Long-term, Open-label, Multicenter Study Assessing Long-term Cardiovascular Risks in Patients Treated With Fingolimod
Phase: PHASE4
Conditions: Multiple Sclerosis
Sponsor: Novartis Pharmaceuticals

 
Official Title: 
Long-term, open-label, multicenter study assessing long-term 
cardiovascular risks in patients treated with fingolimod 
NCT Number: 
NCT02232061 
 
Document Date: 
 
Protocol Version 1: 08 August 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 

Global Clinical Development - General Medicine 
FTY720/Fingolimod 
Clinical Trial Protocol CFTY720D2409 
Long-term, open-label, multicenter study assessing long-
term cardiovascular risks in patients treated with 
fingolimod 
Authors: 
 
Document type: 
Amended protocol version (v01) Clean 
EUDRACT number: 
2014-001241-24 
Version number: 
v01 
Development phase: 
IV 
Release date: 
08-Aug-2019
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed  
without the consent of Novartis 
Template version 14-Jul-2016 

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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................. 8 
Protocol summary ................................................................................................................ 9 
Amendment 1 .................................................................................................................... 10 
1 
Introduction ....................................................................................................................... 11 
1.1 
Background ............................................................................................................ 11 
1.2 
Purpose .................................................................................................................. 12 
2 
Study objectives ................................................................................................................. 12 
2.1 
Primary objective(s) .............................................................................................. 12 
 
 13 
 
 13 
3 
Investigational plan ........................................................................................................... 13 
3.1 
Study design .......................................................................................................... 13 
3.2 
Rationale of study design ...................................................................................... 13 
3.3 
Rationale of dose/regimen and duration of treatment ........................................... 14 
3.4 
Rationale for choice of comparator ....................................................................... 14 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 14 
3.6 
Risks and benefits .................................................................................................. 14 
4 
Population .......................................................................................................................... 14 
4.1 
Inclusion criteria .................................................................................................... 15 
4.2 
Exclusion criteria ................................................................................................... 15 
5 
Treatment ........................................................................................................................... 15 
5.1 
Protocol requested treatment ................................................................................. 15 
5.1.1 
Study treatment ..................................................................................... 15 
5.1.2 
Additional study treatment .................................................................... 15 
5.2 
Treatment arms ...................................................................................................... 15 
5.3 
Treatment assignment, randomization ................................................................... 15 
5.4 
Treatment blinding ................................................................................................ 15 
5.5 
Treating the patient ................................................................................................ 15 
5.5.1 
Patient numbering ................................................................................. 15 
5.5.2 
Dispensing the study treatment ............................................................. 16 
5.5.3 
Handling of study treatment .................................................................. 16 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 16 

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5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 16 
5.5.6 
Rescue medication ................................................................................ 16 
5.5.7 
Concomitant treatment .......................................................................... 16 
5.5.8 
Prohibited Treatment ............................................................................. 16 
5.5.9 
Discontinuation of study treatment ....................................................... 17 
5.5.10 
Withdrawal of consent .......................................................................... 17 
5.5.11 
Loss to follow-up .................................................................................. 18 
5.5.12 
Emergency breaking of assigned treatment code .................................. 18 
5.5.13 
Study completion and post-study treatment .......................................... 18 
5.5.14 
Early study termination ......................................................................... 18 
6 
Visit schedule and assessments ......................................................................................... 18 
6.1 
Information to be collected on screening failures.................................................. 20 
6.2 
Patient demographics/other baseline characteristics ............................................. 20 
6.3 
Treatment exposure and compliance ..................................................................... 20 
6.4 
Effectiveness .......................................................................................................... 21 
6.5 
Safety ..................................................................................................................... 21 
6.5.1 
Physical and neurological examination ................................................. 21 
6.5.2 
Fingolimod first-dose monitoring ......................................................... 21 
6.5.3 
Vital signs.............................................................................................. 21 
6.5.4 
Height and weight ................................................................................. 21 
6.5.5 
Laboratory evaluations .......................................................................... 22 
6.5.6 
Electrocardiogram (ECG) ..................................................................... 22 
6.5.7 
Ophthalmic evaluations ......................................................................... 22 
6.5.8 
Pregnancy and assessments of fertility ................................................. 22 
6.5.9 
Appropriateness of safety measurements .............................................. 23 
6.6 
Other assessments .................................................................................................. 23 
6.6.1 
Resource utilization ............................................................................... 23 
6.6.2 
Pharmacokinetics .................................................................................. 23 
6.6.3 
Pharmacogenetics/pharmacogenomics ................................................. 23 
6.6.4 
Other biomarkers ................................................................................... 23 
7 
Safety monitoring .............................................................................................................. 23 
7.1 
Adverse events ....................................................................................................... 23 
7.2 
Serious adverse events ........................................................................................... 25 
7.2.1 
Definition of SAE ................................................................................. 25 
7.2.2 
SAE reporting........................................................................................ 26 
7.3 
Liver safety monitoring ......................................................................................... 27 

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7.4 
Renal safety monitoring ......................................................................................... 27 
7.5 
Pregnancy reporting ............................................................................................... 27 
7.6 
Prospective suicidality assessment ........................................................................ 27 
8 
Data review and database management ............................................................................. 27 
8.1 
Site monitoring ...................................................................................................... 27 
8.2 
Data collection ....................................................................................................... 28 
8.3 
Database management and quality control ............................................................ 28 
8.4 
Data Monitoring Committee .................................................................................. 28 
8.5 
Adjudication Committee ........................................................................................ 28 
9 
Data analysis ...................................................................................................................... 29 
9.1 
Analysis sets .......................................................................................................... 29 
9.2 
Patient demographics and other baseline characteristics ....................................... 29 
9.3 
Treatments ............................................................................................................. 29 
9.4 
Analysis of the primary variable(s) ....................................................................... 30 
9.4.1 
Variable(s) ............................................................................................. 30 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 30 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 30 
9.4.4 
Supportive analyses ............................................................................... 30 
 
 31 
 
 31 
 
 31 
 
 31 
 
 32 
 
 32 
 
 32 
 
 32 
9.6 
Interim analyses ..................................................................................................... 32 
9.7 
Sample size calculation ......................................................................................... 32 
10  Ethical considerations ........................................................................................................ 33 
10.1 
Regulatory and ethical compliance ........................................................................ 33 
10.2 
Informed consent procedures ................................................................................. 33 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 33 
10.4 
Publication of study protocol and results............................................................... 34 
11  Protocol adherence ............................................................................................................ 34 
11.1 
Protocol Amendments ........................................................................................... 34 
12  References ......................................................................................................................... 34 

