Conditions: Relapsing Forms of Multiple Sclerosis
Keywords: Fingolimod FTY720 Relapsing forms of MS Multiple Sclerosis Efficacy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 4125
Healthy volunteers: no

Brief summary:
The purpose of this study was to collect long-term safety and tolerability, long-term efficacy, and health outcome data in all patients currently ongoing in the fingolimod multiple sclerosis clinical development program. This study combined all currently ongoing Phase II and III fingolimod extension studies as well as ongoing and newly planned studies into one single long-term extension protocol that provided patients with continuous treatment until fingolimod was registered, commercially available, and reimbursed in the respective countries.

Detailed description:
This study had two parts:

* Part 1, collecting long-term safety, tolerability, efficacy and health outcomes data through approximately 30-Jun-2016 until all end of study (EOS) visits of Part 1 and last follow-up visit through Jan-2017 and
* Part 2, collecting limited safety and tolerability data until approximately 30 Jun 2018, in a subset of patients who participated in Part 1, and other eligible patients from ongoing fingolimod trials.

Arms:
arm 1: Open-label fingolimod 0.5 mg, taken orally once daily

Interventions: intervention 1: Fingolimod
Intervention descriptions: intervention 1: 0.5 mg/day

Protocol document:
Prot_000.pdf: 
Clinical Development
FTY720 (Fingolimod)
Protocol No. CFTY720D2399 / NCT01201356
A single arm, open-label, multicenter study evaluating the 
long-term safety and tolerability of 0.5 mg fingolimod 
(FTY720) administered orally once daily in patients with 
relapsing forms of multiple sclerosis (LONGTERMS)
Document type:
Amended Protocol Version
EUDRACT number:
2010-020515-37
Version number:
v11 Clean
Development phase:
IIIb
Release date:
1 Apr 2016
Template Version 26-May-2009
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................9
Amendment 11 - present...........................................................................................................10
Amendment 10 – March 2016..................................................................................................11
Amendment 9 – September 2015 .............................................................................................12
Amendment 8 – August 2014...................................................................................................13
Amendment 7 – August 2013...................................................................................................14
Amendment 6 – July 2012........................................................................................................15
Amendment 5-February 2012...................................................................................................17
Amendment 4-October 2011 ....................................................................................................18
Amendment 3-May 2011..........................................................................................................20
Amendment 2-March 2011.......................................................................................................21
Amendment 1-July 2010 ..........................................................................................................22
Protocol synopsis...............................................................................................................23
1
Introduction .......................................................................................................................27
1.1
Background............................................................................................................27
1.2
Purpose ..................................................................................................................29
2
Study objectives.................................................................................................................29
2.1
Primary objectives .................................................................................................29
2.2
Secondary objectives .............................................................................................30
30
3
Investigational plan ...........................................................................................................30
3.1
Study design...........................................................................................................30
3.2
Rationale of study design.......................................................................................31
3.3
Rationale of dose/regimen, duration of treatment .................................................31
3.4
Rationale for choice of comparator .......................................................................32
3.5
Purpose and timing of interim analyses/design adaptations..................................32
4
Population..........................................................................................................................32
4.1
Inclusion criteria ....................................................................................................32
4.2
Exclusion criteria...................................................................................................32
5
Treatment...........................................................................................................................34
5.1
Investigational and control treatment ....................................................................34
5.2
Treatment arms......................................................................................................34


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5.3
Treatment assignment............................................................................................34
5.4
Treatment blinding.................................................................................................34
5.5
Treating the patient................................................................................................34
5.5.1
Patient numbering .................................................................................34
5.5.2
Dispensing the study treatment.............................................................35
5.5.3
Supply, storage and tracking of study treatment...................................35
5.5.4
Instructions for prescribing and taking study treatment........................36
5.5.5
Permitted dose adjustments and interruptions of study treatment ........37
5.5.6
Rescue medication ................................................................................38
5.5.7
Concomitant treatment..........................................................................38
5.5.8
Prohibited treatment..............................................................................38
5.5.9
Discontinuation of study treatment and premature patient 
withdrawal.............................................................................................39
5.5.10
Emergency unblinding of treatment assignment...................................40
5.5.11
Study completion and post-study treatment..........................................40
5.5.12
Early study termination.........................................................................40
6
Visit schedule and assessments .........................................................................................40
6.1
Patient demographics/other baseline characteristics .............................................46
6.2
Previous Study Details...........................................................................................46
6.3
Treatment exposure and compliance .....................................................................47
6.4
Efficacy..................................................................................................................47
6.4.1
MS relapse.............................................................................................47
6.4.2
Expanded Disability Status Scale (EDSS)............................................48
6.4.3
Magnetic resonance imaging (MRI) .....................................................48
6.4.4
Multiple Sclerosis Functional Composite (MSFC)...............................49
6.4.5
Appropriateness of efficacy assessments..............................................50
6.5
Safety.....................................................................................................................50
6.5.1
Physical/neurological examination .......................................................50
6.5.2
Skin assessments...................................................................................51
6.5.3
Vital signs..............................................................................................51
6.5.4
Laboratory evaluations..........................................................................51
6.5.5
Ophthalmologic exams/ Optical coherence tomography (OCT) ..........53
6.5.6
Electrocardiogram (ECG) .....................................................................53
6.5.7
Pulmonary function tests.......................................................................53
6.5.8
Pregnancy and assessments of fertility .................................................54
6.5.9
Appropriateness of safety measurements..............................................54


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55
55
55
56
56
56
56
56
7
Safety monitoring..............................................................................................................57
7.1
Adverse events.......................................................................................................57
7.2
Serious adverse event reporting.............................................................................58
7.3
Pregnancies............................................................................................................59
8
Data review and database management.............................................................................59
8.1
Site monitoring ......................................................................................................59
8.2
Data collection.......................................................................................................60
8.3
Database management and quality control............................................................60
9
Data analysis......................................................................................................................60
9.1
Analysis sets ..........................................................................................................61
9.1.1
Subgroup ...............................................................................................62
9.2
Patient demographics and other baseline characteristics.......................................62
9.3
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance)............................................................................................................62
9.4
Analysis of the primary variable(s) .......................................................................62
9.4.1
Variable.................................................................................................62
9.4.2
Handling of missing values/censoring/discontinuations.......................64
9.4.3
Supportive analyses...............................................................................64
9.5
Analysis of secondary variables ............................................................................64
9.5.1
Efficacy variables..................................................................................64
66
9.6
Sample size calculation..........................................................................................66
9.7
Power for analysis of key secondary variables......................................................67
9.8
Interim analyses.....................................................................................................67
10 Ethical considerations........................................................................................................67
10.1
Regulatory and ethical compliance........................................................................67
10.2
Informed consent procedures.................................................................................67
10.3
Responsibilities of the investigator and IRB/IEC..................................................68


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10.4
Publication of study protocol and results...............................................................68
11 Protocol adherence ............................................................................................................68
11.1
Protocol Amendments ...........................................................................................68
12 References (available upon request)..................................................................................69
13 Appendices ........................................................................................................................70
Appendix 1:  Clinically notable laboratory values and vital signs....................................70
Appendix 2:  Multiple Sclerosis Functional Composite Measure (MSFC) ......................72
Appendix 3:  New York Heart Association Functional Classification..............................74
Appendix 4:  Guidance for Monitoring of patients taking their first dose of the study 
drug....................................................................................................................................75
Appendix 5:  Guidance on safety monitoring....................................................................78
Appendix 6:  Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.....................................................................................................................81
Appendix 7: Guidance for Ophthalmic Monitoring ..........................................................83
Appendix 8: EDSS Assessment Criteria ...........................................................................85
List of tables
Table 6-1
Assessment schedule (Study Part One).................................................41
Table 6-2
Assessment schedule (Study Part Two)................................................44
Liver Event and Laboratory Trigger Definitions......................................................................81
Follow Up Requirements for Liver Events and Laboratory Triggers ......................................81


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List of abbreviations
9-HPT
9-hole peg test
AE
adverse event
ACTH
adrenocorticotropic hormone
Alb
albumin
ALP
alkaline phosphotase
ALT
alanine aminotransferase
ARR
annual relapse rate
AST
aspartate aminotransferase
AV
atrioventricular
BPM
beats per minute
eCRF
electronic case report/record form
CPO
Country Pharma Organization
CRO
Contract Research Organization
CSR
Clinical Study Report
DLCO
carbon monoxide diffusing capacity test
DS&E
Drug Safety & Epidemiology
ECG
electrocardiogram
EDC
electronic data capture
EDSS 
expanded disability status scale
EOS
end of study
FDF
First dose of fingolimod
FEV1
forced expiratory volume over 1 second test
FSH
follicle-stimulating hormone
FVC
forced vital capacity test
GGT
gamma-glutamyl-transferase
HbA1c
glycated hemoglobin
HCG
human chorionic gonadotropin
HR
heart rate
IB
investigator’s brochure


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ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ID
identification
IEC
Independent Ethics Committee
IFN
interferon
IN
Investigator Notification
IRB
Institutional Review Board
IRT
Interactive Response Technology
LFT
liver function test
LN
lymph nodes
LUC
large unstained cells
MedDRA
medical dictionary for regulatory activities
MRI
magnetic resonance imaging
MS
multiple sclerosis
NPDR
non-proliferative diabetic retinopathy
OCT
optical coherence tomography
p.o.
by mouth
PFT
pulmonary function test
PPMS
primary progressive multiple sclerosis
PT/INR
prothrombin time / international normalized ratio
RBC
red blood cell
RMP
risk management plan
RRMS
relapsing remitting multiple sclerosis
SAE
serious adverse event
s.c.
subcutaneously
SPMS
secondary progressive multiple sclerosis
SUSAR
suspected unexpected serious adverse reactions


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TBL
total bilirubin
ULN
upper limit of normal range


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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; 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
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 11 - present
Amendment rationale
The purpose of this amendment is to add information inadvertently deleted from Amendment 
10 during the publishing process.  This study is ongoing with approximately 4,150 enrolled 
patients.  The amendment changes will provide further clarification on the conduct of the 
protocol.
Changes to the protocol
Footnotes for Table 6-2 were inadvertently deleted from the previous amendment, and have 
been re-inserted in this version to provide further guidance for implementation of the protocol.  
Additionally, minor administrative errors have been updated throughout the document.
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.
The changes described in this amended protocol are non-substantial and do not require 
IRB/IEC approval prior to implementation.


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Summary of previous amendments 
Amendment 10 – March 2016
Amendment Rationale
As the final label and reimbursement guidelines were unknown at the outset of the fingolimod 
clinical program, some patients enrolled in the core trials and subsequently transitioned into 
this protocol are currently ineligible for commercially reimbursed Gilenya.  Based on the 
assumption that continued study participation means there is a positive benefit-risk paradigm 
for these patients, Novartis elected to extend this protocol for up to two additional years, to 
allow continued fingolimod use until countries and investigators can find alternate treatment 
solutions.  Therefore, this protocol is being amended to update the study design, offering 
continued patient participation in a subset of patients (those unable to obtain access 
to/reimbursement for commercial Gilenya) for an additional (approximately) two years, 
through June 2018.  In keeping with the original protocol objective, safety and tolerability 
data will continue to be collected during this time period.
This study is ongoing with approximately 4,150 enrolled patients.  Endorsement of this 
amendment will allow patients whose disease is being managed by fingolimod to have 
continued access, while allowing for continued collection of long-term safety and tolerability 
data.
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 underlined for insertions.
The major changes made to the protocol are summarized in this section. Other minor changes 
are incorporated directly into the protocol. The major changes include the following:

Updates to Study objectives (Section 2), Study design (Section 3.1), Rationale of study 
design (Section 3.2), Rationale of dose/regimen, duration of treatment (Section 3.3), 
Population (Section 4), Study completion and post-study treatment (Section 5.5.11), 
Discontinuation of study treatment (Section 5.5.9), Laboratory evaluations (Section 6.5.4), 
Data analysis (Section 9), Guidance on Safety Monitoring (Section 13, Appendix 5), and 
the Schedule of assessments (Table 6-1).

 Liver event and Laboratory trigger 
Definitions and Follow-up Requirements (Section 13, Appendix 6), and the Schedule of 
assessments for Part Two (Table 6-2).


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A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.
Amendment 9 – September 2015
Amendment rationale
The protocol is 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.  Second, this amendment provides details regarding 
the Study Completion visit scheduling for all patients, and re-introduces hematology testing at 
every visit.
Notably, there have been reports of isolated cases of cryptococcal meningitis in 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 has been reported in patients receiving fingolimod. The physical 
examination section has been amended to ask patients 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.
This study planned to end by 30-Jun-2016 in order to collect 60 months or more of long-term 
safety data for the majority of Phase II/III patients.   Guidance regarding scheduling of the 
Study Completion visit is provided in order to streamline the study closure processes, 
specifically designating the Study Completion visit to occur at or shortly after sixty months of 
study participation for those patients who would reach 60 months by 30-Jun-2016.  Patients 
not reaching 60 months by 30-Jun-2016 will have their study completion on or around 30-Jun-
2016 (+/- 30 day visit window), and patient who have already reached 60 months should have 
their Study Completion visit at their next six monthly visit, or 30-Jun-2016, whichever comes 
first.
Hematology testing has been re-instituted at the six monthly visits (i.e., every study visit) to 
provide additional lymphocyte count information to study sites.  
This study is an ongoing study with approximately 4,150 enrolled patients.  These changes 
will ensure that study patients receive the same information and care that patients on 
commercial Gilenya will receive, provide additional lymphocyte monitoring, and clarify the 
upcoming study completion visit scheduling.


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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 underlined for insertions.
The major changes made to the protocol are summarized in this section. Other minor changes 
are incorporated directly into the protocol. The major changes include the following: 

Updates to the Background (Section 1.1), Physical/neurological exam (Section 6.5.1), 
Skin assessments (Section 6.5.2), and Guidance on safety monitoring (Appendix 5) based 
on investigator brochure (Edition 18) updates.

Updates to Study design (Section 3.1), Rationale of study design (Section 3.2), Population 
(Section 4), Study completion and post-study treatment (Section 5.5.11), and the Schedule 
of assessments (Table 6-1) related to Study Completion visit scheduling and/or re-
introduction of hematology sampling at the 6-monthly visits.
A copy of this amended protocol will be sent to the Institutional Review Boards
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.
Amendment 8 – August 2014
Amendment rationale 
The primary objective of this study is to evaluate the continued safety and tolerability of 
fingolimod over longer periods of time. The Gilenya Risk Management Plan (RMP) provides 
guidance for the minimum safety monitoring required. During a review of the protocol, it was 
identified that the protocol has more stringent monitoring frequency than recommended in the 
RMP and standard of care. Thus, in an effort to reduce patient and site burden, in addition to 
managing internal resources, some clinical monitoring has been amended to reflect current 
RMP guidance.
This is an ongoing study with approximately 4,000 enrolled patients. These changes will 
reduce patient and site burden while continuing to collect data supporting the study objectives, 
without negatively impacting standard of care or the final study results.
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 underlined for insertions.


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The major changes made to the protocol are summarized in this section. Other minor changes 
are incorporated directly into the protocol. The major changes, outlined in Section 6, include 
the following: 

MRI frequency changed from annually to one at EOS

Clinical laboratory collection changed from a biennial to annual collection, with urine 
pregnancy tests for females being substituted at the visits during which other clinical 
laboratory testing has been removed.
Additionally minor administrative changes have been made to either correct or clarify 
verbiage.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.
Amendment 7 – August 2013
Amendment rationale
Varicella zoster virus (VZV) antibody testing and surveillance in patients enrolled in this 
extension, including patients enrolled from core studies prior to implementation of mandatory 
pre-treatment anti-VZV antibody serology, has been clarified in accordance with the 2013 
Core Data Sheet (CDS) update. The language is reinforced to ensure that previous history of 
varicella or varicella vaccination is adequately documented by a health care professional and 
wording has been strengthened regarding the need for patients to be tested for antibodies to 
determine prior VZV exposure and to vaccinate if negative.
The title of the study was changed back to the original version in response to feedback from 
the central ethics committee for France. This change indicates that only uncontrolled efficacy 
data are collected in this study, which may be subject to bias, as compared to the more 
rigorous efficacy data collected in a double-blind randomized study. Furthermore, the title 
clarifies that only patients with relapsing MS were included in the core studies from which the 
patients in trial D2399 are enrolled. 
Several additional administrative changes were made to clarify the revised screening 
laboratory tests and schedule of assessments, which were implemented in Amendment 6.
Reversion of title back to original title will allow French cohort of patients to continue in the 
trial and ensure additional awareness of VZV guidance for all countries.  


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Changes to the protocol
The major changes made to the protocol are summarized in this section. Other minor changes 
are incorporated directly into the protocol. The major changes include the following:

Clarified VZV antibody guidance has been added.

The protocol title has been modified.
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.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.
Amendment 6 – July 2012
Amendment rationale
A protocol amendment was released in February 2012 with preliminary recommendations for 
additional first-dose monitoring beyond 6 hours for patients meeting specific defined criteria, 
as well as country-specific guidelines for Germany which included continuous ECG 
monitoring during the 6-hour observation period.
This amendment implements final recommendations on first dose monitoring at treatment re-
initiation (since recruitment is completed no treatment initiation per se will occur under this 
protocol). In addition, it removes the country-specific guidelines for Germany, as the 
monitoring procedures and safety assessments mandated in the protocol are deemed 
appropriate for adequately protecting the safety of patients with an increased risk of 
cardiovascular problems. However, this amendment clarifies that any additional procedures or 
assessments that may be required as per local prescribing information must be followed.
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 underlined for insertions. 
The major changes made to the protocol are summarized in this section. Other minor changes 
are incorporated directly into the protocol. The major changes include the following: 

Exclusion criteria related to the cardiovascular conditions are updated.

Exclusion of patients taking medications that lower heart rate has been added.

Germany country-specific recommendations removed; additional procedures and 
assessments required by local prescribing information should be followed accordingly.


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
Appendix 4 Guidance for monitoring of patients taking their first dose of the study 
drug is updated to reflect final guidance.
A copy of this amended protocol will be sent to the Institutional Review Board (IRBs)/ 
Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, as the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.


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Amendment 5-February 2012
Amendment rationale
In November 2011, there was a sudden, unexplained death of a patient within 24 hours after 
the administration of the first dose of fingolimod 0.5 mg.  While the cause of death was
unknown and the role of fingolimod had not been confirmed or excluded, the event prompted 
a thorough review of cardiac safety data from clinical trials as well as spontaneous reports in 
the post-marketing setting. 
Following this review, additional observation beyond 6 hours is recommended for individuals 
who may be at risk of later occurring events based on certain defined criteria.  To that end, 
changes to the protocol are implemented in all countries to specify which ECG abnormalities 
and heart rate thresholds should lead to continued observation of patients beyond the 
mandatory 6-hour first dose observation period.
Continued observation beyond 6 hours is required for patients who, at the end of the first dose 
observation period, have a heart rate (HR) of <45 beats per minute (bpm), new onset second 
degree or higher AV block, or if the HR at 6 hours post-dose is the lowest value post-dose. 
Given that QT prolongation in the presence of marked bradycardia may be associated with 
increased risk of ventricular arrhythmias, it is specified that continued observation will also be 
required for patients whose QTc on the 6-hour ECG is 500 msec or greater. Continued 
observation should be maintained until the event leading to the continued observation has
resolved.  These criteria are in addition to those already in place, i.e. patients with 
symptomatic bradycardia and those in whom the 6-hour HR is the nadir of the observation 
period.
In addition to the guidance above, patients initiating or re-initiating treatment in Germany will 
also require continuous ECG monitoring during the 6-hour observation period. If this 
continuous ECG monitoring shows either persistent second degree AV block Mobitz type I at 
6 hours, second degree AV Mobitz type II or higher, AV block at any time, or a HR at 6 hours 
post-dose that is 20 bpm or more lower than the pre-dose HR, extended monitoring will be 
necessary until the event leading to the extended monitoring has resolved. These guidelines 
will be specified where required throughout the protocol.
Patient enrollment started in September 2010.  At the time of this amendment, approximately 
3750 patients have enrolled into the study.  It is not expected that the changes implemented in 
this amendment will affect the patient population.
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 underlined for insertions. 
The major changes made to the protocol are summarized in this section. Other minor changes 
are incorporated directly into the protocol. The major changes include the following: 

Exclusion criteria related to the cardiovascular conditions are updated.


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
Appendix 4 Guidance for monitoring of patients taking their first dose of the study drug is 
updated.

Only for Germany: Patients requiring first dose monitoring will receive continuous 6-hour 
ECG monitoring after the first dose or upon re-initiation of fingolimod treatment after an 
interruption of greater than 14 consecutive days.
A copy of this amended protocol will be sent to the Institutional Review Board (IRBs)/ 
Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, as the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.
Amendment 4-October 2011
Amendment rationale
This Amendment aims to further define the extended follow-up for patients who previously 
completed the phase II or III fingolimod clinical development studies in an interventional trial 
setting through 30-Jun-2016. It extends the enrollment to patients who have completed 
CFTY720D2309/E1 as well as the re-enrollment of CFTY720D2399 patients who have 
previously completed this study based on the original CFTY720D2399 study endpoint of local 
approval and reimbursement. Furthermore, this amendment will define additional assessments 
to evaluate the long-term efficacy of fingolimod in phase II and III trial patients. Lastly, this 
amendment aims to bring the study schedule of assessments as well as the safety monitoring 
guidelines in alignment with the fingolimod prescribing information of major countries where 
the medication has been registered.
As indicated in Amendment 3, patients who were participating in the fingolimod phase II/III 
development program have 2.5 to over 8 years of long-term exposure. The patient population 
included in these trials is particularly suitable for long-term evaluation for several reasons: 
patients have met specific inclusion/exclusion criteria, are well characterized at baseline, have
a well-documented clinical course throughout their participation in the individual clinical 
trials and include patients who were randomized to placebo or active comparator during their 
core studies. Thus, these patients already have documented long-term data on the safety and 
efficacy of fingolimod treatment, coupled with careful baseline assessments. Maintaining 
these patients in the context of an interventional study will allow for the continued collection 
of rigorous long-term data. Therefore, in addition to following long-term safety, this 
amendment adds assessments to obtain additional long-term efficacy data, including 
confirmed relapse data and EDSS-based disability progression, as well as MRI assessments 
measuring lesion burden and brain atrophy. 
Contrary to patients included in the phase II and pivotal MS studies, patients having 
participated in phase IIIb studies have limited fingolimod exposure in predominantly 
uncontrolled studies of short duration. Since these studies focused on specific safety 
assessments, MS baseline characteristics were not as well documented since patient selection 


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was not based on disease activity and history and the clinical course of MS during these short 
trials was not followed based on rigorous efficacy assessments, such as relapse confirmation, 
blinded EDSS rating, and MRI. Therefore, these patients will continue to follow the current 
study endpoint of local approval and reimbursement. The patients who are not eligible for 
reimbursement will be allowed to remain in this study for an additional 180 days.  
Phase II/III patients, who met the original study endpoint in CFTY720D2399 of approval and 
reimbursement for fingolimod in their respective countries will be invited to rejoin this study 
in order to continue participation through 30-Jun-2016 and add to the collection of long-term 
safety and efficacy data. In addition, patients from the CFTY720D2309/E1 study who may 
not have had the opportunity to enroll into this study based on the original study endpoint will 
also be invited to participate in this study through 30-Jun-2016.
The schedule of assessments, frequency of visits, and the safety monitoring guidelines have
been updated to reflect the fingolimod prescribing information of major countries where the 
medication has already been approved. Any additional assessments required by the local 
labels should be performed as required in the context of routine clinical care. In addition 
efficacy measurements, i.e. MRI assessments (including brain atrophy), relapse data, and 
disability progression, have been added for patients with a documented baseline in order to 
obtain additional long-term efficacy data.
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 underlined for insertions.
The major changes made to the protocol are summarized in this section. Other minor changes 
are incorporated directly into the protocol. The major changes include the following:

Phase IIIb study patients not eligible for reimbursement can remain in the study 180 days 
post fingolimod reimbursement.

Patients from CFTY720D2309/E1 can enter the trial and phase II/III patients who 
previously completed this trial can re-enter for long-term follow-up.

Inclusion/Exclusion criteria are updated.

First dose monitoring required following interruptions of study drug of greater than 14 
consecutive days; previously, following interruption of 8 days or greater.

Optional pulmonary function testing (PFT) is added.

Skin exams are no longer required; remain as optional.


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
OCT and Ophthalmic exam frequency is adjusted.

EDSS certification requirement added for investigators evaluating Phase II/III patients; 
collection of functional EDSS scores added for the Phase II/III patients.

Visit frequency adjusted to every 6 months, starting with Visit 6.

MRI testing added for Phase II/III patients.

Definition of “confirmed relapses” is added; the confirmed relapse information is to be 
collected.

Several laboratory tests are no longer being collected (HbA1c, HIV, hepatitis B and C, 
herpes simplex virus 1 and 2, and rubeola).

Changes to contraception requirements and to safety guidelines for pregnant patients.

Changes to safety guidelines for patients with elevated liver function tests, diagnosis of 
macular edema or basal cell carcinoma.
A copy of this amended protocol will be sent to the Institutional Review Board (IRBs)/ 
Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, as the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.
Amendment 3-May 2011
Amendment rationale
Study CFTY720D2399 includes patients who previously participated in the fingolimod phase 
II (D2201) and phase III (D2301, D2302, D2309) studies and their associated extension trials 
(CFTY720D2201E1, CFTY720D2301E1, CFTY720D2302E1, CFTY720D2309E1). In 
addition, patients who have participated in and completed ongoing phase IIIb studies of 
fingolimod are also eligible.  Patients who participated in the phase IIIb trials initiated 
treatment with fingolimod only recently. Patients who were participating in the phase II/III 
development program have 2-7 years of continuous exposure and met specific 
inclusion/exclusion criteria and have very well documented clinical course over those years. 
These latter patients provide valuable long-term data on safety and efficacy of fingolimod 
treatment, coupled with careful baseline assessments.
The rationale of this amendment is to allow further follow-up of those patients who previously 
completed the Phase II or III fingolimod clinical development trials in an interventional trial 
setting through 30-Jun-2016.  In addition, this amendment will allow the re-enrollment of 
those phase II/III patients who have completed participation in one of the phase II/III 
extension studies, who remain on fingolimod therapy and wish to continue on fingolimod in a 
clinical trial setting.


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Those patients originating from the phase IIIb program will be offered to transition into 
observational studies to collect long-term safety data in the setting of standard medical 
practice upon approval and reimbursement of fingolimod in the respective country, as 
foreseen in the original version of this protocol.
Changes to the protocol
The changes made throughout the protocol update the study end for the Phase II/III patients to 
fingolimod registration, commercially availability and reimbursement OR through 30-June-
2016, whichever is later. 
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.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, as the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.
Amendment 2-March 2011
Amendment rationale
The rationale for this amendment in Norway is to revise the study endpoint to 01-Aug-2012 is
to allow patients who complete ongoing studies to receive continuous treatment with 
fingolimod and to collect long-term safety data for approximately 12 months following the 
completion of prior trial. As the study has not yet started in Norway, there is no impact on the 
patients or the study itself.
Additionally, the Exclusion criterion 10c is updated to be in accordance with the 
recommended wording in the Summary of Product Characteristics for fingolimod, as agreed 
upon by CHMP. The exclusion is expanded to arrhythmia requiring current treatment with 
Class Ia or III antiarrhythmic medications.
Changes to the protocol
The changes made throughout the protocol are specific to Norway and update the study 
endpoint to reflect the time point approximately 12 months following the completion of the 
previous fingolimod trial or maximally through 01-Aug-2012. 
The References section is updated to correct clerical errors.
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.


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The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, as the changes herein affect the Informed Consent, sites in 
Norway are required to update and submit for approval a revised Informed Consent that takes 
into account the changes described in this amended protocol.
Amendment 1-July 2010
Amendment rationale

The rationale for this amendment in the UK is to revise the study endpoint to 31-Dec-2012 
to be in line with the Commission Directive 2005/28/EC and the requirements of the UK
Health Authority.  As the study has not yet started, there is no impact on the patients or the 
study itself.

The rationale for this amendment in Poland is to revise the study endpoint to 31-Dec-2012 
in order to continue to provide patients treatment through what is considered a reasonable 
period of time for reimbursement  to be achieved in Poland where thereafter patients can, 
if within their treatment plan, receive commercial supply as prescribed by their physician.  
As the study has not yet started, there is no impact on the patients or the study itself.
Changes to the protocol
The changes made throughout the protocol are specific to Poland and the UK and update the 
study endpoint to reflect until fingolimod is registered and through approximately one-year 
post approval or maximally through 31-Dec-2012.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using 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.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 


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Protocol synopsis
Title of study: 
A single arm, open-label, multicenter study evaluating the long-term, safety and tolerability of 0.5 mg 
fingolimod (FTY720) administered orally once daily in patients with relapsing forms of multiple 
sclerosis.
Purpose and rationale: 
The purpose of this study is to collect long-term safety, tolerability, efficacy, and health outcomes data 
in patients who participated in the fingolimod multiple sclerosis clinical development program.
Objectives: 
Primary Objectives:
This study is designed to evaluate the long-term safety and tolerability of fingolimod 0.5 mg/day in 
patients with MS for the duration of the study.
Secondary Objectives:
This study will also evaluate long-term efficacy of fingolimod 0.5 mg/day in patients with MS, as 
measured by disability progression, brain volume (atrophy), T1- (non-enhanced) and T2-weighted 
lesion volume and MS relapse occurrence in Study Part One.
Population: 
Approximately 5000 patients who have completed ongoing or planned clinical trials in the MS 
development program with fingolimod are expected to be enrolled in >500 centers worldwide. 
Inclusion/Exclusion criteria: 
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. Patients who have completed designated ongoing or planned Novartis global clinical trials with 
fingolimod and are unable to obtain fingolimod outside a clinical trial.
Exclusion Criteria:
Patients fulfilling any of the following criteria are not eligible for inclusion in this study:
1.
Premature permanent discontinuation from any fingolimod study due to:
a.
An adverse event or serious adverse event or laboratory abnormality.
b.
Conditions leading to permanent study drug discontinuation.
2.
Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG laboratory 
test (> 5 mIU/ml).  Patients who temporarily or permanently discontinued from any fingolimod 
study because of pregnancy can be re-enrolled.
3.
Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, UNLESS they are using highly effective contraception during the study and for 2 
months after stopping treatment. ‘Highly effective contraception’ defined as contraception 
which results in less than 1% unwanted pregnancies when used properly according to the 
label.
      


