlapping immune effects, dose titration, washout intervals between therapies, direct 
conversion-related adverse events, conversion between S1P receptor modulators, patient 
tolerability and adherence, which are compulsory to appropriately address the benefit: risk 
needs of a patient. Furthermore, recent market research from the United States reported that 
there is a significant percentage of patients with transitioning RMS that are being treated with 
another class of drugs known as infusion DMTs, specifically, natalizumab (an α4-integrin 
antagonist, humanized monoclonal antibody) or ocrelizumab (a monoclonal antibody that 
targets CD20 marker on B-lymphocytes), for which a safety gap on DMT conversion continues 
to persist. Natalizumab, is broadly used in patients with advancing RMS. However, many 
patients need to switch to an alternative therapy due to safety, tolerability, effectiveness, or 
access reasons. Ocrelizumab has a prolonged immunosuppressive effect primarily resulting 
from a rapid reduction of lymphocyte B-cells, with a median time of 72 weeks (range 27-175 
weeks) for this cell counts to return to normal after last infusion. It is expected that patients who 
are currently treated with natalizumab and/or ocrelizumab will convert to siponimod for reasons 
of safety, tolerability, effectiveness or access. Therefore it is critical to generate data to guide 
discussions between healthcare providers and patients at the time point of conversion, 
immediate and short term safety, and effectiveness after conversion. 
 
 
1.2 
Purpose 
The purpose of this study is to assess initial safety and tolerability of converting patients from 
approved oral, injectable and infusion RMS DMTs to siponimod. The results of this study will 
guide clinically relevant decisions related to the transition from frequently used RMS DMTs to 
siponimod and provide clinically relevant data on safety and tolerability for healthcare 
providers who are considering converting patients from currently approved RMS DMT to 
siponimod. 
 
 
2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints 
 
Objective(s) 
Endpoint(s) 
Primary Objective(s) 
• 
The primary objective is to evaluate overall safety and 
tolerability profile of siponimod in advancing RMS 
patients who are converting from currently approved 
oral, injectable or infusion RMS DMT. 
Endpoint(s) for primary objective(s) 
• 
Occurrence of any study-drug related 
adverse events during 6-month treatment 
period 
 
 
Secondary Objective(s) 
• 
To evaluate treatment satisfaction with siponimod in 
advancing RMS patients using outcomes based on the 
Treatment Satisfaction Questionnaire for Medication 
(TSQM-9). 
• 
To evaluate cardiac safety during siponimod treatment 
initiation 
Endpoint(s) for secondary objective(s) 
• 
Occurrence of any adverse events 
• 
Change from Baseline in the TSQM-9 
 
• 
Change from Baseline in heart rate to 6 
hours after 1st treatment 
 


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Objective(s) 
Endpoint(s) 
• 
To evaluate treatment persistence with siponimod 
• 
Occurrence of hospitalizations 
• 
Patient retention 
 


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3 
Study design 
This is a 6-month, open-label, multi-center, single arm design, including 300-400 advancing 
RMS patients, evaluating overall safety and tolerability profile when acutely converting to 
siponimod from oral or injectable or infusion RMS DMTs. This study consists of two primary 
parts: The Screening Period and the Core Treatment Period, plus a 30-day follow-up telephone 
call at the end of treatment/study visit. This study includes a virtual cohort of patients, i.e., the 
patient will remain in their own home and complete study assessments via an online technology. 
This virtual cohort of the study is being done in parallel to, but separate from, other sites that 
will conduct study visits in the traditional manner, i.e., with all assessments performed at the 
study center. 
• The patient cohort will be stratified by pre-treatment groups and may include injectable, 
oral and infusion DMTs used in RMS: interferon beta-1a (Avonex®, Rebif®), interferon 
beta-1b (Betaseron®, Extavia®), glatiramer acetate (Copaxone®, generic glatiramer 
acetate), peginterferon beta-1a (Plegridy®), teriflunomide (Aubagio®), fingolimod 
(Gilenya®, including generic forms of fingolimod), dimethyl fumarate (Tecfidera®, 
including generic forms of dimethyl fumarate, Vumerity® (diroximel fumarate)), 
natalizumab (Tysabri®), and ocrelizumab (Ocrevus®). 
• Patients fulfilling the inclusion criteria, including genotyping, will undergo immediate 
conversion (please see below for exceptions) to siponimod, with “immediate” defined as 
cessation of the existing DMT and initiation of siponimod within 24 hours, followed by 
subsequent 5-day dose titration. Per inclusion criteria and screening phase testing 
requirements, fingolimod patients will undergo all required screening and/or baseline 
testing, including genotyping for CYP2C9*1*1. 
• Patients converting specifically from teriflunomide will undergo accelerated 
elimination prior to converting to siponimod over 11-14 days to allow for adequate 
drug elimination and minimize drug-drug interactions, in line with the Aubagio ® 
USPI. 
• Patients converting from fingolimod will immediately convert to siponimod 
maintenance dose of 2mg, with no dose-titration. 
• Patients treated with infusion DMT natalizumab (Tysabri®) will undergo at least a 4 
week washout period at the time of consent, prior to converting to dose-titrated 
siponimod. 
• Patients treated with infusion DMT ocrelizumab (Ocrevus®) will undergo at least 14 
week washout period at the time of consent, prior to converting to dose-titrated 
siponimod. 
• All patients initiating siponimod treatment, expect those converting from fingolimod, will 
be titrated over 5 days to achieve a maintenance dose of 2mg by Day 6 with the following 
schedule of siponimod: 


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Figure 3-1 
Siponimod Target Daily Dose 
 
 
 
Patients who have completed the treatment period successfully, will be given the option to 
terminate from the study or be referred to the MAYZENT patient services hub for post-trial 
continuity of treatment programs, where the benefit risk is acceptable and discussed with the 
patient and investigator. Patients who terminate prior to the end of the treatment period or who 
withdraw permanently due to siponimod related AE or SAE should follow up with their primary 
neurologist for continued treatment options as quickly as possible. 
 
Figure 3-2 
Exchange Study Design 
 
 
 
 
 
 
 
 
 


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4 
Rationale 
4.1 
Rationale for study design 
The clinical development program of siponimod has demonstrated both a favorable efficacy 
and benefit: risk profile in RMS and SPMS patients. While there is a fair amount of data on the 
overall safety profile of siponimod, less data exists to describe the safety and tolerability profile 


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during conversion from existing DMTs to siponimod in a broader population than included in 
the Phase II and Phase III development program and to determine how health outcomes changes 
when patients start treatment with siponimod both short- and long-term. 
This prospective open-label treatment study design supports the need for increased human 
exposure to a new medicine to further evaluate the safety on the immediate conversion of oral 
injectable, and infusion DMTs to siponimod in patients with advancing RMS. A treatment 
period of 6 months will allow achieving assessment of potential overlapping immune effects 
from previous DMT at steady state of oral siponimod. Further, this 6-month treatment period 
will increase the knowledge of the safety profile of siponimod. The data from the study will 
give HCPs a better understanding of what the potential safety implications will be with an acute 
conversion of existing DMTs to siponimod. 
This study will include a virtual cohort of patients, i.e., the patient will remain in their own 
home and complete study assessments via an online technology. This virtual cohort of the study 
is being done in parallel to, but separate from, other sites that will conduct study visits in the 
traditional manner, i.e., with all assessments performed at the study center. This study design 
element will potentially offer patients better access to a clinical trial 
 
 
 
 


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4.2 
Rationale for dose/regimen and duration of treatment 
In the siponimod Phase III (EXPAND) trial, siponimod treatment was initiated with a 5-day 
dose titration, starting with 0.25mg once daily on day 1 and 2, followed by once daily doses of 
0.5mg on day 3 (two tablets of 0.25mg), 0.75 mg on day 4 (three tablets of 0.25mg) and 1.25mg 
on day 5 (five tablets of 0.25mg) to reach the maintenance dose of siponimod 2mg starting on 
day 6. It is currently unknown whether this titration regimen is needed among patients who are 
converting from existing S1P receptor modulators (e.g., fingolimod) to siponimod. 
Given the recent development of S1P receptor modulators over the last few years in general, 
transition between emerging S1P treatments has not been broadly assessed. Sustained 
fingolimod induced receptor internalization of S1P receptors has been demonstrated in a 
number of separate studies (Jo et al., 2005); (Oo et al., 2007); (Mullershausen et al., 2009). Both 
siponimod and fingolimod are thought to act as a functional S1P1R antagonist, causing 
complete internalization and down‐regulation of the S1P1 receptor found on lymphocytes 
(Matloubian et al., 2004); (Chiba et al., 2006); (O’Sullivan et al., 2016). Through this on-going 
study, there is clinical utility in substantiating the hypothesis that a direct switch between S1P 
receptor modulators is clinically safe and effective in sustaining therapeutic coverage. 
Therefore, in this study amendment, we suggest to omit the siponimod titration regimen for 
only those patients converting from fingolimod strata as part of the investigative approach in 
understanding the role of titration, or lack of, when converting between the two S1P receptor 
modulators to ensure patients are not undertreated. 


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The EXPAND trial demonstrated that 288 (26%) of 1096 patients receiving siponimod and 173 
(32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0.79, 95% CI 0.65– 
0.95; relative risk reduction 21%; p=0.013; (Kappos L et al Lancet 2018). Headache, 
nasopharyngitis, urinary tract infection, and falls were the most frequent adverse events, being 
reported in more than 10% of patients in both treatment groups. There were no observed cases 
of Mobitz type II or higher degree atrioventricular block. 
Because of the success of siponimod in the EXPAND trial, the data was used as a reference and 
led to 2mg as the maintenance dose for all the patients in this Phase IIIb study with a 6-month 
treatment in the core treatment period for all patients. The data collected from this Phase IIIb 
study will be important to provide a better understanding of the safety profile when acutely 
converting advancing RMS patients to siponimod from standard of care oral, injectable or 
infusion DMTs. 
 
4.3 
Rationale for choice of control drugs 
Not Applicable. 
 
4.4 
Purpose and timing of interim analyses/design adaptations 
Shortly before the scheduled completion of enrollment in this study, an interim analysis will be 
performed. Since pre-specification of the parameters relevant for the sample size calculations 
(disease activity, enrollment rate, and dropout rate) has uncertainty, it is reasonable to re-assess 
the pre-study assumptions prior to the completion of the enrollment period. For the purpose of 
earlier dissemination, an interim analysis on the safety data will be conducted at the time of 
approximately 50 patients completing their Visit 5 (Day 168). This analysis may result in an 
increase in the total number of patients enrolled in the study. The maximum number of patients 
is specified in section 5. Additional interim analyses may be conducted at additional time points 
based on study enrollment to evaluate continued efficacy and safety data (for example, 50% 
enrollment). These interim analyses will also allow for an evaluation of the infusion strata. 
 
4.5 
Risks and benefits 
When adhering to the inclusion/exclusion criteria and PIs guidance on safety conditions, 
providing close clinical monitoring, avoiding prohibited treatments, the risk to patients in this 
trial will be minimized. 
The risk profile of siponimod includes bradyarrhythmia (including conduction effects) 
occurring post-first dose in patients with heart rate (HR) less than 55 beats per min (bpm) and 
liver transaminase elevation. Risks associated with S1P modulators, but not observed with 
siponimod to date include clinically relevant bronchoconstriction, increased frequency of 
infections, hypertension and posterior reversible encephalopathy syndrome. There may be yet 
unknown risks to MS patients taking siponimod, which may be serious and unforeseen. There 
is little data from phase III/IIIb clinical trials asserting safety relevant to acute conversion of 
siponimod from current standard of care treatments. 
With limited treatment options for patients with advancing RRMS and patients progressing to 
or currently diagnosed with SPMS, siponimod has demonstrated the potential to be an effective 
treatment that addresses the current unmet needs for this population. 


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Women of child bearing potential and sexually active males must be informed that taking the 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during the 
study. Thus, they must agree to adhere to the contraception requirements outlined in the 
exclusion criteria in order to participate in the trial. If there is any question that the patient will 
not reliably comply, they should not be entered or continue in the study. 
 
4.6 
Rationale for public health emergency mitigation procedures 
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial 
integrity are listed in relevant sections. Notification of the Public health emergency should be 
discussed with Novartis prior to implementation of mitigation procedures, and 
permitted/approved by Local or Regional Health Authorities and Ethics Committees as 
appropriate. 
 
 
 
5 
Population 
This study includes advancing RMS patients. Because the transition of disease activity from 
RRMS to SPMS is not well-characterized, introducing a functional definition of advancing 
RMS for purposes of this study is aimed to help identify patients who may be demonstrate onset 
of relatively fixed impairment indicative or worsening disease activity or progressive disease 
activity. 
The study population will consist of out-patient, male and female patients, ≥18-65 (inclusive) 
years of age, with an EDSS score >2.0-6.5, inclusive, with advancing RMS with or without 
progressive features. The diagnosis of MS with initial relapsing remitting disease course is 
defined by the 2010 revised McDonald criteria (Polman et al 2011). EDSS >2 defines the 
beginning of relatively fixed impairment. Worsening denotes an increase in neurological 
dysfunction and/or disability, with or without evidence of relapses or disease activity on MRI 
(Lublin et al 2013). Progression denotes the continuous or steady worsening of neurological 
impairment over at least 6 months (Rovaris et al 2006) not explained by incomplete recovery 
from relapses (Lublin et al 2013). 
Patients who have been previously treated with other MS therapies, such as interferon beta-1a, 
interferon beta-1b, glatiramer acetate, fingolimod, fumarates (dimethyl fumarate, diroximel 
fumarate), teriflunomide, natalizumab or ocrelizumab for at least 3 months at the time of 
consent may participate. Approximately 300-400 patients will be randomized from up to 80 
study sites in the USA. The study plans to screen approximately 570 patients. 
At the time of enrollment, patients are eligible if they are identified as clinically appropriate 
advancing RMS patients and eligible to receive siponimod, as well as meeting all other 
eligibility criteria. 
 
5.1 
Inclusion criteria 
Patients eligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study. 


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2. Male or female aged 18 to 65 years (inclusive) at screening 
3. Patients with advancing RMS as defined by the principal investigator 
4. Prior history of relapsing MS (RMS), with or without progressive features, according to 
the 2010 Revised McDonald or Lublin criteria (Lublin et al 2013) 
5. Disability status at screening with an EDSS score of >2.0 to 6.5 (inclusive) 
6. Having been continuously treated with beta-interferons, glatiramer acetate, fingolimod, 
fumarates (dimethyl fumarate, diroximel fumarate), or teriflunomide for at least 3 months 
at the time of consent OR having had last natalizumab dose at least 4 weeks before 
screening OR last ocrelizumab dose 14 weeks prior to screening. 
 
5.2 
Exclusion criteria 
Patients meeting any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator in order to ensure that the study 
population will be representative of all eligible patients: 
1. Patients with an active chronic disease (or stable but treated with immune therapy) of the 
immune system other than MS (e.g., rheumatoid arthritis, scleroderma, Sjogren’s 
syndrome, Crohn’s disease, ulcerative colitis, etc.) or with a known immunodeficiency 
syndrome (AIDS, hereditary immune deficiency, drug-induced immune deficiency). 
2. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test. 
3. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception while 
taking study treatment and for 30 days (30 days = 5 times the terminal half-life of 
siponimod) after stopping study treatment. Highly effective contraception methods 
include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment 
• Male sterilization (at least 6 months prior to screening). For female patients on the 
study, the vasectomized male partner should be the sole partner for that patient 
• Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS), or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal hormone 
contraception. 
• In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking study treatment. 


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• Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal 
ligation at least six weeks ago. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of child bearing potential. 
4. Sexually active males unwilling to use a condom during intercourse while taking study 
treatment and for 30 days (30= 5 times the terminal half-life of siponimod) after stopping 
study treatment. A condom is required for all sexually active male participants to prevent 
them from fathering a child AND to prevent delivery of study treatment via seminal fluid 
to their partner. In addition, male participants must not donate sperm for the time period 
specified above. 
If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the ICF. 
 
5. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin), treated or untreated, within the past 5 years, regardless of whether there is 
evidence of local recurrence or metastases. 
6. Diabetes mellitus, unless well controlled and without known organ complications 
including but not limited to heart disease reduced renal function, significant retinal 
pathology or neuropathy. 
7. Diagnosis of macular edema 1 year prior to screening. 
8. Patients with active systemic bacterial, viral, or fungal infections or known to have AIDS 
or have positive HIV antibody. 
9. Positive results of screening period testing for serological markers for hepatitis A, B, C 
and E, indicating acute or chronic infection: 
• anti-HAV IgM 
• HBs Ag and/or anti-HBc IgM 
• anti-HEV IgM (if positive IgG and/or IgM, perform HEV-RNA PCR and if negative, 
patient can be included). 
Note: If the treating physician suspects false positive hepatitis serology results, such as an 
antibody pattern indicating acute hepatitis infection but no corresponding elevated liver 
enzymes and no signs or symptoms of liver disease, a HEV-RNA PCR will be performed 
and will be the deciding factor to determine whether the patient has hepatitis A, B, C, or E. 
If negative, the treating physician may document (in source data and in a eCRF comment) 
that the serology results are considered false positive and consider including the patient. 
10. Negative for varicella-zoster virus IgG antibodies at Screening unless there is other 
evidence of immunity to VZV based on the CDC criteria 
(https://www.cdc.gov/chickenpox/hcp/immunity.html; see Appendix 1) 
11. Have received any live or live-attenuated vaccines (including for varicella-zoster virus or 
measles) within 2 months of screening. 
12. Have been treated with any of the medications listed below: 


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• Intravenous immunoglobulin within 2 months prior to screening 
• Immunosuppressive/chemotherapeutic medications (e.g., azathioprine, methotrexate) 
within 6 months prior to screening 
• Cyclophosphamide within 2 years prior to screening 
• More than 24 months prior treatment exposure to natalizumab 
• Rituximab, ofatumumab, ublituximab or cladribine within 2 years prior to 
randomization 
• Alemtuzumab at any time 
• Any mitoxantrone during previous 2 years prior to randomization or evidence of 
cardiotoxicity following mitoxantrone or a cumulative life-time dose of more than 60 
mg/m2 
• If patients treated with teriflunomide cannot or will not undergo the accelerated 
elimination process Appendix 6. 
• Stem cell transplantation 
• Lymphoid irradiation, bone marrow transplantation or other immunosuppressive 
treatments with effects potentially lasting over 6 months, at any time. 
13. Patients with any medically unstable condition as determine by the investigator. 
14. Any of the following conditions or treatments that may affect cardiovascular function 
within the last 6 months: 
• Heart rate < 55 bpm at screening 
• Cardiac conduction disorders such as incomplete left bundle branch block or second 
degree AV block Mobitz type I (Mobitz I) (either history or observed at screening) 
• Minor ECG findings at screening PR interval: >200 msec; QRS duration ≥120 msec; 
QTcF >430 msec (males); QTcF >450 msec (females) 
• History of or current significant cardiac disease including cardiac failure (NYHA 
functional class II-IV), myocarditis, cardiomyopathy, angina pectoris or myocardial 
infarction (within 6 months), unstable angina (within 6 months), stroke (within 6 
months), TIA (within 6 months), decompensated heart failure requiring 
hospitalization (within 6 months) or uncontrolled arterial hypertension 
• History of (within the 6 months) or current cardiac disease such as heart failure 
NYHA class I, history of myocardial infarction prior to enrollment. 
• Patients receiving treatment with beta-blockers for cardiac disease/comorbidities 
• Any other condition which, in the opinion of the investigator, has a potential for AV 
conduction suppression and/or other risk factors that may require expanded cardiac 
monitoring 
• Patients diagnosed with right bundle branch block, either at the Screening visit for 
entry of the study or during the conduct of the study 
15. Any of the following pulmonary conditions: 
• History of or active severe respiratory disease, including COPD, or pulmonary 
fibrosis, 
• Tuberculosis, except for history of successfully treated tuberculosis or a history of 
prophylactic treatment after positive PPD skin reaction 


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• Patient with severe asthma or asthma requiring regular treatment with oral steroids 
16. Patients with any of the following hepatic conditions prior to screening: 
• history of alcohol abuse, chronic liver or biliary disease 
• total or conjugated bilirubin greater than 1.5 times ULN range, unless in the context 
of Gilbert’s syndrome 
• alkaline phosphatase (AP) greater than 1.5 times the ULN range 
• AST (SCOT), ALT (SGPT) or Gamma-glutamyl-transferase (GGT) greater than 3 
times the ULN range within the last 6 months 
17. Any of the following abnormal laboratory values prior to screening: 
• Serum creatinine > 1.7 mg/dL (150 umol/L) 
• White blood cells (WBC) count <3,500/mm3 (<3.5 x 10(9)/L), while on oral DMT’s 
at screening, except fingolimod 
• Lymphocyte count <500/mm3 (<0.5 x 10(9)/L) while on all DMT’s at screening 
except fingolimod 
• Serum potassium > ULN 
• Or other clinically significant laboratory assessment (i.e. hypomagnesemia or 
hypokalemia) 
• For patients previously exposed to natalizumab, anti-JCV antibody positive and index 
> 1.5 
18. Patients with the following neurological/psychiatric disorders prior to screening: 
• History of substance abuse (drug or alcohol) or any other factor (i.e. serious 
psychiatric condition) that may interfere with the patient’s ability to cooperate and 
comply with the study protocol 
• Progressive neurological disorder, other than MS, which may affect participation in 
the study or require the use of medications not allowed by the protocol 
19. Use of other investigational drugs at the time of enrollment or within prior 30 days; or five 
elimination half-lives, or until the expected pharmacodynamics effect has returned to 
baseline, whichever is longer. 
20. History of hypersensitivity to the study drug or to drugs of similar chemical classes. 
21. Homozygosity for CYP2C9*3/*3 or heterozygous for CYP2C9*2/*3 or CYP2C9*1/*3 
(to be tested at screening) or refusal to test for CYP2C9 variants. 
22. Concomitant use of MAYZENT and drugs that cause moderate CYP2C9 and moderate or 
strong CYP3A4 inhibition (Appendix 4). 
23.  Concomitant use of MAYZENT and drugs that cause moderate CYP2C9 and strong 
CYP3A4 induction (Appendix 4). 
24. Use of cannabinoid or cannabidiol products 30 days prior to screening. 
25. Any other disease or condition, which could interfere with participation in the study 
according to the study protocol, or with the ability of the patients to cooperate and comply 
with the study procedures. 


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Note 1: If a patient fails on one or more laboratory (or other) assessment criteria, as part of the 
screening process, the assessment (s) may be repeated at the discretion of the investigator and 
the patient may be included if criteria are then met, provided the assessments are completed 
within the screening period. 
Note 2: In certain cases rescreening of patients that were previously determined ineligible may 
be permitted. When a patient is re-screened, a new patient identification number will be 
assigned and all screening assessments must be repeated. Each patient may be rescreened no 
more than 1 time. 
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients. 
 
 
6 
Treatment 
6.1 
Study treatment 
6.1.1 
Investigational and control drugs 
Chemical Name: 
Siponimod 
Other Names: 
BAF312, Mayzent ® 
Classification: 
Oral sphingosine 1-phosphate receptor modulator 
The investigational drug siponimod will be provided as film coated tablets. Please refer to the 
pharmacy manual provided for specific instructions. 
The study medication will be administered orally, once daily, with or without food. 
Should titrated patient miss one day of titration or more, the patient will need to restart the 
titration with Day 1 dosing (0.25mg), including Day 1 cardiac assessments (pre-dose ECG and 
6-hour post dose heart rate). It is strongly recommended, during the titration phase, that a 
member of the study staff contact the patient, once daily via phone, to remind them to take their 
study medication as required. This is because restarting the titration will require the patient to 
come in for an unscheduled visit to do a pre-dose ECG assessment and 6 hour post-dose heart 
rate (holter telemetry monitoring). 
Furthermore, if maintenance treatment (2mg) is interrupted for 4 or more consecutive daily 
doses, treatment must be re-initiated with the 5-day titration, including pre-dose ECG and 6- 
hour post-dose heart rate (holter telemetry monitoring) at an unscheduled visit. Treatment 
interruptions for up to 3 missed consecutive daily doses does not require re-titration, and 
treatment should be continued at the maintenance dose level. 
If the patient has missed greater than 30 consecutive days of treatment, using his/her best 
medical judgement, the PI should consider terminating the patient from the study. 


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Table 6-1 
Core Treatment Period 
 
Treatment 
arm 
# of 
patient’s 
Type of study 
drug 
Compound 
Min. 
Dose 
Max. 
Dose 
Frequency 
Formulation 
Admin 
Route 
Generic 
acceptabl 
e 
Arm 1 
300 - 400 
Investigational 
Siponimod 
0.25 
mg 
2 mg 
Daily 
Tablet 
Oral 
No 
 
6.1.2 
Additional study treatments 
No other treatment beyond investigational drug and control drug are included in this trial. 
 
6.1.3 
Treatment arms/group 
All patients, except those converting from fingolimod, will be assigned at visit 1 (Day 1) to the 
following single-treatment arm: Siponimod 0.25mg (initial dose). Following initial dose, the 
titration schedule will be as follows: Day 2 (0.25mg), Day 3 (0.5mg), Day 4 (0.75mg), Day 5 
(1.25mg) and Day 6 and for the rest of the study (2.0mg) as shown in Table 6-3. 
 
6.1.4 
Treatment duration 
The planned duration of the core treatment period is 6 months. Patients may discontinue from 
treatment earlier due to unacceptable toxicity, disease progression and/or at the discretion of 
the investigator or Novartis. For patients who in the opinion of the investigator are still deriving 
clinical benefit from siponimod, every effort will be made to continue study treatment. 
 
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the patient enrolls into the study. All medications, procedures and significant 
non-drug therapies (including physical therapy and blood transfusions) administered after the 
patient enrolls into the study must be recorded on the appropriate Electronic Case Report Forms 
(eCRF). Each concomitant drug must be assessed against all exclusion criteria/prohibited 
medications. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started. If the patient is already 
enrolled, contact Novartis to determine if the patient should continue participation in the study. 
 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the patient enrolls into the study. 
Since heart rate is an important variable affecting the QT interval, starting medications affecting 
QT-prolongation (e.g. beta-blockers), during siponimod treatment initiation (e.g., the first 10 
days) should be avoided whenever possible. Beta-blocker treatment for non-cardiac treatment 
purposes can be introduced in patients who are receiving a maintenance dose of study treatment. 
Experience with siponimod is limited in patients receiving concurrent therapy with heart-rate 
lowering calcium channel blockers (such as verapamil or diltiazem), or other medications that 
may decrease heart rate (e.g., ivabradine or digoxin). Concomitant use of these medications 
during siponimod initiation may be associated with severe bradycardia and heart block; because 


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of these potential effects on heart rate, siponimod should not be initiated in patients who are 
concurrently treated with these medications. 
 
6.2.2 
Prohibited medication 
Use of the medications displayed in Table 6-2 is NOT allowed throughout the study duration 
due to increased risk of immunosuppression with siponimod (CYP2C9 is the major 
metabolizing enzyme for siponimod). 
If one of these prohibited medications is taken during the treatment period, the prohibited 
medication must be stopped immediately. Additional action may be required per the direction 
of the Novartis. 
 
Table 6-2 
Prohibited medication 
Medication 
Prohibition 
period 
Immunosuppressive/chemotherapeutic 
medications or procedures, including 
 
 
Action taken 
 
Discontinue or Interrupt study treatment, 
increase vigilance regarding infections. 
cyclosporine, azathioprine, 
methotrexate, cyclophosphamide, 
mitoxantrone, lymphoid irradiation and 
hematopoietic stem cell 
transplantation 
duration of 
study 
NOTE: Restarting study treatment in 
patients exposed to these medications 
must first be discussed with the Novartis 
Medical Advisor. 
 
Monoclonal antibodies targeting the 
immune system, including, rituximab, 
ofatumumab, and alemtuzumab, 
ublitixumab 
duration of 
study 
Discontinue study treatment, increase 
vigilance regarding infections. 
 
Any concomitant medication which 
inhibits cardiac conduction, e.g. 
verapamil-type and diltiazem-type 
calcium channel blockers or cardiac 
glycosides 
 
Potent inducers of CYP2C9 (Appendix 
4) 
 
6.3 
Treating the patient 
6.3.1 
Patient numbering 
 
duration of 
study 
 
 
 
duration of 
study 
 
Discontinue study treatment 
 
 
 
Discontinue study treatment 
Each patient is identified in the study by a Patient Number (Patient No.), that is assigned when 
the patient consents and enters the screening period in the study; the number is retained as the 
primary identifier for the patient throughout his/her entire participation in the trial. The Patient 
Number consists of the Center Number, (as assigned by Novartis to the study site), with a 
sequential patient number suffixed to the Center Number. This provides each patient with a 
unique number across the entire database. Once assigned to a patient, the Patient Number will 
not be reused. 


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Upon signing the informed consent form, the patient is assigned the next sequential number by 
the investigator. The investigator or his/her staff will contact the IRT and provide the assigned 
patient study identification number along with the requested identifying information of the 
patient to register them into the IRT. The site will enter this number on the electronic case 
report form (eCRF) in the electronic data capture system (EDC). 
If the patient fails to be assigned to treatment for any reason, the IRT must be notified within 2 
days that the patient was not assigned to treatment. The reason for not being assigned to 
treatment will be entered on the Screening Phase Disposition eCRF. 
 
6.3.2 
Treatment assignment 
Patients will receive siponimod on Day 1 (Visit 1). The initial dose given to all patients, except 
fingolimod strata, will be 0.25 mg. The initial siponimod dose given to patients converting 
from fingolimod will be given 2 mg. Fingolimod patients will receive an additional telephone 
call, from site staff, at the end of Day 1 as part of additional safety measures. 
 
6.4 
Treatment blinding 
This is an open label study. 
 
6.5 
Dose escalation and dose modification 
Siponimod dose adjustments are not permitted. Any dose interruptions due to adverse events 
should be documented in the eCRF and dose administration record. 
 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
Compliance will be assessed by the investigator and/or study personnel at each visit using pill 
counts and information provided by the patient/caregiver. This information should be captured 
in the source document at each visit. Patient compliance should be at 100% during the titration 
period. During the maintenance treatment period, patient compliance should be at 80% 
minimum. The investigator and/or study personnel will counsel the patient if compliance is 
below 80%. Study drug accountability will also be determined by the site monitor while 
performing routine site visits and at the completion of the study. 
Duration of the study titration and maintenance study drug exposure will be calculated based 
upon the start and stop dates recorded in the Dosage Administration Record eCRF. 
 
6.6.2 
Emergency breaking of assigned treatment code 
Not applicable- Open label 
 
6.7 
Preparation and dispensation 
Each study site will be supplied with siponimod as described in the pharmacy manual. 
Siponimod will be administered to the patient orally. 






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Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the patient source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB) (and/or CDS for marketed drugs). This information 
will be included in the patient informed consent and should be discussed with the patient during 
the study as needed. Any new information regarding the safety profile of the investigational 
drug that is identified between IB updates will be communicated as appropriate, for example, 
via an investigator notification or an aggregate safety finding. New information might require 
an update to the informed consent and then must be discussed with the patient. 
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements. 
Male patients must be informed that if a female partner becomes pregnant while he is enrolled 
in the study, contact with the female partner will be attempted to request her consent to collect 
pregnancy outcome information. 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
Patients might be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience. This information is provided in the consent form and explains that the 
data will be kept anonymized, and will be used to understand where improvement can be made 
in the clinical trial process. This questionnaire would not ask about the patient’s disease or 
symptoms and therefore will not be considered to be trial data. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that may challenge the ability to obtain 
a standard written informed consent due to limits that prevent an on-site visit, Investigator 
may conduct the informed consent discussion remotely (e.g. telephone, videoconference) if 
allowable by a local Health Authority. 
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented 
and appropriately documented (e.g. the presence of an impartial witness, sign/dating separate 
ICFs by trial participant and person obtaining informed consent, etc.). 
 
8 
Visit schedule and assessments 
Assessment schedule Table 8-1 lists all of the assessments and when they are performed. All 
data obtained from these assessments must be supported in the patient’s source documentation. 
 
Disease Modifying Therapy Washout Regimen 


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Pre-treatment strata drug name 
Washout Interval Guidance 
Interferon-beta/glatiramer acetate 
None; immediate conversion to dose-titrated 
siponimod 
Fumarates (dimethyl fumarate, diroximel 
fumarate) 
None; immediate conversion to dose-titrated 
siponimod 
Teriflunomide 
11-14 day accelerated elimination protocol 
(Appendix 6) prior to starting dose-titrated 
siponimod 
Fingolimod 
None; immediate conversion to siponimod 
maintenance dose 2mg 
Natalizumab 
Last natalizumab dose at least 4 weeks prior 
to screening 
Ocrelizumab 
Last ocrelizumab dose at least 14 weeks prior 
to screening 
 
 
No washout is required for patients converting from interferon-beta or fumarates (dimethyl 
fumarate, diroximel fumarate) prior to starting dose-titrated siponimod. 
An accelerated elimination (Appendix 6) interval will be required for patients taking 
teriflunomide before the patient can start treatment with siponimod. At least 2 weeks with 
successful accelerated teriflunomide elimination procedure as described in the product label 
should be conducted for these patients. If accelerated elimination is not possible, the patient 
cannot participate in the study. 
No washout period or titration regimen is required for patients converting from fingolimod to 
siponimod and CYP2C9 *1/*1, *1/*2, or *2/*2 genotyped patients will start directly on 2mg 
maintenance dose upon entering the treatment period. 
At least a 4 week interval will be required for patients converting from natalizumab. 
At least a 14 week interval will be required for patients converting from ocrelizumab. 
• On Visit 1 (Day 1, baseline), patients who met eligibility criteria will have pre-dose body 
temperature, respiration rate, blood pressure, ECG and heart rate assessed prior to initial 
dose of siponimod. 6 hours after the initial dose of siponimod, heart rate will be 
measured again. The study site personnel will instruct the patient on how to obtain the 6- 
hour post dose heart rate. Pre-dose ECG may be obtained via vendor-supplied ECG vest 
and pre-dose HR may be obtained either manually (see below for guidance) or via ECG. 
Post-dose HR may be obtained via vendor-supplied HR monitoring device. 
• During all other study visits, outside of Day 1 (screening, V2, V3, V4 and V5) a qualified 
study personnel, as determined by the PI, will assess the patient’s heart rate. 
• Patients will then follow the normal visit schedule in the treatment period and should 
complete all of the relevant assessments as indicated in Table 8-1. 


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Patients should have all visits/assessments as outlined in the Assessment schedule Table 8-1 or 
as close to the designated day/time as possible with an allowed visit window of +3 days for visit 
1 (BSL), an allowed visit window of ± 5 days for visits 2, 3, 4, 5 and an allowed ±7 days for 
the 30-day telephone follow-up. Missed or rescheduled visits should not lead to automatic 
discontinuation. 
Patients who prematurely discontinue the study for any reason should be scheduled for a visit 
as soon as possible, at which time all of the assessments listed for the final visit will be 
performed. At this final visit, all dispensed investigational product should be reconciled, and 
the adverse event and concomitant medications recorded on the eCRF. 
 
End of Treatment/Study (EOT/S) Visit Schedule 
For patients who complete the core treatment period of the study, the end of treatment/study 
visit should be conducted. No study drug should be taken on the day of EOT/S. 
For patients who discontinue study medication prematurely in the core treatment period, the 
end of treatment/study visit should be conducted when they stop taking study medication. 
A follow-up telephone call, 30 days after the end of treatment/study visit, will be conducted for 
all patients who randomize. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study 
visits, alternative methods of providing continuing care may be implemented by the 
investigator as the situation dictates. If allowable by a local Health Authority and depending 
on operational capabilities, phone calls, virtual contacts (e.g. tele consult) or visits by site staff/ 
home nursing staff to the participant´s home, can replace on-site study visits, for the duration 
of the disruption until it is safe for the participant to visit the site again. 










