Conditions: Relapsing Multiple Sclerosis (RMS)
Keywords: Relapsing Multiple Sclerosis (RMS) Fingolimod Adult Pediatric China
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 98
Healthy volunteers: no

Brief summary:
The main purpose of this study was to assess the efficacy and safety of 0.5mg Fingolimod (Gilenya) in Chinese patients with relapsing multiple sclerosis (RMS)

Detailed description:
This was a 24-month, open-label, multicenter, interventional, single-arm study to collect efficacy and, safety of oral fingolimod 0.5 mg/day in approximately 100 relapsing multiple sclerosis (RMS) participants in China.

The study consisted of three Phases:

* Screening (up to 1 month): After signing informed consent, participants entered a Screening Phase to determine eligibility according to inclusion and exclusion criteria.
* Treatment Period (24 months): On visit Day 1, all eligibility criteria were confirmed, including a pre-dose ECG and vital signs. The first dose of study drug was taken in the clinic on Day 1 and the participant was monitored for 6 hours after the first dose administration before discharge. Participants returned to site for evaluation at month 1 and then every three months until the end of treatment up to 24 months.
* Follow Up (2 months): Subjects who completed Treatment Period or discontinued from treatment returned for the Follow-up visit 2 months after the last dose of study drug.

Arms:
arm 1: Fingolimod 0.5 mg capsule taken orally once daily

Interventions: intervention 1: Fingolimod 0.5mg
Intervention descriptions: intervention 1: Subjects received fingolimod 0.5mg capsule QD up to month 24

Protocol document:
Prot_000.pdf: 
Novartis Research and Development 
FTY720 
Clinical Trial Protocol CFTY720D2419 / NCT04667949
A 24-month, open-label, prospective, multicenter 
interventional, single-arm study assessing the efficacy and 
safety of fingolimod (Gilenya) 0.5 mg in relapsing multiple 
sclerosis (RMS) patients in China 
Document type: 
Amended Protocol Version 
EUDRACT number: 
Not applicable 
Version number: 
03 (Clean) 
Clinical Trial Phase: 
IV 
Release date: 
13 Jun 2023 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 2.0 dated 01-Aug-2018 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................. 9 
Amendment 03 （13-Jun-2023) ........................................................................................ 11 
Amendment 02 （11-Oct-2021) ........................................................................................ 13 
Amendment 01 （28-Aug-2020) ...................................................................................... 15 
Protocol summary .............................................................................................................. 18 
1 
Introduction ....................................................................................................................... 20 
1.1 
Background ............................................................................................................ 20 
1.2 
Purpose .................................................................................................................. 22 
2 
Objectives and endpoints ................................................................................................... 22 
3 
Study design ...................................................................................................................... 23 
4 
Rationale ............................................................................................................................ 24 
4.1 
Rationale for study design ..................................................................................... 24 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 24 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 25 
 
 25 
4.5 
Risks and benefits .................................................................................................. 25 
4.5.1 
Imaging Risk ......................................................................................... 25 
4.6 
Rationale for Public Health Emergency mitigation procedures ............................ 26 
5 
Population .......................................................................................................................... 26 
5.1 
Inclusion criteria .................................................................................................... 26 
5.2 
Exclusion criteria ................................................................................................... 27 
6 
Treatment ........................................................................................................................... 29 
6.1 
Study treatment ...................................................................................................... 29 
6.1.1 
Investigational and control drugs .......................................................... 29 
6.1.2 
Additional study treatments .................................................................. 29 
6.1.3 
Treatment arms/group ........................................................................... 29 
6.1.4 
Treatment duration ................................................................................ 29 
6.2 
Other treatment(s) .................................................................................................. 29 
6.2.1 
Concomitant therapy ............................................................................. 29 
6.2.2 
Prohibited medication ........................................................................... 30 


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6.2.3 
Rescue medication ................................................................................ 30 
6.3 
Participant numbering, treatment assignment, randomization .............................. 30 
6.3.1 
Participant numbering ........................................................................... 30 
6.3.2 
Treatment assignment, randomization .................................................. 31 
6.4 
Treatment blinding ................................................................................................ 31 
6.5 
Dose escalation and dose modification.................................................................. 31 
6.5.1 
Dose modifications ................................................................................ 31 
6.5.2 
Follow-up for toxicities ......................................................................... 31 
6.6 
Additional treatment guidance ............................................................................... 33 
6.6.1 
Treatment compliance ........................................................................... 33 
6.6.2 
Emergency breaking of assigned treatment code .................................. 33 
6.7 
Preparation and dispensation ................................................................................. 33 
6.7.1 
Handling of study treatment and other treatment .................................. 34 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 34 
7 
Informed consent procedures ............................................................................................ 35 
8 
Visit schedule and assessments ......................................................................................... 36 
8.1 
Screening ............................................................................................................... 41 
8.1.1 
Information to be collected on screening failures ................................. 41 
8.2 
Participant demographics/other baseline characteristics ....................................... 41 
8.3 
Efficacy .................................................................................................................. 41 
8.3.1 
Efficacy assessment 1 ........................................................................... 41 
8.3.2 
Efficacy assessment 2 ........................................................................... 42 
8.3.3 
Appropriateness of efficacy assessments .............................................. 44 
8.4 
Safety ..................................................................................................................... 44 
8.4.1 
Laboratory evaluations .......................................................................... 45 
8.4.2 
Electrocardiogram (ECG) ..................................................................... 46 
8.4.3 
Pregnancy and assessments of fertility ................................................. 46 
8.4.4 
Other safety evaluations ........................................................................ 47 
8.4.5 
Appropriateness of safety measurements .............................................. 50 
8.5 
Additional assessments .......................................................................................... 50 
8.5.1 
Clinical Outcome Assessments (COAs) ............................................... 50 
 
 51 
9 
Study discontinuation and completion .............................................................................. 51 
9.1 
Discontinuation ...................................................................................................... 51 
9.1.1 
Discontinuation from study treatment and from study ......................... 51 
9.1.2 
Discontinuation from study ................................................................... 52 


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9.1.3 
Lost to follow-up ................................................................................... 52 
9.2 
Withdrawal of informed consent/opposition to use data/ biological samples ....... 53 
9.2.1 
Early study termination by the sponsor ................................................. 53 
9.3 
Study completion and post-study treatment .......................................................... 54 
10 Safety monitoring and reporting ........................................................................................ 54 
10.1 
Definition of adverse events and reporting requirements ...................................... 54 
10.1.1 
Adverse events ...................................................................................... 54 
10.1.2 
Serious adverse events .......................................................................... 55 
10.1.3 
SAE reporting........................................................................................ 56 
10.1.4 
Pregnancy reporting .............................................................................. 57 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 57 
10.2 
Additional Safety Monitoring ................................................................................ 58 
10.2.1 
Liver safety monitoring ......................................................................... 58 
11 Data Collection and Database management ...................................................................... 59 
11.1 
Data collection ....................................................................................................... 59 
11.2 
Database management and quality control ............................................................ 59 
11.3 
Site monitoring ...................................................................................................... 59 
12 Data analysis and statistical methods ................................................................................ 60 
12.1 
Analysis sets .......................................................................................................... 60 
12.2 
Participant demographics and other baseline characteristics ................................. 61 
12.3 
Treatments ............................................................................................................. 61 
12.4 
Analysis of the primary endpoint(s) ...................................................................... 61 
12.4.1 
Definition of primary endpoint(s) ......................................................... 61 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 61 
12.4.3 
Handling of missing values/censoring/discontinuations ....................... 61 
12.4.4 
Sensitivity and Supportive analyses ...................................................... 62 
12.5 
Analysis of secondary endpoints ........................................................................... 62 
12.5.1 
Safety endpoints .................................................................................... 62 
 
 63 
 
 63 
12.8 
Sample size calculation.......................................................................................... 63 
12.8.1 
Primary endpoint(s) ............................................................................... 63 
13 Ethical considerations and administrative procedures ...................................................... 64 
13.1 
Regulatory and ethical compliance ........................................................................ 64 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 64 
13.3 
Publication of study protocol and results............................................................... 65 


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13.4 
Quality Control and Quality Assurance ................................................................. 65 
14 Protocol adherence ............................................................................................................ 65 
14.1 
Protocol amendments............................................................................................. 66 
15 References ......................................................................................................................... 67 
16 Appendices ........................................................................................................................ 68 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs ......................... 68 
16.2 
Appendix 2 New York Heart Association Functional Classification .................... 70 
16.3 
Appendix 3 McDonald criteria .............................................................................. 71 
16.4 
Appendix 4 EDSS Assessment Criteria ................................................................. 73 
16.5 
Appendix 5 Guidance for Monitoring of patients taking their first dose of the 
study drug .............................................................................................................. 75 
16.6 
Appendix 6 Guidance for Ophthalmic Monitoring ............................................... 79 
16.7 
Appendix 7 Guidance on safety monitoring .......................................................... 81 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 22 
Table 6-1 
Investigational drug ............................................................................... 29 
Table 6-2 
Guidance on specific clinical and diagnostic assessments which 
can be  performed to rule out possible alternative causes of 
observed LFT abnormalities. ................................................................ 32 
Table 8-1 
Assessment Schedule ............................................................................ 38 
Table 8-2 
Assessments & Specifications............................................................... 44 
Table 8-3 
Laboratory Evaluations ......................................................................... 45 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 58 
Table 12-1 
ARR data on RRMS from historical studies ......................................... 63 
Table 16-1 
Criteria For Notable Laboratory Abnormalities .................................... 68 
Table 16-2 
Heart rate table for cardiac release criteria ........................................... 76 
Table 16-3 
Liver event and laboratory trigger definitions ...................................... 81 
List of figures 
Figure 3-1 
Study design .......................................................................................... 24 
 


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List of abbreviations 
AE 
Adverse Event 
ACTH 
Adrenocorticotropic Hormone 
AKI 
Acute Kidney Injury 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANA 
Antinuclear Antibody 
ARR 
Annualized Relapse Rate 
ASMA 
Anti-Smooth Muscle Antibody 
AST 
Aspartate Aminotransferase 
AV 
Atrio-ventricular  
BCVA 
Best Corrected Visual Acuity  
CBC 
Complete Blood Count 
CD-
transferrin 
Carbohydrate-deficient Transferrin 
 
 
CDS 
Core Data Sheet  
CFR 
Code of Federal Regulation 
CKD 
Chronic Kidney Disease 
CMV 
Cytomegalovirus 
CO 
Carbon Monoxide  
COVID-
19 
Coronavirus disease 2019 
CHF 
Congestive hearts failure 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CVD 
Cardiovascular Disease 
DILI 
Drug Induced Liver Injury 
DLCO 
Carbon Monoxide Diffusing Capacity  
DMT 
Disease Modifying Therapies 
DNA 
DeoxyriboNucleic Acid 
EBV 
Epstein-Barr virus 
EC 
Ethics committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EDSS 
Expanded Disability Status Scale 
eGFR 
Estimated Glomerular Filtration Rate 
EMA 
European Medicines Agency 
ERCP 
Endoscopic Retrograde Cholangiopancreatography 
EOS 
End of Study 
EOT 
End of Treatment 


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FDA 
Food and Drug Administration 
FEV1 
Forced Expiratory Volume within 1 Second  
FS 
Functional System 
FSH 
Follicle-Stimulating Hormone 
GBCA 
Gadolinium-based Contrast Agent 
GCP 
Good Clinical Practice 
GGT 
Glutamyltransferase 
GLDH 
Glutamate Dehydrogenase 
h 
Hour 
HA 
Health Authority 
HAV 
Hepatitis type A virus 
HbA1c 
Hemoglobin A1c 
HBsAg 
Hepatitis B Surface Antigen 
HBc 
hepatitis B Core 
HBV 
Hepatitis Type B Virus 
HCV 
Hepatitis Type C Virus 
HEV 
Hepatitis Type E Virus 
HIV 
Human Immunodeficiency Virus 
HSV 
Herpes Simplex Virus 
i.v. 
intravenous 
 
 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
I/E 
Inclusion/Exclusion 
IFN 
Interferon 
IG 
Immunoglobulin  
IgA 
Immunoglobulin A 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
JC virus 
John Cunningham virus 
LFT 
Liver Function Test 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical dictionary for regulatory activities 
mg 
milligram(s) 
ml 
milliliter(s) 


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MRI 
Magnetic Resonance Imaging 
MS 
Multiple Sclerosis 
NA 
Not Applicable 
  
 
NMPA 
National Medical Products Administration 
NFS 
Nephrogenic Systemic Fibrosis 
NYHA 
New York Heart Association 
OCT 
Optical Coherence Tomography  
PAC 
Post Approval Commitment  
PD 
Proton Density 
PFT 
Pulmonary Function Test  
PML 
Progressive Multifocal Leukoencephalopathy 
PRMS 
Progressive Relapsing Multiple Sclerosis 
PT 
Preferred Term 
QC 
Quality Check 
RBC 
Red Blood Cell  
RMS 
Relapsing Multiple Sclerosis 
RNA 
Ribonucleic Acid 
RRMS 
Relapsing-remitting Multiple Sclerosis 
s.c. 
subcutaneous 
SAE 
serious adverse event 
SD 
standard deviation 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SOC 
System Organ Class  
SPMS 
Secondary Progressive Multiple Sclerosis 
SSE 
Skin Self Examination 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
T1D 
Type 1 Diabetes 
T3 
triiodothyronie 
T4 
tetraiodothyronine 
TBIL 
Total Bilirubin 
TEAE 
Treatment-emergent Adverse Event  
TSH 
Thyroid Stimulating Hormone 
UK 
United Kingdom 
ULN 
upper limit of normal 
WBC 
white blood cell(s) 
WHO 
World Health Organization 
 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Control drug 
A study drug 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. 
Dosage 
Dose of the study treatment given to the participant in a time unit ((e.g. 100 
milligram (mg) once a day, 75 mg twice a day)) 
Early withdrawal 
Point/time when the participant exits from the study prior to the planned 
completion of all study drug administration and assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned. 
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 
Enrollment 
Point/time of participant entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol) 
End of Study 
(EOS) 
EOS, used in the context of individual participants, refers to EOS visit 
End of Treatment 
(EOT) 
EOT refers to EOT visit. Any participants who discontinue from treatment 
should follow the assessments of the EOT visit. 
Epoch 
Interval of time in the planned conduct of a study. An epoch is associated with 
a purpose (e.g. screening, randomization, treatment, follow-up), which applies 
across all arms of a study. 
Investigational 
drug 
The study drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and Directive 2001/20/EC and is 
synonymous with “investigational new drug” or “test substance” 
Part 
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a single 
dose part and a multiple dose part, or a part in patients with established 
disease and in those with newly-diagnosed disease. 
Patient 
An individual with the condition of interest 
Period 
A minor subdivision of the study timeline; divides phases into smaller functional 
segments such as screening, baseline, titration, washout, etc. 
Screen Failure 
A participant who is screened but is not treated or randomized 
Stage 
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc. 
Study completion 
Point/time at which the the last participant finishes his/her last visit. 
Study drug 
discontinuation 
Point/time when participant permanently stops taking study drug for any 
reason; may or may not also be the point/time of premature participant 
withdrawal. 
Study 
drug/treatment 
Any drug (or combination of drugs) administered to the participant as part of 
the required study procedures; includes investigational drug, active drug run-
ins or background therapy. 
Study treatment 
discontinuation 
When the participant permanently stops taking study treatment prior to the 
defined study treatment completion date 


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Participant 
An individual who has consented to participate in this study. The term 
Participant may be used to describe either a healthy volunteer or a patient. 
Participant 
number 
A unique number assigned to each participant upon signing the informed 
consent. This number is the definitive, unique identifier for the participant and 
should be used to identify the participant throughout the study for all data 
collected, sample labels, etc. 
Treatment 
number 
A unique identifier assigned in non-randomized studies to each dosed 
participant, corresponding to a specific treatment arm  
Variable 
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested in the 
study 
Withdrawal of 
consent (WoC) 
 Withdrawal of consent from the study occurs when the participant explicitly 
requests to stop use of their data and/or biological samples AND no longer 
wishes to receive study treatment AND does not agree to further protocol 
required assessments. This request should be in writing (depending on local 
regulations) and recorded in the source documentation. This request should be 
distinguished from a request to discontinue the study. Other study participant's 
privacy rights are described in the corresponding informed consent form. 


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Amendment 03 （13-Jun-2023) 
The major purpose for the protocol amendment is: 1. To clarify and further detail the 
identification and situation when EOS visit is required in the study. 2. To describe more clearly 
about the analysis of T2 lesion-related MRI parameters that will be analyzed as secondary 
endpoints in Table 2-1 & section 8.3.2; T2 lesion volume is the parameter for disease burden 
and new/newly enlarged T2 lesion number is the parameter for inflammatory activity, which 
would be the appropriate endpoint to evaluate the efficacy of fingolimod on MRI lesion activity; 
1. Change language in Table 2-1 and Section 8.3.2 from “T2 lesion- new/newly enhancing 
lesion number and volume” to “T2 lesion volume, new/newly enlarged T2 lesion 
number”. 
2. In Table 8-1, add footnote “Any participants who discontinue from study should follow 
the assessments of the EOS visit if they agree. If EOT and EOS will be on the same day, 
only EOS visit is required.”  
3. In Table 8-1, add footnote “EOS MRI only required when EOS occurred within 30 days 
after the last dose and there is no MRI at EOT.” to provide more clarification on EOS MRI 
assessment. 
4. Change language under Section 8.4.2 from “Premature discontinuation visit (EOT)” to 
“Premature discontinuation from treatment (EOT), premature discontinuation from study 
(EOS)”, to add situation for EOS visit.  
5. Remove “(EOT)” in the second paragraph under Section 8, and add “(see Table 8-1 for 
details)” to avoid discrepancy with table 8-1. 
 
Other changes were made as below: 
1. Use “participant” instead of “subject” to align with the Novartis protocol template Version 
5. 
2. In List of abbreviations, update “EOT” from “end of trial” to “end of treatment” to correct 
discrepancy.  
3. In Glossary of terms, add “End of Study (EOS)” and “End of Treatment (EOT)” to 
provide definition of the EOS and EOT in context.  
4. In Glossary of terms, update “Study completion” to correctly describe the term. 
5. In Glossary of terms, update “Withdrawal of consent (WoC)” to align with the Novartis 
protocol template Version 5. 
6. Under Section 1.1, update therapies available in China for patients with RRMS. 
7. 
 
 
 
 
8. Language about Public Health Emergency mitigation procedures updated in Section 4.6 
and Section 8 to align with the Novartis protocol template Version 5. 
9. Under Section 6.2.1, change language from “MS treatment” to “MS disease modifying 
treatment”, in order to make description more accurate.        


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10. Under Section 6.2.2, change language from “IFN- ß, teriflunomide” to “other MS DMT 
(including but not limited to IFN- ß , teriflunomide)”, in order to make statement more 
accurate.  
11. Update language under Section 7 to align with the Novartis protocol template Version 5. 
12. Add “Data and samples collected from participants prior to screen failure may still be 
analyzed.” under section 8.1.1 to align with the Novartis protocol template Version 5. 
13. Under Section 8.3.1, change “Annualized relapse rate (ARR)” to “MS relapse” to 
correctly reflect section content.  
14. 
 
 
 
 
15. Update language under Section 9.1.3 to align with the Novartis protocol template Version 
5. 
16. Update language under Section 9.2 to align with the Novartis protocol template Version 5. 
17. Update language under Section 9.3 to align with the Novartis protocol template Version 5. 
18. Remove “Dose Reduced/increased” under Section 10.1.1 Adverse events, as this is not 
applicable in study. 
19. Update language under Section 10.1.4 Pregnancy reporting to align with the Novartis 
protocol template Version 5. 
20. Change language under Section 12.8.1 Primary endpoint(s) from "Considering 20% drop-
out rate, the total sample size will be 100 subjects" to "Considering 20% drop-out rate, the 
total sample size will be around 100 participants." to make statement more accurate. 
21. In Table 16.1, update Creatinine SI Units from “≥176umol/dL” to “≥176umol/L” to 
correct unit error. 
22. In Table 16.1, remove item Eosinophils as this value will not be analyzed.  
 
 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
 


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Amendment 02 （11-Oct-2021) 
Amendment rationale 
In response to the public health emergency (e.g. the COVID-19 pandemic), this protocol 
amendment introduces the possibility to collect safety information remotely, ship IMP directly 
to patients’ home, collect PRO remotely and conduct consent remotely in the situation where it 
is not safe for the participants to attend on-site visit. The measures are temporary and should 
only be used in justified cases as assessed by the investigator (Section 4.6 Rationale for Public 
Health Emergency mitigation procedures; Section 6.7 Preparation and dispensation; Section 7 
Informed consent procedures and Section 8 Visit schedule and assessments). 
In addition, the ophthalmic guidance on diagnosis of macular edema is updated in this 
amendment. The OCT criteria in protocol 1.0 was referring to the optical coherence tomography 
(OCT) criteria made more than ten years ago. Since the OCT has shown major improvements 
in technology, old criteria (center point thickness>210 microns for OCT-3 or >200 microns for 
OCT-2) was outdated. Besides, the value may vary between different machines in local hospital, 
so it will be more reasonable to make a diagnosis based on ophthalmologist judgement with 
support of medical condition and OCT exam.  To align with the advanced OCT technology and 
harmonize the diagnosis of macular edema with various OCT machines, the protocol is 
amended to include the confirmative diagnosis of macular edema based on the ophthalmologist 
judgement with the support of medical condition and OCT exam (Section 8.4.2 Ophthalmic 
examination and Section 16.6 Appendix 6 Guidance for Ophthalmic Monitoring). 
Other updates or changes to provide more clarity were made as below:  
1. Remove the maximum 5 days requirement for the use of corticosteroids under section 8.4.4.4 
Infection based on local clinical practice in treating MS relapse 
2. Remove the Proton Density (PD) under section 8.3.2 efficacy assessment 2 for editorial 
reasons; details of sequences collected are specified in vendor documents.  
3. Change the language from “In case of new findings in the MRI images in comparison with 
the previous available MRI which are not compatible with MS lesions, the study drug will be 
discontinued” to “In case of new findings in the MRI images in comparison with the previous 
available MRI which are not compatible with MS lesions, the study drug will be interrupted”, 
as the study drug may be restarted once the diagnosis clearly rules out e.g. progressive 
multifocal leukoencephalopathy (PML), this is specified under Appendix 7 Guidance on safety 
monitoring.  
 
4.Clarify the detail definition of highly effective contraception which consistent with China 
label under section 5.2 Exclusion criteria to align with the Novartis newest protocol template.  
In addition, editorial updates were made to align to the Novartis newest protocol template and 
to provide consistency throughout the protocol. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using underlined for insertions.  
 


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IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment 


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Amendment 01 （28-Aug-2020) 
Amendment rationale 
The major purpose for the protocol amendment is to clarify the guidance and procedures related 
to exclusion criteria in the protocol per China clinical practice. Tests for excluding participants 
with severe active infections, active chronic infections (hepatitis, tuberculosis), Severe liver 
impairment (Child-Pugh class C) are listed in Table 8-1 Assessment Schedule. Hepatitis B test, 
Chest CT test and Prothrombin time were specified to be used for the patient screening.  
Other major changes were made as below:  
1. Detailed Pulmonary function monitoring guidance is added under Section 8.4.4.3. 
Pulmonary function test is required at the screening visit. Related changes are 
reflected in following sections in the protocol:  
2. 5.2 
Exclusion criteria #18   Updated the description of severe uncontrolled 
respiratory disease in pulmonary function test 
3. Table 8-1 Assessment Schedule changed from as needed to S in screening visit 
4. Section 8.4.5 Appropriateness of safety assessments 
5. Changes due to the updated protocol template Version 3.0 language under Section 
6.5.2.1 Follow up on potential drug-induced liver injury (DILI) cases  
6. Changes were made to incorporate applicable changes in the Liver Safety Monitoring 
Guidance according to the China fingolimod label under Section 16.7- Appendix 16.7 
Guidance on monitoring of participants with elevated liver function tests   
7. Changes were made to clarify the electrocardiogram (ECG) requirement for baseline 
and first dose monitoring in Table 8-1 Footnote # 11 and 8.4.2  ECG   
8. 
 
 
 
9. More clarification on the MRI acquisition process in Section 8.3.2  Efficacy 
assessment 2. and Table 8-1 Footnote # 9.   
10. Section 4.5 Risks and Benefits: Added COVID-19 risk related to Gilenya 
11. Section 4.5.1 Imaging Risk and Section 5.2  Exclusion criteria #19 – to incorporate Gd 
based contrast language and list MRI exclusions  
 
Changes were incorporated to address the COVID-19 pandemic in the following sections: 
• Section 6.7 Preparation and dispensation 
• Section 7 Informed Consent Procedures 
• Section 8 Visit Schedule and Assessments 
• Section 8.4 Safety  
• Section 8.4.1 Laboratory evaluations  
• Section 12 Data analysis and statistical methods 


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Other change incorporated in this amendment:  
1. Table 2-1 Objectives and related endpoints:
 
 
2. Table 8-1 Assessment Schedule: Screening time was changed to -30 to -1 days; EDSS test 
X was added in the screening field to be consistent with Section 5.1 Inclusion criteria #6; 
Footnote 2 and 3 Provided detailed description on participants who complete the study to 
be consistent with section 9.1 Discontinuation. Addition of new column for ‘EOT Visit’ 
and marked applicable assessments at EOT visit; Correction of documentation type for 
Drug accountability (X to S); Removal of ‘Visit numbers’ row. 
3. Modified Footnotes #1 and #10. 
4. Section 8.2 Participant demographics/other baseline characteristics: Removed date of birth 
since it will not be collected in the study; Added race. 
5. 
 
6. Section 10.1.3 SAE reporting: Removed the wordings “following the last administration 
of study treatment if there are post-treatment follow-up visits with no required 
procedures” since it’s not applicable for the study.  
7. Section 12.5 Analysis of secondary endpoints: Removed month 6 from analysis on MRI 
data to make it consistent with the study procedure.
 
8. Section 16.6 Appendix 6 Provided more detailed guidance for Ophthalmic Monitoring. 
Section 8.4.4.2 Ophthalmic examination was been updated accordingly. 
9. Section 15: Addition of Ledneva et al 2009 and deletion of Kurtzke 1983 references. 
10. 
 
11. List of abbreviations and Protocol Summary were aligned according to the updates made 
in the protocol body, basis the amendment. 
12. Section 16.7: Updated the Guidance on monitoring participants with A) notable 
lymphopenia and B) elevated BP. 
13. Section 16.5: Updated the citations. 
14. Section 16.4: Updated the EDSS steps 4.0, 4.5, 5.0, and 5.5. 
15. Section 16.3 and Table 16-1: Clarifications made in the table. 
16. Section 12.5.1: Deletion of sentence “For those participants who withdraw from the study, 
the analyses will include all data collected up to 2 months after treatment discontinuation 
unless explicitly stated otherwise”. 
17. Section 10.2.1: Added the example of CRF ‘AE page, concomitant medical page’ with 
respect to documentation of follow-up information. 