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List of tables 
Table 5-1 
Prohibited treatment: ............................................................................. 17 
Table 6-1 
Recommended assessment schedule, including mandatory 
evaluations............................................................................................. 19 
Table 9-1 
Probability of seeing at least one serious cardiovascular event in 
D2409 .................................................................................................... 32 
 

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List of abbreviations 
ADEM 
Acute disseminated encephalomyelitis 
AE 
 
Adverse event 
ATC  
Anatomic therapeutic chemical 
CFR 
 
US code of federal regulations 
CI 
 
Confidence interval 
CNS 
 
Central nervous system 
CRA  
Clinical research associate 
CRF 
 
Case report/record form 
CRO  
Contract research organization 
DMT  
Disease modifying therapy 
DS&E  
Drug safety & epidemiology 
ECG  
Electrocardiogram 
EDC  
Electronic data capture 
EDSS  
Expanded disability status scale 
EMA  
European medicine agency 
FDA  
Food and drug administration 
GCP 
 
Good clinical practices 
HDL  
High density lipoprotein 
ICF 
 
Informed consent form 
ICH 
 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
 
Independent ethics committee 
IFN 
 
Interferon 
i.m. 
 
intra-muscular 
IN 
 
Investigator notification 
IR 
 
Incidence rate 
IRB 
 
Institutional review board 
ISS 
 
Integrated safety summary 
i.v. 
 
Intra-venous 
MedDRA 
Medical dictionary for regulatory activities 
MI 
 
Myocardial infarction 

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MS 
 
Multiple sclerosis 
OCT  
Optical coherence tomography 
PFT 
 
Pulmonary function test 
PML  
Progressive multiform leucoencephalopathy 
PPMS  
Primary progressive multiple sclerosis 
PRES  
Posterior reversible encephalopathy syndrome 
PRMS  
Progressive relapsing multiple sclerosis 
RRMS  
Relapsing remitting multiple sclerosis 
SAE 
 
Serious adverse event 
SAP 
 
Statistical analysis plan 
s.c. 
 
Sub-cutaneous 
SPMS  
Secondary progressive multiple sclerosis 
SUSAR 
Suspected unexpected serious adverse reaction 
WBC  
White blood cell 
WHO  
World health organization 
 

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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Enrollment 
Point/time of patient entry into the study at which informed 
consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol) 
Protocol 
A written account of all the procedures to be followed in a trial, 
which describes all the administrative, documentation, analytical 
and clinical processes used in the trial. 
Study treatment 
Any single drug administered to the patient as part of the required 
study procedures 
Subject Number  
A number assigned to each patient who enrolls into the study  
Variable 
A measured value or assessed response that is determined in 
specific assessments and used in data analysis to evaluate the 
drug being tested in the study 

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Protocol summary 
 
Protocol number 
CFTY720D2409 
Title 
Long-term, open-label, multicenter study assessing long-term 
cardiovascular risks in patients treated with fingolimod 
Brief title 
Study assessing the long-term cardiovascular risks in patients treated 
with fingolimod 
Sponsor and Clinical 
Phase 
Novartis, Phase 4  
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
This study is a post-authorization follow-up measure to assess the long-
term cardiovascular risk of fingolimod in patients who experience a 
serious cardiovascular event during the first 24-hours of fingolimod 
treatment initiation in study FTY720D2406. 
Primary Objective(s) 
To estimate the long-term cardiovascular risk of fingolimod, as defined by 
the incidence of selected cardiovascular events over the course of the 
study, in patients who experienced a cardiovascular event during 
treatment initiation or re-initiation in the study D2406. 
 
 
Study design 
This is a single-arm, open-label, long-term safety study. 
Population 
The study will enroll MS patients who sustained a serious cardiovascular 
event during their fingolimod treatment initiation or re-initiation in the 
D2406 study. 
Inclusion criteria 
Patients in study D2406 who experience a cardiovascular event within 
24-hours of fingolimod treatment initiation or re-initiation having led to 
overnight monitoring or met seriousness criteria  
Exclusion criteria 
Patients receiving an investigational drug except if this is part of a 
Novartis sponsored MS study lasting less than 1 month. 
Study treatment 
Fingolimod 0.5mg/day. 
Efficacy assessments 
None  
Safety assessments 
ECG, vital signs and adverse events 
Other assessments 
None 
Data analysis 
The proportion (with 95%CI) of patients with at least one selected 
cardiovascular adverse events will be summarized.  
Results will be compared with the proportion of D2406 patients who also 
experienced a selected cardiovascular event but who did not have a 
cardiovascular event during the first 24 hours after initiation of fingolimod 
treatment in D2406. 
Key words 
Long-term cardiovascular risks, fingolimod, MS 

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Amendment 1 
Amendment rationale 
Amendment 1 to protocol CFTY720D2409 is developed to align with the recent safety related 
updates  to the Fingolimod label (SmPC) and to introduce administrative changes in the 
protocol to align with the language of D2406, the parent study from which patients are being 
enrolled into D2409 study.   
Changes to the protocol 
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 underlining for insertions. 
The changes applied are the following: 
 Discontinuation section (5.5.9) has been updated to warn about the potential occurrence of 
severe exacerbation of disease upon fingolimod discontinuation. 
 Pregnancy section (6.5.8) has been updated to inform about the contraindication in 
pregnancy (and in women of child bearing potential not applying highly effective 
measures of contraception) recently added to the SmPC 
 
 
  
 Clarification that First Dose Monitoring events qualifying for participation in 
FTY720D2406 can be considered during initiation or re-initiating of Fingolimod treatment  
 Clarification that ECG reading should be done by a qualified physician 
 Other minor editorial changes. 
 

