Conditions: Relapsing Multiple Sclerosis
Keywords: Relapsing Multiple Sclerosis RMS Relapsing Multiple Sclerosis (RMS) Multiple Sclerosis MS Multiple Sclerosis (MS) Fingolimod FLUENT Immune Phenotype adult FTY720
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 382
Healthy volunteers: no

Brief summary:
A study of immune phenotype biomarkers in patients with Relapsing Multiple Sclerosis (RMS) after treatment with 0.5mg fingolimod

Detailed description:
This study used a 2-cohort, nonrandomized, open-label, multicenter design. Cohort 1: The first cohort was to be comprised of approximately 200 patients with RMS, who were newly prescribed commercially available fingolimod 0.5 mg/day. Cohort 2: The second cohort was to be comprised of approximately 200 RMS patients who had been on commercially available fingolimod 0.5 mg/day continuously without interruption of treatment for at least ≥ 2 years. Patients from both cohorts were recruited simultaneously from up to 125 MS centers in the United States. Both cohorts ran concurrently. The study consisted of 2 periods: Screening (up to 4 weeks) and Treatment period from Baseline (end of screening period considered as Day 1) up to 12 months with visits conducted at 3,6 and 12 months with a 14 day follow-up post treatment..

Arms:
arm 1: RMS patients who were newly prescribed commercially available fingolimod 0.5mg per day arm 2: RMS patients who had been on commercially available fingolimod 0.5mg per day continuously for ≥ 2 years

Interventions: intervention 1: Fingolimod
Intervention descriptions: intervention 1: Commercially available 0.5mg hard capsules, taken orally once per day

Protocol document:
Prot_000.pdf: 
US Clinical Development and Medical Affairs - General Medicine 
FTY720/Fingolimod 
Clinical Trial Protocol CFTY720DUS40 / NCT03257358  
 A 12-Month, prospective, multicenter, two-cohort, 
nonrandomized, open-label study in adult patients with 
Relapsing Multiple Sclerosis (RMS), to investigate changes 
in immune phenotype biomarkers after treatment with 0.5 
mg fingolimod (FTY720)        
[FLUENT] 
Document type: 
Clinical Trial Protocol 
Version number: 
00 (Original Protocol) 
Clinical trial phase: 
IV  
Release date: 
16-Jun-2017
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.2 (July 2016) 


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Table of contents  
Table of contents ..........................................................................................................2 
List of tables .................................................................................................................5 
List of figures ...............................................................................................................5 
List of abbreviations .....................................................................................................6 
Glossary of terms..........................................................................................................8 
Protocol summary .........................................................................................................9 
1 
Introduction ................................................................................................................16 
1.1 
Background .....................................................................................................16 
1.2 
Purpose ...........................................................................................................16 
2 
Study objectives and endpoints....................................................................................17 
2.1 
Objectives and related endpoints ......................................................................17 
3 
Investigational plan.....................................................................................................18 
3.1 
Study design ....................................................................................................18 
3.1.1 
Screening period (screening to treatment)..........................................19 
3.1.2 
Treatment Period (Baseline to 12 Months) ........................................19 
3.2 
Rationale for study design ................................................................................19 
3.3 
Rationale for dose/regimen, route of administration and duration of treatment ...20 
3.4 
Rationale for choice of comparator ...................................................................21 
3.5 
Purpose and timing of primary analyses/design adaptations ...............................21 
3.6 
Risks and benefits ............................................................................................21 
4 
Population ..................................................................................................................21 
4.1 
Inclusion criteria ..............................................................................................21 
4.2 
Exclusion criteria .............................................................................................22 
5 
Fingolimod Treatment.................................................................................................22 
5.1 
Fingolimod treatment .......................................................................................22 
5.1.1 
Fingolimod and control drugs ...........................................................22 
5.1.2 
Additional treatment.........................................................................23 
5.2 
Fingolimod Treatment cohorts..........................................................................23 
5.3 
Fingolimod Treatment assignment and randomization .......................................23 
5.4 
Fingolimod Treatment blinding ........................................................................23 
5.5 
Treating the patient ..........................................................................................23 
5.5.1 
Patient numbering ............................................................................23 
5.5.2 
Dispensing Fingolimod.....................................................................24 
5.5.3 
Handling of Fingolimod and additional treatment ..............................24 
5.5.4 
Instructions for prescribing and taking Fingolimod ............................24 


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5.5.5 
Permitted dose adjustments and interruptions of Fingolimod 
treatment..........................................................................................24 
5.5.6 
Rescue medication ...........................................................................24 
5.5.7 
Concomitant medication ...................................................................24 
5.5.8 
Prohibited medication.......................................................................24 
5.6 
Study completion and discontinuation ..............................................................25 
5.6.1 
Study completion .............................................................................25 
5.6.2 
Unscheduled visit .............................................................................25 
5.6.3 
Withdrawal of informed consent .......................................................25 
5.6.4 
Loss to follow-up .............................................................................26 
5.6.5 
Early study termination by the sponsor..............................................26 
6 
Visit schedule and assessments....................................................................................26 
6.1 
Information to be collected on screen failures ...................................................28 
6.2 
Rescreening .....................................................................................................28 
6.3 
Patient recruitment...........................................................................................28 
6.4 
Assessments ....................................................................................................28 
6.4.1 
Informed consent..............................................................................28 
6.4.2 
Inclusion/ Exclusion criteria .............................................................28 
6.4.3 
Demographics ..................................................................................28 
6.4.4 
Multiple Sclerosis Medical History and Previous Therapies ...............29 
6.4.5 
Drug regimen ...................................................................................29 
6.4.6 
Relapsing Multiple Sclerosis.............................................................29 
6.4.7 
Magnetic Resonance Imaging Review...............................................29 
6.4.8 
Patient Determined Disease Steps (PDDS) ........................................29 
6.4.9 
Biomarkers and Hematology Assessments ........................................30 
6.4.10 
Steroid use for MS ...........................................................................31 
6.5 
Efficacy...........................................................................................................31 
6.5.1 
Appropriateness of efficacy assessments ...........................................31 
6.6 
Safety ..............................................................................................................31 
6.6.1 
Pregnancy and assessments of fertility ..............................................32 
6.7 
Other assessments ............................................................................................32 
6.7.1 
Clinical Outcome Assessments (COAs) ............................................32 
7 
Safety monitoring .......................................................................................................32 
7.1 
Adverse events ................................................................................................32 
7.2 
Serious adverse events .....................................................................................34 
7.2.1 
Definition of Serious Adverse Events................................................34 


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7.2.2 
Serious Adverse Event reporting .......................................................34 
7.3 
Pregnancy reporting .........................................................................................35 
7.3.1 
Reporting to Novartis .......................................................................35 
7.3.2 
Pregnancy Registry ..........................................................................36 
8 
Data review and database management ........................................................................36 
8.1 
Site monitoring ................................................................................................36 
8.2 
Data collection.................................................................................................36 
8.3 
Database management and quality control ........................................................37 
8.4 
Data Monitoring Committee.............................................................................37 
8.5 
Adjudication Committee ..................................................................................37 
9 
Data analysis ..............................................................................................................37 
9.1 
Analysis sets....................................................................................................38 
9.2 
Patient demographics and other baseline characteristics ....................................38 
9.3 
Treatments.......................................................................................................38 
9.4 
Analysis of the primary variable(s) ...................................................................38 
9.4.1 
Primary Variable(s) ..........................................................................38 
9.4.2 
Statistical model, hypothesis, and method of analysis ........................39 
9.4.3 
Handling of missing values/censoring/discontinuations .....................39 
9.4.4 
Sensitivity analyses ..........................................................................39 
9.5 
Analysis of secondary variables........................................................................39 
9.5.1 
Efficacy variables.............................................................................39 
9.5.2 
Safety variables ................................................................................39 
9.5.3 
Biomarkers ......................................................................................41 
 
41 
9.7 
Interim analyses...............................................................................................41 
9.8 
Sample size calculation ....................................................................................41 
10 Ethical considerations .................................................................................................42 
10.1 
Regulatory and ethical compliance ...................................................................42 
10.2 
Informed consent procedures............................................................................42 
10.3 
Responsibilities of the investigator and IRB/IEC...............................................42 
10.4 
Publication of study protocol and results...........................................................43 
10.5 
Quality Control and Quality Assurance.............................................................43 
11 Protocol adherence......................................................................................................43 
11.1 
Protocol amendments .......................................................................................43 
12 References..................................................................................................................44 


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13 Appendix 1: 2010 Revisions to the McDonald diagnosis criteria for MS .......................46 
14 Appendix 2: Clinically notable laboratory values .........................................................47 
15 Appendix 3: Patient Determined Disease Steps (PDDS) ...............................................48 
 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................17 
Table 6-1 
Assessment schedule ........................................................................27 
Table 6-2 
Biomarkers ......................................................................................30 
 
List of figures 
Figure 3-1 
Study design ....................................................................................19 
 


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List of abbreviations 
AE 
Adverse Event 
ALC 
Absolute Lymphocyte Count 
AV 
Atrioventricular 
B cell 
A Sub-type of White Blood Cells 
CD 
Cluster Differentiation 
CCR 
C-C Chemokine Receptor  
CFR 
US Code of Federal Regulations  
CNS 
Central Nervous System 
CRF 
Case Report/Record Form (paper or electronic) 
CXCR 
C-X-C Chemokine Receptor 
DS 
Disease Steps 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EDDS 
Expanded Disability Status Scale 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDO 
First Dose Observation 
GCP 
Good Clinical Practice 
Gd 
Gadolinium 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IN 
Investigator Notification 
IRB 
Institutional Review Board 
JCV 
John Cunningham Virus 
MedDRA 
Medical dictionary for regulatory activities  
MRI 
Magnetic Resonance Imaging 
MS 
Multiple Sclerosis 
NARCOMS 
North American Research Committee on Multiple Sclerosis 
 
 
NK 
Natural Killer Cells 
PDDS 
Patient Determined Disease Steps 
PML 
Progressive Multifocal Leukoencephalopathy 
PRO 
Patient Related Outcome 
QM 
Quality Management 
QTc 
Measure of the time between the start of the Q wave and the end of the T wave in the 
heart's electrical cycle. 
RBC 
Red Blood Cell 
RMS 
Relapsing Multiple Sclerosis 
SAE 
Serious Adverse Event 
SDC 
Study Discontinuation Completion 
S1PR1 
Sphingosine 1-phosphate receptor 


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SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
T cell 
A Sub-type of White Blood Cells 
TCM 
T Central Memory Cells 
TEM 
TIA 
T Effector Memory Cells 
Transient Ischemic Stroke 
Tn 
Naïve T Cells 
UNS 
Unscheduled Visit 
USPI 
United States Package Insert 
WBC 
White Blood Cell 
WHO 
World Health Organization  
WoC 
Withdrawal of Consent 


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Glossary of terms 
Cohort  
A specific group of patients/subjects fulfilling certain criteria 
Dosage 
Dose of the Fingolimod treatment given to the patient in a time unit 
(e.g., 0.5mg once a day) 
Electronic Data Capture 
(EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical 
study data using data collection systems, such as Web-based 
applications, interactive voice response systems and clinical laboratory 
interfaces. 
EDC includes the use of Electronic Case Report Forms (eCRF’s) 
which are used to capture data transcribed from paper source forms 
used at the point of care. 
Enrollment 
Point/time of patient entry into the study at which informed consent 
must be obtained (e.g., prior to starting any of the procedures 
described in the protocol) 
Period 
A portion of the study which serves a specific purpose. Typical epochs 
are: screening/recruitment, treatment, and follow-up 
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.” 
Part  
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: 
a single dose part and a multiple dose part, or a part in 
patients/subjects with established disease and in those with newly-
diagnosed disease. 
Patient/subject ID  
A unique number assigned to each patient upon signing the informed 
consent  
Source Data/Document 
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a 
dataset, a spreadsheet or even hard-coded data, such as paper or 
eSource. 
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), 
placebo/comparator active drug run-ins or background therapy 
Variable 
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being 
tested in the study 
Withdrawal of consent 
(WoC) 
Withdrawal of consent from the study is defined as when a patient 
does not want to participate in the study any longer, and does not want 
any further visits or assessments, and does not want any further study 
related contact, and does not allow analysis of already obtained 
biologic material 
 


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Protocol summary 
 
Protocol number 
CFTY720DUS40 
Full Title 
A 12-Month, prospective, multicenter, two-cohort, nonrandomized, 
open-label study in adult patients with Relapsing Multiple Sclerosis 
(RMS), to investigate changes in immune phenotype biomarkers 
after treatment with 0.5mg fingolimod. [FLUENT] 
Brief title 
 
A Study of immune phenotype biomarkers in patients with 
Relapsing Multiple Sclerosis (RMS) after treatment with 0.5mg 
fingolimod  
Sponsor and Clinical 
Phase 
Novartis Pharmaceutical Corporation 
Phase IV 
Investigation type 
Drug 
Study type 
Interventional  
Purpose and 
rationale 
The purpose of this study is to characterize phenotypic changes in 
the cellular components (biomarkers) of the innate (monocytes, 
neutrophils and NK cells) and adaptive (peripheral blood T cells and 
B cells) immune system, in patients with relapsing Multiple 
Sclerosis (RMS), initiating fingolimod therapy of 0.5mg/per day up 
to 12 Months of treatment in two treatment cohorts (Cohort 1 
includes, fingolimod naïve patients, and Cohort 2 includes those who 
have been on fingolimod 0.5mg/day  continuously for ≥ 2 years.).  
The study design is nonrandomized, open labeled and relies on the 
approved USPI (United States package insert) based enrollment 
criteria and thereby reflects real world conditions of routine clinical 
practice. 
Primary 
Objective(s)  
The primary objective of this study aims at characterizing 
phenotypic changes in the cellular components (biomarkers) of the 
innate (monocytes, neutrophils and NK cells) and adaptive 
(peripheral blood T cells, B cells) immune system including their 
subtypes, in patients with RMS, initiating fingolimod therapy of 
0.5mg/day up to 12 Months of treatment (Cohort 1) and those 
patients who have been on fingolimod 0.5mg/day continuously for ≥ 
2 years (Cohort 2). Both cohorts will continue treatment for the next 
12 Months. 
Secondary 
Objectives 
Secondary objectives are to investigate the association between  
anti-John Cunningham virus (JCV) antibody status/index and 
phenotypic changes in innate and T and B cell subsets in patients on 
fingolimod therapy. 


