Conditions: Cognition Brain Volume Loss
Keywords: RRMS, Cognition, brain, Fingolimod, Multiple Sclerosis, neurodegeneration, Brain atrophy, gray matter atrophy, thalamic atrophy, biomarkers, BICAMS Battery,
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 4
Healthy volunteers: yes

Brief summary:
This was a 24-month, open-label, multicenter study with a single treatment arm design.

Primary objective of this study was:

-To investigate the effects of Fingolimod on cognitive performance in highly active relapsing remitting multiple sclerosis patients

Secondary objectives of this study were:

* To investigate the correlation between the effect of fingolimod on cognitive performances and MRI data.
* To evaluate the effect of fingolimod on biomarkers (24 hydroxy cholesterol, osteopontin and matrix metalloproteinases) related to neurodegeneration
* To investigate the effect of fingolimod on brain gray matter atrophy and thalamic atrophy.

Polulation The hope was to recruit a minimum of 80 relapsing remitting MS (RRMS) patients according to the McDonald criteria.

Detailed description:

Arms:
arm 1: 0.5 mg p.o fingolimod daily

Interventions: intervention 1: 0,5 mg Fingolimod
Intervention descriptions: intervention 1: 0.5 mg p.o fingolimod daily

Protocol document:
Prot_SAP_000.pdf: 
Clinical Development 
[FTY720/Fingolimod] 
Clinical Trial Protocol [CFTY720DTR05] / NCT02575365
Effect of Fingolimod (Gilenya®) on neurodegeneration, brain 
atrophy and cognitive impairment in relapsing remitting multiple 
sclerosis patients 
Authors: 
 
 
 
Document type: 
Clinical Trial Protocol  
EUDRACT number: 
Not Applicable 
Version number: 
V1.0  
Development phase: 
IV  
Release date: 
07.07.2015 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
NCDS Template Version 03-Feb-2012


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Table of Contents 
 
Table of Contents .............................................................................................................. 2 
List of tables ....................................................................................................................... 4 
Glossary of terms .............................................................................................................. 6 
Protocol synopsis .......................................................................................................... 7 
1 
Introduction ....................................................................................................................... 11 
1.1 
Background ............................................................................................................ 11 
1.2 
Purpose .................................................................................................................. 13 
2 
Study objectives and endpoints ......................................................................................... 13 
2.1 
Primary objective ................................................................................................... 13 
2.2 
Secondary objectives ............................................................................................. 13 
2.3 
Primary and secondary endpoints: ......................................................................... 13 
2.3.1 
Primary endpoint: .................................................................................. 13 
2.3.2 
Secondary endpoints: ............................................................................ 13 
3 
Investigational plan ........................................................................................................... 14 
3.1 
Study design........................................................................................................... 14 
3.2 
Rationale of dose/regimen, route of administration and duration of treatment ..... 15 
3.3 
Rationale for choice of comparator ....................................................................... 15 
3.4 
Purpose and timing of interim analyses/design adaptations .................................. 15 
3.5 
Risks and benefits .................................................................................................. 16 
4 
Population .......................................................................................................................... 16 
4.1 
Inclusion criteria .................................................................................................... 16 
4.2 
Exclusion criteria ................................................................................................... 16 
5 
Treatment ........................................................................................................................... 17 
5.1 
Protocol requested treatment ................................................................................. 17 
5.1.1 
Investigational treatment ....................................................................... 17 
5.1.2 
Additional study treatment .................................................................... 17 
5.2 
Treatment arms ...................................................................................................... 17 
5.3 
Treatment assignment, randomization ................................................................... 17 
5.4 
Treating the patient ................................................................................................ 18 
5.4.1 
Patient numbering ................................................................................. 18 
5.4.2 
Dispensing the investigational treatment .............................................. 18 
5.4.3 
Handling of study treatment .................................................................. 18 
5.4.4 
Instructions for prescribing and taking study treatment ........................ 19 
5.4.5 
Permitted dose adjustments and interruptions of study treatment ........ 19 


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5.4.6 
Rescue medication ................................................................................ 20 
5.4.7 
Concomitant treatment .......................................................................... 20 
5.4.8 
Prohibited Treatment ............................................................................. 20 
5.4.9 
Discontinuation of study treatment and premature patient 
withdrawal ............................................................................................. 21 
5.4.10 
Study completion and post-study treatment .......................................... 22 
5.4.11 
Early study termination. ........................................................................ 22 
6 
Visit schedule and assessments ......................................................................................... 23 
6.1 
Information to be collected on screening failures .................................................. 24 
6.2 
Patient demographics/other baseline characteristics ............................................. 24 
6.3 
Treatment exposure and compliance ..................................................................... 24 
6.4 
Efficacy .................................................................................................................. 25 
6.4.1 
Cognitive Tests...................................................................................... 25 
6.4.2 
Magnetic Resonance Imaging (MRI) Assessments .............................. 27 
6.4.3 
Biomarkers ............................................................................................ 28 
6.4.4 
Expanded Disability Status Scale (EDSS) ............................................ 28 
6.5 
Safety ..................................................................................................................... 28 
6.5.1 
Laboratory evaluations .......................................................................... 28 
6.5.2 
Electrocardiogram (ECG) ..................................................................... 28 
6.5.3 
Optical Cohorence Tomography (OCT) ............................................... 29 
6.5.4 
Pregnancy and assessments of fertility ................................................. 29 
7 
Safety monitoring .............................................................................................................. 29 
7.1 
Adverse events ....................................................................................................... 29 
7.2 
Serious adverse event reporting ............................................................................. 31 
7.3 
Pregnancy  reporting .............................................................................................. 32 
8 
Data review and database management ............................................................................. 32 
8.1 
Site monitoring ...................................................................................................... 32 
8.2 
Data collection ....................................................................................................... 33 
8.3 
Database management and quality control ............................................................ 33 
8.4 
Data Monitoring Committee .................................................................................. 33 
8.5 
Adjudication Committee ........................................................................................ 33 
9 
Data analysis ...................................................................................................................... 34 
9.1 
Analysis sets .......................................................................................................... 34 
9.2 
Patient demographics and other baseline characteristics ....................................... 34 
9.3 
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance) ............................................................................................................ 34 
9.4 
Analysis of Efficacy Variables .............................................................................. 34 
9.4.1 
Primary efficacy endpoint: .................................................................... 34 


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9.4.2 
Secondary efficacy endpoints: .............................................................. 34 
9.4.3 
Statistical model, hypothesis, and method of analysis .......................... 35 
9.4.4 
Supportive analyses ............................................................................... 37 
9.5 
Safety variables ...................................................................................................... 37 
9.6 
Sample size calculation .......................................................................................... 37 
9.7 
Interim analyses ..................................................................................................... 38 
10 Ethical considerations ........................................................................................................ 38 
10.1 
Regulatory and ethical compliance ........................................................................ 38 
10.2 
Informed consent procedures ................................................................................. 38 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 39 
10.4 
Publication of study protocol and results............................................................... 39 
11 Protocol adherence ............................................................................................................ 39 
11.1 
Protocol Amendments ........................................................................................... 39 
12 References ......................................................................................................................... 40 
13 Appendix 1: 2010 Revisions to the McDonald diagnosis criteria for MS Guidelines 
from International Panel on the diagnosis of MS .............................................................. 43 
 
 
List of tables 
Table 6-1 
Assessment schedule ..................................................................... 23 
 


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List of abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
ECG 
Electrocardiogram 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
i.v. 
intravenous 
IRB 
Institutional Review Board 
p.o. 
oral 
RRMS 
relapsing remitting multiple sclerosis 
SAE 
serious adverse event 
 
 
 


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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) 
Epoch  
The planned stage of the subjects’ participation in the study. Each epoch 
serves a purpose in the study as a whole. Typical epochs are: 
determination of subject eligibility, wash-out of previous treatments, 
exposure of subject to treatment or to follow-up on subjects after treatment 
has ended. 
Investigational drug 
The drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.” 
Investigational treatment 
All investigational drug(s) whose properties are being tested in the study 
as well as their associated treatment controls.  
This includes any placebos, any active controls, as well as approved drugs 
used outside of their indication/approved dosage or tested in a fixed 
combination.  
Investigational treatment generally does not include other treatments 
administered as concomitant background therapy required or allowed by 
the protocol when used within approved indication/dosage 
Subject Number  
A number assigned to each patient who enrolls into the study  
Part  
A subdivision of a single protocol into major design components. These 
parts often are independent of each other and have different populations or 
objectives. For example, a single dose design, a multiple dose design that 
are combined into one protocol, or the same design with different patient 
populations in each part. 
Period 
A subdivision of a cross-over study 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the planned 
completion of all investigational/study treatment administration and all 
assessments (including follow-up) 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or when 
study/investigational treatment was discontinued whichever is later 
Study drug/ treatment 
Any single drug or combination of drugs administered to the patient as part 
of the required study procedures; includes investigational drug (s), active 
drug run-ins or background therapy  
Study/investigational treatment 
discontinuation 
Point/time when patient permanently stops taking study/investigational 
treatment  for any reason; may or may not also be the point/time of 
premature patient withdrawal 
Variable 
Information used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified time points 
 
 
 


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Protocol synopsis 
  
Protocol 
number 
CFTY720DTR05 
Title 
Effect of Fingolimod on neurodegeneration, brain atrophy and cognitive 
impairment in relapsing remitting multiple sclerosis patients 
Brief title 
 