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18. Section 10.1.4: Added the sentence “If a female trial participant becomes pregnant, the 
study treatment should be stopped, and the trial participant must be asked to read and sign 
pregnancy consent form to allow the Study Doctor ask about her pregnancy”. 
19. Section 9: Corrected the section heading. 
20. Section 8.3.2: Section heading corrected. 
21. Section 5.2 #4: Updated for ‘Screening’ QTc interval  
22. Section 5.1 # 4 and #5: Clarification added regarding the number of documented relapses 
23. 
 
 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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Protocol summary 
Protocol 
number 
CFTY720D2419 
Full Title 
A 24-month, open-label, prospective, multicenter interventional, single-arm study 
assessing the efficacy and safety of Fingolimod (Gilenya) 0.5 mg in relapsing 
multiple sclerosis(RMS) patients in China. 
Brief title 
Study of efficacy and safety of Fingolimod (Gilenya) in relapsing multiple 
sclerosis participants in China. 
Sponsor and 
Clinical Phase 
Novartis 
Phase IV 
Investigation 
type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
The purpose of this open-label, prospective, multi-center interventional, single-
arm study in patients with relapsing form of MS, is to further explore the efficacy 
and safety profile of fingolimod in Chinese population.  
Based on that MS is a rare disease worldwide and a placebo controlled arm is 
deemed as unethical to participant because of other available DMTs in China, an 
open-label, single arm design is considered to be adequate for this study, as 
fingolimod is an approved therapy and continues to be effective and safe for 
RMS participants across various countries in the world.  
Primary 
Objective(s)  
To evaluate the efficacy of fingolimod 0.5mg on annualized relapse rate (ARR) in 
participants with RMS treated for up to 24 months. 
Secondary 
Objectives 
1. To evaluate the safety and tolerability of fingolimod 0.5mg in participants with 
RMS treated for up to 24 months. 
2. To evaluate the efficacy of fingolimod 0.5mg on MRI lesions. 
Study design 
This is a 24-month, open-label, multicenter, interventional, single-arm study to 
collect efficacy, safety and health outcome data of fingolimod (Gilenya) 
0.5 mg/day in China. 
Population 
The study population will consist of relapsing multiple sclerosis participants, 
aged 10-65 years (inclusive) with weight > 40 kg. 
Inclusion 
criteria 
1. Written informed consent must be obtained before any assessment is 
performed. 
2. Male or Female with age: 
• 
18 to 65 years old inclusive; 
• 
10 to 17 years old inclusive with weight > 40kg. 
3. Clinical definite diagnosis of Multiple Sclerosis according to the 2010 
Revised McDonald criteria. 
4. Participants with a diagnosis of relapsing multiple sclerosis prior to their 
enrollment to the study (signing the study consent form): 
• 
At least two documented relapses during the past 2 years, or 
• 
At least one documented relapse during the last year 
5. With RMS that never used fingolimod before enrollment (including naive 
participants and participants who switched from previous DMTs). 
6. Participants with EDSS score of 0 - 6.0 (inclusive) at Screening. 
Key Exclusion 
criteria 
1. Conditions include in contraindication section and special warning section as 
latest approval label in China. 


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2. Patients treated with any other investigational drug for MS in the period. 
3. Pregnant or nursing woman or woman of child-bearing potential not using 
effective contraception. 
4. Patient intolerant to undergo MRI or presents contraindications to 
MRI (e.g., metallic implants, metallic foreign bodies, pacemaker, 
defibrillator) and the use of gadolinium-based agents (e.g. people with 
severe kidney failure, patients with previous severe 
allergic/anaphylactoid reaction to a gadolinium-based contrast agent; 
patients with severe renal disease (( Estimated Glomerular Filtration 
Rate (eGFR) <30 mL/min/1.73 m2),) or acutely deteriorating renal 
function, who would be at risk of nephrogenic systemic fibrosis). 
5. Pediatric participant without confirmed history of chickenpox or confirmed 
documentation of a full vaccination course against varicella zoster virus 
(VZV). 
6. Any disability that may prevent the participants from completing all study 
requirements, as assessed by the treating physician (e.g., mental disorder, 
blindness or deafness that is not appropriate for age, severe language 
difficulty).  
7. Current medical or neurological condition that might impact efficacy 
assessments e.g. dementia, schizophrenia, bipolar disorder, major 
depression, history of multiple traumatic brain injuries, alcohol/drug abuse or 
dependence currently, or dependence within the last two years. 
Study 
treatment 
Fingolimod 0.5mg will be administered daily treated for up to 24 months. 
Efficacy 
assessments 
• 
MS relapse 
• 
 
• 
Magnetic Resonance Imaging (MRI) 
Key safety 
assessments 
• 
Physical/neurological examination 
• 
Vital signs 
• 
Skin assessments 
• 
Laboratory evaluations 
• 
ECG 
• 
First dose monitoring 
• 
Ophthalmologic exams / Optical coherence tomography (OCT) 
• 
Pulmonary function test 
Other 
assessments 
 
Data analysis 
All data will be analyzed using with summaries and/or statistical models 
appropriately. Annualized relapse rate (ARR) will be analyzed using a negative 
binomial model. Number and proportion of patients with new and newly enlarged 
T2 lesions will be statistically summarized as well as the number and proportion 
for patients with Gd-enhanced T1 lesions and the change of volume of T1 hypo-
intense lesions from baseline. All safety 
 
 will also be statistically summarized appropriately. 
Key words 
Multiple sclerosis, relapse, efficacy, safety 


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1 
Introduction 
1.1 
Background 
Multiple Sclerosis (MS) is a chronic, immune-mediated disease of the central nervous 
system characterized by inflammation, demyelination and axonal/neuronal destruction, 
ultimately leading to severe disability (Trapp et al 1998, Sospedra and Martin 2005). Globally, 
the median estimated incidence of MS is 2.5 per 100,000 (ranging from 1.1 to 4.0 per 100,000) 
and the median estimated prevalence is 30.0 per 100,000 (ranging from 5.0 to 80.0 per 100,000) 
WHO and Multiple Sclerosis International Federation. 2008. At diagnosis, approximately 85% 
of patients have relapsing-remitting MS (RRMS), characterized by recurrent, acute episodes 
(relapses) of neurological symptoms. Approximately 50% of these patients progress to 
secondary progressive MS (SPMS) within 10 years, 90% within 25 years, when a less 
inflammatory, and more neurodegenerative. SPMS can also be segregated based on whether 
patients continue to experience relapses (relapsing form of SPMS) or not (purely progressive 
SPMS). About 10-15% of MS patients present with a primary progressive course (PPMS) 
defined by a continuous accumulation of neurological disability from symptom onset without 
superimposed exacerbations or remissions. Progressive relapsing MS (PRMS; chronic 
progressive from onset with infrequent relapses) is the least frequent form of MS 
(Keegan and Noseworthy 2002). So typically recurrent acute episodes (relapses) of 
neurological symptoms, which are followed by a complete or partial recovery is the basic 
feature of MS. 
In China, several therapies are approved for patients with RRMS and fall within 4 classes of 
products: anti-CD20 monoclonal antibody (ofatumumab), dimethyl fumarate, DHODH 
inhibitor (teriflunomide), and S1P receptor modulator (siponimod, fingolimod and ozanimod). 
All are considered as immunomodulatory or immunosuppressive medications. Beta interferons 
have multiple immune actions but the means by which the drugs are effective in MS remains 
unknown. They have shown modest (~30%) effect on relapses and in the case of IFN β -1a, on 
disability (Goodin et al 2002). Teriflunomide, an orally active drug that inhibits lymphocyte 
proliferation. It selectively and reversibly inhibits dihydro-orotate dehydrogenase, an enzyme 
in the de novo synthesis pathway of pyrimidines, resulting in reduced proliferation of peripheral 
T- and B- lymphocytes, and hence reduce numbers of lymphocytes crossing the blood-brain 
barrier and causing CNS damage (Bar Or et al 2014) . Fingolimod (Gilenya) is a chemical entity 
for once daily oral administration which has been submitted to health authorities in the USA 
and in Europe late 2009 and subsequently in other countries worldwide to obtain market 
authorization. Since August 2010, fingolimod has been approved more than 70 countries for 
treatment of patients with relapsing of MS. Fingolimod is rapidly phosphorylated in vivo, and 
fingolimod-phosphate (fingolimod-P) acts as an agonist of G protein-coupled receptors for 
sphingosine-1 phosphate (S1P). More particularly, fingolimod-P acts as “super agonist” of the 
S1P1 receptor on thymocytes and lymphocytes, inducing internalization and degradation of that 
receptor. This renders these cells unresponsive to S1P1 signaling, thus depriving them of a signal 
necessary for egress from lymph nodes and secondary lymphoid tissues. The downstream result 
of this fingolimod induced interdiction of S1P1 signaling is a marked reduction in the number 
of both B and T lymphocytes in the intravascular compartment and a decrease in recirculation 
of these cells to extravascular compartments, including the CNS. 


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Prior to submission, the efficacy profile of fingolimod was evaluated in five main studies. In 
two of the phase III clinical trials, Study CFTY720D2301 (acronym FREEDOMS I) and 
CFTY720D2309 (acronym FREEDOMS II), each 24-month placebo-controlled study, 
fingolimod demonstrated reduction of relapse rate, disability progression, MRI lesion counts 
and rate of brain atrophy (Kappos et al 2010) . In another Phase III trial, study CFTY720D2302 
(acronym TRANSFORMS), a large active controlled study vs. intramuscular interferon beta-
1a, fingolimod showed a significant reduction in relapse rate over the 12-month treatment 
period and reduced magnetic resonance imaging (MRI) lesion counts and rate of brain atrophy 
Kappos et al 2010. Study CFTY720D2399 (acronym LONGTERMS), an open-label, phase IIIb 
extension study, indicated that fingolimod treatment for up to 14 years had a sustained benefits 
for control of disease activity and disability progression without emerging safety concerns 
Cohen et al 2019.In the controlled pediatric study CFTY720D2311 (acronym PARADIGMS), 
it compared the efficacy of fingolimod to intramuscular interferon beta-1a in pediatric patients. 
It showed the annualized relapse rate (ARR), was significantly lower in patients treated with 
fingolimod than in patients who received interferon beta-1a. 
The safety profile of fingolimod has been well characterized with approximately 296,714 
patients in both clinical trials and the post –marketing setting, with the total patient exposure 
now at approximately 746,745 patient year by 30 Nov 2019. The safety profile in pediatric 
patients was overall similar to that seen in adult patients Chitnis et al 2018. 
During the course of the fingolimod clinical development, several areas were identified as safety 
areas of note: bradyarrhythmias upon treatment initiation or on restarting after an interruption 
of fingolimod therapy of more than 14 days, liver transaminase elevations, hypertension, 
macular edema and infection. 
Initiation of fingolimod treatment results in a transient decrease in heart rate and infrequently 
induces atrio-ventricular (AV) block. In MS clinical trials, the mean maximal decrease in heart 
rate after the first dose intake was 12~ 13 bpm and was seen at ~6 hours post-dose. Heart rates 
below 40 beats per minute were rarely observed in patients on fingolimod 0.5 mg/day. Heart 
rate progressively returned to baseline within 1 month of dose initiation despite continued 
dosing. In addition, a mild increase in blood pressure of approximately 2 mmHg diastolic and 
3 mmHg systolic on average. This onset after approximately 1 months of treatment initiation 
persisted with continued treatment but reversed upon cessation of therapy. Hypertension was 
reported as an adverse event in 6.5% of patients on fingolimod 0.5 mg/day and in 3.3 % of 
patients on placebo in the 2-years placebo controlled study. 
Liver enzyme elevations were seen in clinical trials. Asymptomatic elevations in serum levels 
of hepatic transaminases ≥3x upper limit of normal (ULN) and ≥5x ULN, were observed in 8.0% 
and 1.8% of patients treated with fingolimod 0.5 mg/day respectively compared to 1.9% and 
0.9% for patients receiving placebo. The majority of elevations occurred within 12 months of 
therapy and returned to normal, generally within 2 months of discontinuation of therapy. 
Macular edema occurred in 0.5% of patients treated with fingolimod 0.5 mg/day. 
Approximately 75% of cases occurred within the first 3-4 months of therapy. The macular 
edema generally improved or resolved spontaneously after drug discontinuation. The risk of 
developing macular edema appears to be increased in MS patients with a history of uveitis. 
There is limited data on fingolimod in MS patients with diabetes mellitus. In earlier renal 


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transplant clinical studies where patients with diabetes mellitus were included, therapy with 
fingolimod 2.5 mg/day and 5 mg/day resulted in a 2-fold increase in the incidence of macular 
edema. MS patients with diabetes mellitus are therefore expected to be at a higher risk for 
macular edema. 
A key pharmacodynamic effect of fingolimod is a dose-dependent reduction of peripheral 
lymphocyte count to 20 - 30% of baseline values. This is due to the reversible sequestration of 
lymphocytes in lymphoid tissues. In multiple sclerosis clinical trials, the overall rate of 
infections (65.1%) at the 0.5 mg dose was similar to placebo Novartis 2019. However, 
bronchitis, herpes zoster and pneumonia, were more common in Gilenya treated patients 
Karlsson G,Francis and Schmouder R,et 2009. Serious infections occurred at a rate of 1.6% in 
the 
fingolimod 
0.5 mg 
group 
versus 
1.4% 
in 
the 
placebo 
group 
(2013) 
2.5 Clinical Overview Rationale for changes to Core Data Sheet (CDS) / A full review and up
date of sections, A full review and update of sections, “Warnings and Precautions”, “Adverse 
Drug Reactions” and “Interactions”  . In a second 2-year placebo controlled study, 
CFTYD2309, which was reported after approval of fingolimod, the safety profile seen in prior 
studies was largely confirmed, however in this study herpes zoster was reported more frequently 
in the fingolimod arms as compared to placebo (2.5% vs. 0.8% respectively) and basal cell 
carcinomas were more frequent in the fingolimod 0.5 mg group (2.8%) as compared to both, 
the fingolimod 1.25 mg and the placebo arms (1.6 and 0.6%) respectively. One fatal primary 
disseminated varicella zoster infection and one fatal herpes simplex encephalitis case have 
occurred in patients receiving the 1.25 mg/day dose; at the fingolimod 0.5 mg dose, one patient 
died in the post-marketing setting due to a disseminated varicella zoster infection in the context 
of high dose steroid treatment. 
As part of a post-approval commitment to China’s health authorities, Novartis is conducting 
this post-approval commitment study (PAC) in order to evaluate the efficacy and safety profile 
of fingolimod in Chinese multiple sclerosis patients. The study will collect safety profile 
information related to clinical practice setting and long-term follow-up including, but not 
limited to infections, cardiac and vascular events (e.g. stroke, myocardial infarction, angina 
pectoris and peripheral vascular disease, second and third degree AV conduction block, 
hypertension), malignancies, pulmonary events, seizures, MS relapses, atypical severe 
neurological events and sudden/unexplained death. 
1.2 
Purpose 
The purpose of this study is to collect 24-month efficacy, safety, tolerability, and health 
outcome data of fingolimod (0.5 mg per Day) in participants with relapsing multiple sclerosis 
(RMS) in China. This is a post approval commitment study for fingolimod. 
2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To evaluate the efficacy of fingolimod 0.5mg 
on annualized relapse rate (ARR) in 
• 
Annualized relapse rate(ARR) 


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Objective(s) 
Endpoint(s) 
participants with RMS treated for up to 24 
months. 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To evaluate the safety and tolerability of 
fingolimod 0.5 mg in participants with RMS 
treated for up to 24 months. 
• Adverse events (AE) and serious adverse 
events (SAE) 
Laboratory tests(hematology, biochemistry) 
• Vital signs 
• Electrocardiogram (ECG) 
• Ophthalmology 
• 
To evaluate the efficacy of fingolimod 0.5 
mg on MRI lesions. 
• 
T1 hypo-intense lesion number and volume; 
T2 lesion volume, new/newly enlarged T2 
lesion number; Gd-enhancing T1 lesion 
number and volume. 
3 
Study design 
This is a 24-month, open-label, multicenter, interventional, single-arm study to collect efficacy, 
safety and health outcome data of fingolimod (Gilenya) 0.5 mg/day in approximately 100 
relapsing multiple sclerosis (RMS) participants in China. 
The study will consist of three Phases (see Figure 3-1): 
Screening (up to 1 month): After signing informed consent, participants will enter a Screening 
Phase to determine eligibility according to inclusion and exclusion criteria. 
The investigator must ensure that all patients meet the inclusion and exclusion criteria to be 
eligible to enter the study. 
Treatment Period (24 months): On visit Day 1, all eligibility criteria will be confirmed, 
including a pre-dose ECG and vital signs. The first dose of study drug will be taken in the clinic 
on Day 1 and the participant will be monitored for at least 6 hours after the first dose 
administration before discharge.  Refer to Section 16.5 for Guidance for monitoring of patients 
taking their first dose of the study drug. 
Then the participants should come to site and be evaluated month 1 and then every three months 
till the end of treatment up to 24 months. 


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Follow Up (2 months): Participants who completed Treatment Period will return for the 
Follow-up visit 2 months after the last dose of study drug. 
Figure 3-1 
Study design 
 
4 
Rationale 
4.1 
Rationale for study design 
The clinical development program of fingolimod has demonstrated the efficacy and safety of 
fingolimod 0.5 mg/day dose for the treatment of participants with relapsing-remitting multiple 
sclerosis globally in clinical studies (CFTY720D2301, CFTY720D2309). Nonetheless there 
was no data from Chinese participants. Along with the local approval of fingolimod to treat 
RMS in China on 12-Jul-2019, National Medical Products Administration (NMPA) in China 
requested, as a post-approval requirement, to collect the efficacy and safety data 
of fingolimod 0.5mg/day in Chinese participants, including number of pediatric participants 
recruited will be based on natural occurrence. 
This study is designed with the aim to obtain the efficacy, safety and health outcome data in 
Chinese RMS participants treated with fingolimod for 24 months. Given the limited population 
size of RMS patients in China because of the rare disease feature, and the concern that a placebo 
controlled arm is deemed as unethical to participant because of other available DMTs in China, 
an open-label, single arm design is considered to be adequate for this study, as fingolimod is an 
approved therapy and continues to be effective and safe for RMS participants across various 
countries in the world.  
 
 
4.2 
Rationale for dose/regimen and duration of treatment 
The dose of Gilenya for participants enrolled in this study is set at 0.5 mg orally administered 
once daily. The dosage of 0.5 mg has been approved in China for the treatment of relapsing 
multiple sclerosis in adults and pediatric participants with age ≥ 10 years old and weight > 40 
kg. 


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4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
Not applicable 
 
 
 
 
 
4.5 
Risks and benefits 
The risk to participants in this study will be minimized by compliance with inclusion/exclusion 
criteria, close clinical monitoring, avoidance of prohibited treatments and adherence to 
investigator guidance regarding specific safety areas. 
The risk profile of fingolimod includes bradyarrhythmia (including conduction effects) 
occurring post first dose, liver transaminase elevation, infection, macular edema, hypertension, 
clinically relevant bronchoconstriction and posterior reversible encephalopathy syndrome. 
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 outlined in the 
protocol. If there is any question that the participant will not reliably comply, they should not 
be entered or continue in the study. 
There is currently no data to inform incidence or severity of COVID-19 in patients receiving 
fingolimod. The immune system effects of fingolimod, integral to their mechanism of action in 
multiple sclerosis, may increase the risk of infections (including viral infections), as disclosed 
in the product label of drug. 
Patients receiving fingolimod, who may have been exposed to individuals with COVID-19, 
who are experiencing protracted flu-like symptoms (particularly shortness of breath) consistent 
with COVID-19, or are confirmed to have COVID-19, should inform treatment physician as 
soon as possible. Whether there will be interruption of the use of fingolimod will be based on 
investigator's judgement. 
4.5.1 
Imaging Risk  
A gadolinium-based contrast agent (GBCA) will be administered as an i.v. bolus during each 
MRI session. There is recent evidence of gadolinium deposition in brain tissues following use 
of GBCAs. Although no symptoms or diseases linked to gadolinium accumulation in the brain 
have been identified, health authorities took a precautionary approach (e.g., GBCA EMA 
restriction re brain deposit), noting that data on the long-term effects in the brain are limited. 
This led to the suspension of several linear GBCAs and the recommendation that another class 
of GBCAs known as macrocyclic agents be used as an alternative solution, as they are deemed 
more stable and have a lower propensity to release gadolinium than linear agents. Although this 
is highly debated, the current belief is that such agents, especially the linear gadolinium agents, 
may also increase the risk of a rare but serious disease called nephrogenic systemic fibrosis 


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(NFS). Few studies showed that use of linear agents in patients with normal kidney function or 
mild-to-moderate CKD (stage 3; eGFR 30-59 ml/min per 1.73 m2) is without clinically 
significant risk of nephrogenic systemic fibrosis (NFS) (Ledneva et al 2009), however they 
should remain contraindicated in patients with acute kidney injury (AKI) or severe renal 
disease  (stage 4 or 5 chronic kidney disease, CKD) (eGFR <30 ml/ min per 1.73 m2). To 
prevent this risk and in accordance with health authority guidance (e.g., GBCA FDA guidance 
re NFS, GBCA UK HA (Health Authority) guidance re NFS), people with severe kidney failure, 
patients with previous severe allergic/anaphylactoid reaction to a gadolinium-based contrast 
agent; patients with severe renal disease (eGFR <30 mL/min/1.73 m2), or acutely 
deteriorating renal function, who would be at risk of nephrogenic systemic fibrosis should be 
excluded from participating in this study as stipulated in the exclusion criterion. 
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 may be implemented. Notification of the Public health emergency as declared by local 
or regional authorities should be discussed among investigators and Novartis All procedures 
adapted to the situation must be submitted, if required as per local regulations, through a 
protocol amendment for approval by local or regional Health Authorities and Ethics 
Committees prior to implementation of mitigation procedures. The measures (refer to Section  
4.6 Rationale for Public Health Emergency mitigation procedures; Section 6.7 Preparation and 
dispensation; Section 7 Informed consent procedures and Section 8 Visit schedule and 
assessments for details) provide the possibility to collect safety information remotely, ship IMP 
directly to patients’ home, collect PRO remotely and conduct consent remotely in situation it is 
not safe for the participants to attend on-site visit. The measures are temporary and should only 
be used in justified cases as assessed by the investigator. 
5 
Population 
The study population will consist of adult relapsing multiple sclerosis participants aged 18-65 
years (inclusive) and in pediatric relapsing multiple sclerosis participants of 10 years of age and 
older weighing more than 40kg. 
Approximately 100 patients will be enrolled from around 10 to 15 centers in China. 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria at 
screening: 
1. Written informed consent must be obtained before any assessment is performed. 
2. Male or Female with age: 
18 to 65 years old inclusive; 
10 to 17 years old inclusive with weight > 40kg. 
3. Clinical definite diagnosis of Multiple Sclerosis according to the 2010 Revised McDonald 
criteria Polman et al 2011 (refer to Section 16.3). 