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4.
Chronic disease of the immune system other than MS which may require immunosuppressive 
treatment.
5.
Severe active infection or active chronic infection.
6.
Previous treatment with cladribine, cyclophosphamide or mitoxantrone.
7.
Treatment with monoclonal antibodies (including Natalizumab) in the past 3 months.
8.
Uncontrolled diabetes (HbA1c>9%).
9.
Macular edema at Baseline.
10. Any medically unstable condition that may interfere with the patient’s ability to cooperate and 
comply with the study procedures, as assessed by the treating physician.
11. Any of the following cardiovascular conditions:
a.
myocardial infarction within the past 6 months prior to enrollment or current unstable 
ischemic heart disease; 
b.
cardiac failure at time of Screening (Class III & IV, according to New York Heart 
Association Classification) or any severe cardiac disease as determined by the 
investigator;
c.
patients receiving current treatment with Class Ia or III antiarrhythmic drugs (e.g., 
quinidine, disopyramide, amiodarone, bretylium, sotalol, ibulitide, azimilide, dofelitide, 
ajmaline, procainamide);
d.
second-degree AV block Type II or third-degree AV block or corrected QTc interval 
450 msec in males or >470 msec in females;
e.
sick sinus syndrome or sino-atrial heart block;
f.
uncontrolled hypertension despite prescribed medications.
12. Any of the following pulmonary conditions during the previous fingolimod study or observed at 
the enrollment visit:
a.
severe respiratory disease or pulmonary fibrosis;
b.
active tuberculosis;
c.
in patients enrolling from studies with regular spirometry: reduction of FEV1, FVC 
and/or DLCO below 60% of core study baseline values or if FEV1, FVC and/or DLCO 
at extension study baseline is the second of two consecutive pulmonary function tests 
with values <80% of core study baseline.
13. Severe liver impairment or chronic liver disease.
14. Positive screening for serological markers for hepatitis A, B, C and E indicating acute or 
chronic infection:

anti-hepatitis A virus IgM,

hepatitis B surface antigen and/or anti-hepatitis B core antigen IgM,

anti-hepatitis C virus IgG or IgM,

anti-hepatitis E virus IgM (if positive IgG: do hepatitis E virus-RNA polymerase chain 
reaction: if negative, patient can be included).
Note: The following patients, assuming they have normal aminotransferase activities, can be 
included in the trial:

those testing positive for hepatitis B surface antibody, indicating hepatitis B immunization -
OR-

those testing positive for anti-hepatitis B core antigen IgG, indicating a cured hepatitis B -
OR-

those testing positive for anti-hepatitis A virus IgG, indicating a cured hepatitis A.
Investigational therapy: 
All patients will receive open-label fingolimod 0.5 mg, taken p.o. once daily.
Study design: 


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This study uses an open-label, multi-center, single treatment arm design allowing patients participating 
in the fingolimod multiple sclerosis clinical development program to enroll to collect additional long-
term safety, tolerability, efficacy, and health outcomes data. 
This study has two parts:

Part One, collecting long-term safety, tolerability, efficacy, and health outcomes data through 
approximately 30-Jun-2016, and 

Part Two*, collecting limited safety data until approximately 30-Jun-2018, in a subset of patients 
participating in Part One, and  other eligible patients from ongoing fingolimod trials (e.g., 
CFTY720D2312).
*Eligibility for Part Two is defined as prior fingolimod study patients who are unable to obtain 
fingolimod outside a clinical trial.
By June 2016, investigators must determine commercial Gilenya eligibility for all active study patients 
(i.e., reimbursed for commercial Gilenya).  Patients able to obtain commercial Gilenya will then have 
their End of Study (Part One) visit and exit the study, regardless of their post-study treatment decision 
(i.e., continuing on Gilenya commercially or transitioning to another treatment option).  Patients 
discontinuing or completing the study at Part One who do not continue on commercial Gilenya must 
return for two follow-up study visits, 3-months and 6-months post-last dose of fingolimod.  Patients 
who choose to continue on commercial Gilenya outside the study are exempted from the follow-up 
visits.
Patients not eligible for reimbursed, commercial Gilenya will be offered continued study participation in 
Part Two until their scheduled study visit closest to 30-Jun-2018 (+/- 30 day visit window), with a 
reduced  assessment schedule (see Table 6-2), for the purpose of collecting additional long-term 
safety and tolerability data in support of the primary study objective.  Patients discontinuing or 
completing the study after entering Part Two who do not continue on commercial Gilenya must return 
for one follow-up study visit, 3-months post-last dose of fingolimod.  Patients who choose to continue 
on commercial Gilenya outside the study are exempted from the follow-up visit.
Safety assessments: 

Physical/neurological examination

Vital signs

Laboratory blood evaluations

Eye exam by treating physician

ECG

Ophthalmologic Exam/Optical coherence tomography (OCT) by ophthalmologist, if clinically 
indicated

Skin assessments, if clinically indicated

Pulmonary function testing, if clinically indicated
Efficacy assessments: 

MS Relapse

Expanded Disability Status Scale (EDSS)

Magnetic Resonance Imaging (MRI)

Multiple Sclerosis Functional Composite (MSFC)


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Data analysis: 
Unless otherwise specified, the following pertains to the entire study (Study Parts One and Two).
Long-term safety will be assessed based on adverse events (AEs), laboratory and vital signs as well 
as other investigations performed when clinically indicated.  Analysis of the safety variables will be 
conducted on the safety set. 
Incident rates (IRs) of adverse events per 100 patient-years will be summarized by highest assigned 
fingolimod dose (fingolimod 0.5 mg/day and any dose of fingolimod).
To further evaluate the risk with longer fingolimod exposure duration, IR if adverse events reported 
with different fingolimod exposure durations will be compared.  
In addition, the incidence of adverse events (new or worsened from the long-term extension baseline) 
reported during the long-term extension will be summarized by primary system organ class and 
preferred term as frequency count and percentage of patients with adverse events.
The incidence of death, serious adverse events (SAEs), AEs leading to discontinuation, and other 
significant AEs will be summarized separately by primary system organ class and preferred term.
Laboratory data will be summarized using summary statistics of raw data and change from baseline 
values. For liver function tests, the frequencies and percentages of patients with elevations of 1, 2, 3, 5, 
and 10 times upper limit of normal will be summarized by visit (Study Part One only).  
Vital sign data will be summarized as descriptive statistics for change from baseline value. The 
incidence rates of notable vital sign abnormalities will be summarized. 
Summary statistics for ECG parameters (including pre-dose ECG for patients who have this evaluation 
done) will be summarized by visit. Incidence of abnormal ECGs by type of abnormality will be 
presented.
The incidence of macular edema events will be summarized as frequency distributions. The patient 
data listing will also be provided.
Pulmonary function test data (FEV1, FVC, and DLCO, percentage of predicted value for these three 
variables, and smoking status) will be summarized.
The skin assessment will be summarized based on abnormal findings.
The safety data will also be summarized by subgroups for the supportive safety analysis purpose.
The safety data obtained after discontinuation of the study drug will be summarized.
Descriptive statistics (along with change from baseline to post-baseline visit, where appropriate) will be 
presented for the following variables: Annual Relapse Rate (ARR), time to relapse (including HR), 
absolute EDSS scores, time to EDSS scores of 4, 6, 7, time to 6-month confirmed disability 
progression, absolute MSFC scores
 


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1
Introduction
1.1
Background
Multiple Sclerosis (MS) is a chronic, demyelinating, immune-mediated disease of the central 
nervous system characterized by inflammation and destruction of myelin and axons (Trapp et 
al 1998, Sospedra et al 2005). Typically recurrent acute episodes (relapses) of neurological 
symptoms, which are followed by a complete or partial recovery, can be observed during the 
relapsing remitting multiple sclerosis (RRMS) disease course. Approximately 50% of these 
patients progress to secondary progressive MS (SPMS) within 10 years, 90% within 25 years. 
Apart from these initially relapsing forms of MS, 10-15% of patients present with primary 
progressive MS (PPMS), which is characterized by steady deterioration of impairment 
without prior experience of relapses (Keegan et al 2002).
Fingolimod (FTY720) is a new chemical entity for once daily oral administration which 
completed phase III development and has obtained marketing authorization in the US, Europe 
and a number of other countries and regions since 2010. 
Pharmacologically, fingolimod targets a novel class of G protein-coupled receptors (GPCRs) 
which bind the pleiotropic sphingolipid mediator sphingosine 1-phosphate (S1P) and acts in 
large part by down-modulating S1P/S1P receptor responses in the immune and the central 
nervous systems. It causes a reversible sequestration of a proportion of CD4+ and CD8+ 
positive T-cells and B-cells from blood and spleen into lymph nodes (LNs) and Peyer’s 
patches, apparently without affecting many of the functional properties of these cells. Under 
normal circumstances, T-cells selectively require S1P1 activation for emigration from the 
thymus, and both T- and B-cells require this receptor for egress from peripheral lymphoid 
organs. FTY720-P (FTY720-phosphate) acts as a super agonist of the S1P1 receptor on 
lymphocytes, inducing its uncoupling/internalization. The internalization of S1P1 renders 
these cells unresponsive to S1P, depriving them of the obligatory signal to egress from 
lymphoid organs and recirculate to peripheral inflammatory tissues. As a consequence, 
autoaggressive T-cells remain trapped in the lymphoid system, i.e. in the autoantigen-draining 
cervical LNs in experimental autoimmune encephalomyelitis (EAE)/MS, and this reduces 
their recirculation to the CNS and abrogates central inflammation.
In a large active controlled study (CFTY720D2302, TRANSFORMS) vs. intramuscular 
interferon beta-1a (IFN β-1a i.m.), fingolimod showed a significant reduction in relapse rate 
over the 12-month treatment period and also significantly improved MRI findings e.g. 
reduction in markers of inflammatory activity in the brain. A significant reduction in the loss 
of brain volume was detected, as compared to IFNb-1a i.m. (Cohen et al. 2010). In a 2-year 
placebo-controlled study (CFTY720D2301, FREEDOMS),
fingolimod demonstrated 
sustained reduction of relapse rate, delayed disability progression and demonstrated reduction 
in markers of inflammatory activity in the brain. As in TRANSFORMS, in FREEDOMS a 
significant reduction in the rate of brain atrophy was observed as compared to placebo as 
early as 6 months after the initiation of treatment, and consistently so at 12 and 24 months 
(Kappos et al. 2010).


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The safety profile of fingolimod has been well characterized in the MS clinical development
program. As of 29-Feb-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 current investigator brochure.
The safety profile observed in the fingolimod MS clinical development program can be 
summarized as follows:

The overall incidence of AEs leading to discontinuation of study drug was slightly higher
for the fingolimod 0.5 mg/day (10.5%) than the placebo group (8.7%), and higher again in
the 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%). 

Specific AEs that were reported more commonly in MS patients treated with fingolimod 
than placebo included elevation of liver enzymes, in particular increases in ALT and GGT, 
reduction in white blood cell counts (lymphocytes and total WBC), transient bradycardia 
following the post first dose of fingolimod, macular edema, hypertension, dyspnea, 
bronchitis, and diarrhea. The AEs most prominently associated with fingolimod treatment, 
e.g. liver enzyme elevations, bradycardia, and macular edema appeared to show a dose 
related response. There were no AEs that appeared to be specifically related to long-term
treatment with fingolimod.

In general, the AE profile of fingolimod in MS patients did not depend on gender, age, or 
previous treatment with disease-modifying drugs. The only exception was liver enzyme 
elevations which were more frequent in male patients than in female patients treated with 
fingolimod.

The overall incidence of infections, including serious infections, was similar in the 
fingolimod treatment groups and the comparator arms (interferon or placebo) in both 
completed phase III studies. A slightly higher frequency of lower respiratory tract 
infections (primarily bronchitis) was observed in fingolimod treated patients, with 
apparent dose effect. Two fatal infections occurred in the fingolimod 1.25 mg/day group: 
one case of disseminated varicella-zoster virus in a sero-negative patient receiving 
concomitant high dose steroid therapy for an MS relapse, and one case of herpes simplex 
encephalitis in a patient in whom initiation of acyclovir therapy was delayed by one week. 
The current data showed no clear relationship between lymphocyte count and the 
incidence of infections on fingolimod treatment.  The accumulated data from the MS 
program do not show an association of fingolimod therapy with the development of 
malignancies. Cases of lymphoma (cutaneous T-cell lymphoproliferative disorders or 
diffuse B-cell lymphoma) were reported in premarketing clinical trials in MS patients 
receiving fingolimod at, or above, the recommended dose of 0.5 mg. Based on the small 
number of reported cases and short duration of exposure, the relationship to fingolimod 
remains uncertain.

Initiation of fingolimod treatment has been associated with atrio-ventricular conduction 
delays usually as first-degree atrio-ventricular blocks (prolonged PR interval on ECG). 
Second-degree atrio-ventricular blocks, usually Mobitz type I (Wenckebach), have been 
observed in less than 0.5% of patients receiving fingolimod 0.5 mg in clinical trials.  The 


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conduction abnormalities typically were transient, asymptomatic, usually did not require 
treatment and resolved within the first 24 hours on treatment.  

The use of fingolimod in women who are or may become pregnant should only be 
considered if the potential benefit justifies the potential risk to fetus. Animal studies have 
shown reproductive toxicity including fetal loss and organ defects, notably persistent 
truncus arteriosus and ventricular septal defect. Furthermore, the receptor affected by 
fingolimod (sphingosine-1-phosphate receptor) is known to be involved in vascular 
formation during embryogenesis. The data available from the use of fingolimod in 
pregnant women are too limited to draw conclusions on safety of fingolimod in pregnancy. 
Since it will take approximately 2 months to eliminate the compound from the body upon 
stopping treatment, risk potential to the fetus may persist and contraception should be 
pursued during that period. The risk of teratogenic effects of fingolimod is being further 
addressed in a specific pregnancy registry. Fingolimod is excreted in milk of treated 
animals during lactation. Because of the potential for serious adverse drug reactions in 
nursing infants from fingolimod, women receiving fingolimod should not breast feed.

The safety and tolerability profile did not change over time, as determined in the pooled 
data of the phase II and III studies and their respective open-label extension studies. In 
particular, the incidence of malignancies and serious infections did not increase over time.
Further long-term data are however needed to better estimate the incidence of rare or time-
dependent adverse events.
The current data showed no significant difference on efficacy between the fingolimod 1.25 
mg/day and the 0.5 mg/day doses in phase III studies. Fingolimod 0.5 mg/day was associated 
with an overall more favorable risk/benefit profile than fingolimod 1.25 mg/day. Based on 
these data, the dose of fingolimod chosen for registration and for further clinical development 
is 0.5 mg/day.
In the post-marketing setting, isolated delayed onset events, including transient asystole and 
the one unexplained death, have occurred within 24 hours of the first dose.  These cases 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 initiated in
patients with a history of cardiovascular or cerebrovascular disease or in those patients taking
heart-rate lowering medications.  Safety assessments in this study specifically address these 
areas of interest in the safety and tolerability profile of fingolimod over the long-term.
1.2
Purpose 
The purpose of this study is to collect long-term safety, tolerability, efficacy, and health 
outcomes data in patients who participated in the fingolimod multiple sclerosis clinical 
development program.
2
Study objectives
2.1
Primary objectives
This study is designed to evaluate the long-term safety and tolerability of fingolimod 0.5 
mg/day in patients with MS for the duration of the study.


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2.2
Secondary objectives
This study will also evaluate long-term efficacy of fingolimod 0.5 mg/day in patients with MS, 
as measured by disability progression, brain volume (atrophy), T1- (non-enhanced) and T2-
weighted lesion volume and MS relapse occurrence in Study Part One.
3
Investigational plan
3.1
Study design
This study uses an open-label, multi-center, single treatment arm design allowing patients 
participating in the fingolimod multiple sclerosis clinical development program to enroll in 
order to collect additional long-term safety, tolerability, efficacy, and health outcomes data. 
This study has two parts:

Part One, collecting long-term safety, tolerability, efficacy, and health outcomes data 
through approximately 30-Jun-2016, and 

Part Two*, collecting limited safety data until approximately 30-Jun-2018, in a subset of 
patients participating in Part One, and  other eligible patients from ongoing fingolimod 
trials (e.g., CFTY720D2312).
*Eligibility for Part Two is defined as prior fingolimod study patients who are unable to 
obtain fingolimod outside a clinical trial.
By June 2016, investigators must determine commercial Gilenya eligibility for all active study 
patients (i.e., reimbursed for commercial Gilenya).  Patients able to obtain commercial
Gilenya will then have their End of Study (Part One) visit and exit the study, regardless of 
their post-study treatment decision (i.e., continuing on Gilenya commercially or transitioning 
to another treatment option).  Patients discontinuing or completing the study at Part One who 
do not continue on commercial Gilenya must return for two follow-up study visits, 3-months 
and 6-months post-last dose of fingolimod.  Patients who choose to continue on commercial 
Gilenya outside the study are exempted from the follow-up visits.  
Patients not eligible for reimbursed, commercial Gilenya will be offered continued study 
participation in Part Two until their scheduled study visit closest to 30-Jun-2018 (+/- 30 day 
visit window), with a reduced  assessment schedule (see Table 6-2), for the purpose of 
collecting additional long-term safety and tolerability data in support of the primary study 
objective.  Patients discontinuing or completing the study after entering Part Two who do not 
continue on commercial Gilenya must return for one follow-up study visit, 3-months post-last 
dose of fingolimod.  Patients who choose to continue on commercial Gilenya outside the 
study are exempted from the follow-up visit.  
Patients enrolling in either part of the study from blinded studies will remain blinded to the 
identity of the treatment in the previous study.  In order to maintain the blind, the monitoring 


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immediately after the first dose of study drug will be performed by a blinded first-dose 
administrator. 
3.2
Rationale of study design
The clinical development program of fingolimod has demonstrated efficacy and a favorable 
benefit/risk ratio of the fingolimod 0.5 mg/day dose in patients with relapsing-remitting 
multiple sclerosis (RRMS), based on reduction in the annualized relapse rate, the reduction in 
risk for disability progression, and reduction of inflammatory activity and brain atrophy in the 
brain as evidenced by MRI. The safety profile of fingolimod has been well characterized in 
comparison to both placebo and a first-line treatment active comparator. The specific areas of 
concern in the safety profile of fingolimod have been identified and are addressed as 
appropriate in this protocol.
This study is designed to collect long-term safety, tolerability, efficacy and health outcomes
data in eligible patients who participated in the fingolimod multiple sclerosis clinical 
development program.
An open-label, non-comparative single arm design is considered adequate for this type of 
long-term extension. Neither a placebo-control can be justified over the long-term nor does 
the logistical burden for patients and study sites justify the use of an active comparator arm.
The visit and assessment schedule has been aligned with common medical practice in the care 
for patients with MS and with fingolimod treatment. Based on the assumption that continued 
study participation means there is a positive benefit-risk paradigm for these patients, Part Two 
of the protocol has been added, offering continued patient participation in a subset of patients 
(those unable to obtain access to/reimbursement for commercial Gilenya) for an additional 
(approximately) two years, through June 2018.  This will allow continued fingolimod use 
until countries and investigators can find alternate treatment solutions.  
In Study Part One, safety and tolerability data will be collected at regular intervals, in addition 
to EDSS assessments and periodic MRI scans, which will document chronic disease 
progression in terms of physical disability and brain tissue loss without undue burden on the 
patient. Study Part Two will collect safety and tolerability data only.
3.3
Rationale of dose/regimen, duration of treatment
The dose and dosing regimen of fingolimod 0.5 mg once a day has been identified in the 
phase III development program of fingolimod in RRMS as providing the best benefit/risk 
ratio and is therefore the proposed dose and regimen in the registration files to the health 
authorities and is the approved dose where fingolimod has been registered.
The duration of treatment of a patient in this trial is dependent on which study the patient 
participated in previously as well as the availability of reimbursement for commercially 
available fingolimod in the respective country. The end of the study is planned for 30 June 
2018 (+/- 3 months).   Individual patient’s end of treatment visits should occur at their routine 
6 monthly scheduled visit closest to 30 June 2018 to ensure all patients complete within the 
window for the end of the study.


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Patients participating in this study will provide clinical data of 7-15 years of exposure, which 
will provide information on the long-term safety, tolerability and efficacy profile to help in 
therapeutic decision making.
[Only in the UK and Poland:  The duration of treatment of a patient in this trial is dependent 
on what study the patient participated in previously (phase II/III vs. other). Phase II/III 
patients will remain in the study maximally through 30-Jun-2016.  Patients, who participated
in any designated global fingolimod MS trial other than phase II/III (e.g. CFTY720D2316, 
CFTY720D2320, etc.), were allowed to remain in the study until the drug was registered and 
through approximately one-year post approval or maximally through 31-Dec-12.]
[Only for Norway: The duration of treatment of a patient in this trial ran for approximately 12 
months following the completion of the previous fingolimod trial or maximally through 01-
Aug-2012.]
3.4
Rationale for choice of comparator
Not applicable.
3.5
Purpose and timing of interim analyses/design adaptations
Periodic interim safety analyses to support regulatory updates may be warranted.
4
Population
Approximately 5000 patients who have completed ongoing or planned clinical trials in the 
MS development program with fingolimod are expected to be enrolled in >500 centers 
worldwide.
This study will pool eligible patients participating in the fingolimod multiple sclerosis clinical 
development program to allow patients to receive continuous treatment with fingolimod and 
to collect long-term safety, tolerability, efficacy, and health outcomes data during Study Part 
One. In Study Part Two, only safety and tolerability data will be collected.
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. Patients who have completed designated ongoing or planned Novartis global clinical
trials with fingolimod and are unable to obtain fingolimod outside a clinical trial.
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study:
1. Premature permanent discontinuation from any fingolimod study due to:
a.
An adverse event or serious adverse event or laboratory abnormality.
b. Conditions leading to permanent study drug discontinuation.
2. Pregnant or nursing (lactating) women where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 


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hCG laboratory test (> 5 mIU/ml).  Patients who temporarily or permanently 
discontinued from any fingolimod study because of pregnancy or nursing (lactating) 
can be re-enrolled.
3. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, UNLESS they are using highly effective contraception during the 
study and for 2 months after stopping treatment. ‘Highly effective 
contraception’defined as contraception which results in less than 1% unwanted 
pregnancies when used properly according to the label.    
     Women are considered post-menopausal and not of child-bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms)  or have had surgical 
bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six 
weeks prior to baseline. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of child bearing potential.
4. Chronic disease of the immune system other than MS which may require 
immunosuppressive treatment.  
5. Severe active infection or active chronic infection.
6. Previous treatment with cladribine, cyclophosphamide or mitoxantrone.
7. Treatment with monoclonal antibodies (including Natalizumab) in the past 3 months.
8. Uncontrolled diabetes (HbA1c>9%).
9. Macular edema at Baseline.
10. Any medically unstable condition that may interfere with the patient’s ability to 
cooperate and comply with the study procedures, as assessed by the treating physician.
11. Any of the following cardiovascular conditions:
a. myocardial infarction within the past 6 months prior to enrollment or current 
unstable ischemic heart disease; 
b. cardiac failure at time of Screening (Class III & IV, according to New York Heart 
Association Classification) or any severe cardiac disease as determined by the 
investigator;
c. patients receiving current treatment with Class Ia and III antiarrhythmic drugs (e.g., 
quinidine, disopyramide, amiodarone, bretylium, sotalol, ibulitide, azimilide, 
dofelitide, ajmaline, procainamide);
d. second-degree AV block Type II or third-degree AV block or corrected QTc
interval 450 msec in males or >470 msec in females;
e. sick sinus syndrome or sino-atrial heart block;
f.
uncontrolled hypertension despite prescribed medications.
12. Any of the following pulmonary conditions during the previous fingolimod study or 
observed at enrollment visit:
a.
severe respiratory disease or pulmonary fibrosis;
b. active tuberculosis;
c.
in patients enrolling from studies with regular spirometry: reduction of FEV1, FVC 
and/or DLCO below 60% of core study baseline values or if FEV1, FVC and/or 


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DLCO at extension study baseline is the second of two consecutive pulmonary 
function tests with values <80% of core study baseline.
13. Severe liver impairment or chronic liver disease.
14. Positive screening for serological markers for hepatitis A, B, C, and E indicating acute 
or chronic infection: 

anti-hepatitis A virus IgM, 

hepatitis B surface antigen and/or anti-hepatitis B core antigen IgM, 

anti-hepatitis C virus IgG or IgM, 

anti-hepatitis E virus IgM (if positive IgG: do hepatitis E virus-RNA polymerase 
chain reaction; if negative, patient can be included).
Note: The following patients, assuming they have normal aminotransferase activities, can 
be included in the trial:

those testing positive for hepatitis B surface antibody, indicating hepatitis B 
immunization -OR-

those testing positive for anti-hepatitis B core antigen IgG, indicating a cured 
hepatitis B -OR-

those testing positive for anti-hepatitis A virus IgG, indicating a cured hepatitis A.
5
Treatment
5.1
Investigational and control treatment
Open-label fingolimod 0.5 mg, taken p.o once daily.
Medication labels will comply with the legal requirements of each country and will be printed 
in the local language.  
5.2
Treatment arms
All patients will receive open-label fingolimod 0.5 mg, taken p.o. once daily.
5.3
Treatment assignment
There is only one treatment arm in this trial which is open-label fingolimod 0.5 mg, taken p.o. 
once daily.
5.4
Treatment blinding
As this trial is open-label single arm trial, treatment will not be blinded during the course of 
the study.
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 


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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 IRT 
system and provide the requested identifying information for the patient to register them into 
the IRT system.  The assigned patient number should be entered in the field labeled “Patient
ID” on the 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 participate for any reason, the IRT 
system must be notified within 2 days that the patient was not enrolled.  The reason for not 
being enrolled will be entered in the source documents.
5.5.2
Dispensing the study treatment
Each study site will be supplied by Novartis with study drug in packaging of identical 
appearance.
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label.  Investigator staff will identify the study drug package(s) to dispense to the 
patient by contacting the IRT system and obtaining the medication number(s). Immediately 
before dispensing the package to the patient, investigator staff will detach the tear-off portion 
of the label from the packaging and affix it to the source document (Drug Label Form) for that 
patient’s unique patient number and if applicable, logged in the IRT system drug 
accountability web-based portal.
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 storage instructions specified on the drug labels. Should a storage excursion occur, the site 
must contact Novartis to determine if the study medication can continue to be used.  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 medication 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 
return all unused study drug and packaging at each visit, and 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.


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5.5.4
Instructions for prescribing and taking study treatment
Study medication will be dispensed at the Baseline visit and each subsequent treatment visit 
thereafter as per the schedule of assessments.  The patients will receive up to 6 bottles of oral 
medication containing 35 capsules per bottle at each visit, which will provide enough 
medication through their next regularly scheduled visit.
The investigator should promote compliance by instructing the patient to take the study drug 
exactly as prescribed and by stating that compliance is necessary for the patient’s safety and 
the validity of the study. The patient should be instructed to contact the investigator if he/she 
is unable for any reason to take the study drug as prescribed.  Instruction should also be given 
to the patient to open and use one bottle at a time.  All unused medication as well as empty 
bottles should be returned to the investigator at the next regularly scheduled visit.
Study medication should be taken once a day, preferably at the same time every day, with or 
without food. 
Once the eligibility of a patient for entry into the study has been confirmed based on the study 
inclusion/exclusion criteria, study medication will be dispensed via the IRT system (see 
Section 5.5.2).
Patients enrolling directly from a blinded study in which a blinded comparator arm exists 
(placebo or active comparator) may require blinded first dose observation, performed by a 
blinded first-dose administrator who cannot discuss the findings with the patients or anyone 
else associated with the clinical trial unless this is required for a medical reason.
If patients transition into this extension study from the comparator arm of an open-label 
controlled study, the first dose of the study drug (capsules) administered at the Baseline visit
in this study must be administered in the clinic under the supervision of the investigator or 
designee, or in accordance with the local label.
Similarly, any patient who re-initiates fingolimod treatment after an interruption, the first dose 
of the study drug (capsules) administered at treatment re-initiation must be administered in the 
clinic under the supervision of the investigator or designee, or in accordance with the local 
label if the following circumstances apply:

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.
Advice from a cardiologist should be sought and overnight monitoring with continuous ECG 
is required under the following circumstances:

The pre-dose ECG shows a QTc interval >470 msec (females) or >450 msec (males) or a 
second degree or higher AV block

The patient has relevant risk factors for QT prolongation, for example, hypokalaemia or 
hypomagnesemia, sick-sinus syndrome, or sino-atrial heart block


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
The patient has known ischemic heart disease, history of myocardial infarction, congestive 
heart failure, history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension 
or severe untreated sleep apnea period

The patient has a history of recurrent syncope or symptomatic bradycardia

The resting heart rate pre-dose is <45
For patients receiving (at treatment re-initiation) beta blockers, heart-rate slowing calcium 
channel blockers (e.g. ivadrabine, verapamil, or diltiazem), or other substances which may 
decrease heart rate such as digoxin, anticholinesteratic agents or pilocarpine, advice from a 
cardiologist should be sought regarding the switch to non-heart-rate lowering medicinal 
products prior to re-initiating treatment. If a switch to non-heart rate lowering drugs is not 
possible, patients have to be observed overnight. 
Patients transferring from blinded placebo-controlled or active comparator trials, or patients
enrolling into the study who have been off fingolimod treatment for 90 days or more will need 
additional visits at 1 and 3 months post-first dose (see Table 6-1 and 6-2).
Patients requiring first dose monitoring should receive the first dose of study drug 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 peroid. Sitting heart rate and blood pressure will also be monitored before the first 
dose of fingolimod and every hour for at least six-hours thereafter. The patient may be
discharged if specific discharge criteria (outlined in Appendix 4) 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 4 for Guidance for monitoring of patients taking 
their first dose of the study drug). 
All medication prescribed and dispensed to the patient and all dose interruptions during the 
study must be recorded on the Dosage Administration Record eCRF.
All drug kits assigned by the IRT system will be recorded in the IRT system.
5.5.5
Permitted dose adjustments and interruptions of study treatment
Study drug dose adjustments are not permitted, although interruptions may be warranted 
based on safety monitoring guidelines and should be recorded on the Dosage Administration 
Record eCRF.
Absolute lymphocyte count <0.2x109/l, if confirmed, should lead to treatment interruption 
until recovery. (See Appendix 5 for safety monitoring guidelines).  Should the patient 
interrupt study drug, and the Investigator decide to re-initiate treatment with study drug, the 
first-dose monitoring procedure may be required for the restart of study drug (see Appendix 4
for details).


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5.5.6
Rescue medication
Not applicable.
5.5.7
Concomitant treatment
All on-going concomitant medications taken at the time of the Baseline visit and during the 
study must be recorded. In addition, any medications that may have been taken during any 
gap between the completion of the prior study and enrollment into this extension study should 
also be recorded, even if the medication is not ongoing at the time of enrollment.  Medications 
that were recorded during the previous study and had a recorded end prior to completion of 
the previous study do not need to be re-recorded in this study. Both the start date and the end 
date 
for 
each 
medication 
should 
be 
captured 
on 
the 
“the 
“Concomitant 
Medications/Significant Non-Drug Therapies eCRF or Steroid treatment of MS relapses eCRF,
as applicable. Use of the following treatments is allowed to manage potential adverse 
reactions associated with the study drug:

anticholinergics (atropine s.c. or i.v.) for treatment of symptomatic bradycardia as the first 
line treatment, up to 3 mg/day;

beta-agonists/sympathomimetics (dopamine drip 5-20µg/kg/min or epinephrine drip 2-10 
µg/min) for treatment of non-responsive bradycardia.
For more recommendations for management of bradycardia, refer to Appendix 4.
A standard short course of intravenous corticosteroids (3-5 days of up to 1,000 mg 
methylprednisolone/day) on an inpatient or outpatient basis is recommended for the treatment 
of relapses if clinically warranted (standard of care procedures should be followed during 
treatment) and should be recorded on the Steroid treatment of MS relapses eCRF.  Tapering 
with oral corticosteroids is not recommended.
The investigator should instruct the patient 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 recorded on the Concomitant medications/Significant 
Non-Drug Therapies eCRF or Steroid treatment of MS relapses eCRF.  
Vaccination may be less effective during and for up to two months after treatment with 
fingolimod. 
5.5.8
Prohibited treatment
Use of the following treatments is NOT allowed concomitantly with the study drug during the 
course of the study:

Immunosuppressive medication (e.g. cyclosporine, azathioprine, methotrexate, 
cyclophosphamide, mitoxantrone, cladribine);

Other concomitant medications: immunoglobulins, monoclonal antibodies, 
adrenocorticotropic hormone (ACTH-other than if used as a short course (e.g. less than 1 
week) for the treatment of MS relapse);

Medications used to treat MS, which may include glatiramer acetate (Copaxone®), 
interferon β-1a i.m. (Avonex®), interferon β-1a s.c. (Rebif®), interferon β-1b 


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(Betaseron®/Betaferon®), natalizumab (Tysabri®), azathioprine, methotrexate or any 
other medications used as MS-disease-modifying agents;

Class Ia (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol)
antiarrhythmics. 
The administration of any live or live attenuated vaccine (including for measles) should be 
avoided while patients are receiving study drug and for 2 months after study drug 
discontinuation. Following Varicella zoster virus (VZV) vaccination, the initiation of study 
drug should be postponed by 1 month to allow full effect of vaccination to occur.
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. 
When a patient withdraws from Study Part One and does not continue on fingolimod, either in 
a study or non-study setting, they must return for two Follow-up visits, 3 months and 6 
months after stopping study drug.  
When a patient withdraws from Study Part Two, and does not continue on fingolimod, either 
in a study or non-study setting, they must return for one Follow-up visit, 3 months after 
stopping study drug.  
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 appropriate eCRF.
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. In addition, study drug must be 
discontinued based on results of safety monitoring as outlined in Appendix 5:  Guidance on 
safety monitoring and Appendix 7:  Guidance for Ophthalmic Monitoring. 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. cardiac failure, diagnosed malignancy, new neurological 
symptoms accompanied by MRI findings unexpected for MS) abnormal laboratory 
value(s) or abnormal test result(s) (e.g ophthalmic findings). 

withdrawal of consent 

pregnancy (please see Section 6.5.8 and Section 7.3)

use of prohibited medications, listed in Section 4.2 and 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)

discontinuation warranted as per local label requirements


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In addition to scheduled visits, patients who discontinue study drug due to adverse events or 
abnormalities on safety monitoring tests must be followed up with additional visits as needed 
in order to confirm the resolution of abnormalities. 
Document the date and primary reason for stopping the study drug on the appropriate page of 
the eCRF.  If study medication is restarted as per protocol, the reason for the interruption of 
treatment and date of interruption should be appropriately documented in the source 
documents as well as in the Dosage Administration eCRF. 
For patients who are lost to follow-up (i.e. those 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 documenting in the source documents steps taken to contact the 
patient, e.g. dates of telephone calls, registered letters, etc.
If a patient permanently discontinues from study drug, the investigator must also contact the 
IRT system to register the patient’s discontinuation from study drug. 
Patients who are prematurely withdrawn from the study will not be replaced by an equal 
number of newly enrolled patients.
5.5.10
Emergency unblinding of treatment assignment
Not applicable as this is an open-label study.  
5.5.11
Study completion and post-study treatment
Study Part One completion is planned for 30 Jun 2016.  Individual patient’s end of treatment 
visits should occur at their routine 6 monthly scheduled visit closest to 30 June 2016 to ensure 
all patients complete within the window for the end of Study Part One.
The end of the study (completion of Study Part Two) is planned for 30 June 2018.   Individual 
patient’s end of treatment visits should occur at their routine 6 monthly scheduled visit closest 
to 30 June 2018 to ensure all patients complete within the window for the end of the study.
The investigator must provide follow-up medical care for all patients who are prematurely 
discontinued from the study, or must refer them back to their referring physician for 
appropriate care. 
5.5.12
Early study termination
The study 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 5.5.9 for a 
prematurely withdrawn patient. The investigator may be informed of additional procedures to 
be followed in order to ensure that adequate consideration is given to the protection of the 
patient’s interests. The investigator will be responsible for informing IRBs and/or ECs of the 
early termination of the trial.
6
Visit schedule and assessments
Table 6-1 and 6-2 list all assessments, and indicates with an “X” the visits when they are 
performed and recorded in the clinical database, with an “S” indicates when a performed


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assessment is to be recorded on source documentation, and an “S1” indicates that source 
documentation should be present to confirm the procedure was performed as part of the 
previous fingolimod trial (Specific to the Baseline visit only). If an “S1” procedure was not 
performed in the previous trial, it has to be performed at Baseline. Assessments performed at 
the final visit of the previous fingolimod trial can fulfill the requirements of the Baseline only 
if they are completed within 14 days of enrollment in CFTY720D2399.
Patients should follow as much as possible the visit schedule with an allowed “visit window” 
of + 5 days for bi-weekly visits, of + 10 days for monthly visits, of + 14 days for quarterly 
visits and of + 30 days for bi-annual visits.  If a visit was performed outside the visit window,
any subsequent visits should be performed according to the original visit schedule.  In the 
study, one month is defined as 30 calendar days.
Upon availability of the locally approved prescribing information, completion of any
additional assessments required by the local label becomes the responsibility of the 
investigator. The assessments should be completed for all patients, unless prohibited by local 
regulations. Any findings qualifying as AEs/SAEs should be reported as such.
Table 6-1
Assessment schedule (Study Part One)
Visit No.*
Base 
line V1
V1121
V2
V3
V4
V5
V6
V7...
Study 
Completion 
or 
Premature 
Dis-
continuation*
*
FU   
1 14
FU
2 14
Study month
Day 
1
Month 
1
Month 
3
Month 
6
Month 
9
Month  
12
Month 
18
Every 6 
Months 
until SC
Informed 
consent
XS
Demography
S1
Inclusion/ 
exclusion 
criteria
XS
Previous 
Study Details
XS
Amendment 4 
Details
Record when Amendment 4 is approved or at Baseline if newly enrolled under Amendment 
4
Amendment 8 
Details
Record the signature date of the Amendment 8 patients informed consent 
Medical history
S1
Concomitant 
meds
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
Pregnancy 
test15
S1
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
Physical/neuro
logical exam
S1
S
S
S
S
S
S
S
S
S
MRI2
XS2a
XS


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Visit No.*
Base 
line V1
V1121
V2
V3
V4
V5
V6
V7...
Study 
Completion 
or 
Premature 
Dis-
continuation*
*
FU   
1 14
FU
2 14
Study month
Day 
1
Month 
1
Month 
3
Month 
6
Month 
9
Month  
12
Month 
18
Every 6 
Months 
until SC
Skin exam     
by a qualified  
physician4
Record as needed
Eye Exam5
S1
XS
XS
XS
OCT/Ophthal
mic Exam
XS5a
XS5a
Record as needed
PFTs3
Record as needed
Vital signs
S1
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
Screening for 
hepatitis A, B, 
C & E and 
uncontrolled 
diabetes
XS
Hematology/
S1
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
Blood 
Chemistry
S1
XS
XS
XS
XS
XS
1/year
XS
XS
XS
Serology6
XS
Dispense 
study drug
S
S
S
S
S
S
S
Collect unused 
study drug
S
S
S
S
S
S
S
First dose 
monitoring7
XS
Record as needed
First Dose 
ECG8
S1
Record as needed
Dosage 
Administration 
Record
XS
XS
XS
XS
XS
XS
XS
XS
EDSS12
S1
XS
XS
XS
XS
XS
XS
XS
MSFC9
S1
XS
XS
XS
XS
XS
XS
XS


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Protocol No. CFTY720D2399
Visit No.*
Base 
line V1
V1121
V2
V3
V4
V5
V6
V7...
Study 
Completion 
or 
Premature 
Dis-
continuation*
*
FU   
1 14
FU
2 14
Study month
Day 
1
Month 
1
Month 
3
Month 
6
Month 
9
Month  
12
Month 
18
Every 6 
Months 
until SC
MS relapse
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
Steroid Use
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
Adverse 
events/ SAEs
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
XS
Study 
Completion
XS
1.  Visit 112 is only applicable for those patients rolling into this trial from any blinded study which has 
comparator treatment arms (placebo, or active comparator, e.g. study CFTY720D2309) or for any patient who 
has been off fingolimod treatment for 90 days or greater.  All other patients will enroll at Baseline-V1 and come 
in 3 months later for V2.
2.  MRIs are required only for patients from phase II/III trials who had MRI assessments in prior FTY trials. Such 
patients will have the first MRI at V5.  If a patient has already had V5 by the time Amendment 4 is approved, the 
patient should have an unscheduled MRI upon the approval of Amendment 4.  Post-Amendment 8 approvals, 
only the Study Completion MRI is required.
2a. Phase II/III patients that enroll /re-enroll into this study under Amendment 8 must have an MRI at the 
Baseline-V1 visit for new patients or at the re-enrollment visit for re-enrolled patients.     
3.  Pulmonary function testing (FEV1, FVC, DLCO) will be performed if clinically indicated.                                     
4.  A qualified physician includes either a dermatologist or a physician who has participated in a licensed training 
program. Record if performed.
5.  An eye exam will be performed by the treating physician.
5a.  A 3-month and 6-month OCT scan and ophthalmic exam will be done by an ophthalmologist on any patient 
who is rolling into this trial from any blinded study which has comparator treatment arms (placebo or active 
comparator, e.g. study CFTY720D2309) or for any patient who has been off fingolimod treatment for 90 days or 
greater. Then, to be recorded if performed.
6.  Serology testing (if not already performed in the previous fingolimod study) will be performed at the Baseline-
V1 visit to measure Varicella-zoster virus IgG antibodies.
7.  Patients enrolling directly from a blinded study may require blinded first-dose observation.  First-dose 
monitoring to be done on any patient who is rolling into this trial from any blinded study which has comparator 
treatment arms (placebo or active comparator, e.g. study CFTY720D2309) or enrolling from the comparator arm 
of an open-label controlled study or for any patient who has been off fingolimod treatment for the durations
outlined in Appendix 4.
8. First dose 12 lead ECGs (pre- and 6 hours post-dose) to be obtained only for those patients rolling into this 
trial from any blinded study which has comparator treatment arms (placebo) or for any patient who re-initiates 
fingolimod after having been off fingolimod treatment for the durations outlined in Appendix 4..   
9.  The MSFC will only be done in patients who had previous MSFC assessments in their previous fingolimod 
study.
 