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Study design 
This study uses a two-cohort, nonrandomized, open-label 
multicenter design.  
Patients will be enrolled from up to 125 sites in the United States 
The study consists of two periods: screening (up to 4 Weeks) and 
fingolimod treatment period (Baseline to 12 Months). The total 
study duration is up to 13 Months. Follow-up Visits will be 
conducted at 3, 6 and 12 Months. 
Fingolimod treatment includes two cohorts. In the first cohort 
approximately 200 patients with RMS, who are newly prescribed 
commercially available fingolimod 0.5mg/day will participate in the 
study. In the second cohort approximately 200 RMS patients who 
have been on commercially available fingolimod 0.5mg/day 
continuously for at least ≥ 2 years will participate in the study.  
Cohort 2 will only serve as a referent cohort for Cohort 1 and is not 
intended to be a direct Cohort 1 comparator as no a priori hypotheses 
are to be examined. 
Population 
The study population will consist of 400 male and female patients (> 
18 years of age) with a diagnosis of RMS. Cohort 1 will include 200 
patients and Cohort 2 will include 200 patients. 
Key Inclusion 
criteria 
• Written informed consent must be obtained before any 
assessment is performed.  
• Males and females ≥ 18 years of age at the time of screening. 
• Patients diagnosed with relapsing forms of MS defined by 
the revised McDonald criteria (2010), Appendix 1. 
• Patients who will start commercially prescribed fingolimod 
therapy 0.5 mg/day or patients already on commercially 
prescribed fingolimod 0.5 mg/day   continuously for at least 
2 years. 
Key Exclusion 
criteria 
Since commercially prescribed fingolimod is being used in the 
study, contraindications as per the USPI will be adhered to which 
include  
• Patients who in the last 6 Months experienced myocardial 
infarction, unstable angina, stroke, Transient ischemic stroke 
(TIA), decompensated heart failure requiring hospitalization 
or Class III/IV heart failure 


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• History or presence of Mobitz Type II second-degree or 
third-degree atrioventricular (AV) block or sick sinus 
syndrome, unless patient has a functioning pacemaker  
• Baseline QTc interval ≥ 500 msec  
• Treatment with Class I a or Class III anti-arrhythmic drugs  
• Patients who are participating in any other clinical trial with 
fingolimod (Cohort 2) 
• Patients who have had a hypersensitivity reaction to 
fingolimod or any of the excipients. Observed reactions 
include rash, urticaria and angioedema upon treatment 
initiation.  
Note: Hypersensitivity reactions, including rash, urticaria, and 
angioedema have been reported with fingolimod in the post-
marketing setting.  
Treatment 
Fingolimod (FTY720D) 
Efficacy assessments • Patient Determined Disease Steps (PDDS)  
• Magnetic Resonance Imaging (MRI based variables) 
Key safety 
assessments 
• Adverse (AE) and Serious Adverse Events (SAE) 
Other assessments 
N/A 
Data analysis 
Novartis or a designated vendor will perform the statistical analysis. 
It is planned that data from all centers that participate in this protocol 
will be combined, so that an adequate number of patients will be 
available for the analysis. 
There will be three analyses in this study.  
1. An interim analysis which is an early assessment to evaluate 
safety of Cohort 2 patients will be conducted when 50% of 
patients in Cohort 2 have completed the Month 6 follow-up 
visit. 
2. A primary analysis based on all data collected on both 
Cohorts 1 and 2 patients will be conducted when all patients 
in Cohorts 1 and 2 complete the Month 6 follow up Visit 
which is the primary time point of interest of the study.  
3. A final follow-up analysis will be conducted when all 
patients in Cohorts 1 and 2 complete the Month 12 follow up 
Visit of the study. 
 


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Analysis sets:  
Enrolled Set: All patients enrolled in one of the two cohorts will be 
included in the Enrolled Set. 
Safety Set: The Safety Set will include all patients who enrolled in 
one of the two cohorts and received at least one dose of fingolimod. 
Patients will be analyzed according to the cohort enrolled. 
Full Analysis Set (FAS):  For this study, the Full Analysis Set is the 
same as the Safety Set. 
Patient demographics and other baseline characteristics:  
Data will be summarized with respect to demographics and baseline 
characteristics by cohort in the Safety Set. 
Primary variables:  
All analyses will be conducted by cohort for the Safety set. 
The primary variables are 
1. Change from Baseline to Month 6 in CD4+ naïve T cells 
(CCR7+CD45RA+) 
2. Change from Baseline to Month 6 in CD4+ central memory T 
cells (CCR7+CD45RA-CD45RO+) 
3. Change from Baseline to Month 6 in CD4+ effector memory T 
cells (CCR7-CD45RA-CD45RO+) 
4. Change from Baseline to Month 6 in CD4+ Th1 cells 
(CXCR3+) 
5. Change from Baseline to Month 6 in CD4+ Th2 cells (CCR4+) 
6. Change from Baseline to Month 6 in CD4+ Th17 cells 
(CCR6+) 
7. Change from Baseline to Month 6 in CD8+ naïve T cells 
(CCR7+CD45RA+) 
8. Change from Baseline to Month 6 in CD8+ central memory T 
cells (CCR7+CD45RA-CD45RO+) 
9. Change from Baseline to Month 6 in CD8+ effector memory T 
cells (CCR7-CD45RA-CD45RO+) 
10. Change from Baseline to Month 6 in naïve B cells 
(CD19+CD27-) 
11. Change from Baseline to Month 6 in memory B cells 
(CD19+CD27+) 
12. Change from Baseline to Month 6 in regulatory B cells 
(CD19+CD24+CD38+) 
13. Change from Baseline to Month 6 in monocytes (CD14+) 
14. Change from Baseline to Month 6 in neutrophils (CD16+) 


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15. Change from Baseline to Month 6 in NK cells (CD56+) 
Descriptive statistics (sample size, mean, standard deviation, 
standard error of mean, minimum, first quartile, median, third 
quartile, interquartile range, and maximum) will be provided. The 
95% confidence interval for the mean will be calculated.  
Analyses will be performed with respect to the actual value of 
primary variables by employing an analysis of covariance 
(ANCOVA) model with gender as a factor and duration of disease 
and corresponding baseline as covariates. The unadjusted as well as 
the adjusted least squares means will be provided together with a p-
value.  
Percent change from baseline mean will also be reported. 
Majority of analyses will be descriptive in nature. The 95% 
confidence intervals will be provided for the estimate of parameters 
of interest.  
No imputation will be performed for missing data related to safety 
or efficacy.  
Efficacy variables:  
The following efficacy variables will be analyzed by cohort using 
data from patients in FAS. 
• Change from Baseline in Patient Determined Disease Steps 
(PDDS) 
• Change from Baseline in T2 lesion burden  
• New Gadolinium (Gd)-enhancing T1 lesion count 
Descriptive statistics (sample size, mean, standard deviation, 
standard error of mean, minimum, first quartile, median, third 
quartile, interquartile range, and maximum) will be provided. The 
95% confidence interval for the mean will be calculated.  
Safety variables:  
The assessment of safety will be based mainly on the frequency of 
adverse events. 
Adverse events will be summarized by presenting the number and 
percentage of patients having any adverse event, having an adverse 
event in each system organ class and having each individual adverse 
event by cohort and overall. Any other information collected (e.g., 
severity or relationship to fingolimod) will be summarized, as 
appropriate. 
Safety Set will be used for the following analyses. 


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In addition to the primary variables, the following secondary 
variables will be analyzed: 
1. Change from Baseline to Months 3, and 12 in CD4+ naïve T 
cells (CCR7+CD45RA+); 
2. Change from Baseline to Months 3, and 12 in CD4+ central 
memory T cells (CCR7+CD45RA-CD45RO+); 
3. Change from Baseline to Months 3, and 12 in CD4+ effector 
memory T cells (CCR7-CD45RA-CD45RO+); 
4. Change from Baseline to Months 3, and 12 in CD4+ Th1 cells 
(CXCR3+); 
5. Change from Baseline to Months 3, and 12 in CD4+ Th2 cells 
(CCR4+); 
6. Change from Baseline to Months 3, and 12 in CD4+ Th17 cells 
(CCR6+); 
7. Change from Baseline to Months 3, and 12 in CD8+ naïve T 
cells (CCR7+CD45RA+); 
8. Change from Baseline to Months 3, and 12 in CD8+ central 
memory T cells (CCR7+CD45RA-CD45RO+); 
9. Change from Baseline to Months 3, and 12 in CD8+ effector 
memory T cells (CCR7-CD45RA-CD45RO+); 
10. Change from Baseline to Months 3, and 12 in naïve B cells  
(CD19+CD27-); 
11. Change from Baseline to Months 3, and 12 in memory B cells 
(CD19+CD27+); 
12. Change from Baseline to Months 3, and 12 in regulatory B cells 
(CD19+CD24+CD38+); 
13. Change from Baseline to Months 3, and 12 in monocytes 
(CD14+); 
14. Change from Baseline to Months 3, and 12 in neutrophils 
(CD16+); 
15. Change from Baseline to Months 3, and 12 in NK cells 
(CD56+); 
16. Change from Baseline to Months 3, 6, and 12 in the anti-JCV 
antibody index; 
17. Change from Baseline to Months 3, 6, and 12 in Hematology 
measurements;  
18. Anti-JCV antibody status (+ or -) at Months 3, 6, and 12. 
For Variable 18, frequency count and percentage together with the 
95% confidence interval for the proportion of anti-JCV antibody 
positive patients will be presented.  


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For Variable 1-17, Descriptive statistics (sample size, mean, 
standard deviation, standard error of mean, minimum, first quartile, 
median, third quartile, interquartile range, and maximum) will be 
provided. The 95% confidence interval for the mean will be 
calculated. 
Correlation coefficients between changes in cellular (T, B and 
monocyte, neutrophil, NK) subsets, efficacy (MRI based variables 
and PDDS) and safety outcomes (anti-JCV antibody status and 
index) will be computed. Analyses of safety data will be by cohort 
based on the Safety Set. 
Descriptive statistics (sample size, mean, standard deviation, 
standard error of mean, minimum, first quartile, median, third 
quartile, interquartile range, and maximum) will be provided. The 
95% confidence interval for the mean will be calculated.  
Sample size estimation:  
Cohort 1: A sample size of 200 patients will be able to detect an 
effect size of 0.30 with 89% power after adjusting for multiplicity of 
testing changes in 15 primary variables, at an overall significance 
level of 0.05. 
In addition, for both cohorts the primary interest is to estimate mean 
change from Baseline at various time points (Months 3, 6, and 12) 
of the primary and secondary variables. A sample size of 200 
patients in each cohort will provide us the precision of estimates 
within 0.14 of the corresponding standard deviation of the variables 
of interest.  
Key words 
Multiple Sclerosis (MS), Relapsing Multiple Sclerosis (RMS), 
Fingolimod, FLUENT, Immune Phenotype 
 


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1 
Introduction 
1.1 
Background 
Fingolimod is a sphingosine 1-phosphate receptor (S1PR1) modulator approved for relapsing 
multiple sclerosis (RMS). This mechanism of action has a differential impact on multiple 
phenotypic subtypes of the immune system. Modulation of S1PRs favors CC-chemokine 
receptor 7 (CCR7)-mediated retention of naïve T (Tn) cells and central memory T (TCM) cells, 
including Th17 cells in lymph nodes, thereby reducing the trafficking of potentially autoreactive 
lymphocytes and preventing their infiltration into the central nervous system (CNS), Mehling 
et al 2008, 2010. Fingolimod reduces the numbers of CD4+ and CD8+ T cells, the effect being 
more pronounced for the CD4+ T cell subset, Song et al 2015. In contrast, effector memory T 
(TEM) cells, which lack CCR7, Sallusto et al 1999 do not regularly circulate through lymph 
nodes and are largely unaffected by fingolimod, Mehling et al 2008 and Brinkmann et al 2009. 
The relative sparing of TEM cells, which are important in immune surveillance, together with 
the preservation of function of sequestered lymphocytes, Kappos et al 2015, Brinkmann et al 
2000, 2001 and 2002, suggests that key features of the immune system are maintained during 
fingolimod therapy. Chronic fingolimod therapy with 0.5mg/day results in lymphocyte counts 
of approximately 30% of the baseline lymphocyte count, Chun, J. and Hartung, H 2010; Francis 
et al 2014.  However, Absolute Lymphocyte Counts (ALC) during fingolimod therapy is not a 
marker of immune competence and not related to risk of infections, Francis et al 2014, Fox et 
al 2014. 
In 2015, in the post marketing setting of longer term treated patients, two opportunistic 
infections Progressive Multifocal Leukoencephalopathy (PML) and Cryptococcal Meningitis 
manifested at a rare frequency, which led to label changes, United States package insert (USPI).  
Since these opportunistic infections had not been described until this point, these new findings 
triggered interest in yet unknown immune system changes in long term continuously treated 
patients. PML is caused by the John Cunningham virus (JCV) and its development is associated 
with the presence of anti-JCV antibodies in serum. PML risk can be stratified in seropositive 
MS patients based on serum anti-JCV antibody levels as measured by the index. The 
significance of anti-JCV antibody index changes during fingolimod treatment and its 
relationship to PML risk is unknown. 
Although fingolimod induces lymphopenia, the relationship between phenotypic changes in the 
innate and adaptive components of the immune system during its long-term administration is 
unknown. Distinct immune subset changes with long term fingolimod treatment are 
incompletely understood and its pivotal trials did not investigate changes within immune cell 
subsets.  
This study is being proposed to investigate the immune profile of patients over time to seek an 
improved understanding of immune effects with long term fingolimod therapy. 
1.2 
Purpose  
The purpose of this study is to characterize changes in the types and sub-types of the innate 
(monocytes, neutrophils and NK cells) and adaptive (peripheral blood T cells and B cells) 


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immune system, in patients with relapsing Multiple Sclerosis (RMS), on fingolimod therapy of 
0.5mg/per day up to 12 Months of treatment in two treatment cohorts (fingolimod naïve patients, 
or those previously treated continuously for at least ≥ 2 years.).  
2 
Study objectives and endpoints 
2.1 
Objectives and related endpoints 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary Objective(s) 
• The primary objective of this study aims 
at characterizing phenotypic changes in 
the cellular components (biomarkers) of 
the innate (monocytes, neutrophils and 
NK cells) and adaptive (peripheral blood 
T cells, B cells) immune system 
including their subtypes, in patients with 
RMS, initiating fingolimod therapy of 
0.5mg/ per day up to 12 Months of 
treatment (Cohort 1) and those patients 
who have been on fingolimod 0.5mg/day 
continuously for ≥ 2 years (Cohort 2). 
Both cohorts will continue treatment for 
the next 12 Months. 
Endpoint(s) for primary objective(s)  
• Change from baseline to Month 6  of 
CD4+ and CD8+ naïve T cells 
(CCR7+CD45RA+), central memory T 
cells (CCR7+CD45RA-CD45RO+), 
and effector memory T cells (CCR7- 
CD45RA-CD45RO+) 
• Change from baseline to Month 6 of 
CD4+ Th1 (CXCR3+), Th2 (CCR4+) 
and Th17 (CCR6+) cells.  
• Change from baseline to Month 6 in 
naïve B cells (CD19+CD27-), memory 
B cells (CD19+CD27+) and regulatory 
B cells (CD19+CD24+CD38+) 
• Change from baseline to Month 6 in 
monocytes (CD14+), neutrophils 
(CD16+) and NK cells (CD56+).  
Secondary Objective(s) 
Secondary objectives are to investigate the 
association between anti-JCV antibody 
status/index and phenotypic changes in 
innate and T and B cell subsets in patients on 
fingolimod therapy of 0.5mg/day. 
 