Effect of Fingolimod on neurodegeneration, brain atrophy and cognitive 
impairment in relapsing remitting multiple sclerosis patients 
Sponsor and 
Clinical Phase 
Novartis  
Phase IV 
Investigation 
type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
Multiple sclerosis (MS) is a neurodegenerative disease in which both 
demyelination and axonal loss occur. 
Cognitive impairment is a major problem in MS and adversely affects patients’ 
quality of life. Cognitive decline may appear early in the disease process and has 
been reported even at disease onset. It has previously been shown that a cognitive 
impairment is present in 53.7% of RRMS patients evaluated at the early disease 
stage during the onset of neurological symptomatology. (7,8)  
Our aim in this study is to investigate the effect of fingolimod on cognitive 
performance. 
Neuronal loss has been historically detected through MRI quantification of brain 
volume. Gray matter atrophy occurs in patients with relapsing forms of MS early 
in the disease course, has a major relationship to physical disability and cognitive 
impairment, and is a putative measure of neuroprotective therapeutic effects. (9)  
The paired thalamic nuclei are gray matter structures on both sides of the third 
ventricle and are involved in a wide range of neurological functions including 
motor, sensory, integrative, and higher cortical functions.(10)  Thalamic location, 
unique neurologic functions, widespread cortical and subcortical connections and 
vulnerability to MS pathology from the earliest clinical disease stages make it a 
critical structure for examining neurodegeneration in MS (11,12) 
Our other aim in this study is to investigate the effect of fingolimod on brain gray 
matter atrophy and thalamic atrophy. 
Cognitive dysfunctions are mainly associated with brain atrophy especially cortical 
grey matter.  (13,14) In this study we will investigate the correlations between the 
effects of fingolimod on cognitive performances and  MRI data. 
For diagnostic, prognostic and treatment monitoring purposes, biomarkers which 
reflect the various neurodegenerative processes, would be helpful. The biomarker 
has to be central nervous system (CNS) specific, and available in concentrations 
that could be measured in cerebrospinal fluid (CSF) or blood. Serum and CSF 
oxysterols and cholesterol precursors have been linked to pathological processes in 
MS in previous studies, and seem to be promising candidate biomarkers. (15-17) 


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In this study we will evaluate the effect of fingolimod treatment on the serum 
levels of a brain specific cholesterol metabolite 24S-hydroxycholesterol (24OHC) 
which is a biomarker reflecting neurodegeneration. (22) 
 We will also evaluate  the effect of fingolimod on plasma levels of osteopontin 
which is a pro-inflammatory cytokine and matrix metalloproteinase which have a 
role in the pathology of multiple sclerosis.(23,24) 
 
Primary 
Objective(s) 
and Key 
Secondary 
Objective 
Primary objective of this study is: 
-To investigate the effects of Fingolimod on cognitive performance in highly 
active relapsing remitting multiple sclerosis patients 
Secondary 
Objectives 
 
Secondary objectives of this study are:  
-To investigate the correlation between the effect of fingolimod on cognitive 
performances and MRI data. 
-To evaluate  the effect of fingolimod on biomarkers (24 hydroxy cholesterol, 
osteopontin and matrix metalloproteinases) related to neurodegeneration  
-To investigate the effect of fingolimod on brain gray matter atrophy and thalamic 
atrophy. 
Study design 
This is a 24-month, open-label, multicenter study with a single treatment 
arm design.  
Population 
We will recruit a minimum of 80 relapsing remitting MS (RRMS) patients 
according to the McDonald criteria.  All subjects will sign an informed consent 
that will be approved by the Ethics Committee.  
Inclusion 
criteria 
1. Diagnosed with RRMS as described in 2010 McDonald criteria  
2. Provided written informed consent prior to any intervention  
3. Female or male patients aged 18-65 years  
4. Unresponsive to treatment with a beta interferon or glatiramer acetate for a 
minimum of one year at and at adequate dose and with high disease 
activity  
(Unresponsive patients: patients with no changes in relapses, increased relapses, 
severer relapses with one-year treatment or those who had had at least one relapse 
during the past one year under previous treatments and one or multiple contrast 
enhancing lesions in cranial MRI or increased T2 lesions in successive MRIs) 
5. EDSS score below 5.5 at screening 
               
Exclusion 
criteria 
1. Patients with primary or secondary progressive or progressive relapsing 
MS 
2. Patients with known contraindications for fingolimod treatment. 
3. Other coexistent autoimmune diseases including Hashimoto thyroiditis, 
systemic lupus erythematosus, rheumatoid anthiritis, psoriasis etc.  
4. Patients with any of the following cardiovascular conditions:  
 
Resting heart rate < 45 bpm/min  


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 
Cardiac failure at any time during the first study visit (Class 
III as per NYHA classification) or significant heart disease as 
judged by the physician  
 
Myocardial infarction during the last 6 months  
 
History of Mobitz Type II grade 2 AV block  
 
Past or current grade 3 AV block  
 
Confirmed history of sick sinus syndrome or sino-atrial heart 
block  
 
arrhythmia requiring current treatment with Class Ia drugs 
(ajmaline, disopyramid, procainamide, quinidine)  
 
hypertension uncontrolled with medication 
5. History of malignancy of any organ system (other than localized basal cell 
carcinoma of the skin), treated or untreated, within the past 5 years, 
regardless of whether there is evidence of local recurrence or metastases. 
6. Pregnant or nursing (lactating) women, where pregnancy is defined as the 
state of a female after conception and until the termination of gestation, 
confirmed by a positive hCG laboratory test. 
7. Negative for varicella-zoster virus IgG antibodies at screening. Patients 
who have negative results for varicella-zoster virus IgG antibodies can be 
included in the study after vaccination for varicella-zoster virus. 
8. Active systemic bacterial, viral or fungal infections, or diagnosis of AIDS, 
Hepatitis B, HepatitisC infection defined as a positive HIV antibody, 
Hepatitis B surface antigen or Hepatitis C antibody tests, respectively 
9. History of previous fingolimod therapy 
10. Patient who received any of the treatments below:  
a. Corticosteroids or adrenocorticotropic hormone (ACTH) during 
the last 1 month  
b. Immunosuppressive 
medications 
such 
as 
azathioprine 
or 
methotrexate etc.  
c. Immunoglobulin treatment during the last 3 months  
d. Cladribine, cyclophosphamide, mitoxantrone, natalizumab at any 
time 
 
Investigational 
and reference 
therapy 
Fingolimod 
Efficacy 
assessments 
Cognitive tests, MRI ,biomarkers, EDSS 
Safety 
assessments 
This study does not include any planned safety analysis 
Other 
Not Applicable 


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assessments 
Data analysis 
Data analysis will be performed after all of the data is collected from the enrolled 
patients. All RRMS patients will be accepted as the analysis sets. 
 
Key words 
Fingolimod, neurodegeneration, brain, atrophy, cognitive, impairment, relapsing, 
remitting, multiple, sclerosis 
 
 
 


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1 
Introduction 
1.1 
Background  
Multiple sclerosis (MS) is the leading cause of neurological disability in young adults and the 
most common demyelinating disorder of the central nervous system. It is widely regarded as a 
chronic autoimmune disorder encompassing both inflammatory (myelin destruction) and 
degenerative (axonal loss) features. Disease onset is thought to be mediated by T lymphocytes 
that recognize myelin antigens, cross the blood brain barrier and drive the immune response 
against oligodendrocytes and myelin sheaths. MS typically presents in relapsing forms, either 
with a relapsing-remitting (RRMS) or secondary progressive (SPMS) course. Patients suffer 
acute self-limiting attacks (relapses) of neurological dysfunction followed by complete or 
incomplete 
remission. 
Between 
relapses, 
patients 
are 
either 
neurologically 
and 
symptomatically stable (RRMS) or continue to deteriorate in function unrelated to relapses 
(SPMS). Currently available therapies for patients with RRMS (interferon β and glatiramer 
acetate) have partial efficacy (about 30-40% reduction in relapse rate and at best a modest 
effect on disability progression). These agents are biologic parenteral treatments requiring 
injections associated with side effects (injection site reactions, flu-like symptoms). Therefore, 
there is a strong medical need for a safe and effective oral treatment of MS. (1)  
Fingolimod is a novel, orally active, synthetic small molecule in clinical development for MS. 
Fingolimod is rapidly phosphorylated in vivo, and fingolimod-phosphate (fingolimod-P) acts 
as agonist of G protein-coupled receptors for sphingosine-1 phosphate (S1P). More 
particularly, fingolimod-P acts as ‘super agonist’ of the S1P1 receptor on thymocytes and 
lymphocytes, inducing internalization of that receptor. This renders these cells unresponsive 
to S1P1 signaling, thus depriving them of a signal necessary for egress from lymph nodes and 
secondary lymphoid tissues. The downstream result of this fingolimod induced interdiction of 
S1P1 signaling is a marked reduction in the number of both B and T lymphocytes in the 
intravascular compartment and a decrease in recirculation of these cells to extravascular 
compartments, including the CNS. In animal immunization models, fingolimod neither 
impaired T-cell activation, expansion, and memory, nor antibody production by B-cells. 
However, fingolimod will reduce the ability of an expanded number of activated effector 
lymphocytes to return to a site of inflammation or infection. 
Emerging preclinical data suggest that the mechanism of action of fingolimod may involve 
CNS effects in addition to the effect on reducing lymphocyte infiltration into the CNS. 
Fingolimod penetrates into the brain, accumulating predominantly in the white matter. S1P 
receptors are widely expressed in the CNS, in particular on neurons and glial cells  and there 
is evidence for S1P signaling on CNS cells with involvement in e.g. survival and modulation 
of process formation in both neurons and oligodendrocytes, neurogenesis, and 
neuroexcitability.(2) In vitro, fingolimod was shown to activate S1P receptors on astrocytes, 
stimulating intracellular pathways that regulate a variety of functions such as cell proliferation 
and migration.(3) Other studies, also in cell culture, demonstrated that fingolimod improved 
the survival and increased the number of progenitor and mature oligodendrocytes. (4,5) 
Furthermore,fingolimod, when directly administered in the brain of rats, in doses which did 
not induce any effect in circulating lymphocytes, significantly suppressed the severity of 


