A 2 Year, Double-blind, Randomized, Multicenter, Active-controlled Core Phase to Evaluate Safety & Efficacy of Daily Fingolimod vs Weekly Interferon β-1a im in Pediatric Patients With Multiple Sclerosis and 5 Year Fingolimod Extension Phase
Phase: PHASE3
Conditions: Multiple Sclerosis
Sponsor: Novartis Pharmaceuticals

Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Development 
[FTY720D/fingolimod] 
Protocol No. CFTY720D2311 / NCT01892722
A two-year, double-blind, randomized, multicenter, active-
controlled Core Phase study to evaluate the safety and 
efficacy of fingolimod administered orally once daily 
versus interferon β-1a i.m. once weekly in pediatric 
patients with multiple sclerosis with five-year fingolimod 
Extension Phase 
Authors: 
 
Document type: 
Amended Protocol Version  
EUDRACT number: 
2011-005677-23 
Version number: 
v07 Clean 
Document Status 
Final 
Development phase: 
IIIb 
Release date: 
16-Nov-2016

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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 .................................................................................................................................... 8 
Amendment 7: released 16-Nov-2016 .................................................................................................... 9 
Amendment 6: released 22-Aug-16 ...................................................................................................... 11 
Amendment 5: released 16-Jun- 2015 .................................................................................................. 12 
Amendment 4: released 23-Oct 2014.................................................................................................... 14 
Amendment 3: released 14-Jul-2014 .................................................................................................... 18 
Amendment 2: released 11-Jul-2013 .................................................................................................... 19 
Amendment 1: released 13 June 2012 .................................................................................................. 21 
Protocol synopsis .................................................................................................................................. 24 
1 
Introduction ........................................................................................................................................... 31 
1.1 
Background ............................................................................................................................. 31 
1.2 
Purpose .................................................................................................................................... 35 
2 
Study objectives .................................................................................................................................... 36 
2.1 
Primary objectives: Core Phase ............................................................................................... 36 
2.2 
Secondary objectives: Core Phase ........................................................................................... 36 
2.3 
Exploratory objectives: Core Phase ......................................................................................... 36 
2.4 
Objectives: Extension Phase .................................................................................................... 37 
3 
Investigational plan ............................................................................................................................... 37 
3.1 
Study design ............................................................................................................................ 37 
3.2 
Rationale of study design ........................................................................................................ 39 
3.3 
Rationale of dose/regimen, duration of treatment ................................................................... 40 
3.4 
Rationale for choice of comparator ......................................................................................... 41 
3.5 
Purpose and timing of interim analyses/design adaptations .................................................... 41 
4 
Population ............................................................................................................................................. 42 
4.1 
Inclusion criteria ...................................................................................................................... 42 
4.2 
Exclusion criteria ..................................................................................................................... 43 
5 
Treatment .............................................................................................................................................. 46 
5.1 
Investigational and control treatment ...................................................................................... 46 
5.2 
Treatment arms ........................................................................................................................ 47 
5.3 
Treatment assignment .............................................................................................................. 48 
5.4 
Treatment blinding .................................................................................................................. 49 
5.5 
Treating the patient .................................................................................................................. 50 
5.5.1 
Patient numbering ................................................................................................. 50 
5.5.2 
Dispensing the study treatment ............................................................................. 50 

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5.5.3 
Supply, storage and tracking of study treatment ................................................... 50 
5.5.4 
Instructions for prescribing and taking study treatment ....................................... 51 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ........................ 52 
5.5.6 
Recommendations for the treatment of MS relapses ............................................ 53 
5.5.7 
Concomitant treatment.......................................................................................... 54 
5.5.8 
Prohibited treatment ............................................................................................. 54 
5.5.9 
Discontinuation of study treatment and premature patient withdrawal ................ 55 
5.5.10 
Study completion and post-study treatment .......................................................... 56 
5.5.11 
Early study termination......................................................................................... 57 
5.5.12 
Emergency breaking of assigned treatment code.................................................. 57 
5.5.13 
Role of site personnel ........................................................................................... 57 
6 
Visit schedule and assessments ............................................................................................................. 61 
6.1 
Information to be collected on screening failures .................................................................... 68 
6.2 
Patient demographics/other baseline characteristics ............................................................... 69 
6.3 
Treatment exposure and compliance ....................................................................................... 69 
6.4 
Efficacy ................................................................................................................................... 69 
6.4.1 
Magnetic resonance imagining (MRI) .................................................................. 69 
6.4.2 
MS relapse ............................................................................................................ 71 
6.4.3 
(Kurtzke’s) Expanded Disability Status Scale (EDSS) ........................................ 72 
 
 73 
6.4.5 
Appropriateness of efficacy assessments .............................................................. 73 
6.5 
Safety ....................................................................................................................................... 73 
6.5.1 
Physical examination ............................................................................................ 73 
6.5.2 
Ophthalmologic examination ................................................................................ 74 
6.5.3 
Vital signs ............................................................................................................. 74 
6.5.4 
Laboratory evaluations ......................................................................................... 75 
 
 76 
6.5.6 
ECG ...................................................................................................................... 77 
6.5.7 
Pulmonary Function Tests .................................................................................... 77 
6.5.8 
Columbia Suicide Severity Rating Scale (C-SSRS) ............................................. 79 
6.6 
Pregnancy and assessments of fertility .................................................................................... 79 
6.7 
Other assessments .................................................................................................................... 80 
 
 80 
6.7.2 
Pharmacokinetics .................................................................................................. 81 
7 
Safety monitoring ................................................................................................................................. 82 
7.1 
Adverse events ........................................................................................................................ 82 
7.2 
Serious adverse event reporting ............................................................................................... 83 
7.3 
Pregnancies .............................................................................................................................. 84 
7.4 
Data Monitoring Committee .................................................................................................... 84 
8 
Data review and database management ................................................................................................ 85 

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8.1 
Site monitoring ........................................................................................................................ 85 
8.2 
Data collection ......................................................................................................................... 85 
8.3 
Database management and quality control .............................................................................. 85 
9 
Data analysis ......................................................................................................................................... 86 
9.1 
Analysis sets ............................................................................................................................ 86 
9.2 
Patient demographics and other baseline characteristics ......................................................... 87 
9.3 
Treatments (study drug, rescue medication, other concomitant therapies, compliance) ......... 87 
9.4 
Analysis of the primary variable(s) ......................................................................................... 88 
9.4.1 
Variable ................................................................................................................ 88 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................................... 88 
9.4.3 
Handling of missing values/censoring/discontinuations ....................................... 88 
9.4.4 
Supportive analyses .............................................................................................. 89 
9.5 
Analysis of secondary variables .............................................................................................. 89 
9.5.1 
Key secondary variable(s) .................................................................................... 89 
9.5.2 
Efficacy variables ................................................................................................. 90 
9.5.3 
Safety variables ..................................................................................................... 92 
 
 93 
9.5.5 
Pharmacokinetics .................................................................................................. 93 
9.6 
Sample size calculation ........................................................................................................... 95 
9.7 
Power for analysis of key secondary variables ........................................................................ 96 
9.8 
Interim analyses ....................................................................................................................... 96 
10 Ethical considerations ........................................................................................................................... 97 
10.1 
Regulatory and ethical compliance .......................................................................................... 97 
10.2 
Informed consent procedures .................................................................................................. 97 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................................... 97 
10.4 
Publication of study protocol and results ................................................................................ 98 
11 Protocol adherence ................................................................................................................................ 98 
11.1 
Protocol Amendments ............................................................................................................. 98 
12 References (available upon request) ..................................................................................................... 99 
13 Appendix 1: Clinically notable laboratory values and vital signs ....................................................... 102 
14 Appendix 2: Guidelines for first dose monitoring .............................................................................. 104 
15 Appendix 3:  Guidance on safety monitoring ..................................................................................... 106 
15.1 
Guidance on the monitoring of patients with elevated blood pressure .................................. 106 
15.2 
Guidance on monitoring of patients with elevated liver function tests ................................. 106 
15.3 
Guidance on monitoring patients with symptoms of neurological deterioration, 
inconsistent with MS ............................................................................................................. 108 
15.4 
Guidance on monitoring of patients with notable lymphopenia ............................................ 108 
15.5 
Guidance on monitoring of patients with infections .............................................................. 109 
15.6 
Guidance on vaccinations ...................................................................................................... 110 
15.7 
Guidance on monitoring of pulmonary function ................................................................... 112 

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15.8 
Guidance for ophthalmic examination .................................................................................. 112 
 115 
Appendix 5: Statistical appendix (Information from a controlled clinical trial with count data) ............... 118 
 
List of tables 
Table 6-1 
Core Phase:  Assessment schedule ........................................................ 63 
Table 6-2 
Core Phase:  Abbreviated schedule of assessments for patients with 
SDD ....................................................................................................... 66 
Table 6-3 
Fingolimod Extension Phase:  Assessment schedule ............................ 67 
Table 6-4 
Severity of MS relapse .......................................................................... 72 
Table 13-1 
Hematology and blood chemistry notable values ............................... 102 
Table 13-2 
Urinalysis clinically notable values .................................................... 103 
Table 13-3 
Vital sign clinically notable values ..................................................... 103 
 
List of figures 
Figure 3-1 
Study design .......................................................................................... 39 

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List of abbreviations 
ADEM 
Acute Disseminated Encephalomyelitis 
AE 
Adverse Event 
Ag 
Antigen 
Alb 
Albumin 
AP 
Alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AV block 
Atrio-Ventricular block 
CDC 
Centers for Disease Control and Prevention 
CNS 
Central Nervous System 
CUA lesion 
Combined Unique Active lesion 
eCRF 
electronic Case Report/Record Form 
BSSR 
blinded sample size re-estimation 
CPO 
Country Pharma Organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CRO 
Contract Research Organization 
DLCO 
Diffusion Lung capacity for Carbon Monoxide 
DKEFS 
Delis-Kaplan Executive Function System 
DMTs 
Disease Modifying Therapies 
DS&E 
Drug Safety & Epidemiology 
DSS 
Disability Status Scale 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EDSS 
Expanded Disability Status Scale 
EOS 
End of Study 
FAS 
Full Analysis Set 
FACS 
Fluorescence Activated Cell Sorting 
Fingolimod-P 
Fingolimod-phosphate 
FEV1 
Forced Expiratory Volume at 1 second 
Gd 
Gadolinium 
GGT 
Gamma-Glutamyl Transferase 
HCG 
Human Chorionic Gonadotropin  
HAV 
Hepatitis A Virus 
HB 
Hepatitis B 
HCV 
Hepatitis C Virus 
HEV 
Hepatitis E Virus 
ICH 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IFN β 
Interferon beta 
Ig 
Immunoglobulin 
i.m. 
intramuscular 
i.v. 
intravenous 
IRB 
Institutional Review Board 

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IVR  
Interactive Voice Response system  
kg 
kilogram 
LFT 
Liver Function Test 
n/neT2 
New/Newly Enlarging T2 lesions 
mg 
milligram 
MRI 
Magnetic Resonance Imaging 
MS 
Multiple Sclerosis 
o.d. 
once a day 
 
 
PPW 
Premature Patient Withdrawal 
PT/INR 
Prothrombin Time/International Normalized Ratio 
RRMS 
Relapsing-Remitting Multiple Sclerosis 
S1P 
sphingosine-1 phosphate 
SAE 
serious adverse event 
SDD 
Study Drug Discontinuation 
 
 
SPMS 
Secondary Progressive Multiple Sclerosis 
 
 
TBL 
Total bilirubin 
 
 
ULN 
Upper Limit of Normal 
VZV 
Varicella-Zoster Virus 

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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 
Enrollment 
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol) 
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 is 
synonymous with “investigational new drug.” 
Medication number 
A unique identifier on the label of each study drug package in studies 
that dispense study drug using an IVR system 
Patient number 
A number assigned to each patient who enrolls in the study. When 
combined with the center number, a unique identifier is created for each 
patient in the study. 
Period 
A minor subdivision of the study timeline; divides phases into smaller 
functional segments such as screening, baseline, titration, washout, etc. 
Premature patient withdrawal 
Point/time when the patient 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 
Randomization number 
A unique identifier assigned to each randomized patient, corresponding 
to a specific treatment arm assignment 
Stage 
A major subdivision of the study timeline; begins and ends with major 
study milestones such as enrollment, randomization, completion of 
treatment, etc. 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or 
when study drug was discontinued whichever is later 
Study drug 
Any drug administered to the patient as part of the required study 
procedures; includes investigational drug and any control drugs 
Study drug discontinuation 
Point/time when patient permanently stops taking study drug for any 
reason; may or may not also be the point/time of premature patient 
withdrawal 
Variable 
Information used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified timepoints 

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Amendment 7: released 16-Nov-2016 
Amendment rationale 
Amendment 7 modifies the study duration from fixed 2 year duration to a flexible duration of 
up to 2 years. The change is being conducted because the study is currently overpowered due 
to the higher than anticipated observed relapse rate. The study shall maintain the required 
power of 80% to detect a 50% relative treatment effect on the annualized relapse rate (two-
sided 5% alpha-level). Accordingly, Novartis proposes to change the trial design from a fixed 
2-year study to an information-based flexible duration design study up to 2 years: 
Higher relapse rates in pediatric versus adult MS are supported by recent literature (Benson et 
al 2014). Also, similar higher ARR rates were consistently seen in young versus older adults 
in the fingolimod Phase 3 RRMS program. Based on the first BSSR of the current study (n > 
100 randomized subjects, data cut off 28-Sep-2015), relapse rates in the enrolled pediatric 
patient population are higher than those seen in adult patients from the fingolimod Phase 3 
RRMS program which were originally used as the basis for the sample size calculation for 
this study. Based on the BSSR the power to detect a 50% relative treatment effect on the 
annualized relapse rate (ARR) is currently at 96%, instead of the protocol-assumed 80%, if 
the study was to be conducted as planned with a 2-year fixed duration in 190 patients.  
It is quite apparent from these lines of direct (current blinded study data) and indirect 
evidence (publications) that the central statistical assumptions made for Study D2311 are 
overly conservative and are no longer valid. Based on these observations, the study design 
will be modified with this amendment (if sufficient information will be achieved by June 
2017) to allow for a flexible study duration in order to retain the power of at least 80% for the 
detection of a 50% relative treatment effect. In line with the ICH harmonized Tripartite 
guideline on “Clinical Investigation of Medicinal Products in the Pediatric Population” [(ICH 
Guideline E11] this will make the study more efficient (shorten exposure time of vulnerable 
pediatric patients to an investigational drug with double dummy design) without loss of 
information or statistical power.
 
 
 
 
Other changes to the protocol include the following. 

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Assessment of Gd enhancement is no longer required at the Month 18 scan and for all MRI 
Extension Phase scans due to concerns of possible accumulation of Gd in the brain for 
patients with repeated MRI scans with Gd enhancement.  This assessment will be optional and 
may be conducted if the sites would normally conduct MRI scans with Gd enhancement in 
their normal practice. 
Efficacy endpoints such as cumulative number of n/ne T2 lesions and number of Gd T1 
lesions are modified to adjust for the variant study durations among patients. The sensitivity 
analysis with missing data imputation method for the primary endpoint and the key second 
endpoint is removed since it is no longer applicable for the new study design with flexible 
study duration. 
Changes to the protocol 
The main changes and Sections affected are listed as follows: 
Protocol Synopsis and Protocol were updated throughout to incorporate the revised study 
design with respect to treatment duration in the Core Phase. 
Section 3.1, 3.3, 3.5 and 4 were updated to describe 
 
 
 
 
 
 
 
All patients that are enrolled in the Core Phase at the time of stopping the study 
will be considered to have completed the study if they return for their final visit.  These 
patients would then be eligible to participate in the Extension Phase if they meet the in/ex 
criteria for the Extension Phase. In accordance with feedback received from health authorities 
and the acknowledgement of the scarcity of pre-pubertal patients in this indication the 
requirement for 20% pre-pubertal patients was removed in order to render recruitment for this 
study feasible. 
Section 5.1 and 5.4 were updated to clarify the blinding rules for patients with a body weight 
of <40 kg at the start of the Core Phase.  These patients will receive blinded medication in the 
Extension Phase if they did not have a dose increase in the Core Phase due to sustained body 
weight to >40 kg at two consecutive visits.   
Section 6 Assessment Schedule Table 6-1 was updated to clarify which patients were required 
to have additional ophthalmology assessments and Assessment Schedule Table 6-3 was 
updated to change the months to be counted from the start of the Extension Phase and to 
provide clarity when PK sample is collected. 
Section 6.4.1 was updated to make Gd administration for the Month 18 MRI and during the 
Extension Phase optional due to concerns for the possible accumulation of Gd in the brain. 
The notification criteria for MRI activity were also updated. 
Section 6.7.1.1 provides clarification that the pediatric Qol assessment is done in patients up 
to <19 years of age. 

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Section 9.1 was revised to include an additional analysis population, fingolimod treated full 
analysis (Fingolimod treated FAS) to be used for long-term efficacy evaluations during 
fingolimod treatment.    
Section 9.4 was modified to remove the language regarding 20% pre-pubertal patients to be 
enrolled, an additional cofactor was added to the binomial regression model and the 
supportive analysis section was updated to remove the  sensitivity analysis using imputation 
for missing data. 
Section 9.5.1 was updated to have the key secondary endpoint adjusted for the flexible study 
duration, and the supportive/sensitivity analysis section was updated to be consistent with 
flexible study duration. 
Section 9.5.2 provides updates to secondary efficacy endpoints to be consistent with a flexible 
duration study.  Statistical analysis methods were also revised. 
Section 9.5.3 provides updates to safety variables to be consistent with a flexible duration 
study and 
 and pulmonary endpoints were revised/ further 
clarified. 
Section 9.5.4 was revised to clarify that the Ped QoL test is only done in patients up to <19 
years of age. 
Section 9.6 was updated to include the revised sample size and to provide information for the 
planned BSSR.  This section was also updated to include the stopping rules for the study 
based on the BSSR. If at the BSSR in H1 2017, the projection is that the estimated amount of 
information until the end of Q2 is sufficient to maintain an 80% power for the primary 
variable, then patients will be requested to come for their end of study visit by June 2017. If at 
the BSSR in H1 2017, the projection is that the estimated amount of information projected 
until the end of Q2 is unlikely to reach 80% power for the primary end point, the study will 
continue as originally planned until all patients complete the full two years of treatment. 
Section 9.7 sample size for key secondary endpoint was updated. 
Section 12 was updated with 2 new references. 
Table 13-3 was updated to provide a vital sign notable range for patients >18 years of age. 
Appendix 5 was added to provide details of the statistical plan to conduct the BSSR. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities as required. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, 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 amended protocol.  

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Amendment 6: released 22-Aug-16 
Amendment rationale 
Amendment 5 was released with a main goal to incorporate details of the 5-year Extension 
Phase into the overall study design. When updating the text to incorporate the Extension 
Phase the section on termination of the study (Section 5.5.11) was inadvertently not updated.  
This amendment is being implemented to provide clarification for the study termination text.  
The text has been revised to allow the study to be terminated as a whole and also to allow for 
termination of just the Core Phase or just the Extension Phase.  
Changes to the protocol 
Section 5.5.11 was updated to provide clarification that the study (overall study or just Core 
or Extension Phase) can be terminated at any time for any reason by Novartis. 
The changes described in this amended protocol are non-substantial and do not require 
IRB/IEC approval prior to implementation. 
Amendment 5: released 16-Jun- 2015 
Amendment rationale 
This study protocol is being amended to provide details for the 5-year Extension Phase of the 
study.  The Extension Phase is being included (in the current protocol) as a phase of the 
overall study since this simplifies the approval process and creates less work for sites to 
implement.  Patients that complete the 2-year Core Phase (on or off of study drug) will be 
eligible to enter a 5-year Extension Phase.  
 
 
 
The protocol is also being amended to address safety updates in the investigator brochure 
(Edition 18) – in particular to provide additional guidance for safety monitoring for 
opportunistic infections and for basal cell carcinoma. 
• Notably, there have been reports of isolated cases of cryptococcal meningitis in adult MS 
patients with relapsing MS receiving fingolimod. As a result, the fingolimod local product 
labeling will be updated to guide prescribers for vigilance, early detection, and diagnosis 
of such cases, should they occur. Similarly, the infection safety monitoring guidance is 
being updated in this protocol. 
• Basal cell carcinoma (BCC) has been reported in adult MS patients receiving fingolimod. 
The physical examination section has been amended to ask patients/caregivers about any 
new or worsening skin lesions and to instruct investigators to refer patients to the 
dermatologist in cases where suspected precancerous or cancerous skin lesions are 
identified.  BCC is very rare in the pediatric population and has a very low metastatic 
potential. In the current protocol, physical exams (which include evaluation of skin) are 
done quarterly during the Core Phase with detailed dermatological examination done at 

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baseline and at the end of the Core Phase. The detailed dermatological examinations will 
be conducted every 2 years during the Extension Phase.  
Changes to the protocol 
The main changes and Sections affected are listed as follows: 
Protocol Synopsis was updated to incorporate the Extension Phase into the overall study 
design. 
Section 1 was updated to refer Investigators to the current IB for exposure and safety updates.  
Section 2 was modified to add the Extension Phase objectives. 
Section 3.1, 3.2 and 3.3 were updated to change terminology to align with the two phase study 
design and to provide a description of the Extension Phase and a brief rationale. 
Section 4,  4.1 and 4.2 were modified to add the Extension Phase study population and to add 
the Extension Phase inclusion and Exclusion criteria. 
Section 5.1, 5.2, 5.3 and 5.4 were modified to include the study treatment arms and to provide 
blinding information for the Extension Phase. 
Section 5.5.1 was modified to include text to indicate that patients retain the same study 
number in the Extension Phase. 
Section 5.5.4 was revised to update the first dose monitoring requirements for the Extension 
Phase and to include text to describe that careful planning of study visits is required to ensure 
that adequate study drug is available for the transition from Core Phase to the Extension 
Phase. 
Section 5.5.7 was updated to indicate that there is no washout period required for IFN, 
dimethyl fumarate and glatiramer acetate for the Extension Phase for patients that stopped 
study drug treatment in the Core Phase and then started treatment with one of these agents. 
Section 5.5.8 provides clarification that the excluded medications in Section 5.5.8 may be 
taken in the Core Phase once a patient permanently discontinued study drug.  Patients starting 
treatment with these agents must meet the inclusion/exclusion criteria for washout 
requirements for entry into the Extension Phase. 
Section 5.5.10 was updated to indicate that the Core Phase results of the Core Phase and the 
Extension Phase results will be reported separately. This will allow for required reporting of 
individual study phases to the Health Authorities. 
Section 5.5.12 was added to provide the procedure for how to conduct an emergency breaking 
of the blinded treatment assignment in case of a medical emergency. 
Section 5.5.12 was added to updated to indicate that the Independent EDSS rater is only 
required during the Core Phase in order to maintain blinding.  
Section 6 was updated to provide Extension Phase visit windows, to provide details for when 
the 3M-FU visit is required and to provide a Table of Extension Phase visits and also to 
provide windows for the Extension Phase visits. 

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Section 6.4.1 was updated to indicate that the Investigator is allowed to view Extension Phase 
MRI’s and that MRI notifications will not be sent during the Extension Phase. 
Section 6.4.2 and 6.4.3 were modified to indicate that a blinded EDSS rater (independent 
evaluating physician) is not required for EDSS readings during the Extension Phase since all 
patients will be treated with fingolimod so blinding is not required. 
Section 6.5.1 was revised to indicate that Investigators should ask the patient if they have any 
new or changed skin lesions as part of each physical examination and to refer patients to the 
dermatologist if suspicious lesions were identified. 
Section 6.5.3 was updated to provide details of the first dose monitoring in the Extension 
Phase.  First dose monitoring by the independent first dose monitoring team is required for the 
first dose of study medication taken in the clinic, but then subsequent restarts or drug dose 
increases may be conducted by the main study team if desired. Blinding is no longer required 
after the first dose administration blinded monitoring. 
Section 6.7.2 was modified to include a single PK assessment in the Extension Phase to 
monitor blood concentrations after one month in the Extension Phase to allow for possible 
dose increase based on the blood concentrations of fingolimod for newly treated patients. 
Section 9.1 was updated to update the Core Phase statistical analysis sets and to add the 
statistical analysis sets for the Extension Phase. 
Section 9.5.1, 9.5.2, 9.5.3, 9.5.4 and 9.5.5 were updated to include the natural log as an offset 
for T2 lesion analysis, to add the Extension Phase efficacy and safety variables and to provide 
a PK assessment at Month 25. 
Section 9.6 was updated to indicate the there was no sample size calculation for the Extension 
Phase.  The Extension Phase sample size is dependent on the number of patients that complete 
the Core Phase and enroll into the Extension Phase. 
Appendix 2 was updated to indicate that First dose monitoring is required by the independent 
first dose monitoring team in the Extension Phase only for the first dose of medication in the 
Extension Phase. 
Appendix 3 Section 15.5 Guidance on monitoring of patients with infections was updated to 
provide additional guidance regarding infections. 
Additional minor clarifications and editorial changes were made throughout the protocol for 
clarity and consistency across sections. 
Summary of previous amendments 
Amendment 4: released 23-Oct 2014 
Amendment rationale 
Amendment 4 implemented modifications based on feedback from 1) the study advisory 
group, 2) infectious disease experts 3) Investigators enrolling patients in the clinical trial and 
4) health authority input.  

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Inflammatory disease activity in MS is expressed as clinical relapses and as inflammatory 
lesions on MRI, both of which have been shown to be predictive of future MS relapse activity. 
The current protocol inclusion criterion defines a population with active disease based on 
prior relapses. This inclusion criterion is now being expanded to additionally allow patients 
with evidence of active disease based on recent MRI activity alone (presence of Gd-enhancing 
lesions within 6 months prior to randomization) to be enrolled. This change reflects the 
current clinical practice in pediatric MS where decision making for switching treatments is 
commonly based on MRI activity and will appropriately increase the pool of patients that can 
be considered for the study (Banwell et al 2011, Yeh et al 2011).  
Experience in the trial thus far has shown that serological testing and interpretation of vaccine 
generated immunity is complex and can be prone to errors. This is also reflected in the 
Centers for Disease Control and Prevention (CDC) guidelines. According to the CDC, “results 
of serum antibody tests in vaccinated persons are difficult to interpret. In vaccinated persons, 
antibody levels are often lower than following natural infection, and commercially available 
tests may not detect such low levels of antibody” (VPD Surveillance Manual 2012). 
“Serologic screening for measles, rubella, or mumps immunity before vaccination is not 
necessary and not recommended if a person has other acceptable evidence of immunity to 
these diseases. Similarly, post vaccination serologic testing to verify an immune response is 
not recommended.” (CDC - Prevention of Measles, Rubella, Congenital Rubella Syndrome, 
and Mumps, 2013).Thus, in the current trial, serological testing for antibodies can lead to 
unnecessary exclusion of otherwise eligible patients and may lead to unwarranted vaccination 
in some patients. On the advice of infectious disease experts two of the serology screening 
exclusion criterion were combined to provide better clarification of the screening 
requirements. The exclusion criterion for positive antibodies to varicella zoster virus (VZV), 
measles, mumps, rubella, diphtheria, pertussis and tetanus was modified to align with the 
CDC criterion for acceptable evidence of immunity to determine a patient’s immune status. 
The modifications made to the serology testing are also now aligned with the current 
prescribing information for fingolimod. Further, it should be noted that there is no safety 
signal for fingolimod in the adult population as far as diseases like measles, mumps, rubella, 
diphtheria, pertussis and tetanus are concerned and there is no requirement of serology testing 
for these antigens in the current prescribing information. Thus, the amended exclusion 
criterion is pragmatic, follows CDC guidance and the current fingolimod prescribing 
information and continues to appropriately filter a safe population to be enrolled in the study. 
The exclusion criterion for patients testing positive for interferon-beta antibodies was 
removed. The clinical significance of presence of antibodies (binding or neutralizing) to 
interferon (especially at a single time point) is not certain (Polman et al 2010). Neutralizing 
antibodies (NAbs) can disappear over time. To be of significance in decision making for 
individual patients, the NAb should be seen to be persistent over time (high titre) and need to 
be correlated to the disease activity in a patient. In patients with low level of NAbs which are 
persistent over 3-6 months, additional testing with myxovirus resistance protein A needs to be 
conducted to determine the significance of NAbs. Hence, excluding otherwise eligible 
patients based on this single point testing is not justified. The neutralizing antibody testing at 
the end of study is retained in the protocol and will be used for sensitivity analysis. 