 
Endpoint(s) for secondary objective(s) 
• Anti-JCV antibody status (+ or -) at 
Months 3, 6, and 12   
• Change from baseline to Months 3, 6, 
and 12  in the anti-JCV antibody index  
• Change from baseline to Months 3 and 
12 in CD4+ and CD8+ naïve T cells 
(CCR7+CD45RA+), central memory T 
cells(CCR7+CD45RA-), and effector 
memory T cells (CCR7-CD45RA-
CD45RO+) 
• Change from baseline to Months 3 and 
12, in CD4+ Th1 (CXCR3+), Th2 
(CCR4+) and Th17 (CCR6+) cells  


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Objective(s) 
Endpoint(s) 
• Change from baseline to Months 3 and 
12 in naïve B cells (CD19+CD27-), 
memory B cells (CD19+CD27+) and 
regulatory B cells 
(CD19+CD24+CD38+)  
• Change from baseline to Months 3 and 
12 in monocytes (CD14+), neutrophils 
(CD16+) and NK cells (CD56+)  
3 
Investigational plan 
3.1 
Study design 
This study uses a two-cohort, nonrandomized, open-label, multicenter design.  
Cohort 1: In the first cohort approximately 200 patients with RMS, who are newly prescribed 
commercially available fingolimod 0.5mg/day will participate in the study.  
Cohort 2: In the second cohort approximately 200 RMS patients who have been on 
commercially available fingolimod 0.5mg/day continuously without interruption of treatment 
for at least ≥ 2 years will participate in the study.  
Patients from both cohorts will be recruited simultaneously from up to 125 MS centers in the 
United States. Both cohorts will run concurrently.  
The study consists of two periods: 
• Screening (up to 4 weeks) 
• Treatment period from Baseline (end of screening period considered as Day 1)  up to 12 
Months 
A schema of the study design is presented in Figure 3-1, while a detailed visit and assessment 
schedule can be found in Table 6-1.  
1. An interim analysis will be conducted when 50% of patients in Cohort 2 have 
completed the Month 6 follow up Visit.  
2. A primary analysis will be conducted when all patients complete the Month 6 follow 
up Visit, which is the primary time point of interest in the study.  
3. A final analysis will be completed when all patients have completed the Month 12 
follow up Visit of the study. 


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Figure 3-1 
Study design  
 
Screening 
period 
(Up to 4 weeks) 
Open-label Treatment Phase 
Cohort 1*   (n=200) 
Cohort 2** (n=200) 
             Month 3            Month 6         Month 12   
 
                                                          Baseline                                                                                                                                                          
* Cohort 1: Patients will begin treatment of fingolimod 0.5mg/day for the next 12 Months 
** Cohort 2: Patients who have been on fingolimod 0.5mg/day continuously for ≥ 2 years will continue treatment of fingolimod 0.5mg/day for 
the next 12 Months 
3.1.1 
Screening period (screening to treatment) 
After signing the informed consent, patients will enter a screening phase. The duration of the 
screening period will be up to 4 weeks. Screening will be used to assess patient eligibility as 
per the USPI.  
Additionally, during this period patients in Cohort 1 will be tapered from prohibited 
medications and treatments if required as per the USPI. 
3.1.2 
Treatment Period (Baseline to 12 Months) 
Once patient eligibility is confirmed, patients from both treatment cohorts will enter the 
treatment period. At Baseline, which is the start of the treatment period, eligible patients in 
Cohort 1 will be prescribed commercially available fingolimod at 0.5mg/day. In Cohort 2 
patients will continue with fingolimod treatment. Patients in both treatment cohorts will be on 
fingolimod (0.5mg/day) treatment from Baseline to 12 Months. Follow-up Visits will be 
conducted at 3, 6 and 12 Months. 
3.2 
Rationale for study design  
The open label, multicenter study used in this study is aligned with the previous Biobank study 
and its extension (CFTY720DDE01 and CFTY720DDE01E1) performed for the indication of 
RMS and is in accordance with the health authority guidelines and feedback, including the 
United States Food and Drug Administration (FDA). 
The studies mentioned above evaluated the immune profile of fingolimod treated patients up to 
48 months (i.e., Baseline, 1 month, 4 months, 6 months and 48 months). An expected reduction 
in CD4+ and CD8+ naïve (Tn) and central memory T cells (TCM), as well as CD19+ B cells, 
persisted up to 48 months. Although CD4+ TEM were spared, a decrease in CD8+ effector 
memory T cells (TEM) was observed at 48 months. In contrast, CD14+ monocytes and CD56+ 
NK cells expanded over the course of treatment. These findings have important implications 
for immune surveillance (i.e., CD8+ TEM reduction) and development of opportunistic 
infection. While these studies assessed temporal changes in cell subsets during long term 


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therapy, their limitation indicated no correlation of changes in distinct cell types with clinical 
efficacy and/or therapeutic risk measures, lack of time points from 6 months to 48 months to 
understand when cellular changes occur, and lack of understanding for phenotype and function 
of T cell and B cell subsets, as well as the innate cell populations examined (e.g., Th1, Th2, 
Th17, CD56+ bright immunoregulatory vs. CD56 dim cytotoxic NK cells, CD14+ pro-
inflammatory M1 vs anti-inflammatory M2 monocytes, etc.). Thus, the proposed FLUENT 
study adds new dimension with T cell and B cell subsets and includes additional time points to 
capture the dynamics and fully appreciate temporal changes in innate and adaptive immune cell 
populations over the course of fingolimod therapy in patients new to fingolimod and those who 
have been on continuous treatment for at least 2 years. Further, FLUENT will collect clinical 
efficacy outcomes (i.e., MRI based variables, PDDS, 
 etc) and therapeutic risk 
measures (i.e., PML risk as determined by anti-JCV antibody status and index) to be correlated 
with observed changes in distinct T cell (i.e., Tn, TCM, TEM, Th1, Th2 and Th17) and B cell 
(i.e., naïve, memory and regulatory) subsets over short and long term therapy. The addition of 
multiple time points is particularly relevant to cohort 2. A single time point would not only 
significantly limit the insights to be gleaned regarding the relationship between 
immunophenotype and clinical information (i.e., clinical efficacy and therapeutic risk) over 
time, the ability to appreciate changes would also be severely diminished and thereby introduce 
increased noise that would impact the interpretation of the data. Thus, FLUENT fills in the gaps 
of Biobank and adds new dimension to these previous studies. 
The study population consists of adult patients with RMS who are either undergoing or are 
candidates for fingolimod therapy (note that a decision to initiate fingolimod has already been 
made). The study is designed to acquire information on immunological markers and clinical 
information in a manner that does not over-burden patients, caregivers or clinical sites but 
provides sufficient information to assess immune status. Its design relies on the approved USPI 
label based enrollment criteria and thereby reflects real world conditions of routine clinical 
practice.  
Cohort 2 will provide data on patients who have been on fingolimod therapy continuously for 
at least 2 years and thereby reflects long term immunophenotypic changes consequent to this 
therapy. Cohort 1 will provide data on patients new to fingolimod therapy and therefore reveals 
acute changes in patients’ immune profile. Data from Cohort 2 will provide a foundation to 
appreciate changes and detect patterns in immune phenotypes in patients newly initiated on 
fingolimod over the long term. Furthermore, Cohort 2 will provide 
 PML risk data on 
patients who have been on fingolimod therapy for an extended period. Cohort 2 will only serve 
as a referent cohort for cohort 1 and is not intended to be a direct Cohort 1 comparator as no a 
priori hypotheses are to be examined.  
The study population will be described in more detail in Section 4 below. 
3.3 
Rationale for dose/regimen, route of administration and duration 
of treatment   
Fingolimod treatment is prescribed to patients at a dose of 0.5mg/day in accordance with the 
product labelling. Please refer to the USPI. 


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3.4 
Rationale for choice of comparator 
No comparator is used in this study. The current study is designed to close the data gap as 
indicated in section 3.2. Once the immune phenotype profiling has been established we may 
plan for comparator studies. 
3.5 
Purpose and timing of primary analyses/design adaptations 
The intention of the primary analyses is to provide results to be reported at medical 
congresses and published to enable data transparency and to provide clinical utility. Safety 
and efficacy variables, which include cellular changes, PML risk (anti-JCV antibody status 
and index), 
, will be analyzed together with demographics and baseline 
characteristics, as well as adverse events and serious adverse events. 
A primary analysis will be conducted when all patients complete the Month 6 follow up 
which is the primary time point of interest in the study.  
3.6 
Risks and benefits  
The study involves a FDA approved dose (0.5mg/day) and indication (RMS) of fingolimod. 
Therefore the study population will be examined within a known benefit/risk profile of 
fingolimod. Any procedural risks will be minimized using compliance with the eligibility 
criteria as well as optimal study procedures.  
Patients will receive the benefit of being systematically monitored over a 12 Month period at 
regular follow-ups for immune phenotype profiling, which would not have taken place during 
normal routine follow up Visits. 
4 
Population 
The study population will consist of male and female patients (> 18 years of age) with a 
diagnosis of MS. In the first cohort approximately 200 patients with RMS, who are newly 
prescribed commercially available fingolimod 0.5mg/day will participate in the study. In the 
second cohort approximately 200 RMS patients who have been on commercially available 
fingolimod 0.5mg/day continuously for at least ≥ 2 years will participate in the study.  
The goal is to include 400 patients (Cohort 1, n=200 and Cohort 2 n=200) from up to 125 centers 
in the United States. Since a 25% screen failure rate is expected, approximately 533 patients 
will be screened. 
Patients who discontinue after they have been enrolled will not be replaced. 
4.1 
Inclusion criteria 
1. Written informed consent must be obtained before any study related assessment is 
performed.  
2. Males and females ≥ 18 years of age at the time of screening. 


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3. Patients diagnosed with relapsing forms of MS defined by the revised McDonald criteria 
(2010), Appendix 1. 
4. Patients who will start commercially prescribed fingolimod therapy 0.5mg/day or patients 
already on commercially prescribed fingolimod 0.5mg/day continuously for ≥ at least > 2 
years. 
4.2 
Exclusion criteria 
Since commercially prescribed fingolimod is being used in the study, contraindications as per 
the USPI will be adhered to which include  
1. Patients who in the last 6 months experienced myocardial infarction, unstable angina, 
stroke, Transient ischemic stroke (TIA), decompensated heart failure requiring 
hospitalization or Class III/IV heart failure 
2. History or presence of Mobitz Type II second-degree or third-degree atrioventricular (AV) 
block or sick sinus syndrome, unless patient has a functioning pacemaker  
3. Baseline QTc interval ≥500 msec  
4. Treatment with Class I a or Class III anti-arrhythmic drugs  
5. Patients who are participating in any other clinical trial with fingolimod (Cohort 2) 
6. Patients who have had a hypersensitivity reaction to fingolimod or any of the excipients. 
Observed reactions include rash, urticarial and angioedema upon treatment initiation. 
Note: Hypersensitivity reactions, including rash, urticaria, and angioedema have been reported 
with fingolimod in the post-marketing setting.  
5 
Fingolimod Treatment 
5.1 
Fingolimod treatment 
Treatment involves routine standard of care with prescribed commercially available fingolimod. 
The drug will not be supplied by Novartis. Physicians will prescribe commercially available 
fingolimod which will be covered by the patient’s insurance or by the patients themselves.  
In Cohort 1 at the start of fingolimod treatment (Baseline), patients will undergo routine first 
dose observation (FDO) as per the USPI at the treating site. Once FDO has been completed in 
Cohort 1, thereafter all doses of fingolimod will be self-administered. In Cohort 2 fingolimod 
is self-administered. 
 Self-administration refers to patient self-treatment of the drug or by a trained caregiver 
regardless of whether dosing occurs at study site or at home. Instruction and training will be 
provided by site staff to patients/caregivers prior to treatment. 
5.1.1 
Fingolimod and control drugs 
Fingolimod is commercially available and marketed in the United States.  
There are no control drugs in this study. 