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clinical Experimental Autoimmune Encephalomyelitis (EAE). This clinical improvement was 
associated with enhanced myelization and axonal protection (6)  
The clinical experience with fingolimod is already extensive. In clinical trials, to date over 
15000 MS patients have been exposed to single or multiple doses of fingolimod. Based on this 
experience, pharmacodynamic effects ascribed to fingolimod are: 1) a rapid and persistent 
reduction of the peripheral lymphocyte count that is reversible after treatment discontinuation, 
2) a predictable reduction in heart rate that is maximal upon treatment initiation and attenuates 
over time under continued treatment, 3) a mild- to moderate increase in airway resistance 
early after treatment initiation. The molecular basis of these effects is well understood and 
compatible with the known mode of action of fingolimod via engagement of S1P receptors. 
An increased incidence of macular edema has been observed with fingolimod (in combination 
with cyclosporine A) in the renal transplantation studies. Regular ophthalmic monitoring in 
the ongoing clinical development program in RRMS patients has revealed cases of macular 
edema both prior to and after study drug initiation. The risk of macular edema in multiple 
sclerosis studies is currently under evaluation in the ongoing program, in which all patients 
are undergoing regular ophthalmology evaluations. 
Multiple sclerosis (MS) is a neurodegenerative disease in which both demyelination and 
axonal loss occur. 
Cognitive impairment is a major problem in MS and adversely affects patients’ quality of life. 
Cognitive decline may appear early in the disease process and has been reported even at 
disease onset. It has previously been shown that a cognitive impairment is present in 53.7% of 
RRMS patients evaluated at the early disease stage during the onset of neurological 
symptomatology. (7,8)  
Neuronal loss has been historically detected through MRI quantification of brain volume. 
Gray matter atrophy occurs in patients with relapsing forms of MS early in the disease course, 
has a major relationship to physical disability and cognitive impairment, and is a putative 
measure of neuroprotective therapeutic effects. (9)  
The paired thalamic nuclei are gray matter structures on both sides of the third ventricle and 
are involved in a wide range of neurological functions including motor, sensory, integrative, 
and higher cortical functions.(10)  Thalamic location, unique neurologic functions, 
widespread cortical and subcortical connections and vulnerability to MS pathology from the 
earliest clinical disease stages make it a critical structure for examining neurodegeneration in 
MS (11,12) 
Cognitive dysfunctions are mainly associated with brain atrophy especially cortical grey 
matter.  (13,14) In this study we will investigate the correlations between the effects of 
fingolimod on cognitive performances and  MRI data. 
For diagnostic, prognostic and treatment monitoring purposes, biomarkers which reflect the 
various neurodegenerative processes, would be helpful. The biomarker has to be central 
nervous system (CNS) specific, and available in concentrations that could be measured in 
cerebrospinal fluid (CSF) or blood. Serum and CSF oxysterols and cholesterol precursors 
have been linked to pathological processes in MS in previous studies, and seem to be 
promising candidate biomarkers. (15-17) 


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1.2 
Purpose  
Our main aim in this study is to investigate the effect of fingolimod on cognitive performance. 
Our other aim in this study is to investigate the effect of fingolimod on brain gray matter 
atrophy and thalamic atrophy. 
In this study we will evaluate the effect of fingolimod treatment on the serum levels of a brain 
specific cholesterol metabolite 24S-hydroxycholesterol (24OHC) which is a biomarker 
reflecting neurodegeneration. (22) We will also evaluate the effect of fingolimod on plasma 
levels of osteopontin which is a pro-inflammatory cytokine and matrix metalloproteinase 
which have a role in the pathology of multiple sclerosis.(23,24) 
2 
Study objectives and endpoints 
2.1 
Primary objective 
Primary objective of this study is: 
-To investigate the effects of Fingolimod on cognitive performance in highly active relapsing 
remitting multiple sclerosis patients  
2.2 
Secondary objectives 
Secondary objectives of this study are:  
-To evaluate the effect of fingolimod on biomarkers (24 hydroxy cholesterol ,osteopontin and 
matrix metalloproteinases) related to neurodegeneration  
-To investigate the effect of fingolimod on brain gray matter atrophy and thalamic atrophy. 
-To investigate the correlation between the effect of fingolimod on cognitive performances 
and MRI data. 
2.3 
Primary and secondary endpoints:  
2.3.1 
Primary endpoint: 
- To evaluate the effects of Fingolimod on cognitive performance in highly active relapsing 
remitting multiple sclerosis patients comparing baseline, month 12 and month 24, as assessed 
by BICAMS battery test. 
 
2.3.2 
Secondary endpoints:  
-To measure the difference in  serum levels of 24S-hydroxycholesterol (24OHC) , osteopontin  
and matrix metalloproteinases (and also MMPI’s)  between baseline and after fingolimod 
treatment at month 12 and month 24. 
-To evaluate the effect of fingolimod on cognitive performance in highly active relapsing 
remitting multiple sclerosis patients comparing baseline, month 12   and month 24, as 
assessed by PASAT and Stroop test.  


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-To evaluate the effect of fingolimod on brain gray matter atrophy and thalamic atrophy by 
comparing MRI data between baseline and month 24.  
-To evaluate the correlation between effect of fingolimod on cognitive performances and 
brain atrophy (gray matter atrophy and thalamic atrophy) by comparing baseline and month 
24.  
3 
Investigational plan 
3.1 
Study design 
This is a 24-month, open-label, multicenter study with a single treatment arm design.  
80 relapsing-remitting MS (RRMS) patients according to the McDonald criteria will be 
recruited in the study.  All subjects will sign an informed consent that will be approved by the 
Ethics Committee. 
Upon signing the informed consent, patients will enter a screening phase to be evaluated for 
eligibility. Screening visit will take place during month -1 to 0. Eligible patients will be given 
the study drug at baseline visit (Visit 1) and these patients will enter the 24-month open-label 
treatment phase.  
At screening period, patient’s eligibility criteria will be confirmed. Patients, who will be 
monitored at the site, will receive their first doses at the clinic, be observed during the 6-hour 
monitoring period. 
Serum samples will be collected from each participant after evaluation for inclusion and 
exclusion criteria at baseline and at months 6, 12 and 24 for measurement of 24 hydroxy 
cholesterol, osteopontin and matrix metalloproteinases (including MMPI’s). 
BICAMS Battery will be used in this study. The Brief International Cognitive Assessment for 
MS (BICAMS) includes 3 cognitive tests, Symbol Digit Modalities Test (SDMT, the second 
edition of the California Verbal Learning Test (CVLT2) and the revised Brief Visuospatial 
Memory Test (BVMTR). BICAMS Battery will be performed to RRMS patients at baseline 
and at months 6, 12 and 24. 
 PASAT will be performed at baseline and at months 6, 12 and 24. 
 Stroop test will be performed at baseline and at months 6, 12 and 24. 
Beck Depression Inventory-II will be performed to distinguish depression and cognitive 
impairment. 
MRI scans will be obtained at baseline and at months 6, 12, 18 and 24 by using 1,5T MRI for 
measuring gray matter atrophy and thalamic atrophy ( a standard scanning protocol will be 
used for MRI  in all centers). 
EDSS will be recorded at baseline and at months 3, 6, 12, 18 and 24. 


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Figure 1: Study protocol flow-chart 
 
 
3.2 
Rationale of dose/regimen, route of administration and duration 
of treatment 
The dose, dose regimen, titration scheme and tapering-off scheme, etc. are in accordance with 
product labeling.  
3.3 
Rationale for choice of comparator 
A comparator arm is not applicable for this study 
3.4 
Purpose and timing of interim analyses/design adaptations 
Interim analysis might be conducted yearly. 


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3.5 
Risks and benefits  
The risk to subjects in this trial will be minimized by compliance with the inclusion/exclusion 
criteria, close clinical monitoring, and minimal study duration which will be planned as 1 year 
enrollment time and 2 years follow up. 
4 
Population 
The study will include 80 relapsing remitting MS (RRMS) patients according to the 
McDonald criteria. All subjects will sign an informed consent that will be approved by the 
Ethics Committee. 
4.1 
Inclusion criteria 
 
1. Diagnosed with RRMS as described in 2010 McDonald criteria (36)  
2. Provided written informed consent prior to any intervention  
3. Female or male patients aged 18-65 years  
4. Unresponsive to treatment with a beta interferon or glatiramer acetate for a minimum 
of one year at and at adequate dose and with high disease activity  
(Unresponsive patients: patients with no changes in relapses, increased relapses, severer 
relapses with one-year treatment or those who had had at least one relapse during the 
past one year under previous treatments and one or multiple contrast enhancing lesions in 
cranial MRI or increased T2 lesions in successive MRIs) 
5. EDSS score below 5.5 at screening  
 
4.2 
Exclusion criteria 
 
1. Patients with primary or secondary progressive or progressive relapsing MS. 
2. Patients with known contraindications for fingolimod treatment. 
3. Other coexistent autoimmune diseases including Hashimoto thyroiditis, systemic lupus 
erythematosus, rheumatoid anthiritis, psoriasis etc.  
4. Patients with any of the following cardiovascular conditions:  
 Resting heart rate < 45 bpm/min  
 Cardiac failure at any time during the first study visit (Class III as per 
NYHA classification) or significant heart disease as judged by the 
physician  
 Myocardial infarction during the last 6 months  
 History of Mobitz Type II grade 2 AV block  
 Past or current grade 3 AV block  