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Based on feedback from investigators and the study advisory group the exclusion criterion for 
prior immunosuppressive/immunomodulatory treatments was revised to reduce the number of 
excluded prior treatments and to specify appropriate washout periods as needed. The protocol 
exclusion of prior use of dimethyl fumarate was removed to allow dimethyl fumarate to be 
taken up to the start of study drug with no washout period required. This change was made 
given the very short half- life (~1h) for dimethyl fumarate (and the active metabolite mono-
methyl fumarate) together with the protocol requirement for patients to have acceptable 
complete blood count prior to start of study drug. The protocol exclusion of prior use of 
teriflunomide was removed to allow teriflunomide to be taken up to 3.5 months of the start of 
study drug. 
The Exclusion criterion for liver enzymes was revised to more closely align with the clinical 
experience with fingolimod. Fingolimod has shown a rather benign liver safety profile 
without any un-confounded cases of severe liver injury. Also, liver safety is being monitored 
closely throughout the study. The exclusion criteria for LFT’s has been altered in adolescents 
in a manner consistent with adult fingolimod trials, but the criteria for pre-pubertal subjects 
have remained unchanged. 
Levels of total alkaline phosphatase have also been allowed to be increased to up to 2 X ULN 
as in adolescents the elevation may be secondary to bone isoforms of the enzyme (growing 
bones; Turan et al 2011). Accordingly, the guidance on isolated elevations of alkaline 
phosphatase has been modified and will not necessarily require study drug discontinuation, 
and would be based on the PI’s discretion if the elevations were thought to be more serious in 
nature. Guidelines for safety monitoring for alkaline phosphatase in Appendix 3 have also 
been updated. 
To assist patients with travel restrictions, blood samples for liver panel assessments for Visit 
51, 71 and 72 may be drawn by a local lab and the results reported to the Investigator within 
48 hrs of obtaining the results. All safety guidelines will be followed and the results of the 
local laboratory values will be included in the eCRFs to document the values. 
 all ‘must’ criteria for permanent 
study drug discontinuation are now provided in a single location in the protocol for clarity. 
Appendix 3 safety monitoring guidelines were updated to provide clarification that 
lymphocyte values obtained from a local lab should also be included in the clinical database 
to ensure that the recovery from low lymphocyte values would be collected. This change was 
made because close monitoring of the recovery of lymphocyte values with fingolimod has not 
been studied in this patient population. Serology guidelines were updated to provide all 
related guidelines in a single location, and in 
 
 
The requirement for chest x-ray at screening and end of study visit was removed because of 
concerns from Investigators that this was an unnecessary radiation exposure to subjects. The 
pulmonary function testing and clinical examination of the respiratory system are considered 
to be adequate screening measures to evaluate pulmonary status. 
Based on discussion with Investigators the central blinded MRI reading center will now 
provide MRI notifications during the course of the study if certain MRI activity criteria are 

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met for a given patient. The study advisory committee agreed to notifications based on " a 
combined unique active (CUA) lesion count (Gd-enhancing lesions + new/enlarging T2 
lesions not associated with Gd-enhancement. This change was made to allow Investigators to 
be notified if patients have significant MRI lesion activity during the course of the study. The 
CUA lesion count was also added as an exploratory objective. 
Changes to the protocol 
The main changes and Sections affected are listed as follows: 
Section 2.3 (Exploratory objectives) 
 
Section 4.1 (Inclusion criteria) was updated to allow for patients with Gd enhancing lesions 
within 6 months of randomization to enroll in the study. 
Section 4.2 (Exclusion criteria) were updated to remove the criteria for exclusion based on 
IFN antibodies, to update the list of excluded medications and time requirements for washout 
periods, to revise the exclusion criteria for liver enzymes, to combine serology screening 
criteria and revise the requirements for serology for VZV, measles, mumps, rubella, 
diphtheria, tetanus and pertussis. 
Section 5.5.7 (Concomitant treatment) was changed to require no washout period for patients 
treated with dimethyl fumarate. 
Section 5.5.9 (Discontinuation of study treatment and premature patient withdrawal) was 
updated to include a list of conditions/findings that require permanent study drug 
discontinuation in a single location. 
Section 5.2.12 (Role of site personnel) was updated to provide clarification for the 
pediatrician and first dose administrator’s duties. 
Section 6 (Visit schedule and assessments) was updated to allow extended time for screening 
assessments if required, chest x-ray was removed from Table 6-1 and IFN antibody testing 
was updated and moved to serology testing (Table 6-1). 
Section 6.4.1 (Magnetic resonance imagining (MRI)) was revised to include criteria for 
central review monitoring for MS related MRI activity. 
Section 6.5.4 (Laboratory evaluations) was updated to include the option for patients with 
travel restrictions to have local labs drawn for liver panel visits 51, 71 and 72.  The serology 
section was simplified to align with other laboratory sections (serology guidelines were 
moved to Appendix 3).  
 
 
Section 6.5.7 (Chest x-ray) was updated to remove the requirement for conducting chest x-
rays during the study. 
Section 9 (Data analysis) was updated to add pubertal status to supportive analysis for primary 
efficacy endpoint, to move key efficacy text to the correct section, to add exploratory 
variables to be summarized by visit with descriptive statistics, to add number of CUA lesions 

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at month 24 and remove SDMT for variables analyzed by rank ANCOVA, to remove chest x-
ray from safety variables, to remove cognitive testing section as cognitive tests are efficacy 
variables. 
Section 12 (References (available upon request)) was updated to add new references. 
Appendix 2 (Guidelines for first dose monitoring) were updated to include only events related 
to first dose monitoring. Additional ECG criteria that apply to the entire study were moved to 
Section 5.5.9 for clarity. 
Appendix 3 Section 15.2 (Guidance on monitoring of patients with elevated liver function 
tests) was updated to revise the guidance for alkaline phosphatase. 
Appendix 3 Section 15.4 (Guidance on monitoring of patients with notable lymphopenia) was 
changed to add a requirement to provide local lab results for lymphocyte monitoring in the 
clinical database. 
Appendix 3 Section 15.6 (Guidance on vaccinations) was updated to provide guidelines for 
screening serology and other guidelines in a single location for clarity and ease of 
implementation. 
Appendix 3 Section 15.8 (Guidance on monitoring of patients with diagnosis of macular 
edema) was updated to remove text for initiating study drug after resolution of macular 
edema. 
 
 
 
Amendment 3: released 14-Jul-2014 
Amendment rationale 
Amendment 3 was created 
 to clarify 
the eligible age range for patients enrolled in Russia. This request was based on the local 
product information for Avonex (interferon-β-1a IM, the comparator used in the study) which 
contraindicates use of Avonex in children below 12 years of age in Russia (i.e. this is included 
in the Contraindication section of the local product information). Per protocol, Inclusion 
Criterion 2, the eligible age range for patients enrolled in the study is 10-17 years, inclusive. 
This amendment clarifies that if the local product information for Avonex specifically 
contraindicates use below a certain age, inclusion of such patients is not permitted in that 
country. 
Changes to the protocol 
The main changes and Sections affected are listed as follows: 
Section 4.1 (Inclusion criteria) criterion 2 was modified to allow for countries like Russia to 
participate if interferon-β-1a IM was specifically contraindicated for use below a certain age 
based on the local product information (Contraindication section) for that country. 

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Amendment 2: released 11-Jul-2013 
Amendment rationale  
Amendment 2 implemented modifications based on requests received from national health 
authorities (e.g. modifications of first dose monitoring guideline with reference to local or 
regional product information for Gilenya in adults; to specify need for follow up of adverse 
events of interest (cardiac, liver, lung, eye) until resolution or stabilization; assessment of 
compliance; inclusion of puberty status as covariate in the statistical analysis) and 
incorporates feedback from investigators to further optimize the protocol and study conduct. 
This amendment also further enhances and clarifies protocol exclusion criteria and safety 
monitoring guidelines related to infections and first dose cardiac effects. These modifications 
are made based on recommendations from pediatric infectious disease and pediatric 
cardiology specialist review of the protocol in the context of the known safety profile of 
fingolimod in adults in this regard. 
This amendment also implements changes to exclusion criteria, assessments, study drug 
discontinuation criteria and safety monitoring related to liver functioning to align these to 
relevant aspects of the Novartis Clinical Safety Standard Hepatotoxicity Guideline and to 
implement the more specific – and partly more conservative - recommendations of the 
Novartis Investigational Liver Expert Team (iLET); given that this study is in a new 
population. In addition, changes related to ECG/QTc findings, pregnancy and suicidality 
assessments are made to further align these with the recent Novartis Clinical Safety Standard 
Guidelines.  
Additionally, an optional, comprehensive cognitive testing battery 
 
 is being implemented to allow evaluation 
of change over time and generation of important data to better understand the utility of these 
tests in clinical studies in pediatric MS. 
Other updates, clarifications and edits throughout the protocol were also made.   
The study enrollment is expected to commence around the time of Amendment 2.  
Changes to the protocol 
The main changes and Sections affected are listed as follows: 
Section 1 (Background) has been updated to include new relevant clinical safety information 
on fingolimod and a summary of relevant information from toxicology studies in neonatal and 
juvenile rats.   
Section 4.1 (Inclusion criteria) criterion 3 was modified to implement the revised diagnosis 
criteria for pediatric MS.   
Section 4.2 (Exclusion criteria) has been modified to update and/or clarify Exclusion criteria 
related to: differential diagnosis; excluded prior immuno-suppressive and immuno-
modulatory medications; additional infectious agents leading to exclusion based on sero-
status; cardiac disease/findings on screening ECG or treatment with QT prolonging drugs; 
hepatic conditions; addition of history of seizures (to reflect the warning and precaution 

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statement in the IFN β-1a i.m. (Avonex) product information); suicidality/riks of suicide; use 
of prior investigational drug or therapy.  
Section 5.1 (Investigational and Control treatment) has been modified to allow initial titration 
of injectable study drug (IFN β-1a i.m. or placebo) to full dose of over 4 weeks and the use of 
prophylaxis and treatment of flu-like symptoms in order to reduce initial tolerability issues 
associated with IFN β-1a i.m. treatment initiation. These measures are standard clinical 
practice at many sites.    
Section 5.5.6 (Recommendations for treatment of MS relapses) has been updated to add a 
maximum dose for i.v. corticosteroids for treatment of MS relapse and to prohibit use of oral 
taper after the i.v. course of steroids. 
Section 5.5.7 (Concomitant treatments) has been modified to clarify that washout is not 
required for patients treated with IFN β or glatiramer acetate and that vigilance is needed 
during concomitant chronic use of medications with hepatotoxic potential as patients may be 
at a higher risk of liver adverse events. 
Section 5.5.9 (Discontinuation of study treatment and premature patient withdrawal) has been 
updated to list ECG abnormalities that should lead to study drug discontinuation per 
ECG/QTc Clinical Standard Guideline. 
Table 6-1 (Schedule of assessments) have been updated to include additional lab visits for 
evaluation of liver enzymes, to add capsule and syringe count as measure of compliance and 
to reflect or clarify other modifications in protocol assessments. 
Section 6.5.2 (Ophthalmic examination) has been modified to omit the optional measurement 
of retinal nerve fiber layer thickness (RNFL) by OCT from the protocol as obtaining a 
meaningful assessment of this parameter in this study is unlikely (small sample size, different 
OCT devices at sites, variability in measurement).  
Section 6.5.4 (Laboratory evaluations) was modified to add phenotyping of T cells and B cells 
to the hematology evaluation and serology testing for antibodies to additional infectious 
agents (herpes simplex virus, EBV, CMV for information on serostatus prior to study entry). 
This section was also updated to provide the complete list of parameter and markers that will 
be evaluated by the central laboratory as part of the exclusion criteria (e.g. infectious agents 
including hepatitis and HIV) or during the study (blood chemistry and endocrinology 
parameters). 
Section 6.5.9 (Columbia Suicide Severity Rating Scale, C-SSRS) was updated to align with 
the current Novartis Clinical Standard Suicidality Guideline and to clarify that for patients 
unable/unwilling to answer the C-SSRS questions in the IVR system themselves and for all 
patients below the age of 12 years, another individual will enter the C-SSRS questions in to 
the IVR system on behalf of the patient. The IVR version of the C-SSRS used in the study has 
not been validated for use in patients below the age of 12 years.  
Section 6.6 (Pregnancy and assessment of fertility) has been modified to include that female 
patients of childbearing potential who are sexually active will perform a monthly urine 
pregnancy test in addition to the serum tests performed at the scheduled visits.  

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Section 14 (Guidance for first dose monitoring) has been updated as recommended by 
pediatric cardiology specialist, local health authority and to align with ECG/QTc Clinical 
Safety Standard Guideline. 
Section 15.2 (Guidance on monitoring of patients with elevated liver function tests) has been 
revised and updated to align with the Novartis Clinical Standard Guideline and the 
recommendations by the iLET.  
Sections 15.5 and 15.6 (Guidance on monitoring of patients with infections, Guidance on 
vaccinations) have been updated as recommended by pediatric infectious disease specialist.  
 
 
  
Additional minor clarifications and editorial changes were made throughout the protocol for 
clarity and consistency across sections. 
Amendment 1: released 13 June 2012 
Amendment rationale  
Amendment 1 implemented changes to the CFTY720D2311 protocol to address 
recommendations and requests received from the 
 
 following their review of the protocol and to align aspects of the 
protocol with the current revised fingolimod (Gilenya™) label.  
The main changes were:  
• The change in study design from open-label/rater-blinded to double-blind/double dummy 
which was implemented in order to reduce the potential for bias that may be introduced in 
an open-label design due to the lack of blinding of patients, caregivers and investigators. 
• The on-line pharmacokinetic (PK) assessment of fingolimod concentration levels at 
Month 1 was expanded to include all patients with a bodyweight of 40 kg or below in 
order to determine the need for an individual dose increase (from 0.25 mg to 0.5 mg) 
based on their individual concentration level rather than on PK results obtained from an 
initial subset of patients in this weight group.  
• In order to align the protocol with the revised fingolimod label, the amendment 
additionally updated and modified (1) specific exclusion criteria, (2) the list of prohibited 
concomitant treatments, (3) selected safety monitoring guidance and (4) clarified the 
potential for drug-drug interaction with concomitant use of systemic ketoconazole.  
In December 2011, the company reported a sudden, unexplained death of a patient within 24 
hours after the administration of the first dose of commercial fingolimod 0.5 mg.  While the 
cause of death is unknown, the role of fingolimod cannot be confirmed or excluded.  The 
reporting of this event prompted a thorough review the cardiac safety data from clinical trials 
as well as spontaneous reports in the post-marketing setting. This resulted in 
recommendations for additional first dose monitoring observation beyond 6 hours across all 
fingolimod protocols in patients meeting specific defined criteria at the end of the 6 hour 
observation period. For this protocol: patients that have a heart rate (HR) of <55 beats per 

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minute (bpm) (in patients 12 years or older) or 60 bpm (in patients below 12 years), new onset 
second degree or higher AV block, HR at 6 hours post-dose is the lowest value post-dose, 
and/or QTc on the 6-hour ECG is 500 msec or greater. 
Other updates, clarifications and edits throughout the protocol were also made.  
The study had not recruited any patients at the time of Amendment 1.  
Changes to the protocol 
Section 1 has been updated to include the latest information on fingolimod. 
Sections 3.1, 3.2, 3.3, 5.4 and 15.4 have been modified to reflect changes necessary due to the 
change in study design from open-label to double-blind, double-dummy. 
Section 4.2 has been updated with changes to the following Exclusion criteria: Exclusion 6: 
modified to also exclude patients treated with antiarrhythmic drugs and heart rate-lowering 
drugs at study entry. Exclusion 14: updated to further clarify exclusions related to severe 
cardiac disease or significant findings on screening ECG. Exclusion18: modified to exclude 
patients with severe renal insufficiency only. 
Section 5.5.5 has been updated to include more specific details on conditions/events that may 
lead to study drug interruptions.  
Section 5.5.7 has been updated to include that concomitant use of systemic ketoconazole may 
lead to an increase in fingolimod plasma levels and thus patients may be at a higher risk for 
adverse events.   
Section 5.5.8 has been updated to add antiarrhythmic drugs and heart rate-lowering drugs to 
list of treatments not allowed concomitantly with study drug due to the potential for additional 
effects of fingolimod on slowing the heart rate. 
Section 5.5.12 has been updated to include a separate First Dose Administrator as part of site 
personnel to avoid potential unblinding of the treating physician that may occur due to the 
well characterized treatment-initiation effect of fingolimod on the heart rate. 
Sections 5.4, 5.5.12 and 6.4.2 have been modified to omit the requirement for confirmation of 
MS relapse by an independent Adjudication Committee. With the change to a double-blinded 
design, this additional confirmation is no longer required.  
Table 6-1 and Table 6-2 have been modified to include Columbia Suicide Severity Rating 
Scale (C-SSRS) at all visits including any unscheduled visits. 
Section 6.6 has been modified to implement the same requirement for highly effective 
contraception in all female patients of childbearing potential as was defined for fingolimod. 
Section 7.3 has been modified to delete reference to the voluntary fingolimod-specific 
pregnancy registry. The double-blinded design of the amended protocol prevents identifying 
potential pregnancies in fingolimod treated patients that may occur in the course of this study.  
Sections 3.3 and 9.5.5 has been updated in regards to on-line PK analysis and individual dose-
adjustment. Section 9.5.5 has additionally been updated to add concomitant medications as a 
covariate to be examined in the population PK analysis. 

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Section 9.1 (Analysis sets) has been updated to add the Per-protocol set to be used for the 
supportive analysis of the primary efficacy variable.  
Appendix 1 has been updated to modify selected laboratory and vital signs notable values for 
the pediatric population. 
Section 14 Guidance for first dose monitoring has been updated in regards to the discharge 
criteria.  
Additional minor clarifications and editorial changes were made throughout the protocol to 
reflect study design change and consistency. 

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Protocol synopsis 
Title of study: A two-year, double-blind, randomized, multicenter, active-controlled Core Phase study 
to evaluate the safety and efficacy of fingolimod administered orally once daily versus interferon β-1a 
i.m. once weekly in pediatric patients with multiple sclerosis with five-year fingolimod Extension Phase 
Purpose: The purpose of this study is to seek regulatory approval for use of fingolimod in a pediatric 
population with MS aged 10 to less than 18 years old. This study is conducted in line with the Pediatric 
Investigational Plan agreed with the EMA (under EU pediatric regulation (EC) No 1901/2006) and the 
post-marketing requirements in the US. 
Objectives:  
Core Phase: 
Primary objective 
To evaluate the efficacy of fingolimod relative to intramuscular IFN β-1a in reducing the frequency of 
relapses as assessed by the annualized relapse rate in children/adolescent MS patients aged 10 to 
less than 18 years treated for up to 24 months. 
Key secondary objective 
To evaluate the efficacy of fingolimod relative to IFN β-1a in reducing the number of new/newly 
enlarging T2 (n/neT2) lesions in children/adolescent MS patients aged 10 to less than 18 years treated 
for up to 24 months. 
Other secondary objectives 
• 
To evaluate the safety of fingolimod relative to IFN β-1a in children/adolescent MS patients. 
• 
To evaluate the effect of fingolimod relative to IFN β-1a in children/adolescent MS patients on 
other relapse-related parameters: 
• 
Time to first relapse 
• 
Proportion of patients relapse-free 
• 
To evaluate the effect of fingolimod relative to IFN β-1a in children/adolescent MS patients on 
T1 Gd-enhancing lesions on brain MRI. 
• 
To study the pharmacokinetics of fingolimod and fingolimod-P in children/adolescent MS 
patients treated for up to 24 months. 
• 
To study the pharmacokinetic/pharmacodynamic relationship for key efficacy and safety 
outcomes in children/adolescent MS patients treated for up to 24 months. 
Exploratory objectives 
• 
To explore the effects of fingolimod relative to IFN β-1a on other MRI measures including change 
in total T2 hyperintense and 
 lesion volumes, 
 and 
brain volume change in children/adolescent MS patients.  
• 
 
• 
 
 
• 
 
Fingolimod Extension Phase: 
• 
To examine long-term safety, tolerability and efficacy parameters in patients treated with 
fingolimod 
• 
To examine the effects of fingolimod on safety, tolerability and efficacy parameters in patients 
who were treated with inferferon-β-1a in the Core Phase. 

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• 
 
 
Population: Male and female patients with multiple sclerosis (MS) aged 10 to less than 18 years will 
be included in this Core Phase study. Patients will be recruited into two cohorts based on their puberty 
status (pre-pubertal, pubertal). The study will be conducted in centers worldwide. Approximately 190 
patients will be randomized to receive either fingolimod or IFN β-1a. 
The population of the Extension Phase will consist of patients who complete participation in the Core 
Phase 
• 
Patients who complete the Core Phase on study drug will be allowed to enter the Extension 
Phase without any further criteria.  
• 
Patients who complete the Core Phase but prematurely discontinued study drug during the 
Core Phase for any reason will be assessed for eligibility in the Extension Phase based on 
the exclusion criteria. 
Inclusion criteria:  
Core Phase: 
1. Written informed consent must be obtained before any assessment is performed. 
2. Male and female patients aged 10-17 years old*, inclusive (i.e., have not yet had their 18th 
birthday) at randomization. 
3. A diagnosis of MS as defined by the revised consensus definition for pediatric MS (Krupp et 
al 2013, Polman et al 2011) 
Central review of the diagnosis of pediatric MS will be required for all patients prior to 
randomization. 
4. At least one MS relapse/attack during the previous year or two MS relapses in the previous 
two years prior to screening, or evidence of one or more Gd enhancing lesions on MRI within 
6 months prior to randomization (including screening MRI). 
5. Expanded Disability Status Scale (EDSS) score of 0 to 5.5, inclusive. 
*Exception: If, in a specific country, use of interferon-β-1a IM in children below a certain age is 
included in the Contraindications section of Avonex (interferon-β-1a IM) local product information, 
inclusion of such patients is not permitted in that country. E.g. the Russian Avonex product information 
lists use in children below the age of 12 years as a contraindication. 
Fingolimod Extension Phase: 
Criterion applies to all patients entering the Extension Phase. 
1. Patients that originally met Core Phase Inclusion criteria and completed the Core phase on or 
off of study drug. 
Exclusion criteria: 
Core Phase: 
1. Patients with progressive MS.  
2. Patients with an active, chronic disease (or stable but treated with immune therapy) of the 
immune system other than MS (e.g. Sjögren’s disease, systemic lupus erythematosus) or with 
a known immunodeficiency syndrome (AIDS, hereditary immune deficiency, drug induced 
immune deficiency) or tested positive for HIV. 
3. Patients with widespread and symmetric white matter alterations in the Screening MRI 
suggestive of other demyelinating disorders (e.g. metabolic disorders, mitochondrial 
disorders). 
4. Patients meeting the definition of ADEM (Krupp et al 2013);   patients meeting criteria for 
neuromyelitis optica (Wingerchuk et al 2006) or tested positive for aquaporin 4 (AQP4) at 
Screening. 

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5. Patients treated with: 
• 
Systemic corticosteroids or adrenocorticotropic hormone (ACTH) in the 30 days prior to 
Screening MRI scan 
• 
High dose intravenous immunoglobulin within 2 months prior to randomization  
• 
Natalizumab within 3 months or teriflunomide within 3 ½ months prior to randomization 
• 
Immunosuppressive/immunomodulatory medications such as azathioprine, 
methotrexate, laquinimod, ofatumumab, ocrelizumab within 6 months prior to 
randomization. 
• 
Alemtuzumab, cladribine, cyclophosphamide, mitoxantrone or rituximab at any time.  
• 
Fingolimod at any time. 
• 
The following antiarrhythmic drugs at Screening: Class Ia (e.g. quinidine, disopyramide) 
or Class III (e.g. amiodarone, sotalol) anti-arrhythmics 
• 
Concurrently treated with heart-rate-lowering drugs at Screening e.g.: Beta blockers, 
heart-rate lowering calcium channel blockers (e.g. verapamil, diltiazem or ivabradine), 
digoxin, anticholinesteratic agents, pilocarpine.  Advice from a cardiologist should be 
sought regarding the switch to non-heart-rate lowering medicinal products. 
6. Patients diagnosed with macular edema during the pre-randomization phase. 
7. Patients with active systemic bacterial, viral or fungal infections, including tuberculosis. 
8. Patients without acceptable evidence of immunity to varicella-zoster virus, mumps, measles, 
rubella, diphtheria, tetanus and pertussis at Randomization (See Appendix 3 Guidance on 
vaccinations for guidance on acceptable evidence of immunity and requirements for serologic 
testing). 
9. Patients who have received any live or live attenuated vaccines (including for varicella-zoster 
virus or measles) within one month prior to randomization. 
10. Patients with a history or presence of malignancy.  
11. Patients with any medically unstable condition, as assessed by the primary treating physician 
at each site. 
12. Patients with any severe cardiac disease or significant findings on the screening ECG, such 
as: 
• 
History of symptomatic bradycardia or recurrent syncope 
• 
Known ischemic heart disease 
• 
History of congenital heart disease (except conditions such as small patent ductus 
arteriosus, atrial septal defect, ventricular septal defect, or an ECG or rhythm 
abnormality, which have been assessed by a pediatric cardiologist and considered to be 
clinically insignificant). 
• 
Cerebrovascular disease 
• 
History of myocardial infarction 
• 
Congestive heart failure 
• 
History of cardiac arrest 
• 
Uncontrolled hypertension despite prescribed medications 
• 
Resting (sitting) heart rate <55 bpm (in patients 12 years or older) and <60 bpm (in 
patients below 12 years) 
• 
Severe untreated sleep apnea. 
• 
Sick sinus syndrome or sino-atrial heart block 
• 
QTcF interval >450 msec in males and >460 msec in females or  relevant risk factors for 
QT prolongation (e.g. hypokalaemia, hypomagnesemia, congenital QT prolongation) or 
treatment with QT prolonging drugs with a known risk of Torsades de pointes (e.g., 
citalopram, chlorpromazine, haloperidol, methadone, erythromycin) or history of familial 
long QT syndrome or known family history of Torsades de Pointes. 

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• 
Second degree Mobitz type II or higher AV block 
13. Patients with any pulmonary conditions, as determined by the investigator, including severe 
asthma defined as per the 2010 WHO uniform definition on severe asthma (Bousquet et al 
2010). 
14. Positive results of screening period testing for serological markers for hepatitis A, B, C, and E 
indicating acute or chronic infection: 
• 
anti-HAV IgM  
• 
HBs Ag and/or anti-HBc IgM 
• 
anti-HCV IgG or HCV-RNA PCR 
• 
anti- HEV IgM (if positive IgG: do HEV-RNA PCR: if negative, patient can be included) 
15. Patients with any of the following hepatic conditions: 
• 
Chronic liver or biliary disease, acute or chronic pancreatitis, with the exception of 
Gilbert’s syndrome 
• 
Liver enzymes  
• 
ALT, AST, alkaline phosphatase, GGT, >2 x upper limit of normal (ULN) range for 
age (for pre-pubertal patients > 1 X ULN or > 2X ULN if currently treated with IFN 
or glatiramer acetate). Elevations of alkaline phosphatase should not be used in 
isolation to exclude subjects, and would require Investigator discretion. 
• 
Bilirubin elevations not in the context of Gilberts Syndrome: Total and conjugated 
bilirubin >1.5 XULN (for pre-pubertal patients >1 X ULN or > 1.5 X ULN if currently 
treated with IFN or glatiramer acetate). 
16. Patients with severe renal insufficiency (GFR <30 ml/min/1.73 m2). 
17. Patients with lymphocyte count < 800 cells/mm3.  
18. Patients with any of the following neurologic /psychiatric disorder: 
• 
History of any type of epileptic seizure(s) as well as psychogenic non-epileptic seizure(s) 
during the past 12 months before screening; 
• 
History of substance abuse (drug or alcohol) or any other factor (i.e., serious psychiatric 
condition) that may interfere with the subject’s ability to cooperate and comply with the 
study procedures; 
• 
Progressive neurological disorder, other than MS, which may affect participation in the 
study or require the use of medications not allowed by the protocol 
19. Patients unable to undergo MRI scans, including those with claustrophobia or a history of 
severe hypersensitivity to gadolinium-DTPA. 
20. Pregnant or nursing females, where pregnancy is defined as the state of a female after 
conception and until the termination of gestation, confirmed by a positive HCG laboratory test. 
21. Female patients of childbearing potential, defined as all females physiologically capable of 
becoming pregnant, unless they agree to abstinence or, if sexually active, the use of 
contraception as defined in Section 6.6. 
22. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes. 
23. Patients with a score of “yes” on item 4 or 5 of the Suicidal Ideation section of the C-SSRS, if 
this ideation occurred in the past 6 months, or with a score of “yes” on any item of the Suicidal 
Behavior section, except for “Non-Suicidal Self Injurious Behavior”, if this behavior occurred in 
the past 2 years. 
24. Patients who have received an investigational drug within 180 days or 5 half-lives of 
randomization, whichever is longer. 
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients. 
Fingolimod Extension Phase: 

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Criteria apply to patients who completed the Core Phase, but prematurely discontinued study drug.  
1. Premature discontinuation of the study drug during the Core Phase due to an adverse event, 
serious adverse event, laboratory abnormality or conditions leading to permanent study drug 
discontinuation due to safety reasons as described in the protocol.  
Note: If a patient was discontinued due to lack of efficacy in the Core Phase, the patient may 
be offered the option to enter the extension trial if the investigator determines it is in the 
patient’s best interest when considering all available treatment options. 
2. Patients with known new events or concomitant medications that would exclude them from 
the Core Phase exclusion criteria.  Serological or other additional tests will not be required. 
Investigational therapy: Core Phase and Fingolimod Extension Phase 
• 
Fingolimod 0.5 mg capsules, administration orally once daily in patients weighing more than 
40 kg (at treatment initiation and/or during study) 
• 
Fingolimod 0.25 mg capsules, administration orally once daily in patients weighing 40 kg or 
less. The dose may be increased to 0.5 mg based on the results of the on-line PK 
assessment or can be increased if the patient has an increase in body weight >40 kg at 2 
consecutive visits at least 3 months apart. 
Reference therapy: Core Phase 
• 
Interferon β-1a 30 µg (Avonex®) pre-filled syringes, administration intramuscular (i.m.) 
injection once weekly  
Matching placebo formulations for blinding of investigational and reference therapies: Core 
Phase 
• 
Matching fingolimod placebo capsules  
• 
Matching interferon β-1a placebo pre-filled syringe 
Study design: 
The study is divided into a Core Phase, which includes the Pre-Randomization Period and the Double-
Blind Treatment Period, and an Extension Phase in which all patients will be treated with fingolimod. 
Core Phase: 
The Core Phase is a 24-month, double-blind, randomized, active-controlled, parallel-group multicenter 
study phase to evaluate the safety and efficacy of fingolimod compared to IFN β-1a in 
children/adolescent patients aged 10-17 (not yet had their 18th birthday) with MS. 
After obtaining informed consent, patients will complete the screening and baseline assessments of 
the pre-randomization period to confirm eligibility for the study. At Day 1, the first visit in the double-
blind treatment period, eligible patients will be randomized to one of the two treatment arms 
(fingolimod or IFN β-1a).  
All patients will be required to remain at the site for at least 6 hours after the first oral capsule intake 
(first dose monitoring on Day 1).  All patients should also receive their first injection at the site. 
Post-randomization visits (after Day 1) are scheduled at 2 weeks, 1 month, 2 months, 3 months and 
then every 3 months during the double-blind treatment period. Additionally, blood sampling for liver 
function tests will be performed at 6 weeks and at 4 and 5 months. 
Blood samples for pharmacokinetic purposes will be collected on Day 1 before and approximately 5-6 
hours after the first oral capsule, and at any time for all other visits. The only exception will be the 
Month 1 visit when two samples will be collected, one at pre-dose (i.e. before the oral dose 
administration) and one approximately 5-6 hours post-dose. 
The end of the Core Phase of the study will be determined by a blinded sample size re-estimation 
(BSSR). The study shall maintain the required power of 80% to detect a 50% relative treatment effect 
on the annualized relapse rate (two-sided 5% alpha-level). Accordingly, Novartis proposes to change 

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the trial design from a fixed 2-year study to an information-based flexible duration design study with 
study duration of up to 2 years: 
 
Patients who prematurely discontinue study drug and remain in the study will be followed in an 
abbreviated schedule of assessments for the duration of the double-blind treatment period. Upon 
discontinuation of the study drug, patients must complete the Visit 14 end of study phase (EOS-CP) 
visit as soon as possible, followed by a 3-month follow-up visit, before continuing in the abbreviated 
schedule of assessments. 
Patients who complete the double-blind treatment phase (on or off study drug) may be eligible to enter 
a long-term Extension Phase to receive treatment with fingolimod. Patients who complete the double-
blind treatment period on study drug, but do not enter the Extension Phase will return for a follow-up 
visit 3 months after the Visit 14- EOS-CP visit. 
Fingolimod Extension Phase: 
The Extension Phase is a 60-month (5 year) study phase for eligible patients who complete the Core 
Phase of the study and meet all inclusion/exclusion criteria.  All patients will be treated with fingolimod 
(either 0.5 mg/d or 0.25 mg/d based on body weight). To comply with local requirements if, in a 
specific country/site the Extension Phase is not allowed by the Health Authority/IRB then that 
country/site will not be required to participate in the Extension Phase. 
The Core Phase treatment will remain blinded until the Core Phase database is locked.  
The first dose of study drug will be provided in the clinic at Visit 15 (the day after study completion of 
the Core Phase), following the first dose monitoring procedures.  The first dose monitoring in the 
Extension Phase must be conducted by the independent first dose administration team and is required 
for all patients in order to maintain blinding of the Core Phase treatment. 
Patients randomized in the Core Phase to receive fingolimod will continue to receive the same dose of 
fingolimod (A dose increase at Visit 15 is possible if the patient had a sustained increase in weight 
to >40 kg at two consecutive visits at least three months apart). Patients randomized to receive 
interferon-β-1a during the Core Phase of the study will be assigned to receive fingolimod (0.5 or 0.25 
mg/d based on body weight; the body weight of a patient must be sustained at >40 kg at two 
consecutive visits at least three months apart for a patient to receive the 0.5 mg/d dose of fingolimod 
at the start of the Extension Phase).  
Visits after Extension Day 1 are scheduled in 2 weeks, 1 month, 2 months, 3 months, 6 months, 9 
months, 12 months and then every 6 months for the duration of the Extension Phase.  
All patients who prematurely discontinue study drug must complete the end of treatment visit 
assessments as soon as possible, followed by a 3-month follow-up visit.  
Efficacy assessments: MS relapses, MRI, EDSS, Cognitive Testing Battery  
Other assessments: Adverse events, physical examination (including skin examination), 
 
 ophthalmologic examination, pulmonary function tests, vital signs, laboratory 
evaluations, ECG, 
 
Data analysis:  
The Core Phase primary efficacy variable is the annualized relapse rate (ARR), which will be analyzed 
using a negative binomial regression model adjusted for treatment, number of relapses in the previous 

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two years before study enrollment, pubertal status, and region. For the primary analysis, the number of 
relapses will include all the confirmed relapses experienced during the study. The time spent in the 
study will correspond to the observation period for all the relapses from first dose on study drug to end 
of study. 
The null hypothesis for the primary analysis states that: there is no reduction in the ARR of patients 
treated with fingolimod 0.5 mg compared to patients treated with IFN β-1a i.m., while the alternative 
hypothesis states there is a reduction of the annualized relapse rate (ARR) in the fingolimod treated 
patients.  
The test of the hypotheses will be based on a negative binomial regression model with log link, using 
treatment, number of relapses in the previous two years before study enrollment, pubertal status, and 
region as covariates. Study centers are consolidated by country. In order to minimize the impact of 
low-enrolling countries on the analysis (such as non-convergence of the analysis model), countries will 
be pooled into regions based on geographical proximity. Details will be provided in the statistical 
analysis plan prior to database lock.   
All patients in the Full Analysis Set (FAS) will be included in the primary analysis, i.e., the number of 
confirmed relapses observed up to the end of patient’s participation in the study. Relapses will be 
counted regardless of whether a patient is on or off study drug. Therefore it is expected that all 
randomized patients can contribute to the primary analysis. The primary analysis model adjusts for 
missing information (early study discontinuations) under some statistical assumptions (non-informative 
dropouts and constant ARR).  
The response variable for this analysis is the number of confirmed relapses for each patient, and the 
quadratic variance estimate will be used. The natural log of (time in study for each patient) will be used 
as the offset to account for the varying lengths of patients’ time in the study. The null hypothesis will be 
rejected if the observed p-value is less than the significance level of 0.05. 
The Extension Phase is designed to obtain long-term safety, tolerability and efficacy data in patients 
treated with fingolimod.  The study will also examine the safety, tolerability and effectiveness of 
converting patients from interferon-β-1a treatment in the Core Phase to fingolimod treatment in the 
Extension Phase. 

