Conditions: Relapsing Remitting Multiple Sclerosis RRMS
Keywords: Multiple sclerosis (MS) MS
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 87
Healthy volunteers: no

Brief summary:
This was a 3-year, prospective, multi-center, open-label study to describe the long term changes of optical coherence tomography (OCT) parameters in RRMS patients under treatment with Fingolimod. It was designed to longitudinally study the degeneration of retinal axons by measuring change in RNFL thickness by latest OCT-technology.

Detailed description:

Arms:
arm 1: No study drug was provided. Fingolimod was to be prescribed according to local label. The decision to prescribe fingolimod had to be made independent of this study.

Interventions: intervention 1: Fingolimod
Intervention descriptions: intervention 1: All subjects received an oral dose of 0.5 mg fingolimod (FTY720) per capsule (hard gelatin capsules) once daily according to local label for the treatment of their MS.

Protocol document:
Prot_001.pdf: 
Novartis Pharma 
Confidential 
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Clinical Study Protocol Version 4.0 incl. Amendment 4 
Protocol No. CFTY720DDE15TS 
Clinical Development 
FTY720 
Protocol No. CFTY720DDE15TS / NCT01705236 
A 3-year multi-center study to describe the long term 
changes of optical coherence tomography (OCT) 
parameters in patients under treatment with Gilenya® 
Author(s): 
 
Document type: 
Clinical Study Protocol 
EudraCT number : 
2012-000674-31 
Development phase: 
IV 
Version No. 
V4.0 (original protocol incl. Amendment 4) 
Release date: 
26-July-2016
Property of Novartis Pharma  
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 


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Protocol No. CFTY720DDE15TS 
 
Signature Pages 
Clinical Study Protocol CFTY720DDE15TS 
A 3-year multi-center study to describe the long term changes of optical 
coherence tomography (OCT) parameters in patients under treatment 
with Gilenya® 
 
EudraCT number: 2012-000674-31 
 
Approved by the following 
Signatures of Novartis Personnel: 
 
Dr. 
  
(Clinical Trial Leader) 
 
signature  
 
date 
 
Dr. 
  
(Trial Statistician) 
 
signature  
 
date 
 
Dr. 
    
 
 
 
signature  
 
date 
 


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Protocol No. CFTY720DDE15TS 
 
 
Signature of Coordinating Investigator: 
 
 Prof. Dr. 
 
(Coordinating Investigator) 
 
signature  
 
date 
 


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Protocol No. CFTY720DDE15TS 
 
Signature Page for Investigator 
 
Clinical Study Protocol CFTY720DDE15TS 
A 3-year multi-center study to describe the long term changes of optical 
coherence tomography (OCT) parameters in patients under treatment 
with Gilenya® 
 
EudraCT number: 2012-000674-31 
 
 
I have read this protocol and agree to conduct this trial in accordance with all 
stipulations of the protocol and in accordance with the principles outlined in the 
Declaration of Helsinki. 
 
 
 (Principal Investigator) 
 
signature  
 
date 
 


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Protocol No. CFTY720DDE15TS 
 
Table of contents 
 
Table of contents ................................................................................................................. 5 
List of figures ...................................................................................................................... 8 
List of tables ........................................................................................................................ 8 
List of abbreviations ............................................................................................................ 9 
Amendment 1 .................................................................................................................... 11 
Glossary of terms .............................................................................................................. 14 
1 
Background ....................................................................................................................... 15 
2 
Study purpose .................................................................................................................... 16 
3 
Objectives .......................................................................................................................... 17 
3.1 
Primary objective .................................................................................................. 17 
3.2 
Secondary objectives ............................................................................................. 17 
 
 17 
4 
Study design ...................................................................................................................... 17 
5 
Population.......................................................................................................................... 18 
5.1 
Inclusion/exclusion criteria ................................................................................... 18 
5.2 
Premature patient withdrawal ................................................................................ 20 
6 
Treatment .......................................................................................................................... 20 
6.1 
Patient numbering .................................................................................................. 20 
6.2 
Investigational treatment ....................................................................................... 21 
6.3 
Concomitant treatment .......................................................................................... 21 
6.4 
Prohibited treatment .............................................................................................. 21 
6.5 
Discontinuation of study treatment and premature patient withdrawal................. 21 
6.6 
Treating the patient ................................................................................................ 23 
6.6.1 
Permitted drug dose adjustments and interruptions .............................. 23 
6.6.2 
Rescue medication ................................................................................ 23 
6.6.3 
Recommendations on treatment of MS relapse .................................... 23 
6.6.4 
Study completion, post-study treatment and early study termination .. 24 
7 
Visit schedule and assessments ......................................................................................... 24 
7.1 
Patient demographics/other baseline characteristics ............................................. 25 
7.2 
Ophthalmologic examination ................................................................................ 26 
7.3 
Optical coherence tomography .............................................................................. 26 
7.4 
Treatment exposure and compliance ..................................................................... 26 
 
 26 
 
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7.6 
Safety ..................................................................................................................... 27 
7.6.1 
Physical examination ............................................................................ 27 
7.6.2 
Vital signs ............................................................................................. 28 
7.6.3 
Laboratory evaluation ........................................................................... 28 
7.6.4 
Pregnancy and assessments of fertility ................................................. 28 
7.7 
MS Relapse ............................................................................................................ 29 
7.8 
Pharmacokinetics ................................................................................................... 29 
7.9 
Pharmacogenetics/pharmacogenomics .................................................................. 29 
7.10 
Other biomarkers ................................................................................................... 29 
8 
Safety monitoring .............................................................................................................. 29 
8.1 
Adverse Events (AEs)/Serious Adverse Events (SAEs) ....................................... 29 
8.1.1 
Reporting of ambulatory ECG (Holter-ECG)-related adverse 
device events ......................................................................................... 30 
8.2 
Serious adverse event reporting ............................................................................ 31 
8.3 
Pregnancies ............................................................................................................ 32 
8.4 
Data Monitoring Board ......................................................................................... 32 
9 
Data review and database management ............................................................................ 32 
9.1 
Site monitoring ...................................................................................................... 32 
9.2 
Data collection ....................................................................................................... 33 
9.3 
Database management and quality control ............................................................ 33 
10 Data analysis ..................................................................................................................... 33 
10.1 
Populations for analysis ......................................................................................... 33 
10.2 
Patient demographics/other baseline characteristics ............................................. 34 
10.3 
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance) ........................................................................................................... 34 
10.4 
Analysis of the primary objective(s) ..................................................................... 34 
10.4.1 
Variable ................................................................................................. 34 
10.4.2 
Statistical hypothesis, model, and method of analysis .......................... 34 
10.4.3 
Handling of missing values/censoring/discontinuations ....................... 34 
10.4.4 
Supportive analyses .............................................................................. 34 
10.5 
Analysis of secondary 
 objectives ................................................ 35 
10.5.1 
Secondary 
 outcomes .................................................. 35 
10.5.2 
Tolerability ............................................................................................ 35 
10.5.3 
Resource utilization .............................................................................. 35 
 
 35 
10.5.5 
Pharmacokinetics .................................................................................. 35 
10.5.6 
Pharmacogenetics/pharmacogenomics ................................................. 35 
10.5.7 
Biomarkers ............................................................................................ 35 
10.5.8 
PK/PD ................................................................................................... 35 
10.6 
Interim analysis ..................................................................................................... 35 
10.7 
Sample size calculation ......................................................................................... 36 


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10.8 
Power for analysis of critical secondary variables ................................................ 36 
11 Discussion and rationale for study design features ........................................................... 36 
12 References (available upon request) ................................................................................. 37 
Appendix 1:  Administrative procedures .......................................................................... 39 
Appendix 2:  Blood Collection Log .................................................................................. 40 
Appendix 3:  Clinically notable vital signs ....................................................................... 41 
Appendix 4:  2010 Revisions to the McDonald diagnosis criteria for MS ....................... 44 
Appendix 5:  New York Heart Association Functional Classification ............................. 46 
Appendix 6:  EDSS Assessment Criteria .......................................................................... 47 
Appendix 7: Guidance on safety monitoring .................................................................... 49 
 
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List of figures 
Figure 4-1:  Study outline ......................................................................................................... 18 
 
List of tables 
Table 7-1:  Assessment schedule ............................................................................................. 25 


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List of abbreviations 
AE 
adverse event 
ACTH 
adrenocorticotropic hormone 
ALT 
alanine aminotransferase/glutamic pyruvic transaminase/GPT 
AST 
aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
AV 
atrioventricular 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
BP 
blood pressure 
CRC 
Central Reading Center 
CRF 
Case Report/Record Form 
CSF 
cerebrospinal fluid 
CNS 
central nervous system 
CRO 
Contract Research Organization 
DMD 
disease modifying drugs 
DS&E 
Drug Safety and Epidemiology 
EAE 
experimental autoimmune encephalomyelitis 
ECG 
Electrocardiogram 
EDC 
electronic data capture 
EDSS 
expanded disability status scale 
FA 
fluorescein angiography 
FDA 
First dose administration 
GCLT 
ganglion cell layer thickness 
GGT 
gamma-glutamyl-transferase 
HCG 
human chorionic gonadotropin 
IB 
investigator’s brochure 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IFN 
interferon 
IRB 
Institutional Review Board 
i.m. 
intramuscular(ly) 
IUD 
intrauterine device 
i.v. 
intravenous(ly) 
LN 
lymph node 
MRI 
magnetic resonance imaging 


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MS 
multiple sclerosis 
 
 
o.d. 
omnia die/once a day 
OCT 
optic coherence tomography 
ON 
optic neuritis 
 
 
 
 
PML 
progressive multifocal leukoencephalopathy 
PCR 
polymerase chain reaction 
p.o. 
per os/by mouth/orally 
PPMS 
primary progressive multiple sclerosis 
 
 
 
 
RBC 
red blood cell 
REB 
Research Ethics Board 
RMP 
risk management plan 
RNFL(T) 
retinal nerve fiber layer (thickness) 
RRMS 
relapsing remitting multiple sclerosis 
SAE 
serious adverse event 
s.c. 
subcutaneously  
 
 
SmPC 
Summary of Product Characteristics 
SPMS 
secondary progressive multiple sclerosis 
TMV 
total macular volume 
ULN 
upper limit of normal range 
VEP 
visual evoked potential 
WBC 
white blood cell count 
WHO 
World Health Organization 


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Amendment 1 
Amendment Rationale 
The protocol is being amended to implement an update to the Gilenya® (fingolimod) label in 
the EU approved by the Committee for Medicinal Products for Human Use (CHMP), as well 
as in Switzerland as approved by Swissmedic. 
The updates to the label provide refined guidance on when existing first dose monitoring 
procedures should be repeated.  
The updates were submitted to both Health Authorities as a Type II Variation by Novartis. 
These recommendations are already included in the US Prescribing Information (PI) and are 
not related to any new safety reports.  
In agreement with the FDA, both EMA and Swissmedic confirmed the positive benefit-risk 
profile for Gilenya when used in accordance with updated labels, which were announced 
earlier this year.  
Novartis informed healthcare professionals in the European Union of these recommendations 
via a Direct Healthcare Professional Communication (DHPC) by January 11, 2013, in 
Switzerland Physicians were informed via a DHPC Letter on January 22nd 2013. 
Changes to the protocol 
 
In patients who are re-initiated after a certain treatment interruption a repetition of 
first-dose-monitoring strategy is necessary.  
 In patients who require pharmacological intervention during the first dose monitoring 
and are monitored overnight in a medical facility the first dose monitoring should be 
repeated after the second dose of fingolimod (For EU only; already implemented in 
Swiss label).  
Additional changes to the protocol 
 One center in Switzerland is added 
 Section 7.6.4 “Pregnancy and assessments of fertility” is updated 
 
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.  
The protocol synopsis has been updated accordingly. In addition, as the changes herein affect 
the Informed Consent, a revised Informed Consent will also be submitted for approval to 
IRB/IEC. 
 
Amendment 2 
Amendment Rationale 
The protocol is being amended to further define blood biomarker sampling and to define the 
period of one month as 28 days. Furthermore, the specifications for contraception and for 
elevated liver function tests are adjusted and some inconsistencies within the protocol are 
corrected. 