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1 
Introduction 
1.1 
Background 
Multiple Sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system 
characterized by inflammation, demyelination and axonal/neuronal destruction, ultimately 
leading to severe disability. MS affects ~ 2.5 million individuals worldwide. At diagnosis, 
approximately 85% of patients have relapsing-remitting MS (RRMS), characterized by 
recurrent, acute episodes (relapses) of neurological symptoms. After 6-10 years, 30-40% of 
patients with RRMS have progressed to secondary progressive MS (SPMS), when a less 
inflammatory, and more neurodegenerative, course of disease takes precedence. SPMS can 
also be segregated based on whether patients continue to experience relapses (relapsing form 
of SPMS) or not (purely progressive SPMS). About 10-15% of MS patients present with a 
primary progressive course (PPMS) defined by a continuous accumulation of neurological 
disability from symptom onset without superimposed exacerbations or remissions. 
Progressive relapsing MS (PRMS; chronic progressive from onset with infrequent relapses) is 
the least frequent form of MS.  
Several therapies are approved for patients with RRMS and fall within 8 classes of products: 
interferon (IFN) (1a and 1b), glatiramer acetate (amino acid copolymer), natalizumab 
(selective adhesion molecule inhibitor), mitoxantrone (chemotherapeutic), fingolimod (S1P 
receptor modulator), teriflunomide (pyrimidine synthesis inhibitor), dimethylfumarate 
(fumarates) and alemtuzumab (anti-CD52). All are considered as immunomodulatory or 
immunosuppressive medications. Beta interferons have multiple immune actions but the 
means by which the drugs are effective in MS remains unknown. They have shown modest 
(~30%) effect on relapses and in the case of IFN-1a, on disability (Goodin et al. 2002). 
Relatively minor differences in efficacy, based on dose frequency, exist between IFN 
products. Glatiramer acetate, a random mixture of amino acid copolymers has an effect on 
relapses similar to IFN- but has not shown an effect on disability (Goodin et al. 2002). 
Natalizumab blocks lymphocyte migration into the CNS by inhibiting interaction of alpha-4 
integrins on lymphocytes with the endothelial receptor VCAM-1 leading to significant 
reductions in relapse rate (68%) and disability (42%) (Polman et al. 2006). The risk of 
progressive multiform leucoencephalopathy (PML) limits use of this product predominantly 
to second-line situations (Ransohoff, 2007). Whether patients negative for antibodies to the JC 
virus (causal agent of PML) will have a lower risk of PML than those positive for antibodies 
(as appears likely based on preliminary reports) remains to be determined. Likewise, 
mitoxantrone, a chemotherapeutic agent, while demonstrating efficacy on relapses, is 
associated with risks of cardiac and hematological events that substantially restrict its use 
(Goodin et al. 2002). Interferon, glatiramer acetate, natalizumab and alemtuzumab are given 
by injection (SC, IM or IV) whereas fingolimod, teriflunomide and dimethylfumarate are oral 
medications. 
Fingolimod (FTY720) 0.5 mg is an oral drug which has been approved in 90 countries for 
treatment of patients with relapsing of MS. Fingolimod 0.5 mg is an effective therapy to 
reduce the risk of relapses in patients with relapsing forms of MS. 

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The safety profile of fingolimod has been well characterized with over 284,000 MS patients 
treated with fingolimod in the context on clinical studies and in the post-marketing setting, 
comprising over 677,779 patient years of exposure by 31-May-2019.  
Upon initiation of fingolimod there is activation of the S1P1 receptor that leads to transient 
negative chronotropy and dromotropy, which are the basis for the monitoring of heart rate and 
BP required for at least six hours upon the initiation of fingolimod. The incidence of 
bradyarrhythmic events and intolerance of these events that requires additional monitoring is 
infrequent. Whether or not such events within the first day of the initiation of fingolimod in 
MS patients have any association with long term risk for major adverse cardiovascular events 
is unknown. 
As part of an EMA post-authorization follow-up measure and an FDA post-approval 
commitment a large observational post-authorization safety study CFTY720D2406 (D2406) is 
being conducted in several countries. This study will provide important information on the 
usage and the safety profile of fingolimod in a real life setting. However given its 
observational nature it does not allow to mandate procedures (e.g. ECG) which would be 
needed in order to properly evaluate whether or not serious cardiovascular events following 
fingolimod initiation have any association with long-term risk for serious cardiovascular 
events. Therefore the current study (D2409) is being implemented. This study will be 
conducted in D2406 patients who experienced such cardiovascular events. It will complement 
D2406 study by collecting all data in a similar manner as the D2406 study in addition to some 
extra mandated examinations.  
For the purpose of this protocol, the term “fingolimod initiation” is used for first initiation as 
well as for re-initiation following fingolimod treatment interruption. 
1.2 
Purpose  
This study is an additional EMA post-authorization follow-up measure to assess the 
cardiovascular risk of fingolimod in those patients who experience a cardiovascular event 
during the first 24-hours of fingolimod treatment initiation in study D2406 which leads to 
overnight monitoring or meets seriousness criteria. 
In addition, this study will also explore the overall safety profile of fingolimod under 
conditions of routine medical practice as in protocol D2406. 
2 
Study objectives 
2.1 
Primary objective(s) 
To estimate the long-term cardiovascular risk of fingolimod in patients who experienced a 
cardiovascular event during treatment initiation, as defined by the incidence of selected 
cardiovascular events over the course of the study. 

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3 
Investigational plan 
3.1 
Study design 
This is a multi-national, long-term safety study. Patients enrolled in study D2406 who 
experienced a cardiovascular event within 24-hours of fingolimod treatment initiation which 
led to overnight monitoring or met serious adverse event criteria, are eligible to participate in 
this study.  
Patients eligible and consenting to study D2409 will discontinue their study D2406 
participation and be followed in study D2409. Study D2409 enrollment period will be open 
until 1-year before the end of study D2406 and the study will last until the end of Study 
D2406 i.e. five years after the last patient has been enrolled in Study D2406. 
Patients who experience a qualifying event in study D2406 should start study D2409 
approximately 6 months after the occurrence of the D2406 qualifying event or as soon as 
possible after the site initiation. 
As part of this study, patients will undergo mandatory assessments on a 6-monthly basis 
including 12-lead ECG, vital signs and a check list for the occurrence of selected events. 
Other assessments will be performed as per routine practice. 
During the course of the study, patients switching to another MS therapy will remain in the 
study provided they fulfill the criteria defined in Section 5.5.9. These patients will have their 
last mandated evaluations 6 months after the discontinuation of fingolimod (see Table 6-1). 
After this time point, they will be followed according to routine practice without additional 
mandatory assessments. 
3.2 
Rationale of study design 
This study is designed to assess the long-term cardiovascular risk of fingolimod in patients 
who experienced a cardiovascular event during fingolimod treatment initiation. As study 
D2406 provides a real-life population treated with fingolimod and allows easy identification 
and enrollment of patients, it was selected as the source of patients for D2409 study. 