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5.1.2 
Additional treatment 
No additional treatments beyond commercially prescribed drug (fingolimod) are included in 
this trial. 
5.2 
Fingolimod Treatment cohorts 
There are two cohorts in this study.  
Cohort 1: Includes commercially prescribed fingolimod naïve patients. 
Cohort 2: Includes patients who have continuously been on commercially prescribed 
fingolimod for ≥ 2 years.  
Both treatment cohorts will remain on the treatment regimen of fingolimod of 0.5mg/day from 
Baseline (Visit 1) to a period of 12 Months. 
5.3 
Fingolimod Treatment assignment and randomization  
There is only one treatment assignment in this study: commercially available 0.5mg/day of 
fingolimod. No randomization will be performed in this study. 
5.4 
Fingolimod Treatment blinding 
The trial is an open-label study, thus fingolimod treatment will not be blinded during the course 
of the study. 
5.5 
Treating the patient  
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
5.5.1 
Patient numbering 
Each patient is uniquely identified by a 7 digit Subject Number which is composed of a  
i) 4 digit site number assigned by Novartis and a  
ii) 3 digit sequential number assigned by the investigator.  
Once assigned to a patient, the Subject Number will not be reused.  
Example: 
At Site 1 and Subject 1, the Subject number assigned is 0001-001 
At Site 1, Subject 2, the Subject number assigned is 0001-002 
Upon signing the informed consent form, the patient is assigned the next sequential number as 
given by the investigator using the next blank case report form (CRF) book available from the 
electronic data capture (EDC) system.  
If an enrolled patient fails to be treated for any reason, the reason will be entered on the 
Screening Study Disposition, Electronic case report form (eCRF).  


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5.5.2 
Dispensing Fingolimod  
Not applicable. No drug is provided by the sponsor company Novartis nor the PI.  
5.5.3 
Handling of Fingolimod and additional treatment  
5.5.3.1 
Handling of Fingolimod treatment  
Not applicable. No drug is provided by the sponsor company Novartis nor the PI.  
5.5.3.2 
Handling of additional treatment  
Not applicable. 
5.5.4 
Instructions for prescribing and taking Fingolimod 
Patients will be prescribed commercially available fingolimod as per their standard of routine 
care (Refer to the USPI). Drug will be covered by the patient’s medical insurance or by the 
patient themselves. 
The investigator must promote compliance by instructing the patient to take the fingolimod 
treatment exactly as prescribed and by stating that compliance is necessary for the patient’s 
safety and the validity of the study. The patient must be instructed to contact the investigator if 
he/she is unable for any reason to take the Fingolimod treatment as prescribed. 
5.5.5 
Permitted dose adjustments and interruptions of Fingolimod treatment  
Not applicable. 
5.5.6 
Rescue medication 
There is no rescue medication being provided/prescribed as part of the study. However, based 
upon safety and other assessments, investigator discretion, or for any reason, patients will be 
free to discontinue participation in the study at any time. 
5.5.7 
Concomitant medication  
Concomitant medication information will be reported as per routine standard of care and 
recorded on the source document. Although no solicited concomitant medication information 
is required for the sponsor, if during the course of the study an adverse reaction (i.e., an adverse 
event associated or suspected with the use of the drug) is noted and Adverse events (AEs) or 
Serious Adverse events (SAEs) are  noted, then the physician must record the events and 
medications as per instructions given in Section 7.1 and Section 7.2 of the protocol.  
5.5.8 
Prohibited medication 
As per USPI.  


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5.6 
Study completion and discontinuation  
5.6.1 
Study completion  
A patient will be considered to have completed the study when the patient has completed the 
last visit planned in the protocol. 
5.6.2 
Unscheduled visit  
An unscheduled visit (UNS) is a spontaneous visit and may take place at any time during the 
course of the clinical trial if and when the Investigator deems it necessary. The UNS 
assessments are detailed in Table 6-1 and must be recorded in the eCRF. 
5.6.2.1 
Study Discontinuation visit 
Patients who discontinue study participation for reasons cited either by the patient or 
Investigator should return to the study site for a study discontinuation completion (SDC) Visit.  
The SDC Visit should be scheduled to occur as soon as possible or at least within 14 Days of 
the last fingolimod treatment. In case this Visit does not occur within 14 Days then the date 
when the patient returns must be documented and reported in the SDC eCRF. At the SDC Visit, 
assessments will be performed as per the assessment schedule as outlined in Table 6-1. 
After SDC, at a minimum, in abbreviated visits, the following data should to be collected at 
clinic visits or via telephone visits:  
• Adverse events/Serious Adverse Events 
If the patient cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the patient, or with a person pre-designated by the patient. This telephone 
contact should preferably be done according to the study visit schedule.   
5.6.3 
Withdrawal of informed consent 
Patients/subjects may voluntarily withdraw consent to participate in the study for any reason at 
any time. Withdrawal of consent from the study is defined as when a patient: 
• Does not want to participate in the study anymore 
or 
• Does not want any further visits or assessments 
or 
• Does not want any further study related contacts 
or 
• Does not allow analysis of already obtained biologic material  
In this situation, the investigator must make every effort (e.g., telephone, e-mail, letter) to 
determine the primary reason for the patient’s decision to withdraw his/her consent and record 
this information.  


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Study participation must be discontinued and no further assessments conducted, and the data 
that would have been collected at subsequent visits will be considered missing.  
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in the 
assessment Table 6-1. 
5.6.4 
Loss to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g., dates of telephone 
calls, registered letters, etc. A patient cannot be considered as lost to follow-up until the time 
point of his/her scheduled end of study visit has passed. 
5.6.5 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the patient 
must be seen as soon as possible and treated as 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 the Institutional Review Board/Independent Ethics Committee 
(IRBs/IECs) of the early termination of the trial. 
6 
Visit schedule and assessments 
Table 6-1 lists all of the assessments and indices with an “X” when the Visits are performed.  
Patients/subjects must be seen for all visits on the designated day, or as close to it as possible. 
Missed or rescheduled visits should not lead to automatic discontinuation. Patients who 
prematurely discontinue the study for any reason should be scheduled for a visit as soon as 
possible, at which time all of the assessments listed for the study discontinuation completion 
visit (SDC) will be performed.  
 


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Table 6-1 
Assessment schedule 
 
Days/ Months 
-Day  up to 
4 weeks  
Screening 
period 
Baseline 
(Day 1) 
Month 3 
Month 6 
Month 12/ 
SDC 
Unscheduled visit 
Visit No 
1 
2 
3 
4 
5/ 99 
Visit Window (days) 
 
 
+7 
+14 
+14/ < 14 
Obtain informed consent 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
 
MS medical history / previous therapies 
X 
 
 
 
 
 
Drug Regimen 
X* 
X^ 
X 
X 
X 
X 
RMS ( Yes/No) 
X 
X 
X 
X 
X 
 
Magnetic Resonance Imaging (MRI) review (if available)** 
X 
X 
X 
X 
X 
 
Patient Determined Disease Steps (PDDS)*** 
 
X 
X 
X 
X 
X 
Collection of blood samples 
 
X 
X 
X 
X 
X 
Steroid use for MS 
X 
X 
X 
X 
X 
X 
AE /SAE 
 
X 
X 
X 
X 
X 
X 
SDC: Study discontinuation completion Visit will take place for those patients who discontinue study participation. This Visit is to be scheduled 
to occur as soon as possible or at least within 14 days of the last fingolimod treatment 
* Drug dosing information at Screening will report first date of treatment, dosage and frequency for patients in Cohort 2 
^ At the Baseline Visit for all patients in Cohort 1 collection of blood samples must be performed prior to administration of the first dose of 
fingolimod 
** MRI  If patient had/ has a MRI that is performed as part of routine standard of care 
*** PDDS is a non-copyrighted patient self-assessment tool which estimates disability in MS patients, Learmonth et al 2013 


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6.1 
Information to be collected on screen failures  
All subjects who sign informed consent but discontinue prior to Visit 2 (Baseline) are 
considered screen failures. 
The Screening Visit Date, Demography, Informed Consent, Inclusion/Exclusion Criteria, 
Subject Rescreening, and the Screening Phase Disposition eCRFs must be completed. The 
Adverse Event eCRF and a paper SAE form must be completed for any SAE that occurs 
during the screening period. Adverse events that are not SAEs will be followed by the 
Investigator and collected only in the source data. The W i t h d r a w a l  of In f o rm ed  
Consent (WoC) eCRF must be completed if consent was withdrawn during the Screening 
period before the subject was enrolled. 
6.2 
Rescreening  
Rescreening may be allowed under certain conditions.  Requests from the Investigator/site 
staff to rescreen patients will be handled on a case-by-case basis with Medical Monitor 
approval required prior to proceeding with rescreening.  Rescreening cannot be done if a 
patient was previously enrolled into the study. 
If a patient rescreens for the study, the patient must sign a new Informed consent form (ICF) 
and must be issued a new patient number prior to any screening assessments conducted under 
the new patient number.  The date of the new informed consent signature must be entered on 
the Informed consent eCRF to correspond to the new patient number.  
6.3 
Patient recruitment 
Patient recruitment will end on June 30th 2018 i.e., the last patient first visit (LPFV). The last 
patient last visit (LPLV) will take place no later than June 30th 2019 (12 Month Visit date).  
6.4 
Assessments  
6.4.1 
Informed consent 
Written informed consent must be obtained prior to any screening procedures at Visit 
1/Screening and will be recorded in the eCRF. 
6.4.2 
Inclusion/ Exclusion criteria 
As per the USPI label all patients must meet all the inclusion and none of the exclusion criteria 
at Visit 1/Screening. A reconfirmation is required at Visit 2/ Baseline prior to administration of 
the drug. This will be recorded in the eCRF. 
6.4.3 
Demographics 
Patient demographic data will be recorded at Visit 1/Screening. Data to be collected on all 
patients include: date of birth, patient initials, age, sex, race and ethnicity. This will be recorded 
in the eCRF. 


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6.4.4 
Multiple Sclerosis Medical History and Previous Therapies 
Relevant medical MS history and previous therapies pertaining to MS will be recorded at Visit 
1/Screening in the eCRF. Significant findings that are observed after the patient has signed the 
informed consent form and that meet the definition of an AE must be recorded in the AE eCRF.  
6.4.5 
Drug regimen 
For patients in Cohort 2, date of first treatment, dose and frequency will be reported at Visit 
1/Screening eCRF. At Visit 2/ Baseline date of treatment, dose and frequency will be reported 
for both Treatment Cohorts in the eCRF. 
At the subsequent visits, patient compliance will be reported: if the patient is taking their 
medication regularly as prescribed, if the patient has missed any doses and how often the 
patients have missed their dose. All information will be recorded in the eCRF at the Visits as 
outlined in the Table 6-1 
The investigator/qualified site staff should promote compliance by instructing patients to 
attend the study visits as scheduled, to take the fingolimod treatment exactly as prescribed, and 
reiterate that compliance is necessary for patient safety and the validity of the study. 
Patients should be instructed to contact the investigator/qualified site staff if he/she is unable 
for any reason to attend a study visit as scheduled, or if he/she is unable for any reason to take 
their prescribed treatment. 
6.4.6 
Relapsing Multiple Sclerosis 
The current condition i.e., if yes or no pertaining to Relapsing multiple sclerosis will be recorded 
in the eCRF at the Visits as outlined in Table 6-1. 
6.4.7 
Magnetic Resonance Imaging Review 
Magnetic Resonance Imaging data, if available from standard of routine care will be reviewed 
and standard MRI measures as outlined below will be recorded in the eCRF at the Visits as 
outlined in Table 6-1. 
• Change from Baseline in T2 lesion burden  
• New Gadolinium (Gd)-enhancing T1 lesion count; 
6.4.8 
Patient Determined Disease Steps (PDDS) 
The PDDS scale, Appendix 3, Learmonth et al 2013, North American Research Committee on 
Multiple Sclerosis (NARCOMS) Registry is a self-assessment scale of MS disease status, 
collected by the NARCOMS at enrollment and in follow-up surveys of adult patients of MS. 
Data from this scale will be recorded in the eCRF at the Visits as outlined in Table 6-1. 
The impact of MS on disease status will be assessed by the following measure:  
• The Patient Determined Disease Steps (PDDS) scale, Appendix 3, NARCOMS 
Registry 
The PDDS self-assessment scale will be completed by the patient at the follow up Visits as 
outlined in the visit schedule Table 6-1. 