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Changes to the protocol 
 Section 3.3, 7.5.5, and 10.5.7: wording has been adjusted to further define blood 
biomarker sampling. A subset of 50 patients was determined. 
 Section 5.1, 6.5 and 7: One month was defined as 28 days and visit 2 is defined as 
inclusion date (section 5.1) 
 Section 6.5 and Appendix 7: wording has been adjusted corresponding to the wording 
of the SmPC; study drug has to be discontinued if liver function tests are repeatedly 
>5x ULN. 
 Section 7.6.3 and Appendix 3: some corrections were made to adjust inconsistencies 
within the protocol and to further define laboratory evaluations. 
 Section 7.6.4: wording has been adjusted to permit also secondary and other forms of 
contraception (Pearl index <1). 
 
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, a revised Informed Consent 
will also be submitted for approval to IRB/IEC. 
 
 
Amendment 3 
Amendment Rationale 
The protocol is being amended to remove blood biomarker sampling from the protocol. 
Changes to the protocol 
 Section 1, 3.3, 7, 7.5.5, 10.5.7, 11, and Appendix 2: Blood biomarker sampling was 
completely removed and wording has been adjusted. 
 Section 9.3: The responsible person for the OCT Quality Control, Dr. 
 
has been added 
 
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, a revised Informed Consent 
will also be submitted for approval to IRB/IEC. 


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Amendment 4 
Amendment Rationale 
The protocol is being amended to clarify the minimum pre-treatment with fingolimod as 28 
days and to adapt the visit schedule to the recommended visit schedule in the fingolimod 
product information. The fingolimod product information recommends visits every 3 months 
of treatment. Therefore a month during the observational period of the study is defined as 28-
31 days depending on the actual length of the respective month. The definition of one month 
as 28 days is removed.     
Changes to the protocol 
 Section 5.1 and table 7-1 are changed according to the amendment rationale.    
 
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. 
 
All changes in the protocol are classified as non-substantial. Therefore an Institutional Review 
Board (IRBs)/Independent Ethics Committee (IECs) approval prior to implementation is not 
necessary. 
 


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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) 
Patient number 
A number assigned to each patient who enrolls in the study; when 
combined with the center number, a unique identifier for each 
patient in the study is created. 
Phase 
A major subdivision of the study timeline; begins and ends with 
major study milestones such as enrollment, randomization, 
completion of treatment, etc. 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the 
planned completion of all study assessments; at this time no further 
assessments are planned 
Stop study participation 
Point/time at which patient came in for a final evaluation  
Variable 
Information used in the data analysis; derived directly or indirectly 
from data collected using specified assessments at specified 
timepoints 


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1 
Background 
Multiple Sclerosis (MS) is a chronic, demyelinating, immune-mediated disease of the central 
nervous system affecting about 2.3 times as many women as men (Alonso & Hernan, 2008). 
With regard to disease pathogenesis, MS is characterized by inflammation and destruction of 
myelin and axons (Trapp et al., 1998, Sospedra & Martin, 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 (about 85% of patients at diagnosis). Approximately 50% of these patients progress to 
secondary progressive MS (SPMS) within 10 years, 90% within 25 years. In these SPMS 
patients a less inflammatory and more neurodegenerative course of disease appears to take 
precedence. 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 & Noseworthy, 2002). 
 
The driving force of disability in MS is axonal loss. In MS, axonal loss seems to be associated 
with thinning of the retinal nerve fiber layer (RNFL). The RNFL contains ganglion cell 
axons that give rise to the optic nerve. Myelination of these fibers begins behind the eye, at 
the level of the lamina cribrosa (Frohman et al. 2008). The RNFL represents a unique region 
of the central nervous system because it lacks myelin and thus, allows for direct imaging of 
axons. It has therefore emerged as a highly interesting potential marker for the evaluation of 
axonal loss in MS. The thickness of the RNFL itself and the amount of change that may 
occur, however, are both very small (few microns) making a reliable assessment of RNFL 
thickness change challenging. Currently, optical coherence tomography (OCT) is the most 
accurate method to measure RNFL thickness. 
 
Optical coherence tomography (OCT) is a validated, sensitive, non-invasive technique that 
uses low-coherence interferometry to obtain cross-sectional images of the retina. 
Commercially available OCT machines show good reproducibility of the measurement of 
RNFL thickness (Serbecic et al, 2010; Syc et al, 2010; Wu et al, 2010). With the latest 
technical improvements such as higher resolution and dual laser beam to overcome eye 
movements these instruments may have a high clinical utility in predicting MS disease course 
and determining treatment response.   
In MS, visible RNFL thinning by OCT may be seen when inflammation causes degeneration 
of axons within the optic nerve, e.g. as a result of optic neuritis (ON), a common 
manifestation in MS. However, RNFL thickness is reduced even in the absence of acute ON, 
making RNFL atrophy a potential structural biomarker of axonal injury or loss in the afferent 
visual pathway (Frohman et al, 2008; Barkhof et al,2009; Talman et al, 2010). Cross-sectional 
studies in patients with MS have shown that RNFL thickness by OCT correlates with 
clinically relevant measures of disability like brain atrophy (Petzold et al, 2010) and cognitive 
decline (Toledo et al, 2008). Limited available longitudinal OCT data indicate that 
progressive RNFL thinning occurs over time in the eyes of MS patients and that this may 
correlate with change in clinically relevant parameters (Costello et al, 2009; Talman et al, 
2010). A recent study in 299 MS patients with a mean follow-up of 18 months showed that 
progressive RNFL thinning observed over time (in eyes with and without prior history of ON) 
was associated with significant visual loss (Talman et al, 2010). Further studies are needed to 
evaluate if changes in RNFL are correlated also with global measures of disability in more 
detail (e.g. EDSS, patient reported outcomes, etc.).  
  


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To address this and to describe the change in RNFL thickness over time a global study is 
planned that includes RRMS patients (either untreated or treated with any approved MS 
disease modifying therapy) and a group of reference subjects (without neurologic or 
ophthalmic disease). Since the global study is not powered to particularly detect changes 
under fingolimod treatment – fingolimod is not even approved in all participating countries – 
the present study focuses on this subpopulation.  
 
Fingolimod (FTY720; Gilenya®) is an oral, once daily disease modifying drug which has been 
approved for the treatment of relapsing MS in the US (on 21-Sep-2010), Europe (on 17-03-
2011) and other countries.  
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 to egress from peripheral lymphoid 
organs. FTY720-P 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. 
 
 
Fingolimod has shown clinical efficacy in several stages of MS. There is indirect evidence of 
neuroprotection by this compound due to its unique mode of action. This study should 
elucidate what changes in RNFLT (retinal nerve fiber layer thickness) occur using late-stage 
spectral domain OCT during oral treatment with fingolimod. In parallel, investigations will 
include the safety of fingolimod and other OCT parameters like changes in total macular 
volume or papillomacular bundles.  
 
In summary, the present study will provide important longitudinal data towards the 
development of the RNFL under fingolimod treatment as assessed by OCT as an outcome 
measure in MS over a period of 36 months.  
2 
Study purpose 
This is a 3-year, prospective, multi-center, open-label study to describe the long term changes 
of optical coherence tomography (OCT) parameters in RRMS patients under treatment with 
Fingolimod. It is designed to longitudinally study the degeneration of retinal axons by 
measuring change in RNFL thickness by latest OCT-technology. Correlations of OCT 
findings with available MRI data and clinical findings may enhance our understanding of the 
relationship between CNS inflammation, tissue injury, regeneration and neurological deficit 
in the context of fingolimod therapy. 


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3 
Objectives 
3.1 
Primary objective 
To evaluate the change in average RNFL thickness (RNFLT) in RRMS patients treated with 
fingolimod over 36 months as assessed by OCT  
3.2 
Secondary objectives 
To evaluate the change in average RNFLT under fingolimod therapy from baseline to months 
12 and 24 as assessed by OCT  
To evaluate change in quadrant RNFLT under fingolimod therapy from baseline to months 
12, 24 and 36 
To evaluate changes in total macular volume (TMV) under fingolimod therapy from baseline 
to months 12, 24 and 36 
To evaluate changes in ganglion cell layer thickness (GCLT) under fingolimod therapy from 
baseline to months 12, 24 and 36 
To compare changes in OCT parameters between eyes with and without history of optic 
neuritis and between right and left eye 
To evaluate safety and tolerability of fingolimod in MS patients followed for up to 36 months 
and specifically to determine the frequency of macular edema under treatment with oral 
fingolimod in this patient population 
 
 
4 
Study design 
This is a multi-center, open-label study in RRMS patients treated with fingolimod. After 
signing the informed consent, patients will enter a Screening Phase (day -28 to day 0) before 
starting the study at Baseline (day 0), followed by a 36-month longitudinal data collection 
phase (see Figure 4-1). Eligibility will be determined at Screening. OCT and other 
assessments will be performed according to the schedule in Table 7-1.    
 
 


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Figure 4-1 
Study outline 
 
5 
Population 
In this study approximately 100 patients with MS are expected to be enrolled in Germany and 
Switzerland.  
The investigator must ensure that all patients who meet the following inclusion and do not 
fulfill any of the exclusion criteria are offered enrollment in the study. No additional 
exclusion parameters can be applied by the investigator, in order that the study population will 
be representative of all eligible patients. 
Patients who drop out after baseline during the longitudinal phase will not be replaced.  
 
The study is planned to be conducted at approximately 10 sites in Germany and 
approximately 1 site in Switzerland.  
5.1 
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. Male or female subjects aged 18-65 years. 
3. Subjects with relapsing remitting MS defined by 2010 revised McDonald criteria (see 
Appendix 4). 
4. Patients with Expanded Disability Status Scale (EDSS) score of 0-6.0 inclusive (see 
Appendix 6). 
5. Patients stable on immunomodulatory treatment with fingolimod for at least 28 days 
and at most 4 months prior to screening according to local label 
6. Neurologically stable with no evidence of relapse within 30 days prior to inclusion 
date (visit 2) 
7. Sufficient ability to read, write, communicate and understand   
 
Exclusion Criteria 
Patients fulfilling any of the following criteria are not eligible for inclusion in this study: 
 
1. Patients who have been treated with: 
Longitudinal phase (36 months) 
n = 100 MS patients 
-28d 
0 
Baseline 
(visit 2) 
Month 3 
(visit 3) 
Month 6 
(visit 4) 
Month 12  
(visit 5) 
Month 36 
(end of trial, visit 7) 
3 
6 
12 
24 
36 
Month 24  
(visit 6) 
Screening 
(visit 1) 


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• systemic corticosteroids or immunoglobulins within 1 month prior to screening; 
• immunosuppressive medications such as azathioprine, cyclophosphamide, or  
methotrexate within 3 months prior to screening; 
• monoclonal antibodies (including natalizumab) within 3 months prior to screening; 
• mitoxantrone within 6 months prior to screening 
• cladribine at any time. 
2. Patients with any medically unstable condition, as assessed by the primary treating 
physician at each site. 
3. Patients with any of the following cardiovascular conditions : 
• history of myocardial infarction or with current unstable ischemic heart disease; 
 • Heart failure (NYHA III-IV) or any severe cardiac disease as determined by the 
Investigator (see Appendix 5); 
• history or presence of a second-degree AV block, Type II or a third-degree AV 
block 
• patients receiving Class Ia (ajmaline, disopyramide, procainamide, quinidine) or 
III antiarrhythmic drugs (e.g., amiodarone, bretylium, sotalol, ibulitide, azimilide, 
dofelitide); 
• proven history of sick sinus syndrome; 
• uncontrolled hypertension 
4. Patients with severe respiratory disease, pulmonary fibrosis, or chronic obstructive 
pulmonary disease (Class III-IV). 
5. Patients with history of specific MRI findings (tumor, subdural haematoma, post-
contusional 
changes, 
territorial 
stroke, 
neurodegenerative 
disorders, 
aneurysm/arteriovenous malformation, evidence of past macroscopic haemorrhage, or 
other relevant MRI findings that would interfere with evaluation) 
6. Any severe disability or clinical impairment that can prevent the patient to meet all 
study requirements at the investigator`s discretion 
7. History of malignancy of any organ system, treated or untreated, within the past 5 
years whether or not there is evidence of local recurrence or metastases, with the 
exception of localized basal cell carcinoma of the skin 
8. Patients who have received an investigational drug (excluding fingolimod) or therapy 
within 90 days or 5 half-lives of screening, whichever is longer. 
9. 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 test (serum) 
10. Patients with any ophthalmologic reason for RNFL pathology other than MS, such as: 
optic neuropathy, active advanced glaucoma, injury of the optic nerve based on the 
ophthalmologist’s clinical judgment 
11. history or presence of severe myopia 


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a. in patients who have not had refractive surgery, a refractive error of greater than 
6.00 diopters 
b. pathologic fundus changes of high myopia, such as retinal pigmentary atrophy, 
besides peripapillary atrophy (atrophy involving the macula) or a staphyloma 
c. in patients that have had previous refractive surgery, an axial eye length of greater 
than 26 mm 
12. Acute optic neuritis within the past 6 months before screening 
13. Evidence of advanced, non-proliferative or proliferative diabetic retinopathy 
14. Presence of retinal conditions associated with edema, subretinal fluid, cysts, etc. 
15. Concomitant use of drugs that may directly affect retinal structure and function (e.g. 
chronic systemic corticosteroids [>30 consecutive days; doses higher than Cushing 
threshold e.g. prednisone 7.5mg/d], intraocular anti-angiogenic drugs [ranibizumab, 
bevacizumab], intraocular steroids etc.) 
 