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The data collection will be aligned to the study D2406 protocol apart from additional 
cardiovascular data in order to facilitate data pooling as well as to allow study D2406 patients 
who did not have any such first-dose event to be used as the comparator to study D2409 
patients.  
3.3 
Rationale of dose/regimen and duration of treatment 
Fingolimod 0.5 mg/day is the dose approved for the indication of relapsing forms of MS. The 
prescription of fingolimod, as well as the decision to discontinue treatment are at the sole 
discretion of the prescribing physicians and the patients and are not part of the study plan.  
Patients will have different duration of follow-up based on when they join the study. Patients 
will be followed until 5 years after the last patient has been enrolled in Study D2406. 
3.4 
Rationale for choice of comparator 
There is no comparator group enrolled in this study. Comparison will be made using 
fingolimod patients enrolled in Study D2406 who did not have any first-dose cardiovascular 
event as they provide a reasonable cohort with similar baseline data collection and allow an 
estimation of the risk of selected cardiovascular events. 
3.5 
Purpose and timing of interim analyses/design adaptations 
A descriptive summary of the data of this study will be compiled on a periodic basis (at least 
yearly) in a pooled manner with data from Study D2406. 
3.6 
Risks and benefits  
The safety profile of fingolimod has been well characterized with over 284,000 MS patients 
treated with fingolimod in the context of clinical studies and in the post-marketing setting, 
comprising over 677,779 patient years of exposure by 31-May-2019. During the course of the 
fingolimod clinical development, several areas were identified as safety areas of note: 
bradyarrhythmias upon treatment initiation, liver transaminase elevations, hypertension and 
macular edema; additional safety areas of interest include infections, malignancies and 
reproductive toxicity. 
All risks related to fingolimod or other MS DMTs are described in the respective patient 
information leaflets. 
Given that the treatment decision is independent from study participation, the additional risk 
for subjects to participate in this study is limited to the added procedures (i.e. a 6-monthly 
ECG) for which no risk is foreseen. 
4 
Population 
This study will include patients with relapsing forms of MS who have been prescribed 
treatment with fingolimod by their treating physician as part of their MS treatment in 
accordance with the routine clinical practice and who in the context of the study D2406 
experienced certain cardiovascular events during their fingolimod initiation. 

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4.1 
Inclusion criteria 
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 
2. Patient experienced a cardiovascular event within 24-hours of fingolimod treatment 
initiation or re-initiation which led to overnight monitoring or met seriousness criteria 
3. Patient experienced this cardiovascular event while participating in the study 
CFTY720D2406  
4. Patient continues receiving fingolimod after the first dose event 
4.2 
Exclusion criteria 
Patients treated with any investigational drug unless it is received as part of a Novartis 
sponsored MS study lasting less than 1 month. 
5 
Treatment 
5.1 
Protocol requested treatment 
5.1.1 
Study treatment 
The study treatment is fingolimod. 
Novartis will provide fingolimod 0.5 mg capsules supplies locally for the duration of the 
study participation according to if required by local regulations. Otherwise, local 
commercially available supplies will be used. Novartis will not provide any other MS 
treatment to patients who may discontinue fingolimod prior to the study end. 
5.1.2 
Additional study treatment 
No additional treatment is requested for this trial. 
5.2 
Treatment arms 
There is only one treatment arm with patients receiving fingolimod 0.5mg/day. 
5.3 
Treatment assignment, randomization 
Not applicable. 
5.4 
Treatment blinding  
Not applicable. 
5.5 
Treating the patient  
5.5.1 
Patient numbering  
Each patient will retain the numbering they had in the study D2406.  

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5.5.2 
Dispensing the study treatment  
Each study site will be supplied if required by local regulations. Otherwise, local 
commercially available supplies will be used. 
5.5.3 
Handling of study treatment  
5.5.3.1 
Handling of study treatment  
Study treatment will be handled as per local procedures. 
5.5.3.2 
Handling of other study treatment  
Not applicable. 
5.5.4 
Instructions for prescribing and taking study treatment  
All dose changes during the study must be recorded on the MS disease modifying therapy 
records eCRF. 
The investigator should promote compliance by instructing the patient to take the study 
treatment exactly as prescribed. The patient should be instructed to contact the investigator if 
he/she is unable for any reason to take the study treatment as prescribed. 
5.5.5 
Permitted dose adjustments and interruptions of study treatment  
Study treatment dose adjustments and/or interruptions are permitted as per investigator 
judgment. 
These changes must be recorded on the MS disease modifying therapy records eCRF. 
5.5.6 
Rescue medication  
Not applicable. 
5.5.7 
Concomitant treatment  
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after being enrolled into the study. All medications, procedures and significant 
non-drug therapies (including physical therapy and blood transfusions) administered after the 
patient was enrolled into the study must be recorded Concomitant Medications eCRF. 
5.5.8 
Prohibited Treatment  
During the course of the study, if a patient switches to an unapproved MS DMT (i.e. marketed 
drug used as MS DMT without however being approved for MS indication), this patient will 
have to stop study participation. If possible, data should then be captured at the time of this 
change in MS therapy independently of the 6-monthly protocol scheduled visit and 6 months 
later. This last time point will constitute the end-of-study data collection point for this patient. 
Patients who start treatment with any investigational drug (MS DMT or not) will have to stop 
the study participation from the day they start this investigational drug. 

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Table 5-1 
Prohibited treatment: 
Medication 
Action to be taken 
Unapproved MS DMT 
Discontinuation from  study 6 months after the end of the 
approved MS DMT 
Investigational drugs 
Discontinuation from study on the day investigational drug is 
started 
5.5.9 
Discontinuation of study treatment  
During the course of the study, a patient may discontinue fingolimod: 
 If this patient then starts another approved MS DMT or does not start any DMT at all (i.e. 
remains off DMT), he/she remains in the study. If possible, data should then be captured 
at the time of this change in MS therapy (either to another DMT or stopping DMTs 
entirely), 6 months later and thereafter as per the recommended data collection schedule 
until the end of the study (see Table 6-1).  
 If this patient switches to an unapproved MS DMT, this patient will have to stop study 
participation as described above in Section 5.5.8. 
Patients may voluntarily discontinue study treatment for any reason at any time.  
The investigator should discontinue study treatment for a given patient if he/she believes that 
continuation would be detrimental to the patient’s well-being. 
Cases of severe exacerbation of the disease have been reported after discontinuation of 
fingolimod in the post-marketing setting. These cases were generally observed within 12 
weeks after stopping fingolimod, but in some cases up to 24 weeks after Gilenya 
discontinuation. Therefore, caution is indicated when stopping Gilenya therapy. If 
discontinuation of Gilenya is deemed necessary, patients should be monitored for relevant 
signs and symptoms and appropriate treatment should be initiated as required. 
5.5.10 
Withdrawal of consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time.  
Withdrawal of consent occurs only when a patient does not want to participate in the study 
anymore and does not want any further visits or assessments and does not want any further 
study related contacts. 
If a patient withdraws consent, the investigator must make every effort (e.g. telephone, e-mail, 
letter) to determine the primary reason for this decision and record this information in 
accordance with local regulations. Upon withdrawal of study participation, study treatment 
(i.e. fingolimod) will no longer be supplied and the patient will return to the prescribed 
medication as decided together with the treating physician. For patients visiting their sites 
infrequently, the site staff should contact the patient by phone at least once per year until 
study completion to collect his/her vital status (i.e. dead or alive, occurrence of SAEs and any 
change in MS treatment. See also section 5.5.9 