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8.1 
Screening 
Screening Period: The duration of the screening period will be approximately 28 days from 
time of signed informed consent (ICF) to determine patients’ eligibility for the study based on 
the inclusion/exclusion criteria and assessments listed below. Patients deemed eligible will 
enter the core treatment period at the Baseline visit. While all screening assessments for the 
patients enrolled at the traditional sites are expected to be conducted on-site, the option for 
home health nursing may be utilized to replace on-site study visits for the remainder of the trial. 
The screening period will include the following assessments (approximately -28 Days): 
• Obtain: signed ICF; patient history; demography; relevant medical history and current 
medical history; prior and concomitant medications 
• Assess: EDSS, physical exam; if the patient is having a MS relapse; neurological exam; 
height; weight; body temperature; respiration rate; blood pressure; heart rate (taken at the 
clinic by a qualified study staff as determined by the PI); lab assessments (blood 
chemistry; pregnancy; 
 CYP2C9 haplotype); ECG (12-lead); CD19+ 
titer only for patients converting from ocrelizumab. 
• Heart rate may be captured via ECG or manual reading. Should the heart rate need to be 
manually measured by a qualified study staff as determined by the PI, sitting heart rate 
should be taken three times after the patient has been sitting for five minutes with their 
back supported and both feet placed on the floor. Repeated sitting measurements should 
be made at 1-2 minute intervals. The average of the 3 heart rates assessed will be noted in 
the eCRF. 
• Patients fulfilling the eligibility criteria may be enrolled into the study 
 
Rescreening: Rescreening may be allowed under certain conditions. Each patient may be 
rescreened no more than once. Request from the investigator/site staff to rescreen patients will 
be handled on a case-by-case basis with Clinical Trial Lead approval required before proceeding 
with the rescreening. Rescreening cannot be done if a patient was previously enrolled in the 
study. 
If a patient rescreens for the study, the patient must sign a new informed consent (ICF) and be 
issued a new patient number prior to any screening assessments being conducted under the new 
patient number. The date of the new informed consent signature must be entered on the 
Informed Consent eCRF to correspond to the new patient number. 
 
8.1.1 
Information to be collected on screening failures 
All patients who have signed informed consent but not entered into the next period will have 
the study completion page for the screening period, demographics, inclusion/exclusion, and 
serious adverse event (SAE) data collected. Adverse events that are not SAEs will be followed 
by the investigator and collected only in the source data. For all patients who have signed 
informed consent and are entered into the treatment period of the study will have all adverse 
events occurring after informed consent is signed recorded on the Adverse Event eCRF. 


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8.2 
Patient demographics/other baseline characteristics 
Patient demographic and baseline characteristic data are to be collected on all patients include 
age, sex, race, and ethnicity. Relevant medical history/current medical condition data includes 
data until the start of study. Physical examination, vital signs, laboratory sampling, pregnancy 
testing, ECG, weight, and previous MS treatment, EDSS, 
 will be recorded on 
eCRF. Where possible, diagnoses and not symptoms, will be recorded. MS medications will 
be recorded on eCRFs designed to facilitate separation from non-MS medications. The last 
RMS DMT administered right before converting to siponimod will be recorded. Likewise, 
detailed MS history and other relevant medical history will be recorded on eCRFs separately 
from relevant non MS medical. In order to collect accurate information about study drug 
exposure, records of study medication dispensed and returned, doses administered and visit 
dates should be maintained for each patient and transcribed into the Dosage Administration 
record eCRF. Compliance will be assessed by the investigator and/or study personnel at each 
visit. The study monitor will perform and document drug accountability during site visits and 
at the end of the study. 
 
 
8.3 
Efficacy/Pharmacodynamics 
Pharmacodynamics assessments are not measured in this study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 
Safety/Tolerability 
Safety assessments and tolerability will be assessed by collecting adverse events (AEs) and 
serious adverse events (SAEs) at all visits during the treatment period. 
For details on AE collection and reporting, refer to AE section. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, regular phone or virtual calls can occur for safety monitoring and discussion of the 
participant´s health status until it is safe for the participant to visit the site again. 


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Table 8-3 
Physical Assessments 
Assessment 
Specification 
 
Physical examination will be performed by a qualified licensed RN, PA or NP (MD/PI must be 
present) or neurologist (MD) at site clinic (traditional sites) or by a licensed RN for sites 
participating virtually (virtual sites) at the visits indicated in the treatment period assessment 
Physical 
examination 
 
 
 
 
 
 
Neurological 
Exam 
 
 
 
Height and 
Weight 
 
 
 
Vital Signs 
schedule and will include an assessment of skin, head, neck, lymph nodes, heart, lungs, 
abdomen, back, neurological function and comments on general appearance. All significant 
findings that are present prior to signing informed consent must be reported on the relevant 
medical history/current medical conditions eCRF. Significant findings made after singing the 
informed consent and being randomized meets the definition of an AE and must be recorded 
on the adverse events eCRF. 
A concise neurological examination will be performed by a qualified licensed RN, PA or NP 
(MD/PI must be present) or neurologist (MD) at site clinic (traditional sites) or by a licensed 
RN for sites participating virtually (virtual sites) at the visits indicated in the treatment period 
assessment schedule and will include clinical history combined with a concise evaluation of 
the mental status, cranial nerves, coordination, sensory, motor and/or gait. In the event of a 
suspected relapse or exacerbation, a comprehensive neurological exam may be needed, at 
the discretion of the physician, to thoroughly evaluate cranial nerve II-XII, reflexes, strength, 
sensory and motor function and gait 
Height, in centimeters (cm) if possible, will be measured at screening visit and end of 
treatment/study visit. Body weight, to the nearest 0.1 kilogram (kg), in indoor clothing, but 
without shoes, will be measured at every visit except Visits 2. 
Vital signs will be assessed at every visit. This will include blood pressure and heart rate 
measurements. BP will be medium sized cuff and the noon-dominant arm in the sitting 
position after 5 minutes of rest. Every effort should be made to use the same arm for the 
patient for all vital signs assessments and where possible, the same person doing the 
assessment. 
Clinically notable vital signs are defined in Appendix 1. 
 
 
 
8.4.1 
Laboratory evaluations 
 
Table 8-4 
Laboratory Assessments 
 
Test Category 
Test Name 
 
Red blood cells, total White blood cells, Differential White blood cells (Basophils, 
Hematology 
 
 
 
Chemistry 
Eosinophils, Lymphocytes, Monocytes, Neutrophils, platelet count, hemoglobin, hematocrit, 
mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration and red blood cell morphology 
Alkaline phosphatase, ALT , AST , Gamma-glutamyl-transferase (GGT), Bicarbonate, 
Calcium, Magnesium, Phosphorus, Chloride, Sodium, Potassium, Creatinine, Creatine 
kinase, Direct Bilirubin, Indirect Bilirubin, Total Bilirubin, Total Cholesterol, LDL, HDL, Total 
Protein, Triglycerides, 
Glucose, amylase 
 
Coagulation 
Prothrombin time (PT) , Partial thromboplastin time (PTT) 
Thyroid 
T3 (free), T4 (free), TSH 
Hepatitis 
markers 
 
 
Additional 
tests 
HBV-DNA, HbsAg, HbsAb, HbcAb, HCV RNA-PCR (baseline) 
Serology: anti-hepatitis A virus IgM, hepatitis B surface antigen and anti-hepatitis B core 
antigen IgM, anti-hepatitis C virus IgG or IgM, anti-hepatitis E virus IgM (positive IgM and/or 
IgM: do HEV-RNA PCR; if negative, patient can be included), 
Anti-VZV IgG, 
CYP2C9 haplotype testing 
 


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Test Category 
Test Name 
CD19+ Titers 
Pregnancy 
Test 
Serum / Urine pregnancy test 
 
 
 
 
Clinical Chemistry 
Blood samples will be collected at the scheduled visits indicated in Table 8-1, and the 
parameters assessed will include: electrolytes (Na, K, Cl, bicarbonate, Ca, Mg, P), random 
glucose, albumin, alkaline phosphatase, creatinine, ALT, AST, GGT, amylase, total bilirubin, 
conjugated bilirubin, total cholesterol, CRP, triglycerides, HDL and LDL. 
 
Hematology 
Blood samples will be collected at the scheduled visits indicated in Table 8-1, and the 
parameters assessed will include: red blood cell count, total and differential WBC count 
(basophils, eosinophils, lymphocytes, monocytes, neutrophils), platelet count, hemoglobin, 
hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration and red blood cell morphology. 
These will be measured at each visit by the central laboratory and will be communicated to the 
site in case of a notable abnormality which could result to a dose change. 
 
Serology 
Serology testing will be conducted at screening only in order to determine the patient’s immune 
status and eligibility for inclusion in the study with respect to a number of viruses; 
A positive result for HIV antibodies or for any of the following serological markers for hepatitis 
A, B, C, and E indicating acute or chronic infection is an exclusion criterion: 
• anti-hepatitis A virus IgM 
• hepatitis B surface antigen and anti-hepatitis B core antigen IgM 
• anti-hepatitis C virus IgG or IgM 
• anti-hepatitis E virus IgM (positive IgG and/or IgM: do HEV-RNA PCR: if negative, 
patient can be included). 
NOTE: If the treating physician suspects false positive Hepatitis serology results, such as an 
antibody pattern indicating acute Hepatitis infection but no corresponding elevated liver 
enzymes and no signs or symptoms HEV-RNA PCR will be performed and will be the deciding 
factor to determine whether the patient has hepatitis A, B, C, or E. If negative, the treating 
physician may document (in source data and in a eCRF comment) that the serology results are 
considered false positive and consider including the patient in the study. 
Anti-VZV IgG will be measured. Patients who are negative for varicella-zoster virus IgG 
antibodies at screening but may be re-screened after successful vaccination. 
 


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CYP2C9 Testing 
CYP2C9 haplotype testing will be conducted once at the screening visit to determine the 
patient’s eligibility to enter into the study. 
 
 
 
 
 
 
8.4.2 
Electrocardiogram (ECG) 
Twelve-lead ECGs will be performed for all patients at Screening, Baseline (Day 1; Pre-dose). 
Clinically significant abnormalities should be recorded on the Medical History/Adverse event 
eCRF page. 
 
If the Day 1 (pre-dose) 12- lead ECG assessment meets any of the following criteria, then dosing 
cannot be initiated. 
The criterion are: 
1. Heart rate < 55 bpm 
2. Cardiac conduction disorders such as incomplete left bundle branch block or second 
degree AV block Mobitz type I (Mobitz I) (either history or observed at screening) 
3. Minor ECG findings: PR interval >200 msec; QRS duration ≥120 msec; QTcF >430 msec 
(males); QTcF >450 msec (females) 
4. Any other condition which, in the opinion of the investigator, has a potential for AV 
conduction suppression 
5. Patients diagnosed with right bundle branch block 
 
If none are met, then the patient can continue with treatment. 
 
Additionally, on baseline Visit 1 (Day 1), heart rate will be monitored and measured for 6 hours 
on a holter telemetry device post initial dose of siponimod. If post-dose HR remains < 45 bpm 
at the end of 6-hour post-dose monitoring period, additional monitoring may be required (see 
Appendix 7). 
 
8.4.3 
Optical Coherence Tomography (OCT) 
OCT is routinely utilized to assess changes or damages to the retina in a variety of diseases such 
as glaucoma, age-related macular degeneration or macular edema. To monitor changes in the 
patients retinal thickness, OCT assessment, measurement if retinal thickness, will be performed 
on Visit 1 (Day 1: prior to treatment; can be done 5 days prior to treatment or on Day 1 prior to 
treatment) and on Visit 4 (Day 84). The OCT machine used should preferably not be changed 


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during the duration of the study. The OCT can be performed by referring ophthalmologist or 
neurologists with clinical training and expertise to assess structural measurement of retinal 
nerve fiber layer thickness, optic nerve head, and macular anatomy AND currently possess 
appropriate OCT equipment in-office. 
Please see Appendix 8 (Guidelines for Ophthalmic Examination and Management of Macular 
Edema) for further details and instructions. 
 
8.4.4 
Pregnancy and assessments of infertility 
Serum pregnancy tests will be conducted for all women who are of child bearing potential at 
the screening, baseline, EOT/S visits of the treatment period. 
Urinary pregnancy tests will be conducted for all women of childbearing potential at all other 
scheduled clinic visits as indicated in the schedule of assessments. 
Relevant participants can perform the urine pregnancy test at home and report the result to the 
site. It is important that participants are instructed to perform the urine pregnancy test first and 
only if the test result is negative proceed with the administration of the study treatment. A 
communication process should be established with the participant so that the Site is informed 
of the pregnancy test results. 
 
Assessments of Fertility 
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child 
bearing potential must also be available as source documentation in the following cases: 
1. surgical bilateral oophorectomy without a hysterectomy 
2. reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile. 
In the absence of the above medical documentation, FSH testing is required of any female 
patient, regardless of reported reproductive/menopausal status at screening/baseline. 
 
 
8.4.5 
Other safety evaluations 
 
 
 
 
 
 
 
 
 
 
 


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Treatment Satisfaction 
The Treatment Satisfaction Questionnaire for Medication (TSQM-9) will be used to 
psychometrically evaluate the patients’ satisfaction with siponimod. The TSQM-9 is a sound 
and valid measure of the major dimensions of patients’ satisfaction with medication and a good 
predictor of adherence across different types of medication and patient population (Atkinson et 
al 2004.) 
 
Other assessments 
MS is associated with a variable combination of symptoms, including sensory loss, imbalance, 
mobility loss, bladder and bowel dysfunction, cognitive dysfunction, spasticity, pain, and sexual 
dysfunction. Measurement of these wide-ranging effects of MS on the lives of patients is 
beyond the scope of clinician-reported endpoints commonly used to evaluate therapeutic 
effectiveness in MS studies. Patient-reported outcome (PRO) measures provide an empirical 
assessment from the patient’s perspective of the benefits of treatment that cannot be gained 
from Magnetic Resonance Imaging (MRI), Expanded Disability Status Score (EDSS), or 
relapse measurement. The use of the C-SSRS (or equivalent) to detect suicidal ideation or 
behavior is currently mandated in studies of CNS active drugs. 
 
Appropriateness of safety measurements 
The safety assessments in this study are standard for S1P modulator treatment in this indication 
and patient population. 


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8.5 
Additional assessments 
8.5.1 
Clinical Outcome Assessments (COAs) 
Patient reported outcomes (PRO) 
The following PROs will be assessed in this study. These questionnaires will be administered 
to patients per scheduled visits listed in the schedule of assessments. 
• 
Treatment Satisfaction Questionnaire for Medical (TSQM-9) 
 
 
 
 
While all screening assessments are expected to be conducted on-site, the option for home 
health nursing may be utilized to replace on-site study visits for the remainder of the trial. In 
this case, home health nurses will provide technology to complete COAs. 
Trial Feedback 
At Visit 1 (baseline), Visit 4 (Day 84), and Visit 5 (Day 168/EOT/S), patients might be asked 
to complete an optional anonymized questionnaire, “Trial Feedback Questionnaire” to provide 
feedback on their clinical trial experience. Responses would be used to understand where 
improvements can be made in the clinical trial process. This questionnaire is not meant to 
collect data about the patient’s disease, symptoms or adverse events and therefore would not be 
considered to be trial data. Should any spontaneous information be collected about AEs, it 
would be transferred to the safety database. Patients may opt in or opt out of completing this 
questionnaire. The data will be used to help understand and conduct clinical trials better in the 
future. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, COA data may be collected remotely. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8.5.3 
Other Assessments 
No additional assessments/tests will be performed on patients entered into this study. 
 
 
9 
Study discontinuation and completion 
9.1 
Discontinuation 
9.1.1 
Discontinuation of study treatment 
Study treatment can be interrupted or discontinued based on investigator’s judgement and 
overall clinical assessment, including in the following cases: 
• Adverse event or serious adverse event (e.g., Serious infections, Symptomatic 
bradyarrhythmia) 
• Abnormal laboratory value(s) including liver function tests 
• Use of prohibited medications. 
All dose changes must be recorded on the Dosage Administration Record eCRF. 
Patients may voluntarily withdraw from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, fail to return for visits or become 
lost to follow up for any other reason. If premature withdrawal occurs for any reason, the 
investigator must make every effort to determine the primary reason for a patient’s premature 
withdrawal from the study and record this information on the corresponding patient’s 
disposition eCRF page. 
Study treatment should be discontinued under the following circumstances: 
• Withdrawal of informed consent 
• Pregnancy 
• Protocol violation that results in a significant risk to the patient’s safety 
• Non-compliance with study treatment 
• Lost to follow up 
• Emergence of certain adverse events, such as malignancy (except successfully treated 
basal cell carcinoma), liver failure or, serious chronic infections (such as HIV). 
Note 1: For a patient with a positive urine pregnancy test, study medication must be 
immediately discontinued and a serum pregnancy test conducted. If the serum test is negative, 
the patient may restart study medication; if siponimod treatment has been interrupted for 4 or 
more consecutive daily doses, treatment must be re-initiated with the 5-day titration pack. If the 
serum test is positive, the patient can either be discontinued from the study or remain in the 
study continuing all scheduled visits, as above. Restart of study medication after the pregnancy 
(and lactation) will be considered on a case by- case basis, as above. Women who need another 
disease modifying treatment during pregnancy will be withdrawn from the study. 


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The investigator must also contact the IRT to register any patient discontinuations from study 
treatment. 
 
 
9.1.2 
Withdrawal of informed consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent (WoC) occurs only when a patient does not want to participate in the 
study anymore; does not want any further visits or assessments and does not want any further 
study related contact. 
At the time a patient withdraws consent, the investigator should make every effort (e.g. 
telephone, e-mail, letter) to determine the primary reason for this decision and record this 
information on the Study Completion eCRF. Study drug must be discontinued and no further 
assessments conducted. All biological material that has not been analyzed at the time of 
withdrawal must not be used. Further attempts to contact the patient are not allowed unless 
safety findings require communicating or follow-up. 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation. 
 