 
5.2 
Premature patient withdrawal 
Patients must be withdrawn from the study for any of the following reasons: 
 
Withdrawal of informed consent 
 
Investigator’s decision (withdrawn in the best interest of the patient for any reason) 
 
Use of prohibited medication (see section 6.4 Prohibited Treatment) 
 
Patients should be withdrawn at any time if the investigator concludes that it would be in the 
patient’s best interest for any reason. Protocol violations should not lead to patient withdrawal 
unless they indicate a significant risk to the patient’s safety. 
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, or fail to return for visits, or 
become lost to follow up for any other reason.  
If premature withdrawal occurs for any reason, the investigator must determine the primary 
reason for a patient’s premature withdrawal from the study and record this information on the 
Study Completion CRF. 
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. 
Patients who are prematurely withdrawn from the study will not be replaced by newly 
enrolled patients. 
6 
Treatment 
6.1 
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). Once assigned to a patient, a patient number 
will not be reused. If the patient fails to be enrolled for any reason, the reason for not being 
enrolled will be entered in the CRF and demography should also be completed.  
6.2 
Investigational treatment 
 
MS medication: Fingolimod (FTY720) 0.5 mg per capsule (hard gelatin capsules) is used to 
be taken p.o. once daily. Fingolimod will be prescribed according to local label. The decision 
to prescribe Fingolimod will be made independent of this study. 
6.3 
Concomitant treatment 
All concomitant medications taken within 30 days prior to Screening (Visit 1) and during the 
study must be recorded on the appropriate CRFs. The investigator should instruct the MS 
patients to notify the study site about any new medications he/she takes after the start of the 
study. 
 
6.4 
Prohibited treatment 
Patients who have met exclusion criteria for exclusionary medications will not be allowed to 
join the study. Concomitant use of drugs that may directly affect retinal structure and function 
(e.g. chronic [>30 consecutive days; doses higher than Cushing threshold e.g. prednisone 7.5 
mg/day] 
systemic 
corticosteroids, 
intraocular 
anti-angiogenic 
drugs 
[ranibizumab, 
bevacizumab] etc.) is not allowed during the study and these participants will have to be 
withdrawn from the study. 
Once the patient has entered the study at Visit 1 and while the patient is on fingolimod 
therapy, use of the following treatments are NOT allowed concomitantly: 
 Immunosuppressive medication (e.g. cyclosporine, azathioprine, methotrexate, 
cyclophosphamide, mitoxantrone, cladribine); 
 Other concomitant medications: immunoglobulins, monoclonal antibodies (including 
natalizumab), IFN- ß, glatiramer acetate, adrenocorticotropic hormone (ACTH) 
 
The administration of any live or live attenuated vaccines (including for measles) is prohibited 
while patients are receiving fingolimod and for 12 weeks after fingolimod discontinuation. 
They may be administered thereafter, once there is confirmation that lymphocyte counts are in 
the laboratory normal range.  
 
6.5 
Discontinuation of study treatment and premature patient 
withdrawal 
 
Study drug must be discontinued for a given patient if the investigator determines that 
continuing it would result in a significant safety risk for that patient. The following 
circumstances require study drug discontinuation: 
 Intolerability of study medication (fingolimod) 


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 The occurrence of an adverse event or clinically significant abnormality that, in the 
judgment of the investigator, warrants discontinuation of treatment 
 Use of prohibited medications, listed in section 6.4  
 
In addition, the following conditions based on safety monitoring guidelines (See Appendix 7) 
should result in fingolimod interruption or discontinuation: 
 Ophthalmic: 
 
- Diagnosis of macular edema 
 
- Decrease in visual acuity or cystic changes in the macula 
 Hepatic: 
 
Repeated confirmation of an increase in ALT > 5 x ULN 
 
Repeated confirmation of an increase in AST > 5 x ULN 
 Blood lymphocyte count less than 100/mm3 
 New neurological symptoms accompanied by MRI findings (according to local 
practice) unexpected for MS 
In case of a decrease of visual acuity an immediate ophthalmologic assessment is required. 
After exclusion of a macula edema or cystic changes in the macula treatment can be 
continued. 
Permanent study drug discontinuation is required upon diagnosis of cancerous skin disorders 
or pregnancy.  
 
Furthermore, all criteria listed under 5.2 for premature patient withdrawal will automatically 
lead to study drug discontinuation. 
In addition to these requirements for study drug discontinuation, the investigator should 
discontinue study drug for a given patient if, on balance, he thinks that continuation would be 
detrimental to the patient’s well-being. 
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 CRF. 
For re-initiation after treatment interruption the same first dose monitoring as for treatment 
initiation should be repeated if treatment is interrupted for: 
 
One day or more during the first 2 weeks of treatment  
 
More than 7 days during weeks 3 and 4 of treatment 
 
More than 2 weeks after 4 weeks of treatment 
If the treatment interruption is of shorter duration than the above, the treatment should be 
continued with the next dose as planned. It is recommended not to initiate or change dosages 
of digoxin, beta-blockers and calcium-channel blockers treatment due to a possible additive 
effect on heart rate reduction. In case these are already initiated advice from a cardiologist is 
necessary according to local label. If study medication is restarted as per protocol, a reason for 
the interruption of treatment and time of interruption should be appropriately documented in 
the source documents as well as in the CRF.  
 


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The following examinations regarding cardiac response observation have to be performed at 
re-start of study drug: 
- 
12-lead ECG prior to and after 6 hours of first administration 
- 
Continuous 6-hour ECG is recommended 
- 
measurement of blood pressure and heart rate (every hour) 
 
In case of clinically significant abnormalities during or at the end of the 6 hours observation 
(criteria defined in the local label), cardiac monitoring will be prolonged and surveillance 
measures implemented as recommended in the label (see also Appendix 7). If study 
medication is restarted, the reason for the interruption of treatment and time of interruption 
should be appropriately documented in the source documents as well as in the CRF.  
 
6.6 
Treating the patient 
6.6.1 
Permitted drug dose adjustments and interruptions 
Fingolimod dose adjustments are not permitted, although interruptions may be warranted 
according to label.  
 
6.6.2 
Rescue medication 
Not applicable. 
6.6.3 
Recommendations on treatment of MS relapse 
Following an onset of MS relapse the patient may have unscheduled visits in the 
investigator’s discretion. Handling of MS relapses will be performed according to local 
practice and standard of care procedures. 
A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis 
is allowed for treatment of relapses as clinically warranted and should be recorded in the 
CRF.  
Steroid treatment should consist of 3-5 days and up to 1,000 mg methylprednisolone/day. 
Standard of care procedures will be followed during treatment. 
Use of any oral tapering is not permitted. 
The use of steroid for MS relapses therapy should be recorded on the “Prior-/concomitant 
medications” CRF. 
Investigators should consider the added immunosuppressive effects of corticosteroid therapy 
and increase vigilance regarding infections during such treatment and in the weeks following 
administration.  
Should a patient show evidence or suspicion of infection, please refer to actual Summary of 
product Characteristics.  
In the event that steroids are administered patients should be reminded of the importance of 
reporting any signs or symptoms of an infection. Special consideration should be given to 
symptoms or signs of herpes simplex or zoster reactivation (e.g. lancinating pain, skin lesions) 
and appropriate antiviral therapy (e.g. acyclovir, valacyclovir) should be promptly initiated 


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and continued for up to 30 days after stopping high dose steroid treatment. An infectious 
disease specialist may be consulted to guide such therapy if needed.  
Should a patient develop any neurological symptoms or signs, unexpected for MS in the 
opinion of the investigator or accelerated neurological deterioration, the investigator should 
immediately schedule an MRI according to local practice.  
In case of acute optic neuritis or MS relapse the OCT assessment should be postponed for at 
least 30 days (at the discretion of the investigator) and the circumstance must be recorded in 
the corresponding CRF. 
6.6.4 
Study completion, post-study treatment and early study termination 
The study will be considered completed for an individual patient when he/she completes visit 
7. 
After premature withdrawal Visit 7 should be scheduled as soon as possible. 
The study can be terminated for reasons stipulated in the study contract. Should this be 
necessary, the patients should be contacted and scheduled for their end of study assessments 
as described in Section 7. Novartis will be responsible for informing IRBs and/or IECs of the 
early termination of the study.  
7 
Visit schedule and assessments 
Table 7-1 lists all of the assessments and indicates with an “X” the visits when they are 
performed and recorded in the clinical database. 
Patients who prematurely withdraw from the study for any reason, should be scheduled for a 
final visit, at which time all of the assessments listed for the final visit will be performed.   
Patients should be seen for all visits on the designated day with an allowed visit window of 
+/- 14 days for visits 3 to 7. 
In addition to the scheduled visits, patients may have unscheduled visits following an 
infection, relapse or for other reasons as indicated in the protocol. All information should be 
collected.  


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Table 7-1 
Assessment schedule 
 
Visit number 
1 
2 
3 
4 
5 
6 
7 
Time of Visit 
Screening 
(d-28 to 
d0) 
Baseline 
 
month  
3 
month  
6 
month 
12 
month 
24 
month 
36 
Information & Informed 
consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Background/ Demography 
X 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
X 
Medical History incl. MS 
history 
X 
 
 
 
 
 
 
Ophthalmologic 
examination1 
X 
 
 
 
 
 
 
Previous MS treatment 
X 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
 
X 
X 
X 
X 
X 
Blood chemistry 
X 
 
X 
X 
X 
X 
X 
SAE/ AEs 
X 
X 
X 
X 
X 
X 
X 
Concomitant treatment 
X 
X 
X 
X 
X 
X 
X 
OCT2 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
1 exclusion of severe myopia, advanced, non-proliferative or proliferative diabetic retinopathy, and retinal conditions associated 
with edema, subretinal fluid, cysts, etc. Results have to be available at baseline  
2 after occurrence of acute optic neuritis or MS relapse OCT should be postponed for 30 days  
 
To allow enough time for ophthalmologic examination by an ophthalmologist a screening 
phase of 28 days is scheduled.  
 
7.1 
Patient demographics/other baseline characteristics 
Patient demographic and baseline characteristic data to be collected for all patients include: 
date of birth, age, sex, ethnicity, pre-treatments and source of patient referral. Relevant 
medical history/current medical condition data includes data until the start of trial. Where 
possible, diagnoses and not symptoms will be recorded.  
Previous MS history (including history of relapses) needs to be 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 will be collected in the study including: date of MS 
diagnosis, date of first MS symptoms, eye history (e.g. optic neuritis, uveitis), MS relapse 
history (past 12 months) and history of medications used to treat MS (past 12 months). These 
data will be collected and recorded in the medical History, Ophthalmology Screening and 
prior-/concomitant medication CRFs. 


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Medications used to treat MS may include glatiramer acetate (Copaxone®), interferon β-1a 
i.m. (Avonex®), interferon β-1a s.c. (Rebif®), interferon β-1b (Betaseron®/Betaferon®), 
natalizumab (Tysabri®), azathioprine, methotrexate or any other medications used as MS-
disease-modifying agents. Patients are not allowed to take these medications during the study. 
Other medications to treat MS-related symptoms should be recorded in the Concomitant 
Medication CRF. MS history should be supplemented by review of the patient’s medical chart 
and/or by documented dialog with the patient’s referring physician.  
7.2 
Ophthalmologic examination 
A complete ophthalmologic examination will be performed by an ophthalmologist as 
described in Table 7-1. The exam will include previous eye history and any new ophthalmic 
symptoms, best corrected visual acuity, dilated ophthalmoscopy and optical coherence 
tomography (OCT) for the measurement of central foveal thickness. Substitution of OCT with 
fluorescein angiography will not be permitted. Details on the ophthalmologic examinations 
are provided in the Guidance for Ophthalmic Monitoring Appendix 7. 
 