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1 
Introduction 
1.1 
Background 
Multiple sclerosis (MS) is a chronic, immune-mediated and demyelinating and likely 
neurodegenerative disorder of the central nervous system (CNS), characterized by 
inflammation, demyelination, and axonal/neuronal destruction ultimately leading to severe 
disability. MS affects up to an estimated 2.5 million individuals worldwide, with females 
affected 2-3 times as frequently as males. At diagnosis approximately 85% of patients overall 
have relapsing-remitting MS (RRMS) characterized by recurrent, acute episodes (relapses) of 
neurological symptoms. Over time patients with RRMS progress to secondary progressive 
MS, when a less inflammatory, and more neurodegenerative, course takes precedence. 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 relapses or remissions. Progressive relapsing MS (PRMS; chronic progressive 
from onset with infrequent relapses) is the least frequent form of MS. 
The average age of onset of MS is 29 years; with the disease being rare before 16 years of 
age. The true incidence of pediatric MS is not known, however,  it is estimated that around 
5% (different estimated range from 0.4 to 10.5% ) of MS cases will manifest the disease in 
childhood and adolescence and that less than 2% will do so before the age of 10 years 
(Renoux et al. 2007; Pohl et al 2008; Chitnis et al. 2009). As a consequence of the rarity of 
onset and diagnosis of MS during childhood the population prevalence estimates for pediatric 
MS are low, ranging from 1.3-2.5/100,000 (Gadoth 2003). Although little prevalence data on 
pediatric MS exist from formal epidemiological studies, existing surveys support these 
estimates (De Sa et al 2006; Melcon et al 2008).  
As in adults, diagnosis of MS in pediatric patients is made based on clinical and MRI features.  
There are distinct challenges in the diagnosis of MS in the pediatric population. The higher 
frequency of acute disseminated encephalomyelitis (ADEM), a disorder whose symptoms can 
overlap clinically and neuroradiologically with MS, and the increased chance of 
leukodystrophies and metabolic disorders, complicates the differential diagnosis of pediatric-
onset MS relative to adult onset MS (Krupp et al 2007, Venkateswaran and Banwell 2010). 
According to the consensus definition proposed by the International Pediatric Study Group 
(Krupp et al 2007), a diagnosis of MS in pediatric patients requires multiple episodes of CNS 
demyelination separated in time and space, as specified for adults. In the pediatric population, 
these events must not meet ADEM criteria. In the absence of at least two clinical events, MRI 
can be used to meet the dissemination in space and time requirements. 
There are few studies on the natural history of pediatric onset MS, and most of these studies 
describe (retrospectively) either single cases or small series. The largest pediatric MS cohort 
described to date is in 394 patients with disease onset at or before 16 years of age (Renoux et 
al 2007). The initial course of MS is more often relapsing-remitting in pediatric onset MS (up 
to 98%) than in adult onset (approximately 85%). The relapse rate in pediatric MS is reported 
to be higher than in adult onset MS (Trojano et al 2002; Weinshenker et al 1989a; 
Weinshenker et al  1989b, Yeh et al 2009). Although MRI features in pediatric MS are less 

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well described, available data show that there are clear similarities to adult onset MS. 
Children, however, tend to have a higher number of T2 lesions at the time of first event than 
adults (Waubant et al 2009) and a lower propensity for lesions to enhance with gadolinium 
(Banwell et al 2007).  A consistent finding in most of the pediatric cohort studies is lower 
disability scores in pediatric MS compared to adult MS, even when disease duration is taken 
into account. In the cohort described by (Renoux et al 2007), the estimated median times from 
onset to the assignment of Disability Status Scale (DSS) scores of 4, 6 and 7 were 20 years, 29 
years and 37 years, respectively. Compared to the adult-onset population, the time to DSS 
scores of 4, 6 and 7 were approximately 10 years longer for patients with childhood onset MS. 
As well, the estimated time to conversion to a secondary progressive course (SPMS) was 
approximately 10 years longer in childhood onset vs. adult onset MS. Despite this slower 
progression of disability, the age of conversion to SPMS was lower by approximately 10 
years in childhood onset vs. adult-onset MS, such that the life-time impact of pediatric MS 
exceeds that of adult-onset MS.  
As in adults, treatment strategies in pediatric MS are focused on treatment of acute relapses, 
treatment of MS symptoms, and disease-modification. The effectiveness of therapies used for 
these purposes have, however, not been demonstrated in pediatric MS populations. 
Several disease modifying therapies are available for the treatment of adult patients with 
relapsing MS (beta interferon, glatiramer acetate, natalizumab, fingolimod) to reduce relapses 
and, except glatiramer acetate, to slow disability progression. Interferon beta and glatiramer 
acetate are frequently used to treat pediatric patients with relapsing MS, though none has been 
studied formally. Based on limited published data, suggesting that the safety profile in 
adolescents is similar to that seen in adults, three interferon beta agents (two IFN β-1a and one 
IFN β-1b) were approved in the EU for the use in adolescent patients with relapsing MS aged 
12 years and above. There are some reports on the use of natalizumab in pediatric MS patients 
(Ghezzi et al 2010), but there are safety concerns regarding its use in this population (Yeh and 
Weinstock-Guttman 2010). There is no experience to date with the use of fingolimod in 
pediatric MS patients.  
Fingolimod in MS 
Fingolimod (GilenyaTM) is an orally active sphingosine-1 phosphate (S1P) receptors 
modulator that is approved for use in adults with relapsing MS in more than 55 countries 
worldwide including the EU and the USA. The approved dose is 0.5 mg per day.  
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 
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The efficacy of fingolimod has been demonstrated in 3 studies (two 2-year placebo-controlled 
studies, Study FTY720D2301 and Study FTY720D2309) and 1 active controlled 1-year study 
(Study FTY720D2302) which evaluated once daily doses of fingolimod 0.5 mg and 1.25 mg 
in adult patients with relapsing-remitting MS (RRMS). In these studies, fingolimod 0.5 mg 
demonstrated a reduction of relapse rate by 48% to 54% relative to placebo while also 
reducing the risk of disability progression by 17% to 30% relative to placebo over 2 years. In 
addition, fingolimod was superior to one of the currently approved first-line MS therapies 
(interferon (IFN) β-1a; Avonex®) in reducing the frequency of relapses over 1 year by up to 
52%. The clinical benefits of fingolimod were further supported by the efficacy seen on 
multiple magnetic resonance imaging (MRI) measures, including reducing the numbers of 
new T2 lesions and Gd-enhancing lesions, the total T2 and T1 lesion burden and increasing 
the proportions of patients free of new lesion activity. Additionally, treatment with fingolimod 
was consistently found to reduce brain atrophy, the first prospective demonstration for an 
approved MS therapy.  In the long-term, open-label extension of a Phase II study 
(FTY720D2201E1), data up to 7 years of exposure showed sustained low levels of MS 
disease activity as manifest by low relapse rates, low lesion counts on brain MRI and low rate 
of disability progression. 
The safety profile of fingolimod has been well characterized in the MS clinical development 
program.  As of 29 February 2012, the MS clinical trials exposure in global and local studies 
is estimated to be approximately 16,500 patient-years, reached in more than 10,000 MS 
patients treated with fingolimod in Phase II, III, IIIb, and IV studies and their extensions. For 
updated exposure and safety information, please refer to the current investigator brochure. 
The overall incidence of AEs leading to discontinuation of study drug was comparable for the 
fingolimod 0.5 mg/day (10.5%) and placebo group (8.7), but higher in fingolimod 1.25 
mg/day group (14.1%). The overall incidence of SAEs was comparable between fingolimod 
groups (11.6% and 10.5% for 1.25 mg/day and 0.5 mg/day, respectively) and placebo 
(12.2%).  
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 and macular edema. 
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 ~ 8 bpm and was seen within the first 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 1-2 mmHg 
diastolic and 2-3 mmHg systolic on average was observed. This onset after approximately 2 
months of treatment initiation and persisted with continued treatment but reversed upon 
cessation of therapy. Hypertension was reported as an adverse event in 6.1% of MS patients 
on fingolimod 0.5 mg/day and in 3.8 % of patients on placebo in the 2-years placebo 
controlled study. 

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Fingolimod treatment led to increases in liver enzymes, (particularly alanine aminotransferase 
(ALT) and gamma-glutamyl-transferase (GGT), of 3-fold the upper limit of normal range in 
approximately 9-10% of fingolimod 0.5 mg treated patients, predominantly during the first 6 
months, and with a strong male predominance. No cases of liver failure have been reported in 
over 4000 patients treated in clinical trials with fingolimod. Liver enzymes returned to normal 
within 6 months after treatment discontinuation. Small increases from baseline in total 
cholesterol and triglycerides were seen for fingolimod treated patients. 
Macular edema occurred in 0.4% 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 
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. 
Dose-dependent reductions in forced expiratory volume over 1 second (FEV1) and diffusion 
lung capacity for carbon monoxide (DLCO) were observed in patients treated with 
fingolimod. In MS controlled trials, mean reduction from baseline in percentage of predicted 
FEV1 at Month 1 was 1.89% for fingolimod 0.5 mg and 0.16% for placebo. At Month 24, the 
reduction from baseline in the percent of predicted values for FEV1 was 2.65% for 
fingolimod 0.5 mg and 1.24% for placebo.  For DLCO, the reductions from baseline in 
percent of predicted values at Month 24 were 3.29% for fingolimod 0.5 mg and 1.16% for 
placebo. The changes in FEV1 appear to be reversible after treatment discontinuation. There 
is insufficient information to determine the reversibility of the decrease of DLCO after drug 
discontinuation. Cough and dyspnea were the most frequently reported respiratory AEs in the 
fingolimod 1.25 mg and 0.5 mg groups, but without significant differences between 
fingolimod patients and placebo [cough 9.1% and 9.6% for fingolimod 1.25 mg and 0.5 mg 
respectively, placebo 10.4%; dyspnea  7.2% and 6.0% for fingolimod 1.25 mg and 0.5 mg 
respectively, placebo 6.2%]. Few patients with a history of asthma experienced changes in 
PFTs to less than 80% or 60% of baseline values at a single visit or 2 consecutive visits. 
Overall, there was no evidence that patients with a history of asthma were at increased risk of 
pulmonary function changes amongst the treatment groups.   
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.  The overall rate of infections (in study D2301 72% on 
fingolimod vs. 72% on placebo) and serious infections (in study D2301 1.6% on fingolimod 
vs. 1.9% on placebo) at the 0.5 mg/day dose, fingolimod was similar to placebo. However, 
lower respiratory tract infections, primarily bronchitis, were more common in fingolimod 
treated patients (in study D2301 8.0% on fingolimod vs. 3.6% on placebo for bronchitis and 
0.5% on vs. 0.2% for pneumonia).  There was no clear relationship between lymphocyte count 
and the incidence of infections on fingolimod treatment. In the clinical trial program, there 
were 3 cases of disseminated herpes infection with organ involvement other than skin in 
patients treated with fingolimod 1.25 mg. Two fatal cases: herpes simplex encephalitis in a 

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patient in whom initiation of acyclovir therapy was delayed by 1 week, and fulminant primary 
varicella infection with hepatitis in a sero-negative patient receiving concomitant high dose 
steroid therapy with taper for a MS relapse. The third case was a patient with disseminated 
herpes zoster with pulmonary involvement treated with fingolimod 1.25 mg who made a 
complete recovery after treatment with acyclovir therapy. In the post-marketing setting, one 
additional fatal case of disseminated varicella zoster virus (VZV) infection has been reported 
in a sero-positive patient treated with fingolimod 0.5 mg in the context of concomitant high 
dose steroid therapy with taper.  Co-administration  with a short course of corticosteroid did 
not increase the overall rate of infection in patients treated with fingolimod in the phase III 
clinical trials.  
In addition, cases of lymphoma (cutaneous T-cell lymphoproliferative disorders or diffuse B-
cell lymphoma) have been reported during the clinical studies in patients receiving fingolimod 
at doses of 0.5 mg or higher. Based on the small number of cases and short duration of 
exposure, the relationship to fingolimod remains uncertain. 
In the post-marketing setting, isolated, delayed onset events, including transient asystole and 
one unexplained death within 24 hours of the first dose, have occurred.  These events have 
been confounded by concomitant medication and/or pre-existing diseases and the relationship 
to fingolimod is uncertain.  Therefore, it is recommended that fingolimod not be administered 
to patients with a history of cardiovascular or cerebrovascular disease or to those patients 
taking heart-rate lowering medication. 
Toxicology studies in neonatal and juvenile rats with special emphasis on potential effects on 
the reproductive system, developing immune system, and neurobehavioral aspects showed 
that treatment-related effects in neonatal/ juvenile animals were comparable to those seen in 
adult rats at comparable doses, with the exception of the absence of smooth muscle 
hypertrophy in the lungs of the juvenile rats. Repeated stimulations with Keyhole Limpet 
Hemocyanin showed a moderately decreased response during the treatment period, but fully 
functional immune reactions at the end of an 8-week recovery period. No adverse effects on 
postnatal development, including behavior and reproductive function were observed (for 
details on the non-clinical safety program see Investigators’ Brochure). 
Clinical experience with fingolimod in a pediatric population is limited; a single oral dose 
study (exposure corresponded to that of 5.0 mg in adults) in 7 renal transplant patients 11-16 
years of age. This study showed that pharmacokinetics and pharmacodynamic responses to 
fingolimod (reduction in lymphocyte counts and in heart rate), were comparable to those seen 
in adults. 
Currently, there is no experience with the use of fingolimod in pediatric MS patients. The 
present study will evaluate the efficacy and safety of fingolimod in children/adolescents aged 
10 to less than 18 years to provide information that will help guide its use in this pediatric 
population. 
1.2 
Purpose  
The purpose of study is to seek regulatory approval for use of fingolimod in a pediatric 
population with MS aged 10 to less than 18 years old. This study is conducted in line with the 

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Pediatric Investigational Plan agreed with the EMA (under EU pediatric regulation (EC) No 
1901/2006) and the post-marketing requirements in the US. 
2 
Study objectives 
2.1 
Primary objectives: Core Phase 
To evaluate the efficacy of fingolimod relative to intramuscular interferon β-1a (IFN β-1a) in 
reducing the frequency of relapses as assessed by the annualized relapse rate (ARR) in 
children/adolescent MS patients aged 10 to less than 18 years treated for up to 24 months. 
2.2 
Secondary objectives: Core Phase 
Key secondary 
To evaluate the efficacy of fingolimod relative to IFN β-1a in reducing the number of 
new/newly enlarging T2 (n/neT2) lesions in children/adolescent MS patients aged 10 to less 
than 18 years treated for up to 24 months. 
Other secondary 
• To evaluate the safety and tolerability of fingolimod relative to IFN β-1a in 
children/adolescent MS patients. 
• To evaluate the effect of fingolimod relative  to IFN β-1a in children/adolescent MS 
patients on other relapse-related parameters: 
• Time to first relapse 
• Proportion of patients relapse-free 
• To evaluate the effect of fingolimod relative to IFN β-1a in children/adolescent MS 
patients on T1 Gd-enhancing lesions on brain MRI. 
• To study the pharmacokinetics of fingolimod and fingolimod-P in children/adolescent MS 
patients treated for up to 24 months. 
• To study the pharmacokinetic/pharmacodynamic relationship for key efficacy and safety 
outcomes in children/adolescent MS patients treated for up to 24 months. 
2.3 
Exploratory objectives: Core Phase 
• To explore the effects of fingolimod relative to IFN β-1a on other MRI measures 
including change in total T2 hyperintense and 
 lesion volumes,
 
 and brain volume 
change in children/adolescent MS patients.  
• 
 
• 
 
 
• 
 

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2.4 
Objectives: Extension Phase 
• To examine long-term safety, tolerability and efficacy parameters in patients treated with 
fingolimod 
• To examine the effects of fingolimod on safety, tolerability and efficacy parameters in 
patients who were treated with inferferon-β-1a in the Core Phase. 
• 
 
  
3 
Investigational plan 
3.1 
Study design 
The study is divided into a Core Phase, which includes the Pre-Randomization Period and the 
Double-Blind Treatment Period, and an Extension Phase in which all patients will be treated 
with fingolimod. 
Core Phase: 
The Core Phase is a 24-month, double-blind, randomized, active-controlled, parallel-group 
multicenter study phase to evaluate the efficacy and safety of fingolimod compared to IFN β-
1a in children/adolescent patients aged 10-17 (i.e. have not yet had their 18th birthday at 
randomization) with MS. The end of the Core Phase of the study will be determined by a 
blinded sample size re-estimation (BSSR). The study shall maintain the required power of 
80% to detect a 50% relative treatment effect on the annualized relapse rate (two-sided 5% 
alpha-level). Accordingly, Novartis proposes to change the trial design from a fixed 2-year 
study to an information-based flexible duration design study with study duration of up to 2 
years: 
After obtaining informed consent, patients will complete the screening and baseline 
assessments of the pre-randomization period to confirm eligibility for the study. On Day 1, the 
first visit in the double-blind treatment period, eligible patients will be randomized to one of 
the two treatment arms (fingolimod or IFN β-1a).  
Patients will be required to remain at the site for at least 6 hours after the first dose of study 
drug (first dose monitoring on Day 1, see Appendix 2).  

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Post-randomization visits (after Day 1) are scheduled at 2 weeks, 1 month, 2 months, 3 
months and then every 3 months during the double-blind treatment period. Additionally, 
blood sampling for liver function tests will be performed at 6 weeks and at 4 and 5 months. 
Blood samples for the purposes of characterizing fingolimod and fingolimod-P 
pharmacokinetics in the study population will be collected on Day 1 before and approximately 
5-6 hours after the first dose of oral study medication, and once at any time at all other visits. 
The only exception will be the Month 1 visit when two samples will be collected, one at pre-
dose (i.e. before the oral capsule administration) and one approximately 5-6 hours post-dose 
for on-line PK assessment of exposure and determination of need for potential dose-
adjustment as described below in Section 3.3. 
Patients who prematurely discontinue study drug and remain in the study will be followed in 
an abbreviated schedule of assessments for the duration of the Core Phase. Upon 
discontinuation of the study drug, patients must complete the end of treatment visit 
assessments as soon as possible, followed by a 3-month follow-up visit, before continuing in 
the abbreviated schedule of assessments. 
Patients who complete the double-blind treatment period (on or off study drug) may be 
eligible to enter a long-term Extension Phase to receive treatment with fingolimod. Patients 
who complete the double-blind treatment period on study drug, but do not enter the Extension 
Phase will return for a follow-up visit 3 months after Visit 14/End of Study-Core Phase (CP). 
Fingolimod Extension Phase: 
The Extension Phase is a 60-month (5 year) study phase for patients who complete the Core 
Phase of the study and meet all inclusion/exclusion criteria.  All patients will be treated with 
fingolimod (either 0.5 mg/d or 0.25 mg/d based on body weight; see Section 5.1). To comply 
with local requirements if, in a specific country/site the Extension Phase is not allowed by the 
Health Authority/IRB then that country/site will not be required to participate in the Extension 
Phase. 
The Core Phase treatment will remain blinded until the Core Phase database is locked.  
The first dose of study drug will be provided in the clinic at Visit 15 (the day after study 
completion of the Core Phase), following the first dose monitoring guidelines in Appendix 2.  
To prevent the risk of unblinding the first dose monitoring procedure for the first/second dose 
in the Extension Phase must be conducted by the independent first dose administration team 
and is required for all patients in order to maintain blinding of the Core Phase treatment. 
Subsequent re-initiation or dose increases in the Extension Phase may be conducted by the 
main study team.  
Patients randomized in the Core Phase to receive fingolimod will continue to receive 
fingolimod. Patients randomized to receive interferon-β-1a during the Core Phase of the study 
will be assigned to receive fingolimod (0.5 or 0.25 mg/d based on body weight; see Section 
5.1).  
Visits after Extension Day 1 are scheduled in 2 weeks, 1 month, 2 months, 3 months, 6 
months, 9 months, 12 months and then every 6 months for the duration of the Extension 
Phase.  

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All patients who prematurely discontinue study drug must complete the end of treatment visit 
assessments as soon as possible, followed by a 3-month follow-up visit.  
 
Figure 3-1 
Study design 
Double-blind Treatment 
Period 
Extension 
Phase 
fingolimod 
Randomization 
Pre-randomization 
Period 
Screening  
 
Day -45 to 
Day -1 
interferon-β-1a i.m. 
Day 1 up to Month 24*   
+ 5 years 
fingolimod  
Baseline  
Day -7 to 
Day -1 
Core Phase 
Open-Label 
Period 
*The 3-MFU visit will be required for those patients that do not go into the Extension Phase. 
3.2 
Rationale of study design 
The Core Phase is designed to evaluate the potential of fingolimod as a treatment for MS in a 
pediatric patient population. The primary endpoint that will be used is the reduction in the 
annualized relapse rate (ARR), a widely used and accepted primary endpoint in Phase III 
studies in the adult population for the evaluation of new MS treatments.   
The study uses a double-blind, double-dummy design with IFN β-1a i.m. once weekly as the 
comparator.  A double-dummy design is necessary in order to blind the study drug (oral 
fingolimod and i.m. injections of IFN β-1a),  This means that patients randomized to the 
fingolimod arm will also receive weekly placebo injections i.m. and patients in the IFN β-1a 
arm will take once daily oral placebo capsules.  
The overall medical care of the patient will be provided by the treating physician (“treating 
physician”) while the assessment of patients with neurological symptoms consistent with MS 
and the determination of the EDSS score will be performed by a blinded rater (“independent 
evaluating physician”), who is not otherwise involved in the patient’s management or care. 
Given the well-characterized heart rate lowering effect of fingolimod on treatment initiation, 
first dose of study drug will be administered by a First Dose Administrator and not by the 
treating physician (refer to Section 5.5.13). The key secondary outcome, T2 lesion activity, on 
brain MRI is an objective measure of disease activity. Lesion counts will be established based 
on review by a central reader who will be blinded to the patients’ treatment. These design 
features further reduce the potential for unblinding and bias in the assessments that may be 

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introduced by potentially unblinding effects of the study drugs. The measures taken to retain 
the rater blinding during the study are further detailed in Section 5.4. 
The Extension Phase is designed to examine the long-term safety, tolerability and efficacy of 
fingolimod (up to 7 years for patients randomized to fingolimod in the Core Phase and up to 5 
years for patients randomized to interferon-β-1a in the Core Phase) as a treatment for MS in a 
pediatric/ young adult patient population. 
3.3 
Rationale of dose/regimen, duration of treatment 
The dose regimen has been selected based on the efficacy and safety results of the adult Phase 
III studies with the aim to yield systemic exposure comparable to that obtained in MS adult 
patients at the 0.5 mg dose. Based on the adult Phase III PK/PD data, it was shown that 
exposure levels were the best predictor of efficacy (i.e., reduction in ARR). 
Clinical experience with fingolimod in a pediatric population comes from a single dose study 
in renal transplant patients 11-16 years of age. Administration of a single oral dose of 
fingolimod scaled for body weight yielded comparable total exposure to fingolimod and 
fingolimod-P in this group of children/adolescents versus adults receiving a fixed dose of 5.0 
mg. As expected from previous clinical experience, pharmacodynamic responses to 
fingolimod, i.e., reduction in lymphocyte counts and in heart rate, were comparable in 
children/adolescents and adults. 
It is known that cytochrome P450 (CYP450) activity, in children/adolescents aged 10-18 
years, is comparable to that of adults (Kearns et al 2003). The relationship between body 
weight and elimination clearance of fingolimod-P has been investigated by integrating the 
evidence from two different and independent sources: a single dose PK study in renal 
transplant patients 11-16 years of age; an analysis of the pooled steady state concentrations 
from two Phase II and two Phase III studies in adult MS patients with relapsing MS. This 
analysis indicates that an allometric scaling method based on normalized body weight with an 
exponent of 0.53 is adequate to describe the relationship between body weight and elimination 
clearance of fingolimod-P. Using this method, fingolimod-P concentrations as a function of 
patient weight and dose were simulated and compared to the observed fingolimod-P 
concentrations from the Phase II/III studies in adult MS patients. The dose regimen yielding 
systemic exposure comparable to that obtained in MS adult patients was then selected. 
Therefore the dose regimen chosen in this study, based on body weight, is: 
• 0.5 mg/day for all patients weighing more than 40 kg  (at treatment initiation and/or 
during the study); 
• 0.25 mg/day for all patients weighing 40 kg or less. This dose may be increased based on 
the results of the Month 1 online pharmacokinetic analysis or if the patient has a sustained 
bodyweight increase to above 40 kg during the study (sustained over at least 2 visits 3 
months apart). 
This approach is expected to provide exposures considered safe and effective based on data 
available in adults. The majority of the study population, aged 10 to less than 18 years, is 
expected to have a bodyweight of at least 30 kg. Children below 20 kg are nonexistent in this 
age range, children below 25 kg occur with a 5% frequency at an age of 10 years. 

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All patients weighing 40 kg or less at start of Core and/or Extension Phase will have blood 
sampling for PK analysis conducted at Month 1 Core Phase and/or Month 1 Extension Phase, 
respectively.  For patients treated with fingolimod, the Month 1 Core Phase  and/or Month 1 
Extension Phase pharmacokinetic samples will be analyzed as soon as possible (online 
analysis) to ensure the systemic exposure is adequate (see Section 6.7, online 
pharmacokinetics, for details). If the systemic exposure is below 65% of the target exposure, 
the dose for the individual patient will be increased to 0.5 mg at the Month 2 Core Phase 
and/or Month 2 Extension Phase visits via the Interactive Voice Response system (IVR 
system). This rapid turnover of the results and fast implementation of a dose adjustment will 
limit the period of potential under-exposure for the fingolimod-treated patient.  
At the Month 2 Core Phase and/or Month 2 of the Extension Phase visit, all patients in the 
<40 kg group will again undergo the first dose monitoring procedure described in Section 3.1 
and in Appendix 2. 
Patients weighing 40 kg or less who have an increase in body weight over 40 kg, sustained 
over at least two visits, 3 months apart, will again undergo the first dose monitoring procedure 
described in Section 3.1 and in Appendix 2. 
The flexible treatment duration of up to 24 months for the Core Phase has been chosen to 
allow for sufficient time to adequately assess the effects on disease activity, as measured by 
relapses and brain MRI, and to determine the safety and tolerability profile of chronic 
treatment in the pediatric MS population. 
The treatment duration of 60 months (five years) for the Extension Phase is a regulatory 
requirement and was chosen to allow for adequate time to assess long-term safety, tolerability 
and look at efficacy parameters in patients treated with fingolimod.  
3.4 
Rationale for choice of comparator 
The use of placebo as a control in the Core Phase of an agent already demonstrated to be 
effective in adults is for ethical reasons not deemed acceptable in the pediatric MS population 
(Ghezzi et al 2010, Banwell and Triplett 2005). 
IFN β-1a once-weekly i.m. is the active comparator selected for the pediatric study. In the EU, 
it is approved for use in patients 12 years and older and is also used in younger patients in the 
absence of an approved treatment. Compared to the other two available IFN β agents, it is 
associated with less frequent injections, fewer injection site reactions and thus less burden for 
the patients. Furthermore, IFN β-1a was the active comparator included in the adult 
fingolimod Phase III program. Use of the same active comparator as in the adult program will 
allow for comparison of safety and efficacy outcomes in the pediatric population to those in 
the adults. 
3.5 
Purpose and timing of interim analyses/design adaptations 
Interim analyses for the Data Monitoring Committee (DMC) may be performed (see Section 
7.4).   
A BSSR will be conducted during the study to provide estimation on ARR and the between-
patient variability. The study shall maintain the required power of 80% to detect a 50% 

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relative treatment effect on the annualized relapse rate (two-sided 5% alpha-level). 
Accordingly, Novartis proposes to change the trial design from a fixed 2-year study to an 
information-based flexible duration design study with study duration of up to 2 years: 
4 
Population 
Core Phase: 
Male and female patients with multiple sclerosis (MS) aged 10 to less than 18 years will be 
included in this Core Phase study.  
Patients will be recruited into two cohorts based on their puberty status (pre-pubertal, 
pubertal). The study will be conducted in centers worldwide. Approximately 190 patients will 
be randomized to receive either fingolimod or IFN β-1a. The maximum treatment duration in 
the Core Phase will not exceed approximately 2 years. There is no minimum duration for 
participation in the Core Phase.   
Fingolimod Extension Phase: 
The population of the Extension Phase will consist of patients who complete the double-blind 
treatment period on or off of study drug and meet the in/exclusion criteria for enrollment in 
the Extension Phase. If the study is stopped early then all patients that are enrolled in the Core 
Phase and that complete the EOS-CP visit will be considered to have completed the Core 
Phase of the study (see Section 9.6). 
• Patients who complete the Core Phase on study drug will be allowed to enter the 
Extension Phase without any further criteria.  
• Patients who complete the Core Phase but prematurely discontinued study drug during the 
Core Phase for any reason will be assessed for eligibility in the Extension Phase based on 
the exclusion criteria. 
4.1 
  Inclusion criteria 
Core Phase: 
Patients eligible for inclusion in this study have to fulfill all of the following criteria: 
1. Written informed consent must be obtained before any assessment is performed. 