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 Confirmed history of sick sinus syndrome or sino-atrial heart block  
 arrhythmia requiring current treatment with Class Ia drugs (ajmaline, 
disopyramid, procainamide, quinidine)  
 hypertension uncontrolled with medication 
5. History of malignancy of any organ system (other than localized basal cell carcinoma 
of the skin), treated or untreated, within the past 5 years, regardless of whether there is 
evidence of local recurrence or metastases. 
6. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, detected by urinalysis 
and confirmed by a positive hCG laboratory test. 
7. Negative for varicella-zoster virus IgG antibodies at screening. Patients who have 
negative results for varicella-zoster virus IgG antibodies can be included in the study 
after vaccination for varicella-zoster virus. 
8. Active systemic bacterial, viral or fungal infections, or diagnosis of AIDS, Hepatitis B, 
Hepatitis C infection defined as a positive HIV antibody, Hepatitis B surface antigen 
or Hepatitis C antibody tests, respectively 
9. History of previous fingolimod therapy 
10. Patient who received any of the treatments below:  
a. Corticosteroids or adrenocorticotropic hormone (ACTH) during the last 1 month  
b. Immunosuppressive medications such as azathioprine or methotrexate etc.  
c. Immunoglobulin treatment during the last 3 months  
d. Cladribine, cyclophosphamide, mitoxantrone, natalizumab at any time 
 
5 
Treatment 
5.1 
Protocol requested treatment 
5.1.1 
Investigational treatment 
Treatment will be 0.5 mg p.o fingolimod daily. The study drug will be provided by Novartis. 
5.1.2 
Additional study treatment 
No additional treatment beyond investigational treatment is requested for this trial. 
5.2 
Treatment arms 
There is only one treatment arm in this study which will include RRMS patients.  
5.3 
Treatment assignment, randomization  
Not Applicable.  


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5.4 
Treating the patient 
5.4.1 
Patient numbering  
Each patient is uniquely identified by a Subject Number which is composed by the site 
number assigned by Novartis and a sequential number assigned by the investigator. Once 
assigned to a patient, the Subject Number will not be reused.  
Upon signing the informed consent form, the patient is assigned the next sequential number as 
given by the investigator using the next blank CRF book.  
5.4.2 
Dispensing the investigational treatment 
Each study site will be supplied the investigational treatment in packaging of identical 
appearance by Novartis. 
The investigational treatment packaging has a 2-part label. A unique medication number is 
printed on each part of this label which corresponds to the treatment. Investigator staff will 
select the investigational treatment to dispense to the patient using the visit number on the 
label. Immediately before dispensing investigational treatment to the patient, investigator staff 
will detach the outer part of the label from the packaging and affix it to the source document 
(Drug Label Form) for that patient’s unique patient number. Study treatments will be 
dispensed to the patients with intervals of 3 months. 
5.4.3 
Handling of study treatment 
5.4.3.1 
Handling of investigational treatment 
Investigational treatment must be received by a designated person at the study site, handled 
and stored safely and properly, and kept in a secured location to which only the investigator 
and designees have access. Upon receipt, all investigational treatment should be stored 
according to the instructions specified on the labels. Clinical supplies are to be dispensed only 
in accordance with the protocol. 
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the investigational treatment but no 
information about the patient except for the visit number. 
The investigator must maintain an accurate record of the shipment and dispensing of 
investigational treatment in a drug accountability log. Monitoring of drug accountability will 
be performed by the field monitor during site visits and at the completion of the trial. Patients 
will be asked to return all unused investigational treatment and packaging at the end of the 
study or at the time of discontinuation of investigational treatment.  
At the end of the study, and as appropriate during the course of the study, the investigator will 
return all unused investigational treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site. 
5.4.3.2 
Handling of other study treatment 
Not applicable. 


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5.4.4 
Instructions for prescribing and taking study treatment 
Prior to administration of the first dose of the study drug the investigator should reconfirm a 
list of concomitant medications taken by the patient. It is recommended not to initiate 
treatment with beta-blockers, calcium-channel blockers or digoxin within one week before or 
after the first dose of the study drug due to a possible additive effect on heart rate reduction. 
The first dose of the study drug must be administered under the supervision of the First Dose 
Administrator or designee. The patient will stay at the study center for a minimum of 6 hours. 
Heart rate and blood pressure will be monitored hourly during the six hour stay and 
discharged if specific discharge criteria are met. Hourly monitoring will be extended if the 
discharge criteria are not met. Some patients may be required to return to the study center for 
6 hours following the 2nd dose. 
The investigator and/or study personnel should promote compliance by instructing the patient 
to take one capsule of the study drug orally once daily with or without a meal, preferably at 
the same time each day and by stating that compliance is necessary for the patient’s safety and 
validity of the study. The patient should be instructed to contact the site if he/she is unable for 
any reason to take the study drug. 
5.4.5 
Permitted dose adjustments and interruptions of study treatment 
Dose adjustments will not be allowed, however drug interruptions will be allowed based on 
the judgment of the Investigator. 
Conditions/events that may lead to the study drug interruptions based on investigator 
judgment and overall clinical assessment: 
• reported serious adverse event;  
• emergency medical condition, unplanned hospitalization, involving use of excluded 
concomitant medications;  
• abnormal laboratory value(s) or abnormal test or examination result(s) (e.g. PFT, liver 
function tests, ophthalmic findings etc.).  
• patient’s non-compliance.  
Should the patient interrupt the study drug, and should the investigator decide in agreement 
with the sponsor to re-initiate treatment with the study drug, depending on the duration of the 
interruption (see below), the first dose at re-start may need to take place under supervision of 
the First Dose Administrator in a similar manner as the first intake of the study medication. It 
is recommended not to initiate beta-blockers, calcium-channel blockers or digoxin treatment 
within one week before or after the day of re-initiation of the study drug administration due to 
a possible additive effect on heart rate reduction. 
When re-starting of study drug monitoring (as for first dose) is mandatory in the following 
cases: 
• 
The treatment lasted for 14 days or less and was interrupted for more than 1 day 


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• 
The treatment lasted for more than 14 days and less than 29 days and was interrupted 
for 7 days or more 
• 
The treatment lasted for 29 days or more and was interrupted for 14 days or more. 
Re-start decision should be made on a case by case basis and should be discussed with the 
Medical Advisor at Novartis. A reason for the interruption of treatment and time of 
interruption should be appropriately documented in the source documents as well as in the 
Dosage Administration Record CRF. All required guidelines for the above maters are given as 
an appendix to this protocol 
5.4.6 
Rescue medication 
A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis 
is allowed for treatment of relapses as clinically warranted. 
Duration of steroid treatment will be under discretion of the investigator (in general it consists 
of 5-10 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 therapy should be recorded in the related section of 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. 
Patients should be reminded of the importance of reporting any signs or symptoms of an 
infection during treatment. 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, valcyclovir) should be promptly initiated 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 and follow the “Guidance on monitoring of patients with 
symptoms or signs of neurological deterioration inconsistent with MS”. Steroids should not be 
taken prior to conducting the unscheduled MRI. 
5.4.7 
Concomitant treatment 
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study.  
5.4.8 
Prohibited Treatment 
Use of the following treatments is NOT allowed concomitantly with the study drug during the 
course of the study: (use can only be considered if the study drug is permanently 
discontinued): 


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- Immunosuppressive 
medication 
(e.g. 
cyclosporine, 
azathioprine, 
methotrexate, 
cyclophosphamide, mitoxantrone, cladribine);  
- Other concomitant medications: immunoglobulins, monoclonal antibodies (including 
natalizumab), INF-ß, glatiramer acetate, adrenocorticotropic hormone (ACTH). The 
administration of any live or live attenuated vaccines (including for measles) is prohibited 
while patients are receiving study drug and for 3 months after study drug discontinuation. 
They may be administered, thereafter, once there is confirmation that lymphocyte counts 
are in the laboratory normal range. Use of the following treatments is allowed to manage 
potential adverse reactions associated with the study drug:  
i. anticholinergics (atropine s.c. or i.v.) for treatment of symptomatic bradycardia 
as the first line treatment, up to 3 mg/day;  
ii. beta-agonists/sympathomimetics (dopamine drip 5-20μg/kg/min or epinephrine 
drip 2- 10 μg/min) for treatment of non-responsive bradycardia.  Standard short 
course of corticosteroids (methylprednisolone i.v.) is allowed for treatment of 
relapses.  
The medications allowed for treatment of adverse reactions and relapses are not considered 
study supplies, and therefore, need to be supplied by the study site. The investigator should 
instruct the patient to notify the study site about any new medications he/she takes after the 
start of the study drug.  
5.4.9 
Discontinuation of study treatment and premature patient withdrawal 
Patients may voluntarily withdraw from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, fail to return for visits, or become 
lost to follow-up for any other reason. 
If premature withdrawal occurs for any reason, the investigator must make every effort to 
determine the primary reason for a patient’s premature withdrawal from the study and record 
this information on the Study Completion CRF  
The investigator should discontinue study treatment for a given patient or withdraw the 
patient from study if, on balance, he/she believes that continuation would be detrimental to the 
patient’s well-being. 
Study drug must be discontinued for a given patient if the investigator determines that 
continuing it would result in a significant risk for that patient. The following conditions/events 
may be considered sufficient to support a decision about the study drug discontinuation in 
individual cases: 
 serious adverse event (e.g. cardiac failure, diagnosed malignancy) 
 abnormal laboratory value(s) including liver function tests or abnormal test result(s) 
(e.g. PFTs, MRI and ophthalmic findings). See below and Appendix 7 and 8 for 
guidance for safety monitoring  
 withdrawal of consent (eg., in case the patient does not consent to continue in the 
study after a confirmed relapse or disability progression)  
 pregnancy  


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 use of prohibited medications, listed in Section 5.1 and 6.6.5  
 adverse events  
 protocol violation  
 unsatisfactory therapeutic effect  
 patient’s condition no longer requires study treatment  
 administrative problems (e.g. patient’s non-compliance)  
In addition, the following conditions based on the Guidance on safety and ophthalmic 
monitoring should result in study drug discontinuation:  
- Hepatic Increase in ALT > 5 x ULN Increase in AST > 5 x ULN  
- New neurological symptoms accompanied by MRI findings unexpected for 
MS  
- Diagnosis of macular edema  
- Decrease in visual acuity with abnormal OCT (increase in central foveal 
thickness of > 20% compared to screening or cystic changes in the macula). 
 