 
An ophthalmological examination is regularly recommended 3-4 months after commencing 
fingolimod therapy (according to local label). If patients report visual disturbances at any time 
while on therapy, evaluation of the fundus, including the macula, should be carried out. 
7.3 
Optical coherence tomography 
Optical Coherence Tomography (OCT) will be assessed for both eyes at Baseline (Visit 2), 
Visit 3, 4, 5, 6, and 7. Anxiety/Stress, Comfort and Satisfaction - Level (Appendix 8) will be 
recorded after the first scan. These assessments will be performed by trained personnel at each 
site. All OCT Scans will be analyzed and quality controlled by a Central Reading Center 
(CRC), see section 9.3. The patients identity will be masked for all information forwarded to 
the CRC during the study. A copy of the OCT images will be retained with the source 
documents at each investigative site.  
7.4 
Treatment exposure and compliance 
In order to collect information about the medications taken, the following records should be 
maintained for each patient participating in this study: records of medication prescribed, 
interruptions in fingolimod intake and intervals between visits.  
Compliance will be assessed by the investigator and/or study personnel at each visit using 
information provided by the patient.  


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7.6 
Safety 
 Physical/neurological examination 
 Vital signs 
 Laboratory evaluation 
7.6.1 
Physical examination 
A complete physical examination will be performed at visits as described in Table 7-1 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. All significant findings that are present prior to start of the 
trial must be reported on the Relevant Medical History/Current Medical Conditions CRF. 
Significant findings made after the start of study which meet the definition of an AE must be 
recorded on the Adverse Event CRF. 


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7.6.2 
Vital signs 
Vital signs will be recorded as described in Table 7-1. Vital signs will include sitting pulse 
rate, sitting systolic and diastolic blood pressure (3 measurements), oral temperature (degrees 
Celsius), body height (cm) and body weight (kg). Height and body weight will only be 
collected at Visit 2; see Appendix 3. 
7.6.3 
Laboratory evaluation 
Routine blood samples (10 ml at each visit; also at unscheduled visits in case of an infection) 
will be collected at the visits described in Table 7-1 and analyzed by a local laboratory.  
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 should not be recorded on the adverse event CRF; 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 CRF.  
Hematology 
Hematology parameters will be collected at the visits described in Table 7-1 and Appendix 2 
and will include: RBC count, total WBC, differential blood count (lymphocytes), platelet 
count, hemoglobin, and hematocrit.  
Chemistry 
Blood samples will be collected at the visits described in Table 7-1 and Appendix 2. 
Measurements will include the following parameters: sodium, potassium, chloride, calcium, 
blood urea nitrogen (BUN), random glucose, alkaline phosphatase, creatinine, Bilirubin, ALT, 
AST, and GGT.  
Notable abnormalities are defined in the Criteria for clinically notable laboratory values and 
vital signs further specified in Appendix 3.  
Abnormal laboratory parameters, inconsistent with clinical presentation of MS or suspicious 
of underlying medical condition, should be repeated for accuracy. 
7.6.4 
Pregnancy and assessments of fertility 
Serum pregnancy test will be performed for all women prior to inclusion. Additional 
pregnancy testing may be performed at the investigator’s discretion during the trial. Patients 
becoming pregnant must discontinue the study. 
Women of child bearing potential must use one of the below listed medically approved 
methods of contraception (Pearl Index <1): 
Primary forms: 
 hormonal contraception (combination oral contraceptives, hormonal transdermal 
patch, combined injected hormones, injected single hormone, implanted hormones, or 
hormonal vaginal ring) 
 tubal sterilization 
 partner's vasectomy 
 intrauterine device (synthetic progestin containing IUDs, IUD copper T380) 
Secondary forms: Barrier forms (always used with spermicide) 
 latex condom 
 diaphragm 


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 cervical cap 
Others: 
 vaginal sponge (contains spermicide) 
 
Oral contraceptives without estrogen (e.g. "mini-pills"), nonsynthetic pregesterone only IUDs, 
female condoms, cervical shield, periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of 
contraception. Reliable contraception should be maintained throughout the study and for 8 
weeks after study drug discontinuation. 
At the discretion of the investigator, total abstinence from sexual intercourse is acceptable in 
cases where the age, career, lifestyle, or sexual orientation of the patient ensures the 
prevention of pregnancy. 
7.7 
MS Relapse 
A patient should report symptoms indicative of an MS relapse at a scheduled visit or any 
other time. 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. Following an onset of MS relapse the patient may have unscheduled visits at the 
discretion of the investigator. Handling of MS relapses will be performed according to local 
practice and standard of care procedures. Details of MS relapse handling will be recorded in 
the corresponding CRF. 
 
7.8 
Pharmacokinetics 
Not applicable. 
 
7.9 
Pharmacogenetics/pharmacogenomics 
Not applicable. 
7.10 
Other biomarkers 
Not applicable. 
8 
Safety monitoring 
8.1 
Adverse Events (AEs)/Serious Adverse Events (SAEs) 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after first drug intake even if the event is not considered to be 
related to drug therapy. Medical conditions/diseases present before obtaining informed 
consent are only considered adverse events if they worsen after starting trial. Abnormal 
laboratory values or test results constitute adverse events only if they induce clinical signs or 
symptoms, are considered clinically significant, require medication discontinuation or require 
therapy. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the trial. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or 


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other assessments. All adverse events must be recorded on the Adverse Events CRF with the 
following information: 
1. its relationship to Fingolimod (suspected/not suspected) 
2. its duration (start and end dates or if continuing at final exam) 
3. whether it constitutes a serious adverse event (SAE) 
An SAE is defined as an event which: 
 is fatal or life-threatening  
 results in persistent or significant disability/incapacity 
 constitutes a congenital anomaly/birth defect 
 requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (e.g. hospitalization for relapse treatment) 
 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 8.2. 
Information about adverse reactions observed in relation to fingolimod can be found in the 
local product labeling. 
All adverse events should be treated appropriately. Treatment may include one or more of the 
following: no action taken (i.e., further observation only); medication temporarily interrupted; 
medication permanently discontinued due to this adverse event; concomitant medication 
given; non-drug therapy given; patient hospitalized/patient’s hospitalization prolonged. The 
action taken to treat the adverse event should be recorded on the Adverse Event CRF.  
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 medication, 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’s Brochure (IB) or will be communicated between IB updates in the form of 
SUSAR reports for the investigator and if applicable in the form of Investigator Notifications. 
This information will be included in the patient informed consent and should be discussed 
with the patient during the study as needed. 
8.1.1 
Reporting of ambulatory ECG (Holter-ECG)-related adverse device 
events   
An adverse device event is any malfunction or deterioration in the characteristics and/or 
performance of a device, as well as any inadequacy in the labeling or the instructions for use 
which, directly or indirectly, might lead to or might have led to the death of a patient/subject, 
or user or of other persons or to a serious deterioration in their state of health. 


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For the purposes of compliance with the Medical Device Directive (MDD), adverse device 
events must be documented on the Adverse Device Event Report Form and submitted to the 
manufacturer of the ambulatory ECG (Holter-ECG) equipment used via fax or email within 
24 hours of learning of the event. The contact details for reporting of ambulatory ECG 
(Holter-ECG)-related adverse device events are provided in the investigator folder provided to 
each site. The original copy of the Adverse Device Event Report Form and the confirmation 
of the submission must be kept in the study participant's file at the site.  
Should an adverse event or Serious Adverse Event be connected to a device-related 
complication, the complication has to be documented and reported 1. to Novartis as AE /SAE 
via AE record and/or SAE report as well as 2. to the ECG manufacturer using the Adverse 
Device Event Report Form. 
 
8.2 
Serious adverse event reporting 
To ensure patient safety, every SAE, regardless of suspected causality to a pharmaceutical 
product or procedure occurring in a study participant after the patient has provided informed 
consent and until 8 weeks after the patient has stopped study participation (defined as time 
last visit) must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after this 8-week period should only be reported to Novartis if the 
investigator suspects a causal relationship to fingolimod. 
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 to fingolimod, complete the SAE Report 
Form in English, and send the completed, signed form by fax within 24 hours to the local 
Novartis Drug Safety & Epidemiology Department. The telephone and telefax number of the 
contact persons in the local department of Drug Safety & Epidemiology, 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, and whether the patient 
continued or withdrew from study participation.  
If the SAE is not previously documented in the Investigator’s Brochure (new occurrence) and 
is thought to be related to the Novartis drug, a Drug Safety & 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. 
Exception: Progression of multiple sclerosis / MS relapse 
Although disease progression of multiple sclerosis, including MS relapses, may be classified 
as medically significant, is often requiring hospitalization or results in a newly acquired 
disability / invalidity and therefore the criteria for an SAE can be met, these adverse events 
should only be documented in the source data and the CRF, respectively. 


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In case of a heavy or unexpected event (e.g. death) according to the investigators judgment a 
single case report may be required. The SAE form should then be filled as usual and the SAE 
reported to the company. 
The responsible physician must verify all information given in the questionnaires of the 
patients for the presence of an adverse event and report this in the CRF respectively 
8.3 
Pregnancies 
Pregnancies are not allowed by the study protocol and women of child bearing potential 
should be excluded from participation in the study unless they use effective contraception as 
described in 7.5.4. Any pregnancy that occurs during study participation should be reported 
by the investigator to the local Novartis Drug Safety & Epidemiology Department using a 
Clinical Trial Pregnancy Form for up to 2 months following the last visit. 
Patients becoming pregnant while on FTY720 should be withdrawn from the study. To ensure 
patient safety each pregnancy must also 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 birth, and the presence or absence of any 
birth defects, congenital abnormalities or maternal and newborn complications. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the Novartis drug of any pregnancy outcome. Any SAE experienced 
during pregnancy must be reported on the SAE Report Form. 
It is recommended that pregnant study participants, administered fingolimod, are registered (if 
they consent) in the fingolimod pregnancy registry. 
 
8.4 
Data Monitoring Board 
Not applicable. 
9 
Data review and database management 
9.1 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs 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 CRFs, the adherence to the protocol and to 
Good Clinical Practice, and the progress of enrollment. 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 CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and 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 CRFs are 


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performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the patients will be disclosed. 
9.2 
Data collection 
Designated investigator staff must enter the information required by the protocol onto the 
Novartis CRFs that are printed on 3-part, non-carbon-required paper. Field monitors will 
review the CRFs for completeness and accuracy and instruct site personnel to make any 
required corrections or additions. The CRFs are forwarded to Data Management by field 
monitors, one copy being retained at the investigational site. Once the CRFs are received by 
Data Management, their receipt is recorded and they are reviewed prior to data entry.  
 
9.3 
Database management and quality control 
Data from the CRFs are entered into the study database by Contract Research Organization 
staff following their own internal standard operating procedures that have been reviewed and 
approved by Novartis. 
Subsequently, the entered data are systematically checked by Data Management staff, using 
error messages printed from validation programs and database listings. Obvious errors are 
corrected by Data Management personnel preliminarily. However, a listing with these 
performed obvious corrections will be sent to the respective investigators for approval. Other 
errors or omissions are entered on Data Query Forms, which are returned to the 
investigational site for resolution. The signed original and resolved Data Query Forms are 
kept with the CRFs at the investigator site, and a copy is sent to Novartis so the resolutions 
can be entered into the database. Quality control audits of all key safety and efficacy data in 
the database are made prior to locking the database. 
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. 
OCT assessments (including last OCT measurement prior to first intake of fingolimod, if 
available) are evaluated and quality controlled centrally by Dr. 
 
, data will be recorded and stored at 
. 
Laboratory samples will be processed locally. 
At the conclusion of the study, the occurrence of any protocol violations will be determined.  
After these actions have been completed and the database has been declared to be complete 
and accurate, it will be locked and made available for data analysis. Any changes to the 
database after that time can only be made by joint written agreement between the Trial 
Statistician and Statistical Reporting and the Clinical Trial Leader. 
10 
Data analysis 
10.1 
Populations for analysis 
The safety set (SS) will consist of all enrolled patients for whom safety information was 
collected. Of note, the statement that a patient had no adverse events also constitutes a safety 
assessment. 