 
9.1.3 
Lost to follow-up 
Study treatment should be discontinued if patient is lost to follow-up. For patients whose status 
is unclear because they fail to appear for study visits without stating an intention to discontinue 
or withdraw, the investigator must show “due diligence” by documenting in the source 
documents steps taken to contact the patient, e.g. dates of telephone calls, registered letters, etc. 
A patient will not be formally considered lost to follow-up until all efforts to contact the patient 
have been exhausted. 
 
 
9.1.4 
Early study termination by sponsor 
The study can be terminated at any time for any reason by Novartis. This may include reasons 
related to the benefit/risk assessment of participating in the study or for regulatory or medical 
reasons. Should this be necessary, the patient should be seen as soon as possible and treated for 
a prematurely withdrawn patient. 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 
patient’s interests. The investigator will be responsible for informing IRBs of the early 
termination of the trial. 
 
 
9.2 
Study completion and post study treatment 
A patient will be considered a core treatment period completer when he/she has completed all 
treatment period visits, up to the EOT/S visit for the core treatment period and including follow- 
up visits where required. 


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The study will be considered completed when all individual patients have either completed or 
prematurely discontinued from the treatment period of the study. The maximum duration of a 
patient who completes the treatment Parts of the study could reach approx. 5 years. 
The investigator must provide follow-up medical care for all patients who prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. 
 
 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
Adverse events must be recorded in the Adverse Events eCRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information: 
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 
• no action taken (e.g. further observation only) 
• (investigational) treatment dosage increased/reduced 
• (investigational) treatment interrupted/withdrawn 
• concomitant medication or non-drug therapy given 
• non-drug therapy given 
• patient hospitalized/patient’s hospitalization prolonged (see Section 10.1.2 for definition 
of SAE) 
• its outcome (not recovered/not resolved; recovered/resolved; recovered/resolved with 
sequelae; fatal; or unknown) 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent, and assessment must be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study drug, the interventions required 
to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB). This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. Any new 
information regarding the safety profile of the medicinal product that is identified between IB 
updates will be communicated as appropriate, for example, via an Investigator Notification or 
an Aggregate Safety Finding. New information might require an update to the informed consent 
and has then to be discussed with the patient. 


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The investigator must also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes might 
reasonably be related to study treatment. This information must be recorded in the investigator’s 
source documents; however, if the AE meets the criteria of an SAE, it must be reported to 
Novartis. 
 
 
10.1.2 
Serious adverse events 
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing)) 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
study drug deterioration. 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the patient or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse (please refer to the ICH- 
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Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
 
 
10.1.3 
SAE reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days (after the last study visit/ following the last 
administration of study treatment if there are post-treatment follow-up visits with no required 
procedures) must be reported to Novartis safety within 24 hours of learning of its occurrence. 
Detailed instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site. Any SAEs experienced after the 30 day period (after 
the last study visit/ following the last administration of study treatment if there are post- 
treatment follow-up visits with no required procedures) should only be reported to Novartis if 
the investigator suspects a causal relationship to study treatment 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
The time of 30 days in the standard text above is the recommended minimum and the SAE form 
should be submitted to Novartis Safety. A longer duration may be appropriate for drugs with 
particularly long elimination half-lives or from drug classes with known late occurring effects, 
or when risk assessment/management objectives require prolonged safety monitoring. Please 
ensure the Informed Consent reflects this 30 day/Post Study Safety Contact. 
 
10.1.4 
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 


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form and should include an assessment of the possible relationship to the investigational/study 
treatment. 
Any SAE experienced during pregnancy and unrelated to the pregnancy must be reported on a 
SAE form. 
 
 
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate eCRF irrespective of whether or not associated with an AE/SAE and reported 
to Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness. 
 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
CRF (Yes/No) 
Document in AE 
eCRF 
 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated 
with an AE 
Only if associated with an 
SAE 
 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not associated 
with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the, 
respective sections. 
 
10.2 
Additional Safety Monitoring 
10.2.1 
Liver safety monitoring 
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
Liver events are divided into two categories: 
• Liver events of special interest (AESI) which consist of elevations of liver function tests 
(LFTs) 
• Medically significant liver events which are considered as serious adverse events (SAEs) 
and which consist of marked elevations of LFTs and / or pre-specified adverse events. 


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Please refer to Appendix 2 for complete definitions of liver events. 
Any liver event which meets the criteria for “medically significant” event as outlined should 
follow the standard procedures for SAE reporting. Every liver event as defined in Table 16-1 
of Appendix 2 should be followed up by the investigator or designated personal at the trial site 
as summarized below: 
• Repeating the LFT to confirm elevation as appropriate 
• Discontinuation of the investigational drug if appropriate 
• Hospitalization of the patient if appropriate 
• A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications) 
• An investigation of the liver event which needs to be followed until resolution. 
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed should be recorded on appropriate eCRF pages, including the liver 
event overview eCRF pages. 
NOTE: If local requirements for liver safety monitoring are more stringent than those outlined 
in this section of the protocol, then the local requirements will take precedence 
 
 
10.2.2 
Prospective suicidality assessment 
The Columbia-Suicide Severity Rating Scale (C-SSRS) (Posner, 2011) is a questionnaire that 
prospectively assesses Suicidal Ideation and Suicidal Behavior. The C-SSRS tool is 
administered via interview with the subject. 
The C-SSRS must be administered at the visits indicated in Table 8-1. 
If the patient does not attend the End of Treatment/Study Visit, the C-SSRS should be 
completed if the site has become aware of a potential suicide-related thought or behavior by 
other communications. 
If, at any time after screening the score is “yes” on item 4 or item 5 of the Suicidal Ideation 
section of the C-SSRS or “yes” on any item of the Suicidal Behavior section, except for the 
“Non-Suicidal Self-Injurious Behavior (NSSI) item, the patient must be referred to a mental 
health care professional for further assessment and/or treatment. The decision on whether the 
study treatment should be discontinued is to be taken by the investigator in consultation with 
the mental health professional to whom the patient is referred. 
In addition, all life-threatening events during the study must be reported as SAEs. For example, 
if a patient answers “yes” to one of the questions in the Suicidal Behavior section, an SAE must 
be reported if the event was life-threatening. 
All events of “Non-Suicidal Self-Injurious Behavior” (question in the Suicidal Behavior 
section) that meet the criteria for AEs (e.g. treatment emergent events or change in severity 
compared to baseline) should be reported as AEs. Patients reporting NSSI behaviors can be 
referred to a mental health care professional at the discretion of the investigator. 


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10.2.3 
Bradycardia 
This is considered an AESI. To ensure patient safety and enhance reliability in determining the 
bradycardia potential of an investigational drug, a standardized process for identification, 
monitoring and evaluation of bradycardia events has to be followed. (Please see Appendix 7 for 
instructions) 
Bradycardia is defined as any pre-dose HR less 55 bpm or post-dose HR bpm less than 45. 
 
11 
Data Collection and Database management 
11.1 
Data collection 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web- 
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on eCRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate 
After final database lock, the investigator will receive copies of the patient data for archiving at 
the investigational site. 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. 
 
 
11.2 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
Randomization codes and data about all study treatment (s) dispensed to the patient and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 


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will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and made available for data analysis. Any changes to 
the database after that time can only be made after written agreement by Novartis development 
management. 
 
 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis/ (or 
designated CRO) representative will review the protocol and data capture requirements (i.e. 
eSource DDE or eCRFs) with the investigators and their staff. During the study, Novartis 
employs several methods of ensuring protocol and GCP compliance and the quality/integrity of 
the sites’ data. The field monitor will visit the site to check the completeness of patient records, 
the accuracy of data capture / data entry, the adherence to the protocol and to Good Clinical 
Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be available 
to assist the field monitor during these visits. Continuous remote monitoring of each site’s data 
may be performed by a centralized Novartis/delegated CRO/CRA organization. Additionally, 
a central analytics organization may analyze data & identify risks & trends for site operational 
parameters, and provide reports to Novartis clinical teams to assist with trial oversight. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
patient’s file. The investigator must also keep the original informed consent form signed by the 
patient (a signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed. 
 
 
11.4 
Virtual patient cohort 
This study includes a virtual cohort, i.e., the patient will remain in their own home and complete 
study assessments via an online technology. The patient interacts with study personnel using 
online communication tools which incorporate telemedicine. This virtual cohort of the study is 
being done in parallel to, but separate from, other sites that will conduct study visits in the 
traditional manner, i.e., with all assessments performed at the study center. 


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The rationale for the virtual cohort is to make the trial accessible to patients who do not live 
close enough to a traditional participating trial site; and to unburden patients who may have 
ambulatory challenges and/or who may have family and job responsibilities that would preclude 
their trial participation at a traditional trial site. Virtual assessments are less time-consuming, 
can be done independent of patient schedule, and do not require travel to a site. 
For patients participating in the virtual cohort of the study, pre-screening is done remotely via 
a telephone call and informed consent is performed remotely using telemedicine and an 
electronic consent form. Study drug is shipped directly to the patient’s home from a central 
certified and GCP compliant distribution center. Appropriate controls are used to ensure that 
the drug is received by the patient. Lab samples and ECG readings are collected from the 
patient, at the patient’s home, by certified healthcare personnel such as a mobile nurse 
practitioner or phlebotomist. Local lab sample collection centers are also incorporated to 
collected patient samples locally. 
Assessments will only be conducted virtually if they can be done without affecting the 
wellbeing of the patient during the study and with the same level of scientific integrity as 
assessments conducted in a physical study center. Some assessments (e.g., EDSS, 
) may 
require the presence of a trained Registered Nurse, Nurse Practitioner or Physician Assistant in 
the patient’s home. If completed in the patient’s home, EDSS will be performed by a Registered 
Nurse, Nurse Practitioner or Physician Assistant certified (Level C) to perform the test. 
While there are parts of study visits that require the virtual trial investigator to participate via 
telemedicine per protocol (for further detail please reference the Study Virtual Cohort Site 
Operations Plan), the virtual investigator may participate in any visits or parts thereof via 
telemedicine. 
Data collected from patients participating in the virtual cohort will be collected electronically 
using purpose-built technology and will be entered into RaveX manually by a virtual study 
coordinator. The data is monitored remotely by CRAs. A central IRB is used for all 
investigators participating the virtual study model, if used. AE/SAE (reporting, assessing and 
follow-ups) will be handled similarly to a traditional model, with the patient contacting study 
personnel or engaging local care for emergencies. 
The virtual patient cohort may terminate new study enrollment at the discretion of the sponsor. 
In this case, any ongoing patients in this cohort will be followed per protocol through end of 
study. Virtual study subject in prescreening will be offered alternative participation through 
our traditional cohort, when subject is amenable 
 
12 
Data analysis and statistical methods 
The analysis will be conducted on all patient data at the end of the treatment phase of the study. 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
 
12.1 
Analysis sets 
The Safety Set includes all patients who received at least one dose of study treatment. 
All analyses will be performed using the Safety Set. 


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12.2 
Patient demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively. 
Categorical data will be presented as frequencies and percentages. For continuous data, number 
of observations, mean, standard deviation, minimum, 25th percentile, median, 75th percentile, 
and maximum will be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term. 
 
 
12.3 
Treatments 
Categorical data will be summarized as frequencies and percentages. For continuous data, 
number of observations, mean, standard deviation, minimum, 25th percentile, median, 75th 
percentile, and maximum will be presented. 
The duration of exposure in (days) to study medication will be summarized by means of 
descriptive statistics. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system. 
 
12.4 
Analysis of the primary endpoint(s) 
The primary aim of this study is to evaluate the overall safety and tolerability profile of 
siponimod 2 mg in patients with relapsing forms of MS who are converting from existing oral, 
injectable or infusion DMTs. 
 
 
12.4.1 
Definition of primary endpoint(s) 
The primary endpoint is the occurrence of adverse event suspected to be related to study 
medication. 
 
 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The number (and percentage) of patients with treatment emergent adverse events suspected to 
be related to study medication will be summarized by primary system organ class and preferred 
term. The 95% confidence interval for the overall rate of adverse event suspected to be related 
to study medication will be calculated. 
A patient with multiple adverse events within a category (overall, primary system organ class, 
or preferred term) is only counted once towards the total of that category. 


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The analysis of the primary variable will also be stratified by pre-treatment. 
 
 
12.4.3 
Handling of missing values/censoring/discontinuations 
No missing data will be imputed. All analyses will be using observed-case approach 
 
 
12.4.4 
Sensitivity and Supportive analyses 
Sensitivity analyses 
No sensitivity analyses are planned. 
 
Supportive analyses 
No supportive analyses are planned. 
 
 
12.5 
Analysis of secondary endpoints 
12.5.1 
Safety endpoints 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate listing for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs). 
The on-treatment period lasts from the date of first administration of study treatment to 30 days 
after the date of the last actual administration of any study treatment. 
 
Adverse events 
All information obtained on adverse events will be displayed by patient. 
The number (and percentage) of patients with treatment emergent adverse events (events started 
after the first dose of study medication or events present prior to start of open-label treatment 
but increased in severity based on preferred term) will be summarized in the following ways: 
• By primary system organ class and preferred term 
• By primary system organ class, preferred term and maximum severity 
• By Standardized MedDRA Query (SMQ) and preferred term 
Separate summaries will be provided for adverse events and other significant adverse events 
leading to discontinuation. 
The number (and proportion) of patients with adverse events of special interest/related to 
identified and potential risks will be summarized. 


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A patient with multiple adverse events within a category (overall, primary system organ class, 
or preferred term) is only counted once towards the total of that category. 
In addition, occurrence of hospitalization will be summarized using frequencies and 
percentages. 
 
 
Vital signs 
All vital signs data will be listed by patient, and visit/time and if ranges are available, 
abnormalities will be flagged. Summary statistics will be provided by visit/time. 
In addition, change in heart rate from Baseline to 6-hour after first treatment will be summarized. 
 
12-lead ECG 
All ECG data will be listed by patient and visit, abnormalities will be flagged. Summary 
statistics will be provided by visit. 
In addition, change in heart rate (and other vitals) from Baseline to 6-hours after first treatment, 
may be summarized. Please see protocol Section 8.4.2 
 
Clinical laboratory evaluations 
All laboratory data will be listed by patient and visit/time and if normal ranges are available 
abnormalities will be flagged. Summary statistics will be provided by visit/time. Shift tables 
using the low/normal/high/ (low and high) classification will be used to compare baseline to the 
worst on-treatment value. 
 
12.5.2 
Patient report outcomes 
Change in TSQM-9 from Baseline to each post-Baseline time point will be summarized by 
providing: number of observations, mean, standard deviation, minimum, 25th percentile, 
median, 75th percentile, and maximum. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12.7 
Interim analyses 
For the purpose of earlier dissemination, an interim analysis on the safety data will be conducted 
at the time of approximately 50 patients completing their Visit 5 (Day 168). 
Additional interim analyses may be conducted at additional time points based on study 
enrollment to evaluate continued efficacy and safety data (for example, 50% enrollment). These 
interim analyses will also allow for an evaluation of the infusion strata. 
 
 
 
Since there will be no hypothesis testing involved, statistical adjustment for the interim analysis 
will not be made at the stage of final analyses of efficacy and safety. 
 
12.8 
Sample size calculation 
12.8.1 
Primary endpoint(s) 
Sample size calculations were based on the rate of study drug related adverse events. During 
the first 6 months, such an AE rate was observed at 45% from the pooled data of patients treated 
with fingolimod 0.5 mg/day in studies CFTY720D2301 and CFTY720D2302. A sample size of 
300 to 400 patients will provide us the precision estimates ranging from 4.9% to 5.6% precision 
(half-width of 95% confidence interval) of the estimated rate of AE. Of the total sample size, 


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approximately 80-100 patients with prior infusion therapy exposure will be enrolled by 
balanced stratification. 
 
 
 
 
 
 
 
 
 
 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 
 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, patient recruitment procedures (e.g., 
advertisements) and any other written information to be provided to patients. Prior to study start, 
the investigator is required to sign a protocol signature page confirming his/her agreement to 
conduct the study in accordance with these documents and all of the instructions and procedures 
found in this protocol and to give access to all relevant data and records to Novartis monitors, 
auditors, Novartis Quality Assurance representatives, designated agents of Novartis, IRBs/IECs, 
and regulatory authorities as required. If an inspection of the clinical site is requested by a 
regulatory authority, the investigator must inform Novartis immediately that this request has 
been made. 
 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (e.g., defined as last patient last 
visit) and finalization of the study report the results of this trial will be submitted for publication 
and posted in a publicly accessible database of clinical trial results, such as the Novartis clinical 
trial results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.) . 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 


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13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented. 
 
14.1 
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for patient safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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15 
References 
Aslanis V, Faller T, Van de Kerkhof E, Schubart A, Wallström E, Beyerbach A. Siponimod 
(BAF312) (and/or its metabolites) penetrates into the CNS and distributes to white matter 
areas. Mult Scler J 2012; 18(10(suppl)): P792. 
Brown B et al. Analysis of cardiac monitoring and safety data in patients initiating 
fingolimod treatment in the home in clinic. BMC Neurol. 2019. 19(1): 287. 
Centers for Disease Control and Prevention (CDC). Assessing Immunity to 
Varicella. https://www.cdc.gov/chickenpox/hcp/immunity.html. Accessed May 22, 2018. 
Chiba K et al. Role of sphingosine 1-phosphate receptor type 1 in lymphocyte egress from 
secondary lymphoid tissues and thymus. Cell Mol Immunol. 2006; 3(1): 11-9. 
Chiba K, Adachi K. Sphingosine 1-phosphate receptor 1 as a useful target for treatment of 
multiple sclerosis. Pharmaceuticals (Basel). 2012; 5(5):514–28. 
Chun J and Hartung HP. Mechanism of action of oral fingolimod (FTY720) in multiple 
sclerosis. Clin Neuropharmacol. 2010. 33(2); 91-101. 
Coller JK, Krebsfaenger N, Klein K, Endrizzi K, Wolbold R, Lang T, et al. The influence of 
CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent antioestrogen Z-4- 
hydroxy-tamoxifen in human liver. Br J Clin Pharmacol. 2002; 54:157–167. 
Fox E, et al. Outcomes of switching directly to oral fingolimod from injectable therapies: 
Results of the randomized, open-label, multicenter, Evaluate Patient Outcomes (EPOC) study 
in relapsing multiple sclerosis. MS ARD. DOI: http://dx.doi.org/10.1016/j.msard.2014.06.005 
Gentile A, Musella A, Bullita S, et al. Siponimod (BAF312) prevents synaptic 
neurodegeneration in experiential multiple sclerosis. J neuoroinflammation 2016; 13(1); 207. 
Gergely P et al. The selective sphingosine 1-phosphate receptor modulator BAF312 redirects 
lymphocyte distribution and has species-specific effects on heart rate. Br J Pharmacol 2012; 
167(5): 1035-47. 
Gergely, P., et al., 2012. The selective sphingosine 1-phosphate receptor modulator 
Siponimod redirects lymphocyte distribution and has species-specific effects on heart rate. Br. 
J. Pharmacol. 167, 1035–1047. 
Goodin et al, 2002. Disease modifying therapies in multiple sclerosis: report of the 
Therapeutics and Technology Assessment Subcommittee of the American Academy of 
Neurology and the MS Council for Practice Guidelines. Neurology. 2002 Jan 22; 58(2):169- 
78. 
Jo E et al. S1P1-selective in vivo-active agonists from high-throughput screening: off-the- 
shelf chemical probes of receptor interactions, signaling, and fate. Chem Bio. 2005. 12(6): 
703-145. 
Kappos et al. Siponimod versus placebo in secondary progressive multiple sclerosis: a 
double-blind randomised, phase 3 study. Lancet, 2018. 