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5.5.11 
Loss to follow-up  
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw, the investigator should show "due diligence" by contacting the 
patient, family or family physician as agreed in the informed consent and by documenting in 
the source documents steps taken to contact the patient. The treating physician should try to 
contact the patient or one of his/her relatives or the general practitioner (if such is known) in 
order to collect the patient’s vital status, including when applicable, the cause of death. 
If, despite three attempts spread over a 6-month period using different modalities (e.g. phone, 
fax, registered receipt letter), the treating physician is not successful in making contact with 
the patient, the patient will be considered lost to follow-up. Patients will be considered lost to 
follow-up from the date of the last successful contact. 
5.5.12 
Emergency breaking of assigned treatment code  
Not applicable. 
5.5.13 
Study completion and post-study treatment  
The study will be considered completed five years after the enrollment of the last patient in 
the study D2406. 
A patient is considered to have completed the study when he/she will have been followed 
until that time-point.  
The study might be prematurely terminated for several reasons see Section 5.5.14. 
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. 
5.5.14 
Early study termination  
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
study patients should be seen as soon as possible. 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 the 
Institutional Review Board/Independent Ethics Committee (IRBs/IECs) of the early 
termination of the trial. 
6 
Visit schedule and assessments 
As part of this study, patients will have mandatory assessments on a 6-monthly basis (i.e. 
ECG and vital signs) as long as they are treated with fingolimod and up to 6 months after a 
potential fingolimod permanent discontinuation. Frequency and nature of other data will be 
captured as per routine practice as described below in Table 6-1.  
The study entry visit should be scheduled approximately 6 months after the patient 
experienced his/her cardiovascular event in the study D2406.  

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At this visit the patient will sign the Study D2409 informed consent and any new data 
pertaining to this patient will need to be captured in the D2409 eCRF. The end of Study 
D2406 will be on the day Study D2409 informed consent is signed. 
For patients who experienced this qualifying event more than 6 months prior to Study D2409 
implementation at the site, the study entry visit should be scheduled as soon as possible after 
site initiation. 
The study recommends a visit window of +/- 1 month for all mandatory evaluations. 
In the study eCRF, fingolimod discontinuation and 6-month follow-up time-points will be 
documented under routine study visits. 
Table 6-1 
Recommended assessment schedule, including mandatory 
evaluations 
Visit/ study time-points Study entry 
visit  
 
Routine 
study visit 
(Every 6 
months)  
Fingolimod 
discontinuation8  
6-
months 
fup9 
Abbreviated 
Routine 
visit10 
End of 
study  
Assessments and data 
collection page 
 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X11 
12-lead ECG 
X 
X 
X 
X 
 
X11 
Selected Adverse 
Events1 
X 
X 
X 
X 
X 
X11 
MS status2 
X 
X 
X 
X 
X 
X 
Laboratory results3 
X 
Record as needed 
Ophthalmic 
examination4 
Record as needed 
1st dose observation5 
Record as needed 
Pregnancy status 
(female of childbearing 
potential only)  
Record as needed 
Dermatological 
examination 
Record as needed 
Additional 
examination6 
Record as needed 
Adverse events7 
Record as needed 
Serious Adverse 
Events7 
Record as needed 
MS disease-modifying 
therapy record 
X 
Record as needed 
Concomitant 
medication 
Record as needed 
Study completion 
 
 
 
 
 
X 
Bold denotes mandatory evaluations 
1  Selected AEs include cardiac and vascular events (e.g. stroke, myocardial infarction, angina pectoris and peripheral 

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Visit/ study time-points Study entry 
visit  
 
Routine 
study visit 
(Every 6 
months)  
Fingolimod 
discontinuation8  
6-
months 
fup9 
Abbreviated 
Routine 
visit10 
End of 
study  
Assessments and data 
collection page 
 
 
 
 
 
 
vascular disease, second and third degree AV block, hypertension), symptomatic bradyarrhythmias on treatment initiation or 
on re-starting after an interruption in fingolimod therapy, eye events (e.g. macular edema), liver events, any infection, 
pulmonary events (e.g. dyspnea, asthma), malignancies (e.g. lymphoma), seizures, atypical MS relapse, other atypical 
severe neurological events (e.g. ADEM, PRES) and sudden/unexplained death. 
2. MS status will capture when available, MS relapses, EDSS. 
3. i) If total and HDL-cholesterol results were not collected as part of the D2406 baseline laboratory results, a sample will 
need to be drawn and analyzed for these 2 parameters. This is the only mandatory laboratory evaluation required for this 
study. ii) Only local laboratory results are being captured. Results of lymphocyte count, total WBC count and liver function 
tests whether normal or abnormal should be captured systematically in the CRF, whenever available.  Other laboratory 
parameter results are to be captured when considered clinically relevant (whether abnormal or not). For ischemic type of 
events, results of prothrombin time/partial thromboplastin time, homocysteine, Activated protein C Resistance, lupus 
anticoagulant, antiphospholipid antibody, protein C, protein S fibrinogen and antithrombin III should be collected if performed. 
4. Ophthalmic evaluation will capture, when available, visual acuity and macular edema status. 
5. To be documented only for patients who re-start fingolimod after an interruption of dosing. 
6. Additional examination (e.g. Chest X-Ray, PFT, Echocardiography…) performed in order to characterize an adverse event 
should be documented.  
7. All events meeting the criteria for an AE or SAE should be reported on the “Adverse events” eCRF page. 
8. Any evaluation performed at the time stopping fingolimod should be documented. 
9. Patients who stopped fingolimod and switched to another approved MS DMT will have the 6 month follow-up visit with the 
mandatory ECG.  
10. Patients discontinuing fingolimod will remain in the study. Only data captured per routine practice will reported. See 
Section 5.5.9 
11. Evaluations are mandatory for patients still on fingolimod at the time of the study completion. These are not mandatory for 
patients who stopped fingolimod prior to this time-point. 
6.1 
Information to be collected on screening failures  
Not applicable. 
6.2 
Patient demographics/other baseline characteristics  
Patient demographics, baseline laboratory results, medical history in particular cardiac 
medical history and fingolimod first-dose-monitoring data will be captured as part of the 
study D2406 eCRF. 
Data required to calculate the Framingham Point Score for 10-Year risk for coronary heart 
disease as well as the European cardiovascular risk score will be collected at study entry visit 
if they were not already captured in study D2406. These are age, gender, smoking status, 
systolic blood pressure and total & HDL cholesterol. 
6.3 
Treatment exposure and compliance  
Although it is expected that patients will receive fingolimod 0.5 mg daily per local prescribing 
information, it is recognized that in a clinical setting, dosing may be delayed or interrupted 
due to personal reasons, physical reasons, physical conditions, or co-morbidities.  Any change 
in fingolimod treatment (e.g. interruption, change in dose or change in drug) and the reason 
for change should be documented in the MS treatment eCRF. This will allow measurement of 
treatment compliance. 