Patients who discontinue study drug should not be considered withdrawn from the study, 
unless one of the conditions listed above have been met. The sponsor should be notified about 
any decision regarding discontinuation of the study medication. Patients who discontinue the 
study drug should be treated according to the best standard of care. 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. A Study Drug Discontinuation CRF should be completed, giving 
the date and primary reason for stopping the study drug. 
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. 
5.4.10 
Study completion and post-study treatment 
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care.  
5.4.11 
Early study termination. 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and treated for a prematurely withdrawn patient. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the patient’s interests. The 
investigator will be responsible for informing IRBs and/or ECs of the early termination of the 
trial. 


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6 
Visit schedule and assessments 
Table 6-1 lists all of the assessments and indicates with an “x” when the visits are performed. 
Table 6-1 
Assessment schedule 
 
Visit 
Screening 
Period 
1(Baseline) 2 
2 
3 
4 
5 
6 
Month 
-1 to 0 
0 
3 
6 
12 
18 
24 
Obtain informed consent 1 
X 
 
 
 
 
 
 
Background / Demography 
X 
 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
MS history / MS treatment 
X 
 
 
 
 
 
 
Concomitant medication  
X 
 
X 
X 
X 
X 
X 
Physical examination 
X 
 
X 
X 
X 
X 
X 
Vital findings 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
 
X 
X 
X 
X 
X 
Serology 
X 
 
 
 
 
 
 
Blood biochemistry 
X 
 
X 
X 
X 
X 
X 
ECG 
X 
X 
 
 
 
 
 
Optical Cohorence Tomography (OCT) 
X 
 
X 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
EDSS 
X 
 
X 
X 
X 
X 
X 
6-hour first dose monitoring 
 
X 
 
 
 
 
 
Beck Depression Inventory (BDI-II) 
 
X 
 
X 
X 
 
X 
PASAT 
 
X 
 
X 
X 
 
X 
Stroop test 
 
X  
 
X 
X 
 
X 
BICAMS Battery 
 
X 
 
X 
X 
 
X 
MRI 
 
X 
 
X 
X 
X 
X 
Collecting serum samples for biomarkers 
 
X 
 
X 
X 
 
X 
Advers events / SAE 
X 
X 
X 
X 
X 
X 
X 
1 All assessments must be performed after obtaining informed consents. 
2 At visit 1, all assessments must be performed before initiating the study drug. 
 
Patients should be seen for all visits on the designated day with an allowed “visit window” of 
“±7” days at visit 2 and “±14” days at visit 3, 4, 5 or as close to it as possible, or as shortly 
after it as possible, or as shortly before it as possible and “±30” days for the last visit 
At a minimum, patients will be contacted for safety evaluations during the 30 days following 
the last study visit or following the last administration of study treatment if there are post-
treatment follow-up visits (whichever is later), including a final contact at the 30-day point. 
Documentation of attempts to contact the patient should be recorded in the source 
documentation.  


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6.1 
Information to be collected on screening failures 
Patients who sign the informed consent form but fail to meet eligibility criteria during the 
Screening Phase will be considered screening failure and the reason will be documented on 
the Screening Record CRF.  
6.2 
Patient demographics/other baseline characteristics 
Data of patient demographics and baseline characteristics will be collected from all patients 
that include: date of birth and sex. Relevant medical history/current medical condition data 
includes data until the start of study drug. If there is, concomitant diseases will be recorded.  
In addition, MS history and MS treatment will be recorded. 
At screening, an ECG will be performed to ensure that the patients continue to meet inclusion 
criteria. Also an ECG will be performed prior to taking the first dose of fingolimod and after 6 
hours of the first dose, the ECG will be repeated. Should any of the cardiac exclusion criteria 
is met based on the ECG results, the patient will not be allowed to participate in the study. 
ECGs will be printed out and will be kept at the study site as a source document. 
6.3 
Treatment exposure and compliance 
In order to collect accurate information about the study drug exposure, the following records 
should be maintained for each patient: records of study medication dispensed and returned, 
dosages administered and intervals between visits.  
Compliance will be assessed by the investigator and/or study personnel at each visit using 
capsule counts and information provided by the patient. A monitor will perform and document 
drug accountability during site visits and at the end of the study. 
Patients who discontinue study medication consecutively for 1 month will be considered 
withdrawn. 
 
 
 
 
 
 


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6.4 
Efficacy 
6.4.1 
Cognitive Tests 
The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) Battery test 
is the primary efficacy assessment criteria. Cognitive tests will be performed to RRMS 
patients at baseline and at months 6, 12 and 24 at the study center. 
The Brief International Cognitive Assessment for MS (BICAMS) 
The Brief International Cognitive Assessment for MS (BICAMS Battery) includes 3 cognitive 
tests, 1-Symbol Digit Modalities Test (SDMT, 2-the second edition of the California Verbal 
Learning Test (CVLT2) and 3-the revised Brief Visuospatial Memory Test (BVMTR).  
 
Symbol Digit Modalities Test (SDMT) will be used as the test of information processing 
speed. It can be completed in 5 minutes for each patient including instructions, practice and 
testing. It’s a highly efficient tool in determination of cognitive impairment in MS patients 
with a sensitivity rate of 82% and specificity rate of 60%. During the SDMT a series of nine 
symbols, each paired with a single digit in a key at the top of a standard sheet of paper similar 
to the one presented below is shown to the patients and patients are asked to voice the digit 
associated with each symbol as rapidly as possible for 90 seconds for the rest of the figures. 
 
≥ 
± 
« Π Ж ψ ∆ ο 
↑ 
1 
2 
3 4 5 
6 7 8 9 
 
 
 
 
 
 
 
 
 
ψ ± 
« Π ψ ∆ 
↑ Ж ± 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ψ « Ж ± ∆ 
↑ 
« ψ Π 
 
 
 
 
 
 
 
 
 
 
California Verbal Learning Test 2 (CVLT2) is an auditory/verbal learning test ant it begins 
with the examiner reading a list of 16 words. Patients listen to the list and report as many of 
the items as possible. There is no instruction as to the order in which items are recalled. After 
recall is recorded, the entire list is read again followed by a second attempt at recall. 
Altogether, there are five learning trials. After 25 min there is a delayed recall trial as well as 
a yes/no recognition memory task. The 16-item list (an example is given below) will have 
words that conform to four semantic categories, in this case sports, vegetables, clothes, and 
tools. Some subjects will recall items in a grouped fashion, and others may recall the list in 
serial order. There are many variables of recall available in the CVLT2, as a second list is 
presented, and after 25 min there is a delayed recall trial as well as a yes/no recognition 
memory task. The list will be read aloud five times in the same order to the patient, at a 
slightly slower rate than one item per second. Patients will be required to recall as many items 
as possible, in any order, after each reading of the list. The CVLT-II can be completed in 5–10 
minutes, including instructions, testing and responses. The CVLT-II (T1-5 version) has been 


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validated with brain MR total lesion area and right superior frontal atrophy, 44 MR T1 and 
FLAIR lesion volume, BPF and third ventricular width32 and MR diffusion measures. 
 
Football 
Paper 
Folder 
Candy 
Notebook 
River 
Boxing 
Envelope 
Island 
Tennis 
Mountain 
Valley 
Billiards 
Cake 
Pie 
Ice cream 
 
Brief Visuospatial Memory Test (BVMTR) will assess visual/spatial memory in BICAMS. 
In this test, six abstract designs such as the figure shown below are presented for 10 seconds. 
The display is removed from view and patients render the stimuli via pencil on paper manual 
responses. Each design receives from 0 to 2 points representing accuracy and location. Thus, 
scores range from 0 to 12. There will be three learning trials, and the primary outcome 
measure is the total number of points earned over the three learning trials. Because there is 
little evidence that the delayed recall trial adds to discriminant validity in MS, as in the 
MATRICS consensus battery, only the initial learning trials will be included for BICAMS. 
 
 
 
Paced Auditory Serial Addition Test ( PASAT) 
The Paced Auditory Serial Addition Test (PASAT) has been widely used in MS trials and is 
viewed as one of the most adequate measures of cognitive dysfunction in multiple sclerosis. 
PASAT was introduced by Gronwall in the 1970s as a clinical tool for measuring the severity 
of brain injury and its recovery. This test is considered to be a measure of sustained attention, 
divided attention, concentration, and information processing speed. 
During the test the participant is asked to listen to a recorded series of single digits (from 1 to 
9) and add each number to the one presented previously under a considerably time pressure. 
MS patients have been found to be impaired compared with healthy controls at the rapid rates 
(1.2 and 1.6 sec), at the slow rates (2.0 and 2.4 sec), or at all of the rates of presentation. In the 
Multiple Sclerosis Functional Composite (MSFC) version, the presentation rate is 3.0 
seconds. 


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The 3-minute version of the PASAT will be used in this study and the number of correct 
answers will be the outcome variable. PASAT will be performed to RRMS patients at 
baseline and at months 6, 12 and 24. 
 