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The Full Analysis Set (FAS) will consist of all enrolled patients for whom data was collected 
and who have at least one post-baseline efficacy assessment. This will be analogous to the ITT 
population. 
The Per Protocol Population will consist of all patients from the FAS-population, for whom 
no major protocol violations are reported. All reported protocol violations will be classified as 
minor or major in a data review meeting prior to data base lock. 
10.2 
Patient demographics/other baseline characteristics 
Background and demographic characteristics will be presented using summary statistics. 
Summary statistics will include n (number of observations), mean, standard deviation, 
median, minimum and maximum values for continuous variables, as well as frequencies and 
percentages for categorical variables. 
10.3 
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance) 
 
All patients will receive a dose of 0.5 mg fingolimod daily according to local label. No study 
drug will be provided. 
Concomitant therapy used both prior to and after start of study drug administration will be 
summarized by treatment group. The WHO Drug Reference Guide will be used for coding of 
medications. 
10.4 
Analysis of the primary objective(s) 
10.4.1 
Variable 
The primary outcome of interest is the rate and pattern of change in RNFL thickness in 
RRMS patients treated with fingolimod from baseline to month 36 as assessed by OCT.  
 
10.4.2 
Statistical hypothesis, model, and method of analysis 
The primary efficacy variable will be presented graphically to investigate the pattern of 
change over time. Change will be assessed from baseline to month 12, month 12 to month 24, 
month 24 to month 36. Change will be presented as absolute changes, as well as percent 
change. Pairwise comparisons will be performed using a t-test. No adjustment for multiple 
comparisons will be made. Additionally, change from baseline to month 12, 24, and 36 will 
be analyzed using a paired t-test under the assumption of normal distribution for the ITT 
population. In case of non-normality a Wilcoxon signed-rank test will be applied instead. 
 
10.4.3 
Handling of missing values/censoring/discontinuations 
Due to the definition of the FAS-population, all patients in this population will have at least 
one post-baseline OCT assessment and hence, no imputation of data is necessary. 
 
10.4.4 
Supportive analyses 
Additionally, the per-protocol population will be analyzed for the primary endpoint. 


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10.5 
Analysis of secondary 
 objectives 
10.5.1 
Secondary 
 outcomes 
Secondary endpoints like changes in quadrant RNFLT, changes in total macular volume 
(TMV), and changes in ganglion cell layer thickness (GCLT) from baseline to months 12, 24, 
and 36 will be evaluated with a paired t-test or Wilcoxon signed-rank test, as appropriate.  
Changes in OCT parameters between eyes with and without history of optic neuritis will be 
evaluated with a paired t-test or Wilcoxon signed-rank test, as appropriate. 
 
 
 
 
 
Additionally, means, standard deviations, median, minimum and maximum will be presented 
for each visit, as will be the change from baseline. These descriptive statistics will also be 
presented for the primary endpoint. 
For all other 
 endpoints summary statistics will be presented. Summary statistics 
will include n (number of observations), mean, standard deviation, median, minimum and 
maximum values at each visit, as well as the change. 
10.5.2 
Tolerability 
Not applicable. 
10.5.3 
Resource utilization 
Not applicable. 
10.5.5 
Pharmacokinetics 
Not applicable. 
10.5.6 
Pharmacogenetics/pharmacogenomics 
Not applicable. 
10.5.7 
Biomarkers  
10.5.8 
Not applicable.PK/PD  
Not applicable. 
10.6 
Interim analysis 
No interim analysis is planned 


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10.7 
Sample size calculation 
Published data varies widely as to the average thinning of RNFL in MS patients and no data is 
available on patients treated with Fingolimod. As this is an explorative study to get a better 
understanding of RNFL thinning in RRMS treated with Fingolimod we will take a 
representative sample of approximately 100 patients with RRMS who are stable on 
Fingolimod.  
10.8 
Power for analysis of critical secondary variables 
Not applicable. 
11 
Discussion and rationale for study design features  
This study will describe the long-term changes of OCT parameters in RRMS patients treated 
with oral fingolimod.  
This is a prospective, 3-year, open-label study in MS patients treated with fingolimod. It is 
designed to evaluate the change in average RNFL thickness in this patient population based 
on a disease modifying treatment with fingolimod. Approximately 100 patients will be 
enrolled to receive representative data from various centers. In the forefront of the study MS 
patients are screened for meeting eligibility criteria based on the defined criteria.  
In detail, the primary objective of the study is to evaluate the change in average RNFL 
thickness (RNFLT) in RRMS patients treated with fingolimod from baseline to month 36 as 
assessed by OCT.  
 
Design, study drug and control 
As this trial aims to investigate changes in OCT parameters of RRMS patients treated with the 
disease modifying substance fingolimod, an open-label design was chosen. All patients will 
receive a dose of 0.5 mg fingolimod daily according to local label. No study drug will be 
provided. 
Choice of control 
Not applicable. 
Choice of design  
This is a prospective, multi-center, open-label study. An observation time of 3 years is needed 
to gain a better understanding of the long term changes of optical coherence tomography 
(OCT) parameters in RRMS patients under treatment with fingolimod. The study is designed 
to longitudinally investigate the degeneration of retinal axons by measuring change in RNFL 
thickness by latest OCT-technology. Correlations of OCT findings with available MRI data 
and clinical findings may enhance our understanding of the relationship between CNS 
inflammation, tissue injury, regeneration and neurological deficit in context of fingolimod 
therapy 
 
Data analysis 
A total of about 100 patients will be enrolled. Details on data analysis and the definition of the 
analysis sets are presented and discussed in section 10. 


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12 
References (available upon request) 
Alonso A, Hernán MA (2008). Temporal trends in the incidence of multiple sclerosis: a 
systematic review. Neurology 8;71(2):129-35. 
Barkhof F, Calabresi PA, Miller DH, Reingold SC (2009) Imaging outcomes for 
neuroprotection and repair in multiple sclerosis trials. Nat Rev Neurol; 5(5):256-66 
Costello F, Hodge W, Pan YI, Freedman M, DeMeulemeester C (2009) Differences in retinal 
nerve fiber layer atrophy between multiple sclerosis subtypes. J Neurol Sci; 15;281(1-2):74-9. 
Doward LC, McKenna SP,Meads DM, Kavyasiddi D, Hampson NE,  Mayo KW. The 
symptomatic, functional, and quality of life impact of multiple sclerosis: Report on a 
qualitative investigation of the patients' perspective. Value in Health. 2005 Nov; 8 (6), A135.  
Frohman EM, Costello F, Stüve O, Calabresi P, Miller DH, Hickman SJ, Sergott R, Conger 
A, Salter A, Krumwiede KH, Frohman TC, Balcer L, Zivadinov R (2008) Modeling axonal 
degeneration within the anterior visual system: implications for demonstrating 
neuroprotection in multiple sclerosis. Arch Neurol; 65(1):26-35. 
Keegan BM, Noseworthy JH (2002) Multiple sclerosis Annu Rev Med. 2002;53:285-302. 
Kurtzke JF, MD (1983) Rating neurologic impairment in multiple sclerosis: An expanded 
disability status scale (EDSS). Neurology; 33: 1444-1452. 
Petzold A, de Boer JF, Schippling S, Vermersch P, Kardon R, Green A, Calabresi PA, 
Polman C (2010) Optical coherence tomography in multiple sclerosis: a systematic review 
and metaanalysis. Lancet Neurol;9(9):921-32. 
Polman, C. H., Reingold, S. C., Banwell, B., Clanet, M., Cohen, J. A., Filippi, M., Fujihara, 
K., Havrdova, E., Hutchinson, M., Kappos, L., Lublin, F. D., Montalban, X., O'Connor, P., 
Sandberg-Wollheim, M., Thompson, A. J., Waubant, E., Weinshenker, B. and Wolinsky, J. S. 
(2011), Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria. 
Annals of Neurology, 69: 292–302. doi: 10.1002/ana.22366 
Serbecic N, Beutelspacher SC, Aboul-Enein FC, Kircher K, Reitner A, Schmidt-Erfurth U. 
Reproducibility of high-resolution optical coherence tomography measurements of the nerve 
fibre layer with the new Heidelberg Spectralis optical coherence tomography. Br J 
Ophthalmol; Epub ahead of print 
Sospedra M, Martin R (2005) Immunology of multiple sclerosis. Annu Rev Immunol. 
2005;23:683-747. 
Syc SB, Warner CV, Hiremath GS, Farrell SK, Ratchford JN, Conger A, Frohman T, Cutter 
G, Balcer LJ, Frohman EM, Calabresi PA (2010) Reproducibility of high-resolution optical 
coherence tomography in multiple sclerosis. Mult Scler;16(7):829-39. 
Talman LS, Bisker ER, Sackel DJ, Long DA Jr, Galetta KM, Ratchford JN, Lile DJ, Farrell 
SK, Loguidice MJ, Remington G, Conger A, Frohman TC, Jacobs DA, Markowitz CE, Cutter 
GR, Ying GS, Dai Y, Maguire MG, Galetta SL, Frohman EM, Calabresi PA, Balcer LJ 
(2010) Longitudinal study of vision and retinal nerve fiber layer thickness in multiple 
sclerosis. Ann Neurol; 67(6):749-60. 
Toledo J, Sepulcre J, Salinas-Alaman A, García-Layana A, Murie-Fernandez M, Bejarano B, 
Villoslada P (2008). Retinal nerve fiber layer atrophy is associated with physical and 
cognitive disability in multiple sclerosis. Mult Scler;14(7):906-12. 
Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L (1998) Axonal transection in 
the lesions of multiple sclerosis. N Engl J Med. 338(5):278-85. Van Agt H, Essink BM, 
Krabbe PRH (1994). Test-retest reliability of health state valuations collected with the 
EuroQol questionnaire. Soc Sci Med;39(11):1537-1544.  


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Wu H, de Boer JF, Chen TC (2010) Reproducibility of Retinal Nerve Fiber Layer Thickness 
Measurements Using Spectral Domain Optical Coherence Tomography. J Glaucoma; Epub 
ahead of print. 
 


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Appendix 1:  Administrative procedures 
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.  
Responsibilities of the investigator and IRB/IEC/REB 
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/REB) before study start. Approval letters concerning protocol and 
informed consent will be filed by Novartis. 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. 
Informed consent   
Eligible patients may only be included in the study after providing written, IRB/IEC/REB-
approved informed consent. 
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.  
Amendments to the protocol 
Any change or addition to the protocol can only be made in a written protocol amendment 
that must be approved by Novartis, the Health Authority and the IRB/IEC/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
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/REB at the study site should 
be informed within 10 working days. 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical trial agreement. 


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Appendix 2:  Blood Collection Log 
This is only an overview on the total volume of blood collected for local laboratory 
assessments at the study visits.  
 