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The PDDS scale focusses mainly on disability of the patient and has nine ordinal levels ranging 
between 0 (normal) and 8 (Bedridden). Lower scores reflect better gait. It takes an estimated 
10-15 minutes to complete the PDDS.   
6.4.9 
 Biomarkers and Hematology Assessments  
Blood samples (approximately 60-80 ml) will be collected as per the Visit schedule outlined in 
Table 6-1. For each Visit a total of up to 80 ml blood will be drawn (please refer to Laboratory 
manual) for biomarker and hematology assessments.  
Note: In Cohort 1 patients it is critical that the blood sample, must be collected prior to 
administration of fingolimod, FDO. 
A central laboratory will be used for analysis of all specimens collected. A laboratory manual 
with information on blood sample collection, handling, shipment of samples, processing and 
reporting of results will be provided. 
6.4.9.1 
Biomarkers 
Table 6-2 
Biomarkers 
 
 
Type of Biomarker 
1 
CD4+ naïve T cells (CD3+CD4+CCR7+CD45RA+) 
2 
CD8+ naïve T cells (CD3+CD8+CCR7+CD45RA+) 
3 
CD4+ central memory T cells (CD3+CD4+CCR7+CD45RA-CD45RO+) 
4 
CD8+ central memory T cells (CD3+CD8+CCR7+CD45RA-CD45RO+) 
5 
CD4+ effector memory T cells (CD3+CD4+CCR7- CD45RA-CD45RO+) 
6 
CD8+ effector memory T cells (CD3+CD8+CCR7- CD45RA-CD45RO+) 
7 
CD4+ Th1 cells (CD3+CD4+CXCR3+) 
8 
CD4+ Th2 cells (CD3+CD4+CCR4+) 
9 
CD4+ Th17 cells (CD3+CD4+CCR6+) 
10 
CD19+ naïve B cells (CD19+CD27-) 
11 
CD19+ memory B cells (CD19+CD27+) 
12 
CD19+ regulatory B cells (CD19+CD24+CD38+) 
13 
Monocytes (CD14+) 
14 
Neutrophils (CD16+) 
15 
NK cells (CD56+) 
16 
Anti-JCV antibody status 
17 
Anti-JCV antibody index 
 
 
 


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Any biomarker samples derived from the sample that remain after the analysis may be stored 
for up to 15 years (depending on the local regulations) to research scientific questions related 
to MS and evaluate additional biomarkers not yet identified in this protocol. The material can 
be destroyed on patient’s request at any time point. 
6.4.9.2 
Hematology Assessments 
Hematology assessments include: red blood cell (RBC) count, RBC morphology, white blood 
cell (WBC) count with absolute and differential (basophils, eosinophils, lymphocytes, 
monocytes, neutrophils and segmented neutrophils), platelet count, hemoglobin and hematocrit 
Clinically notable laboratory findings are defined in Appendix 2.  
6.4.10 
Steroid use for MS 
The use of steroids i.e., if yes or no, steroid name, dose, start date, current use or stop date, will 
be recorded in the eCRF at the Visits as outlined in Table 6-1. 
6.5 
Efficacy  
1. PDDS 
2. MRI based variables if available 
6.5.1 
Appropriateness of efficacy assessments  
The Patient Determined Disease Steps (PDDS) scale is a standard outcome efficacy assessment 
in MS to characterize the disease status in this patient population, Appendix 3, Learmonth et al 
2013, NARCOMS Registry .  
The PDDS is an alternative to other, more complex, self-reported versions of the Expanded 
Disability Status Scale (EDDS) that have correlated well with the classical EDSS, Lechner-
Scott et al 2003. Researchers could adopt the PDDS in clinical research and practice involving 
patients with MS alongside the EDSS or when the EDSS is impractical, too costly, or 
inconvenient. The PDDS scale is simple, economical, and efficient in comparison to the EDSS 
and Disease Steps (DS) and offers a potentially useful Patient related outcome (PRO) of 
disability for clinical research and practice in MS, Learmonth et al 2013.  
The MRI data that is readily available on file includes clinical information in a manner that does 
not over-burden patients, caregivers or clinical sites 
6.6 
Safety  
Standard of routine care of patients will be followed at the investigator site. Information will be 
captured in the source document and retained in the patient files. The sponsor is not soliciting 
safety data capture for this study. However, if during the course of the study an adverse reaction 
(i.e., an AE associated or suspected with the use of the drug) is noted and the AEs or SAEs are 
noted, then the physician must record the events as per instructions given in Section 7.1 and 
Section 7.2 of the protocol.  


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6.6.1 
Pregnancy and assessments of fertility  
Standard of routine care of patients is to be followed. The sponsor is not soliciting pregnancy 
data. However, if a patient is being treated with fingolimod and becomes pregnant, the 
Investigator must report this pregnancy according to the protocol Section 7.3.  
6.7 
Other assessments  
6.7.1 
Clinical Outcome Assessments (COAs)  
6.7.1.1 
Patient Reported Outcomes (PRO)  
All PDDS questionnaires will be kept with the patient’s file as a source document. Completed 
questionnaires will be reviewed and examined by the investigator, for responses that may 
indicate AEs or SAEs. The investigator should review not only the responses to the questions 
in the questionnaires but also for any unsolicited comments written by the patient. If AEs or 
SAEs are confirmed, then the physician must record the events as per instructions given in 
Section 7.1 and Section 7.2 of the protocol.  
7 
Safety monitoring  
7.1 
Adverse events  
An adverse event is any untoward medical occurrence (e.g., 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 until 
the end of study visit. Therefore, an AE may or may not be temporally or causally associated 
with the use of fingolimod. 
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred. 
The occurrence of adverse events must 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 findings, laboratory test 
findings, 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 must 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 laboratory and other test abnormalities 
are included in Appendix 2. 


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Adverse events must be recorded in the Adverse Events eCRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information: 
the severity grade 
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
its relationship to the Fingolimod treatment  
• Yes 
• No 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:  
• no action taken (e.g., further observation only)  
• Fingolimod treatment dosage increased/reduced 
• Fingolimod treatment interrupted/withdrawn 
• concomitant medication or non-drug therapy given  
• non-drug therapy given  
• patient hospitalized/patient’s hospitalization prolonged (see Section 7.2 for definition of 
SAE) 
• its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent, and assessment must be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study drug, the interventions required 
to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB). This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. Any new 
information regarding the safety profile of the medicinal product that is identified between IB 
updates will be communicated as appropriate, for example, via an Investigator Notification or 
an Aggregate Safety Finding. New information might require an update to the informed consent 
and has then to be discussed with the patient. 
The investigator must 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 fingolimod treatment. This information must be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis. 


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7.2 
Serious adverse events  
7.2.1 
Definition of Serious Adverse Events  
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria: 
• is fatal or life-threatening  
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
• 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, e.g., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to Annex IV, ICH-E2D Guideline). 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the patient or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse (please refer to Annex IV, ICH-E2D Guideline). 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
7.2.2 
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/ following the last 
administration of fingolimod treatment if there are post-treatment follow-up visits with no 
required procedures] must be reported to Novartis safety within 24 hours of learning of its 


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occurrence. Any SAEs experienced after the 30 day period [after the last study visit/ following 
the last administration of fingolimod treatment if there are post-treatment follow-up visits with 
no required procedures] should only be reported to Novartis safety if the investigator suspects 
a causal relationship to fingolimod treatment.  
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to each specific 
component of fingolimod treatment, (if fingolimod treatment consists of several components) 
complete the SAE Report Form in English, and submit the completed form within 24 hours to 
Novartis. Detailed instructions regarding the submission process and requirements for signature 
are to be found in the investigator folder provided to each site.  
Follow-up information is submitted as instructed in the investigator folder. Each re-occurrence, 
complication, or progression of the original event must be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, and whether the patient continued or withdrew 
from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or USPI (new 
occurrence) and is thought to be related to the fingolimod 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 fingolimod 
treatment that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with EU Guidance 2011/C 172/01 or as per national regulatory 
requirements in participating countries. 
7.3 
Pregnancy reporting  
7.3.1 
Reporting to Novartis 
To ensure patient safety, each pregnancy occurring after signing the informed consent 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 must be recorded on the Pharmacovigilance 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 fingolimod treatment.  


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Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form. 
7.3.2 
Pregnancy Registry 
A pregnancy registry has been established to collect information about the effect of 
fingolimod use during pregnancy. Physicians are encouraged to enroll pregnant patients, or 
pregnant women may register themselves in the fingolimod pregnancy registry by calling 
 at 
, sending an email to 
 or visiting 
www.gilenyapregnancyregistry.com. Clinicaltrials.gov Identifier: NCT01285479 
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 data capture requirements with the investigators and 
their staff. During the study, Novartis employs several methods of ensuring protocol and Good 
clinical practice (GCP) compliance and the quality/integrity of the sites’ data. The field monitor 
will visit the site to check the completeness of patient records, the accuracy of data capture / 
data entry, the adherence to the protocol, the progress of enrollment and to Good Clinical 
Practice. Key study personnel must be available to assist the field monitor during these visits.  
Continuous remote monitoring of each site’s data may be performed by a designated vendor or 
a centralized Novartis CRA organization. Additionally, a central analytics organization may 
analyze data & identify risks & trends for site operational parameters, and provide reports to 
Novartis Clinical Teams to assist with trial oversight. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by the 
patient (a signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients/subjects will be disclosed. 
8.2 
Data collection  
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to US CFR 21Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system until 


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they have been trained. Automatic validation programs check for data discrepancies and, by 
generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of data to Novartis or to a designated vendor working on behalf of Novartis. The 
Investigator must certify that the data entered into the Electronic Case Report Forms are 
complete and accurate. After database lock, the investigator will receive copies of the patient 
data for archiving at the investigational site.  
8.3 
Database management and quality control  
Either Novartis or a designated vendor working on behalf of Novartis will review the data 
entered into the eCRFs by investigational staff for completeness and accuracy and instruct the 
site personnel to make any required corrections or additions. Queries are sent to the 
investigational site using an electronic data query. Designated investigator site staff is required 
to respond to the query and confirm or correct the data. 
Previous or current steroid medications or therapies for MS entered into the database will be 
coded using the World Health Organization (WHO) Drug Reference List, which employs the 
Anatomical Therapeutic Chemical classification system. 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 vendor. 
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and made available for data analysis. Any changes to the database after that time can 
only be made after written agreement by a responsible party at Novartis. 
8.4 
Data Monitoring Committee  
Not required. 
8.5 
Adjudication Committee  
Not required. 
9 
Data analysis 
Novartis or a designated vendor will perform the statistical analysis. 
The analysis will be conducted on patient data at the designated time points as indicated below. 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
There will be three analyses in this study.  
1. An interim analysis which is an early assessment to evaluate safety of Cohort 2 
patients will be conducted when 50% of patients in Cohort 2 have completed the 
Month 6 follow-up visit. 


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2. A primary analysis based on all data collected on both Cohorts 1 and 2 patients will 
be conducted when all patients in Cohorts 1 and 2 complete the Month 6 follow up 
Visit, which is the primary time point of interest of the study.  
3. A final follow-up analysis will be conducted when all patients in Cohorts 1 and 2 
complete the Month 12 follow up Visit of the study. 
9.1 
Analysis sets  
Enrolled Set: All patients enrolled in one of the two cohorts will be included in the Enrolled Set. 
Safety Set: The Safety Set will include all patients who enrolled in one of the two cohorts and 
received at least one dose of fingolimod during the study. Patients will be analyzed according 
to the cohort enrolled. 
Full Analysis Set: For this study, the Full Analysis Set is the same as the safety set defined 
above. 
9.2 
Patient demographics and other baseline characteristics  
Data will be summarized with respect to demographics and baseline characteristics by cohort 
for patients in the Safety Set. 
9.3 
Treatments 
Exposure to fingolimod will be presented using summary statistics by cohort for patients in the 
Safety Set. 
9.4 
Analysis of the primary variable(s) 
9.4.1 
Primary Variable(s) 
All analyses will be conducted by cohort for the Safety Set. 
The primary variables are:  
1. Change from Baseline to Month 6 in CD4+ naïve T cells (CCR7+CD45RA+) 
2. Change from Baseline to Month 6 in CD4+ central memory T cells (CCR7+CD45RA-
CD45RO+) 
3. Change from Baseline to Month 6 in CD4+ effector memory T cells (CCR7-CD45RA-
CD45RO+) 
4. Change from Baseline to Month 6 in CD4+ Th1 cells (CXCR3+) 
5. Change from Baseline to Month 6 in CD4+ Th2 cells (CCR4+) 
6. Change from Baseline to Month 6 in CD4+ Th17 cells (CCR6+) 
7. Change from Baseline to Month 6 in CD8+ naïve T cells (CCR7+CD45RA+) 
8. Change from Baseline to Month 6 in CD8+ central memory T cells (CCR7+CD45RA-
CD45RO+) 
9. Change from Baseline to Month 6 in CD8+ effector memory T cells (CCR7-CD45RA-
CD45RO+) 
10. Change from Baseline to Month 6 in naïve  B Lymphocytes (CD19+CD27-) 


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11. Change from Baseline to Month 6 in memory B Lymphocytes (CD19+CD27+) 
12. Change from Baseline to Month 6 in regulatory B Lymphocytes (CD19+CD24+CD38+) 
13. Change from Baseline to Month 6 in monocytes (CD14+) 
14. Change from Baseline to Month 6 in neutrophils (CD16+) 
15. Change from Baseline to Month 6 in NK cells (CD56+) 
Descriptive statistics (sample size, mean, standard deviation, standard error of mean, minimum, 
first quartile, median, third quartile, interquartile range, and maximum) will be provided. The 
95% confidence interval for the mean will be calculated.  
Analyses will be performed with respect to the actual value of primary variables by employing an 
analysis of covariance (ANCOVA) model with gender as a factor and duration of disease and 
corresponding baseline as covariates. The unadjusted as well as the adjusted least squares means 
will be provided together with a p-value. 
Percent change from baseline mean will also be reported. 
9.4.2 
Statistical model, hypothesis, and method of analysis 
Majority of analyses will be descriptive in nature. The 95% confidence intervals will be 
provided for the parameters of interest.  
9.4.3 
Handling of missing values/censoring/discontinuations 
No imputation will be performed for missing data related to safety or efficacy.  
9.4.4 
Sensitivity analyses 
Not applicable. 
9.5 
Analysis of secondary variables 
Secondary variables consist of both efficacy and safety variables. 
9.5.1 
Efficacy variables 
The following efficacy variable will be analyzed by cohort using data from patients in FAS. 
• Change from Baseline in Patient Determined Disease Steps (PDDS); 
• Change from Baseline in T2 lesion burden; 
• New Gd-enhancing T1 lesion count 
Descriptive statistics (sample size, mean, standard deviation, standard error of mean, minimum, 
first quartile, median, third quartile, interquartile range, and maximum) will be provided. The 
95% confidence interval for the mean will be calculated.  
9.5.2 
Safety variables 
The assessment of safety will be based mainly on the frequency of adverse events. 
Adverse events will be summarized by presenting the number and percentage of patients having 
any adverse event, having an adverse event in each system organ class and having each 


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individual adverse event by cohort and overall. Any other information collected (e.g., severity 
or relationship to fingolimod) will be summarized, as appropriate. 
Serious adverse events and adverse events leading to discontinuation of study will be 
summarized by system organ class and preferred term for each cohort and overall. 
Safety Set will be used for the following analyses. 
In addition to variables presented in Section 9.4.1, the following secondary variables will be 
analyzed: 
1. Change from Baseline to Months 3, and 12 in CD4+ naïve T cells (CCR7+CD45RA+); 
2. Change from Baseline to Months 3, and 12 in CD4+ central memory T cells 
(CCR7+CD45RA-CD45RO+); 
3. Change from Baseline to Months 3, and 12 in CD4+ effector memory T cells (CCR7-
CD45RA-CD45RO+); 
4. Change from Baseline to Months 3, and 12 in CD4+ Th1 cells (CXCR3+); 
5. Change from Baseline to Months 3, and 12 in CD4+ Th2 cells (CCR4+); 
6. Change from Baseline to Months 3, and 12 in CD4+ Th17 cells (CCR6+); 
7. Change from Baseline to Months 3, and 12 in CD8+ naïve T cells (CCR7+CD45RA+); 
8. Change from Baseline to Months 3, and 12 in CD8+ central memory T cells 
(CCR7+CD45RA-CD45RO+); 
9. Change from Baseline to Months 3, and 12 in CD8+ effector memory T cells (CCR7-
CD45RA-CD45RO+); 
10. Change from Baseline to Months 3, and 12 in naïve B cells  (CD19+CD27-); 
11. Change from Baseline to Months 3, and 12 in memory B cells (CD19+CD27+); 
12. Change from Baseline to Months 3, and 12 in regulatory B cells (CD19+CD24+CD38+); 
13. Change from Baseline to Months 3, and 12 in monocytes (CD14+); 
14. Change from Baseline to Months 3, and 12 in neutrophils (CD16+); 
15. Change from Baseline to Months 3, and 12 in NK cells (CD56+); 
16. Change from Baseline to Months 3, 6, and 12 in the anti-JCV antibody index; 
17. Change from Baseline to Months 3, 6, and 12 in Hematology measurements; 
18. Anti-JCV antibody status (+ or -) at Months 3, 6, and 12. 
For Variable 18, frequency count and percentage together with the 95% confidence interval for 
the proportion of JCV antibody positive patients will be presented.  
For Variables 1-17, Descriptive statistics (sample size, mean, standard deviation, standard error 
of mean, minimum, first quartile, median, third quartile, interquartile range, and maximum) will 
be provided. The 95% confidence interval for the mean will be calculated. 
In addition, correlation coefficients between changes in cellular (T, B and monocyte, neutrophil, 
NK) subsets and efficacy (MRI based variables and PDDS) and safety outcomes (anti-JCV 
antibody status and index) will be computed. Analyses of safety data will be by cohort based 
on the Safety Set. 