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4. Participants with a diagnosis of relapsing multiple sclerosis prior to their enrollment to the 
study (signing the study consent form): 
• At least two documented relapses during the past 2 years, or 
• At least one documented relapse during the last year 
5. With RMS that never used fingolimod before enrollment (including naive participants and 
participants who switched from previous DMTs). 
6. Participants with EDSS score of 0 - 6.0 (inclusive) at Screening. 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria at screening will not be eligible for this study. 
1. History of myocardial infarction, unstable angina pectoris, stroke/transient ischemic 
attack, decompensated heart failure with hospitalization or New York Heart Association 
(NYHA) Class III/IV heart failure (refer to Section 16.2) in the previous 6 months. 
2. Treatment with Class Ia or Class III anti-arrhythmic drugs. 
3. History or presence of Mobitz Type II 2nd degree or 3rd degree AV block or sick sinus 
syndrome, unless the participant has a pacemaker. 
4. Screening and Baseline QTc interval ≥ 500 msec. 
5. History of symptomatic bradycardia or recurrent syncope. 
6. History of cardiac arrest, uncontrolled hypertension or severe sleep apnea. 
7. Macular edema during screening visit. 
8. Increased risk for opportunistic infections, including immunocompromised participants : 
• currently receiving immunosuppressive therapies  
• immunocompromised by prior therapies where in the respective approved medication 
labels suggested wash out of the previous ongoing MS Disease Modifying Therapies 
(DMT) is not being conducted prior to ICF 
• absolute lymphocyte count is below 0.2 x 109/L 
9. Known active malignancies. 
10. Use of teriflunomide within 3.5 months prior to baseline, except if active washout (with 
either cholestyramine or activated charcoal) was done prior to fingolimod first dose in 
study. 
11. Under MS investigational drug clinical study. 
12. Severe active infections, active chronic infections (hepatitis, tuberculosis), as assessed by 
the treating physician. 
13. Severe liver impairment（Child-Pugh class C). 
14. Pregnant or nursing woman or woman of child-bearing potential not using highly effective 
contraception. 
Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant. Highly effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 


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participant. 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 bilateral 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. 
• 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 if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate 
history of vasomotor symptoms)). Women are considered not of child bearing potential if 
they are post-menopausal or have had surgical bilateral oophorectomy (with or without 
hysterectomy), total hysterectomy or bilateral 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. 
15. Pediatric participant without confirmed history of chickenpox or confirmed documentation 
of a full vaccination course against varicella zoster virus. 
16. Any disability that may prevent the participants from completing all study requirements, 
as assessed by the treating physician (e.g., mental disorder, blindness or deafness that is 
not appropriate for age, severe language difficulty).  
17. Current medical or neurological condition that might impact efficacy assessments e.g. 
dementia, schizophrenia, bipolar disorder, major depression, history of multiple traumatic 
brain injuries, alcohol/drug abuse or dependence currently, or dependence within the last 
two years. 
18. Advanced, severe progressive or unstable disease that may interfere with the safety, 
tolerability and study assessments, or put the participant at special risk, e.g. uncontrolled 
diabetes ((hemoglobin A1c (HbA1c)>9%)), severe uncontrolled respiratory disease 
(including but not limited to pulmonary fibrosis, abnormal pulmonary function tests 
values lower than 70% of predicted at screening), human immunodeficiency virus (HIV) 
infection, severe renal impairment. 
19. Patient intolerant to undergo MRI or presents contraindications to MRI (e.g., metallic 
implants, metallic foreign bodies, pacemaker, defibrillator) and the use of gadolinium-
based agents (e.g. people with severe kidney failure, patients with previous severe 
allergic/anaphylactoid reaction to a gadolinium-based contrast agent; patients with 


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severe renal disease (eGFR<30 mL/min/1.73 m2), or acutely deteriorating renal function, 
who would be at risk of nephrogenic systemic fibrosis). 
20. History of hypersensitivity to any of the Gilenya ingredients. 
21. Participant will be excluded from participation, if they have participated in any other 
unapproved therapy clinical study within last 6 months of the ICF signature date. 
6 
Treatment 
6.1 
Study treatment 
It is a single-arm, open-label study. The participants will take capsules of 0.5 mg fingolimod 
for oral administration.  
6.1.1 
Investigational and control drugs 
Table 6-1 
Investigational drug 
Investigational 
Drug 
(Name and 
Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Sponsor (global 
or local) 
Fingolimod 
(Gilenya) 0.5mg 
Capsule  
Oral use 
Open label   
Sponsor (global) 
6.1.2 
Additional study treatments 
No other treatment beyond investigational drug is included in this trial. 
6.1.3 
Treatment arms/group 
All participants will receive open-label fingolimod 0.5 mg, orally, once daily. 
6.1.4 
Treatment duration 
The planned duration of treatment is 24 months. Participants may be discontinued from 
treatment earlier due to unacceptable toxicity whether it is related to study drug or not, disease 
progression and/or treatment is discontinued at the discretion of the investigator or the 
decision of participant or serious non-compliance to study protocol. For participants who in the 
opinion of the investigator are still deriving clinical benefit from fingolimod, every effort will 
be made to continue provision of study treatment. 
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
All drug used in previous MS disease modifying treatment should be captured on the "Previous 
MS disease modifying Treatment" eCRF. 
All other concomitant medications taken within 30 days prior to Screening and during the study 
the respective information needs to be recorded in the eCRF. The investigator should instruct 


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the participant to notify the study site about any new medications he/she takes after the start of 
the study drug. Both the start date and the end date, for each medication should be captured on 
the Concomitant Medication CRF. 
Use of the following treatments are recommended to manage potential adverse reactions 
associated with the study drug: 
• anticholinergics (atropine s.c. or i.v.) for treatment of symptomatic bradycardia as the first 
line treatment, up to 3 mg/day; 
• beta-agonists/sympathomimetics (dopamine drip 5-20 μg/kg/min or epinephrine drip 2-10 
μg/min) for treatment of non-responsive bradycardia. 
For more recommendations for management of bradycardia, refer to Section 16.5. 
A short course of intravascular corticosteroids (methylprednisolone) is allowed for the 
treatment of MS relapses. 
The medications allowed for treatment of adverse reactions and MS relapses are not considered 
study supplies, and therefore, need to be supplied by the study site or only 0.5mg fingolimod 
will be supplied by sponsor. 
6.2.2 
Prohibited medication 
Use of the following treatments are NOT allowed during the whole course of the study (use can 
be considered if the study drug has been permanently discontinued): 
• anti-neoplastic; 
• immunomodulatory or immunosuppressive therapies should be prohibited due to the risk 
of additive immune system effects (e.g. cyclosporine, azathioprine, methotrexate, 
cyclophosphamide); 
• other concomitant treatment: immunoglobulins (IGs), monoclonal antibodies (including 
rituximab), other MS DMTs (including but not limited to IFN- ß, teriflunomide), 
adrenocorticotropic hormone (ACTH); 
• during and for up to two months after treatment with fingolimod, vaccination may be less 
effective. The use of live attenuated vaccines may carry a risk of infections and should 
therefore be avoided. 
6.2.3 
Rescue medication 
Not applicable. 
6.3 
Participant numbering, treatment assignment, randomization 
6.3.1 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is first enrolled for screening and is retained as the primary 
identifier for the participant throughout his/her entire participation in the study. The Participant 
No. consists of the Center Number (Center No.) (as assigned by Novartis to the investigative 
site) with a sequential participant number suffixed to it (assigned by the investigator), so that 


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each participant is numbered uniquely across the entire database. Upon signing the informed 
consent form (ICF), the participant is assigned to the next sequential Participant No. available. 
6.3.2 
Treatment assignment, randomization 
No randomization will be performed in this study. There is only one treatment arm in this study, 
which is fingolimod 0.5 mg, orally, once daily. 
6.4 
Treatment blinding 
As this study is open-label single arm study, treatment will not be blinded during the course of 
the study. 
6.5 
Dose escalation and dose modification 
6.5.1 
Dose modifications 
Not applicable. 
6.5.2 
Follow-up for toxicities 
6.5.2.1 
Follow up on potential drug-induced liver injury (DILI) cases 
Participants with transaminase increase combined with TBIL increase may be indicative of 
potential DILI and should be considered as clinically important events. 
The threshold for potential DILI may depend on the participant’s baseline aspartate 
aminotransferase (AST)/ALT and TBIL value; participants meeting any of the following 
criteria will require close follow-up as outlined below: 
• For participants with normal alanine aminotransferase (ALT) and AST and TBIL value at 
baseline: AST or ALT > 3.0 x ULN combined with TBIL > 2.0 x ULN 
• For participants with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline] OR [AST or ALT > 300 U/L] whichever occurs first combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN] 
As DILI is essentially a diagnosis of exclusion, other clinical causes of abnormal liver tests 
should be considered and their role clarified before DILI is assumed as the cause of liver injury. 
A detailed history, including relevant information such as review of ethanol consumption, 
concomitant medications, herbal remedies, supplement consumption, history of any pre-
existing liver conditions or risk factors, should be collected. 
Laboratory tests should include ALT, AST, total bilirubin（TBIL）, direct and indirect 
bilirubin, glutamyltransferase (GGT), prothrombin time/ international normalized ratio (INR), 
alkaline phosphatase, albumin, and creatine kinase. If available, testing of Glutamate 
Dehydrogenase (GLDH) is additionally recommended. 
Perform 
relevant 
examinations 
((Ultrasound 
or 
MRI, 
Endoscopic 
Retrograde 
Cholangiopancreatography (ERCP)) as appropriate, to rule out an extrahepatic cause of 
cholestasis. Cholestasis is defined as an alkaline phosphatase (ALP) elevation > 2.0 x ULN with 


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R value < 2 in participants without bone metastasis, or elevation of the liver-specific ALP 
isoenzyme in participants with bone metastasis. 
• Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the 
ULN for both values. It denotes whether the relative pattern of ALT and/or ALP elevation 
is due to cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury. 
For children, there are caveats to calculating the R-ratio as normal levels of ALP are 
higher than in adults with standard ranges varying by developmental age. In clinical 
situations where it is suspected that ALP elevations are from an extrahepatic source, the 
GGT can be used if available. GGT may be less specific than ALP as a marker of 
cholestatic injury, since GGT can also be elevated by enzyme induction or by ethanol 
consumption. It is more sensitive than ALP for detecting bile duct injury.  
Table 6-2 
Guidance on specific clinical and diagnostic assessments which can 
be performed to rule out possible alternative causes of observed LFT 
abnormalities. 
Disease 
Assessment 
Hepatitis A, B, C, E 
• IgM anti- hepatitis type A virus (HAV); Hepatitis B 
surface antigen (HBsAg), IgM & IgG anti - hepatitis B 
core (HBc),HBV deoxyriboNucleic acid (DNA); anti- 
hepatitis type C virus (HCV), HCV ribonucleic 
acid (RNA), IgM & Ig Ganti- hepatitis type E virus 
(HEV), HEV RNA 
CMV, HSV, EBV infection 
• IgM & IgG anti-CMV (Cytomegalovirus), IgM & 
IgG anti- herpes simplex virus (HSV); IgM & IgG 
anti- epstein-barr virus (EBV) 
Autoimmune hepatitis 
• 
antinuclear antibody (ANA) & anti-smooth muscle 
antibody (ASMA) titers, total Immunoglobulin M (IgM), 
Immunoglobulin G (IgG), Immunoglobulin E (IgE), 
Immunoglobulin A (IgA) 
Alcoholic hepatitis 
• 
Ethanol history, GGT, mean corpuscular volume (MCV), 
carbohydrate-deficient transferrin (CD-transferrin) 
Nonalcoholic steatohepatitis 
• 
Ultrasound or MRI 
Hypoxic/ischemic hepatopathy 
• 
Medical history: acute or chronic congestive hearts 
failure (CHF), hypotension, hypoxia, hepatic venous 
occlusion. Ultrasound or MRI 
Biliary tract disease 
• 
Ultrasound or MRI, ERCP as appropriate 
Wilson disease (if <40 yrs old) 
• 
Caeruloplasmin 
Hemochromatosis 
• 
Ferritin, transferrin 
Alpha-1-antitrypsin deficiency 
• 
Alpha-1-antitrypsin 
Other causes should also be considered based upon participants’ medical history 
((hyperthyroidism / thyrotoxic hepatitis – triiodothyronine (T3), tetraiodothyronine (T4), 
Thyroid Stimulating Hormone (TSH); Cardiovascular Disease (CVD) / ischemic hepatitis – 
ECG, prior hypotensive episodes; type 1 diabetes (T1D) / glycogenic hepatitis)). 
Following appropriate causality assessments, as outlined above, the causality of the treatment 
is estimated as “probable” i.e. >50% likely, if it appears greater than all other possible causes 
of liver injury combined. The term “treatment-induced” indicates probably caused by the 


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treatment, not by something else, and only such a case can be considered a DILI case and should 
be reported as an SAE. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant,” and thus, meet the definition of SAE and should reported as SAE using the term 
“potential drug-induced liver injury.” All events should be followed up with the outcome clearly 
documented. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
The investigator must promote compliance by instructing the participant to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the participant's 
safety and the validity of the study. The participant must also be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as prescribed. 
Compliance will be assessed by the investigator and/or study personnel at each visit using pill 
counts and information provided by the participant. This information should be captured in the 
source document at each visit. All study treatment dispensed and returned must be recorded in 
the Drug Accountability Log. 
6.6.2 
Emergency breaking of assigned treatment code 
Not applicable. 
6.7 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section. 
A unique medication number is printed on the study drug label. As per the treatment assigned 
to the participant, investigator staff will select the study treatment to dispense to the participant. 
The study drug has a 2-part label (base plus tear-off label), immediately before dispensing the 
package to the participant, site personnel will detach the outer part of the label from the package 
and affix it to the participant's source document. 
Per Section 4.6, during a Public Health emergency delivery of IMP directly to a participant's 
home may be permitted (if allowed by Local or Regional Health Authorities and Ethics 
Committees as appropriate) in the event the Investigator has decided that an on-site visit by the 
participant is no longer appropriate or possible, and that it is in the interest of the participant's 
health to administer the study treatment even without performing an on-site visit. The dispatch 
of IMP from the site to the participant’s home remains under the accountability of the 
Investigator. Each shipment/provisioning will be for a maximum of 13 weeks supply. Sufficient 
supply will be provided for the participants in situations when the participants cannot visit sites 
for a longer period of time. In this case, regular phone calls or virtual contacts (every 3 months 
or more frequently if needed) will occur between the site and the participant for instructional 
purposes, safety monitoring, investigation of any adverse events, ensuring participants continue 


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to benefit from treatment, and discussion of the participant's health status until the participants 
can resume visits at the study site. 
6.7.1 
Handling of study treatment and other treatment 
6.7.1.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels and in the Investigator’s Brochure. Clinical supplies are to 
be dispensed only in accordance with the protocol. Technical complaints are to be reported to 
the respective Novartis Country Organization Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Participants will be 
asked to return all unused study treatment and packaging at the end of the study or at the time 
of discontinuation of study treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis/sponsor monitor or to the Novartis address provided in the 
investigator folder at each site. 
6.7.1.2 
Handling of additional treatment 
Not Applicable. 
6.7.2 
Instruction for prescribing and taking study treatment 
• Fingolimod (Gilenya) 0.5 mg, 1 capsule, orally. 
• Once daily, preferably always at the same time of the day, with or without food. 
• The first dose of the study drug administered at the Day 1 visit, should be taken in the 
clinic preferably on or before 12:00 PM (noon). The participant will be monitored by the 
site staff for at least 6 hours until discharge criteria are met (refer to Section 16.5 for 
Guidance for monitoring of patients taking their first dose of the study drug). Monitoring 
of re-initiation of first dose will be performed when: interruption of 1 day or more within 
the first 2 weeks of treatment, interruption of more than 7 days during the 3rd week and the 
4th week of treatment and interruption of more than 14 days after the first month of 
treatment in a similar manner as the first intake of the study drug (refer 
to Section 16.5 for Guidance for monitoring of patients taking their first dose of the study 
drug). 
• The treatment will last up to 24 months. 


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• It is recommended not to initiate treatment with beta-blockers, calcium-channel blockers 
or digoxin within one week before or after the first dose of the study drug due to a 
possible additive effect on heart rate reduction. 
• Site staff will make sure to dispense sufficient amount of study drug to participants. The 
amount should cover the period until participants come back to the clinic at the latest visit 
window allowed in the protocol. When the participants return for the following study visit, 
the site staff will count the capsules left, log the amount left into a drug accountability log 
and re-distribute the drug to the participants following the same procedure described 
above. 
• It is a single-arm open label study. Participant eligible for the study will be treated with 
fingolimod (Gilenya). 
• Participants should be instructed to swallow whole capsule and not to chew or open it. 
• If vomiting occurs during the course of treatment, participants should not take fingolimod 
(Gilenya) again before the next scheduled dose. 
• Participants should be instructed not to make up missed doses. A missed dose is defined as 
a case when the full dose is not taken within 8 hours after the approximate time of the 
usually daily dosing. That day's dose should be omitted and the participant should 
continue treatment with the next scheduled dose. 
7 
Informed consent procedures 
The Investigator or his/her representative will explain the nature of the study, including the risks 
and benefits, to the participant or their legally authorized representative and answer all questions 
regarding the study. 
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representatives will be required to sign a statement of informed consent that meets 
the requirements of FDA 21 CFR 50, local regulations, ICH guidelines, privacy and data 
protection requirements, where applicable, and the IRB/IEC or study center. 
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 participant source documents. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
A copy of the ICF(s) must be provided to the participant or their legally authorized 
representative. 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her level of understanding. If the participant is capable of doing so, he/she 


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must indicate agreement by personally signing and dating the written informed consent 
document. 
Information about common side effects already known about the investigational treatment can 
be found in the Investigator's Brochure (IB) (and/or Core Data Sheet for marketed drugs). This 
information will be included in the participant informed consent and should be discussed with 
the participant upon obtaining consent and also 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 participant. 
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. 
The following informed consents are included in this study: 
• Main study consent for adults, which also included: 
o A subsection that requires a separate signature for the ‘Optional Consent for 
Additional Research’ to allow future research on data/samples collected during 
this study 
o Optional consent for activities that may be done outside of the study site 
• Child Assent for 7-11 years old participants 
• Adolescent Assent for 12-17 years old participants  
• As applicable, Parent Legal Guardian consent 
• As applicable, Pregnancy Follow-up consent for the pregnant participants 
• As applicable, Pregnancy Follow-up consent for parent legal guardian of pregnant 
participants 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
As per Section 4.6, during a Public Health emergency 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 
There are mandatory scheduled visits in the context of this interventional study. Table 8-1 lists 
all assessments scheduled at each visit. It is planned that participants should come to site and 


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be evaluated every three months till the end of treatment, following by two months' follow-up 
visit after the last treatment of fingolimod. 
Participants who discontinue from study should be scheduled for a final evaluation visit (see 
Table 8-1 for details) if they agree, 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 not 
previously reported must be recorded on the CRF. 
At the onset of any symptom indicative of a relapse during the study, participants may have 
unscheduled visits to confirm relapse and collect information. In addition, participants may 
have unscheduled visits for other reasons, including but not limited to infection, blurred vision. 
In case of MS relapse, these visits are essential for relapse evaluation and confirmation and 
have to be carefully documented on the Unscheduled Visit eCRFs. Exams to confirm relapse is 
based on investigator's discretion. During unscheduled visits for other reasons, information 
should be collected per Unscheduled Visit eCRFs. 
Participants should follow as much as possible the visit schedule with an allowed “visit window” 
of ± 3 days for Month 1 and Month 3 visit and ± 5 days for Month 6, Month 9, Month 12, Month 
15, Month 18, Month 21, Month 24 and 2-month follow up visit. In case a visit was performed 
outside the visit window, subsequent visits should be performed according to the original visit 
schedule and as applicable per study label guidelines necessary first dose monitoring should be 
performed at site. In the study, one month is defined as 30 calendar days. 
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, national and local regulations and depending 
on operational capabilities, phone calls, virtual contacts (e.g. tele consultation) or visits by site 
staff/off-site healthcare professional(s) staff to the participant´s home, can replace certain 
protocol assessments, for the duration of the disruption until it is safe for the participant to visit 
the site again. If the Investigator delegates tasks to an off-site healthcare professional, the 
Investigator must ensure the individual(s) is/are qualified and appropriately trained to perform 
assigned duties. The Investigator must oversee their conduct and remain responsible for the 
evaluation of the data collected.


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Table 8-1 
Assessment Schedule 
Period Screening 
Treatment Period 
 
 
 
Follow-up 
Visit2 
Visit Name Screening Day 1 Month 1 Month 3 Month 6 
Month 9 
Month 12 Month 15 Month 18 Month 21 Month 24 
EOT3 
EOS4 
Follow-up 
Visit 
Days 
-30  
1 to 1 27 to 33 87 to 93 175 to 185 265 to 275 355 to 365 445 to 455 535 to 545 625 to 635 715 to 725 
NA 
NA 
775 to 785 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
 
 
  
Demography 
X 
  
  
  
  
  
  
  
  
  
  
 
 
  
Inclusion / Exclusion criteria6 
X 
X 
  
  
  
  
  
  
  
  
  
 
 
  
MS history/current medical 
conditions7 
X 
  
  
  
  
  
  
  
  
  
  
 
 
  
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug dispensation1 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
 
 
  
Drug accountability1 
  
  
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
  
1st dose observation8 
  
X 
  
  
  
  
  
  
  
  
  
 
 
  
Pregnancy and assessments 
of fertility9 
S 
  
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Body Height 
X 
  
  
  
  
  
  
  
  
  
  
 
 
  
Body Weight 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
S 
S 
  
  
S 
  
S 
  
S 
  
S 
S 
S 
S 
MS relapse10 
 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EDSS 
X 
MRI11 
X 
  
  
  
  
  
X 
  
  
  
X 
X 
X5 
  
Ophthalmic examination12 
X 
  
  
X 
X 
  
X 
  
  
  
X 
X 
X 
X 
Dermatological examination 
S 
  
  
  
S 
  
S 
  
S 
  
S 
S 
S 
S 
Electrocardiogram (ECG)13 
X 
X 
X 
X 
X 
  
X 
  
X 
  
X 
X 
X 
X 
Hematology 
X 
  
X 
X 
X 
X 
X 
  
X 
  
X 
X 
X 
X 
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Period Screening 
Treatment Period 
 
 
 
Follow-up 
Visit2 
Visit Name Screening Day 1 Month 1 Month 3 Month 6 
Month 9 
Month 12 Month 15 Month 18 Month 21 Month 24 
EOT3 
EOS4 
Follow-up 
Visit 
Days 
-30  
1 to 1 27 to 33 87 to 93 175 to 185 265 to 275 355 to 365 445 to 455 535 to 545 625 to 635 715 to 725 
NA 
NA 
775 to 785 
HIV screen 
S 
  
  
  
  
  
  
  
  
  
  
 
 
  
Chemistry 
X 
  
X 
X 
X 
X 
X 
  
X 
  
X 
X 
X 
X 
Hepatitis B test14 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest CT (Computed 
Tomography) 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prothrombin time 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
S 
  
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Reported AE/SAE 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulmonary function tests 
S 
as 
needed 
as 
needed 
as 
needed as needed as needed as needed as needed as needed as needed as needed As needed 
As 
needed 
as needed 
 
 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S 
Assessment 
to 
be 
recorded 
in 
the 
source 
documentation 
only 
1 Drug accountability and dispensation will not be performed after participants discontinued the study or the study 
treatment. 
2Participants that complete 24 months treatment period will complete the 2 months follow up visit; Participants that 
prematurely discontinue therapy and stay in the study for the whole 24 months will complete the 2-month follow up visit. 
3 Any participants who discontinue from treatment should follow the assessments of the EOT visit. 
4 Any participants who discontinue from study should follow the assessments of the EOS visit. If EOT and EOS will be 
on the same day, only EOS visit is required. 
5 EOS MRI only required when EOS occurred within 30 days after the last dose and there is no MRI at EOT. 
6 
Inclusion/exclusion 
criteria 
need 
to 
be 
checked 
again 
before 
first 
dose 
of 
study 
drug. 
7 Previous medical history will be collected for each participant in order to capture pre-existing medical conditions.  The 
number 
of 
documented 
relapse 
in 
previous 
1 
year 
and 
2 
years 
will 
be 
collected. 


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Period Screening 
Treatment Period 
 
 
 
Follow-up 
Visit2 
Visit Name Screening Day 1 Month 1 Month 3 Month 6 
Month 9 
Month 12 Month 15 Month 18 Month 21 Month 24 
EOT3 
EOS4 
Follow-up 
Visit 
Days 
-30  
1 to 1 27 to 33 87 to 93 175 to 185 265 to 275 355 to 365 445 to 455 535 to 545 625 to 635 715 to 725 
NA 
NA 
775 to 785 
8 Participants who newly initiate fingolimod therapy or restart fingolimod after dose interruption should be observed for 
6 hours after treatment initiation per the local label. Monitoring of reinitiating of first dose will be performed when: 
interruption of 1 day or more within the first 2 weeks of treatment, interruption of more than 7 days during weeks 3 and 
4 
of 
treatment 
and 
interruption 
of 
more 
than 
14 
days 
after 
the 
first 
month 
of 
treatment. 
9 Blood pregnancy test will be performed at screening visit. Urine or Serum pregnancy test will be performed at following 
visits. 
10 Unscheduled visits are required to confirm MS relapse and additional EDSS assessments may be conducted. 
11 All participants will undergo MRI scanning of the brain at Screening, provided the participant meets all other 
Inclusion/Exclusion (I/E) criteria, Month 12 and Month 24 in accordance with the study Imaging Acquisition Guidelines. 
If 
required, 
unscheduled 
MRI 
scans 
will 
be 
conducted 
based 
on 
investigator’s 
judgement. 
12 Screening visit and Month 3 visit will include ophthalmic symptoms, best corrected visual acuity and optical coherence 
tomography(OCT) for the measurement of central foveal thickness. All the other scheduled visits, the content will include 
any 
new 
ophthalmic 
symptoms 
and 
best 
corrected 
visual 
acuity. 
13 ECG to be obtained on Day 1 before Fingolimod dose administration and 6 hours post-first dose The first ECG will be 
performed on Day 1 to check the I/E criteria again. If the participant is eligible to be enrolled, the ECG result will be 
recorded as pre-dose ECG. The second ECG will be performed at 6 hours post dose. If extended monitoring is required, 
ECG will be performed by the end of extended monitoring. If study drug treatment is interrupted and treatment re-
initiation meets the requirement for observation, the above procedures will be performed, identical to procedures 
conducted at Day 1. 
14 Hepatitis B test include: HBV surface antigen, surface antibody, E antigen, E antibody, core antibody; if abnormal 
finding on HBV surface antigen, HBV DNA copies test will be performed. 


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8.1 
Screening 
It is permissible to re-screen a participant if s/he fails the initial screening; re-screening should 
only occur after a participant has failed screening and re-screening window time is at the 
discretion of the investigator. A new participant ID should be assigned to the re-screened 
participant. 
As per Section 4.6, during a Public Health emergency, 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. In exceptional cases and after discussing with the study team, 
participant go to another hospital for safety test will be permitted. 
8.1.1 
Information to be collected on screening failures 
Participants who sign an informed consent form and is subsequently found to be ineligible prior 
to starting treatment will be considered as a screen failure. The reason for screen failure should 
be recorded on the appropriate Case Report Form. The demographic information, informed 
consent, and inclusion/exclusion pages must also be completed for screen failure participants. 
No other data will be entered into the clinical database for participants who are screen failures, 
unless the participant experienced a serious adverse event during the screening period. Data and 
samples collected from participants prior to screen failure may still be analyzed. 
Participants who have passed screening and fail to start treatment will be considered as an early 
terminator. The reason for early termination will be recorded on the appropriate Case Report 
Form. 
8.2 
Participant demographics/other baseline characteristics 
Participant demographic and baseline characteristic data will be collected from the participant 
which included: age, race, sex, ethnicity, height and weight.   
Previous MS history (including diagnosis and history of relapses), and current medical 
condition will be collected and recorded on CRF. 
8.3 
Efficacy 
MS relapse activity and neurological impairment of MS as measured by Expanded Disability 
Status Scale (EDSS) (refer to Section 16.4 for EDSS assessment criteria) will be obtained in 
order to characterize the disease activity. 
8.3.1 
Efficacy assessment 1 
MS relapse 
General definition of relapse: Appearance of a new neurological abnormality or worsening of 
previously stable or improving pre-existing neurological abnormality, separated by at least 30 


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days from onset of a preceding clinical demyelinating event. The abnormality must be present 
for at least 24 hours and occur in the absence of fever (< 37.5 °C) or infection. 
Definition of confirmed relapse: A relapse must be confirmed by the Treating Physician. It is 
recommended that this occur within 7 days of the onset of symptoms. A relapse is confirmed 
when it is accompanied by an increase of at least half a step (0.5) on the EDSS or an increase 
of 1 point on two different Functional Systems (FS) of the EDSS or 2 points on one of the FS 
(excluding Bowel/Bladder or Cerebral FS). 
Only confirmed relapses will be included in the primary efficacy analysis. However, the 
relapse-related analyses will be repeated using all relapses to assess the sensitivity of the results. 
Reporting of relapse : A participant may report symptoms indicative of a relapse at a scheduled 
visit or at any other time. Participants will be instructed to immediately contact the treating 
physician if he/she develops new or re-occurring or worsening neurological symptoms. At each 
scheduled visit, the participant will also be asked whether any such symptoms have occurred. 
Upon reporting of symptoms indicative of a relapse, the treating physician will assess in an 
appropriate manner whether the symptoms occur in the presence of fever or infection. If fever 
or infection can be excluded, a neurological examination by the treating physician must be 
arranged as soon as possible. If fever or infection cannot be excluded, the neurological 
examination will be postponed until the fever or the infection has ceased (provided, that the 
symptoms indicative of a relapse are still present). Treatment with steroids should not begin 
prior to the assessment by the investigator.  
Based on results of the neurological examination (change in FS and EDSS scores), the treating 
physician will assess if the relapse meets the criteria for “confirmed relapse” as per protocol 
and record relapse on the Summary of MS Relapses eCRF. 
8.3.2 
Efficacy assessment 2 
Expanded Disability Status Scale (EDSS). 
The EDSS is an ordinal scale used for assessing neurologic impairment in MS based on a 
neurological examination. It consists of scores in each of seven functional systems (FSs) that 
are then combined to determine the EDSS steps [ranging from 0 (normal) to 10 (death due to 
MS)]. The FSs are Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel & Bladder, and 
Cerebral functions. The FSs and EDSS steps will be assessed in a standardized manner. EDSS 
is a widely used and accepted instrument to evaluate disability status at a given time and, 
longitudinally, to assess disability progression in clinical studies in MS. 
 