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Visit No.*
Base 
line V1
V1121
V2
V3
V4
V5
V6
V7...
Study 
Completion 
or 
Premature 
Dis-
continuation*
*
FU   
1 14
FU
2 14
Study month
Day 
1
Month 
1
Month 
3
Month 
6
Month 
9
Month  
12
Month 
18
Every 6 
Months 
until SC
 
12.  For patients who previously participated in phase II/III trials only (CFTY720D2201/E1, CFTY720D2301/E1, 
CFTY720D2302/E1, CFTY720D2309/E1, etc), EDSS will be assessed by a certified treating Physician (all phase 
II/III investigators and any new raters who join during the study will be required to provide one-time proof of 
Neurostatus EDSS certification). Physicians assessing EDSS for patients from phase IIIb trials do not have to be 
certified, and individual functional scores are not required.                                                                                         
 
 
 
  
 
14.  Follow up visits (FU) should be scheduled 3 months and 6 months (+/- 14 days) after the last dose of study 
medication.  The follow-up visits should be done only on patients who have stopped the study but do not 
continue onto fingolimod, either in a study or non-study setting.
15. Serum pregnancy tests are collected at visits where chemistry is collected.  At other visits, urine pregnancy 
tests will be performed on-site with kits provided by the central lab. 
* At each visit the patient must be reminded of the importance of remaining vigilant for infections and, in women 
of child-bearing age, practicing contraception per protocol.
** The Study Completion (SC) assessments to be performed if a patient has prematurely discontinued or if 
completed the study per protocol.  For active patients, Study Completion assessments will be performed when 
the patient reaches 60 months participation in this study.  For patients who have passed the 60 month milestone 
at the time of Amendment 10 approval at their study site must conduct their Study Completion visit at the next 6-
monthly timepoint, or 30-Jun-2016, whichever comes first.
Table 6-2
Assessment schedule (Study Part Two)
Visit No.*
Visit 
201A1
Visit 
201B2
Visit 
2112
Visit 
2122
Visit 
202
Visit 
203
Visit 
204…
Study 
Comp
letion 
or 
Prem
ature 
DC9
FU310
Study month
Day11
Day12
(First 
Dose 
Monitor)
Month 
12
Month 
32
Month 
+6/6
Month 
+12/12
Every 6 
Months 
until SC
Informed 
consent3
XS
XS
Demography3
S1
S1
Inclusion/ 
exclusion criteria
XS
XS
Previous Study 
XS
XS


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Details3
Medical History3
S1
S1
Concomitant 
meds
XS
XS
XS
XS
XS
XS
XS
XS
XS
Physical/ 
neurological 
exam
S1
S1
S
S
S
S
S
S
S
Skin exam by a 
qualified 
physician4
Record in source as needed
Eye Exam5
S1
S1
S
S
OCT/Ophthalmic 
Exam
S6
S6
PFTs
Record in source as needed
Vital signs
S1
S1
XS
XS
XS
XS
XS
XS
XS
Hematology/ 
Chemistry/ 
Pregnancy7
S
S
S
S
S
S
S
Dispense study 
drug
S
S
S
S
S
S
Collect unused 
study drug
S
S
S
S
S
S
First dose 
monitoring8
XS
Record as needed
First Dose ECG8
XS
Dosage 
Administration 
Record
XS
XS
XS
XS
XS
XS
XS
MS relapse
XS
XS
XS
XS
XS
XS
XS
XS
XS
Steroid Use
XS
XS
XS
XS
XS
XS
XS
XS
XS
Adverse events/ 
SAEs
XS
XS
XS
XS
XS
XS
XS
XS
XS
Study Completion
XS
1.  Visit 201A is applicable for current patients or those transitioning from another open-label fingolimod study
2.  Visits 201B, 211 and 212 are applicable only for those patients transitioning from a blinded fingolimod study 
which has comparator treatment arms (placebo, or active comparator, e.g. study CFTY720D2312), from the 
comparator arm of an unblinded fingolimod study, or for patients who have interrupted treatment for durations as 
outlined in Appendix 4.  
3. Informed consent, demography, previous study details, and medical history are only applicable if the patient 
enters Study Part Two from another study (i.e., not applicable for patients transitioning from Study Part One). 
4.  A qualified physician includes a dermatologist OR a physician who has participated in a licensed training 
program. 
5.  To be performed by the treating physician.
6.  A 3-month and 6-month OCT scan will be done by an ophthalmologist for patients who enroll into this trial from 
any blinded study which has comparator treatment arms (placebo or active comparator, e.g. study 


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CFTY720D2312) OR for any patient who has been off fingolimod treatment for 90 days or greater. Then, to be 
recorded if performed.
7.  Tests will be analyzed locally; results will not be recorded in the eCRF, but will remain as source 
documentation for ongoing safety assessment (clinically significant lab abnormalities should be reported as AEs).
8.  First dose 12 lead ECGs (pre- and 6 hours post-dose) to be obtained only for those patients transitioning from 
a blinded fingolimod study which has comparator treatment arms (placebo, or active comparator, e.g. study 
CFTY720D2312), from the comparator arm of an unblinded fingolimod study, or for patients who have interrupted 
treatment for durations as outlined in Appendix 4.
9.  The Study Completion (SC) assessments to be performed if a patient has prematurely discontinued or if 
completed the study per protocol.
10.  Extension follow-up visit (EFU) should be scheduled 3 months (+/- 14 days) after the last dose of study 
medication.  The follow-up visit should be done only for patients who have stopped the study but do not continue 
onto fingolimod, either in a study or non-study setting.
* At each visit the patient must be reminded of the importance of remaining vigilant for infections and, in women of 
child-bearing age, practicing contraception per protocol.
In addition to the above scheduled visits, patients may have unscheduled visits following an 
onset of MS relapse or for other reasons as necessary. All information should be collected per 
Unscheduled Visit eCRFs.
6.1
Patient demographics/other baseline characteristics
Patient demographic and baseline characteristic data were collected from the patient during 
the previous fingolimod study which included: date of birth, age, sex, race, ethnicity, pre-
treatments and source of patient referral. Relevant medical history/current medical condition 
data includes data until the start of study drug. Where possible, diagnosis and not symptoms 
were recorded. These data will be mapped to this dataset from the patient’s previous 
fingolimod study.
The demography data collected in this study (date of birth and gender) will ensure the patients 
are linked to their previous study history.
Previous MS history (including history of relapses) was documented in the patient’s medical 
chart and/or in documented dialog with the patient’s referring physician. Information relating 
to a patients MS history was collected during the previous fingolimod study which included: 
date of MS diagnosis, date of first MS symptoms, eye history (e.g. optic neuritis, uveitis), MS 
relapse history and history of medications used to treat MS and will be transferred directly 
into the database from the patient’s previous fingolimod study.
The same information will be collected for any gap between the previous study (core or 
extension study, e.g. CFTY720D2309 or CFTY720D2309E) and this study.
6.2
Previous Study Details
In order to collect accurate information about the patient’s previous fingolimod study details,
the following records will be collected at the enrollment visit for each patient: the patient’s 
previous fingolimod study number, center number, and patient number.


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Upon the implementation of Amendment 4, the following information will be collected: the 
date of full approval for Amendment 4, whether or not the patient is re-enrolling into this 
study (defined as a patient who previously completed CFTY720D2399 based on the original 
study endpoint who is now re-entering the study using the originally assigned patient ID 
number) and the date of re-enrollment. In addition, data will be collected on any potential 
treatment gap during the time a patient may have temporarily been out of a fingolimod study
and whether or not the patient went onto commercially available medication during the gap, if 
applicable.
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 patient receiving study medication: records of study medication 
dispensed and returned, dosages administered and intervals between visits. Appropriate data 
should be transcribed on the Dosage Administration Record (DAR) eCRF. To allow for 
accurate study reporting, the DAR will be closed at the completion of Study Part One and a 
new DAR eCRF will be opened in the Study Part Two.
Compliance will be assessed by the investigator and/or study personnel at each visit using 
capsule 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
MS relapse activity and neurological impairment of MS as measured by the Expanded 
Disability Status Scale (EDSS), Magnetic Resonance Imaging (MRI) and by the Multiple 
Sclerosis Functional Composite (MSFC) will be obtained in Study Part One only in order to 
characterize the disease activity over the long term.
6.4.1
MS relapse
General definition of relapse: Appearance of a new neurological abnormality or worsening of 
previously stable or improving pre-existing neurological abnormality, separated by at least 30 
days from onset of a preceding clinical demyelinating event. The abnormality must be present 
for at least 24 hours and occur in the absence of fever (<37.5°C) or infection.
Definition of confirmed relapse (For Study Part One only): A relapse must be confirmed by 
an EDSS certified Physician (see Section 6.4.2). It is recommended that this occur within 7 
days of the onset of symptoms. A relapse is confirmed when it is accompanied by an increase 
of at least half a step (0.5) on the EDSS or an increase of 1 point on two different Functional 
Systems (FS) of the EDSS or 2 points on one of the FS (excluding Bowel/Bladder or Cerebral 
FS). 
A patient should report symptoms indicative of a MS relapse at a scheduled visit or at any 
other time during the study. Patients must be instructed to immediately contact the study site 
if he/she develops new, reoccurring or worsening neurological symptoms. Standard therapy 
with corticosteroids can be used. 
For suspected MS relapses reported by the patients between the scheduled visits, the 
investigator will determine whether to bring the patient in for an unscheduled visit based on 


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the patient’s condition and standard of care. For patients who come in for an unscheduled visit 
at the time of the suspected MS relapse, an EDSS evaluation must be performed to verify the 
relapse.  Relapse severity will be determined based on relapse EDSS scores.
Upon receiving a report of symptoms indicative of a relapse, the investigator will assess 
whether the symptoms occur in the presence of fever or infection. If fever or infection can be 
excluded, the investigator will determine whether the patient will come in for an unscheduled 
visit and EDSS evaluation. If fever or infection cannot be excluded, the neurological 
examination will be postponed until the fever or the infection has ceased, provided that the 
symptoms indicative of a relapse are still present at that time. 
All relapses, confirmed (Study Part One only) and unconfirmed, will be recorded on the 
Summary of MS Relapses eCRF.  Atypical relapses should be documented as adverse events 
or serious adverse events, depending on severity of relapse.
6.4.2
Expanded Disability Status Scale (EDSS)
EDSS will be determined only during Study Part One, based on neurological examination at 
scheduled visits according to Table 6-1 and in the setting of a suspected MS relapse.
EDSS is a scale for assessing neurologic impairment in MS. It is a two-part system including:
(1) a series of scores in each of eight functional systems, and (2) the EDSS steps (ranging 
from 0 (normal) to 10 (death due to MS). The functional systems are Visual, Brain Stem, 
Pyramidal, Cerebellar, Sensory, Bowel and Bladder, Cerebral and other functions. It is 
recommended that fatigue will not be included into the Cerebral score of the EDSS.
For patients coming from phase II/III studies, EDSS will be assessed by a treating physician
who has been EDSS trained.  A one-time Neurostatus certification is required for all 
evaluating physicians who have patients enrolled from phase II/III studies.  If a new rater is 
brought on board at any time throughout the study, proof of certification of that rater will be 
required at that time before any EDSS assessments can be done by the new rater. A certified
backup evaluating physician should be appointed to conduct neurological examination ONLY 
when the primary evaluating physician is unavailable due to illness, vacation, or travel. 
Blinding of the evaluators is not required in this protocol and the PI can serve as the rater 
provided training requirements have been met. 
For patients who transferred from trials other than the phase II/III trials, the individual 
functional scores do not need to be collected, and the evaluating physician performing EDSS 
assessments does not have to carry a certification.
EDSS assessments are detailed in Table 6-1. Refer to Appendix 8 for information on 
Expanded Disability Status Scale (EDSS).
6.4.3
Magnetic resonance imaging (MRI) 
MRIs were added in Amendment 4, and are required only during Study Part One for the phase 
II/III patients who had MRI assessments in their prior fingolimod trial.  Until Amendment 8
approval, annual MRIs are performed starting at Visit 5. 
Patients who have already 
completed V5 at the time of Amendment 4 approval should have an MRI recorded at the 


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nearest MRI visit (e.g., V7, V9). Upon Amendment 8 approval, the MRI schedule is revised 
to one MRI at Study Completion as outlined in Table 6-1.
Any phase II/III patients who newly enroll or re-enroll into this study under Amendment 8
should have an MRI at the Baseline-V1 visit for newly enrolled patients, or at the re-
enrollment visit (re-enrolled patients will enter back into the study based on where they 
previously left off when they completed the study based on the original endpoint; for example, 
if V3 was the last completed visit, V4 would be where the patient will begin again).
Assessment of disease activity by MRI will include evaluation of:

T1-weighted hypointense lesion volume.

T2-weighted new/enlarging hyperintense lesion count and total T2 volume.

Brain volume.
The Investigator will be able to review all MRIs during the study. For analysis purposes, the 
MRIs will be reviewed and reported by a central MRI reader.  
Scanning
All sequences/scans will be performed according to the MRI manual.
The radiologist and 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 if not done previously with the same MRI Central Reader, perform and 
submit a dummy scan, so-called “dummy or dry run” 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.
Data handling and evaluation
During the study, the quality of each scan performed will be assessed by the MRI reader. 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. 
6.4.4
Multiple Sclerosis Functional Composite (MSFC)
The MSFC, performed only during Study Part One, is a composite measure encompassing the 
major clinical dimensions of arm, leg and cognitive function. The MSFC consists of three 
objective quantitative tests of neurological function: 

Nine hole peg test (arm dimension) measurement: right and left arm scores; metric: time 
in seconds to insert and remove 9 pegs.

Timed 25 foot walk (leg dimension); measurement: a walk of 25 feet; metric: time taken 
in seconds.


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
PASAT-3 min (cognitive function); measurement: paced auditory serial addition test, 3 
minute version; metric: number of correct answers.
The PASAT-3 min auditory test tapes will be provided to the sites in the local language.  
Refer to Appendix 2 for information on Multiple Sclerosis Functional Composite (MSFC).
MSFC will be assessed by a physician or qualified individual at each site on patients who 
have conducted the MSFC in their previous fingolimod studies. MSFC assessments are 
detailed in Table 6-1. Refer to Appendix 2 for information on Multiple Sclerosis Functional 
Composite (MSFC).
6.4.5
Appropriateness of efficacy assessments 
MS relapse, MRI, as well as EDSS assessments in this patient population are standard 
outcome efficacy assessments in MS and serve to characterize the patient population included 
in this study as well as their disease activity and neurological status over the long-term in this 
study.
MSFC assessments will be continued in patients who had assessments done in their previous 
fingolimod studies to describe their functional status over the long-term in this study.
6.5
Safety

Physical/neurological examination

Vital signs

Laboratory blood evaluations

Eye exam by treating physician

ECG

Ophthalmologic exams / Optical coherence tomography (OCT) by ophthalmologist, if 
clinically indicated

Skin assessments, if clinically indicated

Pulmonary function testing, if clinically indicated
6.5.1
Physical/neurological examination
A complete physical examination will be performed as described in Table 6-1 and 6-2, and 
will include an assessment of skin, head and neck, lymph nodes, breast, heart, lungs, abdomen, 
back, and comments on general appearance. Initial neurological examination will be a part of 
the physical examination. Investigators should ask the patient 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, refer to Section 
6.5.2. All significant findings present prior to start of the study drug have been reported on 
the Relevant Medical History/Current Medical Conditions eCRF from the patient’s previous 
fingolimod trial. Significant findings made after the start of study drug in this study which 
meet the definition of an AE must be recorded on the Adverse Event eCRF.


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6.5.2
Skin assessments
If, during the course of the study, a patient has any dermatologic findings suspicious for being 
precancerous or cancerous, or if a skin disorder is diagnosed, this information should be 
documented on the Dermatologic Examination and/or Adverse Events eCRFs.
6.5.3
Vital signs
Vital signs will be recorded as described in Table 6-1 and 6-2. Vital signs will include sitting 
pulse rate, sitting systolic and diastolic blood pressure, oral temperature (degrees Celsius). 
Height and body weight were collected at the screening visit of the patient’s previous 
fingolimod trial.
Refer to Complete Guidelines for the monitoring of patients taking their first dose of the study 
drug as described in Appendix 4.
6.5.4
Laboratory evaluations
Screening laboratory tests and routine blood samples as described in Table 6-1 will be 
collected and analyzed by the central lab during Study Part One.  During Study Part Two, 
laboratory tests will be collected and analyzed by the study site (i.e., locally, not using a 
central lab).  
For Study Part One, details regarding collection of samples, shipment of samples, reporting of 
results, lab normal ranges and alerting abnormal values will be supplied to the site before site 
initiation in a study laboratory manual. The results of the analysis will be made available to 
each site by the central lab at the earliest 48 hours after receipt of the samples by the central 
lab. Extreme values, specified in the “Criteria for clinically notable laboratory values and vital 
signs” are further specified in Appendix 1, which will generate a “phone alert” to the 
investigator. 
For Study Part Two, samples will be collected and reported in accordance with local
laboratory policies.  Lab results will not be recorded in the eCRF, but will remain as source 
documentation for ongoing safety assessment.
Investigators will be asked to comment on any abnormalities on the respective lab result page, 
including a notation of the clinical significance of each abnormal finding in the patient’s 
source documents. The laboratory sheets will be filed with the patient source documents.
Abnormal laboratory values or test results should be recorded as adverse events only if they 
induce clinical signs or symptoms, are considered clinically significant or require therapy. 
Abnormal laboratory values alone should not be recorded on the adverse event eCRF; 
however, any diagnoses (or signs or symptoms, if a diagnosis is not possible) associated with 
the abnormal findings should be recorded on the adverse event eCRF.
6.5.4.1
Hematology
Hematology parameters will be collected as described in Table 6-1 and 6-2, and will include: 
RBC count, total and differential WBC count (basophils, eosinophils, lymphocytes, 
monocytes, neutrophils, WBC segments), platelet count, hemoglobin, hematocrit, MCV, 


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MCH, MCHC, LUC, RBC morphology. Notable abnormalities are defined in the Criteria for 
clinically notable laboratory values and vital signs further specified in Appendix 1.
 
 
 
6.5.4.2
Clinical Chemistry
Blood samples will be collected as described in Table 6-1 and 6-2, and will include the 
following parameters: sodium, potassium, chloride, calcium, magnesium, phosphate, blood 
urea nitrogen (BUN), random glucose, albumin, alkaline phosphatase, creatinine, ALT, AST, 
GGT, amylase, total bilirubin, conjugated bilirubin, total cholesterol, triglycerides, HDL and
LDL. Abnormal laboratory parameters, inconsistent with clinical presentation of MS or 
suspicious of underlying medical condition, should be repeated for accuracy.    If an increase
of amylase above the clinically notable value (≥300 U/L) is observed at any subsequent visits, 
a lipase should be tested to determine the origin of elevated amylase (pancreatic versus extra 
pancreatic). Refer to the Guidance on monitoring patients with elevated liver function tests in
Appendix 5.
It is recommended that patients without a health care professional confirmed history of 
chickenpox or documentation of a full course of vaccination with varicella vaccine undergo 
antibody testing to varicella zoster virus (VZV) before initiating fingolimod. Serology testing 
will therefore be performed at Baseline for any patient that has not undergone this testing 
during participation in their previous fingolimod trial to determine the patient's immune status 
(IgG antibodies will be measured) for varicella zoster virus. A full course of vaccination for 
antibody-negative patients with varicella vaccine is recommended prior to commencing 
treatment with fingolimod.
Patients who are negative for varicella-zoster virus IgG antibodies at baseline, and wish to be 
immunized, will need to interrupt study treatment for 2 months prior to vaccination. 
Following vaccination, the re-initiation of study drug should be postponed for 1 month to 
allow full effect of vaccination to occur. Patients who have been tested for VZV antibodies 
and have confirmed negative test results may continue participation, provided they are 
counseled on the importance of avoiding possible sources of exposure and the importance of 
informing their physician promptly, should any symptoms of infection develop.  Patients who 
choose not to be vaccinated may enroll into this trial, per discretion of the investigator. A 
positive IgG antibody result does not indicate active infection per se, but only evidence of 
prior exposure to viral antigens through past infection or vaccination. Patients with prior 
infection may be at risk of viral reactivation (e.g. shingles) and should be instructed to inform 
the investigator of any signs or symptoms suggestive of these conditions, so that prompt 
treatment may be initiated.
Patients will also be tested for uncontrolled diabetes and serological markers for hepatitis A, 
B, C and E indicating acute or chronic infection at baseline as part of the revised screening 
laboratory assessments as described in Table 6-1.
Please refer to the Guidance on monitoring of patients with infections in Appendix 5.


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6.5.5
Ophthalmologic exams/ Optical coherence tomography (OCT)
An eye examination will be performed by the treating physician as described in Table 6-1.  
The treating physician should refer the patient to an ophthalmologist for an exam and/or OCT 
if clinically warranted. An OCT and ophthalmologic exam will be performed by an 
ophthalmologist at Month 3 for any patient rolling into this study from a blinded study which 
has comparator treatment arms (placebo or active comparator) and for any patient who has 
been off fingolimod treatment for 90 days or greater.  The OCT will be done to evaluate the 
presence of any abnormalities consistent with macular edema.  
Patients with a history of or newly diagnosed uveitis after initiation of study drug may require 
more frequent ophthalmic evaluations. Refer to the Guidance for Ophthalmic Monitoring
Appendix 7 for details on monitoring of patients with uveitis during the study.
Continuation of fingolimod in patients with macular edema has not been evaluated. A 
decision on whether or not study drug should be re-initiated after resolution of macular edema 
needs to take into consideration the potential benefits and risks to the individual patient.
Patients that are diagnosed with macular edema should be followed-up monthly after 
diagnosis of macular edema and more frequently if needed, based on the ophthalmologist’s 
judgment. Further ophthalmologic evaluations will be conducted until such time as resolution 
is confirmed or no further improvement is expected by the ophthalmologist (based on a 
follow-up period of not less than 3 months). If the patient does not show definite signs of 
improvement on examination by specialist testing (e.g. OCT) 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. 
Please refer to the Guidance for Ophthalmic Monitoring Appendix 7 for complete guidance 
for patients with diagnosis of macular edema.
6.5.6
Electrocardiogram (ECG)
First dose ECGs will be collected as described in Table 6-1 and 6-2. Two ECGs are required 
for first-dose monitoring and will be performed for those patients rolling into this trial from a 
blinded trial, a trial which has a comparator treatment arm, as well as for any patient who has 
been off fingolimod treatment for the duration outlined in Appendix 4.
The first ECG will be performed prior to the study drug administration; the second ECG will 
be performed approximately 6-hours post-first dose, prior to the patient being discharged. If 
study drug treatment is interrupted and treatment re-initiation meets the requirement for 
observation (See Appendix 4), the above procedures will be repeated.
6.5.7
Pulmonary function tests
Pulmonary function tests (PFTs) evaluating forced expiration volume within 1 second (FEV1), 
forced vital capacity (FVC) and carbon monoxide diffusing capacity (DLCO) will be 
performed, when clinically indicated in the opinion of the treating physician.


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6.5.8
Pregnancy and assessments of fertility
Pregnancy tests will be performed for all women as detailed in Table 6-1 and 6-2. During 
Study Part One, visits requiring serum pregnancy tests will be performed by the central lab; 
those visits requiring urine pregnancy tests will be performed locally using a urine dipstick kit 
provided by the central lab.  During Study Part Two, pregnancy tests will be performed 
locally, serum at visits where blood chemistry samples are collected, and urine at any other 
time points.
Patients becoming pregnant must interrupt the study drug. If patients interrupt treatment 
because of a pregnancy, they can remain in the study and re-start fingolimod treatment after 
delivery and discontinuation of nursing.  Pregnant patients continuing in the study during dose
interruption will need to have regular visits and complete assessments deemed safe for her by 
the Principal Investigator.  Prior to resuming fingolimod therapy and the mandatory on-site 
first-dose monitoring, patients must have a negative serum pregnancy test and must no longer 
be nursing.
6.5.9
Appropriateness of safety measurements
Beside routine safety assessments like physical and neurological examination, vital signs and 
laboratory assessments, few specific additional safety assessments are recommended in this 
extension study, based on the mechanism of action of fingolimod and previous clinical data.
Effects of fingolimod on heart rate and conduction are expected and known based on the 
mechanism of action and previous clinical data. Clinically symptomatic cardiac events or 
clinically relevant ECG abnormalities have been reported at very low frequencies in the 
clinical development program, especially with the fingolimod 0.5 mg/day dose treatment.
Therefore, upon initiation of the first dose of fingolimod, there must be a mandatory on site 
monitoring for a minimum of 6 hours, with additional monitoring as appropriate; refer to 
Appendix 4 for detailed recommendations.
In addition to routine ophthalmologic examinations, OCT may be continued in this extension 
study for the evaluation of retinal thickness and the detection of macular edema. Macular 
edema is an adverse event of special interest in patients treated with fingolimod because of the 
higher incidence seen in treated patients compared to active and placebo control groups, 
particularly when higher doses were evaluated in the clinical development program. The 
majority of cases of macular edema observed in patients treated with fingolimod occurred 
within the first four months after initiation of treatment. Therefore, an OCT scan is foreseen to 
be completed at three and six months after treatment initiation/re-initiation for patients 
meeting this requirement as outlined in Section 5.5.4.
In the fingolimod clinical development program, there is limited experience in multiple 
sclerosis patients with diabetes mellitus. Patients with diabetes mellitus are at increased risk of 
macular edema and may require additional ophthalmologic observation, as determined by the 
investigator.
As dose-dependent reversible reduction was observed in forced expiratory volume of patients 
treated with fingolimod, pulmonary function testing will be performed, if clinically indicated.


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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 refers to the investigational drug, fingolimod given 
during this 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 Event eCRF pages 
with the following information:
1. the severity grade (mild, moderate, 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 fulfills one or several 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 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.
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 temporarily interrupted; 
study drug permanently discontinued due to this adverse event; concomitant medication given; 
non-drug therapy given; patient hospitalized/patient’s hospitalization prolonged. Refer to the 


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Guidance on Safety Monitoring (Appendix 5). 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 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 (Dear Doctor’s letter). 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 6 weeks 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 6 week 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 Clinical 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 and is thought to be 
related to the Novartis study drug, 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 drug that this SAE has been reported. Suspected 
Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to the 


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competent authorities and relevant ethics committees in accordance with Directive 
2001/20/EC or as per national regulatory requirements in participating countries.
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. 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.  Pregnant women should be encouraged to participate in the 
pregnancy registry to collect additional safety data on this population.
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 Novartis study drug of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.
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.


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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 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 Electronic Case Report Forms 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
Designated CRO personnel working on behalf of Novartis 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. 
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 
the designated CRO (Part One only).
MRI readings will be processed centrally and the results will be sent electronically to the 
designated CRO.
ECGs will be done locally and the outcomes will be entered into the database.
Data about all study drug dispensed to the patient and all IRT recorded information will be 
tracked using an Interactive Response Technology system (IRT). The system will be supplied
by a vendor, who will also manage the database. The database will be sent electronically to a 
designated CRO.
9
Data analysis
Unless otherwise mentioned, all data collected from the first dose of fingolimod in the 
original core/extension studies, if available, and in this long-term follow-up study will be 
analyzed to evaluate the long-term safety, tolerability, and effectiveness of fingolimod 0.5 
mg/day in patients with MS.  The baseline relative to the first dose of fingolimod (FDF 
baseline) will be used where change from baseline is analyzed.  All the summaries will be 
provided by the highest assigned fingolimod dose, (i.e., fingolimod 0.5 mg/day) and any dose 
of fingolimod.


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During Study Part Two, only adverse events, first dose monitoring, vital signs, 
Ophthalmological exam/OCT, and relapse are collected. The analysis including data from 
Study Part Two will be specified in the relevant sections.
The follow-up data after discontinuation of the study treatment in Study Part One or Study 
Part Two will also be summarized where appropriate.
Summary statistics for continuous variables will include N, mean, standard deviation, 
minimum, lower quartile, median, upper quartile and maximum.
Summary statistics for discrete variables will be presented in terms of absolute and relative 
frequencies.  AE incidence adjusted by exposure is also used to evaluate the risk over time 
and presented as number of patients experiencing at least one event per 100 patient years of 
the at-risk population.
9.1
Analysis sets
Assignment of patients into the different analysis sets will be performed prior to locking the 
database and beginning the data analysis.
Summary statistics will be provided for patient disposition (completers and premature study 
discontinuations) in this long-term follow-up study.
A table on number and percentage of patients with each protocol deviation in this long-term 
follow-up study will be provided. 
In addition, the number of patients per analysis set will be tabulated.
Enrolled set 
The Enrolled set will consist of all patients who were assigned a subject ID in this long-term 
follow-up study.
Safety set 
The Safety set will consist of all patients that received at least one dose of study drug in this 
long-term follow-up study.
Fingolimod safety set 
The fingolimod safety set will include all patients who entered the long-term follow up study
and received at least one dose of fingolimod in any study, i.e., in the original core/extension 
MS studies or this long-term follow up study.
Fingolimod Full Analysis Set
The fingolimod full analysis set (FAS) will include all patients who entered the long-term 
follow-up study and received at least one dose of fingolimod in any study, i.e., in the original 
core/extension MS studies or this long-term follow up-study.