Novartis 
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Confidential 
Page 87  
Protocol No. CBAF312AUS02 
 
Kappos et al. Switching from natalizumab to fingolimod: A randomized, placebo-controlled 
study in RRMS. Neurology. 2015 85(1):29–39. doi:10.1212/WNL.0000000000001706 
Leurs CE, et al. 2018. Switching natalizumab to fingolimod within 6 weeks reduces 
recurrence of disease activity in MS patients. Mult Scler. 2018 Oct; 24(11):1453-1460. doi: 
0.1177/1352458517726381 
Lublin et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 
2014 Jul 15; 83(3):278-86. 
Matloubian M et al. Lymphocyte egress from thymus and peripheral lymphoid organs is 
dependent on S1P receptor 1. Nature. 2004. 427(6972):355-60. 
Mao-Draayer et al. Siponimod enriches regulatory T and B lymphocytes in secondary 
progressive multiple sclerosis. JCI Insight. 2020. 13; 5(3):e134251. 
McDonald et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the 
International Panel on the diagnosis of multiple sclerosis. Ann Neurol. 2001 July; 50(1): 121- 
7. 
Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major importance in human drug 
metabolism. Br J Clin Pharmacol. 1998; 45:525–538. 
Montalban et al 2010. MRI criteria for MS in patients with clinically isolated syndromes. 
Neurology. 2010 Feb 2; 74(5):427-34. 
MS Society. Secondary Progressive MS (SPMS). https://www.mssociety.org.uk/what-is- 
ms/types-of-ms/secondary-progressive-spms. Accessed January 13, 2018. 
Mullershausen F et al. Persistent signaling induced by FTY720-phosphate is mediated by 
internalized S1P1 receptors. Nat Chem Biol. 2009. 5(6):428-34. 
O’Sullivan C, et al. The dual S1PR1/S1PR5 drug BAF312 (Siponimod) attenuates 
demyelination in organotypic slice cultures. J Neuroinflammation 2016; 12:31. 
Pilotto A, Seripa D, Franceschi M, Scarcelli C, Colaizzo D, Grandone E, et al. Genetic 
susceptibility to nonsteroidal anti-inflammatory drug-related gastroduodenal bleeding: role of 
cytochrome P450 2C9 polymorphisms. Gastroenterology. 2007; 133:465–471. 
Polman et al. 2005. Diagnostic criteria for multiple sclerosis: 2005 revisions to the 
“McDonald Criteria.” Ann Neurol. 2005 Dec; 58(6): 840-6. 
Polman et al. 2011. Diagnostic criteria for multiple sclerosis: 2010 Revisions to the 
McDonald criteria. Ann Neurol. 2011 Feb; 69(2): 292-302. 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, 
Melvin GA, Greenhill L, Shen S, Mann JJ. "The Columbia–Suicide Severity Rating Scale: 
Initial Validity and Internal Consistency Findings From Three Multisite Studies With 
Adolescents and Adults". American Journal of Psychiatry. 2011 Dec; 168 (12): 1266–77. 
Rovaris et al. Secondary progressive multiple sclerosis: current knowledge and future 
challenges. Lancet Neurol. 2006 Apr 5(4):343-54. 


Novartis 
Amended Protocol Version No. 05 (clean) 
Confidential 
Page 88  
Protocol No. CBAF312AUS02 
 
Sanna, M.G., et al., 2004. Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, 
respectively, regulate lymphocyte recirculation and heart rate. J. Biol. Chem. 279, 13839– 
13848. 
Selmaj K, Li DK, Hartung HP, et al. Siponimod for patients with relapsing –remitting 
multiple sclerosis (BOLD): an adaptive dose-ranging randomized phase II. Lancet Neurol 
2013; 12(8): 756-67. 
Shah R et al. A First Look at the Characteristics of Patients with Multiple Sclerosis 
Initiating Siponimod Therapy in the United States. Poster presented at: The 8th Joint 
ECTRIMS-ACTRIMS Meeting (MS Virtual); September 11-13, 2020. P0835. 
Snelder N et al. Characterization and prediction of cardiovascular effects of fingolimod and 
siponimod using a systems pharmacology modeling approach. J Pharmacol Exp Ther. 2017. 
360(2):356-367. 
Subei AM and Cohen JA. Sphingosine 1-phosphate receptor modulator in multiple sclerosis. 
CNS Drugs. 2015. 29(7):565-75. 
Swanton et al. 2006. Modification of MRI criteria for multiple sclerosis in patients with 
clinically isolated syndromes. J Neurol Neurosurg Psychiatry. 2006 Jul; 77(7): 830-833. 
Swanton et al. 2007. MRI criteria for multiple sclerosis in patients presenting with clinically 
isolated syndromes: a multicenter retrospective study. Lancet Neurol 2007 Aug; 6(8): 677-86. 
Tintore et al. Isolated demyelinating syndromes: comparison of different MR imaging 
criteria to predict conversion to clinical definite multiple sclerosis. AJNR Am J Neruoradiol. 
2000 Apr 21(4): 702-6. 
Tremlett H, Yinshan Z, Devonshire V. National history of secondary-progressive multiple 
sclerosis. Mult Scler 2008; 14(3): 314-24. 
Ufer et al. Impact of siponimod on vaccination response in a randomized, placebo-controlled 
study. Neurol Neuroimmunol Neuroinflamm. 2017; 4:e398. 
Vormfelde S, Brockmoller J, Bauer S, Herchenhein P, Kuon J, Meineke I, et al. Relative 
impact of genotype and enzyme induction on the metabolic capacity of CYP2C9 in healthy 
volunteers. Clin Pharmacol Ther. 2009; 1:54–61. 
Yuping Chen, Stephen S. Ferguson, Masahiko Negishi, and Joyce A. Goldstein. Induction of 
Human CYP2C9 by Rifampicin, Hyperforin, and Phenobarbital Is Mediated by the Pregnane 
X Receptor. Journal of Pharmacology and Experimental Therapeutics February 1, 2004, 308 
(2) 495-501; DOI: https://doi.org/10.1124/jpet.103.058818. 


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16 
Appendices 
16.1 
Appendix 1: Vital signs 
Notable Vital Signs and Body Weight 
Vital Sign Variable 
Notable Criteria 
Pulse (beats/min) 
>120 bpm 
Or 
< 55 bpm 
Systolic BP (mmHg) 
 160 mmHg 
Or 
 90 mm Hg 
Diastolic BP (mmHg) 
 100mmHg or 
 50 mmHg 
Temperature (°C) 
>38.3 °C/ 101°F 
Body weight (kg) 
± 7% from baseline weight 


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16.2 
Appendix 2: Liver event definition and follow up requirements 
Table 16-1 
Liver Event and Laboratory Trigger Definitions 
Definition/ threshold 
LIVER LABORATORY 
TRIGGERS 
• 
3 x ULN < ALT / AST ≤ 5 x ULN 
• 
1.5 x ULN < TBL ≤ 2 x ULN 
 
LIVER EVENTS 
• 
ALT or AST > 5 × ULN 
• 
ALP > 2 × ULN (in the absence of known bone pathology) 
• 
TBL > 2 × ULN (in the absence of known Gilbert syndrome) 
• 
ALT or AST > 3 × ULN and INR > 1.5 
• 
Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and 
TBL > 2 × ULN (mainly conjugated fraction) without notable increase 
in ALP to > 2 × ULN) 
• 
Any clinical event of jaundice (or equivalent term) 
• 
ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia 
• 
Any adverse event potentially indicative of a liver toxicity* 
 
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage- 
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver 
neoplasms TBL: total bilirubin; ULN: upper limit of normal 
 
 
Table 16-2 
Follow Up Requirements for Liver Events and Laboratory Triggers 
 
Criteria 
Actions required 
Follow-up monitoring 
 
• 
Discontinue the study treatment 
immediately 
 
Potential Hy’s Law casea 
 
 
 
ALT or AST 
 
 
 
> 8 × ULN 
 
 
 
 
 
 
> 3 × ULN and INR > 1.5 
• 
Hospitalize, if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate eCRF 
 
• 
Discontinue the study treatment 
immediately 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate eCRF 
• 
Discontinue the study treatment 
immediately 
• 
Hospitalize, if clinically 
appropriate 
• 
Establish causality 
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc 
(frequency at investigator 
discretion) 
 
 
 
 
 
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc 
(frequency at investigator 
discretion) 
 
 
 
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc 
(frequency at investigator 
discretion) 
 


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Criteria 
Actions required 
Follow-up monitoring 
• 
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate eCRF 
 
• 
Repeat LFT within 48 hours 
• 
If elevation persists, continue 
follow-up monitoring 
 
> 5 to ≤ 8 × ULN 
 
 
 
 
 
 
 
 
> 3 × ULN accompanied 
by symptomsb 
 
 
 
 
> 3 to ≤ 5 × ULN (patient 
is asymptomatic) 
 
ALP (isolated) 
 
 
> 2 × ULN (in the 
absence of known bone 
pathology) 
 
 
TBL (isolated) 
 
 
 
> 2 × ULN (in the 
absence of known 
Gilbert syndrome) 
 
 
 
 
> 1.5 to ≤ 2 × ULN 
(patient is asymptomatic) 
• 
If elevation persists for more than 
2 weeks, discontinue the study 
drug 
• 
Establish causality 
• 
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate eCRF 
• 
Discontinue the study treatment 
immediately 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate eCRF 
• 
Repeat LFT within the next week 
• 
If elevation is confirmed, initiate 
close observation of the patient 
 
• 
Repeat LFT within 48 hours 
• 
If elevation persists, establish 
causality 
• 
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate eCRF 
 
• 
Repeat LFT within 48 hours 
• 
If elevation persists, discontinue 
the study drug immediately 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate eCRF 
• 
Repeat LFT within the next week 
• 
If elevation is confirmed, initiate 
close observation of the patient 
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc 
(frequency at investigator 
discretion) 
 
 
 
 
 
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc 
(frequency at investigator 
discretion) 
 
 
 
Investigator discretion 
Monitor LFT within 1 to 4 weeks 
 
 
 
Investigator discretion 
Monitor LFT within 1 to 4 weeks 
or at next visit 
 
 
 
 
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc 
(frequency at investigator 
discretion) 
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated (indirect) bilirubin) 
 
Investigator discretion 
Monitor LFT within 1 to 4 weeks 
or at next visit 
 


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Criteria 
Actions required 
Follow-up monitoring 
• 
Discontinue the study treatment 
immediately 
 
Jaundice 
 
 
 
 
 
 
Any AE potentially 
indicative of a liver 
toxicity* 
• 
Hospitalize the patient 
• 
Establish causality 
• 
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate eCRF 
• 
Consider study treatment 
interruption or discontinuation 
• 
Hospitalization if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate eCRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc 
(frequency at investigator 
discretion) 
 
 
 
 
 
Investigator discretion 
 
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN 
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level 
after a maximum of 6 months, (4) liver transplantation, and (5) death. 
Based on investigator’s discretion investigation(s) for contributing factors for the liver event can 
include: serology tests, imaging and pathology assessments, hepatologist’s consultancy; obtaining more 
detailed history of symptoms and prior or concurrent diseases, history of concomitant drug use, 
exclusion of underlying liver disease. 
 
 
16.3 
Appendix 3: Specific Renal Alert Criteria and Actions and Event 
Follow-up 
Guidance on monitoring patients with elevated blood pressure: Patients who have at least two 
out of the three sitting readings of blood pressure (systolic BP ≥ 140 and/or diastolic BP ≥ 90 
mmHg) should be followed up in one month by an unscheduled visit if the scheduled visit is 
not due. Should systolic BP ≥ 140 and/or diastolic BP ≥ 90 mmHg values will be confirmed 
in two sitting readings out of three in the second visit, the patient should be referred to his 
primary care physician, an independent internist or to the specialty hypertension clinic for 
evaluation, diagnosis and treatment of hypertension. A standard referral letter provided by 
Novartis should explain a reason for referral and the information about the investigational 
drug (BAF312). 
Patients with BP values of >180/110 mmHg on any visit during the study should be 
immediately referred to evaluation, diagnosis and treatment of hypertension. 
The study drug should not be discontinued, unless the physician has a reason to do so. 
A newly diagnosed hypertension as well as an aggravation of a preexisting condition must 
be reported as an AE. 
Guidance on monitoring of patients with notable lymphopenia: The absolute total WBC, 
neutrophil and lymphocyte counts will be measured at each visit by the central laboratory. If 


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the circulating lymphocyte level drops to <0.2 x109/L when the patient is receiving the 
minimum study drug dose allowed in the study protocol, the lymphocyte count should be 
repeated in one week by the central lab to confirm the reading. If the repeat test confirms the 
lymphocyte count is below 0.2x109/L or 200 cells/mm3, the study drug must be interrupted 
and the lymphocytes count needs to be monitored weekly until the level returns to 0.2 x 109/L, 
then monthly until the level reaches 0.6x109/L values. The patient should be continuously 
evaluated and monitored for infections. 
Re-initiation of the study drug can only be considered once the lymphocyte counts increase 
above 0.6x109/L. 
Guidance on monitoring of patients with symptoms of neurological deterioration inconsistent 
with MS course: Should a patient develop any unexpected neurological or psychiatric 
symptom/signs in the opinion of investigator (e.g. cognitive deficit, behavioral changes, 
cortical visual disturbances or any other neurological cortical symptoms/signs any 
symptom/sign suggestive of an increase of intracranial pressure) or accelerated neurological 
deterioration, the investigator should schedule a complete physical and neurological 
examination as soon as possible before beginning any treatment. 
Guidance on monitoring of patients with infections: All infections that develop during the 
study will be reported as AEs on the respective AE eCRF pages. Treatment and additional 
evaluations will be performed at discretion of the investigator. 
The investigator should remind the patient of the risk of infections and instruct them to 
promptly report any symptoms of infections to the investigator. The patients must also be 
reminded to always carry their Patient Information Card (with site contact information and 
which identifies them as participants in a clinical study with an investigational agent with 
potential immunosuppressive effects) and to show this to any local healthcare provider they 
may consult and ask that the Primary Treating Physician be contacted. 
In the case of suspected or confirmed serious or atypical infection, BAF312 treatment 
interruption should be considered. The investigator should inform the Novartis Medical 
Advisor of any such cases. The elimination half-life of approximately 30 hours allows 
washout of the compound within a week. 
When evaluating a patient with a suspected infection, the most sensitive tests available should 
be used (i.e. that directly detect the pathogen, as with PCR). 
The investigator should consider early treatment with specific antimicrobial therapy on the 
basis of clinical diagnosis or suspicion thereof (e.g. antiviral treatment for herpes simplex or 
zoster) in consultation with infectious disease experts, as appropriate. The investigator should 
inform the Novartis Medical Advisor of any such cases. 
Investigators should consider the added immunosuppressive effects of corticosteroid therapy 
for treatment of MS attack/relapse and increase vigilance regarding infections during such 
therapy and in the weeks following administration. 


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16.4 
Appendix 4: List of generic names of potent inhibitors/inducers 
of CYP2C9/CYP3A4 
The aim of this document is to provide a specific list of drugs that should not be co- 
administered with siponimod, and a list of drugs that should only be used with additional 
vigilance. 
Due to the constant information arising on drugs, these lists are by no mean exhaustive and 
medical judgment should always prevail. These lists are adapted to the patient population and 
the exclusion criteria of the CBAF312AUS02. 
Siponimod is extensively metabolized, mainly via CYP2C9 (79.3%), followed by CYP3A4 (18.5%). 
CYP2C9 is polymorphic and the genotype influences the fractional contributions of the two oxidative 
metabolism pathways to overall elimination. Physiologically based PK modeling indicates a differential 
CYP2C9 genotype-dependent inhibition and induction of CYP3A4 pathways. With decreased CYP2C9 
metabolic activity in the respective genotypes, a larger effect of the CYP3A4 perpetrators on siponimod 
exposure is anticipated. 
Because of a significant increase in exposure to siponimod, concomitant use of siponimod and 
drugs that cause moderate CYP2C9 and moderate or strong CYP3A4 inhibition is not allowed. 
This concomitant drug regimen can consist of a moderate CYP2C9/CYP3A4 dual inhibitor (e.g., 
fluconazole) or a moderate CYP2C9 inhibitor in combination with a separate - moderate or 
strong CYP3A4 inhibitor. Caution should be exercised for concomitant use of siponimod with 
moderate CYP2C9 inhibitors. 
Because of a significant decrease in siponimod exposure, concomitant use of siponimod and drugs that 
cause moderate CYP2C9 and strong CYP3A4 induction is not allowed for all patients. This concomitant 
drug regimen can consist of moderate CYP2C9/strong CYP3A4 dual inducer (e.g., rifampin or 
carbamazepine) or a moderate CYP2C9 inducer in combination with a separate strong CYP3A4 inducer. 
Caution should be exercised for concomitant use of MAYZENT with moderate CYP2C9 inducers. 
 