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9.5.3 
Biomarkers 
See Sections 9.4.1, 9.5.1 and 9.5.2 
9.7 
Interim analyses 
As previously mentioned, two interim analyses of data will be performed prior to the final 
analysis at Month 12.  
1. The first interim analysis is an early assessment to evaluate safety of Cohort 2 patients.  
This will be conducted when 50% of patients in Cohort 2 have completed the Month 6 
follow up. For this analysis, primary variables, demographics, baseline characteristics, 
adverse events, and serious adverse events will be summarized.   
2. The second interim analysis is the primary analysis for this study. This analysis will be 
conducted when all patients in Cohorts 1 and 2 complete Month 6 (primary time point 
of interest) of study. All data collected on patients from both Cohorts 1 and 2 will be 
included in this analysis.  These data will be analyzed as mentioned in Sections 9.4, 9.5, 
and 9.6.  
This is an open-label, single arm study, and has no active control. The first interim analysis is 
a summarization of data from Cohort 2 only and no confirmatory hypothesis will be tested. 
Thus, the multiplicity adjustment of the level of significance for the primary analysis due to the 
first interim analysis is not relevant in this study.  Results obtained from these interim analyses 
may be reported and published externally for communication to health care professions, as 
appropriate. 
9.8 
Sample size calculation 
Cohort 1: A sample size of 200 patients will be able to detect an effect size of 0.30 with 89% 
power after adjusting for multiplicity of testing changes in 15 primary variables, at an overall 
significance level of 0.05. 
In addition, for both cohorts the primary interest is to estimate mean change from Baseline at 
various time points (Months 3, 6, and 12) of the primary and secondary variables. A sample 


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size of 200 patients in each cohort will provide us the precision of estimates within 0.14 of the 
corresponding standard deviation of the variables of interest.  
10 
Ethical considerations  
10.1 
Regulatory and ethical compliance  
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21, and Japanese 
Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in the 
Declaration of Helsinki. 
10.2 
Informed consent procedures  
Eligible patients/subjects may only be included in the study after providing written (witnessed, 
where required by law or regulation), IRB/IEC-approved informed consent, or, if applicable 
after such consent has been provided by a legally acceptable representative(s) of the patient. In 
cases where the patient’s representative gives consent, the patient must be informed about the 
study to the extent possible given his/her understanding. If the patient is capable of doing so, 
he/she must 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 (e.g., all of the procedures described in the protocol). The process of 
obtaining informed consent must be documented in the patient source documents.  
Novartis will provide to investigators in a separate document a proposed ICF23 that complies 
with the ICH GCP guideline and regulatory requirements and is considered appropriate for this 
study. Any changes to the proposed consent form suggested by the investigator must be agreed 
to by Novartis before submission to the IRB/IEC, and a copy of the approved version must be 
provided to the Novartis monitor after IRB/IEC approval. 
Women of child bearing potential must be informed that taking the fingolimod treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they must 
not be entered in the study. 
10.3 
Responsibilities of the investigator and IRB/IEC  
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g., 
advertisements) and any other written information to be provided to patients/subjects. Prior to 
study start, the investigator is required to sign a protocol signature page confirming his/her 
agreement to conduct the study in accordance with these documents and all of the instructions 
and procedures found in this protocol and to give access to all relevant data and records to 
Novartis monitors, auditors, Novartis Quality Assurance representatives, designated agents of 
Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site 


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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  
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. 
10.5 
Quality Control and Quality Assurance  
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections. 
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance, a group independent from those involved in 
conducting, monitoring or performing quality control of the clinical trial. The clinical audit 
process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
11 
Protocol adherence  
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of patients/subjects should 
be administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented.  
11.1 
Protocol amendments  
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate hazard 
to patients/subjects may be implemented immediately provided the health authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed. 


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12 
References  
Brinkmann, V., Pinschewer, D., Chiba, K. and Feng, L. (2000). FTY720: a novel 
transplantation drug that modulates lymphocyte traffic rather than activation. Trends in 
Pharmacological Sciences, 21(2), pp.49-52. 
Brinkmann, V., Chen, S., Feng, L., Pinschewer, D., Nikolova, Z. and Hof, R. (2001). FTY720 
alters 
lymphocyte 
homing 
and 
protects 
allografts 
without 
inducing 
general 
immunosuppression. Transplantation Proceedings, 33(1-2), pp.530-531. 
Brinkmann, V. (2002). The Immune Modulator FTY720 Targets Sphingosine 1-Phosphate 
Receptors. Journal of Biological Chemistry, 277(24), pp.21453-21457. 
Brinkmann, V. (2009). FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the 
immune and the central nervous system. British Journal of Pharmacology, 158(5), pp.1173-
1182. 
Chun, J. and Hartung, H. (2010). Mechanism of Action of Oral Fingolimod (FTY720) in 
Multiple Sclerosis. Clinical Neuropharmacology, 33(2), pp.91-101. 
Fox, E., Edwards, K., Burch, G., Wynn, D., LaGanke, C., Crayton, H., Hunter, S., Huffman, C., 
Kim, E., Pestreich, L., McCague, K. and Barbato, L. (2014). Outcomes of switching directly to 
oral fingolimod from injectable therapies: Results of the randomized, open-label, multicenter, 
Evaluate Patient OutComes (EPOC) study in relapsing multiple sclerosis. Multiple Sclerosis 
and Related Disorders, 3(5), pp.607-619. 
Francis, G., Kappos, L., O’Connor, P., Collins, W., Tang, D., Mercier, F. and Cohen, J. (2014). 
Temporal profile of lymphocyte counts and relationship with infections with fingolimod 
therapy. Multiple Sclerosis Journal, 20(4), pp.471-480. 
Kappos L, Antel J, Comi G, Montalban X, O'Connor P, Polman CH, Haas T, Korn 
AA, Karlsson G, Radue EW. (2006). FTY720 D2201 Study Group.Oral fingolimod (FTY720) 
fo relapsing multiple sclerosis. N Engl J Med, Sep 14;355(11):1124-40. 
Lechner-Scott, J., Kappos, L., Hofman, M., Polman, C., Ronner, H., Montalban, X., Tintore, 
M., Frontoni, M., Buttinelli, C., Amato, M., Bartolozzi, M., Versavel, M., Dahlke, F., Kapp, J. 
and Gibberd, R. (2003). Can the Expanded Disability Status Scale be assessed by 
telephone?. Multiple Sclerosis, 9(2), pp.154-159. 
Learmonth, Y., Motl, R., Sandroff, B., Pula, J. and Cadavid, D. (2013). Validation of patient 
determined disease steps (PDDS) scale scores in persons with multiple sclerosis. BMC 
Neurology, 13(1). 
Mehling, M., Brinkmann, V., Antel, J., Bar-Or, A., Goebels, N., Vedrine, C., Kristofic, C., 
Kuhle, J., Lindberg, R. and Kappos, L. (2008). FTY720 therapy exerts differential effects on T 
cell subsets in multiple sclerosis. Neurology, 71(16), pp.1261-1267. 
 Mehling, M., Lindberg, R., Raulf, F., Kuhle, J., Hess, C., Kappos, L. and Brinkmann, V. (2010). 
Th17 central memory T cells are reduced by FTY720 in patients with multiple 
sclerosis. Neurology, 75(5), pp.403-410. 
Polman, C., Reingold, S., Banwell, B., Clanet, M., Cohen, J., Filippi, M., Fujihara, K., 
Havrdova, E., Hutchinson, M., Kappos, L., Lublin, F., Montalban, X., O'Connor, P., Sandberg-
Wollheim, M., Thompson, A., Waubant, E., Weinshenker, B. and Wolinsky, J. (2011). 


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Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria. Annals of 
Neurology, 69(2), pp.292-302. 
Sallusto, F., Lenig, D., Förster, R., Lipp, M. and Lanzavecchia, A. (1999). Two subsets of 
memory T lymphocytes with distinct homing potentials and effector functions. Nature, 
401(6754), pp.708-712. 
Song, Z., Yamasaki, R., Kawano, Y., Sato, S., Masaki, K., Yoshimura, S., Matsuse, D., Murai, 
H., Matsushita, T. and Kira, J. (2015). Peripheral Blood T Cell Dynamics Predict Relapse in 
Multiple Sclerosis Patients on Fingolimod. PLOS ONE, 10(4), p.e0124923. 
USPI: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022527s008lbl.pdf  


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13 
Appendix 1: 2010 Revisions to the McDonald diagnosis 
criteria for MS 
Revision to the McDonald diagnosis criteria for MS 
 
Clinical Presentation 
Additional Criteria to Make diagnosis 
≥ 2 attacks, objective clinical 
evidence of ≥ 2 lesions or 
objective clinical evidence of 1 
lesion with reasonable 
historical evidence of a prior 
attack 
None 
≥  2 attacks; objective clinical 
evidence of 1 lesion 
Dissemination in space (DIS) demonstrated by: 
≥ 1 T2 lesion in at least 2 of 4 MS typical regions of the CNS 
(periventricular, juxtacortical, infratentorial, spinal cord); OR 
Await a further clinical attack implicating a different CNS site 
1 attack, objective clinical 
evidence of ≥ 2 lesions 
Dissemination in time (DIT) 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 
1 attack, objective clinical 
evidence of 1 lesion (clinically 
isolated syndrome) 
Dissemination in space and time demonstrated by: 
For DIS: 
≥ 1 T2 lesion in at least 2 of 4MS typical CNS regions 
(periventricular, juxtacortical, infratentorial, spinal cord); OR 
Await a second clinical attack 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 
Insidious neurological 
progression suggestive of MS 
(PPMS) 
One year of disease progression (retrospectively or 
prospectively) AND 2 out of 3 of the following criteria: 
1. Evidence of DIS in the brain based on ≥ 1 T2 lesion in MS-
characteristic regions (periventricular, juxtacortical or 
intratentorial); 
2. Evidence of 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) 


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14 
Appendix 2: Clinically notable laboratory values  
Only selected lab parameters identified as notable which have been shown to be sensitive to 
fingolimod exposure are included. 
 
Laboratory Variable  
Standard Units  
 
SI Units 
 
Hematology variables 
Hemoglobin   
 
≤10.0 g/dL  
 
 
≤100 g/L 
Platelets                            
≤100 k/mm3  
 
≤100 x 109/L 
≥600 k/mm3  
 
≥600 x 109/L 
White Blood Cells  
 
≤2.0 k/mm3  
 
≤2.0 x 109/L 
≥15 k/mm3 
 
 
≥15 x 109/L 
 
Hematology variables - differential 
  
Neutrophils                             ≤ 1,000 /mm3  
 
≤1 x 109/L 
≥12000/mm3  
 
≥12 x 109/L 
Lymphocytes   
 
<200/mm3 
 
 
<0.2 x 109/L 
≥8000/mm3  
 
≥8 x 109/L 
 
 
 
 
 
 
 
 
 
 
 
 


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15 
Appendix 3: Patient Determined Disease Steps (PDDS) 
Please read the choices listed below and choose the one that best describes your own situation. 
This scale focuses mainly on how well you walk. You might not find a description that reflects 
your condition exactly, but please mark the one category that describes your situation the closest. 
 
0 
Normal 
I may have some mild symptoms, mostly sensory due 
to MS but they do not limit my activity. If I do have an 
attack, I return to normal when the attack has passed. 
1 
Mild Disability 
I have some noticeable symptoms from my MS but 
they are minor and have only a small effect on my 
lifestyle. 
2 
Moderate Disability 
I don't have any limitations in my walking ability. 
However, I do have significant problems due to MS 
that limit daily activities in other ways.  
3 
Gait Disability 
MS does interfere with my activities, especially my 
walking. I can work a full day, but athletic or 
physically demanding activities are more difficult than 
they used to be. I usually don't need a cane or other 
assistance to walk, but I might need some assistance 
during an attack 
4 
Early Cane 
I use a cane or a single crutch or some other form of 
support (such as touching a wall or leaning on 
someone's arm) for walking all the time or part of the 
time, especially when walking outside. I think I can 
walk 25 feet in 20 seconds without a cane or crutch. I 
always need some assistance (cane or crutch) if I want 
to walk as far as 3 blocks 
5 
Late Cane 
To be able to walk 25 feet, I have to have a cane, 
crutch or someone to hold onto. I can get around the 
house or other buildings by holding onto furniture or 
touching the walls for support. I may use a scooter or 
wheelchair if I want to go greater distances. 
6 
Bilateral Support 
To be able to walk as far as 25 feet I must have 2 canes 
or crutches or a walker. I may use a scooter or 
wheelchair for longer distances. 
7 
Wheelchair/ Scooter 
My main form of mobility is a wheelchair. I may be 
able to stand and/or take one or two steps, but I can't 
walk 25 feet, even with crutches or a walker. 
8 
Bedridden 
Unable to sit in a wheelchair for more than one hour. 
 