 
 
Routine Laboratory = 
Total blood volume 
 
 
V1 (Screening) 
10 ml 
 
 
V3 
10 ml 
 
 
V4  
10 ml 
 
 
V5  
10 ml 
 
 
V6 
10 ml 
 
 
V7 
10 ml 
 
 
 


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Appendix 3:  Clinically notable vital signs 
Only selected laboratory parameters 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) 
>3x ULN, <5x ULN 
F: > 105 U/L <175 U/L, 
M: >150 U/L <250 U/L> 
F: > 105 U/L <175 U/L 
M: >150 U/L <250 U/L 
Gamma Glutamyltransferase 
> 130 U/L 
> 130 U/L 
SGPT (ALT) 
>3x ULN, <5x ULN 
F: > 105 U/L <175 U/L, 
M: >150 U/L <250 U/L 
F: > 105 U/L <175 U/L 
M: >150 U/L <250 U/L 
Alkaline Phosphatase 
> 280 U/L 
> 280 U/L 
Total bilirubin 
 2.0 mg/dL 
 34.2 mol/L 
RENAL FUNCTION / METABOLIC AND ELECTROLYTE VARIABLES 
Glucose  
200 mg/dL 
11.1 mmol/L 
Creatinine 
2.0 mg/dL 
176 umol/L 
Chloride 
≤ 85 mEq/L 
≥ 119 mEq/L 
≤ 85 mmol/L 
≥ 119 mmol/L 
BUN 
≤ 2 mg/dL 
≥ 30 mg/dL 
≤ 0.7 mmol/L 
≥ 10.7 mmol/L 
Sodium 
< 130 mEq/L 
> 150 mEg/L 
< 130 mmol/L 
>150 mmol/L 
Potassium 
≤ 3.0 mEq/L 
≥ 6.0 mEq/L 
≤ 3.0 mmol/L 
≥ 6.0 mmol/L 
Calcium 
≤ 7.5 mg/dL 
≥ 11.6 mg/dL 
≤ 1.87 mmol/L 
≥ 2.89 mmol/L 
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 
Red blood cells RBCs 
<3,300,000/mm³ 
>6,800,000/mm³ 
<3.3 x 1012/L 
>6.8 x 1012/L 
HEMATOLOGY VARIABLES: DIFFERENTIAL 


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Notable Values 
Lymphocytes 
<100/mm3 
8000/mm3 
<0.1 x 109/L 
8 x 109/L 
 


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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) 
140 mmHg  or Increase of 20 mmHg from baseline 
Or 
 90 mmHg  or Decrease of  20 mmHg from baseline 
Diastolic BP (mmHg) 
 90 mmHg or Increase of  15 mmHg from baseline 
Or 
 50 mmHg or Decrease of  15 mmHg from baseline 


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Appendix 4:  2010 Revisions to the McDonald diagnosis criteria for MS  
Guidelines from International Panel on the diagnosis of MS 
(Polman et. al, 2011) 
Clinical Presentation 
Additional Data Needed for MS Diagnosis 
2 or more attacksa; objective clinical evidence 
of 2 or more lesions or objective clinical 
evidence of 1 lesion with reasonable 
historical evidence of a prior attackb 
 
Nonec 
2 or more attacksa; objective clinical evidence 
of 1 lesion 
 
Dissemination in space, demonstrated by 
 
 ≥ 1 T2 lesion in at least two out of four 
MS-typical regions of the CNS 
(periventricular, juxtacortical, infratentorial, 
or spinal cord)d 
OR 
 
Await a further clinical attacka 
implicating a different CNS site 
 
1 attacka; objective clinical evidence of 2 or 
more lesions 
 
Dissemination in time, demonstrated by 
 
 
Simultaneous presence of asymptomatic 
gadolinium-enhancing and non-enhancing 
lesions at any time. 
OR 
 
A new T2 and/or gadolinium-enhancing 
lesion(s) on follow-up MRI, irrespective 
of its timing with reference to a baseline 
scan. 
OR 
 
Await a second clinical attacka 
 
1 attacka; objective clinical evidence of 1 
lesion (clinically isolated syndrome) 
 
Dissemination in space and time, 
demonstrated by: 
For DIS 
 ≥ 1 T2 lesion in at least two out of four 
MS-typical regions of the CNS 
(periventricular, juxtacortical, 
infratentorial, or spinal cord)d 
OR 
 
Await a second clinical attacka 
implicating a different CNS site 
AND 
For DIT 
 
Simultaneous presence of asymptomatic 
gadolinium-enhancing and non-enhancing 
lesions at any time. 
OR 


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 A new T2 and/or gadolinium-enhancing 
lesion(s) on follow-up MRI, irrespective 
of its timing with reference to a baseline 
scan. 
OR 
 Await a second clinical attacka 
 
Insidious neurological progression suggestive 
of MS (PPMS) 
 
One year of disease progression 
(retrospectively or prospectively determined) 
PLUS 
Two out of the three following criteriad 
1. Evidence for DIS in the brain based on ≥ 1 
T2+ lesions in the MS-characteristic 
periventricular, juxtacortical or infratentorial 
regions 
2. Evidence for DIS in the spinal cord based 
on ≥ 2 T2+ lesions in the cord 
3. Positive CSF (isoelectric focusing evidence 
of oligoclonal bands and/or elevated IgG 
index) 
 
 
 If the Criteria are fulfilled and there is no better explanation for the clinical presentation, the 
diagnosis is MS; if suspicious, but the Criteria are not completely met, the diagnosis is 
“possible MS”; if another diagnosis arises during the evaluation that better explains the 
clinical presentation, then the diagnosis is “not MS.” 
 
a. An attack (relapse; exacerbation) is defined this as patient-reported or objectively observed events typical of 
an acute inflammatory demyelinating event in the CNS, current or historical, with duration of at least 24 hours, 
in the absence of fever or infection. It should be documented by contemporaneous neurological examination, but 
some historical events with symptoms and evolutionm characteristic for MS, but for which no objective 
neurological findings are documented, can provide reasonable evidence of a prior demyelinating event. Reports 
of paroxysmal symptoms (historical or current) should, however, consist of multiple episodes occurring over not 
less than 24 hours. Before a definite diagnosis of MS can be made, at least one attack must be corroborated by 
findings on neurological examination, visual evoked potential (VEP) response in patients reporting prior visual 
disturbance, or MRI consistent with demyelination in the area of the CNS implicated in the historical report of 
neurological symptoms.  
b. Clinical diagnosis based on objective clinical findings for two attacks is most secure. Reasonable historical 
evidence for one past attack, in the absence of documented objective neurological findings, can include historical 
events with symptoms and evolution characteristics for a prior inflammatory demyelinating event; at least one 
attack, however, must be supported by objective findings. 
c. No additional tests are required. However, it is desirable that any diagnosis of MS 
be made with access to imaging based on these Criteria. If imaging or other tests 
dGadolinium-enhancing lesions are not required; symptomatic lesions are excluded from consideration in subjects with 
brainstem or spinal cord syndromes. 
MS = multiple sclerosis; CNS = central nervous system; MRI = magnetic resonance imaging; DIS = dissemination in space; 
DIT = dissemination in time; PPMS = primary progressive multiple sclerosis; CSF = cerebrospinal fluid; IgG = 
immunoglobulin G 


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Appendix 5:  New York Heart Association Functional Classification 
(The Criteria Committee of the New York Heart Association, 1994) 
 
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 6:  EDSS Assessment Criteria 
EXPANDED DISABILITY STATUS SCALE 
0 = 
normal neurological exam (all FS grade 0) 
1.0 =  no disability, minimal signs in one FS (one FS grade 1) 
1.5 = no disability, minimal signs in more than one FS (more than one FS grade 1) 
2.0 = minimal disability in one FS (one FS grade 2, others 0 or 1) 
2.5 = minimal disability in two FS (two FS grade 2, others 0 or 1) 
3.0 = moderate disability in one FS (one FS grade 3, others 0 or 1) though fully ambulatory; 
or mild disability in three or four FS (three/four FS grade 2, others 0 or 1) though fully 
ambulatory 
3.5 = fully ambulatory but with moderate disability in one FS (one FS grade 3) and mild 
disability in one or two FS (one/two FS grade 2) and others 0 or 1; or fully ambulatory 
with two FS grade 3 (others 0 or 1); or fully ambulatory with five FS grade 2 (others 0 
or 1) 
4.0 = ambulatory without aid or rest for >500 meters; up and about some 12 hours a day 
despite relatively severe disability consisting of one FS grade 4 (others 0 or 1) or 
combinations of lesser grades exceeding limits of previous steps 
4.5 = ambulatory without aid or rest for >300 meters; up and about much of the day, 
characterized by relatively severe disability usually consisting of one FS grade 4 and 
combination of lesser grades exceeding limits of previous steps 
5.0 = ambulatory without aid or rest for >200 meters (usual FS equivalents include at least 
one FS grade 5, or combinations of lesser grades usually exceeding specifications for 
step 4.5) 
5.5 = ambulatory without aid or rest >100 meters 
6.0 = unilateral assistance (cane or crutch) required to walk at least 100 meters with or 
without resting 
6.5 = constant bilateral assistance (canes or crutches) required to walk at least 20 meters 
without resting 
7.0 = unable to walk 5 meters even with aid, essentially restricted to wheelchair; wheels self 
and transfers alone; up and about in wheelchair some 12 hours a day 


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


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Appendix 7: Guidance on safety monitoring 
Patients with recorded elevated blood pressure values (systolic BP >140 and/or diastolic BP 
> 90 mmHg) should have their blood pressure controlled during the same visit. Patients who 
have two readings of elevated blood pressure (systolic BP >140 and/or diastolic BP >90 
mmHg) should be followed up in one month by an unscheduled visit if the scheduled visit is 
not due. Should systolic BP >140 and/or diastolic BP >90 mmHg values will be confirmed in 
the next 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 must be considered by the 
investigator. 
After a treatment interruption of fingolimod for more than 14 days, patients have to be 
observed for cardiac events as described in the recommendations for first dose monitoring. 
 
Recommendations for first dose monitoring (also in case of re-initation of 
fingolimod after treatment interruption) 
Clinicians should be particularly mindful of patients who have a low pulse at baseline 
(spontaneously or through drug induced ß-receptor blockade), prior to administration of the 
study drug.  
Be aware that fingolimod causes transient heart rate lowering and may cause AV conduction 
delays following initiation of treatment. This also applies to recommencing treatment after an 
interruption of more than 14 days. 
All patients will be monitored for a period of at least 6 hours for signs and symptoms of 
bradycardia. The monitoring includes a 12-lead ECG prior and 6 hours after the first dose, 
continuous 6-hour ECG recording (recommended) after the first dose as well as blood 
pressure and heart rate measurement every hour. Should post-dose bradyarrhythmia-related 
symptoms occur, appropriate clinical management should be initiated and observation should 
be continued until the symptoms have resolved.  
If the patient’s heart rate at the end of the 6-hour period is the lowest following first dose 
administration, the monitoring should be extended by at least 2 hours and until the heart rate 
increases. 
In those patients with evidence of clinically important cardiac effects during the first 6 hours, 
monitoring should be extended according to local label. 
 
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.  
Because of additive effects on heart rate, Fingolimod is not recommended in patients 
receiving beta blockers or other substances which may decrease heart rate. Fingolimod should 
not be co-administered [for Switzerland: is contraindicated] with Class Ia (e.g. quinidine, 
procainamide) or Class III (e.g. amiodarone, sotalol) antiarrythmic medicinal products). 


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Recommendations for management of bradycardia  
Be aware that fingolimod causes transient heart rate lowering and may cause AV conduction 
delays following initiation of treatment. This also applies to recommencing treatment after an 
interruption of more than 14 days. 
All patients should be observed for a period of at least 6 hours for signs and symptoms of 
bradycardia (according to local label). Should post-dose bradyarrhythmia-related symptoms 
occur, appropriate clinical management should be initiated and observation should be 
continued until the symptoms have resolved.  
Monitoring measures will be implemented as foreseen by the local label 
Clinicians should be particularly mindful of patients who have a low pulse (<55bpm) at 
baseline (spontaneously or through drug induced ß-receptor blockade), prior to administration 
of the study drug.  
Atropine (s.c. or i.v.) 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 µg/kg/min or epinephrine drip 2-10 µg/min 
 Performance of transcutaneous pacing may also be considered 
In the setting of decreased blood pressure, isoproterenol should be avoided/used with caution. 
 
 
Guidance on monitoring of patients with elevated liver function tests 
In case of detection of elevated ALT/AST values > 5 times the upper limit of the normal 
range (ULN), additional blood chemistry panel including ALT, AST, AP, GGT, total and 
conjugated bilirubin, albumin should be performed.   
If ALT/AST values are repeatedly 5 times the ULN, the study drug must be suspended and 
not resumed until values have normalized. Patients who develop symptoms suggestive of 
hepatic dysfunction such as unexplained vomiting or jaundice, should have liver enzymes 
checked and fingolimod should be discontinued if significant liver injury is confirmed.  
In case of isolated elevation of bilirubin over 2.0 mg/dl (34.2 umol/L), the investigator must 
discontinue fingolimod administration. Additional evaluations may be performed at the 
discretion of the investigator. 
An interruption or discontinuation of the study drug should be clearly documented and 
reflected on Dosage Administration Record CRF. 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 by the local laboratory. In case of lymphocyte alert, lymphocyte count should be 


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repeated in two weeks by the local laboratory. If the repeat test confirms the lymphocyte 
count is below 0.1x109/L or 100 cells/mm3, the study drug must be discontinued and the 
lymphocytes count needs to be monitored every two weeks until levels reach 0.6x109/L 
values. Recovery of lymphocyte counts is expected to take several weeks given the long half-
life of fingolimod. The patient should be evaluated and monitored for infections on a regular 
basis during this period. As shown recently (data presented at AAN 2011: S30.001 
Lymphocytes and Fingolimod-Temporal patterns and relationship with infections) a 
lymphocyte count between 100-200 cells/mm3 is not associated with a higher infection risk. 
Therefore, a cut-off of 100 cells/mm3 is regarded as appropriate for this study. After 
termination of the study the recommendations defined in the local label will prevail, in 
Germany a limit of 200 cells/mm3 will be considered in agreement with the SmPC. 
 