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9.1.1
Subgroup
All analyses including data collected during Study Part two will be conducted based on the 
subgroup of patients who entered Study Part Two, which includes all patients with at least one 
dose of study medication after completing Study Part One. 
9.2
Patient demographics and other baseline characteristics
Demographic and background information collected from the clinical studies (core & 
extensions) from which the patients are transferred to this long-term extension study will be 
summarized.  Background information includes prior MS treatment including previous 
exposure to fingolimod, relevant medical history / current medical conditions, duration of the 
disease, and baseline EDSS.  Identification of clinical study participation prior to transfer into 
this long-term extension study will also be provided.  Summaries will be provided based on 
the enrolled set.
9.3
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)
Use of concomitant medications in this long-term follow-up study will be listed and 
summarized based on the Safety set to support the analysis including data from Study Part 
One or based on the subgroup of patients who entered Study Part Two of the Safety set to 
support the analyses including data from Study Part Two.
9.4
Analysis of the primary variable(s)
9.4.1
Variable
Long-term safety will be assessed based on adverse events (AEs), laboratory and vital signs as 
well as other investigations performed when clinically indicated. 
Analysis of the safety variables will be conducted on

Safety set: for any analyses including data collected during the long-term follow up study 
only

Fingolimod safety set: for analyses including data from first dose of fingolimod in the 
original core/extension study, if there is any, and in the long-term follow up study.
Given the nature of the design, the data will be presented using descriptive statistics and no 
inferential analyses are planned.  
9.4.1.1
Adverse events (AEs)
Incidence rates (IRs) of adverse events per 100 patient-years will be summarized by highest 
assigned fingolimod dose (fingolimod 0.5 mg/day and any dose of fingolimod) based on the 
fingolimod safety set.
To further evaluate the risk with longer fingolimod exposure duration, adverse events reported 
with different fingolimod exposure durations will be assessed based on the fingolimod safety 
set.  


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In addition, the incidence of adverse events (new or worsened from the long-term extension 
baseline) reported during the long-term follow up study will be summarized by primary 
system organ class and preferred term as frequency count and percentage of patients with 
adverse events based on the safety set.  

Any adverse events

Serious adverse events (SAEs)

Suspected study drug related adverse events

Adverse events leading to discontinuation

Deaths
All information pertaining to serious adverse events and deaths noted during this study will be 
listed by center and patient number.
The same analysis including data collected during the Study Part Two will be conducted for 
the subgroup of patients who entered Study Part Two.
9.4.1.2
Laboratory
Laboratory data collected up to the end of Study Part One will be summarized by presenting 
summary statistics of actual values and change from the first dose of fingolimod FDF baseline 
values and by presenting shift tables using clinically notable ranges (FDF baseline to most 
extreme post-baseline value). For liver function tests, the frequencies and percentages of 
patients with elevations of 1, 2, 3, 5, and 10 times upper limit of normal will be summarized 
by visit.  
A listing of laboratory data for patients with abnormal findings will be provided. In Study Part 
Two, only local laboratory test is performed for AE reporting purpose according to local 
policies and no laboratory data is reported in the clinical data base for analysis.
9.4.1.3
Vital signs
Vital sign data collected up to the end of Study Part One will be summarized as descriptive 
statistics for change from FDF baseline value. The incidence rates of notable vital sign 
abnormalities will be summarized. 
A listing of vital sign data for patients with abnormal findings will be provided.
The same analysis including data collected during the Study Part Two will be conducted for 
the subgroup of patients who entered Study Part Two.
9.4.1.4
Electrocardiograms
Analysis will be performed for first dose ECGs during the long-term follow up study based on 
the safety set.
Summary statistics for ECG parameters (including pre-dose ECG for patients who have this 
evaluation done) will be summarized by time point and visit. Incidence of abnormal ECGs
will be presented.
A listing of ECG data for patients with abnormal findings will be provided.


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The same analysis including data collected during the Study Part Two will be conducted for 
the subgroup of patients who entered Study Part Two.
9.4.1.5
Ophthalmic assessments
The incidence of macular edema events during Study Part One will be summarized as 
frequency distributions based on the safety set. The patient data listing will also be provided.
During Study Part Two, ophthalmic assessments will be conducted for safety monitoring 
purposes at the Month 1 visit and Month 3 visit only for patients who transitioned from a 
blinded fingolimod study with comparator treatment arms. The patient is not reported in the 
clinical database for analysis.
9.4.1.6
Pulmonary function tests
Pulmonary function test data (FEV1, FVC, and DLCO, percentage of predicted value for these 
three variables, and smoking status) collected during Study Part One will be listed based on
the safety set. During Study Part Two, PFT assessment will be conducted as need for safety 
monitoring purpose and the patient data is not reported in the clinical database for analysis.
9.4.1.7
Skin assessment
The skin assessments during Study Part One will be listed for those who had abnormal 
findings based on the safety set. During Study Part Two, skin assessment will be conducted 
as need for safety monitoring purpose and the patient data is not reported in the clinical 
database for analysis.
9.4.2
Handling of missing values/censoring/discontinuations
Missing values will not be imputed.
9.4.3
Supportive analyses
In addition, adverse events will be summarized by subgroup that will be defined in the 
statistical analysis plan, such as:

Duration of fingolimod exposure.

Previous core/extension trials: Phase II/III studies (i.e., D2201, D2301, D2302, and 
D2309).
The follow-up safety data after discontinuation of the study drug will be summarized.
9.5
Analysis of secondary variables
9.5.1
Efficacy variables
The following long-term efficacy data will be evaluated as secondary endpoints in the trial.  
Time-to-event variables will use FDF baseline visit as the start date.  Estimates will be 
provided for patients who have taken at least one dose of fingolimod.


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9.5.1.1
MS Relapse
Descriptive statistics on the Annual Relapse Rate (ARR) will be presented. ARR (for each 
patient) is calculated as the total number of relapses divided by total number of days on study, 
multiplied by 365.25. The ARR for the whole treatment group is the mean of ARRs from all 
patients in the group. Data on time to relapse will also be summarized.   In addition, model 
based estimates will be obtained by fitting a negative binomial regression model adjusted for 
the number of relapses in the last two years at core baseline and FDF baseline EDSS score, 
with the logarithm of the duration of the observation period as the offset variable.  All the 
analyses will be done for all relapses (confirmed and unconfirmed) and for confirmed relapses.
All MS relapses are collected during Study Part Two for safety monitoring purposes. Analysis 
including any relapse data collected during Study Part Two will be conducted based on the 
fingolimod safety set for the subgroup of patients who entered Study Part Two.
9.5.1.2
MRI
Descriptive statistics on number of new / newly enlarging T2 lesions, T2 lesion total volume, 
T1 black hole volume and brain volume (atrophy) for change from previous scan and change 
from FDF baseline will be presented by  time for appropriate subgroups of patients. Model 
based estimates will also be provided for the following endpoints: 
New / newly enlarging T2 lesions: the annualized rate of new/newly enlarging T2 lesions 
will be estimated based on a negative binomial regression model with log-link. The number of 
new / newly enlarging T2 lesions relative to FDF baseline will be used as the response 
variable, and the natural log of the time (in years) of the MRI-assessment from the 
baseline/screening scan will serve as the offset variable to adjust for the various lengths of 
follow-up times between patients. The model will include treatment and baseline volume of 
T2 lesions as continuous covariates.
Brain volume: Percent brain volume change from baseline will be estimated based on a 
mixed effects model with repeated measures and auto-regressive within-subject covariance 
structure of first order will be used with visit, treatment, core baseline normalized brain 
volume, number of Gd-enhancing lesions at FDF baseline, and T2 lesion volume at FDF 
baseline as fixed effects, and individual patient as a random effect. Kenward and Rogers’ 
adjustment for the degrees of freedom will be applied. Annualized rate of brain atrophy 
(ARBA) will also be estimated based on the same mixed effects model.
9.5.1.3
EDSS
Descriptive statistics on absolute EDSS scores (overall and by function), change from FDF
baseline, and count (%) based on EDSS change categories will be presented. The proportion
of patients with 6-month confirmed disability progression will be presented. Data on time to 
6-month confirmed disability progression, and EDSS score of 4, 6, 7 will be summarized. 
EDSS will be used for the confirmation of MS relapse and the confirmation of disability 
progression.  Disability progression in this study is defined as an increase in the EDSS score 
by 1.5 point for patients with an FDF baseline EDSS of 0, 1 point for patients with an FDF
baseline EDSS of ≥1 and ≤5.5, and by 0.5 points for patients with an FDF baseline 
EDSS >5.5, confirmed after 6 months and at all intermediate EDSS assessments.


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9.5.1.4
MSFC
Descriptive statistics on absolute MSFC scores and change from FDF baseline will be 
presented for patients who have done this evaluation. 
The MSFC is based on 3 components (dimensions): leg, arm, and cognitive function and the 
corresponding tests are 25-foot Timed Walk (T25FW), 9-Hole Peg Test (9HPT), and Paced 
Auditory Serial Addition Test (PASAT3). The scores for these 3 components are combined to 
create a single score that is used to detect changes over time. This is done by creating z-scores 
for each component and averaging them to create the overall z-score. In general, z-scores 
involve comparing each test result with that found in a reference population, a process call 
standardization. The z-score for each component is calculated by subtracting the mean of the 
reference population from the test result and then dividing by the standard deviation of the 
reference population. The mean and standard deviation from the test results at core baseline 
visit will be used as the reference population. The exact formulas will be given in the 
statistical analysis plan.
9.6
Sample size calculation
Given that this is a long-term extension study with primary descriptive purpose, no formal 
sample size calculation will be used to determine enrollment in this study. The sample size is 
defined by the number of patients coming from ongoing/new core/extension trials that meet 
the inclusion and exclusion criteria. It is estimated that about 5000 patients will be enrolled in 
this trial. 


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9.7
Power for analysis of key secondary variables
Not applicable.
9.8
Interim analyses
Periodic interim safety analyses to support regulatory updates and interim reports may be 
warranted.
As this is an open-label, multi-center, single treatment arm long-term safety and tolerability 
study without formal hypothesis tests, there is no relevance on blinding or alpha-adjustment.
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.
Women of child bearing potential should 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.


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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 
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)
Cohen JA, Barkhof F, Comi G, et al (2010). Oral fingolimod or intramuscular interferon for 
relapsing multiple sclerosis. The New England Journal of Medicine; 362(5):402-15. 
Doward LC, McKenna SP, Meads DM, et al (2005). The symptomatic, functional, and quality 
of life impact of multiple sclerosis: Report on a qualitative investigation of the 
patients’perspective. Value in Health; 8(6), A135. 
Fischer JS, Jak JS, Kniker JE et al (2001). Multiple Sclerosis Functional Composite (MSFC) 
Administration and scoring manual. Revised, October 2001. National Multiple Sclerosis 
Society.
Kappos L, Radue EW, O’Connor P, et al (2010). A placebo-controlled trial of oral fingolimod 
in relapsing multiple sclerosis. The New England Journal of Medicine; 362(5):387-401. 
Keegan BM and Noseworthy JH (2002). Multiple sclerosis. Annual Review of Medicine; 
53:285-302.
Panitch, H, Goodin, DS, et al (2002). Randomized, comparative study of interferon ß-1a 
treatment regimens in MS. The EVIDENCE trial. Neurology; 59:1496-1506.
Sospedra M and Martin R (2005). Immunology of multiple sclerosis. Annual Review of 
Immunology; 23:683-747.
Trapp BD, Peterson J, Ransohoff M, et al (1998). Axonal transection in the lesions of multiple 
sclerosis. The New England Journal of Medicine; 338:278-85.


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13
Appendices
Appendix 1:  Clinically notable laboratory values and vital signs
Only selected lab parameters identified as notable which have been shown to be sensitive to 
fingolimod exposure are included.
CRITERIA FOR NOTABLE LABORATORY ABNORMALITIES
Notable Values
Laboratory Variable
Standard Units
SI Units
LIVER FUNCTION AND RELATED VARIABLES
SGOT (AST)
>82 U/L
>82 U/L
SGPT (ALT)
>90 U/L
>90 U/L
Total bilirubin
2.0 mg/dL
34.2 mol/L
Alkaline Phosphatase
>280 U/L
>280 U/L
RENAL FUNCTION / METABOLIC AND ELECTROLYTE VARIABLES
Glucose `
200 mg/dL
11.11 mmol/L
Creatinine
2.0 mg/dL
176 umol/L
Amylase
300 U/L
300 U/L
Cholesterol
240 mg/dL
6.21 mmol/L
Triglycerides
≥300 mg/dL
≥3.39 mmol/L
BUN
≤ 2 mg/dL
≥ 30 mg/dL
≤ 0.7 mmol/L
≥ 10.7 mmol/L
Sodium
< 125 mEq/L
>154 mEq/L
< 125 mmol/L
>154 mmol/L
Chloride
≤85 mEq/L
≥119 mEq/L
≤85 mmol/L
≥119 mmol/L
Potassium
≤ 3.0 mEq/L
≥ 6.0 mEq/L
≤ 3.0 mmol/L
≥ 6.0 mmol/L
Magnesium
≤ 1.0 mg/dL
≥ 3.0 mg/dL
≤ 0.40 mmol/L (in all other 
countries)
≤ 0.41 mmol/L (in Canada)
Calcium
≤ 7.5 mg/dL
≥ 11.6 mg/dL
≤ 1.87 mmol/L
≥ 2.89 mmol/L
Phosphate
≤ 2.0 mg/dL
≥ 5.3 mg/dL
≤ 0.65 mmol/L
≥ 1.71 mmol/L


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Notable Values
HEMATOLOGY VARIABLES
Hemoglobin
10.0 g/dL
100 g/L
Platelets (Thrombocytes)
100 k/mm3
600 k/mm3
100 x 109/L
600 x 109/L
Leukocytes (WBCs)
2.0 k/mm3
15 k/mm3
2.0 x 109/L
15 x 109/L
HEMATOLOGY VARIABLES: DIFFERENTIAL
Granulocytes (Poly, Neutrophils)
1,000 /mm3
12000/mm3
1 x 109/L
12 x 109/L
Lymphocytes
<200/mm3
8000/mm3
<0.2 x 109/L
8 x 109/L
Red blood cells
<3,300,000/mm3
>6,800,000/mm3
<3.3 x 1012/L
>6.8 x 1012/L
NOTABLE VITAL SIGNS
Vital Sign Variable
Notable Criteria
Pulse (beats/min)
>120bpm or Increase of 15 bpm from baseline
Or
< 50bpm or Decrease of 15 bpm from baseline
Systolic BP (mmHg)
160 mm Hg  or Increase of 20 mm Hg from baseline
Or
90 mm Hg  or Decrease of 20 mm Hg from baseline
Diastolic BP (mmHg)
100 mmHg or Increase of 15 mm Hg from baseline
Or
50 mmHg or Decrease of 15 mm Hg from baseline
Temperature (°C)
>38.3°C/ 101°F
Body Weight (kg)
±7% from baseline weight


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Appendix 2:  Multiple Sclerosis Functional Composite Measure (MSFC)
MSFC-INSTRUCTIONS
(from the "Administration and Scoring Manual for the Multiple Sclerosis Functional 
Composite Measure (MSFC)" by Fischer JS et al, 2001)
STANDARDIZING MSFC ADMINISTRATION
The MSFC should be administered as close to the beginning of a study visit as possible, but 
definitely before the patient does a distance walk. MSFC components should be administered 
in the following order:
1. Trial 1, Timed 25-Foot Walk
2. Trial 2, Timed 25-Foot Walk
3. Trial 1, Dominant Hand, 9-HPT
4. Trial 2, Dominant Hand, 9-HPT
5. Trial 1, Non-Dominant Hand, 9-HPT
6. Trial 2, Non-Dominant Hand, 9-HPT
7.
PASAT
INSTRUCTIONS FOR THE TIMED 25 FOOT WALK
DESCRIPTION
The Timed 25-Foot Walk is a quantitative measure of lower extremity function. It is the first 
component of the MSFC administered at each visit. The patient is directed to one end of a 
clearly marked 25-foot (7.62 m) course and is instructed to walk 25 feet (7.62 meter) as 
quickly as possible, but safely. The task is immediately administered again by having the 
patient walk back the same distance. Patients may use assistive devices when doing this task. 
In clinical trials, it is recommended that the study physician selects the appropriate assistive 
device for each patient.
MATERIALS NEEDED
Stopwatch, clipboard, Timed 25-Foot Walk Record Form, marked 25-foot (7.62 m) distance 
in an unobstructed hallway, assistive device (if needed).
TIME LIMIT PER TRIAL
3 minutes (180 seconds) per trial.


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INSTRUCTIONS FOR THE 9-HOLE PEG TEST
DESCRIPTION
The 9-HPT is a quantitative measure of upper extremity (arm and hand) function. The 9-HPT 
is the second component of the MSFC to be administered. Both the dominant and non-
dominant hands are tested twice (two consecutive trials of the dominant hand, followed 
immediately by two consecutive trials of the non-dominant hand). It is important that the 9-
HPT be administered on a solid table (not a rolling hospital bedside table) and that the small 
rubber feet are fixed under the 9-HPT apparatus (or the apparatus be anchored by other 
method).
MATERIALS NEEDED
9-HPT apparatus, stopwatch, clipboard, 9-HPT Record Form
TIME LIMIT PER TRIAL
5 minutes (300 seconds)
INSTRUCTIONS FOR THE PACED AUDITORY SERIAL ADDITION TEST (PASAT)
DESCRIPTION
The PASAT is a measure of cognitive function that specifically assesses auditory information 
processing speed and flexibility, as well as calculation ability. The PASAT is the last measure 
administered at each visit. It is presented on audio CD to control the rate of stimulus 
presentation. Single digits are presented every 3 seconds and the patient must add each new 
digit to the one immediately prior to it. The test result is the number of correct sums given 
(out of 60 possible). To minimize familiarity with stimulus items in clinical trials and other 
serial studies, two alternate forms have been developed; the order of these should be 
counterbalanced across testing sessions.
MATERIALS NEEDED
CD player, audio CD with PASAT stimuli, clipboard, PASAT Record Forms.


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Appendix 3:  New York Heart Association Functional Classification
Class I
Patients have cardiac disease but without the resulting limitations of physical 
activity. Ordinary physical activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain.
Class II
Patients have cardiac disease resulting in slight limitation of physical activity. 
They are comfortable at rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain.
Class III
Patients have cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary physical activity 
causes fatigue, palpitation, dyspnea, or anginal pain.
Class IV
Patients have cardiac disease resulting in inability to carry on any physical 
activity without discomfort. Symptoms of cardiac insufficiency or of the 
anginal syndrome may be present even at rest. If any physical activity is 
undertaken, discomfort is increased.


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Appendix 4:  Guidance for Monitoring of patients taking their first dose of 
the study drug 
Initiation of fingolimod treatment results in a transient decrease in heart rate. After the first 
dose, the heart rate decrease starts within an hour and the Day 1 decline is maximal within 6 
hours. With continued dosing, heart rate returns to baseline within one month of chronic 
treatment. In patients receiving fingolimod 0.5 mg this decrease in heart rate, as measured by 
pulse, averages approximately 8 beats per minute (bpm). Heart rates below 40 bpm were 
rarely observed. Patients who experienced bradycardia were generally asymptomatic but some 
patients experienced mild to moderate symptoms.
Initiation of fingolimod treatment has been associated with AV conduction delays, usually as 
first-degree atrio-ventricular blocks. Second-degree AV blocks, usually Mobitz type I 
(Wenckebach) have been observed in less than 0.5% of patients receiving Gilenya 0.5 mg in 
clinical trials. The conduction abnormalities typically were transient, asymptomatic, usually 
did not require treatment and resolved within the first 24-hours on treatment. Isolated cases of 
transient, spontaneously resolving complete AV block have been reported during post-
marketing use of fingolimod 0.5 mg. 
Therefore, guidance on the monitoring of patients taking their first dose or re-initiating 
treatment after interruption of treatment is provided.
The on-site first-dose administration monitoring is mandatory for the following patients:

At the Baseline visit, in all patients enrolling into this trial from blinded controlled 
trials and patients from open-label controlled trials coming off the comparator arm.

Patients who are off fingolimod 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.
If applicable, the independent first-dose monitoring physician is responsible for monitoring 
following the 1st intake of the study drug and management of bradycardia symptoms should 
these occur. He/she must review vital signs during 6-hour monitoring, post-dose ECG and 
assess discharge criteria at 6 hours post-dose. 
Baseline or pre-dose ECG should be provided by the site and be available for comparison to 
the post-dose ECG in order to determine if discharge criteria are met. The pre-dose ECG will 
help detect potential risk factors, in particular atrio-ventricular (AV) conduction and rhythm 
disorders. The 6-hour ECG will help detect otherwise asymptomatic electrocardiographic 
events (specifically conduction delays) prior to discharging the patient from the clinic.
Sitting heart rate and blood pressure should be measured prior to the 1st dose of the study drug 
and every hour for at least 6 hours thereafter.   If required, this would be performed by the 
independent first-dose monitoring physician. When obtaining the pre-dose heart rate prior to 
the 1st dose intake, the patient should be allowed to rest sitting for 5 minutes. Then the sitting 


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heart rate should be taken. The sitting heart rate and blood pressure measurements should be 
collected three times to produce three baseline readings for both heart rate and blood pressure 
(prior to the 1st dose of the study drug only). For comparison to the post-dose heart rate values, 
the lowest pre-dose value of heart rate should be used. 
Patients should receive the first dose of the study drug in the outpatient setting and at a time 
which will allow for the required 6-hour post-dose monitoring as well as additional 
monitoring beyond that time point, if necessary.
After 6 hours monitoring, patients may be discharged if all of the following discharge criteria 
are met:

Pulse rate at discharge must be at least 45 bpm

Pulse rate at discharge must not be the lowest hourly value measured during the 
observation period (suggesting that the maximum pharmacodynamic effect on the heart is 
not yet manifest)

Patients must have no symptoms associated with decreased pulse rate or rhythm 
abnormalities

ECG at 6 hours should not show any significant abnormalities  (e.g. second-degree or 
third-degree AV block, QTc ≥ 500 ms) 
Should post-dose bradyarrhythmia-related symptoms occur, the patient should be monitored 
until the symptoms have resolved. Should a patient require pharmacologic intervention during 
the first dose observation, overnight monitoring with continuous ECG in a medical facility 
should be instituted and the first dose monitoring strategy should be repeated after the second 
dose of fingolimod. 
Overnight monitoring with continuous ECG is required if the ECG at 6 hours shows a QTc 
interval ≥500 msec 
Advice from a cardiologist should be sought and overnight monitoring with continuous ECG 
is required under the following circumstances:

The pre-dose ECG shows a QTc interval >470 msec (females) or >450 msec (males) or a 
second degree or higher AV block

The patient has relevant risk factors for QT prolongation, for example, hypokalaemia or 
hypomagnesemia, sick-sinus syndrome, or sino-atrial heart block

The patient has known ischemic heart disease, history of myocardial infarction, congestive 
heart failure, history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension 
or severe untreated sleep apnea period

The patient has a history of recurrent syncope or symptomatic bradycardia
For patients concurrently treated with beta-blockers or other heart-rate lowering drugs (such 
as verapamil, diltiazem, digoxin or ivabradine) advice from a cardiologist should be sought 
regarding switch to non heart-rate lowering drugs. If a switch to non-heart rate lowering drugs 
is not possible, overnight continuous ECG monitoring is required.


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In addition to protocol mandated safety assessments and monitoring procedures, additional 
procedures and assessments may be required as per local prescribing information and should 
be followed accordingly.
Patients should have written instruction on when to return to clinic and a 24-hour contact
phone number to call in the event of any new or warranted symptoms (chest pain, dizziness, 
palpitations, syncope, nausea and vomiting, etc.). Patients should be instructed not to drive 
themselves after the first dose of study drug administration.
If a patient requires treatment for bradycardia/bradyarrhythmia during the first-dose 
observation period, the patient should be hospitalized for overnight monitoring and the first-
dose monitoring procedures should be repeated for the second dose of study drug.
Recommendations for management of bradycardia 
Prior to the administration of study drug, clinicians should be particularly mindful of patients 
who have a low pulse at baseline or those patients switching to a non-heart rate lowering drug 
and the advice of a cardiologist should be sought.  
Atropine (sc or iv) is recommended as the first line treatment of bradycardia, up to a 
maximum daily dose of 3 mg.
Furthermore, the common guidelines for treatment of bradycardia (e.g. ACLS guidelines) 
should be followed as appropriate:

In case of clinical symptoms or hypotension, administration of atropine 1 mg, repeated 
administration in 3-5 minutes.

If heart rate and/or blood pressure remains unresponsive, consider administration of 
dopamine drip 5-20 ug/kg/min or epinephrine drip 2-10 ug/min.

Performance of transcutaneous pacing may also be considered.
In the setting of decreased blood pressure, isoproterenol should be avoided/used with caution.


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Appendix 5:  Guidance on safety monitoring
Guidance on monitoring of patients with elevated blood pressure
Patients who have at least two out of the three sitting readings of blood pressure (systolic BP 
≥140 and/or diastolic BP ≥90 mmHg) should be followed up in one month by an unscheduled 
visit if the scheduled visit is not due. If systolic BP ≥140 and/or diastolic BP ≥90 mmHg 
values are confirmed in two sitting readings out of three in the second visit, the patient should 
be referred to his primary care physician, an independent internist or to the specialty 
hypertension clinic for evaluation, diagnosis and treatment of hypertension.
Patients with BP values of >160/100 mmHg on any visit during the study should be 
immediately referred as above for evaluation, diagnosis and treatment of hypertension. 
Newly diagnosed hypertension as well as an aggravation of a preexisting condition must be 
reported as an AE and discontinuation of the study drug may be considered by the investigator.
Guidance on monitoring of patients with elevated liver function tests
For detailed guidance on handling specific laboratory or AE pattern, refer to Appendix 6.
For any unscheduled laboratory assessments performed locally, an identical sample should 
also be sent to the central laboratory (Study Part One only) for analysis and capture in the 
central database. 
An interruption or discontinuation of the study drug should be clearly documented and 
reflected on Dosage Administration Record eCRF.  AE/SAEs need to be filed as appropriate.
Guidance on monitoring of patients with notable lymphopenia 
Fingolimod results in sequestration of a proportion of the circulating lymphocytes in lymph 
nodes with resultant reduction in circulating lymphocyte counts. Average circulating 
lymphocytes counts are expected to be around 0.5-0.6 x109 /L or 500-600 cells/mm3.  As such, 
the absolute total WBC, neutrophil and lymphocyte counts will be measured at each visit y. If 
the absolute lymphocyte count drops below 0.2x109/L or 200 cells/mm3 lymphocyte counts 
should be repeated regularly, at least monthly, and the patient should be reminded of the risk 
of infections and instructed to promptly report any symptoms of infections to the investigator.
If monthly site visits create a logistical burden for the patient, local lymphocyte testing can be 
performed, with an eCRF comment added that lymphocyte counts were obtained locally and 
reviewed by the investigator. Study drug should be temporarily interrupted at the discretion 
of the investigator. Recovery of lymphocyte counts is expected to take approximately 1-2 
months after stopping study drug given the long half-life of fingolimod. The patient should be 
evaluated and monitored for infections on a regular basis during this period.
Guidance on monitoring of patients with symptoms of neurological
deterioration, inconsistent with MS course
Should a patient develop any manifestations that, in opinion of the investigator, are atypical 
for multiple sclerosis including unexpected neurological or psychiatric symptom/signs (e.g. 


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rapid cognitive decline, behavioral changes, cortical visual disturbances or any other 
neurological cortical symptoms/sign), or any symptom/sign suggestive of an increase of 
intracranial pressure or accelerated neurological deterioration, the investigator should 
schedule a complete physical and neurological examination and an MRI as soon as possible 
and before beginning any steroid treatment. Conventional MRI as defined in the protocol as 
well as Fluid-attenuated Inversion Recovery (FLAIR) and Diffusion-weighted imaging (DWI) 
sequences are recommended for differential diagnosis of Posterior reversible encephalopathy 
syndrome. The MRI must be evaluated by the local neuroradiologist. The investigator will 
contact the Medical Advisor at Novartis to discuss findings and diagnostic possibilities as 
soon as possible. AE/SAEs need to be filed as appropriate.
In case of new findings in the MRI images in comparison with the previous available MRI 
which are not compatible with MS lesions, the study drug may be discontinued and other 
diagnostic evaluations need to be performed at the discretion of the investigator. In case of 
presence of new hyperintense T2-weighted lesions in the MRI which may be infectious in 
origin it is recommended to collect a cerebrospinal fluid sample if indicated. Analysis of the 
CSF sample including cellular, biochemical and, microbiological analysis (e.g. herpes virus, 
JC virus), to confirm/exclude an infection (e.g. PML) should be performed. In the event of 
suspected CNS infection, a CSF aliquot should be sent to a central laboratory (designated by 
the sponsor) for confirmatory testing.
Only when the differential diagnosis evaluations have excluded other possible diagnosis than 
MS and after discussion with the Medical Advisor at Novartis, the study drug may be 
restarted.
Guidance on monitoring of patients with infections
All infections that develop during the study will be reported as AEs. Investigators are 
requested to specifically ask about infections at each visit. Treatment and additional 
evaluations will be performed at discretion of the investigator. 
The investigator should 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), should remind the patient of the risk of infections, and instruct them to 
promptly report any symptoms of infections to the investigator. The patients must also be 
reminded to always carry their Patient Information Card (with site contact information and 
which identifies them as participants in a clinical study with an investigational agent with 
potential immunosuppressive effects) and to show this to any local healthcare provider they 
may consult and ask that the investigator be contacted. 
When evaluating a patient with a suspected infection, the most sensitive tests available should 
be used (i.e. that directly detect the pathogen, as with PCR). 
The investigator should consider early treatment with antimicrobial therapy on the basis of 
clinical diagnosis or suspicion thereof (e.g. antiviral treatment for herpes simplex or zoster) in 
consultation with infectious disease experts, as appropriate. 
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, 


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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 
medical expert of any such cases.
Investigators should consider the added immunosuppressive effects of corticosteroid therapy 
for treatment of MS attack/relapse and increase vigilance regarding infections during such 
therapy and in the weeks following administration.
Profiling of infection risk in study patients based on anti-viral IgG antibody test results
As a conservative measure before initiation of any immune-modulating drug, patients without 
a history of chickenpox or without vaccination against varicella zoster virus (VZV) should be 
tested for antibodies to VZV. VZV vaccination of antibody-negative patients should be 
considered prior to commencing treatment with fingolimod, following which initiation of 
study drug should be postponed for at least 1 month to allow full effect of vaccination to 
occur.
Serology testing for antibody status of varicella zoster virus (VZV) is performed in the study 
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 or vaccination. These patients may, however, 
be at risk for viral reactivation, which may manifest as VZV virus IgG positive: Shingles.
The investigator should instruct the patient to be alert to and report any symptoms or signs 
suggestive of shingles, so that appropriate antiviral treatment can be initiated in consultation 
with a local infectious disease expert (if needed). 
It is also important to ask the patient to report if they are exposed to anyone who has recently 
received a live or live attenuated vaccine and manifested a skin rash after the vaccination so 
that it can be decided, in consultation with an infectious disease expert, if antiviral therapy is 
warranted. 
It should be noted that live or live attenuated vaccines should be avoided while patients are 
taking study drug and for 2 months after study drug discontinuation. Vigilance for infection 
should be continued throughout this time period. Following VZV vaccination, the initiation 
of study drug should be postponed for 1 month to allow full effect of vaccination to occur.
Vaccination may be less effective during and for up to two months after treatment with 
fingolimod. 


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Appendix 6:  Liver event and Laboratory trigger Definitions and Follow-
up Requirements
Liver Event and Laboratory Trigger Definitions
Definition/ threshold
LIVER LABORATORY TRIGGERS

3 x ULN < ALT / AST 5 x ULN

1.5 x ULN < TBL 2 x ULN
LIVER EVENTS

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known bone pathology)

TBL > 2 × ULN (in the absence of known Gilbert syndrome)

ALT or AST > 3 × ULN and INR > 1.5 

Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and 
TBL > 2 × ULN [mainly conjugated fraction] without notable 
increase in ALP to > 2 × ULN)

Any clinical event of jaundice (or equivalent term)

ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia

Any adverse event potentially indicative of a liver toxicity*
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms
TBL: total bilirubin; ULN: upper limit of normal 
Follow Up Requirements for Liver Events and Laboratory Triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law 
casea

Discontinue the study treatment 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
ALT or AST
> 8 × ULN

Discontinue the study treatment 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
> 3 × ULN and INR > 
1.5

Discontinue the study treatment 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
> 5 to ≤ 8 × ULN

Repeat LFT within 48 hours

If elevation persists, continue follow-up 
monitoring

If elevation persists for more than 2 
weeks, discontinue the study drug

Establish causality
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)


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Criteria
Actions required
Follow-up monitoring

Complete liver CRF
> 3 × ULN 
accompanied by 
symptomsb

Discontinue the study treatment 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
> 3 to ≤ 5 × ULN 
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks 
ALP (isolated)
> 2 × ULN (in the 
absence of known 
bone pathology)

Repeat LFT within 48 hours

If elevation persists, establish causality

Complete liver CRF
Investigator discretion
Monitor LFT within 1 to 4 weeks or at 
next visit
TBL (isolated)
> 2 × ULN (in the 
absence of known 
Gilbert syndrome)

Repeat LFT within 48 hours

If elevation persists, discontinue the study 
drug immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
Test for hemolysis (e.g., reticulocytes, 
haptoglobin, unconjugated [indirect] 
bilirubin)
> 1.5 to ≤ 2 × ULN
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the patient 
Investigator discretion
Monitor LFT within 1 to 4 weeks or at 
next visit
Jaundice

Discontinue the study treatment 
immediately

Hospitalize the patient

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
Any AE potentially 
indicative of a liver 
toxicity*

Consider study treatment interruption or 
discontinuation 

Hospitalization if clinically appropriate

Establish causality

Complete liver CRF
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable values at 
three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a maximum of 6 
months, (4) liver transplantation, and (5) death.