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2. Male and female patients aged 10-17 years old*, inclusive (i.e., have not yet had their 18th 
birthday) at randomization. 
3. A diagnosis of MS as defined by the revised consensus definition for pediatric MS, 
(Krupp et al 2013, Polman et al 2011). 
4. Central review of the diagnosis of pediatric MS will be required for all patients prior to 
randomization. 
5. At least one MS relapse/attack during the previous year or two MS relapses in the 
previous two years prior to screening or evidence of one or more Gd enhancing lesions on 
MRI within 6 months prior to randomization (including screening MRI). 
6. Expanded Disability Status Scale (EDSS) score of 0 to 5.5, inclusive. 
*Exception: If, in a specific country, use of interferon-β-1a IM in children below a certain age 
is included in the Contraindications section of Avonex (interferon-β-1a IM) local product 
information, inclusion of such patients is not permitted in that country. E.g. the Russian 
Avonex product information lists use in children below the age of 12 years as a 
contraindication. 
Fingolimod Extension Phase: 
Criterion applies to all patients entering the Extension Phase. 
1. Patients that originally met Core Phase Inclusion criteria and completed the Core phase on 
or off of study drug. 
4.2 
Exclusion criteria 
Core Phase: 
Patients fulfilling any of the following criteria are not eligible for inclusion in this study: 
1. Patients with progressive MS.  
2. Patients with an active, chronic disease (or stable but treated with immune therapy) of the 
immune system other than MS (e.g. Sjögren’s disease, systemic lupus erythematosus) or 
with a known immunodeficiency syndrome (AIDS, hereditary immune deficiency, drug 
induced immune deficiency) or tested positive for HIV at Screening. 
3. Patients with widespread and symmetric white matter alterations in the Screening MRI 
suggestive of other demyelinating disorders (e.g. metabolic disorders, mitochondrial 
disorders). 
4. Patients meeting the definition of ADEM (Krupp et al. 2013); patients meeting criteria for 
neuromyelitis optica (Wingerchuk et al 2006) or tested positive for aquaporin 4 (AQP4) at 
Screening. 
5. Patients treated with: 
• Systemic corticosteroids or adrenocorticotropic hormone (ACTH) in the 30 days prior 
to Screening MRI scan  
• High dose intravenous immunoglobulin within 2 months prior to randomization  
• Natalizumab within 3 months or teriflunomide within 3 ½ months prior to 
randomization 

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• Immunosuppressive/immunomodulatory medications such as, azathioprine, 
methotrexate, laquinimod, ofatumumab, ocrelizumab within 6 months prior to 
randomization.  
• Alemtuzumab, cladribine, cyclophosphamide, mitoxantrone or rituximab at any time 
• Fingolimod at any time 
• The following antiarrhythmic drugs at Screening: Class Ia (e.g. quinidine, 
disopyramide) or Class III (e.g. amiodarone, sotalol) anti-arrhythmics 
• Concurrently treated with heart-rate-lowering drugs at Screening e.g.: Beta blockers, 
heart-rate lowering calcium channel blockers (e.g. verapamil, diltiazem or 
ivabradine), digoxin, anticholinesteratic agents, pilocarpine.  Advice from a 
cardiologist should be sought regarding the switch to non-heart-rate lowering 
medicinal products. 
6. Patients diagnosed with macular edema during the pre-randomization phase 
7. Patients with active systemic bacterial, viral or fungal infections, including tuberculosis. 
8. Patients without acceptable evidence of immunity to varicella-zoster virus, mumps, 
measles, rubella, diphtheria, tetanus and pertussis at Randomization (See Appendix 3 
Guidance on vaccinations for guidance on acceptable evidence of immunity and 
requirements for serologic testing). 
9. Patients who have received any live or live attenuated vaccines (including for varicella-
zoster virus or measles) within one month prior to randomization. 
10. Patients with a history or presence of malignancy.  
11. Patients with any medically unstable condition, as assessed by the investigator. 
12. Patients with any severe cardiac disease or significant findings on the screening ECG, 
such as: 
• History of symptomatic bradycardia or recurrent syncope 
• Known ischaemic heart disease 
• History of congenital heart disease (except conditions such as small patent ductus 
arteriosus, atrial septal defect, ventricular septal defect, or an ECG or rhythm 
abnormality, which have been assessed by a pediatric cardiologist and considered to 
be clinically insignificant). 
• Cerebrovascular disease 
• History of myocardial infarction 
• Congestive heart failure 
• History of cardiac arrest 
• Uncontrolled hypertension despite prescribed medications 
• Resting (sitting)  heart rate <55 bpm (in patients 12 years or older) and <60 bpm (in 
patients below 12 years) 
• Severe untreated sleep apnea 
• Sick sinus syndrome or sino-atrial heart block 
• QTcF interval >450 msec in males and >460 msec in females or  relevant risk factors 
for QT prolongation (e.g. hypokalaemia, hypomagnesemia, congenital QT 

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prolongation) or treatment with QT prolonging drugs with a known risk of Torsades 
de pointes (e.g. citalopram, chlorpromazine, haloperidol, methadone, erythromycin) 
or history of familial long QT syndrome or known family history of Torsades de 
Pointes.  
• Second degree Mobitz type II or higher AV block  
13. Patients with any pulmonary conditions, as determined by the investigator, including 
severe asthma defined as per the 2010 WHO uniform definition on severe asthma 
(Bousquet et al 2010). 
14. Positive results of screening period testing for serological markers for hepatitis A, B, C 
and E indicating acute or chronic infection: 
• anti-HAV IgM  
• HBs Ag and/or anti-HBc IgM 
• anti-HCV IgG or HCV-RNA PCR  
• anti- HEV IgM or IgG (if positive IgG: do HEV-RNA PCR: if negative, patient can 
be included) 
15. Patients with any of the following hepatic conditions: 
• Chronic liver or biliary disease, acute or chronic pancreatitis, with the exception of 
Gilbert’s syndrome; 
• Liver enzymes  
• ALT, AST, alkaline phosphatase, GGT, >2 x upper limit of normal (ULN) range 
for age (for pre-pubertal patients > 1 X ULN or > 2X ULN if currently treated 
with IFN or glatiramer acetate). Elevations of alkaline phosphatase should not be 
used in isolation to exclude subjects, and would require Investigator discretion. 
• Bilirubin elevations not in the context of Gilberts Syndrome: Total and 
conjugated bilirubin >1.5 X ULN (for pre-pubertal patients >1 X ULN or > 1.5 X 
ULN if currently treated with IFN or glatiramer acetate). 
16. Patients with severe renal insufficiency (GFR <30 ml/min/1.73 m2). 
17. Patients with lymphocyte count < 800 cells (mm3).  
18. Patients with any of the following neurologic/psychiatric disorder: 
• History of any type of epileptic seizure(s) as well as psychogenic non-epileptic 
seizure(s) during the past 12 months before screening; 
• History of substance abuse (drug or alcohol) or any other factor (i.e., serious 
psychiatric condition) that may interfere with the subject’s ability to cooperate and 
comply with the study procedures; 
• Progressive neurological disorder, other than MS, which may affect participation in 
the study or require the use of medications not allowed by the protocol 
19. Patients unable to undergo MRI scans, including claustrophobia or history of 
hypersensitivity to gadolinium-DTPA. 
20. Pregnant or nursing females, where pregnancy is defined as the state of a female after 
conception and until the termination of gestation, confirmed by a positive HCG laboratory 
test. 

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21. Female patients of childbearing potential, defined as all females physiologically capable 
of becoming pregnant, unless they agree to abstinence or, if sexually active, the use of 
contraception as defined in Section 6.6.  
22. History of hypersensitivity to any of the study drugs or to drugs of similar chemical 
classes.  
23. Patients with a score of “yes” on item 4 or 5 of the Suicidal Ideation section of the 
C-SSRS, if this ideation occurred in the past 6 months, or with a score of “yes” on any 
item of the Suicidal Behavior section, except for “Non-Suicidal Self Injurious Behavior”, 
if this behavior occurred in the past 2 years. 
24. Patients who have received an investigational drug or therapy within 180 days or 
5 half-lives of randomization, whichever is longer. 
No additional exclusions may be applied by the investigator, in order to ensure that the 
study population will be representative of all eligible patients. 
Fingolimod Extension Phase: 
Criteria apply to patients who completed the Core Phase, but prematurely discontinued study 
drug.  
1. Premature discontinuation of the study drug during the Core Phase due to: 
• an adverse event, 
• serious adverse event, 
• laboratory abnormality 
• other conditions leading to permanent study drug discontinuation due to safety 
reasons as described in protocol Section 5.5.9. 
Note: If a patient was discontinued due to lack of efficacy in the Core Phase, the patient 
may be offered the option to enter the extension trial if the investigator determines it is in 
the patient’s best interest when considering all available treatment options. 
2. Patients with known new events or concomitant medications (washout periods required 
prior to Visit 15) that would exclude them from the Core Phase exclusion criteria.  
Serological or other additional tests will not be required. 
5 
Treatment 
5.1 
Investigational and control treatment 
Investigational drug: Core Phase and Fingolimod Extension Phase 
Two dose-strengths will be used (depending on the patients’ body weight) with the aim to 
achieve systemic exposure in the pediatric population that is comparable to that obtained in 
MS adult patients at the 0.5 mg dose: 
• Fingolimod 0.5 mg capsule, administration orally once daily in patients weighing more 
than 40 kg  

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• Fingolimod 0.25 mg capsule, administration orally once daily in patients weighing 40 kg 
or less (patients weighing ≤ 40 kg at the start of the Extension Phase will receive the 0.5 
mg/d dose if they had a dose increase at Month 2 during the Core Phase) 
Dose adjustments to ensure exposure is appropriate may be implemented in patients with a 
body weight 40 kg or less based on online PK assessment (see Section 3.3).  During the 
course of the study any patient receiving the lower fingolimod dose of 0.25 mg who reaches 
the weight of more than 40 kg (sustained over at least 2 visits, 3 months apart), will be 
automatically switched to the 0.5 mg dose strength. Dose adjustments for any other reason are 
not permitted. Patients in the IFN β-1a arm whose bodyweight increases to above 40 kg 
during the Core Phase (sustained over at least 2 visits, 3 months apart), will have a sham 
increase in their oral dose. The dose increases will be done in a blinded fashion (refer to 
Section 3.3). 
Oral study drug may be taken with or without food, preferably at the same time every day.  
Study medication will be dispensed at the randomization visit (Day 1). 
Control treatment: Core Phase 
Interferon β-1a (Avonex®), administration intramuscular (i.m.) injection once weekly 
The first dose of IFN β-1a i.m. at Day 1 will be administered intramuscularly at the site by the 
First Dose Administrator or nurse. Site personnel will provide training to the patients and their 
parents/caregivers on the correct procedure for administration of i.m. injections. A patient 
leaflet and/or oral instructions will be provided. The patient leaflet and/or oral instructions 
describe information related to the i.m. study drug including storage information, precautions 
and instructions for administering i.m. injections. This information should be reviewed with 
the patient and his/her parents/caregivers to ensure that they understand the correct procedure. 
Injectable study drug may be initiated at ¼ or ½ volume per clinical practice at the individual 
sites. Full dose should, however, be achieved by the fourth week of injections. Prophylaxis 
and treatment of flu-like symptoms with e.g. paracetamol/acetaminophen may be performed 
per clinical practice at the site.  
Matching placebo capsules and syringes: Core Phase 
• Matching fingolimod placebo capsules for oral administration once daily. 
• Matching IFN β-1a placebo in pre-filled syringes for i.m. injection once weekly. 
The fingolimod capsules (0.25 mg and 0.5 mg) and matching placebo capsules will be 
identical in appearance and will be packed in identical bottles. Both, the IFN β-1a and its 
matching placebo will be packed and supplied in pre-filled syringes. 
5.2 
Treatment arms 
Core Phase: 
Randomized patients will be assigned to fingolimod + matching IFN placebo injection or IFN 
β-1a injection + matching fingolimod placebo capsule in a ratio of 1:1.  

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Fingolimod Extension Phase: 
All patients will receive fingolimod in the Extension Phase. 
5.3 
Treatment assignment 
Core Phase: 
At Visit 3, all eligible patients will be randomized via Interactive Voice Response (IVR) 
system to one of the two treatment arms. The investigator or his/her delegate will contact the 
IVR system after confirming that the patient fulfills all the inclusion/exclusion criteria. The 
IVR system will assign a randomization number to the patient, which will be used to link the 
patient to a treatment arm and will specify a unique medication number for the first package 
of study drug to be dispensed to the patient. The randomization number will not be 
communicated to the caller.    
Fingolimod Extension Phase: 
At Visit 15 (first Extension Phase visit), all eligible patients will be assigned via Interactive 
Voice Response (IVR) system to receive either 0.25 mg/d or 0.5 mg/d fingolimod.  
Patients randomized in the Core Phase to receive fingolimod will continue to receive the same 
dose of fingolimod that they were receiving at Visit 14 / EOS-CP (End of Core Phase 
treatment) Note:  A dose increase at Visit 15 is possible if the patient had a sustained increase 
in weight to >40 kg at two consecutive visits at least three months apart.  
Patients randomized to receive interferon-β-1a during the Core Phase of the study will be 
assigned to receive fingolimod (0.5 or 0.25 mg/d based on body weight as described in 
Section 5.1. Note: The body weight of a patient must be sustained at >40 kg at two 
consecutive visits at least three months apart for a patient to receive the 0.5 mg/d dose of 
fingolimod at the start of the Extension Phase. 
The randomization numbers for the Core Phase will be generated using the following 
procedure to ensure that treatment assignment is unbiased. A patient randomization list will be 
produced by the IVR system provider using a validated system that automates the random 
assignment of patient numbers to randomization numbers. These randomization numbers are 
linked to the different treatment arms, which in turn are linked to medication numbers. A 
separate medication list will be produced by or under the responsibility of Novartis Drug 
Supply Management using a validated system that automates the random assignment of 
medication numbers to study drug packs containing each of the study drugs.  
Randomization will be stratified by region, due to the anticipated low number of patients that 
will be enrolled at each site, and by puberty status (pre-pubertal and pubertal). 
The randomization scheme for patients will be reviewed and approved by a member of the 
Biostatistics Quality Assurance Group. 

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5.4 
Treatment blinding 
Core Phase: 
This study will be conducted using a double-blind, double dummy design. 
Patients randomized to one of the two treatment groups will be given the following 
medications: 
Fingolimod Group: 
0.25mg or 0.5 mg fingolimod capsule orally once daily +  
IFN β-1a matching placebo i.m. injection once weekly 
IFN β-1a Group: 
IFN β-1a 30 µg i.m. injection once weekly + 
fingolimod matching placebo capsule orally once daily 
The study medication assignments will be blinded and will remain blinded for the entire 
double-blind Treatment Period and until the database lock for the Core Phase has been 
completed.  
Patients, treating physician, site personnel, independent evaluating physician, First Dose 
Administrator and all Novartis personnel, involved in the study, with the exception of 
Novartis Drug Supply Management (DSM), Novartis on-line PK analyst, Novartis 
independent statistician and independent programmer for DMC, will remain blinded to the 
identity of the treatment from the time of randomization of the first patient until database lock. 
During this time period, the treatment codes will be accessible only to authorized personnel 
(those mentioned above and DMC members). The following measures will be taken to protect 
the blinding of the Independent Evaluating Physician (“rater”): 
• Prohibited access of “rater” to patient records, laboratory data etc. 
• Separate binders of worksheets and eCRF materials for “treating physician” and 
“rater”  
• Prohibited cross-over of “treating physician” and “rater” 
• Appropriate clothing for patients to cover potential injection sites during neurological 
examinations 
• Limited interactions between evaluating physician and patients: permitting only a 
minimum required to perform the EDSS rating.  
Fingolimod Extension Phase: 
All patients in the Extension Phase will be treated with fingolimod, but the dose they received 
during the Core Phase (interferon or fingolimod) will remain blinded until the Core Phase 
database has been locked. 
For any patient that is ≤ 40 kg at the start of the Core Phase the Extension Phase dose of 
fingolimod will remain blinded if the patient did not have a dose increase during the Core 
Phase due to sustained body weight increase to >40 kg at two consecutive visits at least 3 
months apart . For these patients the Extension Phase dose will remain blinded until the Core 
Phase database lock or until the patient has a dose increase to 0.5 mg (increase in body weight 
to >40 kg sustained at 2 consecutive visits at least 3 months apart). This blinding is required in 

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order to maintain the blind of the Core Phase medication as some patients’ may have had a 
dose increase during the Core Phase at the Month 2 visit based on the online PK results. 
5.5 
Treating the patient 
5.5.1 
Patient numbering 
Each patient is uniquely identified in the study by a combination of his/her center number and 
patient number. The center number is assigned by Novartis to the investigative site. Upon 
signing the informed consent form, the patient is assigned a patient number by the 
investigator. At each site, the first patient is assigned patient number 1, and subsequent 
patients are assigned consecutive numbers (e.g. the second patient is assigned patient number 
2, the third patient is assigned patient number 3). The investigator or his/her staff will contact 
the IVR system and provide the requested identifying information for the patient to register 
them into the IVR system. For studies using eCRFs, only the assigned patient number should 
be entered in the field labeled “Patient ID” on the electronic data capture (EDC) data entry 
screen (e.g. enter ‘1’, ‘2’, etc.).  Once assigned to a patient, the patient number will not be 
reused. If the patient fails to be randomized for any reason, the IVR system must be notified 
within 2 days that the patient was not randomized. The reason for not being randomized will 
be entered on the Screening Log, and the Demography eCRF should also be completed.  The 
patient will retain the same number throughout the Core and Extension Phase. 
5.5.2 
Dispensing the study treatment 
Each study site will be supplied by Novartis with study drug. 
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to one of the 2 treatment arms. Investigator staff will 
identify the study drug package(s) to dispense to the patient by contacting the IVR system and 
obtaining the medication number(s). Immediately before dispensing the package to the 
patient, investigator staff will detach the outer part of the label from the packaging and affix it 
to the source document (Drug Label Form) for that patient’s unique patient number.  
5.5.3 
Supply, storage and tracking 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 assistants have access. Upon receipt, all study drugs should be stored according to 
the instructions specified on the drug labels. Clinical supplies are to be dispensed only in 
accordance with the protocol. 
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the drug, but no information about the 
patient except for the randomization number. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
drug in a drug accountability ledger. Monitoring of drug accountability will be performed by 
the field monitor during site visits and at the completion of the trial. Patients will be asked to 

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return all unused study drug and packaging at the end of the study or at the time of study drug 
discontinuation.  
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all used and unused study drug, packaging, drug labels, and a copy of 
the completed drug accountability ledger to the Novartis monitor or to the Novartis address 
provided in the investigator folder at each site. 
5.5.4 
Instructions for prescribing and taking study treatment 
The study medication (fingolimod + matching placebo syringes or IFN β-1a + matching 
placebo capsules) will be dispensed starting at the Randomization Visit (Visit 3). Drug will 
then be dispensed at scheduled visits throughout the double-blind treatment period and 
Extension Phase according to Table 6-1 and Table 6-3. 
Oral capsules (fingolimod or matching placebo) must be taken once a day, preferably at the 
same time every day, with or without food. Injectable study drug (IFN β-1a or matching 
placebo) must be injected intramuscularly (i.m.) once a week. Site personnel will provide 
training to the patients and their parents/caregivers on the correct procedure for administration 
of intramuscular injections. A patient leaflet and/or oral instructions will be provided. The 
patient leaflet describes information related to the IFN β-1a i.m. study drug including storage 
information, precautions and instructions for administering i.m. injections. This information 
should be reviewed with the patient and his/her parents/caregivers to ensure that they 
understand the correct procedure. 
The first dose of the study drug (oral capsule and i.m. injection) at Visit 3 (Day 1), Visit 6 
(Month 2, for patients ≤40 kg), Visit 15 (First dose in Extension Phase) and at Visit 18 
(Month 2 of Extension Phase, for patients ≤40 kg) must be taken at the clinic. All patients will 
need to be monitored in the clinic for at least 6 hours or longer if discharge criteria are not met 
(see Appendix 2 for Guidance for monitoring of patients taking their first dose of the study 
drug). Subsequent doses can be taken at home, unless Day 2 monitoring is required as per 
Appendix 2. 
For any patient that has been off oral study drug under the following durations: 
• The treatment lasted for 14 days or less and was interrupted for 1 day or more, or 
• The treatment lasted for more than 14 days and less than 29 days and was interrupted for 
more than 7 consecutive days, or 
• The treatment lasted for 4 weeks or more and was interrupted for more than 14 
consecutive days. 
The first dose of study drug administered either at the Randomization visit (Day 1, Visit 3) or 
after an interruption of treatment in the Core Phase must be administered in the clinic under 
the supervision of the independent first dose administrator. 
Study medication must also be administered by the independent first dose administrator for 
the first dose visit in the Extension Phase (Visit 15).  First dose monitoring will be required 
for study drug interruptions in the Extension Phase, but the 6 hour monitoring does not need 
to be conducted by the independent first dose administrator. 

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Patients should receive the first dose of study drug (oral capsule and i.m. injection) at the 
study center at a time which will allow for the required 6-hour post-dose monitoring to occur 
as well as to allow for additional time for extended monitoring, if necessary. The patient will 
stay at the study center for a minimum of 6 hours to monitor for signs and symptoms of 
bradycardia. All patients will have an ECG performed prior to dosing and at the end of the 6-
hour monitoring period. Sitting heart rate and blood pressure will also be monitored before the 
first dose of study drug and every hour for at least six-hours thereafter. The patient may be 
discharged if specific discharge criteria (outlined in Appendix 2) are met. Hourly monitoring 
will be extended until findings have resolved if the discharge criteria are not met and should 
pharmacologic intervention be required during first dose observation, overnight monitoring in 
a medical facility should be instituted and the first dose monitoring procedures should be 
repeated upon the 2nd dose (see Appendix 2 for Guidance for monitoring of patients taking 
their first dose of the study drug). In addition, other patients 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 Appendix 2. 
Throughout the study careful planning of patient visits is required to make sure that a patient 
will have enough study drug to last until the next scheduled visit.  Particular care in planning 
of patient visits is required for the transition between the Core Phase and Extension Phase. 
The EOS-CP and first Extension Phase visit need to be scheduled to ensure that the patient 
has enough study drug to complete the Core Phase of the study and enter the Extension Phase 
without study drug interruption.  
At the completion of the Core Phase (Visit 14/EOS-CP), after the patient takes the last dose of 
study drug in the Core Phase, the site will contact IVR to change the status of the patient to 
completed.  No study drug will be dispensed at Visit 14/EOS-CP.  At Visit 15 the site will 
need to call the IVR system to enroll the patient into the Extension Phase and to dispense 
study drug. 
The investigator and/or study personnel should promote compliance by instructing the patient 
and his/her parents/caregivers to take the study drug exactly as prescribed and by stating that 
compliance is necessary for the patient’s safety and validity of the study. The patient and 
his/her parent/caregiver should be instructed to contact the site if he/she is unable to take the 
study drug as prescribed for any reason. As a measure of compliance, all remaining 
capsules/unused syringes must be returned to the site at each visit for counting. The counts 
will be recorded in the eCRF. 
All dosages prescribed and dispensed to the patient and all dose changes during the study will 
be recorded in the IVR system and Drug Administration Record in the eCRF. 
5.5.5 
Permitted dose adjustments and interruptions of study treatment 
With the exception of the dose adjustments described in Section 5.1, study drug dose 
adjustments for any other reason are not permitted. 
Conditions/events that may lead to the study drug interruptions based on investigator 
judgment and overall clinical assessment: 
• reported serious adverse event; 

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• emergency medical condition, unplanned hospitalization, involving use of excluded 
concomitant medications; 
• abnormal laboratory value(s) or abnormal test or examination result(s) (e.g. PFT, ECG, 
ophthalmic findings etc.); 
• hypersensitivity to the study medication; 
• patient’s non-compliance. 
Should the patient interrupt the study drug, both oral capsule and i.m. study drug must be 
interrupted. Should the investigator decide in agreement with the sponsor to re-initiate 
treatment with study drug, depending on the duration of the interruption, the first dose intake 
at re-start may need to take place at the study site to ensure at least 6-hour monitoring by the 
First Dose Administrator in a similar manner as the first intake of the study medication 
(Section 5.5.4 and Appendix 2).  When re-starting study drug, monitoring (as for first dose) is 
mandatory in the following cases: 
• The treatment lasted for 14 days or less and was interrupted for 1 day or more, or 
• The treatment lasted for more than 14 days and less than 29 days and was interrupted for 
more than 7 consecutive days or 
• The treatment lasted for 4 weeks or more and was interrupted for more than 14 
consecutive days 
If study drug is interrupted for more than 2 weeks after the first month of treatment the effects 
on heart rate and atrio-ventricular conduction may recur on reintroduction of treatment and 
thus, for study drug interruption of this duration, the same procedures as for initial dosing will 
apply. 
Re-start decision should be made on a case-by-case basis. A reason for the interruption of 
treatment and time of interruption should be appropriately documented in the source 
documents as well as in the Dosage Administration Record eCRF.  
5.5.6 
Recommendations for the treatment of MS relapses  
MS relapses may be treated as follows:  
A standard short course of corticosteroids (methylprednisolone) on an inpatient or outpatient 
basis is allowed for treatment of relapses as clinically warranted. Steroid treatment should 
consist of 20-30 mg/kg/day or up to a maximum of 1,000 mg methylprednisolone i.v. for 3-5 
days (Kuntz et al 2010). Standard of care will be followed during treatment. Taper with oral 
steroids is not permitted.  
The use of steroid therapy for the treatment of MS relapse must be recorded on the steroid 
specific eCRF.  
Investigators should consider the added immunosuppressive effects of corticosteroid therapy 
and increase vigilance regarding infections during such treatment and in the weeks following 
administration. Should a patient show evidence or suspicion of infection, please refer to the 
Guidance on monitoring of patients with infections outlined in Appendix 3. 
In the event that steroids are administered, patients and their parents/caregivers should be 
reminded of the importance of reporting any signs or symptoms of an infection. Special 

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consideration should be given to symptoms or signs of herpes simplex or zoster reactivation 
(e.g. lancinating pain, skin lesions). Appropriate therapy should be promptly initiated and 
patients should be closely followed up as clinically warranted. An infectious disease specialist 
may be consulted to guide such therapy if needed.  
Should a patient develop any symptom or signs, unexpected for MS in the opinion of the 
investigator or accelerated neurological deterioration, the investigator should immediately 
schedule an MRI and follow Guidance on monitoring of patients with symptoms or signs or 
neurological deterioration inconsistent with MS outlined in Appendix 3. 
5.5.7 
Concomitant treatment 
The investigator should instruct the patients and their parents/caregivers to notify the study 
site about any new medications he/she takes after the start of the study drug. All medications 
and significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient starts treatment with study drug must be listed on the 
Concomitant medications/Significant non-drug therapies after start of study drug eCRF.  
The investigator should instruct the patient and his/her parents/caregivers to notify the study 
site about any new medications he/she takes after the start of the study drug. All medications 
and significant non-drug therapies (including physical therapy) administered after the patient 
starts treatment with study drug must be listed on the Concomitant medications/Significant 
non-drug therapies after start of study drug eCRF. 
Patients with pre-existing dimethyl fumarate, IFN β or glatiramer acetate at Screening may 
continue drug intake up to the day before Day 1 of the study (i.e. there is no need for a 
washout period). There is also no washout period required for these drugs for enrollment in 
the Extension Phase for patients’ that discontinued study drug during the Core Phase and were 
treatment with these agents. 
Concomitant use of ketoconazole in patients treated with fingolimod may lead to an increase 
in fingolimod plasma concentrations. Patients who initiate ketoconazole during the study 
should be informed and the investigator should be vigilant as these patients may be at a higher 
risk of adverse events. 
Special consideration should be given towards chronic treatment with medication which has a 
hepatotoxic potential and the investigator should be vigilant as these patients may be at a 
higher risk of liver adverse events. 
Use of the treatments to manage potential bradycardia after first dose administration is 
allowed. For recommendations on the management of bradycardia, refer to Appendix 2.  
5.5.8 
Prohibited treatment 
Patients who have met exclusion criteria for exclusionary medications will not be allowed to 
join the study. Once the patient has entered the study at Visit 3 and while the patient is on 
therapy, use of the following treatments are NOT allowed concomitantly with the study drug: 
• Immunosuppressive medication (e.g. cyclosporine, azathioprine, methotrexate, 
cyclophosphamide, mitoxantrone, cladribine, rituximab, alemtuzumab); 

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• Other concomitant medications: immunoglobulins, monoclonal antibodies (including 
natalizumab), IFN ß, glatiramer acetate, teriflunomide, dimethyl fumarate, 
adrenocorticotropic hormone (ACTH). 
• Class Ia (e.g. quinidine, disopyramide) or Class III (e.g. amiodarone, sotalol) anti-
arrhythmics 
• Heart-rate-lowering drugs (e.g.:  Beta blockers); heart-rate lowering calcium channel 
blockers (e.g. verapamil, diltiazem or ivabradine) 
• Digoxin, anticholinesteratic agents, pilocarpine 
Careful planning is required if these medications are taken during the Core Phase (after the 
patient discontinued study drug treatment) then the patient must meet the washout exclusion 
criteria for these medications before entry into the Extension Phase.  Washout of these 
medications must occur with adequate time to complete the full washout period prior to 
enrollment in the Extension Phase at Visit 15.   
The administration of any live or live attenuated vaccine is prohibited while patients are 
receiving study drug and for 2 months after last dose of study drug. 
5.5.9 
Discontinuation of study treatment and premature patient withdrawal 
Patients may voluntarily withdraw from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, fail to return for visits, or become 
lost to follow-up for any other reason. 
If premature withdrawal occurs for any reason, the investigator must make every effort to 
determine the primary reason for a patient’s premature withdrawal from the study and record 
this information on the Study Phase Completion eCRF for Core Phase and Study Completion 
eCRF for Extension Phase. 
Study drug must be discontinued for a given patient if the investigator determines that 
continuing it would result in a significant risk for that patient. The following conditions/events 
may be considered sufficient to support a decision about the study drug discontinuation in 
individual cases: 
• Serious adverse event (e.g. diagnosed malignancy) 
• Abnormal laboratory value(s) or abnormal test result(s); see below and Appendix  3 for 
guidance for safety monitoring 
• Sexual activity in girls who do not agree to the use of contraception as defined in Section 
6.6 
• Use of prohibited medications (Section 5.5.8) 
• Adverse events 
• Protocol deviation 
• Unsatisfactory therapeutic effect 
• Patient’s condition no longer requires study treatment 
• Administrative problems (e.g. patient’s non-compliance) 
The following conditions must result in permanent study drug discontinuation: 

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• Hepatic (Appendix 3: Section 15.2) 
• Increase in ALT or AST >8 x ULN (with confirmed value on a repeat lab within 48 
hours) or 
• “Hy’s law” criterion is met or 
• The occurrence of new elevations greater than 5 X the ULN for ALT/AST in patients 
where study drug was re-initiated after drug stoppage for liver enzyme elevations. 
• Ophthalmic (Appendix 3: Section 15.8)  
• Diagnosis of macular edema. 
• If systemic immunosuppressive treatment (other than corticosteroids) is required for 
treatment of uveitis. 
• First/Redose Criteria (Appendix 2) 
• Any hemodynamically compromising cardiac arrhythmias. 
• Patients who meet the criteria requiring overnight hospitalization again on Day 2. 
• ECG abnormalities (all visits including first/redose) 
• Absolute QTcF > 500 msec, confirmed by repeat ECG measurements (within 24 
hours).  
• New complete heart block (third degree AV block) or second degree AV block 
Mobitz type II. 
• ECG abnormalities (non-first/redose visits) 
• Resting heart rate < 40 or > 120 bpm observed after 1st dose monitoring and 
confirmed on repeat measure.  
• Increase in QRS duration > 25% from Baseline (Day 1 pre-dose) observed after 1st 
dose monitoring and confirmed on repeat ECG measure (within 24 hours). 
• Pregnancy 
• Withdrawal of consent 
Patients who discontinue study drug should not be considered withdrawn from the study, 
unless one of the reasons listed above for study withdrawal are met. Patients who discontinue 
the study drug should be treated according to the best standard of care and followed as 
indicated in Table 6-2. 
A Study Drug Discontinuation eCRF should be completed, giving the date and primary reason 
for stopping the study drug. 
5.5.10 
Study completion and post-study treatment 
The Core Phase will be considered completed for an individual patient when he/she completes 
the double-blind treatment period (up to Month 24 or earlier in case the Core Phase ends once 
80% power has been obtained to detect a 50% difference for the primary endpoint (see 
Section 9.6), or in case of premature study discontinuation. A subset of patients may not have 
completed the full 3M FU data by the time of database lock for the Core Phase CSR; however 
this information will be reported in the Extension Phase CSR).  