Table 16-3 
Dual moderate CYP2C9/strong or moderate CYP3A4 inhibitors 
 
Fluconazole 
 
 
Table 16-4 
Moderate CYP2C9 inhibitors 
 
Phenybutazone 
Oxandrolone 
Milk thistle 
Ataciguat 
AZD1981 
Azapropazone 
Tienilic acid 
Piperine 
Bucolome 
Fluconazole 
amiodarone 
Benzbromarone 
 
 
Table 16-5 
Strong CYP3A4 inhibitors 
 
Viekira Pak 
Elvitegravir/ritonavir 
Telithromycin 
Indinavir/ritonavir 
Saquinavir/ritonavir 
Grapefruit juice DS 


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Tipranavir/ritonavir 
Lopinavir/ritonavir 
Ceritinib 
Ritonavir 
Itraconazole 
Conivaptan 
Cobicistat 
Voriconazole 
Nefazodone 
Ketoconazole 
Mifepristone 
Nelfinavir 
Indinavir 
Mibefradil 
Saquinavir 
Troleandomycin 
LCL161 
Ribociclib 
Telaprevir 
Clarithromycin 
Idelalisib 
Danoprevir/ritonavir 
Posaconazole 
Boceprevir 
 
 
Table 16-6 
Moderate CYP3A4 inhibitors 
 
Erythromycin 
GSK2647544 
Grapefruit juice 
Fluconazole 
Aprepitant 
Tofisopam 
Atazanavir/ritonavir 
Casopitant 
Cyclosporine 
Darunavir 
Amprenavir 
ACT-178882 
Diltiazem 
Faldaprevir 
Ciprofloxacin 
Darunavir/ritonavir 
Imatinib 
Magnolia vine (Schisandra 
sphenanthera) 
Dronedarone 
Verapamil 
Isavuconazole 
Crizotinib 
Ravuconazole 
Cimetidine 
Atazanavit 
Nutepitant 
FK1706 
Letermovir 
Nilotinib 
 
 
Table 16-7 
Dual moderate CYP2C9/moderate or strong CYP3A4 inducers 
 
Rifampin 
Enzalutamide 
 
 
Table 16-8 
Moderate CYP2C9 inducers 
 
Rifampin 
Enzalutamide 
Ritonavir 


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Table 16-9 
Strong CYP3A4 inducers 
 
Rifampin 
Carbamazepine 
Mitotane 
Enzalutamide 
Avasimibe 
St John’s Wort extract 
Rifapentine 
Lumacaftor 
Apalutamide 
Rifabutin 
Phenytoin 
Phenobarbital 
 
 
Table 16-10 
Moderate CYP3A4 inducers 
 
Ritonavir and St John’s Wort 
Nafcillin 
Semagacestat 
Talviraline 
Efavirenz 
Lopinavir 
Tipranavir and ritonavir 
Daclatasvir and asunaprevir and beclubuvir 
Dabrafenib 
Modafinil 
Lesinurad 
PF-06282999 
Bosentan 
Etravirine 
Genistein 
Lersivirine 
Thioridazine 
Telotristat ethyl 
 
 
*Source: University of Washington, Drug Interaction Database (www.druginteractioninfo.org). 


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16.5 
Appendix 5: Assessing Immunity to Varicella 
(https://www.cdc.gov/chickenpox/hcp/immunity.html) 
 
Evidence of immunity to varicella includes any of the following: 
Documentation of age-appropriate varicella vaccination; 
• Preschool-age children (i.e., age 12 months through 3 years): 1 dose 
• School-age children, adolescents, adults: 2 doses 
• Laboratory evidence of immunity or laboratory confirmation of disease 
• Birth in the United States before 1980 (Should not be considered evidence of immunity 
for health care personnel, pregnant women, and immunocompromised persons) 
• Diagnosis or verification of a history of varicella or herpes zoster by a health care provider 
To verify a history of varicella, health care providers should inquire about: 
• an epidemiologic link to another typical varicella case or to a laboratory confirmed case, 
or 
• evidence of laboratory confirmation, if testing was performed at the time of acute disease 
Persons who have neither an epidemiologic link nor laboratory confirmation of varicella should 
not be considered as having a valid history of disease. For these persons, a second dose of 
vaccine is recommended if they previously received only one dose. If a health care provider 
verifies the diagnosis based on the above criteria, then vaccination is not needed 
 
 
16.6 
Appendix 6: Teriflunomide Accelerated Elimination Program (for 
patients treated with teriflunomide at screening or within 8 
months prior to screening) 
All patients treated with teriflunomide at screening or within 8 months prior to screening should 
undergo accelerated teriflunomide elimination program. This can be done anytime during the 
Screening Period if a switch in therapy for the patient is imminent or during the Treatment 
Period, Visit 1, after all inclusion criterion are met by the patient. 
Recommended rapid elimination procedure is the administration of oral cholestyramine 8 g 
three times per day for 11 days. If patients do not tolerate this regimen, then the dosage may 
be reduced to 4 g three times per day. Teriflunomide levels are not required for this study 
however could be completed as part of standard of care. 
If tolerability issues persist, cholestyramine administration does not need to occur on 
consecutive days unless there is an acute need to lower teriflunomide levels. 
As an alternative to cholestyramine, oral activated charcoal administered as 50 g twice a day 
for 11 days may be used. 
It needs to be documented in the eCRF which elimination treatment was used. 


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16.7 
Appendix 7: Recommendations for the management of 
bradycardia 
Initiating treatment results in a decrease in HR. If any of the following abnormalities are present 
after 6 hrs. (even in the absence of symptoms), additional monitoring should be conducted: 
• Day 1: HR 6 hrs. post-dose <45 bpm 
If post-dose symptomatic bradycardia, bradyarrhythmia, or conduction related symptoms occur, 
or there is evidence of new-onset second-degree or higher AV block or QTc ≥500 msec, initiate 
appropriate management; monitor ECG and symptoms until resolved if no pharmacological 
treatment is required. 
The study site personnel should be particularly mindful of patients who have a low pulse at 
baseline (spontaneously or through drug-induced ß-receptor blockade), prior to administration 
of the study drug. A cardiologist should be consulted if needed. 
Atropine (subcutaneous or intravenous) is recommended as the first-line treatment of 
bradycardia, up to a maximum daily dose of 3 mg. 
Furthermore, the common guidelines for treatment of bradycardia (e.g. ACLS guidelines) 
should be followed as appropriate: 
• In case of clinical symptoms of bradycardia, administration of atropine 1 mg, with 
repeated administration in 3-5 minutes is recommended. 
• If heart rate and/or blood pressure remain unresponsive, consider administration of 
dopamine drip 5-20 ug/kg/min or epinephrine drip 2-10 ug/min. 
• Transcutaneous pacing may also be considered. 
• In the setting of decreased blood pressure, isoproterenol should be avoided or used with 
caution. 
• If a patient requires treatment for bradycardia/bradyarrhythmia during the first dose, the 
patient should be hospitalized for overnight monitoring and this monitoring procedure 
should be repeated for the second dose of study drug. 


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16.8 
Appendix 8: Guidelines for Ophthalmic examination and 
management of Macular Edema 
A complete ophthalmic examination and Optical Coherence Tomography (OCT) assessment 
are scheduled at baseline (Day 1) and Visit 4 (Day 84), as indicated in the assessment schedules 
for both CP study assessments (Table 8-1). 
 
This appendix provides details of the ophthalmic examination requirements in the study. 
 
A standard visual acuity chart with equal space between letters and between lines should be 
used for the visual acuity assessment. As noted in Section 8.4.5., the OCT machine used should 
preferably not be changed during the course of the study to allow for comparison of central 
foveal thickness within each patient across time points. 
(1) Ophthalmic monitoring for general MS population Baseline visit: 
At the baseline visit this eye examination will include; 
• ophthalmic history 
• best corrected visual acuity measurement 
• ophthalmoscopy (may include contact lens biomicroscopy to examine the macula and 
optic disc). 
• measurement of central foveal thickness by OCT (required for all patients regardless of 
the results of visual acuity or ophthalmoscopy). 
N.B. Ophthalmic findings should be recorded. 
 
If there is a suspicion of macular edema by ophthalmoscopy and increased central foveal 
thickness by OCT, then a fluorescein angiogram may be performed (at the discretion of the 
ophthalmologist). Patients with diagnosed macular edema at baseline should discontinue from 
the study. 
 
Visit 4 
At scheduled study visits the eye examination will include; 
• ophthalmic history 
• best corrected visual acuity measurement 
• ophthalmoscopy (may include contact lens biomicroscopy to examine the macula and 
optic disc). 
• measurement of central foveal thickness by OCT (required for all patients regardless of 
the results of visual acuity or ophthalmoscopy). 


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N.B. Ophthalmic findings should be recorded. 
 
During the study if there are complaints of decreased vision or identification of worsening visual 
acuity (equal to or more than two lines on a standard eye chart using best corrected vision) then 
an unscheduled ophthalmic exam should be performed at which the eye examination will 
include; 
• best corrected visual acuity measurement 
• ophthalmoscopy (may include contact lens biomicroscopy to examine the macula and 
optic disc). 
• measurement of central foveal thickness by OCT 
N.B. Ophthalmic findings should be recorded. 
 
The OCT can be performed by referring ophthalmologists or neurologists with clinical training 
and expertise to assess structural measurement of retinal nerve fiber layer thickness, optic nerve 
head, and macular anatomy AND currently possess appropriate OCT equipment in-office. 
 
In case of suspected macular edema based on the ophthalmoscopy or if a relevant increase of 
central foveal thickness is observed, then a fluorescein angiogram may be performed to 
diagnose and characterize macular edema (at the discretion of the ophthalmologist), if present. 

SAP_001.pdf: 


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Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason 
for update 
Outcome for update 
Section and title 
impacted 
(Current) 
25-01-
2019 
Prior 
to 
DB 
lock 
Creation of 
final SAP 
N/A - First version 
NA 
30-
August-
2022 
Prior 
to DB 
lock 
Protocol 
v05 
Amendment 2.0 
Section 1, 2 
 


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Table of contents 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 6 
1.1 
Study design............................................................................................................. 6 
 
 7 
1.2 
Study objectives and endpoints ............................................................................... 9 
2 
Statistical methods ............................................................................................................. 10 
2.1 
Data analysis general information ......................................................................... 10 
2.1.1 
General definitions ................................................................................ 10 
2.2 
Analysis sets .......................................................................................................... 12 
2.2.1 
Subgroup of interest .............................................................................. 13 
2.3 
Patient disposition, demographics and other Baseline characteristics ................... 13 
2.3.1 
Patient disposition ................................................................................. 13 
2.3.2 
Demographics and other Baseline characteristics ................................. 14 
2.3.3 
Medical history/current medical conditions .......................................... 14 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 14 
2.4.1 
Study treatment / compliance ................................................................ 14 
2.4.2 
Prior, concomitant and post therapies ................................................... 15 
2.4.3 
Prior MS DMT treatment ...................................................................... 15 
2.5 
Analysis of the primary objective .......................................................................... 15 
2.5.1 
Primary endpoint ................................................................................... 16 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 16 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 16 
2.5.4 
Sensitivity and Supportive analyses ...................................................... 16 
2.6 
Analysis of secondary objectives ........................................................................... 16 
2.6.1 
Secondary endpoints ............................................................................. 16 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 17 
2.6.3 
Handling of missing values/censoring/discontinuations ....................... 17 
2.7 
Safety analyses ....................................................................................................... 17 
2.7.1 
Adverse events (AEs) ............................................................................ 17 
2.7.2 
Serious adverse events .......................................................................... 18 
2.7.3 
Adverse events of special interest / grouping of AEs ........................... 18 
2.7.4 
Deaths .................................................................................................... 19 
2.7.5 
Laboratory data ..................................................................................... 19 
2.7.6 
Other safety data ................................................................................... 21 


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2.7.7 
ECG ....................................................................................................... 21 
2.7.8 
Pregnancy and assessments of infertility .............................................. 21 
2.7.9 
Vital signs.............................................................................................. 21 
2.8 
Pharmacokinetic endpoints .................................................................................... 22 
2.9 
PD and PK/PD analyses......................................................................................... 22 
2.10 
Patient-reported outcomes ..................................................................................... 22 
 
 23 
 
 23 
 
 23 
 
 24 
 
 24 
 
 24 
 
 24 
 
 24 
2.13 
Interim analysis ...................................................................................................... 24 
2.14 
Sample size calculation .......................................................................................... 25 
3 
Change to protocol specified analyses .............................................................................. 25 
4 
Appendix ........................................................................................................................... 25 
4.1 
Imputation rules ..................................................................................................... 25 
4.1.1 
Study drug ............................................................................................. 25 
4.1.2 
AE date imputation ............................................................................... 25 
4.1.3 
Concomitant medication date imputation ............................................. 26 
4.2 
AEs coding/grading ............................................................................................... 28 
4.3 
Laboratory parameters derivations ........................................................................ 28 
4.4 
Refer to the main sections in SAP Statistical models ............................................ 28 
4.4.1 
Primary analysis .................................................................................... 28 
4.4.2 
Key secondary analysis ......................................................................... 28 
4.5 
Rule of exclusion criteria of analysis sets.............................................................. 28 
5 
Reference ........................................................................................................................... 32 


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List of abbreviations 
 
AE 
Adverse event 
AESI 
Adverse Event of Special Interest 
ARR 
Annualised Relapse Rate 
CSR 
Clinical Study report 
DAR 
Dose Administration Record 
DMT 
Disease Modifying Therapy 
ECG 
Electrocardiogram 
EOS 
End of Study 
eCRF 
Electronic Case Report Form 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
MS 
Multiple Sclerosis 
 
 
 
 
PK 
Pharmacokinetics 
 
 
RMS 
Relapsing Multiple Sclerosis 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMQ 
Standardized MedDRA Query 
SOC 
System Organ Class 
TFLs 
Tables, Figures, Listings 
TSQM-9 
Treatment Satisfaction Questionnaire for Medication  
WHO 
World Health Organization 
 


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1 
Introduction 
This document contains details of the statistical methods which will be used in the phase IIIb 
clinical trial CBAF312AUS02. The statistical analysis described in this SAP is based on the 
study protocol no. BAF312AUS02 Amendment Version 05 and will be presented in the Clinical 
Study Report (CSR). This document will also describe planned analysis for an interim analysis.   
The purpose of this study is to assess early phase safety and tolerability of converting patients 
from approved oral, injectable or infusion RMS DMTs to siponimod. The results of this phase 
IIIb clinical trial CBAF312AUS02 will guide clinically relevant decisions related to the 
transition from frequently used RMS DMTs to siponimod and provide clinically relevant data 
on safety and tolerability for healthcare providers who are considering converting patients from 
currently approved RMS DMT to siponimod.  
1.1 
Study design 
This is a 6-month, open-label, multi-center, single treatment arm design, including 300-400 
advancing RMS patients, evaluating overall safety and tolerability profile when acutely 
converting to siponimod from oral, injectable or infusion RMS DMTs. This study consists of 
two parts: The Screening Period and Core Treatment Period. 
• The patient cohort will be stratified by pre-treatment groups and may include injectable, 
oral or infusion DMTs used in RMS: interferon beta-1a (Avonex®, Rebif®), interferon 
beta-1b (Betaseron®, Extavia®), glatiramer acetate (Copaxone®, generic glatiramer 
acetate), peginterferon beta-1a (Plegridy®), teriflunomide (Aubagio®), fingolimod 
(Gilenya®, including generic forms of fingolimod), dimethyl fumarate (Tecfidera®, 
including generic forms of dimethyl fumarate, Vumerity® (diroximel fumarate)), 
natalizumab (Tysabri®), and ocrelizumab (Ocrevus®). 
• Patients fulfilling the inclusion criteria, including genotyping, will undergo immediate 
conversion (please see below for exceptions) to siponimod, with “immediate” defined 
as cessation of the existing DMT and initiation of siponimod within 24 hours, followed 
by subsequent 5-day dose titration. Per inclusion criteria and screening phase testing 
requirements, fingolimod patients will undergo all required screening and/or Baseline 
testing, including genotyping for CYP2C9*1*1. 
- 
Patients converting specifically from teriflunomide will undergo accelerated elimination 
prior to converting to siponimod over 11-14 days to allow for adequate drug elimination 
and minimize drug-drug interactions, in line with the Aubagio ® USPI. 
- 
Patients converting from fingolimod will immediately convert to siponimod 
maintenance dose of 2mg, with no dose-titration. 
- 
Patients treated with infusion DMT natalizumab (Tysabri®) will undergo at least a 4 
week washout period at the time of consent, prior to converting to dose-titrated 
siponimod. 
- 
Patients treated with infusion DMT ocrelizumab (Ocrevus®) will undergo at least 14 
week washout period at the time of consent, prior to converting to dose-titrated 
siponimod. 


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• All patients initiating siponimod treatment, except those converting from fingolimod, 
will be titrated over 5 days to achieve a maintenance dose of 2mg by Day 6 with the 
following schedule of siponimod: 
 
Figure 1: EXCHANGE study design 
 
 
Approximately 300-400 patients will be enrolled in this study from up to 80 study sites in the 
USA. The study plans to screen approximately 570 patients. 
 
 
Since this is a single arm open-label trial, randomization is not being considered. 
The primary aim of this study is to evaluate the overall safety and tolerability profile of 
siponimod 2 mg in patients with relapsing forms of MS who are converting from existing oral, 
injectable or infusion DMTs. The primary analysis will be performed at Visit 5 i.e. End of 
Study.  
An interim analyses on the safety data will be conducted at the time of approximately 50 patients 
complete their Visit 5 (Day 168).  