Stroop Test: 
The Stroop Color and Word Test assesses cognitive processing and provides valuable 
diagnostic information on brain dysfunction, cognition, and psychopathology. It is based on 
the observation that individuals can read words much faster than they can identify and name 
colors. It is a five minute test is applicable for those between the ages of 15 and 90.  
This test was adapted from the paper-based Stroop Color-Word Interference Test (Golden, 
1978) and consists of three 60-s trials, each of which was preceded by a set of eight practice 
items to insure the participant understood the task to follow. In the first trial (word reading, 
W), participants will read color words (RED, BLUE, YELLOW, GREEN) printed in black 
letters; in the second trial (color naming, C), they will name the colors used to print a row of 
four Xs; and in the third trial (color-word naming, CW), they will name the color of the print 
for a set of incongruent Stroop stimuli (e.g., BLUE printed with red letters). In each trial, the 
stimulus item appeared on the paper, the participant will respond verbally to the item, and 
either the experimenter (E-press condition) immediately will show the next item. The number 
of items completed in the allotted time will be recorded. In addition to the W, C, and CW 
scores, the combined score for word-reading and color-naming (W + C) might be examined as 
a particularly good measure of processing speed. Also, a measure of relative interference (RI) 
will be computed by dividing the difference between the color-naming and the color-word 
naming scores by the color-naming score (RI ¼ [C 2 CW]/C). 
Stroop test will be performed to RRMS patients at baseline and at months 6, 12 and 24. 
 
Beck Depression Inventory (BDI-II) 
BDI-II is the 1996 revision of BDI. It is a multiple-choice inventory including 21 items and it 
takes ~ 10 minutes to complete.  
Beck Depression Inventory will be assessed to distinguish depression and cognitive 
impairment. The maximum total score is 63 and scores 0-13 indicates minimal depression, 14-
19 indicates mild depression, 20-28 indicates moderate depression and 29-63 indicates severe 
depression. Beck Depression Inventory will be also performed to distinguish depression and 
cognitive impairment. 
6.4.2 
Magnetic Resonance Imaging (MRI) Assessments 
MRI scans will be obtained at baseline and at months 6, 12, 18 and 24 by using 1,5T MRI for 
measuring gray matter atrophy and thalamic atrophy.  
A standard scanning protocol will be used for MRI in all centers. 
 
MRI scanning protocol: 
MR imaging studies will be performed using a 1.5 Tesla scanner with a dedicated head coil. 
Patients will be placed in supine position.    


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For volumetric measurements, 3D T1 FFE sequence will be obtained. Parameters will be as 
TE: 2.3 ms, TR: 5.1ms, Flip angle: 8°, 1 mm slice thickness, TFE factor: 232, TFE shots: 46 
 
MRI scans will be sent to the Kocaeli University Faculty of Medicine which is the center of 
the study coordinator investigator for atrophy analysis.  
6.4.3 
Biomarkers  
Serum samples will be collected at baseline and at months 6, 12 and 24 from each participant 
after evaluation for inclusion and exclusion criteria for measurement of 24 hydroxy 
cholesterol, osteopontin and matrix metalloproteinases (including MMPI’s). 
6.4.4 
Expanded Disability Status Scale (EDSS) 
EDSS is a scale for assessing neurologic impairment in MS (Kurtzke 1983) including (1) a 
series of scores in each of eight functional systems, and (2) the EDSS steps (ranging from 0 
(normal) to 10 (death due to MS). The functional systems are Visual, Brain Stem, Pyramidal, 
Cerebellar, Sensory, Bowel & Bladder, Cerebral and Other functions. It is recommended that 
fatigue is not included in the Cerebral score of the EDSS. 
EDSS will be assessed by the investigator at each site, who has successfully completed his/her 
certification requirements. EDSS assessments are scheduled at screening and at month 3, 6, 
12, 18 and 24. 
6.5 
Safety 
6.5.1 
Laboratory evaluations 
6.5.1.1 
Hematology 
Hematology parameters will be collected at screening and other visits as shown in the 
assessment schedule and will include:  WBC count, absolute lymphocytes, platelet, absolute 
neutrophil count, and hemoglobin. 
6.5.1.2 
Clinical chemistry 
Blood samples will be collected at screening and at each scheduled visit to verify a 
patient’s eligibility and will include but not limited to the following parameters:  
AST, ALT, BUN, Creatinine, Total Cholesterol, Triglycerides, LDL-K, HDL-K, TSH, ST4, 
Glucose, HbA1c  
 
6.5.2 
Electrocardiogram (ECG) 
A standard 12 lead ECG will be performed at screening, right before the intake of the first 
dose of the study drug and after 6 hours of the intake of the study drug. Interpretation of the 
tracing must be made by a qualified physician and documented on the ECG section of the 
CRF. Each ECG tracing should be labeled with the study and subject number, date, and kept 
in the source documents at the study site. Clinically significant abnormalities should also be 
recorded on the Medical History/Adverse event CRF page. Clinically significant findings 
must be discussed with the Novartis Medical Monitor prior to enrolling the patient in the 
study. 


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6.5.3 
Optical Cohorence Tomography (OCT) 
An optical coherence tomography for the eyes will be performed in screening and in Visit 2. 
The tracing of the OCT must be made by a qualified physician and documented on the OCT 
section of the CRF. Each OCT tracing should be labeled with the study and subject number, 
date, and kept in the source documents at the study site. Clinically significant abnormalities 
should also be recorded on the Medical History/Adverse event CRF page. Clinically 
significant findings must be discussed with the Novartis Medical Monitor prior to enrolling 
the patient in the study. 
6.5.4 
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have a urine pregnancy test. A 
positive urine pregnancy test requires immediate interruption of study drug until serum β-hCG 
is performed and found to be negative. If positive, the patient must be discontinued from the 
trial. 
7 
Safety monitoring  
7.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or 
other assessments. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
 they induce clinical signs or symptoms,  
 they are considered clinically significant,  
 they require therapy.  
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for labs and other test abnormalities are 
included in Appendix 1. 
Adverse events should be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them accompanied by the following information. 
 the severity grade  
 mild: usually transient in nature and generally not interfering with normal activities 


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 moderate: sufficiently discomforting to interfere with normal activities 
 severe: prevents normal activities 
 its relationship to the (select what is applicable) 
study treatment (no/yes), or 
investigational treatment (no/yes), or  
the other study treatment(non-investigational) (no/yes), or 
both or indistinguishable, 
 its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported. 
 whether it constitutes a serious adverse event (SAE)  
 action taken regarding study  treatment  
 whether other medication or therapies have been taken (concomitant medication/non-drug 
therapy) 
 its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
An SAE is any adverse event (appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s) or medical conditions(s) which meets any one of the following criteria  
 is fatal or life-threatening  
 results in persistent or significant disability/incapacity 
 constitutes a congenital anomaly/birth defect 
 requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
 elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent  
 treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission  
 social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
 is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2. 
All adverse events should be treated appropriately. Treatment may include one or more of the 
following: no action taken (i.e. further observation only); [study/investigational] (select) 
treatment dosage adjusted/temporarily interrupted; study drug(s) permanently discontinued; 


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concomitant medication given; non-drug therapy given. 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 study treatment, the 
interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed. 
The investigator should also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information should be recorded in the 
investigator’s source documents, however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis. 
7.2 
Serious adverse event reporting 
 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until  30 days  after the last study visit must be reported to 
Novartis within 24 hours of learning of its occurrence. Any SAEs experienced after the 4 
weeks period should only be reported to Novartis if the investigator suspects a causal 
relationship to study treatment.  
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event. 
Information about all SAEs (either initial or follow up information)  is collected and recorded 
on the paper Serious Adverse Event Report Form. The investigator must assess the 
relationship to each specific component of study treatment (if study treatment consists of 
several drugs) complete the SAE Report Form in English, and send the completed, signed 
form by fax within 24 hours after awareness of the SAE to the local Novartis Drug Safety and 
Epidemiology Department. The telephone and fax number of the contact persons in the local 
department of Drug Safety and Epidemiology, specific to the site, are listed in the investigator 
folder provided to each site. The original copy of the SAE Report Form and the fax 
confirmation sheet must be kept with the case report form documentation at the study site. 
Follow-up information should be provided using a new paper SAE Report Form stating that 
this is a follow-up to a previously reported SAE 
Follow- up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the 
patient continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. 


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If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the investigational treatment a Drug Safety 
and Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same 
investigational treatment that this SAE has been reported. 
Local Novartis Turkey Drug Safety Department will report all fatal or life-threatening 
suspected unexpected serious adverse reactions (SUSARs) to Ministry of Health as per The 
Regulation on Clinical Trials and  Guidance on the collection, verification and submission of 
Adverse Event/Reaction Reports Occurring During Clinical Trials of Medicinal Products 
and Biological Products. 
7.3 
      Pregnancy  reporting 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. 
Any SAE experienced during pregnancy must be reported on the SAE Report Form. 
8 
Data review and database management 
8.1 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and 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, the progress of enrollment, and to ensure that study treatment is being 
stored, dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the field monitor during these visits. 
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 of data that will be used for all primary variables. Additional 


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checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed. 
8.2 
Data collection 
Designated investigator staff 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 the Medical Documents 
Reception Center of Novartis [or CRO working on behalf of Novartis] by field monitors or by 
the investigational site, with one copy being retained at the investigational site. Once the 
CRFs are received by Novartis [or CRO working on behalf of Novartis], their receipt is 
recorded, the original copy is placed in Central Files, and the non-carbon-required copy is 
forwarded to the responsible Data Management staff for processing.   
8.3 
Database management and quality control 
Data from the CRFs are entered into the study database by Novartis Data Management staff 
using single data entry. Verification is performed manually by a separate member of the Data 
Management staff by comparing the Case Report Form to the data entered into the database. 
Data from the CRFs are entered into the study database by Contract Research Organization 
(CRO) 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. 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. 
Adverse events will be coded using the Medical dictionary for regulatory activities 
(MedDRA) terminology. 
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). 
8.4 
Data Monitoring Committee 
Not required. 
8.5 
Adjudication Committee 
Not required. 