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The results of the Core Phase and Extension Phase will be summarized and written in separate 
documents. 
The Extension Phase will be considered completed for an individual patient when he/she 
completes the extension phase (Month 60 of Extension Phase [EOS visit], including any 
required 3 month follow-up visits or earlier in case of premature study discontinuation). 
5.5.11 
Early study termination 
The study (overall study or just Core or Extension Phase) can be terminated at any time for 
any reason by Novartis. Should this be necessary, the patient should be seen as soon as 
possible and treated as described in Section 6 for a prematurely withdrawn patient. If the Core 
Phase of the study is terminated then the patient may be eligible for participation in the 
Extension Phase if they satisfy the inclusion/exclusion criteria.  The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the patient’s interests. The investigator will be 
responsible for informing IRBs and/or ECs of the early termination of the trial. 
5.5.12 
Emergency breaking of assigned treatment code 
Emergency treatment code breaks should only be undertaken when it is essential to treat the 
patient safely and efficaciously. Most often, investigational treatment discontinuation and 
knowledge of the possible treatment assignments are sufficient to treat a study patient who 
presents with an emergency condition. Emergency treatment code breaks are performed using 
the IVR System. When the investigator contacts the system to break a treatment code for a 
patient, he/she must provide the requested patient identifying information and confirm the 
necessity to break the treatment code for the patient. The investigator will then receive details 
of the investigational drug treatment for the specified patient and a fax or email confirming 
this information. The system will automatically inform the Novartis monitor for the site and 
the Global Trial Lead (GTL) that the code has been broken. 
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IVR system in case of emergency. The investigator will inform the patient how to 
contact his/her backup in cases of emergency when he/she is unavailable. The investigator 
will provide protocol number, study name if available, patient number, and instructions for 
contacting the local Novartis Country Pharma Organization CPO (or any entity to which it has 
delegated responsibility for emergency code breaks) to the patient in case an emergency 
treatment code break is required at a time when the investigator and backup are unavailable 
5.5.13 
Role of site personnel 
In order to facilitate the required study contact at each investigational site, it is essential that 
the Primary Investigator will assign the following site personnel: 
• Primary Treating Physician, a pediatrician specialized in neurology or a neurologist 
experienced in treating pediatric MS patients. The Primary Investigator usually serves as 
the Primary Treating Physician; 
• Independent Evaluating Physician, a neurologist (experienced with assessing pediatric MS 
patients) not involved in the clinical care and management of the study patients; 

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• Pediatrician (unless the Primary Treating Physician is a pediatrician) 
• Primary treating Nurse/Study Coordinator 
• First Dose Administrator 
• MRI technician 
• Neuroradiologist 
• Ophthalmologist 
• Pulmonary function test (PFT) laboratory technician  
Where specified, evaluations described in the protocol must be performed only by the 
personnel indicated. 
Primary Treating Physician 
The primary treating physician will be responsible for: 
• Overall conduct of the study at the study site 
• Management of the routine clinical care of the study patients 
• Confirmation of patient’s eligibility for randomization 
• Assessment and treatment of adverse events and MS relapses 
• Referral of patients with neurological symptoms consistent with MS relapse to the 
Independent Evaluating Physician for EDSS  
• Monitoring of adverse events in subjects who have permanently discontinued study drug 
• Ensuring that all treating site personnel are informed of concomitant medications excluded 
per protocol (e.g. the use of steroids other than for the treatment of MS relapses) 
• Ensuring that the need for increased vigilance regarding infections during and in the 
weeks following administration of corticosteroids is explained to the patients and his/her 
parent/caregiver 
It is strongly recommended that the Primary Treating Physician remains unchanged 
throughout the entire course of the study. Occasionally, the Primary Treating Physician may 
designate other medical personnel (i.e., a back-up physician or nurse) at the study site to 
perform some of the tests and evaluations listed above. 
Independent Evaluating Physician: Required for Core Phase only 
The Independent Evaluating Physician will be responsible for: 
• Assessing patients with neurological symptoms consistent with MS relapse (as referred by 
the Primary Treating Physician) and obtaining an EDSS score needed for relapse 
confirmation. 
• Obtaining an EDSS score based on detailed neurological examinations as per Table 6-1 or 
Table 6-2.  
The Independent Evaluating Physician must not be involved in any other aspect of the 
patient’s care and/or management. 

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To ensure consistency across sites, the Independent Evaluating Physician must participate in 
the standardized training session on EDSS scoring (unless already certified at required level in 
past 12 months) prior to enrollment of subjects at their site. Re-certification will be required 
annually. 
The communication of new findings on the neurological examination from the Independent 
Evaluating Physician to the Primary Treating Physician is permitted. The roles of the Primary 
Treating Physician and the Independent Evaluating Physician, including their back-ups, are 
not interchangeable. The Independent Evaluating Physician must remain blinded to adverse 
events, concomitant medications, laboratory data and any other data that have the potential of 
revealing the treatment assignment. The patients and his/her parent/caregiver should be 
instructed to take care not to reveal the patient’s treatment to the Independent Evaluating 
Physician. 
It is strongly recommended that the Independent Evaluating Physician remains unchanged 
throughout the entire course of the study. 
Pediatrician  
The pediatrician will be responsible for: 
• Serving as a consultant to the Primary Treating Physician for management of the routine 
care of the patient 
• Guiding the assessment of the pubertal changes according to the Tanner stages, as well as 
bone age as applicable, refer to Section 6.5.5). These assessments may also be conducted 
by other health care professionals experienced with these assessments. 
• Perform a skin examination at Screening and end of study (if not performed by a 
dermatologist, Section 6.5.1) 
Primary Treating Nurse/Study Coordinator 
The Treating Nurse/Study Coordinator will be responsible for: 
• Assisting the primary treating physician  in patient management, including the assessment 
and treatment of adverse events and disease relapses and the recording of adverse events, 
concomitant medications and monitoring of compliance (returned capsule and syringe 
counts) 
• Scheduling visits and assessments as outlined in the protocol, maintaining proper source 
documentation and transcription of the data to the eCRFs 
• Coordination with and between the study selected central labs, drawing and processing lab 
samples 
• Assisting patients in the completion of questionnaires 
First-dose Administrator  
The First-dose Administrator will:  
• Ensure that facilities for monitoring and treatment of symptomatic bradycardia are 
available if needed 

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• Monitor1st dose intake of the assigned study medication, and if applicable monitor, at 
protocol required re-start or at oral dose increase according to the procedure outlined 
in Appendix 2. Administer first i.m. injection (IFN or dummy placebo). 
• Review vital signs and ECG at 6 hours post-dose administration and make a decision 
regarding patients’ eligibility for discharge as described in Appendix 2.  
• Clinically monitor the patient for at least 6 hours post-dose, record vital signs, ECG 
findings, bradycardia events occurring post 1st dose administration. All other adverse 
events should be reported to the primary treating physician. 
• Monitor the patient beyond 6 hours, if indicated (if discharge criteria are not met at 6 
hours post-dose and prolonged monitoring is required) 
• Determine whether the 2nd dose should also be administered in the clinic on the next day. 
• Provide written instructions to the patient upon discharge with contact information for 
emergencies, instruct the patient to avoid driving by himself/ herself on the day of 
discharge 
• Ensure that the patient or primary treating physician/nurse do not have access to or are 
informed of vital signs values to avoid unblinding of the patient or site personnel, unless it 
is medically warranted 
• Maintain and ensure accuracy of completeness of eCRFs during 1st dose monitoring and 
transferring them directly to the Data Management (care must be taken to ensure that this 
data remains blinded from the site personnel) 
The First-dose Administrator can be supported by a nurse or other health care professional as 
appropriate (not otherwise involved in the patient care). 
MRI technician 
An MRI technician will be responsible for: 
• Familiarization with the MRI manual procedures and the study specific MRI protocol 
• Performance of a “dry” or “dummy” run using the MRI parameters outlined by the MRI 
protocol 
• Accommodation of patients for the MRI scan as per request of the treating nurse and 
performance of high-quality MRI scans using the study specific parameters stored in the 
designated MRI scanner for the duration of the study 
• Submission of the MRIs in the appropriate format to the central MRI reader immediately 
upon completion 
Neuroradiologist 
A neuroradiologist will be responsible for: 
• Previewing each MRI scan performed for the study patients 
• Contacting the Primary Treating Physician in case of unexpected findings detected on the 
MRI scan 

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Ophthalmologist 
• The Ophthalmologist will perform the ophthalmic examinations as per protocol 
Pulmonary Function Test Laboratory Technician 
• Pulmonary function test (PFT) technician will perform PFTs per local standard practice 
for pediatric patients 
6 
Visit schedule and assessments 
The Core Phase will consist of two periods: a pre-randomization period consisting of 
screening and baseline visits, and a double-blind treatment period. The Extension Phase 
consists of a fingolimod treatment period.  
The day of randomization in the Core Phase is defined as Day 1 of the study (Visit 3), which 
is the first day of study drug administration. Entry in the Extension Phase occurs at Visit 15 
immediately following the completion of the Core Phase. 
Table 6-1, Table 6-2 and Table 6-3 lists all assessments and indicates with an “X” the visits 
when they are performed.  
Patients should follow the visit schedule with an allowed visit window as follows: 
• ± 2 days for Visit 4 and Visit 16 
• ± 5 days for Visit 5 and all monthly visits 
• ± 10 days for all quarterly and biannual visits 
• + 14 days for Visit 15 (should be completed within 14 days of completion of Visit 14 / 
EOS-CP). Date of completion of Core Phase should be entered in the Study phase 
completion eCRF (date entered should be 1 day before Visit 15; first Extension Phase 
visit). Study drug should not be interrupted between the end of the Core Phase and the 
start of the Extension Phase. 
Visit windows can be extended on a case-by-case basis to accommodate scheduling (please 
consult Sponsor for approval). The pre-randomization period may be extended with approval 
from the sponsor on a case by case basis to accommodate additional time needed to complete 
the screening assessments (e.g., additional lab tests, time to be (re)vaccinated, time to allow 
lab parameters to come within protocol requirements, etc.). 
In addition to the scheduled visits, patients may have unscheduled visits following an onset of 
an MS relapse or for safety follow-up.  
Patients who prematurely discontinue study drug during the Core Phase should be encouraged 
to remain in the study. Patients who prematurely withdraw (PPW – Premature Patient 
Withdrawal) from the study for any reason should be scheduled for a final Visit 14 (EOS-CP) 
assessment at the time of discontinuation from study drug as outlined in Table 6-1). A follow-
up visit should then be scheduled three months after the last dose of the study drug. If the 
patient is unable to return to the site for the Visit 14 / EOS-CP assessments, every effort 
should be made to contact the patient by telephone for safety evaluations during the 3 months 

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following the last dose of study drug, including a final contact at the 90-day point (3-month 
follow up). 
Patients who prematurely discontinue study drug (SDD) during the Core Phase, and remain in 
the study will follow an abbreviated schedule of assessments (see Table 6-2). At the time of 
SDD, patients must complete the Visit 14 / EOS-CP assessments (as end of treatment 
assessments), followed by a 3-month follow-up visit prior to continuing in the abbreviated 
schedule of assessments. If a patient who is being followed in the abbreviated schedule of 
assessments prematurely withdraws from the study, the patient should be scheduled for a final 
visit (EOS-CP according to Table 6-2) at the time of study discontinuation. 
Patients who have completed the Core Phase, as per Table 6-1 or Table 6-2, may be eligible to 
enter the long-term extension study (Table 6-3). Patients who complete the Core Phase on 
study drug, but choose not to enter the Extension Phase should return for a 3-month follow-up 
visit.  
Patients who prematurely discontinue study drug (SDD) during the Extension Phase, may 
remain in the study and be followed at yearly visits (see Table 6-2). At the time of SDD, 
patients must complete the Visit 30 assessments (as end of treatment assessments), followed 
by a 3-month follow-up visit. 

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Table 6-1 
Core Phase:  Assessment schedule 
Phase 
Pre-
Randomizatio
n 
Double-blind Treatment Phase 
Period 
Scre
ening 
Base 
line 
Visit No. 
1 
2 
3 
4 
5 
51 
6 
7 
71 
72 
8 
9 
10 
11 
12 
13 
14/ 
EOS
-CP 
FU
# 
Study month 
-45 
days 
-7 
days 
Day 
1 
½ 
1 
1 ½ 
2 
3 
4 
5 
6 
9 
12 
15 
18 
21 
24 
+3 
mo 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Background, 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Incl/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MS history/MS 
treatment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy 
test** 
X 
X 
 
X 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
 
X 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Skin exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
PK1 
 
 
X 
X 
X 
 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Ophthalmologic 
examination2 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
* 
X 
* 
 
X * 
 
X 
 
Tanner stages5  
 
X 
Pulmonary 
Function Tests 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Vital signs 
X 
X 
X 
X 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology/ 
Blood chemistry 
4 
X14 
X 
 
X 
X 
X6 
X 
X 
X6 
X6 
X 
X 
X 
X 
X 
X 
X14 
X 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X10 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
First Dose 
Administration 
monitoring 
 
 
X 
 
 
 
X13 
As needed11 
 
 
Fingolimod 
drug supply 
 
 
X 
 
 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
IFN β-1a drug 
supply 
 
 
X 
 
 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 

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Phase 
Pre-
Randomizatio
n 
Double-blind Treatment Phase 
Period 
Scre
ening 
Base 
line 
Visit No. 
1 
2 
3 
4 
5 
51 
6 
7 
71 
72 
8 
9 
10 
11 
12 
13 
14/ 
EOS
-CP 
FU
# 
Study month 
-45 
days 
-7 
days 
Day 
1 
½ 
1 
1 ½ 
2 
3 
4 
5 
6 
9 
12 
15 
18 
21 
24 
+3 
mo 
Capsule/syring
e count 
 
 
 
 
 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
 
X7 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
MRI 
X8 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X9 
 
EDSS 
X 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
MS relapse 
X 
X 
X 
X 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS12 
X 
X 
X 
X 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
IVR 
X 
 
X 
 
 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Adverse 
events/SAEs 
 
 
X 
X 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Study Phase 
Completion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 

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Phase 
Pre-
Randomizatio
n 
Double-blind Treatment Phase 
Period 
Scre
ening 
Base 
line 
Visit No. 
1 
2 
3 
4 
5 
51 
6 
7 
71 
72 
8 
9 
10 
11 
12 
13 
14/ 
EOS
-CP 
FU
# 
Study month 
-45 
days 
-7 
days 
Day 
1 
½ 
1 
1 ½ 
2 
3 
4 
5 
6 
9 
12 
15 
18 
21 
24 
+3 
mo 
 
1. Two PK samples collected at Visit 3 (Randomization) and Visit 5 (Month 1) pre-oral dose and approximately 6 
hours post-oral dose; one PK sample collected at other specified visits. 
2. Ophthalmologic examination includes OCT at Screening and EOS visits.  
 
4. Laboratory results must be available prior to randomization to evaluate inclusion/ exclusion criteria. 
 
 
 
6. Blood sample for liver panel only (see Section 6.5.4 for patients with travel restrictions) 
7. ECG to be obtained on Day 1 before first dose administration or if dose increase or restart of study drug after 
having been off treatment for the durations referenced in 11, 6 hours post-first dose and at discharge (if patient 
monitored longer than 6 hours). 
8. MRI scan must be performed within 30 days prior to randomization. 
9. EOS-CP MRI is not required for patients who discontinue within 4 weeks of a completed, scheduled scan. 
10. IFN β neutralizing antibodies evaluated at Visit 14 / EOS-CP. 
11. Patient who reaches the weight of 40 kg sustained over at least 2 visits (3 months apart) and needs to have 
dose increase or will reinitiate treatment after interruption of study drug (Section 5.5.5) for the following durations: 
The treatment lasted for 14 days or less and was interrupted for 1 day or more, or 
The treatment lasted for more than 14 days and less than 29 days and was interrupted for more than 7 consecutive 
days, or 
The treatment lasted for 4 weeks or more and was interrupted for more than 14 consecutive days. 
12. To be completed at every visit including any unscheduled visits. 
13. The patients with BW 40 kg or less potentially increase in dose based on on-line PK assessment. First-dose 
monitoring done. 
14. T cell and B cell phenotyping 
# Patients who prematurely discontinue study drug should complete the 3 month follow-up visit and then be allowed 
to enter the abbreviated schedule of assessments at the next scheduled study visit (Table 6-2).  
Patients who complete the Core Phase but do not enter the Extension Phase should complete the 3 month follow-
up visit.   
*Visits required only in patients with history of diabetes mellitus or uveitis, or newly diagnosed uveitis  
**if applicable (please refer to Section 6.6. for details), plus monthly urine pregnancy tests (e.g. home test) between 
scheduled serum tests, if applicable. 
 

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Table 6-2 
Core Phase:  Abbreviated schedule of assessments for patients with 
SDD 
Phase 
Double-blind Treatment Phase 
Visit No.1 
8 
9 
10 
11 
12 
13 
14/ EOS-
CP 
Study month 
6 
9 
12 
15 
18 
21 
24 
Physical exam 
X 
 
X 
 
X 
 
X 
Skin exam 
 
 
 
 
 
 
X 
Pulmonary Function Tests 
X 
 
X 
 
X 
 
X 
MS relapses 
X 
X 
X 
X 
X 
X 
X 
MS treatment/Concomitant 
medications/Steroids 
X 
X 
X 
X 
X 
X 
X 
EDSS 
X 
X 
X 
X 
X 
X 
X 
MRI 
X 
 
X 
 
X 
 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Hematology/Blood chemistry 
X 
 
X 
 
X 
 
X 
Urinalysis 
X 
 
X 
 
 
 
X 
C-SSRS4 
X 
X 
X 
X 
X 
X 
X 
AE/SAE reporting (if any) 
X 
X 
X 
X 
X 
X 
X 
1. The abbreviated schedule should be adopted at the appropriate visit after the 3 month follow-up visit.  
 
. 
 
4. To be completed at every visit including any unscheduled visits. 
 

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Table 6-3 
Fingolimod Extension Phase:  Assessment schedule 
Phase 
Fingolimod Treatment 
Visit No. # 
15 
16 
17 
18 
19 
20 
21 
22 
23 to 29 
Study 
Completion 
(Visit 30)*** 
FU 2 
Study month # 
Day 1 
 1 
½  
1 
 
2 
 
3 
 
6 
 
9 
 
12 
 
every 6 
months15 
60  
 
Incl/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (serum) 3** 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
 
 
 
 
X 
X 
 
X 
1 / year 
X 
X 
Skin Exam 
 
 
 
 
 
 
 
 
1 / 2 years 
X 
 
Ophthalmologic Examination 
6  
 
 
 
 
X 
X 
 
X 
As 
Needed 
X 
 
Pulmonary Function Tests 
 
 
X 
 
X 
X 
 
X 
As 
Needed 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology/ Blood 
chemistry 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
 
 
 
 
 
X 
 
X 
1 / year 
X 
 
Fingolimod drug supply 7 
X 
 
 
X 
X 
X 
 
X 
X 
 
 
ECG  
X 8 
 
X 
 
 
 
 
X 
1 / year 
X 
 
MRI 
 
 
 
 
 
X 
 
X 
1 / year 9 
X 
 
EDSS 10 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
MS relapse 11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events/SAEs13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetic sample 
FTY720/FTY720-P14 
 
 
X 
 
 
 
 
 
 
 
 
First Dose Administration* 
X 
 
 
X 14 
As needed 
 
 

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Phase 
Fingolimod Treatment 
Visit No. # 
15 
16 
17 
18 
19 
20 
21 
22 
23 to 29 
Study 
Completion 
(Visit 30)*** 
FU 2 
Study month # 
Day 1 
 1 
½  
1 
 
2 
 
3 
 
6 
 
9 
 
12 
 
every 6 
months15 
60  
 
1. Assessments and first dose administration will occur on day 1 of the Extension Phase (ideally the day after the 
completion of the Core Phase), visit should be completed within 14 days of Visit 14 / EOS-CP. For ease of 
scheduling, if needed, some Visit 14 / EOS-CP assessments may be completed in the morning prior to dosing at 
Visit 15  
2. Follow-up visit should be scheduled 3 months (±10 days) after the last dose of study medication.  
3. Additional pregnancy tests may be collected at Investigators discretion during the study. 
 
 
 
6. Optical Coherence Tomography will be conducted at the Core Phase EOS-CP Visit and then at the end of the 
study. 
7. Study drug dispensation will occur at scheduled visits. 
8. ECG to be obtained before fingolimod first dose administration in the extension and 6 hours post-first-dose. 
9. MRI assessments are required to be done annually.  If MRI’s would be conducted more frequently for routine 
medical practice then MRI’s may be conducted as often as every 6 months. 
10. Additional unscheduled EDSS assessments may be conducted to confirm relapse. 
11. Unscheduled visits required to confirm MS relapse. 
12. To be completed at every visit including any unscheduled visits. 
13. Adverse events that happen prior to the first dose intake in the Extension Phase should be recorded as having 
occurred in the Core Phase of the study. 
14. The patients with BW 40 kg or less potentially increase in dose based on on-line PK assessment. PK collected 
at Visit 17 and first-dose monitoring done at Visit 18. 
15. Assessments occur at each biannual visit (every 6 months) unless specified otherwise. 
# Visit numbering is sequential following the Core Phase visit numbering.  All patients will complete Visit 14 prior to 
entry in the Extension Phase.  Study month reflects the time in the Extension Phase since patients may enter the 
Extension Phase after various durations of time in the Core Phase. 
* The first dose monitoring at Visit 15 must be conducted by the independent first dose monitoring team in a 
blinded fashion.  All additional first dose monitoring visits may be done by the main clinical team (monitoring is not 
blinded). 
**if applicable (please refer to Section 6.6 of Core Phase protocol. for details), plus monthly urine pregnancy tests 
(e.g. home test) between scheduled serum tests. 
*** Patients that discontinue treatment with fingolimod must complete the end of visit assessments (Visit 30) at the 
time of study drug discontinuation and then must complete the 3-month follow-up visit.  Patients may then come 
back at the next yearly visit and have monitoring visits yearly at 36, 48, 60, 72 and 84 Months. 
6.1 
Information to be collected on screening failures 
Patients who have signed the informed consent form, but fail to meet eligibility criteria for 
enrollment during the Screening Phase will be deemed screen failures and a reason will be 
documented on the Screening Log eCRF. Only demography data will be collected. . If a 
patient does not meet In/Ex criteria they may be re-screened. In general a patient should not 
be re-screened more than once, although in some  circumstances, if the clinical situation 
warrants, a 2nd re-screening may be appropriate (please contact sponsor for approval). 

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6.2 
Patient demographics/other baseline characteristics 
Patient demographic data and baseline characteristic data to be collected on the Demography 
eCRF will include date of birth, age, sex, race, ethnicity and Tanner stage. Relevant medical 
history includes data until the start of study drug and will capture pre-existing medical 
conditions and any medications taken to treat these conditions. Where possible, diagnoses, 
and not symptoms should be recorded. MS history and previous MS treatment will also be 
collected.  
6.3 
Treatment exposure and compliance 
In order to collect accurate information about the study drug exposure, the following records 
should be maintained for each randomized patient: records of study medication dispensed and 
returned, dosages administered and intervals between visits. These data should be transcribed 
on the Dosage Administration Record eCRF. Any events that are considered adverse events 
that do result in an interruption of dosing must be recorded on the Adverse Events eCRF page. 
Compliance will be assessed by the investigator and/or study personnel at each visit using 
capsule and syringe counts and information provided by the patient. A monitor will perform 
and document drug accountability during site visits and at the end of the study. 
6.4 
Efficacy 
Efficacy assessments will include: 
• MS relapse 
• MRI 
• EDSS 
• 
 
6.4.1 
Magnetic resonance imagining (MRI) 
All patients will undergo MRI scanning of the brain according to Table 6-1, Table 6-2 and 
Table 6-3.  
Core Phase MRI scans will be read blinded (with no information on treatment assignment) at 
the central MRI reading center. Prior to the start of the study, the neuroradiologist and MRI 
technician from each center will receive an MRI Manual, outlining technical implementation, 
image quality requirements and MRI administrative procedures. Each site will be asked to 
program the MRI scanner that is designated for evaluation of the study patients and perform 
and submit a dummy scan (so-called “dummy or dry run”) to the MRI reading center to assess 
the image quality and to evaluate the compatibility of the electronic data carrier. Once the 
dummy run has been accepted, all the parameter settings for the study specific MRI sequences 
must remain unchanged for the duration of the study. 
Each MRI scan performed during the Core Phase needs to be previewed by a local 
neuroradiologist (see Section 5.5.13). The Primary Treating Physician needs to be contacted 
in case of unexpected findings (e.g. not consistent with MS) detected on the MRI scan.  

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During the study, the quality of each scan performed will be assessed by the central blinded 
MRI reading center. The MRI scan should be sent to the central MRI reading center within 3 
working days, if possible. As soon as the scan is received by the central MRI reading center, it 
will be evaluated for quality, completeness and adherence to the protocol. Confirmation of 
MRI quality or a description of the quality problems, if detected, will be communicated to the 
site. If scan is incomplete or incorrectly performed, the study center will be asked to repeat it 
as soon as possible. After completion of the quality check, all scans will be analyzed 
according to the MRI protocol.  
The central blinded MRI reading center will provide MRI notifications during the Core Phase 
of the study if certain MRI activity criteria are met for a given patient. MRI notifications will 
be based on combined unique active (CUA) lesion counts (defined as Gd-enhancing lesions + 
new/enlarging T2 lesions not associated with Gd-enhancement for scans performed after Gd 
administration or just new/enlarging T2 lesions for scans done without Gd (Gd administration 
is optional for Month 18 scan).  
The Investigator will be notified if the following criteria are met: 
• 5 or more Gd-enhancing lesions on month 6 scan and 5 or more CUA lesions on month 12 
scan – notification triggered at Month 12  
• 5 or more CUA lesions on month 12 scan and 5 or more new/enlarging T2  lesions on 
month 18 scan – notification triggered at Month 18 
• 5 or more new/enlarging T2 lesions on month 18 scan and 5 or more new/enlarging T2 
lesions on month 24 scan  - notification triggered at Month 24 
Extension Phase MRI scans will be read by the central MRI reading center as was done in the 
Core Phase using the same procedure and study specific MRI sequences.  During the 
Extension Phase the Investigator will also be allowed to review the Extension Phase MRI’s 
for disease activity and safety findings.  MRI alerts for disease activity will not be reported by 
the Central Reader during the Extension Phase.   
Restrictions for MRI schedule 
To avoid interferences caused by steroids for the treatment of MS relapse, the following 
restrictions apply for this study: 
• In case of relapse, if an MRI would have been scheduled within 30 days of the initiation of 
steroid treatment, MRI should be performed before steroid treatment is initiated. 
• No MRI scan should be performed while a patient is on intravenous steroid therapy and 
within the following 30 days upon termination of steroid therapy. 
As a result of these restrictions, MRI scheduling can be adjusted accordingly. In case a visit is 
performed outside the visit window, any subsequent visits should be performed according to 
the original visit schedule. 
Scanning 
All sequences/scans will be performed according to the MRI manual. 