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6.4 
Effectiveness 
In order to document the disease evolution of the study population, MS status including 
number of relapses and EDSS, should be collected whenever available. 
6.5 
Safety 
The following information should be collected in the context of this study in line with the 
different local label recommendations and whenever available:  
 Physical and neurological examination findings, together with the occurrence of selected 
adverse events 
 Fingolimod first dose monitoring data  
 Vital signs  
 ECG 
 Laboratory evaluations results  
 Ophthalmologic examinations results  
 Dermatological examination result 
 Other examination (e.g. Chest X-ray, Pulmonary function test…) 
6.5.1 
Physical and neurological examination  
A physical examination may be performed at a routine clinical visit and may include an 
assessment of skin, head and neck, lymph nodes, breast, heart, lungs, abdomen, back and/or 
comments on general appearance. A neurological examination may also be a part of the 
physical examination. Significant findings that occur during the study which meet the 
definition of an AE as defined per this protocol (see Section 7.1 ) should be recorded on the 
Adverse Event eCRF. 
6.5.2 
Fingolimod first-dose monitoring 
For any patient stopping and re-starting fingolimod, first-dose monitoring should be fully 
documented in the eCRF for each patient (e.g. vital signs, ECG, documentation in any event if 
available). 
6.5.3 
Vital signs  
Vital signs are to be recorded at each half-year visit as long as the patient is on fingolimod 
therapy and if applicable, 6 months after discontinuation from fingolimod. After this time-
point, vital signs may be recorded at routine clinical visits. Vital signs may include sitting 
pulse rate, sitting systolic and diastolic blood pressure. 
6.5.4 
Height and weight  
Body weight may be recorded at each routine clinical visit while height is collected in study 
D2406 and will not be collected again in study D2409. 

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6.5.5 
Laboratory evaluations 
Patients for whom total and HDL-cholesterol results were not collected at the time of the 
study D2406 baseline will need to have a sample drawn and analyzed. Results will be 
collected in the eCRF. 
All available results for lymphocyte counts, total WBC counts, and liver function tests, 
whether or not clinically significant should be recorded.  
Additionally, results from tests performed to characterize an adverse event should be collected 
to properly document the event irrespective of normal or abnormal. This might include but is 
not limited to a complete white blood cell differential count or antibody titers for serious 
infections. 
In this context, in case of ischemic type of events, results of prothrombin time/partial 
thromboplastin time, homocysteine, Activated protein C Resistance, lupus anticoagulant, 
antiphospholipid antibody, protein C, protein S fibrinogen and antithrombin III should also be 
recorded if available. 
6.5.6 
Electrocardiogram (ECG)  
A standard 12-lead ECG will be performed on a 6-monthly basis. Interpretation of the tracing 
shall be made by a qualified physician and documented on the ECG section of the eCRF. 
Each ECG tracing should be labeled with the study number, patient number, date, and kept in 
the source documents at the study site. 
Clinically significant abnormalities should be recorded on the relevant section of the AE 
eCRF page as appropriate. 
6.5.7 
Ophthalmic evaluations 
Any ophthalmic evaluations performed as part of routine clinical practice, should be recorded. 
Ophthalmic evaluation may include but is not limited to fundoscopy, visual acuity and OCT, 
if needed. Ophthalmic examinations should be performed according to the local label for the 
purpose of detecting macular edema.  
6.5.8 
Pregnancy and assessments of fertility  
According to the updated SmPC, Fingolimod is contraindicated for pregnant women and 
women of childbearing potential (WOCBP) not using effective contraception. Females who 
are pregnant or nursing a child cannot participate in this trial. It must be confirmed that the 
subject is not pregnant at the time of study entry.  
For a female patient of childbearing potential, defined as physiologically capable of becoming 
pregnant, participating in the study, it is mandatory for them to use an appropriate form of 
birth control. Contraception is required as described below. These highly effective methods of 
birth control have a less than 1% chance of unwanted pregnancy during one year, if used 
appropriately according to the instructions of the manufacturer. 
 Use of a combination of any two of the following (a+b or a+c or b+c): 

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a. Use of oral, injected or implanted hormonal methods of contraception or other forms of 
hormonal contraception that have comparable efficacy (failure rate <1%), for example 
hormone vaginal ring or transdermal hormone contraception (in case of oral 
contraception you should have been using the same pill on a stable dose for a minimum 
of 3 months before taking study treatment), 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS), 
c. Use of an occlusive cap (diaphragm or cervical/vault cap) by you, or a condom by your 
male partner combined with a spermicidal foam/gel/film/cream/vaginal suppository. 
Since it takes approximately 2 months to eliminate fingolimod from the body after stopping 
treatment, a potential risk to the fetus may persist and contraception should be pursued for 2 
months after finishing study treatment.  
If WOCBP becomes pregnant during the study while being treated with fingolimod, they must 
discontinue the treatment and shall immediately inform the treating physician to discuss 
management options. In addition, the event should be reported as per Section 7.5. 
6.5.9 
Appropriateness of safety measurements  
The safety measurements collected in this study were selected based on actual or potential 
signals identified as part of the fingolimod clinical development program as well as the risk 
management plan. 
6.6 
Other assessments 
There is no other assessment performed in the context of this study. 
6.6.1 
Resource utilization  
Not applicable. 
6.6.2 
Pharmacokinetics  
Not applicable. 
6.6.3 
Pharmacogenetics/pharmacogenomics  
Not applicable. 
6.6.4 
Other biomarkers  
Not applicable. 
7 
Safety monitoring  
7.1 
Adverse events  
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 