SAP_001.pdf: 
Clinical Development 
FTY720/Fingolimod 
CFTY720DUS40 / NCT03257358 
A 12-Month, prospective, multicenter, two-cohort, 
nonrandomized, open-label study in adult patients with 
Relapsing Multiple Sclerosis (RMS), to investigate changes 
in immune phenotype biomarkers after treatment with 0.5 
mg fingolimod (FTY720) [FLUENT] 
Statistical Analysis Plan (SAP) 
Author: 
, Ph.D.; 
, Ph.D. 
Document type: 
SAP Documentation 
Document status: 
Final v2.0 
Release date: 
20 Sep 2019 
Number of pages: 
14 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Document History – Changes compared to previous final version of SAP 
 
Date 
Time point 
Reason for 
update 
Outcome for 
update 
Section and title 
impacted 
(Current) 
16-Jan-2018 
Prior to DB lock 
Creation of 
initial version 
First version 1.0 
NA 
20-Sep-2019 
Just prior to DB 
lock 
Analyses added 
to original 
scope or 
modified 
Final version 2.0 Analyses added 
to Sections 2.7.1 
and 2.8.2 
 


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SIGNATURE PAGE 
 
Prepared by:  
 
 
 
 
 
 
 
 
 
Date (DDMMMYYYY) 
 
 
 
 
 
 
 
 
Approved by : 
 
 
 
 
 
 
 
 
, Novartis 
Pharmaceuticals Corporation 
 
Date (DDMMMYYYY) 
 


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Table of contents 
Table of contents ..........................................................................................................4 
List of abbreviations .....................................................................................................6 
1 
Introduction ..................................................................................................................7 
1.1 
Study design ......................................................................................................7 
1.2 
Study objectives and endpoints...........................................................................7 
2 
Statistical methods ........................................................................................................7 
2.1 
Data analysis general information.......................................................................7 
2.1.1 
General definitions .............................................................................8 
2.2 
Analysis sets......................................................................................................8 
2.3 
Patient disposition, demographics and other baseline characteristics ....................9 
2.3.1 
Patient disposition ..............................................................................9 
2.3.2 
Protocol Deviations ............................................................................9 
2.3.3 
Demographics ....................................................................................9 
2.3.4 
MS History/Baseline disease characteristics ........................................9 
2.4 
Past or present MS symptoms with Location.......................................................9 
2.5 
MS previous therapies........................................................................................9 
2.6 
Fingolimod treatment / compliance / Dose interruption .......................................9 
2.7 
Analysis of the primary objective .....................................................................10 
2.7.1 
Primary endpoint..............................................................................10 
2.7.2 
Statistical hypothesis, model, and method of analysis ........................11 
2.7.3 
Handling of missing values/censoring/discontinuations .....................11 
2.8 
Analysis of the key secondary objective ...........................................................11 
2.8.1 
Efficacy variables.............................................................................11 
2.8.2 
Safety variables ................................................................................11 
2.8.3 
Handling of missing values/censoring/discontinuations .....................12 
2.8.4 
Adverse events (AEs) .......................................................................12 
2.9 
Interim analysis ...............................................................................................13 
3 
Sample size calculation ...............................................................................................14 
4 
Change to protocol specified analyses..........................................................................14 
5 
Appendix....................................................................................................................14 
5.1 
Imputation rules...............................................................................................14 
5.1.1 
Concomitant Medications Start/End Date ..........................................14 
5.1.2 
Adverse Events Start/End Date .........................................................14 
5.2 
Statistical models .............................................................................................15 
5.2.1 
Primary analysis ...............................................................................15 


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5.2.2 
Key secondary analysis ....................................................................15 
5.3 
Reference ........................................................................................................16 


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List of abbreviations 
AE 
Adverse event 
ANCOVA 
analysis of covariance 
CSR 
Clinical Study report 
FAS 
Full Analysis Set 
eCRF 
Electronic Case Report Form 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
NCI 
National Cancer Institute 
o.d. 
Once Daily 
qd 
Qua’que di’e / once a day 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TFLs 
Tables, Figures, Listings 
WHO 
World Health Organization 
 
 
 


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1 
Introduction 
This Statistical Analysis Plan (SAP) outlines the planned methods and reports to be used in the 
statistical analysis of study “CFTY720US40”. The purpose of the SAP is to document in details the 
statistical methods and analysis conventions to be used in the completion of the Clinical Study Report 
(CSR). Specifically, this document will: 
1. Briefly review the objectives, design and endpoints of the study 
2. Describe the targeted overall patient enrollment 
3. Define the analysis populations  
4. Define the rules for determining the outcome of the endpoints 
5. Provide an overview of the planned primary, secondary and exploratory statistical analyses. 
The reader of this SAP is encouraged to also read the clinical protocol for details on conduct of this 
study. 
1.1 
Study design 
This study uses a two-cohort, nonrandomized, open-label multicenter design. Patients will be enrolled 
from up to 125 sites in the United States. The study consists of two periods: screening (up to 4 Weeks) 
and fingolimod treatment period (Baseline to 12 Months). The total study duration is up to 13 Months. 
Follow-up Visits will be conducted at 3, 6 and 12 Months. Fingolimod treatment includes two cohorts. 
In the first cohort approximately 200 patients with RMS, who are newly prescribed commercially 
available fingolimod 0.5mg/day will participate in the study. In the second cohort approximately 200 
RMS patients who have been on commercially available fingolimod 0.5mg/day continuously for at 
least ≥ 2 years will participate in the study. Cohort 2 will only serve as a referent cohort for Cohort 1 
and is not intended to be a direct Cohort 1 comparator as no a priori hypotheses are to be examined. 
1.2 
Study objectives and endpoints 
The primary objective of this study aims to characterize phenotypic changes in the cellular 
components (biomarkers) of the innate (monocytes, neutrophils and NK cells) and adaptive (peripheral 
blood T cells, B cells) immune system including their subtypes, in patients with RMS, initiating 
fingolimod therapy of 0.5mg/day up to 12 Months of treatment (Cohort 1) and those patients who have 
been on fingolimod 0.5mg/day continuously for ≥ 2 years (Cohort 2). Both cohorts will continue 
treatment for the next 12 Months. 
Secondary objectives are to investigate the association between anti-John Cunningham virus (JCV) 
antibody status/index and phenotypic changes in innate and T and B cell subsets in patients on 
fingolimod therapy. 
 
 
2 
Statistical methods 
2.1 
Data analysis general information 
Interim analysis/final analysis will be performed 
   
SAS® Software version 9.4 or later will be used in this study as primary statistical analysis software.  


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Statistical methods used in reporting for both efficacy and safety are described below. 
In general, categorical measurements will be summarized by frequency counts and percentages. 
Continuous variables will summarized by numbers of patients, means, standard deviations, standard 
error of mean, first quartile, medians, third quartile, interquartile range, minimums, and maximums.  
In summary statistics of means and medians, one more decimal place beyond the reported data will be 
displayed, and 2 more decimal places will be displayed for the standard deviation. The minimum and 
maximum will keep the same decimal places as the reported data. 
Statistical tests will be performed at a 2-sided significance level of 0.05 unless otherwise stated. All p-
values will be rounded up to 4 decimal places. For example, any p-value strictly greater than 0.0049 
and less than or equal to 0.0050 will get displayed as 0.0050. This guarantees that on any printed 
statistical output, the unrounded p-value will always be less than or equal to the displayed p-value. A 
displayed p-value of 0.0001 will always be understood to mean ≤0.0001. Likewise, any p-value 
displayed as 1.0000 will be understood to mean >0.9999 and ≤1. 
All collected data from the eCRFs (including electronic data) and derived analytical data will be 
included in the listing.  
All summaries will be presented by Cohort.  
2.1.1 
General definitions  
As described in the study protocol, fingolimod treatment refers to Fingolimod 0.5 mg/per day.  
The last available assessment on or prior to the reference start date is taken as baseline assessment.   
For quantitative measurements, 
Change from Baseline will be calculated as:  
         Change from baseline = Test Value at Visit X – Baseline Value 
The date of first administration of fingolimod treatment (Day 1) is defined as the first date when a non-
zero dose of fingolimod treatment was administrated. For the sake of simplification, the date of first 
administration of fingolimod treatment will be also referred to start date of fingolimod treatment. 
The date of last administration of fingolimod treatment is derived as the last date on or prior to cut-off 
date when a non-zero dose of fingolimod treatment was administrated.  
The study day describes the day of the event or assessment date, relative to the reference start date 
(start date of fingolimod treatment or randomization date depending on the type of assessment). The 
study day will be displayed in data listings. For summaries of vital signs, physical examinations, 
laboratory data, ECG, etc., assessments will be assigned to a visit based on windowing. Observations 
from Day 2 through Day 135 will be assigned to the 3-month visit. Days 136 through Day 270 will be 
assigned to the 6-month visit, and Days 271 and beyond will be assigned to the 12-month visit. If more 
than one observation occurs within a given window, the one closest to the target day will be used. 
2.2 
Analysis sets 
Enrolled Set: All patients enrolled in one of the two cohorts will be included in the Enrolled Set. 
Safety Set: The Safety Set will include all patients who enrolled in one of the two cohorts and received 
at least one dose of fingolimod during the study. Patients will be analyzed according to the cohort 
enrolled. 
Full Analysis Set: For this study, the Full Analysis Set is the same as the safety set defined above. 


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2.3 
Patient disposition, demographics and other baseline characteristics 
2.3.1 
Patient disposition 
The number of patients enrolled, number of screen failure, patients treated,  reasons for not receiving 
fingolimod treatment, patients who discontinued the fingolimod treatment and reasons for fingolimod 
treatment discontinuation, number and percentage of patients by end of study status will be 
summarized. 
In addition, the number of patients in each analysis population and reasons for exclusion from a 
population will also be summarized. 
A listing of patient disposition will be provided for all enrolled patients, with the extent of their 
participation in the study and the reason for discontinuation.  
2.3.2 
Protocol Deviations 
Major protocol deviations will be summarized by cohort. All protocol deviations will be listed, with a 
flag indicating major or minor.  
2.3.3 
Demographics  
Demographics (age, gender, race, and ethnicity) will be summarized by cohort for the Safety Set.  
2.3.4 
MS History/Baseline disease characteristics 
Baseline disease characteristics will be summarized by cohort for the Safety Set.  
• 
Time (in years) from MS diagnosis to first treatment date, calculated as: (Date of MS 
diagnosis – date of Day 1  + 1)/ 365.25. 
• 
Time (in years) from first MS symptoms to first treatment date, calculated as: (Date of 
first MS diagnosis – date of Day 1 + 1)/ 365.25. 
• 
Number of relapses in the last year/ Number of required steroids  
• 
Number of relapses in the last 2 years/ Number of required steroids 
• 
Time (in years) from most recent relapse to Day 1, calculated as: (Date of MS diagnosis – 
date of Day 1  + 1)/ 365.25. 
Listings will be provided for demographic and baseline disease characteristics. 
2.4 
Past or present MS symptoms with Location 
Number of each MS symptom/location/persistency/severity by prior and post fingolimod treatment 
will be provided for the Safety Set.  
All past and present MS symptoms will be listed for the Safety Set.  
2.5 
MS previous therapies 
All MS previous therapies will be coded by medication name and will be summarized by preferred 
term.  
2.6 
Fingolimod treatment / compliance / Dose interruption  
The duration of fingolimod treatment exposure (days) for patients who took at least one dose of 
fingolimod treatment will be summarized with descriptive statistics. Duration will be calculated as: 


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Duration of  exposure (days) = (Date of last administration of fingolimod treatment – Date of first 
administration of fingolimod treatment) +1 . 
The actual number of days of fingolimod treatment exposure will be calculated as: 
Actual days of fingolimod treatment exposure = (Date of last administration of fingolimod 
treatment – Date of first administration of fingolimod treatment) +1 – days not on treatment. 
Compliance(%)   will be calculated as:  
         Compliance (%) = actual days of fingolimod treatment exposure / duration of exposure *100 
2.7 
Analysis of the primary objective 
2.7.1 
Primary endpoint 
All analyses will be conducted by cohort for the Safety Set. There are 22 primary endpoints for this 
study, and Change from Baseline to Month 6 will be calculated as:  
         Change from baseline to Month 6 = Observed Value at Month 6 (Days 136 to 270) – Baseline 
Value 
1. Change from Baseline to Month 6 in CD4+ naïve T cells (CCR7+CD45RA+) 
2. Change from Baseline to Month 6 in CD4+ central memory T cells (CCR7+CD45RACD45RO+) 
3. Change from Baseline to Month 6 in CD4+ effector memory T cells (CCR7-CD45RACD45RO+) 
4. Change from Baseline to Month 6 in CD4+ Th1 cells (CXCR3+) 
5. Change from Baseline to Month 6 in CD4+ Th2 cells (CCR4+) 
6. Change from Baseline to Month 6 in CD4+ Th17 cells (CCR6+) 
7. Change from Baseline to Month 6 in CD8+ naïve T cells (CCR7+CD45RA+) 
8. Change from Baseline to Month 6 in CD8+ central memory T cells (CCR7+CD45RACD45RO+) 
9. Change from Baseline to Month 6 in CD8+ effector memory T cells (CCR7-CD45RACD45RO+) 
10. Change from Baseline to Month 6 in naïve B Lymphocytes (CD19+CD27-) 
11. Change from Baseline to Month 6 in memory B Lymphocytes (CD19+CD27+) 
12. Change from Baseline to Month 6 in regulatory B Lymphocytes (CD19+CD24+CD38+) 
13. Change from Baseline to Month 6 in monocytes (CD14+) 
14. Change from Baseline to Month 6 in neutrophils (CD16+) 
15. Change from Baseline to Month 6 in NK cells (CD56+) 
16. Change from Baseline to Month 6 in Total CD4+ Absolute Cell Counts 
17. Change from Baseline to Month 6 in Total CD4+ Differential Cell Counts 
18. Change from Baseline to Month 6 in Total CD8+ Absolute Cell Counts 
19. Change from Baseline to Month 6 in Total CD8+ Differential Cell Counts 
20. Change from Baseline to Month 6 in Total CD19+ Absolute Cell Counts 
21. Change from Baseline to Month 6 in Total CD19+ Differential Cell Counts 
 
 
Descriptive statistics (sample size, mean, standard deviation, standard error of mean, minimum, 
first quartile, median, third quartile, interquartile range, and maximum) will be provided. The 
95% confidence interval for the mean will be calculated.  
Analyses will be performed with respect to the actual value of primary variables by employing an 
analysis of covariance (ANCOVA) model with gender as a factor and duration of disease at Baseline 
(either time since first symptom or time since diagnosis) and corresponding baseline as covariates. The 
unadjusted as well as the adjusted least squares means will be provided together with a p-value.  
Percent change from baseline mean will also be reported. 