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1.2 
Study objectives and endpoints 
 
Objectives 
Endpoints  
Primary 
 
The primary objective is to evaluate overall safety 
and tolerability profile of siponimod in advancing 
RMS patients who are converting from currently 
approved oral, injectable or infusion RMS DMT. 
Occurrence of any study-drug related 
adverse events during 6-month treatment 
period 
Secondary  
 
To evaluate treatment satisfaction with siponimod in 
advancing RMS patients using outcomes based on 
the Treatment Satisfaction Questionnaire for 
Medication (TSQM-9). 
Change from Baseline in the TSQM-9 
To evaluate cardiac safety during siponimod 
treatment initiation 
• 
Change from Baseline in heart rate to 
6 hours after 1st treatment 
• 
Occurrence of any adverse Events 
• 
Occurrence of hospitalizations 
 
To evaluate treatment persistence with siponimod 
• 
Patient retention 


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2 
Statistical methods 
This section contains information that will be used to draft CSR Section 9.7 on statistical 
analysis. 
2.1 
Data analysis general information 
All data will be analyzed by Novartis using the statistical software SAS version 9.4 or higher 
according to the data analysis Section 12 of the study protocol, which is available in Appendix 
16.1.1 of the CSR.  Important information is given in the following sections and details are 
provided, as applicable, in Appendix 16.1.9 of the CSR. 
In general, for continuous data, number of observations, mean, standard deviation, minimum, 
25th percentile, median, 75th percentile, and maximum will be presented. Categorical data will 
be presented as frequencies and percentages. 
2.1.1 
General definitions  
2.1.1.1 Study treatment 
The investigational drug siponimod is formulated in film coated tablet, which contains 0.25mg, 
0.5mg, 1.0mg and 2.0mg siponimod as siponimod fumaric co-crystal (active ingredient). 
All eligible patients in the core treatment period will start the treatment with a 5-day dose 
titration pack continuing to a maintenance dose of 2.0 mg.  
Patients on fingolimod enrolled on / after Amendement 3 of the protocol, will directly start with 
the maintenance dose. Therefore, patients on fingolimod will have 2 groups: 
1. Fingolimod with titration dose (patients enrolled in the Protocol versions 0, 1 and 2) 
2. Fingolimod with direct maintenance dose (patients enrolled in  Amendment 3 or after). 
 
Figure 2 Siponimod Target Daily Dose 
Treatment Schedule for All Pre-treatment 
groups (including Fingolimod under Protocol Version 0,1 and 2): 
 
Titration Dose 
Day of Treatment 
Target Dose 
1 
0.25 mg 
2 
0.25 mg 
3 
0.5 mg 
4 
0.75 mg 
5 
1.25 mg 
Maintenance Dose 
Day of Treatment 
Target Dose 
6 and beyond 
2 mg 
 
 


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Treatment Schedule for  
Fingolimod Patients (enrolled in Amendment 3 or after): 
 
Maintenance Dose Only 
Day of Treatment 
Target Dose 
1 and beyond 
2 mg 
 
2.1.1.2 Study day 
Study day is defined with respective to the first day on which treatment with Siponimod starts. 
The date of first administration of study medication is defined as Day 1 and the day before is 
defined as Day -1.  
Therefore, for any particular date, study day will be calculated as follows: 
• 
For dates on or after the first date of study medication administration, 
Study day = Assessment date – Date of first administration of study medication + 1; 
• 
For dates prior to the first date of study medication administration, 
Study day = Assessment date – Date of first administration of study medication. 
2.1.1.3 Baseline definition 
Baseline visit (Visit 1) is defined as the day on which patients start with their first dose of 
Siponimod. 
Baseline is defined as the last measurement on or prior to Baseline visit. 
Post-Baseline assessments 
Post-Baseline values are defined as assessments taken after the start of study treatment.  
When change from Baseline is of interest, the following formula will be for each scheduled 
visit and time-point where Baseline and post-Baseline values are both available:  
Change from Baseline = Post-Baseline value – Baseline value. 
2.1.1.4 Visit Window 
Visit-windows will be used for the data that is summarized by visit; they are based on the study 
evaluation schedule and comprise a set of days around the nominal visit day. For any 
assessment, there are the protocol defined scheduled visits around which visit windows were 
created to cover the complete range of days within the study.  The visit windows are shown in 
Table 1. These apply to measurements taken at every visit. For assessments collected less often 
different visit windows will be applied as detailed below. 
When visit windows are used, all visits will be re-aligned, i.e., they will be mapped into one of 
the visit windows. E.g., if the Week 4 visit of a patient is delayed and occurs on Day 46 instead 
of on Day 29, say, it will be re-aligned to visit window Week 8. In the case of major deviations 
from the visit schedule, or due to unscheduled visits, several assessments of a patient may fall 


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in a particular visit window (either scheduled or unscheduled). Statistical approaches to handle 
multiple assessments in a given visit window are specified below. 
Of note, patients are allowed to have gaps in visits. 
Table 1 
Assessment windows for scheduled visits 
 
Visit Name 
Days 
Scheduled 
Day of Visit 
Visit Window 
Screening 
-28 Days 
-28 
-28 days to Day 1* 
Baseline (Visit 1) 
Day 1 
1 
Day 1 - 4 
Visit 2 
Day 7 
7 
             Day 5 - 18 
Visit 3 
Day 28 
28 
             Day 19 - 56 
Visit 4 
       Day 84 
84 
      Day 57 - 126  
Visit 5/EOS 
 Day 168 
168 
             Day 127 - 183 
Follow up visits 
Follow up visits 
198 
             Day 184 -  205 
Day 1*: refers to the day 1 before dose administration. 
For parameters which are not collected at every visit, visit windows defined in Table 1 will be 
combined. For example, if a parameter is measured at Day 28 and Day 84 only, Day 28 visit 
window will extend from Day 5 to Day 56 (combining Day 7 to Day 28 visit windows). If more 
than one assessment falls into the interval, the rules defined in Section 2.1.1.5 below are applied. 
2.1.1.5 Multiple assessments within visit windows 
When there are multiple assessments in a particular visit window, the following rules are applied 
to select one value “representing” the patient in summary statistics in a visit window (See Table 
1 ). 
For Baseline assessment, definition see Section 2.1.1.3. For post-Baseline visit windows the 
following applies (unless otherwise specified): 
• For quantitative variables, the closest to the actual visit is chosen (if two assessments have 
the same distance, then the earlier one will be chosen);  
• For qualitative variables, the worst record is selected. It is noted that in the analyses 
performed, worst case is always well defined. 
In case qualitative variables are based on quantitative variables, the visit will be assigned to the 
quantitative variable, and this visit will be used for the derived qualitative variable. 
 
 
2.2 
Analysis sets 
Safety set: The Safety Set includes all patients who received at least one dose of study 
treatment. 
All analyses will be performed using the Safety Set. 




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• Patient Not Withdrawn As Per Protocol - Withdrawal criteria met but patient not 
withdrawn 
• Treatment Deviation - Wrong treatment or incorrect dose 
• Prohibited concomitant medication 
• Other 
2.3.2 
Demographics and other Baseline characteristics 
The following common background, demographics and Baseline characteristics data will be 
analyzed as described below: 
Continuous variables: 
• Age (which is derived from date of birth and the screening assessment date) 
• Height (cm) 
• Weight (kg) 
• Body Mass Index (BMI) 
Categorical variables: 
• Age group (< =30 years, 31 - <= 40 years, 41 - <=50 years, 51 - <=60 years, > 
60 years) 
• Gender 
• Race 
• Ethnicity 
Multiple Sclerosis History and the expanded disability status scale will also be presented with 
all the parameters collected according to the eCRF.  
The above characteristics will be repeated on the required subgroups.  
Unless otherwise specified, summary statistics will be presented for continuous variables for  
all patients (total) in the safety set.  The number and percentage of patients in each category 
will be presented for categorical variables for all patients (total) in the safety set. 
2.3.3 
Medical history/current medical conditions 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
terminology (MedDRA, current version at database lock). History/conditions and current 
medical conditions at Baseline will be summarized for the safety set by primary system organ 
class and preferred term, and overall. Verbatim recorded history/conditions will be listed 
together with the coded terms, date of diagnosis/surgery and whether the problem was ongoing 
at start of the study.  
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
Duration of exposure to the study treatment (siponimod) will be calculated as the number of 
days exposed to the treatment with siponimod over the specified period (expressed as: 


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Duration of exposure = last known date of siponimod administration  –  first known date of 
siponimod administration  + 1). 
The duration of exposure (in days) will be summarized for the safety set as:  
• a continuous variable with the standard descriptive statistics, and  
• a categorical variable classified into <=4 weeks, >4 to <=8 weeks, >8 to <=12 weeks, >12 
to <=16 weeks, >16 to <=20 weeks and >20 to <=24 weeks. 
A data listing of the drug doses administered by patients will be provided. 
Investigator reported compliance from eCRF 
Compliance will be calculated based on the DAR data. Compliance data will be summarized 
descriptively as a continuous and categorical variable. 
The number and percentages of patients in each of the compliance categories mentioned in the 
eCRF, i.e., Poor (< 25%), Average (≥ 25% to < 50%), Good (≥ 50% to <75%), Very good (≥ 
75% to ≤100%) and Overdose or misuse (>100%) will be summarized. In case of over 
compliance (> 100%) the reason will be listed. 
The compliance will be provided for overall study period, titration and maintenance phase.  
The exposure will be presented for the overall population along with the subgroups, if needed.  
2.4.2 
Prior, concomitant and post therapies 
Each medication has the start and end dates recorded. Prior medications are defined as those 
medications which were taken and stopped prior to the first dose of study drug. Concomitant 
medications are defined as those medications which were taken on or after the first dose of 
study drug but not prior to the first dose of study drug. Prior/concomitant medications are 
defined as those medications which were taken prior to and continued after the first dose of the 
study drug. All prior and concomitant medications will be summarized by primary system organ 
class and preferred term. All prior/concomitant medications will be summarized as concomitant 
medications, and will not be included in prior medication outputs.  
Surgical and medical procedures (non-drug therapies) will be summarized by primary system 
organ class and preferred term. All summaries will be on the safety set. 
2.4.3 
Prior MS DMT treatment 
Number and percentage of patients on prior MS DMT treatments will be presented. Along with 
the number and percentage, the duration of previous MS DMTs before switching to Siponimod 
will also be presented. The MS DMT information will also be repeated on the subgroups if 
needed.  
2.5 
Analysis of the primary objective 
The primary objective is to evaluate overall safety and tolerability profile of siponimod in 
advancing RMS patients who are converting from currently approved oral, injectable or 
infusion RMS DMTs. 
The primary aim of this study is to evaluate the overall safety and tolerability profile of 
siponimod 2mg in patients with relapsing forms of MS. 


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2.5.1 
Primary endpoint 
The primary endpoint is the occurrence of any study drug related treatment emergent adverse 
events during 6-month treatment period.   
2.5.2 
Statistical hypothesis, model, and method of analysis 
The number (and percentage) of patients with treatment emergent adverse events suspected to 
be related to study medication will be summarized by primary system organ class and preferred 
term.  
The 95% exact binomial confidence interval for the overall rate of adverse event suspected to 
be related to study medication will be calculated. 
A patient with multiple adverse events within a category (overall, primary system organ class, 
or preferred term) is only counted once towards the total of that category. 
The analysis of the primary variable will also be stratified by prior MS DMTs. Along with the 
overall treament emergent adverse events suspected to be related to study medication, a 
subgroup analysis by prior MS DMTs will also be provided.   
Analysis of primary endpoint will be based on the Safety Set. 
No formal hypothesis is being tested for the primary endpoint.  
2.5.3 
Handling of missing values/censoring/discontinuations 
No missing data will be imputed. All analyses will be using observed-case approach.  
2.5.4 
Sensitivity and Supportive analyses 
Neither sensitivity analysis nor supportive analysis is planned for the study.  
2.6 
Analysis of secondary objectives 
The following are the secondary objective(s) planned for the study: 
1. To evaluate treatment satisfaction with siponimod in advancing RMS patients using 
outcomes based on the Treatment Satisfaction Questionnaire for Medication (TSQM-
9). 
2. To evaluate cardiac safety during siponimod treatment initiation 
3. To evaluate treatment persistence with siponimod 
All secondary analyses will also be based on the Safety Set. 
2.6.1 
Secondary endpoints 
2.6.1.1 Treatment Satisfaction Questionnaire for Medication (TSQM-9) 
Please refer to Section 2.10 for details.  
2.6.1.2 Change from Baseline in heart rate 
The change from Baseline in heart rate to 6 hours after 1st treatment will be summarized by  
number of observations, mean, standard deviation, minimum, 25th percentile,  median, 75th 
percentile, and maximum.  


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The above analysis will also be performed on the subgroup of prior MS DMTs.  
2.6.1.3 Occurrence of any adverse events 
Refer to Section 2.7.1 for details on the occurrence of any adverse events.  
2.6.1.4 Occurrence of hospitalizations 
Summary statistics will be provided for number of hospitalizations per patient occurred during 
treatment period. Number and percentages of patients having at least one hospitalization during 
treatment period will be provided.  
2.6.1.5 Patient retention 
The number of patients who complete the study will comprise patient retention. Number (and 
percentage) of patients completed study will be provided. Number of patients who are enrolled 
into the study, continued the study and discontinued the study will be presented.  
2.6.2 
Statistical hypothesis, model, and method of analysis 
No formal hypothesis is being tested for the secondary endpoint.  
2.6.3 
Handling of missing values/censoring/discontinuations 
No missing data will be imputed.  
2.7 
Safety analyses 
All safety analyses will be based on the Safety Set. Subgroup analysis will be performed on the 
AE tables as required.  
2.7.1 
Adverse events (AEs) 
The number (and percentage) of patients with treatment emergent adverse events (events 
started after the first dose of study medication to 30 days after the date of the last actual 
administration of any study treatment or events present prior to start of treatment but 
increased in severity based on preferred term) will be summarized. 
 
AEs will be listed separately.  
 
Adverse events by System Organ Class and Preferred Term 
All adverse events starting on or after the first treatment will be coded utilizing the MedDRA 
version xx (during the database lock) dictionary, tabulated, and analyzed by primary system 
organ class and preferred term. 
Primary system organ classes will be sorted alphabetically and, within each primary system 
organ class, the preferred terms will be sorted in descending order of frequency.  
If a patient reported more than one adverse event with the same preferred term, the adverse 
event will be counted only once. If a patient reported more than one adverse event within the 
same primary system organ class, the patient will be counted only once at the system organ 
class level. 
All adverse events will also be summarized by Standardized MedDRA Query (SMQ) and 
preferred term.  


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AEs by severity 
All adverse events will be summarized by maximum severity, primary system organ class and 
preferred term. If a patient reports more than one adverse event within the same primary system 
organ class, only one adverse event will be counted for that patient at the highest severity level 
in the total row for each primary system organ class. If a patient reported more than one adverse 
event with the same preferred term, the highest (maximum) severity will be presented. Missing 
severity will be assumed to be severe in the summary table. 
AEs leading to permanent study drug discontinuation 
Treatment emergent adverse events leading to permanent study drug discontinuation, regardless 
of study drug relationship, will be summarized by primary system organ class and preferred 
term. 
AEs requiring dose adjustment or interruption 
Treatment emergent adverse events requiring dose adjustment or interruption, regardless of 
study drug relationship, will be summarized by primary system organ class and preferred term. 
AEs requiring occurrence of hospitalization 
Treatment emergent adverse events leading to hospitalization, regardless of study drug 
relationship, will be summarized by primary system organ class and preferred term. 
Number of hospitalizations 
Summary statistics using frequency and percentage will be provided for number of 
hospitalizations per patient occurred during treatment period.  
 
  
2.7.2 
Serious adverse events 
Number and percentage of patient with serious adverse events, regardless of study drug 
relationship, will be presented by primary system organ class and preferred term. 
SAEs will also be listed separately. 
2.7.3 
Adverse events of special interest / grouping of AEs 
The number (and proportion) of patients with adverse events of special interest/related to 
identified and potential risks will be summarized by primary system organ class and preferred 
term.  
The following will be considered as an AESI for the study: 
1. Infections and Infestations (VZV infections, herpes virus infections),  
2. Bradyarrhythmia/bradycardia,  
3. Elevated liver functions tests,  
4. Malignancies (basal cell carcinoma),  
5. Thromboembolic events,  


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6. Convulsions,  
7. Macular edema,  
8. Bronchoconstriction, 
9. Hypertension 
2.7.4 
Deaths 
A listing for death including on treatment and post treatment deaths will be provided. The on-
treatment period lasts from the date of first administration of study treatment to 30 days after 
the date of the last actual administrations of any study treatment.  
2.7.5 
Laboratory data 
The summary of laboratory evaluations will be presented for the following groups of laboratory 
tests (hematology, clinical chemistry, serology, CYP2C9 Testing and 
 
). Descriptive summary statistics for the change from Baseline to each study visit will 
be presented in the tabular form.  
All laboratory data will be listed by patient and visit/time and if normal ranges are available 
abnormalities will be flagged.  
In addition, shift tables will be provided for all parameters to compare a patient’s Baseline 
laboratory evaluation relative to the visit’s observed value.  For the shift tables, the normal 
laboratory ranges will be used to evaluate whether a particular laboratory test value was normal, 
low, or high for each visit value relative to whether or not the Baseline value was normal, low, 
or high. 
 
The following laboratory parameters will be analyzed:  
 
Hematology will include red blood cell count, total and differential WBC count 
(basophils, eosinophils, lymphocytes, monocytes, neutrophils), platelet count, hemoglobin, 
hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration and red blood cell morphology. 
 
Clinical Chemistry will include electrolytes (Na, K, Cl, bicarbonate, Ca, Mg, P), random 
glucose, albumin, alkaline phosphatase, creatinine, ALT, AST, GGT, amylase, total bilirubin, 
conjugated bilirubin, total cholesterol, CRP, triglycerides, HDL and LDL. 
 
Shift tables using the low/normal/high/ (low and high) classification will be used to compare 
Baseline to the worst on-treatment value. 
 