Re-initiation of the study drug can only be considered once the lymphocyte counts increase 
above 600 cells/mm3 as confirmed by the local lab after discussion with the Clinical Trial 
Leader at Novartis. 
 
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. 
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 Clinical Trial Leader at Novartis to discuss findings and diagnostic possibilities as 
soon as possible. AE/SAEs need to be filed as appropriate. 
In case of new findings in the MRI images in comparison with the previous available MRI 
which are not compatible with MS lesions, the study drug will be 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 in consultation with the sponsor be sent to a 
central laboratory (to be 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 Clinical Trial Leader 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. In case of infections an 


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unscheduled visit should be conducted. Treatment and additional evaluations will be 
performed at discretion of the investigator.  
The investigator should remind the patient of the risk of infections and to 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 specific antimicrobial therapy on the 
basis of clinical diagnosis or suspicion thereof (e.g. antiviral treatment for herpes simplex or 
zoster) in consultation with infectious disease experts, as appropriate. The investigator should 
inform the Novartis medical expert of any such cases. 
Investigators should consider the added immunosuppressive effects of corticosteroid therapy 
for treatment of MS attack/relapse and increase vigilance regarding infections during such 
therapy and in the weeks following administration. 
 
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. Although there have been no 
confirmed cases of macular edema in the multiple sclerosis Phase II study, careful ophthalmic 
monitoring is being implemented to permit early detection of this event, should it occur. A 
complete ophthalmic examination by an ophthalmologist will be conducted in accordance 
with Table 7-1. Similar assessments must be performed at an unscheduled ophthalmology 
visit for any patient who presents with new visual symptoms or decrease in visual acuity. The 
following assessments will be performed at the ophthalmic examinations: 
1. Best corrected visual acuity using a visual acuity chart with equal spacing between letters 
and between lines 
2. Dilated ophthalmoscopy for inspection of the macula and the optic disc 
3. Optical Coherence Tomography (OCT) 
 
Guidance on monitoring patients for possible macular edema 
At baseline, if there is a suspicion of macular edema by dilated ophthalmoscopy or OCT 
(increased central foveal thickness or cystic changes in the fovea), the patient not be enrolled. 
A fluorescein angiogram may be performed to rule out vascular leakage in such cases. Based 
on ophthalmic monitoring during the study, study drug must be discontinued 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 must be followed-up 1 month and 3 months after diagnosis of macular edema 
and more frequently if needed based on the ophthalmologist’s judgment. Further 
ophthalmologic evaluations until such time as resolution is confirmed or no further 
improvement is expected by the ophthalmologist (based on a follow-up period of not less than 


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3 months). These evaluations will include repeat best-corrected visual acuity, fundus 
examination, and OCT. Fluorescein angiography (FA) is repeated at the discretion of the 
ophthalmologist. If the patient does not show definite signs of improvement on examination 
by specialist testing (e.g. OCT, FA) after 6-8 weeks after discontinuation of study drug, then 
therapy for macular edema in conjunction with an ophthalmologist experienced in the 
management of this condition should be initiated. 
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 in independent panel if needed.


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SAP_000.pdf: 
Clinical Development 
CFTY720 / Fingolimod / Gilenya® 
CFTY720DDE15TS (PASSOS) / NCT01705236
 A 3-year multi-center study to describe the long term 
changes of optical coherence tomography (OCT) 
parameters in patients under treatment with Gilenya® 
Statistical Analysis Plan (SAP) 
Author: 
, CRO Statistician 
, Trail Statistician 
Document type: 
SAP Documentation 
Document status: 
Final 1.0 
Release date: 
26-MRZ-2019
Number of pages: 
17 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
29-
Jan-
2019 
Prior 
to DB 
lock 
Creation of 
first 
draft 
version 
N/A - First version 
NA 
18-
MRZ-
2019 
Prior 
to DB 
lock 
After 
review 
by 
Novartis 
Biomarkers are no longer applicable 
Relative 
change 
defined 
as 
M36/Baseline 
Normality investigated graphically not 
by Shapiro-Wilk test 
several 
26-
MRZ-
2019 
Prior 
to DB 
lock 
Finalization Version change from draft to final 1.0 
Version number 
only 
 
 
 
 
 
 
 
 


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Signature Page 
CFTY720DDE15TS 
 
 
 
Dr. 
 
(Clinical Trial Lead) 
 
 
 
 
 
 
Date, Signature 
 
 
 
(Trial Statistician) 
 
 
 
 
Date, Signature 
 
 
 
(CRO Statistician) 
 
 
 
 
Date, Signature 
 


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Table of contents 
Table of contents ................................................................................................................. 4 
List of abbreviations ............................................................................................................ 6 
1 
Introduction ......................................................................................................................... 7 
1.1 
Study design............................................................................................................. 7 
1.2 
Study objectives and endpoints ............................................................................... 7 
2 
Statistical methods ............................................................................................................... 9 
2.1 
Data analysis general information ........................................................................... 9 
2.1.1 
General definitions .................................................................................. 9 
2.2 
Analysis sets .......................................................................................................... 10 
2.2.1 
Subgroup of interest .............................................................................. 10 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 10 
2.3.1 
Patient disposition ................................................................................. 10 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 10 
2.4.1 
Study treatment / compliance ................................................................ 10 
2.4.2 
Prior, concomitant and post therapies ................................................... 11 
2.5 
Analysis of the primary objective .......................................................................... 11 
2.5.1 
Primary endpoint ................................................................................... 11 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 11 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 11 
2.5.4 
Supportive analyses ............................................................................... 11 
2.6 
Analysis of the key secondary objective ............................................................... 11 
2.7 
Analysis of secondary efficacy objective(s) .......................................................... 12 
2.7.1 
Secondary endpoints ............................................................................. 12 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 12 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 12 
2.8 
Safety analyses ....................................................................................................... 12 
2.8.1 
Adverse events (AEs) ............................................................................ 13 
2.8.2 
Deaths .................................................................................................... 13 
2.8.3 
Laboratory data ..................................................................................... 13 
2.8.4 
Other safety data ................................................................................... 13 
2.9 
Pharmacokinetic endpoints .................................................................................... 14 
2.10 
PD and PK/PD analyses......................................................................................... 14 
 
 14 
2.12 
Biomarkers ............................................................................................................. 14 
2.13 
Not applicable.Other Exploratory analyses ........................................................... 14 


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2.14 
Interim analysis ...................................................................................................... 14 
3 
Sample size calculation ..................................................................................................... 14 
4 
Change to protocol specified analyses .............................................................................. 15 
5 
Appendix ........................................................................................................................... 15 
5.1 
Imputation rules ..................................................................................................... 15 
 
 15 
5.3 
Statistical models ................................................................................................... 15 
5.3.1 
Primary analysis .................................................................................... 15 
5.3.2 
Key secondary analysis ......................................................................... 15 
5.4 
Rule of exclusion criteria of analysis sets.............................................................. 16 
6 
Reference ........................................................................................................................... 17 


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List of abbreviations 
 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Classification 
CRF 
Case report/record form 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study report 
 
 
FAS 
Full Analysis Set 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
 
 
OCT 
optic coherence tomography 
 
 
 
 
PPS 
Per-Protocol Set 
 
 
 
 
RAP 
Report and Analysis Process 
RNFL(T) 
retinal nerve fiber layer (thickness) 
RRMS 
relapsing remitting multiple sclerosis 
SAF 
Safety Set 
SAP 
Statistical Analysis Plan 
 
 
SOC 
System Organ Class 
TFLs 
Tables, Figures, Listings 
TMV 
Total Macular volume 
 
 


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1 
Introduction 
 
This statistical analysis plan (SAP) describes the statistical methods for the final analysis of this 
study. The final statistical analysis serves as basis for the Clinical Study Report (CSR). This 
SAP displays the analysis of the PASSOS study and has the following reference documents: 
 Study Protocol, Version 4.0 (Original protocol incl. Amendment 4), dated 26-JUL-2016 
1.1 
Study design 
This is a multi-center, open-label study in RRMS patients treated with fingolimod. After signing 
the informed consent, patients will enter a Screening Phase (day -28 to day 0) before starting 
the study at Baseline (visit 2/day 0), followed by a 36-month longitudinal data collection phase. 
Visits are performed at month 3 (visit 3), month 6 (visit 4), month 12 (visit 5), month 24 (visit 
6), and month 36 (visit 7). Eligibility will be determined at Screening. OCT and other 
assessments will be performed according to the schedule in Table 7-1 of the Clinical Study 
Protocol (CSP). 
1.2 
Study objectives and endpoints 
The primary objective is to evaluate the change in average RNFL thickness (RNFLT) in RRMS 
patients treated with fingolimod over 36 months as assessed by OCT. The average RNFL 
thickness following OCT assessment will be calculated for the left and right eye per visit and 
per patient.  The following table describe the objectives and endpoints: 
 
Objective 
Endpoint 
Primary 
To evaluate the change in 
average 
RNFL 
thickness 
(RNFLT) in RRMS patients 
treated with fingolimod over 
36 months as assessed by 
OCT 
Absolute Difference in mean RNFLT from 
baseline (BL) to M36 (or last values in case 
of missing data) in the full analysis set 
(FAS). Mean RNFLT is the average of valid 
measurements of right and left eye. 
Sensitivity analyses are performed with the 
Per-Protocol Set (PPS) and for relative 
change (M36/BL) 
Secondary 
To compare changes in OCT 
parameters between eyes with 
and without history of optic 
neuritis  
Absolute Difference in RNFLT from 
baseline (BL) to M36 (or last values in case 
of missing data) in the full analysis set 
(FAS) for: 
- 
eyes with versus without optic 
neuritis 
Secondary 
To evaluate the change in 
average 
RNFLT 
under 
fingolimod 
therapy 
from 
Absolute Difference and ratios in average 
RNFLT from baseline (BL) to M12 
respectively M24 (or last values in case of 
missing data) in the full analysis set (FAS). 


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Objective 
Endpoint 
baseline to months 12 and 24 
as assessed by OCT  
 
Secondary 
To 
evaluate 
change 
in 
quadrant 
RNFLT 
under 
fingolimod 
therapy 
from 
baseline to months 12, 24 and 
36 
Absolute Difference and ratios in average 
quadrant RNFLT from baseline (BL) to 
M12, resp. M24 resp. M36 (or last values in 
case of missing data) in the full analysis set 
(FAS). 
Quadrant RNFLT are: 
- 
Nasal-inferior 
- 
Nasal-superior 
- 
Temporal.inferior 
- 
Temporal-superior 
Secondary 
To evaluate changes in total 
macular 
volume 
(TMV) 
under 
fingolimod 
therapy 
from baseline to months 12, 
24 and 36 
Absolute Difference and ratios in average 
TMV from baseline (BL) to M12, resp. M24 
resp. M36 (or last values in case of missing 
data) in the full analysis set (FAS). 
 