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Appendix 7: Guidance for Ophthalmic Monitoring
Fingolimod has previously been associated with a two-fold increase in the risk of macular 
edema in renal transplant patients receiving cyclosporine. 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.
An ophthalmic examination by an ophthalmologist or neurologist will be conducted in 
accordance with Table 6-1 and 6-2. Similar assessments must be performed at an unscheduled 
ophthalmology visit for any patient who presents with new visual symptoms or decrease in 
visual acuity. 
1. The ophthalmic examinations will consist of best corrected visual acuity using a visual 
acuity chart with equal spacing between letters and between lines. If patients report 
visual disturbances at any time while on therapy, evaluation of the fundus, including 
the macula, should be carried out by an ophthalmologist.
2. Optical Coherence Tomography (OCT) scan should be performed if considered 
clinically indicated. OCT is required for patients transferring into this trial from a 
blinded study with a comparator arm at the Month 3 and Month 6 visits and in patients 
transferring from the control arm of open-label controlled studies.  The OCT will be 
done to evaluate the presence of any abnormalities consistent with macular edema. 
Guidance on monitoring patients for possible macular edema
When macular edema is suspected, a complete ophthalmic evaluation should be performed 
including, but not limited to, best-corrected visual acuity, dilated ophthalmoscopy, fundus 
examination and OCT. Patients with history of uveitis and patients with diabetes mellitus are 
at an increased risk of macular edema and may require more frequent ophthalmic evaluations, 
per investigator’s discretion.
Based on ophthalmic monitoring during the study, study drug must be interrupted in any 
patient who meets one of the following criteria:

Patient who is diagnosed to have macular edema.

Patient who has a decrease in visual acuity (2 line or greater loss on low or normal 
contrast chart) and an abnormal OCT (> 20% increase in central foveal thickness
compared to baseline OCT or cystic changes in the fovea).
A fluorescein angiogram is recommended to evaluate for the presence of vascular leakage in 
these patients and patients must be encouraged to stay in the study to track resolution of these 
changes during subsequent visits.  
These patients should be followed-up 1 month and 3 months after diagnosis of macular edema 
and more frequently, if needed, based on the investigator’s judgment. Further ophthalmologic
evaluations will be conducted until such time as resolution is confirmed or no further 
improvement is expected by the ophthalmologist (based on a follow-up period of not less than 
3 months). These evaluations will include repeat best-corrected visual acuity, fundus 
examination and OCT. Fluorescein angiography (FA) is repeated at the discretion of the 


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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.
Continuation of fingolimod in patients with macular edema has not been evaluated. A 
decision on whether or not study drug should be re-initiated after resolution of macular edema 
needs to take into consideration the potential benefits and risks to the individual patient.
An interruption or discontinuation of the study drug should be clearly documented and 
reflected on Dosage Administration Record eCRF. AE/SAEs need to be filed as appropriate.  
For patients discontinuing study drug for any of the above ophthalmic reasons, copies of the 
colored OCT and fluorescein angiography (if performed) as well as source documents of 
ophthalmic examination should be kept at the site as source documents. These documents may 
need to be submitted for review by an independent panel, if needed. 
Guidance on monitoring patients with uveitis
Patients with a history of uveitis or findings compatible with active uveitis at baseline can 
enter the study given that there is no evidence of macular edema in the baseline ophthalmic 
examination.
In order to specifically assess the risk of macular edema in the MS population with co-
existing uveitis, each patient with findings in any ophthalmic examination compatible with 
active uveitis (e.g., significant anterior chamber cell or flare, vitreous cell or flare, pars 
planitis, vasculitis, chorioretinitis) under the discretion of the investigator should undergo an 
ophthalmic examination. It is the discretion of the investigator to determine the frequency of 
these ophthalmic examinations. Adjustments to the schedule can be made to align these 
evaluations with other planned study visits. 
The diagnosis of macular edema will lead to study drug interruption (refer to Guidance for 
monitoring of patients with macular edema above).


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Appendix 8: EDSS Assessment Criteria
EXPANDED DISABILITY STATUS SCALE
0 = normal neurological exam (all FS grade 0)
1.0 = no disability, minimal signs in one FS (one FS grade 1)
1.5 =
no disability, minimal signs in more than one FS (more than one FS grade 1)
2.0 =
minimal disability in one FS (one FS grade 2, others 0 or 1)
2.5 =
minimal disability in two FS (two FS grade 2, others 0 or 1)
3.0 =
moderate disability in one FS (one FS grade 3, others 0 or 1) though fully
ambulatory; or mild disability in three or four FS (three/four FS grade 2, others 0 or 1)
though fully ambulatory
3.5 =
fully ambulatory but with moderate disability in one FS (one FS grade 3) and
mild disability in one or two FS (one/two FS grade 2) and others 0 or 1;
or fully ambulatory with two FS grade 3 (others 0 or 1);
or fully ambulatory with five FS grade 2 (others 0 or 1)
4.0 =
ambulatory without aid or rest for some 500 meters; up and about some 12 hours a day 
despite relatively severe disability consisting of one FS grade 4 (others 0 or 1) or 
combinations of lesser grades exceeding limits of previous steps
4.5 =
ambulatory without aid or rest for some 300 meters; up and about much of the day,
Characterized by relatively severe disability usually consisting of one FS grade 4
and combination of lesser grades exceeding limits of previous steps
5.0 =
ambulatory without aid or rest for about 200 meters (usual FS equivalents include at
least one FS grade 5, or combinations of lesser grades usually exceeding
specifications for step 4.5)
5.5 =
ambulatory without aid or rest about 100 meters
6.0 =
unilateral assistance (cane or crutch) required to walk about100 meters with
or without resting
6.5 =
constant bilateral assistance (canes or crutches) required to walk at least 20
meters without resting
7.0 =
unable to walk 5 meters even with aid, essentially restricted to wheelchair;
wheels self and transfers alone; up and about in wheelchair some 12 hours a day
7.5 =
unable to take more than a few steps; restricted to wheelchair; may need some
help in transferring and in wheeling self
8.0 =
essentially restricted to bed or chair or perambulated in wheelchair, but out of
bed most of day; retains many self-care functions; generally has effective use of
arms
8.5 =
essentially restricted to bed much of the day; has some effective use of arm(s);
retains some self-care functions
9.0 =
helpless bed patient; can communicate and eat


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9.5 =
totally helpless bed patient; unable to communicate effectively or eat/swallow
10.0 = death due to MS

SAP_001.pdf: 
 
 
 
 
 
 
Clinical Development 
 
FTY720 (Fingolimod) 
 
CFTY720D2399 / NCT01201356 
 
 
A single arm, open-label, multicenter study evaluating the 
long-term safety and tolerability of 0.5 mg fingolimod 
(FTY720) administered orally once daily in patients with 
relapsing forms of multiple sclerosis 
 
RAP Module 3 – Detailed Statistical Methodology for 
D2399 final CSR full analysis – long-term follow-up study 
part I 
 
 
 
Author: 
Trial Statistician; 
Novartis Trial Statistician; 
Novartis 
 
Document type: 
RAP Documentation 
 
Document status: 
Final v2.0 Amendment 1 
Release date: 
JUN20, 2017 
 
 
 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Document History – Changes compared to previous version of RAP module 3. 
 
Version 
Date 
Changes 
Draft v.1.0 
16JAN2016 
Draft v.1.1 
03APR2016 
Draft v.1.2 
14SEP2016 
Final v.2.0 
07NOV2016 
Final v.2.0 Amendment 1 
20JUN2017 
1.Update section 9.2 to include 8x criteria for liver 
function summary 
2.Update section 9.6 to include DM summary in 
OPH summary and extra listing for visual acuity. 
4. Updated patient disposition part per DR2 
comment 
5. Updated protocol deviation part per table label 
update 
6. AE part, wording update 


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Table of contents 
List of abbreviations ........................................................................................................... 5 
1 
Overview ............................................................................................................................. 7 
2 
General strategies of data presentation ............................................................................... 9 
2.1 
Allocated treatment ................................................................................................. 9 
2.2 
Precision rules ......................................................................................................... 9 
2.3 
Time frames, baseline, and visit windows .............................................................. 9 
2.3.1 
Database lock for Study part I ................................................................ 9 
2.3.2 
Study day .............................................................................................9 
2.3.3 
Baseline and post-baseline ................................................................... 10 
2.3.4 
Variables Summarized by Visits .......................................................... 10 
2.4 
Imputation of Incomplete Dates ............................................................................ 13 
2.5 
Analysis sets .......................................................................................................... 13 
2.5.1 
Subgroups ............................................................................................. 14 
3 
Patient Disposition ............................................................................................................ 15 
4 
Protocol Deviations ........................................................................................................... 15 
5 
Background and demographic characteristics .................................................................. 15 
5.1 
Core study ............................................................................................................. 15 
5.2 
Demographics ....................................................................................................... 15 
5.3 
MS disease history characteristics before enrollment in core study ..................... 16 
5.4 
MS medication history prior to enrollment in core study ..................................... 16 
6 
Study drug ......................................................................................................................... 17 
6.1 
Duration of exposure ............................................................................................. 17 
7 
Concomitant medication ................................................................................................... 17 
7.1 
Imputation of concomitant medication start date .................................................. 17 
7.2 
Imputation of concomitant medication end date ................................................... 18 
7.3 
Concomitant medication analyses ......................................................................... 18 
8 
Efficacy evaluation ........................................................................................................... 19 
8.1 
Analysis of MS Relapses ...................................................................................... 19 
8.1.1 
Relapse date imputations and handling of duplicate relapse 
records .................................................................................................. 19 
8.1.2 
Annualized relapse rates ....................................................................... 21 
8.1.3 
Time in study ........................................................................................ 22 
8.1.4 
MS relapses analyses ............................................................................ 22 
8.2 
Analysis of MRI .................................................................................................... 23 


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8.2.1 
Annualized rates of new T2 lesions ...................................................... 23 
8.2.2 
Total volume of T2 lesions and T1 hypointense lesion ........................ 24 
8.2.3 
Percent brain volume change (PBVC).................................................. 24 
8.2.4 
Annualized rate of brain volume change (ARBA) ............................... 25 
8.3 
Analysis of EDSS scores ....................................................................................... 25 
8.3.1 
By-visit summaries ............................................................................... 25 
8.3.2 
EDSS score of 4/6/7 or greater ............................................................. 26 
8.3.3 
Analysis of 6-month confirmed disability progression ........................ 26 
8.4 
Analysis of Multiple Sclerosis Functional Composite (MSFC) ........................... 28 
29 
29 
29 
30 
30 
31 
32 
9 Safety evaluation ................................................................................................................33 
9.1 
Adverse events ...................................................................................................... 33 
9.1.1 
Imputation of adverse event start date .................................................. 33 
9.1.2 
Adverse events analyses ....................................................................... 34 
9.1.2.1 
Adverse events during long-term follow-up study part I ..................... 34 
9.1.2.2 
Adverse events during the fingolimod treatment period ...................... 35 
9.2 
Laboratory ............................................................................................................. 37 
9.3 
Routine vital signs ................................................................................................. 37 
9.4 
Routine Electrocardiograms during the long-term follow-up study ..................... 38 
9.5 
Dose monitoring administration ............................................................................ 38 
9.5.1 
Vital signs ............................................................................................. 39 
9.5.2 
Electrocardiograms ............................................................................... 39 
9.6 
Ophthalmic assessments ........................................................................................ 39 
9.7 
Pulmonary function tests ....................................................................................... 40 
9.8 
Skin assessment ..................................................................................................... 40 
10 Sample size and power considerations ...........................................................................40 
Appendices ....................................................................................................... 41 
Appendix A: Clinically notable laboratory values .......................................... 41 
Appendix B: Clinically notable Vital sign values ........................................... 43 


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List of abbreviations 
 
AE 
adverse event 
ALT 
alanine aminotransferase 
ARR 
annual relapse rate 
AST 
aspartate aminotransferase 
AV 
atrioventricular 
BPM 
beats per minute 
eCRF 
electronic case report/record form 
CPO 
Country Pharma Organization 
CRO 
Contract Research Organization 
DLCO 
carbon monoxide diffusing capacity test 
DS&E 
Drug Safety & Epidemiology 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EDSS 
expanded disability status scale 
FDD 
First dose of study drug (among all studies) 
FDF 
First dose of fingolimod 
FEV1 
forced expiratory volume over 1 second test 
FSH 
follicle-stimulating hormone 
FVC 
forced vital capacity test 
GGT 
gamma-glutamyl-transferase 
HbA1c
glycated hemoglobin 
HCG 
human chorionic gonadotropin 
HR 
heart rate 
IB 
investigator’s brochure 
ICH 
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IFN 
interferon 
IN 
Investigator Notification 


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IRB 
Institutional Review Board 
LN 
lymph nodes 
LUC 
large unstained cells 
MRI 
magnetic resonance imaging 
MS 
multiple sclerosis 
NPDR 
non-proliferative diabetic retinopathy 
OCT 
optical coherence tomography 
p.o. 
by mouth 
PFT 
pulmonary function test 
PPMS 
primary progressive multiple sclerosis 
RBC 
red blood cell 
RMP 
risk management plan 
RRMS 
relapsing remitting multiple sclerosis 
SAE 
serious adverse event 
s.c. 
subcutaneously 
SPMS 
secondary progressive multiple sclerosis 
SUSAR 
suspected unexpected serious adverse reactions 
 
 
ULN 
upper limit of normal range 


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1 
Overview 
Study CFTY720D2399 is a single arm, open-label, multicenter study evaluating the long- 
term, safety, tolerability and efficacy of 0.5 mg fingolimod (FTY720) administered orally 
once daily in patients with relapsing forms of multiple sclerosis (MS). This study allows 
MS patients who have participated in clinical studies with fingolimod to be transferred in, 
some patients who already complete CFTY720D2399 are eligible to re-enter if qualified. 
The term ‘long-term follow-up’ is used to define this CFTY720D2399 study throughout  
this document, indicating that CFTY720D2399 is the extension of all historical fingolimod 
studies. Prior fingolimod studies include CFTY720D2201/E1, CFTY720D2301/E1, 
CFTY720D2302/E1, 
CFTY720D2309/E1, 
CFTY720D2312, 
CFTY720D2316, 
CFTY720D2320, CFTY720D2324, CFTY720D2325, CFTY720D2399E1 and 
CFTY720D2402. Patients from other ongoing or newly starting fingolimod MS studies may 
roll over to the long-term follow-up study once they are eligible. Generally, a patient with 
previous fingolimod trial experience may participate the study series in the order of core 
study, extension study, the CFTY720D2399E1 study and the long-term follow-up study . 
Patients can transfer into the long-term follow-up study directly either from the core, 
extension or CFTY720D2399E1. 
Note that CFTY720D2399E1 is an intermediate study, which occurs after a patient’s core  
or extension study and before the long-term follow-up study. Patients from studies 
CFTY720D2302E1 and CFTY720D2309E1 may roll over directly into the long-term 
follow-up study, or they may roll over into the CFTY720D2399E1 study first, and then into 
the long-term follow-up study . The CFTY720D2399E1 study was closed out early due to a 
low enrollment rate. 
Approximately 5000 patients who have completed ongoing or planned clinical trials in the 
MS development program with fingolimod are expected to be enrolled in >500 centers 
worldwide into this long-term follow-up study. 
Upon signing the informed consent, patients will be transferred into this study from one of 
the ongoing fingolimod core/extension studies (CFTY720D2201/E1, CFTY720D2301/E1, 
CFTY720D2302/E1, CFTY720D2309/E1, etc.), as well as from designated ongoing or 
newly starting fingolimod MS studies. In addition, phase II/III patients that have already 
completed CFTY720D2399, CFTY720D2309/E1, or one of the phase II/III extension 
studies will be able to enroll into this study. Patients will be provided with fingolimod 0.5 
mg/day once a day treatment until study completion. 
Patients who participated in double-blind studies and are directly entering this study will 
remain blinded to the identity of the treatment in the previous study. In order to maintain 
the blind, the monitoring immediately after the first dose of study drug will be performed 
by a blinded first-dose administrator. 
This study has two parts: 
Part One will collect long-term safety, tolerability, efficacy, and health outcomes data 
through approximately 30-Jun-2016. Part Two will collect limited safety data until 
approximately 30-Jun-2018 from a subset of patients participating in Part One and other 


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eligible patients from ongoing fingolimod trials (e.g., CFTY720D2312). Eligibility for Part 
Two is defined as prior fingolimod study patients who are unable to obtain fingolimod 
outside a clinical trial. 
By June 2016, investigators must determine commercial Gilenya eligibility for all active 
study patients (i.e., reimbursed for commercial Gilenya). Patients able to obtain commercial 
Gilenya will then have their End of Study (Part One) visit and exit the study, regardless of 
their post-study treatment decision (i.e., continuing on Gilenya commercially or 
transitioning to another treatment option). Patients discontinuing or completing the study at 
Part One who do not continue on commercial Gilenya must return for two follow-up study 
visits, 3-months and 6-months post-last dose of fingolimod. Patients who choose to 
continue on commercial Gilenya outside the study are exempted from the follow-up visits. 
Patients not eligible for reimbursed, commercial Gilenya will be offered continued study 
participation in Part Two until their scheduled study visit closest to 30-Jun-2018 (+/- 30 day 
visit window), with a reduced assessment schedule (see protocol Table 6-2), for the purpose 
of collecting additional long-term safety and tolerability data in support of the primary 
study objective. Patients discontinuing or completing the study after entering Part Two who 
do not continue on commercial Gilenya must return for one follow-up study visit, 3-months 
post-last dose of fingolimod. Patients who choose to continue on commercial Gilenya 
outside the study are exempted from the follow-up visit. 
The duration of treatment of a patient in this trial is dependent on which study the patient 
participated in previously as well as the availability of reimbursement for commercially 
available fingolimod in the respective country. The study part I is planned to end by 30-Jun- 
2016 in order to collect 6 months or more of long-term safety data for the majority of Phase 
II/III patients. Guidance regarding scheduling of the Study Completion visit is provided in 
order to streamline the study closure processes, specifically designating the Study 
Completion visit to occur at or shortly after sixty months of study participation for those 
patients who would reach 60 months by 30-Jun-2016. Patients not reaching 60 months by 
30-Jun-2016 will have their study completion on or around 30-Jun-2016 (+/- 30 day visit 
window), and patient who have already reached 60 months should have their Study 
Completion visit at their next six monthly visit, or 30-Jun-2016, whichever comes first. 
This analysis plan will describe the analyses which will be conducted on the CFTY720D 
series studies (from initial core/extension study to the long-term follow-up study ) for Final 
CSR full analysis - long-term follow-up study part I. Patients participating in this study will 
provide clinical data of up to 15 years of exposure, which will provide information on the 
long-term safety, tolerability and efficacy profile of 0.5 mg fingolimod (FTY720) 
administered orally once daily in patients with relapsing forms of multiple sclerosis (MS) to 
help in therapeutic decision making. The full analysis will address safety updates for 
opportunistic infections and for basal cell carcinoma, since basal cell carcinoma has been 
reported in patients receiving fingolimod. Two follow-up visits (3-month and 6-month 
follow-up) are required after study completion to continuously monitor study safety. 
Unless otherwise mentioned, all data collected from the first dose of fingolimod in the 
core/extension studies up to the end of the long-term follow-up study part I will be analyzed 
to evaluate the endpoints. 


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2 
General strategies of data presentation 
Statistical Analysis System (SAS) version 9.1 or higher will be used to perform all analyses. 
In general, variables will be summarized using frequency distributions for categorical 
variables and summary statistics for continuous variables. Summary statistics for 
continuous variables will include n, mean, standard deviation, minimum, first quartile (Q1), 
median, third quartile (Q3) and maximum. 
Note that, for CFTY720D2312 and CFTY720D2402 patients, the core study data is not 
included for any summary, and only information in the long-term follow-up study part I is 
included for listing purposes. 
 
2.1 
Allocated treatment 
All patients during the long-term follow-up study are treated with fingolimod 0.5 mg per 
day. The summaries for data collected during the long-term follow-up study part I will only 
present one total group (the same as fingolimod any dose). However, patients may have 
been assigned a different dose (5 mg, 1.25 mg) in their initial fingolimod trial. The 
summaries for data collected from first dose of fingolimod among all studies will be 
presented by highest assigned dose of fingolimod; only two groups will be presented: 
fingolimod 0.5 mg and fingolimod any dose. 
 
2.2 
Precision rules 
Whenever possible, the minimum and maximum values of the data will be presented to the 
same precision as the raw data; the mean, median, quartile 1, and quartile 3 will be 
presented to one more decimal place, and standard deviation will be presented to two more 
decimal places than the raw data. 
 
2.3 
Time frames, baseline, and visit windows 
This section defines the study and data time frames, baseline, and rules for visit windows. 
 
2.3.1 
Database lock for Study part I 
There are two database locks for this study. The analyses specified in this document include 
data from study part I with a database lock planned around 30th Jun 2017. All qualified 
patients will have end of study visit scheduled around 31st Oct 2016, which gives time for 6-
month follow-up by end of Apr 2017. The 2nd data base lock is planned around 2018 for 
study part 2, in which patients from the long-term follow-up study are kept for another 2 
years after finishing study part I. The analysis plan for study part II will be provided in a 
separate analysis plan. 
 
2.3.2 
Study day 
The day of first administration of fingolimod study drug is defined as Day 1. Day 1  does 
not need to occur in the long-term follow-up study. 


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All other study days will be labeled relative to Day 1. Thus, study day for a particular event 
date on or after Day 1 is calculated as: (Date of event – Date of first dose of fingolimod 
study drug + 1). An event that occurs prior to Day 1 is calculated as: (Date of event – Date 
of first dose of fingolimod study drug). 
In addition to calculating study day with respect to the first dose date of fingolimod drug 
across all studies, study day will also be calculated relative to the first dose date of 
fingolimod during the long-term follow-up study. 
The number of days after permanent study drug discontinuation will be calculated as (Date 
of event – Date of last dose of fingolimod study drug). 
The duration of an event will be calculated as (Event end date –  Event start  date + 1).  
Day 0 will not be used. 
 
2.3.3 
Baseline and post-baseline 
Unless otherwise specified, the baseline relative to the first dose of fingolimod (FDF) will 
be used throughout this study. It is defined as the last available measurement made prior to 
administration of the first dose of fingolimod among all studies a patient has participated in. 
The baseline can also be defined relative to the first dose of fingolimod during the long- 
term follow-up study in certain cases (i.e. ECG summary by visit), which is defined as the 
last available measurement made prior to administration of the first dose of fingolimod 
during the long-term follow-up study. The baseline relative to first dose of study drug in the 
core study (e.g. demographic information, core baseline characteristics) is also used for 
mentioned sections. 
Post-baseline assessments are assessments made after the baseline assessment. 
 
2.3.4 
Variables Summarized by Visits 
Below are the visit windowing rules used for visits as defined in the Virtual Data 
Warehouse (VDW) RAP M4 draft version 4.3. 
Visit windows will be widely used to align visits across studies. They are based on the 
assessment schedule of the pivotal studies and comprise a set of days around the nominal 
visits. The same visit windows will apply to all studies. Visit-windows are non-overlapping; 
all together they cover the entire study period. Generally, visit-windows are not 
symmetrical around the nominal visit day. Among all the analysis, ECG, dose monitoring 
and ‘end of study’ summary for related panels will not use visit-window. Corresponding 
summaries are based on nominal visits. 
Visit windows will be used to present summary statistics by visit. Efficacy data sets 
consider only scheduled visits, while safety datasets consider both scheduled and 
unscheduled visits. For efficacy analysis, if multiple assessments are available within a visit 
window, the record closest to the target day will be selected (if more than one assessment is 
equidistant to the target day, the later assessment will be used). For safety analysis, multiple 
assessments within a visit window will be averaged (for quantitative variables) or the worst 
record (for qualitative variables) will be selected. A follow-up visit-window will be used for 
data collected after last dose of fingolimod, which only consider scheduled assessments. 


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Similar rules (record selection either by date closest to target day or by averaging records 
within the same window) will be applied for efficacy and safety analysis respectively. 
Unless otherwise specified, the following vital sign/lab visit windows are derived with 
respect to the first dose date of fingolimod among all studies. 
 
Table 1 
Visit-windows for vital signs and laboratory values 
 
Visit 
Start day (time) 
Target Day (time) 
End day (time) 
Week 2** 
3 
14 
22 
Month 1 
23 
30 
45 
Month 2 
46 
60 
75 
Month 3 
76 
91 
136 
Month 6 
137 
182 
227 
Month 9 
228 
273 
319 
Month 12 
320 
365 
410 
… 
every 3 months 
Month X (row i) 
Si=Integerpart((Di+Di-1) /2)+1 
Di = Integerpart(X*365.25/12) 
Ei=Integerpart((Di+1+Di) /2) 
... 
... 
Every 3 months 
... 
Month X (last row) 
Slast 
Dlast 
Elast=Dlast+( Dlast-Slast) 
- Unless otherwise specified, Day 1 is defined as the first dose day of fingolimod among all studies. 
- Baseline will refer to the last value prior to the intake of the first dose of fingolimod. (Measurements labeled as “pre-dose” 
assessments will not be used as baseline values if the actual time variable suggests that the value has been obtained after the 
first dose of study medication: exceptions are body weight and temperature for which Day 1 records can be used as baseline 
irrespective of the actual time on day 1). 
- Multiple results per patient within a visit window will be averaged for summary statistics by considering both scheduled and 
unscheduled visits.. 
- This visit windowing approach will only be used for summary statistics. (All individual assessments including unscheduled 
visits will be used to analyze notable and abnormal values, in shift tables and on listings.) 
- ** Week 2 for laboratory values will include day 1 post-baseline as the start day. 
 
 
Table 2 Visit-windows for efficacy data (non-EDSS) domains 
 
Visit 
Start day (time) 
Target Day (time) 
End day (time) 
Month 3 
1 
91 
136 
Month 6 
137 
182 
273 
Month 12 
274 
365 
547 
Month 24 
548 
730 
912 
Year 3 (M36) 
913 
1095 
1278 
Year 4 (M48) 
1279 
1461 
1643 
Year 5 M(60) 
1644 
1826 
2008 
Year 6 (M72) 
2009 
2191 
2373 
Year 7 (M84) 
2374 
2556 
2739 
Year8 (M96) 
2740 
2922 
3104 
Year 9 
3105 
3287 
3469 
Year 10 
3470 
3652 
3834 
Year 11 
3835 
4017 
4200 


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… 
every 12 months 
Month X (row i) 
Si=Integerpart((Di+Di-1) /2)+1 
Di = Integerpart(X*365.25/12) 
Ei=Integerpart((Di+1+Di) /2) 
... 
... 
Every 12 months 
... 
Month X (last 
row) 
Slast 
Dlast 
Elast=Dlast+( Dlast-Slast) 
- Day 1 is defined as the first dose day of fingolimod among all studies. 
- Baseline will refer to the last MRI value prior to Day 1. 
- For MRI: Visits 777 and 779 (study drug discontinuation assessments: the last scheduled scan is the reference scan), will 
be included in the visit windowing approach. However, 777 will only be used in a visit window if no other scheduled visit is 
available in the same window, if another scheduled visit is present, then the scheduled visit will take priority over 777. 
- If multiple assessments are available within a visit window, the record closest to the target day will be selected (if more than 
one assessment is at the same distance to the target day, the later one will be used for summary statistics (after 
unscheduled visits are excluded). 
 
Table 3 Visit-windows for EDSS efficacy data 
 
Visit 
Start day (time) 
Target Day (time) 
End day (time) 
Month 3 
1 
90 
135 
Month 6 
136 
180 
225 
Month 9 
226 
270 
315 
Month 12 
316 
360 
405 
Month 15 
406 
450 
495 
Month 18 
496 
540 
585 
Month 21 
586 
630 
675 
Month 24 
676 
720 
765 
Month 27 
766 
810 
855 
Month 30 
856 
900 
945 
Month 33 
946 
990 
1035 
Month 36 
1036 
1080 
1125 
: 
: 
: 
: 
Month 72 
2116 
2160 
2205 
: 
: 
every 3 months 
: 
- Day 1 is defined as the first dose day of fingolimod among all studies. 
- Expanded Disability Status Scale (EDSS) scores will be summarized by visits occurring every 3 months from the date of 
first dose of study drug (for example at Month 3, Month 6, etc.). 
- Baseline will refer to the last value prior to the intake of the first dose of fingolimod among all studies. 
- If multiple assessments are available within a visit window, the record closest to the target day will be selected (if more than 
one assessment is at the same distance to the target day, the later one will be used for summary statistics (after 
unscheduled visits are excluded). 
 
Table 4 Follow-up visit windows (applicable to several panels: e.g. VSN, LAB, EDSS, 
MSFC, 
) 
 
Visit label 
Start day (time) 
Target Day (time) 
End day (time) 
FU (Month 3) 
Day 1 p.l.d 
Day 90 p.l.d 
Day 135 p.l.d 
FU (Month 6) 
>= Day 136 p.l.d 
Day 180 p.l.d 
- Follow-up visit windows are defined relative to study drug discontinuation in the respective pool (unscheduled visits will be 
excluded). 
- p.l.d = post last dose. 


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2.4 
Imputation of Incomplete Dates 
Incomplete or partial dates will be imputed (where appropriate, and will follow Virtual Data 
Warehouse (VDW) imputation rules – refer to VDW MAP M8) to decide on the inclusion 
or exclusion of related events in the summary tables. Each incomplete date will be split into 
its day, month, and year components, and an imputation rule will be applied. However in 
data listings, the dates as available in the database should be listed (without imputation). 
General imputation rules from the VDW MAP M3, draft version 3.0 are given below. 
Specific imputation rules may apply to certain panels (e.g. concomitant medications) and 
are described in the relevant sections. If no imputation rules are described then the general 
imputation rules apply to partially missing or impossible dates: 
• If the year is missing or impossible (e.g. 12-Jan-1911), then the date will be 
imputed as missing. 
• If the year is not missing and possible, but the month is impossible or 
missing (e.g. 17-XXX-2010), then the year will be kept and July 1st will be 
imputed (1-July-2010). 
• If the year and the month are not missing and possible, but the Day is 
impossible or missing (e.g. 31-FEB-2009), then the year and month will be 
kept, the 15th will be imputed (15-FEB-2009). 
 
2.5 
Analysis sets 
The following analysis sets will be defined. 
• Enrolled set: The enrolled set will include all patients who entered the long-term 
follow-up study part I (excludes long-term follow-up study screen failures), but will 
exclude patients with protocol deviation severity code of 8 (8=exclude from all analyses) 
in the long-term follow-up study part I. 
• Safety set: The safety set will include all patients who entered the long-term follow-up 
study part I and received at least one dose of fingolimod in any study, but will exclude 
patients with protocol deviation severity codes of 5 (5=exclude from all safety analyses) 
and 8 (8=exclude from all analyses) in the long-term follow-up study part I. Note that 
all data reported in the long-term follow-up study part I will be analyzed, including 
assessments or events which started before the long-term follow-up study part I. 
• Fingolimod safety set: The fingolimod safety set will include all patients who entered 
the long-term follow-up study part I and received at least one dose of fingolimod in any 
study, but will exclude patients with protocol deviation severity codes of 5 (5=exclude 
from all safety analyses) and 8 (8=exclude from all analyses) during the core study prior 
to entry to the long-term follow-up study part I. For patients with such protocol 
deviations after the core study, record level data associated with the protocol deviations 
will be excluded from the analysis. 
- Day 1 p.l.d is defined as the first day after the last dose day of fingolimod. 


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• Fingolimod full analysis set: The fingolimod full analysis set will include all patients 
who entered the long-term follow-up study part I and received at least one dose of 
fingolimod in any study but will exclude patients with protocol deviation severity codes 
of 0 (0=exclude from all efficacy analyses) and 8 (8=exclude from all analyses) during 
the core study prior to entry to the long-term follow-up study part I. For patients with 
such protocol deviations after the core study, record level data associated with the 
protocol deviations will be excluded from the analysis. 
• Follow-up set: The follow-up set will consist of all patients in the safety set who have 
any follow-up visit data or at least one safety record after the study drug discontinuation. 
It will be used for summary of adverse events and concomitant medications with 
occurrences after last dose of fingolimod only. 
Patient disposition, core study, protocol deviations, analysis sets, demographics, and 
baseline and history information will be summarized based on the enrolled set. Efficacy 
analyses will be summarized based on the fingolimod full analysis set. Safety summaries 
that include only long-term follow-up study part I data will be based on safety set, while 
other safety assessments that include data from the first dose of fingolimod among all 
studies, will be summarized based on fingolimod safety set. 
A summary of the number and percentage of patients in each analysis set (enrolled set, 
safety set, fingolimod safety set, fingolimod full analysis set, and follow-up set) will be 
summarized. Percentages will be based on the enrolled set. A listing of patient assignment 
into each analysis set will also be displayed. 
 
2.5.1 
Subgroups 
The following subgroups are defined for AE analysis: 
1. Duration of fingolimod treatment up to the end of the long-term follow-up study 
part I (yearly interval): 
• Year 1 subgroup: patients on fingolimod treatment >= 0 year (>= 1 day) 
• Year 2 subgroup: patients on fingolimod treatment >= 1 year (>= 360 
days) 
• Year 3 subgroup: patients on fingolimod treatment >= 2 year (>= 720 
days) 
• Year 4 subgroup: patients on fingolimod treatment >= 3 year (>= 1080 
days) 
• Year 5 subgroup: patients on fingolimod treatment >= 4 year (>= 1440 
days) 
• Year N subgroup: patients on fingolimod treatment >= N -1 year (>= (N - 
1) x 360 days) 
2. Patients from Phase II/III studies: This subgroup includes patients who have 
enrolled in any of the following studies: D2201, D2301, D2302, and D2309 
before entering the long-term follow-up study part I. 