 
 
 
 
 EDSS assessments obtained on an unscheduled visit can only 
be used to mark the onset of a possible sustained progression. 


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Patient who dies due to MS will be counted as progression. A patient who misses one or more 
scheduled visits that are preceded
 
 
MRI parameters: T1 hypo-intense lesion number and volume; T2 lesion volume, 
new/newly enlarged T2 lesion number; Gd- enhancing T1 lesion number and 
volume; 
All participants will undergo MRI scanning of the brain in accordance with the study Imaging 
Acquisition Guidelines during the Screening visit (up to 30 days prior to day 1), provided the 
participant meets all other I/E criteria, and then for the Month 12 and Month 24 visits. Each 
MRI scan performed for the study needs to be centrally reviewed by a neuro-radiologist from 
the sponsor designated imaging vendor as part of the efficacy analysis. Each site investigator 
will be responsible to have a qualified neuro-radiologist review each MRI scan to determine if 
there may be any incidental findings unrelated to the planned observations within the study 
protocol detected on the images. Refer to Section 16.7 Appendix 7 for Guidance on Safety 
monitoring. 
Participant suspected MS relapse could undergo additional MRI scan on his/her own account 
in alignment with the investigator. To avoid potential interference caused by steroids used for 
the treatment of MS relapses, the following restrictions will be applied for this study: 
x In case of relapse, if an MRI would have been scheduled within 30 days of the initiation of 
steroid treatment, this MRI should be performed before steroid treatment is initiated. 
x No MRI scan should be performed while a participant is on intravenous steroid therapy 
and within 30 days after termination of steroid therapy. 
Scanning 
The contrast medium may occasionally cause nausea and vomiting. Allergic reactions may also 
occur very rarely and, in extremely rare instances, can be potentially serious and require 
immediate anti-anaphylactic treatment (i.v. epinephrine, dopamine, steroids, etc.)  
T1-weighted images before and after administration of Gadolinium contrast medium as well as 
T2-weighted images will be performed. 
Prior to the start of the study, a radiologist and technician from each center will receive an 
Imaging Acquisition Guideline, outlining technical implementation, image quality check (QC) 
requirements and MRI administrative procedures. Each site will be asked to program the MRI 
scanner acquisition technical parameters that are designated for evaluation of the study 
participants, perform and submit a phantom test scan using a QC phantom or equivalent, to 
generate images that will be transferred to the sponsors designated CRO to assess the image 
quality and to evaluate the compatibility of the electronic data carrier. Following the acceptance 
of the phantom test scan, all the parameter settings for the study specific MRI sequences must 
remain unchanged for the duration of the study unless the site is directed to adjust the settings 
by the imaging CRO following consultation with the sponsor.       
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8.3.3 
Appropriateness of efficacy assessments 
MS relapse, EDSS assessments as well as MRI parameters in this patient population are 
standard efficacy assessments in MS and serve to characterize the patient population included 
in this study as well as their disease activity and neurological status over the study. 
8.4 
Safety 
Safety assessments are specified as below with the assessment schedule detailing when each 
assessment is to be performed. If the COVID-19 pandemic limits or prevents on-site study visits, 
phone calls or virtual contacts should be conducted for safety monitoring and discussion of the 
participant´s health status, until the participant can again visit the site. In exceptional cases and 
after discussing with Novartis, safety tests could be performed outside of the investigator sites.  
For details on AE collection and reporting, refer to AE section. 
• Physical/neurological examination 
• Vital signs 
• Skin assessments 
• Laboratory evaluations 
• ECG 
• First dose monitoring 
• Ophthalmologic exams / Optical coherence tomography (OCT) 
• Pulmonary function test 
As per Section 4.6, during a Public Health regular phone or virtual calls can occur (every 12 
weeks or more frequently if needed) for safety monitoring and discussion of the participant’s 
health status until it is safe for the participant to visit the site again. 
Table 8-2 
Assessments & Specifications 
Assessment 
Specification 
Physical  
A physical examination may be performed at a scheduled visit and may include 
an assessment of skin, head and neck, lymph nodes, breast, heart, lungs, 
abdomen, back and/or comments on general appearance. A neurological 
examination may also be a part of the physical examination.  
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are present prior 
to signing informed consent must be recorded on the appropriate CRF that 
captures medical history. Significant findings made after signing informed consent 
which meet the definition of an Adverse Event must be recorded as an adverse 
event. 
Vital signs 
Vital signs include temperature, blood pressure and pulse measurements. 
Sitting pulse rate and blood pressure will be recorded at each visit and should be 
obtained after the patient has 5 minutes of rest. The pulse should be measured 
just prior to obtaining the blood pressure measurement. After the participant has 
been sitting for five minutes, with back supported and both feet placed on the 
floor, systolic and diastolic blood pressure will be measured three times using an 
automated validated device, e.g. OMRON, with an appropriately sized cuff. The 


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Assessment 
Specification 
repeated sitting measurements will be made at 1 - 2 minute intervals and the 
mean of the three measurements will be used.  
Clinically notable vital signs are defined in Appendix 1. 
Skin 
assessments 
A complete skin examination will be performed by a dermatologist or qualified 
physician as described in Table 8-1. The purpose of a skin examination at 
baseline is to exclude participants with suspicious skin lesions (pre-cancerous, 
cancerous) from the study and to document a baseline assessment in order to 
monitor participants with non-suspicious lesions for the duration of the study. 
It is recommended that all participants perform a skin self examination (SSE) on a 
monthly basis. Participants should be instructed on how to properly conduct these 
examinations.  If the participant reports new or changed lesion(s) during the 
study, a skin exam should be performed by a dermatologist. 
In case of findings at any visit, suspicious for being precancerous or cancerous 
skin disorders, the investigator will refer the participant to a qualified physician for 
further examination and a biopsy may be required to rule out or to confirm 
diagnosis. Upon completion of the examination any new findings during the study 
will be transcribed in the Adverse Event eCRF. 
8.4.1 
Laboratory evaluations 
Laboratory samples will be collected as described in Table 8-3 and analyzed by the local lab. 
Investigators will be asked to comment on these abnormalities on the respective lab result page, 
including a notation of the clinical significance of each abnormal finding in the participant's 
source documents. The laboratory sheets will be filed with the source documents. Mandatory 
hematology and chemistry test results should be recorded on the eCRF. 
Any diagnosis (or signs or symptoms if a diagnosis is not possible) associated with the abnormal 
findings should be recorded on the adverse event eCRF. 
Clinically notable laboratory findings are defined in Appendix 1. 
In case of increases in liver function test (LFT), refer to Appendix 7 Guidance on Safety 
Monitoring. 
In case of decreases in lymphocytes, refer to Guidance on monitoring of participants with 
notable lymphopenia in Appendix 7 Guidance on Safety Monitoring. 
If the COVID-19 pandemic limits or prevents on-site study visits, the method of collection of 
samples may be modified by Novartis if applicable and if modified, will be communicated to 
the Investigator. In exceptional cases and after discussing with Novartis, safety tests could be 
performed outside of the investigator sites. 
Table 8-3 
Laboratory Evaluations 
Test Category 
Test Name 
Hematology 
Hemoglobin, Platelets, White blood cells (WBC), Differential 
(Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, 
Other) 


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Test Category 
Test Name 
Hepatitis B test 
HBV surface antigen, surface antibody, E antigen, E antibody, core 
antibody; if abnormal finding on HBV surface antigen, HBV DNA 
copies test will be performed. 
Coagulation 
Function 
Prothrombin time 
Chemistry 
ALT , AST , Creatinine, Direct Bilirubin, Total Bilirubin, Total 
Cholesterol 
Urinalysis 
Macroscopic Panel /Dipstick (Color, Blood, Glucose) 
Additional tests 
HIV antibodies 
Pregnancy Test 
Serum / Urine pregnancy test  
8.4.2 
Electrocardiogram (ECG) 
ECGs will be collected at Screening visit, Day1, Month 1, Month 3, Month 6, Month 12, Month 
18, Month 24, Premature discontinue from treatment (EOT), premature discontinue from study 
(EOS), Follow-up visit according to the assessment schedule and as needed if study drug is 
restarted after interruption. 
At Day1, two to three ECGs will be performed. The first ECG will be performed on Day 1 to 
check the I/E criteria again. If the participant is eligible to be enrolled, the ECG result will be 
recorded as pre-dose ECG. The second ECG will be performed approximately 6-hours post-
first-dose. If extended monitoring is needed, then a third ECG will be performed by the end of 
extended monitoring. 
If study drug treatment is interrupted and treatment re-initiation meets the requirement for 
observation, the above procedures will be repeated, identical to procedures conducted at Day 1. 
For any ECGs with participant safety concerns, an additional ECG must be performed to 
confirm the safety finding. Clinically significant abnormalities must be recorded on the CRF as 
adverse events. 
 
All the below ECG parameters will be captured in the eCRF: heart rate, PR interval, QRS 
duration, QT and QTc interval. Any diagnoses (or signs or symptoms if a diagnosis is not 
possible) associated with the abnormal findings should be recorded on the adverse event eCRF. 
8.4.3 
Pregnancy and assessments of fertility 
To confirm an eligibility of a woman of child bearing potential for the study, a blood pregnancy 
test should be performed at Screening visit. Participants, who are determined and documented 
to be surgically-sterile or post-menopausal for 12 months or longer prior to Screening, are not 
required to undergo pregnancy testing. 
Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse 
with a male partner and women whose partners have been sterilized by vasectomy or other 
means, unless they meet the following definition of post-menopausal: 12 months of natural 


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(spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum follicle-
stimulating hormone (FSH) levels >40 mIU/m or 6 weeks post surgical bilateral oophorectomy 
with or without hysterectomy OR are using one or more of the following highly effective  
contraception: surgical sterilization, hormonal contraception, and double-barrier methods. 
Acceptable methods of contraception may include total abstinence at the discretion of the 
investigator in cases where the age, career, lifestyle, or sexual orientation of the participant 
ensures compliance. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. Reliable 
contraception should be maintained throughout the study and for 2 months after study drug 
discontinuation. 
Additional Urine or Serum Pregnancy tests may be performed at scheduled assessment visit. 
The positive urine test needs to be confirmed with serum test. 
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 
participant regardless of reported reproductive/menopausal status at screening/baseline. 
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, if participants cannot 
visit the site to have urine or serum pregnancy tests, urine pregnancy test kits for home use may 
be used if allowed by local regulations. 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 and can verify the pregnancy test results (e.g., following 
country specific measures). 
8.4.4 
Other safety evaluations 
8.4.4.1 
First dose monitoring 
For safety concern, the first dose of fingolimod administered at Day 1 in this study must be 
administered in the clinic under the supervision of the investigator. It is recommended that the 
first dose be administered in the morning, before 12 noon to allow for adequate monitoring time. 
The patient will stay at the study center for a minimum of 6 hours. Heart rate and blood pressure 
will be monitored hourly during the six hour stay and discharged if specific discharge criteria 
(outlined in Section 16.5) are met. Hourly monitoring will be extended if the discharge criteria 
are not met. Some participants may be required to return to the study center for 6 hours 
following the 2nd dose if they meet the monitoring criteria as outlined in Section 16.5. 
The investigator should promote compliance by instructing the patient to take the study drug 
exactly as prescribed and by stating that compliance is necessary for the participant’s safety and 


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the validity of the study. The participant should be instructed to contact the investigator if he/she 
is unable for any reason to take the study drug as prescribed. 
Should the participant interrupt the study drug, and should the investigator decide in agreement 
with the sponsor to re-initiate treatment with the study drug, the first dose intake at re-start must 
take place at the study site to ensure 6-hour monitoring by the First Dose Administrator in a 
similar manner as the first intake of the study drug. It is recommended not to initiate beta-
blockers and calcium-channel blockers treatment in 24-hours prior or concomitant to re-
initiation of the study drug administration due to a possible additive effect on heart rate 
reduction. 
Monitoring of reinitiating of first dose will be performed when: interruption of 1 day or more 
within the first 2 weeks of treatment, interruption of more than 7 days during weeks 3 and 4 of 
treatment and interruption of more than 14 days after the first month of treatment. 
8.4.4.2 
Ophthalmic examination 
A complete ophthalmic examination will be performed by an ophthalmologist as described 
in Table 8-1. 
At Screening and Month 3, Best Corrected Visual Acuity (BCVA) and Optical Coherence 
Tomography (OCT) for the measurement of central foveal thickness will be collected. 
At all other scheduled visits, BCVA and new ophthalmic symptoms will be collected. In the 
case of confirmed of visual acuity decline, an optical coherence tomography will be conducted 
by the investigator's discretion. 
Details on the ophthalmic examinations are provided in the Guidance for Ophthalmic 
Monitoring Section 16.6. 
The ophthalmologist will describe examination findings on an examination worksheet provided 
by the investigative site. The worksheet will be transferred to the site where the data will be 
transcribed to the Ophthalmic Examination eCRF. 
Participants with newly diagnosed uveitis after initiation of study drug will require more 
frequent ophthalmic evaluations. Refer to Section 16.6 for the Guidance for Ophthalmic 
Monitoring for details on monitoring of participants with uveitis during the study. 
During the study, participants with a diagnosis of macular edema must interrupt the study drug. 
These patients must be followed-up 1 month and 3 month after diagnosis of macular edema and 
more frequently if needed based on the ophthalmologist’s judgement. Further ophthalmologic 
evaluations until such time as resolution is confirmed or no further improvement is expected by 
the ophthalmologist (based on a follow up period of not less than 3 months). If the participant 
does not show definite signs of improvement on examination by specialist testing (e.g. OCT, 
FA) 6-8 weeks after interruption of study drug, then therapy for macular edema in conjunction 
with an ophthalmologist experienced in the management of this condition should be initiated.  
 
Re-initiation of the study drug can only be considered if the macular edema has resolved 
completely, the individual risk-benefit is favorable (as determined by the Investigator, in 
agreement with the Ophthalmologist) and after discussion with the Novartis Medical Advisor. 


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The patients must have follow up ophthalmic examinations at one month after study drug is re-
initiated, three months later and then every 3 months up to one year, and every 6 months 
thereafter. 
8.4.4.3 
Pulmonary function test 
Pulmonary Function tests evaluating forced expiratory volume within 1 second (FEV1) and 
carbon monoxide (CO) diffusing capacity (DLCO) will be performed for all the patients at 
screening period and can be performed when participants with any reported AE related to 
respiratory disease during the treatment period, as per investigator discretion.  
The FEV1 describes the volume (in Liters) that is expelled within one second of forced 
expiration after a maximal inspiration and reflects the large airway resistance. A decrease in 
FEV1 serves as a good parameter for detection of an obstructive ventilatory defect. 
Gas exchange is assessed by the DLCO evaluated by the single breath holding method. It is a 
measurement of carbon monoxide (CO) transfer from the lung over a breath-holding period to 
pulmonary capillary blood. Because the CO binds readily to hemoglobin, the diffusion capacity 
needs to be corrected for hemoglobin in order to reflect an altered lung gas transport rather than 
altered hemoglobin. 
Based on the investigator’s judgement, pulmonary function test (PFT) can be performed when 
participants with AE related to respiratory disease during the treatment period. In case of 
reduction of FEV1 and/or DLCO below 80% of baseline values the patient’s pulmonary status 
will require a follow-up as soon as possible. Should the repeat PFT values (FEV1 and/or DLCO) 
remain below 80% of baseline values, the patient will be referred to pneumologist 
(pulmonologist) for further evaluation and treatment. In case of reduction of FEV1 and/or 
DLCO below 60% of baseline value in any visit, the study drug is recommended to be 
interrupted and suggest to refer the patient a pneumologist (pulmonologist) immediately for 
further evaluation and treatment. In case of persistent reduction of FEV1, and/or DLCO below 
80% of baseline values over 3-month period despite of appropriate treatment, the Primary 
Treating Physician may consider an interruption of the study drug. This decision may be 
discussed with Novartis Medical Advisor. Investigators will be asked to comment on the result 
of pulmonary function test. The pulmonary function test report will be filed with the source 
documents. Abnormal results and any diagnoses (or signs or symptoms if a diagnosis is not 
possible) associated with the abnormal findings should be recorded on the adverse event eCRF. 
8.4.4.4 
Infection 
The immune system effects of fingolimod may increase the risk of infections, including 
opportunistic infections. Before initiating study treatment, a complete blood count (CBC) will 
be collected and active infections are excluded. During the study treatment, a complete blood 
count will be collected regularly. Participants receiving fingolimod should report any signs or 
symptoms of infection to their investigator during therapy. Because elimination of fingolimod 
after discontinuation of fingolimod may take up to two months, vigilance for infection should 
be continued throughout this period. However, co-administration of a short course of 
corticosteroids treatment for relapse did not increase the overall rate of infection in participants 
treated with fingolimod in the Phase III clinical trials, compared to placebo.  


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8.4.5 
Appropriateness of safety measurements 
Beside routine safety assessments (physical and neurological examination, vital signs and 
laboratory assessments) few specific additional safety assessments are recommended in this 
study which are expected and known based on the mechanism of action of fingolimod and 
previous clinical data. 
Effects of fingolimod on heart rate and conduction are expected and known based on 
mechanism of action and previous clinical data. Although clinically symptomatic cardiac events 
or clinically relevant ECG abnormalities have been reported at very low frequencies in the 
clinical development program especially with fingolimod 0.5mg/day dose treatment initiation 
of fingolimod will be monitored over 6 hours at the investigational site in this study. 
Ophthalmologic examinations will be conducted in this study based on its previous use in the 
evaluation of retinal thickness and the detection of macular edema. Macular edema is an adverse 
event of special interest in participants treated with fingolimod because of the higher incidence 
seen in treated participants compared to active and placebo control groups, particularly when 
higher doses were evaluated in the clinical development program. The majority of cases of 
macular edema observed in participants treated with fingolimod occurred within the first three 
to four months after initiation of treatment. Therefore, an OCT scan is foreseen to be completed 
at Screening and Month 3. 
Annual complete skin examinations have also been included to support regular monitoring of 
participants for the potential development of new skin cancers during the study. 
Minor dose-dependent reductions in FEV1 and DLCO values were observed with fingolimod 
treatment starting at month 1 and remaining stable thereafter. And the reduction of FEV1 and 
DLCO from baseline value is resolved after treatment discontinuation. So pulmonary function 
tests will be conducted in all the participants at the screening and can be performed when 
participants with any reported AE related to respiratory disease, as per the investigator’s 
discretion.  
8.5 
Additional assessments 
8.5.1 
Clinical Outcome Assessments (COAs) 
The impact of multiple sclerosis on neurologic impairment will be assessed by Expanded 
Disability Status Scale (EDSS). 
The objectives of EDSS are to confirm relapse 
 
, it can be used in all the MS participants. The EDSS is an 
ordinal scale used for assessing neurologic impairment in MS based on a neurological 
examination. The scale consists of seven functional systems (FSs) and an ambulation score that 
are then combined to determine the EDSS steps. The FSs are Visual, Brain Stem, Pyramidal, 
Cerebellar, Sensory, Bowel & Bladder, and Cerebral functions. EDSS steps (ranging from 
0(normal) to 10(death due to MS)), the higher score means the worsening of neurological status. 
The FSs and EDSS steps will be assessed in a standardized manner. 


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EDSS assessments are scheduled at screening visit, 
 
 In the case of MS relapse, EDSS assessment is required at 
every unscheduled visit to confirm relapse.  
     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9 
Study discontinuation and completion 
9.1 
Discontinuation 
9.1.1 
Discontinuation from study treatment and from study 
Discontinuation of study treatment for a participant occurs when study treatment is permanently 
stopped for any reason (prior to the planned completion of the study drug administration, if any) 
and can be initiated by either the participant or the investigator. 
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being. 
Discontinuation from study treatment is required under the following circumstances: 
• Participant/guardian decision 
• Pregnancy 


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• Use of prohibited treatment as per recommendations in the prohibited treatment section 
• Any situation in which continued study participation might result in a safety risk to the 
participant 
Take into consideration the following to establish the list of circumstances under which study 
treatment must be discontinued: 
• Adverse events, abnormal laboratory values or abnormal test result that indicate a safety 
risk to the participant. Refer to Section 16.7 for Guidance for safety monitoring 
• Unsatisfactory therapeutic effect 
• Participant’s condition no longer requires study treatment 
If discontinuation from study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s discontinuation from study treatment and 
record this information. 
Participants who discontinue from study treatment should be asked to agree to return for the 
end of treatment (EOT) and follow up visits indicated in the Assessment Schedule Table 8-1 
(refer to section 8). 
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. 
This telephone contact should preferably be done according to the study visit schedule. 
After discontinuation from study treatment, at a minimum, in abbreviated visits, the following 
data should be collected at clinic visits or via telephone/email contact: 
• New / concomitant treatments 
• Adverse Events / Serious Adverse Events 
9.1.2 
Discontinuation from study 
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason. If the 
participant agrees, a final evaluation  at the time of the participant’s study discontinuation 
should be made as detailed in the assessment table (refer to Section 8). 
9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits or fail to 
respond to any site attempts to contact them without stating an intention to discontinue from 
study treatment or discontinue from study or withdraw consent/ exercise data privacy rights, 
the investigator must show "due diligence" by documenting in the source documents steps taken 
to contact the participant, e.g. dates of telephone calls, registered letters, etc. A participant 
should not be considered as lost to follow-up until due diligence has been completed or until 
the end of the study. 


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9.2 
Withdrawal of informed consent/opposition to use data/ 
biological samples 
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent/ exercise the use of their data/privacy rights  occurs in countries 
where the legal justification to collect and process the data is consent and only when a 
participant: 
• Explicitly requests to stop use of their data 
and 
• No longer wishes to receive study treatment 
• Does not want any further visits or assessments (including further study-related contacts) 
This request should be per local regulations (e.g. in writing) and recorded in the source 
documentation.  
Withdrawal of consent impacts ability to further contact the participant, collect follow-up data 
(e.g. to respond to data queries) and potentially other country-specific restrictions. It is 
therefore very important to ensure accurate recording of withdrawal vs. discontinuation 
based on the protocol definitions of these terms. 
In this situation, the Investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw their 
consent/exercise data privacy rights and record this information. The Investigator shall clearly 
document if the participant has withdrawn his/her consent for the use of data in addition to a 
study discontinuation. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. If the 
participant agrees, a final evaluation at the time of the participant’s study withdrawal of consent/ 
exercise data privacy rights should be made as detailed in the assessment table (refer to Section 
8). 
Further details on withdrawal of consent or the exercise of participants' data privacy rights are 
included in the corresponding informed consent form. 
9.2.1 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason.  
Reasons for early termination: 
• Unexpected, significant, or unacceptable safety risk to participants enrolled in the study 
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
• Discontinuation of study drug development 


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In taking the decision to terminate, Novartis will always consider the participant welfare and 
safety. Should early termination be necessary, participants must be seen as soon as possible and 
treated as a participant who discontinued from study treatment and treated as a prematurely 
withdrawn participant. 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 
participant’s interests. The investigator or sponsor depending on the local regulation will be 
responsible for informing IRBs/IECs of the early termination of the trial. 
9.3 
Study completion and post-study treatment 
Study completion is defined as when the last participant finishes their 2-month follow up visit 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator (e.g. Each participant will be required to complete the study 
in its entirety and thereafter no further study treatment will be made available to them in the 
scope of the trial). 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a participant 
or clinical investigation participant after providing written informed consent for participation 
in the study. Therefore, an AE may or may not be temporally or causally associated with the 
use of a medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on study related medical 
questions or problems. 
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments. 
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1.  The severity grade 
mild: usually transient in nature and generally not interfering with normal activities  
moderate: sufficiently discomforting to interfere with normal activities 
severe: prevents normal activities 
2. its relationship to fingolimod. 


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3. its duration (start and end dates) or if the event is ongoing and the outcome of not 
recovered/not resolved must be reported 
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. action taken regarding with study treatment 
AEs associated with infections will be recorded on the AE eCRF pages. Refer to Section 16.7 
Appendix 7 to see Guidance on monitoring patients with infections. 
All adverse events will be treated appropriately per investigators clinical judgement. Treatment 
may include one or more of the following: 
• Dose not changed 
• Drug interrupted/permanently discontinued 
Refer to Section 16.7 for Guidance on safety monitoring. 
6. Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB). 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
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 participant 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). 


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• 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 
deterioration in condition (e.g. hospitalization for relapse treatment) 
• 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 participant'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 participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
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 participant 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-
E2D Guidelines). 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication.  
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 
10.1.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days after the last study visit must be reported to 
Novartis safety immediately, without undue delay, under no circumstances later than 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. Information about 
all SAEs is collected and recorded on the eSAE with paper backup Serious Adverse Event 
Report Form; all applicable sections of the form must be completed in order to provide a 
clinically thorough report. 
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 


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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. 
Any SAEs experienced after the 30 day period should only be reported to Novartis Safety if the 
investigator suspects a causal relationship to study treatment. 
10.1.4 
Pregnancy reporting 
Pregnancies 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent form should be presented to the trial participant. The participant must be 
given adequate time to read, review and sign the pregnancy consent form. This consent form is 
necessary to allow the Investigator to collect and report information regarding the pregnancy.  
To ensure participant safety, woman of child-bearing potential should report immediately to the 
investigator any pregnancy during and up to two months following discontinuation of 
fingolimod treatment. Each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. Study drug will be 
discontinued but participants can still stay in the study for follow-up visit.  
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 
form and should include an assessment of the possible relationship to the study treatment any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported. After consent 
is provided, the pregnancy reporting will occur up to one year after the estimated date of 
delivery. 
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, participant or 
consumer (EMA (European Medicines Agency) 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. 