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study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal product. 
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 tests, or 
other assessments. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
 they induce clinical signs or symptoms,  
 they are considered clinically significant,  
 they require therapy.  
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes, or 
values which are considered to be non-typical in patient with underlying disease. Investigators 
have the responsibility for managing the safety of individual patient and identifying adverse 
events. 
Adverse events should be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information. 
 the severity grade 
 mild: usually transient in nature and generally not interfering with normal activities 
 moderate: sufficiently discomforting to interfere with normal activities 
 severe: prevents normal activities 
 its relationship to the study treatment 
 its duration (start and end dates) 
 whether it constitutes a serious adverse event (SAE - see Section 7.2 for definition of 
SAE) 
 action taken regarding study treatment  
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 treatment dosage adjusted/temporarily interrupted  
 study treatment permanently discontinued due to this adverse event  
 concomitant medication given  
 non-drug therapy given  
 patient hospitalized/patient’s hospitalization prolonged  
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 

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necessary) of any changes in severity, the suspected relationship to the study drug and the 
interventions required to treat it. 
Information about common side effects already known about the study treatment can be found 
in the respective patient information leaflets. Investigators should inform study patients at the 
most nearest subsequent protocol visit about most updated safety information (adverse drug 
reaction) updated in the local label. 
The investigator should also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information should be recorded in the 
investigator’s source documents, however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis. 
7.2 
Serious adverse events 
7.2.1 
Definition of SAE  
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the 
following criteria: 
 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) 
 elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
 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. 
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if more severe. 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 

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Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All AEs (serious and non-serious) are captured on the eCRF, SAEs also require individual 
reporting to DS&E as per Section 7.2.2. 
7.2.2 
SAE reporting  
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 12 weeks after the patient has stopped study participation 
(defined as time of last visit) must be reported to Novartis within 24 hours of learning of its 
occurrence. Any SAEs experienced after the 12 weeks period should only be reported to 
Novartis if the investigator suspects a causal relationship to study treatment.  
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 (either initial or follow up information) is collected and recorded 
on the paper Serious Adverse Event Report Form. The investigator must assess the 
relationship to the study treatment, complete the SAE Report Form in English, and send the 
completed, signed form by fax within 24 hours after awareness of the SAE to the local 
Novartis Drug Safety and Epidemiology Department. The telephone and fax 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 should be provided using a new paper SAE Report 
Form stating that this is a follow-up to a previously reported SAE. 
Follow- up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the 
patient continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. 
If the SAE is not previously documented in the Package Insert (new occurrence) and is 
thought to be related to the study treatment a Drug Safety and 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 study treatment that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with EU 
Guidance 2011/C 172/01 or as per national regulatory requirements in participating countries. 

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7.3 
Liver safety monitoring  
Not applicable 
7.4 
Renal safety monitoring  
Not applicable 
7.5 
Pregnancy reporting  
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications. 
Pregnancy should be recorded 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 treatment. 
Any SAE experienced during pregnancy must be reported on the SAE Report Form. 
7.6 
Prospective suicidality assessment 
Not applicable. 
8 
Data review and database management  
8.1 
Site monitoring 
Before study initiation, at a site initiation visit, a Novartis representative will review the 
protocol and CRFs with the investigators and their staff. During the study, Novartis employs 
several methods of ensuring protocol and GCP compliance and the quality/integrity of the 
sites’ data. The field monitor will visit the site to check the completeness of patient records, 
the accuracy of entries on the eCRFs, the adherence to the protocol and to Good Clinical 
Practice. Key study personnel must be available to assist the field monitor during these visits.  
Continuous remote monitoring of each site’s data may be performed by a centralized Novartis 
CRA organization. Additionally, a central analytics organization may analyze data & identify 
risks & trends for site operational parameters, and provide reports to Novartis Clinical Teams 
to assist with trial oversight. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs 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). 

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The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
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 using fully validated software that conforms to US CFR 21Part 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 Electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site.  
8.3 
Database management and quality control  
Novartis staff and a CRO working on behalf of Novartis review the data entered into the 
CRFs 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. If the electronic query system is not used, a paper Data Query 
Form will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it 
back to Novartis staff that will make the correction to the database. The signed copy of the 
Data Query Form is kept at the investigator site. 
Medications entered into the database will be coded using the WHO Drug Reference List, 
which employs the Anatomical Therapeutic Chemical classification system. Concomitant 
procedures, non-drug therapies and adverse events will be coded using the Medical dictionary 
for regulatory activities (MedDRA) terminology. 
The occurrence of relevant 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 after written agreement by Novartis Development management. 
8.4 
Data Monitoring Committee 
Not required. 
8.5 
Adjudication Committee  
Not required. 

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9 
Data analysis  
This section describes the analyses which will be performed to specifically address the study 
D2409 objectives. In addition all data from studies D2406 and D2409 will be analyzed and 
summarized in a pooled manner. These analyses are described as part of the study D2406 
protocol and are not always repeated here. 
The purpose of this study is to estimate the long-term cardiovascular risk of fingolimod in 
patients who sustained a significant cardiovascular event during treatment initiation in study 
D2406. Descriptive summary statistics (incidence and incidence rates, with respective 95% 
confidence intervals (CI)) will be generated when applicable and be included in the annual 
periodic safety updates that are required by the health authorities. 
9.1 
Analysis sets  
The D2409 Safety set will consist of all patients who signed Study D2409 informed consent. 
9.2 
Patient demographics and other baseline characteristics  
Patient demographic and baseline characteristics, as recorded in the Study D2406 database, 
will be summarized for the D2409 Safety set. 
Patient demographic and baseline characteristic data will be described by means of absolute 
and relative frequencies for categorical variables and mean, standard deviation, minimum and 
maximum for continuous variables. Categorical variables will include sex, race, ethnicity, 
country, year of birth (grouped) and age. Continuous variables will include age, height and 
weight. 
In addition, Framingham score as well as the European cardiovascular risk score will be 
summarized separately for D2409 Safety set, and for the D2406 fingolimod patients who did 
not experience a cardiovascular event during treatment initiation. 
Relevant medical history/current medical condition data; MS history and MS treatment data 
will also be summarized by frequency of such conditions and treatments. Duration of MS and 
duration of previous MS treatment at D2406 study entry will be described with mean, median, 
standard deviation, minimum and maximum. 
9.3 
Treatments  
Overall exposure to treatments will be presented for the D2409 Safety set. 
Duration of exposure the study treatment is the number of days from the day of first dose at or 
after D2406 study entry until the last day of this treatment in the D2409 study. The days when 
the patient did not take any treatment of interest will be excluded, i.e. duration of exposure 
will exclude periods of temporary interruption of treatment.  
Patients will be considered as being on continuous fingolimod therapy if their fingolimod 
treatment interruption is less than 45 consecutive days. 
Duration of exposure to the study treatment will be described with mean, standard deviation, 
minimum and maximum. Frequency and percentage of patients exposed for a minimum 