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9 
Data analysis  
9.1 
Analysis sets  
Data analysis will be performed after all of the data is collected from the enrolled patients. All 
RRMS patients will be accepted as the analysis sets.  
The statistical analyses of this study will be performed by a Contract Research Organization 
9.2 
Patient demographics and other baseline characteristics   
Data collected for patient demographics and the baseline characteristics will be summarized 
by descriptive statistics with summary tables. 
9.3 
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)  
Data collected for treatments will be summarized by descriptive statistics with summary 
tables. 
9.4 
Analysis of Efficacy Variables 
9.4.1 
Primary efficacy endpoint: 
The primary end-point was planned as evaluating the effects of Fingolimod on cognitive 
performance in highly active, RRMS patients comparing cognitive performance at baseline 
and at Month 24, after treatment for two years as assessed by BICAMS battery test.  
 
In this study, it is proposed to observe an increase of 3 points in SDMT testing (which roughly 
equals to 5 % increase in SDMT overall score) is meaningful and in our study, with treatment 
we may expect a 5% increase in cognitive functioning during a considerably longer duration 
of treatment and follow-up. 
9.4.2 
Secondary efficacy endpoints: 
The metric for the PASAT assessment is the number of correct answers. 
 The Stroop test yields three scores based on the number of items completed on each of the 
three stimulus sheets. 
 
All MRI analysis will be performed at the Kocaeli University Faculty of Medicine which is 
the center of the study coordinator investigator. 
SIENAX—cross-sectional method will be used to measure atrophy.  (25)  
Whole brain volume, total gray matter volume, cortical gray matter volume and deep gray 
matter volume will be measured.  
White matter lesions will be segmented by using k nearest neighbor classification with tissue-
type priors, The resulting lesion volume will be normalized for head size to create normalized 
lesion volume (26,27)  Lesion filling will be applied to minimize the effect of hypointense 
lesions on atrophy measurements (28). Normalized whole-brain volume, normalized gray 


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matter volume (NGMV), and normalized white matter volume (NWMV) will be  measured 
with SIENAX (part of FSL [Functional MRI of the Brain, or FMRIB, Software 
Library] 5.0.2, http://www.fmrib.ox.ac.uk/fsl) by using optimized parameters for brain 
extraction  (29,30).  
Deep gray matter volumes will be measured by using FSL FIRST software (31). Cortical 
thickness 
will 
be 
measured 
by 
using 
FreeSurfer 
5.1 
software (https://surfer.nmr.mgh.harvard.edu/) (32,33). FreeSurfer uses the T1-weighted 
image to locate the white matter and pial surface. The distance between both surfaces gives 
the cortical thickness at each location.   
Thalamic and intracranial volumes will be segmented automatically. Thalamic volumes and 
thalamic fractions will be calculated as ratios of the left and right thalamic volume to the 
intracranial volume. 
Correlation between effect of fingolimod on cognitive performances and brain atrophy will be 
explored. 
9.4.3 
Statistical model, hypothesis, and method of analysis 
The basic hypothesis of the study is improvements in cognitive tests in RRMS patients. The 
sample size calculation for the study has been based on an improvement with treatment in a 
cognitive test (SDMT). 
9.4.3.1 
Data analysis 
General Approach 
 
All Statistical analyses will be performed with MedCalc Statistical Software version 13.1.2 
(MedCalc Software bvba, Ostend, Belgium; http://www.medcalc.org; 2014) at the 5% 
significance level using 2-sided tests or 2-sided Confidence Intervals.  
Descriptive Statistics 
The quantitative variables will be summarized using the following parameters: 
- 
Number of non-missing data (n), 
- 
Mean,  
- 
Standard deviation, 
- 
2-sided 95% CI of the mean, 
- 
Median, 
- 
Minimum, 
- 
Maximum. 
 
The qualitative variables will be summarized using the following parameters: 
- 
Number of non-missing data (n), 
- 
Counts and percentages. 
Missing data or unknown responses will not be counted in the percentages. 
Comparisons of Two Groups 


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Student t test will be used for comparisons of two independent normally distributed groups, 
Mann Whitney u test will be used for comparisons of two independent non-normally 
distributed groups. 
Paired samples t test will be used for comparisons of two dependent normally distributed 
groups, Wilcoxon Signed Rank test will be used for comparisons of two independent normally 
distributed groups. 
 For comparisons of categorical and independent data Chi-Square test or Fisher Exact test 
(where appropriate) will be used. 
To asses categorical and dependent variables Mc Nemar test will be used. 
Normality of continuous data will be tested by using Shapiro-Wilk test. 
Comparisons of Several Groups 
All continuous data (non-normally distributed) with several dependent groups (Baseline, 12th 
month, 1. Year) will be compared by Friedman’s test.  
Normally distributed continuous data with several dependent groups (Baseline, 12th month, 1. 
Year) will be compared by Repeated Measures ANOVA test.  
Continuous, normally distributed data with several independent groups will be compared by 
ANOVA test. For statistically significant results, Post Hoc comparisons will be done with 
Tukey HSD test. 
Continuous, non-normally distributed data with several independent groups will be compared 
by Kruskal-Wallis test. For statistically significant results, Post Hoc comparisons will be done 
with Mann Whitney u test. 
9.4.3.2 
Statistical Methods by Evaluation of Study Objective 
Primary Objective: 
Primary objective of the study will be evaluated by the statistical methods which are stated 
below: 
 Calculated scores of BICAMS (SDMT, CVLT2 and BVMTR) at baseline, 12th month 
and 24th month will be compared by using Repeated Measures ANOVA (if variables 
are non-normally distributed Friedman Test). 
Post-Hoc comparisons will be done with Tukey test. (if Friedman test was used, 
Wilcoxon Signed Rank test will be used for Post-Hoc comparisons.) 
 
Secondary Objectives: 
Secondary objectives of the study will be evaluated by the statistical methods which are stated 
below: 
 


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 The effect of fingolimod on biomarkers (24OHC, Osteopontin and Metalloproteinase) 
at months 6, 12, 24 will be evaluated by comparing the levels of biomarkers. The 
evaluation among time points will be made by using Repeated Measures ANOVA.  
 The effect of fingolimod on brain gray matter atrophy and thalamic atrophy will be 
evaluated by comparing MRI parameters at baseline, 6th, 12th, 24th months. 
The comparison among time points will be made by Repeated Measures ANOVA. (if 
variables are non-normally distributed Friedman Test). 
 Investigation the effect of fingolimod on cognitive performance in highly active 
relapsing remitting multiple sclerosis patients comparing baseline, 12th   and 24th 
month, as assessed by PASAT and Stroop test will be made by Repeated Measures 
ANOVA. (if variables are non-normally distributed Friedman Test). 
 Correlation between cognitive performance and MRI data will be calculated by using 
Pearson Correlation Coefficient (or Spearman Correlation Coefficient) between 
PASAT, STROOP and BICAMS tests scores and MRI parameters. 
9.4.4 
Supportive analyses  
Not Applicable 
9.5 
Safety variables 
Adverse and serious advers events and pregnancies will be summarized.  
9.6 
Sample size calculation 
The primary objective of this study was set as investigating the effects of Fingolimod on 
cognitive performance in highly active relapsing remitting multiple sclerosis (RRMS) 
patients. Thus the primary end-point was planned as evaluating the effects of Fingolimod on 
cognitive performance in highly active, RRMS patients comparing cognitive performance at 
baseline and at Month 24, after treatment for two years as assessed by BICAMS battery test.  
 
The Symbol Digit Modalities Test (SDMT) is one of the best known tests for detecting the 
cognitive impairment in patients with organic cerebral dysfunctions. The SDMT has a high 
sensitivity in detecting the presence of brain damage with providing data on cognitive 
functioning over time in response to treatment. The scoring of SDMT varies between 0-110 
and in a study which evaluated age-related cognitive decline, baseline SDMT values for 50-64 
years age group was 52.9 and for the 65+age group was 45.9 (34). 
   
There are currently various clinical work is on-going for detection of decremetal or 
incremental changes of cognitive function in RRMS patients and in a recent publication by 
Benedict et al  which evaluated  cognitive decline in RRMS patients, the mean SDMT score 
was found to be 53.1 for stable RRMS patients at baseline. In this study, the authors 
concluded that the increment of decline on SDMT was 3.5 raw score points, or roughly 6%.  it 
was concluded that in overall,  there seems to be an emerging consensus that a score change 
of 3–4 points on SDMT is clinically meaningful (35). 
In this study, it is proposed to observe an increase of 3 points in SDMT testing (which roughly 
equals to 5 % increase in SDMT overall score) is meaningful and in our study, with treatment 


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we may expect a 5% increase in cognitive functioning during a considerably longer duration 
of treatment and follow-up. 
As per published literature, any cognitive improvement on the basis of SDMT test at a rate 
of % 5 should be evaluated as a significant improvement for RRMS patient with cognitive 
dysfunction. Thus, in this study we have postulated to reach a 5 % improvement in SDMT test 
at 24 months when compared to baseline in the cognitively impaired RRMS patients.  
Thus, on the basis of percentage improvement expected and by setting alpha at 0.05 and 
without considering power (no treatment group comparisons will be made); a minimum of 73 
RRMS patients has been calculated to be enrolled. However, due to debilitating nature of 
RRMS as a disease and considerably longer duration of treatment and/or follow-up, a 10 % 
LFU should be expected and for providing coverage for such cases, 80 RRMS patients should 
be enrolled to the study.  
9.7 
Interim analyses  
Interim analysis might be conducted yearly. 
10 
Ethical considerations 
10.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki. 
10.2 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative of the patient. 
In cases where the patient’s representative gives consent, the patient should be informed about 
the study to the extent possible given his/her understanding. If the patient is capable of doing 
so, he/she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. Informed consent must be obtained before 
conducting any study-specific procedures (i.e. all of the procedures described in the protocol). 
The process of obtaining informed consent should be documented in the patient source 
documents.  
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval. 