Secondary 
To 
evaluate 
changes 
in 
ganglion cell layer thickness 
(GCLT) under fingolimod 
therapy from baseline to 
months 12, 24 and 36 
Absolute Difference and ratios in average 
GCLT from baseline (BL) to M12, resp. 
M24 resp. M36 (or last values in case of 
missing data) in the full analysis set (FAS). 
Secondary 
To 
evaluate 
safety 
and 
tolerability of fingolimod in 
MS patients followed for up 
to 36 months and specifically 
to determine the frequency of 
macular 
edema 
under 
treatment 
with 
oral 
fingolimod in this patient 
population 
Incidence of adverse events, serious adverse 
events and (S)AEs at least possible related 
to fingolimod in the Safety Set (SAF) 
Incidence of macular edema (AE of special 
interest) 


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2 
Statistical methods 
2.1 
Data analysis general information 
CRO 
 perform the final analysis. The software SAS, version 9.2 is 
used for analysis. The data base lock is done when all patient data are documented, entered into 
the clinical database, all data checks are completed, the data from reading center (OCT data) 
are received/checked and the data review meeting was compled. 
Continuous variables are displayed by descriptive sample statistics which include: N, mean, 
standard deviation, minimum, median and maximum. 
Categorical variables are displayed by frequencies and percentages. 
No hypothesis is to be tested. Thus, the results – including p-values – have to be interpreted in 
an exploratory manner. 
P-values are not adjusted for multiplicity. 
2.1.1 
General definitions  
The following terms are defined for the rest of the document: 
Baseline 
Visit 2 at month 0 (labelled V2/M0/BL) 


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Last value until Visit x 
The last (post-baseline) value documented until Visit x, i.e. missing 
or invalid data are replaced by the last available value. Baseline 
values are not carried forward. 
2.2 
Analysis sets 
The analysis sets were defined in section 10 of the Clinical Study Protocol (CSP): 
The Safety Set (SAF) consists of all patients treated with investigational drug (fingolimod) for 
whom safety information was collected. Of note, the statement that a patient has had no adverse 
events also constitutes a safety assessment. 
The Full Analysis Set (FAS) consists of all patients treated with investigational drug 
(fingolimod) for whom data was collected and who have at least one post-baseline efficacy 
assessment. This is analogous to the ITT population. 
The Per Protocol Population consists of all patients from the FAS population, for whom no 
major protocol violations are reported. All reported protocol violations will be classified as 
minor or major in a data review meeting prior to data base lock. 
 
2.2.1 
Subgroup of interest 
No subgroup analyses are performed. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
Background and demographic characteristics are presented using summary statistics for SAF, 
FAS and PPS. 
2.3.1 
Patient disposition 
The disposition of all enrolled patients displays the number and reasons of screening failures. 
The disposition of all patients in the treatment period (i.w. who received at least one dose of 
fingolimod) displays the number and reasons for premature discontinuation from the study. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
The total exposure (i.e., last fingolimod administration from study completion CRF – date of 
V2/D0/BL + 1 day) is displayed by sample statistics. It should be noted that patients are allowed 
to be pre-treated for 1 to 4 month according to the inclusion criteria. The total drug exposure 
per 100 subject years is presented also. 
The interruption in fingolimod treatment is displayed by incidences, reason, number of 
interruption and total duration per patient. 


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2.4.2 
Prior, concomitant and post therapies 
Prior and concomitant medication is coded by WHO-DD. Frequencies of Anatomic 
Therapeutical Classes (ATC) and preferred terms within ATCs are displayed. Here, each patient 
with multiple medications is counted only once in that class. 
2.5 
Analysis of the primary objective 
2.5.1 
Primary endpoint 
The primary endpoint is the change, i.e. difference, in mean RNFLT from baseline to month 36 
(or last values in case of missing data) in the full analysis set. Mean RNFLT is the average of 
valid measurements of the right and left eye. 
Sensitivity analyses are performed with the Per-Protocol Set (PPS) and for the relative change 
assessed by the M36/BL. 
 
2.5.2 
Statistical hypothesis, model, and method of analysis 
No hypothesis is to be tested. 
Descriptive pairwise comparisons are performed using a paired t-test in case of normality, In 
case of non-normality a Wilcoxon signed-rank test is applied instead. No adjustment for 
multiple comparisons are made. For each parameter the normality distribution is graphically 
proved for the change from BL to M36. Differences as well as pre-post ratios are displayed. 
When non-normality is detected for the change to M36 the changes to M12 respectively M36 
are analysed also non-parametrically. 
The primary efficacy variable is presented graphically by standard boxplots for each time point. 
Sample statistics are presented for each time point and changes (differences as well as ratios) 
to each time point. 
 
2.5.3 
Handling of missing values/censoring/discontinuations 
Missing values are replaced by the last available value. Post-baseline values are carried forward 
but no baseline values. 
An analysis without replacing the missing data is performed as sensitivity analysis. 
2.5.4 
Supportive analyses 
A comparison for eyes with versus without optic neuritis is done by a mixed model including 
the subject as random factor. LSMeans for RNFLT in eyes with versus withour optic neuritis 
are displayed as well as the difference including p-value. 
2.6 
Analysis of the key secondary objective 
There is no key secondary objective. 


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2.7 
Analysis of secondary efficacy objective(s) 
2.7.1 
Secondary endpoints 
The following endpoints are defined as secondary: 
- 
change from baseline to month 36 in quadrant RNTFT, i.e. nasal-superior, nasal-inferior, 
temporal-superior, and temporal-superior RNFLT 
2.7.2 
Statistical hypothesis, model, and method of analysis 
No hypothesis is to be tested. P-values are displayed as descriptive measures. 
Analysis is similar to the primary endpoint. All analyses are done with the FAS only. 
Correlations in the change from baseline to month 12, month 24 and month 36 are presented by 
the Pearson correlation coefficient or Spearman Rank correlation coefficient, depending on 
distribution of data. Normality was graphically investigated.. 
Correleations are displayed graphically by scatter plots. Here, only changes from baseline to 
last value until Month 36 are displayed. 
2.7.3 
Handling of missing values/censoring/discontinuations 
Missing values are replaced by the last available value. According to the definition of FAS (at 
least one post-baseline value of the primary parameter is required) all patients have a value after 
baseline. 
In contrast to the primary parameter no sensitivity analysis without replacing the missing data 
is performed. 
 
2.8 
Safety analyses 
All safety analyses were presented for the SAF population. 


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2.8.1 
Adverse events (AEs) 
Adverse events which started before BL/M0 were listed only. Analyses were performed on AEs 
which started at/after BL/M0. 
The incidence of adverse events is displayed with n, percentage and 95% confidence interval 
for the SAF. Here, different types of AEs are presented: 
(1) Any AE 
(2) AE with suspected relationship to fingolimod 
(3) AE leading to study drug dosage adjustment/temporary interruption 
(4) AE leading to permanent study drug discontinuation 
(5) Serious adverse event 
(6) Non-Serious AE 
(7) Death 
For AEs of type (1) to (6) a two-level frequency table for MedDRA system organ classes (SOC) 
and Preferred Terms (PT) within SOC are presented. Here, a patient with multiple occurrences 
is counted only once on the respective class. 
The maximum severity of (several) AEs occurring in a patient ist displayed for PTs within 
SOCs, SOCs and overall. 
For AEs of type (7),  (5), and (3) separate listings are generated. 
2.8.1.1 
Adverse events of special interest / grouping of AEs 
Not applicable 
2.8.2 
Deaths 
See above. 
2.8.3 
Laboratory data 
Abnormal laboratory values or test results constituted adverse events only if they induce clinical 
signs or symptoms, were considered clinically significant, require medication discontinuation 
or required therapy. Then they should be documented as AEs. Therefore, no separate analysis 
of laboratory data applies. 
2.8.4 
Other safety data 
2.8.4.1 
ECG and cardiac imaging data 
Not applicable. 


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2.8.4.2 
Vital signs 
Sample statistics of vital signs were presented for V2/BL/M0 as well as the last value until 
V7/M36 and the change (i.e. difference) between these time points. The average of the three 
measurements of blood pressure war analysed. 
Abnormal values for pulse, diastolic and systolic blood pressure was defined in the study 
protocol. A shift table for abnormal values at baseline versus post-baseline was presented. For 
the post-baseline period, an abnormality was counted if it occurred at any visit after V2/BL/M0.  
2.9 
Pharmacokinetic endpoints   
No pharmacokinetic endpoints were defined.  
 
2.10 
PD and PK/PD analyses 
No pharmacodynamics/pharmakokinetic endpoints were defined. 
 
2.12 
Biomarkers 
2.13 
 Not applicable.Other Exploratory analyses 
Not applicable. 
2.14 
Interim analysis 
Not applicable. 
3 
Sample size calculation 
Published data varies widely as to the average thinning of RNFL in MS patients and no data is 
available on patients treated with Fingolimod. As this is an explorative study to get a better 
understanding of RNFL thinning in RRMS treated with Fingolimod we will take a 
representative sample of approximately 100 patients with RRMS who are stable on Fingolimod 


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4 
Change to protocol specified analyses 
The change in ganglion cell layer thickness (GCLT) was defined as secondary endpoint, but 
OCT measured the ganglion cell inner plexiform layer (GCIP). This was done because both 
layers are not clearly separable by OCT. The volume of GCIP is declared as usual parmeter. 
5 
Appendix 
5.1 
Imputation rules 
. 
Missing dates are completed by 15th for missing days and 6th for missing months.  
Imputation of primary and secondary parameters are described above. 
5.3 
Statistical models 
5.3.1 
Primary analysis 
See 2.5 Analysis of the primary objective.  
5.3.2 
Key secondary analysis 
The SAS syntax for mixed model to compare RNFLT in eyes with versus without optic neuritis 
is: 
proc mixed data=test5; 


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  class patno opt_neur ; 
  model rnflt = opt_neur; 
  random patno; 
  lsmeans krank / tdiff pdiff; 
run; 
RNTFL ist the difference from BL to last value until M36. Here no average over both eyes is 
calculated, but each measurement is included in the dataset and flagged in OPT_NEUR if the 
respective eye was affected by optic neuritis history. 
5.4 
Rule of exclusion criteria of analysis sets  
Table 1 
Protocol deviations that cause subjects to be excluded 
Deviation 
ID 
Description of Deviation 
Exclusion in Analyses 
I1 
Informed consent not obtained 
Excluded from all analyses 
I3 
Subject aged < 18 
Excluded from PP analysis 
I4 
Subject not diagnosed with RRMS 
Excluded from all efficacy analyses 
I5 
Subject with EDDS > 6.0 at baseline visit 
Exclude from PP analysis 
I6 
Subject not stable on Fingolimod for at least  
28 days and at most 4 months prior to 
screening 
Excluded from PP analysis 
I7 
Evidence of acute relapse within 30 days 
prior to baseline visit 
Excluded from PP analysis 
E1 
Forbidden concomitant medication 
Case by case review: excluded from 
PP analysis  
E3  
Subject is suffering from a cardiovascular 
condition 
Case by case review: excluded from 
PP analysis (if relevant for primary 
parameter) 
E4 
Subject suffering from severe respiratory 
disease 
Case by case review: excluded from 
PP analysis  
E5 
Subjects with history of specific MRI findings 
Excluded from PP analysis 
E7 
Subject with a history of a malignancy of any 
organ system within the past 5 years 
Excluded 
from 
PP 
analysis 
(Exception: 
localized 
basal 
cell 
carcinoma of the skin) 
E8 
Use of other investigational drug/therapy 
within 90 days or 5 half-lives of screening 
Case by case review: excluded from 
PP analysis  
E9 
Pregnant or nursing women  
Excluded from PP analysis 
E10 
Subject with any ophthalmologic reason for 
RNFL pathology other than MS 
Case by case review: excluded from 
PP analysis 
E11 
History or active severe myopia 
Case by case review: excluded from 
PP analysis 
E12  
Acute optic neuritis within the last 6 months 
prior to screening 
Excluded from PP analysis 


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Deviation 
ID 
Description of Deviation 
Exclusion in Analyses 
E13 
Evidence of advanced diabetic retinopathy 
Excluded from PP analysis 
E14 
Presence of retinal conditions 
Case by case review: excluded from 
PP analysis 
E15 
Concomitant use of drugs that may directly 
affect retinal structure and function 
Case by case review: excluded from 
PP analysis 
S1 
Treatment regime changed 
Excluded from PP analysis 
O1  
Baseline OCT measurements not performed 
Excluded from PP analysis 
O3 
Difference between visit 7 and baseline ≤ 
1035 days 
Excluded from PP analysis 
 
Table 2 
Subject Classification 
Analysis Set 
PD ID that 
    
cause subjects to be excluded 
Non-PD criteria that cause  
subjects to be excluded 
ENR 
NA 
Not having informed consent; 
Not having screening epoch disposition page 
(i.e. date for Screening visit, vis1n=1) 
SAF 
NA 
No dose of fingolimod taken 
FAS 
I1 
Not in SAF 
No post-baseline efficacy data are collected 
PPS 
I1, I3, I4, I5, I6, I7 
E1, E3 to E15 
S1, O1, O3 
 
 
6 
Reference 
None