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duration (i.e.  1 week, 1 month, 3 months, 6 months, etc.) will be reported along with the 
summary statistics of duration of exposure. 
Percentage of patients discontinuing fingolimod as well as the reason for discontinuation will 
be reported. 
Concomitant medications/significant non-drug therapies will be summarized by ATC code 
and preferred term. 
9.4 
Analysis of the primary variable(s) 
The primary objective is to estimate the long-term cardiovascular risk, as measured by the 
proportion of patients experiencing at least one selected cardiovascular event, in patients with 
long-term exposure to fingolimod once they have been identified as being at risk during 
treatment initiation in study D2406. 
9.4.1 
Variable(s) 
The primary variable will be the proportion of patients in the D2409 Safety Set who 
experienced at least one selected cardiovascular events. 
Selected cardiovascular events include, but are not limited to, sudden unexplained death, 
cardiovascular death, myocardial infarction (MI), Q-wave MI, stroke (ischemic or 
hemorrhagic), unstable angina requiring hospitalization, congestive heart failure requiring 
hospitalization, complete heart block, ventricular fibrillation, torsade de pointes, hypertensive 
emergency and any other suspected life threatening cardiovascular condition. An exhaustive 
list of MedDRA preferred terms will be part of the analysis plan.  
9.4.2 
Statistical model, hypothesis, and method of analysis 
The proportion of patients with at least one selected cardiovascular adverse events post 
treatment initiation will be summarized for the D2409 Safety Set. Corresponding exact 95% 
confidence interval (Clopper-Pearson 1934) will be calculated.  
9.4.3 
Handling of missing values/censoring/discontinuations 
Reasonable attempts should be made to limit the amount of missing data related to safety and 
patient outcomes to ensure that important information related to the primary objective of the 
study, evaluation of the long-term safety of fingolimod, is captured.  No imputation will be 
made on the eCRFs for missing data and further details of how missing data will be handled 
will be outlined in the SAP. 
9.4.4 
Supportive analyses  
In order to put the D2409 data into perspective, a comparison will be made with the patients 
in D2406 who did not experience a D2409 qualifying event. Specifically, the proportion of 
patients in this latter subset who subsequently experience at least one selected cardiovascular 
adverse events will be summarized along with corresponding exact 95% confidence interval 
(Clopper-Pearson 1934) and compared with that of D2409.  

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Furthermore, matching techniques will be used to identify a sample from the other DMT 
cohort in the D2406 study which shares same background cardiac risk as the D2409 patients. 
Background variables used in the matching will include the Framingham score (10 year risk) 
for cardiovascular disease. The proportion of patients experiencing at least one selected 
cardiovascular adverse events post treatment initiation will be summarized for this matched 
sample, along with corresponding exact 95% confidence interval (Clopper-Pearson). 
 
 
 
 
 
 
 
 

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9.6 
Interim analyses  
Interim reports will be generated yearly according to reporting requirements using data pooled 
from D2406 and D2409 studies. The enrolment numbers, baseline characteristics of patients 
as well as incidence of events reported will be described in a pooled manner. 
9.7 
Sample size calculation 
There is no sample size calculation since patient number will be driven by the proportion of 
fingolimod patients in D2406 study experiencing a cardiovascular event during treatment 
initiation which leads to overnight monitoring or meets seriousness criteria, and consenting to 
participate into this D2409 study. Based on observed incidence of such cardiovascular event 
occurring during the fingolimod first initiation in the clinical trial setting (1.4% based on 
patients from ISS January 2012 submission, Group D and Group E), it is estimated that 
approximately 40 patients may be enrolled in this study. 
This small sample size and its associated power constitute the limitation to this study. 
Table 9-1 provides the operating characteristics of this study based on a sample size of 40 
patients, that is, it gives the probability of seeing at least one selected cardiovascular event in 
the D2409 study, for a range of a priori true proportions.  
Table 9-1 
Probability of seeing at least one serious cardiovascular event in 
D2409 
True proportion 
Sample size 
Probability of seeing at least 
one event 
0.001 
40 
0.039 
0.003 
40 
0.113 
0.005 
40 
0.182 
0.007 
40 
0.245 
0.01 
40 
0.331 
0.025 
40 
0.637 
0.05 
40 
0.871 
0.1 
40 
0.985 

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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 CFR 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(s) 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. 
Women of child bearing potential should be informed that taking the study treatment may 
involve unknown risks to the fetus. 
10.3 
Responsibilities of the investigator and IRB/IEC  
Before initiating a trial, the investigator/institution should obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to patients. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made. 

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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 
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances should an 
investigator collect additional data or conduct any additional procedures for any research 
related purpose involving any investigational drugs. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented. 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 prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately provided the Health Authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring should be followed. 
12 
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sclerosis: Subcommittee of the American Academy of Neurology and the MS Council for 
Clinical Practice Guidelines. Neurology; 58: 169-78 
Polman CH, O'Connor PW, Havrdova E, et al (2006). A randomized, placebo-controlled trial 
of natalizumab for relapsing multiple sclerosis. N Engl J Med; 354(9): 899-910. 
Ransohoff RM (2007). Natalizumab for Multiple Sclerosis. N Engl J Med; 356: 2622-2629. 
Clopper CJ, Pearson ES (1934). The use of confidence or fiducial limits illustrated in the case 
of the binomial. Biometrika, 26; 404–413.