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3 
Patient Disposition 
All screen failures in the long-term follow-up study will be listed along with their primary 
reason for failing screening. 
The number and percentage of patients who completed the long-term follow-up study part I, 
and who discontinued the long-term follow-up study part I, along with the primary reason 
for discontinuation, will be summarized for the enrolled set. The number and percentage of 
patients who are expected to have follow-up visits and who returned for 3-month and 6- 
month follow-up visits will also be summarized. 
The patients who discontinued from the long-term follow-up study part I and corresponding 
reasons will be listed for the enrolled set. Additionally, a similar listing will be provided for 
the enrolled set of patients from D2312 and D2402 studies who discontinued early from the 
long-term follow-up study part I . 
 
4 
Protocol Deviations 
The number and percentage of patients in the enrolled set with each protocol deviation in 
the long-term follow-up study part I will be displayed by protocol deviation category. 
Additionally, patients with at least one protocol deviation during the long-term follow-up 
study part I and patients with at least one protocol deviation causing exclusion from any 
analysis set (deviation severity codes 0, 5, or 8) will be summarized. 
The protocol deviation data will be listed as well. 
Additionally, the investigator comments during the long-term follow-up study part I will be 
listed. 
 
5 
Background and demographic characteristics 
5.1 
Core study 
The core study refers to the first fingolimod MS study the patient enrolled in. The number 
and percentage of patients in each core study prior to transfer into the long-term follow-up 
study will be provided. 
 
5.2 
Demographics 
Using data collected from the patient’s core study, the following demographic variables will 
be summarized for the enrolled set and the subgroup of enrolled set patients from phase 
II/III studies: sex, age (years), age groups [<18, 18-30, 31-40, 41-55, >55], race, ethnicity, 
baseline weight, baseline height, and baseline BMI. Baseline height and weight will be 
derived as the last non-missing assessment prior to first dose of any drug among all studies 
a patient has participated in. Baseline BMI will be derived based on baseline height and 
weight. Age will be calculated as the (core study’s demographic screening or baseline visit 
date – patient’s birth date +1) / 365.25. 


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Unless otherwise specified, age is presented in the listings in 3 ways: age 1 is the age at the 
visit where demographic data is collected (screening or baseline visit of core study); age 2 
is the age at first dose of fingolimod among all studies; age 3 is the age at last dose of 
fingolimod. 
 
5.3 
MS disease history characteristics before enrollment in core 
study 
Using data collected from the patient’s core study, the following MS disease history 
characteristics will be summarized for the enrolled set: duration of MS since diagnosis in 
years, duration of MS since first symptoms in years, number of relapses in the last year 
prior to enrollment in the core study, number of relapses in the last 2 years prior to 
enrollment in the core study, time since the onset of the most recent relapse (in months) 
prior to enrollment in the core study, and duration from MS diagnosis date to last dose date 
of study drug (in years). The baseline EDSS score and the duration of exposure to 
fingolimod prior to first dose in the long-term follow-up study part I will also be 
summarized for the enrolled set. Note that not all parameters are collected across all studies. 
The following definitions will be used in calculations involving MS disease history 
characteristics: one year is defined as 365.25 days and one month is defined as 30 days. 
For the MS disease history summary, the variable Duration of MS since diagnosis (years) 
will be derived for each patient as: (first dose date of any study drug among all studies a 
patient has participated in – the MS diagnosis date + 1)/365.25. Duration of MS since first 
symptom (years) is calculated as (first dose date of any study drug among all studies a 
patient has participated in – the first MS symptom date +1) / 365.25. The time since the 
onset of the most recent relapse (months) is computed as (first dose date of any study drug 
among all studies a patient has participated in – the most recent relapse onset date prior to 
enrollment in the core study + 1)/30. The duration from MS diagnosis date to last dose date 
of study drug (in years) is calculated as (last dose date of any study drug among all studies a 
patient has participated in - the MS diagnosis date + 1)/365.25. Note that the first dose date 
of any study drug among all studies a patient has participated in may not be fingolimod. 
 
5.4 
MRI baseline characteristics 
The MRI baseline characteristics will be summarized for number of Gd-enhanced T1 
lesions, number of T2 lesions, total volume of T1 hypointense lesions, total volume of T2 
lesions, volume of Gd-enhanced T1 lesions and normalized brain volume at both core 
baseline and fingolimod baseline if applicable. This summary is based on enrolled set. 
 
5.5 
MS medication history prior to enrollment in core study 
For the MS medication history of disease-modifying drugs (DMDs), treatment-naïve 
patients are defined as those who never took MS disease-modifying medications prior to 
enrollment in core study. The number and percentage of treatment-naïve patients and 
patients who took categories of MS DMDs will be summarized for the enrolled set. 


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6 
Study drug 
6.1 
Duration of exposure 
The duration of exposure to fingolimod study drug will be defined as the number of days 
from first dose date of fingolimod among all studies to last dose date of the long-term 
follow-up study part I, excluding the days for which the patient did not take fingolimod (i.e., 
periods of temporary interruption). The number and percentage of patients being exposed  
for a minimum of 1 day, 90 days, 180 days, 360 days, etc. will be presented. Summary 
statistics of duration of exposure will also be provided. Patient-years of exposure will be 
reported and is calculated as the (sum of the total number of days on fingolimod study drug 
for all patients in the treatment group)/365.25. The above summaries will be presented for 
the fingolimod safety set and the subgroup of fingolimod safety set patients from Phase  
II/III studies. 
Similar summaries will be provided for the duration of exposure to fingolimod study drug 
during the long-term follow-up study part I, which is defined as the number of days from 
first dose date of fingolimod in the long-term follow-up study to the last dose date, 
excluding the days for which the patient did not take fingolimod. Duration of exposure to 
fingolimod study drug during the long-term follow-up study part I will be presented for the 
safety set. 
The fingolimod dose administration records during the long-term follow-up study part I will 
be listed for the safety set. 
 
7 
Concomitant medication 
7.1 
Imputation of concomitant medication start date 
Missing or partial concomitant medication start dates are imputed following the VDW 
MAP Module 8 ‘Concomitant Medication Start Date Imputation (#IMPUTMED)’ section 
(displayed below): 
Concomitant Medication Start Date Imputation (#IMPUTMED) 
The following table explains the notation used in the logic matrix. Please note that missing 
start dates will not be imputed. 
 
Day 
Month 
Year 
Partial CMD Start Date 
Not used 
MON 
YYYY 
Treatment Start Date (TRTSTD) 
Not used 
TRTM 
TRTY 
 
The following matrix explains the logic behind the imputation. 
 
MON 
MISSING 
MON < TRTM 
MON = TRTM 
MON > TRTM 
YYYY 
MISSING 
(C) 
Uncertain 
(C) 
Uncertain 
(C) 
Uncertain 
(C) 
Uncertain 
YYYY < TRTY 
(D) 
Before Treatment Start 
(A) 
Before Treatment Start 
(A) 
Before Treatment Start 
(A) 
Before Treatment Start 


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YYYY = TRTY 
(C) 
Uncertain 
(A) 
Before Treatment Start 
(C) 
Uncertain 
(B) 
After Treatment Start 
YYYY > TRTY 
(E) 
After Treatment Start 
(B) 
After Treatment Start 
(B) 
After Treatment Start 
(B) 
After Treatment Start 
 
The following table is the legend to the logic matrix. 
 
Relationship 
Before Treatment Start 
Partial date indicates CMD start date prior to Treatment Start Date 
After Treatment Start 
Partial date indicates CMD start date after Treatment Start Date 
Uncertain 
Partial date insufficient to determine relationship of CMD start date to Treatment Start Date 
Imputation Calculation 
NC / Blank 
No convention 
(A) 
15MONYYYY 
(B) 
MAX( 01MONYYYY, TRTSTD+1 ) 
(C) 
IF CMDTYP1C IN (1, 3) THEN TRTSTD-1  
ELSE IF CMDTYP1C IN (., 2) THEN TRTSTD+1 
(D) 
01JULYYYY 
(E) 
01JANYYYY 
 
7.2 
Imputation of concomitant medication end date 
Partial or missing concomitant end dates will be imputed such that the imputed end date is 
the latest possible date (i.e. last day of month if day is missing, last day of year if both 
month and day are missing). These imputation rules will tend to consider medications with 
an unknown start and/or end date to be “concomitant”. See VDW MAP Module 8 variable 
CMDEND1O specifications for details. 
 
7.3 
Concomitant medication analyses 
Concomitant medications are defined as medications, other than the study drug, that are 
reported during the study. All medications recorded on the CFTY720D2399 concomitant 
medications / significant non-drug therapies CRF will be coded using the current Hybrid 
DTD_DDE Dictionary. Concomitant medications and significant non-drug therapies, which 
are recorded in the CFTY720D2399 database and taken at any time from first dose date of 
fingolimod among all studies to last dose date of fingolimod + 45 days, will be summarized 
for the safety set by Anatomical Therapeutic Chemical (ATC) class and preferred term. The 
summary will show the number and percentage of patients receiving at least one drug of a 
particular ATC class and at least one drug in a particular preferred term (PT). To determine 
if any particular treatment is needed after discontinuation of fingolimod, concomitant 
medications and significant non-drug therapies, which are recorded in the CFTY720D2399 
database and taken after last dose date of fingolimod, will be summarized in the same way 
as above for the follow-up set. 
Note that concomitant medications which are recorded on the CFTY720D2399 concomitant 
medications / significant non-drug therapies CRF can include medications that may have 
been taken during any gap between the completion of the prior study and enrollment into 
this long-term follow-up study, even if the medication is not ongoing at the time of 
enrollment. 


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All concomitant medications recorded during the long-term follow-up study part I will be 
listed. The concomitant medications taken after study drug discontinuation but up to or after 
45 days will be flagged. Records for steroid treatment of MS relapse during the long-term 
follow-up study part I will be listed for the safety set. 
 
8 
Efficacy evaluation 
The secondary objective of this study is to evaluate the long-term efficacy of fingolimod 0.5 
mg in patients with relapsing forms of MS. 
Long-term efficacy will 
be assessed in terms of MS relapse, MRIs, EDSS, MSFC, and health outcomes. 
 
8.1 
Analysis of MS Relapses 
8.1.1 
Relapse date imputations and handling of duplicate relapse records 
 
The start date of a relapse should never be missing. However, missing or partial dates may 
be expected from some non-phase III trials where data checking may be less vigorous than 
in phase III trials. To avoid an artificial inflation of the number of relapses by low quality 
data, missing dates for relapses will only be imputed if the end date of the relapse is after 
the first dose of the initial study (i.e. if the relapse happened at least partially within the 
study). If partial or complete end dates are before the first dose date of the initial study, then 
no imputation will be done. If partial or complete relapse end dates are after the first dose of 
the initial study, the following algorithm will be applied: 
 
Firstly, drop blanks and impute missing or partially missing start dates 
1. Drop complete blanks: If the relapse onset date is invalid (e.g. “No”, “None”) or 
completely missing and there is no information recorded across all variables, the 
onset date will be set to missing. 
2. Otherwise, if the record is not empty or the onset date is partially missing, check if 
another record may be available for the same relapse. Concretely: 
a. If a relapse onset date has a missing day-part (XX-MM-YYYY), where XX 
represents the missing or invalid part, the onset date will be imputed by the 
onset date of another treatment-emergent relapse record with a non-missing 
start date for the same patient within the same month and year, if such a 
relapse is available (choose the first one if more than one is available). 
b. If a relapse onset date has a missing day- and month part (XX-XX-YYYY, 
the onset date will be imputed by the onset date of another treatment- 
emergent relapse record for the same patient within the same year, if such a 
relapse is available (choose the first one if more than one is available). 
3. Otherwise, if the onset date of a relapse is completely or partially missing, the onset 
will be imputed with the first possible day within the available non-missing date- 
part, or the first-dose date, or the relapse end-date minus 90, whatever occurs latest. 


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Secondly, impute the end date 
The imputation of missing or partially missing end dates will be done after the imputation 
of start dates. 
1. If the end date of a relapse is completely missing, it will be imputed as 90 days after 
the onset date. 
2. If the end date of a relapse is partially missing, it will be imputed as the maximum 
of the relapse start day plus one or the minimum of either 90 days after the onset 
date, or as the last possible day based on the non-missing parts of the end-date (e.g. 
XXDEC2007 where XX indicated the missing end day would be imputed as 31- 
DEC-2007 if the onset date of the relapse was 26-NOV-2007). 
 
Thirdly, handle duplicate relapse records: 
After the imputation of start and end-dates is completed, records which refer to the same 
relapse (30-day rule) will be combined into a new artificial record. This step will help to 
consolidate core and extension databases where the same relapse may be recorded more 
than once, and it will help to ensure consistent relapse rules even for studies with a less 
vigorous date management. 
1. For each patient relapses will be sorted by onset date (source or imputed). 
2. Combine relapses for which the distance between onset dates is <30 days: 
Starting from the first relapse within each patient, the distance from each relapse to 
the next will be tested. If the onset date of a relapse is less than 30 days from the 
onset date of a previous one, an artificial record will be created using the “worst” or 
“most severe” information from both records (Conservative approach). The 
following rules apply: 
a. Onset date: use the minimum of the candidate dates with the highest degree of 
completeness. The degree of completeness is defined in descending order: 1. 
Original date, 2. Only day-part imputed, 3. Day and Month part imputed, 4. Day, 
Month and Year imputed. 
Example: an original date entered by the investigator has the higher degree of completeness 
compared to a partial/imputed date. An imputed date with just the day-part imputed has the 
higher degree of completeness compared to a completely imputed date. Rationale: amongst the 
candidate-dates with the highest reliability/completeness – choose the first/worst. 
b. End date: use the maximum of the candidate dates with the highest degree of 
completeness. The degree of completeness is defined in descending order: 1. 
Original date, 2. Only day-part imputed, 3. Day and Month part imputed, 4. Day, 
Month and Year imputed. 
Example: an original date entered by the investigator has the higher degree of completeness 
compared to a partial/imputed date. An imputed date with just the day-part imputed has the 
higher degree of completeness compared to a completely imputed date. Rationale: amongst the 
candidate-dates with the highest reliability/completeness – choose the last/worst. 


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c. When two records are combined from two consecutive phases (e.g. one from an 
initial study, the other one from an extension) the combined record will be 
considered as belonging to the first phase. 
Example: A relapse may have started at the end of an extension but ended in an Umbrella study. 
The same relapse may then be captured in the extension and also in the Umbrella study. When 
the two records are combined into one, the relapse – according to its start date – will be 
considered in the extension phase. Programmatically: Ext1n will take the minimum value of the 
two combined records. 
d. Hospitalization: “yes” is worse than “no” 
e. Severity: “severe” is worse than “moderate” is worse than “mild” is worse than 
“unknown” 
f. Steroids: “yes” is worse than “no” 
g. Relapse confirmed: “yes” is worse than “no” 
h. Recovery: “none” is worse than “partial” is worse than “complete” 
i. 
Daily activity: “affected” is worse than “not affected” 
 
Lastly, truncate the duration of all relapses to a maximum of 90 days 
1. For each relapse record, check whether the duration from onset to end date is less or 
equal to 90 days, if this is not the case do the following: 
a. Determine the degree of completeness of the start and end-date. The degree 
of completeness is defined in descending order: 1. Original date, 2. Only 
day-part imputed, 3. Day and Month part imputed, 4. Day, Month and Year 
imputed. 
Example: an original date entered by the investigator has the higher degree of completeness 
compared to a partial/imputed date. An imputed date with just the day-part imputed has the 
higher degree of completeness compared to a completely imputed date. 
b. Keep the date with the higher degree of completeness fixed and update the 
other date, so that the duration the relapse is maximized to 90 days 
Rationale: If one of the dates has to be replaced to keep truncate the duration of the relapse 
to 90 days, keep the date with the higher degree of completeness/reliability fixed (either the 
end- or the start date) and replace the other one. 
c. If the onset- and end-date have the same degree of completeness, keep the 
start date fixed and impute the end-date such that the duration of the relapse 
is maximized to 90 days. 
2. If a relapse is recorded as ongoing at the final exam, impute an end date such that 
the duration is maximized to 90 days. 
 
8.1.2 
Annualized relapse rates 
Annualized relapse rate (ARR) is defined as the number of relapses experienced during a 
specific period of time adjusted to a one-year period. The ‘number of relapses’ can refer to 


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either the number of confirmed relapses or the number of all relapses (including both 
confirmed and unconfirmed relapses). 
Confirmation of relapses is not collected in the following studies: CFTY720D2316, 
CFTY720D2320, CTY720D2399E1, and the long-term follow-up study prior to protocol 
amendment 4. Therefore, the number of confirmed relapses during this time is not able to 
be reported. Additionally, confirmed relapses will not be reported for patients from the 
CFTY720D2324 study since it is a phase IIIb study and confirmation is not collected in the 
long-term follow-up study for patients coming from previous studies that are not phase 
II/III. The number of unconfirmed relapses is also not able to be reported for study 
CTY720D2399E1 since the study does not collect relapse start dates. However, note that 
the time during which number of relapses is not able to be counted and the time off study 
for patients who re-enrolled into the long-term follow-up study will still be included in the 
time in study, which can make the ARR appear lower than it actually is. If confirmation of a 
relapse is missing or not collected, the relapse will be treated as an unconfirmed relapse. 
Therefore, ARR based on all relapses (confirmed or unconfirmed) should be considered a 
more reliable estimation of relapse rate than ARR based on confirmed relapse. 
The group level (aggregate) ARR will be calculated as follows: (total number of relapses) / 
(total number of days in the study for all patients for that specific period of time) x 365.25. 
 
8.1.3 
Time in study 
For the analysis of ARR from first dose of fingolimod to end of study treatment, the time in 
study (days) is calculated as: last dose date of fingolimod – first dose date of fingolimod 
among all studies + 1 day. Similarly, the time in study from first dose of fingolimod among 
all studies to end of follow-up is calculated as: last available visit/evaluation date across all 
panels – first dose date of fingolimod among all studies + 1 day. 
For the analysis of ARR from first dose of fingolimod among all studies to end of a 
particular month (i.e. “Month 6”, “Month 12”, “Month 24”, and every 12 months from then 
on), “Month 0 to X” time in study will be calculated as minimum of (first dose date of 
fingolimod + integerpart(X/12*365.25) where X denotes the month, last available 
visit/evaluation date across all panels) – first dose date of fingolimod + 1 day. 
 
8.1.4 
MS relapses analyses 
MS relapses analyses will be conducted on the fingolimod full analysis set. All analyses 
will be done for all relapses (confirmed and unconfirmed) and for confirmed relapses. 
A summary of ARRs will be presented by time period (cumulative time intervals: ‘Month 0 
to Month 6’, ‘Month 0 to Month 12’, ‘Month 0 to Month 24’, ‘Month 0 to Month 36’, … 
incremented by 1 year for each successive interval, plus ‘Month 0 to end of study  
treatment’ and ‘Month 0 to end of follow-up’) from first dose of fingolimod among all 
studies. The summary will include number of patients summarized, number of relapses, 
time in study (days), and group level ARR. In addition, model based estimates of ARR and 
corresponding two-sided 95% confidence interval will be obtained by fitting a negative 
binomial regression model adjusted for the number of relapses in the last two years prior to 


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enrolment in the core study and EDSS score at first dose of fingolimod baseline, with the 
logarithm of the time in study as the offset variable. 
A summary of relapse characteristics will be displayed by time period (consecutive yearly 
intervals: ‘Month 0 to Month 12’, ‘Month 12 to Month 24’, etc., plus ‘End of study 
treatment to End of follow-up’) from first dose of fingolimod among all studies. Relapse 
characteristics will be summarized at a patient level (the number and percent of patients 
with at least one relapse type) and at a relapse event level (the number and percent of a 
particular type of relapse out of the total number of relapses). The types of relapses being 
summarized include: relapses which affect daily activities, relapses which require steroids, 
and relapses which require hospitalization. 
The time to first onset of relapse from first dose date of fingolimod among all studies will 
be analysed. Specifically, the number of patients at risk, the cumulative number of patients 
with relapse, the Kaplan-Meier (KM) estimate of the percent of patients without relapse and 
corresponding standard error and two-sided 95% CI will be provided at each yearly time 
point (1 year = 360 days). Patients with no relapse, patients for whom follow-up ends 
before a confirmed relapse occurs, and patients who drop out prior to the relapse will all be 
censored, i.e. the time to event for these patients will be the time in study (from first dose of 
fingolimod among all studies to last available visit/evaluation date across all panels). 
A Kaplan-Meier plot of time to first relapse from first dose of fingolimod to end of the 
long-term follow-up study part I will be presented. 
 
8.2 
Analysis of MRI 
MRIs are required only for patients from phase II/III trials who had MRI assessments in 
prior fingolimod trials. MRI parameters analyzed in this study include: number of 
new/newly enlarging T2 lesions, volume of T2 lesions, T1 hypointense (black hole) volume, 
percent brain volume change, and annualized rate of brain volume change. MRI data will be 
analyzed for the fingolimod full analysis set. 
 
8.2.1 
Annualized rates of new-/newly enlarging T2 lesions 
Annualized rate of new/newly enlarging T2 lesions is defined as the number of new or 
newly enlarging T2 lesions experienced during a specific period of time adjusted to a one- 
year period. The group level annualized rate of new/newly enlarging T2 lesions will be 
calculated as follows: (total number of new/newly enlarging T2 lesions) / (total number of 
days in the study for all patients for that specific period of time) x 365.25. The number of 
days in study will be calculated based on MRI scan date and first dose date of fingolimod. 
The annualized rate will be provided from first dose of fingolimod. 
In addition to a group level annualized rate estimate, another annualized rate estimate and 
corresponding two-sided 95% confidence interval will be presented from a negative 
binomial (NB) regression model adjusted for total volume of T2 lesions at first dose of 
fingolimod baseline. Log (time in study) will be the offset variable. 
These annualized rate summaries will be presented by cumulative yearly intervals: Month 0 
to Month 3, Month 0 to Month 6, Month 0 to Month 12, Month 0 to Month 24, etc. 


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In general the number of new/newly enlarging T2 lesions is provided by the reading center. 
It is obtained by comparing two scans (e.g. the baseline scan to the Month 24 scan). If an 
assessment is provided by the reading center, then this should be used. Derived parameters 
should only be used when no assessment from the reading center is available. It is of note 
that any such derived number is an approximation. When an assessment is not provided by 
the reading center (i.e. 2399 results relative to FDF), derivation rules regarding number of 
new/newly enlarging T2 lesions relative to FDF baseline should be followed as below: 
• Patients who were randomized to fingolimod in core: new/newly enlarging T2 
lesions relative to FDF baseline = new/newly enlarging T2 lesions relative to core 
baseline. 
• Patients who were randomized to another treatment (placebo or interferon) than 
fingolimod in core and switched to fingolimod in extension: 
o If the record of extension FDD was available in the extension database, 
new/newly enlarging T2 lesions relative to FDF baseline = new/newly 
enlarging T2 lesions relative to extension FDD. 
o If no records relative to extension FDD were available, new/newly enlarging 
T2 lesions relative to FDF baseline = max(result relative to FDD – end of 
core result relative to FDD, 0). 
 
8.2.2 
Total volume of T2 lesions and T1 hypointense lesion 
Total volume of T2 lesions and T1 hypointense lesion (black hole) volume will be 
summarized separately by presenting descriptive statistics for change from FDF baseline 
values by visit. 
 
8.2.3 
Percent brain volume change (PBVC) 
Descriptive statistics on normalized brain volume at core baseline and percent brain volume 
change from FDF baseline will be presented by visit. Additionally, a mixed effects model 
with repeated measures will be used with visit, normalized brain volume at core baseline, 
T2 lesion volume at first dose of fingolimod baseline and Gd-T1 lesion count at first dose 
of fingolimod baseline as fixed effects and individual patient as a random effect. Kenward 
and Rogers’ adjustment for the degrees of freedom will be applied. Based on this model, 
least square mean, standard error, and a two-sided 95% CI will be displayed for each group. 
When an assessment is not provided by the reading center (i.e. 2399 results relative to FDF), 
derivation rules regarding percent brain volume change from FDF baseline should be 
followed as below: 
• Patients who were randomized to fingolimod in core: PBVC relative to FDF 
baseline = PBVC relative to FDD. 
• Patients who were randomized to a treatment (placebo or interferon) other than 
fingolimod in core and switched to fingolimod in extension: 
o If the record of extension FDD was available in the extension database, 
PBVC relative to FDF baseline = PBVC relative to extension FDD. 


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o If no records relative to FDF baseline were available in the extension, the 
formula stated below was used to get the PBVC relative to FDF baseline: 
p2=100*[(p3-p1)/(p1+100)]. 
where p1=PBVC relative to FDD at end of core, p2=PBVC relative to FDF, 
p3=PBVC relative to FDD, and p3 = [(1+p1/100)*(1+p2/100)-1]*100). 
 
8.2.4 
Annualized rate of brain volume change (ARBA) 
The annualized rate of brain volume change is an “averaged annual percentage change” in 
brain volume. The logic of interest rates applies. The formula for ARBA is as below: 
ARBA = [(SIENA/100+1) ^ (365.25/#days)-1]*100 
SIENA=(Vk/V0-1)*100 
k=days/365.25 
where V0 is the brain volume at time 0, and Vk is the brain volume at time k (where k is the 
time in years). 
The annualized rate of brain volume change relative to FDF baseline will be calculated 
from the SIENA estimate of the percentage brain volume change relative to FDF baseline 
and the number of days in study relative to FDF. For the calculation of k and V0, below 
rules should be followed: 
• Patients who were randomized to fingolimod: k = MRI date – first dose date +1; V0 
= brain volume at FDD 
• Patients who were randomized to a treatment (placebo or interferon) other than 
fingolimod in core and switched to fingolimod in extension control treatment: k = 
MRI date – first dose date of extension +1; V0 = brain volume at extension FDD (if 
there is record), or at the end of core (if there is no record at extension FDD) . 
Descriptive statistics on ARBA will be presented by visit. Additionally, a mixed effects 
model with repeated measures will be used with visit, normalized brain volume at core 
baseline, T2 lesion volume at first dose of fingolimod baseline and Gd-T1 lesion count at 
first dose of fingolimod baseline as fixed effects and individual patient as a random effect. 
Kenward and Rogers’ adjustment for the degrees of freedom will be applied. Based on this 
model, least square mean, standard error, and a two-sided 95% CI will be displayed for 
each group. 
 
 
8.3 
Analysis of EDSS scores 
The EDSS scores are used for the confirmation of MS relapse and the confirmation of 
disability progression. All EDSS summaries are based on the fingolimod full analysis set. 
 
8.3.1 
By-visit summaries 
Overall EDSS score and EDSS functional system scores will be summarized by presenting 
descriptive statistics for baseline, post-baseline, and change from baseline values by visit. 
EDSS functional systems are: visual, sensory, brainstem, bowel and bladder, pyramidal, 
cerebral, and cerebellar. 


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The number and percentage of patients will be summarized based on EDSS (overall score) 
change categories: improvement, stable, and deterioration. If baseline EDSS score is <=5, 
improvement is indicated by an EDSS score change of <= -1, stable is indicated by an 
EDSS score change of > -1 and <= 0.5, deterioration is indicated by an EDSS score change 
of > 0.5; if baseline EDSS score is > 5, improvement is indicated by an EDSS score change 
of <= -0.5, stable is indicated by an EDSS score change of > -0.5 and <= 0, deterioration is 
indicated by an EDSS score change of > 0. Within each visit window, the record with worst 
category will be selected. 
 
8.3.2 
EDSS score of 4/6/7 or greater 
The time to first EDSS score of 4/6/7 or greater from first dose of fingolimod among all 
studies will be analysed for patients with a baseline EDSS score of less than X, where X=4, 
6, or 7 depending on the analysis being conducted. Specifically, the number of patients at 
risk, the cumulative number of patients with event, the Kaplan-Meier (KM) estimate of the 
percent of patients without event and corresponding standard error and two-sided 95% CI 
will be provided at each yearly time point (1 year = 360 days). 
A Kaplan-Meier plot of 3 Kaplan-Meier curves showing time to first EDSS score of X or 
greater from first dose of fingolimod to the end of the long-term follow-up study Part will 
be provided, where X is 4, 6, and 7. 
The time to event/censoring for Kaplan-Meier analyses will be calculated as follows: 
For patients with EDSS score of 4/6/7 or greater: 
Time to event = first assessment date (after first dose date of fingolimod 
among all studies) that patient has an EDSS score of X or greater – first dose 
date of fingolimod among all studies +1 day. 
For patients who do not have EDSS score of 4/6/7 or greater (in other words, 
censored): 
Time to censoring = last EDSS assessment date – first dose date of 
fingolimod +1 day. If the patient does not have post-baseline EDSS 
assessment, then that patient will be censored at Day 1 (Time to censoring 
=1). 
A patient will be censored if the patient exits the study without receiving an EDSS score of 
4/6/7 or greater after first dose of fingolimod among all studies. 
 
8.3.3 
Analysis of 6-month confirmed disability progression 
Disability progression in this study is defined based on an increase in the EDSS score by 
1.5 point for patients with a FDF baseline EDSS score of 0, 1 point for patients with FDF 
baseline EDSS of >=1 and <=5.5, and by 0.5 points for patients with an FDF baseline 
EDSS>5.5, confirmed after 6 months and all intermediate EDSS assessments. A 6-month 
confirmed disability progression is defined as a 6-month sustained increase from the 
reference (potential onset of progression) value in the EDSS scores. i.e., every EDSS score 
(scheduled or unscheduled)  within  a 6-month  duration  after the  first  progression  should 


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meet the progression criteria as specified above. The confirmation can only happen at a 
scheduled visit. 
To evaluate disability progression, all available scheduled and unscheduled EDSS 
assessments after the reference time point (e.g. Day 1) will be compared to the EDSS at the 
reference time point to assess if the change from the reference time point meets the 
disability progression criteria. The disability progression onset date will be the date of the 
first EDSS score meeting the disability progression criteria. 
The disability progression confirmation can only happen at a scheduled visit and in the 
absence of a relapse. Note that the end of study or early discontinuation visit and the 
follow-up visit are protocol specified visits and will be treated as scheduled visits and thus 
can be used to confirm a disability progression if applicable. Specifically, the confirmation 
visit for 6-month confirmed disability progression will be the first scheduled visit meeting 
the following conditions: 
• The confirmation visit needs to be ≥166 days from the potential onset 
date and the disability progression criterion needs to be met at that visit 
(and all visits in between the onset and the confirmation). 
• The EDSS is not performed during a relapse (information collected as a 
flag in the CRF). 
• All available EDSS scores (scheduled or unscheduled) between the 
disability progression onset and this visit meet the disability progression 
criteria. 
If the first scheduled visit after ≥166 days for a “6-month confirmed disability progression” 
does not meet the conditions above, the subsequent scheduled visits will be checked until a 
confirmation visit is found. If a confirmation visit cannot be found, then above process will 
be repeated to look for the next disability progression onset and its confirmation visit or 
until it is certain that no confirmation visit can be found for the progression onset. 
A patient is considered to have a 6-month confirmed disability progression if a progression 
onset with a confirmation visit is found. Otherwise, the patient is considered not to have a 
6-month confirmed disability progression and will be referred to as a censored patient. 
If a patient died due to MS (EDSS=10), he or she will be considered to have a 6-month 
confirmed disability progression, irrespective of the EDSS at the reference time point or the 
change in EDSS. 
The time to first 6-month confirmed disability progression from first dose of fingolimod 
among all studies until the end of the long-term follow-up study part I will be summarized 
in a yearly interval for fingolimod full analysis set. Specifically, the number of patients at 
risk, the cumulative number of patients with event, the Kaplan-Meier (KM) estimate of the 
percent of patients without 6-month confirmed disability progression and corresponding 
standard error and two-sided 95% CI will be provided at each yearly time point (1 year = 
360 days). 


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T25FWZ   = (T25FWmean  − T 25FWbaseline - mean )/ T 25FWbaseline - stdev 
• The average scores from the 4 trials on the 9-Hole Peg Test (9HPT). The 2 trials for 
each hand are averaged, converted to the reciprocals of the mean times for each 
hand and then the 2 reciprocals are averaged, i.e. 
9HPTZ  = (9HPTmean − 9HPTbaseline- mean )/ 9HPTbaseline- stdev 
• The number of correct answers from the PASAT 3, i.e. 
PASAT3Z = (PASAT3mean  − PASAT3baseline- mean )/ PASAT3baseline- stdev 
Finally, these individual z-scores are averaged to create an overall composite score: 
MSFCZ = 13 9HPTZ   − T 25FWZ   + PASAT 3Z  
The negative value of the T25FT z-score is taken to make the direction of change the same 
as the other components. In computing MSFCz for each patient, if any of the individual 
scores (9HPTz, T25FWz, or PASAT3z) are missing, then MSFCz will be missing as well. 
Descriptive statistics on baseline, post-baseline, and change from baseline will be presented 
for MSFC z-score and each subscale score by visit for the fingolimod full analysis set. 
 


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9 
Safety evaluation 
The primary objective of this study is to evaluate the long-term safety and tolerability of 
fingolimod 0.5 mg in patients with relapsing forms of MS. 
Long-term safety will be assessed in terms of adverse events (AEs), laboratory, vital signs 
(including dose administration monitoring), electrocardiograms (ECG) dose administration 
monitoring, ophthalmic assessments, pulmonary function tests, and skin assessments. 
Except for summaries specifically for follow-up (e.g. summaries of Month 3 and Month 6 
follow-up visits), serious adverse events, or adverse events after last dose date of 
fingolimod until end of follow-up, post-baseline safety summaries (not including listings) 
will limit reporting to only include assessments with dates from first dose date of 
fingolimod among all studies to last dose date of fingolimod + 45 days. 
 
9.1 
Adverse events 
9.1.1 
Imputation of adverse event start date 
Missing or partial adverse event start dates are imputed following the VDW MAP Module 8 
‘Adverse Event Start Date Imputation (#IMPUTAEV)’ section (displayed below): 
Adverse Event Start Date Imputation (#IMPUTAEV) 
The following table explains the notation used in the logic matrix. Please note that missing 
start dates will not be imputed. 
Note, it may happen that the imputed AE start is after AE end date. Missing AE end date is 
not imputed by STL. 
 