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2.7.2 
Statistical hypothesis, model, and method of analysis 
The majority of analyses will be descriptive in nature. The 95% confidence intervals will be provided 
for the parameters of interest. 
This is an open-label, single arm study, and has no active control. And there is no confirmatory 
hypothesis to be tested. Thus, the multiplicity adjustment of the level of significance for the primary 
analysis is not relevant in this study.  
2.7.3 
Handling of missing values/censoring/discontinuations 
No imputation will be performed for efficacy endpoints. 
2.8 
Analysis of the key secondary objective 
Secondary variables consist of both efficacy and safety variables. 
2.8.1 
Efficacy variables 
MS relapses that occur while on study will be summarized by cohort for the FAS. The number of 
patients with at least one relapse, along with the total number of episodes across all patients, will be 
presented. The proportion of episodes requiring steroid use, proportion requiring hospitalization, and 
proportion at each severity level will be summarized. All steroid treatment of MS relapses will be 
coded by World Health Organization (WHO) drug anatomical therapeutic chemical (ATC) 
classification. All steroid treatment of MS relapses will be summarized by ATC level 2 and preferred 
term.  
All past and present MS symptoms will be listed for the FAS.  
The following additional efficacy variables will be analyzed by cohort using data from patients in FAS. 
1. Change from Baseline in Patient Determined Disease Steps (PDDS); 
2. Change from Baseline in T2 lesion burden; 
3. New Gd-enhancing T1 lesion count 
 
Descriptive statistics (sample size, mean, standard deviation, standard error of mean, minimum, 
first quartile, median, third quartile, interquartile range, and maximum) will be provided. The 
95% confidence interval for the mean will be calculated. 
2.8.2 
Safety variables 
The Safety Set will be used for the following analyses. 
1. The assessment of safety will be based mainly on the frequency of adverse events. 
2. Change from Baseline to Months 3, and 12 in CD4+ naïve T cells (CCR7+CD45RA+); 
3. Change from Baseline to Months 3, and 12 in CD4+ central memory T cells 
(CCR7+CD45RA-CD45RO+); 
4. Change from Baseline to Months 3, and 12 in CD4+ effector memory T cells (CCR7-
CD45RA-CD45RO+); 
5. Change from Baseline to Months 3, and 12 in CD4+ Th1 cells (CXCR3+); 
6. Change from Baseline to Months 3, and 12 in CD4+ Th2 cells (CCR4+); 
7. Change from Baseline to Months 3, and 12 in CD4+ Th17 cells (CCR6+); 
8. Change from Baseline to Months 3, and 12 in CD8+ naïve T cells (CCR7+CD45RA+); 
9. Change from Baseline to Months 3, and 12 in CD8+ central memory T cells(CCR7+CD45RA-
CD45RO+); 


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10. Change from Baseline to Months 3, and 12 in CD8+ effector memory T cells (CCR7-
CD45RA-CD45RO+); 
11. Change from Baseline to Months 3, and 12 in naïve B cells (CD19+CD27-); 
12. Change from Baseline to Months 3, and 12 in memory B cells (CD19+CD27+); 
13. Change from Baseline to Months 3, and 12 in regulatory B cells (CD19+CD24+CD38+); 
14. Change from Baseline to Months 3, and 12 in monocytes (CD14+); 
15. Change from Baseline to Months 3, and 12 in neutrophils (CD16+); 
16. Change from Baseline to Months 3, and 12 in NK cells (CD56+); 
17. Change from Baseline to Months 3, 6, and 12 in the anti-JCV antibody index; 
18. Change from Baseline to Months 3, 6, and 12 in Hematology measurements; 
19. Anti-JCV antibody status (+ or -) at Months 3, 6, and 12. 
20. Change from Baseline to Months 3, and 12 in Total CD4+ Absolute Cell Counts 
21. Change from Baseline to Months 3, and 12 in Total CD4+ Differential Cell Counts 
22. Change from Baseline to Months 3, and 12 in Total CD8+ Absolute Cell Counts 
23. Change from Baseline to Months 3, and 12 in Total CD8+ Differential Cell Counts 
24. Change from Baseline to Months 3, and 12 in Total CD19+ Absolute Cell Counts 
25. Change from Baseline to Months 3, and 12 in Total CD19+ Differential Cell Counts 
For safety Variable 1, please refer to section 2.11.4 for more details. 
For safety Variable 19, the frequency count and percentage together with the 95% confidence interval 
for the proportion of JCV antibody positive patients will be presented. The shift from baseline to 
Months 3, 6, and 12 in anti-JCV screening index will also be summarized. 
For safety Variables 2–18, descriptive statistics (sample size, mean, standard deviation, standard error 
of mean, minimum, first quartile, median, third quartile, interquartile range, and maximum) will be 
provided. The 95% confidence interval for the mean will be calculated. 
In addition, correlation coefficients between changes in cellular (T, B and monocyte, neutrophil, NK) 
subsets and efficacy (MRI based variables and PDDS) and safety outcomes (anti-JCVantibody status 
and index) will be computed. Analyses of safety data will be by cohort based on the Safety Set. 
2.8.3 
Handling of missing values/censoring/discontinuations 
No impuatition will be performed for safety endpoints. 
2.8.4 
Adverse events (AEs) 
All AE verbatim descriptions will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), Version 19.1 or the most updated version.    
Treatment-emergent adverse events (TEAEs) are defined as AEs that started or worsened in severity 
on or after the first dose of fingolimod treatment and no later than the last treatment date + 14.  
All TEAEs will be summarized by presenting the number and percentage of patients having at least 
one TEAE, and the number of TEAEs that occurred in each System Organ Class (SOC) and Preferred 
Term (PT). A patient with multiple occurrences of an AE will be counted only once in the 
corresponding AE category.   
In the TEAE summary outputs, adverse events will be sorted by descending percent of patients. 
The AE summaries below will be performed: 
• 
An overall summary of the number and percentage of patients  


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• 
TEAEs, regardless of fingolimod relationship by SOC and PT 
• 
TEAEs suspected to be fingolimod-related by SOC and PT 
• 
TEAEs, regardless of fingolimod treatment relationship by SOC, PT and maximum severity 
TEAEs starting after the first dose of fingolimod treatment with a missing severity will be classified as 
severe. If a patient reports a TEAE more than once within that System Organ Class (SOC)/ Preferred 
Term (PT), the AE with the highest severity will be used in the corresponding severity summaries. 
2.8.4.1 
 Deaths and Serious Adverse Events 
TEAEs leading to Death are those events with “Outcome” response recorded as “Fatal” on the 
Adverse Events page of the eCRF. Number of patients with TEAEs leading to death will be 
summarized by SOC and PT.  A listing of all TEAEs leading to death will be provided.  
All reported deaths will be listed. Death will also be summarized for overall and for on treatment 
period (from first dose to 14 days after last dose). The number of deaths and the primary cause of 
death will be presented by treatment group in the summary table.  
Serious adverse events are those events with a response of “Yes” for the item “Was AE Serious” on 
the AE form. Summaries of incidence rates (frequencies and percentages) of serious AEs by SOC and 
PT will be prepared. A patient data listing of all SAEs will be provided. 
In summary, following summaries of TEAEs will be provided: 
• 
TEAEs leading to death, by SOC and PT 
• 
Serious TEAEs, regardless of fingolimod treatment relationship, by SOC and PT 
• 
TEAEs leading to fingolimod treatment discontinuation, regardless of fingolimod treatment 
relationship, by SOC and PT 
 
Listings to be provided are : 
• 
AEs leading to Deaths (CRF Adverse Event page: AE outcome is Fatal.) 
• 
Serious AEs 
• 
AEs leading to dose discontinuation 
2.9 
Interim analysis 
Two interim analyses of data will be performed prior to the final analysis at Month 12. 
1. The first interim analysis is an early assessment to evaluate safety in Cohort 2 patients. This will 
be conducted when 50% of patients in Cohort 2 have completed the Month 6 follow up. For this 
analysis, primary variables, demographics, baseline characteristics, adverse events, and serious 
adverse events will be summarized. 
2. The second interim analysis is the primary analysis for this study. This analysis will be 
conducted when all patients in Cohorts 1 and 2 complete Month 6 (primary time point of interest) 
of study. All data collected on patients from both Cohorts 1 and 2 will be included in this analysis. 
These data will be analyzed as mentioned in protocol Sections 9.4, 9.5, and 9.6. 
This is an open-label, single arm study, and has no active control. The first interim analysis is a 
summarization of data from Cohort 2 only and no confirmatory hypothesis will be tested. Thus, the 
multiplicity adjustment of the level of significance for the primary analysis due to the first interim 
analysis is not relevant in this study. Results obtained from these interim analyses may be reported and 
published externally for communication to health care professions, as appropriate. 


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3 
Sample size calculation 
Cohort 1: A sample size of 200 patients will be able to detect an effect size of 0.30 with 89% power 
after adjusting for multiplicity of testing changes in 15 primary variables, at an overall significance 
level of 0.05. 
In addition, for both cohorts the primary interest is to estimate mean change from Baseline at various 
time points (Months 3, 6, and 12) of the primary and secondary variables. A sample size of 200 
patients in each cohort will provide us the precision of estimates within 0.14 of the corresponding 
standard deviation of the variables of interest. 
4 
Change to protocol specified analyses 
Not applicable. 
5 
Appendix 
5.1 
Imputation rules 
In general, other than for partial dates, missing data will not be imputed and will be treated as missing. 
Partial date will be imputed as below: 
• 
If year is missing (or completely missing), do not impute; 
• 
15th of the month will be used to impute the initial diagnosis date if only the day is missing; 
• 
July of the year will be used to impute as the initial diagnosis date if both the day and the 
month are missing; 
 
5.1.1 
Concomitant Medications Start/End Date 
Partial missing start/end date to concomitant medications will be imputed as below: 
Start date of concomitant medications 
• 
If only the day of the month is missing, use the first day of the month to replace the missing 
part.  
• 
If both the day and the month are missing, January 1stwill be used to replace the missing part.  
• 
If Day, Month and Year are all missing, use a date one day before the first date of fingolimod 
treatment. 
End date of concomitant medications 
• 
If only Day is missing, use the last day of the month. 
• 
If Day and Month are both missing, use the last day of the year. 
• 
If Day, Month and Year are all missing, assign ‘continuing’ status to stop date 
 
5.1.2 
Adverse Events Start/End Date 
Missing or partial missing date to the onset date of AE will be imputed as below: 
• 
If the AE onset date is completely missing, the AE start date will be imputed as the first date 
of fingolimod treatment; 


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• 
If the AE onset date is partial missing, then  
o If both the year and the month are available and the year and the month are the 
corresponding year and month of the first dosing date, then the AE start date will be 
imputed as the first dosing date; 
o If both the year and the month are available and the year and the month are not equal to the 
corresponding year and month of the first dosing date, then the AE start date will be 
imputed as the 1st date of the month; 
o If only the year is available and the available year is the corresponding year of the first 
dosing date, then the AE start date will be imputed as the first dosing date; 
o If only the year is available, and the available year is not equal to the corresponding year of 
the first date of fingolimod treatment, then the AE start date will be imputed as the 
January1st of the year;  
Adverse event end date will be imputed as below for the partial date only. 
• 
If both the year and the month are available, AE end date will be imputed as the last day of 
the month; 
• 
If only the year is available, AE end date will be imputed as the December 31st of the year. 
If the imputed AE end date is after the death date, then the date of the death will be imputed as the 
AE end date. 
For adverse events continuing at the cut-off date, the end date will not be imputed and instead will be 
reported as “ongoing”.  
5.2 
Statistical models 
5.2.1 
Primary analysis 
The primary statistical analysis will use an analysis of covariance (ANCOVA) model with gender as a 
factor and the duration of disease and baseline as covariates.  The primary analysis population will be 
the Safety Set. The unadjusted as well as the adjusted least squares means will be provided together 
with a p-value. 
5.2.2 
Key secondary analysis 
The correlation of changes from baseline in cellular (T, B and monocyte, neutrophil, NK) subsets with 
efficacy (MRI based variables and PDDS) and safety outcomes (anti-JCV antibody status and index) 
will be estimated within each cohort for each assessment time separately. Analyses involving the MRI 
based variables or the PDDS will be conducted on the FAS, while analyses of safety outcomes will use 
the Safety Set. 
A Pearson correlation coefficient will be used to estimate the correlation of changes in cellular subsets 
with changes in T2 lesion volume, changes in PDDS score, and changes in anti-JCV index. 
The correlation between changes in cellular subsets and number of new Gd-enhancing T1 lesions will 
be estimated by a Spearman coefficient. 
The relationship between changes in cellular subsets and anti-JCV antibody status (positive or 
negative) will be assessed using a t-test to compare the mean change in cellular subset across anti-JCV 
antibody status. 


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5.3 
Reference 
Not applicable.