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Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF 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 participant safety and enhance reliability in determining the hepatotoxic potential of 
fingolimod, a standardized process for identification, monitoring and evaluation of liver events 
has to be followed. 
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as AE/SAE): 
• Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter 
• Liver events, which will require close observation, follow-up monitoring and contributing 
factors are recorded on the appropriate CRFs 
Please refer to Section 16.7 for complete definitions of liver laboratory triggers and liver events. 
Every liver event defined in Section 16.7 should be followed up by the investigator at the study 
site, as summarized below. Additional details on actions required in case of liver events are 
under investigator's discretion. Repeat liver chemistry tests to confirm elevation. 
• These liver chemistry repeats should be performed using the local laboratory used by the 
site. Repeated laboratory test results must be reported as appropriate. 
• If the initial elevation is confirmed, close observation of the participant will be initiated, 
including consideration of treatment interruption if deemed appropriate. 
• Discontinuation of the investigational drug (refer to the Discontinuation of study treatment 
section), if appropriate 
• Hospitalization of the participant if appropriate 
• Causality assessment of the liver event 


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• The follow-up of the liver event based on investigator's discretion can includes: 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 
All follow-up information and procedures performed must be recorded as appropriate in the 
CRF (e.g. AE page, concomitant medical page). 
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 CRFs) (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 participant 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 
World Health Organization (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. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource DDE or 


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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 participant 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. 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 participant 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 CRFs must be traceable to these source documents in the 
participant’s file. Data not requiring a separate written record will be defined before study start 
and will be recorded directly on the CRFs. The investigator must also keep the original informed 
consent form signed by the participant (a signed copy is given to the participant). 
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 CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 
12 
Data analysis and statistical methods 
The analysis will be conducted on all participant data at the time of end of study (i.e. including 
data from the Safety Follow-up epoch). 
 
There will be no hypothesis testing performed in this study. Data will be mainly statistically 
described. In general, categorical data will be presented as frequency and percentage; 
continuous data will be summarized by mean, standard deviation (SD), median, minimum, and 
maximum. For primary efficacy endpoints, the point estimate and confidence interval will be 
model-based. Additional analysis populations may be defined and sensitivity analyses may be 
conducted to evaluate the impact of COVID-19 pandemic. 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
12.1 
Analysis sets 
The Full Analysis Set (FAS) comprises all participants who have signed the Informed Consent 
and who have received at least one dose of study treatment. The FAS will be used for the 
summary of demography and baseline characteristics as well as for all efficacy analyses. 


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The Safety Set includes all participants who have signed the Informed Consent and 
who have received at least one dose of study treatment. The Safety Set will be used for all safety 
analyses. 
12.2 
Participant demographics and other baseline characteristics 
Demographics, MS disease history, MRI baseline characteristics will be listed and summarized 
with descriptive statistics as appropriate. Relevant medical histories and current medical 
conditions at baseline will be coded by system organ class (SOC) and preferred term (PT). 
12.3 
Treatments 
Exposure to investigational study drug is defined as the number of days spent on study treatment. 
Intermediate treatment interruptions will be subtracted from drug exposure. Exposure to 
investigational study drug will be summarized with number and percentage of participants by 
time category, and with summary statistics of the number of participant years of exposure. 
Prior and concomitant medications will be coded according to the WHO Drug Reference List 
dictionary, with Anatomical Therapeutic Classification (ATC) class and preferred term. 
Concomitant medications prior to and after the start of the study treatment will be listed. 
12.4 
Analysis of the primary endpoint(s) 
12.4.1 
Definition of primary endpoint(s) 
The primary endpoint is the annualized relapse rate (ARR), which is defined as the number 
confirmed MS relapses in a year. 
Only confirmed relapses will be considered for the primary analyses. The definitions of relapses 
and confirmed relapses are given in Section 8.3.1. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
In the primary analysis, the ARR will be estimated by a negative binomial regression model 
with log-link function, the cumulative number of confirmed MS relapses per participant as the 
response variable, number of relapses in the previous year (or two years) before enrollment, 
baseline EDSS and baseline number of Gd-enhancing T1 lesions at baseline as covariates. 
Natural log of time on study in years will be used as the offset variable to account for the varying 
lengths of participants' time in the study. The adjusted ARR (i.e., model-based estimate adjusted 
for covariates) and the corresponding 95% confidence interval will be obtained. 
The primary analysis will be performed for FAS.  
12.4.3 
Handling of missing values/censoring/discontinuations 
For participants who early withdraw from the study, the number of relapses up to the study 
discontinuation will be used for the primary analysis. No imputation will be applied to the 
incomplete study duration. 


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The primary negative binomial regression model with an offset for the time in study adjusts for 
missing information (drop-out) under the assumption of non-informative drop-out, information 
is missing at random, and constant relapse rate over time. 
12.4.4 
Sensitivity and Supportive analyses 
The primary analysis will be repeated based on all reported MS relapses (rather than on only 
the confirmed ones) for FAS population. 
A summary of ARR time-based and ARR patient-based will also be given. Time-based ARRs 
are calculated by taking the total number of relapses observed for all participants in FAS divided 
by the total number of days in study of those participants and multiplied by 365.25 days. Also 
patient-based ARR is presented, where individual ARRs are computed and summarized over 
participants for FAS population. For above ARR calculations, the analysis will consider 
confirmed relapses only.  
Additional sensitivity analyses may be defined in the analysis plan. 
12.5 
Analysis of secondary endpoints 
The following MRI efficacy variables will be statistically summarized based on FAS: 
• The number and proportion of patients with new and newly enlarged T2 lesions at 12 
month and 24 months; 
• The number and proportion of patients with Gd-enhanced T1 lesions at 12 month and 24 
months; 
• Change and % change from baseline in volume of T1 hypo-intense lesions at month 12 
and month 24. 
12.5.1 
Safety endpoints 
For all safety analyses, the safety set will be used. 
Safety assessments will include: adverse events (AEs), laboratory tests, vital signs, ophthalmic 
examinations, dermatology assessment, and ECG data. 
An AE will be considered as treatment-emergent adverse event (TEAE) if it starts on or after 
first treatment with fingolimod during the study. TEAE will be summarized by presenting the 
number and percentage of participants experiencing adverse events by system organ class 
(SOC), preferred term (PT) and severity of adverse events.  
Severe AEs, serious AEs, drug related AEs and the AEs leading to premature discontinuation 
of study drug will be presented in a similar format as adverse events. 
Laboratory and vital sign data will be presented by clinical notable ranges.  
The clinical notable abnormality of ophthalmic and dermatology data will be summarized as 
AE. 
The (uncorrected) QT interval of ECG will be corrected according to the Bazett’s and Fridericia 
formulae and then summarized by visit. Abnormal findings from ECG will be summarized as 
AE as well. 


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For the first dose administration monitoring, the change from pre-dose of pulse rate and BP at 
each hour will be summarized and the individual plots over time will be provided. The incidence 
rate of abnormal ECG findings at pre-dose and 6 hours post-dose, as well as the corrected QT 
change in category from pre-dose to 6 hours post-dose will be presented. 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
12.8 
Sample size calculation 
12.8.1 
Primary endpoint(s) 
The assumption of true ARR is based on previous studies of fingolimod and literature review 
(see Table 12-1). ARR ranged from 0.16 to 0.21 in non-Chinese populations from three 
controlled studies for fingolimod 0.5 mg (FREEDOMS, FREEDOMS II, TRANSFORMS). The 
similar ARR was reported in Chinese population treated by teriflunomide 14 mg (ARR = 0.18, 
TOWER). Two observational studies reported ARR at 0.38 in Chinese population treated by 
interferon-β 250 µg , and ARR at 0.21 in non-Chinese population treated by teriflunomide 14 
mg (Teri-RADAR). The ARR reported in Chinese population from placebo group was 0.63 
(TOWER). The true ARR is assumed ranging from 0.20 to 0.38 for this Chinese interventional 
study. 
Table 12-1 
ARR data on RRMS from historical studies 
Study/Refere
nce 
Study 
Population 
ARR 
(FTY 0.5 mg) 
ARR 
(placebo) 
ARR 
(Interferon-
β 250 µg) 
ARR 
(Teriflunomide 
14 mg) 
Interventional studies 


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Study/Refere
nce 
Study 
Population 
ARR 
(FTY 0.5 mg) 
ARR 
(placebo) 
ARR 
(Interferon-
β 250 µg) 
ARR 
(Teriflunomide 
14 mg) 
FREEDOMS 
(non-Chinese) 
RRMS 
0.18 
(0.15, 0.22) 
0.40 
(0.34, 0.47) 
 NA 
  NA 
 FREEDOMS 
II 
(non-Chinese) 
RRMS 
0.21 (0.17, 
0.25) 
0.40 
(0.34, 0.48) 
  NA 
  NA 
TRANSFORM
S 
(non-Chinese) 
RRMS 
0.16 
(0.12, 0.21) 
  NA 
0.33 
(0.26, 0.42) 
  NA 
TOWER, 
NCT0075188
1 (Chinese) 
RRMS 
  NA 
0.63 
(0.44, 0.92) 
  NA 
0.18 
(0.09, 0.36) 
Observational studies 
NCT0037007
1, 2006 
(Chinese) 
RRMS 
  NA 
  NA 
0.38 
(-,-) 
  NA 
Teri-RADAR, 
2019 
(non-Chinese) 
RRMS 
  NA 
  NA 
  NA 
0.21 
(0.11, 0.39) 
Assume ARR follows negative binomial distribution (~ NB(µ, k)). The dispersion parameter k 
is set as 1 based on the historical data. The 95% upper limit and lower limit of estimated ARR 
are calculated by normal approximation approach for sample size estimation. Assuming ARR 
at 0.25, sample size of 80 participants will serve the 95% probability for estimated ARR within 
[0.13 to 0.37], which will be lower than the ARR observed in Chinese population treated by 
interferon-β 250 µg. Assuming ARR at 0.38, sample size of 80 is expected to show a lower 
ARR than placebo, with 95% probability within [0.22, 0.54]. So the sample size of 80 
participants is considered. Considering 20% drop-out rate, the total sample size will be around 
100 participants. 
Sample size calculation was performed in nQuery. 
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 International Council for Harmonization (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, 


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written informed consent form, consent form updates, participant recruitment procedures (e.g. 
advertisements) and any other written information to be provided to participants. 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 (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. 
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 participants 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. 


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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 participant 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 participant 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 
References are available upon request 
(2013) 2.5 Clinical Overview Rationale for changes to Core Data Sheet (CDS) / A full review 
and update of sections, A full review and update of sections, “Warnings and Precautions”, 
“Adverse Drug Reactions” and “Interactions”. 
Bar-Or A, Pachner A, Menguy-Vacheron F, et al (2014) Teriflunomide and its mechanism of 
action in multiple sclerosis p. 59-74. 
Chitnis T, Arnold DL, Banwell B, et al (2018) Trial of fingolimod versus interferon bata-1a in 
pediatric multiple sclerosis p. 1017-1027. 
Cohen JA, Tenenbaum N, Bahtt A, et al (2019) Extended treatment with fingolimod for 
relapsing multiple sclerosis: the 14-year LONGTERMS study results p. 1-16. 
EuroQol Group (1990) EuroQol-a new facility for the measurement of health-related quality 
of life p. 199-208. 
Goodin DS, Frohman EM, Garmany GP, et al (2002) Disease modifying therapies in multiple 
sclerosis p. 169-78. 
Kappos L, Radue EW, O’Connor P, et al (2010) A placebo-controlled trial of oral fingolimod 
in relapsing Multiple Sclerosis p. 387-401. 
Karlsson G, Francis G, Schmouder R, et al (2009) 2.5 Clinical Overview in Multiple 
Sclerosis,"Adverse Drug Reactions" p. 184-185. 
Keegan BM, Noseworthy JH (2002) Multiple sclerosis. Annual review of Medicine p. 285-
302. 
Ledneva E, Karie S, Launay-Vacher V, et al (2009) Renal Safety of Gadolinium-based 
Contrast Media in Patients with Chronic Renal Insufficiency. Radiology; 250(3): 618-28 
Novartis (2019) Gilenya Core Data Sheet p. 11-16. 
Polman CH, Reingold S, Banwell B, et al (2011) Diagnostic criteria for multiple 
sclerosis:2010 revisions to the McDonald criteria p. 292-302. 
Sospedra M, Martin R (2005) Immunology of MS p. 683-747. 
Trapp BD, Peterson J, Ransohoff RM, et al (1998) Axonal transection in the lesions of MS p. 
278-285. 
WHO and Multiple Sclerosis International Federation. (2008) Atlas: multiple sclerosis 
resources in the world 2008.  


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16 
Appendices 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs 
Table 16-1 
Criteria For Notable Laboratory Abnormalities  
Notable Values 
Laboratory Variable 
Standard Units 
SI Units 
Serum glutamic oxaloacetic 
transaminase (SGOT) (AST) 
>82 U/L 
>82 U/L 
Serum glutamic pyruvic 
transaminase (SGPT) (ALT) 
>90 U/L 
>90 U/L 
Total bilirubin 
≥ 2.0 mg/dL 
≥ 34.2 μmol/L 
RENAL FUNCTION / METABOLIC  VARIABLES 
Creatinine 
≥2.0 mg/dL 
≥176umol/L 
Cholesterol 
≥ 240 mg/dL 
≥ 6.21 mmol/L 
Triglycerides 
≥ 300 mg/dL 
≥ 3.39 mmol/L 
HEMATOLOGY VARIABLES 
Hemoglobin 
≤ 10.0 g/dL 
≤ 100g/L 
Platelets (Thrombocytes) 
≤ 100 k/mm3 
≤ 100 x 109/L 
≥ 600 k/mm3 
≥ 600 x 109/L 
Leukocytes (WBCs) 
≤ 2.0 k/mm3 
≤ 2.0 x 109/L 
≥ 15 k/mm3 
≥ 15x 109/L 
HEMATOLOGY VARIABLES: DIFFERENTIAL 
Granulocytes (Poly, 
Neutrophils) 
≤ 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 
Red blood cells (RBCs) 
<3,300,000/mm3 
<3.3 x 1012/L  
>6,800,000/mm3 
>6.8 x 1012/L 
 
NOTABLE VITAL SIGNS AND BODY WEIGHT 
Vital Sign Variable 
Notable Criteria 
Pulse (beats/min) 
>120bpm or Increase of ≥ 15bpm from baseline  
Or 
< 50bpm or Decrease of ≥ 15bpm from baseline 
Systolic BP (mmHg) 
≥ 160 mmHg or Increase of ≥ 20mmHg from baseline 
Or 
≤ 90 mmHg or Decrease of ≥ 20mmHg from baseline 
Diastolic BP (mmHg) 
≥ 100 mmHg or Increase of ≥ 15mmHg from baseline 
Or 
≤ 50 mmHg or Decrease of ≥ 15mmHg from baseline 
Temperature (°C) 
>38.3 °C/ 101°F 


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Body weight (kg)  
± 7% from baseline weight 


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16.2 
Appendix 2 New York Heart Association Functional 
Classification 
Class I 
Patients have cardiac disease but without the resulting limitations of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal 
pain. 
Class II 
Patients have cardiac disease resulting in slight limitation of physical activity. They are 
comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain. 
Class III 
Patients have cardiac disease resulting in marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, 
dyspnea, or anginal pain. 
Class IV 
Patients have cardiac disease resulting in inability to carry on any physical activity 
without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be 
present even at rest. If any physical activity is undertaken, discomfort is increased. 


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16.3 
Appendix 3 McDonald criteria 
Clinical Presentation 
Additional Data Needed for MS Diagnosis 
no less than 2 attacka ; objective clinical 
evidence of ≥2 lesions or objective clinical 
evidence of 1 lesion with reasonable historical 
evidence of a prior attackb 
Nonec 
no less than 2 attacka; objective clinical evidence 
of 1 lesion 
Dissemination in space, demonstrated by: 
≥1 T2 lesion in at least 2 of 4 MS-typical regions 
of the CNS (periventricular, juxtacortical, 
infratentorial, or spinal cord) d; or 
Await a further clinical attacka implicating a 
different CNS site 
1 attacka; objective clinical evidence of ≥2 
lesions 
Dissemination in space, demonstrated by: 
Simultaneous presence of asymptomatic 
gadolinium-enhancing and nonenhancing 
lesions at any time;or 
A new T2 and/or gadolinium-enhancing lesion(s) 
on follow-up MRI, irrespective of its timing with 
reference to a baseline scan; or 
Await a second clinical attacka 
1 attacka; objective clinical evidence of 1 lesion 
(clinically isolated syndrome) 
Dissemination in space, demonstrated by: 
For DIS: 
≥1 T2 lesion in at least 2 of 4 MS-typical regions 
of the CNS(periventricular, juxtacortical, 
infratentorial, or spinal cord) d; or 
Await a second clinical attacka implicating a 
different CNS site; and 
Dissemination in time, demonstrated by: 
For DIT: 
Simultaneous presence of asymptomatic 
gadolinium-enhancing and nonenhancing 
lesions at any time; or 
A new T2 and/or gadolinium-enhancing lesion(s) 
on follow-up MRI, irrespective of its timing with 
reference to a baseline scan; or 
Await a second clinical attacka 
Insidious neurological progression suggestive of 
MS(PPMS) 
1 year of disease progression(retrospectively or 
prospectively determined) plus 2 of 3 of the 
following criteria d: 
1.Evidence for DIS in the brain based on ≥1 T2 
lesions in the MS-characteristic(periventricular, 
juxtacortical, or infratentorial) regions 
2.Evidence for DIS in the spinal cord based on 
≥2 T2 lesions in the cord 
3.Positive CSF(isoelectric focusing evidence of 
oligoclonal bands and/or elevated IgG index) 
If the Criteria are fulfilled and there is no better explanation for the clinical presentation, the 
diagnosis is “MS”; if suspicious, but the Criteria are not completely met, the diagnosis is “possible 


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


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16.4 
Appendix 4 EDSS Assessment Criteria 
EXPANDED DISABILITY STATUS SCALE 
0 = normal neurological exam (all FS grade 0) 
1.0 = no disability, minimal signs in one FS (one FS grade 1) 
1.5 = no disability, minimal signs in more than one FS (more than one FS grade 1) 
2.0 = minimal disability in one FS (one FS grade 2, others 0 or 1) 
2.5 = minimal disability in two FS (two FS grade 2, others 0 or 1) 
3.0 = moderate disability in one FS (one FS grade 3, others 0 or 1) though fully ambulatory; or 
mild disability in three or four FS (three/four FS grade 2, others 0 or 1) though fully ambulatory 
3.5 = fully ambulatory but with moderate disability in one FS (one FS grade 3) and mild 
disability in one or two FS (one/two FS grade 2) and others 0 or 1;  
or fully ambulatory with two FS grade 3 (others 0 or 1);  
or fully ambulatory with five FS grade 2 (others 0 or 1) 
4.0 = ambulatory without aid or rest for ≥500 meters; up and about some 12 hours a day despite 
relatively severe disability consisting of one FS grade 4 (others 0 or 1) or combinations of lesser 
grades exceeding limits of previous steps 
4.5 = ambulatory without aid or rest for ≥300 meters; up and about much of the day, 
characterized by relatively severe disability usually consisting of one FS grade 4 and 
combination of lesser grades exceeding limits of previous steps 
5.0 = ambulatory without aid or rest for ≥200 meters (usual FS equivalents include at 
least one FS grade 5, or combinations of lesser grades usually exceeding specifications for step 
4.5) 
5.5 = ambulatory without aid or rest for ≥100 meters 
6.0 = unilateral assistance (cane or crutch) required to walk at least 100 meters with or without 
resting 
6.5 = constant bilateral assistance (canes or crutches) required to walk at least 20 meters without 
resting 
7.0 = unable to walk 5 meters even with aid, essentially restricted to wheelchair; 
wheels self and transfers alone; up and about in wheelchair some 12 hours a day 
7.5 = unable to take more than a few steps; restricted to wheelchair; may need some help in 
transferring and in wheeling self 
8.0 = essentially restricted to bed or chair or perambulated in wheelchair, but out of bed most 
of day; retains many self-care functions; generally has effective use of arms 
8.5 = essentially restricted to bed much of the day; has some effective use of arm(s); 


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retains some self-care functions 
9.0 = helpless bed patient; can communicate and eat 
9.5 = totally helpless bed patient; unable to communicate effectively or eat/swallow 
10.0 = death due to MS 


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16.5 
Appendix 5 Guidance for Monitoring of patients taking their first 
dose of the study drug 
At treatment initiation, fingolimod induces a dose dependent reduction in heart rate 
(by approximately 12-13 bpm at 0.5 mg) that is maximal within 6 hours after the first dose 
administration, and then attenuates over days to weeks with continued dosing. This effect is 
asymptomatic in the vast majority of patients. No medical intervention to treat that effect was 
needed in any of the patients in the Phase II and III MS trials. Concomitant changes on the 
ECG/Holter were restricted to transient second degree type I atrio-ventricular block 
(Wenckebach) of benign nature, on day 1 of treatment. One case of third degree atrio-ventricular 
block 3 hours after first dose administration of fingolimod 1.25 mg was reported. This incident 
was self-limiting without symptoms, no sequelae and lasted 30 seconds. Please see Investigator 
Brochure for more details. As such, the following guidelines have been put in place to support 
the safe initiation of therapy with fingolimod. 
At the Day 1 visit, participant enroll into this study is naive participant who has never use 
fingolimod before recruitment, so first dose administration monitoring will be mandatory on-
site monitoring as described below. 
Pre-dose ECG should be provided by the site and be available for comparison to the post-dose 
ECG in order to determine if discharge criteria are met. Sitting heart rate and blood pressure 
should be measured prior to the 1st dose of the study drug then every hour for at least 6 hours 
thereafter (by the First Dose Administrator). When obtaining the pre-dose heart rate prior to the 
1st dose intake, the participant should be allowed to rest sitting for 5 minutes. Then the sitting 
heart rate should be taken. The sitting heart rate and blood pressure measurements should be 
collect three times to produce three baseline readings for both heart rate and blood pressure 
(prior to the 1st dose of the study drug only). For comparison to the post-dose heart rate values, 
the lowest pre-dose value of heart rate should be used. Participants should receive the first dose 
of the study drug before 12:00 PM (noon) in the outpatient setting. Participants may be 
discharged after 6 hours ONLY if ALL of the following discharge criteria are met. 
• Heart rate at discharge must be at least 51 bpm(in patient 18 years or older), 55 bpm(in 
patients 12 years or older) or 60 bpm (in children ≥10 years and below 12) 
• Heart rate at discharge must be greater than 80% of baseline value ( Table 16-2 below) 
• Heart rate at discharge must not be the lowest hourly value measured during the 
observation period (which would be suggestive of a continuing progressive decline in 
heart rate) 
• Participants must have no symptoms associated with decreased heart rate 
• ECG at 6 hours should not show any new significant abnormalities other than sinus 
bradycardia not observed at the patient’s pre-dose ECG 
Participants should have written instruction on when to return to clinic and a 24 hour 
contact phone number to call in the event of any new or warranted symptoms (chest pain, 
dizziness, palpitations, syncope, nausea and vomiting, etc.). Participants should be instructed 
not to drive themselves after the first dose of study drug administration. 
Participants whose heart rate drops by more than 30% (as a result of strong sensitivity to the 
study drug) from pre-dose at any time during the 6-hour monitoring period may be discharged, 


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provided they meet the discharge criteria, but must return on Study Day 2 to take the second 
dose of the study drug and must be monitored as on Study Day 1. 
If the above discharge criteria are not met, participants should continue to be observed until 
they are met. Participants experiencing any symptomatic event associated with reduction of the 
heart rate in the first 24 hours must take the Day 2 dose of study drug at the study center and 
must be monitored hourly for 6 hours before discharge. After the 6 hour monitoring participants 
may be discharged only if they meet the discharge criteria described above. 
Table 16-2 
Heart rate table for cardiac release criteria  
Baseline Heart Rate 
Minimum HR at 6hr post 1st 
dose of the study drug 
eligible for release 
HR reduction within 6hr 
monitoring indicating need 
for monitoring after 2nd dose 
45 
40 
31 
46 
40 
32 
47 
40 
33 
48 
40 
33 
49 
40 
34 
50 
40 
35 
51 
40 
35 
52 
41 
36 
53 
42 
37 
54 
43 
38 
55 
44 
39 
56 
45 
39 
57 
45 
40 
58 
46 
41 
59 
47 
41 
60 
48 
43 
61 
49 
43 
62 
50 
43 
63 
50 
44 
64 
51 
45 
65 
52 
46 
66 
53 
46 
67 
54 
47 
68 
54 
48 
69 
55 
48 
70 
56 
49 
71 
57 
50 
72 
58 
50 
73 
58 
51 
74 
59 
52 
75 
60 
53 


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Baseline Heart Rate 
Minimum HR at 6hr post 1st 
dose of the study drug 
eligible for release 
HR reduction within 6hr 
monitoring indicating need 
for monitoring after 2nd dose 
76 
61 
53 
77 
62 
54 
78 
62 
55 
79 
63 
55 
80 
64 
56 
81 
65 
57 
82 
66 
57 
83 
66 
58 
84 
67 
59 
85 
68 
60 
86 
69 
60 
87 
70 
61 
88 
70 
62 
89 
71 
62 
90 
72 
63 
91 
73 
64 
92 
74 
64 
93 
74 
65 
94 
75 
66 
95 
76 
67 
96 
77 
67 
97 
78 
68 
98 
78 
69 
99 
79 
69 
100 
80 
70 
101 
81 
71 
102 
82 
71 
103 
82 
72 
104 
83 
73 
105 
84 
74 
106 
85 
74 
107 
86 
75 
108 
86 
76 
109 
87 
76 
110 
88 
77 
111 
89 
78 
112 
90 
78 
113 
90 
79 
114 
91 
80 


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Baseline Heart Rate 
Minimum HR at 6hr post 1st 
dose of the study drug 
eligible for release 
HR reduction within 6hr 
monitoring indicating need 
for monitoring after 2nd dose 
115 
92 
81 
116 
93 
81 
117 
94 
82 
118 
94 
83 
119 
95 
83 
120 
96 
84 
121 
97 
85 
122 
98 
85 
123 
98 
86 
124 
99 
87 
125 
100 
88 
126 
101 
88 
127 
102 
89 
128 
102 
90 
129 
103 
90 
130 
104 
91 
Recommendations for management of bradycardia 
Clinicians should be particularly mindful of participants who have a low heart rate at pre-
dose (spontaneously or through drug induced β-receptor blockade), prior to administration of 
the study drug. 
Atropine (sc or iv) 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 or hypotension, administration of atropine 1 mg, 
repeated administration in 3-5 minutes 
• If heart rate and/or blood pressure remains unresponsive, consider administration 
of dopamine drip 5-20 ug/kg/min or epinephrine drip 2-10 ug/min 
• Performance of transcutaneous pacing may also be considered 
In the setting of decreased blood pressure, isoproterenol should be avoided/used with caution. 


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16.6 
Appendix 6 Guidance for Ophthalmic Monitoring 
Fingolimod has previously been associated with a two-fold increase in the risk of 
macular edema in renal transplant patients receiving cyclosporine. There have been macular 
edema cases in the treatment of fingolimod, therefore careful ophthalmic monitoring is being 
implemented to permit early detection of this event, should it occur. 
 A complete ophthalmic examination by an ophthalmologist will be conducted in 
accordance with Table 8-1. Similar assessments must be performed at an unscheduled 
ophthalmology visit for any participant who presents with new visual symptoms or decrease in 
visual acuity. 
 The following assessments will be performed at the ophthalmic examinations: 
1. Best corrected visual acuity using a visual acuity chart with equal spacing between letters 
and between lines 
2. Optical Coherence Tomography (OCT) is required for participants at Screening and Month 
3 visit. OCT may be required at other visits to evaluate macular thickness under the 
investigator’s discretion. 
 