 
Day 
Month 
Year 
Partial Adverse Event Start Date 
Not used 
MON 
YYYY 
Treatment Start Date (TRTSTD) 
Not used 
TRTM 
TRTY 
 
 
The following matrix explains the logic behind the imputation. 


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MON 
MISSING 
MON < TRTM 
MON = TRTM 
MON > TRTM 
YYYY 
MISSING 
NC 
NC 
NC 
NC 
YYYY < TRTY 
( D ) 
( C ) 
( C ) 
( C ) 
YYYY = TRTY 
(B) 
( C ) 
(A) 
(A) 
YYYY > TRTY 
(E) 
(A) 
(A) 
(A) 
 
 
The following table is the legend to the logic matrix. 
 
 
Relationship 
Before Treatment Start 
Partial date indicates AE start date prior to Treatment Start Date 
After Treatment Start 
Partial date indicates AE start date after Treatment Start Date 
Uncertain 
Partial date insufficient to determine relationship of AE start date to Treatment Start Date 
Imputation Calculation 
NC / Blank Uncertain 
No convention 
(A) After Treatment Start or 
Uncertain 
MAX( 01MONYYYY, TRTSTD+1 ) 
(B) Uncertain 
TRTSTD+1 
(C) Before Treatment Start 
15MONYYYY 
(D) Before Treatment Start 
01JULYYYY 
(E) After Treatment Start 
01JANYYYY 
 
9.1.2 
Adverse events analyses 
All adverse events (AEs) recorded on the adverse events CRF will be coded using the 
current Medical Dictionary for Regulatory Activities (MedDRA). Note that adverse events 
that started or were ongoing during any gap between the completion of the prior study and 
enrollment into this CFTY720D2399 study, even if the adverse event was not ongoing at 
the time of CFTY720D2399 enrollment, can be recorded on the CFTY720D2399 adverse 
events CRF. 
In AE summaries, primary system organ classes will be displayed in alphabetical order and 
preferred terms (within each system organ class) will be sorted by descending frequency in 
the fingolimod any dose column. 
There are two categories of AE summaries in this study which are presented in the sections 
below. 
 
9.1.2.1 
Adverse events during long-term follow-up study part I 
Adverse events reported during the long-term follow-up study part I will be summarized for 
the safety set. Unless otherwise specified, all non-serious adverse events recorded in the 
CFTY720D2399 database with onset on or after first dose date of fingolimod among all 
studies to last dose date of fingolimod + 45 days are included. All serious adverse events 


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(SAEs) recorded in the CFTY720D2399 database with onset on or after the first dose date 
of fingolimod among all studies are also included in the summaries. 
Adverse events reported during the long-term follow-up study part I will be summarized by 
primary system organ class (SOC) and preferred term (PT), and will show the number and 
percentage of patients with at least one adverse event in each SOC or PT category. 
Similarly, adverse events by study drug relationship (AEs suspected to be study drug 
related, AEs not suspected to be study drug related, and AEs regardless of study drug 
relationship), SAEs, SAEs by study drug relationship, suspected study drug related AEs, 
and AEs leading to study drug discontinuation will also be summarized by SOC and PT. 
AEs and SAEs which are not considered to be known effects of fingolimod treatment (i.e., 
excluding those listed in the most recent version of Core Data Sheet), will be summarized 
by PT only. 
To determine which AEs occur after discontinuation of fingolimod treatment, all AEs 
reported with onset date after the last dose of fingolimod until the end of the long-term 
follow-up study part I will be summarized by SOC and PT for the follow-up set. 
Principal cause of death during the long-term follow-up study part I will be summarized by 
SOC and PT. All deaths recorded in the CFTY720D2399 database with onset on or after the 
first dose date of fingolimod (among all studies) will be included in the summary. 
All information pertaining to any AE with severity information, SAEs, AEs leading to study 
drug discontinuation, deaths and neoplasms system organ class events that reported during 
the long-term follow-up study part I will be listed for the safety set. Additionally, adverse 
events, SAEs and all deaths recorded during the long-term follow-up study part I will be 
listed for the subgroup of patients from studies D2312 and D2402 in the enrolled set. 
 
9.1.2.2 
Adverse events during the fingolimod treatment period 
Unless otherwise specified, all non-serious adverse events with onset on or after first dose 
date of fingolimod among all studies to last dose date of fingolimod + 45 days are included. 
All serious adverse events (SAEs) with onset on or after the first dose date of fingolimod 
among all studies are also included in the summaries. Also, unless otherwise specified, 
adverse events will be summarized for the fingolimod safety set, by primary system organ 
class and preferred term, and will show the number of patients with at least one adverse 
event and the incidence rate of adverse events per 100 patient-years in each SOC or PT 
category. 
The AE incidence rate (IR) is calculated per 100 patient-years. IR is defined as: the number 
of patients experiencing at least one event in a particular category, over the total patient- 
years of the “at risk” population for that event multiplied by 100. An underlying Poisson 
process for incidence rate within treatment group is assumed. 
To calculate the total patient-years (time at risk) of the “at risk” population: 
1. For patients who have a particular AE category, sum the number of days from first 
dose date of fingolimod among all studies to the first occurrence of that particular 
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2. For patients who did not have a particular AE category, sum the number of days 
from first dose date of fingolimod among all studies to last dose date of fingolimod 
+ 45 days. 
3. Add the time at risk for patients who had a particular AE category with the time at 
risk for patients who did NOT have a particular AE category. This is the total time 
at risk of that AE category. 
4. Divide the total time at risk by 365.25. 
Incidence rate of adverse events will be presented for the fingolimod safety set and for the 
subgroup of fingolimod safety set patients from phase II/III studies, by SOC and PT. 
Incidence rate of AEs, excluding AE listed in the core data sheet, will be presented by PT. 
Incidence rate of AEs that fulfill the risk search term (defined in the case retrieval sheet) 
will be presented by risk name and lower level terms. Similarly, all above indicated AE IR 
summaries will be conducted for SAEs. 
To further evaluate the long-term AE rate (based on patient count and percentage) within a 
particular fingolimod treatment duration, an analysis based on yearly intervals since first 
dose of fingolimod will be conducted. For summaries on this set of patients, all AEs and 
SAEs with onset on or after first dose date of fingolimod (among all studies) to last dose 
date of fingolimod are included. Each yearly interval will contain 360 days. For example: 
Year 1 will consist of Day 1 to Day 360, Year 2 will consist of Day 361 to Day 720, Year 3 
will consist of Day 721 to Day 1080, Year 4 will consist of Day 1081 to Day 1440, Year 5 
will consist of Day 1441 to Day 1800, and so on. Patients will be summarized within a 
particular yearly interval if they have been receiving study treatment for at least one day in 
that particular interval. The number and percentage of these patients who have adverse 
events with onset date occurring during the interval will be summarized. For example, for 
the Year 1 group, patients with at least one day exposure to fingolimod will be included, 
and AEs with onset date occurring between Day 1 and Day 360 will be summarized. For 
the Year 2 group, patients with at least 361 days exposure to fingolimod will be included, 
and AEs with onset date occurring between Day 361 and Day 720 will be summarized. The 
same will be done for other intervals. 
Adverse events summarized by year will include the following: 
• Adverse events, by yearly interval, primary system organ class, and 
preferred term 
• Serious adverse events, by yearly interval, primary system organ class, and 
preferred term 
• Adverse events that fulfill the risk search term, by yearly interval 
• Serious adverse events that fulfill the risk search term, by yearly interval 
Intervals will be included based on the length of fingolimod exposure. Risk search terms are 
defined in Novartis’ case retrieval sheet. Associated summaries will be presented by risk 
name and lower level terms. 


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9.2 
Laboratory 
Hematology and blood chemistry data will be summarized separately by presenting 
descriptive statistics for baseline, post-baseline, and change from baseline values by lab 
parameter and visit. Shift tables (baseline to post-baseline values) based on normal range 
categories (low, normal, high, high & low) will be summarized separately for hematology 
and blood chemistry by lab parameter and visit. 
Summaries of incidence of notable lab abnormalities for hematology and blood chemistry, 
reported from first dose of fingolimod among all studies, will present the number and 
percentage of patients with lab assessments satisfying notable criteria by visit. An overall 
study visit will be generated to indicate any notable abnormalities from post-baseline visits 
(including follow-up visits). Criteria for clinically notable laboratory values are specified in 
Appendix A. Percentages are based on the number of patients with non-missing lab result. 
A similar summary for patients with elevated liver function test values (elevation of 1, 2, 3, 
5, 8 and 10 times the upper limit of normal) will be provided. 
All summaries will be based on the fingolimod safety set. 
Patients in the fingolimod safety set with notable post-baseline laboratory abnormalities 
will be listed separately for hematology and blood chemistry. All lab parameters with 
clinically notable criteria will be listed for a particular patient and visit if at least one of the 
parameters shows an abnormality. These listings will also indicate whether the lab result 
was above or below the normal range. 
Patients with positive pregnancy test results during the long-term follow-up study part I will 
be listed for the safety set. 
 
9.3 
Routine vital signs 
Vital signs include sitting pulse rate, sitting systolic and diastolic blood pressure, and oral 
temperature. Height and body weight were collected at the screening visit of the patient’s 
previous fingolimod trial. First dose monitoring vital signs values will be excluded from 
routine vital signs summaries and listing. 
Vital signs data will be summarized by presenting descriptive statistics for baseline, post- 
baseline, and change from baseline values by parameter and visit. The incidence of notable 
vital sign abnormalities reported from first dose of fingolimod among all studies will 
present the number and percentage of patients satisfying notable criteria by visit. An overall 
study visit will be generated to indicate any notable abnormalities from post-baseline visits 
(including follow-up visits). Criteria for clinically notable vital signs values are specified in 
Appendix B. Both summaries are based on the fingolimod safety set. 
Patients in the fingolimod safety set with notable vital sign abnormalities will be listed. All 
vital sign parameters with clinically notable criteria will be listed for a particular patient and 
visit if at least one of the parameters shows an abnormality. The listing will also indicate 
whether the vital sign result was above or below the normal range. 


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9.4 
Routine Electrocardiograms during the long-term follow-up 
study 
Routine ECGs are only collected during the long-term follow-up study before protocol 
amendment 4 was approved. ECG parameters include QTc interval, QT interval, QTc 
interval (Fridericia), PR interval, RR interval, and QRS duration. The dose monitoring 
ECGs will be excluded from routine ECG summaries. 
ECG data will be summarized by presenting descriptive statistics for baseline, post-baseline, 
and change from baseline values (relative to the first dose of fingolimod during the long- 
term follow-up study) by parameter and nominal visit. Incidence of abnormal ECGs will be 
presented by nominal visit. 
A listing of ECG data for patients with abnormal findings will be provided for safety set. 
 
9.5 
Dose monitoring administration 
First-dose monitoring should be done on any patient who enrolls into this long-term follow- 
up study part I from any blinded study which has comparator treatment arms (placebo or 
active comparator, e.g. study CFTY720D2309) or enrolls from the comparator arm of an 
open-label controlled study or for any patient who has been off fingolimod 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. 
Patients requiring first dose monitoring should receive the first dose of fingolimod 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 may be discharged if specific discharge criteria (refer to Protocol Appendix 4) 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. 
A dose administration monitoring summary will be provided for the safety set for 
first/second/restart of fingolimiod dose during the long-term follow-up study part I, and will 
include yes or no categorical summaries for the following: discharged at 6 hours, required 
extended monitoring after 6 hours, discharged but returned for monitoring, hospitalization, 
required Day 2 monitoring in the clinic (only recorded for first dose monitoring), study drug 
permanently discontinued, had symptomatic and/or treated bradycardia, and SAEs reported. 
The denominator for first/second dose monitoring data is based on the number of patients 
with assessment done; the denominator for restart monitoring data is based on the number 
of restarts. 


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9.5.1 
Vital signs 
During the long-term follow-up study part I, hourly vital signs, including sitting pulse rate 
and blood pressure will be monitored before the first dose of fingolimod and every hour for 
at least six-hours thereafter. 
Hourly dose monitoring of vital signs will be summarized separately and will not be 
included in the by-visit summaries of routine vital signs. Descriptive statistics of pre-dose, 
post-dose, and change from pre-dose values will be summarized by parameter and time 
point for first dose monitoring, second dose monitoring, and dose monitoring after study 
drug restart. Summaries will be based on the safety set and include dose monitoring data 
during the long-term follow-up study part I only. 
 
9.5.2 
Electrocardiograms 
During the long-term follow-up study part I, all patients requiring first dose monitoring will 
have an electrocardiogram (ECG) performed prior to dosing and at the end of the 6-hour 
monitoring period. 
The hourly dose monitoring ECG will be summarized. Descriptive statistics of pre-dose, 
post-6 hour dose, and change from pre-dose values will be summarized by parameter and 
time point for first dose monitoring and second dose monitoring. The incidence of patients 
with abnormal ECG monitoring records will be summarized by time point, finding type, 
and finding. 
Patients with abnormal dose monitoring ECG findings records will be listed. Summaries 
and listing will be based on the safety set and include dose monitoring data during the long- 
term follow-up study part I only. 
 
9.6 
Ophthalmic assessments 
Ophthalmic assessments are done for patients who enter the long-term follow-up study  
from blinded studies with comparator treatments arms or patients who have been off 
fingolimod for 90 days or greater. Assessments are completed as needed. 
The incidence of macular edema events during the long-term follow-up study part I will be 
summarized for the safety set. The number and percentage of patients with any macular 
edema events and particular event type (macular edema presence in left or right eye) will be 
provided based on either dilated assessment or OCT assessment (by olphthalmologist) if 
available. The number and percentage of patients with history of diabetes mellitus and the 
number and percentage of patients with history of diabetes mellitus and macular edema 
assessment done will also be provided to support data summary. 
The patients with macular edema events during the long-term follow-up study part I will 
also be listed for the safety set. All records will be listed for a particular patient if there is at 
least one macular edema event. A separate listing for visual acuity assessment during the 
long-term follow-up study part I will be provided as support. 


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9.7 
Pulmonary function tests 
Pulmonary function tests are only done as needed during the study to monitor safety. It 
includes parameters: forced expiration volume in 1 second (FEV1), forced vital capacity 
(FVC), diffusion capacity for carbon monoxide (DLCO), and the derived FEV1/FVC ratio. 
Observed values, percentage of predicted values for these four parameters, respiratory 
infection status, and smoking status during the long-term follow-up study part I will be 
listed for the safety set. 
 
9.8 
Skin assessment 
Skin assessment is only done as needed during this study to monitor safety. Patients with 
skin abnormalities (any dermatologic findings suspicious for being precancerous or 
cancerous, or if a skin disorder, for example abnormal cancerous lesion, is diagnosed) 
during the long-term follow-up study part I will be listed for the safety set. 
 
10 
Sample size and power considerations 
Given that this is a long-term follow-up study with primary descriptive purpose, no formal 
sample size calculation will be used to determine enrollment in this study. The sample size 
is defined by the number of patients coming from ongoing/new core/extension trials that 
meet the inclusion and exclusion criteria. It is estimated that about 5000 patients will be 
enrolled in this trial. 


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Appendices 
Appendix A: Clinically notable laboratory values 
Only selected lab parameters identified as notable which have been shown to be sensitive to 
fingolimod exposure are included. 
 
CRITERIA FOR NOTABLE LABORATORY ABNORMALITIES 
 
Notable Values 
Laboratory Variable 
Standard Units 
SI Units 
LIVER FUNCTION AND RELATED VARIABLES 
SGOT (AST) 
>82 U/L 
>82 U/L 
SGPT (ALT) 
>90 U/L 
>90 U/L 
Total bilirubin 
 2.0 mg/dL 
 34.2 mol/L 
Alkaline Phosphatase 
>280 U/L 
>280 U/L 
RENAL FUNCTION / METABOLIC AND ELECTROLYTE VARIABLES 
Glucose ` 
200 mg/dL 
11.11 mmol/L 
Creatinine 
2.0 mg/dL 
176 umol/L 
Amylase 
 300 U/L 
 300 U/L 
Cholesterol 
 240 mg/dL 
 6.21 mmol/L 
Triglycerides 
≥300 mg/dL 
≥3.39 mmol/L 
BUN 
≤ 2 mg/dL 
≥ 30 mg/dL 
≤ 0.7 mmol/L 
≥ 10.7 mmol/L 
Sodium 
< 125 mEq/L 
>154 mEq/L 
< 125 mmol/L 
>154 mmol/L 
Chloride 
≤85 mEq/L 
≥119 mEq/L 
≤ 85 mmol/L 
≥119 mmol/L 
Potassium 
≤ 3.0 mEq/L 
≥ 6.0 mEq/L 
≤ 3.0 mmol/L 
≥ 6.0 mmol/L 
Magnesium 
≤ 1.0 mg/dL 
≥ 3.0 mg/dL 
≤ 0.40 mmol/L (in all other 
countries) 
≤ 0.41 mmol/L (in Canada) 
Calcium 
≤ 7.5 mg/dL 
≥ 11.6 mg/dL 
≤ 1.87 mmol/L 
≥ 2.89 mmol/L 
Phosphate 
≤ 2.0 mg/dL 
≥ 5.3 mg/dL 
≤ 0.65 mmol/L 
≥ 1.71 mmol/L 


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Notable Values 
HEMATOLOGY VARIABLES 
Hemoglobin 
10.0 g/dL 
100 g/L 
Platelets (Thrombocytes) 
100 k/mm3 
600 k/mm3 
100 x 109/L 
600 x 109/L 
Leukocytes (WBCs) 
2.0 k/mm3 
15 k/mm3 
2.0 x 109/L 
15 x 109/L 
HEMATOLOGY VARIABLES: DIFFERENTIAL 
Granulocytes (Poly, Neutrophils) 
 1,000 /mm3 
12000/mm3 
 1 x 109/L 
 12 x 109/L 
Lymphocytes 
<200/mm3 
8000/mm3 
<0.2 x 109/L 
8 x 109/L 
Red blood cells 
<3,300,000/mm3 
>6,800,000/mm3 
<3.3 x 1012/L 
>6.8 x 1012/L 


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Appendix B: Clinically notable Vital sign values 
CRITERIA FOR NOTABLE VITAL SIGN ABNORMALITIES 
 
NOTABLE VITAL SIGNS 
Vital Sign Variable 
Notable Criteria 
Pulse (beats/min) 
>120bpm or Increase of 15 bpm from baseline 
Or 
< 50bpm or Decrease of 15 bpm from baseline 
Systolic BP (mmHg) 
160 mm Hg or Increase of 20 mm Hg from baseline 
Or 
 90 mm Hg or Decrease of  20 mm Hg from baseline 
Diastolic BP (mmHg) 
 100 mmHg or Increase of  15 mm Hg from baseline 
Or 
 50 mmHg or Decrease of  15 mm Hg from baseline 
Temperature (°C) 
>38.3°C/ 101°F 
Body Weight (kg) 
±7% from baseline weight 
 


 
 
 
 
 
 
Clinical Development 
 
FTY720 (Fingolimod) 
 
CFTY720D2399 / NCT01201356 
 
 
A single arm, open-label, multicenter study evaluating the 
long-term safety and tolerability of 0.5 mg fingolimod 
(FTY720) administered orally once daily in patients with 
relapsing forms of multiple sclerosis 
 
RAP Module 3 – Detailed Statistical Methodology for 
D2399 final CSR full analysis – study part 2 
 
 
 
Author: 
 
Trial Statistician; 
Novartis 
Trial Statistician 
 
Document type: 
RAP Documentation 
 
Document status: 
Final Version 1.0 
Release date: 
26NOV2018 
 
 
 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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CFTY720D2399 
 
 
Table of contents 
List of abbreviations ................................................................................................. 4 
1 
Overview ................................................................................................................... 5 
2 
General strategies of data presentation...................................................................... 5 
2.1 
Allocated treatment ....................................................................................... 5 
2.2 
Precision rules ............................................................................................... 5 
2.3 
Time frames, baseline, and visit windows .................................................... 6 
2.3.1 
Database lock for Study part 2...................................................... 6 
2.3.2 
Study day .................................................................................. 6 
2.3.3 
Baseline and post-baseline ............................................................ 6 
2.3.4 
Variables Summarized by Visits .................................................. 7 
2.4 
Imputation of Incomplete Dates .................................................................... 8 
2.5 
Analysis sets .................................................................................................. 8 
2.5.1 
Subgroups ..................................................................................... 9 
3 
Protocol Deviations ................................................................................................. 10 
4 
Patient Disposition .................................................................................................. 10 
5 
Background and demographic characteristics ........................................................ 11 
5.1 
Core study ................................................................................................... 11 
5.2 
Demographics ............................................................................................. 11 
5.3 
MS disease history characteristics before enrollment in core study ........... 11 
5.4 
MS medication history prior to enrollment in core study ........................... 12 
6 
Study drug ............................................................................................................... 12 
6.1 
Duration of exposure ................................................................................... 12 
7 
Concomitant medication ......................................................................................... 12 
7.1 
Imputation of concomitant medication start date ........................................ 12 
7.2 
Imputation of concomitant medication end date ......................................... 13 
7.3 
Concomitant medication analyses ............................................................... 13 
8 
Efficacy evaluation ................................................................................................. 14 
8.1 
Analysis of MS Relapses ............................................................................ 14 
8.1.1 
Relapse date imputations and handling of duplicate relapse 
records ........................................................................................ 14 
8.1.2 
Annualized relapse rates ............................................................. 16 
8.1.3 
Time in study .............................................................................. 17 
8.1.4 
MS relapses analyses .................................................................. 17 
9 
Safety evaluation ..................................................................................................... 18 


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CFTY720D2399 
 
9.1 
Adverse events ............................................................................................ 18 
9.1.1 
Imputation of adverse event start date ........................................ 18 
9.1.2 
Adverse events analyses ............................................................. 19 
9.1.2.1 
Adverse events during the study part 2 ...................................... 20 
9.1.2.1.1 
Occurrence of adverse events ..................................................... 20 
9.1.2.1.2 
Incidence rate of adverse events ................................................. 21 
9.1.2.1.3 
Regulatory adverse events report ............................................... 21 
9.1.2.2 
Adverse events during the fingolimod treatment period ............ 22 
9.2 
Laboratory ................................................................................................... 22 
9.3 
Routine vital signs ....................................................................................... 22 
9.4 
Dose monitoring administration .................................................................. 23 
9.4.1 
Vital signs ................................................................................... 23 
9.4.2 
Electrocardiograms ..................................................................... 23 
10 Sample size and power considerations ................................................................... 24 
Appendices .............................................................................................. 25 
Appendix A: Clinically notable Vital sign values .................................. 25 


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List of abbreviations 
AE 
adverse event 
ARR 
annual relapse rate 
BPM 
beats per minute 
eCRF 
electronic case report/record form 
ECG 
electrocardiogram 
FDD 
First dose of study drug (among all studies) 
FDF 
 First dose of fingolimod 
HR 
heart rate 
MS 
multiple sclerosis 
p.o. 
by mouth 
SAE 
serious adverse event 
s.c. 
subcutaneously 


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1 
Overview 
Study CFTY720D2399 is a single arm, open-label, multicenter study evaluating the long- 
term, safety, tolerability and efficacy of 0.5 mg fingolimod (FTY720) administered orally 
once daily in patients with relapsing forms of multiple sclerosis (MS). The term ‘study part 
2’ is used to define the last extension phase of CFTY720D2399 study throughout this 
document, indicating that CFTY720D2399 is the extension of all historical fingolimod 
studies, and the term ‘study part 2’ means that this CFTY720D2399 study is the extension 
phase of CFTY720D2399 study part 1, which is completed in Jul2017. This study allows 
prior fingolimod study patients who are unable to obtain fingolimod outside a clinical trial to 
get access to the drug. These patients include a subset of patients participating in part 1, and 
other eligible patients from ongoing fingolimod trials (e.g.,CFTY720D2312). The purpose of 
study part 2 is to obtain additional long-term safety and tolerability data. 
The end of the study treatment visit is planned for 30 June 2018. Individual patient’s end of 
treatment visits should occur at their routine 6 monthly scheduled visit closest to 30 June 
2018 to ensure all patients complete within the window for the end of the study. 
 
2 
General strategies of data presentation 
Statistical Analysis System (SAS) version 9.3 or higher will be used to perform all analyses. 
In general, variables will be summarized using frequency distributions for categorical 
variables and summary statistics for continuous variables. Summary statistics for continuous 
variables will include n, mean, standard deviation, minimum, first quartile (Q1), median, third 
quartile (Q3) and maximum. 
Note that, the population sets are derived based on Virtual Data Warehouse, which does not 
include CFTY720D2312 and CFTY720D2402 studies, thus patients from the 2 studies are 
not included for any summary, and only information in the study part 2 (from part 2 raw 
data) is included for listing purposes. 
 
2.1 
Allocated treatment 
All patients during the study part 2 are treated with fingolimod 0.5 mg per day, even though 
patients may have been assigned a different dose (5 mg, 1.25 mg) in their initial fingolimod 
trial. Unless otherwise specified, all summaries will only present the “fingolimod 0.5 mg” 
group, which indicates the dose level used during the study part 2. For adverse events by 
yearly interval, additional summaries will be provided by “highest fingolimod dose 0.5 mg” 
group, which indicates the subjects’ highest fingolimod dose throughout all fingolimod 
trials. 
 
 
2.2 
Precision rules 
Whenever possible, the minimum and maximum values of the data will be presented to the 
same precision as the raw data; the mean, median, quartile 1 (Q1), and quartile 3 (Q3) will 


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be presented to one more decimal place, and standard deviation will be presented to two more 
decimal places than the raw data. 
 
2.3 
Time frames, baseline, and visit windows 
This section defines the study and data time frames, baseline, and rules for visit windows. 
 
2.3.1 
Database lock for Study part 2 
The analyses specified in this document include data from study part 2 with a database lock 
planned around December 2018/January 2019. All qualified patients will participate until 
their scheduled visit closest to 30-Jun-2018 (+/- 3 months), which gives time for one follow- 
up study visit 3-months post last dose of fingolimod, for patients who discontinuing or 
completing the study after entering part 2 and who do not continue on commercial Gilenya. 
 
2.3.2 
Study day 
The day of first administration of any dose of fingolimod study drug is defined as Day 1. Day 
1 does not need to occur in the study part 2. 
All other study days will be labeled relative to Day 1. Thus, study day for a particular event 
date on or after Day 1 is calculated as: (Date of event – Date of first dose of fingolimod study 
drug + 1). An event that occurs prior to Day 1 is calculated as: (Date of event – Date of first 
dose of fingolimod study drug). 
In addition to calculating study day with respect to the first dose date of fingolimod drug 
across all studies, study day will also be calculated relative to the first dose date of fingolimod 
during the study part 2. 
The number of days after permanent study drug discontinuation will be calculated as (Date 
of event – Date of last dose of fingolimod study drug). 
The duration of an event will be calculated as (Event end date – Event  start  date + 1).  
Day 0 will not be used. 
 
2.3.3 
Baseline and post-baseline 
For the summary of change from baseline in vital signs, the baseline is defined as end of 
study visit from study part 1 or last assessment of that patient (excluding follow-up) in 
extension study part 1 if the subject’s end of study visit is missing. 
The baseline relative to first dose of fingolimod among all studies a subject has participated 
in, which is defined as the last available measurement made prior to administration of the 
first dose of fingolimod, will be used for efficacy summaries. 
The baseline relative to first dose of study drug in the core study (e.g. demographic 
information, core baseline characteristics) is also used for mentioned sections. 
Post-baseline assessments are assessments made after the baseline assessment. 


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2.3.4 
Variables Summarized by Visits 
Below are the visit windowing rules used for visits as defined in the Virtual Data Warehouse 
(VDW) RAP M4 draft version 4.3. 
Visit windows will be widely used to align visits across studies. They are based on the 
assessment schedule of the pivotal studies and comprise a set of days around the nominal 
visits. The same visit windows will apply to all studies. Visit windows are non-overlapping; 
all together they cover the entire study period. Generally, visit-windows are not symmetrical 
around the nominal visit day. Among all the analysis, only efficacy summaries will use visit 
window. Safety summaries will be based on nominal visits. 
Visit windows will be used to present summary statistics by visit. Efficacy data sets consider 
only scheduled visits. For efficacy analysis, if multiple assessments are available within a 
visit window, the record closest to the target day will be selected (if more than one assessment 
is equidistant to the target day, the later assessment will be used). 
Unless otherwise specified, the following visit windows are derived with respect to the first 
dose date of fingolimod among all studies. 
 
Table 1 Visit-windows for efficacy data (MS relapse) 
 
Visit 
Start day (time) 
Target Day (time) 
End day (time) 
Month 3 
1 
91 
136 
Month 6 
137 
182 
273 
Month 12 
274 
365 
547 
Month 24 
548 
730 
912 
Year 3 (M36) 
913 
1095 
1278 
Year 4 (M48) 
1279 
1461 
1643 
Year 5 M(60) 
1644 
1826 
2008 
Year 6 (M72) 
2009 
2191 
2373 
Year 7 (M84) 
2374 
2556 
2739 
Year8 (M96) 
2740 
2922 
3104 
Year 9 
3105 
3287 
3469 
Year 10 
3470 
3652 
3834 
Year 11 
3835 
4017 
4200 
… 
every 12 months 
Month X (row i) 
Si=Integerpart((Di+Di-1) /2)+1 
Di = Integerpart(X*365.25/12) 
Ei=Integerpart((Di+1+Di) /2) 
... 
... 
Every 12 months 
... 
Month X (last 
row) 
Slast 
Dlast 
Elast=Dlast+( Dlast-Slast) 
- Day 1 is defined as the first dose day of fingolimod among all studies. 
- If multiple assessments are available within a visit window, the record closest to the target day will be selected (if more than 
one assessment is at the same distance to the target day, the later one will be used for summary statistics (after 
unscheduled visits are excluded). 


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Table 2 Follow-up visit windows for efficacy data (MS relapse) 
 
Visit label 
Start day (time) 
Target Day (time) 
End day (time) 
FU (Month 3) 
Day 1 p.l.d 
Day 90 p.l.d 
- Follow-up visit windows are defined relative to study drug discontinuation in the respective pool (unscheduled visits will be 
excluded). 
- p.l.d = post last dose. 
- Day 1 p.l.d is defined as the first day after the last dose day of fingolimod. 
 
2.4 
Imputation of Incomplete Dates 
Incomplete or partial dates will be imputed (where appropriate, and will follow Virtual Data 
Warehouse (VDW) imputation rules – refer to VDW MAP M8) to decide on the inclusion or 
exclusion of related events in the summary tables. Each incomplete date will be split into its 
day, month, and year components, and an imputation rule will be applied. However in data 
listings, the dates as available in the database should be listed (without imputation). 
General imputation rules from the VDW MAP M3, draft version 3.0 are given below. 
Specific imputation rules may apply to certain panels (e.g. concomitant medications) and are 
described in the relevant sections. If no imputation rules are described then the general 
imputation rules apply to partially missing or impossible dates: 
• If the year is missing or impossible (e.g. 12-Jan-1911), then the date will be 
imputed as missing. 
• If the year is not missing and possible, but the month is impossible or missing 
(e.g. 17-XXX-2010), then the year will be kept and July 1st will be imputed 
(1-July-2010). 
• If the year and the month are not missing and possible, but the Day is 
impossible or missing (e.g. 31-FEB-2009), then the year and month will be 
kept, the 15th will be imputed (15-FEB-2009). 
 
2.5 
Analysis sets 
The following analysis sets will be defined. Analyses done on the fingolimod safety set and 
fingolimod full analysis set summarize all data starting from first dose of fingolimod among 
all studies, while other analysis sets generally summarize all data from the study part 2 only. 
• Enrolled set: The enrolled set will include all patients who entered the study part 2 
(excludes long-term extension study screen failures), but will exclude patients with 
protocol deviation severity code of 8 (8=exclude from all analyses) in the study part 2. 
• Safety set: The safety set is a subset of the fingolimod safety set and will include all 
patients who entered the study part 2 and received at least one dose of fingolimod in any 
study, but will exclude patients with protocol deviation severity codes of 5 (5=exclude 
from all safety analyses) and 8 (8=exclude from all analyses) in the study part 2. Note 
that all data reported in the study part 2 will be analyzed, including assessments or 
events which started before the study part 2, unless otherwise specified. For example, 
adverse events which may have been continuing at the end of the long-term follow-up 


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study part 1 may be recorded in the study part 2 database with updated end date. These 
adverse events will be reported in listings and summarized if event occurs after first 
dose of fingolimod among all studies. 
• Fingolimod safety set: The fingolimod safety set will include all patients who entered 
the study part 2 and received at least one dose of fingolimod in any study, but will 
exclude patients with protocol deviation severity codes of 5 (5=exclude from all safety 
analyses) and 8 (8=exclude from all analyses) during the core study prior to entry to the 
long-term follow-up study part 1. For patients with such protocol deviations after the 
core study, record level data associated with the protocol deviations will be excluded 
from the analysis. 
• Fingolimod full analysis set: The fingolimod full analysis set will include all patients 
who entered the study part 2 and received at least one dose of fingolimod in any study 
but will exclude patients with protocol deviation severity codes of 0 (0=exclude from all 
efficacy analyses) and 8 (8=exclude from all analyses) during the core study prior to 
entry to the long-term extension study part 1. For patients with such protocol deviations 
after the core study, record level data associated with the protocol deviations will be 
excluded from the analysis. 
• Follow-up set: The follow-up set will consist of all patients in the safety set who have 
any follow-up visit data or at least one safety record after the study drug discontinuation. 
It will be used for summary of adverse events and concomitant medications with 
occurrences after last dose of fingolimod only. 
Patient disposition, core study, protocol deviations, analysis sets, demographics, and 
baseline and history information will be summarized based on the enrolled set. Efficacy 
analyses will be summarized based on the fingolimod full analysis set. Safety summaries 
that include only study part 2 data will be based on safety set or follow-up set as specified. 
A summary of the number and percentage of patients in each analysis set will be summarized. 
Percentages will be based on the enrolled set. A listing of patient assignment into each 
analysis set will also be displayed. 
 