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Sequences for T1 hypointense images (with and without contrast medium, gadolinium-DTPA 
[use of contrast medium is optional at Month 18 and for all Extension Phase MRI’s; sites may 
use contrast medium if this would normally be done as part of the sites routine clinical 
practice]), T2-weighted (T2 and PD) images and brain volume will be performed.  
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. 
6.4.2 
MS relapse 
The initial assessment, management and reporting of MS relapse is made by the Primary 
Treating Physician.  
MS relapse definition: appearance of a new neurological abnormality or worsening of 
previously stable or improving pre-existing neurological abnormality, separated by at least 30 
days from onset of a preceding clinical demyelinating event (McDonald et al 2001). The 
abnormality must have been present for at least 24 hours and occurred in the absence of fever 
(< 37.5°C) or known infection.  
Diagnosing MS relapses during the study: a patient may report symptoms indicative of a 
relapse at a scheduled visit or at any other time. Patients will be instructed to immediately 
contact the Primary Treating Physician if he/she develops new or re-occurring or worsening 
neurological symptoms. At each scheduled visit, the patient will also be asked whether any 
such symptoms have occurred. If a patient reports new neurological symptoms or worsening 
of previous symptoms, an unscheduled visit is to be planned as soon as possible, ideally 
within 7 days. During this visit, the treating physician will first assess whether the 
new/worsening neurological abnormality is consistent with the definition of MS relapse 
above. If so, the standard neurological examination (for the EDSS score) should be performed 
by the Independent Evaluating Physician (EDSS rater). If there is any doubt in the opinion of 
the treating physician, the default must always be to refer the case to the Independent 
Evaluating Physician to perform an EDSS rating.  
During the Extension Phase the EDSS assessment needs to be completed by a qualified EDSS 
rater. Blinding of EDSS ratings is not required during the Extension Phase since all patients 
will be treated with fingolimod.  However, it is highly recommended that the EDSS rater used 
in the Core Phase continues to monitor the EDSS in the Extension Phase for consistency of 
readings. If a rater change is required then adjudication/discussion between “Core Phase 
Rater” and “Extension Phase Rater” should be done if there are differences between the last 
Core Phase evaluation and the first Extension Phase evaluation. Co-ratings are also 
recommended.  Every effort should be made for the rater to remain the same throughout the 
study. 
Confirmation of MS relapse: the definition of a confirmed MS relapse is one accompanied by 
a clinically relevant change in the EDSS performed by the Independent Evaluating 
Physician/EDSS rater for Core/Extension Phase respectively, i.e. an increase of at least 0.5 
points on the EDSS score, or an increase of 1 point on two FSs or 2 points on one FS, 
excluding changes involving bowel/bladder or cerebral FS compared to the previous available 
rating (the last EDSS rating that did not occur during a relapse). 

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The main relapse-related analyses will be based on confirmed relapses. All relapses, 
confirmed and unconfirmed, will be recorded in the eCRF. 
The severity of relapses will be calculated centrally according to criteria in Table 6-4. 
Table 6-4 
Severity of MS relapse  
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 
(Panitch et al 2002)  
6.4.3 
 (Kurtzke’s) Expanded Disability Status Scale (EDSS) 
EDSS will be determined, based on neurological examination, by the Independent Evaluating 
Physician during the Core Phase and by a certified EDSS rater during the Extension Phase at 
scheduled visits according to Table 6-1, Table 6-2 and Table 6-3 and in case of a suspected 
MS relapse. 
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. 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.  
The Independent Evaluating Physician/EDSS rater is a neurologist or otherwise qualified 
healthcare professional who has successfully completed the EDSS certification (at the highest 
level) within the past 12 months. During the Core Phase the Independent Evaluating Physician 
conducts the EDSS ratings and is otherwise not involved in the treatment of the patient. 
During the Extension Phase EDSS ratings may be done by a qualified healthcare professional 
that has successfully completed the EDSS certification.   
EDSS assessments are to be performed at scheduled visits according to Table 6-1,Table 6-2 
and Table 6-3 and in case of an MS relapse.  

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6.4.5 
Appropriateness of efficacy assessments  
MS relapse, MRI and EDSS are standard efficacy assessments in MS and are used in both the 
adult and the pediatric populations. They serve to characterize the patient population included 
in this study as well as their disease activity and neurological status. 
 
 
 
6.5 
Safety 
Safety assessments will include: 
• Physical examination (including skin) 
• 
 
• Ophthalmologic examination including Optical Coherence Tomography (OCT) 
• Pulmonary function tests (PFTs) 
• Vital signs 
• Laboratory evaluations 
• Electrocardiogram (ECG) 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
Medical history, including MS history and prior MS treatments will be assessed at Visit 1. 
Concomitant medications will be assessed at every visit following informed consent.  
6.5.1 
Physical examination 
A physical examination will be performed according to Table 6-1, Table 6-2 and Table 6-3 
and will include an assessment of skin, head and neck, lymph nodes, breast, heart, lungs, 
abdomen, back and comments on general appearance. A complete neurological examination 
will be part of the initial physical examination at screening. Investigators should ask the 
patient/guardian if they have any new or changed skin lesions as part of each physical 
examination. If skin lesions (suspected to be precancerous or cancerous) are identified during 
the physical examination, the patients should be referred to a dermatologist.  
A complete examination of the skin will be performed by a dermatologist or the study 
pediatrician according to Table 6-1, Table 6-2 and Table 6-3. 
Information for all physical examinations (including skin exams) must be included in the 
source documentation at the study site. Significant findings that are present prior to the start of 
study drug must be included in the Relevant Medical History/Current Medical Conditions 
screen on the patient’s eCRF. Significant findings made after the start of study drug which 
meet the definition of an Adverse Event must be recorded on the Adverse Event eCRF. 

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6.5.2 
Ophthalmologic examination 
A complete ophthalmologic examination will be performed according to Table 6-1 or Table 6-
3 by an ophthalmologist. At each scheduled visit the following assessments will be 
performed: 
• Eye history (medical history at baseline, AEs during the study) 
• Best corrected visual acuity measurements using a standard visual acuity chart with equal 
space between letters and between lines (results must be provided in Snellen equivalent or 
decimal score) 
• Dilated ophthalmoscopy to examine the macula and optic disc (may include contact lens 
biomicroscopy) 
• 
 
 
 
Optical coherence tomography (OCT) to measure central foveal thickness/center point 
thickness should be performed according to Table 6-1 or Table 6-3. An OCT should also be 
performed if there is suspicion of macular edema by dilated ophthalmoscopy at any visit. 
Further explorations, such as a fluorescein angiogram, to confirm/rule out macular edema 
should be performed at the discretion of the ophthalmologist 
Patients with medical history of diabetes mellitus or uveitis or newly diagnosed uveitis at 
screening or during the study will require special evaluation and additional ophthalmic 
evaluation (see Appendix 3).  
6.5.3 
Vital signs 
Vital signs will be recorded according to the schedule in Table 6-1, Table 6-2 and Table 6-3. 
Vital signs will include height, weight, sitting pulse rate, sitting systolic and diastolic blood 
pressure, and oral temperature (degrees Celsius). 
Heart rate (pulse) 
Sitting radial pulse after 5 minutes of rest should be measured just prior to blood pressure 
measurement.  
At least 6 hour monitoring in the clinic will be required on Day 1 (Visit 3) and Visit 15 after 
first dose of study drug in the Core and Extension Phase, respectively. This is also required in 
the event of an increase in fingolimod dose from 0.25 mg to 0.5 mg (see Section 3.3) and at 
any restart of study drug dosing after an interruption as specified in Section 5.5.5. Details of 
the monitoring during treatment initiation, dose increase or study drug restart are provided in 
Appendix 2.   
In the Extension Phase, Visit 15 first dose monitoring must be done by the independent first 
dose monitoring team.  All subsequent monitoring visits required per protocol for dose 
increases or study drug interruptions may be performed by the main study team since all 
patients will be treated with fingolimod in the Extension Phase and thus blinding is not 
required after the first dose of Extension Phase medication has been provided to a patient. 

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Blood pressure 
Sitting blood pressure will be recorded according to the schedule in Table 6-1, Table 6-2 and 
Table 6-3. Every effort should be made to have the same study personnel obtaining blood 
pressure readings for an individual patient at each visit at the same time of day with the same 
equipment. Using a calibrated standard sphygmomanometer with the appropriate cuff size, 
arterial blood pressure determinations will be made. With the arm supported at the level of the 
heart, systolic and diastolic blood pressure will be recorded. The cuff should not be deflated at 
a rate greater than 2 mmHg/sec. 
At each visit after the patient has been resting (i.e., not active) for 5 minutes, systolic/diastolic 
blood pressure will be measured three times. For blood pressure measurements during first 
dose monitoring on Day 1, refer to Appendix 2. 
6.5.4 
Laboratory evaluations 
Routine blood and urine samples will be analyzed by the central laboratory. Details about 
collection, shipment of samples, reporting of results, laboratory normal ranges and alerting 
abnormal values will be provided in the study laboratory manual, supplied to the site before 
site initiation. With the exception of total and differential white blood cell count, which will 
be blinded to the sites (refer also to Section 15.4), the results of the analysis will be made 
available to each center by the central laboratory at the earliest 48 hours after receipt of the 
samples by the central laboratory.  
Hematology 
Complete blood cell count (CBC) analysis including red blood cell (RBC) count, total and 
differential white blood cell (WBC) count (basophils, eosinophils, lymphocytes, monocytes, 
neutrophils, WBC segments), platelet count, hemoglobin, hematocrit, MCV, MCH, MCHC 
and RBC morphology will be performed according to Table 6-1, Table 6-2 and Table 6-3. 
Additionally, phenotyping of T cells (naïve T cells, T central memory cells and T effector 
memory cells) and B cells using FACS flow cytometry will be performed according to Table 
6-1. 
Blood chemistry 
All laboratory samples are preferred to be collected at the same time of the day. Fasting status 
should be clearly identified on the laboratory requisition form accompanying the samples.  
Blood chemistry is to be obtained according to Table 6-1,Table 6-2 and Table 6-3 and will 
include sodium, potassium, chloride, calcium, magnesium, phosphate, blood urea nitrogen 
(BUN), uric acid, random glucose, albumin, alkaline phosphatase, creatinine, cystatin C, 
ALT, AST, GGT, amylase, total bilirubin, conjugated bilirubin, total cholesterol, 
triglycerides, HDL and LDL. Abnormal laboratory parameters should be repeated for 
accuracy. A blood sample for liver function tests only (ALT, AST, GGT, alkaline 
phosphatase, total bilirubin, conjugated bilirubin) will be obtained according to Table 6-1. 
Serum pregnancy testing and home pregnancy testing will be performed according to Table 6-
1 and Table 6-3. 

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To assist for patients with travel restrictions blood samples for liver panel assessments as 
described in Table 6-1 (Visits at 6 weeks, 4 and 5 months) may be drawn by a local lab and 
the results report sent to the Investigator within 48 hours of obtaining the results.  
If any significant findings are observed on these reports (See Appendix 3 Section 15.2 
guidelines), a confirmatory blood sample should be drawn by the site and sent to the central 
laboratory.  
If no significant findings are observed then the results of the local laboratory values (including 
reference ranges) should be included in liver eCRF to document the values.  
Blood samples for these visits may also be obtained by other methods as appropriate in a 
particular country or region and processed through the central laboratory (e.g., flying nurse, 
local phlebotomist etc.). Please follow Appendix 3 Section 15.2 guidelines of the protocol for 
liver safety monitoring for these visits. 
Blood Chemistry criteria that require permanent study drug discontinuation are listed in 
Section 5.5.9. 
Serology 
Serology testing will be performed according to Table 6-1 and will include the following (for 
documentation of serology status or for assessment of exclusion criteria): herpes simplex 
virus-1, herpes simplex virus-2, hepatitis A, B, C and E, human immunodeficiency virus 
(HIV), Epstein Barr virus (EBV), cytomegalo virus (CMV), AQP4 auto-antibodies and IFN-β 
neutralizing antibodies. Varicella-zoster virus, mumps, measles, rubella, diphtheria, tetanus, 
pertussis may also be tested in patients without evidence of immunity. Please refer to 
Appendix 3 Guidance on Vaccinations and Guidance on monitoring of patients with 
infections for guidelines based on screening serology status and for general monitoring 
guidelines. 
Endocrinology 
The following parameters will be tested for according to Table 6-1, Table 6-2 and Table 6-3: 
Insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein (IGFBP3); 
follicle stimulating hormone (3FSH) and stradiol (E-2) in girls, testosterone, LH (luteinizing 
hormone) in boys. 
Urine measurements 
Urinalysis will include urine protein, glucose, leucocytes, blood, specific gravity, pH, ketone, 
bilirubin and urobilinogen and will be obtained according to Table 6-1, Table 6-2 and Table 
6-3. 

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Assessment of Tanner stages should be performed per local practice, guided by a pediatrician 
or health care professional experienced with this assessment. The Tanner scale assesses 
physical development in children, adolescents and adults (Marshall and Tanner 1970). The 
scale defines the physical measurements of development based on external primary and 
secondary sex characteristics. Tanner staging (breast development in girls and testes size in 
boys) is important for accurate interpretation of bone age and endocrine laboratory results.  
Patients with a Tanner Stage < II are considered pre-pubertal. 
 
6.5.6 
ECG 
A standard 12-lead ECG will be obtained as follows (Table 6-1 and Table 6-3): 
• At Visit 1 to assess eligibility for study entry (all patients) 
• Visit 3 and Visit 15 during first dose monitoring of the Core and Extension Phase: two 
ECGs will be performed. The first ECG will be performed prior to the study drug 
administration and the second ECG will be performed post-dose, approximately at the end 
of the 6-hour monitoring period.  
• At any visit if a dose-increase or restart of study drug is to occur as specified in Section 
5.5.5, with first dose monitoring as above and in Appendix 2. 
• Other scheduled visits (all patients) according to Table 6-1 and Table 6-3. 
Digital ECG devices will be provided to each clinical site by the central ECG reader for the 
duration of the study. Detailed information about recording and transmission of the studies 
will be outlined in the study specific manual provided by the center reader.   
ECG criteria that require permanent study drug discontinuation are listed in Section 5.5.9. 
6.5.7 
Pulmonary Function Tests 
Pulmonary function tests evaluating FEV1, FVC and DLCO will be performed according to 
the visit schedule in Table 6-1,Table 6-2 and Table 6-3. During the study, if the patient reports 
any respiratory symptoms such as dyspnea, shortness of breath, chest tightness or wheezing, 
or pulmonary function test abnormalities, please refer to Appendix 3 for monitoring guidance.  

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The tests will be conducted in all patients who are enrolled into the study and in the manner 
consistent with the standard laboratory practice.  
Spirometry 
The technician should demonstrate the appropriate technique to the subject and follow the 
standard procedure for the pediatric population. The quality of the tests must be accounted for 
including the technicians’ comments (especially when, despite proper coaching of the subject, 
full collaboration cannot be achieved).  
A minimum of 3 acceptable maneuvers will be performed at each visit. The acceptability 
criteria are a satisfactory start of test and a satisfactory end of test. In addition, the technician 
should observe that the subject understood the instructions and performed the maneuver with 
a maximum inspiration, a good start, a smooth continuous exhalation and maximal effort. The 
largest FVC and the largest FEV1 will be recorded, after examining the data from all of the 
acceptable curves, even if the 2 values do not come from the same curve. 
For each test (FEV1, FVC, DLCO), the absolute value as well as the percent of predicted value 
will be recorded in the eCRF. FEV1/FVC ratio (expressed in %) will be calculated centrally. 
Forced expiratory volume in 1 second (FEV1) and Forced vital capacity (FVC): 
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. 
The FVC denotes the volume of gas (in Liters) that is exhaled during a forced expiration 
starting from a position of full inspiration and ending at complete expiration. This parameter 
is normal or might be slightly decreased in obstructive disease, but shows a mild to severe 
decrease in restrictive disease. 
Diffusion capacity of carbon monoxide (DLCO): 
Gas exchange is assessed by the carbon monoxide diffusing capacity (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. 
The average of at least 2 acceptable tests that meet the repeatability requirement of either 
being within 3 ml CO/min/mmHg (or 1 mmol/min/kPa) of each other or within 10% of the 
highest value should be reported. 
A DLCO test is acceptable if it fulfills all the following criteria: 
• Use of proper quality-controlled equipment  
• Inspired volume of >85% of largest vital capacity in < 4 seconds 
• A stable calculated breath hold for 10±2 seconds. There should be no evidence of leaks, or 
Valsalva, or Mueller maneuvers 
• Expiration in <4 seconds (and sample collection time <3 seconds), with appropriate 
clearance of dead space and proper sampling/analysis of alveolar gas 

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All values must be corrected for hemoglobin concentration. 
The DLCO can be expressed in both CI conventional units: ml CO/min/torr (or ml 
CO/min/mmHg), and SI units: mmol CO/min/kPa (Conversion factor: SI units x 2.986 = CI 
units).  
6.5.8 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS, a questionnaire that prospectively assesses Suicidal Ideation and Suicidal 
Behavior using a semi-structured interview to probe patient responses, must be administered 
according to Table 6-1 and Table 6-3 and also at unscheduled visits. 
If, at any time after screening and/or baseline, the score is yes” on item 4 or item 5 of the 
Suicidal Ideation section of the C-SSRS or “yes” on any item of the Suicidal Behavior 
section, the patient must be referred to a mental health care professional for further 
assessment and/or treatment. The decision on whether the study treatment should be 
discontinued is to be taken by the investigator in consultation with the mental health care 
professional to whom the patient is referred. 
The C-SSRS will be administered by an IVR system with the patient entering responses 
directly into the IVR system. For patients unable/unwilling to do so or where self-reporting by 
minors is not permitted by the local regulatory authority, and for all patients below the age of 
12, another individual (e.g. parent/other family member/caregiver/qualified site staff) will 
enter the answers to the C-SSRS questions into the IVR system on behalf of the patient. 
The investigators must review reports received from the system for any answers indicative of 
suicidal ideation and adverse events on the Visit day the questionnaire was performed and 
before the patient is discharged. Adverse events ascertained through the administration of the 
C-SSRS will be documented. 
6.6 
Pregnancy and assessments of fertility 
Females of child-bearing potential are defined as all females physiologically capable of 
becoming pregnant. This includes female children and adolescents who are menarchal or who 
become menarchal during the study.  
Serum pregnancy test will be performed by the central laboratory for all females of child-
bearing potential according to the schedule in Table 6-1 and Table 6-3. 
Although it is expected that this study will enroll mostly girls who are not sexually active, 
some may be sexually active. All menarchal girls and their parents/caregivers should be 
informed about the potential risks of pregnancy and the need to prevent pregnancy during the 
study.  
It is important to be sensitive in introducing this issue, as understanding and comprehension 
of a child about puberty, sexual activity, pregnancy and contraception varies with age. These 
discussions with the patient and her parents/caregivers are therefore best performed by 
investigators familiar with the child/adolescent and her family and are part of the circle of 
care. The investigator should also discuss the management of the pregnancy test results with 
the patient and her parents/caregivers. These discussions may vary across countries and 
regions and should be guided by requirements of the local regulatory authority.   

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Female patients of childbearing potential who are sexually active will perform a urine 
pregnancy test (e.g. via home pregnancy test kit) monthly (in the months between clinic Visits 
and serum pregnancy testing). In the event of a positive urine pregnancy test, the patient must 
immediately contact the investigator.  Additional pregnancy tests may be performed at the 
investigator’s discretion during the study. Patients becoming pregnant must discontinue study 
drug. 
Female patients of child-bearing potential must be informed of the potential teratogenic risk 
with fingolimod and the need for highly effective contraception to prevent pregnancy while 
on study drug and for 2 months after stopping study drug should they be or become sexually 
active. 
Use of a combination of any two of the following methods of contraception (a+b or a+c or 
b+c) should be used as appropriate:  
a) use of oral, injected or implanted hormonal methods of contraception 
b) placement of an intrauterine device or intrauterine system  
c) barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/vaginal suppository  
Contraception must be used during the study and for 2 months after stopping study drug. The 
decision on the contraceptive method should be reviewed at least every 3 months to evaluate 
the individual need and compatibility of the method chosen. 
6.7 
Other assessments 

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6.7.2 
Pharmacokinetics  
Blood collection and processing 
All blood samples will be taken anytime during the visit except at Visit 3 (Randomization), 
Visit 5 (Month 1) and Visit 17 (Month 1 of Extension Phase).  
At Visit 3, one blood sample will be collected before administration of the study drug (oral 
capsule), and another one approximately 6 hours post-dose (oral capsule). 
At Visit 5 and Visit 17, one blood sample will be collected at pre-dose (24 hours post last 
dose of the study drug, and before the new administration) and a second collection 
approximately 6 hours post-dose. Patients should be instructed NOT to take the dose at home 
on this day of the visit. Instead they should be asked to bring the fingolimod capsule with 
them to the visit and take it after the pre-dose sample is drawn. 
Blood samples (1.8 mL) will be collected into a sodium citrate vacuum tube, by either direct 
venipuncture or an insertion of an indwelling cannula into a forearm vein. Immediately after 
each tube of blood is drawn, it should be inverted gently several times to ensure the mixing of 
tube contents (e.g., anticoagulant). Prolonged sample contact with the rubber stopper should 
be avoided. The tube should be placed upright in a test tube rack surrounded by ice until 
transfer.  Within 30 min of blood collection the tubes must be frozen at ≤ -18°C and must be 
transferred to a ≤ -70°C freezer within 3 months of collection pending analysis. Alternatively, 
the tubes can be transferred directly to a ≤ -70°C immediately after sample collection. 
All samples will be given a unique sample number. The actual dosing date and time and 
actual sample collection date and time will be entered on the PK blood collection page of the 
eCRF. Sampling problems will be noted in the Notes field of the eCRFs. 
Blood samples will be shipped to the central laboratory on a regular basis, except those from 
Visit 5 and Visit 17 that should be sent as soon as possible after collection to allow for the 
online pharmacokinetic analysis (i.e. those samples drawn from patients with a body weight 
of 40 kg or less). 
Details on labeling of the pharmacokinetic samples and shipment instructions will be included 
in the laboratory manual provided by the Central Laboratory. 
Analytical Method 
Fingolimod and fingolimod-P will be measured in whole blood using a validated LC-MS/MS 
with a LLOQ of 0.020 ng/mL and of 0.025 ng/mL, respectively. 

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7 
Safety monitoring 
7.1 
Adverse events 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after starting the study drug even if the event is not considered to 
be related to study drug. Study drug includes the investigational drug under evaluation and the 
comparator drug or placebo that is given during any phase of the study. Medical 
conditions/diseases present before starting study drug are only considered adverse events if 
they worsen after starting study drug. Abnormal laboratory values or test results constitute 
adverse events only if they induce clinical signs or symptoms, are considered clinically 
significant, or require therapy. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or 
other assessments. All adverse events must be recorded on the Adverse Events eCRF with the 
following information: 
1. the severity grade (mild, moderate or severe) 
2. its relationship to the study drug(s) (suspected/not suspected) 
3. its duration (start and end dates or if continuing at final exam) 
4. whether it constitutes a serious adverse event (SAE) 
An SAE is defined as an event which: 
• is fatal or life-threatening  
• 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) 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug 
• 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  
• social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2. 

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All adverse events should be treated appropriately. Treatment may include one or more of the 
following: no action taken (i.e. further observation only); study drug dosage 
adjusted/temporarily interrupted; study drug permanently discontinued due to this adverse 
event; concomitant medication given; non-drug therapy given; patient hospitalized/patient’s 
hospitalization prolonged. The action taken to treat the adverse event should be recorded on 
the Adverse Event eCRF.  
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed. 
7.2 
Serious adverse event reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until 3 months after the patient has stopped study 
participation (defined as time of last dose of study drug taken or last visit whichever is later) 
must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after this 3 months period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study drug.  
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form. The investigator must assess the relationship of any SAE to study drug, complete the 
SAE Report Form in English, and send the completed, signed form by fax within 24 hours to 
the local Novartis Drug Safety and Epidemiology Department. The telephone and telecopy 
number of the contact persons in the local department of Drug Safety and Epidemiology, 
specific to the site, are listed in the investigator folder provided to each site. The original copy 
of the SAE Report Form and the fax confirmation sheet must be kept with the case report 
form documentation at the study site. 
Follow-up information is sent to the same person to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow-up to the previously reported 
SAE and giving the date of the original report. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation.  
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 Novartis study drug, a Drug Safety and 

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Epidemiology 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 drug 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 Directive 2001/20/EC or as per national regulatory requirements in 
participating countries. 
Although MS relapses are considered medically significant and are frequently associated 
with hospitalization and thus, meet the definition for SAEs, these events will be reported 
on the MS relapse eCRF instead of the SAE form unless, in the judgement of the 
investigator, a MS relapse is unusually severe or unexpected and warrants specific 
notification as an SAE. 
7.3 
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study drug must be reported to 
Novartis within 24 hours of learning of its occurrence and the study drug needs to be 
discontinued immediately. The pregnancy should be followed up to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study drug of any pregnancy outcome. Any SAE experienced 
during pregnancy must be reported on the SAE Report Form. 
7.4 
Data Monitoring Committee 
A Data Monitoring Committee (DMC) will be in place to oversee the study. The DMC will be 
an external board comprised of various specialists (also relevant to the pediatric MS 
population being studied). Details will be provided in the DMC charter.  
The DMC will be responsible for on-going review of enrollment, safety and, if requested by 
the DMC, efficacy data and will provide regular assessments on the safety and overall risk to 
benefit ratio of the study conduct, advise the sponsor of a need for protocol 
modification/amendment in order to minimize potential risk for patients, request additional 
information or make recommendation including stopping of enrollment and/or treatment, if 
needed.  
A Novartis designee will be responsible for the timely coordination and delivery of the data to 
the DMC on a regular basis. The chair of the DMC will be responsible for providing 
summaries/executive reports of each DMC meeting to Novartis, arranging on-going 
communication between members of the DMC, arranging meetings and maintaining files with 
all correspondence pertaining to the study.  

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The responsibilities of the DMC may be terminated by Novartis once safety review by the 
DMC is no longer needed. 
8 
Data review and database management 
8.1 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and eCRFs with the investigators and their staff. 
During the study, the field monitor will visit the site regularly to check the completeness of 
patient records, the accuracy of entries on the eCRFs, the adherence to the protocol and to 
Good Clinical Practice, the progress of enrollment, and to ensure that study drug is being 
stored, dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the eCRF entries. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion 
criteria, documentation of SAEs, and the recording of data that will be used for all primary 
and safety variables. Additional checks of the consistency of the source data with the eCRFs 
are performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the patients will be disclosed. 
8.2 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRFs) using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies and, 
by generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to the CRO working on behalf of Novartis. The Investigator must certify 
that the data entered into the eCRF are complete and accurate. After database lock, the 
investigator will receive a CD-ROM or paper copies of the patient data for archiving at the 
investigational site.  
8.3 
Database management and quality control 
Novartis staff review the data entered into the eCRFs by investigational staff for completeness 
and accuracy and instruct the site personnel to make any required corrections or additions. 
Queries are sent to the investigational site using an electronic data query. Designated 
investigator site staff is required to respond to the query and confirm or correct the data.  