At baseline, if there is a suspicion of macular edema and increased central foveal thickness by 
OCT, then a fluorescein angiogram may be performed (at the discretion of the ophthalmologist). 
Participants with diagnosed macular edema at Screening should be deemed a screening failure 
and should not be enrolled. Patients with history of uveitis and patients with diabetes mellitus 
are at an increased risk of macular edema and may require more frequent ophthalmic 
evaluations, per investigator’s discretion. 
  
 
 
During the study, participants with a diagnosis of macular edema during the study must interrupt 
the study drug. These patients must be followed-up 1 month and 3 month after diagnosis of 
macular edema and more frequently if needed based on the ophthalmologist’s judgement. 
Further ophthalmologic evaluations until such time as resolution is confirmed or no further 
improvement is expected by the ophthalmologist (based on a follow up period of not less than 
3 months). These evaluations will include repeat best corrected visual acuity, fundus 
examination and OCT. Fluorescein angiography (FA) is performed at the discretion of the 
ophthalmologist. If the participant does not show definite signs of improvement on examination 
by specialist testing (e.g. OCT, FA) 6-8 weeks after interruption of study drug, then therapy for 
macular edema in conjunction with an ophthalmologist experienced in the management of this 
condition should be initiated.  
 
An interruption or discontinuation of the study drug should be clearly documented and reflected 
on eCRF. AE/SAEs need to be filed as appropriate. 


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Re-initiation of the study drug can only be considered if the macular edema has resolved 
completely, the individual risk-benefit is favorable (as determined by the Investigator, in 
agreement with the Ophthalmologist) and after discussion with the Novartis Medical Advisor. 
The patients must have follow up ophthalmic examinations at one month after study drug is re-
initiated, three months later and then every 3 months up to one year, and every 6 months 
thereafter. 
For participants discontinuing study drug for any of the above ophthalmic reasons, copies and 
source documents of the related ophthalmic examination should be kept at the site as source 
documents. These documents may need to be submitted for review by an independent panel if 
needed. 
Guidance on monitoring patients with uveitis 
Participants with a history of uveitis or findings compatible with active uveitis at baseline 
can enter the study given that there is no evidence of macular edema in the baseline 
ophthalmic examination. 
In order to specifically assess the risk of macular edema in the MS population with 
coexisting uveitis, each participant with findings in any ophthalmic examination compatible 
with active uveitis (e.g., significant anterior chamber cell or flare, vitreous cell or flare, pars 
planitis, vasculitis, chorioretinitis) under the discretion of the investigator should undergo an 
ophthalmic examination. It is the discretion of the investigator to determine the frequency of 
these ophthalmic examinations. Adjustments to the schedule can be made to align these 
evaluations with other planned study visits. 
The diagnosis of macular edema may lead to study drug interruption. But the decision on 
whether or not fingolimod therapy should be interrupted needs to take into account the potential 
benefits and risks for the individual participant.  


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16.7 
Appendix 7 Guidance on safety monitoring 
Guidance on monitoring of patients with elevated blood pressure 
Participants 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 recommended referred to his primary care 
physician, an independent internist or to the specialty hypertension clinic for evaluation, 
diagnosis and treatment of hypertension. Participants with BP values of >160/100 mmHg on 
any visit during the study should be immediately referred as above for evaluation, diagnosis 
and treatment of hypertension. Newly diagnosed hypertension as well as an aggravation of a 
pre-existing condition must be reported as an AE and discontinuation of the study drug may be 
considered by the investigator. 
Guidance on monitoring of participants with elevated liver function tests 
Table 16-3 
Liver event and laboratory trigger definitions  
 
Definition/ threshold 
Liver laboratory triggers 
If ALT, AST and total bilirubin normal at 
baseline:  
• 
ALT or AST > 5 × ULN 
• 
ALP> 2 × ULN (in the absence of known bone 
pathology) 
• 
Total bilirubin > 3 × 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 Total bilirubin > 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* 
If ALT or AST abnormal at baseline: 
• 
ALT or AST > 2x baseline or > 300 U/L 
(whichever occurs first) 
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; non-infectious hepatitis; benign, malignant and unspecified liver neoplasms ULN: 
upper limit of normal 
 
During clinical trials, elevations 3 times the upper limit of normal (ULN) or greater in liver 
transaminases occurred in 8% of patients treated with fingolimod 0.5 mg compared to 2% of 
placebo patients. Elevations of 5 times the upper limit of normal occurred in 2% of patients on 
fingolimod and 1% of patients on placebo. Serum transaminase levels returned to normal within 
approximately 2 months after discontinuation of fingolimod. 


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If repeat ALT/AST values reach 5 times the ULN, the study drug will be interrupted until the 
results return within the normal range. More frequent monitoring should be instituted, including 
serum bilirubin, alkaline phosphatase (ALP) and other evaluations per discretion of the 
investigator. The study drug may be re-started once results return within normal range and per 
discretion of the investigator. 
 
Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained 
vomiting, abdominal pain, fatigue, anorexia, jaundice or dark urine, should have liver enzymes 
checked, and fingolimod should be discontinued if significant liver injury is confirmed. Re-
initiation of study drug will be dependent on whether or not another cause of liver injury is 
determined, and on the benefits to the patient of resuming therapy versus the risks of recurrence 
of liver dysfunction and per the discretion of the investigator. 
 
More frequent liver monitoring may be instituted based on the clinical judgement in the below 
condition: 
• For participants with normal ALT and AST and TBIL value at baseline: detection of 
elevated ALT/AST values of >3.0 x ULN and total bilirubin > 2.0 x ULN 
• For participants with elevated AST or ALT or TBIL value at baseline: detection of 
elevated [AST or ALT > 2 x baseline ] OR [AST or ALT > 300U/L] (whichever 
occurs first) combined with [TBIL > 2 x baseline AND > 2.0 x ULN 
 
Patients should be monitored for signs and symptoms of any hepatic injury. Measure liver 
transaminase and bilirubin levels promptly in patients who report symptoms that may indicate 
liver injury, including new or worsening fatigue, anorexia, right upper abdominal discomfort, 
dark urine, or jaundice. In this clinical context, if the patient is found to have ALT/AST values 
of >3.0 x ULN with total bilirubin > 2.0 x ULN, treatment with fingolimod may be interrupted 
based on the clinical judgement. Treatment should not be resumed if a plausible alternative 
etiology for the signs and symptoms cannot be established, because these patients are at risk for 
severe drug-induced liver injury. 
 
Because fingolimod exposure is doubled in patients with severe hepatic impairment, these 
patients should be closely monitored, as the risk of adverse reactions is greater. 
 
Re-initiation of the study drug shall be considered once the liver enzymes are within the normal 
reference range and/or patients have clinically recovered from liver injury signs based on your 
clinical judgement, and kindly reach out to Medical Advisor at Novartis for any further 
clarification. In case it is agreed to re-start the study drug, weekly liver function test may be 
performed for patient’s safety. Advise patients that they should contact their physician if they 
have any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or 
dark urine. The deterioration of new elevations above 2 times the ULN with worsening of liver 
injury clinical signs/symptoms based on investigator’s clinical judgement may lead to 
permanent discontinuation of study drug in the best interest of patient’s safety. 


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An interruption or discontinuation of the study drug should be clearly documented and reflected 
on Dosage Administration Record eCRF. AE/SAEs need to be filed as appropriate. 
 
Guidance on monitoring of participants with notable lymphopenia 
Fingolimod results in sequestration of a proportion of the circulating lymphocytes in 
lymph nodes with resultant reduction in circulating lymphocyte counts. Average circulating 
lymphocytes counts are expected to be around 0.5-0.6 x109/L or 500-600 cells/mm3. Please see 
Investigator Brochure for more details. As such, the absolute total WBC, neutrophil 
and lymphocyte counts will be measured at each visit by the local laboratory. In case of 
lymphocyte alert, lymphocyte count should be repeated in two weeks by the local laboratory. If 
the repeat test confirms the lymphocyte count is below 0.2 x109/L or 200 cells/mm3, the study 
drug must be interrupted and the lymphocytes count needs to be monitored every two weeks 
until levels reach around 0.5-0.6 x109/L or 500-600 cells/mm3 values. Recovery of lymphocyte 
counts is expected to take several weeks given the long half life of fingolimod. The participant 
should be evaluated and monitored for infections on a regular basis during this period. 
Re-initiation of the study drug can only be considered once the lymphocyte counts is around   
0.5-0.6 x109/L or 500-600 cells/mm3as confirmed by the local lab, for further detailed 
information please refer to the latest Investigator Brochure or label of fingolimod. 
Guidance on monitoring of participants with symptoms of neurological deterioration, 
inconsistent with MS course 
Should a participant develop any manifestations that, in opinion of the investigator, are 
atypical for multiple sclerosis including unexpected neurological or psychiatric symptom/signs 
(e.g. rapid cognitive decline, behavioral changes, cortical visual disturbances or any 
other neurological cortical symptoms/sign), or any symptom/sign suggestive of an increase 
of intracranial pressure or accelerated neurological deterioration, the investigator may schedule 
a complete physical and neurological examination and an MRI as soon as possible and before 
beginning any steroid treatment. Conventional MRI as defined in the protocol as well as Fluid-
attenuated Inversion Recovery (FLAIR) and Diffusion-weighted imaging (DWI) sequences are 
recommended for differential diagnosis of posterior reversible encephalopathy syndrome. The 
MRI must be evaluated by the local neuro-radiologist and investigator. The investigator will 
contact the Medical Representative at Novartis to discuss findings and diagnostic possibilities 
as soon as possible. AE/SAEs need to be filed as appropriate. 
In case of new findings in the MRI images in comparison with the previous available MRI 
which are not compatible with MS lesions, the study drug will be interrupted and other 
diagnostic evaluations need to be performed at the discretion of the investigator. In case of 
presence of new hyper-intense T2-weighted lesions in the MRI which may be infectious in 
origin it is recommended to collect a cerebrospinal fluid sample if indicated. Analysis of the 
CSF sample including cellular, biochemical and, microbiological analysis ((e.g. herpes virus, 
John Cunningham virus (JC virus)), to confirm/exclude an infection ((e.g. progressive 
multifocal leukoencephalopathy (PML)) should be performed.  


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Only when the differential diagnosis evaluations have excluded other possible diagnosis than 
MS and after discussion with the Medical Representative at Novartis, the study drug may be 
restarted. 
Guidance on monitoring of participants with infections 
Initiation of treatment with Fingolimod should be delayed in patients with severe active infection until 
resolution. If a patient develops a serious infection, suspension of Fingolimod should be considered 
and consideration of benefit-risk should be undertaken prior to re-initiation of therapy.  
All infections that develop during the study will be reported as AEs. Investigators are requested 
to specifically ask about infections at each visit. Treatment and additional evaluations will be 
performed at discretion of the investigator. 
The investigator should remind the participant of the risk of infections and to instruct them 
to promptly report any symptoms of infections to the investigator. 
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 expert 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. 
 It is also important to ask the patient to report if they are exposed to anyone who has recently 
received a live or live attenuated vaccine and manifested a skin rash after the vaccination so 
that it can be decided, in consultation with an infectious disease expert, if antiviral therapy is 
warranted. 
It should be noted that live or live attenuated vaccines are prohibited while patients are 
taking study drug and for 2 months after study drug discontinuation. They may be 
administered, thereafter, once there is confirmation that lymphocyte counts are in the normal 
range. 

SAP_001.pdf: 
Clinical Development 
FTY720/Fingolimod/Gilenya® 
CFTY720D2419 / NCT04667949
A 24-month, open-label, prospective, multicenter 
interventional, single-arm study assessing the efficacy and 
safety of fingolimod (Gilenya) 0.5mg in relapsing multiple 
sclerosis (RMS) patients in China 
Statistical Analysis Plan (SAP) 
Document type: 
SAP Documentation 
Document status: 
Final Amendment 5 
Release date: 
7-April-2025
Number of pages: 
37 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Template Version 6.0, Effective from 23-Nov-2022 


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SAP Amendment 5 
 
Study No: CFTY720D2419 
 
Document History – Changes compared to previous final version of SAP 
Date 
Time point 
Reason for update 
Outcome for update 
Section and title 
impacted 
(Current) 
30-Jan-2022 
Prior to 
interim DB 
lock 
Creation of final 
version 
N/A - First version 
NA 
25-May-
2022 
Prior to 
interim DB 
lock 
Creation of amendment 
1 
Typo of “fingolimod” 
Section 2.1 
 
 
 
Add abbreviation of 
“Functional score” 
List of abbreviation 
 
 
 
Add rule of baseline for vital 
signs and ECG 
Section 2.1.2.1 
 
 
 
Add time points for first dose 
monitoring ECG and Vital 
signs 
Section 2.1.2.1.1 
 
 
 
Add the multiple assessment 
rules 
Section 2.1.2.3 
 
 
 
TEAE will be reported 
Section 2.8.1 
 
 
 
Modify the names of 
cholesterol, Neutrophils and 
Lymphocytes 
Section 2.8.3 
 
 
 
Modify ECG parameters 
Section 2.8.4.1 
 
 
 
Add rule of non by-visit 
summaries 
Section 2.8.4.1 
 
 
 
Add the listings of clinical 
notable vital signs 
Section 2.8.4.2 
 
 
 
Add dermatology evaluations 
Section 2.8.4.4 
 
 
 
Add first dose (second 
dose/restart dose) monitoring 
Section 2.8.5 
 
 
 
Add summary statistics for 
vital signs measurements and 
ECG parameters. 
Section 2.8.6 
 
 
 
 
 
 
 
 
Add the definition of Severity 
of MS relapses 
Section 5.1.4.3 
 
 
 
Add one reference  
Section 6 
1-July-2022 
Prior to 
interim DB 
lock 
Creation of amendment 
2 
 
 
 
 
 
 
Add sensitivity analyses on 
laboratory, ECG and vital sign 
data 
Section 2.8.3 
Section 2.8.4.1 
Section 2.8.4.2 
 
 
 
 
 
29-
December-
2022 
Prior to 
interim DB 
lock 
Creation of amendment 
3 
Add the mapping rule to ECG 
Section 2.1.2.1 
 
 
 
Refine multiple assessments 
Section 2.1.2.3 
 
 
 
Refine analysis sets which are 
only for final analysis 
Section 2.2 


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Study No: CFTY720D2419 
 
Date 
Time point 
Reason for update 
Outcome for update 
Section and title 
impacted 
(Current) 
 
 
 
Add approved MS disease-
modifying drugs list 
Section 2.3.3 
 
 
 
Delete the endpoint of the 
volume of new or enlarged T2 
lesions, add the volume of T2 
lesions 
Section 2.7.1 
 
 
 
Refine MRI analysis period 
Section 2.7 
 
 
 
Delete eosinophils from criteria 
for notable laboratory 
abnormalities 
Section 2.8.3 
 
 
 
Modify the unit of creatinine 
Section 2.8.3 
 
 
 
 
 
 
 
 
 
 
 
 
13-
November-
2024 
Prior to final 
DB lock 
Creation of amendment 
4 
Update the list of abbreviations 
List of abbreviations 
 
 
 
Update the protocol version 
Section 1 
 
 
 
Change Gd-enhancing lesion 
into Gd-enhancing T1 lesion 
Section 2.7 
 
 
 
 
 
 
 
Add frequency distribution 
analysis of key hematological 
parameters 
Section 2.8.3 
 
 
 
Change section number from 
Section 3.1.1 to Section 3.1 
Section 3.1.1 
2-April-2025 
Prior to final 
DB lock 
Creation of amendment 
5 
Change language in Table 1-1 
Section 1.2 and 
Section 2.7.1 
 
 
 
Clarify the data handling for 
MRI parameters 
Section 2.5.3 
 
 
 
Clarify the covariates 
Section 2.7.2 
 
 
 
Delete MS medication history 
of DMT by PT 
Section 2.3.3 
 
 
 
Add the summary of most 
common TEAEs 
Section 2.8.1 


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Study No: CFTY720D2419 
 
Table of contents 
Table of contents .................................................................................................................... 4 
List of tables ........................................................................................................................... 6 
List of figures.......................................................................................................................... 6 
List of abbreviations ............................................................................................................... 7 
1 
Introduction ......................................................................................................................... 8 
1.1 
Study design ................................................................................................................ 8 
1.2 
Study objectives and endpoints .................................................................................. 9 
2 
Statistical methods ............................................................................................................. 10 
2.1 
Data analysis general information ............................................................................ 10 
2.1.1 
General definitions ................................................................................ 10 
2.1.2 
Visit windows........................................................................................ 11 
2.2 
Analysis sets ............................................................................................................. 15 
2.2.1 
Subgroup of interest .............................................................................. 15 
2.3 
Patient disposition, demographics and other baseline characteristics ...................... 15 
2.3.1 
Patient disposition ................................................................................. 15 
2.3.2 
Background and demographic characteristics ....................................... 15 
2.3.3 
MS baseline disease characteristics ...................................................... 16 
2.3.4 
Medical history...................................................................................... 16 
2.4 
Treatments (study treatment, concomitant therapies, compliance) .......................... 17 
2.4.1 
Exposure to study treatment / compliance ............................................ 17 
2.4.2 
Prior, concomitant and post therapies ................................................... 17 
2.5 
Analysis of the primary objective ............................................................................. 18 
2.5.1 
Primary endpoint ................................................................................... 18 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 19 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 19 
2.5.4 
Supportive analyses ............................................................................... 19 
2.6 
Analysis of the key secondary objective .................................................................. 20 
2.7 
Analysis of secondary efficacy objective(s) ............................................................. 20 
2.7.1 
Secondary endpoints ............................................................................. 20 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 21 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 21 
2.8 
Safety analyses .......................................................................................................... 21 
2.8.1 
Adverse events (AEs) ............................................................................ 22 
2.8.2 
Deaths .................................................................................................... 23 
2.8.3 
Laboratory data ..................................................................................... 23 


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2.8.4 
Other safety data ................................................................................... 25 
2.8.5 
First dose (second dose/restart dose) monitoring .................................. 27 
2.8.6 
Safety evaluation after last administration of study treatment .............. 28 
2.9 
Pharmacokinetic endpoints ....................................................................................... 28 
2.10 
PD and PK/PD analyses ............................................................................................ 29 
 
 29 
2.12 
Biomarkers ................................................................................................................ 30 
 
 30 
 
 30 
 
 31 
 
 32 
3 
Sample size calculation ..................................................................................................... 32 
3.1 
Primary endpoint(s) .................................................................................................. 32 
4 
Change to protocol specified analyses .............................................................................. 33 
5 
Appendix ........................................................................................................................... 34 
5.1 
Imputation rules ........................................................................................................ 34 
5.1.1 
Study drug ............................................................................................. 34 
5.1.2 
AE date imputation ............................................................................... 34 
5.1.3 
Concomitant medication date imputation ............................................. 34 
5.1.4 
Other imputations .................................................................................. 34 
5.2 
AEs coding/grading .................................................................................................. 36 
5.3 
Laboratory parameters derivations ........................................................................... 36 
5.4 
Statistical models ...................................................................................................... 37 
5.4.1 
Primary analysis .................................................................................... 37 
5.4.2 
Key secondary analysis ......................................................................... 37 
5.5 
Rule of exclusion criteria of analysis sets ................................................................. 37 
6 
Reference ........................................................................................................................... 37 
 


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Study No: CFTY720D2419 
 
List of tables 
Table 1-1 
Objectives and related endpoints ............................................................ 9 
Table 2-1 
General Definitions ............................................................................... 10 
 
 12 
Table 2-3 
Visit-windows for MRI ......................................................................... 12 
Table 2-4 
Visit-windows for routine laboratory values......................................... 12 
Table 2-5 
Visit-windows for vital signs* .............................................................. 13 
Table 2-6 
Visit-windows for Electrocardiogram (ECG) ....................................... 13 
Table 2-7 
Visit-windows after study drug discontinuation ................................... 14 
Table 2-8 
Criteria for notable laboratory abnormalities ........................................ 23 
Table 2-9 
Criteria for newly occurring liver enzymes abnormalities .................... 24 
Table 2-10 
Abnormality criteria for corrected QT interval ..................................... 25 
Table 2-11 
Vital signs clinically notable values ...................................................... 26 
 
 29 
 
 30 
Table 3-1 
ARR data on RRMS from historical studies ......................................... 33 
Table 5-1 
Severity of MS relapses ........................................................................ 36 
Table 5-2 
Creatinine clearance calculation ........................................................... 36 
Table 5-3 
Protocol deviations that cause subjects to be excluded ......................... 37 
Table 5-4 
Subject Classification ............................................................................ 37 
 
List of figures 
Figure 1-1 
Study design ............................................................................................ 9 
 


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Study No: CFTY720D2419 
 
List of abbreviations 
AE 
Adverse event 
AESI 
Adverse Events of Special Interest 
ALT 
Alanine aminotransferase 
ARR 
Annualized Relapse Rate 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Classification 
bid 
bis in diem/twice a day 
BP 
Blood Pressure 
 
 
CI 
Confidence Interval 
CRF 
Case Report/Record Form (paper or electronic) 
CSR 
Clinical Study report 
DBL 
Database Lock 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
(e)EDSS 
(electronic) Expanded Disability Status Scale 
EOS 
End of Study 
EOT 
End of Treatment 
 
 
eCRF 
Electronic Case Report Form 
eCRS 
Electronic Case Retrieval Sheet 
FAS 
Full Analysis Set 
FS 
Functional score 
Gd 
Gadolinium 
 
 
KM 
Kaplan-Meier 
LDD 
Last Dose Date 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
MRI 
Magnetic Resonance Image 
MS 
Multiple Sclerosis 
NB 
Negative binomial 
 
 
NMPA 
National Medical Products Administration 
PDS 
Programming Datasets Specifications 
PK 
Pharmacokinetics 
PRO 
Patient-reported Outcomes 
PT 
Preferred Term 
RMS 
Relapsing MS 
SAE 
Serious Adverse Event 
SAF 
Safety Set 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SCR 
All screened subjects 
SOC 
System Organ Class 
TEAE 
Treatment Emergent AE 
TFLs 
Tables, Figures, Listings 


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Study No: CFTY720D2419 
 
ULN 
Upper Limit of Normal 
VAS 
Visual Analog Scale 
WBC 
White blood cell 
WHO 
World Health Organization 
1 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to describe the implementation of the 
statistical analysis planned in the protocol for study CFTY720D2419. 
There will be one report resulting from this SAP: The clinical study report (CSR) of the D2419 
study. 
 
 
The final CSR will be completed after the final database lock. 
This document is consistent with the current study protocols (version 03 original protocol). 
1.1 
Study design 
This is a 24-month, open-label, multicenter, interventional, single-arm study to collect efficacy, 
safety and health outcome data of fingolimod (Gilenya) 0.5 mg/day in approximately 100 
relapsing multiple sclerosis (RMS) subjects in China. 
The study will consist of three Phases (see Figure 1-1): 
Screening (up to 1 month): After signing informed consent, subjects will enter a Screening 
Phase to determine eligibility according to inclusion and exclusion criteria. 
The investigator must ensure that all subjects meet the inclusion and exclusion criteria to be 
eligible to enter the study. 
Treatment Period (24 months): On visit Day 1, all eligibility criteria will be confirmed, 
including a pre-dose ECG and vital signs. The first dose of study drug will be taken in the clinic 
on Day 1 and the subject will be monitored for at least 6 hours after the first dose administration 
before discharge. Refer to [Protocol Section 16.5] for Guidance for monitoring of subjects 
taking their first dose of the study drug. 
Then the subjects should come to site and be evaluated at month 1 and then every three months 
till the end of treatment up to 24 months. 
Follow Up (2 months): Subjects who completed Treatment Period will return for the Follow-
up visit 2 months after the last dose of study drug. 


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Study No: CFTY720D2419 
 
Figure 1-1 
Study design 
 
 
 
 
1.2 
Study objectives and endpoints 
Table 1-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To evaluate the efficacy of fingolimod 0.5mg on 
annualized relapse rate (ARR) in subjects with 
RMS treated for up to 24 months. 
• 
Annualized relapse rate (ARR) 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To evaluate the safety and tolerability of 
fingolimod 0.5 mg in subjects with RMS treated 
for up to 24 months. 
• 
Adverse events (AE) and serious adverse events 
(SAE) 
• 
Laboratory tests (hematology, biochemistry) 
• 
Vital signs 
• 
Electrocardiogram (ECG) 
• 
Ophthalmology 
• 
To evaluate the efficacy of fingolimod 0.5 mg on 
MRI lesions. 
• 
T1 hypo-intense lesion number and volume; T2 
lesion volume, new/newly enlarged T2 lesion 
number; Gd-enhancing T1 lesion number and 
volume. 


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2 
Statistical methods 
2.1 
Data analysis general information 
Novartis statistical and programming team will be performing the CSR analysis as planned in 
this document unless otherwise specified. The Statistical Analysis System (SAS) 9.4 and/or R 
3.6.1 or higher versions will be used. 
Unless otherwise stated, summary tables/figures/listings will be on all subjects in the respective 
analysis sets. Categorical data will be presented as frequencies and percentages. For continuous 
data, mean, standard deviations, median, 25th and 75th percentiles (optional), minimum and 
maximum will be presented. 
 
  
For efficacy analyses in the final CSR, all available data until EOT (i.e. excluding the data 
collected in the safety follow-up part) will be considered and no other cut-offs will be applied. 
For safety analyses in the final CSR, only data up to and including the safety cutoff of 45 days 
(5 times the half-life of fingolimod, 9 days) after the last dose administration of study drug will 
be considered. For safety analyses on the follow-up period, all data (including assessments or 
events more than 45 days after the last dose of study drug) will be considered. 
Presentation of p-values: p-values from statistical tests will be presented with 3 decimal places, 
or as <.001 where applicable. Statistically significant p-values will be flagged with an asterisk. 
In general, this is when p-values ≤0.05. 
2.1.1 
General definitions  
The table below summarizes some general definitions to be used in the rest of the document. 
Table 2-1 
General Definitions 
Study treatment/Study drug 
The investigational drug (fingolimod) will be referred as 
study treatment or study drug. 
Study Day 1 or Day 1 
The date of first administration of study drug/first dose 
date. 
Study Day 
All other study days will be labeled relative to Day 1. For 
events with dates on or after Day 1, study day for the 
event is calculated as (event start date – first dose date 
+ 1). For events with dates before Day 1, study day for 
the event is calculated as (event start date – first dose 
date). 
Day 0 will not be used. 
Duration of an event 
Duration of an event is calculated as (event end date – 
event start date +1). 
1 month 
30 days; to be used in determining target days of 
scheduled visits 
 
 
Day post-study drug discontinuation 
Day post-study drug discontinuation for a particular 
event is calculated as (event start date – study drug 
discontinuation date).  