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Table 2 
Criteria for notable abnormalities 
Laboratory Variable  
SI Units 
Standard Units 
LIVER FUNCTION AND RELATED VARIABLES 
SGOT (AST) 
>82 U/L 
>82 U/L 
SGPT (ALT) 
>90 U/L 
>90 U/L 
Gamma Glutamyltransferase 
(GGT) 
> 130 U/L 
> 130 U/L 
Bilirubin (total) 
>= 2.0 mg/dL 
>= 34.2 mol/L 
Alkaline phosphatase, serum 
>280 U/L 
>280 U/L 
RENAL FUNCTION / METABOLIC AND ELECTROLYTE VARIABLES 
Glucose 
>= 200 mg/dL 
>= 11.11 mmol/L 
Creatinine 
>= 2.0 mg/dL                          
>= 176 umol/L 
Amylase 
>= 300 U/L 
>= 300 U/L 
Cholesterol (total) 
>= 240 mg/dL 
>= 6.21 mmol/L 
Triglycerides 
>= 300 mg/dL 
>= 3.39 mmol/L 
HEMATOLOGY VARIABLES 
Haemoglobin 
<= 10.0 g/dL 
<= 100 g/L 
Platelet count (direct) 
<= 100 k/mm3 
<= 100 x 109/L 
 
>= 600 k/mm3 
>= 600 x 109/L 
WBC (total) 
<= 2.0 k/mm3 
<= 2.0 x 109/L 
 
>= 15 k/mm3 
>= 15 x 109/L 
HEMATOLOGY VARIABLES: DIFFERENTIAL 
Neutrophils (Seg. + Bands) 
<= 1,000 /mm3 
<= 1 x 109/L 
 
>= 12000/mm3 
>= 12 x 109/L 
Lymphocytes 
< 200/mm3 
< 0.2 x 109/L 
 
>= 8000/mm3 
>= 8 x 109/L 
RBC 
< 3,300,000/mm3 
< 3.3 x 1012/L 
 
> 6,800,000/mm3 
> 6.8 x 1012/L 
                                          
 
 
 
 


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Table 3 
Criteria for abnormal criteria for by visit summaries 
 
Laboratory Variable (unit) 
Criteria 
Albumin (g/L) 
<LLN 
Bilirubin (direct/conjugated)(umol/L))             >ULN 
 
>2xULN 
Gamma Glutamyltransferase (GGT)(U/L)       >ULN 
 
>3xULN 
Glucose (mmol/L)                                             >ULN 
Cholesterol (HDL) (mmol/L) 
>ULN 
Cholesterol (LDL) (mmol/L) 
>ULN 
SGOT (AST) (U/L) 
>ULN 
 
>2xULN 
 
>3xULN 
 
 
SGPT (ALT) (U/L) 
>ULN 
 
>2xULN 
 
>3xULN 
 
>5xULN 
 
 
Cholesterol (total) (mmol/L)                            >ULN 
 
2.7.6 
Other safety data 
2.7.7 
ECG  
Twelve-lead ECGs will be performed for all patients at Screening and will be presented. All 
ECG data will be listed by patient and visit/time, abnormalities will be flagged. Summary 
statistics for observed and change from Baseline will be provided by visit. 
2.7.8 
Pregnancy and assessments of infertility 
For pregnancy, serum/urine test will be performed. Summary for the tests will be presented at 
Baseline and Week 24. 
2.7.9 
Vital signs 
Vital signs measurements include pulse, systolic blood pressure, diastolic blood pressure, 
temperature, body weight and heart rate. The following summaries will be presented on the 
safety set. 
2.7.9.1.1 Summary of absolute values and change from Baseline 


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Vital signs including the changes from Baseline will be summarized at the scheduled visits and 
time points.  
Change in heart rate from Baseline to 6-hour after first treatment will be summarized as the 
secondary endpoint. 
All vital signs data will be listed by patient and visit/time and if ranges are available, 
abnormalities will be flagged. 
2.7.9.1.2 Notable absolute values and change from Baseline 
The number and percentage of patients with newly occurring or worsening notable values, 
including notable change from Baseline, will be summarized by vital sign parameter and post-
Baseline visit. An additional section will be included for abnormalities occurring at any time 
point over the treatment period, considering all post-Baseline data from scheduled, unscheduled 
and premature discontinuation visits. Notable absolute values and notable changes from 
Baseline for each vital sign parameter are defined in the Table 4 : 
Table 4 Criteria for notable vital sign abnormalities 
 
Vital Sign Variable 
 Notable Criteria 
Pulse (beats/min) 
>120 bpm Or < 50 bpm 
Systolic BP (mmHg) 
≥ 160 mmHg Or ≤ 90 mm Hg 
Diastolic BP (mmHg) 
≥ 100mmHg Or  ≤ 50 mmHg 
Temperature (°C) 
>38.3 °C/ 101°F 
Body weight (kg) 
± 7% from Baseline weight 
2.8 
Pharmacokinetic endpoints   
Not Applicable.  
2.9 
PD and PK/PD analyses 
Not Applicable. 
2.10 
Patient-reported outcomes 
Treatment Satisfaction Questionnaire for Medication (TSQM-9) will be assessed as a PRO for 
the study.  
The Treatment Satisfaction Questionnaire for Medication (TSQM-9) will be used to 
psychometrically evaluate the patients’ satisfaction with Siponimod. The TSQM-9 is a sound 
and valid measure of the major dimensions of patients’ satisfaction with medication and a good 
predictor of adherence across different types of medication and patient population. 
With the TSQM-9, scale scores are calculated by adding the items loading on each dimension. 
The lowest possible score is subtracted from this composite score and divided by the greatest 
possible score minus the lowest possible score. This provides a transformed score between 0 
and 1 that should be multiplied by 100.   
 




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2.13 
Interim analysis 
For the purpose of earlier dissemination, an interim analysis on the safety data will be conducted 
at the time of approximately 50 patients completing their Visit 5 (Day 168). 




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If YYYY<TRTY and MON<TRTM, then AE start date=15-MON-YYYY which is prior to 
start of trt 
If YYYY<TRTY and MON=TRTM, then AE start date=15-MON-YYYY which is prior to 
start of trt 
If YYYY<TRTY and MON>TRTM, then AE start date=15-MON-YYYY which is prior to 
start of trt 
If YYYY=TRTY and MON missing, then AE start date=TRTSTDT+1  
If YYYY=TRTY and MON<TRTM, then AE start date=15-MON-YYYY which is prior to 
start of trt 
If YYYY=TRTY and MON=TRTM, then AE start date=max (1-MON-YYYY, TRTSTDT 
+1) 
If YYYY=TRTY and MON>TRTM, then AE start date=max (1-MON-YYYY, TRTSTDT 
+1) 
If YYYY>TRTY and MON missing, then AE start date=1-JAN-YYYY  
If YYYY>TRTY and MON<TRTM, then AE start date=max (1-MON-YYYY, TRTSTDT 
+1)  
If YYYY>TRTY and MON=TRTM, then AE start date=max (1-MON-YYYY, TRTSTDT 
+1) 
If YYYY>TRTY and MON>TRTM, then AE start date=max (1-MON-YYYY, TRTSTDT 
+1) 
AE END DATE IMPUTATION (CQVA149A2340) 
AE end date = min (last visit date, last know date of contact for discontinued patients, DEC 
31, date of death), if MON is missing and YYYY is present. 
AE end date = min (last visit date, last know date of contact for discontinued patients, last day 
of the Month, date of death), if day is missing, MON and YYYY present. 
 
Impute Date Flag (CQVA149A2340) 
If not a complete date: 
• If year of the imputed date <> YYYY then date flag = Y (not possible since missing dates 
will not be imputed), 
• else if month of the imputed date <> MON then date flag = M, 
• else if day of the imputed date <> day of original date then date flag = D, 
• else date flag = null. 
4.1.3 
Concomitant medication date imputation 
CM start date imputation 
Rules for imputing the CMD start date: 
Here TRTSTDT = treatment start date, 
1.      If the CMD start date year value is missing, the imputed CMD start date is set to 
TRTSTDT-1, if not after the CMD end date. Thus the imputed CMD start date = 
minimum (TRTSTDT-1, CMD end date). 


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2.      If the CMD start date year value is less treatment start date year value, the CMD 
started before treatment start. Therefore: 
a)      If the CMD year is less than treatment start year and the CMD month is 
missing, the imputed CMD start date is set to 01JulYYYY. 
b)      Else if the CMD year is less than the treatment start year and the CMD 
month is not missing, the imputed CMD start date is set to 15MONYYYY. 
      3. If the CMD start date year value is greater than treatment start date year value, the 
CMD started after treatment start. Therefore: 
a) If the CMD year is greater than the treatment start year and the CMD month 
is missing, the imputed CMD start date is set to 01JanYYYY. 
b) Else if the CMD year is greater than the treatment start year and the CMD 
month is not missing, the imputed CMD start date is set to 01MONYYYY. 
      4. If the CMD start date year value is equal to treatment start date year: 
a) If the CMD month is missing or the CMD month is equal to treatment start 
month, then the imputed CMD start date is set to the minimum (TRTSTDT-1, 
CMD end date). 
b) Else if the CMD month is less than the treatment start month, the imputed 
CMD start date is set to 15MONYYYY. 
c) Else if the CMD month is greater than the treatment start month, the 
imputed CMD start date is set to 01MONYYYY. 
 
CMD end date imputing: 
1.      If the CMD end date is completely missing (and "Ongoing at final examination" 
was not answered "Yes"), the CMD end date will be the  
maximum of treatment end date +1 day and CMD start date. 
2.      If a partial CMD end date is reported (day is missing or day and month are 
missing), the CMD end date will be imputed by the maximum  
possible date, i.e.  
        the end of the reported month if day is missing, or  
         the end of the reported year if day and month are missing provided that the 
imputed date is not before the CMD start date,          otherwise CMD end 
date will be equal to CMD start date. 
3. CMTime since first symptoms of AD noticed by patient/caregiver (in years), for the 
partial dates in the data, the dates will be imputed as: 
• If month and year are present, the 1st of the month is considered as the date. For 
example, if March 2015 is present, it will be imputed as 1st March 2015.  
• If only year is present, January will be considered as the month and 1st as the 
date. For example, only 2015 is present, it will be imputed  as 1st January 2015. 
4.1.3.1 
Prior therapies date imputation 
Same as Concomitant medication date imputation. 
4.1.3.2 
Post therapies date imputation 
Same as Concomitant medication date imputation. 


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4.2 
AEs coding/grading 
Latest version of MedDRA will be used.  
4.3 
Laboratory parameters derivations 
4.4 
Refer to the main sections in SAP Statistical models 
4.4.1 
Primary analysis 
Not Applicable 
4.4.2 
Key secondary analysis 
Not Applicable 
4.5 
Rule of exclusion criteria of analysis sets  
The protocol deviations defined for this study are the followings:  
Table 5 Protocol deviations that cause patients to be excluded 


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Deviation 
Code 
Text Description 
Severity/ Analysis 
Classify action Code 
INCL01 
Signed informed consent not obtained prior to 
participation in the study 
49 
INCL02 
ge of patient is not between 18 to 65 years 
(inclusive) at screening 
49 
INCL03 
Patient is not with advancing RMS as defined by the 
principal investigator 
49 
INCL04 
Not having prior history of relapsing MS (RMS), with 
or without progressive features, according to the 
2010 Revised McDonald or Lublin criteria 
49 
INCL05 
Disability status at screening is not defined as 
EDSS score of ≥2.0 to 6.5 (inclusive) 
49 
INCL06 
Not treated with b-interferons, glatiramer acetate, 
fingolimod, dimethyl fumarate, or teriflunomide 3 
months at IC, had last natalizumab 4 wks prior 
SCREEN, or had ocrelizumab 14 wks prior 
SCREEN 
49 
EXCL01 
Patients with an active chronic disease of the 
immune system other than MS or with a known 
immunodeficiency syndrome (AIDS, hereditary 
immune deficiency, drug-induced immune 
deficiency) 
49 
EXCL02 
Pregnant or nursing (lactating) women, where 
pregnancy is defined as the state of a female after 
conception and until the termination of gestation, 
confirmed by a positive Hcg laboratory test 
49 
EXCL03a 
Women of child bearing potential unless using 
highly effective methods of contraception while 
taking study treatment and for 30 days after 
stopping study treatment 
49 
EXCL03b 
Post-menopausal women and not of child bearing 
potential if they had 12 months of natural 
amenorrhea or surgical bilateral oophorectomy, total 
hysterectomy or tubal ligation at least six week ago 
49 
EXCL04 
Sexually active males unwilling to use a condom 
during intercourse while taking study treatment and 
for 30 days (30= 5 times the terminal half-life of 
Siponimod) after stopping study treatment 
49 
EXCL05 
History of malignancy of any organ system other 
than localized basal cell carcinoma of the skin 
treated or untreated within the past 5 years 
regardless of evidence of local recurrence or 
metastases 
49 
EXCL06 
Diabetes mellitus, unless well controlled and without 
known organ complications including but not limited 
to heart disease reduced renal function, significant 
retinal pathology or neuropathy 
49 
EXCL07 
Diagnosis of macular edema 1 year prior to 
screening 
49 


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EXCL08 
Patients with active systemic bacterial, viral, or 
fungal infections or known to have AIDS or have 
positive HIV antibody 
49 
EXCL09 
Positive results of screening period testing for 
serological markers for hepatitis A, B, C and E, 
indicating acute or chronic infection 
49 
EXCL10 
Negative for varicella-zoster virus IgG antibodies at 
Screening unless there is other evidence of 
immunity to VZV based on the CDC criteria 
49 
EXCL11 
Have received any live or live-attenuated vaccines 
(including for varicella-zoster virus or measles) 
within 2 months of screening 
49 
EXCL12 
Treated with protocol restricted medication and 
therapies prior to screening and randomization as 
defined in exclusion criteria 12 
49 
EXCL13 
Patients with any medically unstable condition as 
determine by the investigator 
49 
EXCL14 
Any of the conditions or treatments that may affect 
cardiovascular function as listed in protocol 
49 
EXCL15 
Pulmonary conditions History or active severe 
respiratory disease or prophylactic treatment or 
Tuberculosis, except history of successful treatment 
of TB or severe asthma or asthma with oral steroids 
49 
EXCL16 
Patients with any of the hepatic conditions as 
described in protocol prior to screening 
49 
EXCL17 
Abnormal laboratory values as defined in exclusion 
criteria prior to screening 
49 
EXCL18 
Patients with the following neurological, psychiatric 
disorders prior to screening 
49 
EXCL19 
Use of other investigational drugs at time of 
enrollment or within prior 30 day or five elimination 
half-lives or until expected pharmacodynamics 
effect has returned to baseline whichever is longer 
49 
EXCL20 
History of hypersensitivity to the study drug or to 
drugs of similar chemical classes 
49 
EXCL21 
Homozygosity for CYP2C9*3/*3 or heterozygous for 
CYP2C9*2/*3 or CYP*1*3 (to be tested at 
screening) or refusal to test for CYP2C9 variants 
49 
EXCL22 
Concomitant use of MAYZENT and drugs that 
cause moderate CYP2C9 and moderate or strong 
CYP3A4 inhibition 
49 
EXCL23 
Concomitant use of MAYZENT and drugs that 
cause moderate CYP2C9 and strong CYP3A4 
induction 
49 
EXCL24 
Use of cannabinoid or cannabidiol products 30 days 
prior to screening 
49 


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EXCL25 
Any other disease or condition which could interfere 
with participation in the study according to the study 
protocol or with ability of patient to cooperate and 
comply with study procedures 
49 
TRT01 
Siponimod dose adjusted and/or interrupted 
49 
TRT02 
Treatment is interrupted for 4 or more consecutive 
daily doses, and treatment not re-titrated per 
protocol 
49 
TRT03 
treatment with 
Immunosuppressive/chemotherapeutic medications 
or procedures and hematopoietic stem cell 
transplantation but study treatment is not 
discontinued or interrupted 
49 
TRT04 
Patient took Monoclonal antibodies targeting the 
immune system, including natalizumab, rituximab, 
ofatumumab, ocrelizumab and alemtuzumab but 
study treatment is not discontinued 
49 
TRT05 
Patient took any other immunomodulatory or 
disease modifying MS treatment but study treatment 
is not interrupted 
49 
TRT06 
Used any concomitant medication which inhibits 
cardiac conduction, e.g. verapamil-type and 
diltiazem-type calcium channel blockers or cardiac 
glycosides but study treatment is not discontinued 
49 
TRT07 
Used Potent inducers of CYP2C9 but study 
treatment is not discontinued 
49 
COMD01 
Patient took prohibited medication 
49 
OTHER01 
Washout period is not there for taking teriflunomide 
before the patient can have their Day 1 visit 
(baseline) and start treatment with siponimod 
49 
OTHER02 
Patients  met eligibility criteria but does not have 
pre-dose body temperature; respiration rate; 
blood pressure; heart rate assessed 
49 
OTHER03 
Study drug taken on the day of EOS 
49 
OTHER04 
Pre-Dose vital signs; pre-dose ophthalmic exam; 
pre-dose ECG; screening labs (with exception of 
); neurological exam 
49 
OTHER05 
On-study Neurological exam not performed 
49 
OTHER06 
Ophthalmology monitoring procedures not followed 
49 
OTHER07 
Patient missed two consecutive lab assessments 
(with exception of 
) 
49 
OTHER08 
Missed visit due to COVID-19 
49 
OTHER09 
Visit done outside of study site due to COVID-19 
49 
OTHER10 
Assessment / procedure changed due to COVID-19 
49 
OTHER11 
Discontinuation due to COVID-19 
49 
TRT08 
Post-dose cardiac monitoring not performed per 
protocol 
49 


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TRT09 
Study Drug Interruption of 4 or more consecutive 
days and re-started without first dose monitoring 
49 
TRT10 
Drug supply method changed due to COVID-19 
49 
TRT11 
Treatment not given due to COVID-19 
49 
OTHER12 
Study Informed consent process not followed 
49 
OTHER13 
SAE not reported to Sponsor in 24 hrs 
49 
OTHER14 
Sample analyzed after withdrawal of consent 
49 
 
Table 6 Patient Classification 
Analysis Set 
PD severity codes that cause a 
patient to be excluded 
Criteria that cause a patient to be excluded 
SAF 
8 
 
 
Table 7 Severity codes with action taken 
Code              Action 
8                     Exclude from all analysis 
49                   Report relevant protocol deviation – include in all analyses 
5 
Reference 
Not Applicable