2.5.1 
Subgroups 
The following subgroups are defined for subject disposition and AE analysis during 
fingolimod treatment period: 
1. Duration of fingolimod treatment up to the end of the study part 2 (yearly 
interval): 
• Year 1 subgroup: patients on fingolimod treatment > 0 year (>= 1 day) 
• Year 2 subgroup: patients on fingolimod treatment > 1 year (>= 361 days) 
• Year 3 subgroup: patients on fingolimod treatment > 2 year (>= 721 days) 
• Year 4 subgroup: patients on fingolimod treatment > 3 year (>= 1081 days) 
• Year 5 subgroup: patients on fingolimod treatment > 4 year (>= 1441 days) 


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• Year N subgroup: patients on fingolimod treatment > N -1 year (>= (N -1) 
x 360+1 days) 
 
 
3 
Protocol Deviations 
The number and percentage of patients in the enrolled set with each protocol deviation in the 
study part 2 will be displayed by protocol deviation category. Additionally, patients with at 
least one protocol deviation during the study part 2 and patients with at least one protocol 
deviation causing exclusion from any analysis set (deviation severity codes 0, 5, or 8) will be 
summarized. 
The protocol deviation data will be listed as well. 
Additionally, the investigator comments during the study part 2 will be listed. 
 
4 
Patient Disposition 
All screen failures in the study part 2 will be listed along with their primary reason for failing 
screening. 
The number and percentage of patients who completed the study part 2, and who discontinued 
the study part 2, along with the primary reason for discontinuation, will be summarized for 
the enrolled set. The number and percentage of patients who are expected to have month 3 
follow-up visit and who returned will also be summarized. The number and percentage of 
patients who move to commercial fingolimod after study completion will also be included. 
To further evaluate the disposition within a particular fingolimod treatment duration, study 
completion and discontinuation will be summarized in separate tables based on patients’ 
fingolimod exposure by cumulative yearly interval. Patients will be summarized within a 
particular yearly interval if they have been receiving study treatment for at least one day in 
that particular interval. For example: year 1 will consist of subjects on fingolimod treatment 
for at least 1 day; year 2 will consist of subjects on fingolimod treatment for at least 361 days, 
year 3 will consist of subjects on fingolimod treatment for at least 721 days and so on. For 
study completion, the number and percentage of patients who completed the study part 2, and 
who move to commercial fingolimod after study completion will be provided by yearly 
exposure group as defined above. For study discontinuation, the number and percentage of 
patients who discontinued the study part 2, along with the reason for discontinuation, and 
who move to commercial fingolimod after study discontinuation will be provided by yearly 
exposure group as defined above. 
The patients who discontinued from the study part 2 and corresponding reasons will be listed 
for the enrolled set. Additionally, a similar listing will be provided for the enrolled set of 
patients from D2312 and D2402 studies who discontinued early from the study part 2. 


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5 
Background and demographic characteristics 
5.1 
Core study 
The core study refers to the first fingolimod MS study the patient enrolled in. The number 
and percentage of patients in each core study prior to transfer into the long-term follow-up 
study will be provided. 
 
5.2 
Demographics 
 
Using data collected from the patient’s core study, the following demographic variables will 
be summarized for the enrolled set: sex, age (years), age groups [<18, 18-30, 31-40, 41-55, 
>55], race, ethnicity, baseline weight, baseline height, and baseline BMI. Baseline height and 
weight will be derived as the last non-missing assessment prior to first dose of any drug 
among all studies a patient has participated in. Baseline BMI will be derived based on 
baseline height and weight. Age will be calculated as the (core study’s demographic screening 
or baseline visit date – patient’s birth date +1) / 365.25. 
Unless otherwise specified, age is presented in the listings in 3 ways: age 1 is the age at the 
visit where demographic data is collected (screening or baseline visit of core study); age 2 is 
the age at first dose of fingolimod among all studies; age 3 is the age at last dose of fingolimod. 
 
5.3 
MS disease history characteristics before enrollment in core 
study 
Using data collected from the patient’s core study, the following MS disease history 
characteristics will be summarized for the enrolled set: duration of MS since diagnosis in 
years, duration of MS since first symptoms in years, number of relapses in the last year prior 
to enrollment in the core study, number of relapses in the last 2 years prior to enrollment in 
the core study, time since the onset of the most recent relapse (in months) prior to enrollment 
in the core study, and duration from MS diagnosis date to last dose date of study drug (in 
years). The duration of exposure to fingolimod prior to first dose in the study part 2 will also 
be summarized for the enrolled set. Note that not all parameters are collected across all studies. 
The following definitions will be used in calculations involving MS disease history 
characteristics: one year is defined as 365.25 days and one month is defined as 30 days. 
For the MS disease history summary, the variable Duration of MS since diagnosis (years) 
will be derived for each patient as: (first dose date of any study drug among all studies a 
patient has participated in – the MS diagnosis date + 1)/365.25. Duration of MS since first 
symptom (years) is calculated as (first dose date of any study drug among all studies a patient 
has participated in – the first MS symptom date +1) / 365.25. The time since the onset of the 
most recent relapse (months) is computed as (first dose date of any study drug among all 
studies a patient has participated in – the most recent relapse onset date prior to enrollment 
in the core study + 1)/30. The duration from MS diagnosis date to last dose date of study drug 
(in years) is calculated as (last dose date of any study drug among all studies a patient has 


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participated in - the MS diagnosis date + 1)/365.25. Note that the first dose date of any study 
drug among all studies a patient has participated in may not be fingolimod. 
 
5.4 
MS medication history prior to enrollment in core study 
For the MS medication history of disease-modifying drugs (DMDs), treatment-naïve patients 
are defined as those who never took MS disease-modifying medications prior to enrollment 
in core study. The number and percentage of treatment-naïve patients and patients who took 
categories of MS DMDs will be summarized for the enrolled set. 
 
6 
Study drug 
6.1 
Duration of exposure 
The duration of exposure to fingolimod study drug during the study part 2, is defined as the 
number of days from first dose date of fingolimod in the study part 2 to the last dose date, 
excluding the days for which the patient did not take fingolimod (i.e., periods of temporary 
interruption). The number and percentage of patients being exposed for a minimum of 1 day, 
90 days, 180 days, 360 days, etc. will be presented. Summary statistics of duration of 
exposure will also be provided. Patient-years of exposure will be reported and is calculated 
as the (sum of the total number of days on fingolimod study drug for all patients in the 
treatment group)/365.25. Duration of exposure to fingolimod study drug during the study part 
2 will be presented for the safety set. 
The fingolimod dose administration records during the study part 2 will be listed for the safety 
set. 
 
7 
Concomitant medication 
7.1 
Imputation of concomitant medication start date 
Missing or partial concomitant medication start dates are imputed following the VDW 
MAP Module 8 ‘Concomitant Medication Start Date Imputation (#IMPUTMED)’ section 
(displayed below): 
Concomitant Medication Start Date Imputation (#IMPUTMED) 
The following table explains the notation used in the logic matrix. Please note that missing 
start dates will not be imputed. 
 
Day 
Month 
Year 
Partial CMD Start Date 
Not used 
MON 
YYYY 
Treatment Start Date (TRTSTD) 
Not used 
TRTM 
TRTY 
 
The following matrix explains the logic behind the imputation. 


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MON 
MISSING 
MON < TRTM 
MON = TRTM 
MON > TRTM 
YYYY 
MISSING 
(C) 
Uncertain 
(C) 
Uncertain 
(C) 
Uncertain 
(C) 
Uncertain 
YYYY < TRTY 
(D) 
Before Treatment Start 
(A) 
Before Treatment Start 
(A) 
Before Treatment Start 
(A) 
Before Treatment Start 
YYYY = TRTY 
(C) 
Uncertain 
(A) 
Before Treatment Start 
(C) 
Uncertain 
(B) 
After Treatment Start 
YYYY > TRTY 
(E) 
After Treatment Start 
(B) 
After Treatment Start 
(B) 
After Treatment Start 
(B) 
After Treatment Start 
 
The following table is the legend to the logic matrix. 
 
Relationship 
Before Treatment Start 
Partial date indicates CMD start date prior to Treatment Start Date 
After Treatment Start 
Partial date indicates CMD start date after Treatment Start Date 
Uncertain 
Partial date insufficient to determine relationship of CMD start date to Treatment Start Date 
Imputation Calculation 
NC / Blank 
No convention 
(A) 
15MONYYYY 
(B) 
MAX( 01MONYYYY, TRTSTD+1 ) 
(C) 
IF CMDTYP1C IN (1, 3) THEN TRTSTD-1  
ELSE IF CMDTYP1C IN (., 2) THEN TRTSTD+1 
(D) 
01JULYYYY 
(E) 
01JANYYYY 
 
7.2 
Imputation of concomitant medication end date 
Partial or missing concomitant end dates will be imputed such that the imputed end date is 
the latest possible date (i.e. last day of month if day is missing, last day of year if both month 
and day are missing). These imputation rules will tend to consider medications with an 
unknown start and/or end date to be “concomitant”. See VDW MAP Module 8 variable 
CMDEND1O specifications for details. 
 
7.3 
Concomitant medication analyses 
Concomitant medications are defined as medications, other than the study drug, that are 
reported during the study. All medications recorded on the CFTY720D2399 concomitant 
medications /significant non-drug therapies CRF will be coded using the current Hybrid 
DTD_DDE Dictionary. Concomitant medications and significant non-drug therapies, which 
are recorded in the CFTY720D2399 part 2 database and taken at any time from first dose 
date of fingolimod among all studies to last dose date of fingolimod + 45 days, will be 
summarized for the safety set by Anatomical Therapeutic Chemical (ATC) class and 
preferred term. The summary will show the number and percentage of patients receiving at 
least one drug of a particular ATC class and at least one drug in a particular preferred term 
(PT). To determine if any particular treatment is needed after discontinuation of fingolimod, 
concomitant medications and significant non-drug therapies, which are recorded in the 
CFTY720D2399 part 2 database and taken after last dose date of fingolimod, will be 
summarized in the same way as above for the follow-up set. 


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Note that concomitant medications which are recorded on the CFTY720D2399 part 2 
concomitant medications / significant non-drug therapies CRF can include medications that 
may have been taken during any gap between the completion of the prior study (part 1) and 
enrollment into this study part 2, even if the medication is not ongoing at the time of 
enrollment. 
All concomitant medications recorded during the study part 2 will be listed. The concomitant 
medications taken after study drug discontinuation but up to or after 45 days will be flagged. 
Records for steroid treatment of MS relapse during the study part 2 will be listed for the safety 
set. 
 
8 
Efficacy evaluation 
The secondary objective of this study is to evaluate the long-term efficacy of fingolimod 0.5 
mg in patients with relapsing forms of MS. Long-term efficacy will be assessed in MS relapse. 
 
8.1 
Analysis of MS Relapses 
8.1.1 
Relapse date imputations and handling of duplicate relapse records 
 
The start date of a relapse should never be missing. However, missing or partial dates may 
be expected from some non-phase III trials where data checking may be less vigorous than 
in phase III trials. To avoid an artificial inflation of the number of relapses by low quality 
data, missing dates for relapses will only be imputed if the end date of the relapse is after the 
first dose of the initial study (i.e. if the relapse happened at least partially within the study). 
If partial or complete end dates are before the first dose date of the initial study, then no 
imputation will be done. If partial or complete relapse end dates are after the first dose of the 
initial study, the following algorithm will be applied: 
 
Firstly, drop blanks and impute missing or partially missing start dates 
1. Drop complete blanks: If the relapse onset date is invalid (e.g. “No”, “None”) or 
completely missing and there is no information recorded across all variables, the onset 
date will be set to missing. 
2. Otherwise, if the record is not empty or the onset date is partially missing, check if 
another record may be available for the same relapse. Concretely: 
a. If a relapse onset date has a missing day-part (XX-MM-YYYY), where XX 
represents the missing or invalid part, the onset date will be imputed by the 
onset date of another treatment-emergent relapse record with a non-missing 
start date for the same patient within the same month and year, if such a relapse 
is available (choose the first one if more than one is available). 
b. If a relapse onset date has a missing day- and month part (XX-XX-YYYY, the 
onset date will be imputed by the onset date of another treatment-emergent 
relapse record for the same patient within the same year, if such a relapse is 
available (choose the first one if more than one is available). 


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3. Otherwise, if the onset date of a relapse is completely or partially missing, the onset 
will be imputed with the first possible day within the available non-missing date-part, 
or the first-dose date, or the relapse end-date minus 90, whatever occurs latest. 
 
Secondly, impute the end date 
The imputation of missing or partially missing end dates will be done after the imputation of 
start dates. 
1. If the end date of a relapse is completely missing, it will be imputed as 90 days after 
the onset date. 
2. If the end date of a relapse is partially missing, it will be imputed as the maximum of 
the relapse start day plus one or the minimum of either 90 days after the onset date, 
or as the last possible day based on the non-missing parts of the end-date (e.g. 
XXDEC2007 where XX indicated the missing end day would be imputed as 31-DEC- 
2007 if the onset date of the relapse was 26-NOV-2007). 
 
Thirdly, handle duplicate relapse records: 
After the imputation of start and end-dates is completed, records which refer to the same 
relapse (30-day rule) will be combined into a new artificial record. This step will help to 
consolidate core and extension databases where the same relapse may be recorded more than 
once, and it will help to ensure consistent relapse rules even for studies with a less vigorous 
date management. 
1. For each patient relapses will be sorted by onset date (source or imputed). 
2. Combine relapses for which the distance between onset dates is <30 days: Starting 
from the first relapse within each patient, the distance from each relapse to the next 
will be tested. If the onset date of a relapse is less than 30 days from the onset date of 
a previous one, an artificial record will be created using the “worst” or “most severe” 
information from both records (Conservative approach). The following rules apply: 
a. Onset date: use the minimum of the candidate dates with the highest degree of 
completeness. The degree of completeness is defined in descending order: 1. 
Original date, 2. Only day-part imputed, 3. Day and Month part imputed, 4. Day, 
Month and Year imputed. 
Example: an original date entered by the investigator has the higher degree of completeness 
compared to a partial/imputed date. An imputed date with just the day-part imputed has the higher 
degree of completeness compared to a completely imputed date. Rationale: amongst the candidate- 
dates with the highest reliability/completeness – choose the first/worst. 
b. End date: use the maximum of the candidate dates with the highest degree of 
completeness. The degree of completeness is defined in descending order: 1. 
Original date, 2. Only day-part imputed, 3. Day and Month part imputed, 4. Day, 
Month and Year imputed. 
Example: an original date entered by the investigator has the higher degree of completeness 
compared to a partial/imputed date. An imputed date with just the day-part imputed has the higher 
degree of completeness compared to a completely imputed date. Rationale: amongst the candidate- 
dates with the highest reliability/completeness – choose the last/worst. 


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c. When two records are combined from two consecutive phases (e.g. one from an 
initial study, the other one from an extension) the combined record will be 
considered as belonging to the first phase. 
Example: A relapse may have started at the end of an extension but ended in an Umbrella study. 
The same relapse may then be captured in the extension and also in the Umbrella study. When the 
two records are combined into one, the relapse – according to its start date – will be considered in 
the extension phase. Programmatically: Ext1n will take the minimum value of the two combined 
records. 
d. Hospitalization: “yes” is worse than “no” 
e. Severity: “severe” is worse than “moderate” is worse than “mild” is worse than 
“unknown” 
f. Steroids: “yes” is worse than “no” 
g. Relapse confirmed: “yes” is worse than “no” 
h. Recovery: “none” is worse than “partial” is worse than “complete” 
i. 
Daily activity: “affected” is worse than “not affected” 
 
Lastly, truncate the duration of all relapses to a maximum of 90 days 
1. For each relapse record, check whether the duration from onset to end date is less or 
equal to 90 days, if this is not the case do the following: 
a. Determine the degree of completeness of the start and end-date. The degree of 
completeness is defined in descending order: 1. Original date, 2. Only day- 
part imputed, 3. Day and Month part imputed, 4. Day, Month and Year 
imputed. 
Example: an original date entered by the investigator has the higher degree of completeness 
compared to a partial/imputed date. An imputed date with just the day-part imputed has the 
higher degree of completeness compared to a completely imputed date. 
b. Keep the date with the higher degree of completeness fixed and update the 
other date, so that the duration the relapse is maximized to 90 days 
Rationale: If one of the dates has to be replaced to keep truncate the duration of the relapse to 
90 days, keep the date with the higher degree of completeness/reliability fixed (either the end- 
or the start date) and replace the other one. 
c. If the onset- and end-date have the same degree of completeness, keep the start 
date fixed and impute the end-date such that the duration of the relapse is 
maximized to 90 days. 
2. If a relapse is recorded as ongoing at the final exam, impute an end date such that the 
duration is maximized to 90 days. 
 
8.1.2 
Annualized relapse rates 
Annualized relapse rate (ARR) is defined as the number of relapses experienced during a 
specific period of time adjusted to a one-year period. The ‘number of relapses’ can refer to 


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either the number of confirmed relapses or the number of all relapses (including both 
confirmed and unconfirmed relapses). 
Confirmation of relapses is not collected in the following studies: CFTY720D2316, 
CFTY720D2320, CTY720D2399E1, and the long-term follow-up study prior to protocol 
amendment 4. Therefore, the number of confirmed relapses during this time is not able to 
be reported. Additionally, confirmed relapses will not be reported for patients from the 
CFTY720D2324 study since it is a phase IIIb study and confirmation is not collected in the 
long-term follow-up study for patients coming from previous studies that are not phase 
II/III. The number of unconfirmed relapses is also not able to be reported for study 
CTY720D2399E1 since the study does not collect relapse start dates. However, note that 
the time during which number of relapses is not able to be counted and the time off study 
for patients who re-enrolled into the long-term follow-up study will still be included in the 
time in study, which can make the ARR appear lower than it actually is. If confirmation of a 
relapse is missing or not collected, the relapse will be treated as an unconfirmed relapse. 
Therefore, ARR based on all relapses (confirmed or unconfirmed) should be considered a 
more reliable estimation of relapse rate than ARR based on confirmed relapse. 
The group level (aggregate) ARR will be calculated as follows: (total number of relapses) / 
(total number of days in the study for all patients for that specific period of time) x 365.25. 
 
8.1.3 
Time in study 
For the analysis of ARR from first dose of fingolimod to end of study treatment, the time in 
study (days) is calculated as: last dose date of fingolimod – first dose date of fingolimod 
among all studies + 1 day. Similarly, the time in study from first dose of fingolimod among 
all studies to end of follow-up is calculated as: last available visit/evaluation date across all 
panels – first dose date of fingolimod among all studies + 1 day. 
For the analysis of ARR from first dose of fingolimod among all studies to end of a particular 
month (i.e. “Month 6”, “Month 12”, “Month 24”, and every 12 months from then on), “Month 
0 to X” time in study will be calculated as minimum of (first dose date of fingolimod + 
integerpart(X/12*365.25) where X denotes the month, last available visit/evaluation date 
across all panels) – first dose date of fingolimod + 1 day. 
 
8.1.4 
MS relapses analyses 
MS relapses analyses will be conducted on the fingolimod full analysis set. All analyses will 
be done for all relapses (confirmed and unconfirmed) and for confirmed relapses. 
A summary of ARRs will be presented by time period (cumulative time intervals: ‘Month 0 
to Month 6’, ‘Month 0 to Month 12’, ‘Month 0 to Month 24’, ‘Month 0 to Month 36’, … 
incremented by 1 year for each successive interval, plus ‘Month 0 to end of study treatment’ 
and ‘Month 0 to end of follow-up’) from first dose of fingolimod among all studies. The 
summary will include number of patients summarized, number of relapses, time in study 
(days), and group level ARR. In addition, model based estimates of ARR and corresponding 
two-sided 95% confidence interval will be obtained by fitting a negative binomial regression 
model adjusted for the number of relapses in the last two years prior to enrolment in the core 


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study and EDSS score at first dose of fingolimod baseline, with the logarithm of the time in 
study as the offset variable. 
A summary of relapse characteristics will be displayed by time period (consecutive yearly 
intervals: ‘Month 0 to Month 12’, ‘Month 12 to Month 24’, etc., plus ‘End of study treatment 
to End of follow-up’) from first dose of fingolimod among all studies. Relapse characteristics 
will be summarized at a patient level (the number and percent of patients with at least one 
relapse type) and at a relapse event level (the number and percent of a particular type of 
relapse out of the total number of relapses). The types of relapses being summarized include: 
relapses which affect daily activities, relapses which require steroids, and relapses which 
require hospitalization. 
The time to first onset of relapse from first dose date of fingolimod among all studies will be 
analysed. Specifically, the number of patients at risk, the cumulative number of patients with 
relapse, the Kaplan-Meier (KM) estimate of the percent of patients without relapse and 
corresponding standard error and two-sided 95% CI will be provided at each yearly time point 
(1 year = 360 days). Patients with no relapse, patients for whom follow-up ends before a 
confirmed relapse occurs, and patients who drop out prior to the relapse will all be censored, 
i.e. the time to event for these patients will be the time in study (from first dose of fingolimod 
among all studies to last available visit/evaluation date across all panels). 
A Kaplan-Meier plot of time to first relapse from first dose of fingolimod to end of the study 
part 2 will be presented. 
 
9 
Safety evaluation 
The primary objective of this study is to evaluate the long-term safety and tolerability of 
fingolimod 0.5 mg in patients with relapsing forms of MS. 
Long-term safety will be assessed in terms of adverse events (AEs), pregnancy tests, vital 
signs (including dose administration monitoring), and electrocardiograms (ECG) dose 
administration monitoring. 
 
9.1 
Adverse events 
9.1.1 
Imputation of adverse event start date 
Missing or partial adverse event start dates are imputed following the VDW MAP Module 8 
‘Adverse Event Start Date Imputation (#IMPUTAEV)’ section (displayed below): 
Adverse Event Start Date Imputation (#IMPUTAEV) 
The following table explains the notation used in the logic matrix. Please note that missing 
start dates will not be imputed. 
Note, it may happen that the imputed AE start is after AE end date. Missing AE end date is 
not imputed by STL. 
 
 
Day 
Month 
Year 
Partial Adverse Event Start Date 
Not used 
MON 
YYYY 


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Treatment Start Date (TRTSTD) 
Not used 
TRTM 
TRTY 
 
 
The following matrix explains the logic behind the imputation. 
 
 
MON 
MISSING 
MON < TRTM 
MON = TRTM 
MON > TRTM 
YYYY 
MISSING 
NC 
NC 
NC 
NC 
YYYY < TRTY 
( D ) 
( C ) 
( C ) 
( C ) 
YYYY = TRTY 
(B) 
( C ) 
(A) 
(A) 
YYYY > TRTY 
(E) 
(A) 
(A) 
(A) 
 
 
The following table is the legend to the logic matrix. 
 
 
Relationship 
Before Treatment Start 
Partial date indicates AE start date prior to Treatment Start Date 
After Treatment Start 
Partial date indicates AE start date after Treatment Start Date 
Uncertain 
Partial date insufficient to determine relationship of AE start date to Treatment Start Date 
Imputation Calculation 
NC / Blank Uncertain 
No convention 
(A) After Treatment Start or 
Uncertain 
MAX( 01MONYYYY, TRTSTD+1 ) 
(B) Uncertain 
TRTSTD+1 
(C) Before Treatment Start 
15MONYYYY 
(D) Before Treatment Start 
01JULYYYY 
(E) After Treatment Start 
01JANYYYY 
 
9.1.2 
Adverse events analyses 
All adverse events (AEs) recorded on the adverse events CRF will be coded using the current 
Medical Dictionary for Regulatory Activities (MedDRA). Note that adverse events that 
started or were ongoing during any gap between the completion of the prior study (part 1) 
and enrollment into this CFTY720D2399 study part 2 can be recorded on the 
CFTY720D2399 part 2 adverse events CRF. 
In AE summaries, primary system organ classes will be displayed in alphabetical order and 
preferred terms (within each system organ class) will be sorted by descending frequency. 
There are two categories of AE summaries in this study: AEs during the long-term follow-up 
study part 2 and AEs during the fingolimod treatment period. 


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9.1.2.1 
Adverse events during the study part 2 
Only AEs captured in CFTY720D2399 study part 2 database will be summarized. Unless 
otherwise specified, all non-serious adverse events recorded in the CFTY720D2399 part 2 
database with an onset at any time from first dose date of fingolimod among all studies to last 
dose date of fingolimod + 45 days are included. All serious adverse events (SAEs) recorded 
in the CFTY720D2399 part 2 database with an onset at any time from first dose date of 
fingolimod among all studies are also included in the summaries. 
Adverse events reported during the study part 2 will be summarized for the safety set. 
There are two subcategories of AE summaries during the study part 2 as below. 
9.1.2.1.1 Occurrence of adverse events 
Adverse events reported during the study part 2 will be summarized by primary system organ 
class (SOC) and preferred term (PT), and will show the number and percentage of patients 
with at least one adverse event in each SOC or PT category. Similarly, adverse events by 
study drug relationship (AEs suspected to be study drug related, AEs not suspected to be 
study drug related, and AEs regardless of study drug relationship), AEs by severity (mild, 
moderate and severe), SAEs, SAEs by study drug relationship, SAEs by severity, suspected 
study drug related AEs, and AEs leading to study drug discontinuation will also be 
summarized by SOC and PT. 
When subjects had AE occurrence on same PT for more than once, but with different 
relationship, the subject will be counted in each category of relationship. When severity are 
different, subject will only be counted once in maximum severity of that PT. 
AEs and SAEs which are not considered to be known effects of fingolimod treatment (i.e., 
excluding those listed in the most recent version of Core Data Sheet), will be summarized by 
PT only. To determine which AEs occur after discontinuation of fingolimod treatment, all 
AEs reported with onset date after the last dose of fingolimod until the end of the study part 
2 will be summarized by SOC and PT for the follow-up set. 
To determine which AEs have occurrence after study part 2 enrollment, newly-occurring AEs 
will be summarized by SOC and PT for the safety set. A newly-occurring AE is defined as 
an AE which starts after part 2 informed consent date. A similar summary will be provided 
for SAEs. 
Principal cause of death during the study part 2 will be summarized by SOC and PT. All 
deaths recorded in the CFTY720D2399 part 2 database with onset on or after the first dose 
date of fingolimod (among all studies) will be included in the summary. 
All information pertaining to any AE with severity information, SAEs, AEs leading to study 
drug discontinuation, deaths and neoplasms system organ class events that reported during 
the study part 2 will be listed for the safety set. Additionally, adverse events, SAEs and all 
deaths recorded during the study part 2 will be listed for the subgroup of patients from studies 
D2312 and D2402 in the enrolled set. 


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9.1.2.1.2 Incidence rate of adverse events 
The AE incidence rate (IR) is calculated per 100 patient-years. IR is defined as: the number 
of patients experiencing at least one event in a particular category, over the total patient-years 
of the “at risk” population for that event multiplied by 100. An underlying Poisson process 
for incidence rate within treatment group is assumed. For the summary time period for 
extension part 2, only AEs with a start date between first dose date of fingolimod during the 
study part 2 and the last dose date of fingolimod + 45 days will be counted; or SAEs with a 
start date on or after first dose date of fingolimod during the study part 2 will be counted. 
To calculate the total patient-years (time at risk) of the “at risk” population: 
1. For patients who have a particular AE category, sum the number of days from first 
dose date of fingolimod during the study part 2 to the first occurrence of that 
particular AE category 
2. For patients who did not have a particular AE category, sum the number of days 
from first dose date of fingolimod during the study part 2 to last dose date of 
fingolimod + 45 days. 
3. Add the time at risk for patients who had a particular AE category with the time at 
risk for patients who did NOT have a particular AE category. This is the total time 
at risk of that AE category. 
4. Divide the total time at risk by 365.25. 
Incidence rate of adverse events will be presented for the safety set. Incidence rate of AEs, 
AEs by relationship, excluding AE listed in the core data sheet, will be presented by PT. 
Similarly, all above indicated AE IR summaries will be conducted for SAEs. 
 
9.1.2.1.3 Regulatory adverse events report 
For the legal requirements of ClinicalTrials.gov and EudraCT, summary of on- 
treatment/treatment emergent non-serious AEs and SAEs and SAE suspected to be related 
to study treatment will be provided by system organ class and preferred term in separate 
tables. The number of subjects with indicated AEs and the occurrences of AEs will be 
provided. The summary will be based on the safety set. Specifically, for the SAE summary, 
the number of deaths resulting from SAEs suspected to be related to study treatment and 
SAEs irrespective of study treatment relationship will be provided at each PT level. 
 
To count the AE occurrence, if for a same patient, several consecutive AEs (irrespective of 
study treatment causality, seriousness and severity) occurred with the same SOC and PT: 
• A single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• More than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE 
 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, 
if at least one SAE is occurring, then one occurrence is calculated for that SAE. 


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9.1.2.2 
Adverse events during the fingolimod treatment period 
To further evaluate the long-term AE rate (based on patient count and percentage) within a 
particular fingolimod treatment duration, an analysis based on yearly intervals since first 
dose of fingolimod will be conducted. For summaries on this set of patients, all AEs and 
SAEs with onset on or after first dose date of fingolimod (among all studies) to last dose 
date of fingolimod are included. Each yearly interval will contain 360 days. For example: 
Year 1 will consist of Day 1 to Day 360, Year 2 will consist of Day 361 to Day 720, Year 3 
will consist of Day 721 to Day 1080, Year 4 will consist of Day 1081 to Day 1440, Year 5 
will consist of Day 1441 to Day 1800, and so on. Patients will be summarized within a 
particular yearly interval if they have been receiving study treatment for at least one day in 
that particular interval. The number and percentage of these patients who have adverse 
events with onset date occurring during the interval will be summarized. For example, for 
the Year 1 group, patients with at least one day exposure to fingolimod will be included, 
and AEs with onset date occurring between Day 1 and Day 360 will be summarized. For 
the Year 2 group, patients with at least 361 days exposure to fingolimod will be included, 
and AEs with onset date occurring between Day 361 and Day 720 will be summarized. The 
same will be done for other intervals. 
Adverse events summarized by year will include the following: 
• Adverse events, by yearly interval, primary system organ class, and preferred 
term 
• Serious adverse events, by yearly interval, primary system organ class, and 
preferred term 
• Adverse events that fulfill the risk search term, by yearly interval 
• Serious adverse events that fulfill the risk search term, by yearly interval 
Intervals will be included based on the length of fingolimod exposure. Risk search terms are 
defined in Novartis’ case retrieval sheet (eCRS). Associated summaries will be presented by 
risk name and lower level terms. 
 
9.2 
Laboratory 
Patients with positive pregnancy test results during the study part 2 will be listed for the safety 
set. 
 
9.3 
Routine vital signs 
Vital signs include sitting pulse rate, sitting systolic and diastolic blood pressure, and body 
temperature. First dose monitoring vital signs values will be excluded from routine vital signs 
summaries and listing. 
Vital signs data will be summarized by presenting descriptive statistics for baseline, post- 
baseline, and change from baseline values by parameter and nominal visit. The incidence of 
notable vital sign abnormalities reported during the study part 2 will present the number and 


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percentage of patients satisfying notable criteria by nominal visit. An overall study visit will 
be generated to indicate any notable abnormalities from post-baseline visits (including 
follow-up visits). Criteria for clinically notable vital signs values are specified in Appendix 
A. Both summaries are based on the safety set. 
Patients in the safety set with notable vital sign abnormalities will be listed. All vital sign 
parameters with clinically notable criteria will be listed for a particular patient and visit if at 
least one of the parameters shows an abnormality. The listing will also indicate whether the 
vital sign result was above or below the normal range. 
 
9.4 
Dose monitoring administration 
A dose administration monitoring summary will be provided for the safety set for 
first/second/restart of fingolimiod dose during the study part 2, and will include yes or no 
categorical summaries for the following: discharged at 6 hours, required extended monitoring 
after 6 hours, discharged but returned for monitoring, hospitalization, required Day 2 
monitoring in the clinic (only recorded for first dose monitoring), study drug permanently 
discontinued, had symptomatic and/or treated bradycardia, and SAEs reported. The 
denominator for first/second dose monitoring data is based on the number of patients with 
assessment done; the denominator for restart monitoring data is based on the number of 
restarts. 
 
9.4.1 
Vital signs 
During the study part 2, hourly vital signs, including sitting pulse rate and blood pressure will 
be monitored before the first dose of fingolimod and every hour for at least six-hours 
thereafter. 
Hourly dose monitoring of vital signs will be summarized separately and will not be included 
in the by-visit summaries of routine vital signs. Descriptive statistics of pre-dose, post-dose, 
and change from pre-dose values will be summarized by parameter and time point for first 
dose monitoring, second dose monitoring, and dose monitoring after study drug restart. 
Summaries will be based on the safety set and include dose monitoring data during the study 
part 2 only. 
 
9.4.2 
Electrocardiograms 
During the study part 2, all patients requiring first dose monitoring will have an 
electrocardiogram (ECG) performed prior to dosing and at the end of the 6-hour monitoring 
period. 
ECG dose monitoring records will be listed for the safety set. 


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10 
Sample size and power considerations 
Given that this is a long-term follow-up study with primary descriptive purpose, no formal 
sample size calculation will be used to determine enrollment in this study. The sample size is 
defined by the number of patients coming from study part 1 and ongoing fingolimod trials. 


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Appendices 
Appendix A: Clinically notable Vital sign values 
CRITERIA FOR NOTABLE VITAL SIGN ABNORMALITIES 
 
NOTABLE VITAL SIGNS 
Vital Sign Variable 
Notable Criteria 
Pulse (beats/min) 
>120bpm or Increase of 15 bpm from baseline 
Or 
< 50bpm or Decrease of 15 bpm from baseline 
Systolic BP (mmHg) 
160 mm Hg or Increase of 20 mm Hg from baseline 
Or 
 90 mm Hg or Decrease of  20 mm Hg from baseline 
Diastolic BP (mmHg) 
 100 mmHg or Increase of  15 mm Hg from baseline 
Or 
 50 mmHg or Decrease of  15 mm Hg from baseline 
Temperature (°C) 
>38.3°C/ 101°F