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10.3 
Responsibilities of the investigator and IRB/IEC 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC) before study start. A signed and dated statement that the protocol and 
informed consent have been approved by the IRB/IEC must be given to Novartis before study 
initiation. Prior to study start, the investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the study in accordance with these documents and all 
of the instructions and procedures found in this protocol and to give access to all relevant data 
and records to Novartis monitors, auditors, Novartis Clinical Quality Assurance 
representatives, designated agents of Novartis, IRBs/IECs, and regulatory authorities as 
required. If an inspection of the clinical site is requested by a regulatory authority, the 
investigator must inform Novartis immediately that this request has been made. 
10.4 
Publication of study protocol and results 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results. 
11 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
trial to request approval of a protocol deviation, as requests to approve deviations will not be 
granted. 
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants.  Under no circumstances should an investigator collect additional data 
or conduct any additional procedures for any research related purpose involving any 
investigational drugs.  
If the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR. 
11.1 
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such 
cases, Novartis should be notified of this action and the IRB/IEC at the study site should be 
informed within 10 working days or less, if required by local regulations.  


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12 
References 
 
1- Hafler DA (2004) Multiple Sclerosis. J Clin Invest. Mar; 113(6):788-94.) 
2- Herr DR, Chun J (2007) Effects of LPA and S1P on the nervous system and 
implications for their involvement in disease. Current drug targets; 8:155-167. 
3- Osinde M, Mullershausen F, Kumlesh KD (2007) Phosphorylated FTY720 stimulates 
ERK phosphorylation in astrocytes via S1P receptors. Neuropharmacology 1210-1218. 
4- Barske C, Osinde M, Mir A, et al (2007) FTY720 (finoglimod) enhances the number 
of progenitor and mature oligodendrocytes. Poster presentation AAN 2007 
5- Jung CG, Kim HJ, Miron VE, et al (2007) Functional consequences of S1P receptor 
modulation in rat oligodendroglial lineage cells. Glia; 55(16):1656-67 
6- Schubart A, et al. (2007) CNS Mediated effects on FTY720 in EAE. Poster 
presentation AAN 2007 
7- Achiron A, Doniger GM, Harel Y, Appleboim-Gavish N, Lavie M, Simon ES (2007) 
Prolonged response times characterize cognitive performance in multiple sclerosis. 
Eur J Neurol 14:1102-8. 
8-  Achiron A, Barak Y. Cognitive impairment in probable multiple sclerosis. J Neurol 
Neurosurg Psychiatry 2003; 74:443-446.) 
9- Healy et al. Journal of Neurology, Neurosurgery, Psychiatry 2009;80:1218-24 
10-  Minagar A, Barnett MH, Benedict RH, et al. The thalamus and multiple sclerosis: 
Modern views on pathologic, imaging, and clinical aspects. Neurology 2013;80:210-
219. 
11-  Cifelli A, Arridge M, Jezzard P, Esiri MM, Palace J, Matthews PM. Thalamic 
neurodegeneration in multiple sclerosis. Ann Neurol 2002;52:650-653. 
12-  Gilmore CP, Donaldson I, Bo L, Owens T, Lowe J, Evangelou N. Regional variations 
in the extent and pattern of grey matter demyelination in multiple sclerosis: a 
comparison between the cerebral cortex, cerebellar cortex, deep grey matter nuclei and 
the spinal cord. J Neurol Neurosurg Psychiatry 2009;80:182-187. 
13- Geurts JJ, Barkhof F. Grey matter pathology in multiple sclerosis. Lancet Neurol 
2008;7:841-851. 
14- Calabrese M, Rinaldi F, Grossi P, Gallo P. (2011) Cortical pathology and cognitive 
impairment in multiple sclerosis. Expert Rev Neurother. Mar;11(3):425-32 
15- Leoni V. Oxysterols as markers of neurological disease: A review. Scand J Clin Lab 
Invest 2009; 69: 22–25.  
16- Leoni V and Caccia C. Oxysterols as biomarkers in neurode¬generative diseases. 
Chem Phys Lipids 2011; 164: 515–524.  
17- Teunissen CE, Dijkstra CD, Polman CH, et al. Decreased levels of the brain specific 
24S-hydroxysterol and cholesterol precursors in serum of multiple sclerosis patients. 
Neurosci Lett 2003; 347: 159–162. 


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13 
Appendix 1: 2010 Revisions to the McDonald diagnosis 
criteria for MS Guidelines from International Panel on the 
diagnosis of MS 
 
Table 1: 2010 McDonald MRI Criteria for Demonstration of DIS 
DIS Can Be Demonstrated by ≥1 T2 Lesiona in at Least 2 of 4 Areas of the CNS: 
 Periventricular 
 Juxtacortical 
 Infratentorial 
 Spinal cordb 
Based on Swanton et al 2006, 2007. 
aGadolinium enhancement of lesions is not required for DIS. 
bIf a subject has a brainstem or spinal cord syndrome, the symptomatic lesions are excluded from the Criteria and do 
not contribute to lesion count. 
MRI = magnetic resonance imaging; DIS = lesion dissemination in space; CNS = central nervous system. 
 
 
Table 2: 2010 McDonald MRI Criteria for Demonstration of DIT 
DIT Can Be Demonstrated by: 
1. A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, with reference to a baseline scan, irrespective of the 
timing of the baseline MRI 
 
2. Simultaneous presence of asymptomatic gadolinium-enhancing and non-enhancing lesions at any time 
Based on Montalban et al 2010. 
MRI = magnetic resonance imaging; DIT = lesion dissemination in time. 
 
Table 3: 2010 McDonald MRI Criteria for Diagnosis of MS in Disease with 
Progression from Onset 
PPMS May be Diagnosed in Subjects With: 
1. One year of disease progression (retrospectively or prospectively determined) 
2. Plus 2 of the 3 following criteriaa: 
A. Evidence for DIS in the brain based on ≥1 T2b lesions in at least 1 area characteristic for 
MS (periventricular, juxtacortical, or infratentorial) 
B. Evidence for DIS in the spinal cord based on ≥2 T2b lesions in the cord 
C. Positive CSF (isoelectric focusing evidence of oligoclonal bands and/or elevated IgG index) 
a If a subject has a brainstem or spinal cord syndrome, all symptomatic lesions are excluded from the Criteria. 
b Gadolinium enhancement of lesions is not required. 
MS = multiple sclerosis; PPMS = primary progressive MS; DIS = lesion dissemination in space; CSF = cerebrospinal 
fluid; IgG = immunoglobulin G. 
 
 
 


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Table 4: 2010 McDonald Criteria for Diagnosis of MS 
Clinical Presentation 
Additional Data Needed for MS Diagnosis 
≥2 attacks a; objective clinical evidence 
of ≥2 lesions or objective clinical 
evidence of 1 lesion with reasonable 
historical evidence of a prior attack b 
None c 
≥2 attacks a; objective clinical evidence 
of 1 lesion 
Dissemination in space, demonstrated by: 
≥1 T2 lesion in at least 2 of 4 MS-typical regions of the CNS (periventricular, juxtacortical, 
infratentorial, or spinal cord)d; or 
Await a further clinical attack a implicating a different CNS site 
1 attack a; objective clinical 
evidence of  ≥2 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 attack a 
1 attack a; objective clinical 
evidence of 1lesion 
(clinically isolated syndrome) 
Dissemination in space and time, demonstrated by: 
For DIS: 
≥1 T2 lesion in at least 2 of 4 MS-typical regions of the CNS (periventricular, juxtacortical, 
infratentorial, or spinal cord)d; or 
Await a second clinical attack a  implicating a different CNS site; and 
For  DIT: 
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 attack a 
Insidious neurological progression 
suggestive of MS (PPMS) 
1 year of disease progression (retrospectively or prospectively determined) plus 2 of 3 of 
the following criteria d: 
1. Evidence for DIS in the brain based on ≥1 T2 lesions in the MS-characteristic 
(periventricular, juxtacortical, or infratentorial) regions 
2. Evidence for DIS in the spinal cord based on ≥2 T2 lesions in the cord 
3. Positive CSF (isoelectric focusing evidence of oligoclonal bands and/or elevated IgG 
index) 
If the Criteria are fulfilled and there is no better explanation for the clinical presentation, the diagnosis is ‘‘MS’’; if suspicious, but the Criteria are not 
completely met, the diagnosis is ‘‘possible 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 as patient-reported or objectively observed events typical of an acute inflammatory demyelinating event 
in the CNS, current or historical, with duration of at least 24 hours, in the absence of fever or infection. It should be documented by contemporaneous 
neurological examination, but some historical events with symptoms and evolution characteristic for MS, but for which no objective neurological 
findings are documented, can provide reasonable evidence of a prior demyelinating event. Reports of paroxysmal symptoms (historical or current) 
should, however, consist of multiple episodes occur- ring over not less than 24 hours. Before a definite diagnosis of MS can be made, at least 1 attack 
must be corroborated by findings on neurological examination, visual evoked potential response in patients reporting prior visual disturbance, or MRI 
consistent with demyelination in the area of the CNS implicated in the historical report of neurological symptoms. 
b Clinical diagnosis based on objective clinical findings for 2 attacks is most secure. Reasonable historical evidence for 1 past attack, in the absence of 
documented objective neurological findings, can include historical events with symptoms and evolution characteristics for a prior inflammatory 
demyelinating event; at least 1 attack, however, must be supported by objective findings. 
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 (for instance, CSF) are undertaken and are negative, extreme caution needs to be taken before making a diagnosis of MS, and 
alternative diagnoses must be considered. There must be no better explanation for the clinical presentation, and objective evidence must be present to 
support a diagnosis of MS. 
d Gadolinium-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.