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Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). 
ECG and CSSRS readings/values will be processed centrally and the results will be sent 
electronically to Novartis (or a designated CRO). 
MRI scans will be processed centrally and the results will be sent electronically to Novartis. 
Randomization codes and data about all study drug(s) dispensed to the patient and all IVR 
recorded dosage changes will be tracked using an Interactive Response Technology (IRT). 
The system will be supplied by a vendor, who will also manage the database. The database 
will be sent electronically to Novartis. 
The occurrence of any protocol deviations will be determined. After these actions have been 
completed and the database has been declared to be complete and accurate, it will be locked 
and made available for data analysis. Any changes to the database after that time can only be 
made by joint written agreement between the Global Head of Clinical Information Sciences 
and the Clinical Franchise Head. 
9 
Data analysis 
The statistical models specified in this section may be modified by including fewer covariates 
in the models in case the pre-specified models do not converge. 
9.1 
Analysis sets 
Core Phase: 
All screened subjects (SCR): The SCR set comprises all subjects who were screened. The 
SCR will be used only for the summary of screening failures. 
Randomized set (RAN): The RAN set comprises all subjects who were assigned a 
randomization number. The RAN will be used for the summaries of subject disposition, 
protocol deviation, demographic, baseline characteristics, and medical history data. 
Full Analysis Set (FAS): The FAS comprises all randomized subjects with assigned 
treatments who took at least one dose of study medication. Subjects will be analyzed 
according to the randomized treatment assignment following the intention-to-treat principle, 
even if they actually received a different treatment. The FAS will be used for all efficacy 
analyses. 
Per-protocol set: Consists of all patients in the full-analysis set who do not have any major 
protocol deviations that could confound the interpretation of analyses conducted on the FAS. 
Major protocol deviations will be determined according to the predefined protocol deviation 
criteria before treatment unblinding. Any efficacy data after study drug discontinuation will 

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be excluded. The per-protocol set will only be used for the supportive analyses of the primary 
efficacy variable. 
Safety Set: The safety set includes all patients who received at least one dose of study 
medication. Subjects will be analyzed according to the actual treatment received. The Safety 
Set will be used for all safety analyses. 
Fingolimod Extension Phase: 
Extension Phase enrolled set: Includes all patients who were enrolled in the Extension Phase, 
whether or not they actually took any extension study medication. The Extension Phase 
enrolled set will be used for the summaries of subject disposition, protocol deviations, 
demographic, baseline characteristics, and medical history data. 
Extension Phase FAS: All patients who entered the Extension Phase and received at least one 
dose of extension study medication. Patients will be analyzed according to the randomized 
treatment in the Core Phase. This analysis set will be used for all within-group efficacy 
analyses. 
Fingolimod Treated FAS: All patients who received at least one dose of fingolimod (in the 
Core Phase for those who were randomized to fingolimod or in Extension Phase for those 
who were randomized to interferon β-1a in the Core Phase and switched to fingolimod in the 
Extension Phase). Patients will be analyzed according to the randomization treatment 
assignment in the Core Phase. This analysis set will be used for all long-term efficacy 
analyses. 
Fingolimod Treated Safety Set: All patients who received at least one dose of fingolimod (in 
the Core Phase for those who were randomized to fingolimod or in Extension Phase for those 
who were randomized to interferon β-1a in the Core Phase and switched to fingolimod in the 
extension phase). Patients will be analyzed according to the actual treatment received in the 
Core Phase. This population will be used for overall exposure to study medication, long-term 
safety analyses and first dose administration summaries. 
9.2 
Patient demographics and other baseline characteristics  
Patient demographics and other baseline characteristics, including Tanner stage, will be 
summarized using frequency distributions (for categorical variables) and descriptive statistics 
of mean, standard deviation, minimum, median and maximum (for continuous variables). 
Background information includes prior medication, past/current medical conditions, duration 
of the disease, pre-baseline relapse rate, baseline MRI assessments and baseline EDSS. 
9.3 
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance) 
The duration (days) of exposure to study medication will be summarized by treatment group. 
Frequency distributions will be used to summarize patient disposition and reasons for 
discontinuation of study medication. Patients who prematurely discontinue the study 
medication will be listed along with the reason for discontinuation. The cumulative 
corticosteroid dose used after start of study medication for the treatment of multiple sclerosis 

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relapses will be summarized by treatment group in dose equivalent to prednisone (the 
conversion factors will be detailed in the statistical analysis plan). The cumulative duration of 
the corticosteroid use will be summarized similarly. The number of study drug capsules and 
syringes returned will be summarized by visits as a measure of compliance.  
9.4 
Analysis of the primary variable(s) 
Core Phase: 
The primary analysis pertaining to the primary efficacy objective will be based on the Full 
Analysis Set (FAS), following the intention-to-treat principle.  
9.4.1 
Variable 
The primary efficacy variable is the annualized relapse rate (ARR), which is defined as the 
average number of confirmed relapses per year (i.e., the total number of confirmed relapses 
divided by the total days in the study multiplied by 365.25).  For the primary analysis, the 
number of relapses will include all the confirmed relapses experienced during the study. The 
time spent in the study will correspond to the observation period for all the relapses from first 
dose on study drug to end of study. 
9.4.2 
Statistical model, hypothesis, and method of analysis 
The null hypothesis for the primary analysis states that: there is no reduction in the annualized 
relapse rate (ARR) in the patients treated with fingolimod compared to the ARR in patients 
treated with IFN β-1a, while the alternative hypothesis states there is a reduction in the ARR 
in fingolimod treated patients.  
The test of the hypotheses will be based on a negative binomial regression model with log 
link, using treatment, number of relapses in the previous two years prior to screening, pubertal 
status, and region as covariates. Study centers are consolidated by country. In order to 
minimize the impact of low-enrolling countries on the analysis (such as non-convergence of 
the analysis model), countries will be pooled into regions based on geographical proximity. 
Details will be provided in the statistical analysis plan prior to database lock.   
The response variable for this analysis is the number of confirmed relapses for each patient, 
and the quadratic variance estimate will be used. The natural log of (time in study for each 
patient) will be used as the offset to account for the varying lengths of patients’ time in the 
study. The null hypothesis will be rejected if the observed p-value is less than the significance 
level of 0.05. 
Model-based estimates of the ARR (aggregated over each treatment group) and its 95% 
confidence intervals, ARR ratio and its 95% confidence intervals and p-value comparing 
fingolimod vs. IFN β-1a will be provided. 
9.4.3 
Handling of missing values/censoring/discontinuations 
All patients in the FAS will be included in the primary analysis, i.e., the number of confirmed 
relapses observed up to the end of patient’s participation in the study. Relapses will be 
counted regardless of whether a patient is on or off study drug. Therefore it is expected that all 

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randomized patients can contribute to the primary analysis. The primary analysis model 
adjusts for missing information (early study discontinuations) under some statistical 
assumptions (non-informative dropouts and constant ARR).  
9.4.4 
Supportive analyses 
To assess the impact of study drug discontinuation to the results observed, a supplementary 
analysis using the same negative binomial model as in the primary analysis to be performed 
on relapses on study drug (i.e., relapses will be counted only up to study drug discontinuation) 
in the  per-protocol set will be performed. 
A supplementary analysis using the same negative binomial model as in the primary analysis 
to be performed on all relapses (i.e., confirmed and unconfirmed relapses) in the full-analysis 
set will be performed. Additional analyses to further assess the robustness of the results 
maybe pre-specified in the statistical analysis plan for the overall population 
 
 
9.5 
Analysis of secondary variables 
9.5.1 
Key secondary variable(s) 
Core Phase: 
The key secondary variable is the annualized rate of the number of new/newly enlarged T2 
lesions (n/neT2) from baseline to end of the study, with duration up to 24 months. 
The null hypothesis for the key secondary analysis states that: there is no reduction in the 
neT2 lesion rate in patients treated with fingolimod 0.5 mg compared to patients treated with 
IFN β-1a, while the alternative hypothesis states there is a reduction in the neT2 lesion rate, in 
fingolimod 0.5 mg treated patients.  
The test of the hypotheses will be based on a negative binomial regression model adjusted for 
treatment, pubertal status, number of T2 lesions at baseline and region. The natural log of 
(years in study for each patient) will be used as the offset. 
For the key secondary analysis, there will be no imputations for missing data. The response 
variable for this analysis is the cumulative number of n/neT2 lesions based on the End of 
Study Core Phase MRI scan, for each patient. The quadratic variance estimate will be used 
and the natural log of time (in years) from randomization to the End of Study-Core Phase 
MRI assessment date for each patient will be used as the offset to account for the varying 
lengths of patients’ time in study.  
The above null hypothesis will be rejected if the observed p-value for treatment comparison 
(based on the n/neT2 rate ratio) is less than the significance level of 0.05. Model-based 
estimates of annualized rate of the number of n/neT2 lesions and their 95% confidence 
intervals, estimate of the n/neT2 annualized rate ratio (i.e., relative treatment effect) and its 
95% confidence intervals and p-value for comparing fingolimod vs. IFN β-1a i.m. will be 
provided.   

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Summary statistics (mean, standard deviation, median, minimum and maximum) of the 
number of n/neT2 will also be provided. 
Additional sensitivity analyses may be considered to further assess the robustness of the 
results.  
Key efficacy variables data will be summarized for the overall population 
 
 
9.5.2 
Efficacy variables 
Core Phase: 
Secondary and exploratory efficacy variables will be summarized by visit. Descriptive 
statistics (mean, standard deviation, median, minimum and maximum) will be provided for 
variables that are of the numeric or continuous type, while frequency distributions (with 
number and percent) will be provided for variables that of the categorical type. 
P-values for the treatment comparisons will be provided. Each inferential analysis will be 
performed at a significance level of 0.05 with no adjustment for multiple analyses. 
Secondary and 
 efficacy variables that are of the continuous or numeric type (such 
as the number of Gd-enhanced T1 lesions per scan, 
 
will be analyzed via a negative 
binomial regression model adjusted for treatment, pubertal status, region, and relevant 
baseline value. 
The volume of Gd-enhanced T1 lesions, change from baseline in T2 hyperintense and 
 
 lesion volume on MRI and percent brain volume change from baseline will be 
analyzed via a rank ANCOVA model adjusted for treatment, pubertal status, region and 
relevant baseline values.  The percent brain volume change from baseline will also analyzed 
via an ANCOVA model with similar factor and covariates.   
Time to event variables (such as the time to first confirmed relapse up to end of study-Core 
Phase) will be analyzed using the log-rank test (for comparing event-time distributions). In 
addition, a Cox regression model adjusted for treatment, number of relapses in the previous 
two year before study enrollment, pubertal status, and region will also be performed. 
Estimates of the hazard ratio and its 95% confidence intervals, and the p-value for treatment 
comparison from the Cox model will be provided.  The Kaplan-Meier estimates of time to 
event variables and the relapse-free proportions at Month 24 will also be provided.  
Fingolimod Extension Phase: 
To examine long-term efficacy of continuous fingolimod treatment vs interferon β-1a switch 
to fingolimod treatment, the following endpoints will be analyzed by Core Phase treatment 
assignment and combined based on Fingolimod Treated FAS if not otherwise specified.   
The efficacy variables will be summarized by visit or yearly intervals for the patients with 
continuous fingolimod treatment and the patients switched from IFN β-1a to fingolimod 
treatment. Descriptive statistics (mean, standard deviation, median, minimum and maximum) 

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will be provided for variables that are of the numeric or continuous type, while frequency 
distributions (with number and percent) will be provided for variables that are of the 
categorical type. 
Nominal p-values will be provided as a measure of the strength of effect without declaring 
statistical significance. 
ARR and time to relapse 
The same negative binomial regression as used in the Core Phase (described in Section 9.4.2) 
will be employed for analyzing relapse rate. From this negative binomial model, ARR (95% 
CI) from Day 1 on fingolimod in Core Phase to end of the study (Core Phase and/or Extension 
Phase) will be obtained for the continuous fingolimod treatment and from Day 1 on 
fingolimod in the extension phase to end of the study for the IFN β-1a switch to fingolimod 
treatment; the ARR ratio (95% CI) and p-values for comparing the two treatment groups will 
also be reported.  In addition, ARR will be analyzed by yearly intervals.  
The Kaplan-Meier estimates (95% CI) of time to first relapse at Month 60 of Extension Phase 
will be provided for the continuous fingolimod treatment and the IFN β-1a switch to 
fingolimod treatment groups.  
To further examine the fingolimod treatment effect on ARR reduction in patients who were 
treated with IFN β-1a in the Core Phase, a within group comparison will be done for patients 
switching from IFN β-1a to fingolimod based on Extension Phase FAS.  A Poisson model 
with repeated measures having main effects for study phase (Core Phase, Extension Phase), 
number of relapses in the previous two year prior to Screening, pubertal status at core 
baseline, and region will be employed using generalized estimating equations. An 
exchangeable working correlation structure will be assumed to address the within subject 
repeated measures (i.e., measurements from Core Phase and Extension Phase). In addition, a 
robust variance estimator will be used to address any extra Poisson variability (i.e., over-
dispersion) that may exist. The natural log of years in the corresponding study phase for each 
patient will be used as the offset.  The ARR (95% CI) and ARR ratio (95% CI) defined as the 
ratio of the ARR estimates for the extension phase relative to the core phase will be presented 
along with the corresponding nominal p-value.  
 MRI endpoints 
The annualized rate of new/newly enlarged T2 lesion (n/neT2) (95% CI), rate ratio (95% CI), 
and nominal p-value for treatment comparison will be provided using the same negative 
binomial model as specified in Section 9.5.1. 
Other MRI endpoints, including patients free of new or newly enlarged T2 lesions, the 
number of Gd-enhanced T1 lesions, patients free of Gd-enhanced T1 lesions, 
 
 volume of Gd-enhanced T1 lesions, 
 
 and percent brain volume change, will be analyzed by visit using 
the same method as planned for the Core Phase.  

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9.5.3 
Safety variables 
Core Phase: 
All safety analyses will be conducted on data from the Safety Analysis set. The assessment of 
safety will be based mainly on the incidence of adverse events and on the incidence of 
clinically notable laboratory abnormalities. Other safety assessments will include laboratory 
data summaries, vital signs, bradycardia events, pulmonary function tests, ophthalmic, and 
ECG data. 
Adverse events will be summarized by presenting, for each treatment group, the number and 
percentage of patients having any adverse event by primary system organ class and preferred 
term. 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. Notable 
events will include death, non-fatal SAEs (including infections) and AEs (including 
infections) leading to discontinuation from the study. The summary will be tabulated by 
treatment group. The incidence rate (adjusted by treatment duration i.e., incidence rate per 
100-patient years) will also be provided for any AE by system organ class and preferred term. 
Laboratory data will be summarized by presenting summary statistics of raw data and change 
from baseline values, by presenting shift tables using clinically notable ranges (baseline to 
most extreme post-baseline value), and by flagging notable values in data listings. For liver 
function tests, the frequencies and percentages of patients with elevations of 1, 2, 3, 5, and 8 
times upper limit normal will be summarized by visit and treatment group. 
The incidence of patients with neutralizing antibodies (Nabs) to IFN at EOS-CP will be 
summarized by treatment group.  
Vital sign data will be summarized by presenting summary statistics for change from baseline 
values (both for the period 6 hours post first dose and for further assessments). The incidence 
of post-baseline notable vital sign abnormalities will be summarized. Further, the frequency 
distribution for pulse by visit and the frequency distribution for percent decline in pulse 
during first 6 hours will be presented. 
 
 
 
Pulmonary function test (PFT) data will consist of the following parameters: FEV1, FVC, and 
DLCO. Summary tables and listings will be produced for percentage of predicted value when 
applicable. For the purpose of the statistical analysis the percentage of predicted value will be 
calculated centrally and this centrally calculated value will be used for the study level 
analysis. The data will be summarized by presenting summary statistics of change from 
baseline. The frequency of patients who had PFT measurements below 80% of predicted, and 
shift tables presenting the frequency of patients with normal (≥80% of predicted when 
applicable) and abnormal (< 80% of predicted when applicable) will be presented. 

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The ophthalmic data will be summarized using the distribution tables, summary statistics, and 
change from baseline by visit and treatment group for visual acuity, OCT, and other 
ophthalmic parameters. The patient listing with these parameters will also be provided. 
ECG intervals will be summarized by presenting summary statistics for change from baseline 
values by visit. The (uncorrected) QT interval will be corrected according to the Bazett’s and 
Fridericia formulae. Maximum increase in corrected QT interval from baseline will be used to 
summarize the frequencies of patients who fulfill the abnormality criteria based on the 
corrected QT interval will be calculated. 
Frequency distribution of treatment-emergent suicidal ideation and behaviors from C-SSRS 
will be summarized. The proportion of patients who have completed suicide, suicide attempt, 
and preparatory actions toward imminent suicidal behavior, suicidal ideation, and self-
injurious behavior without suicidal intent will be summarized by treatment group.  
Safety data will be summarized for the overall population and listings provided for the pre-
pubertal subgroup. 
Follow-up data will be summarized to assess patients’ safety after discontinuation of the study 
drug. 
Fingolimod Extension Phase: 
All safety endpoints, including adverse events (adjusted by the duration of fingolimod 
exposure), bradycardia events, laboratory tests, vital signs, pulmonary function tests, 
ophthalmic examinations, C-SSRS,  ECG data, and 
  will 
also be summarized based on the long-term safety data during fingolimod treatment , by core 
treatment and combined using the Fingolimod Treated Safety Set. 
 
 
9.5.5 
Pharmacokinetics 
Online pharmacokinetics 
All patients who have a body weight of 40 kg or less at study entry in the Core or Extension 
Phase will have samples taken at Month 1 of the Core Phase and/or Extension Phase, 
respectively for on-line pharmacokinetic analysis. Only patients in the fingolimod group in 

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the Core Phase or patients switched from interferon b-1a to fingolimod in the Extension Phase 
will have their samples analyzed. 
The Month 1 Core Phase and/or Extension Phase pharmacokinetic samples from all patients 
treated with fingolimod weighing 40 kg or less will be evaluated for dose optimization (need 
for increase to 0.5 mg). These samples will be analyzed within one month (online analysis) to 
ensure the systemic exposure is adequate. The results should be available for the Month 2 
Core Phase and/or Extension Phase visit where the dose adjustment, if needed, would take 
place.  
The pre-dose concentration at Month 1 Core Phase and/or Extension Phase and the 
approximately 6-hour post-dose concentration (good marker of fingolimod-P peak 
concentration), will be averaged to provide a surrogate for the average concentration (Cav).  
If in a patient weighing 40 kg or less, who has been receiving 0.25 mg/day fingolimod, Cav is 
greater than 65% of target concentration of 1.35 ng/mL, i.e. 0.9 ng/mL, the patient will 
continue on the 0.25 mg dose. If in such a patient Cav is smaller than 65% of the target 
concentration i.e. smaller than 0.9 ng/mL, the dose will be increased to 0.5 mg/day.   
Population pharmacokinetic analysis 
Core Phase: 
A population pharmacokinetic analysis will be used to characterize the key pharmacokinetic 
parameters in this patient population. Additionally, this analysis will also determine whether 
there are population covariates that affect the pharmacokinetics of fingolimod-P when 
administered to this patient population.  
The effect of covariates on pharmacokinetic parameters will be explored. Covariates 
examined will include age, weight, gender, and ethnicity, as well as comedications such as 
oral ketoconazole which has been shown to interact with fingolimod or fingolimod-P in adults 
(increase in fingolimod and fingolimod-P plasma concentrations). The choice of covariates to 
be included in the model will be guided by exploratory plots of random effects (inter-
individual variability parameters) against covariates. Those that are judged to show evidence 
of a relationship with the random effects will be tested for entry into the model, using the 
likelihood-ratio test with p < 0.05. The final covariate model will be derived using a rigorous 
and acceptable model building procedure.  
Population pharmacokinetic/pharmacodynamic analysis 
Core Phase: 
Population PK/PD modeling approaches will be used to relate the individual fingolimod PK 
parameter estimates to key efficacy measurements (MRI-related, relapse-related). A modeling 
plan will be prepared before final clinical data lock providing details for the proposed PK/PD 
analysis. 

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9.6 
Sample size calculation 
Core Phase: 
The sample size calculations are based on the primary efficacy variable, the annualized 
relapse rate (ARR). The sample size calculations and power considerations follow the method 
outlined in Keene et al, 2007 with a constant dispersion parameter k and were programmed 
manually using the SAS software. 
Different scenarios of the anticipated treatment effect between fingolimod 0.5 mg versus IFN 
β-1a, have been evaluated based on the available data on fingolimod and on IFN β-1a in the 
Phase III program in adults. In the TRANSFORMS study (FTY720D2302), a double-blind, 
one-year study, fingolimod 0.5 mg was directly compared to interferon beta-1a i.m. The ARR 
(0.21) in patients treated with fingolimod 0.5 mg was reduced by 52% compared to the ARR 
(0.43) in patient treated with IFN beta-1a.  
The initial assumptions for this study (based on adult patient data) are as follows:  Assuming a 
50% relative reduction (from 0.72 to 0.36) in the relapse rate over 24 months (ARR: λ1=0.18 
for fingolimod, λ2=0.36 for interferon beta-1a), a sample size of 95 patients per treatment 
group (or 190 total) would be needed for a 24-months study in order to provide 80% statistical 
power to detect such a reduction at a two-sided alpha level of 0.05 (with dispersion parameter 
of k=0.82). This corresponds to information I= 16.36 (equation 2 in Appendix 5).  
The study duration can be revised based on BSSR; the power for the primary statistical test 
will be retained at 80%. 
BSSR and End of Study: 
Analysis based data reviews of the aggregate relapse data will be conducted to re-estimate the 
amount of information (I) generated by the study based on the relapse activity (λ) of the 
recruited patient population and the observed dispersion parameter (κ) in the accumulated 
study data. All patients will be treated as one group, and the treatment code will not be 
revealed in the process. Such BSSR’s provide an adequate means to check assumptions that 
were made at the planning stage of a clinical study protocol. They do not pose a scientific risk 
in terms of bias or type-I-error control and can be used to modify the sample size or study 
duration if this is indicated by the results. 
Designs which provide the same amount of information also provide the same power (for a 
constant treatment effect, λ1/λ2, and alpha). As in a BSSR (Friede and Schmidli 2010), fitting 
a negative binomial model to the aggregate data (i.e., the relapse data of all patients 
combined) provides an estimate of the overall ARR λ and the dispersion parameter κ. For an 
assumed rate ratio (clinically meaningful difference of 50%) of θ = λ1/λ2, estimates can be 
obtained of the ARRs in the two groups, λ1 = 2*λ*θ /(1+θ) for fingolimod, and λ2=2*λ/(1+ θ) 
for interferon beta-1a.  Based on the estimated values from the BSSR, the information (I) can 
be determined as follows (see equation 3 Appendix 5). 
Information Ireview = [2/ (λ1 Ttotal ) + 2/(λ2 Ttotal ) + 4 κ T2total/Ttotal2  ]-1   
 
where λ1, λ2, and κ are the re-estimated values assuming a rate ratio=50% at the BSSR. 

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• If the Information from the BSSR ensures that the targeted 80% power for the 
primary analysis is maintained, then the Core Phase of the study will complete. It 
means that the study has collected equivalent or more information than initially 
planned (≥80% power for the primary objective of the study). All patients can roll over 
into the Extension Phase.  
• 
 
 
 
 
 
 
• Any data collected during follow up period but after the Core Phase data base lock 
will be reported in the Extension Phase.   
Fingolimod Extension Phase: 
The sample size for the Extension Phase can only be estimated on the basis of expected drop-
out rate in the Core Phase.  Assuming the drop-out rate to be 15%, we can expect to have 
approximately 162 patients eligible for the Extension Phase. 
9.7 
Power for analysis of key secondary variables 
Core Phase: 
For a 24-month study and assuming a fingolimod rate of n/neT2 lesions over 24 months of 2.3 
a sample size of 95 per treatment group (or 190 total) will provide approximately 88% 
statistical power to detect a relative reduction of 50% (i.e., from 4.6 to 2.3) in the fingolimod 
group compared to the interferon beta-1a group. This sample size calculation assumes that the 
number of n/neT2 lesions over 24 months follows a negative binomial distribution. A negative 
binomial dispersion estimate of 2.0 was assigned which is within the 95% confidence interval. 
Using the same assumptions as above with a dispersion estimate of 2.67 will provide 
approximately 79% statistical power to detect a relative reduction of 50% (i.e., from 4.6 to 
2.3) in the fingolimod group. These estimates were based on the FREEDOMS study 
(FTY720D2301).   
As illustrated by the above sample size calculations, sample size requirements for the n/ne T2 
endpoint are lower than those for the primary endpoint. It is therefore assumed that the power 
for the key secondary endpoint can be maintained at ≥80% even if the study duration is 
revised based on the results from the BSSR. 
9.8 
Interim analyses 
Interim analyses for the Data Monitoring Committee (DMC) may be performed (see Section 
7.4). 

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10 
Ethical considerations 
10.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki. 
10.2 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative of the patient. 
In cases where the patient’s representative gives consent, the patient should be informed about 
the study to the extent possible given his/her understanding. If the patient is capable of doing 
so, he/she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. Informed consent must be obtained before 
conducting any study-specific procedures (i.e. all of the procedures described in the protocol). 
The process of obtaining informed consent should be documented in the patient source 
documents.  
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval. 
Females 16 years or older, or in case there is a concern that a female patient of child-bearing 
potential is or might become sexually active, as assessed by the investigator, the patient and 
her parents/caregivers should be informed about the potential risks of pregnancy and the need 
to prevent pregnancy during the study. Please also refer to Section 6.6.  
Females of childbearing potential who are or might become sexually active, should also be 
informed that taking the study drug 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 requirement for the duration of the study.  If there is any question that the 
patient will not reliably comply, they should not be entered in the study. 
10.3 
Responsibilities of the investigator and IRB/IEC 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC) before study start. A signed and dated statement that the protocol and 
informed consent have been approved by the IRB/IEC must be given to Novartis before study 
initiation. 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 

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and records to Novartis monitors, auditors, Novartis Clinical Quality Assurance 
representatives, designated agents of Novartis, IRBs/IECs/REBs, 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. 
10.4 
Publication of study protocol and results 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results. 
11 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
trial to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the 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 it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR. 
11.1 
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. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such 
cases, Novartis should be notified of this action and the IRB/IEC at the study site should be 
informed within 10 working days. 

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12 
References (available upon request) 
Banwell, B. Bar-Or A, Giovannoni G, et al. (2011) Therapies for multiple sclerosis: 
considerations in the pediatric patient. Nature Reviews Neurology, 7; 109–122. 
Banwell B, Shroff M, Ness JM, et al (2007) MRI features of pediatric multiple sclerosis. 
Neurology; 68(Suppl 2):S46-53.  
Benson LA, Healy BC, Gorman MP, et al (2014) Elevated relapse rates in pediatric compared 
to adult MS persist for at least 6 years. Mult Scler Relat Disord; 3(2):186-93.  
Banwell B, Tremlett H (2005). Coming of age: The use of immunomodulatory therapy in 
children with multiple sclerosis. Neurology; 64(5):778-779.  
Boiko A, Vorobeychik G, Paty D, et al (2002) Early onset multiple sclerosis – A longitudinal 
study. Neurology; 59:1006-1010. 
Bousquet J, Mantzouranis E, Cruz AA, et al (2010) Uniform definitions of asthma severity, 
control and exacerbations: Document presented for the World Health Organization 
Consultation on Severe Asthma. J Allergy Clin Immunol; 126(5):926-938. 
CDC (2012) Mumps: Chapter 9. VPD Surveillance Manual. 5th Edition: 1-18. 
CDC (2013) Prevention of Measles, Rubella, Congenital Rubella Syndrome, and Mumps. 
Morbidity and Mortality Weekly Report (MMWR); 62(RR04):1-34. 
Chitnis T, Glanz B, Jaffin S, et al (2009) Demographics of pediatric-onset multiple sclerosis 
in an MS center population from the Northeastern United States. Mult Scler; 15(5):627-631. 
Chitnis T, Tardieu M, Amato MP, et al (2013). International Pediatric MS Study Group 
Clinical Trials Summit: Meeting report. Neurology; 80:1161–1168. 
Cohen JA, Barkhof F, Comi G, et al (2010) Oral fingolimod or interferon for relapsing 
multiple sclerosis. N Engl J Med; 362(5):402-415. 
De Sá J, Paulos A, Mendes H, et al (2006) The prevalence of multiple sclerosis in the District 
of Santarém, Portugal. J Neurol; 253(7):914-918. 
Friede T, Schmidli H, (2010) Blinded Sample Size Reestimation with Negative Binomial 
Counts in Superiority and Non-inferiority Trials. Methods Inf Med; 6: 618-624. 
Gadoth N (2003) Multiple sclerosis in children. Brain Dev; 25(4):229-232. 
Ghezzi A, Banwell B, Boyko A, et al (2010) The management of multiple sclerosis in 
children: a European view. Mult Scler; 16(10):1258-1267.  
Ghezzi A, Pozzilli C, Grimaldi LME, et al (2010) Safety and efficacy of natalizumab in 
children with multiple sclerosis. Neurology; 75(10):912-917. 
Jacobs LD, Beck RW, Simon JH, et al (2000) Intramuscular interferon beta-1a therapy 
initiated during a first demyelinating event in multiple sclerosis.  CHAMPS Study Group. N 
Engl J Med; 343(13):898-904. 

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Kappos L, Freedman MS, Polman CH, et al (2007) Effect of early versus delayed interferon 
beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-
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in relapsing multiple sclerosis. N Engl J Med; 362(5):387-401. 
Kearns GL, Abdel-Rahman S, Alander SW, et al (2003) Developmental Pharmacology-drug 
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Krupp LB, Tardieu M, Amato MP, et al (2013) International Pediatric Multiple Sclerosis 
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Kuntz  NL, Chabas D, Weinstock-Guttman B, et al (2010) Treatment of multiple sclerosis in 
children and adolescents. Expert Opin Pharmacother; 11(4):505-520. 
Lurbe E, Cifkova R, Cruickshankd JK, et al (2009) Management of high blood pressure in 
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Dis Child; 45(239):13-23. 
McDonald WI, Compston A, Edan G, et al (2001) Recommended diagnosis criteria for 
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10th May 2012. 
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beta-1a treatment regimens in MS: The EVIDENCE Trial. Neurology; 59(10):1496-1506. 
Pinhas-Hamiel O, Sarova-Pinhas I, Achiron A (2001) Multiple sclerosis in childhood and 
adolescence: clinical features and management. Paediatr Drugs; 3(5):329-336. 
Pohl D, Waubant E, Banwell B, et al (2007) Treatment of pediatric multiple sclerosis and 
variants. Neurology; 68(16 Suppl 2):S54-65. 
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Polman CH, Bertolotto A, Deisenhammer F, at al. (2010) Recommendations for clinical use 
of data on neutralizing antibodies to interferon-beta therapy in multiple sclerosis. Lancet 
Neurol; 9: 740–50. 
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childhood onset. N Engl J Med; 356(25):2603-2613. 
Ruggieri M, Pollizi A, Pavone L, et al (1999) Multiple sclerosis in children under 6 years of 
age. Neurology; 53(3):478-484. 
Ruggieri M, Iannetti P, Polizzi A, et al (2004) Multiple sclerosis in children under 10 years of 
age. Neurol Sci; 25 (Suppl 4):S326-335.  
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Children and Adolescents (2005) US. Department of Health and Human Services. NIH 
Publication No. 05-5267. 
Trojano M, Liguori M, Boscoe Zimatore G, et al (2002) Age related disability in multiple 
sclerosis. Ann Neurol; 51(4):475-480. 
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Children and Evaluation of Alkaline Phosphatase z-scores in Different Types of Rickets. J 
Clin Res Ped Endo; 3(1):7-11 
Venkateswaran S, Banwell B (2010) Pediatric multiple sclerosis. Neurologist; 16(2):92-105. 
Weinshenker BG, Bass B, Rice GP, et al (1989a) The natural history of multiple sclerosis: a 
geographically based study. I. Clinical course and disability. Brain; 112(Part 1):133-146. 
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Waubant E, Chabas D, Okuda DT, et al (2009) Difference in disease burden and activity in 
pediatric patients on brain magnetic resonance imaging at time of multiple sclerosis onset vs 
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neuromyelitis optica. Neurology; 66: 1485-1489. 
Yeh EA, Chitnis T, Krupp L, et al (2009) Pediatric multiple sclerosis. Nat Rev Neurol; 
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With Refractory Multiple Sclerosis. Archives Neurology; 68(4): 437-444. 