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Baseline 
Baseline is the last assessment with non-missing value 
obtained prior to the first administration of study drug. 
No visit windows will be needed for the identification of 
baseline assessment.  
For pulse and blood pressure vital sign values, the 
baseline is the average of the non-missing values of the 
3 measurements taken on the last visit prior to the first 
administration of study drug.  
On-treatment period 
 
 
 
 
On-treatment period includes days from the first dose 
date until the last dose date. This definition applies to 
efficacy analyses only.  
For calculation of compliance to study drug 
administration, same definition will be used. 
Off-treatment period 
Off-treatment period includes days after the last dose 
date. This definition applies to both efficacy and safety 
analyses. 
Safety cutoff  
Safety cutoff: Unless explicitly otherwise stated (e.g. 
SAEs and deaths), data up to and including the safety 
cutoff of 45 days after permanent study drug 
discontinuation will be included in the analysis and data 
beyond this time point for a given subject will be 
excluded from the safety analysis. The safety cutoff of 
45 days (5x9 days) takes the half-life of the 
investigational drug into consideration. The safety cutoff 
applies to safety analyses only. 
Nominal visits 
Nominal visits are defined as all scheduled visits as per 
the clinical study protocol including the EOS and EOT 
visits. The definition of nominal visit excludes 
unscheduled visits. 
End of Study (EOS)  
EOS, used in the context of individual subjects, refers to 
EOS visit.  
End of Treatment (EOT) 
EOT refers to EOT visit. Only subjects who prematurely 
discontinue study drug but agree to continue to follow 
the schedule of assessments in the treatment period will 
have EOT visit. 
End of treatment period date 
This date is the date of discontinuation/study phase 
completion as recorded in the Treatment disposition 
CRF page. 
Last assessment on drug 
It is the last assessment with non-missing value taken 
before or on the date of last administration of study 
drug. No visit windows will be needed for the 
identification of the last assessment on drug evaluation. 
2.1.2 
Visit windows 
2.1.2.1 
Visit windows for treatment period 
Visit-windows will be used for both efficacy and safety data summaries by visit. Visit windows 
define a time period “around” the targeted visit date as defined in the evaluation schedule of the 
clinical study protocol. Visit-windows are non-overlapping and defined without gaps between 


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consecutive visit windows. The width of visit windows may vary over the course of the study 
period. 
Baseline assessments are defined in Section 2.1.1 and do not require a visit window.  
The purpose of visit windows is to analyze data based on the actual study days (rather than 
"nominal" visits). E.g. if a subject’s Month 1 visit is delayed; it is possible that the Month 1 data 
be re-aligned to visit-window Month 2 and be summarized under Month 2. 
- For efficacy analyses all nominal visits (i.e. excluding unscheduled visits) will be mapped 
into one of the defined visit-windows. 
 
 
 
 -For safety analyses all visits (scheduled and unscheduled) will be mapped to visit windows. 
Safety data from unscheduled visits may be reported separately if applicable.  
It is possible that more than one assessment of a subject fall into a particular visit-window. 
Section 2.1.2.3 deals with the statistical approaches to handle multiple visits in a given visit-
window. 
Tables displaying summary statistics “by visit” will also use the term visit-window as column 
header; this is to remind the reviewer that multiple assessments of a subject might be 
summarized. Below tables provide visit-windows definitions for applicable parameters. 
Table 2-3 
Visit-windows for MRI 
Visit-window 
Start day 
Target Day 
End day 
Month 12 
1 
360 
540 
Month 24 
541 
720 
900 
Table 2-4 
Visit-windows for routine laboratory values 
Visit-window 
Start day 
Target Day 
End day 
Month 1 
1 
30 
60 
Month 3 
61 
90 
135 
Month 6 
136 
180 
225 
Month 9 
226 
270 
315 
Month 12 
316 
360 
450 
Month 18 
451 
540 
630 
Month 24 
631 
720 
810 


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Table 2-5 
Visit-windows for vital signs*  
Visit-window 
Start day 
Target Day 
End day 
Month 1 
1 
30 
60 
Month 3 
61 
90 
135 
Month 6 
136 
180 
225 
Month 9 
226 
270 
315 
Month 12 
316 
360 
405 
Month 15 
406 
450 
495 
Month 18 
496 
540 
585 
Month 21 
586 
630 
675 
Month 24 
676 
720 
765 
*Data collected from Day 1 protocol scheduled visit will not be mapped to the visit windows due to different data 
collection on those visits. 
Table 2-6 
Visit-windows for Electrocardiogram (ECG) 
Visit-window 
Start day 
Target Day 
End day 
Month 1 
1 
30 
60 
Month 3 
61 
90 
135 
Month 6 
136 
180 
270 
Month 12 
271 
360 
450 
Month 18 
451 
540 
630 
Month 24 
631 
720 
810 
*Data collected from Day 1 protocol scheduled visit will not be mapped to the visit windows 
due to different data collection on those visits.  
For vital signs, the mean of the FTY Day 1 pre-dose value will be used as FTY baseline. If 
unavailable, the last available (including unscheduled) value before the first dose will be used. 
Missing Day 2 pre-dose values are not imputed. Day 2 assessments are only collected in subjects 
that meet Day 1 protocol monitoring guidelines. 
For ECG, the FTY Day 1 pre-dose value will be used as FTY baseline. If unavailable, the last 
available (including unscheduled) value before the first dose will be used. Missing Day 2 pre-
dose values are not imputed. Day 2 assessments are only collected in subjects that meet Day 1 
protocol monitoring guidelines. 
2.1.2.1.1 Time points for first dose monitoring ECG and Vital signs 
The first dose monitoring for Gilenya treatment will be analyzed. 
The vital sign values at specified hours as recorded in the database will be used. For the second 
dose vital signs, data will be summarized similarly. 
2.1.2.2 
Visit windows after study drug discontinuation 
For summaries of data collected after study drug discontinuation, data from both treatment 
period and safety follow-up period will be considered. All reporting will be done based on visit 
windows defined relative to the last administration of study drug. 


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The visit window definitions are provided in Table 2-7 where the Start day and End day are 
relative to the date of last administration of study drug. For the “Last assessment on drug”, the 
last assessment with non-missing value taken before or on the date of last administration of 
study drug will be summarized (no visit window applies). For the “Month 3 after LDD (last 
dose date)” visit-window, assessments taken at least 1 day after but no more than 135 days after 
the date of last administration of study drug will be considered. LDD stands for last dose date 
and will be footnoted in applicable outputs. 
Table 2-7 
Visit-windows after study drug discontinuation 
Visit-window 
Start day  
Target Day 
End day 
Last assessment on drug 
NA 
NA 
NA (see above or section 2.1.1) 
Month 3 after LDD 
2  
90 
135 
Month 6 after LDD 
136 
180 
225 
Month 9 after LDD 
226 
270 
315 
Month 12 after LDD 
316 
360 
405 
Month 15 after LDD 
406 
450 
495 
Month 18 after LDD 
496 
540 
585 
Month 21 after LDD 
586 
630 
675 
Month 24 after LDD 
676 
720 
765 
Month 27 after LDD 
766 
810 
855 
2.1.2.3 
Multiple assessments within visit windows 
It is possible that multiple assessments of a subject fall into the same visit-window (e.g. due to 
unscheduled visits). All results (scheduled and unscheduled) will be displayed in listings, but 
only one value (observed or derived) will be selected for summary statistics by visit-window. 
If multiple unscheduled visits within visit window are allocated to the same missed scheduled 
visit: 
For quantitative variables, the unscheduled assessment closest to the target day will be 
selected. If more than one assessment is at the same distance to the target day, the later one will 
be selected. For tables displaying the worst case scenario, such as notable abnormalities, all 
assessments within a visit window will be used to identify the worst (e.g. the maximum or the 
minimum depending on parameter). Where applicable it will be defined for each parameter 
what the worst case is. 
For qualitative variables, the worst record is selected; it is noted that in the relevant data 
subsection, worst case is always well defined.  
Note that “Last assessment on study drug” is not like other visit-windows where multiple 
assessments could occur. The assessment to be summarized at that time point is the last on drug 
observation which is the last observation a subject has while he or she is on fingolimod. 
Therefore, the above multiple assessment rules do not apply. 
In addition, the multiple assessment rules do not apply to the first dose/second dose / restart 
dose (if applicable) monitoring data. 


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2.2 
Analysis sets 
Full Analysis Set (FAS): The FAS comprises all subjects who have signed the Informed 
Consent and who have received at least one dose of study treatment. The FAS will be used for 
the summary of demography and baseline characteristics as well as for all efficacy analyses. 
Safety Set (SAF): The SAF includes all subjects who have signed the Informed Consent and 
who have received at least one dose of study treatment. The Safety Set is identical to FAS in 
this study and will be used for all safety analyses in the final analysis. 
All screened subjects (SCR): The SCR set comprises all subjects who have signed the 
Informed Consent and were screened. 
2.2.1 
Subgroup of interest 
Subgroups for efficacy safety analyses: 
• Age at baseline (Adult, Child): adult group is defined as subjects who have baseline age 
≥18; child group is defined as subjects who have baseline age < 18. This subgroup is 
defined to assess the efficacy and safety of fingolimod on adult and pediatric subjects 
separately. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
2.3.1 
Patient disposition 
The number and percentage of subjects who were screened but did not continue into the 
Treatment Period will be presented, along with the reason for discontinuation being “Screen 
Failure”. Data collected on the Disposition CRF page will be used to summarize this 
information. The summary will be on the SCR set. 
The number and percentage of subjects who completed the treatment period on treatment or 
prematurely discontinued the study treatment will be presented, along with the primary reason 
for discontinuation. Data collected on the Treatment disposition CRF page will be used to 
summarize this information. The summary will be on the FAS. 
The number and percentage of subjects who completed the study (i.e. the Treatment Period) or 
prematurely discontinued the study prior to the end of the treatment period will be presented, 
along with the primary reason for discontinuation. Data collected on the Study disposition CRF 
page will be used to summarize this information. The summary will be on the FAS. Subjects 
who prematurely discontinue the study treatment will be listed along with the reason for 
discontinuation. 
Protocol deviations will be summarized by deviation categories for the FAS. In addition, 
protocol deviations that led to exclusion from the analysis set will be listed. 
All summaries in this section will be presented by age group and then overall. 
2.3.2 
Background and demographic characteristics  
All analyses in this section will be presented by age group on FAS. 


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Background characteristics include subject demographic characteristics (sex, race and ethnicity 
collected on the Demography CRF), age at screening, height, body weight and BMI at baseline.  
Age, baseline height, body weight and derived BMI will be presented. These variables will be 
summarized for the FAS using frequency distributions (for categorical variables) and 
descriptive statistics of mean, standard deviation, minimum, median and maximum (for 
continuous variables).  
2.3.3 
MS baseline disease characteristics 
All analyses in this section will be presented by age group on FAS. 
MS baseline characteristics, MS disease history and MS medication history will be summarized 
by age group and then overall for the FAS. 
MS baseline characteristics include baseline EDSS and key MRI parameters (e.g. number of 
Gd-enhancing T1 lesions and T2 lesion volume).  
MS disease history includes duration of MS since diagnosis (years), duration of MS since first 
symptom (years), number of relapses in the last 12 months prior to screening, number of 
relapses in the 12 to 24 months prior to screening, and time since onset of most recent relapse 
(months) prior to screening.  
Duration of MS since diagnosis (years) will be derived as [(first dose date − MS diagnosis start 
date + 1) / 365.25]. Duration of MS since first symptom (years) will be derived as [(first dose 
date − first MS symptom date + 1) / 365.25]. Time since onset of most recent relapse (months) 
will be derived as [(first dose date − most recent relapse onset date + 1) / (365.25 / 12)]. In these 
calculations, partial dates (if any) will be imputed according to the rules specified in  
Section 5.1.4.1. 
MS medication history of previous disease-modifying drugs (coded by World Health 
Organization (WHO) drug dictionary) will be summarized. The number and proportion of 
treatment-naïve subjects (i.e. subjects who have not been treated with any disease- modifying 
drug before study enrollment) will also be presented. Approved MS disease-modifying drugs 
list: interferon beta-1a, interferon beta-1b, peginterferon beta-1a, glatiramer acetate, 
natalizumab, mitoxantrone hydrochloride, mitoxantrone, dimethyl fumarate, fumaric acid, 
teriflunomide, fingolimod, daclizumab, siponimod, ozanimod, diroximel fumarate, 
monomethyl fumarate, cladribine, alemtuzumab, ocrelizumab, ofatumumab, ponesimod, etc. 
2.3.4 
Medical history 
Medical history will be summarized by age group on the FAS (or listed for the Child group if 
more appropriate). Any condition entered on the Medical History CRF will be coded using the 
Medical Dictionary for Drug Regulatory Affairs (MedDRA) dictionary. The medical history 
will be summarized by primary system organ class (SOC) and preferred term. 


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2.4 
Treatments (study treatment, concomitant therapies, 
compliance) 
2.4.1 
Exposure to study treatment / compliance 
The Safety Set will be used for the analyses in this section. Summaries will be presented by age 
group and then overall. 
Duration of exposure to study drug expressed in days is defined as the number of days spent 
on study treatment. Intermediate treatment interruptions will be subtracted from drug exposure, 
i.e. the duration of exposure to study treatment (in days) will be calculated as (last dose date − 
first dose date + 1 − Ʃ [days with temporary study treatment interruption]), where any day with 
no drug taken is considered a study treatment interruption.  
Exposure to investigational study drug will be summarized with number and percentage of 
subjects by time category, and with summary statistics of the number of patient years of 
exposure. 
Duration of exposure to study treatment will be summarized descriptively by duration category 
(i.e. ≥ 1 month, ≥ 2 months, ≥ 3 months, ≥ 6 months, ≥ 9 months, ≥ 12 months, ≥ 15 months, ≥ 
18 months, ≥ 21 months). Descriptive statistics of duration in days will also be provided. The 
number of patient years is calculated as the sum of the duration of exposure for all subjects in 
the group. 
Compliance to the study treatment administration schedule will be calculated as duration 
of exposure to study treatment in (days) / duration of on-treatment period (as defined in  
Table 2-1) (in days) × 100%. This rule means that compliance will be measured during the time 
interval the subject took study treatment, i.e. premature discontinuation from study treatment 
will not be considered non-compliance. Compliance to study treatment administration will be 
summarized descriptively on the SAF. In addition, compliance will be summarized with 
cumulative number and percentage of subjects in each compliance category (i.e. ≥ 20%, ≥ 30%, 
≥ 40%, ≥ 50%, ≥ 60%, ≥ 70%, ≥ 80%, ≥ 90%, ≥ 95%, ≥ 98%, = 100%). 
2.4.2 
Prior, concomitant and post therapies 
Analyses described in this section will be performed on the SAF. Summaries will be presented 
by age group (or listings for the Child group if more appropriate) and then overall. 
2.4.2.1 
Concomitant medication 
Records on the Concomitant Medications CRF page will be coded using the WHO drug 
dictionary. All medications will be classified as prior, concomitant or post study treatment 
discontinuation medication as follows: 
• Prior medications are defined as drugs taken and stopped prior to first dose of study 
medication. 
• Concomitant medications are defined as drugs taken at least once between the first and 
last dose of study medication (including those which were started prior to first dose and 
continued into the treatment period). 


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• Post-study treatment discontinuation medications are defined as drugs started after the 
discontinuation of study medication. 
Medications will be categorized into one (and only one) of the above classes based on recorded 
or imputed start and end dates. When incomplete or missing, dates will be imputed according 
to Novartis standards (details will be given in programming datasets specifications (PDS) 
document). If both the start date and the end date are completely missing and medication has 
not been collected on the “Previous MS Disease Modifying Treatment” page, the medication 
will be classified into concomitant medication category. 
Medications in each of these three categories will be summarized by Anatomical Therapeutic 
Chemical (ATC) code and preferred term (and/or listed, if appropriate). ATC level 1 and level 
3 (e.g. M [Musculo-skeletal system], M01A [anti-inflammatory and anti-rheumatic products, 
non-steroids], etc.) will be used. 
Data collected from the Previous MS disease modifying treatment pages will not be included 
in this summary. 
2.4.2.2 
Surgical and medical procedures 
Records on the Prior or Concomitant non-drug therapies/procedures CRF page will be coded 
using the MedDRA dictionary. All procedures will be classified as prior, concomitant or post-
study treatment discontinuation procedure, in the same way as done for concomitant 
medications. Surgical and medical procedures in each of these three categories will be 
summarized separately by system organ class and preferred term (and/or listed, if appropriate). 
Imputation rules for start and end dates will be the same as for the concomitant medications. 
2.5 
Analysis of the primary objective 
All analyses for primary objective will be conducted using the FAS. 
2.5.1 
Primary endpoint 
Two variables are required for the calculation of the ARR (excluding covariates): 
• The cumulative number of confirmed MS relapses by subject is the response variable in 
the negative binomial model. All confirmed relapses with a start date on or after the date 
of first administration of study drug and prior to or on the end of treatment period date will 
be included in the analysis. Additional details are provided in Section 5.1.4. 
• The definition of a confirmed MS relapse is one accompanied by a clinically relevant 
change in the EDSS assessment, i.e. an increase of at least 0.5 points on the EDSS 
(total) score, or an increase of at least 1 point on at least two Functional scores (FSs), 
or an increase of at least 2 points on at least one FS, excluding changes involving 
bowel/bladder or cerebral FS, compared to the last EDSS assessment taken in the 
absence of (confirmed or unconfirmed) relapse and prior to the current relapse. EDSS 
obtained on the date as indicated on the Summary of MS Relapse eCRF page will be 
used. If such EDSS assessment is missing or not meeting the criteria to confirm the 
relapse, all other EDSS assessments taken within 30 days from the relapse start date 
(i.e. EDSS assessment date – relapse start date <=30) and before the relapse end date 


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(EDSS assessment date < relapse end date) will be checked. If at least one of such 
available EDSS assessments meets the criteria, the relapse is a confirmed relapse. 
Otherwise, the relapse is considered an unconfirmed relapse. 
• The time in study by subject will be used as an offset variable to adjust for the various 
length subjects have been observed (due to premature study discontinuation) and at-risk of 
a confirmed MS relapse in the study. Time in study for ARR will be calculated as (end of 
treatment period date – first dose date+1)/365.25. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
In the primary analysis, the ARR will be estimated by a negative binomial regression model 
with log-link function, the cumulative number of confirmed MS relapses per subject as the 
response variable, number of relapses in the previous two years before enrollment and baseline 
EDSS as continuous covariates. Natural log of time on study in years will be used as the offset 
variable to account for the varying lengths of subjects’ time in the study. The adjusted ARR (i.e. 
model-based estimate adjusted for covariates) and the corresponding 95% confidence interval 
will be obtained. 
In case of non-convergence, continuous covariates may be removed from the regression model 
in the order of: baseline EDSS, number of relapses in the previous two years. 
The primary analysis will only be performed for the Adult group.  
2.5.3 
Handling of missing values/censoring/discontinuations 
According to the protocol, subjects who discontinue study treatment should remain in the study 
and follow the assessment schedule. The primary analysis will use all available data up to the 
end of treatment period date, irrespective of on or off study treatment.  
For subjects who early withdraw from the study, the number of relapses up to the study 
discontinuation will be used for the primary analysis. No imputation will be applied to the 
incomplete study duration. 
The primary negative binomial regression model with an offset for the time in study adjusts for 
missing information (drop-out) under the assumption of non-informative drop-out, information 
is missing at random, and constant relapse rate over time. 
2.5.4 
Supportive analyses 
The primary analysis will be repeated to analyze all reported MS relapses (confirmed and 
unconfirmed) for Adult group. 
ARR time-based and ARR patient-based by age group will be provided for confirmed relapses 
and then for all relapses (confirmed and unconfirmed). ARRs using a “time-based approach” 
are calculated by taking the total number of relapses observed for all subjects within an age 
group divided by the total number of days in study of all subjects within the group and 
multiplied by 365.25 days. “Patient-based approach” is calculated in the way where individual 
ARRs are computed and summarized over subjects within an age group.  
Listings of relapses along with their confirmation status (confirmed or unconfirmed) will be 
presented by age group. 


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2.6 
Analysis of the key secondary objective 
Not applicable as there is no key secondary objective in this study. 
2.7 
Analysis of secondary efficacy objective(s) 
All analyses for secondary efficacy objectives will be conducted using the FAS. 
For MRI parameters, only assessments taken within 30 days from the last dose date will be 
included in the analysis. 
2.7.1 
Secondary endpoints 
Secondary efficacy endpoints include: 
• To estimate annualized rate of new or newly enlarged T2 lesions, below variables will be 
derived: 
• The total number of new or newly enlarged T2 lesions within 30 days from the last 
dose date will be derived by taking the sum of number of new or newly enlarged T2 
lesions from all scheduled MRI scans (as compared to the previous scan) with a non-
missing value within 30 days from the last dose date. 
• The time (in years) from screening scan will be calculated as (date of last scheduled 
MRI scan with a non-missing value for the number of new or enlarging T2 lesions 
within 30 days from the last dose date – date of screening scan +1)/365.25. 
• Volume of T2 lesions. 
• To estimate the number of Gd-enhancing T1 lesions per scan, below variables will be 
derived: 
• The total number of Gd-enhancing T1 lesions within 30 days from the last dose date 
will be derived by taking the sum of number of Gd-enhancing T1 lesions from the all 
scheduled MRI scan with a non-missing value within 30 days from the last dose date. 
Any Gd-enhanced T1 data obtained less than 30 days after the termination of steroid 
therapy which is used to treat MS relapses will not be included in analysis of Gd-
enhancing T1 lesion related endpoint. 
• The number of MRI scans will be derived by counting the number of scheduled MRI 
scans with non-missing values for the number of Gd-enhancing T1 lesions within 30 
days from the last dose date (i.e. the number of scans contributed to the derivation of 
the above variable: the total number of Gd-enhancing T1 lesions within 30 days from 
the last dose date). 
• Volume of Gd-enhancing T1 lesions. 
• Number of T1 hypo-intense lesions. 
• Volume of T1 hypo-intense lesions.  
Change and % change in volume of T2 lesions, Gd-enhancing T1 lesions and T1 hypo-intense 
lesions from baseline will only be defined for subjects with both baseline and post-baseline 
values and will be calculated as: 
change from baseline = post-baseline value – baseline value; 


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% change from baseline = change from baseline / baseline value*100. 
2.7.2 
Statistical hypothesis, model, and method of analysis 
Methods of analyses for efficacy endpoints defined in Section 2.7.1 are described below. 
• The annualized rate of new or newly enlarged T2 lesions for Adult group will be estimated 
by a negative binomial regression model with log-link function, the total number of new 
or newly enlarged T2 lesions within 30 days from the last dose date (per subject) as the 
response variable. Natural log of time from screening scan in years will be used as the 
offset. The model will include baseline age and baseline volume of T2 lesions as 
continuous covariates. The estimated number of new or newly enlarged T2 lesions will be 
obtained together with the corresponding 95% confidence interval. 
Supportive analyses: similar analyses may also be conducted to obtain the estimated 
annualized rate of new or newly enlarged T2 lesions at month 0 to month 12 and at month 
12 to month 24 for Adult group. 
Descriptive summary statistics (mean, median, standard deviation, min, max) for the 
number of new or newly enlarged T2 lesions will be provided by age group and by visit. 
Number and percentage of subjects free of new or newly enlarged T2 lesions will also be 
provided by age group. 
• The number of Gd-enhancing T1 lesions per scan for Adult group will be estimated by a 
negative binomial regression model with log-link function, the total number of Gd-
enhancing T1 lesions within 30 days from the last dose date (per subject) as the response 
variable. Natural log of the number of MRI scans will be used as the offset. The model 
will include baseline age and number of Gd-enhancing T1 lesions at baseline as 
continuous covariates. The estimated number of Gd-enhancing T1 lesions per scan will be 
obtained together with the corresponding 95% confidence interval. 
Supportive analyses: descriptive summary statistics (mean, median, standard deviation, 
min, max) for the number of Gd-enhancing T1 lesions will be provided by age group and 
by visit. Number and percentage of subjects free of Gd-enhancing T1 lesions will also be 
provided by age group. 
• Descriptive summary statistics (mean, median, standard deviation, min, max) will be 
provided by age group and by visit for the following: volume of T2 lesions, volume of Gd-
enhancing T1 lesions, number of T1 hypo-intense lesions, volume of T1 hypo-intense 
lesions, change and % change in volume of T2 lesions, Gd-enhancing T1 lesions and T1 
hypo-intense lesions from baseline. 
2.7.3 
Handling of missing values/censoring/discontinuations 
As a general rule, missing data will not be imputed in any secondary endpoint analyses. For 
MRI parameters, only assessments taken within 30 days from the last dose date will be included 
in the analysis. 
2.8 
Safety analyses 
All safety analyses will be conducted using the SAF. The safety cutoff is defined as 45 days (5 
times the half-life of fingolimod, 9 days) after the last dose administration of study drug. Unless 


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explicitly otherwise stated, only data up to and including the safety cut-off will be included in 
the analysis and data beyond this time point for a given subject will be excluded from the safety 
analysis.  
The assessment of safety will be primarily based on the frequency of adverse events (including 
death and non-fatal serious adverse events). Additional safety assessments include laboratory 
tests, vital sign measures, ECG evaluations, ophthalmic and dermatology. Clinically significant 
findings in these additional safety assessments and other will be reported as adverse events and 
analyzed as such.  
2.8.1 
Adverse events (AEs) 
An adverse event (AE) is any untoward medical occurrence (i.e. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation subject after providing written informed consent for participation in the study. 
That means that a subject can report AEs before having started study medication. For reporting 
purposes, the main focus will be on treatment emergent adverse event (TEAE), defined as any 
AE which started on or after the day of first dose of study medication or events present prior to 
the start of treatment but increased in severity based on preferred term.  
Except for serious TEAEs and deaths, only TEAEs up to and including the safety cut-off will 
be included in the analyses. All serious TEAEs and deaths will be included, regardless of the 
safety cut-off. 
TEAEs will be reported by primary system organ class (SOC) and preferred term (PT) 
according to the most recent Medical Dictionary for Regulatory Activities (MedDRA). The 
MedDRA version used for reporting the study will be specified in a footnote of the tables, 
figures or listings (TFLs).  
Overview of TEAE will be provided. The number and percentage of subjects reporting any 
TEAEs (referred to as incidence of any TEAEs in the following) will be summarized by age 
group, primary SOC and preferred term. Separate summaries will be provided for serious 
TEAEs, drug related TEAEs, TEAEs leading to permanent discontinuation of study treatment, 
TEAEs causing study treatment interruption, and most common TEAEs (≥10% in any of the 
age groups), which could be replaced by listings (for Child or even for both Adult and Child) if 
more appropriate. Additionally, the incidence of any TEAEs will also be summarized by age 
group, primary SOC, preferred term, and maximum severity (Mild, Moderate and Severe). 
Missing severity will not be imputed. 
If a subject reported more than one AE within the same primary SOC, the subject will be 
counted only once with the maximum severity at the SOCs level, where applicable.  
All AEs will be presented in listings. 
2.8.1.1 
Adverse events of special interest / grouping of AEs 
Selected tables will be produced for Adverse Events of Special Interest (AESI) (i.e. risks), 
which will be defined in the electronic case retrieval sheet (eCRS) at the time of analysis 
implementation (i.e. study DBL). Specifically, incidence of TEAEs that fulfill the risk search 
terms as defined in eCRS will be summarized by age group, risk name and preferred term. 