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13 
Appendix 1: Clinically notable laboratory values and vital 
signs 
The clinically notable laboratory and vital sign values to be used for this study are listed 
below. 
Table 13-1 
Hematology and blood chemistry notable values 
Hematology 
Less Than 
Greater Than 
Hemoglobin 
10 g/dL 
20 g/dL 
Hematocrit 
30 vol% 
60 vol% 
RBCs 
3,300,000/mm3 
6,800,000/mm3 
WBCs 
3000/mm3 
15,000/mm3 
Granulocytes (Poly, neutrophils) 
1000 mm3 
 
12000/mm3 
 
Lymphocytes 
200 mm3 
 
8000 mm3 
 
Platelets 
100,000/mm3 
600,000/mm3 
Chemistry 
 
 
Glucose 
70 mg/dL 
120 mg/dL (fasting) 
200 mg/dL (random) 
Calcium 
7.5 mg/dL 
11.6 mg/dL 
Sodium 
130 mEq/L 
150 mEq/L 
Potassium 
3.0 mEq/L 
5.2 mEq/L 
Chloride 
85 mEq/L 
119 mEq/L 
BUN 
2 mg/dL 
30 mg/dL 
Creatinine 
0.2 mg/dL 
1.6 mg/dL 
Total bilirubin 
0 mg/dL 
1.2 mg/dL 
SGOT (AST) 
0 U/L 
100 U/L 
SGPT (ALT) 
0 U/L 
110 U/L 
GGT 
0 U/L 
120 U/L 
LDH 
0 U/L 
500 U/L 
Alkaline Phosphatase* 
10 -<13 years  
13 - < 16years 
16 -<18 years 
18 years and above 
 
42 U/L (m) / 51U/L (f) 
74U/L (m) / 50 U/L (f) 
52 U/L (m) / 47 U/L (f) 
37 U/L (m) / (f) 
 
362 U/L (m) / 332 U/L (f) 
390 U/L (m) / 162 U/L (f) 
171 U/L (m) / 119 U/L (f) 
116 U/L (m) / (f) 
Total Protein 
4.0 g/dL 
9.5 g/dL 
Albumin 
2.5 g/dL 
6.0 g/dL 
Uric Acid 
1.5 mg/dL 
10.0 mg/dL 
*Normal ranges according to NIH Clinical Centre [http://cclnprod.cc.nih.gov/dlm/testguide.nsf; 10th May 
2012 

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Table 13-2 
Urinalysis clinically notable values 
Parameter 
Abnormality 
WBC 
>5 
RBC 
>5 
Protein 
+ or greater* 
Glucose 
+ or greater* 
* Trace should proceed +, otherwise ++ or greater 
 
Table 13-3 
Vital sign clinically notable values 
Vital Sign 
Age group 
Notable criteria 
Heart Rate 
<12 years 
>130 bpm or increase of ≥15 
bpm from baseline 
Or 
 
 
<70 bpm or decrease of ≥15 
bpm from baseline 
 
≥12 years 
>120 bpm or increase of ≥15 
bpm from baseline 
Or 
 
 
<50 bpm or decrease of ≥15 
bpm from baseline 
Systolic Blood Pressure 
<12 years 
≥125 mmHg or increase of ≥20 
mmHg from baseline 
Or 
 
 
<70 mmHg or decrease of ≥20 
mmHg from baseline 
 
≥12 to <18 years 
≥160 mmHg or increase of ≥20 
mmHg from baseline 
Or 
 
≥12 years 
<90 mmHg or decrease of ≥20 
mmHg from baseline 
 
≥18 years 
≥180 mmHg or increase of ≥20 
mmHg from baseline 
Diastolic Blood Pressure 
<12 years 
≥85 mmHg or increase of ≥15 
mmHg from baseline 
Or 
 
 
<50 mmHg or decrease of ≥15 
mmHg from baseline 
 
≥12 to <18 years 
≥95 mmHg or increase of ≥15 
mmHg from baseline 
Or 
 
≥12 years 
<50 mmHg or decrease of ≥15 
mmHg from baseline 
 
≥18 years 
≥105 mmHg or increase of ≥15 
mmHg from baseline 
 
Temperature 
 
>38.3 °C  or a change of 1.1 °C 

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Vital Sign 
Age group 
Notable criteria 
from baseline 
Weight 
 
≥7% decrease from baseline 
weight  
14 
Appendix 2: Guidelines for first dose monitoring 
Patients must have their first intake/injection of study drug in the Core and Extension Phase at 
the site and monitored by the independent First-dose Administrator.  An ECG must be 
obtained and evaluated prior to the first dose of study drug and 6 hours after. Baseline or pre-
dose ECG should be available for comparison to the post-dose ECG. Sitting heart rate and 
blood pressure must be measured prior to the first dose of the study drug and then every hour 
for at least 6 hours thereafter.  
When obtaining the sitting heart rate the patient should be allowed to rest for 5 minutes. Prior 
to the first dose of study drug, the sitting heart rate and blood pressure measurements should 
be repeated twice to produce three readings for both heart rate and blood pressure.  
Patients should receive the first dose of study drug before 12:00 PM (noon) at the site. 
Patients may be discharged after 6 hours ONLY if the following discharge criteria are met: 
• Heart rate (sitting) at discharge must be at least 55 bpm (in patients 12 years or older) or 
60 bpm (in children below 12)   
• Heart rate (sitting) 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) 
• Patients must have no symptoms in sitting or standing position associated with decreased 
heart rate or received treatment for bradycardia 
• ECG at 6 hours should not show any new significant abnormalities, other than 
asymptomatic sinus bradycardia, not observed at the patient’s pre-dose ECG (e.g. 
prolongation of QT/QTcF interval, persistent new onset 2nd degree (Mobitz Type I 
(Wenkebach) or higher AV block, 3rd degree AV block at any time during monitoring). 
The same monitoring procedure applies also to the re-initiation of study drug after 
interruption (Section 5.5.5) and at the time of individual dose-increase (Section 3.3).  In the 
Core Phase, re-initiation of study drug monitoring must be done by the independent first dose 
monitoring team in order to maintain the blind.  However, in the Extension Phase monitoring 
for re-initiation of study drug or dose increases may be conducted by the main study team.  
Patients who are off study drug treatment for the following durations: 
• The treatment lasted for 14 days or less and was interrupted for 1 day or more, or 
• The treatment lasted for more than 14 days and less than 29 days and was interrupted for 
more than 7 consecutive days, or 
• The treatment lasted for 4 weeks or more and was interrupted for more than 14 
consecutive days. 

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Patients should have written instruction on when to return to the 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, vomiting, etc.). 
If the above discharge criteria are not met, patients should continue to be observed until they 
are met (the observation must last for at least 2 hours even if the criteria are met earlier).  
However, patients experiencing any symptomatic event associated with reduction of the heart 
rate, a heart rate of < 45 bpm at the end of the 6-hour monitoring, received treatment for 
bradycardia, or had relevant changes on the ECG, not resolving by the end of the 6-hour 
monitoring (e.g. ECG at 6 hours shows a QTcF interval ≥500 msec), must be hospitalized 
overnight.  For those patients, the Day 2 dose of study drug should be given in the hospital 
according to monitoring and discharge criteria described above.  
First/redose study drug discontinuation criteria are listed below and all ECG and other reasons 
requiring permanent study drug discontinuation are described in Section 5.5.9: 
• First/Redose Criteria  
• Any hemodynamically compromising cardiac arrhythmias. 
• Patients who meet the criteria requiring overnight hospitalization again on Day 2  
• Absolute QTcF > 500 msec, confirmed by repeat ECG measurements (within 24 
hours).  
• New complete heart block (third degree AV block) or second degree AV block 
Mobitz type II. 
Patient with symptomatic events or relevant changes on ECG should be followed until 
symptoms/ECG finding have resolved or condition has stabilized. 
In addition to the above described first dose monitoring and discharge criteria required per 
protocol, additional monitoring post first dose may be required in some countries/regions per 
the local product information for Gilenya for the treatment of adult RRMS. Of note, in some 
regions, like in the EU, the Product Information recommends to perform additional 
continuous (real time) ECG monitoring during the first 6 hours post first dose.  
Recommendations for the management of bradycardia 
In case of bradycardia causing cardiorespiratory compromise (e.g., hypotension or peripheral 
hypoperfusion), atropine is recommended as the first line treatment of bradycardia. The initial 
dose should be 0.01 mg/kg (10 mcg/kg), up to a maximum dose of 1 mg. Furthermore, the 
common guidelines for treatment of bradycardia (e.g., 2005 AHA for cardiopulmonary 
resuscitation: pediatric advance support) should be followed as appropriate. 

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15 
Appendix 3:  Guidance on safety monitoring 
15.1 
Guidance on the monitoring of patients with elevated blood 
pressure 
In children and adolescents, the normal range of blood pressure (BP) is determined by body 
size and age. Standardized BP norms, based on sex, age and height, as well as 
recommendations for diagnosing, management and treatment of high blood pressure in 
children and adolescents have been published (NIH Publication No. 05-5267, Lurbe et al. 
2009). 
Using the standardized reference tables as described in these reference, if the BP is greater 
than the 95th percentile, BP should be staged.  
• If BP is Stage 1 (95th percentile to 99th percentile plus 5 mmHg), BP measurements should 
be repeated within 1 month 
• If BP is Stage 2 (>99th percentile plus 5 mmHg), prompt referral should be made for 
evaluation and treatment.  
• If the patient is symptomatic, immediate referral and treatment are indicated. 
The study drug should not be discontinued, unless the physician has a reason to do so.  A 
newly diagnosed hypertension as well as an aggravation of a preexisting condition must be 
reported as an AE.  
15.2 
Guidance on monitoring of patients with elevated liver function 
tests 
ALT/AST  
In case of detection of (asymptomatic) elevated ALT/AST values >3 times the upper limit of 
the normal range (ULN), additional blood chemistry panel including ALT, AST, AP, GGT, 
total and conjugated bilirubin should be performed within a week. If the elevation is 
confirmed, close observation of the patient and monitoring of liver function tests (LFTs) 
regularly at time intervals of 1 to 4 weeks (at investigator’s discretion) should be initiated. 
In case of detection of elevated ALT/AST values >3 times ULN which are accompanied by 
symptoms (general malaise, fatigue, abdominal pain, nausea or vomiting, rash with 
eosinophilia) study drug needs to be discontinued immediately; hospitalize patient if clinically 
appropriate; establish causality. Further follow-up should include ALT, AST, TBL, Alb, 
PT/INR, AP and GGT until resolutionc (see below definition; frequency at investigator 
discretion). 
In case of detection of elevated ALT/AST values ≥5 times the ULN, Blood chemistry liver 
panel including ALT, AST, AP, GGT, Alb, PT/INR, total and conjugated bilirubin must  be 
performed within 48 hours. If ALT/AST elevation persists for more than 2 weeks, study drug 
administration must be interrupted. The patient should be followed up bi-weekly, until no 
further increase in AST/ALT is observed. Further follow-up should include ALT, AST, TBL, 
Alb, PT/INR, AP and GGT until resolutionc (frequency at investigator discretion). 

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If ALT/AST values reach 8 times the ULN, and the value is confirmed on a repeat lab within 
48 hours, the study drug must be permanently discontinued (Section 5.5.9). Follow-up should 
include ALT, AST, TBL, Alb, PT/INR, AP and GGT until resolutionc (frequency at 
investigator discretion). 
Alkaline phosphatase (AP)  
Isolated elevation of alkaline phosphatase will not necessarily require study drug 
discontinuation, and would be based on the PI’s discretion if the elevations were thought to be 
more serious in nature. 
Bilirubin 
In case of isolated elevation of bilirubin over 1.5 ULN (in the absence of Gilbert’s syndrome), 
the lab needs to be repeated within 48 hours. If elevation persists, the patient must discontinue 
the study drug; hospitalize if clinically indicated; establish causality. Additional evaluations 
may be performed at the discretion of the investigator.  
In case of isolated elevation of bilirubin above 2 ULN (in the absence of Gilbert’s syndrome) 
the patient must discontinue the study drug (hospitalize if clinically indicated) and establish 
causality. 
Follow-up on ALT, AST, TBL, Alb, PT/INR, AP and GGT until resolutionc (frequency at 
investigator discretion) and also test for hemolysis (e.g., reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin). 
Concomitant elevation of ALT/AST and bilirubin (Potential Hy’s Law case) 
In case of elevation of ALT/AST >3 times the ULN and total bilirubin >2 times the ULN but 
without increase in AP >2 times the ULN (i.e. “Hy’s law” criterion is met), study drug must 
be discontinued immediately and patient be hospitalized if clinically indicated; causality 
should be determined and the event reported as an AE/SAE as appropriate. The follow-up 
should include ALT, AST, TBL, Alb, PT/INR, AP and GGT until resolutionc (frequency at 
investigator discretion). 
Patients with clinical symptoms; jaundice; reinitiation of study drug  
Patients who develop symptoms suggestive of hepatic dysfunction, such as, but not limited to, 
unexplained vomiting, abdominal pain, fatigue, anorexia, dark urine, should have liver 
enzymes checked, and study drug should be discontinued if significant liver injury is 
confirmed.  
In case of jaundice the patient must discontinue the study drug immediately, should be 
hospitalized and causality established. The follow-up should include ALT, AST, TBL, Alb, 
PT/INR, AP and GGT until resolutionc (frequency at investigator discretion). 
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. 

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Re-initiation of the study drug should only be considered once the ALT/AST decrease is 
below 2 times the ULN. In case of re-starting the study drug, it is recommended that 
ALT/AST is assessed weekly for the 1st month and then monthly for the 2nd and 3rd months. 
The occurrence of new elevations greater than 5 times the ULN for the ALT/AST values will 
lead to permanent discontinuation of the study drug (Section 5.5.9). In cases of confirmed 
diagnosis of hepatic dysfunction, patients should be followed until symptom resolution (see 
below for definition)c or until the condition stabilizes. 
Liver-specific events must be recorded in the appropriate eCRF. SAEs must be filed as 
appropriate. 
Any interruption or discontinuation of the study drug should be clearly documented in the 
Dosage Administration Record eCRF. AE/SAEs must be filed as appropriate. 
c Resolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable values at three 
subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a maximum of 6 months, (4) liver 
transplantation, and (5) death. 
15.3 
Guidance on monitoring patients with symptoms of neurological 
deterioration, inconsistent with MS 
Should a patient develop any unexpected neurological or psychiatric symptoms/signs or 
accelerated neurological deterioration, the investigator should schedule a complete physical 
and neurological examination and an MRI as soon as possible. Discontinuation of study drug 
should be considered. In case of new unexpected findings in the MR images, mainly if not 
compatible with MS lesions, it is recommended to obtain a CSF sample for cellular, 
biochemical and microbiological analysis (e.g. herpes virus, JC virus). Further diagnostic 
evaluations should be performed at discretion of the investigator. Steroid treatment should 
only be started once an infectious origin has been excluded or properly treated.  
The MRI must be evaluated by the local neuroradiologist. A copy of the unscheduled MRI 
should be sent to the central MRI reading center as soon as possible. AE/SAEs need to be 
filed as appropriate. The investigator will contact the Medical Advisor at Novartis to discuss 
findings and diagnostic possibilities as soon as possible. 
Only when the differential diagnosis evaluations have excluded other possible diagnosis than 
MS the study drug may the restart of study drug be considered.   
15.4 
Guidance on monitoring of patients with notable lymphopenia  
The absolute total WBC, neutrophil and lymphocyte counts will be measured at each visit by 
the central laboratory and will be blinded from the sponsor and the investigator and will only 
be communicated to the site in case of a notable abnormality (refer to Appendix 1 for notable  
abnormalities). For lymphocyte count this is defined as <0.2 x109/L, in which case the 
lymphocyte count should be repeated in two weeks by the central lab to confirm the reading.  
If the repeat test confirms the lymphocyte count is below 0.2x109/L or 200 cells/mm3, the 
study drug must be discontinued and the lymphocytes count needs to be monitored monthly 
until levels return back to normal limits (by local laboratory for monitoring levels). If monthly 
site visits create a logistical burden for the patient, local lymphocyte testing can be performed, 
and ideally an additional sample should also be sent to central laboratory for analysis. In the 

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event that central laboratory analysis is not available, the results of the local laboratory values 
(including reference ranges) should be included in the eCRF to document recovery of values. 
The patient should be evaluated and monitored for infections on a regular basis. Re-initiation 
of the study drug can only be considered once the lymphocyte counts are back within normal 
limits. 
15.5 
Guidance on monitoring of patients with infections 
The investigator should be vigilant for risk of infections, including opportunistic infections, 
with bacterial (e.g. atypical mycobacteria) viral (e.g. HSV, VZV, JCV or fungal (e.g. 
cryptococcus agents) and should remind the patient of the risk of infections and to instruct 
them to promptly report any symptoms of infections to the investigator. Investigators are 
requested to specifically ask about infections at each visit. All infections that develop during 
the study will be reported as AEs. The investigator will be notified in case of notably 
abnormal values for total WBC (<3000 cells/mm3), neutrophil (<1000 cells/mm3) and 
lymphocyte (<200 cells/mm3) counts. The patient should be evaluated and monitored for 
infections on a regular basis. The investigator should consider early treatment with specific 
antimicrobial therapy on the basis of clinical diagnosis or suspicion thereof in consultation 
with infections disease experts, as appropriate. The infectious disease expert may conduct 
additional evaluations, including laboratory, if deemed necessary for treatment decisions. 
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. 
Profiling of infection risk in study patients based on anti-viral IgG antibody test results 
Serology testing for antibody status of herpes simplex virus-1 and 2 (HSV-1, HSV-2) is 
performed at screening to profile infection risk in study patients. The investigator should 
inform the patients of their immune status based on these serology results and of the potential 
risks of primary infections or viral reactivation while taking study drug.  
A positive IgG antibody test result does not indicate active infection per se, but only evidence 
of exposure to viral antigens via past infection. These patients may, however, be at risk for 
viral reactivation, which may manifest as:   
• HSV-1 IgG positive: Cold sores 
• HSV-2 IgG positive: Herpes genitalis 
The investigator should instruct the patient to be alert to and report any symptoms or signs 
suggestive of cold sores, genital ulcers or shingles, so that appropriate anti-viral treatment can 
be initiated in consultation with a local infectious disease expert (if needed). A negative IgG 
antibody test result for HSV-1 and HSV-2 places patient at risk for more severe and atypical 
manifestations of primary infection in the event they are exposed to these viruses while they 
are immunosuppressed (taking study drug and/or corticosteroids). Patients should be 
instructed to promptly report any exposure to these viruses e.g. to a person with cold sores, 
herpes genitalis, or measles, respectively. In case of exposure, early treatment with 
appropriate antiviral drugs and/or post exposure prophylaxis with immunoglobulin should be 
considered in consultation with a local infectious disease expert. 

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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. 
The Investigator should consider early treatment with specific therapy on the basis of clinical 
diagnosis of infection or suspicion thereof (e.g., antiviral treatment for herpes simplex or 
varicella zoster virus [VZV]; treatment for cryptococcus) in consultation with infectious 
disease experts, as appropriate. Investigators should be aware that in the post-marketing 
setting with Gilenya, isolated cases of cryptococcal meningitis have been reported. Patients 
reporting symptoms and signs (such as, but not limited to, headache accompanied with stuff 
neck, sensitivity to light, fever, confusion, tiredness, body aches, chills, vomiting, and/or 
nausea) consistent with meningitis should undergo prompt diagnostic evaluation. If 
cryptococcal meningitis is diagnosed, appropriate treatment should be initiated as soon as 
possible. The Investigator should inform the Novartis and CRO medical experts of any such 
cases. See also section 15.3 for guidance on JC virus 
Suspension of treatment with Gilenya should be considered if a patient develops a serious 
infection, and consideration of benefit-risk should be undertaken prior to re-initiation of 
therapy.  
15.6 
Guidance on vaccinations 
Guidance on Screening serology: 
Proof of immunity is required for VZV, measles, mumps, rubella, diphtheria, pertussis and 
tetanus. 
Varicella-zoster virus (VZV): 
Patients must have evidence of immunity to varicella which includes any of the following:  
• Documentation of age appropriate varicella vaccination (2 doses of varicella vaccine 
for school-age children and adolescents) 
• Laboratory evidence of immunity or laboratory confirmation of disease.  
• Diagnosis or verification of a history of varicella or herpes zoster by a health care 
provider 
To verify a history of varicella, health care providers should inquire about: 
• an epidemiologic link to another typical varicella case or to a laboratory 
confirmed case, or 
• evidence of laboratory confirmation, if testing was performed at the time of acute 
disease. 
With this evidence patients may enter the study without testing for antibodies. 
• Patients who do not have evidence of immunity may still be screened for participation 
in the study, but will need to be tested for antibodies to VZV antigen as part of the 
screening labs and may enter the study if they receive the full course of VZV vaccine. 
• A patient may be randomized in the trial 1 month after the last dose of vaccination 
without further serology testing for VZV. 

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Measles, Mumps and Rubella (MMR): 
Patients must have evidence of immunity to MMR which includes any of the following:  
• Documentation of age appropriate MMR vaccination (2 doses of MMR for school-age 
children and adolescents) 
• Laboratory evidence of immunity or laboratory confirmation of prior disease. 
With this documentation patients may enter the study without testing for antibodies to 
these antigens.  
• Patients who do not have evidence of immunity to MMR may still be screened for 
participation in the study, but will need to be tested for antibodies to MMR antigens 
as part of the screening labs and if negative will need to be vaccinated prior to 
enrollment in the study.  Once vaccinated no further testing is required.  
The last dose of the vaccine should be given at least 4 weeks prior to randomization 
Diphtheria, tetanus and pertussis (DTP): 
Patients must have evidence of immunity to DTP which includes any of the following:  
• Documented proof of age appropriate vaccination (including boosters). 
With this documentation patients may enter the study without testing for antibodies to 
these antigens. 
• Patients who do not have evidence of immunity may still be screened for participation 
in the study, but will need to be tested for DTP antibodies as part of the screening labs 
and if negative will need to be vaccinated prior to enrollment in the study. Once 
vaccinated no further testing is required. 
• Booster dose for diphtheria, tetanus and pertussis may be given at least 2 weeks prior 
to randomization. Once vaccinated no further serology testing is required. 
Hepatitis: 
• Patients who are positive for any of the following serology markers for hepatitis A, B, 
C and E are excluded from the study: 
• anti-HAV IgM  
• HBs Ag and/or anti-HBc IgM 
• anti-HCV IgG or HCV by RNA PCR 
• anti-HEV IgM or IgG (if IgG positive, HEV-RNA PCR should be performed, if  
PCR is negative patient can be included). 
Note: Patients who have been vaccinated against HBV (only anti-HBs-IgG would be 
detectable from the HBV serologic markers) and patients cured from previous 
HAV or HBV infection with normal liver transaminases values are not excluded. 
Herpes simplex virus-1, herpes simplex virus-2: 
• Patients who are negative for anti-herpes simplex virus-1 IgG or anti-herpes simplex 
virus-2 IgG antibodies are not excluded but should be informed of their status (refer 
to Appendix 3 Section 15.5 above). 
Epstein Barr virus (EBV), cytomegalo virus (CMV) 

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• Patients are not excluded from participation. Serology is obtained for documentation 
purposes.  
General Guidance: 
In addition, any live or live attenuated vaccine that, as per the local vaccination schedule, 
would be scheduled during the duration of the study must be administered at least one month 
prior to entering the study to allow the full effect of the vaccination to occur. Vaccinations 
with live or live attenuated vaccines are prohibited while the patients are taking study drug 
and for two months after study drug discontinuation.  
Vaccines containing dead or inactivated microorganisms or derived purified products can be 
administered while the patient is on study drug (e.g., inactivated seasonal influenza vaccine, 
tetanus, inactivated hepatitis B, DTP). Data from a vaccination study have shown that subjects 
treated with fingolimod are able to mount an immune response to influenza vaccine (refer to 
fingolimod Investigators Brochure for further details). 
15.7 
Guidance on monitoring of pulmonary function 
Patients reporting any respiratory symptoms such as dyspnea, shortness of breath, chest 
tightness or wheezing should be scheduled to be seen for a clinical assessment. In case of 
clinically relevant respiratory symptoms, the patient should be referred to a pulmonologist for 
assessment and treatment, if warranted. It is recommended to perform a spirometry for 
evaluation of pulmonary function, including FEV1, FVC and DLCO for comparison to the 
baseline assessment. Further exploratory evaluations should be performed at the discretion of 
the pulmonologist.   
In case of persistent respiratory symptoms or pulmonary function abnormalities over a 3-
month period, despite appropriate treatment, the Primary Treating Physician should consider 
an interruption/discontinuation of the study drug. Patient should be followed until symptoms 
resolved or condition has stabilized. 
Any patient with abnormal pulmonary function tests (PFTs), including patients that have 
discontinued study drug, should be followed until PFTs return to within the normal range for 
the age or until the condition has stabilized. 
15.8 
Guidance for ophthalmic examination  
Unscheduled ophthalmic examinations in case of visual complaints/worsening 
of vision  
During the study, if there are visual complaints or any worsening of visual acuity then an 
ophthalmic examination should be scheduled to evaluate visual acuity and the macula and 
optic disc by dilated ophthalmoscopy (may include lens biomicroscopy). An OCT should be 
performed if there is objective evidence of worsening visual acuity equal to two or more lines 
on a standard eye chart using best corrected vision or if the ophthalmologist determines that 
an OCT should be conducted. If patients report visual disturbances at any time while on 
therapy, evaluation of the fundus, including the macula, should be carried out by an 

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ophthalmologist.  Further explorations, such as fluorescein angiography (FA), should be 
performed at the discretion of the ophthalmologist. 
Guidance on monitoring of patients with diagnosis of macular edema 
Patients with diagnosis of macular edema must permanently discontinue the study drug 
(Section 5.5.9). 
These patients must be followed up with monthly ophthalmologic evaluations until such time 
when 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 
repeated at the discretion of the ophthalmologist. If the patient does not show definite signs of 
improvement on examination by specialist testing (e.g. OCT, FA) after 6-8 weeks after 
discontinuation of study drug, then therapy for macular edema in conjunction with an 
ophthalmologist experienced in the management of this condition should be initiated. Patients 
should be followed until symptom resolution or until the condition stabilizes. 
Discontinuation of the study drug should be clearly documented and reflected on Dosage 
Administration Record eCRF and AE/SAEs must be reported as appropriate. For patients 
diagnosed with macular edema copies of the colored OCT and FA images, if available, should 
be kept by the investigative site as source documents. 
Guidance on monitoring of patients with diabetes mellitus or uveitis 
Each patient with a history of diabetes mellitus, history of uveitis and/or findings in the 
screening ophthalmic evaluations compatible with uveitis (e.g., significant anterior chamber 
cell or flare, vitreous cell or flare, pars planitis, vasculitis, chorioretinitis) must undergo more 
frequent and extensive ophthalmic examinations, as follows:  
Ophthalmic visits should be scheduled at Months 3, 6 and every 3 months for the first year 
and then every 6 months thereafter per protocol. In addition to the assessments performed in 
the ophthalmic scheduled visits (i.e., best corrected visual acuity and dilated 
ophthalmoscopy), an OCT should be performed at each visit to evaluate the macula.  
In case of visual complaints or worsening of vision in patients with history of diabetes 
mellitus or uveitis, please refer to the previous guidance on monitoring patients presenting 
with visual complaints or worsening of vision.  
If a patient with or without previous history of uveitis presents with active uveitis without 
macular edema during the study, the patient may stay on study drug and will receive treatment 
at the discretion of the local ophthalmologist. Patients with active uveitis must have a follow 
up ophthalmic examinations at one month after uveitis diagnosis, three months later, then 
every 3 months up to one year, and every 6 months thereafter until symptom resolution or 
until the condition stabilizes.  
If systemic immunosuppressive treatment (other than corticosteroids) is required for treatment 
of uveitis, the study drug must be permanently discontinued.  

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The diagnosis of macular edema will lead to permanent study drug discontinuation (refer to 
guidance for monitoring of patients with macular edema above). 

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Appendix 5: Statistical appendix (Information from a controlled 
clinical trial with count data) 
Background 
The ARR is the primary clinical endpoint in Study D2311. The trial compares fingolimod 
with a IFN beta-1a.  
Objective 
To mathematically derive the information obtained from a clinical trial in MS on the ARR 
ratio of test vs. control, on the log-scale based on a negative binomial distribution. The 
information is defined as the reciprocal of the estimate’s variance, as in group sequential 
designs. 
Model 
We assume that the number of relapses follows a negative binomial distribution, which is a 
common assumption in MS trials. More specifically, the available data for patient i in 
treatment arm j is:  
Yij = number of relapses in follow-up time Tij,  
for  i=1,…nj  and j=1,2 (1=test, 2=control).  
The negative binomial model is then written as: 
Yij  ~ NegBin( λj Tij , κ ) ,  
with annual relapse rate λj (>0) and over-dispersion parameter κ (>0). 
With this parametrization,  
E(Yij) = μij   and Var(Yij) = μij (1 + κ μij), where μij  = λj Tij. 
An estimate of λj is given by  rj =  Y.j / T.j , where Y.j  = Σi Yij  and T.j  =  Σi Tij. 
Using the delta-method (see details in a next section), a normal approximation for the 
logarithm of the estimated relapse rate ratio is obtained: 
log(  r1 / r2 ) ~ N( log(λ1 / λ2) , 1/(λ1 T.1) + 1/(λ2 T.2)  
+ κ { Σi Ti12 / T.12  +  Σi Ti22 / T.22 } ) 
The information is the reciprocal of the variance, ie Information: 
Equation 1: I = [ 1/(λ1 T.1 ) + 1/(λ2 T.2 ) + κ { Σi Ti12 / T.12  +  Σi Ti22 / T.22 } ]-1 
For the case where Tij =T, nj = n,  
Equation 2: Information I =  [ 1/n { 1/(λ1T) + 1/ (λ2T) + 2 κ} ]-1 
Of note: Study designs with different parameterizations, but an equivalent amount of 
information also have an equivalent power for the detection of the specified treatment effect at 
a fixed alpha-level. 

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BSSR of the information 
As in a BSSR (Friede and Schmidli 2010), fitting a negative binomial model to the aggregate 
data (ie the relapse data of all patients combined) provides an estimate of the overall annual 
relapse rate λ and of the dispersion κ. For an assumed rate ratio of θ= λ1/λ2, we obtain 
estimates of the annual relapse rates in the two groups, λ1 and λ2.  
We also make the assumption that  the follow-up times in the two groups are the same, ie that  
T.1= T.2 = Ttotal/2 , where Ttotal is the total of the follow-up times at the review time. We 
further assume that the sum of the squared follow-up times is the same in both groups. ie that  
Σi Ti12 = Σi Ti22   = Σj Σi Tij2 / 2 = T2total/2. 
The evaluation of the Information (1) based on blinded information is then 
Equation 3: Information I = [  2/(λ1 Ttotal ) + 2/(λ2 Ttotal ) + 4 κ T2total/Ttotal2  ]-1   
where λ1, λ2, and κ are the re-estimated values at the BSSR. 
Note:  if Tij =T, nj = n, then Ttotal = 2 n T, and T2total = 2 n T2, and one obtains again (2). 
Additional details (delta-method) 
For a random variable X with expectation μ and variance σ2 , the transformed random variable 
g(X) has approximatly expectation  g(μ)  and variance   σ2 g’(μ)2 (delta-method).  
For the estimate of λj  given by  rj =  Y.j / T.j , we have 
E( rj ) = λj   and  Var( rj ) =  λj / T.j  + κ λj2 Σi Tij2 / T.j2       
Using the delta-method, the log-transformed annual relapse rate estimate has expectation and 
variance 
E( log( rj ) ) = log(λj ) 
Var( log( rj ) ) =   1/ (λj  T.j ) + κ  Σi Tij2 /   T.j2       
Hence, approximately:    
log( rj ) ~ N(  log(λj )  ,  1/ (λj  T.j ) + κ  Σi Tij2 /   T.j2   ) 
Note that for the special case of  Tij = T, we obtain:  
log( rj ) ~ N(  log(λj )  ,  1/ (λj  n T ) + κ / n  )  
This approximation is used for sample size calculation and re-calculation with negative 
binomial count data (Keene 2007; Friede and Schmidli 2010).