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Similarly, separate summaries will be provided for serious TEAEs that fulfill the risk search 
terms as defined in the eCRS (could be replaced by listing for Child if more appropriate). 
Additionally, incidence of any TEAEs that fulfill the search terms as defined in the eCRS will 
also be summarized by age group, risk name, preferred term and maximum severity. 
2.8.2 
Deaths 
Detailed listing for deaths will also be provided. All deaths as recorded in the final database (i.e. 
up to DBL) will be included. 
2.8.3 
Laboratory data 
The summary of laboratory evaluations will be presented for two groups of laboratory tests: 
Hematology and Chemistry. On presenting summary statistics, laboratory data will be grouped 
and displayed in an alphabetical order within the Hematology and Chemistry groups and 
subgroups.  
Descriptive summary statistics (mean, median, standard deviation, Min and Max) of the change 
from baseline in the laboratory result to each study visit-window by age group will be presented. 
Change from baseline will only be summarized for subjects with both baseline and post-baseline 
values and will be calculated as: 
change from baseline = post-baseline value − baseline value 
For continuous variables databased as <lower limit, these will be imputed as being half of the 
lower limit. 
The number and percentage of subjects with notable laboratory abnormalities (as defined in 
Table 2-8 below) at any time post baseline will be presented by age group (or listing for the 
Child group if more appropriate). Frequency (%) distribution of key hematological parameters 
(absolute lymphocytes, absolute neutrophils, leukocytes, and platelet count), with categories 
defined by either upper limit of normal (ULN), actual values, or a ratio of actual value, will be 
presented by age group (or listing for the Child group if more appropriate). 
Table 2-8 
Criteria for notable laboratory abnormalities  
Notable Values 
Laboratory Variable 
Standard Units 
SI Units 
Serum glutamic oxaloacetic 
transaminase (SGOT) (AST) 
>82 U/L 
>82 U/L 
Serum glutamic pyruvic 
transaminase (SGPT) (ALT) 
>90 U/L 
>90 U/L 
Total bilirubin 
≥ 2.0 mg/dL 
≥ 34.2 μmol/L 
RENAL FUNCTION / METABOLIC VARIABLES 
Creatinine 
≥2.0 mg/dL 
≥176 umol/L 
Total cholesterol 
≥ 240 mg/dL 
≥ 6.21 mmol/L 
Triglycerides 
≥ 300 mg/dL 
≥ 3.39 mmol/L 
HEMATOLOGY VARIABLES 
Hemoglobin 
≤ 10.0 g/dL 
≤ 100g/L 
Platelets (Thrombocytes) 
≤ 100 k/mm3 
≤ 100 x 109/L 
≥ 600 k/mm3 
≥ 600 x 109/L 


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Leukocytes (WBCs) 
≤ 2.0 k/mm3 
≤ 2.0 x 109/L 
≥ 15 k/mm3 
≥ 15x 109/L 
HEMATOLOGY VARIABLES: DIFFERENTIAL 
Neutrophils(absolute) 
≤ 1,000/mm3 
≤ 1 x 109/L 
≥12000/mm3 
≥ 12 x 109/L 
Lymphocytes(absolute) 
<200/mm3 
<0.2 x 109/L 
≥8000/mm3 
≥8 x 109/L 
Red blood cells (RBCs) 
<3,300,000/mm3 
<3.3 x 1012/L  
 
>6,800,000/mm3 
>6.8 x 1012/L 
RBC and Triglycerides are not collected on the “Hematology - Local Lab Results” page.  
Number of subjects with newly occurring liver enzymes abnormalities at any time post-baseline 
will be summarized. Newly occurring liver enzymes abnormalities are defined in the table 
below. 
Table 2-9 
Criteria for newly occurring liver enzymes abnormalities  
Laboratory Variable (unit) 
Criteria 
SGOT (AST) (U/L) 
>ULN 
>=2xULN 
>=3xULN 
>=5xULN 
>=10xULN 
>=20xULN 
SGPT (ALT) (U/L) 
>ULN 
>=2xULN 
>=3xULN 
>=5xULN 
>=10xULN 
>=20xULN 
Bilirubin (total) (umol/L)) 
>ULN 
>=2xULN 
>=34.2 umol/L 
ULN=upper limit of normal; normal range in the local laboratory of each site will be applied to subjects in that 
site. 
The results are presented in cumulative form, i.e. the highest actual laboratory value/upper limit value was 
used. If the value is >= 20 x ULN, it is also included in the >= 10 x ULN category and all the above categories. 
For the patients who missed the visits, but took off-site laboratory evaluations due to COVID19 
(lockdown, site issue, subject concern or other), the off-site laboratory data will be included to 
analyze. The sensitivity analysis will be conducted to assess laboratory data (WBC, neutrophils, 
lymphocytes, ALT, AST, total bilirubin and platelets), with the only change to exclude off-site 
laboratory data. For this sensitivity analysis, summary of patients with clinically notable 
laboratory abnormalities by age group and summary of patients meeting potentially clinically 
significant criteria based on laboratory data will be presented. 


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2.8.4 
Other safety data 
2.8.4.1 
ECG and cardiac imaging data 
ECG data will be collected at selected scheduled visits as specified in [Protocol Table 8-1]. 
Clinically significant findings from ECG evaluations will be reported as AEs and included in 
the analysis of AEs. ECG parameters include mean heart rate, mean PR interval, mean 
uncorrected QT interval, mean QRS duration, and QT corrected using Fridericia’s correction 
formula (all as collected on the ECG CRF). Descriptive statistics of each ECG parameter will 
be provided for each baseline and post-baseline visit-window by age group. Similar summaries 
will also be provided for change from baseline ECG parameters for each post-baseline visit-
window. Criteria in corrected QT interval as defined in Table 2-10 will be provided for each 
criterion by age group (or listing for the Child group if more appropriate). 
Table 2-10 
Abnormality criteria for corrected QT interval 
 
 Male subjects 
Female subjects 
1 
>450 msec 
>470 msec 
2 
>500 msec 
> 520 msec 
3 
30 - 60 msec increase from Baseline 
4 
>60 msec increase from Baseline 
For first dose administration monitoring, ECG parameters and change from pre-dose in ECG 
parameters by timepoint during 1st and 2nd dose (if necessary) administration will be 
summarized by age group. The number and percentage of subjects meeting the criteria in 
corrected QT interval (at any timepoint post-dose during 1st and 2nd dose (if necessary) 
administration) will be presented by age group (or listing for the Child group if more 
appropriate).  
For non by-visit summaries, visits defined by visit-windows will not be used. All available data 
from scheduled and unscheduled visits will be considered. 
For the patients who missed the visits, but took off-site ECG evaluations due to COVID19 
(lockdown, site issue, subject concern or other), the off-site ECG data will be included to 
analyze. The sensitivity analysis will be conducted to assess ECG data, with the only change to 
exclude off-site ECG data. For this sensitivity analysis, number and percentage of patients 
meeting the criteria in corrected QT interval and the corrected QT interval criteria (at any 
timepoint post-dose during first/second dose administration) by age group will be presented. 
2.8.4.2 
Vital signs 
Vital sign measurements include sitting systolic and diastolic blood pressures, sitting pulse, 
body temperature, height and body weight. 
Three sitting measurements of blood pressure (SBP and DBP) and pulse will be taken at each 
vital sign assessment. 
For post-baseline assessments, the blood pressure and pulse values will be the average of the 
non-missing values of the 3 measurements. If more than one blood pressure/pulse assessment 
(scheduled or unscheduled) exists in a particular visit-window (as defined in Section 2.1.2.1), 


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derivation should follow the rules as defined in Section 2.1.2.3. Derivation of baselines for 
blood pressure and pulse are provided in Section 2.1.1. 
Height will be collected at screening visit only and will only be summarized as demographics. 
Analyses of vital sign measurements (excluding data collected on Day 1 protocol scheduled 
visit) using descriptive summary statistics (mean, median, standard deviation, min, max) for the 
change from baseline for each post-baseline visit-window will be performed. These descriptive 
summaries will be presented by vital sign parameter and age group. Change from baseline will 
only be summarized for subjects with both baseline and post-baseline values and will be 
calculated as: 
change from baseline = post-baseline value − baseline value 
The number and percentage of subjects with clinically notable vital signs (at any time post-
baseline) will be presented by age group Listings of clinical notable vital signs during treatment 
period will be presented by age group. 
Clinical notable vital signs values are defined in the table below.  
Table 2-11 
Vital signs clinically notable values 
NOTABLE VITAL SIGNS AND BODY WEIGHT 
Vital Sign Variable 
Age 
Notable Criteria 
Heart Rate (bpm) 
 
< 12 years 
>130bpm or Increase of ≥ 15bpm from baseline  
Or  
< 70bpm or Decrease of ≥ 15bpm from baseline 
≥ 12 years 
>120bpm or Increase of ≥ 15bpm from baseline  
Or  
< 50bpm or Decrease of ≥ 15bpm from baseline 
Systolic BP (mmHg) 
 
< 12 years 
≥ 125 mmHg or Increase of ≥ 20mmHg from baseline 
Or  
≤ 70 mmHg or Decrease of ≥ 20mmHg from baseline 
≥ 12 to < 18 
years 
≥ 160 mmHg or Increase of ≥ 20mmHg from baseline 
Or  
≤ 90 mmHg or Decrease of ≥ 20mmHg from baseline 
≥ 18 years 
≥ 180 mmHg or Increase of ≥ 20mmHg from baseline 
Or  
≤ 90 mmHg or Decrease of ≥ 20mmHg from baseline 
Diastolic BP (mmHg) 
 
 
< 12 years 
≥ 85 mmHg or Increase of ≥ 15mmHg from baseline 
Or  
≤ 50 mmHg or Decrease of ≥ 15mmHg from baseline 
≥ 12 to < 18 
years 
≥ 95 mmHg or Increase of ≥ 15mmHg from baseline 
Or  
≤ 50 mmHg or Decrease of ≥ 15mmHg from baseline 
≥ 18 years 
≥ 105 mmHg or Increase of ≥ 15mmHg from baseline 
Or  
≤ 50 mmHg or Decrease of ≥ 15mmHg from baseline 
Temperature (°C) 
All 
>38.3 °C/ 101°F 
Body weight (kg)  
All 
± 7% from baseline weight 


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For first dose administration monitoring, pulse, sitting systolic, diastolic blood pressures and 
their change from pre-dose will be summarized by timepoint and age group during 1st and 2nd 
dose (if necessary) administration. Boxplots on these three parameters will also be provided as 
graphical presentation. The number and percentage of subjects with clinically notable values 
for these three parameters (at any timepoint post-dose during 1st and 2nd dose (if necessary) 
administration) will also be presented by age group (or listing for the Child group if more 
appropriate). 
For the patients who missed the visits, but took off-site vital sign measurements due to 
COVID19 (lockdown, site issue, subject concern or other), the off-site vital sign data will be 
included to analyze. The sensitivity analysis will be conducted to assess vital sign data (heart 
rate, SBP and DBP), with the only change to exclude off-site vital sign data. For this sensitivity 
analysis, number and percentage of patients with clinically notable vital sign abnormalities and 
patients with clinically notable vital sign values at any timepoint post-dose during first/second 
dose administration by age group will be presented. 
2.8.4.3 
Ophthalmic evaluations 
If any subject reports a TEAE of macular edema (occurs after first dose and before safety cutoff), 
a listing with assessments of optical coherence tomography (OCT) at the time of screening, 
diagnosis and resolution (if resolved) will be provided. This listing can be omitted if no such 
subject in the study. 
2.8.4.4 
Dermatology evaluations 
If any subject reports a TEAE of skin lesions (occurs after first dose and before safety cutoff), 
a listing with skin lesions will be provided. This listing can be omitted if no such subject in the 
study. 
2.8.5 
First dose (second dose/restart dose) monitoring 
Any cases where restarting first dose monitoring after study drug interruption was required but 
was not performed will be reported as a PD. 
2.8.5.1 
Vital signs 
Hourly vital signs including pulse, SBP and DBP are collected for the first dose, second dose 
(if necessary), and restarting of dose after interruption (if applicable).  
2.8.5.2 
ECG 
ECG will be performed at pre-dose, 6 hours post dose, and >6 hours post dose during the first 
dose, second dose (if necessary), and restarting of dose after interruption (if applicable). 
2.8.5.3 
Dose monitoring experience 
The first dose/second dose (if necessary) /restart dose (if applicable) monitoring experience 
refers to the information collected on the dose administration monitoring eCRFs (e.g. whether 
subjects are discharged after 6 hours post-dose or extended monitoring is required after 6 hours 


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post-dose, whether subjects are hospitalized, whether subjects discontinue the study drug 
permanently, and whether SAE is reported, etc.). 
All data with yes/no responses will be summarized. 
2.8.5.4 
Data summaries 
Summaries on the FTY SAF set by treatment group include: 
• Frequency (%) distribution of categorized sitting pulse or change (or percent change) from 
pre-dose sitting pulse during first dose administration (note that categories are given in 
table shells) 
• Summary of the overall dose monitoring experience (1st dose, 2nd dose (if necessary), and 
restart dose (if applicable))  
• Incidence of notable vital sign abnormalities based on the notable criteria in Table 2-8 (1st 
dose and 2nd dose (if necessary)) 
• Summary statistics and changes from pre-dose in ECG parameters by time point during 
1st and 2nd dose (if necessary) administration  
• Incidence of abnormal QTc interval as defined by the abnormality criteria in Table 2-10 
during 1st and 2nd dose (if necessary) administration 
2.8.6 
Safety evaluation after last administration of study treatment 
The SAF will be used for analyses in this section. 
Safety data collected after last administration of study treatment includes adverse events, vital 
signs, routine laboratory parameters and ECG. No safety cutoff date will be applied in the 
analyses defined in this section. Safety data within the safety cutoff date but after last 
administration of study treatment will also be included. Only subjects who prematurely 
discontinue the study treatment will be included. 
The number and percentage of subjects with at least one TEAEs that started after the date of 
last administration of study treatment will be reported by SOC, preferred term, and age group. 
The subset of subjects in the SAF who had data reported after the date of last administration of 
study treatment will be included in the analysis and the number of subjects in this subset will 
be the denominator in calculating the percentage.  
Summary statistics for vital signs measurements and changes from baseline. These descriptive 
summaries will be presented by vital sign parameter, treatment group and visit-window. 
Summary statistics for each ECG parameter and change from baseline. These descriptive 
summaries will be presented by vital sign parameter, treatment group and visit-window. 
In addition, subjects with notable lab abnormalities or clinically notable vital signs will be listed. 
2.9 
Pharmacokinetic endpoints  
Not applicable. 


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2.10 
PD and PK/PD analyses 
Not applicable. 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
  
• 
 


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2.12 
Biomarkers 
Not applicable. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 


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• 
  
• 
 
• 
 
• 
 
 
 
 
 
• 
 
• 
 
• 
 
 
 


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• 
 
 
 
 
 
 
 
 
 
Analysis sets: 
Full Analysis Set (FAS): around fifty subjects (including early withdrawn subjects) who had 
signed the Informed Consent and who had received approximately one year of study treatment. 
The FAS will be used for the summary of demography and baseline characteristics as well as 
for all efficacy analyses. 
Safety Set (SAF): all subjects who had signed the Informed Consent and who had received at 
least one dose of study treatment. The SAF will be used for the summary of demography and 
baseline characteristics as well as for all safety analyses. 
All screened subjects (SCR): all subjects who had signed the Informed Consent and were 
screened. 
 
 
 
 
 
 
3 
Sample size calculation 
3.1 
Primary endpoint(s) 
The assumption of true ARR is based on previous studies of fingolimod and literature review 
(see Table 3-1). ARR ranged from 0.16 to 0.21 in non-Chinese populations from three 
controlled studies for fingolimod 0.5 mg (FREEDOMS, FREEDOMS II, TRANSFORMS). The 
similar ARR was reported in Chinese population treated by teriflunomide 14 mg (ARR = 0.18, 
TOWER). Two observational studies reported ARR at 0.38 in Chinese population treated by 
interferon-β 250 µg, and ARR at 0.21 in non-Chinese population treated by teriflunomide 14 
mg (Teri-RADAR). The ARR reported in Chinese population from placebo group was 0.63 
(TOWER). The true ARR is assumed ranging from 0.20 to 0.38 for this Chinese interventional 
study. 


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Table 3-1 
ARR data on RRMS from historical studies 
Study/Reference 
Study 
Population 
ARR 
(FTY 0.5 mg) 
ARR 
(placebo) 
ARR 
(Interferon-β 
250 µg) 
ARR 
(Teriflunomide 
14 mg) 
Interventional studies 
FREEDOMS 
(non-Chinese) 
RRMS 
0.18 
(0.15, 0.22) 
0.40 
(0.34, 0.47) 
 NA 
 NA 
 FREEDOMS II 
(non-Chinese) 
RRMS 
0.21 (0.17, 
0.25) 
0.40 
(0.34, 0.48) 
 NA 
 NA 
TRANSFORMS 
(non-Chinese) 
RRMS 
0.16 
(0.12, 0.21) 
 NA 
0.33 
(0.26, 0.42) 
 NA 
TOWER, 
NCT00751881 
(Chinese) 
RRMS 
 NA 
0.63 
(0.44, 0.92) 
 NA 
0.18 
(0.09, 0.36) 
Observational studies 
NCT00370071, 
2006 
(Chinese) 
RRMS 
 NA 
 NA 
0.38 
(-,-) 
 NA 
Teri-RADAR, 
2019 
(non-Chinese) 
RRMS 
 NA 
 NA 
 NA 
0.21 
(0.11, 0.39) 
Assume ARR follows negative binomial distribution (~ NB(µ, k)). The dispersion parameter k 
is set as 1 based on the historical data. The 95% upper limit and lower limit of estimated ARR 
are calculated by normal approximation approach for sample size estimation. Assuming ARR 
at 0.25, sample size of 80 subjects will serve the 95% probability for estimated ARR within 
[0.13 to 0.37], which will be lower than the ARR observed in Chinese population treated by 
interferon-β 250 µg. Assuming ARR at 0.38, sample size of 80 is expected to show a lower 
ARR than placebo, with 95% probability within [0.22, 0.54]. So the sample size of 80 subjects 
is considered. Considering 20% drop-out rate, the total sample size will be around 100 subjects. 
Sample size calculation was performed in nQuery. 
4 
Change to protocol specified analyses 
 
 
 
 
 
 
 
 
 
 
 


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5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
Missing or partial dates are not allowed in completing the study treatment CRF pages. The end 
date of study treatment will be the last end date. 
5.1.2 
AE date imputation 
Incomplete or missing start and end dates of AE records will be imputed according to Novartis 
standards (details will be given in programming data sets specifications (PDS) document). 
5.1.3 
Concomitant medication date imputation 
Incomplete or missing start and end dates of concomitant medication records will be imputed 
according to Novartis standards (details will be given in programming data sets specifications 
(PDS) document 
5.1.3.1 
Prior therapies date imputation 
Same handling as for concomitant medications. 
5.1.3.2 
Post therapies date imputation 
Same handling as for concomitant medications. 
5.1.4 
Other imputations 
5.1.4.1 
MS disease baseline characteristics 
For the calculation of duration or time since relevant history events (MS disease baseline 
characteristics), partial dates will be imputed for the MS diagnosis start date, the first MS 
symptom date, and the most recent relapse onset date via below imputation rules: 
• If the year is missing or impossible (e.g. 12-Jan-1911), then the date will be imputed as 
“missing”. 
• If the year is not missing and possible, but the month is impossible or missing (e.g. 17-
XXX-2010), then the year will be kept and date will be imputed as July 1st (e.g. 1-July-
2010). 


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• If the year and the month are not missing and possible, but the day is impossible or 
missing (e.g. 31-FEB-2009), then the year and month will be kept, and date will be 
imputed as 15th (e.g. 15-FEB-2009). 
• The imputed dates should be prior to the screening visit date. That is, if imputed dates are 
on or after the screening visit date, the dates will be imputed to be one day before the 
screening visit date. 
• To guarantee the first MS symptom date is earlier than the MS diagnosis start date, and 
most recent relapse onset date is not earlier than the first MS symptom date after the 
imputation.If, after imputation, MS diagnosis date is before first MS symptom date, then 
the imputed first MS symptom date will be set to MS diagnosis date; or if, after 
imputation, most recent relapse onset date is before the first MS symptom date, then the 
imputed relapsed onset date should be set to the first MS symptom date. 
5.1.4.2 
Relapse date imputation 
Missing or partial dates are not expected for the start and end dates of relapses on the Summary 
of MS relapse CRF pages. In case partial dates (unknown day with month and year available) 
exist in the final database, the following rules will apply: 
• The start date will be imputed as the first day of the month or the first dose date if it 
occurs in the same month as the first dose date. 
• The end date will be imputed as the last day of the month or truncated to have a duration 
of maximally 90 days (whatever comes first). 
5.1.4.3 
Data handling for relapses within 30 days of onset of previous 
relapses or relapses with duration beyond 90 days 
According to the protocol definition of MS relapses, the start date of a new relapse has to be at 
least 30 days after the start date of a previous relapse (i.e. start date of a new relapse – start date 
of a previous relapse ≥ 30). If a relapse is recorded with a start date < 30 days after the start date 
of a previous relapse, the below data manipulation will be done to combine them into a single 
relapse by creating a new relapse record with the following information: 
• Start date: Take the earliest start date. 
• End date: Take the latest end date. If one of the end dates is missing, set it to missing. 
• Date of EDSS intended to confirm the relapse:  
• Take the date of EDSS by which the relapse can be confirmed. 
• If more than one EDSS assessments meet the above criterion, take the date of the 
EDSS from which the worst severity value is derived. 
• If no EDSS assessment meets the above criterion, take the earliest date of EDSS as 
captured on the Summary of MS Relapse CRF page. 
• Severity: Take the value representing the worst case (severe > moderate > mild > missing) 
(as specified in Table 5-1)  
• “Did the relapse affect daily activities?”, “Hospitalization?”, “Steroid used?”, “Recovery 
status”: For each of these characteristics, take the value representing the worst case (yes > 
no for the first 3 questions; no > partial > complete recovery for the last question).  


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Table 5-1 
Severity of MS relapses  
Mild relapse 
Moderate relapse 
Severe relapse 
EDSS increase of 0.5 point 
EDSS increase of 1 or 2 points 
Exceeding moderate criteria 
or  
or 
Or 
1-point FS change in one to three 
systems 
2-point FS change in one or two 
systems 
Exceeding moderate criteria 
 
or 
Or 
 
1-point change in four or more 
systems 
Exceeding moderate criteria 
Definition is based on the EDSS obtained to confirm the relapse as compared to the last EDSS (scheduled or 
unscheduled) taken in the absence of (confirmed or unconfirmed) relapse and prior to the current relapse. 
EDSS refers to total score; FS refers to functional score; all of the 7 functional scores are considered in this 
derivation. 
According to the protocol definition of MS relapses, the maximum duration of a relapse is 
furthermore limited to 90 days. If a relapse is recorded with a duration longer than 90 days, the 
end date will be truncated to have a duration of exactly 90 days. This applies also to the artificial 
records created by the above procedure. Missing end date of relapse is not allowed. In the rare 
cases that missing end date exists in the final database, it will be imputed so that the duration 
of relapse is exactly 90 days. 
5.2 
AEs coding/grading 
AEs are coded using the Medical dictionary for regulatory activities (MedDRA) terminology. 
The latest MedDRA version will be used and will be described in the footnote of relevant 
outputs. 
5.3 
Laboratory parameters derivations 
For each subject, the estimated creatinine clearance values (without collecting urine) will be 
calculated using the Cockcroft-Gault formula (as specified in Table 5-2). In these calculations, 
the body weight is the last measurement collected on or before the day when the subject takes 
the laboratory test and age should also be calculated based on the time when the subject takes 
the laboratory test.  
If the creatinine value is collected in the unit µmol/L (SI unit), it will be converted to mg/dL in 
order to use the formulas. The conversion is via the equation below: 
• mg/dL = 88.4 µmol/L (e.g. creatinine = 2.0 mg/dL = 176.8 µmol/L). 
Table 5-2 
Creatinine clearance calculation 
Variable 
Formula 
Creatinine clearance [mL/min] 
using Cockcroft-Gault formula 
(Cockcroft and Gault 1976)  
= (140 – A) × W / (72 × C) × G 
 Where 
A is age [years] 
W is body weight [kg] 
C is the serum concentration of creatinine [mg/dL] 
G is a constant: G=1 for males and G=0.85 for females. 
The estimated creatinine clearance will be included as one of the laboratory parameters. 


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5.4 
Statistical models 
5.4.1 
Primary analysis 
The SAS procedure GENMOD will be used to conduct the analysis on the negative binomial 
regression model. In GENMOD, the log of the dispersion parameter will be used (lognb) as an 
option in model statement. The natural log of time in year is used as an offset by specifying 
offset option in the model statement. 
5.4.2 
Key secondary analysis 
Not applicable as there is no key secondary objective in this study. 
5.5 
Rule of exclusion criteria of analysis sets  
Subject classification in the analysis sets is entirely based on protocol deviation and non-
protocol deviation criteria. Details are provided in Table 5-3 and Table 5-4. 
Table 5-3 
Protocol deviations that cause subjects to be excluded 
Deviation ID 
Description of Deviation 
Exclusion in Analysis sets 
INCL01 
Written informed consent was never obtained 
Excluded from all analysis sets 
Table 5-4 
Subject Classification 
Analysis Set 
PD ID that cause subjects to be 
excluded 
Non-PD criteria that cause  
subjects to be excluded 
FAS 
INCL01 
No study treatment taken 
SAF 
INCL01 
No study treatment taken 
6 
Reference 
Cockcroft DW, Gault MJ (1976) Prediction of creatinine clearance from serum creatinine. 
Nephron; 16:31-41. 
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